Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[C:11](=[O:22])[N:12]([CH2:15][C:16]3O[CH:19]=[N:18][C:17]=3[CH3:21])[CH2:13][CH2:14][C:3]1=2.C([NH2:25])=O>O>[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[C:11](=[O:22])[N:12]([CH2:15][C:16]3[N:25]=[CH:19][NH:18][C:17]=3[CH3:21])[CH2:13][CH2:14][C:3]1=2
Reactant: Cc1ncoc1CN1CCc2c(c3ccccc3n2C)C1=O
Reactant: NC=O
Solvent: O
Product: Cc1[nH]cnc1CN1CCc2c(c3ccccc3n2C)C1=O

Procedure:
A mixture of 2,3,4,5-tetrahydro-5-methyl-2-[(4-methyloxazol-5-yl)methyl]-1H-pyrido[4,3-b]indol-1-one (100 mg) in formamide (20 ml) was heated at 180° for 24 h. The mixture was then cooled, diluted with water (100 ml) and extracted with dichloromethane (3×100 ml). The combined organic extracts were concentrated in vacuo and the residue was purified by FCC eluting with System A (100:8:1) to give the title compound (40 mg) as a solid. The 1H-n.m.r. and t.l.c. data for this material were consistent with those obtained for the product of Example 20.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13](O)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:13]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:33][CH:34]=2)=[O:14])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=C(O)[C@H](Cc1ccccc1)NS(=O)(=O)c1ccc(Br)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NC(=O)[C@H](Cc2ccccc2)NS(=O)(=O)c2ccc(Br)cc2)cc1

Procedure:
The procedure described in Example 180 was repeated, except that (S)-2-(4-bromobenzenesulfonylamino)-3-phenylpropanoic acid (2 g) and ethyl 4-aminobenzoate were condensed in dichloromethane (100 ml) in the presence of N,N'-dicyclohexylcarbodiimide (1.29 g). The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was recrystallized from a mixture of carbon tetrachloride and ethanol to obtain (S)-2-(4-bromobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-phenylpropanamide (623 mg).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](OCC)=[O:13])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:27]#[N:28])([CH3:26])[CH3:25])=[CH:20][CH:19]=1.C(O)C.[BH4-].[Na+]>ClCCl>[Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([CH2:12][OH:13])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH3:26])([CH3:25])[C:27]#[N:28])=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(C(C)(C)C#N)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C#N)c1ccc(Nc2c(CO)cnc3ccc(Cl)nc23)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Ethyl 6-chloro-4-((4-(2-cyanopropan-2-yl)phenyl)amino)-1,5-naphthyridine-3-carboxylate (8.1 g, 20.5 mmol) was added to a mixed solvent of ethanol (120 mL) and dichloromethane (12 mL), to the system added sodium borohydride (5.4 g, 143 mmol) in batches, stirred at room temperature for 24 h, ethanol was removed under reduced pressure, adjusted pH of the solution to be neutral with 1 N dilute hydrochloric acid and extracted with 200 mL of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting 9.0 g of a crude solid was used directly in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22]=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][N:14]([CH3:22])[CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=O
Reactant: CN1CCC(NC[C@H]2CCN(C(=O)OC(C)(C)C)C2)CC1
Solvent: C1CCOC1
Product: CN1CCC(N(C)C[C@H]2CCN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 90.7 %

Procedure:
To a solution of (R)-3-[(1-methyl-piperidin-4-ylamino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (100 mg, 0.34 mmol) and paraformaldehyde (20 mg, 0.67 mmol) in THF (4 mL) was added MP-(OAc)3BH resin (Argonaut; 2.55 mmol/g; 330 mg, 0.84 mmol) and the reaction mixture was agitated at room temperature for 96 hours. Then, the reaction mixture was filtered and concentrated in vacuo to afford (R)-3-{[methyl-(1-methyl-piperidin-4-yl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (96 mg, 92%) as an orange oil. The residue was used without further purification.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:6]([OH:8])=[O:7].[CH3:15][Si]([Cl:19])(C)C>CO>[ClH:19].[NH2:2][CH2:3][CH2:4][CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:6]([O:8][CH3:15])=[O:7]
Reactant: NCCC(C(=O)O)c1ccccc1
Reactant: C[Si](C)(C)Cl
Agent: Cl
Solvent: CO
Product: COC(=O)C(CCN)c1ccccc1
Temperature: 20 °C
Reaction time: 12 h

