Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][NH2:12])[N:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7]=2[CH:19]=1.[NH2:20][C:21]1[C:26]([C:27]#[N:28])=[C:25](Cl)[N:24]=[CH:23][N:22]=1.C(N(CC)CC)C>C(O)(C)C>[NH2:20][C:21]1[C:26]([C:27]#[N:28])=[C:25]([NH:12][CH2:11][C:9]2[N:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7]3[CH:19]=[C:3]([F:2])[CH:4]=[CH:5][C:6]=3[N:10]=2)[N:24]=[CH:23][N:22]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: NCc1nc2ccc(F)cc2n1-c1ccccc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: N#Cc1c(N)ncnc1NCc1nc2ccc(F)cc2n1-c1ccccc1
Yield: 48.7 %

Procedure:
(6-Fluoro-1-phenyl-1H-benzoimidazol-2-yl)methylamine hydrochloride (0.113 g, 0.4 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (0.123 g, 0.8 mmol), triethylamine (0.28 mL, 2 mmol) in isopropanol (2 mL) was heated to 80° C. in a sealed tube for 2 h. After cooling the pink solid was removed by filtration and washed with isopropanol (0.5 mL). This material was purified by column chromatography (Si—PCC, gradient 0-4% MeOH in DCM). Product containing fractions were evaporated to a white solid. This was triturated with diethyl ether and dried to give 371 as a white solid, (70 mg, 69%). LCMS (Method C): RT 3.54 min [M+H]+ 360.02. 1H NMR δ (ppm) (DMSO-d): 7.87 (1H, s), 7.69 (1H, t, J=5.2 Hz), 7.65 (1H, dd, J=8.80, 4.87 Hz), 7.64-7.46 (5H, m), 7.22 (2H, s), 7.06 (1H, ddd, J=9.86, 8.79, 2.53 Hz), 6.87 (1H, dd, J=8.97, 2.51 Hz), 4.62 (2H, d, J=5.37 Hz)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[C:14]([NH2:23])[C:13]=2[N:12]=[C:11]1[CH2:24][CH2:25][CH2:26][CH3:27].[C:28]1([N:34]=[C:35]=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[NH2:23][C:14]1[C:13]2[N:12]=[C:11]([CH2:24][CH2:25][CH2:26][CH3:27])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:35]([NH:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:36])[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCN
Reactant: O=C=Nc1ccccc1
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCNC(=O)Nc1ccccc1

Procedure:
Using the general method of Example 145, 1-(8-aminooctyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (1.2 g, 3.26 mmol) was reacted with phenyl isocyanate to provide 1.59 g of N-[8-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)octyl]-N′-phenylurea as an off white powder, m.p. 153–155° C. Analysis: Calculated for C29H38N6O. 0.20 H2O: % C, 71.05; % H, 7.89; % N, 17.14; Found: % C, 70.86; % H, 7.97; % N, 16.87. 1H NMR (300 MHz, DMSO-d6) δ 8.34 (s, 1H), 8.01 (d, J=7.8 Hz, 1H), 7.61 (dd, J=8.3, 1.0 Hz, 1H), 7.43–7.36 (m, 3H), 7.26–7.17 (m, 3H), 6.87 (t, J=7.3 Hz, 1H), 6.49 (s, 2H), 6.08 (m, 1H), 4.49 (m, 2H), 3.05 (m, 2H), 2.91 (m, 2H), 1.80 (m, 4H), 1.43–1.29 (m, 12H), 0.95 (t, J=7.3 Hz, 3H);
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([CH:15]([F:17])[F:16])[N:12]3[N:18]=[CH:19][C:20]([C:21](O)=[O:22])=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:24][C:25]1[CH:26]=[C:27]([S:31]([NH:34][CH:35]2[CH2:37][CH2:36]2)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1>>[CH:35]1([NH:34][S:31]([C:27]2[CH:26]=[C:25]([NH:24][C:21]([C:20]3[CH:19]=[N:18][N:12]4[C:13]([CH:15]([F:16])[F:17])=[CH:14][C:9]([C:4]5[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=5)=[N:10][C:11]=34)=[O:22])[CH:30]=[CH:29][CH:28]=2)(=[O:33])=[O:32])[CH2:37][CH2:36]1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12
Reactant: Nc1cccc(S(=O)(=O)NC2CC2)c1
Product: O=C(Nc1cccc(S(=O)(=O)NC2CC2)c1)c1cnn2c(C(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12

