Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:23])=[C:4]([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:18]=2)[C:5]([O:11][CH3:12])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:30].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[C:3]([CH3:23])=[C:4]([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:18]=2)[C:5]([O:11][CH3:12])=[C:6]([CH:8]([NH2:30])[CH3:9])[CH:7]=1
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1-c1cncc(S(C)(=O)=O)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Solvent: C1CCOC1
Product: COc1c(C(C)N)cc(Cl)c(C)c1-c1cncc(S(C)(=O)=O)c1
Temperature: 25 °C

Procedure:
A mixture of 1-{5-chloro-2-methoxy-4-methyl-3-[5-(methylsulfonyl)pyridin-3-yl]phenyl}ethanone (0.035 g, 0.099 mmol), ammonium acetate (0.08 g, 1 mmol) and 1.0 M sodium cyanoborohydride in tetrahydrofuran (THF) (0.25 mL, 0.25 mmol) in methanol (0.2 mL) and acetonitrile (0.2 mL) was heated at 65° C. overnight. The mixture was cooled to room temperature (rt), quenched with sat. NaHCO3 solution, and extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the desired product, which was used in the next step directly (0.024 g, 69%). LCMS calculated for C16H17ClNO3S (M−NH2)+: m/z=338.1. found: 338.0.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=1>CC1C=CC=CC=1>[N:1]1([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc(OCCCCl)cc1
Reactant: C1CNCCN1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(OCCCN2CCNCC2)cc1
Reaction time: 8 h
Yield: 98.5 %

Procedure:
A mixture of 224 parts of piperazine, 97 parts of ethyl 4-(3-chloropropoxy)benzoate and 1044 parts of methylbenzene was stirred overnight at reflux temperature. After cooling, the reaction mixture was washed with water (3×), dried, filtered and evaporated, yielding 115.2 parts (98.5%) of ethyl 4-[3-(1-piperazinyl)propoxy]benzoate (interm. 1). In a similar manner there was also prepared ethyl 4-[2-(1-piperazinyl)ethoxy]benzoate (interm. 2).
Reaction SMILES: C(OC)(OC)OC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:22]([C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1)=O.[CH3:33][CH:34]1[O:39][CH:38]([CH3:40])[CH2:37][NH:36][CH2:35]1.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>CN(C)C=O.C(O)(=O)C>[CH3:40][CH:38]1[O:39][CH:34]([CH3:33])[CH2:35][N:36]([CH2:22][C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=2)[CH2:37]1.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CC1CNCC(C)O1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CC1CN(Cc2ccc(C(=O)O)cc2)CC(C)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetic acid (0.34 mL), trimethyl orthoformate (0.66 mL), and sodium triacetoxyborohydride (0.53 g) are successively added to 4-formyl-benzoic acid (150 mg) and 2,6-dimethyl-morpholine (115 mg) dissolved in dimethylformamide (3 mL). The solution is stirred at room temperature overnight. Trifluoroacetic acid (50% in water) is added, the solution is stirred for another 2 h and then concentrated under reduced pressure. The residue is purified by HPLC on reversed phase (MeCN/H2O) to give the title compound as its trifluoroacetic acid salt.
Reaction SMILES: C(=N[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1)C(C)C.Cl.[OH2:21]>C1(C)C=CC=CC=1>[O:13]([C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[CH:6]=[O:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)C=NCc1cccc(Oc2ccccc2)c1
Reactant: O
Agent: Cl
Solvent: Cc1ccccc1
Product: O=Cc1cccc(Oc2ccccc2)c1
Yield: 91 %

