Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][N:11]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[S:14][CH:13]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:12]3=O)=[N:7][C:6]=2[CH:28]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:30]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][N:11]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[S:14][CH:13]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:12]3=[S:30])=[N:7][C:6]=2[CH:28]=1
Reactant: CCOC(=O)CC1Sc2ccccc2N(Cc2nc3cc(F)ccc3s2)C1=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1Sc2ccccc2N(Cc2nc3cc(F)ccc3s2)C1=S
Yield: 71.5 %

Procedure:
To 10 ml of toluene were added 720 mg of the compound of Example 1 and 770 mg of phosphorus pentasulfide. The mixture was heated to reflux for 4 hours. After the mixture has been cooled, the insoluble substance was filtered off and the solvent was distilled off. The residue was purified by silica gel chromatography to give 535 mg of the title compound. The structural formula and physical data of this compound are shown in Table 23.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([O:11][C:12](=[O:27])[NH:13][C:14]1[C:15]([CH3:26])=[N:16][O:17][C:18]=1[C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=1)[CH3:10].[CH2:28]([O:30][C:31](=[O:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1)[CH3:29]>>[CH2:28]([O:30][C:31](=[O:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:22]2[CH:23]=[CH:24][C:19]([C:18]3[O:17][N:16]=[C:15]([CH3:26])[C:14]=3[NH:13][C:12]([O:11][CH:9]([C:3]3[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=3[F:1])[CH3:10])=[O:27])=[CH:20][CH:21]=2)=[CH:35][CH:34]=1)[CH3:29]
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)c1cc(F)ccc1F
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(=O)OC(C)c3cc(F)ccc3F)cc2)cc1

Procedure:
Following the procedure described in Example 36, Step 6, [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid 1-(2,5-difluoro-phenyl)-ethyl ester and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester were reacted to provide (4′-{4-[1-(2,5-difluoro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-acetic acid ethyl ester, which was hydrolyzed to the acid as described in Example 34, Step 2.
Reaction SMILES: [C:1]([Cu])#N.[Li]C.CCOCC.FC(F)(F)S(O[C:17]1[C:24]2([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=3)[N:20]([CH2:21][CH2:22][CH2:23]2)[C:19](=[O:34])[C:18]=1[C:35]1[CH:40]=[C:39]([Cl:41])[CH:38]=[C:37]([Cl:42])[CH:36]=1)(=O)=O.[NH4+].[OH-]>C1COCC1>[Cl:42][C:37]1[CH:36]=[C:35]([C:18]2[C:19](=[O:34])[N:20]3[C:24]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=4)([C:17]=2[CH3:1])[CH2:23][CH2:22][CH2:21]3)[CH:40]=[C:39]([Cl:41])[CH:38]=1
Reactant: N#Cc1ccc(CC23CCCN2C(=O)C(c2cc(Cl)cc(Cl)c2)=C3OS(=O)(=O)C(F)(F)F)cc1
Reactant: N#C[Cu]
Agent: [Li]C
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1=C(c2cc(Cl)cc(Cl)c2)C(=O)N2CCCC12Cc1ccc(C#N)cc1
Reaction time: 0.5 h
Yield: 14 %

Procedure:
To a suspension of CuCN (22.5 mg, 0.25 mmol) in dry THF (2 ML) at −78° C., under nitrogen atmosphere, was added a solution of MeLi in Et2O (1.4 M, 0.37 mL, 0.5 mmol). The mixture was stirred for 30 min and treated drop wise with a solution of 7a-(4-cyanobenzyl)-6-(3,5-dichlorophenyl)-5-oxo-2,3,5,7a-tetrahydro-1H-pyrrolizin-7-yl trifluoromethanesulfonate 26 (50 mg, 0.09 mmol) in THF (1 mL). The reaction was stirred for 2 h at −78° C. and 20 min. at −20° C. The reaction was treated with 10% aqueous NH4OH (10 ml), stirred at rt. for 10 min. and extracted with Et2O (4×10 mL). The extracts were combined sat. NaCl solution (10 ml), dried (MgSO4) and solvent removed. The resulting oil was purified using preparative HPLC to give 4-{[6-(3,5-Dichlorophenyl)-7-methyl-5-oxo-2,3-dihydro-1H-pyrrolizin-7a(5H)-yl]methyl}benzonitrile IX (5 mg, 14%), LCMS (m/z) 397/399 (M++H), HPLC Retention Time/Condition 1: 1.86 min.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH2:4][OH:5]>C(Cl)(Cl)Cl.[O-2].[Mn+4].[O-2]>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: Nc1ccc(Cl)cc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: Nc1ccc(Cl)cc1C=O
Yield: 88.7 %

