Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([P:3]([CH2:10][CH2:11][CH:12]=[O:13])(=[O:9])[O:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:2].CC(C)=[O:16].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O>[CH2:1]([P:3]([O:4][CH2:5][CH2:6][CH2:7][CH3:8])([CH2:10][CH2:11][C:12]([OH:16])=[O:13])=[O:9])[CH3:2]
Reactant: CCCCOP(=O)(CC)CCC=O
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CCCCOP(=O)(CC)CCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
20.6 g (0.1 mop of butyl ethyl-(2-formylethyl)phosphinate (produced as in Example 10) in 500 ml of acetone are mixed with 0.11 mol of Jones reagent (12.7 g of chromium trioxide in 36.7 ml of water and 11.0 ml of concentrated sulfuric acid) at 0° C. by dropwise addition. The reaction mixture is additionally stirred for 3½ hours with ice cooling and 1 hour at room temperature. After 12 ml of isopropanol have been added, the mixture is poured onto ice-water. Volatile constituents are subsequently distilled off in vacuo. The residue is taken up in tetrahydrofuran and extracted, Insoluble salts were filtered, off. The solvent of the filtrate was removed in vacuo and the residue was recrystallized from acetone to obtain 17.3 g (78% of theory) of 3-(ethylbutoxyphosphinyl)propionic acid as oil,
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12](OC)=[C:11]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:26]>CO>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([Cl:26])=[C:11]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1c(-c2ccc(Cl)cc2)cnn(Cc2ccccc2)c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CO
Product: O=c1c(Cl)c(-c2ccc(Cl)cc2)cnn1Cc1ccccc1
Temperature: 75 °C
Reaction time: 4 h
Yield: 66 %

Procedure:
A mixture of 2-benzyl-5-(4-chlorophenyl)-4-methoxypyridazin-3(2H)-one (13.8 g, 42.23 mmol) and POCl3 (20.0 mL) was stirred at 75° C. for 4 h. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was cooled in an ice bath and water (200 mL) was added. The undissolved material was filtered and washed with water (3×150 mL). To the solid thus obtained was added MeOH (100 mL). The resultant mixture was sonicated for 10 mins, and then was filtered. The collected solid was washed with MeOH (2×50 mL). The solid was then dried in an vacuum oven at 50° C. to give the title compound, 2-benzyl-4-chloro-5-(4-chlorophenyl)pyridazin-3(2H)-one, (9.2 g, 66%) as a light brown solid. HPLC: 3.75 min; M+H=331. 1H NMR (CDCl3, 500 MHz): δ 7.73 (1H, s), 7.50 (2H, d, J=10.0 Hz), 7.47 (2H, d, J=10.0 Hz), 7.42 (2H, d, J=10.0 Hz), 7.30-7.38 (3H, m), 5.39 (2H, s).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[S:6](N)([NH2:9])(=[O:8])=[O:7]>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][NH:5][S:6](=[O:8])(=[O:7])[NH2:9]
Reactant: NS(N)(=O)=O
Reactant: COCCN
Solvent: C1CCOC1
Product: COCCNS(N)(=O)=O
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 36.4 %

Procedure:
According to Reference Example 9-26, tetrahydrofuran (3 mL) and 2-methoxyethylamine (0.36 mL, 4.2 mmol) were added to sulfamide (400 mg, 4.2 mmol) and the mixture was stirred by use of a microwave chemical reactor at 300 W at 100° C. for 10 minutes. The solvent was evaporated off under reduced pressure, and purification by silica gel column chromatography (hexane/ethyl acetate=1/0 to 1/4) was performed to give N-(2-methoxyethyl)sulfuric diamide (Compound GF) (236 mg, yield: 37%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][C:9]#[CH:10])([CH3:4])([CH3:3])[CH3:2].[CH3:12][O:13][C:14]([C:16]1[S:17][C:18](Br)=[CH:19][CH:20]=1)=[O:15]>CCOC(C)=O.[Pd].C(N(CC)CC)C>[CH3:12][O:13][C:14]([C:16]1[S:17][C:18]([C:10]#[C:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:11])=[CH:19][CH:20]=1)=[O:15]
Reactant: COC(=O)c1ccc(Br)s1
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#CCNC(=O)OC(C)(C)C)s1
Temperature: 25 °C
Yield: 63406.2 %

