Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)CO[C:5]2([C:13]3[C:8](=[CH:9][CH:10]=[C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=3)[N:7]([CH2:19][C:20]([O:22]C)=[O:21])[C:6]2=[O:24])[O:4]C1.C(O)(C(F)(F)F)=O>O1CCOCC1.O>[CH3:18][S:15]([NH:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:19][C:20]([OH:22])=[O:21])[C:6](=[O:24])[C:5]2=[O:4])(=[O:16])=[O:17]
Reactant: COC(=O)CN1C(=O)C2(OCC(C)(C)CO2)c2cc(NS(C)(=O)=O)ccc21
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1ccc2c(c1)C(=O)C(=O)N2CC(=O)O
Temperature: 80 °C
Reaction time: 24 h
Yield: 95.4 %

Procedure:
A solution of methyl 2-(5,5-dimethyl-5′-(methylsulfonamido)-2′-oxospiro[[1,3]dioxane-2,3′-indoline]-1′-yl)acetate (200 mg, 0.502 mmol) in dioxane/water 1:1 (7 ml) and TFA (0.193 ml, 2.510 mmol) was stirred at 80° C. overnight. TFA (0.271 ml, 3.51 mmol) was freshly added and stirring at 80° C. was continued for 24 hours. Then TFA (0.155 ml, 2.008 mmol) was freshly added and stirring at 80° C. was continued for additional 48 hours. The volatiles were removed under vacuum and the crude was purified by flash chromatography on silica gel (DCM:MeOH from 99.5:0.5 to 7:3+0.5% AcOH), affording 2-(5-(methylsulfonamido)-2,3-dioxoindolin-1-yl)acetic acid (143 mg, 0.479 mmol, 96% yield). MS/ESI+ 298.9 [MH]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8]([NH:11][CH2:12][C@H:13]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14]2)(=[O:10])=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:20][C:21]1([CH3:46])[C:30]([CH3:31])=[CH:29][C:28]2[N:27]=[CH:26][N:25]=[C:24]([N:32]3[CH2:38][C:37]4[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][C:36]=4[O:35][CH2:34][CH2:33]3)[C:23]=2[CH2:22]1>>[NH2:1][C:2]1[C:7]([S:8]([NH:11][CH2:12][C@H:13]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14]2)(=[O:10])=[O:9])=[CH:6][C:5]([C:40]2[CH:41]=[CH:42][C:36]3[O:35][CH2:34][CH2:33][N:32]([C:24]4[C:23]5[CH2:22][C:21]([CH3:20])([CH3:46])[C:30]([CH3:31])=[CH:29][C:28]=5[N:27]=[CH:26][N:25]=4)[CH2:38][C:37]=3[CH:39]=2)=[CH:4][N:3]=1
Reactant: CC1=Cc2ncnc(N3CCOc4ccc(B(O)O)cc4C3)c2CC1(C)C
Reactant: CN1CC[C@H](CNS(=O)(=O)c2cc(Br)cnc2N)C1
Product: CC1=Cc2ncnc(N3CCOc4ccc(-c5cnc(N)c(S(=O)(=O)NC[C@H]6CCN(C)C6)c5)cc4C3)c2CC1(C)C

Procedure:
Prepared according to the method of 5 by using 2-amino-5-bromo-N-{[(3S)-1-methylpyrrolidin-3-yl]methyl}pyridine-3-sulfonamide (reagent preparation 25) and [4-(6,6,7-trimethyl-5,6-dihydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, Methanol-d4): 8.35 (s, 1H), 8.25 (s, 1H), 8.07 (s, 1H), 7.37 (s, 1H), 7.32 (d, 1H), 6.97 (d, 1H), 6.07 (s, 1H), 4.58 (s, 2H), 4.23 (m, 2H), 3.84 (m, 2H), 2.86 to 2.78 (m, 3H), 2.72 (m, 2H), 2.63 (s, 2H), 2.46 (m, 1H), 2.40 (s, 3H), 2.34 (m, 1H), 1.93 (m, 1H), 1.83 (s, 3H), 1.46 (m, 1H), 0.99 (s, 6H); MS (EI) for C31H39N7O3S: 590 (MH+).
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([CH3:25])[NH:23][CH:24]=2)=[CH:16][CH:15]=1)C1C=CC=CC=1>CO.[Pd]>[CH3:25][C:22]1[NH:23][CH:24]=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:12][CH2:11][NH2:10])=[CH:15][CH:16]=2)[N:21]=1
Reactant: Cc1nc(-c2ccc(OCCNC(=O)OCc3ccccc3)cc2)c[nH]1
Agent: [Pd]
Solvent: CO
Product: Cc1nc(-c2ccc(OCCN)cc2)c[nH]1
Reaction time: 4 h
Yield: 102.5 %

