Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]2[CH:38]=[C:37]([CH3:39])[C:32]3[NH:33][C:34]([CH3:36])=[N:35][C:31]=3[CH:30]=2)[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:36][C:34]1[NH:33][C:32]2[C:37]([CH3:39])=[CH:38][C:29]([NH:28][C:24]3[N:25]=[CH:26][N:27]=[C:22]([N:17]4[CH2:18][CH2:19][CH:14]([N:10]5[CH2:9][CH2:8][C:7]6[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=6[NH:12][C:11]5=[O:13])[CH2:15][CH2:16]4)[CH:23]=3)=[CH:30][C:31]=2[N:35]=1
Reactant: Cc1nc2cc(Nc3cc(Cl)ncn3)cc(C)c2[nH]1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Nc4cc(C)c5[nH]c(C)nc5c4)ncn3)CC1)C(=O)N2

Procedure:
265 mg (0.962 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 250 mg (0.913 mmol) (6-chloro-pyrimidin-4-yl)-(2,7-dimethyl-1H-benzimidazol-5-yl)-amine and 1.00 mL (5.81 mmol) DIPEA were refluxed in 1.5 mL DMF. After the reaction had ended the reaction mixture was diluted with some DMF and microfiltered. The filtrate was purified by preparative HPLC. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:19])=[C:5]([CH3:18])[C:6]2[O:11][C:10]([C:13](O)=[O:14])([CH3:12])[CH2:9][CH2:8][C:7]=2[C:16]=1[CH3:17].S(Cl)([Cl:22])=O>CN(C)C=O.ClCCCl>[CH3:1][O:2][C:3]1[C:4]([CH3:19])=[C:5]([CH3:18])[C:6]2[O:11][C:10]([C:13]([Cl:22])=[O:14])([CH3:12])[CH2:9][CH2:8][C:7]=2[C:16]=1[CH3:17]
Reactant: COc1c(C)c(C)c2c(c1C)CCC(C)(C(=O)O)O2
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1c(C)c(C)c2c(c1C)CCC(C)(C(=O)Cl)O2

Procedure:
To a solution composed of 3.0 g of (3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-benzopyran-2-yl)carboxylic acid, 2 drops of N,N-dimethylformamide and 50 ml of 1,2-dichloroethane was added 1.1 ml of thionyl chloride and the mixture was refluxed for 2 hours. After cooling, the reaction mixture was evaporated under reduced pressure to remove the low-boiling substances. This procedure gave (3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-benzopyran-2-yl)carbonyl chloride in a quantitative yield of 3.39 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:13]=2[C:14]([OH:16])=[O:15])[N:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:34](O)[C:35]#[CH:36].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:13]=2[C:14]([O:16][CH2:36][C:35]#[CH:34])=[O:15])[N:6]=1
Reactant: C#CCO
Reactant: COc1cc(OC)nc(Oc2cccc(F)c2C(=O)O)n1
Agent: O=C([O-])[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C#CCOC(=O)c1c(F)cccc1Oc1nc(OC)cc(OC)n1
Yield: 53.1 %

Procedure:
2-(4,6-dimethoxypyrimidin-2-yl)oxy-6-fluorobenzoic acid (3.0 g) and carbonyldiimidazole (1.8 g) was dissolved in tetrahydrofuran (50 ml), and the solution was refluxed under heating for one hour. The reaction solution was cooled. Then, propargyl alcohol (2.0 g) and potassium carbonate (1.7 g) were added thereto, and the mixture was refluxed under heating for one hour. The mixture was poured into water and extracted with ethyl ether. The extract was washed with water and dried. Then, the solvent was distilled off, and the residue thereby obtained was purified by silica gel column chromatography to obtain propargyl 2-(4,6-dimethoxypyrimidin-2-yl)oxy-6-fluorobenzoate (1.8 g). Yield: 53%, white crystals, Melting point: 49°-50° C.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[C:12]2[N:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6][CH2:5][CH2:4]1.[CH3:13][N:14]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:17][N:16]=[C:15]1[CH:25]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.CC(O)=O>[CH3:1][N:2]([CH2:25][C:15]1[N:14]([CH3:13])[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:17][N:16]=1)[CH:3]1[C:12]2[N:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6][CH2:5][CH2:4]1
Reactant: Cn1c(C=O)nnc1-c1ccccc1
Reactant: CNC1CCCc2cccnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN(Cc1nnc(-c2ccccc2)n1C)C1CCCc2cccnc21
Temperature: 65 °C
Reaction time: 18 h

