Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:12])[CH2:9][C:10]#[N:11].B.O1CCCC1.B.Cl>CO>[ClH:1].[NH2:11][CH2:10][CH2:9][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[OH:12]
Reactant: N#CCC(O)c1ccccc1Cl
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: NCCC(O)c1ccccc1Cl
Temperature: 75 °C
Yield: 176.1 %

Procedure:
3-(2-Chloro-phenyl)-3-hydroxy-propionitrile (740 mg, 4.07 mmol) was slowly treated with a solution of borane-tetrahydrofuran complex (9 mL, 8.96 mmol, 1M in tetrahydrofuran) at 0° C. After bubbling ceased, the reaction mixture was heated to 75° C. for 2 hours and 1.1 eq of additional borane was added to drive the reaction to completion. The reaction mixture was concentrated. The white solid obtained was treated with methanol (14 mL), followed by hydrogen chloride (2M in diethyl ether, 14 mL). The resulting mixture was heated to reflux for 2 hours, allowed to cool to ambient temperature and then concentrated at reduced pressure. To the residue was added aqueous hydrochloric acid (10 mL, 1 N) followed by diethyl ether (20 mL). The aqueous layers were separated and concentrated at reduced pressure and dried to give the product as a white solid (796 mg, 88%).
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]=[C:14]([C:16]3[CH:20]=[CH:19][NH:18][N:17]=3)[O:13][N:12]=2)[CH2:7][CH2:6]1.[H-].[Na+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[Br:1][C:2]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]=[C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:17]=3)[O:13][N:12]=2)[CH2:7][CH2:6]1
Reactant: CCOC(=O)CBr
Reactant: Fc1ccc(Br)c(OC2CCN(c3noc(-c4cc[nH]n4)n3)CC2)c1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)Cn1ccc(-c2nc(N3CCC(Oc4cc(F)ccc4Br)CC3)no2)n1

Procedure:
The title compound was prepared in a similar manner as described in Example 7 (step 4) from 4-(2-bromo-5-fluorophenoxy)-1-[5-(1H-pyrazol-3-yl)-1,2,4-oxadiazol-3-yl]piperidine, sodium hydride and ethyl bromoacetate and obtained as the more polar isomer.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[Cl:8][C:9]1[CH:10]=[C:11]([C:33](O)=[O:34])[C:12]2[CH2:13][C:14]([CH3:32])([CH3:31])[CH:15]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH:20]=3)[NH:16][C:17]=2[CH:18]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[Cl:8][C:9]1[CH:10]=[C:11]([C:33]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:34])[C:12]2[CH2:13][C:14]([CH3:31])([CH3:32])[CH:15]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)[CH:20]=3)[NH:16][C:17]=2[CH:18]=1
Reactant: CC1(C)Cc2c(cc(Cl)cc2C(=O)O)NC1c1cccc(N2CCOCC2)c1
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2c(cc(Cl)cc2C(=O)NS(C)(=O)=O)NC1c1cccc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.1 %

Procedure:
To a suspension of 60% sodium hydride (200 mg, 5.0 mmol) in N,N-dimethylformamide (1.5 mL) was added methanesulfonamide (494 mg, 5.2 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 7-chloro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid (200 mg, 0.5 mmol) and 1,1′-carbonyldiimidazole (170 mg, 1.04 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of methanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-[7-chloro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carbonyl]-methanesulfonamide (48 mg, 20%) as a white solid: LC/MS m/e calcd for C23H28ClN3O4S (M+H)+: 478.01, observed: 478.1.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH2:7][N:6]1[C:20]1[N:21]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:22]=[C:23]([CH3:25])[CH:24]=1)=[O:4].[OH-].[Li+]>>[CH2:26]([N:21]1[C:20]([N:6]2[CH2:7][C@H:8]([S:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])(=[O:11])=[O:12])[CH2:9][C@H:5]2[C:3]([OH:4])=[O:2])=[CH:24][C:23]([CH3:25])=[N:22]1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1c1cc(C)nn1Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccccc3Cl)C[C@H]2C(=O)O)n(Cc2ccccc2)n1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-1-(2-benzyl-5-methyl-2H-pyrazol-3-yl)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound as yellow oil which was used in the next step without further purification. MS (ESI): m/z=460.3 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[N:9]=[N:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=2)[CH2:3][CH2:2]1.[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>ClC(Cl)C>[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:1]2[CH2:6][CH2:5][CH:4]([NH:7][C:8]3[N:9]=[N:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=3)[CH2:3][CH2:2]2)=[CH:21][CH:20]=1
Reactant: FC(F)(F)c1ccc(NC2CCNCC2)nn1
Reactant: O=Cc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(Cl)Cl
Product: Fc1ccc(CN2CCC(Nc3ccc(C(F)(F)F)nn3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.9 %