Procedure:
80 g (0.316 mol) of N-isobutylidene-3-phenoxybenzylamine is dissolved in 80 ml of toluene; to the solution is then added 4 g (0.036 mol) of potassium-tert-butylate, and the mixture is refluxed for 4 hours. After cooling of the reaction mixture, 35 g of 37% hydrochloric acid (about 0.35 mol) and 50 ml of water are added, and the toluene phase is separated. The toluene is distilled off to leave 57 g (0.288 mol) of 3-phenoxybenzaldehyde, corresponding to a yield of 91% of theory.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[CH:15]1([CH2:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[N:25]=[N:26][C:27]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:28][CH:29]=2)=[O:23])[CH2:17][CH2:16]1>>[CH:15]1([CH2:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[N:25]=[N:26][C:27]([N:30]3[CH2:31][CH2:32][N:33]([C:7](=[O:8])[C:6]4[CH:10]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[C:11]([F:14])([F:13])[F:12])[CH2:34][CH2:35]3)=[CH:28][CH:29]=2)=[O:23])[CH2:17][CH2:16]1
Reactant: O=C(Cl)c1cc(F)ccc1C(F)(F)F
Reactant: O=C(NCCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: O=C(NCCCC1CC1)c1ccc(N2CCN(C(=O)c3cc(F)ccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 5-Fluoro-2-trifluoromethylbenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-cyclopropylpropyl)amide, the title compound was obtained as a white powder (28% yield). 1H NMR (400 MHz, CDCl3) δ 8.07, 7.89, 7.76, 7.28-7.24, 7.10-7.08, 7.02, 4.06-4.03, 3.90-3.86, 3.82-3.72, 3.51, 3.37, 1.76-1.70, 1.30, 0.70-0.67, 0.44-0.40, 0.03-0.003.
Reaction SMILES: [O:1]1[CH2:4][CH:3]([CH2:5][CH2:6][OH:7])[CH2:2]1.C1N2CCN(CC2)C1.[S:16](Cl)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>C(Cl)Cl>[O:1]1[CH2:4][CH:3]([CH2:5][CH2:6][O:7][S:16]([C:19]2[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:2]1
Reactant: OCCC1COC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCC2COC2)cc1
Reaction time: 0.25 h

Procedure:
At 0° C., to a solution of 2-(3-oxetanyl)ethanol (according to the synthesis procedure in the reference: Journal of American Chemical Society, 2009, 131, 2786-2787.) (193 mg, 1.89 mmol) in CH2Cl2 (15 mL) was added DABCO (847 mg, 7.56 mmol) and TsCl (1.43 g, 7.56 mmol) was then added dropwise, the mixture was stirred for 15 minutes. After filtration, the filter cake was washed with CH2Cl2 and the filtrate was washed twice with water. The organic phase was dries over anhydrous sodium sulphate. The solvent was evaporated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 5:1) to afford the target compound.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:24])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH:14][S:15]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:8]=1.Br[CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=1>CN(C=O)C>[CH3:3][O:4][C:5](=[O:24])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][N:14]([CH2:26][CH2:27][O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=2)[S:15]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:8]=1
Reactant: COC(=O)Cc1cccc(CNS(=O)(=O)c2cccnc2)c1
Reactant: Clc1cccc(OCCBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(CN(CCOc2cccc(Cl)c2)S(=O)(=O)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.8 %

Procedure:
To a solution of sodium hydride (60% in mineral oil, 0.016 g, 0.3996 mmol) in 2 mL DMF was added (3-((pyridine-3-sulfonylamino)-methyl)-phenyl)-acetic acid methyl ester (from Preparation 14, 0.096 g, 0.333 mmol) at 0° C. and the reaction was stirred at room temperature for 30 minutes. After cooling to 0° C., 1-(2-bromo-ethoxy)-3-chloro-benzene (from Preparation 29, 0.094 g, 0.399 mmol) was added and the reaction was stirred at room temperature overnight. The DMF was removed in vacuo. The residue was diluted with EtOAc and the organic solution was washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica gel (0.5% MeOH/CH2Cl2 to 2% MeOH/CH2Cl2) to afford the title compound of Step A (0.025 g). MS 475 (M+1).
Reaction SMILES: [OH2:1].[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])/[CH:11]=[CH:12]\[C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.O.O.O.O.O.O.O.O.[OH-].[Ba+2:26].[OH-]>O>[OH2:14].[OH2:1].[NH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:16])/[CH:11]=[CH:12]\[C:13]([O-:15])=[O:14])=[CH:7][CH:8]=1.[NH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:16])/[CH:11]=[CH:12]\[C:13]([O-:15])=[O:14])=[CH:7][CH:8]=1.[Ba+2:26]
Reactant: Nc1ccc(NC(=O)/C=C\C(=O)O)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(NC(=O)/C=C\C(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 142.9 %