Procedure:
In a nitrogen-purged Parr flask, benzyl-{2-[4-(2-methyl-1H-imidazol-4-yl)-phenoxy]-ethyl}-carbamate (78 mg, 0.22 mmol) was dissolved in methanol (15 ml), and 10% Pd/C (20mg) was added in one portion. The material was then hydrogenated at about 45 psi for about four hours. The reaction mixture was then filtered through a pad of diatomaceous earth and the filter pad was washed with methanol. The filtrate was concentrated in vacuo, and the resulting material (49 mg, 100% yield) was carried on without further purification. LRMS ([M+H]+)=218.2.
Reaction SMILES: [C:1](O)(=O)C(O)=O.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)[CH2:15][CH3:16])=[CH:10][CH:9]=1.C=O>C(O)=O>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([N:17]([CH2:18][CH2:19][CH2:20][N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)[CH3:1])[CH2:15][CH3:16])=[CH:10][CH:9]=1
Reactant: CCC(NCCCn1ccnc1)c1ccc(Cl)cc1
Reactant: O=C(O)C(=O)O
Agent: C=O
Solvent: O=CO
Product: CCC(c1ccc(Cl)cc1)N(C)CCCn1ccnc1
Temperature: 95 °C

Procedure:
n-[1-(4-Chlorophenyl)propyl]-3-(imidazol-1-yl)propylamine (13.9 g, free base of Example 30) was added in portions to formic acid (11.75 g, 98-100%) at 0° C. Formaldehyde (9.6 g, 37%) was added and the mixture heated at 95° C. for 6 hours. Work-up as described in Example 90 gave N-[1-(4-chlorophenyl)propyl]-3-(imidazol-1-yl)-N-methylpropylamine as an oil which was not distilled.
Reaction SMILES: [OH-].[Na+].FC1C=CC(S([N:13]2[C:21]3[C:16](=[C:17]([CH2:24][N:25]4[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]4)[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=3)[CH:15]=[CH:14]2)(=O)=O)=CC=1>CCO>[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16]([CH:15]=[CH:14][NH:13]2)=[C:17]([CH2:24][N:25]2[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH2:30]2)[CH:18]=1
Reactant: COc1cc(CN2CCN(C(=O)OC(C)(C)C)CC2)c2ccn(S(=O)(=O)c3ccc(F)cc3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(CN2CCN(C(=O)OC(C)(C)C)CC2)c2cc[nH]c2c1

Procedure:
40% W/w aq. NaOH (1 mL) was added to tert-butyl 4-({1-[(4-fluorophenyl)sulfonyl]-6-methoxy-1H-indol-4-yl}methyl)piperazine-1-carboxylate (626 mg, 1.12 mmol) in EtOH (10 mL). The reaction was refluxed for 1.5 h, allowed to attain rt. and extracted with DCM (2×50 mL) and water (40 mL). The organic layers were combined, dried and concentrated to give 450 mg crude product. Purification was performed by preparative HPLC/UV (System A, 30-65% MeCN, 0.1% NH4OAc). The residue was extracted with DCM and water and the organic layer was dried, filtered and concentrated to give the title compound (130 mg, 32%, from 1-[(4-fluorophenyl)sulfonyl]-6-methoxy-4-vinyl-1H-indole; prepared according to the method of Intermediate 33) as a light brown solid. MS (ESI+) for C19H27N3O3 m/z 346 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[C:15]([S:20][CH:21]([NH:28][C:29](=[O:32])[CH2:30]O)[C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:35])=O>ClCCl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[C:15]([S:20][CH:21]([NH:28][C:29](=[O:32])[CH2:30][Cl:35])[C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(NC(=O)c2cccnc2SC(NC(=O)CO)c2ccncc2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc(NC(=O)c2cccnc2SC(NC(=O)CCl)c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
N-(4-tert-Butylphenyl)-2-(2-hydroxyacetylaminopyridin-4-ylmethylthio)pyridine-3-carboxamide (Compound No. 12-8, 250 mg, 0.55 mmol) was suspended in anhydrous dichloromethane (5.0 mL) under ice-cooling, and thionyl chloride (80 μL, 1.1 mmol) was added thereto. The mixture was stirred for 6 hours at room temperature, and the solvent was evaporated under reduced pressure. The resulting solid was filtered off with ethyl acetate and washed with diethyl ether to give 270 mg of the target compound quantitatively as a pale yellow solid.
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])(CC)C.CN(C)[CH:19]=[O:20].Cl>O1CCCC1.C(OCC)(=O)C>[NH:8]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=2[CH:19]=[O:20])=[N:11][N:10]=[N:9]1
Reactant: c1ccc(-c2nnn[nH]2)cc1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]C(C)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=Cc1ccccc1-c1nnn[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.5 %

