Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:33]=1>>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7]([C:6]2[CH:21]=[C:2]([C:32]3[CH:31]=[N:30][CH:29]=[C:28]([F:27])[CH:33]=3)[C:3]([N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[N:4][CH:5]=2)=[O:8])=[CH:11][CH:12]=1
Reactant: CN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cc1Br
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Product: CN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cc1-c1cncc(F)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 169 using 5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-((2-hydroxyethyl)(methyl)amino)nicotinamide (Stage 179.1) and 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine to afford an off-white foam. HPLC (Condition 4) tR=5.51 min, UPLC-MS (Condition 3) tR=1.07 min, m/z=467.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.69 (s, 3H) 3.39-3.61 (m, 4H) 4.65 (t, J=5.08 Hz, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.77-7.94 (m, 3H) 8.11 (d, J=2.35 Hz, 1H) 8.50-8.63 (m, 2H) 8.74 (d, J=2.35 Hz, 1H) 10.21 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][C:10]#[C:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].C(O)C>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCCC#Cc1ccc(C#N)cc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCCc1ccc(C#N)cc1
Yield: 87.3 %

Procedure:
A suspension of [4-(4-cyanophenyl)but-3-ynyl]carbamic acid tert-butyl ester 56 (5.2 g, 19.2 mmol) and 10% palladium on carbon (2.5 g, wet) in ethanol/THE (30 mL, 1:1) was stirred overnight under 1 atmosphere of hydrogen. After purging with nitrogen, the reaction mixture was suction filtered through a pad of Celite. The solvent was removed from the filtrate by evaporation. The residue was chromatographed on silica gel, eluting with methylene chloride/ethyl acetate (30:1), to afford the pure product 57 (4.6 g, 87%) as an oil. 1H NMR (300 MHz, CDCl3) δ 1.44 (s, 9H), 1.51 (m, 2H), 1.65 (m, 2H), 2.69 (t, 2H), 3.14 (m, 2H), 4.52 (br s, 1H), 7.27 (d, 2H), 7.56 (d, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](SC(C)C)=[N:6][CH:7]=1.O[O:13][S:14]([O-:16])=O.[K+].C(=O)(O)[O-].[Na+].O1C[CH2:26][CH2:25][CH2:24]1>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:14]([CH:25]([CH3:26])[CH3:24])(=[O:16])=[O:13])=[N:6][CH:7]=1
Reactant: C1CCOC1
Reactant: O=S([O-])OO
Reactant: CC(C)Sc1ccc(Br)cn1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: CC(C)S(=O)(=O)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 5-bromo-2-isopropylthiopyridine from Step 1 (2.03 g, 8.75 mmol) in tetrahydrofuran (50 ml) and methanol (25 ml) at 0° C. was added oxone (15.8 g, 25.8 mmol) and then saturated aqueous sodium bicarbonate (25 ml). The resulting mixture was stirred at room temperature for 6 hours. The mixture was quenched with aqueous sodium bicarbonate and partitioned between ethyl acetate and water. The crude product from the organic phase was chromatographed on silica gel eluting with 20% ethyl acetate in hexane to afford the 5-Bromo-2-isopropylsulfonylpyridine compound as a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])=O.[C:16]1([P:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Br>C(O)(=O)C.C(#N)C.C(OCC)C>[CH3:13][O:12][C:10]1[CH:11]=[C:3]2[C:4](=[CH:8][C:9]=1[O:14][CH3:15])[C:5](=[O:6])[O:7][CH:1]2[PH2:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COc1cc(C=O)c(C(=O)O)cc1OC
Agent: Br
Solvent: CCOCC
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1cc2c(cc1OC)C([PH2](c1ccccc1)(c1ccccc1)c1ccccc1)OC2=O
Temperature: 90 °C
Yield: 97.1 %