Procedure:
Under a nitrogen atmosphere, into a reaction vessel were charged 10.0 g (44.6 mmol) of (2Z)-4-[(4-aminophenyl)amino]-4-oxo-2-butenoic acid mono-hydrate obtained by the same method as in Production Example 2 and 70 ml of water, a solution prepared by dissolving 7.04 g (22.3 mmol) of barium hydroxide octa-hydrate in 30 ml of water was added at 20 to 30° C., and the mixture was stirred at room temperature for 2 hours. Thereafter, the mixture was condensed under reduced pressure and the solvent was distilled off to obtain a residue to which 50 ml of ethanol and 50 ml of 2-propanol were added, and the mixture was stirred at room temperature overnight, the deposited crystal was isolated by filtration, and dried under reduced pressure at 45° C., to obtain 12.4 g of barium bis{(2Z)-4-[(4-aminophenyl)amino]-4-oxo-2-butenoate}di-hydrate as a yellow solid. Yield: 98.3%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[CH:12][C:11]3=[O:26])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Br[CH2:28][CH2:29][Cl:30].C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.O>[Cl:30][CH2:29][CH2:28][N:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][CH:17]=4)=[CH:12][C:11]3=[O:26])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: ClCCBr
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cc2)ccn1-c1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: O=c1cc(-c2ccc(C(F)(F)F)cc2)ccn1-c1ccc2c(cnn2CCCl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
To a solution of 1-(1H-indazol-5-yl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one (120 mg, 0.338 mmol) in DMSO (2.0 mL) was added 2-bromo-1-chloroethane (485 mg, 3.38 mmol) and Cs2CO3 (330 mg, 1.01 mmol), and the reaction was stirred at ambient temperature for 3 h. The reaction was diluted with H2O (25 mL) and extracted with EtOAc (3×25 mL). The extracts were washed with brine (25 mL), dried over Na2SO4, and concentrated. Flash chromatography (Biotage 25+M column, CH2Cl2/MeOH, 99:1 to 98:2) yielded the title compound (72 mg, 51%): 1H NMR (500 MHz, CDCl3) δ 8.11 (s, 1H), 7.76-7.73 (m, 5H), 7.59-7.47 (m, 3H), 6.92-6.91 (m, 1H), 6.53-6.51 (m, 1H), 4.74-4.71 (m, 2H), 4.00-3.98 (m, 2H).
Reaction SMILES: C(O)(=O)C(O)=O.[N+:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[CH2:13][CH2:14][NH2:15])([O-:9])=[O:8].[Br:19][C:20]1[CH:21]=[C:22]([CH2:29][C:30](Cl)=[O:31])[CH:23]=[C:24]([Br:28])[C:25]=1[O:26][CH3:27]>C(Cl)Cl.[OH-].[Na+]>[Br:19][C:20]1[CH:21]=[C:22]([CH2:29][C:30]([NH:15][CH2:14][CH2:13][C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([N+:7]([O-:9])=[O:8])[CH:11]=2)=[O:31])[CH:23]=[C:24]([Br:28])[C:25]=1[O:26][CH3:27]
Reactant: NCCc1cccc([N+](=O)[O-])c1
Reactant: COc1c(Br)cc(CC(=O)Cl)cc1Br
Agent: O=C(O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1c(Br)cc(CC(=O)NCCc2cccc([N+](=O)[O-])c2)cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 3-nitro-phenethylamine oxalate (1.792 g, 0.007 mol) in methylene chloride (45 mL), 1 N NaOH (45 mL) was added. It was stirred at room temperature to get a clear solution. A solution of 3,5-dibromo-4-methoxyphenyl acetyl chloride (0.0072 mol) in methylene chloride was added. Stirring was continued overnight and the completion of the reaction was monitored by thin layer chromatography. The reaction mixture was washed with 1N HCl and 1N NaOH, extracted with methylene chloride. The combined extracts were dried over anhydrous sodium sulfate and concentrated. The solid obtained was crystallized from ethyl acetate-hexanes mixture. Yield 2.159 g, 65%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]2[S:20][CH:21]=[C:22]([CH3:23])[C:8]=2[C:7]=1O)=[O:5])[CH3:2].C(OC(C1C(=O)N(CC2C=CC=CC=2)C2SC=CC=2C=1[N:47]1[CH2:52][CH2:51][N:50]([C:53]([C:55]2[S:56][CH:57]=[CH:58][CH:59]=2)=[O:54])[CH2:49][CH2:48]1)=O)C>>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]2[S:20][CH:21]=[C:22]([CH3:23])[C:8]=2[C:7]=1[N:47]1[CH2:52][CH2:51][N:50]([C:53]([C:55]2[S:56][CH:57]=[CH:58][CH:59]=2)=[O:54])[CH2:49][CH2:48]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(O)c2c(C)csc2n(Cc2ccccc2)c1=O
Reactant: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2ccsc2n(Cc2ccccc2)c1=O
Product: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2c(C)csc2n(Cc2ccccc2)c1=O
Yield: 16 %

