Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:8])([CH2:6][NH2:7])[C:3]([OH:5])=[O:4].[C:9]1(=O)[O:14][C:12](=[O:13])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12.C(N(CC)CC)C.O>C1(C)C=CC=CC=1>[O:13]=[C:12]1[C:11]2[C:10](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9](=[O:14])[N:7]1[CH2:6][C:2]([F:8])([F:1])[C:3]([OH:5])=[O:4]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCC(F)(F)C(=O)O
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CC(F)(F)C(=O)O
Temperature: 25 °C
Yield: 95.1 %

Procedure:
A suspension of 2,2-difluoro-3-aminopropionic acid A1 (7.08 g, 56.6 mmol) in 250 ml of toluene was treated with phthalic anhydride (8.80 g, 59.4 mmol) and triethylamine (20 mL, 14.35 g, 14.4 mmol) and refluxed with water removed by a Dean-Stark trap, drained 5 times at intervals. After cooling to ambient temperature the solvent was removed in vacuo at 30° C. The residue obtained was partitioned between ethyl acetate and ˜2N HCl (aq) with the aqueous phase extracted a second time with ethyl acetate. Evaporation at 30° C. (in vacuo) of the combined organic phases that had been washed with ˜2N HCl, brine and dried (Na2SO4) afforded 3-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-2,2-difluoro-propionic acid (13.74 g) A2.
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[CH2:2][OH:3].C(N(C(C)C)CC)(C)C.[Si:22](OS(C(F)(F)F)(=O)=O)([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24].O>C(Cl)Cl>[CH2:6]([O:5][C:1](=[O:4])[CH2:2][O:3][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: O=C(CO)OCc1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[Si](OCC(=O)OCc1ccccc1)(C(C)C)C(C)C
Temperature: 25 °C
Yield: 78.7 %

Procedure:
To a solution of benzyl glycolate (46.91 g, 0.282 mol) and diisopropylethylamine (74 mLs, 0.423 mol) in CH2Cl2, cooled via water bath, was added a solution of TIPSOTf (95 g, 0.31 mol) in CH2Cl2. The resulting mixture was allowed to warm to ambient temperature then poured into water, washed twice with 10% aqueous NaHSO4, dried over Na2SO4 and concentrated in vacuo. Flash chromatography (SiO2, 0 to 5% EtOAc in hexanes) afforded 71.6 g of 663.
Reaction SMILES: NC1SC2C=C(C)C=CC=2C=1C(OCC)=O.FC1C=CC=CC=1[N+]([O-])=O.[CH3:27][C:28]1[CH:29]=[CH:30][C:31]2[C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:34]([NH:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[N+:48]([O-])=O)[S:33][C:32]=2[CH:51]=1.Cl.[Sn+2]>C(O)C.CS(C)=O>[NH2:48][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=1[NH:41][C:34]1[S:33][C:32]2[CH:51]=[C:28]([CH3:27])[CH:29]=[CH:30][C:31]=2[C:35]=1[C:36]([O:38][CH2:39][CH3:40])=[O:37]
Reactant: CCOC(=O)c1c(Nc2ccccc2[N+](=O)[O-])sc2cc(C)ccc12
Agent: CCOC(=O)c1c(N)sc2cc(C)ccc12
Agent: Cl
Agent: O=[N+]([O-])c1ccccc1F
Solvent: CCO
Solvent: CS(C)=O
Product: CCOC(=O)c1c(Nc2ccccc2N)sc2cc(C)ccc12