Procedure:
To a solution of N-methyl-5,6,7,8-tetrahydroquinolin-8-amine, 5, (0.39 g, 2.40 mmol) in 1,2-dichloroethane (4 mL) was added 4-methyl-5-phenyl-4H-1,2,4-triazole-3-carbaldehyde, 36, (0.41 g, 2.20 mmol), sodium triacetoxyborohydride (0.84 g, 3.90 mmol), and AcOH (1 drop). The reaction mixture was heated to 65° C. and stirred for 18 h. The reaction mixture was cooled to room temperature, poured into saturated aqueous NaHCO3 (10 mL) and extracted with ethyl acetate (2×10 mL). The combined organic phases were washed with brine then dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified via chromatography on basic alumina (0-5% methanol/dichloromethane) yielding BP: 1H NMR (400 MHz, CDCl3) δ 8.39, (d, J=4.8 Hz, 1H), 7.58-7.53 (m, 2H), 7.46-7.39, (m, 3H), 7.32, (d, J=8.4 Hz, 1H), 7.01, (dd, J=7.2, 4.4 Hz, 1H), 4.04-3.92, (m, 2H), 3.78, (d, J=14.0 Hz, 1H), 2.85-2.74, (m, 1H), 2.71-2.62 (m, 1H), 3.33, (s, 3H), 2.12-1.94 (m, 3H), 1.74-1.62 (m, 1H); ESI+ MS: m/z (rel intensity) 334 (100, M+H).
Reaction SMILES: [F:1][C:2]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:3]=1[CH2:4][C:5]1[C:6]([NH:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])=[C:7]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=2)[C:8]2[C:15](=[O:16])[N:14]3[C@@H:10]([CH2:11][CH2:12][CH2:13]3)[C:9]=2[N:17]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[NH2:62][C@H:63]1[C:71]2[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=2)[CH2:65][CH2:64]1>ClCCl>[F:1][C:2]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:3]=1[CH2:4][C:5]1[C:6]([NH:27][C:28](=[O:33])[C:29]([F:30])([F:32])[F:31])=[C:7]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH:62][C@H:63]3[C:71]4[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=4)[CH2:65][CH2:64]3)=[O:24])=[CH:20][CH:19]=2)[C:8]2[C:15](=[O:16])[N:14]3[C@@H:10]([CH2:11][CH2:12][CH2:13]3)[C:9]=2[N:17]=1
Reactant: N[C@@H]1CCc2ccccc21
Reactant: O=C(O)c1ccc(-c2c(NC(=O)C(F)(F)F)c(Cc3ccc(F)cc3F)nc3c2C(=O)N2CCC[C@@H]32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: O=C(N[C@@H]1CCc2ccccc21)c1ccc(-c2c(NC(=O)C(F)(F)F)c(Cc3ccc(F)cc3F)nc3c2C(=O)N2CCC[C@@H]32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the 2.0 ml dichloromethane solution containing the acid (G, 4-{(9aS)-2-(2,4-difluorobenzyl)-5-oxo-3-[(trifluoroacetyl)amino]-7,8,9,9a-tetrahydro-5H-pyrido[2,3-a]pyrrolizin-4-yl}benzoic acid, 956 mg, 1.8 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (691 mg, 3.6 mmol) and 1-hydroxybenzotriazole hydrate, 480 mg (R)-(−)-1-aminoindan (3.6 mmol) was added. The resulting mixture was stirred at room temperature for 3 hours. Diluted with dichloromethane. Washed with water and brine subsequently. Dried with sodium sulfate. Upon the removal of the solvent, the residue was purified with flash chromatography. 320 mg of the title compound as a light yellowish solid was obtained. NMR (400 MHz, CDCl3) δ 7.95 (m, 2H), 7.32 (m, 5H), 6.95 (m, 4 m), 5.62 (m, 1H), 4.59 (m, 1H), 4.15 (m, 1H), 3.55 (s, 2H), 3.15 (m, 1H), 3.06 (m, 1H), 2.90 (m, 1H), 2.58 (m, 1H), 2.32 (m, 2H), 2.02 (m, 1H), 1.25 (m, 1H) ppm. ESI-MS m/z 647 (M+H)+, 645 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].CC[O:12][CH:13]=[C:14]([C:20](OCC)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[CH2:18]([O:17][C:15]([C:14]1[C:13](=[O:12])[C:6]2[C:4](=[CH:3][C:2]([Cl:1])=[C:8]([F:9])[CH:7]=2)[NH:5][CH:20]=1)=[O:16])[CH3:19]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccc(F)c(Cl)c1
Product: CCOC(=O)c1c[nH]c2cc(Cl)c(F)cc2c1=O
Reaction time: 2 h
Yield: 118.8 %