Procedure:
This compound was prepared from 7-benzyl-4-hydroxy-3-methyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyrdine-5-carboxylic acid ethyl ester (61) by applying the method described for the preparation of 7-benzyl-6-oxo-4-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid ethyl ester (62). Yield 16%; MP 195° C. 1H-NMR (DMSO-d6) δ 1.29 (t, J=7.2 Hz, 3H), 2.53 (d, J=1.2 Hz, 3H), 4.29 (q, J=7.2 Hz, 2H), 5.27 (s, 2H), 6.94 (d, J=1.2 Hz, 1H), 7.16 (m, 1H) 7.28 (m, 3H), 7.33 (m, 2H), 7.43 (dd, J=0.8, 3.6 Hz, 1H), 7.79 (dd, J=0.8, 4.8 Hz, 1H) ppm; EIMS m/z 522 (M+1).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH3:13][N:14]([CH2:16][CH:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([OH:27])[CH:23]=2)[CH2:18]1)[CH3:15].[CH3:28][O:29][C:30]1[CH:46]=[CH:45][C:33]([C:34]([O:36][C:37]2[CH:42]=[CH:41][C:40]([CH2:43]O)=[CH:39][CH:38]=2)=[O:35])=[CH:32][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:15][N:14]([CH2:16][CH:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:27][CH2:43][C:40]3[CH:39]=[CH:38][C:37]([O:36][C:34]([C:33]4[CH:32]=[CH:31][C:30]([O:29][CH3:28])=[CH:46][CH:45]=4)=[O:35])=[CH:42][CH:41]=3)[CH:23]=2)[CH2:18]1)[CH3:13]
Reactant: CN(C)CC1CCc2cc(O)ccc2C1
Reactant: COc1ccc(C(=O)Oc2ccc(CO)cc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Oc2ccc(COc3ccc4c(c3)CCC(CN(C)C)C4)cc2)cc1
Reaction time: 3 h
Yield: 53.8 %