Procedure:
To a solution of 5-phenyl-1H-tetrazole (500 mg, 3.42 mmol) in 10 mL of dry tetrahydrofuran was added dropwise s-butyllithium (1.04 mol/L, 6.6 mL, 6.9 mmol) under nitrogen at −78° C. After the reaction mixture was stirred at the same temperature for 30 min, N,N-dimethylformamide (2 mL, 30 mmol) was added dropwise. After the reaction mixture was stirred at room temperature for 10 min, 1M HCl (10 mL) was added. The solution was allowed to warm up to room temperature, diluted with ethyl acetate, and extracted. The extract was washed with brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by recrystallization (hexane 2.5 mL, ethyl acetate 2.5 mL) to obtain the title compound (390 mg, 99%).
Reaction SMILES: [Cl-].[NH4+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:11][CH2:12][NH:13][C:14](OC2C=CC=CC=2)=[O:15])=[CH:6][CH:5]=1.C([N:33](CC)CC)C>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:11][CH2:12][NH:13][C:14]([NH2:33])=[O:15])=[CH:6][CH:5]=1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)NC(CCNC(=O)Oc1ccccc1)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(CCNC(N)=O)c1ccc(Cl)cc1
Reaction time: 24 h
Yield: 100.5 %

Procedure:
Ammonium chloride (113 mg, 2.11 mmol) was added in one portion to tert-butyl N-[1-(4-chlorophenyl)-3-(phenoxycarbonylamino)propyl]carbamate (Intermediate 109) (427 mg, 1.05 mmol) and triethylamine (0.882 mL, 6.33 mmol) in DMF (3 mL). The resulting solution was stirred at 0.352 molar for 24 hours. The reaction mixture was concentrated and diluted with EtOAc (20 mL) and washed with water (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford tert-butyl 1-(4-chlorophenyl)-3-ureidopropylcarbamate (346 mg, 100%),
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.[CH2:16]([NH2:18])[CH3:17]>C1COCC1>[CH2:16]([NH:18][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1)[CH3:17]
Reactant: COc1ccc2nc(Cl)c(C=O)cc2c1
Reactant: CCN
Solvent: C1CCOC1
Product: CCNc1nc2ccc(OC)cc2cc1C=O
Temperature: 160 °C
Reaction time: 6 h
Yield: 76 %

