Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([NH:10][C@@H:11]([CH3:16])[C:12]([O:14]C)=[O:13])=[O:9])[CH2:3][CH2:2]1.[OH-].[K+:18]>CO>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([NH:10][C@@H:11]([CH3:16])[C:12]([O-:14])=[O:13])=[O:9])[CH2:3][CH2:2]1.[K+:18]
Reactant: COC(=O)[C@H](C)NC(=O)CN1CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C[C@H](NC(=O)CN1CCOCC1)C(=O)[O-]
Reaction time: 3 h
Yield: 92 %

Procedure:
Crude (S)-methyl 2-(2-morpholinoacetamido)propanoate was dissolved in methanol (10 mL) and KOH (20 mL of a 1N solution, 0.020 mmol). The reaction mixture was stirred for 3 h then concentrated, dissolved in methanol, and filtered. The filtrate was concentrated to provide potassium (S)-2-(2-morpholinoacetamido)propanoate (8.38 g, 92% over 2 steps) as a colorless oil. MS (EI) for C9H15KN2O4, found 217.2 [M−K]+.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][N:17]([S:20]([CH3:23])(=[O:22])=[O:21])[C:16]([CH3:25])([CH3:24])[CH2:15]3)[N:8]2[CH3:11])=[C:4]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[N:3]=1.[CH2:32]([C:34]1[NH:35][C:36]2[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=2[N:38]=1)[CH3:33].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:24][C:16]1([CH3:25])[N:17]([S:20]([CH3:23])(=[O:21])=[O:22])[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][C:7]2[N:8]([CH3:11])[C:9]3[C:5]([N:6]=2)=[C:4]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[N:3]=[C:2]([N:35]2[C:36]4[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=4[N:38]=[C:34]2[CH2:32][CH3:33])[N:10]=3)[CH2:15]1
Reactant: CCc1nc2ccccc2[nH]1
Reactant: Cn1c(CCN2CCN(S(C)(=O)=O)C(C)(C)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CCN3CCN(S(C)(=O)=O)C(C)(C)C3)n(C)c2n1
Temperature: 120 °C
Yield: 49.1 %

Procedure:
A mixture of 2-chloro-8-[2-(4-methanesulfonyl-3,3-dimethylpiperazin-1-yl)ethyl]-9-methyl-6-morpholin-4-yl-9H-purine (35 mg, 0.07 mmol), 2-ethylbenzimidazole (12 mg, 0.08 mmol), Pd2(dba)3 (1.7 mg, 2.5 mol %), Xphos (3.5 mg, 10 mol %) and Cs2CO3 (36 mg, 0.11 mmol) in dioxane (1.5 mL) was purged with argon gas then heated at 120° C., for 24 h, in a sealed tube. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3/MeOH in DCM. The resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 20 mM triethylamine in water on a gradient of acetonitrile 30-90%) to give 575 (20 mg, 46%) as a pale beige solid. LCMS: (Method I): RT 2.74 min, [M+H]+ 582.2 1H NMR (400 MHz, CDCl3d): δ 8.01-7.96 (m, 1 H), 7.79-7.75 (m, 1 H), 7.28-7.25 (m, 2 H), 4.50-3.96 (m, 4 H), 3.86 (t, J=4.7 Hz, 4 H), 3.78 (s, 3 H), 3.50-3.44 (m, 2 H), 3.36 (q, J=7.4 Hz, 2 H), 3.04 (t, J=7.4 Hz, 2 H), 2.94 (s, 3 H), 2.87 (t, J=7.4 Hz, 2 H), 2.64-2.58 (m, 2 H), 2.38 (s, 2 H), 1.50 (s, 6 H), 1.45 (t, J=7.4 Hz, 3 H)
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][C:27]2[CH:39]=[CH:38][C:30]([O:31][CH2:32][CH2:33][CH2:34][C:35](O)=[O:36])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:43]([O:47][C:48](=[O:57])[C@H:49]([CH2:51][O:52]C(C)(C)C)[NH2:50])([CH3:46])([CH3:45])[CH3:44]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][C:27]2[CH:39]=[CH:38][C:30]([O:31][CH2:32][CH2:33][CH2:34][C:35]([NH:50][C@H:49]([C:48]([O:47][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:57])[CH2:51][OH:52])=[O:36])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCC(=O)O)cc2)cc1
Reactant: CC(C)(C)OC[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCC(=O)N[C@@H](CO)C(=O)OC(C)(C)C)cc2)cc1