Procedure:
A mixture of prop-2-ynyl-carbamic acid tert-butyl ester (from Preparation 41, 1.67 mmol, 0.011 mmol), 5-bromo-thiophene-2-carboxylic acid methyl ester (2.50 g, 0.011 mmol), tetrakistriphenylpyosphine(O) palladium (0.622 g, 0.0538 mmol), Cul (0.102 g, 0.538 mmol) and triethylamine (1.57 mL, 0.011 mmol) in 50 mL acetronitrile was heated at reflux for 16 h. The reaction was cooled to room temperature, diluted with 75 mL EtOAc, washed with 5.5% HCl, water and brine, dried over MgSO4, filtered and concentrated in vacuo to an oil. The product was purified via flash chromatography (9:1 to 4:1 hexanes:EtOAc) to afford the title compound of Step A as an oil (2.06 g). MS 313 (M+18).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34][CH:35]([CH3:37])[CH3:36])[CH2:24][CH:23]2[OH:38])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].C(N(CC)CC)C.CS(C)=[O:48]>C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34]([CH:35]([CH3:36])[CH3:37])=[O:48])[CH2:24][C:23]2=[O:38])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11]
Reactant: CS(C)=O
Reactant: CC(C)Sc1ccccc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(O)C1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)S(=O)c1ccccc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(=O)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To the solution of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-(2-isopropylthiophenyl)piperidin-3-ol (60 mg) obtained in Step 1 in 5 ml of dimethyl sulfoxide (DMSO), was added 0.093 ml of triethylamine (0.66 mmol). The reaction mixture was cooled to 0° C. Pyridine-SO3 complex (103 mg, 0.66 mmol) was added to the reaction mixture, which was then stirred for about 2 hours at room temperature. The reaction mixture was diluted with 100 ml of ethyl acetate, washed with brine. The resulting organic layer was dried on sodium sulfate. The resulting residue was purified with column chromatography to give 50 mg of the titled compound.
Reaction SMILES: [NH:1]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@H:2]([C:19]([O:21]CC1C=CC=CC=1)=[O:20])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][P:11]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1.C([O-])=O.[NH4+]>CO.C(O)(=O)C.[Pd]>[NH:1]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[C@H:2]([C:19]([OH:21])=[O:20])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][P:11]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][CH:9]=1
Reactant: CCOP(=O)(OCC)Oc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOP(=O)(OCC)Oc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1

Procedure:
The title compound was prepared by reaction of crude BocTyr(PO3Et2)OBzl (1 mmol) and ammonium formate (4 mmol) with 10% Pd on charcoal for 20 min. at 50° C. in methanol/acetic acid mixture. After the filtration of the catalyst the solvent was concentrated in vacuo and the residue was dissolved in EtOAc and washed several times with a solution of satured NaCl. The organic phase was dried (Na2SO4) and concentrated, giving an oil 270 mg (70% yield), that was used without purification for the next step. FAB mass spectroscopy: m/z 409 [MNa]+. H1NMR (200 mhz, DMSO-d6) d (ppm)=7.3-7 (dd, 4H, aromatics), 4.1 (m, 4H, P—O—CH2—CH3), 3-2.7 (m, 2H, CH—CH2—F), 1.4-1.2 (m, 15H, CH3—CH2+tBu).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1.[C:12]([NH2:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:14])[CH3:13].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([Cl:11])=[CH:6][C:7]=1[C:8]([NH:21][C:12]([CH3:14])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:13])=[O:9]
Reactant: CC(C)(N)c1ccccc1
Reactant: O=C(Cl)c1cc(Cl)cnc1Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(NC(=O)c1cc(Cl)cnc1Cl)c1ccccc1
Yield: 93.9 %