Procedure:
The title compound was prepared from 5-(3,4-dichloro-phenyl)-7-difluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.7) and 3-amino-N-cyclopropyl-benzenesulfonamide [CAS 459434-39-0] according to general procedure II. Light yellow solid. MS (ISP) 550.0 [(M−H)−]; mp 254° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:25])=[C:6]([CH:24]=1)[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:9]=1.[C:26]1([CH3:35])[CH:31]=[CH:30][C:29]([C:32](Cl)=[O:33])=[CH:28][CH:27]=1.O>N1C=CC=CC=1>[CH3:35][C:26]1[CH:31]=[CH:30][C:29]([C:32]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH3:25])=[C:6]([NH:7][C:8]3[CH:13]=[C:12]([C:14]([F:16])([F:17])[F:15])[N:11]=[C:10]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[N:9]=3)[CH:24]=2)=[O:33])=[CH:28][CH:27]=1
Reactant: Cc1ccc(N)cc1Nc1cc(C(F)(F)F)nc(-c2ccncc2)n1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(C(=O)Nc2ccc(C)c(Nc3cc(C(F)(F)F)nc(-c4ccncc4)n3)c2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 94 %

Procedure:
A mixture of 4-(5-amino-2-methylanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (20 mg, 0.058 mmol) and p-toluoyl chloride in pyridine (5 ml) was stirred at room temperature for 15 h. Then water was added to the mixture. The resulting precipitate was filtered, washed with excess water and dried to give a tan solid (26 mg, 94%). 1H NMR (CDCl3): 8.77 (dd, J=1.8, 4.5 Hz, 2H), 8.29 (dd, J=1.8, 4.5 Hz, 2H), 8.00 (s, 1H), 7.83 (s, 1H), 7.78 (d, J=8.1 Hz, 2H), 7.38 (dd, J=2.1, 8.4 Hz, 1H), 7.34 (s, 1H), 7.31 (d, J=7.5 Hz, 2H), 7.01 (s, 1H), 6.73 (s, 1H), 2.44 (s, 3H), 2.29 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:7]([C:6]2[CH:10]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[N+:11]([O-:13])=[O:12])=[O:9])=[N:16][CH:17]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Cl)cn1)c1cc(F)ccc1[N+](=O)[O-]
Yield: 72 %

Procedure:
A solution of 5-fluoro-2-nitrobenzoic acid (10.0 g, 54 mmol, 1.0 equiv.), 2-amino-5-chloropyridine (9.02 g, 1.3 equiv.), in 80 mL of pyridine was treated with phosphorous oxychloride (25.3 g, 3.0 equiv.) for 30 minutes. The volatile was evaporated and the residue was redissolved into EtOAc, washed with 1N HCl, saturated aqueous NaHCO3 and saturated aqueous NaCl. The organic layer was dried over Na2SO4, filtered, and evaporated. The product was triturated with diethyl ether to give N-(5-chloro-2-pyridinyl)-(2-nitro)-5-fluorophenylcarboxamide (11.5 g, 72%). MS found for C12H7ClFN3O'(M+H)+: 296, (M+2+H): 298.
Reaction SMILES: [Na].[CH3:2][C:3]1[C:8]([O:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:7]([CH2:15][O:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:6]([CH2:22]Cl)=[CH:5][N:4]=1.[SH2:24]>CN(C)C=O>[CH3:2][C:3]1[C:8]([O:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:7]([CH2:15][O:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:6]([CH2:22][SH:24])=[CH:5][N:4]=1
Reactant: S
Reactant: CCOC(=O)OCc1c(CCl)cnc(C)c1OC(=O)OCC
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOC(=O)OCc1c(CS)cnc(C)c1OC(=O)OCC