Procedure:
To a stirred solution of 2-chloro-6-methoxyquinoline-3-carbaldehyde (1.51 g, 6.80 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added ethylamine (2 M in THF, 33.8 mL, 67.6 mmol) and the mixture was stirred at 160° C. for 6 h under microwave irradiation. After cooling to RT, the volatiles were removed under vacuum at 40° C. and the resulting yellow oil was taken up in a mixture of THF:1 N aq. HCl=1:1 (50 mL) and stirred for 15 min at RT. THF was removed at 40° C. under vacuum and the residue was then neutralised with a saturated NaHCO3 aqueous solution before to be extracted with CH2Cl2 (100 mL). The organic phase was washed with brine (20 mL), dried over MgSO4, filtered, and concentrated at 40° C. under vacuum to give 2-(ethylamino)-6-methoxyquinoline-3-carbaldehyde SLA 28162 as an orange oil (1.19 g, 76% yield).
Reaction SMILES: B#B.[C:3]([N:22]1[CH2:25][CH:24]([OH:26])[CH2:23]1)(=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[ClH:27]>O1CCCC1>[ClH:27].[CH2:3]([N:22]1[CH2:25][CH:24]([OH:26])[CH2:23]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCCCCCCC(=O)N1CC(O)C1
Agent: B#B
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCN1CC(O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 85 ml of 0.98 M diborane in tetrahydrofuran, maintained at about 10° C. under a nitrogen atomosphere, add a solution of 8.16 g 1-octadecanoyl-3-hydroxyazetidine in 420 ml dry tetrahydrofuran over a period of 1.5 hours. Stir for one hour at room temperature then heat for 1.5 hours at 55°-60° C. Allow the reaction mixture to cool to room temperature and cautiously acidify with 30 ml 6 M aqueous hydrochloric acid. Reflux for one hour and distill in vacuo until about 150 ml solvent is removed. Dilute the residue with 450 ml water and basify with 20 ml 50% aqueous sodium hydroxide. Extract three times with 150 ml portions of ethyl ether, dry the combined ethereal extracts over anhydrous sodium sulfate, and strip off solvent in vacuo. Dissolve the residue in 150 ml ethanol containing 12 ml 1.9 M ethereal hydrochloric acid and reflux under nitrogen for 0.5 hour. Remove the solvent in vacuo and triturate the residue with 280 ml ethyl ether to obtain 1-octadecyl-3-hydroxyazetidine hydrochloride, m.p. 108.5°-115° C. Stir this hydrochloride salt with 120 ml water, 10 ml 2.5 M sodium hydroxide and 40 ml methylene chloride for one hour. Separate the layers and extract the aqueous layer three times with 100 ml portions of methylene chloride. Combine the organic layer and extracts, dry over anhydrous sodium sulfate and remove the solvents in vacuo to obtain 1-octadecyl-3-hydroxyazetidine, m.p. 75.5°-78° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]([CH3:23])[C:9]([NH:11][C:12]1[N:13]=[C:14](Br)[C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:10])([CH3:4])([CH3:3])[CH3:2].[C:25]([C:27]1[CH:31]=[CH:30][S:29][CH:28]=1)#[CH:26].CCN(C(C)C)C(C)C>CN1C(=O)CCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]([CH3:23])[C:9](=[O:10])[NH:11][C:12]1[N:13]=[C:14]([C:26]#[C:25][C:27]2[CH:31]=[CH:30][S:29][CH:28]=2)[C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)Nc1cc2ccccc2c(Br)n1
Reactant: C#Cc1ccsc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(NC(=O)OC(C)(C)C)C(=O)Nc1cc2ccccc2c(C#Cc2ccsc2)n1

Procedure:
A mixture of tert-butyl-N-[1-[(1-bromoisoquinolin-3-yl)amino]-1-oxopropan-2-yl]-carbamate B4a (150 mg, 0.38 mmol), 3-ethynylthiophene (45 mg, 0.42 mmol), copper(I) iodide (7 mg, 0.04 mmol), Dichlorobis(triphenylphosphine)palladium(II) (27 mg, 0.04 mmol) and DIPEA (200 μl, 2 mmol) is stirred under argon atmosphere in NMP (1 ml) for 1 h at 80° C. The mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 102 mg (64%). HPLC-MS: M+H=422; tR=1.99 min (*Method—4).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH2:11][CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:15][CH2:14]2)[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:26])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[C:9]([CH2:11][CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:15][CH2:14]2)[CH:8]=[CH:7][C:3]=1[C:4]([Cl:26])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: CCCCC[C@H]1CC[C@H](CCc2ccc(C(=O)O)c(F)c2)CC1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCC[C@H]1CC[C@H](CCc2ccc(C(=O)Cl)c(F)c2)CC1

Procedure:
First, 2.1 g (6.4 mmol) of 2-fluoro-4-(2-(trans-4-pentyl-cyclohexyl)ethyl)benzoic acid was mixed with 1.1 g (9.6 mmol) of thionyl chloride, 0.1 ml of pyridine, and 3 ml of toluene, and reacted at 80° C. for 3 hours. Excess amount of thionyl chloride and toluene were distilled off at a reduced pressure to obtain a crude 2-fluoro-4-(2-(trans-4-pentyl-cyclohexyl)ethyl)benzoyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4]/[CH:5]=[CH:6]/[C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][C:11]([NH:17][CH2:18][C:19]1[O:20][C:21]([CH3:24])=[CH:22][CH:23]=1)=[N:12]2.[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][C:11]([NH:17][CH2:18][C:19]1[O:20][C:21]([CH3:24])=[CH:22][CH:23]=1)=[N:12]2
Reactant: COC(=O)C/C=C/c1cccc2nc(NCc3ccc(C)o3)ccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CCCc1cccc2nc(NCc3ccc(C)o3)ccc12