Procedure:
In a similar manner to Step 1 of Example 16, 2,5-dichloropyridine-3-carbonylchloride (669 mg, 3.19 mmol) was dissolved in dichloromethane (13 mL), and the solution was treated with cumylamine (0.505 mL, 3.51 mmol), triethylamine (0.667 mL, 4.79 mmol) and DMAP (39.0 mg, 0.319 mmol), followed by purification by slurry using diisopropylether/hexane to obtain 2,5-dichloro-N-(1-methyl-1-phenylethyl)nicotinamide (926 mg, yield 94%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[N:3]=1.[NH2:17][C:18]1[S:19][CH:20]=[CH:21][N:22]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(OCC)(=O)C.O1CCOCC1>[Si:10]([O:9][CH2:8][C:4]1[N:3]=[C:2]([NH:17][C:18]2[S:19][CH:20]=[CH:21][N:22]=2)[CH:7]=[CH:6][CH:5]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: Nc1nccs1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(Br)n1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1cccc(Nc2nccs2)n1
Temperature: 100 °C
Reaction time: 4.5 h

Procedure:
A mixture of 7.85 g of 2-bromo-6-(((tert-butyl(dimethyl)silyl)oxy)methyl)pyridine, 3.12 g of 2-aminothiazole, 1.50 g of 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene, 1.35 g of tris(dibenzylideneacetone)dipalladium(0)-chloroform complex, 13.8 g of potassium phosphate and 80 ml of 1,4-dioxane was stirred at 100° C. for 4.5 hours, cooled to room temperature and diluted with ethyl acetate. An insoluble matter was filtered off using Celite and the resulting ethyl acetate solution was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated. The residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=10/1 to 1/1) to give the title compound.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[C:3]([OH:5])=[O:4].O.O1CCOCC1.[CH2:20]([O:27][C:28](Cl)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>[OH-].[Na+]>[CH2:20]([O:27][C:28]([NH:1][C@@H:2]([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[C:3]([OH:5])=[O:4])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NC(CC1CCCCC1)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(N[C@@H](CC1CCCCC1)C(=O)O)OCc1ccccc1
Reaction time: 8 h
Yield: 1 %

Procedure:
290 g (1.7 mol) of 2-amino-3-cyclohexylpropionic acid are dissolved in 375 ml of 4N NaOH. The solution is made up to 2 l with water and 500 ml of dioxane are added. 255 ml (1.7 mol) of benzyloxycarbonyl chloride are added dropwise at pH 10 under pH-state conditions. After 8 h, the solution is extracted twice using diethyl ether and acidified to pH 2 using 1N hydrochloric acid. The product is extracted 3 times using 200 ml of ethyl acetate each time. After washing the organic extract, drying over sodium sulphate and concentrating, 5 g of the title compound are obtained.
Reaction SMILES: CN1C(C)=[C:9]2[C:4]([N:5]([CH3:15])[C:6](=[O:14])[N:7]([CH3:13])[C:8]2=[O:12])=N1.Br[CH2:17][C:18]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26]2[CH:31]=[C:30]([F:32])[C:29]([O:33][CH2:34][C:35]([F:38])([F:37])[F:36])=[C:28]([F:39])[CH:27]=2)[N:25]=1)=[O:19].[H-].[Na+]>CN(C=O)C>[F:39][C:28]1[CH:27]=[C:26]([C:24]2[N:25]=[C:21]([NH:20][C:18](=[O:19])[CH2:17][N:25]3[C:9]4[C:8](=[O:12])[N:7]([CH3:13])[C:6](=[O:14])[N:5]([CH3:15])[C:4]=4[CH:23]=[C:24]3[CH3:26])[S:22][CH:23]=2)[CH:31]=[C:30]([F:32])[C:29]=1[O:33][CH2:34][C:35]([F:38])([F:37])[F:36]
Reactant: O=C(CBr)Nc1nc(-c2cc(F)c(OCC(F)(F)F)c(F)c2)cs1
Reactant: Cc1c2c(=O)n(C)c(=O)n(C)c2nn1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c(c(=O)n(C)c(=O)n2C)n1CC(=O)Nc1nc(-c2cc(F)c(OCC(F)(F)F)c(F)c2)cs1