Procedure:
2-Amino-5-chlorobenzyl alcohol (4.8 g, 30 mmol) and activated manganese (IV) oxide (21 g, 240 mmol) were refluxed in chloroform (100 mL) for 1 hour. The contents were allowed to cool, filtered through diatomaceous earth and concentrated in vacuo to afford the 2-amino-5-chlorobenzaldehyde as a dark solid (4.14 g, 81%): mp 74-76° C. 1H NMR (CDCl3, 300 MHz) 9.80 (s, 1H), 7.42 (s, 1H), 7.23 (d, 1H, J=7.0 Hz), 6.60 (d, 1H, J=7.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH:21]4[CH2:27][CH2:26][CH2:25][CH2:24][C:23](=[O:28])[CH2:22]4)=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:29][Mg+].[Br-]>C1COCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH:21]4[CH2:27][CH2:26][CH2:25][CH2:24][C:23]([OH:28])([CH3:29])[CH2:22]4)=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCCCC(NC(=O)N2CCN(c3ccnc4cc(Cl)ccc34)CC2)C1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC1(O)CCCCC(NC(=O)N2CCN(c3ccnc4cc(Cl)ccc34)CC2)C1
Reaction time: 5 h

Procedure:
To a stirred solution of 4-(7-chloro-4-quinolinyl)-N-(3-oxocycloheptyl)-1-piperazinecarboxamide (8 mg, 0.02 mmol) in THF (3 mL) was added a solution of MeMgBr (3M, 0.1 mL) at 0° C. After 5 h at 0° C., the reaction mixture was quenched with MeOH and Na2CO3 (sat. 50 mL). The reaction mixture was extracted with CH2Cl2, washed with brine, and dried over Na2SO4. Concentration in vacuo followed by preparative TLC gave the title product. LC-MS: 401 (M++1). 1H NMR (CDCl3) δ 8.78 (d, 1H), 8.05 (s, 1H), 7.95 (d, 1H), 7.45 (m, 1H), 6.85 (d, 1H), 5.75 (d, 1H), 4.45 (d, 1H), 4.05 (m, 1H), 3.65 (m, 4H), 3.20 (m, 4H), 1.55–1.95 (m, 10H), 1.35 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:31])[N:19]([CH2:23][C:24]5([F:30])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:34]([F:37])([F:36])[F:35])[CH:3]=1.[CH:38](=O)[CH3:39]>>[Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:31])[N:19]([CH2:23][C:24]5([F:30])[CH2:29][CH2:28][N:27]([CH2:38][CH3:39])[CH2:26][CH2:25]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:34]([F:37])([F:36])[F:35])[CH:3]=1
Reactant: CC=O
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1CC1(F)CCNCC1
Product: CCN1CCC(F)(CN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)CC1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(1-ethyl-4-fluoropiperidin-4-yl)methyl]-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(4-fluoropiperidin-4-yl)methyl]-1,3-thiazolidine-2,4-dione (Example 303) and acetaldehyde following General Procedure R2.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30]C(=O)C)[C@@H:22]([O:23]C(=O)C)[C@H:17]([O:18]C(=O)C)[C@H:12]1[O:13]C(=O)C.[CH3:34][O:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=O)=[CH:38][CH:37]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:40][C:39]1[CH:43]=[CH:44][C:36]([O:35][CH3:34])=[CH:37][CH:38]=1)=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][OH:30])[C@@H:22]([OH:23])[C@H:17]([OH:18])[C@H:12]1[OH:13]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(Cl)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: COc1ccc(Cc2cn([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3cccc(Cl)c23)cc1