Procedure:
The product from Example 233 and O-tert-butyl L-serine tert-butyl ester hydrochloride were processed as described in Example 251A to provide the titled compound.
Reaction SMILES: Cl.[NH2:2][C:3]1([C:9]([O:11][CH3:12])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[S:13](Cl)([Cl:16])(=[O:15])=[O:14].[Sb](Cl)(Cl)(Cl)(Cl)Cl>C(#N)C>[Cl:16][S:13]([NH:2][C:3]1([C:9]([O:11][CH3:12])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)(=[O:15])=[O:14]
Reactant: COC(=O)C1(N)CCCCC1
Reactant: O=S(=O)(Cl)Cl
Agent: Cl
Agent: Cl[Sb](Cl)(Cl)(Cl)Cl
Solvent: CC#N
Product: COC(=O)C1(NS(=O)(=O)Cl)CCCCC1
Temperature: 80 °C
Yield: 85 %

Procedure:
To a suspension of methyl 1-aminocyclohexane-1-carboxylate HCl salt (4.06 g, 20.9 mmol) in acetonitrile (37 ml) was added sulfuryl chloride (26.2 ml, 326 mmol) and antimony pentachloride (0.17 ml, 2.4 mmol). The reaction was heated at 80° C. using a calcium sulfate drying tube overnight. The reaction was concentrated in vacuo to give methyl 1-(chlorosulfonylamino)cyclohexane-1-carboxylate (85%) as a yellow oil that was used without further purification. This material was converted to N-hydroxy-1-{[4-(4-chlorophenyl)piperazine-1-sulfonyl]amino}cyclohexane-1-carboxamide by following Examples 2 and Example 13 except that the reaction was heated at 45° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][NH2:6])[CH3:2].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.C(N(C(C)C)C(C)C)C.C([O-])(O)=O.[Na+]>O1CCCC1>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: CCOCCN
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOCCNS(=O)(=O)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 90.2 %

Procedure:
(2-Ethoxyethyl)amine (0.178 g, 2.0 mmol) was added to a stirred solution of 4-bromobenzenesulfonyl chloride (0.256 g, 1.0 mmol) in tetrahydrofuran (10 mL) at 0 C, followed by addition of N-ethyl-N,N-diisopropylamine (0.260 g, 2.0 mmol). The resulting mixture was stirred at 0° C. for 10 min, and was then allowed to return to room temperature. A saturated solution of NaHCO3 (aq) was added and the phases were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over Na2SO4, and the solvent was evaporated to give the crude product. Purification by column chromatography using ethyl acetate/heptane (1:10 to 1:1) as the eluent gave 0.278 g (90% yield) of the title compound: MS (ES) m/z 294 and 296 (M++1).
Reaction SMILES: CO[C:3](=[O:38])[N:4]=[C:5](SC)[C:6]([C:20]1[CH:25]=[C:24]([CH2:26][CH3:27])[CH:23]=[C:22]([O:28][CH2:29][C:30](=[O:34])[N:31]([CH3:33])[CH3:32])[C:21]=1[F:35])=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1.Cl.[NH:40]([C:42]1[CH:50]=[CH:49][CH:48]=[CH:47][C:43]=1[C:44]([OH:46])=[O:45])[NH2:41].COC(=O)N=C(SC)C(=NC1C=CC(C#N)=CC=1)C1C=C(OC)C=C(OC)C=1F>>[CH3:32][N:31]([CH3:33])[C:30]([CH2:29][O:28][C:22]1[C:21]([F:35])=[C:20]([CH:6]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:18]=[C:17]([CH3:19])[O:16][N:15]=3)=[CH:12][CH:13]=2)[C:5]2[NH:4][C:3](=[O:38])[N:40]([C:42]3[CH:50]=[CH:49][CH:48]=[CH:47][C:43]=3[C:44]([OH:46])=[O:45])[N:41]=2)[CH:25]=[C:24]([CH2:26][CH3:27])[CH:23]=1)=[O:34]
Reactant: NNc1ccccc1C(=O)O
Reactant: CCc1cc(OCC(=O)N(C)C)c(F)c(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)c1
Agent: COC(=O)N=C(SC)C(=Nc1ccc(C#N)cc1)c1cc(OC)cc(OC)c1F
Agent: Cl
Product: CCc1cc(OCC(=O)N(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ccccc3C(=O)O)c(=O)[nH]2)c1
Yield: 60.2 %