Procedure:
A mixture of 3-chloro-4-fluoroaniline (1.46 g) and diethyl ethoxymethylene malonate (2.16 g) was heated at 120°-130° C. After 2 hours, the resulting ethanol was evaporated off. The residue was added to diphenyl ether (50 ml) and refluxed for 1 hour. After the solution cooled, the resulting precipitate was filtered, washed with benzene, and dried. The solid was recrystallized from N,N-dimethylformamide (DMF) to give 7-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester (3.2 g).
Reaction SMILES: [F:1][C:2]([F:22])([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=1)[C:3]1[N:12]=[C:11](O)[C:10]2[C:5](=[CH:6][C:7]([CH3:14])=[CH:8][CH:9]=2)[N:4]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>N1C=CC=CC=1>[F:1][C:2]([F:22])([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=1)[C:3]1[N:12]=[C:11]([SH:32])[C:10]2[C:5](=[CH:6][C:7]([CH3:14])=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1ccc2c(O)nc(C(F)(F)c3ccc(F)cn3)nc2c1
Solvent: c1ccncc1
Product: Cc1ccc2c(S)nc(C(F)(F)c3ccc(F)cn3)nc2c1
Temperature: 170 °C

Procedure:
To 2-(difluoro(5-fluoropyridin-2-yl)methyl)-7-methylquinazolin-4-ol (413 mg, 1.35 mmol) were added Lawesson's reagent (820 mg, 2.03 mmol) and pyridine (3.5 mL), and the mixture was heated at 170° C. in a microwave reactor for 20 min. The mixture was partitioned between EtOAc (30 mL) and saturated aq NaHCO3 (50 mL), and the separated aqueous phase was extracted with EtOAc (2×30 mL). The combined organic layers were washed with 2N HCl and brine, dried over Na2SO4, and concentrated under reduced pressure onto Celite. The mixture was purified by silica get chromatography eluting with 0-30% EtOAc/hexanes to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-7-methylquinazoline-4-thiol as an impure mixture (0.249 g). LCMS (ESI) m/z 322 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[N:8]=[CH:7][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][OH:18])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[N:21]#[C:22][NH2:23].OS(C(F)(F)F)(=O)=O>C1COCC1>[C:22](=[NH:21])([O:18][CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C:6]2[CH:7]=[N:8][C:3]([C:2]([F:19])([F:1])[F:20])=[CH:4][CH:5]=2)=[CH:11][CH:12]=1)[NH2:23]
Reactant: N#CN
Reactant: OCCc1ccc(Oc2ccc(C(F)(F)F)nc2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCOC1
Product: N=C(N)OCCc1ccc(Oc2ccc(C(F)(F)F)nc2)cc1
Temperature: 55 °C
Yield: 57 %

Procedure:
To a solution of 2-(4-{[6-(trifluoromethyl)-3-pyridinyl]oxy}phenyl)ethanol (1.95 g, 6.88 mmol) and cyanamide (0.5 g, 11.89 mmol) in dry THF (20 mL) under nitrogen was added triflic acid (1 mL, 11.26 mmol). The mixture was heated at 55° C. for 4 h. Purification via reverse phase flash chromatography afforded the title compound (1.72 g, 3.92 mmol, 57.0% yield) as a white solid. LCMS: rt=2.42 min, [M+H+]=326
Reaction SMILES: [CH3:1][C:2](=[O:8])[CH2:3][CH2:4][C:5](=[O:7])[CH3:6].[CH2:9](O)[CH2:10][OH:11].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.C(OCC)(=O)C>[CH3:6][C:5]1([CH2:4][CH2:3][C:2](=[O:8])[CH3:1])[O:11][CH2:10][CH2:9][O:7]1
Reactant: CC(=O)CCC(C)=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CC(=O)CCC1(C)OCCO1

