Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=[O:11].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C1COCC1.C(OCC)(=O)C>[O:16]1[CH2:17][CH2:18][N:13]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[CH2:9][C:10]([OH:12])=[O:11])[CH2:14][CH2:15]1
Reactant: O=C(O)Cc1ccccc1CCl
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)Cc1ccccc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.4 %

Procedure:
To a suspension of 2-(2-(chloromethyl)phenyl)acetic acid (2.00 g, 10.8 mmol) in THF (20 mL) was added morpholine (1.89 g, 21.7 mmol) and the solution was stirred at room temperature for 3 hours. The reaction mixture was then diluted with ethyl acetate and extracted with H2O (2×). The aqueous phase was lyophilized and the residue was purified by silica gel chromatography (Biotage/0-10% methanol-CH2Cl2) to give the title compound 2-(2-(Morpholinomethyl)phenyl)acetic acid as a colorless solid (2.22 g, 87%). 1H NMR (400 MHz, CD3OD) δ 7.37-7.44 (m, 3H), 7.29-7.33 (m, 1H), 4.24 (s, 2H), 3.83 (br s, 4H), 3.68 (s, 2H), 3.14 (br s, 4H). LCMS: Anal. Calcd. for C13H17NO3: 235. found: 236 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=2)[C:3]=1[C:18]([OH:20])=O.Cl.C(N=C=NCCCN(C)C)C.[F:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:36][CH:35]=1>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:15])([F:16])[F:17])[CH:8]=2)[C:3]=1[C:18]([N:43]1[CH2:42][CH2:41][N:40]([C:37]2[CH:36]=[CH:35][C:34]([F:33])=[CH:39][CH:38]=2)[CH2:45][CH2:44]1)=[O:20]
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: Nc1onc(-c2cccc(OC(F)(F)F)c2)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Nc1onc(-c2cccc(OC(F)(F)F)c2)c1C(=O)N1CCN(c2ccc(F)cc2)CC1
Yield: 73.4 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(3-(trifluoromethoxy)phenyl)isoxazol-4-carboxylic acid (530 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(4-fluorophenyl)piperazine (332 mg, 1.84 mmol), a white solid required compound (609 mg, 1.35 mmol, 73%) was obtained.
Reaction SMILES: COC1C=CC(C([NH:18][C:19]2[N:27]=[C:26]([Cl:28])[N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][N:23]3[C@@H:29]2[CH2:33][C@H:32]([N:34](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C@@H:31]([OH:49])[C@H:30]2[OH:50])C2C=CC(OC)=CC=2)=CC=1.[C:51]([OH:57])([C:53]([F:56])([F:55])[F:54])=[O:52]>ClCCl>[F:54][C:53]([F:56])([F:55])[C:51]([OH:57])=[O:52].[NH2:34][C@H:32]1[CH2:33][C@@H:29]([N:23]2[CH:22]=[N:21][C:20]3[C:24]2=[N:25][C:26]([Cl:28])=[N:27][C:19]=3[NH2:18])[C@H:30]([OH:50])[C@@H:31]1[OH:49]
Reactant: COc1ccc(C(Nc2nc(Cl)nc3c2ncn3[C@@H]2C[C@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)[C@@H](O)[C@H]2O)c2ccc(OC)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(Cl)nc2c1ncn2[C@@H]1C[C@H](N)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(1R,2S,3R,5S)-3-(6-{[Bis-(4-methoxy-phenyl)-methyl]-amino}-2-chloro-purin-9-yl)-5-(di-Boc-amino)-cyclopentane-1,2-diol (600 mg, 0.84 mmol) is dissolved in dichloromethane (4 ml). TFA (2 ml) is added and the reaction mixture is stirred at room temperature. The reaction is shown to be complete by LCMS after 18 hours. The solvent is removed in vacuo and the title compound is obtained after purification by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water—0.1% TFA). 1H nmr (MeOD, 400 MHz); 8.10(s, 1H), 4.80(m, 1H), 4.60(m, 1H), 4.30(m, 1H), 3.60(m, 1H), 2.85(m, 1H), 2.30(m, 1H). MS (ES+) m/e 285 (MH+).
Reaction SMILES: C(O)(=O)C1C=CC=CC=1.[NH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]2[N:22]([CH2:23][C:24]3[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=3[C:26]#[N:27])[C:21](=[O:32])[N:20](C)[C:19](=[O:34])[CH:18]=2)[CH2:12]1.[ClH:35]>C1COCC1.O1CCOCC1>[NH2:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]2[N:22]([CH2:23][C:24]3[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=3[C:26]#[N:27])[C:21](=[O:32])[NH:20][C:19](=[O:34])[C:18]=2[Cl:35])[CH2:12]1
Reactant: Cl
Reactant: Cn1c(=O)cc(N2CCCC(N)C2)n(Cc2ccccc2C#N)c1=O
Agent: O=C(O)c1ccccc1
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: N#Cc1ccccc1Cn1c(N2CCC[C@@H](N)C2)c(Cl)c(=O)[nH]c1=O