Procedure:
A solution of 0.4 moles sodium in absolute dimethylformamide is saturated by passing in hydrogen sulfide for 5 hours. There is then added in portions 0.05 moles of 2-methyl-3-ethoxycarbonyloxy-4-ethoxycarbonyloxymethyl-5-chloromethylpyridine and the mixture stirred overnight at room temperature with hydrogen sulfide slowly bubbling through the mixture. The reaction mixture is then concentrated in vacuo and taken up between ethyl acetate and water containing acetic acid. The ethyl acetate layer is removed, dried over sodium sulfate and concentrated to give 2-methyl-3-ethoxycarbonyloxy-4-ethoxycarbonyloxymethyl-5-mercaptomethylpyridine.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:15](=[O:26])[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O.C([O-])([O-])=O.[Na+].[Na+]>ClCCl>[NH2:7][CH:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]([NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=1)=[O:26]
Reactant: CC(C)(C)OC(=O)NC(C(=O)NCc1ccc(C#N)cc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(CNC(=O)C(N)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 100.2 %

Procedure:
A solution of give (RS)-[(4-cyano-benzylcarbamoyl)-phenyl-methyl]-carbamic acid tert-butyl ester (0.77 g, example 86.1) in dichloromethane (20 ml) was cooled to 0° C. and treated with trifluoro acetic acid (5 ml). The reaction mixture was stirred at rt for 5 hrs, then diluted with dichloromethane, cooled to 0° C. and brought to pH 9 by dropwise addition of saturated aqueous Na2CO3. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give (RS)-2-amino-N-(4-cyano-benzyl)-2-phenyl-acetamide (0.56 g). Off-white amorphous solid. MS 266.2 ([M+H]+)
Reaction SMILES: CN([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)CCCCCCCCCCCO.[N+:23]([C:26]1[CH:31]=[CH:30][C:29]([NH:32][NH2:33])=[CH:28][CH:27]=1)([O-:25])=[O:24].C(O)(=O)C>O>[N+:23]([C:26]1[CH:27]=[CH:28][C:29]([NH:32][N:33]=[CH:19][C:18]2[CH:17]=[CH:16][CH:15]=[CH:22][CH:21]=2)=[CH:30][CH:31]=1)([O-:25])=[O:24]
Reactant: CN(CCCCCCCCCCCO)c1ccc(C=O)cc1
Reactant: NNc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(NN=Cc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
A mixture of 8.62 g of 4-[N-methyl-N-(11-hydroxyundecyl)-amino]-benzaldehyde, 4.33 g of 4-nitrophenylhydrazine and 25 ml of glacial acetic acid were [sic] refluxed for 30 minutes and left to stand overnight at room temperature. 70 ml of ice water were added to the resulting reaction mixture and the mixture was stirred thoroughly After the water had been removed from the reaction mixture, the reaction product, which had now precipitated, was separated off and then subjected to preliminary purification by boiling with active carbon in acetone. The prepurified product was then purified by flash chromatography on silica gel, a mixture of hexane and ethyl acetate in a volume ratio of 6:4 being used as the mobile phase. A total of 3.4 g of 4'-N-methyl-N-(11-hydroxyundecyl)-amino]-benzaldehyde-4-nitrophenylhydrazone were obtained, corresponding to a yield of 28% of theory. In its IR spectrum, this product, in the form of a KBr pellet, had bands at 3,400, 3,250, 1,585, 1,510, 1,490, 1,460, 1,320, 1,290, 1,270, 1,170, 1,100, 830 and 810 cm-1.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:7][N:6]([C:8]([NH:10][CH2:11][CH3:12])=[NH:9])[N:5]=[CH:4]1)[CH3:2].CCN(C(C)C)C(C)C.Cl[S:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1)(=[O:25])=[O:24]>C(Cl)Cl>[CH2:11]([NH:10][C:8](=[N:9][S:23]([C:26]1[CH:27]=[CH:28][C:29]([C:30]([OH:32])=[O:31])=[CH:33][CH:34]=1)(=[O:25])=[O:24])[N:6]1[CH2:7][CH:3]([CH2:1][CH3:2])[CH:4]=[N:5]1)[CH3:12]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCNC(=N)N1CC(CC)C=N1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCNC(=NS(=O)(=O)c1ccc(C(=O)O)cc1)N1CC(CC)C=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.5 %