Procedure:
4-Chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole obtained in Example 1-(3) and 4-methoxybenzoyl chloride were treated in a manner similar to Example 3 to give the titled compound as a colorless powder. APCI-Mass m/Z 434/436 (M+H). 1H-NMR (DMSO-d6) δ 3.20-3.27 (m, 1H), 3.36-3.48 (m, 3H), 3.60-3.71 (m, 2H), 3.71 (s, 3H), 4.20 (s, 2H), 4.53 (t, J=5.6 Hz, 1H), 5.10 (d, J=5.1 Hz, 1H), 5.16 (d, J=5.0 Hz, 1H), 5.21 (d, J=5.6 Hz, 1H), 5.40 (d, J=9.0 Hz, 1H), 6.84 (d, J=8.7 Hz, 2H), 7.03 (d, J=7.6 Hz, 1H), 7.09 (t, J=7.9 Hz, 1H), 7.15 (d, J=8.7 Hz, 2H), 7.20 (s, 1H), 7.54 (d, J=8.2 Hz, 1H).
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH:5]=[C:6]([CH3:8])[CH3:7])[C:2]1([CH:10]1[CH:15]([O:16][CH3:17])[CH:14]([OH:18])[CH2:13][CH2:12][C:11]1([CH2:20][Cl:21])[OH:19])[CH3:9].[C:22]([N:26]=[C:27]=[O:28])(=[O:25])[CH:23]=[CH2:24].O>ClCCl>[C:22]([NH:26][C:27]([O:18][CH:14]1[CH2:13][CH2:12][C:11]([CH2:20][Cl:21])([OH:19])[CH:10]([C:2]2([CH3:9])[O:1][CH:3]2[CH2:4][CH:5]=[C:6]([CH3:7])[CH3:8])[CH:15]1[O:16][CH3:17])=[O:28])(=[O:25])[CH:23]=[CH2:24]
Reactant: C=CC(=O)N=C=O
Reactant: COC1C(O)CCC(O)(CCl)C1C1(C)OC1CC=C(C)C
Solvent: ClCCl
Solvent: O
Product: C=CC(=O)NC(=O)OC1CCC(O)(CCl)C(C2(C)OC2CC=C(C)C)C1OC
Reaction time: 0.5 h
Yield: 36.7 %

Procedure:
To a solution of 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1,4-cyclohexanediol (418 mg) in dichloromethane (5 ml) was added dropwise acryloylisocyanate (300 mg). The mixture was stirred for 30 minutes at room temperatures. To the reaction mixture was added water, which was subjected to extraction with ethyl acetate. The extract solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline solution, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (carrier 20 g, developing solvent: hexane-ethyl acetate=4:1) to afford 4-O-(acryloylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1,4-cyclohexanediol (200 mg, yield 38%) as colorless crystals.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH2:13])=[CH:7][CH:6]=1)([O-:4])=[O:3].[CH2:14]([N:18]1[C:23](Cl)=[CH:22][C:21](=[O:25])[N:20]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[F:33])[C:19]1=[O:34])[CH2:15][CH2:16][CH3:17].C(N(CC)CC)C.O>CN1CCCC1=O>[CH2:14]([N:18]1[C:23]([NH:13][CH2:12][CH2:11][C:8]2[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:10][CH:9]=2)=[CH:22][C:21](=[O:25])[N:20]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[F:33])[C:19]1=[O:34])[CH2:15][CH2:16][CH3:17]
Reactant: NCCc1ccc([N+](=O)[O-])cc1
Reactant: CCCCn1c(Cl)cc(=O)n(Cc2ccccc2F)c1=O
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CCCCn1c(NCCc2ccc([N+](=O)[O-])cc2)cc(=O)n(Cc2ccccc2F)c1=O
Temperature: 75 °C
Reaction time: 16 h
Yield: 41.4 %