Procedure:
Compound 4 (100 mg) in THF (2 mL) was treated with 4M HCl in dioxane (1 mL) at rt for 1 h, concentrated, and then purified by LC-MS to give the title compound. 1H-NMR (400 MHz, DMSO-D6): δ ppm 12.0 (s, 1H), 7.88 (d, J=7.6 Hz, 1H), 7.68 (t, J=7.7 Hz, 1H), 7.49 (t, J=7.7 Hz, 1H), 7.36 (d, J=7.8 Hz, 1H), 5.09-5.21 (m, 2H), 3.17 (m, 2H), 2.96 (t, J=11.1 Hz, 1H), 2.86 (d, J=10.6 Hz, 1H), 2.65 (m, 1H), 1.90 (d, J=11.6 Hz, 1H), 1.57 (d, J=13.1 Hz, 1H), 1.19-1.31 (m, 1H), 1.03-1.15 (m, 1H). MS (ES) [m+H] calc'd for C17H19ClN5O2, 360.1; found, 360.1.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]([CH3:16])=[C:10]([C:12](=[O:15])[CH2:13]Br)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1([CH:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:30]1([CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:24]2[CH2:25][CH2:26][N:27]([CH2:13][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[NH:8][C:9]=3[CH3:16])=[O:15])[CH2:28][CH2:29]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: Cc1[nH]c(-c2ccccc2)nc1C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1[nH]c(-c2ccccc2)nc1C(=O)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reaction time: 8 h

Procedure:
10 Grams (0.036 mol) of 2-phenyl-4-(2-bromoethanoyl)-5-methyl-1H-imidazole and 8.5 grams (0.034 mol) of N-(diphenylmethyl)piperazine and 5 grams (0.036 mol) of potassium carbonate were added to 300 ml of ethanol. The mixture was refluxed under stirring overnight. After cooling, the salts were removed by filtration and the solvent was removed under reduced pressure. The residue was extracted by dichloromethane and washed twice with water. The organic layer was dried over sodium sulfate and evaporated. Trituration of the residue with ethanol gave a white precipitate, 1-diphenylmethyl-4-[2-(2-phenyl-5-methyl-1H-imidazol-4-yl)-2-oxoethyl]piperazine, which was used in the next reaction step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:14])=O>>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: Cc1ccc(F)c(C(=O)O)c1
Reactant: O=S(Cl)Cl
Product: Cc1ccc(F)c(C(=O)Cl)c1

Procedure:
A mixture of 2-fluoro-5-methylbenzoic acid (41.05 g, 0.266 mol) in thionyl chloride (200 mL) is refluxed for 45 min., during which time it becomes homogeneous. After cooling, the thionyl chloride is evaporated to yield 2-fluoro-5-methylbenzoyl chloride, as a yellow liquid, which is dissolved in CH2Cl2 (500 mL), and cooled to 0° C. To this solution is added 2-(trimethylsilyl)-ethanol (48.65 mL, 40.14 g, 0.34 mol), followed by triethylamine (85.86 g, 118.3 mL, 0.85 mol), and the solution is warmed to room temp. over 1 h. The solution is then washed with 1 N HCl (2×500 mL), water (1×250 mL) and brine (1×100 mL), dried (MgSO4), evaporated and chromatographed (silica, 5% EtOAc/hexane) to yield (2-trimethylsilyl)-ethyl 2-fluoro-5-methylbenzoate, as a yellow oil.
Reaction SMILES: [C:1]1([C:5]([OH:7])=[O:6])[CH2:4][CH2:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[Cl:14][CH2:15][CH2:16][CH2:17][CH2:18]O.C(N(CC)CC)C.C1(C(Cl)=O)CCC=1>C(Cl)Cl>[Cl:14][CH2:15][CH2:16][CH2:17][CH2:18][O:6][C:5]([C:1]1[CH2:4][CH2:3][CH:2]=1)=[O:7]
Reactant: O=C(O)C1=CCC1
Reactant: OCCCCCl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(Cl)C1=CCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCCCCCl)C1=CCC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 38.2 %