Procedure:
A mixture of 1 g (4.64 mmol) of 4-amino-2-phenylbutyric acid hydrochloride and 0.67 ml (5.1 mmol) of trimethylsilyl chloride in 50 ml of methanol is heated at reflux for 2 hours. The mixture is subsequently stirred at 20° C. for 12 hours and then concentrated under reduced pressure, triturated in 50 ml of ethyl ether and then filtered. This gives 0.9 g of the expected product in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH2:13]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)[CH3:14]>>[Cl:1][C:2]1[N:3]([C:18]2[CH:19]=[CH:20][C:15]([CH2:13][CH3:14])=[CH:16][CH:17]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Reactant: CCc1ccc(B(O)O)cc1
Product: CCc1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1
Yield: 73 %

Procedure:
2-Chloro-1H-indole-3-carboxaldehyde is reacted with 4-ethylphenylboronic acid as described in Step 1 of Example 29 to afford 2-chloro-1-(4-ethyl-phenyl)-1H-indole-3-carboxaldehyde (73% yield) as a light yellow solid. ESI/MS 284 (M+H); RT=4.04 min; NMR 10.12 (1H, s); 8.20 (1H, d, J=9 Hz); 7.54 (4H, m); 7.38 (2H, m); 7.28 (1H, d); 2.77 (2H, q); 1.28 (3H, t).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Cl:27])C(=O)C1.CCOC(C)=O>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]2)=[CH:6][C:7]=1[Cl:27]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)C1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c(Cl)c2)C1
Temperature: 70 °C
Reaction time: 1 h
Yield: 51.3 %

Procedure:
To a stirred solution of tert-butyl 3-(4-aminophenyl)pyrrolidine-1-carboxylate (2.00 g, CAS-908334-28-1) in DMF (15 ml) was added NCS (1.07 g) and the mixture was stirred at 70° C. for 1 hour. The reaction mixture was then cooled to room temperature and poured into EtOAc and extracted sequentially with water and with saturated brine. The organic layer was dried over Na2SO4 and then concentrated in vacuo. The residue was purified by column chromatography (SiO2, gradient: 0% to 55% EtOAc in hexanes) to afford tert-butyl (RS)-3-(4-amino-3-chlorophenyl)pyrrolidine-1-carboxylate (1.16 g, 51%) as a yellow oil which was used in the next step without further purification. MS (ISP): 299.0 ([{37Cl}M+H]+), 297.2 ([{35Cl}M+H]+), 243.0 ([{37Cl}M+H—C4H8]+), 241.1 ([{35Cl}M+H—C4H8]+).
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[C@@H:11]2[C@@:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])([N:7]=[C:8]([NH2:12])[S:9][CH2:10]2)[CH2:5][O:4]1.S(=O)(=O)(O)O.[N+:25]([O-])([OH:27])=[O:26].[OH-].[Na+]>C(O)(C(F)(F)F)=O.C(Cl)(Cl)Cl>[F:19][C:14]1[CH:15]=[CH:16][C:17]([N+:25]([O-:27])=[O:26])=[CH:18][C:13]=1[C@:6]12[CH2:5][O:4][C@H:3]([CH2:2][F:1])[C@H:11]1[CH2:10][S:9][C:8]([NH2:12])=[N:7]2
Reactant: NC1=N[C@@]2(c3ccccc3F)CO[C@H](CF)[C@H]2CS1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: NC1=N[C@@]2(c3cc([N+](=O)[O-])ccc3F)CO[C@H](CF)[C@H]2CS1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.1 %

