Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C=P(C)(C)C)#N.[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23]2>C1(C)C=CC=CC=1>[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:24]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23]2
Reactant: CCOC(=O)c1cc2cc(F)ccc2[nH]1
Reactant: OCCOCc1ccccc1
Agent: CP(C)(C)=CC#N
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2cc(F)ccc2n1CCOCc1ccccc1
Temperature: 20 °C
Yield: 88.1 %

Procedure:
94 μl (0.657 mmol) of 2-benzyloxyethanol and 50.4 mg (0.438 mmol) of (cyanomethylene)trimethylphosphorane (Tet. Lett., 1996, 37, 2459-2462) are added to a solution of 68 mg (0.329 mmol) of ethyl 5-fluoro-1H-indole-2-carboxylate in 2 ml of toluene, stirred at 20° C. The reaction mixture is heated at 110° C. for 12 hours and then concentrated under reduced pressure, taken up in 20 ml of ethyl ether, filtered over a celite buffer and concentrated under reduced pressure. The residue obtained is purified by preparative HPLC, elution being carried out with a mixture of water, acetonitrile and trifluoroacetic acid. 99 mg of a yellow oil are thus isolated.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][C@H:11]([CH2:13][OH:14])[O:10][C:9]2=[O:15])[CH:5]=[CH:4][C:3]=1[N:16]1[CH2:20][CH:19]2[CH2:21][C:22]3([CH2:27][CH:18]2[CH2:17]1)[O:26][CH2:25][CH2:24][O:23]3.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][C@H:11]([CH2:13][O:14][S:36]([CH3:35])(=[O:38])=[O:37])[O:10][C:9]2=[O:15])[CH:5]=[CH:4][C:3]=1[N:16]1[CH2:20][CH:19]2[CH2:21][C:22]3([CH2:27][CH:18]2[CH2:17]1)[O:26][CH2:25][CH2:24][O:23]3
Reactant: CS(=O)(=O)Cl
Reactant: O=C1O[C@@H](CO)CN1c1ccc(N2CC3CC4(CC3C2)OCCO4)c(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@H]1CN(c2ccc(N3CC4CC5(CC4C3)OCCO5)c(F)c2)C(=O)O1
Reaction time: 1 h

Procedure:
21.4 g (56.6 mmol) of 2-[2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-3-oxazolidinyl]phenyl]-hexahydro-1H-spiro[cyclopenta[c]pyrrol-5,2′-[1,3]dioxolane] prepared in the step 7 was dissolved in 200 ml of methylene chloride, 19.7 ml (141.5 mmol) of triethylamine was added, the temperature was lowered to 0° C., and then, 8.76 ml (113.2 mmol) of methansulfonyl chloride was added dropwise over 15 minutes, and the mixture was stirred for 1 hour. After the reaction was completed, the reaction mixture was diluted with 200 mL of methylene chloride, washed with water and a saturated aqueous solution of sodium chloride, and then, dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: I[C:2]1[C:10]2[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1.[CH3:18][NH:19][C:20]([NH:22][C:23]1[S:24][C:25]2[CH:31]=[C:30](B3OC(C)(C)C(C)(C)O3)[CH:29]=[CH:28][C:26]=2[N:27]=1)=[O:21].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:11][C:9]1[C:10]2[C:2]([C:30]3[CH:29]=[CH:28][C:26]4[N:27]=[C:23]([NH:22][C:20]([NH:19][CH3:18])=[O:21])[S:24][C:25]=4[CH:31]=3)=[CH:3][N:4]([CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: Nc1ncnc2c1c(I)cn2C1CCOCC1
Reactant: CNC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CNC(=O)Nc1nc2ccc(-c3cn(C4CCOCC4)c4ncnc(N)c34)cc2s1
Temperature: 25 °C
Yield: 48.9 %