Procedure:
A mixture of 2-(4-nitro-phenyl)-ethylamine hydrochloride salt (Fluka) (7.85 g, 38.7 mmol), 1-butyl-6-chloro-3-(2-fluorobenzyl)-1H-pyrimidine-2,4-dione (8.0 g, 25.8 mmol) and triethylamine (10.7 mL, 77 mmol) in N-methyl-pyrrolidin-2-one (200 mL) was stirred at 75° C. for 16 hours. The reaction was then mixed with water and extracted with ethyl acetate (3×). The combined ethyl acetate layers were dried (magnesium sulfate) and concentrated. Column chromatography afforded 1-butyl-3-(2-fluorobenzyl)-6-[2-(4-nitro-phenyl)-ethylamino]-1H-pyrimidine-2,4-dione (4.7 g, 41%) as a solid. 1H NMR (CDCl3, 200 MHz) δH 0.84 (t, 3H), 1.11–1.50 (m, 4H), 3.10 (t, 2H), 3.48 (m, 2H), 3.70 (t, 2H), 4.36 (t, 1H), 4.94 (t, 1H), 5.20 (s, 2H), 6.95–7.10 (m, 2H), 7.17–7.30 (m, 2H), 7.39 (d, 2H), 8.20 (d, 2H).
Reaction SMILES: [OH:1][C@H:2]1[C@@H:6]2[O:7][C:8]([CH3:11])([CH3:10])[O:9][C@@H:5]2[O:4][C@H:3]1[C:12]([OH:14])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C[N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1.N1CCOCC1>O1CCCC1>[OH:1][C@H:2]1[C@@H:6]2[O:7][C:8]([CH3:10])([CH3:11])[O:9][C@@H:5]2[O:4][C@H:3]1[C:12]([N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1)=[O:14]
Reactant: CN1CCOCC1
Reactant: CC1(C)O[C@@H]2O[C@@H](C(=O)O)[C@@H](O)[C@@H]2O1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CC1(C)O[C@@H]2O[C@@H](C(=O)N3CCOCC3)[C@@H](O)[C@@H]2O1
Reaction time: 1 h
Yield: 48 %

Procedure:
To a suspension of (3aS,5R,6S,6aS)-6-Hydroxy-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxole-5-carboxylic acid (9.0 g, 44.2 mmol) and HBTU (25.1 g, 66.3 mmol, N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate) in tetrahydrofuran was added 4-methylmorpholine (7.3 mL, 66.3 mmol) at room temperature. After 1 h, morpholine (5.8 mL, 66.3 mmol) was added to the mixture at room temperature. After 12 h, the resulting mixture was filtered and the filter cake was washed with tetrahydrofuran. The filtrate was concentrated in vacuo, and the crude was purified by silica gel column chromatography to provide the title compound (5.8 g, 48%) as a yellow solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[O:10]1[CH2:12][C@@H:11]1[CH2:13]OS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O>CN(C)C=O>[O:7]([CH2:13][C@H:11]1[CH2:12][O:10]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@H]2CO2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(OC[C@H]2CO2)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 81.1 %

Procedure:
Add phenol (1.089 g, 11.572 mmol) to a slurry of sodium hydride (0.347 g, 14.465 mmol) in N,N-dimethylformamide (77.1 mL) and stir at room temperature for 40 minutes. Add 3-nitrobenzenesulfonic acid (R)-1-oxiranylmethyl ester (3.00 g, 11.572 mmol) and stir at room temperature for 16 hours (J. Org. Chem., 54, 1296-1304 (1989). Quench with saturated aqueous ammonium chloride (75 mL), dilute with water (75 mL) and extract with diethyl ether (3×300 mL). Combine the organic extracts, wash with saturated aqueous sodium bicarbonate (200 mL), saturated aqueous ammonium chloride (200 mL), dry (magnesium sulfate), filter and purify (silica gel chromatography, eluting with 10:90 to 50:50 ethyl acetate:hexanes) to give the desired compound as a clear liquid (1.410 g, 81.1%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH3:15])[C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].[I:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH3:15])[C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:21]([C:20]3[CH:24]=[CH:25][C:17]([I:16])=[CH:18][CH:19]=3)=[O:22])[CH2:13][CH2:14]2)=[N:7][CH:8]=1)[CH3:2]
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: CCc1cnc(N2CCNCC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Yield: 90.5 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 161 and using 1-(5-ethyl-3-methylpyridin-2-yl)piperazine (2.46 g) described in Preparation Example 53 and 4-iodobenzoyl chloride (3.36 g), the title compound (4.72 g) was obtained.
Reaction SMILES: [CH2:1]1CCN2C(=NCCC2)CC1.[C:12]([OH:20])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl.O>[C:12]([O:20][CH3:1])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccccc1
Reactant: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccccc1
Temperature: 90 °C