Procedure:
Cyclobut-1-enecarboxylic acid (2.04 mmol, 200 mg) was dissolved in 1.5 mL dry CH2Cl2. The solution was cooled to 0° C. and oxalyl dichloride (4.08 mmol, 345 μL) was added. The temperature of the solution was raised to rt, and the mixture was allowed to react for 1 h. The solvent was evaporated to generate a viscous oil. 4-chlorobutanol (1.36 mmol, 148 mg) and triethylamine (2.72 mmol, 379 μL) were dissolved in 1.0 mL dry CH2Cl2, and the solution was stirred at 0° C. for 45 min before being added to a vial containing cyclobut-1-enecarboxylic chloride. The reaction mixture was stirred for 16 h at rt. The CH2Cl2 solution was concentrated by rotary evaporation, and then purified by flash column chromatography (60% CH2Cl2/pentane) to yield 21 as a colorless oil (98 mg, 38%). 1H-NMR (500 MHz, CDCl3) δ 6.73 (s, 1H), 4.11 (t, J=6.0 Hz, 2H), 3.54 (t, J=6.0 Hz, 2H), 2.68 (t, J=6.0 Hz, 2H), 2.43 (m, 2H), 1.81 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 162.27, 146.69, 138.71, 63.31, 44.58, 29.31, 29.20, 27.20, 26.20.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[CH3:15])[N:5]=[C:4]([CH3:16])[N:3]=1.[NH2:17][C:18]1[CH:26]=[C:25]2[C:21]([CH:22]=[N:23][NH:24]2)=[CH:20][CH:19]=1>>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([CH3:15])=[C:8]([C:6]2[N:5]=[C:4]([CH3:16])[N:3]=[C:2]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([CH:22]=[N:23][NH:24]4)=[CH:20][CH:19]=3)[CH:7]=2)[CH:13]=1
Reactant: Cc1nc(Cl)cc(-c2cc(Cl)ccc2C)n1
Reactant: Nc1ccc2cn[nH]c2c1
Product: Cc1nc(Nc2ccc3cn[nH]c3c2)cc(-c2cc(Cl)ccc2C)n1
Yield: 64 %

Procedure:
Following the method described in Example 38 (alternate method), 4-chloro-6-(5-chloro-2-methyl-phenyl)-2-methyl-pyrimidine and 6-aminoindazol provided the title compound (64% yield). 1H NMR (DMSO-d6) δ 2.32 (s, 3H, CH3), 2.57 (s, 3H, CH3), 6.78 (s, 1H, Ar), 7.18 (dd, 1H, J=8.7 Hz, J=1.6 Hz, Ar), 7.36 (d, 1H, J=8.2 Hz, Ar), 7.43 (dd, 1H, J=8.2 Hz, J=2.3 Hz, Ar), 7.49 (d, 1H, J=2.2 Hz, Ar), 7.69 (d, 1H, J=8.6 Hz, Ar), 7.97 (s, 1H, Ar), 8.33 (s, 1H, Ar), 9.75 (s, 1H, NH), 12.89 (s, 1H, NH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:29][CH3:30])[C:12]([NH:17][C@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH3:28])=[N:13][C:14]=1[CH2:15][CH3:16].ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC.BrC[CH2:62][F:63]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:29][CH3:30])[C:12]([NH:17][C@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH2:62][F:63])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@H]1c2ccccc2C[C@@H]1OC
Reactant: FCCBr
Agent: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@H]1c2ccccc2C[C@@H]1O
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@H]1c2ccccc2C[C@@H]1OCCF