Procedure:
Under N2 atmosphere, 2.27 g 4,N-diethyl-4,5-dihydro-pyrazole-1-carboxamidine was dissolved in 30 mL dry DCM, and 5.17 ml DiPEA and 2.98 g of 4-(chlorosulfonyl)benzoic acid were added. The mixture was stirred overnight at room temperature and evaporated to dryness. The residue was purified by flash chromatography (first column with DCM/MeOH/NH4OH 92:7.5:0.5; second column with DCM/MeOH/Acetic acid 92:7.5:0.5) to yield 0.26 g (4%) of product (mono-DiPEA salt) as an off-white amorphous powder. 1H NMR (400 MHz, CDCl3) δ 0.98 (t, J=7.4 Hz, 3H), 1.27 (t, J=7.2 Hz, 3H), 1.53-1.81 (m, 2H), 3.15-3.30 (broad peak, 1H), 3.43-3.66 (broad peak, 3H), 4.01-4.20 (broad peak, 1H), 6.97 (br. s., 1H), 7.90 (d, J=8.1 Hz, 2H), 8.14 (d, J=8.1 Hz, 2H), 9.69 (br. s., 1H).
Reaction SMILES: [H-].[Na+].[C@H:3]1([OH:10])[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]1[OH:9].F[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1.[OH-].[Na+]>CN(C=O)C.O>[C@H:3]1([O:10][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]1[O:9][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1
Reactant: O[C@H]1CCCC[C@@H]1O
Reactant: N#Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(O[C@H]2CCCC[C@@H]2Oc2ccc(C#N)cc2)cc1
Reaction time: 8 h
Yield: 83.7 %

Procedure:
Sodium hydride (7.1 g, 0.3 mol) was dispersed in 200 ml DMF and added with (1S,2S)-cyclohexane-1,2-diol (11.42 g, 98.3 mmol) while cooling with ice. The mixture after being cooled with ice for another one hour was reacted at room temperature for 2 hours and cooled again, followed by addition of p-fluorobenzonitrile (25 g, 206 mmol). After the reaction was continued overnight, the mixture was added carefully with 5 ml water to inactivate excess sodium hydroxide, followed by distillation of DMF in pressure. The residue was added with 200 ml water and then extracted with ethyl acetate, followed by washing with a saturated solution of sodium chloride thereby obtaining a coarse crystalline product. The crystalline product was then recrystallized from 200 ml isopropanol thereby obtaining the intended product (26.2 g, 82.3 mmol, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[OH:14].C([O:17][C:18]([C:20]1[N:21]=[C:22]([CH2:25]Br)[S:23][CH:24]=1)=[O:19])C>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[O:14][CH2:25][C:22]1[S:23][CH:24]=[C:20]([C:18]([OH:19])=[O:17])[N:21]=1
Reactant: CCOC(=O)c1csc(CBr)n1
Reactant: Oc1ccc(-c2ccccc2)cc1Cl
Product: O=C(O)c1csc(COc2ccc(-c3ccccc3)cc2Cl)n1

Procedure:
2-(3-Chloro-biphenyl-4-yloxymethyl)-thiazole-4-carboxylic acid was prepared using general procedure B from 2-chloro-4-phenylphenol (available from TCI America, Portland, Oreg.) and 2-bromomethyl-thiazole-4-carboxylic acid ethyl ester (Intermediate 3). Yield: 82 mg. Mass spectrum (ES) MH+=346.
Reaction SMILES: [C:1](OCC)(OCC)(OCC)[CH3:2].[Cl:12][C:13]1[C:22]([NH2:23])=[C:21]([NH:24][CH2:25][C:26]2[O:30][N:29]=[C:28]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH:27]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1>Cl.N1C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:12][C:13]1[C:22]2[N:23]=[C:1]([CH3:2])[N:24]([CH2:25][C:26]3[O:30][N:29]=[C:28]([C:31]4[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=4)[CH:27]=3)[C:21]=2[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:14]=1
Reactant: Nc1c(Cl)nc2ccccc2c1NCc1cc(-c2ccc(F)cc2)no1
Reactant: CCOC(C)(OCC)OCC
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1nc2c(Cl)nc3ccccc3c2n1Cc1cc(-c2ccc(F)cc2)no1
Yield: 61.8 %

