Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:20][CH:19]([CH3:21])[N:18]2[CH:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:22]([OH:26])[CH2:23][CH2:24][CH3:25])=[CH:14][CH:13]=3)[CH2:9]1)=O)(C)(C)C.[CH:27]1([CH2:30]Br)[CH2:29][CH2:28]1>>[CH:27]1([CH2:30][O:26][CH:22]([C:15]2[N:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[CH2:11][C@H:10]2[N:18]3[C@H:19]([CH3:21])[CH2:20][NH:8][CH2:9]2)[CH2:23][CH2:24][CH3:25])[CH2:29][CH2:28]1
Reactant: CCCC(O)c1ccc2c(n1)N1C(C)CN(C(=O)OC(C)(C)C)CC1C2
Reactant: BrCC1CC1
Product: CCCC(OCC1CC1)c1ccc2c(n1)N1[C@@H](CNC[C@H]1C)C2

Procedure:
(4R,9aR)-6-(1-(RS)-Cyclopropylmethoxy-butyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene di-trifluoroacetate (53 mg) was made from 6-(1-hydroxy-butyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (54 mg), using cyclopropylmethyl bromide (29 μl) in place of methyl iodide, according to the procedure described in Example 63 to afford the product as a colorless oil: HPLC [Xterra; 50/80; 255 nm] 99.6%, 2.29 min; MS (ES) 316.4 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)([CH2:12][CH2:13][CH2:14]OS(C)(=O)=O)[C:8]1=[O:28].I.[NH:37]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[N:39]=[C:38]1[NH:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][CH2:14][N:50]2[CH2:49][CH2:48][CH:47]([NH:46][C:38]3[NH:37][C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=4[N:39]=3)[CH2:52][CH2:51]2)([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:8]1=[O:28]
Reactant: COc1cc(CN2CCC(CCCOS(C)(=O)=O)(Cc3ccc(F)cc3)C2=O)cc(OC)c1OC
Reactant: c1ccc2[nH]c(NC3CCNCC3)nc2c1
Agent: I
Product: COc1cc(CN2CCC(CCCN3CCC(Nc4nc5ccccc5[nH]4)CC3)(Cc3ccc(F)cc3)C2=O)cc(OC)c1OC

Procedure:
Prepare by the method of Example 4.1 using 1-(3,4,5-trimethoxybenzyl)-3-(4-fluorophenylmethyl)-3-(3-methanesulfonyloxypropyl)-2-oxopyrrolidine and (1H-benzimidazol-2-yl)(piperidin-4-yl)amine hydriodic acid salt to give the title compound: Rf=0.55 (silica gel, 2% triethylamine/methanol).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([N:10]([CH2:12][C:13]1[S:17][CH:16]=[C:15]([C:18]2[CH:19]=[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=2)[NH:23][CH:22]=[C:21]3[CH:30]2[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:38])=[O:37])[CH2:32][CH2:31]2)[CH:14]=1)[CH3:11])[CH3:9].[CH3:41]NCC>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:39]([S:36]([N:33]1[CH2:34][CH2:35][CH:30]([C:21]2[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=[C:18]([C:15]4[CH:14]=[C:13]([CH2:12][N:10]([CH3:11])[CH2:8][CH2:9][CH3:41])[S:17][CH:16]=4)[CH:19]=3)[NH:23][CH:22]=2)[CH2:31][CH2:32]1)(=[O:37])=[O:38])[CH3:40]
Reactant: CCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Reactant: CCNC
Solvent: O=C(O)C(F)(F)F
Product: CCCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Yield: 32.4 %

Procedure:
The title compound was prepared according to the general procedure of 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting methyl(propyl)amine (73 mg, 1.0 mmol) for N-methylethanamine to afford 20.0 mg of the title compound (32.4%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][CH:9]([OH:14])[CH2:10]2)=[O:5])[CH3:2].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH2:1]([O:3][C:4]([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][CH:9]([O:14][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:10]2)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)N1C2CCC1CC(O)C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1C2CCC1CC(OS(C)(=O)=O)C2
Reaction time: 2 h