Procedure:
In the same manner as in Starting Material Synthesis Example 4 and using ethyl 2-amino-6-methylbenzo[b]thiophene-3-carboxylate (4.18 g), 2-fluoronitrobenzene (2.5 g) and dimethyl sulfoxide (50 ml), crude crystals (7.5 g) of ethyl 6-methyl-2-(2-nitroanilino)benzo[b]thiophene-3-carboxylate were obtained. Without purification, in the same manner as in Starting Material Synthesis Example 21 and using ethanol (50 ml), 18% hydrochloric acid (70 ml) and tin(II) chlorihe.dihydrate (16 g), ethyl 2-(2-aminoanilino)-6-methylbenzo[b]thiophene-3-carboxylate (3.7 g) was obtained.
Reaction SMILES: [C:1]12([C:8]3[C:9]([O:13][C:14]4[N:19]=[CH:18][C:17]([NH:20][C:21](=[O:27])[C@@:22]([CH3:26])([CH2:24][CH3:25])[NH2:23])=[CH:16][CH:15]=4)=[CH:10][CH:11]=[CH:12][C:7]=3[CH2:6][O:5][CH2:4]1)[CH2:3][CH2:2]2.Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH2:24]([C@@:22]1([CH3:26])[NH:23][C:29](=[O:31])[N:20]([C:17]2[CH:18]=[N:19][C:14]([O:13][C:9]3[C:8]4[C:1]5([CH2:4][O:5][CH2:6][C:7]=4[CH:12]=[CH:11][CH:10]=3)[CH2:2][CH2:3]5)=[CH:15][CH:16]=2)[C:21]1=[O:27])[CH3:25]
Reactant: CC[C@@](C)(N)C(=O)Nc1ccc(Oc2cccc3c2C2(CC2)COC3)nc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC[C@@]1(C)NC(=O)N(c2ccc(Oc3cccc4c3C3(CC3)COC4)nc2)C1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 129.7 %

Procedure:
To a solution of N1-[6-(1H-spiro[2-benzopyran-4,1′-cyclopropan]-5-yloxy)-3-pyridinyl]-isovalinamide (Intermediate 141, 40 mg) in dry dichloromethane (8 mL) TEA (0.076 mL, 0.544 mmol) was added and the reaction mixture was cooled to 0° C. A solution of triphosgene (14.54 mg, 0.049 mmol) in dry dichloromethane (4 ml) was slowly added and the reaction mixture was stirred for 3 hours at the same temperature. The reaction was quenched with water (10 ml) and two phases separated. The organic layer was dried over sodium sulphate, filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using 10 g SNAP column and cyclohexane/ethyl acetate as eluents from 7:3 to 3:7 as eluent. This afforded the title compound (25 mg) as a white solid.
Reaction SMILES: [C:1]([S:5][C:6]1[C:11]([CH2:12]Cl)=[CH:10][CH:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:16][C:17](=[O:29])[CH2:18][CH2:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([OH:27])=[C:22]([F:28])[CH:21]=1)[CH3:15]>>[CH2:14]([O:16][C:17](=[O:29])[CH2:18][CH2:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([O:27][CH2:12][C:11]2[C:6]([S:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[N:7][CH:8]=[CH:9][CH:10]=2)=[C:22]([F:28])[CH:21]=1)[CH3:15]
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Reactant: CC(C)(C)Sc1ncccc1CCl
Product: CCOC(=O)CCc1cc(F)c(OCc2cccnc2SC(C)(C)C)c(F)c1
Yield: 86 %

Procedure:
2-t-Butylsulfanyl-3-chloromethyl-pyridine (0.08 g, 0.37 mmol) obtained in Step C of Preparation Example 17 and 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester obtained in Step D of Preparation Example 2 were used to react in the same manner as in Step A of Example 1 to obtain the title compound (0.13 g, 86%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=2[CH:17]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])[C:22]([Cl:37])=[CH:21][N:20]=1>>[Cl:37][C:22]1[C:23]([NH:25][C:26]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])=[N:24][C:19]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=3[CH:17]=2)=[N:20][CH:21]=1
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)CCC(C)(C)c2ccc(N)cc21
Product: CCN1C(=O)CCC(C)(C)c2ccc(Nc3ncc(Cl)c(Nc4c(F)cccc4C(=O)NC)n3)cc21