Procedure:
(4aS,5S,7aS)-5-(fluoromethyl)-7a-(2-fluorophenyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine (45.85 g, 161.26 mmol) was dissolved in TFA (192 mL), and the solution was cooled to 0° C. Sulfuric acid (conc., 33.65 mL, 161.26 mmol) was added, followed by fuming nitric acid (7.78 mL, 185.44 mmol) dropwise over 25 mins. After stirring at 0° C. for 30 mins, the reaction mixture was poured onto ice (500 g)/CHCl3 (500 mL) and basified to pH 12 with 6N NaOH (aq.). The two layers were separated and the aqueous layer was extracted with CHCl3 (2×500 mL). The combined organic extracts were dried over MgSO4 and concentrated to give the product as a light orange foam (52.11 g, 98%). 1H NMR (400 MHz, CDCl3) δ ppm 2.80 (dd, J=13.26, 3.92 Hz, 1H) 3.03 (dt, J=7.77, 3.82 Hz, 1H) 3.08 (dd, J=13.39, 3.28 Hz, 1H) 3.85 (dd, J=8.84, 2.27 Hz, 1H) 4.49-4.67 (m, 4H) 7.22 (dd, J=10.99, 8.97 Hz, 1H) 8.16-8.23 (m, 1H) 8.43 (dd, J=6.82, 2.78 Hz, 1H).
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)[CH:9]=[CH:10][CH:11]=1.[CH2:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24][NH:23]1>CCO>[CH2:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24][N:23]1[CH2:3][C@@H:2]([OH:1])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)[CH:7]=1
Reactant: c1cc(OC[C@H]2CO2)cc(-c2cccc3cccnc23)c1
Reactant: c1ccc2c(c1)CCNC2
Solvent: CCO
Product: O[C@@H](COc1cccc(-c2cccc3cccnc23)c1)CN1CCc2ccccc2C1
Temperature: 120 °C
Yield: 26.8 %

Procedure:
The mixture of compound (R)-8-(3-(oxiran-2-ylmethoxy)phenyl)quinoline (270 mg, 1 mmol), 1,2,3,4-tetrahydroisoquinoline (133 mg, 1 mmol) in EtOH (5 mL) was stirred at 120° C. under microwave heating for 30 min. The solvent was then removed by concentration and the crude product was purified by HPLC separation to yield the desired (R)-1-(3,4-dihydroisoquinolin-2(1H)-yl)-3-(3-(quinolin-8-yl)phenoxy)propan-2-ol (110 mg, Yield 26.8%). 1H NMR (400 MHz, METHANOL-d4): 8.82 (dd, J1=4.0 Hz, J2=1.6 Hz, 1H), 8.41 (d, J=8.0 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.76 (d, J=7.2 Hz, 1H), 7.69 (dd, J1=J2=7.6 Hz, 1H), 7.56-7.53 (m, 1H), 7.43 (dd, J1=J2=7.6 Hz, 1H), 7.24 (s, 1H), 7.20-7.01 (m, 6H), 4.30 (br.s, 1H), 4.17-4.06 (m, 2H), 3.77 (s, 2H), 2.90-2.74 (m, 6H). LCMS (m/z): 412.2 (M+1).
Reaction SMILES: Cl.O1[C:6]2([CH2:11][CH2:10][CH:9]([NH:12][C:13]3[N:18]=[C:17]([N:19]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH:21]=[N:20]4)[CH:16]=[CH:15][N:14]=3)[CH2:8][CH2:7]2)[O:5]CC1.[OH-].[Na+]>C1COCC1>[N:19]1([C:17]2[CH:16]=[CH:15][N:14]=[C:13]([NH:12][CH:9]3[CH2:8][CH2:7][C:6](=[O:5])[CH2:11][CH2:10]3)[N:18]=2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[N:20]1
Reactant: c1ccc2c(c1)cnn2-c1ccnc(NC2CCC3(CC2)OCCO3)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C1CCC(Nc2nccc(-n3ncc4ccccc43)n2)CC1
Temperature: 80 °C
Yield: 102.2 %