Procedure:
A suspension of 2-formyl-4,5-dimethoxy-benzoic acid (6.43 g, 30.62 mmoles), obtained as described in example 2, triphenyl-phosphine (8.3 g, 30.62 mmoles), 30% HBr in acetic acid (8.26 ml, 30.62 mmoles) and glacial acetic acid (20 ml) under N2 was heated at 90° C. for 4.5 hours. The mixture was brought to dryness, re-dissolved in acetonitrile (50 ml) and diluted with ethyl ether up to turbidity, then cooled and filtered, and the filtrate was washed with ethyl ether and dried under vacuum to give 13.6 g of the title compound (yield: 83%).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[CH3:16][O:17][C:18]1[CH:32]=[C:31]2[C:21]([NH:22][CH:23]=[C:24]2[CH2:25][CH:26]([C:28]([OH:30])=[O:29])[NH2:27])=[CH:20][CH:19]=1.C(Cl)(Cl)Cl>CO>[C:12]([OH:14])(=[O:13])[CH3:11].[C:28]([CH:26]([NH:27][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:25][C:24]1[C:31]2[C:21](=[CH:20][CH:19]=[C:18]([O:17][CH3:16])[CH:32]=2)[NH:22][CH:23]=1)([OH:30])=[O:29]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: COc1ccc2[nH]cc(CC(N)C(=O)O)c2c1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(=O)O
Product: COc1ccc2[nH]cc(CC(Nc3nc4ccc(Cl)cc4cc3C(=O)O)C(=O)O)c2c1
Yield: 85 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 5-methoxy-DL-tryptophan to provide the title compound in 85% yield as yellow needles (flash chromatography on SiO2, eluent CHCl3, MeOH, AcOH—10, 1, 0.2).
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]Br)=[CH:3][CH:2]=1.[I-:15].[Na+]>CC(C)=O>[C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][I:15])=[CH:3][CH:2]=1
Reactant: [I-]
Reactant: Cc1ccc(CCCCCCBr)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1ccc(CCCCCCI)cc1

Procedure:
6-(p-Tolyl)hexyl iodide [VIa; Ar is 4-CH3C6H4, R is H] was prepared from 6-(p-tolyl)hexyl bromide (Preparation C14) and sodium iodide in acetone according to the procedure of Preparation D2 above.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH2:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[N:3]=1.C(N(CC)CC)C.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:5]=[C:4]([CH2:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[N:3]=1
Reactant: O=S(=O)(Cc1cc(Cl)nc(Cl)n1)c1ccccc1
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(Cc1cc(N2CCOCC2)nc(Cl)n1)c1ccccc1
Temperature: -5 °C
Yield: 57.1 %