Procedure:
Diethyl azodicarboxylate (40% toluene solution, 950 mg) was added dropwise to THF solution (3 ml) of 2-[(N,N-dimethylamino)methyl]-6-hydroxytetralin (150 mg), 4-(hydroxymethyl)phenyl 4-methoxybenzoate (570 mg) and triphenylphosphine (574 mg) at room temperature, which was stirred for 3 hours. The reaction mixture was concentrated, and the residue was purified using alumina column chromatography (development solvent; hexane˜hexane:ethyl acetate=6:1), and recrystallized (ethyl acetate-hexane) to give the titled compound (175 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:17][C:18]#[N:19]>>[CH3:12][O:13][C:14]1[CH:15]=[C:16](/[C:17](=[CH:6]/[C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N+:1]([O-:3])=[O:2])/[C:18]#[N:19])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1ccc(/C(C#N)=C/c2ccccc2[N+](=O)[O-])cc1OC
Yield: 83.6 %

Procedure:
2-Nitrobenzaldehyde (1.51 g) and 3,4-dimethoxybenzyl cyanide (1.77 g) were subjected to condensation in accordance with process A of (production process 2), to thereby produce the target product (2.59 g, yield: 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([CH:13]=[O:14])[C:10]([CH3:15])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH:16]1([Mg]Br)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>O1CCCC1>[CH:16]1([CH:13]([C:11]2[C:10]([CH3:15])=[N:9][N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH:12]=2)[OH:14])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Br[Mg]C1CCCCC1
Reactant: Cc1nn(-c2cccc(Cl)c2)cc1C=O
Solvent: C1CCOC1
Product: Cc1nn(-c2cccc(Cl)c2)cc1C(O)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51 %

Procedure:
To a solution (5 mL) of 1-(3-chlorophenyl)-3-methyl-1H-pyrazole-4-carbaldehyde (0.35 g) synthesized in the above-mentioned (2) in tetrahydrofuran under ice-cooling was added dropwise cyclohexylmagnesium bromide (2.4 mL, 1M tetrahydrofuran solution). After the completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (0.25 g, 51%) as a pale-yellow oil.
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:15])([F:14])[C:5]1[N:10]=[CH:9][C:8]([C@H:11]([NH2:13])[CH3:12])=[CH:7][CH:6]=1.C(N(CC)C(C)C)(C)C.Cl[C:26]1[C:27]2[CH2:35][N:34]([C:36]3[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][N:37]=3)[CH2:33][CH2:32][C:28]=2[N:29]=[CH:30][N:31]=1>C(#N)C>[CH3:42][C:39]1[CH:40]=[CH:41][C:36]([N:34]2[CH2:33][CH2:32][C:28]3[N:29]=[CH:30][N:31]=[C:26]([NH:13][C@@H:11]([C:8]4[CH:9]=[N:10][C:5]([C:4]([F:14])([F:3])[F:15])=[CH:6][CH:7]=4)[CH3:12])[C:27]=3[CH2:35]2)=[N:37][CH:38]=1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)nc1
Reactant: C[C@@H](N)c1ccc(C(F)(F)F)nc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCc3ncnc(N[C@H](C)c4ccc(C(F)(F)F)nc4)c3C2)nc1
Temperature: 180 °C
Reaction time: 0.21 h

Procedure:
To a stirred solution of (R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethanamine dihydrochloride (44 mg, 0.17 mmol) and N,N-diisopropylethylamine (73 μL, 0.42 mmol) in acetonitrile (1.1 mL) was added 4-chloro-5,6,7,8-tetrahydro-6-(5-methylpyridin-2-yl)pyrido[4,3-d]pyrimidine (30 mg, 0.1 mmol). The reaction was capped and heated in the microwave for 10 hours at 180° C. The reaction mixture was quenched with excess water and allowed to stir for 10-15 minutes. The precipitated product was filtered, washed with water and dried in vacuum oven to obtain the title compound as a light tan solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH:7]([N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([N+:19]([O-])=O)=[CH:14][CH:15]=2)[CH2:10]1)[CH3:8])=[O:5])[CH3:2].O.O.[Sn](Cl)(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:19][C:13]1[CH:12]=[C:11]2[C:16]([CH2:17][CH2:18][N:9]([CH:7]([CH3:8])[CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:10]2)=[CH:15][CH:14]=1
Reactant: CCOC(=O)CC(C)N1CCc2ccc([N+](=O)[O-])cc2C1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC(C)N1CCc2ccc(N)cc2C1
Yield: 93.3 %