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine but substituting (1S,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and 1-bromo-2-fluoroethane and making non-critical variations provided the title compound as a solid: MS (ESI+) for C25H26Cl2FN3O m/z 475 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][OH:13])=[CH:7][CH:6]=1.[C:18](Cl)(=[O:21])[CH2:19][CH3:20].O.[C:24]1(C)[CH:29]=CC=C[CH:25]=1>>[C:18]([O:13][CH2:12][CH2:11][C:8]1[CH:7]=[CH:6][C:5]([N:4]2[C:3]3[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=3[N:1]=[C:25]2[CH2:24][CH3:29])=[CH:10][CH:9]=1)(=[O:21])[CH2:19][CH3:20]
Reactant: CCC(=O)Cl
Reactant: Cc1ccccc1
Reactant: Nc1ccccc1Nc1ccc(CCO)cc1
Solvent: O
Product: CCC(=O)OCCc1ccc(-n2c(CC)nc3ccccc32)cc1
Yield: 58 %

Procedure:
To a stirred suspension of 2-[4-(2-aminoanilino)phenyl]ethanol (1.6 g, 7 mmol) in toluene (70 mL) was added propionyl chloride (1.5 g, 16 mmol) dropwise at 0° C., and the reaction mixture was heated at reflux temperature for 2 h. After cooling, the mixture was poured into water (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with 2N aqueous NaOH (50 mL) and brine (50 mL), then dried (MgSO4). Removal of solvent gave 1.3 g (58%) of the title compound as brown solids: MS (EI) m/z 322 (M+)
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]1[CH2:16][CH2:15][CH:14]([CH2:17][C@H:18]([NH2:22])[C:19]([OH:21])=O)[CH2:13][CH2:12]1.[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH2:33][CH2:34][NH2:35])[CH2:28][CH2:27]2>>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:22][C@@H:18]([CH2:17][CH:14]1[CH2:13][CH2:12][CH2:11][CH2:16][CH2:15]1)[C:19]([NH:35][CH2:34][CH2:33][N:29]1[C:30]2[C:26](=[CH:25][C:24]([F:23])=[CH:32][CH:31]=2)[CH2:27][CH2:28]1)=[O:21]
Reactant: NCCN1CCc2cc(F)ccc21
Reactant: N[C@@H](CC1CCCCC1)C(=O)O
Reactant: Clc1nc2ccccc2s1
Product: O=C(NCCN1CCc2cc(F)ccc21)[C@H](CC1CCCCC1)Nc1nc2ccccc2s1

Procedure:
The title compound was prepared from 2-chlorobenzothiazole, L-cyclohexylalanine and 2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylamine using the procedure analogous to that described in example 2. HPLC-MS calcd. for C26H31FN4OS (M+H+) 467.22, found 467.5.
Reaction SMILES: [N+:1]([C:4]1[NH:8][N:7]=[C:6]([CH2:9][C:10]([OH:12])=O)[N:5]=1)([O-:3])=[O:2].[CH2:13]([C@@H:20]1[NH:25][CH2:24][CH2:23][N:22]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH:35]3[CH2:38][CH2:37][CH2:36]3)[CH:27]=2)[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([C@H:20]1[CH2:21][N:22]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH:35]3[CH2:38][CH2:37][CH2:36]3)[CH:27]=2)[CH2:23][CH2:24][N:25]1[C:10](=[O:12])[CH2:9][C:6]1[N:5]=[C:4]([N+:1]([O-:3])=[O:2])[NH:8][N:7]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Reactant: O=C(O)Cc1n[nH]c([N+](=O)[O-])n1
Product: COc1ccc(N2CCN(C(=O)Cc3n[nH]c([N+](=O)[O-])n3)[C@@H](Cc3ccccc3)C2)cc1OC1CCC1