Procedure:
A commercially available hexan-2,5-dion (137 g) was dissolved in benzene (300 ml). Thereafter, ethylene glycol (100 ml) and p-toluenesulfonic acid (11.4 g) were added to the solution, and the mixture was then dehydrated by heating to reflux for 5 hours. The reaction product was diluted with ethyl acetate, and then washed with an aqueous saturated sodium bicarbonate solution and a saturated saline solution. The organic layer was then dried over anhydrous sodium sulfate. The solvent was-distilled off under a reduced pressure, and the residue was subjected to vacuum distillation (80° C. to 82° C./3 mmHg) to obtain 4-(2-methyl[1,3]dioxolan-2-yl)butan-2-one (56.83 g).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)=[C:4]([C:16]2[CH:21]=[CH:20][C:19](Cl)=[CH:18][CH:17]=2)[CH:3]=1.[C:23]1([SH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:15][S:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[N:6]=[N:7][C:2]([S:14][C:11]3[CH:12]=[CH:13][CH:8]=[CH:9][CH:10]=3)=[CH:3][C:4]=2[C:16]2[CH:21]=[CH:20][C:19]([S:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)=[CH:9][CH:10]=1
Reactant: Sc1ccccc1
Reactant: CSc1ccc(-c2nnc(Cl)cc2-c2ccc(Cl)cc2)cc1
Product: CSc1ccc(-c2nnc(Sc3ccccc3)cc2-c2ccc(Sc3ccccc3)cc2)cc1

Procedure:
In a similar manner as in Example 2, 6-chloro-4-(4-chlorophenyl)-3-[4-(methylthio)phenyl]pyridazine (150 mg, 0.303 mmol) and thiophenol (119 mg) were reacted as starting materials at 150° C. for 20 hours and post-treatment was then conducted, whereby the title compound was obtained as a pale yellow crystalline powder (85.0 mg, 39.8%). Melting point: 53.3-56.2° C.(diethyl ether-hexane).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=1.[CH:21](O)=O>>[CH3:20][S:19][C:16]1[CH:17]=[CH:18][C:13]([N:12]2[C:3]3[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=3[N:1]=[CH:21]2)=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(N)c(Nc2ccc(SC)cc2)c1
Reactant: O=CO
Product: COC(=O)c1ccc2ncn(-c3ccc(SC)cc3)c2c1
Yield: 74 %

Procedure:
A solution of methyl 4-amino-3-[[4-(methylthio)phenyl]amino]benzoate (5.78 g, 20.0 mmol) in formic acid (50 mL) was stirred at 100° C. overnight. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from hexane/ethyl acetate to give the title compound (4.44 g, yield 74%) as colorless crystals.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:7]([CH2:17][O:18][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:6]1)(=[O:3])[CH3:2].C(O)(=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([O:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[C@H:7]([CH2:17][OH:18])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1C[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)N(C(=O)OC(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(=O)O[C@H]1C[C@@H](CO)N(C(=O)OC(C)(C)C)C1
Reaction time: 24 h
Yield: 79.8 %