Procedure:
The title compound was prepared with a procedure analogous to that used to prepare example 381 by combining 8-Amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide to yield a yellow solid (38%). LCMS: m/z=511.18 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.52 (s, 1H), 7.34 (d, 1H, J=7.6 Hz), 7.14 (m, 5H), 3.54 (m, 2H), 3.35 (s, 3H), 2.86 (s, 3H), 2.20 (m, 2H), 1.95 (m, 2H), 1.26 (s, 6H), 1.06 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11](=O)[CH2:10][N:9]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[S:21])[CH2:10][N:9]=1
Reactant: O=C1CN=C(c2ccccc2F)c2ccccc2N1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Product: Fc1ccccc1C1=NCC(=S)Nc2ccccc21

Procedure:
A mixture of 1,3-dihydro-5-(o-fluorophenyl)-2H-1,4-benzodiazepin-2-one [Sternbach et al., J. Org. Chem. 27, 3788 (1962)] and P2S5 can be reacted in the same manner as in preparation I to produce 1,3-dihydro-5-(o-fluorophenyl)-2H-1,4-benzodiazepine-2-thione. This latter compound can then be substituted in the procedure of Exmple 1 to produce 6-(o-fluorophenyll)-1methyl-4H-s-triazolo[4,3-a] [1,4] benzodiazepine.
Reaction SMILES: Br[C:2]1([CH3:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C([SnH](CCCC)CCCC)CCC.[CH2:22]([O:29][C:30]([NH:32][C:33](=[CH2:38])[C:34]([O:36][CH3:37])=[O:35])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N(C(C)(C)C#N)=NC(C)(C)C#N>C1C=CC=CC=1>[CH2:22]([O:29][C:30]([NH:32][CH:33]([CH2:38][C:2]1([CH3:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)[C:34]([O:36][CH3:37])=[O:35])=[O:31])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: C=C(NC(=O)OCc1ccccc1)C(=O)OC
Reactant: CC1(Br)CCCCC1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Product: COC(=O)C(CC1(C)CCCCC1)NC(=O)OCc1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 1-bromo-1-methylcyclohexane (7.200 g, 3.0 equiv), tributyltin hydride (8 mL, 2.2 equiv), methyl 2-(benzyloxycarbonylamino)acrylate (3.120 g, 13.26 mmol, 1.0 equiv), and 2,2′-azobisisobutyronitrile (0.370 g, 0.17 equiv) in benzene (30 mL) was heated at 100° C. for 6 h. After the reaction mixture was evaporated under reduced pressure, the crude methyl 2-(benzyloxycarbonylamino)-3-(1-methylcyclohexyl)propanoate was used directly in the next step without further purification. MS ESI +ve m/z 356 (M+Na).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:13](CC2C=CC(OC)=CC=2)[C:14]2[CH:15]=[C:16]([CH:25]=[CH:26][CH:27]=2)[C:17]([NH:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[O:18])[C:5]2[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=2)[N:7]=1.[CH3:37][O:38][C:39]1[CH:40]=[C:41]([CH:43]=[C:44]([N:46]2[C:50]([CH3:51])=[N:49][N:48]=[N:47]2)[CH:45]=1)[NH2:42]>CO>[C:11]([C:8]1[N:6]2[N:7]=[C:2]([NH:42][C:41]3[CH:43]=[C:44]([N:46]4[C:50]([CH3:51])=[N:49][N:48]=[N:47]4)[CH:45]=[C:39]([O:38][CH3:37])[CH:40]=3)[CH:3]=[C:4]([NH:13][C:14]3[CH:15]=[C:16]([CH:25]=[CH:26][CH:27]=3)[C:17]([NH:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[O:18])[C:5]2=[N:10][CH:9]=1)#[N:12]
Reactant: COc1cc(N)cc(-n2nnnc2C)c1
Reactant: COc1ccc(CN(c2cccc(C(=O)NCCN(C)C)c2)c2cc(Cl)nn3c(C#N)cnc23)cc1
Solvent: CO
Product: COc1cc(Nc2cc(Nc3cccc(C(=O)NCCN(C)C)c3)c3ncc(C#N)n3n2)cc(-n2nnnc2C)c1