Procedure:
Aqueous HCl (3 M, 40 mL) was added to (1,4-dioxaspiro[4.5]dec-8-yl)-(4-indazol-1-yl-pyrimidin-2-yl)-amine (1.89 g, 5 mmol) in THF (40 mL), and the resulting mixture heated to 80° C. for 1 h. The reaction mixture was cooled and poured onto a mixture of ice and aqueous NaOH (1 M, 120 mL), and the resulting suspension filtered. The collected solids were washed with water, taken up in DCM/MeOH, and a portion of the solvent evaporated under reduced pressure. The resulting suspension was filtered, the collected solids washed with hexanes, and dried under reduced pressure to give 4-(4-indazol-1-ylpyrimidin-2-ylamino)-cyclohexanone (1.57 g, 95% yield) as a white powder. MS=308 [M+H]+; MP=211.8-213.2° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([F:12])=[C:7]([OH:13])[CH:6]=[CH:5]2.[CH3:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=1B1OC(C)(C)C(C)(C)O1)[C:18]([O:20]C)=[O:19]>>[F:12][C:8]1[C:7]([OH:13])=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([C:24]1[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=1[CH3:14])=[CH:3]2
Reactant: Oc1ccc2cc(Br)ccc2c1F
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Product: Cc1cc(C(=O)O)ccc1-c1ccc2c(F)c(O)ccc2c1

Procedure:
Followed the coupling procedure described in Example 29 starting from 6-bromo-1-fluoronaphthalen-2-ol (Intermediate 13) and methyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate. 1H-NMR (DMSO-d6, 300 MHz, TMS): δ 12.90 (b, 1H), 10.17 (b, 1H), 7.84-7.97 (m, 4H), 7.70 (d, 1H), 7.54 (d, 1H), 7.41 (d, 1H), 7.30 (t, 1H), 2.33 (s, 3H). MS (ESI): m/z=295.25 [MA]−.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([NH:10][CH:11]1[CH2:17][CH2:16][C:15]2[CH:18]=[CH:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:14]=2[C:13](=[O:25])[CH2:12]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>>[CH2:3]([NH:10][CH:11]1[CH2:17][CH2:16][C:15]2[CH:18]=[CH:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:14]=2[CH:13]([OH:25])[CH2:12]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1CC(NCc2ccccc2)CCc2ccc([N+](=O)[O-])cc21
Agent: [BH4-]
Agent: [Na+]
Product: O=[N+]([O-])c1ccc2c(c1)C(O)CC(NCc1ccccc1)CC2
Reaction time: 4 h
Yield: 29.1 %

Procedure:
An aqueous solution (92 ml) of sodium borohydride (18.29 g) was added dropwise to a stirred solution of 7-benzylamino-3-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one (25.01 g) at ambient temperature over 20 minutes. The resulting mixture was stirred for 4 hours and allowed to stand overnight at the same temperature and evaporated in vacuo. The residue was diluted with water and extracted twice with dichloromethane. The combined extracts were washed with brine, dried over sodium sulfate, treated with 4N hydrogen chloride in ethyl acetate, and evaporated in vacuo. The residue was suspended in methanol and filtered. The filtrate was evaporated in vacuo, diluted with ammonia aqueous solution, and extracted twice with dichloromethane. The combined extracts were washed with brine, dried over sodium sulfate, and chromatographed over silica gel using dichloromethane-methanol. The eluate was evaporated in vacuo and the residue was washed with diethyl ether to afford 7-benzylamino-3-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (7.33 g) as a dark yellow powder (diastereomers mixture).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C[Al](C)C.C[O:23][C:24](=O)/[CH:25]=[C:26](\[NH:28][C:29](=O)[CH2:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1)/[CH3:27].O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[C:24](=[O:23])[CH:25]=[C:26]([CH3:27])[N:28]=[C:29]2[CH2:30][O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=2)[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Nc1ccc(NCCN2CCOCC2)c(F)c1
Reactant: COC(=O)/C=C(/C)NC(=O)COc1cccc(F)c1
Agent: C[Al](C)C
Solvent: O
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2ccc(NCCN3CCOCC3)c(F)c2)c(COc2cccc(F)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
To a solution of 2-fluoro-N1-(2-morpholinoethyl)benzene-1,4-diamine (0.33 g, 1.38 mmol) in DCM (20 mL) was added trimethylaluminium (2.1 mL, 4.2 mmol, 2 M in toluene) slowly and the mixture was stirred at rt for 0.5 h. A solution of (Z)-methyl-3-(2-(3-fluorophenoxy)acetamido)but-2-enoate (0.37 g, 1.38 mmol) in DCM (5 mL) was added slowly and the resulting mixture was stirred at rt for 24 h. 50 mL of water was then added to the mixture slowly and the mixture was extracted with CH2Cl2 (50 mL×2). The combined organic phases were washed with brine (100 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc) to give the title compound as a pale yellow solid (0.5 g, 79%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]2[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][CH:7]=1.[H][H]>[Pd].[O-]S([O-])(=O)=O.[Ba+2].CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(C(=O)O)c1C=Cc1cccc(Cl)c1
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Product: COc1cccc(C(=O)O)c1CCc1cccc(Cl)c1
Yield: 87 %