Procedure:
To a stirred mixture of (2S,4S)-4-acetoxy-1-tert-butoxycarbonyl-2-tert-butyldiphenylsilyloxymethypyrrolidine (23.3 g, 46.9 mmol) and acetic acid (6.0 ml, 104.8 mmol) in THF (470 ml) was added TBAF (93.8 ml, 93.8 mmol) at 0° C. After 24 h stirring, the mixture was concentrated in vacuo. The resulting residue was diluted with EtOAC and aq. NH4Cl and extracted with EtOAc. The combined extracts were washed with brine, which were dried over Na2SO4 and concntrated in vacuo. The residue was chromatographed on silica gel (700 g, CHCl3/EtOAc (4/1)], to give (2S,4S)-4-acetoxy-1-tert-butoxycarbonyl-2-pyrrolidinemethanol (9.70 g, 8%) as a colorless oil. 1H-NMR (CDCl3) δ1.47 (s, 9H), 1.63 (m, 1H), 1.81 (m, 1H), 2.07 (s, 3H), 234 (m, 1H), 3.42 (dd, J=12.7, 0.9 Hz, 1H), 3.62-3.85 (m, 3H), 4.48 (br, 1H), 5.20 (br, 1H).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH:14]=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.N1(C2C=C[C:24]([CH:25]=[O:26])=CC=2)C=CC=N1>>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH:12]=[CH:13][CH:14]=[CH:24][CH:25]=[O:26])=[CH:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=CC=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=CC=CC=Cc1ccc(-n2cccn2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 3-[4-(1H-pyrazol-1-yl)phenyl]-2-propenal (prepared as described in Reference Example 30) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 225 (M+H)+.
Reaction SMILES: [ClH:1].[CH3:2][S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10]N.Cl.O.[NH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.Cl>C(O)C>[ClH:1].[CH3:2][S:3][C:4]1[C:5]2[NH:10][C:17]3[CH2:18][CH2:19][NH:14][CH2:15][C:16]=3[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=C1CCNCC1
Reactant: CSc1ccccc1NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: CSc1cccc2c3c([nH]c12)CCNC3
Temperature: 25 °C
Yield: 91.3 %

Procedure:
1-[2-(methylsulfanyl)phenyl]hydrazine hydrochloride (27 g, 141.9 mmol) and 4-piperidone monohydrate hydrochloride (21.8 g, 141.9 mmol) were dissolved in ethanol (350 mL) and heated at reflux for 45 minutes. Concentrated HCl (30 mL) was added and heated at reflux for 12 h. The reaction was cooled to room temperature, filtered, washed with cold isopropyl alcohol (50 mL), and dried to give an off white solid, 6-(methylsulfanyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (33 g, 92%). 1H NMR (CD3OD, 300 MHz) δ 7.24 (d, 1H, J=8.7 Hz), 7.08 (dd, 1H, J=0.7, 7.3 Hz), 6.93 (t, 1H, J=7.7 Hz), 3.29-3.27 (m, 2H), 3.17 (t, 2H, J=5.85 Hz), 2.85 (t, 2H, J=5.65 Hz), 2.44 (s, 3H) ppm.
Reaction SMILES: [F:1][CH:2]([F:38])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]5[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=5[CH:32]=O)[O:27][N:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1.[CH3:39][O:40][NH2:41]>>[CH3:39][O:40][N:41]=[CH:32][C:31]1[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=1[CH:28]1[O:27][N:26]=[C:25]([C:23]2[N:24]=[C:20]([CH:17]3[CH2:18][CH2:19][N:14]([C:12](=[O:13])[CH2:11][N:5]4[C:6]([CH:8]([F:10])[F:9])=[CH:7][C:3]([CH:2]([F:38])[F:1])=[N:4]4)[CH2:15][CH2:16]3)[S:21][CH:22]=2)[CH2:29]1
Reactant: O=Cc1ccccc1C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)F)cc4C(F)F)CC3)n2)=NO1
Reactant: CON
Product: CON=Cc1ccccc1C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)F)cc4C(F)F)CC3)n2)=NO1