Procedure:
Example 255 was prepared from 253D and 3-methoxy-5-(5-methyl-1H-tetrazol-1-yl)aniline following the procedure as described in Example 6. HPLC: Rt=3.11 min. (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min. gradient, monitored at 220 nm). MS (ES): m/z=512.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:18]([CH2:19][C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])[C:17](=[O:26])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:27][CH2:28][CH2:29][CH2:30]Cl)[CH:15]=3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].C([O-])([O-])=O.[K+].[K+].[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.[I-].[Na+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:18]([CH2:19][C:20]([NH:22][CH:23]([CH3:24])[CH3:25])=[O:21])[C:17](=[O:26])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:27][CH2:28][CH2:29][CH2:30][N:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)[CH:15]=3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C1CCNCC1
Reactant: CC(C)NC(=O)Cn1c(-c2ccc(F)c(Cl)c2)nc2ccc(OCCCCl)cc2c1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)NC(=O)Cn1c(-c2ccc(F)c(Cl)c2)nc2ccc(OCCCN3CCCCC3)cc2c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 88.5 %

Procedure:
To a suspension of 2-[2-(3-chloro-4-fluorophenyl)-6-(3-chloropropoxy)-4-oxo-4H-quinazolin-3-yl]-N-isopropylacetamide (120 mg, 0.26 mmol) in acetonitrile (1 mL) was added K2CO3 (178 mg, 1.29 mmol), piperidine (0.76 mL, 0.77 mmol) and sodium iodide (20 mg, 0.13 mmol). The resultant mixture was heated to 80° C. in a tightly capped vial with stirring for 20 h. The mixture was then cooled to room temperature and poured into ice water (8 mL). The resultant white solid was collected by filtration and the filter cake was washed with cold diethyl ether (3×10 mL). The crude product was purified by chromatography on silica gel with methanol:dichloromethane (1:9, v/v) as eluent to afford 2-[2-(3-chloro-4-fluorophenyl)-4-oxo-6-(3-piperidin-1-ylpropoxy)-4H-quinazolin-3-yl]-N-isopropylacetamide (120 mg, 0.23 mmol, 91%). The HCl salt was prepared by treating the freebase with 5% HCl in ethanol (xs.) followed by removal of the ethanolic HCl in vacuo. The resultant HCl salt was redissolved in ethanol and the ethanol removed in vacuo (3×) to help remove residual HCl. The HCl salt thus obtained was then triturated with diethyl ether and collected by filtration affording 2-[2-(3-chloro-4-fluorophenyl)-4-oxo-6-(3-piperidin-1-ylpropoxy)-4H-quinazolin-3-yl]-N-isopropylacetamide hydrochloride (EXAMPLE 2a) as a white crystalline solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](Cl)=[O:15].[Cl-].[Al+3].[Cl-].[Cl-]>>[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([C:4]1[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=1)=[O:15]
Reactant: Oc1ccccc1
Reactant: O=C(Cl)CCCCCBr
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCCCCBr)c1ccc(O)cc1
Yield: 20.1 %

Procedure:
Phenol (0.88 g), 6-bromohexanoyl chloride (2.0 g) and aluminum chloride (1.4 g) were reacted and treated in the same manner as in Preparation Example 105 to give 0.51 g of 6-bromo-1-(4-hydroxyphenyl)-1-hexanone.
Reaction SMILES: [Li+].[F:2][C:3]([F:23])([F:22])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]([O-])=[O:20])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.Cl.[Cl:58][C:59]1[CH:66]=[C:65]([NH:67][CH:68]2[CH2:73][CH2:72][NH:71][CH2:70][CH2:69]2)[CH:64]=[CH:63][C:60]=1[C:61]#[N:62]>CN(C)C=O.ClCCl.O1CCCC1>[Cl:58][C:59]1[CH:66]=[C:65]([NH:67][CH:68]2[CH2:73][CH2:72][N:71]([C:19](=[O:20])[CH2:18][CH2:17][CH2:16][N:13]3[CH2:12][CH2:11][N:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([F:22])([F:2])[F:23])=[CH:5][CH:6]=4)[CH2:15][CH2:14]3)[CH2:70][CH2:69]2)[CH:64]=[CH:63][C:60]=1[C:61]#[N:62]
Reactant: N#Cc1ccc(NC2CCNCC2)cc1Cl
Reactant: O=C([O-])CCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1ccc(NC2CCN(C(=O)CCCN3CCN(c4ccc(C(F)(F)F)cc4)CC3)CC2)cc1Cl
Reaction time: 0.08 h