Procedure:
(E)-4-{2-[(5-Methyl-furan-2-ylmethyl)-amino]-quinolin-5-yl}-but-3-enoic acid methyl ester (290 mg, 0.86 mmol) was dissolved in 45 mL ethanol. Palladium on charcoal (10%, 92 mg, 0.086 mmol) was added and the reaction mixture war hydrogenated with a hydrogen balloon overnight. The palladium was filtered off and the solvent was evaporated. The title compound was obtained as a brown oil (256 mg, 88%), MS: m/e=339.1 (M+H+).
Reaction SMILES: [C:1]([S:4][CH2:5]/[C:6](=[CH:10]\[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)/[C:7]([OH:9])=O)(=[O:3])[CH3:2].[NH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>>[O:9]=[C:7]([NH:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])/[C:6](/[CH2:5][S:4][C:1](=[O:3])[CH3:2])=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1
Reactant: CC(=O)SC/C(=C\c1ccc(-c2ccccc2)cc1)C(=O)O
Reactant: NCCC(=O)OCc1ccccc1
Product: CC(=O)SC/C(=C\c1ccc(-c2ccccc2)cc1)C(=O)NCCC(=O)OCc1ccccc1
Yield: 56 %

Procedure:
The (Z)-2-acetylthiomethyl-3-(4-phenylphenyl) propenoic acid obtained in step C is coupled with benzyl β-alaninate according to the experimental procedure described in Example 1 (step D). Yield: 56% (purification by flash chromatography, eluent: ether/petroleum ether 6/4) m.p. 79° C. IR (nujol): 3280, 1740, 1690, 1640, 1620 cm-1 1H NMR (CDCl3 /TMS): 7.75 (s, 1H); 7.65 to 7.20 (m, 14H); 7.05 (t, 1H, J=5 Hz); 5.0 (s, 2H); 4.15 (s, 2H); 3.65 (q. app., 2H, J app.=6 Hz); 2.65 (t, 2H, J=6Hz); 2.30 (s, 3H). Microanalysis: C28H27O4NS Calc. % C=71.01 H=5.75 N=2.96 Found. % C=71.08 H=5.60 N=2.46
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][N:7]=[C:6](SC)[C:5]=2[N:4]=[CH:3]1.[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][NH2:17]>>[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][NH:17][C:6]1[C:5]2[N:4]=[CH:3][N:2]([CH3:1])[C:10]=2[CH:9]=[CH:8][N:7]=1
Reactant: NCc1ccccc1Cl
Reactant: CSc1nccc2c1ncn2C
Product: Cn1cnc2c(NCc3ccccc3Cl)nccc21

Procedure:
A mixture of 17.9 of 1-methyl-4-methylthio-1H-imidazo(4,5-c)pyridine (m.p. 170°-175°) and 28 g of o-chlorobenzylamine is heated to 170°-180° for 20 hours. After cooling and customary working up, 4-o-chlorobenzylamino-1-methyl-1H-imidazo(4,5-c)pyridine of m.p. 173°-176° is obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@@:4]1([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[C:34]([N:36]=[C:37](SC)[S:38][CH3:39])#[N:35]>C(#N)C>[C:34]([N:36]=[C:37]([S:38][CH3:39])[NH:1][CH2:2][CH2:3][C@@:4]1([C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1)#[N:35]
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCN)(c2ccc(F)cc2)OC1=O
Reactant: CSC(=NC#N)SC
Solvent: CC#N
Product: CSC(=NC#N)NCC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3F)cc2)C(=O)O1
Yield: 100.5 %

Procedure:
A mixture of (R)-6-(2-aminoethyl)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluoro phenyl)-1,3-oxazinan-2-one (40 mg, 0.09 mmol) and dimethyl cyanocarbonimidodithioate (40 mg, 0.27 mmol) in acetonitrile (4 mL) was heated to reflux overnight. The solvent was removed to give methyl N′-cyano-N-(2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl)carbamimidothioate (50 mg, crude), which was used for the next step without purification.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[NH:15][C:16](=[O:19])[CH2:17]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:20]([C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[NH:15][C:16](=[O:19])[CH2:17][N:36]1[CH2:37][CH2:38][CH:33]([C:30]2[CH:31]=[CH:32][C:27]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:28][CH:29]=2)[CH2:34][CH2:35]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Oc2ccc(C3CCNCC3)cc2)cc1
Reactant: Cc1cccc(Cc2ccccc2)c1NC(=O)CBr
Product: Cc1cccc(Cc2ccccc2)c1NC(=O)CN1CCC(c2ccc(Oc3ccccc3)cc2)CC1