Procedure:
Prepared by the method outlined for Example 189 using (5-Nitro-1H-[1,2,4]triazol-3-yl)-acetic acid and 3(S)-benzyl-1-(3-cyclobutoxy-4-methoxy-phenyl)-piperazine (Example 7, Compound 95) as starting materials to afford product as an oil. LC/MS (Method B) 3.18 min, [M+1]+ 507. Potency class B.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C([Li])CCC.[CH2:14]([CH:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)[CH2:15][CH2:16][CH2:17][CH3:18].Cl>C1(C)C=CC=CC=1.CCCCCC>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:22]2[CH2:23][CH2:24][CH:19]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:20][CH:21]=2)=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: CCCCCC1CCC(=O)CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCCCCC1CC=C(c2ccc(Br)cc2)CC1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
236 Grams (1 mol) of p-dibromobenzene and 1 l of dry toluene were introduced into a three-neck flask in dry nitrogen atmosphere to carry out dissolution with stirring at 50° C. To the resulting solution was dropwise added 525 ml of a hexane solution of 1.67 N commercial n-butyllithium (0.88 mol), over 30 minutes. After dropping, the temperature was maintained at 50° C. further for 30 minutes, and then lowered down to 25° C. To this solution was dropwise added a solution obtained by dissolving 135 g (0.8 mol) of 4-n-pentylcyclohexanone in 125 ml of toluene, over 30 minutes, followed by continuing stirring for 30 minutes at 30° C., and then 250 ml of 6 N hydrochloric acid was added dropwise while maintaining the temperature at 30° C. or lower (the first step). The resulting organic layer was separated, 25 g of potassium hydrogen sulfate was added thereto, and after hexane was distilled off with stirring, the resulting residue was concentrated until the liquid temperature reached 110° C. to complete the dehydration reaction (the second step). The resulting concentrate was distilled under a reduced pressure to take a fraction of 160°~170° C./1 mm Hg, whereby there was obtained 160 g of 1-(p-bromophenyl)-4-n-pentylcyclohexene (R=n-C5H11 and n=1 in said formula (B)) (yield: 62.4%), which was then twice recrystallized from ethanol to give a crystal having a melting point of 67°~68° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:13](Cl)([O:15]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1>C(#N)C.C(Cl)Cl>[Cl:11][C:10]1[C:2]2[NH:1][C:13](=[O:15])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1c(Cl)cccc1C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CC#N
Product: O=c1[nH]c2c(Cl)cccc2c(=O)o1
Temperature: 55 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 2-amino-3-chlorobenzoic acid (0.86 g, 5.00 mmol) in anhydrous acetonitrile (10 mL), a solution of triphosgene (0.49 g, 1.65 mmol) in anhydrous CH2Cl2 (5 mL) and anhydrous pyridine (0.79 g, 10.0 mmol) were added, drop-wise at 55° C., simultaneously over a period of 10 minutes. After the addition was complete, the reaction mixture was stirred at 55° C. for another 2 hours. The solvents were removed under vacuum and water (50 mL) was added. The separated solid was filtered, washed with water, followed by chilled CH2Cl2 (10 mL) and dried under vacuum to give 8-chloro-1H-benzo[d][1,3]oxazine-2,4-dione as an off-white solid. Yield 0.82 g (83%).
Reaction SMILES: [H-].[Na+].[CH:3]1[CH:4]=[CH:5][N:6]2[CH2:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[N:9]([C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:35])[C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=4[Cl:34])=[CH:21][CH:20]=3)=[O:18])[CH2:8][C:7]=12.[I-].C[CH:38]=[N+:39]=[CH:40]C.O1CCC[CH2:43]1>C(OCC)C>[CH3:38][N:39]([CH2:40][N:25]([C:22]1[CH:21]=[CH:20][C:19]([C:17]([N:9]2[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[CH2:12][N:6]3[CH:5]=[CH:4][CH:3]=[C:7]3[CH2:8]2)=[O:18])=[CH:24][CH:23]=1)[C:26](=[O:35])[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[Cl:34])[CH3:43]
Reactant: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1ccc(Cl)cc1Cl
Reactant: C1CCOC1
Reactant: CC=[N+]=CC
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOCC
Product: CN(C)CN(C(=O)c1ccc(Cl)cc1Cl)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension under argon of 0.072 g of sodium hydride (60% in oil) in 10 ml of tetrahydrofuran is added 0.71 g of N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2,4-dichlorobenzamide and the mixture stirred at room temperature for 1 hour. To the mixture is added N,N-dimethylmethyleneammonium iodide and the mixture stirred 20 hours. The mixture is diluted with diethyl ether (30 ml), filtered and the filtrate concentrated under vacuum. The residue is triturated with hexane to give 0.76 g of white solid, m.p. 126°-129° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]2[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=2)=[CH:5][CH:4]=1.C(Cl)Cl.[OH:35][CH:36]([CH2:41][CH3:42])[C:37]([O:39][CH3:40])=[O:38].C(N(CC)CC)C>CCOCC>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([O:35][CH:36]([C:37]([O:39][CH3:40])=[O:38])[CH2:41][CH3:42])=[O:28])=[CH:25][CH:24]=2)=[CH:5][CH:4]=1
Reactant: CCC(O)C(=O)OC
Reactant: O=C(Cl)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCC(OC(=O)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 10.0 g. 4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoyl chloride hydrochloride in 200 ml. methylene chloride added dropwise a solution of 3 g. methyl α-hydroxybutyrate and 5 g. triethylamine in 100 ml. ether. After 17 hours stirring at room temperature, the precipitate is collected and washed with several portions of ether. The ether solution is washed with water, dried and evaporated to yield 1-(methoxycarbonyl)propyl 4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoate as a white solid.
Reaction SMILES: [C:1]([C:3](=[C:7](SC)SC)[C:4]([NH2:6])=[O:5])#[N:2].[NH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][CH:14]=1.O.[NH2:23][NH2:24]>CCO>[NH2:2][C:1]1[NH:24][N:23]=[C:7]([NH:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](=[O:18])[NH2:19])=[CH:15][CH:14]=2)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CSC(SC)=C(C#N)C(N)=O
Reactant: NN
Reactant: NC(=O)c1ccc(N)cc1
Solvent: CCO
Solvent: O
Product: NC(=O)c1ccc(Nc2n[nH]c(N)c2C(N)=O)cc1
Temperature: 75 °C