Procedure:
2,4-dichloro-6-[(phenylsulfonyl)methyl]pyrimidine (6 g, 19.8 mmol) was dissolved in DCM (50 mL) and stirred (under nitrogen) at −5° C. Triethylamine (3.06 mL, 21.8 mmol) was added to give a clear brown solution. Morpholine (1.65 mL, 19.8 mmol) was dissolved in DCM and added dropwise keeping the reaction below −5° C. The cooling bath was then removed and the reaction mixture stirred at room temperature for 1 hour. The reaction mixture was then washed with water (50 mL), dried over magnesium sulphate, filtered and concentrated in vacuo. The crude material was chromatographed on silica, eluting with 0-50% ethyl acetate in DCM to give the desired material as a white solid (4 g).
Reaction SMILES: BrC1C=CC([C:8]([OH:10])=[O:9])=NC=1.Cl[C:12](N(C)C)=[C:13]([CH3:15])[CH3:14].[NH2:19][C:20]1[CH2:25][O:24][CH2:23][C@:22]([C:27]2[N:32]=[C:31]([NH:33][C:34]([C:36]3[CH:41]=[CH:40][C:39]([Br:42])=[CH:38][N:37]=3)=[O:35])[CH:30]=[CH:29][CH:28]=2)([CH3:26])[N:21]=1.CCN(CC)CC>C(Cl)Cl>[C:13]([O:10][C:8](=[O:9])[NH:19][C:20]1[CH2:25][O:24][CH2:23][C@:22]([C:27]2[CH:28]=[CH:29][CH:30]=[C:31]([NH:33][C:34]([C:36]3[CH:41]=[CH:40][C:39]([Br:42])=[CH:38][N:37]=3)=[O:35])[N:32]=2)([CH3:26])[N:21]=1)([CH3:15])([CH3:14])[CH3:12]
Reactant: CC(C)=C(Cl)N(C)C
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: C[C@@]1(c2cccc(NC(=O)c3ccc(Br)cn3)n2)COCC(N)=N1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cccc(NC(=O)c3ccc(Br)cn3)n2)COC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 5-bromopyridine-2-carboxylic acid (34.5 mg, 0.171 mmol) in DCM (2 ml) was added 1-chloro-N,N,2-trimethylpropenylamine (0.045 ml, 45.7 mg, 0.342 mmol) and the reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was then added dropwise to a dry solution of (−)-5-(6-amino-pyridin-2-yl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (enantiomer 1 from procedure step j) above, 47.6 mg, 0.155 mmol) and NEt3 (0.048 ml, 34.6 mg, 0.342 mmol) in DCM (2 ml) at 0° C. The reaction mixture was allowed to warm to rt and to stir for 20 min at rt. The reaction mixture was diluted with DCM and quenched with H2O. The phases were separated and the aq. phase was extracted with DCM. The combined org. phases were washed with brine, dried over Na2SO4, filtered and twice purified by HPLC (Alltech Grom Saphir65 Si 10 μM column 150×30 mm, gradient 1 n-heptane:EtOAc 0-1.2 min 85:15, 1.2-9 min 0:100, 9-12 min 0:100, gradient 2 n-heptane:EtOAc:MeOH 0-1.2 min 47:50:3, 1.2-9 min 0:60:40, 9-12 min 0:60:40, flow 50 ml/min, detection 254 nm]. HPLC RtH4=1.10 min; ESIMS: 490, 492 [(M+H)+].
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[CH3:8][NH:9][C:10](=[O:47])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:32]1[NH:33][C:34]([C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:38]=2)=[CH:35][NH+:36]=1)[NH:17][C:18](C1CCCN(C2C=CC=CN=2)C1)=[O:19].CCN(C(C)C)C(C)C.[CH2:57]([N:64]=C=O)[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[CH2:57]([NH:64][C:18]([NH:17][C@H:16]([C:32]1[NH:33][C:34]([C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:38]=2)=[CH:35][NH+:36]=1)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]([NH:9][CH3:8])=[O:47])=[O:19])[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1
Reactant: CNC(=O)CCCCC[C@H](NC(=O)C1CCCN(c2ccccn2)C1)c1[nH]c(-c2ccc3ccccc3c2)c[nH+]1
Reactant: O=C=NCc1ccccc1
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)CCCCC[C@H](NC(=O)NCc1ccccc1)c1[nH]c(-c2ccc3ccccc3c2)c[nH+]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The amine from Example 327, BB2 (1 eq.) was dissolved in DCM, then DIPEA (1 eq.) and benzyl isocyanate were added. After stirring for 1 hr at RT the solvent were removed under reduced pressure and the crude was purified by preparative RP-HPLC, using H2O (0.1% TFA) and MeCN (+0.1% TFA) as eluents (column: C18). The desired fractions were lyophilized to afford the titled compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 8.36 (1H, s), 8.16 (1H, s), 8.07 (1H, d, J=8.6 Hz), 8.02-7.93 (2H, m), 7.91 (1H, dd, J=8.6 Hz, J2=1.5 Hz), 7.71-7.55 (3H, m), 7.35-7.19 (5H, m), 6.75-6.67 (2H, m), 4.97-4.87 (1H, m), 4.30-4.15 (2H, m), 2.53 (3H, d, J=4.6 Hz), 2.04 (2H, t, J=7.4 Hz), 1.97-1.83 (2H, m), 1.55-1.44 (2H, m), 1.42-1.22 (4H, m). MS (ES) C29H33N5O2 requires: 483, found: 484 (M+H)+.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.C([O:37][C@@H:38]([CH3:42])[C:39](Cl)=[O:40])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:39](=[O:40])[C@@H:38]([OH:37])[CH3:42])[CH2:32][CH2:33]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Agent: Cl
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)[C@H](C)O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f23) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3=[CH:12][S:13][CH:14]=[C:9]3[C:8](=O)[NH:7][C:6]=2[CH:16]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:18]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3=[CH:12][S:13][CH:14]=[C:9]3[C:8](=[S:18])[NH:7][C:6]=2[CH:16]=1
Reactant: O=C1Nc2cc(F)ccc2Nc2cscc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Product: Fc1ccc2c(c1)NC(=S)c1cscc1N2