Procedure:
2-{3-[2-(1-{[3,5-Bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}benzaldehyde (150 mg) and O-methylhydroxylamine (24 mg) were reacted analogously to I-40 (step 4). This gave 2-{3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}benzaldehyde 0-methyloxime (169 mg).
Reaction SMILES: [CH:1]1([N:7]2[CH2:10][CH:9]([OH:11])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:13]1[N:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16].[H-].[Na+:23]>CN(C)C=O>[CH:1]1([N:7]2[CH2:8][CH:9]([O:11][C:13]3[C:14]([C:15]([O-:17])=[O:16])=[CH:18][CH:19]=[CH:20][N:21]=3)[CH2:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Na+:23]
Reactant: O=C(O)c1cccnc1Cl
Reactant: OC1CN(C2CCCCC2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C([O-])c1cccnc1OC1CN(C2CCCCC2)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
A solution of 105 g (0.68 mole) of 1-cyclohexyl-3-azetidinol and 106 g (0.68 mole) of 2-chloronicotinic acid in 400 ml of dry dimethylformamide was added at a rapid drop to 52 g (1.35 mole) of 60% sodium hydride/mineral oil suspended in 400 ml of dry dimethylformamide at 60° C. Mild exothermic reaction was noted. After stirring for 2 hr at 60° C., the mixture was filtered. The filter cake was washed with ethylacetate and dried at 80° C./2 mm to give 174 g (86%) of crude title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([O:18][CH:19]([CH3:21])[CH3:20])[C:13]([O:15]CC)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:22][O:23][C:24]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27]>>[CH:19]([O:18][CH:12]([CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([CH2:2][NH:1][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:31]([C:33]([F:35])([F:36])[F:34])=[CH:32][C:24]=2[O:23][CH3:22])[CH:4]=1)[C:13]([OH:15])=[O:14])([CH3:20])[CH3:21]
Reactant: COc1cc(C(F)(F)F)ccc1C(=O)O
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CN)c1)OC(C)C
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1CNC(=O)c1ccc(C(F)(F)F)cc1OC
Yield: 62.9 %

Procedure:
0.15 g of ethyl 3-[3-(aminomethyl)-4-methoxyphenyl]-2-isopropoxypropanoate and 0.24 g of 2-methoxy-4-(trifluoromethyl)benzoic acid were treated in the same manners as in Example 19d) and then in Example 1d), to give 0.15 g of 2-isopropoxy-3-[4-methoxy-3-({[2-methoxy-4-(trifluoromethyl)benzoyl]amino}methyl)phenyl]propanoic acid as a pale yellow oil.
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH:3]=[CH:2]1.[C:8]1([P:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CC(C)=O>[C:21]1([P:14](=[C:2]2[CH2:3][C:4](=[O:6])[NH:5][C:1]2=[O:7])([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C1C=CC(=O)N1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)=O
Product: O=C1CC(=P(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N1
Yield: 92 %

Procedure:
In an anhydrous acetone (60 mL), a solution including maleimide (6 g, 61.81 mmol) and triphenylphosphine (16.2 g, 61.76 mmol) was refluxed for 1 hour. After cooling, a precipitate was filtered, and a filter cake was washed with cold acetone (20 mL). Under reduced pressure, the washed filter cake was dried to obtain a white solid Compound 36a (20.428 g, 92%). The solid was used in following steps without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:44])[C@H:15]([NH:24][C:25]([C@@H:27]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][N:28]2[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:26])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:10][CH2:9]1.[CH2:45]([N:47]=[C:48]=[O:49])C>CC#N>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][C@@H:15]([NH:24][C:25]([C@@H:27]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][N:28]2[C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])=[O:26])[C:14]([N:11]2[CH2:12][CH2:13][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1][C:48]([NH:47][CH3:45])=[O:49])[CH2:9][CH2:10]2)=[O:44])=[CH:22][CH:21]=1
Reactant: CCN=C=O
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2N)CC1
Solvent: CC#N
Product: CNC(=O)Nc1ccccc1C1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)CC1
Yield: 78.5 %

Procedure:
To a 50 mL round-bottomed flask equipped with stirring was added tert-butyl 3-(N-{(1R)-2-[4-(2-aminophenyl)piperidyl]-1-[(4-chlorophenyl)methyl]-2-oxoethyl}carbamoyl)(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (Example 20) (462 mg, 0.75 mmol) followed by CH3CN (15 mL) and ethylisocyanate (Chemservice, Inc.) (45.6 mg. 0.80 mmol). The reaction mixture was stirred at RT for 16 h, then the solvent was removed in vacuo. The resulting yellow oil was dissolved in EtOAc (20 mL) and washed with satd NaHCO3 (20 mL) and satd NaCl (20 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (100% EtOAc) provided the title compound as a white foam (397 mg). MS (ESI, pos. ion) m/z: 674 (M+1); MS (ESI, neg. ion) m/z: 672 (M−1). Calc'd for C37H44ClN5O0: 673.30.