Procedure:
A mixture of 5-iodo-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (402) (100 mg, 0.29 mmol), 1-methyl-3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)urea (J-2) (127 mg, 1.3 eq, 0.38 mmol), Pd(PPh3)4 (38 mg, 0.1 eq, 0.03 mmol) and Na2CO3 (2 N, 2 mL) in DME (10 mL) was stirred at reflux for 30 min. under argon. The mixture was cooled to room temperature, and then concentrated in vacuo. Brine (10 mL) was added to the residue and then extracted with ethyl acetate (3×30 mL). The combined organic layer was washed with brine (10 mL), dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography eluting with MeOH/DCM (1/30) to afford the desired product, 1-(6-(4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzo[d]thiazol-2-yl)-3-methylurea (403) (60 mg 58% yield) as a white solid. ESI-MS m/z: 424.05 [M+H]+.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[C:28]12([CH2:38][NH:39][C:40]([C:42]3[C:43]([CH3:57])=[N:44][N:45]([C:47]4[N:52]=[C:51]([C:53](O)=[O:54])[C:50]([CH3:56])=[CH:49][N:48]=4)[CH:46]=3)=[O:41])[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH2:29]1)[CH2:35]2.[NH:58]1[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:28]12([CH2:38][NH:39][C:40]([C:42]3[C:43]([CH3:57])=[N:44][N:45]([C:47]4[N:52]=[C:51]([C:53]([N:58]5[CH2:63][CH2:62][O:61][CH2:60][CH2:59]5)=[O:54])[C:50]([CH3:56])=[CH:49][N:48]=4)[CH:46]=3)=[O:41])[CH2:29][CH:30]3[CH2:31][CH:32]([CH2:33][CH:34]([CH2:36]3)[CH2:35]1)[CH2:37]2
Reactant: Cc1cnc(-n2cc(C(=O)NCC34CC5CC(CC(C5)C3)C4)c(C)n2)nc1C(=O)O
Reactant: C1COCCN1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cnc(-n2cc(C(=O)NCC34CC5CC(CC(C5)C3)C4)c(C)n2)nc1C(=O)N1CCOCC1
Reaction time: 8 h

Procedure:
BOP (88 mg, 8 mmol) is added to a solution of 2-{4-[(adamantan-1-ylmethyl)-carbamoyl]-3-methyl-pyrazol-1-yl}-5-methyl-pyrimidine-4-carboxylic acid (41 mg, 0.1 mmol), morpholine (13 mg, 0.15 mmol) and DIEA (39 mg, 0.3 mmol) in DCM (3 mL). The solution is stirred overnight, evaporated and partitioned between EtOAc and saturated aqueous sodium bicarbonate. The organic layer is washed with brine, dried and evaporated. Purification by PTLC, eluting with a mixture of 5% MeOH and 1% TEA in DCM, affords the title compound. 1H NMR (CDCl3): 8.80 (s, 1H), 8.65 (s, 1H), 5.93 (s, 1H), 3.81 (s, 4H), 3.63-3.66 (m, 1H), 3.46 (s, 1H), 3.29 (t, 1H), 3.10-3.15 (m, 2H), 2.85-2.90 (m, 1H), 2.58 (s, 3H), 2.31 (s, 3H), 1.99 (s, 3H), 1.53-1.73 (m, 12H). MS (M+1)=479.37; RT=1.30 min. *IC50.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([C:14]([F:17])([F:16])[F:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:10]([C:14]([F:17])([F:15])[F:16])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cl
Reactant: FC(F)(F)C1CN(Cc2ccccc2)CCN1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)N1CCN(Cc2ccccc2)CC1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-benzyl-3-(trifluoromethyl)piperazine 34a (1.0 mmol) and pyridine (1.1 mmol) in DCM (5 mL), is added ethyl chloroformate (1.1 mmol). The resulting mixture is stirred at rt for 1 h. After the reaction is complete, the reaction mixture is diluted with DCM (15 mL) and washed with water. The organic layer is separated, dried over Na2SO4, filtered, and concentrated to afford ethyl 4-benzyl-2-(trifluoromethyl)piperazine-1-carboxylate 34b, which is used without purification. MS (m/z) (M+1)+: 317.1.
Reaction SMILES: [CH:1]([Si:4]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:37])[CH3:36])[O:5][CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:18]3[CH:19]=[C:20]([O:23][C@H:24]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[C@@H:27]([NH2:34])[CH2:26][CH2:25]4)[CH:21]=[CH:22][C:17]3=[N:16][N:15]=2)[CH2:10][CH2:9]1)([CH3:3])[CH3:2].ClC(Cl)(Cl)C[O:44][C:45](=O)[NH:46][C:47]1[N:48]([C:56]2[CH:61]=[CH:60][C:59]([CH3:62])=[CH:58][CH:57]=2)[N:49]=[C:50]([C:52]([CH3:55])([CH3:54])[CH3:53])[CH:51]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:52]([C:50]1[CH:51]=[C:47]([NH:46][C:45]([NH:34][C@@H:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:24]([O:23][C:20]3[CH:21]=[CH:22][C:17]4[N:18]([C:14]([N:11]5[CH2:10][CH2:9][CH:8]([CH2:7][CH2:6][O:5][Si:4]([CH:35]([CH3:37])[CH3:36])([CH:1]([CH3:2])[CH3:3])[CH:38]([CH3:40])[CH3:39])[CH2:13][CH2:12]5)=[N:15][N:16]=4)[CH:19]=3)[CH2:25][CH2:26]2)=[O:44])[N:48]([C:56]2[CH:61]=[CH:60][C:59]([CH3:62])=[CH:58][CH:57]=2)[N:49]=1)([CH3:55])([CH3:53])[CH3:54]
Reactant: CC(C)[Si](OCCC1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1)(C(C)C)C(C)C
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCC(CCO[Si](C(C)C)(C(C)C)C(C)C)CC5)n4c3)c3ccccc32)cc1
Yield: 81 %