Procedure:
In a similar fashion 7-fluoro-4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one is treated with phosphorus pentasulfide to give 7-fluoro-4,9-dihydro-10H-thieno[3,4-b][1,5]-benzodiazepine-10-thione.
Reaction SMILES: O=[C:2]([CH2:9][CH3:10])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.O>C1C=CC=CC=1>[N:11]1([C:2]([CH2:9][CH3:10])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CCOC(=O)CC(=O)CC
Reactant: C1CCNC1
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C=C(CC)N1CCCC1
Temperature: 25 °C
Yield: 100.8 %

Procedure:
Ethyl 3-oxopentanoate (2.5 mL, 17.6 mmole) and pyrrolidine (1.4 mL, 17.1 mmole) were dissolved in benzene and added to a 100 mL flask fitted with a Dean-Stark water separator. The reaction was stirred at reflux for 3 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure and the product was dried in vacuo, affording ethyl 3-(pyrrolidin-1-yl)pent-2-enoate (3.4 g, 98% yield). The product was used without further purification.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1.Br[CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.O.C(OCC)(=O)C>[O:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]1[CH2:15][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)c2ccccc12
Reactant: BrCC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1ccc(OCC2CCCCO2)c2ccccc12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 4-hydroxynaphthaldehyde (1 g, 5.8 mmol), 2-bromomethyl tetrahydropyran (1 g, 5.8 mmol) and powdered K2CO3 (1.2 g, 8.7 mmol) in dimethyl formamide was stirred at 60° C. overnight. The mixture was taken up in water and ethyl acetate. The organic layer was separated and washed with water, brine, dried over MgSO4, filtered, and concentrated. The product was purified by silica gel column chromatography using ethyl acetate/hexane.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2I)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:23]1([C:26]#[CH:27])[CH2:25][CH2:24]1>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Si:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:27]#[C:26][CH:23]2[CH2:25][CH2:24]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(Nc2ccccc2I)CC1
Reactant: C#CC1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC1CCC(Nc2ccccc2C#CC2CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [4-(tert-butyldimethylsilanyloxy)cyclohexyl]-(2-iodophenyl)amine (4.47 g, 10.4 mmol) in triethylamine (70 mL) was added copper(I) iodide (198 mg, 1.04 mmol), followed by bis(triphenylphosphine)palladium(II) chloride (730 mg, 1.04 mmol) and cyclopropylacetylene (1.73 mL, 20.8 mmol). The reaction was stirred under nitrogen at room temperature overnight. After the reaction mixture was concentrated, the residue was dissolved in ether and filtered through Celite. Concentration gave the crude product, which was used without further purification in quantitative yield. LC-MS (C23H35NOSi calc'd 369) m/z 370 (M+H).
Reaction SMILES: [CH:1]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1.Cl>CC(C)=O>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:9][S:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:8])=[O:7])=[O:21])=[CH:15][CH:14]=1
Reactant: NS(=O)(=O)C1CCCC1
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(Nc1ccc(Cl)cc1)NS(=O)(=O)C1CCCC1
Reaction time: 2 h
Yield: 68.3 %