Procedure:
The same procedure was carried out as in Example (2f), except that 0.409 g of {2-(3-dimethylcarbamoylmethoxy-5-ethyl-2-fluorophenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester and 0.160 g of 2-hydrazinobenzoic acid hydrochloride were used instead of respectively the [2-(4-cyanophenylimino)-2-(2-fluoro-3,5-dimethoxyphenyl)-1-methylsulfanylethylidene]carbamic acid methyl ester and (1-oxypyridin-2-yl)hydrazine, to give the title compound (0.280 g) as a white solid.
Reaction SMILES: C(OC(C1C=CN(C(C)C)C=1C(C1C=CC(Cl)=CC=1)O)=O)C.[NH2:23][C:24]1[CH:25]=[C:26]([Cl:40])[C:27](=[O:39])[N:28]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[CH:29]=1.C[O:42][C:43]([C:45]1[CH:49]=[C:48]([Br:50])[N:47]([CH:51]([CH3:53])[CH3:52])[C:46]=1[CH:54]([C:56]1[CH:61]=[CH:60][C:59]([Cl:62])=[CH:58][CH:57]=1)O)=O.ClC1C=C(C=CC=1F)N>>[Br:50][C:48]1[N:47]([CH:51]([CH3:52])[CH3:53])[C:46]2[CH:54]([C:56]3[CH:57]=[CH:58][C:59]([Cl:62])=[CH:60][CH:61]=3)[N:23]([C:24]3[CH:25]=[C:26]([Cl:40])[C:27](=[O:39])[N:28]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=4)[CH:29]=3)[C:43](=[O:42])[C:45]=2[CH:49]=1
Reactant: COc1ccc(Cn2cc(N)cc(Cl)c2=O)cc1
Reactant: COC(=O)c1cc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1
Agent: CCOC(=O)c1ccn(C(C)C)c1C(O)c1ccc(Cl)cc1
Agent: Nc1ccc(F)c(Cl)c1
Product: COc1ccc(Cn2cc(N3C(=O)c4cc(Br)n(C(C)C)c4C3c3ccc(Cl)cc3)cc(Cl)c2=O)cc1

Procedure:
The title compound was prepared in analogy to the procedure described for Step D2, but 2-[(4-chloro-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid ethyl ester (Step E4) and 5-amino-3-chloro-1-(4-methoxy-benzyl)-1H-pyridin-2-one (Step O4) were used instead of 5-bromo-2-[(4-chloro-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid methyl ester and 3-chloro-4-fluoroaniline respectively to afford the title compound as a green-blue foam. tR: 5.47 min (HPLC 1); ESI-MS: tR=1.33 min, [M+H]+ 568/570/572 (LC-MS 1); TLC: Rf=0.30 (1:1 EtOAc/heptanes).
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[CH3:10][C:11]1([CH3:36])[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:21](O)=[O:22])[CH:18]=2)[NH:13][CH:12]1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:25]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[CH3:10][C:11]1([CH3:36])[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:21]([NH:9][S:6]([CH:3]3[CH2:5][CH2:4]3)(=[O:8])=[O:7])=[O:22])[CH:18]=2)[NH:13][CH:12]1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:25]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N2CCNCC2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(C(=O)NS(=O)(=O)C3CC3)ccc2NC1c1cccc(N2CCNCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.6 %