Procedure:
A mixture of Intermediate 66c (178 mg, 0.316 mmol) and (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 128 mg, 0.316 mmol) in 1,4-dioxane (3 mL) and DIPEA (83 μL, 0.474 mmol) was stirred at 95° C. for 4 h. The cooled mixture was concentrated in vacuo. The residue was purified by FCC, using 0-10% MeOH in DCM, to give the title compound as a brown foam (208 mg, 81%). LCMS (Method 3): Rt 5.96 min, m/z 819 [MH+].
Reaction SMILES: OC1C2N=NNC=2C=CC=1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC.Cl.[NH2:33][CH:34]1[C:40](=[O:41])[N:39]([CH3:42])[C:38]2[CH:43]=[CH:44][CH:45]=[CH:46][C:37]=2[C:36]2[CH:47]=[CH:48][CH:49]=[CH:50][C:35]1=2.[C:51](O)(=[O:55])[C@H:52]([CH3:54])[OH:53]>C1COCC1>[OH:53][C@@H:52]([CH3:54])[C:51]([NH:33][CH:34]1[C:40](=[O:41])[N:39]([CH3:42])[C:38]2[CH:43]=[CH:44][CH:45]=[CH:46][C:37]=2[C:36]2[CH:47]=[CH:48][CH:49]=[CH:50][C:35]1=2)=[O:55]
Reactant: C[C@H](O)C(=O)O
Reactant: CN1C(=O)C(N)c2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@H](O)C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydroxybenzotriazole (344 mg, 2.55 mmol), diisopropylethylamine (659 mg, 5.1 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (488 mg, 2.55 mmol) were added to a cooled (0° C.) solution of 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one hydrochloride (700 mg, 2.55 mmol) and L-(+)-lactic acid (252 mg, 2.8 mmol) in THF (7 ml) and stirred overnight at r.t. The solvent was evaporated, the residue was taken up in dichloromethane and washed with water. The organic phase was dried over Na2SO4 and evaporated. Upon chromatographic purification (silica gel, dichloromethane/methanol=1:0−9:1) the title compound (820 mg, quant.) was obtained as a white solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[NH2:14][C:15]1[N:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18].O>N1C=CC=CC=1>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]1[O:6][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][CH:22]=[N:23][C:15]=2[N:14]=1
Reactant: Nc1ncccc1C(=O)O
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Solvent: O
Solvent: c1ccncc1
Product: O=c1oc(-c2ccccc2C(F)(F)F)nc2ncccc12
Temperature: 25 °C
Yield: 59.4 %