Procedure:
DBU (2.5 g, 16.4 mmol) was added to a mixture of benzoic acid (2.0 g, 16.4 mmol) in DMC (20 mL) and the resulting mixture was heated to reflux (90° C.) for 2.5 hours. The reaction mixture was cooled to ambient temperature and diluted with CH2Cl2 (50 mL) and water (40 mL). The organic layer was separated and washed in sequence with 2 M HCl (2×40 mL), saturated aqueous NaHCO3 (40 mL) and water (2×40 mL). The organic layer was dried over Na2SO4, filtered and concentrated under vacuum to give methyl benzoate as an oil. The yield of the methyl benzoate as determined by HPLC was 97-98% conversion.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[CH3:14][O:15][C:16]1[N:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[CH3:23].N1C=CC=CC=1>O1CCOCC1>[CH3:14][O:15][C:16]1[N:21]=[CH:20][C:19]([NH:22][S:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])=[CH:18][C:17]=1[CH3:23]
Reactant: COc1ncc(N)cc1C
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: COc1ncc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1C
Yield: 76.3 %

Procedure:
The title compound (2.69 g, 8.32 mmol) was prepared from 2-nitrobenzenesulfonyl chloride (2.41 g, 10.9 mmol), 6-methoxy-5-methylpyridin-3-amine (1.66 g, 12.0 mmol) and pyridine (2.64 mL, 32.7 mmol) in 1,4-dioxane (25 mL) at rt using the methods of (IntA1), step 1.
Reaction SMILES: [CH3:1][NH2:2].CS(O[CH2:8][CH2:9][CH:10]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)(=O)=O>C1COCC1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH:10]([NH:18][C:19](=[O:20])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:9][CH2:8][NH:2][CH3:1])=[CH:12][CH:13]=1
Reactant: CN
Reactant: CC(C)(C)OC(=O)NC(CCOS(C)(=O)=O)c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CNCCC(NC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Temperature: 125 °C
Yield: 90 %

Procedure:
Methylamine gas was bubbled into a solution of 3-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propyl methanesulfonate (Intermediate 31) (70 mg, 0.19 mmol) in THF (5 mL) at 22° C. over a period of 5 minutes. The mixture was sealed into a microwave tube. The reaction was heated to 125° C. for 30 minutes in the microwave reactor and cooled to ambient temperature. The mixture was evaporated and the residue was purified by flash silica chromatography, elution gradient 4 to 8% (10:1 MeOH/conc. NH3 (aq)) in DCM. Pure fractions were evaporated to dryness to afford tert-butyl 1-(4-chlorophenyl)-3-(methylamino)propylcarbamate (52 mg, 90%) as a colourless oil.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[NH:15][C:16]([NH2:25])=[C:17]3[C:21]([N:22]=2)=[N:20][C:19]([O:23][CH3:24])=[N:18]3)[CH2:10][CH2:9]1.Br[CH2:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1>>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]3[CH2:27][CH2:28][CH2:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][O:31]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1
Reactant: BrCCCC1CCCCO1
Reactant: COc1nc2nc(OCCC3CC3)[nH]c(N)c-2n1
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1CCCC1CCCCO1

Procedure:
Prepared similarly to Intermediate 216 from 2-[(2-cyclopropylethyl)oxy]-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 2-(3-bromopropyl)tetrahydro-2H-pyran.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].[CH3:11][OH:12].[ClH:13]>C(OCC)C>[ClH:13].[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[NH:7])[O:12][CH3:11])=[CH:4][C:3]=1[CH3:10]
Reactant: CO
Reactant: Cc1cc(C#N)ccc1Br
Agent: Cl
Solvent: CCOCC
Product: COC(=N)c1ccc(Br)c(C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-Bromo-3-methylbenzonitrile (15.0 g, 76.5 mmol) was dissolved in dry methanol (3.1 ml, 76.5 mmol) and dry diethyl ether (108 ml), cooled to 0-5°, then saturated with HCl (g). Stirred for 18 hours at room temperature and the solid collected by filtration, then dried in vacuo to yield the title compound as white needle-like crystals (19.3 g, 95%).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C:13]1[N:14]=[CH:15][C:16]([NH:19][C:20]([NH:22][C:23]2[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=2[O:30][CH3:31])=[O:21])=[N:17][CH:18]=1.O.NN>CCO.CN(C=O)C>[NH2:3][CH2:12][C:13]1[N:14]=[CH:15][C:16]([NH:19][C:20]([NH:22][C:23]2[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=2[O:30][CH3:31])=[O:21])=[N:17][CH:18]=1
Reactant: COc1ccc(C)cc1NC(=O)Nc1cnc(CN2C(=O)c3ccccc3C2=O)cn1
Agent: NN
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: COc1ccc(C)cc1NC(=O)Nc1cnc(CN)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
To a stirred solution of 1-[5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-pyrazin-2-yl]-3-(2-methoxy-5-methyl-phenyl)-urea (16 mg, 38 μmol) in 380 μL 95% EtOH and 100 μL DMF at room temperature in a capped reaction vial was added hydrazine monohydrate (3.8 μL, 76 μmol). After stirring overnight at room temperature, a white precipitate formed. The precipitate was filtered off, dried and triturated with EtOAc to remove phthalimide based impurities to provide the product as a white solid (7.9 mg, 72%). 1H-NMR (400 MHz, d6-DMSO) δ 9.54 (s, 1H), 8.80 (s, 1H), 8.46 (s, 1H), 8.02 (s, 1H), 6.93 (d, 1H), 6.79 (d, 1H), 4.51 (d, 2H), 4.39 (br s, 2H), 3.89 (s, 3H), 2.23 (s, 3H). LRLCMS (ESI, Positive) m/e 288.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:14])=[C:4]([C:8]([CH3:13])=[C:9]([F:12])[C:10]=1[F:11])[C:5](O)=[O:6].S(Cl)([Cl:17])=O>>[Cl:1][C:2]1[C:3]([F:14])=[C:4]([C:8]([CH3:13])=[C:9]([F:12])[C:10]=1[F:11])[C:5]([Cl:17])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(F)c(F)c(Cl)c(F)c1C(=O)O
Product: Cc1c(F)c(F)c(Cl)c(F)c1C(=O)Cl