Procedure:
For the synthesis of the title compound, 6.0 g of 2-[2-(3-chlorophenyl)-vinyl]-3-methoxybenzoic acid, 0.6 g of Pd/BaSO4 (5%), 4 l of hydrogen and 150 ml of methanol are employed in method J (variant 1). Yield: 87%; m.p.: 91° C.; C16H15ClO3 (Mr=290.75)
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])[CH2:11][C:12]([CH3:25])([C:14]2[C:19](=[O:20])[C:18]([CH3:21])=[C:17]([CH3:22])[C:16](=[O:23])[C:15]=2[CH3:24])[CH3:13])=[CH:5][CH:4]=1.C(Br)(Br)(Br)[Br:28].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:28][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])[CH2:11][C:12]([CH3:25])([C:14]2[C:19](=[O:20])[C:18]([CH3:21])=[C:17]([CH3:22])[C:16](=[O:23])[C:15]=2[CH3:24])[CH3:13])=[CH:5][CH:4]=1
Reactant: CC1=C(C)C(=O)C(C(C)(C)CC(=O)Nc2ccc(CO)cc2)=C(C)C1=O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC1=C(C)C(=O)C(C(C)(C)CC(=O)Nc2ccc(CBr)cc2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 31 %

Procedure:
To a mixture of N-(4-(hydroxymethyl)phenyl)-3-methyl-3-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)butanamide (1.35 g, 3.98 mmol) and carbon tetrabromide (3.96 g, 11.9 mmol) in methylene chloride (30 ml), Ph3P (1.30 g, 4.77 mmol) was added at 0° C. The mixture was stirred for 3 hours at room temperature. The compound was directly purified with silica chromatography using heptane/ethyl acetate as eluent to give a yield of 31%. 1H NMR (300 MHz, CD2Cl2) δ 7.41 (d, J=8.7, 2H), 7.32 (d, J=8.7, 2H), 7.25 (s, br, 1H, NH), 4.50 (s, 2H, CH2Br), 3.00 (s, 2H, CH2), 2.14 (s, 3H, CH3), 1.95 (d, 6H, CH3), 1.48 (s, 6H, CH3). MS (m/e): 418, 420 (1:1, M+).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[N+:26]([O-])=O)[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.CO.[H][H]>[Ni].O1CCCC1>[NH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[NH:19][CH2:18][CH2:17][CH2:16][N:13]1[CH2:12][CH2:11][CH:10]([N:6]2[C:5]3[CH:29]=[CH:30][C:2]([Cl:1])=[CH:3][C:4]=3[NH:8][C:7]2=[O:9])[CH2:15][CH2:14]1
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCN(CCCNc2ccccc2[N+](=O)[O-])CC1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccccc1NCCCN1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)CC1
Yield: 70.5 %