Procedure:
0.43 g of 2-[2-(ethoxycarbonyl)-1-methylethyl]-7-nitro-1,2,3,4-tetrahydroisoquinoline was dissolved in 10 ml of ethanol, and 1.23 g of tin chloride dihydrate was added to the solution. The solution was heated under reflux for 30 minutes to allow for the reaction to take place. The resulting solution was made basic by adding saturated aqueous solution of sodium bicarbonate, and the insoluble content was separated by using celite. The solution was extracted with ethyl acetate, washed with saturated aqueous solution of sodium chloride, and dried with anhydrous sodium sulfate. After separating the desiccant by filtration, the residue was concentrated under reduced pressure to obtain 0.36 g of 7-amino-2-[2-(ethoxycarbonyl)-1-methylethyl]-1,2,3,4-tetrahydroisoquinoline, which was a brown oily product (yield: 93%).
Reaction SMILES: Br[C:2]1[C:3]([CH3:16])=[C:4]([O:13][CH2:14][CH3:15])[C:5]2[O:9][CH:8]([CH3:10])[CH2:7][C:6]=2[C:11]=1[CH3:12].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1>>[CH2:14]([O:13][C:4]1[C:5]2[O:9][CH:8]([CH3:10])[CH2:7][C:6]=2[C:11]([CH3:12])=[C:2]([N:28]2[CH2:27][CH2:26][N:25]([C:22]3[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=3)[CH2:30][CH2:29]2)[C:3]=1[CH3:16])[CH3:15]
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: CCOc1c(C)c(Br)c(C)c2c1OC(C)C2
Product: CCOc1c(C)c(N2CCN(c3ccc(OC)cc3)CC2)c(C)c2c1OC(C)C2
Yield: 48.5 %

Procedure:
By using 5-bromo-7-ethoxy-2,4,6-trimethyl-2,3-dihydro-1-benzofuran (570 mg, 2.0 mmol) synthesized in Reference example 84 and 1-(4-methoxyphenyl)piperazine (768 mg, 4.0 mmol), the reaction was carried out in the same manner as Example 21 to synthesize the title compound 385 mg (yield 48%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[N:12][C:11]=2[CH3:20])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.[CH2:31]([C:33]1[CH:38]=[CH:37][N:36]=[C:35](Br)[CH:34]=1)[CH3:32]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:19])[F:18])=[N:12][C:11]=2[CH3:20])=[CH:4][C:3]=1[C:35]1[CH:34]=[C:33]([CH2:31][CH3:32])[CH:38]=[CH:37][N:36]=1
Reactant: CCc1ccnc(Br)c1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(B2OC(C)(C)C(C)(C)O2)c1
Product: CCc1ccnc(-c2cc(NC(=O)c3ccc(C(F)(F)F)nc3C)ccc2Cl)c1

Procedure:
N-(4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide (˜1 mmol) was used in Procedure A with 4-ethyl-2-bromopyridine (1 mmol). Purified by silica gel chromatography (0-60% ethyl acetate/hexanes) to yield N-(4-chloro-3-(4-ethylpyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide as a tan solid: MS (Q1) 419 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH2:26][O:27][CH3:28])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[C:30](Cl)(=[O:32])[CH3:31]>>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([C:30](=[O:32])[CH3:31])[CH2:25][CH2:26][O:27][CH3:28])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CC(=O)Cl
Reactant: COCCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Product: COCCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)C(C)=O

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: {6-methoxy-2′-[(2-methoxy-ethylamino)-methyl]-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid methyl ester and acetyl chloride.