Procedure:
Cyclopentanesulfonamide (9.7 g) was dissolved in acetone (300 ml) and 1N NaOH (65 ml) was added. To the resulting solution was added p-chlorophenylisocyanate (9.5 g) dissolved in acetone (100 ml). The solution was allowed to stir for two hours and was then treated with 1N HCl (65 ml). The resulting solid was collected and treated with 1N NaOH (100 ml). This mixture was treated with 1N HCl (100 ml) and the resulting solid collected. The solid was dissolved in acetone, water was added and the acetone was stripped off. The solid material was collected and dried to provide 12.8 g of product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:16]=[C:15]3[N:17]([C:31]4[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=4)[C:34]#[N:35])[C:18](=[O:30])[N:19]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[CH:20]([CH3:21])[C:14]3=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1.C(N(CC)CC)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>ClCCl>[C:34]([C:33]1[CH:32]=[C:31]([N:17]2[C:15]3[N:16]=[C:11]([NH:10][C:6]4[CH:5]=[C:4]([CH2:3][CH2:2][O:1][S:47]([CH3:46])(=[O:49])=[O:48])[CH:9]=[CH:8][CH:7]=4)[N:12]=[CH:13][C:14]=3[CH:20]([CH3:21])[N:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:18]2=[O:30])[CH:38]=[CH:37][CH:36]=1)#[N:35]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(N2C(=O)N(c3cccc(C#N)c3)c3nc(Nc4cccc(CCO)c4)ncc3C2C)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(N2C(=O)N(c3cccc(C#N)c3)c3nc(Nc4cccc(CCOS(C)(=O)=O)c4)ncc3C2C)cc1
Reaction time: 0.75 h

Procedure:
(±)-3-[7-[3-(2-Hydroxy-ethyl)-phenylamino]-3-(4-methoxy-phenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-benzonitrile (0.67 mg; 1.27 mmol) (from Example 4 supra) was suspended in dichloromethane (13 mL). The mixture was treated with triethylamine (0.23 mL; 1.65 mmol) and methane-sulfonyl chloride (0.13 mL; 1.68 mmol) (Aldrich). The solid went into solution as the methanesulfonyl chloride was added. After 45 minutes, the reaction was shown by thin layer chromatography to be complete. The reaction was diluted with additional dichloromethane and washed with water and then brine. The organic phase was dried over anhydrous sodium sulfate, concentrated and dried under high vacuum to give crude (±)-methanesulfonic acid (2-{3-[8-(3-cyano-phenyl)-6-(4-methoxy-phenyl)-5-methyl-7-oxo-5,6,7,8-tetrahydro-pyrimido[4,5-d]pyrimidin-2-ylamino]-phenyl}-ethyl)-ester as a foam. This material was used in the next step without further purification. (Yield: 0.76 g, 95.4%).
Reaction SMILES: C[C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[N+:11]([CH3:14])([O-:13])=[O:12].[C:15]([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH3:15][C:9]1[CH:2]=[C:3]([CH:4]=[CH:14][N+:11]([O-:13])=[O:12])[CH:6]=[CH:7][C:8]=1[OH:10]
Reactant: C[N+](=O)[O-]
Reactant: CC(=O)[O-]
Reactant: Cc1cc(O)ccc1C=O
Agent: [NH4+]
Solvent: CC(=O)O
Product: Cc1cc(C=C[N+](=O)[O-])ccc1O
Temperature: 110 °C
Yield: 88.6 %

Procedure:
The 2-methyl-4-hydroxy-benzaldehyde (980 mg, 6.3 mmol), nitromethane (2.0 mL, 37.7 mmol) and ammonium acetate (1.9 g, 25.1 mmol) were dissolved in acetic acid (9 mL) and the reaction heated at 110° C. for 2 h. The reaction is concentrated under reduced pressure and the residue partitioned between ether and water. Separate the layers and dry with Na2SO4, filter and concentrate under reduced pressure. Purify the crude by flash chromatography (eluent: EtOAc/hexane 20/80 and 30/70) afforded the title compound (1.0 g). 1H-NMR (CDCl3, 200 MHz): 7.94 (d, 1H, J=13.4 Hz), 7.50 (d, 1H, J=13.6 Hz), 7.34-7.27 (m, 2H), 6.82 (d, 1H, J=8.1 Hz), 2.28 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][C:4]1([C:13]([F:16])([F:15])[F:14])[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5]1.[Cl:19][S:20](O)(=[O:22])=[O:21]>C(Cl)(Cl)Cl>[Cl:19][S:20]([C:11]1[CH:10]=[CH:9][C:7]2[O:8][C:4]([CH2:3][C:2]([F:1])([F:17])[F:18])([C:13]([F:15])([F:14])[F:16])[O:5][C:6]=2[CH:12]=1)(=[O:22])=[O:21]
Reactant: O=S(=O)(O)Cl
Reactant: FC(F)(F)CC1(C(F)(F)F)Oc2ccccc2O1
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Cl)c1ccc2c(c1)OC(CC(F)(F)F)(C(F)(F)F)O2
Temperature: 0 °C
Yield: 71.8 %