Procedure:
2-(Trifluoromethyl)benzoyl chloride (4.2 ml, 29.2 mmol) is added dropwise to a solution of 2-aminonicotinic acid (2.04 g, 14.76 mmol) in 20 ml of pyridine. The reaction mixture is heated at 158 C. for 30 min then cooled to room temperature. The reaction is poured into 200 ml of water and an oil forms which solidifies upon stirring. The solid is collected by vacuum filtration and washed with water and diethyl ether. The product is dried to give 2-(2-trifluoromethyl-phenyl)-pyrido[2,3-d][1,3]oxazin-4-one (2.56 g, 60% yield) which may be used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12]Br.O>C(O)(=O)C>[Br:12][C:8]1[C:9]([CH3:11])=[CH:10][C:2]([OH:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: BrBr
Reactant: Cc1ccc(C(=O)O)c(O)c1
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(O)c(C(=O)O)cc1Br
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To a solution of 2-hydroxy-4-methylbenzoic acid (5.00 g) in acetic acid (70.0 mL) was added dropwise bromine (1.68 mL), and the mixture was stirred at room temperature for 5.5 hr. To the reaction mixture was added water, and the precipitate was collected by filtration, and dried under reduced pressure to give the title compound (6.78 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[CH2:10][CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:10][CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: ClCCN1CCCC1
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1cccc(OCCN2CCCC2)c1
Reaction time: 48 h
Yield: 43.1 %

Procedure:
3-bromo-phenol (5.34 g, 30.9 mmol, 1 equiv), 1-(2-chloro-ethyl)-pyrrolidine (5.24 g, 30.9 mmol, 1 equiv) and potassium carbonate (K2CO3) (34 g, 24.7 mmol, 8 equiv) were weighed out into a 500 mL round bottom flask, were diluted with 150 mL DMF and stirred for 2 days. The contents were poured onto ethyl acetate water mixture and extracted once. The organic layer was separated, washed with brine and dried over sodium sulfate (Na2SO4). Filtration followed by concentration provided crude product as a pale yellow oil. Column chromatography (1:9 ethyl acetate/hexanes) provided desired product as a yellow oil (3.6 g, 43% yield). 1H NMR (DMSO-d6): δ 1.65-1.69 (m, 4H), 2.72 (s, 1H), 2.75 (t, J=5.8 Hz, 2H), 2.88 (s, 1H), 4.06 (t, J=5.8 Hz, 2H), 6.95 (dd, J=8.35 Hz, 1H), 7.11 (d, J=7.7, 1H), 7.13-7.14 (m, 1H), 7.22 (t, J=8.1 Hz, 1H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.Br[C:12]([F:19])([F:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>CS(C)=O.[Cu]>[F:18][C:12]([F:19])([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: O=[N+]([O-])c1cccc(I)c1
Agent: [Cu]
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)c1cccc([N+](=O)[O-])c1
Temperature: 70 °C
Yield: 50 %

Procedure:
To a solution of 1-iodo-3-nitrobenzene (1.450 g, 5.82 mmol) and ethyl 2-bromo-2,2-difluoroacetate (1.3 g, 6.40 mmol) in anhydrous DMSO (10 ml) was added Copper powder (0.740 g, 11.64 mmol). The mixture was purged with N2 and heated at 70° C. in a sealed vial for 17 h. After being cooled to room temperature, the reaction mixture was poured into 20% aqueous NH4Cl solution (100 mL) and was extracted with EtOAc (2×100 mL). The organic extract was washed with brine (2×30 mL), dried over Na2SO4 and concentrated. The residue was purified by flash chromatography to obtain ethyl 2,2-difluoro-2-(3-nitrophenyl)acetate (0.714 g).
Reaction SMILES: [Mg].BrC(Br)C.Br[CH2:7][CH2:8][CH:9]1[O:13][CH2:12][CH2:11][O:10]1.[CH2:14]([Si:17]([CH3:20])([CH3:19])Cl)[CH:15]=[CH2:16]>O1CCCC1>[CH2:14]([Si:17]([CH2:7][CH2:8][CH:9]1[O:13][CH2:12][CH2:11][O:10]1)([CH3:20])[CH3:19])[CH:15]=[CH2:16]
Reactant: BrCCC1OCCO1
Reactant: C=CC[Si](C)(C)Cl
Agent: CC(Br)Br
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CC[Si](C)(C)CCC1OCCO1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a slurry of magnesium (2.43 g) in dry tetrahydrofuran (50 mL), few drops of dibromoethane (˜50 μL) was added under argon and stirred at room temperature for 10 min. The reaction mixture was cooled to 10° C. and 2-(2-bromoethyl)-1,3-dioxolane (10.9 g) was introduced dropwise during 10 min and allowed to stir at room temperature for 2 hours. The resulting reaction mixture was cooled to −10° C. and allyldimethylchlorosilane (6.73 g) was added dropwise during 10 min. and stirred over night at room temperature. Finally, the reaction content was quenched with aqueous NaHCO3 (15 mL) and extracted with ether (3×50 mL). The combined organic layer was dried and concentrated under mild vacuum to obtain the crude product, which was advanced to the next step without further purification (yield 9.5 g).
Reaction SMILES: Cl[C:2]1[C:3]2[S:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C-:11]#[N:12].[K+]>>[N:5]1[C:4]2[CH:8]=[CH:9][S:10][C:3]=2[C:2]([C:11]#[N:12])=[N:7][CH:6]=1
Reactant: [C-]#N
Reactant: Clc1ncnc2ccsc12
Agent: [K+]
Product: N#Cc1ncnc2ccsc12