Procedure:
To a suspension of 60% sodium hydride (196 mg, 4.9 mmol) in N,N-dimethylformamide (1.5 mL) was added cyclopropanesulfonamide (605 mg, 5.0 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 3,3-dimethyl-2-(3-piperazin-1-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (180 mg, 0.5 mmol) and 1,1′-carbonyldiimidazole (162 mg, 1.0 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 cyclopropanesulfonamide 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 cyclopropanesulfonic acid [3,3-dimethyl-2-(3-piperazin-1-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (74 mg, 32%) as a light yellow solid: LC/MS m/e calcd for C25H32N4O3S (M+H)+: 469.61, observed: 469.0.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:21])[CH:19]=[CH2:20]>CN(C)C=O>[C:18]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1)(=[O:21])[CH:19]=[CH2:20]
Reactant: NC(=O)c1ccc(N)cc1
Reactant: C=CC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1ccc(C(N)=O)cc1
Yield: 60 %

Procedure:
4-Aminobenzamide (29 mmol) and triethylamine (33 mmol) were dissolved in dimethylformamide (100 mL) and acryloyl chloride (33 mmol) was dropped thereinto under ice-cooling. After the completion of the addition, the resultant mixture was stirred at room temperature for 2 hours. After filtering off the precipitate, the solvent was distilled off. Then the solid matter thus obtained was recrystallized from a solvent mixture of water with methanol to give 4-acrylamidobenzamide at a yield of 60%.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[CH2:24][CH2:23][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][NH:13][C:12]2=[O:22])[CH2:10][CH2:9]1)=[O:7].Cl[C:35]1[N:40]=[CH:39][CH:38]=[CH:37][N:36]=1>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:14][N:13]([C:35]3[N:40]=[CH:39][CH:38]=[CH:37][N:36]=3)[C:12]2=[O:22])[CH2:23][CH2:24]1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Reactant: Clc1ncccn1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)N(c1ncccn1)CN2c1ccccc1

Procedure:
The title compound, MS: m/e=550.1 (M+H+), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one and 2-chloropyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH2:15][CH3:16])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[OH:17].[CH:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=O)=[CH:23][CH:22]=1)([CH3:20])[CH3:19]>O1CCOCC1>[CH2:15]([CH:9]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]3[N:1]=[C:25]([C:24]4[CH:28]=[CH:29][C:21]([CH:18]([CH3:20])[CH3:19])=[CH:22][CH:23]=4)[O:17][C:3]=3[CH:4]=2)=[N:13][NH:12][C:11](=[O:14])[CH2:10]1)[CH3:16]
Reactant: CC(C)c1ccc(C(=O)Cl)cc1
Reactant: CCC1CC(=O)NN=C1c1ccc(N)c(O)c1
Solvent: C1COCCO1
Product: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(C(C)C)cc3)oc2c1
Temperature: 200 °C
Reaction time: 0.25 h

Procedure:
200 mg (857 μmol) 6-(4-amino-3-hydroxy-phenyl)-5-ethyl-4,5-dihydro-2H-pyridazin-3-one are placed in 5 ml dioxane. 175 mg (958 μmol) 4-isopropyl-benzoyl chloride are added and the mixture is stirred for 15 min at 200° C. in the microwave. The solvent is eliminated by rotary evaporation in vacuo and the residue is separated through silica gel (eluant cyclohexane/EA).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([Sn](C)(C)C)[S:10][C:3]=12.Br[C:16]1[S:17][CH:18]=[CH:19][N:20]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:16]3[S:17][CH:18]=[CH:19][N:20]=3)[S:10][C:3]=12
Reactant: C[Sn](C)(C)c1cc2nccc(Cl)c2s1
Reactant: Brc1nccs1
Product: Clc1ccnc2cc(-c3nccs3)sc12
Yield: 46.2 %

Procedure:
This material was prepared by coupling of 7-chloro-2-(trimethylstannyl)thieno[3,2-b]pyridine 39a (0.140 g, 0.42 mmole) and 2-bromo-1,3-thiazole (0.038 ml, 0.42 mmole) with tereakis(triphenylphosphine)palladium(0.019 g) in a manner as previously described in example 39b to give a yellow solid (0.049 g, 46%). 1H NMR (300 MHz, CDCl3) δ 8.59 (1H, d, J=5.1 Hz), 7.93 (1H, s), 7.89 (1H, d, J=3.4 Hz), 7.45 (1H, d, J=3.4 Hz), 7.30 (1H, d, J=5.1 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:30][C:17]3[C:18]4[CH:26]=[CH:25][C:24]([C:27](O)=[O:28])=[CH:23][C:19]=4[O:20][CH2:21][CH2:22][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.[Cl-].[NH4+].C[N:34](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:30][C:17]3[C:18]4[CH:26]=[CH:25][C:24]([C:27]([NH2:34])=[O:28])=[CH:23][C:19]=4[O:20][CH2:21][CH2:22][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: O=C(O)c1ccc2c(c1)OCCc1cc(-c3ncnn3-c3ccc(F)cc3F)sc1-2
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccc2c(c1)OCCc1cc(-c3ncnn3-c3ccc(F)cc3F)sc1-2