Procedure:
Pyridine hydrochloride (0.020 g, 0.19 mmol), triethyl orthoacetate (2.3 g, 14 mmol), 2-chloro-N4-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}quinoline-3,4-diamine (3.5 g, 9.5 mmol), and toluene (50 mL) were combined and treated according to the method of Part A of Example 26 to provide 2.307 g of 4-chloro-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-2-methyl-1H-imidazo[4,5-c]quinoline as a pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH:11]=[CH:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O.S(=O)(=O)(O)O.[H][H]>[Pd].CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(C=CC(=O)c2ccc([N+](=O)[O-])cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1ccc(CCCc2ccc(N)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 67 %

Procedure:
Under an argon atmosphere, to a mixture of 5.0 g of methyl 4-[3-(4-nitrophenyl)-3-oxoprop-1-en-1-yl]benzoate and 150 mL of methanol was added dropwise 5.0 mL of concentrated sulfuric acid under ice-cooling. Under an argon atmosphere, to the reaction mixture was added 500 mg of palladium on carbon under ice-cooling, followed by replacing with hydrogen (3 atm) at room temperature and then stirring at room temperature for 24 hours. The insoluble materials were filtered off on a celite layer and the filtrate was concentrated under reduced pressure. The residue was neutralized by the addition of a saturated aqueous sodium hydrogen carbonate solution under ice-cooling, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform) to obtain 2.9 g of methyl 4-[3-(4-aminophenyl)propyl]benzoate as a pink oil.
Reaction SMILES: C([Li])CCC.C(OCC)C.Br[C:12]1[CH:13]=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2.CN(OC)[C:24](=[O:28])[CH2:25][CH2:26][CH3:27]>C1COCC1>[N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[C:12]([C:24](=[O:28])[CH2:25][CH2:26][CH3:27])[CH:13]=1
Reactant: Brc1cnc2ccccc2c1
Reactant: CCCC(=O)N(C)OC
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCC(=O)c1cnc2ccccc2c1
Temperature: 0 °C
Yield: 58.1 %

Procedure:
In a dry 3-necked flask under argon at -50° C., n-butyl lithium (0.0025 M, 0.021 ml) was added to 150 ml diethylether. Then 4.16 grams 3-bromoquinoline in 2 ml THF was added dropwise while stirring and maintaining the temperature at -60° C. to -55° C. The solution was stirred for 30 minutes, and 2.3 grams N-methyl-N-methoxybutanamide were then added dropwise at -50° C. and the solution was stirred an additional 30 minutes The solution was then allowed to warm to 0° C. and stirred for one hour. The reaction was quenched with a saturated solution of ammonium chloride and the THF layer separated, washed with brine, separated, and dried over magnesium sulfate. Filtration through diatomaceous earth, followed by concentration and subsequent thin layer chromatography (35% ethylacetate/65% CH2Cl2) gave a total yield of 2.03 g (51%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[F:16][C:17]([F:24])([F:23])[C:18]([NH:20][CH2:21]O)=[O:19]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:21][NH:20][C:18](=[O:19])[C:17]([F:24])([F:23])[F:16])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccccc1Cl
Reactant: O=C(NCO)C(F)(F)F
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(CNC(=O)C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.4 %