Procedure:
4-[4-(4-Trifluoromethyl-phenyl)-piperazin-1-yl]-butyric acid lithium salt (16 mg; 0.05 mmol, prepared in accordance with Example 3), diisopropylethyl amine (25 μL; 0.15 mmol) and tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (19 mg; 0.05 mmol) are diluted in a 2 to 1 mixture of dimethylformamide and tetrahydrofuran (1.5 mL) and the resulting solution is stirred for 5 minutes. A solution of 2-chloro-4-(piperidin-4-ylamino)-benzonitrile hydrochloride (14 mg; 0.05 mmol, prepared in accordance with Example 104) in dimethylformamide (0.5 mL) is added and the reaction is then stirred for 2 hours at room temperature. Following dilution with dichloromethane (10 mL), the organic layer is sequentially washed with water (5 mL), aq. sat. sodium hydrogen carbonate (3×5 mL), is dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained is finally purified by preparative HPLC to deliver the desired product in pure form (12 mg; 0.02 mmol). The structure was confirmed using Protocol I-B. Calculated mass=534; observed mass=534; HPLC retention time=4.52 min.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].Cl.[NH2:12][CH2:13][C:14]([NH2:16])=[O:15].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[C:3]=1[NH:12][CH2:13][C:14]([NH2:16])=[O:15]
Reactant: NCC(N)=O
Reactant: N#Cc1cccc(Br)c1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1cccc(Br)c1NCC(N)=O
Temperature: 100 °C
Yield: 85 %

Procedure:
10.0 g (50.0 mmol) 3-bromo-2-fluorobenzonitrile, 11.1 g (100.0 mmol) glycinamide hydrochloride and 17.3 g (125 mmol) K2CO3 were suspended in 90 ml DMSO and heated at 100° C. for 4 h. Having cooled down to room temperature, the solvent was concentrated and water was added. The resulting precipitate was sucked off and washed with water. 10.8 g (85%) 2-(2-bromo-6-cyano-phenylamino)acetamide was obtained. ESI-MS [m/z]: 254, 256 [M+H]+
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:9]3[CH:19]=[CH:18][NH:17][C:10]=3[N:11]=[CH:12][C:13]=2[N+:14]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.O.[Sn](Cl)Cl>CCO>[CH:1]1([NH:7][C:8]2[C:13]([NH2:14])=[CH:12][N:11]=[C:10]3[NH:17][CH:18]=[CH:19][C:9]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1cnc2[nH]ccc2c1NC1CCCCC1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1cnc2[nH]ccc2c1NC1CCCCC1
Temperature: 55 °C
Yield: 81.5 %