Procedure:
Following the procedures in Examples 47 and 235, 2-(1-(2,4-difluorophenyl)-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylic acid was reacted with ammonium chloride, HATU and DIPEA in THF to give 328 as a colorless solid after reverse phase HPLC. MS: (ESI+) 425.0
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:14](=[S:21])[NH:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[N:12][CH:11]=[N:10]1)#[N:2].[CH3:22]C([O-])(C)C.[K+].CI.O>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([C:14]([S:21][CH3:22])=[N:15][CH2:16][Si:17]([CH3:18])([CH3:20])[CH3:19])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[N:12][CH:11]=[N:10]1)#[N:2]
Reactant: CC(C)(C)[O-]
Reactant: C[Si](C)(C)CNC(=S)c1ccc(-n2cncn2)c(C#N)c1
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: CSC(=NC[Si](C)(C)C)c1ccc(-n2cncn2)c(C#N)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 64 %

Procedure:
To a solution of 3-cyano-4-(1H-1,2,4-triazol-1-yl)-N-[(trimethylsilyl)methyl]benzene-carbothioamide (1.5 g) in THF was added t-BuOK (0.64 g) under cooling (0° C.). After stirring for 15 minutes, methyl iodide (0.81 g) was added dropwise to the mixture under cooling (0° C.). The reaction liquor was returned to room temperature and stirred for 2 hours. Water was added to the reaction mixture, and aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, subsequently dried over magnesium sulfate. After filtering the reaction mixture, the solvent was distilled off under reduced pressure, and the resulting mixture was purified by silica gel chromatography, to obtain methyl 3-cyano-4-(1H-1,2,4-triazol-1-yl)-N-[(trimethylsilyl)methyl]benzenecarbimidothioate at a yield of 64%.
Reaction SMILES: [OH-].[Na+].[NH2:3][CH2:4][C:5]([OH:7])=O.[CH:8]([N:11]=[C:12]=[O:13])([CH3:10])[CH3:9].Cl>O>[CH:8]([N:11]1[C:5](=[O:7])[CH2:4][NH:3][C:12]1=[O:13])([CH3:10])[CH3:9]
Reactant: NCC(=O)O
Reactant: CC(C)N=C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)N1C(=O)CNC1=O
Temperature: 5 °C

Procedure:
To a solution of 3.6 g of sodium hydroxide in 75 ml of water was added 7.5 g of glycine. The solution was cooled to 5° C. and treated with 9.8 ml of isopropylisocyanate. After 5 h the reaction mixture was neutralised with 50 ml concentrated hydrochloric acid added dropwise to the slurry. This mixture was refluxed for 2 h then cooled to rt. The product was extracted with ethyl acetate to give 10.9 g of a colourless oil. 1H NMR (400 MHz, deuteriochloroform): δ=1.45 (6H, d, J=7 Hz), 3.92 (2H, s), 4.35 (1H, septet, J=7 Hz), 6.39 (1H, br s).
Reaction SMILES: [Li+].CCC[CH2-].[Cl:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[CH:13](OCC)=[O:14]>C1COCC1>[Cl:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[CH:13]=[O:14]
Reactant: Clc1cccnc1
Reactant: CCOC=O
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1ccncc1Cl
Temperature: -70 °C
Reaction time: 4 h
Yield: 55 %