Procedure:
A suspension of D2 (1.7 g, 5.32 mmol), 4-fluorobenzaldehyde (0.66 g, 5.32 mmol), di-isopropylethylamine (1.37 g, 10.6 mmol) and triacetoxyborohydride on resin (Argonaut Technologies; 2.2 mmol/g; 3 eq.) in dichloroethane (10 ml) was stirred at room temperature for 18 h. After this period, the reaction mixture was filtered and the solvents evaporated in vacuo. The crude product was purified by chromatography (silica; 2%-6% ammonia in methanol (7 M)/dichloromethane) to give E2 (0.79 g, 42%). C17H18F4N4 requires 354; Found 355 (MH+); mp: 163.3-165.3° C. 1H NMR (DMSO-D6) δ 1.48 (q, J=10.8 Hz, 2H), 1.95 (br.d, J=12.5 Hz, 2H), 2.09 (t, J=11.1 Hz, 2H), 2.78 (br.d, J=11.3 Hz, 2H), 3.47 (s, 2H), 3.89 (br.s, 1H), 6.94 (d, J=9.4 Hz, 1H), 7.15 (t, J=8.8 Hz, 2H), 7.34 (dd, J=8.3, 5.7 Hz, 2H), 7.53 (br.d, J=7.3 Hz, 1H), 7.63 (d, J=9.4 Hz, 1H)
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[F:13].[Sn](Cl)Cl.Cl.[OH-].[Na+]>CC(O)C.O>[F:14][CH:2]([F:1])[O:3][C:4]1[C:5]([F:13])=[C:6]([NH2:10])[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(OC(F)F)c1F
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Nc1cccc(OC(F)F)c1F
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 1-difluoromethoxy-2-fluoro-3-nitro-benzene (2.16 g, 10.43 mmol) and tin(II) chloride (6.92 g, 36.5 mmol) in 2-propanol (100 ml) was added carefully HCl (37%, 10.28 ml, 125 mmol) and the mixture was stirred for 30 min at 110° C. The reaction mixture was cooled to RT, diluted with water and the pH adjusted to 10 by addition of 2N NaOH. The mixture was extracted with EtOAc and the organic layer was dried over Na2SO4, filtered and concentrated to afford the titled compound. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.06 (t, 1H), 6.95 (m, 1H), 6.87 (m, 1H), 6.55 (td, 1H), 5.04 (bs, 2H). tR (HPLC conditions f): 1.93 min.
Reaction SMILES: [F:1][CH:2]([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[O-:11][C:12]#[N:13].[Na+]>C(O)(=O)C.O>[F:1][CH:2]([F:10])[C:3]1[CH:4]=[C:5]([NH:6][C:12]([NH2:13])=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: N#C[O-]
Reactant: Nc1cccc(C(F)F)c1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)Nc1cccc(C(F)F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Water (10 mL) is added dropwise to a mixture of 3-(difluoromethyl)aniline (2.00 g, 13.97 mmol) in glacial acetic acid (6 mL). A solution of sodium cyanate (1.00 g, 15.38 mmol) in water (10 mL) is added dropwise, and the mixture is stirred at room temperature for 4 h. The precipitate is filtered, washed with water and dried under reduced pressure. Yield: 1.80 g; ESI mass spectrum [M+H]+=187, Retention time HPLC: 0.70 min (Z012_S04).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N:9]([CH3:11])[CH3:10])[C:4]=1B(O)O.[CH3:15][O:16][C:17](=[O:38])[C@H:18]([CH2:30][C:31]1[CH:36]=[CH:35][C:34](Br)=[CH:33][CH:32]=1)[NH:19][C:20](=[O:29])[C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:28]>>[CH3:15][O:16][C:17](=[O:38])[C@H:18]([CH2:30][C:31]1[CH:32]=[CH:33][C:34]([C:4]2[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=2[N:9]([CH3:11])[CH3:10])=[CH:35][CH:36]=1)[NH:19][C:20](=[O:29])[C:21]1[C:22]([Cl:28])=[CH:23][CH:24]=[CH:25][C:26]=1[Cl:27]
Reactant: COc1cccc(N(C)C)c1B(O)O
Reactant: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1c(Cl)cccc1Cl
Product: COC(=O)[C@H](Cc1ccc(-c2c(OC)cccc2N(C)C)cc1)NC(=O)c1c(Cl)cccc1Cl