Procedure:
Compound 6.2 is reacted with potassium cyanide according to a procedure in Miyashita, A. et. al. (Heterocycles 39, 1994, 345) to yield thieno[3,2-d]pyrimidine-4-carbonitrile (compound 7.1).
Reaction SMILES: ClC(OCC)=O.[C:7]([CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1)(O)=[O:8].C(N(CC)CC)C>O1CCCC1>[OH:8][CH2:7][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1
Reactant: CCOC(=O)N1CCC(C(=O)O)CC1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(CO)CC1
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
A solution of 0.67 g of ethyl chloroformate in 2 ml of tetrahydrofuran was added to a solution of 1.01 g of ethyl 4-carboxypiperidine-1-carboxylate and 0.72 g of triethylamine in 20 ml of tetrahydrofuran at -10° to -5° C., and the mixture was stirred for 30 minutes. The resultant crystalline precipitate was filtered off, the filtrate was added to a solution of 0.57 g of sodium borohydride in 10 ml of water with ice cooling over 30 minutes, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was made acidic with 1N hydrochloric acid with ice cooling and then extracted with ether. The ether layer was washed in sequence with water, saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography. Elution with a hexane-ethyl acetate (1:1 v/v) mixture gave 0.69 g of ethyl 4-hydroxymethylpiperidine-1-carboxylate
Reaction SMILES: [NH2:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]([CH:6](O)[CH2:7][NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][C:3]=1[Cl:17].S(Cl)([Cl:20])=O>>[NH2:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]([CH:6]([Cl:20])[CH2:7][NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][C:3]=1[Cl:17]
Reactant: CC(C)(C)NCC(O)c1cc(Cl)c(N)c(Cl)c1
Reactant: O=S(Cl)Cl
Product: CC(C)(C)NCC(Cl)c1cc(Cl)c(N)c(Cl)c1

Procedure:
Under N2 atmosphere, 27.72 g of 4-amino-α-[(tert-butylamino)methyl]-3,5-dichlorobenzyl alcohol is added to 200 ml of thionyl chloride stirred at 0-5%C. After addition is completed, the reaction mixture is stirred at ambient temperature for 3 hours. Subsequently, the mixture is evaporated to dryness in vacuo to afford 37.34 g of yellow solid, which is used as is.
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[CH2:12]([C:14]1(O)[C:22]2[C:17](=[CH:18][C:19]([F:23])=[CH:20][CH:21]=2)[CH2:16][CH2:15]1)[CH3:13].[CH3:25][S:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:36]=1[NH:35][CH:34]=[CH:33]2>ClCCl>[CH2:12]([C:14]1([C:33]2[C:32]3[C:36](=[C:28]([CH2:27][S:26][CH3:25])[CH:29]=[CH:30][CH:31]=3)[NH:35][CH:34]=2)[C:22]2[C:17](=[CH:18][C:19]([F:23])=[CH:20][CH:21]=2)[CH2:16][CH2:15]1)[CH3:13]
Reactant: CSCc1cccc2cc[nH]c12
Reactant: CCC1(O)CCc2cc(F)ccc21
Agent: [Cl-]
Agent: [In+3]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC1(c2c[nH]c3c(CSC)cccc23)CCc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
515 mg (2.33 mmol) of indium(III) chloride and 0.17 ml (2.22 mmol) of trifluoroacetic acid were added to 400 mg (2.22 mmol) of the compound from Example 135A and 393 mg (2.22 mmol) of the compound from Example 8A in 12 ml of dichloromethane at 0° C., and the mixture was stirred at RT for 1 h. It was diluted with dichloromethane, washed with water, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 33 mg (4% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl[C:16]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH2:29]C)[N:19]=[CH:18][N:17]=1>CN(C=O)C>[CH3:29][O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:20]1[N:19]=[CH:18][N:17]=[C:16]([NH:1][C:2]2[CH:3]=[C:4]([CH2:8][S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=2)[CH:21]=1
Reactant: CCOc1ccccc1-c1cc(Cl)ncn1
Reactant: CN(C)S(=O)(=O)Cc1cccc(N)c1
Solvent: CN(C)C=O
Product: COc1ccccc1-c1cc(Nc2cccc(CS(=O)(=O)N(C)C)c2)ncn1
Temperature: 80 °C