Procedure:
THF (200 mL) is chilled to −70° C. in a dry flask under N2, and N-butyllithium (24.4 mL, 55.0 mmol) is added drop-wise. The reaction is placed in an ice bath and DIA (7.71 mL, 55.0 mmol) in THF (20 mL) is added drop-wise. The solution is again chilled to −70° C., and 3-chloropyridine (4.75 mL, 50.0 mmol) in THF (20 mL) is added drop-wise. The reaction is allowed to stir for 4 h at −70° C. and ethyl formate (4.44 mL, 55.0 mmol) in THF (20 mL) is added. The reaction is stirred for an additional 3 h at −70° C. and quenched with H2O (500 mL). The layers are allowed to separate, and the aqueous layer is extracted with EtOAc (3×250 mL). The combined organic layer is dried over MgSO4, filtered, and concentrated to a dark brown solid. The crude material is chromatographed over 250 g slurry-packed silica, eluting with 50% EtOAc/hexane to give 3-chloroisonicotinaldehyde (C120) as an off-white solid (55% yield). MS (EI) for C6H4ClNO, m/z: 141 (M)+.
Reaction SMILES: [C:1]([OH:18])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9].Cl.[CH3:20]O>>[C:1]([O:18][CH3:20])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([NH:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:9]
Reactant: CO
Reactant: O=C(O)CCCCCCC(=O)Nc1ccccc1
Agent: Cl
Product: COC(=O)CCCCCCC(=O)Nc1ccccc1
Temperature: 50 °C

Procedure:
Suberanilic acid (Compound 3, 249.3 g, 1.0 mole) and methanol (0.4-0.5 L) are combined and heated to 45-55° C. The pH is adjusted to ≦2 using hydrochloric acid, and the batch temperature is maintained at 45-55° C. until the reaction is complete. The reaction is quenched with deionized water (0.1-0.2 L). The batch is cooled to 25-30° C. and seeded to induce crystallization, and then cooled to 0-10° C. The batch is filtered, and the cake washed with a 50:50 (v/v) methanol/water solution (0.28-0.34 L) at 0-10° C. The wet cake is dried at a maximum of 46° C. under vacuum to yield methyl suberanilate.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[F:15][C:16]1[CH:17]=[C:18]([Mg]Br)[CH:19]=[C:20]([F:23])[C:21]=1[F:22].Cl>O1CCCC1>[O:1]=[C:2]([C:18]1[CH:17]=[C:16]([F:15])[C:21]([F:22])=[C:20]([F:23])[CH:19]=1)[CH2:7][CH2:6][CH2:5][CH2:4][NH:3][C:8](=[O:9])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: Fc1cc([Mg]Br)cc(F)c1F
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCCC(=O)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Yield: 36 %

Procedure:
To a solution of tert-butyl 2-oxopiperidine-1-carboxylate (0.30 g, 1.51 mmol) in tetrahydrofuran (8 mL) cooled to −78° C. was added slowly over 15 minutes 0.3 M 3,4,5-trifluorophenylmagnesium bromide in tetrahydrofuran (3.30 mL, 1.66 mmol) and the mixture was then allowed to warm to 25° C. over 30 minutes. The reaction mixture was poured slowly into an ice cold solution of 0.5 N hydrochloric acid (100 mL), and extracted twice with ethyl acetate (2×50 mL). The combined organic extracts were dried over anhydrous sodium sulfate then filtered and concentrated. The residue was purified by silica gel column chromatography (diethyl ether/hexanes 1:4) to give tert-butyl 5-oxo-5-(3,4,5-trifluorophenyl)pentylcarbamate (0.18 g, 36% yield). MS (EI) for C16H20F3NO3: 332 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].C(N(CC)CC)C.O1CCOCC1.[C:23](=O)([O:29]C(C)(C)C)[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]>O1CCOCC1.O.C(OCC)(=O)C>[C:25]([O:24][C:23]([NH:5][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[NH2:1])=[O:29])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: NCc1ccccc1N
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccccc1N
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2-Aminobenzylamine (5.0 g, 40.9 mmol) and triethylamine (4.1 g, 40.9 mmol) were dissolved in a mixed solvent (50 ml) of dioxane-water (2:1). A dioxane solution (8.9 g/10 ml) of di-t-butyl carbonate was added dropwise to the solution under cooling with ice water. The mixture was stirred for 2 hours as it was. After the reaction mixture was diluted with ethyl acetate, an aqueous phase was removed, and an organic phase was washed 3 times with water and once with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was crystallized from diisopropyl ether-hexane to obtain 6.70 g of the title compound.