Procedure:
2-Methoxy-6-(N,N-dimethylamino)benzene boronic acid was coupled with N-(2,6-dichlorobenzoyl)-4-bromo-L-phenylalanine methyl ester to give N-(2,6-dichlorobenzoyl)-4-[2-(N,N-dimethylamino)-6-methoxyphenyl]-L-phenylalanine methyl ester. The preparation of the boronic acid and the coupling reaction was carried out in a similar manner as described in Example 7.
Reaction SMILES: [CH3:1][CH:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14](=O)[CH3:15])=[CH:8][CH:7]=1)[CH2:3][CH3:4].N1C=CC=CC=1.Cl.[CH2:24]([O:26][NH2:27])[CH3:25]>O1CCCC1>[CH2:24]([O:26][N:27]=[C:14]([CH2:13][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH:2]([CH3:1])[CH2:3][CH3:4])=[CH:7][CH:8]=1)[CH3:15])[CH3:25]
Reactant: CCC(C)Oc1ccc(CCC(C)=O)cc1
Reactant: CCON
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCON=C(C)CCc1ccc(OC(C)CC)cc1

Procedure:
Following the procedure of Example 1, 4-[4-(1-methylpropoxy)phenyl]-2-butanone (4.41 g, 20.0 mmol) and pyridine (3 ml) in 45 ml of tetrahydrofuran are reacted with ethoxyamine hydrochloride (4.41 g, 45.2 mmol) to give 4-[4-(1methylpropoxy)phenyl]-2-butanone O-ethyloxime, as a mixture of syn and anti stereo isomers. MS m/e 263 (M ).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:22])[C@@H:19]([OH:21])[CH3:20])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.B(O)(O)[C:30]1[CH:35]=[N:34][C:33]([O:36][CH3:37])=[N:32][CH:31]=1>>[OH:21][C@@H:19]([CH3:20])[C:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:3][C:2]([C:30]4[CH:31]=[N:32][C:33]([O:36][CH3:37])=[N:34][CH:35]=4)=[N:7][C:6]=3[CH:8]=2)[CH2:13][CH2:14]1)=[O:22]
Reactant: C[C@H](O)C(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: COc1ncc(B(O)O)cn1
Product: COc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(C(=O)[C@H](C)O)CC4)cc3n2)cn1
Yield: 46.5 %