Procedure:
To a solution of N-cyclohexyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-amine (0.15 g, 0.57 mmol) in EtOH (10 mL) was added tin (II) chloride dihydrate (0.65 g, 2.9 mmol). The reaction mixture was heated at about 55° C. for about 1 h. The solvent was removed under reduced pressure and EtOAc (75 mL) and saturated aqueous NaHCO3 (25 mL) were added. The solid that formed was collected by vacuum filtration, washed with EtOAc (25 mL), and discarded. The filtrate was washed with saturated aqueous NaHCO3 (3×20 mL), dried over anhydrous MgSO4, filtered, and concd to give N-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-4,5-diamine (0.107 g, 87%) as a brown residue: LC/MS (Table 1, Method c) Rt=1.21 min; MS m/z 231 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]2[C@H:11]([CH3:12])[CH2:10][C:9](=[O:13])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:14][C:15]([F:35])([F:34])[C:16]1[N:17]=[C:18]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[N:19]([CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:20]=1.C(N(CC)CC)C>CN1CCCC1=O>[CH3:12][C@H:11]1[C:3]2[C:2]([N:31]3[CH2:30][CH2:29][CH:28]([C:18]4[N:19]([CH2:21][CH2:22][N:23]5[CH2:24][CH2:25][CH2:26][CH2:27]5)[CH:20]=[C:16]([C:15]([F:34])([F:35])[F:14])[N:17]=4)[CH2:33][CH2:32]3)=[N:7][CH:6]=[N:5][C:4]=2[NH:8][C:9](=[O:13])[CH2:10]1
Reactant: FC(F)(F)c1cn(CCN2CCCC2)c(C2CCNCC2)n1
Reactant: C[C@@H]1CC(=O)Nc2ncnc(Cl)c21
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: C[C@@H]1CC(=O)Nc2ncnc(N3CCC(c4nc(C(F)(F)F)cn4CCN4CCCC4)CC3)c21
Temperature: 130 °C
Yield: 70.2 %

Procedure:
Add (R)-4-chloro-5-methyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (28.30 g, 143.20 mmol), 4-(4-trifluoromethyl-1-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidine (49.83 g, 1.10 eq) and triethylamine (43.47 g, 3.0 eq) in N-methylpyrrolidinone (86 mL). Heat the reaction mixture to 130° C. Cool the reaction mixture to room temperature after 2 hours. Pour the reaction mixture over ice/water (500 mL) with stirring. Extract with ethyl acetate (4×200 mL). Wash the organics with saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate and concentrate in vacuo. Suspend the solid in hexanes and stir for 30 minutes. Filter and dry under vacuum. Add 75% methyl tert-butyl ether in hexanes (800 mL) and heat to reflux. Cool the mixture to room temperature. Filter, wash with 75% methyl tert-butyl ether in hexanes (200 mL), and dry under vacuum at 40° C. to give the title compound (48.00 g, 70%). MS (ES) m/z=478 [M]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[O:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[B-](F)(F)F)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[K+].O(C1C=CC=CC=1Br)C1C=CC=CC=1.C([Li])CCC.B(OC(C)C)(OC(C)C)OC(C)C.F.[K].C(=O)(O)[O-].[Na+]>O1CCCC1.C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O.C(O)C>[Cl:1][C:2]1[C:3]2[C:10]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[O:17][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:9][N:8]([CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: F[B-](F)(F)c1ccccc1Oc1ccccc1
Reactant: Clc1ncnc2c1c(I)cn2C1CCCC1
Agent: Cl[Pd]Cl
Agent: Brc1ccccc1Oc1ccccc1
Agent: CC(C)OB(OC(C)C)OC(C)C
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Clc1ncnc2c1c(-c1ccccc1Oc1ccccc1)cn2C1CCCC1
Temperature: 105 °C