Procedure:
A mixture of 64 parts of 5-chloro-1,3-dihydro-1-{1-[3-(2-nitrophenylamino)propyl]-4-piperidinyl}-2H-benzimidazol-2-one in 200 parts of methanol and 225 parts of tetrahydrofuran is hydrogenated at normal pressure and at room temperature with 10 parts of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off over hyflo and the filtrate is evaporated. The residue is crystallized from a mixture of 2-propanol and ethanol. The product is filtered off and dried, yielding 42 parts (70.5%) of 1-[1-{3-[N-(2-aminophenyl)amino]propyl}-4-piperidinyl]-5-chloro-1,3-dihydro-2H-benzimidazol-2-one; mp. 196° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:24])[N:10]([CH2:22][OH:23])[CH:11]=[C:12]3[C:17]=2[NH:16][C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[S:13]3)=[CH:4][CH:3]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:24])[N:10]([CH2:22][O:23][C:25](=[O:27])[CH3:26])[CH:11]=[C:12]3[C:17]=2[NH:16][C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[S:13]3)=[CH:4][CH:3]=1
Reactant: O=c1c(-c2ccc(Cl)cc2)c2c(cn1CO)Sc1ccccc1N2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCn1cc2c(c(-c3ccc(Cl)cc3)c1=O)Nc1ccccc1S2
Yield: 58 %

Procedure:
To 1.0 g. of 4-(4-chlorophenyl)-2-(hydroxymethyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one (2.8 mmol.) in 8 ml. of pyridine was added 4 ml. of acetic anhydride (42.3 mmol.), and the resulting suspension was stirred at room temperature for about 1 hour. The resulting solution was then concentrated under a nitrogen atmosphere, and the residue was titurated with methanol to yield a yellow precipitate which was washed with methanol and then air-dried to yield 4-(4-chlorophenyl)-2-[(acetyloxy)methyl]-5H-pyrido[3,4-b][1,4]-benzothiazin-3(2H)-one as a yellow solid (0.65 g; 58% yield) having the structural formula, ##STR12## a melting point in the range of 119°-120° C. and the following elemental analysis:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Br:5][C:6]1[CH:7]=[N:8][N:9]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:10]=1.CCN(CC)CC>C(Cl)Cl>[Br:5][C:6]1[CH:7]=[N:8][N:9]([CH:11]2[CH2:16][CH2:15][N:14]([C:1](=[O:3])[CH3:2])[CH2:13][CH2:12]2)[CH:10]=1
Reactant: Brc1cnn(C2CCNCC2)c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(n2cc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acetyl chloride (312 μl, 4.35 mmol) is added dropwise, under stirring at 0° C., to a solution of 4-(4-Bromo-pyrazol-1-yl)-piperidine (as obtained in preparation 89, 1 g, 4.34 mmol), Et3N (1.824 ml, 13.04 mmol) in CH2Cl2. The cooling bath is then removed and the reaction mixture stirred at RT for an additional 1 h. The mixture is then diluted with de-ionized water and the phases are separated. The organic phase is washed several times with de-ionized water and the aqueous layer re-extracted with CH2Cl2. The combined organic layers are washed with brine, dried over Na2SO4, filtered and the filtrate is concentrated in vacuo. The residue is used without further purification in the next step, and afford the title compound as yellow solid, Rt=0.786 min (Acquity HPLC BEH C18, 2.1×50 mm, 1.7 micron, detection 215 nM, 0.1 min 2% CH3CN in H2O, 2% to 100% CH3CN in H2O in 1.5 min, 0.4 min 100% CH3CN+0.1% TFA, flow rate 1.0 ml/min); MS: 272 (M+1, 79Br)+
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[C:7](=[C:8]([O:18][CH3:19])[CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)[CH:6]=[CH:5]2)[CH2:3][CH2:2]1.[CH2:20](I)C>>[CH:1]1([N:4]2[C:12]3[C:7](=[C:8]([O:18][CH2:19][CH3:20])[CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)[CH:6]=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCI
Reactant: CCOC(=O)c1cc(OC)c2ccn(C3CC3)c2c1
Product: CCOC(=O)c1cc(OCC)c2ccn(C3CC3)c2c1

Procedure:
The compound was prepared according to the procedure for ethyl 1-cyclopropyl-4-methoxy-1H-indole-6-carboxylate but using EtI in place of MeI.