Procedure:
136 g of 2-(2,2,2-trifluoroethyl)-2-trifluoromethyl-1,3-benzodioxole were dissolved in 125 ml of chloroform. 175 g of chlorosulphonic acid were added dropwise at 0° C., while stirring, and the mixture was subsequently stirred at room temperature until the evolution of gas had ended. It was then poured onto 750 g of ice-water, the phases were separated and the aqueous phase was extracted with chloroform. The combined organic phases were washed with ice-water and sodium bicarbonate solution, dried with magnesium sulphate and freed from readily volatile constituents on a rotary evaporator. 133 g of product were obtained (=72% of theory), and the melting point was 55° to 57° C. 19F-NMR: -60.8 and -86.5 ppm. 1H-NMR: 3.13 ppm.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14](=[O:25])[NH:15][CH:16]3[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]3)[NH:11][C:8]2=[N:9][CH:10]=1)=[O:4].[H-].[Na+].Br[CH2:29][C:30]1[CH:34]=[C:33]([C:35]2[S:36][C:37]([Cl:40])=[CH:38][CH:39]=2)[O:32][N:31]=1.O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14](=[O:25])[NH:15][CH:16]3[CH2:21][CH2:20][N:19]([CH:22]([CH3:23])[CH3:24])[CH2:18][CH2:17]3)[N:11]([CH2:29][C:30]3[CH:34]=[C:33]([C:35]4[S:36][C:37]([Cl:40])=[CH:38][CH:39]=4)[O:32][N:31]=3)[C:8]2=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnc2[nH]c(C(=O)NC3CCN(C(C)C)CC3)cc2c1
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cnc2c(c1)cc(C(=O)NC1CCN(C(C)C)CC1)n2Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.5 %

Procedure:
To a solution of 1.2 g 2-(1-Isopropyl-piperidin-4-ylcarbamoyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid methyl ester in 20 mL DMF, 91 mg sodium hydride (95%) were added at 0° C. Then the reaction mixture was warmed to RT and stirred for 30 min. After cooling again to 0° C., 967 mg 3-Bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole [prepared by adopting a procedure described by Ewing, William R.; Becker, Michael R.; Choi-Sledeski, Yong Mi; Pauls, Heinz W.; He, Wei; Condon, Stephen M.; Davis, Roderick S.; Hanney, Barbara A.; Spada, Alfred P.; Burns, Christopher J.; Jiang, John Z.; Li, Aiwen; Myers, Michael R.; Lau, Wan F.; Poli, Gregory B; PCT Int. Appl. (2001), 460 pp. WO 0107436 A2] were added and the mixture was stirred for 2 h at RT. Then 50 mL of water were added and the precipitate was collected by filtration to yield 630 mg pure product. The filtrate was concentrated under reduced pressure and the residue purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). After lyophilization further 371 mg of product were obtained as a solid.
Reaction SMILES: NCCC(O)=O.[C:7]1([CH2:13][CH2:14][O:15][CH2:16][CH:17]=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:19](#[N:23])[CH2:20][C:21]#[N:22]>C(O)C>[C:7]1([CH2:13][CH2:14][O:15][CH2:16][CH:17]=[C:20]([C:19]#[N:23])[C:21]#[N:22])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=CCOCCc1ccccc1
Reactant: N#CCC#N
Agent: NCCC(=O)O
Solvent: CCO
Product: N#CC(C#N)=CCOCCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.6 %

Procedure:
β-Alanine (0.6 g) was added to a solution of [2-phenylethoxy]acetaldehyde (8.0 g) and malononitrile (3.5 g) in ethanol (100 ml). The mixture was stirred at room temperature for 3 hours. The solid was filtered off, washed with fresh ethanol and dried to yield the subtitled compound (5.85g, 54%).