Procedure:
A mixture of 4-chloro-7-cyclopentyl-5-iodopyrrolo[2,3-d]pyrimidine (1.26 g) and potassium (2-phenoxyphenyl)trifluoroborate (1.0 g, prepared by reacting 2-phenoxybromobenzene with butyllithium in tetrahydrofuran at -70° C. followed by triisopropyl borate (IV) followed by potassium hydrogen fluoride by a method analogous to that described in J. Org. Chem. 1995, 60, 3020-3027), in degassed toluene (40 ml), ethanol (10 ml) and water (10 ml) was stirred under nitrogen and bis(triphenylphosphine)palladium (II) chloride (0.25 g) was added followed by sodium bicarbonate (2.0 g). The mixture was stirred and heated at 105° C. for 16 hours and then cooled to ambient temperature. The mixture was separated and the upper layer was evaporated under reduced pressure to give a residue which was purified by flash column chromatography on silica using petroleum ether/ether (2:1) as a mobile phase to give 4-chloro-7-cyclopentyl-5-(2-phenoxyphenyl)pyrrolo[2,3-d]pyrimidine which was used directly in the next part of this example.
Reaction SMILES: [CH:1]([C:3]1[S:7][CH:6]=[C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][CH:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][O:32][CH3:33])(=[O:28])=[O:27])[CH2:22][CH2:21]2)[CH:4]=1)=O.[CH3:34][C:35]([NH2:38])([CH3:37])[CH3:36].[BH4-].[Na+]>>[CH3:34][C:35]([NH:38][CH2:1][C:3]1[S:7][CH:6]=[C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][CH:12]=[C:11]3[CH:20]2[CH2:21][CH2:22][N:23]([S:26]([CH2:29][CH2:30][CH2:31][O:32][CH3:33])(=[O:27])=[O:28])[CH2:24][CH2:25]2)[CH:4]=1)([CH3:37])[CH3:36]
Reactant: COCCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C=O)c4)cc23)CC1
Reactant: CC(C)(C)N
Agent: [BH4-]
Agent: [Na+]
Product: COCCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CNC(C)(C)C)c4)cc23)CC1

Procedure:
Following the general procedure in example 281, 5-(5-formyl-3-thienyl)-3-(1-{[3-(methyloxy)propyl]sulfonyl}-4-piperidinyl)-1H-indole-7-carboxamide (40 mg, 0.08 mmol), (1,1-dimethylethyl)amine (70 mg, 0.8 mmol) and NaBH4 (30.26 mg, 0.8 mmol) were reacted to form the desired product which was purified by Gilson HPLC (CH3CN/Water, 0.1% TFA) (8.4 mg, 19%).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][C@H:10]([CH3:13])[CH2:11][OH:12])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH2:14][C:15]1[CH:16]=[C:17]([S:20]([F:23])(=[O:22])=[O:21])[S:18][CH:19]=1.NC1SC(S(F)(=O)=O)=CC=1.Cl>C(#N)C.O.O1CCOCC1>[Br:1][C:2]1[C:3]([NH:9][CH:10]([CH3:13])[CH2:11][OH:12])=[N:4][C:5]([NH:14][C:15]2[CH:16]=[C:17]([S:20]([F:23])(=[O:22])=[O:21])[S:18][CH:19]=2)=[N:6][CH:7]=1
Reactant: Nc1csc(S(=O)(=O)F)c1
Reactant: C[C@H](CO)Nc1nc(Cl)ncc1Br
Agent: Cl
Agent: Nc1ccc(S(=O)(=O)F)s1
Solvent: CC#N
Solvent: C1COCCO1
Solvent: O
Product: CC(CO)Nc1nc(Nc2csc(S(=O)(=O)F)c2)ncc1Br

Procedure:
324 mg (1.2 mmol) of (R)-2-(5-bromo-2-chloro-pyrimidin-4-ylamino)-propan-1-ol is added to a suspension of 330 mg of a mixture that consists of 4-amino-thiophene-2-sulfonyl fluoride and 5-amino-thiophene-2-sulfonyl fluoride (ratio: 3:1) in 5 ml of acetonitrile, 0.5 ml of water and 0.5 ml of a 4 molar solution of hydrochloric acid in 1,4-dioxane. The reaction mixture is stirred under reflux for 26 hours. After cooling, the batch is concentrated by evaporation, and the residue is stirred with ethanol. The precipitate that is formed is suctioned off and stirred with warm water. In turn, the solid is suctioned off and dried. 152 mg (0.37 mmol, 31% of theory) of the product 4-[5-bromo-4-(2-hydroxy-1-methyl-ethylamino)-pyrimidin-2-ylamino]-thiophene-2-sulfonyl fluoride is obtained.