Procedure:
To a solution of 3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid ethyl ester (1.250 g, 6.28 mmol) in dichloromethane (62 mL) was added triethylamine (1.40 mL, 10.0 mmol) and methanesulfonyl chloride (0.722 mL, 9.38 mmol) dropwise. The solution was stirred 2 hrs, washed with sodium bicarbonate, dried over MgSO4, filtered, and concentrated. The crude oil (1.74 g) was taken on with no purification. 1H NMR (300 MHz, CDCl3) δ ppm 1.26 (t, J=7.1 Hz, 3H), 2.04 (m, 6H), 2.18 (m, 2H), 3.02 (s, 3H), 4.14 (q, J=7.1 Hz, 2H), 4.29 (m, 2H), 5.02 (m, 1H); MS (ESI+Q1MS) m/z 278 [M+H]+
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([CH3:13])[CH2:11][OH:12])([O-:3])=[O:2].CCN(CC)CC.[Cl:21][C:22](OC(Cl)(Cl)Cl)=[O:23]>C1COCC1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([CH3:13])[CH2:11][O:12][C:22]([Cl:21])=[O:23])([O-:3])=[O:2]
Reactant: CC(CO)c1ccccc1[N+](=O)[O-]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(COC(=O)Cl)c1ccccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 95.8 %

Procedure:
A solution of 2-(2-nitrophenyl)propanol (500 mg, 2.76 mmol) and Et3N (279 mg, 0.385 ml, 2.76 mmol, dist. over KOH) in THF (6.75 ml, dist. over CaH2) was dropped into a solution, cooled to 0° C., of trichloromethyl chloroformate (655 mg, 3.3 mmol) in THF (6.75 ml, see above). It was stirred for 1 h while being cooled in an ice bath and stirred for 1 h at room temperature. The mixture was filtered over Celite. Rewashing the filter cake with THF and removing the solvent and excess reagent from the pooled filtrates by distillation at 30° C. in a high vacuum yielded 2-(2-nitrophenyl)propoxycarbonyl chloride (644 mg, 96%) as a light brown oil.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[CH:10]=[C:9]([NH2:12])[CH2:8][C:7]([CH3:14])([CH3:13])[C:6]=2[NH:5][C:4](=[O:15])[CH2:3]1.F[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][CH:2]1[C:11]2[CH:10]=[C:9]([NH:12][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N+:23]([O-:25])=[O:24])[CH2:8][C:7]([CH3:14])([CH3:13])[C:6]=2[NH:5][C:4](=[O:15])[CH2:3]1
Reactant: CC1CC(=O)NC2=C1C=C(N)CC2(C)C
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC1CC(=O)NC2=C1C=C(Nc1ccccc1[N+](=O)[O-])CC2(C)C

Procedure:
This compound, m.p. 205°14 211°, was prepared similarly to Preparation 20 using 3,4-dihydro-4,8,8-trimethyl-6-amino-2-(1H)-quinolone, 1-fluoro-2-nitrobenzene, and sodium carbonate as starting materials.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6](Cl)(=[O:8])=[O:7].[NH2:10][C:11]1[CH:12]=[C:13]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15]>N1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:10][C:11]1[CH:12]=[C:13]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15])(=[O:8])=[O:7]
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NS(=O)(=O)c1cccs1
Yield: 89 %