Procedure:
Dissolved 0.500 g 2-cyano-3,3-bis(methylthio)acrylamide in 15 mL EtOH and added 4-Aminobenzamide (1.0 eq.). Stirred reaction at 75° C. until starting amide was absent by HPLC. Once complete (18 hrs), reaction was brought to room temperature and filtered to obtain a light yellow powder as product. Product was allowed to dry under vacuum for 1 hr. Product was then suspended in 10 mL EtOH and hydrazine hydrate (1 eq.) was added dropwise. Reaction was heated at 75° C. until intermediate was absent (HPLC). Once intermediate was absent (18 hrs), reaction was brought to room temperature and filtered to obtain 5-amino-3-((4-carbamoylphenyl)amino)-1H-pyrazole-4-carboxamide as a yellow powder. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:29]N1C(=O)CCC1=O>C(Cl)Cl>[Br:29][CH2:8][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCCc1cccs1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCc1cccs1
Yield: 40.8 %

Procedure:
Compound 46-2 (1.29 g) was dissolved in methylene chloride (30 ml), triphenylphosphine (2.62 g) and N-bromosuccinimide (1.76 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (50 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (760 mg) as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH2:20]O)[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:23].C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOCC>C(Cl)Cl>[Br:23][CH2:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[O:13][CH2:12][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cccc(OCc2ccc3ccc(Cl)cc3n2)c1
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: Clc1ccc2ccc(COc3cccc(CBr)c3)nc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
To the benzylic alcohol of Step 2 (47.0 g, 157 mmol) and CBr4 (60.08 g, 181 mmol) in CH2Cl2 (750 mL) at 0° C., a solution of 1,2-bis(diphenylphosphino) ethane (DIPHOS, 36.29 g, 91.1 mmol) in CH2Cl2 (350 mL) was added and the resulting mixture was stirred at 0° C. for 45 min. and at r.t. for 30 min. Ether was then added and the mixture was filtered through a pad of silica and the silica was washed with EtOAc:toluene 20:80 to yield 40.35 g (70%) of the pure title compound.