Procedure:
To a solution of 2-chlorobenzoic acid (500 mg, 3.49 mmol) in cone. H2SO4 was added 2,2,2-trifluoro-N-(hydroxymethyl)acetamide (547 mg, 3.49 mmol). The mixture was stirred at rt for 16 h. The reaction mixture was poured into ice-water and the precipitate obtained, was collected by filtration, dried and the re-crystallized from toluene/butan-2-one (7:1) to afford 800 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 13.47 (br s, 1H), 10.06 (br s, 1H), 7.71 (s, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.43 (d, J=9.9 Hz, 1H), 4.42 (d, J=6.0 Hz, 2H); MS (m/z): 280.18 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:11][CH3:12])[C:5]([CH:6]=O)=[CH:4][N:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:23][C:24](OC)=[O:25])[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]2[C:5]([CH:6]=[C:23]([C:17]3[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=[C:15]([O:14][CH3:13])[CH:16]=3)[C:24](=[O:25])[N:11]2[CH3:12])=[CH:4][N:3]=1
Reactant: COC(=O)Cc1cc(OC)cc(OC)c1
Reactant: CNc1c(C=O)cnc(Cl)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OC)cc(-c2cc3cnc(Cl)c(C)c3n(C)c2=O)c1
Temperature: 105 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
A mixture of 6-chloro-5-methyl-4-(methylamino)nicotinaldehyde (3.11 g, 16.8 mmol), methyl 2-(3,5-dimethoxyphenyl)acetate (4.25 g, 20.2 mmol) and potassium carbonate (2.8 g, 20.3 mmol) in N,N-dimethylformamide (100 mL) was stirred at 105° C. overnight. LCMS monitored the reaction was completed. The reaction mixture was cooled to RT and quenched by water. The precipitate was filtered and dried to get the title compound (5.5 g, crude) as a yellow solid. MS (ES+) C18H17ClN2O3 requires: 344, 346. Found: 345, 347 [M+H]+.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:20][O:21][C:22](=[O:64])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[C:38]([Cl:41])[CH:39]=3)[N:34]([CH:42]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:33]=2[CH2:55][CH2:56][N:57]=[N+]=[N-])=[CH:25][C:24]=1[O:60][CH:61]([CH3:63])[CH3:62].O>C1COCC1>[CH3:20][O:21][C:22](=[O:64])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[C:38]([Cl:41])[CH:39]=3)[N:34]([CH:42]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:33]=2[CH2:55][CH2:56][NH2:57])=[CH:25][C:24]=1[O:60][CH:61]([CH3:62])[CH3:63]
Reactant: COC(=O)c1ccc(OCCc2c(CCN=[N+]=[N-])n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCCc2c(CCN)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1OC(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 20.9 %

Procedure:
Ph3P (polymer support: 3 mmol Ph3P/gram) (0.100 g, 0.30 mmol) was added to a solution of the azide from Step 6 (0.100 g, 0.16 mmol) in THF (2 mL). Reaction was stirred at room temperature for 24 hours. Then water (0.5 mL) was added and reaction was stirred at room temperature overnight. Reaction solution was filtered and the filtrate was concentrated by rotary evaporation. The resulting residue was purified with silica gel prep plates and 2% MeOH in dichloromethane as eluent. Obtained 0.020 g of 4-{2-[2-(2-Amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-2-isopropoxy-benzoic acid methyl ester in 21% yield.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[S:24][C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[NH:13][C:12](=[O:21])[CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:32][CH2:33][N:34]([CH3:36])[CH3:35]>CN(C=O)C.CCOC(C)=O>[CH:1]1([C:7]2[C:8]3[S:24][C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[N:13]([CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[C:12](=[O:21])[CH2:11]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)CCCl
Reactant: COC(=O)c1cc2c(s1)c(C1CCCCC1)c1n2CC(=O)Nc2ccccc2-1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2c(s1)c(C1CCCCC1)c1n2CC(=O)N(CCN(C)C)c2ccccc2-1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution (0.1 M) of methyl 12-cyclohexyl-6-oxo-6,7-dihydro-5H-thieno[2′,3′:4,5]pyrrolo[1,2-d][1,4]benzodiazepine-10-carboxylate (from Step 4) in DMF was treated with sodium hydride (1.5 eq., 60% suspension in mineral oil) at 0° C. and then stirred at RT for 30 min. 2-Chloro-N,N-dimethylethylamine (2.0 eq.) was added and the solution stirred at 45° C. for 2 h. After cooling to RT, the suspension was diluted with EtOAc and washed with water, and brine. The organic phase was dried over sodium sulfate and the solvent evaporated in vacuo to give the title compound as a solid. 1H-NMR (400 MHz, DMSO-d6, 300 K, δ) 8.14 (s, 1H), 7.74-7.45 (m, 4H), 5.04-5.01 (d, J 12, 1H), 4.43-4.40 (d, J 12, 1H), 4.18-4.15 (m, 1H), 3.83 (s, 3H), 3.65-3.61 (m, 1H), 2.90-2.82 (m, 1H), 2.15-2.06 (m, 2H), 1.81-1.23 (m, 10H). MS (ES+) m/z: 466 [M+H]+.