Procedure:
Prepared according to the procedure described for Example 121 using 2-thiophenesulfonyl chloride (1.82 g, 10 mmol), 3-amino-4-methoxy-N-phenyl-benzamide (2.43 g, 10 mmol), and pyridine (25 mL) to afford the product (3.457 g); m.p. 180-183° C. after trituration in hexanes/ethyl acetate (1:1).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:10][C:6]=2[C:5](=[O:16])[N:4]([CH3:17])[N:3]=1.[H-].[Na+].Cl[CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[C:5](=[O:16])[N:4]([CH3:17])[N:3]=1
Reactant: CCOC(=O)c1cc2c(Cl)nn(C)c(=O)c2[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Cl)nn(C)c(=O)c2n1COCC[Si](C)(C)C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
A solution of Example 74d (0.41 g, 1.6 mmol) in dimethylformamide (15 mL) was treated with 60% sodium hydride (0.096 g, 2.4 mmol) at room temperature. The reaction mixture was stirred for 30 min, and then was treated with (2-(chloromethoxy)ethyl)trimethylsilane (0.40 g, 2.4 mmol). The reaction mixture was then stirred for 2 hours. It was partitioned between ethyl acetate and water. The aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 20% ethyl acetate to afford 0.50 g (81%) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([CH2:9][CH2:10][NH:11]C(OC(C)(C)C)=O)[N:6]=[CH:5]1.C(N(CC)CC)C.C1C(=O)N([O:33][C:34]([CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=2)=O)C(=O)C1>C(Cl)Cl>[OH:44][C:41]1[CH:40]=[CH:39][C:38]([CH2:37][CH2:36][C:34]([NH:1][CH2:2][CH2:3][N:4]2[CH:8]=[C:7]([CH2:9][CH2:10][NH2:11])[N:6]=[CH:5]2)=[O:33])=[CH:43][CH:42]=1
Reactant: CC(C)(C)OC(=O)NCCc1cn(CCN)cn1
Reactant: O=C(CCc1ccc(O)cc1)ON1C(=O)CCC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NCCc1cn(CCNC(=O)CCc2ccc(O)cc2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The following materials are introduced into a reaction vessel: 5 mg (0.02 mmol) of compound VII dissolved in 0.5 ml methylene chloride; 2.8 μl (0.02 mmol) of triethylamine; and last 5.3 mg (0.02 mmol) of N-succinimidyl-3-(4-hydroxyphenyl)propionate dissolved in 0.5 ml of methylene chloride. The solution is stirred for 2 hours at room temperature and then evaporated. The residue is dissolved in 0.5 ml of trifluoroacetic acid, and hydrolysis is allowed to proceed for 1 hour and 15 minutes at room temperature. The solution is evaporated, the residue then being separated on a reversed-phase column PepRPC (Pharmacia AB) with an 0.1% trifluoroacetic acid - acetonitrile gradient. At about 7% acetonitrile compound XIX is eluted. The structure has been confirmed by NMR analysis, the NMR data being the following: 2H-imidazole 8.3, 5H-imidazole 7.2, O-H-hydroxyphenyl 7.1, m-H-hydroxyphenyl 6.85, 1-CH2 -imidazole 4.15, --CH2NHCO 3.55, --CH2N + H3 3.25 t, 4-CH2 -imidazole 3.05 t, p-CH2 -hydroxyphenyl 2.75 t, --CH2CO 2.5 t.
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([CH3:23])[C:5]([O:6][C:7]2[C:12]([CH3:13])=[C:11]([NH:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:10]=[C:9]([CH3:20])[N:8]=2)=[C:4]([CH3:24])[CH:3]=1.[CH3:25][C:26]([CH3:28])=[O:27]>C1COCC1>[CH2:16]([CH:15]([NH:14][C:11]1[CH:10]=[C:9]([CH3:20])[N:8]=[C:7]([O:6][C:5]2[C:21]([CH3:23])=[CH:22][C:2]([C:26]([OH:27])([CH3:28])[CH3:25])=[CH:3][C:4]=2[CH3:24])[C:12]=1[CH3:13])[CH2:18][CH3:19])[CH3:17]
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(Br)cc2C)c1C
Reactant: CC(C)=O
Solvent: C1CCOC1
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C(C)(C)O)cc2C)c1C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of [2-(4-bromo-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl)-amine in dry THF was added n-butylithium at −78° C. After stirring at −78° C. for 10 min, acetone was added and the resulting mixture was stirred at −78° C. for 30 min, the dry-ice bath was removed. After stirring for 5 min, the mixture was quenched with brine and extracted with ethyl acetate. The organic layer was separated, dried, and concentrated to dryness. The residue was purified through silica gel chromatography to give the title compound. 1H NMR(CDCl3) d 7.17(s, 2H), 6.08(s, 1H), 3.73(d, 1H), 3.33(m, 1H), 2.19(s, 3H), 2.15(s, 3H), 2.12(s, 6H), 1.4-1.7(m, 4H), 1.26(s, 6H), 0.96(t, 6H) ppm.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Cl[CH:26]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(OC(N1CCC2NN(C3CCCCCC3)C(C3C=CC(Cl)=CC=3)C=2CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH:26]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: ClC1CCCCCC1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Agent: CC(C)(C)OC(=O)N1CCC2=C(CC1)C(c1ccc(Cl)cc1)N(C1CCCCCC1)N2
Product: Clc1ccc(-c2nn(C3CCCCCC3)c3c2CCNCC3)cc1
Yield: 21.3 %