Procedure:
The compound (13) synthesized in Reference Example 13 and the compound (4) synthesized in Reference Example 4 were used to produce the above compound in the same way as Example 1.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[Cl:26])=[C:16]([C:27](OCC)=[O:28])[CH:15]=[N:14][C:13]=12)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1>>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[Cl:26])=[C:16]([C:27]([N:42]3[CH2:43][CH2:44][CH:39]([C:36]4[CH:35]=[CH:34][C:33]([F:32])=[CH:38][CH:37]=4)[CH2:40][CH2:41]3)=[O:28])[CH:15]=[N:14][C:13]=12)(=[O:8])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)c1cnc2c(S(=O)(=O)NC(C)(C)C)cnn2c1Nc1cc(F)ccc1Cl
Reactant: Fc1ccc(C2CCNCC2)cc1
Product: CC(C)(C)NS(=O)(=O)c1cnn2c(Nc3cc(F)ccc3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 66.3 %

Procedure:
Using ethyl 3-(N-tert-butylsulfamoyl)-7-(2-chloro-5-fluorophenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylate (4.16 g, 8.85 mmol) obtained in step 3 and 4-(4-fluorophenyl)piperidine (2.04 g, 11.4 mmol) instead of 4-phenylpiperidine, and in the same manner as in Example 1 step 4, the title compound (3.54 g, 77%) was obtained.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[Cl:5][C:6]1[CH:15]=[C:14]([S:16][CH2:17][C:18]([F:21])([F:20])[F:19])[CH:13]=[C:12]([Cl:22])[C:7]=1[O:8][CH2:9][CH2:10]Br>>[Cl:22][C:12]1[CH:13]=[C:14]([S:16][CH2:17][C:18]([F:20])([F:21])[F:19])[CH:15]=[C:6]([Cl:5])[C:7]=1[O:8][CH2:9][CH2:10][NH:4][CH2:1][CH2:2][CH3:3]
Reactant: CCCN
Reactant: FC(F)(F)CSc1cc(Cl)c(OCCBr)c(Cl)c1
Product: CCCNCCOc1c(Cl)cc(SCC(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
5 g of n-Propylamine were added to 2.38 g of 2-[2,6-dichloro-4-(2,2,2-trifluoroethylthio)-phenoxy]-ethyl bromide, and the mixture was stirred at room temperature for 8 hours and then under reflux for 3 hours. The excess of n-propylamine was evaporated. To the residue were added 20 ml of water, 20 ml of a 5% aqueous solution of potassium hydroxide and 100 ml of toluene. The mixture was stirred, and the organic layer was separated, washed with water and dried over anhydrous sodium sulfate. Low-boiling compounds were evaporated under reduced pressure. There were obtained 2.16 g of crude N-{2-[2,6-dichloro-4-(2,2,2-trifluoroethylthio)-phenoxy]-ethyl}-N-(propyl)-amine having a refractive indes of nD20 =1.5210, which were used without further purification) for the preparation of compound No. 1 shown above.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][N:15]2[CH2:24][CH2:23][C:18]3(OCC[O:19]3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.Cl>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][N:15]2[CH2:16][CH2:17][C:18](=[O:19])[CH2:23][CH2:24]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2ccccc2CN2CCC3(CC2)OCCO3)cc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=C1CCN(Cc2ccccc2-c2ccc(Cl)cc2)CC1
Temperature: 85 °C
Yield: 100.1 %

Procedure:
8-((4′-Chlorobiphenyl-2-yl)methyl)-1,4-dioxa-8-azaspiro[4.5]decane (4.73 g, 13.76 mmol) was dissolved in dioxane (50 mL) and water (30 mL). Hydrochloric acid (37%, 14.3 mL, 174 mmol) was added, and the reaction was heated to 85° C. for 26 hours. After cooling to room temperature, the volatiles are removed in vacuo. The remaining aqueous phase is basified to pH ˜9 with 2M NaOH, and then extracted with CH2Cl2. The organic layers are dried over MgSO4 and concentrated to afford the title compound (4.13 g, 100% yield). MS (ESI) m/e (M+H)+: 300.4