Procedure:
(S)-1-(4-((2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (61 mg) was reacted with 35 mg of 2-methoxypyrimidin-5-yl-5-boronic acid via General Procedure A to give 33.3 mg of 209. MS (Q1) 500.3 (M)+
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:14][CH2:13][S:12][CH:11]2[C:15]([O:17]C)=[O:16])(=[O:9])=[O:8])=[CH:3][CH:2]=1.B(Br)(Br)Br>C(Cl)Cl>[C:1]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:14][CH2:13][S:12][CH:11]2[C:15]([OH:17])=[O:16])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: COC(=O)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
A solution was made containing Intermediate 6, e.g., methyl 3-([1,1′-biphenyl]-4-ylsulfonyl)-1,3-thiazolidine-2-carboxylate (2.0 g, 5.5 mmol, 1 eq), in dry DCM (50 ml). The flask was cooled down to −20° C. in a dry-acetone bath. A solution of boron tribromide (5.55 g, 22.0 mmol) in dry DCM (30 ml) was added drop wise over a period of 10 minutes. The reaction mixture was stirred for 1 h at 0° C. The reaction mixture was diluted with DCM (50 ml) and washed with a 1M HCl solution (2×50 ml) and with brine (50 ml) before drying over magnesium sulfate, filtering and removal of solvent in vacuo. The desired product of general structure (VIII), e.g., 3-([1,1′-biphenyl]-4-ylsulfonyl)-1,3-thiazolidine-2-carboxylic acid, was isolated as a white powder (1.8 g, 94%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)=[O:32]>>[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31]([N:33]1[CH2:34][CH2:35][N:36]([C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][N:8]([C:12]4[CH:17]=[C:16]([N:18]5[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]5)[N:15]=[C:14]([NH2:25])[N:13]=4)[CH2:9]3)=[CH:4][CH:3]=2)[CH2:37][CH2:38]1)=[O:32]
Reactant: O=C(c1ccco1)N1CCNCC1
Reactant: CN1CCN(c2cc(N3CCc4ccc(Br)cc4C3)nc(N)n2)CC1
Product: CN1CCN(c2cc(N3CCc4ccc(N5CCN(C(=O)c6ccco6)CC5)cc4C3)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 30 starting from 4-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine and 1-(2-furoyl)piperazine (Acros Organics, Cat. No. 23505). LCMS (M+H)+: m/z=503.2.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:14][O:15][C@H:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([O:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27])[CH2:17]1.C([Sn]([N:41]=[N+:42]=[N-:43])(CCCC)CCCC)CCC.C(O)(C(F)(F)F)=O>C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:14][O:15][C@H:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([O:22][CH2:23][CH2:24][CH2:25][C:26]2[N:41]=[N:42][NH:43][N:27]=2)[CH2:17]1
Reactant: Cc1cccc(-c2nc(CO[C@H]3CCC[C@@H](OCCCC#N)C3)c(C)o2)c1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: Cc1ccccc1C
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(-c2nc(CO[C@H]3CCC[C@@H](OCCCc4nn[nH]n4)C3)c(C)o2)c1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
333 mg of (1R,3S)-4-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]butyronitrile are dissolved in 5 ml of xylene, and 919 mg of tributyltin azide are added. The mixture is stirred at 120° C. for 18 h and, after cooling, titurated with 0.5 ml of TFA. The solvent is removed under reduced pressure and the residue is purified by RP-HPLC. This gives (1R,3S)-5-{3-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]propyl}-2H-tetrazole as a colorless oil. C22H29N5O3 (411.51), MS (ESI): 412 (M+H+).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([CH3:16])=[N:10]2)(=[O:3])[CH3:2].[H][H]>C(O)(=O)C.[Pt]>[C:1]([NH:4][C:5]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([CH3:16])[NH:10]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1c(F)ccc2nc(C)ccc12
Reactant: [H][H]
Agent: [Pt]
Solvent: CC(=O)O
Product: CC(=O)Nc1c(F)ccc2c1CCC(C)N2

Procedure:
In one liter of acetic acid were dissolved 95 g of 5-acetamido-6-fluoroquinaldine. To this mixture were added 10 g of five percent platinum on charcoal. The mixture was hydrogenated with hydrogen gas at 30 psi on a Paar apparatus for five hours. The amount of hydrogen used was 61 psi (verus 62 psi theoretical). The catalyst was removed by filtration, and the filtrate was concentrated to 250 ml and decanted into cold stirred sodium hydroxide solution. The white precipitate was separated by filtration and triturated with a chloroform/hexane (50/50) mixture to provide white crystals of 5-acetamido-6-fluorotetrahydroquinaldine, m.p. 168°-170° C. The structural assignment was confirmed by infrared spectral analysis.
Reaction SMILES: [F:1][CH:2]([F:33])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:27]=[CH:28][CH:29]=[C:30]([O:31][CH3:32])[C:5]=2[N:4]=1.[Cl:34][CH2:35][S:36](Cl)(=[O:38])=[O:37].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Cl:34][CH2:35][S:36]([NH:26][CH:23]1[CH2:24][CH2:25][N:20]([C:10]2[N:9]=[C:8]([N:7]3[C:6]4[CH:27]=[CH:28][CH:29]=[C:30]([O:31][CH3:32])[C:5]=4[N:4]=[C:3]3[CH:2]([F:1])[F:33])[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=2)[CH2:21][CH2:22]1)(=[O:38])=[O:37]
Reactant: O=S(=O)(Cl)CCl
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCC(N)CC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCC(NS(=O)(=O)CCl)CC2)n1
Yield: 56 %