Procedure:
The title compound (22 mg) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.30 mmol) using chloro-cycloheptane (1.0 mmol) in place of chloro-cyclobutane according to Example 238. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-cycloheptyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C20H26ClN3, 343.18. found, m/z 344.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.40-7.34 (m, 4H), 4.31-4.27 (m, 1H), 3.39-3.37 (m, 2H), 3.28-3.26 (m, 2H), 3.17-3.16 (m, 2H), 2.95-2.92 (m, 2H), 2.04-2.01 (m, 2H), 1.92-1.90 (m, 2H), 1.77-1.75 (m, 2H), 1.63-1.53 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:12]([NH:14][S@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])[CH3:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Li+].[CH3:22][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:12]([N:14]([CH3:22])[S@:15]([C:17]([CH3:19])([CH3:18])[CH3:20])=[O:16])[CH3:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: C[C@@H](N[S@@](=O)C(C)(C)C)c1cc(Cl)cc(C(F)(F)F)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: C[C@H](c1cc(Cl)cc(C(F)(F)F)c1)N(C)[S@@](=O)C(C)(C)C
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
To a solution of (S)-N-((R)-1-(3-chloro-5-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (1.5 g, 4.6 mmol) in anhydrous THF (20 mL) under N2 atmosphere was dropwise added LHMDS (9.2 mL, 1 M in THF, 9.2 mmol) at −60° C. The reaction was stirred for 30 min at −60° C., followed by addition of MeI (1.04 g, 6.9 mmol). The reaction was stirred at room temperature for another 3 h and quenched with water at 0° C. The resulting mixture was extracted with EtOAc (2×100 mL). The combined organic layers were dried over anhydrous Na2SO4 and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE/EtOAc=5/1 to 2/1) to give the title compound (1.2 g, yield: 76.5%); m/z (ES+): 342 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([O:11][CH:12]2[CH2:15][CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[C:3]([O:11][CH:12]3[CH2:15][CH2:14][CH2:13]3)=[N:4][CH:5]=[C:6]([CH:10]=2)[C:7]([OH:9])=[O:8])=[CH:19][CH:18]=1
Reactant: O=C(O)c1cnc(OC2CCC2)c(Br)c1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnc(OC2CCC2)c(-c2ccc(Cl)cc2)c1
Temperature: 100 °C

Procedure:
5-Bromo-6-cyclobutoxy-nicotinic acid (example 78 a; 1.531 g, 5.63 mmol), 4-chloro-phenylboronic acid (968 mg, 6.19 mmol), potassium carbonate (1.56 g, 11.3 mmol) and tetrakis(triphenylphosphine)palladium (325 mg, 281 μmol) were suspended in THF (38 mL) and water (38 mL). The reaction mixture was stirred at reflux temperature (100° C.) over the weekend. THF was removed and the residue was partitioned between water (pH=2) and ethyl acetate; the organic phases were combined, dried with MgSO4 and concentrated in vacuo to obtain the title compound (quant.) as off-white solid; MS (ESI) 302.2 (M−H)−.
Reaction SMILES: Cl.[CH:2]1([NH:8][NH2:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:10]([O:12][C:13](=[O:25])[C:14](=[CH:21]N(C)C)[C:15](=O)[C:16]([F:19])([F:18])[F:17])[CH3:11].C([O-])(=O)C.[Na+]>C(O)C>[CH2:10]([O:12][C:13]([C:14]1[CH:21]=[N:9][N:8]([CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[C:15]=1[C:16]([F:17])([F:18])[F:19])=[O:25])[CH3:11]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)C(F)(F)F
Reactant: NNC1CCCCC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnn(C2CCCCC2)c1C(F)(F)F
Temperature: 70 °C
Yield: 58.5 %