Procedure:
A mixture of (3-aminophenyl)-N,N-dimethylmethanesulfonamide (0.107 g, 0.50 mmol) and 4-chloro-6-(2-ethoxyphenyl)-pyrimidine (0.110 g, 0.10 mmol) in DMFA (3 mL) was stirred at 80° C. till the reaction completion (TLC control), then concentrated in vacuo and the residue was recrystallized from isopropanol to give C-{3-[6-(2-methoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-N,N-dimethyl-methanesulfonamide (Compound 20)
Reaction SMILES: B(F)(F)F.CSC.C[O:9][C:10]1[CH:11]=[C:12]([C:17]2[N:21]([CH2:22][C:23]#[N:24])[N:20]=[CH:19][C:18]=2[C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[NH:37][C:38](=[O:40])[CH3:39])[CH:26]=2)[CH:13]=[C:14]([CH3:16])[CH:15]=1>ClCCl>[OH:9][C:10]1[CH:11]=[C:12]([C:17]2[N:21]([CH2:22][C:23]#[N:24])[N:20]=[CH:19][C:18]=2[C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[NH:37][C:38](=[O:40])[CH3:39])[CH:26]=2)[CH:13]=[C:14]([CH3:16])[CH:15]=1
Reactant: COc1cc(C)cc(-c2c(-c3ccnc(-c4ccccc4NC(C)=O)c3)cnn2CC#N)c1
Agent: FB(F)F
Solvent: CSC
Solvent: ClCCl
Product: CC(=O)Nc1ccccc1-c1cc(-c2cnn(CC#N)c2-c2cc(C)cc(O)c2)ccn1
Reaction time: 24 h

Procedure:
Borontrifluoride-dimethylsulfide (0.13 mL, 1.2 mmol) was dropwise added to a solution of the methoxy compound (52.5 mg, 0.12 mmol) prepared in Example 38 in dichloromethane (4 mL) at room temperature under nitrogen atmosphere, and stirred for 24 hours. The reaction mixture was concentrated by vacuum distillation. The residue was treated in ethyl acetate (100 mL) and brine (50 mL) and the organic layer was dried over anhydrous magnesium sulfate and distilled under vacuum. Purification through column chromatography (silica gel, ethyl acetate) afforded pure hydroxy products (29 mg, 58%).
Reaction SMILES: [C:1]([N:5]1[CH2:31][CH2:30][CH2:29][CH2:28][C:8]2[C:9]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[C:10]3[C:19]4[CH:18]=[C:17]([NH2:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:32])([CH3:4])([CH3:3])[CH3:2].[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([N:5]1[CH2:31][CH2:30][CH2:29][CH2:28][C:8]2[C:9]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[C:10]3[C:19]4[CH:18]=[C:17]([NH:20][S:34]([CH3:33])(=[O:36])=[O:35])[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:32])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(cc1N)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1NS(C)(=O)=O)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Temperature: 25 °C

Procedure:
To a solution of 12.5 mg 20b in 2 mL methylene chloride was added 3.2 μL methanesulphonyl chloride and 9.2 μL N,N-diisopropylethylamine. The mixture was stirred at room temperature. After 1 h the mixture was diluted with methylene chloride and was washed with water. The organic phase was dried and concentrated. The crude product was purified by preparative HPLC on a reversed phase C18 column to give 1.8 mg of compound 29a.