Procedure:
Reaction of 1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinamine (Example 17) with chloromethanesulfonyl chloride and K2CO3 in CH2Cl2 gave chloro-N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}methanesulfonamide in 56% yield: mp (CH2Cl2/MeOH) 230-232° C.; 1H NMR (DMSO-d6) δ 7.88 (d, J=8.0 Hz, 1H), 7.87 (br, 1H), 7.69 (t, JHF=52.9 Hz, 1H), 7.41 (t, J=8.2 Hz, 1H), 6.95 (d, J=7.9 Hz, 1H), 4.95 (s, 2H), 4.59-4.49 (m, 2H), 3.98 (s, 3H), 3.81-3.79 (m, 4H), 3.70-3.69 (m, 4H), 3.55 (br, 1H), 3.22-3.12 (m, 2H), 1.96 (br, 2H), 1.46-1.41 (m, 2H); Anal. Calcd. for C22H27ClF2N8O4S: C, 46.1; H, 4.75; N, 19.6. Found: C, 46.4; H, 4.8; N, 19.6%
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[NH:10][N:9]([NH:14][C:15]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([O:29]C)=O)(=[O:20])=[O:19])=[O:16])[N:8]=1.[CH3:31][SH:32]>C1(C)C=CC=CC=1>[CH3:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[NH:10][N:9]([NH:14][C:15]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([S:32][CH3:31])=[O:29])(=[O:20])=[O:19])=[O:16])[N:8]=1
Reactant: CS
Reactant: COC(=O)c1ccccc1S(=O)(=O)NC(=O)NN1N=C(OC)C=C(C)N1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COC1=NN(NC(=O)NS(=O)(=O)c2ccccc2C(=O)SC)NC(C)=C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trimethylaluminum (6.0 m, 2M) was charged via syringe to 15 ml dry toluene under nitrogen atmosphere and 3.8 g N-[(4-methoxy-6-methyltriazin-2-yl)aminocarbonyl]-2-methoxycarbonylbenzenesulfonamide was added portionwise. After stirring at room temperature for one hour, methyl mercaptan (gas) was passed through the reaction mixture until the initial temperature rise subsided, whereupon the addition was discontinued. The reaction mixture was allowed to stir at room temperature for 1 hour, and quenched with 25 ml of 10% HCl. The resultant white suspension was filtered to give 2.9 g white solid which showed infrared absorption peaks at 1740, 1690 cm-1, consistent for N-[(4-methoxy-6-methyltriazin-2-yl)aminocarbonyl]-2-(methylthio)carbonylbenzenesulfonamide.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1.NC(N)=[S:21]>CO>[C:11]([O:10][C:8](=[O:9])[CH2:7][N:6]1[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=[C:2]1[SH:21])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)Cn1c(Cl)nc2ccccc21
Reactant: NC(N)=S
Solvent: CO
Product: CC(C)(C)OC(=O)Cn1c(S)nc2ccccc21
Yield: 92.9 %