Procedure:
Cyclohexyl-hydrazine hydrochloride (0.276 g, 1.59 mmol, CAS #24214-73-1, purchased from Aldrich), 2-dimethylaminomethylene-4,4,4-trifluoro-3-oxo-butyric acid ethyl ester (0.459 g, 1.67 mmol) and anhydrous sodium acetate (0.188 g, 2.29 mmol) were combined in ethanol (2.9 mL) and heated at 70° C. for 15 hours. After cooling to room temperature, the reaction mixture was partitioned between methylene chloride and water. The organic phase was washed with water and brine. Each aqueous phase was back extracted with a second portion of methylene chloride. The two organic phases were combined, dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography, eluting with a 5-40% ethyl acetate-hexanes gradient, yielded 1-cyclohexyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (0.270 g, 55%). Mass spectrum: m/z: 291.3 (M+H).
Reaction SMILES: [C:1]([NH:4][CH2:5][C@H:6]([OH:13])[CH2:7][C:8](OCC)=[O:9])(=[O:3])[CH3:2].O.[NH2:15][NH2:16]>CO>[C:1]([NH:4][CH2:5][C@H:6]([OH:13])[CH2:7][C:8]([NH:15][NH2:16])=[O:9])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C[C@@H](O)CNC(C)=O
Reactant: NN
Solvent: O
Solvent: CO
Product: CC(=O)NC[C@H](O)CC(=O)NN
Temperature: 65 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
A 5.00 g (26.4 mmol) of ethyl (R)-4-acetylamino-3-hydroxybutyrate (optical purity: 95%e.e.) was dissolved in 20 ml of methanol, and 2.00 g (39.6 mmol) of hydrazine monohydrate was added thereto dropwise at room temperature. After the addition, the mixture was heated to 65° C. and then stirred overnight. After the mixture was cooled to room temperature, 20 ml of methanol was added thereto and crystallization was carried out at 10° C. to give 3.90 g (84%) of the title compound. Melting point: 177.5° C. Optical purity: >99.9%e.e.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:24])=[CH:4][C:5]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][CH:11]=3)[S:7][C:6]=2[C:22]=1[F:23].CCOCC.[CH2:30](Br)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[F:1][C:2]1[C:3]([O:24][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:4][C:5]2[CH:9]=[C:8]([C:10]3[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:14][CH:15]=3)[S:7][C:6]=2[C:22]=1[F:23]
Reactant: CCCCCCc1ccc(-c2cc3cc(O)c(F)c(F)c3s2)cc1
Reactant: CCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCC(C)=O
Product: CCCCCCCOc1cc2cc(-c3ccc(CCCCCC)cc3)sc2c(F)c1F

Procedure:
is obtained by reacting 2,3-difluoro-4-ethoxythiophenol (obtainable analogously to Reference 7 from 2,3-difluoro-4-ethoxyaniline [189751-13-1]) and 4-hexylphenacyl bromide analogously to Reference 5 to give 6,7-difluoro-2-(4-hexylphenyl)-5-ethoxybenzo[b]thiophene, ether cleavage by means of hydrobromic acid/acetic acid to give 6,7-difluoro-2-(4-hexylphenyl)-5-hydroxybenzo[b]thiophene and Williamson ether synthesis using heptyl bromide in 2-butanone in the presence of potassium carbonate.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]2[C:14]([CH3:16])([CH3:15])[C:13]2([Cl:18])[Cl:17])(=O)=O)=CC=1.[C-:20]#[N:21].[K+].O>CN(C)C=O>[Cl:18][C:13]1([Cl:17])[C:14]([CH3:15])([CH3:16])[CH:12]1[CH2:11][C:20]#[N:21]
Reactant: Cc1ccc(S(=O)(=O)OCC2C(C)(C)C2(Cl)Cl)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)C(CC#N)C1(Cl)Cl
Temperature: 100 °C
Yield: 106.5 %

Procedure:
6.48 g of 2,2-dichloro-3,3-dimethylcyclopropylmethyl p-toluenesulfonate and 2.0 g of potassium cyanide were suspended in 20 ml of dimethyl formamide, and the mixture was heated at 100° C. for 24 hours with stirring. After cooling, 50 ml of water was added to the reaction mixture. The mixture was extracted with hexane. The hexane layer was washed with water, and dried over sodium sulfate. After drying, the hexane was evaporated under reduced pressure to give 3.8 g of 2,2-dichloro-3,3-dimethylcyclopropylacetonitrile, the desired compound shown above. The boiling point of the product was 96° to 98° C. at 14 mmHg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].C(N(CC)CC)C.ClC(OCC)=O.Cl.[C:24](=S)=[S:25]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:5]=[C:24]=[S:25])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: Nc1ccc(F)c(F)c1
Reactant: S=C=S
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Fc1ccc(N=C=S)cc1F
Temperature: 25 °C
Yield: 70.2 %