Procedure:
Employing 3-chloro-2,4,5-trifluoro-6-methylbenzoic acid (185 mg) and thionyl chloride (600 μl ), the procedure of Reference Example 18 is repeated to give 3-chloro-2,4,5-trifluoro-6-methylbenzoyl chloride (183 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:13])[C:7](=[CH:11][CH:12]=1)[C:8]([OH:10])=O)([O-:3])=[O:2].[NH2:14][CH2:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1>CN(C)C=O>[NH2:13][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][C:7]=1[C:8]([NH:21][CH2:20][C:19]1[CH:22]=[CH:23][C:16]([C:15]#[N:14])=[CH:17][CH:18]=1)=[O:10]
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: N#Cc1ccc(CN)cc1
Solvent: CN(C)C=O
Product: N#Cc1ccc(CNC(=O)c2ccc([N+](=O)[O-])cc2N)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
31.7 g (0.17 mol) of 4-nitro-anthranilic acid are dissolved in 350 ml dimethylformamide and after the addition of 45.4 g (0.28 mol) of N,N′-carbonyldiimidazole stirred for 30 minutes at 50° C. Then a solution of 23 g (0.17 mol) of 4-aminomethyl-benzonitrile in 100 ml dimethylformamide is added dropwise and stirred for 2 hours at 50° C. The solution is evaporated down, dissolved in ethyl acetate and extracted with sodium hydrogen carbonate solution. The combined organic extracts are dried and evaporated down. The residue is chromatographed on silica gel and eluted with methylene chloride/ethanol (97:3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][C:14]=1[N+:15]([O-])=O)[O:6][CH2:7][CH2:8][N:9]([CH3:11])[CH3:10].[H][H]>C(OCC)(=O)C.[Pd]>[CH3:10][N:9]([CH3:11])[CH2:8][CH2:7][O:6][C:5]1[CH:12]=[CH:13][C:14]([NH2:15])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc(OCCN(C)C)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(OCCN(C)C)ccc1N
Yield: 90.6 %

Procedure:
A mixture of [2-(3-Methoxy-4-nitrophenoxy)ethyl]dimethylamine (1.0 g, 4.2 mmol) and 5% Pd—C (0.2 g) in ethyl acetate (75 mL) was shaken under 50 psi of hydrogen for 24 hours. The mixture was filtered through Celite and evaporated, providing 0.80 g of the product as a light gold oil, in 91% yield: 1H NMR (CDCl3) δ 2.33 (s, 6H), 2.69 (t, J=5.8 Hz, 2H), 3.82 (s, 3H), 4.00 (t, J=5.8 Hz, 2H), 6.35 (dd, J=8.3 Hz, J=2.6 Hz, 1H), 6.50 (d, J=2.6 Hz, 1H), 6.63 (d, J=8.3 Hz, 1H).