Procedure:
According to the procedure described in: Migawa, M. T.; Girardet, J.-L.; Walker II, J. A.; Koszalka, G. W.; Chamberlain, S. D.; Drach, J. C.; Townsend, L. B., J. Med. Chem. 1998, 41, 1242-1251, a solution of tert-butyl (2-chloro-benzoimidazol-1-yl)-acetate (Intermediate 2-I, 7 g, 26.3 mmol) and thiourea (7.98 g, 105 mmol) in methanol (100 ml) is refluxed for 2 h. The mixture is cooled down and most of the methanol is removed in vacuo. After addition of saturated aqueous NH4Cl solution (150 ml), the resulting aqueous phase is extracted three times with Et2O. The combined organic phases are washed with brine and dried over Na2SO4. The solvent is evaporated in vacuo and the residue dried under high vacuum, yielding the title compound (6.46 g) in 93% as a white powder: tR=6.14 min (LC-1), ESI-MS (neg.): m/z 263.31 [M−H]+; 1H-NMR (CDCl3): δ (ppm) 1.50 (s, 9H, tBu), 4.94 (s, 2H, CH2CO2), 6.99-7.05 (m, 1 Harom), 7.16-7.24 (m, 1Harom), 10.69 (bs, 1H, SH).
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([O:15][CH3:16])[CH:14]=1)[CH2:10]O>C1COCC1>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([O:15][CH3:16])[CH:14]=1)[CH2:10][Br:2]
Reactant: COc1cc(CO)cc(OC)c1
Reactant: BrP(Br)Br
Solvent: C1CCOC1
Product: COc1cc(CBr)cc(OC)c1
Reaction time: 0.38 h
Yield: 92 %

Procedure:
Phosphorus tribromide (0.4 eq) was added to the alcohol 304 (25 g, 0.13 mol) in THF (100 mL) very slowly at −10° C. and the mixture which resulted was stirred for 15-30 min at the same temperature. By this time all the starting material had disappeared (TLC). The reaction mixture was quenched by addition of ice-cold H2O (100 mL) and then filtered through a Buchner funnel. The filtrate was diluted with brine (100 mL) and extracted with EtOAc (3×300 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The crude oil was purified by FCC (20% ethylacetate in hexane) to afford the bromide 305 as a white solid (92%)a: 1H NMR (500 MHz, CDCl3) δ 6.61 (2H, d, J=2.3 Hz), 6.46 (1H, t, J=2.3 Hz), 4.5 (2H, s), 3.85 (6H, s). 13C NMR (125 MHz, CDCl3): δ 161.3, 140.2, 107.4, 101.0, 55.8, 34.1. The spectral data for 305 were in excellent accord with data previously reported on it (Seidel et al., 1990)1. This material was employed directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]([O-])(=[O:11])[CH3:10].[Na+].C(OC(=O)C)(=O)C.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1.O>[C:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)(=[O:11])[CH3:10]
Reactant: Oc1ccc(F)cc1
Reactant: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccccc1
Product: CC(=O)Oc1ccc(F)cc1
Yield: 128.9 %

Procedure:
4-Fluorophenol (112.1 g, 1.0 mole), sodium acetate (68.89 g, 0.74 mole) and acetic anhydride (107.6 g, 1.05 mole) were mixed in benzene (220 ml) with stirring and heated under reflux for 2 hours. After cooling, water (500 ml) and sodium bicarbonate (100 g, 1.19 mole) were added to the reaction mixture and the mixture was stirred. The mixture was allowed to stand to separate into layers and the aqueous layer was extracted with benzene (500 ml). The organic layers were combined, dried over anhydrous sodium sulfate and distilled to obtain the title compound (147 g, 95.4%), b.p. 84°-86° C./16 mmHg.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](N2CCCC2)=[O:9])=[N:6][CH:5]=[CH:4][N:3]=1.[C:15]1([Mg]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O1CCCC1>O>[NH2:1][C:2]1[C:7]([C:8](=[O:9])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: Br[Mg]c1ccccc1
Reactant: Nc1nccnc1C(=O)N1CCCC1
Solvent: C1CCOC1
Solvent: O
Product: Nc1nccnc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Aminopyrazine-3-carboxylic acid pyrrolidide (63.4 g. or 0.33 mol) was added to a solution of freshly prepared phenylmagnesium bromide (305 g.) in 1 l. of tetrahydrofuran while the temperature was kept at 20°-30° by cooling with an ice bath. After stirring at room temperature for 2 hours, the mixture was hydrolyzed by addition of 2 l. of water. The aqueous layer was extracted twice with 500 ml. of methylene chloride. The extracts were combined with the organic layer, dried over sodium sulfate and evaporated. The brown residue was slurried with ether to yield 37.5 g. (56%) of yellow crystals of the above-named product.