Procedure:
3,4-Difluoroaniline (600 g) and 1410 g of triethylamine were mixed and, with ice cooling and stirring, 389 g of carbon disulfide was dropped in during 2.5 hours. The mixture was stirred at the same temperature for 2 hours more whereupon crystals gradually appeared. The mixture was gradually warmed up to the room temperature, stirred for 2 hours, and kept in a refrigerator for two nights. Chloroform (2 liters) was added to the reaction mixture in which crystals were solidified, the mixture was stirred to make it suspended, and ethyl chloroformate was dropped in at 10° C. (inner temperature) during 2 hours. The mixture was stirred 3.5 hours more at room temperature. After the reaction, the reaction solution was poured over into ice water, the mixture was made weekly acidic with concentrated hydrochloric acid, and the chloroform layer was collected. This was washed with water, dried and concentrated and the residue was purified by a column chromatography (n-hexane/silica gel) to give 558.6 g of 3,4-difluorophenyl isothiocyanate in colorless oil.
Reaction SMILES: S(Cl)([Cl:3])=O.[N+:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[S:15][C:16]2[C:21]([N:22]=1)=[CH:20][C:19]([CH2:23]O)=[CH:18][N:17]=2)([O-:7])=[O:6].CN(C=O)C>C(Cl)Cl>[Cl:3][CH2:23][C:19]1[CH:20]=[C:21]2[N:22]=[C:14]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[N+:5]([O-:7])=[O:6])[S:15][C:16]2=[N:17][CH:18]=1
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1ccccc1-c1nc2cc(CO)cnc2s1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1-c1nc2cc(CCl)cnc2s1
Reaction time: 1 h
Yield: 95 %

Procedure:
Thionyl chloride (3.1 mol, 227 mL) was slowly added to a room temperature suspension of (2-(2-nitrophenyl)thiazolo[5,4-b]pyridin-6-yl)methanol (0.62 mol, 180 g) in CH2Cl2 (1.8 L). DMF (5 mL) was added and the reaction became homogeneous. The reaction was stirred for 1 h, then concentrated under reduced pressure. The crude product was dissolved in CH2Cl2 (150 mL) and concentrated under reduced pressure. The crude product was chased with hexane (200 mL×3)) and dried under vacuum for 16 h to give 6-(chloromethyl)-2-(2-nitrophenyl)thiazolo[5,4-b]pyridine as a tan solid (180 g, 94% yield).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][NH:14][CH2:13][CH:12]([C:16]([O:18][CH3:19])=[O:17])[CH2:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:27](Cl)(=[O:29])[CH3:28]>ClCCl>[C:27]([N:14]1[CH2:15][CH:10]([C:7]2[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][OH:1])=[CH:9][CH:8]=2)[CH2:11][CH:12]([C:16]([O:18][CH3:19])=[O:17])[CH2:13]1)(=[O:29])[CH3:28]
Reactant: COC(=O)C1CNCC(c2ccc(CCO)cc2)C1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CC(c2ccc(CCO)cc2)CN(C(C)=O)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 5.58 g (9.33 mmol, purity 44%) of the compound from Example 56A in dichloromethane (80 ml) was admixed with 2.60 ml (1.89 g, 18.7 mmol) of triethylamine and then cooled to 0° C. At this temperature, 0.33 ml (0.37 g, 4.67 mmol) of acetyl chloride was added dropwise and the mixture was stirred for 2 h. A further 0.13 ml (0.15 g, 1.86 mmol) of acetyl chloride was added and the mixture was stirred for 1 h. Subsequently, the reaction solution was washed with aqueous 1 N hydrochloric acid, and the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by means of column chromatography (silica gel, dichloromethane/methanol 30:1), and the crude product obtained was purified once more by means of preparative HPLC. Yield: 1.17 g (41% of theory)