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 2 (50 mg, 0.258 mmol) with 2-bromo-N-{4-(3,5-difluoro-4-(2,2,2-trifluoroethoxy)phenyl)-1,3-thiazol-2-yl}acetamide (133 mg, 0.308 mmol) in the presence of NaH (16 mg, 0.375 mmol) in dry DMF (5.0 mL) to give 60 mg of the product as a white solid; 1H NMR (δ ppm, 300 MHz, DMSO-d6) 2.26 (s, 3H), 3.16 (s, 3H), 3.34 (s, 3H), 4.80-4.90 (m, 2H), 5.33 (s, 2H), 6.07 (s, 1H), 7.71 (d, J=9.3 Hz, 2H), 7.83 (s, 1H), 12.75 (br s, 1H); ESI-MS (m/z) 544.55 (M+H)+.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH2:17])=[CH:12][CH:11]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23](Cl)=[C:24]([N+:29]([O-:31])=[O:30])[CH:25]=[N:26]2)=[CH:21][CH:20]=1.C(N(CC)CC)C>ClCCl>[C:4]([O:3][C:1](=[O:2])[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:23]2[C:22]3[C:27](=[CH:28][C:19]([Br:18])=[CH:20][CH:21]=3)[N:26]=[CH:25][C:24]=2[N+:29]([O-:31])=[O:30])=[CH:12][CH:11]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1Cl
Reactant: CC(C)(C)OC(=O)NCc1ccc(CN)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1ccc(CNc2c([N+](=O)[O-])cnc3cc(Br)ccc23)cc1
Reaction time: 16 h
Yield: 93.4 %

Procedure:
1-(N-BOC-aminomethyl)-4-(aminomethyl)benzene (5.0 g, 21 mmol) in dichloromethane (50 mL) was added dropwise to a mixture of 7-bromo-4-chloro-3-nitroquinoline (5.81 g, 20 mmol) and triethylamine (5.63 mL) in dichloromethane (60 mL). The reaction was stirred for 16 hours and then washed sequentially with water and saturated aqueous sodium chloride. The organic fraction was dried over sodium sulfate, filtered and concentrated to provide a yellow crystalline solid. Recrystallization from 2-propanol yielded 9.1 g of tert-butyl{4-[(7-bromo-3-nitroquinolin-4-ylamino)methyl]benzyl}carbamate as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([OH:15])=O)[S:10][C:11]=1[CH3:12].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[F:39])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].FC1C=CC=C(F)C=1C[C@@H](C(O)=O)N.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:17][C@H:18]([CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])[CH2:31][C:32]2[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=2[F:39])=[O:15])[S:10][C:11]=1[CH3:12]
Reactant: Cc1sc(C(=O)O)cc1-c1c(Cl)cnn1C
Reactant: N[C@@H](Cc1cc(F)ccc1F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: N[C@@H](Cc1c(F)cccc1F)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1sc(C(=O)N[C@@H](Cc2cc(F)ccc2F)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (219 mg, 0.85 mmol) [prepared according to the procedure of Example 158], 2-[(2S)-2-amino-3-(2,5-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (290 mg, 0.82 mmol) [prepared according to the procedure of Preparation 18 except substituting 2,5-difluoro-L-phenylalanine (3.02 g, 15.0 mmol) for 2,6-difluoro-L-phenylalanine] and PyBrop (481 mg, 1.03 mmol) in chloroform (8.5 mL). DIEA (750 μL, 4.29 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (246 mg, 0.44 mmol, 52%): LC-MS (ES) m/z=555 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[NH:13]1[CH2:16][CH:15]([NH:17][C:18](=[O:35])[CH2:19][NH:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([C:31]([F:34])([F:33])[F:32])[CH:29]=3)[N:24]=[CH:23][N:22]=2)[CH2:14]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH2:1]([NH:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([N:13]2[CH2:14][CH:15]([NH:17][C:18](=[O:35])[CH2:19][NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:31]([F:32])([F:34])[F:33])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH2:16]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCNC(=O)C1CCC(=O)CC1
Reactant: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCNC(=O)C1CCC(N2CC(NC(=O)CNc3ncnc4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
Reaction of N-ethyl-4-oxocyclohexanecarboxamide with N-(azetidin-3-yl)-2-((6-(trifluoromethyl)quinazolin-4-yl)amino)acetamide (as prepared in Example 1 Step G) in the presence of TEA and NaBH(OAc)3 as described in Example 1, Step H afforded the product. 1H NMR (DMSO-d6) δ: 0.97 (t, J=7.20 Hz, 3 H) 1.25 (d, J=16.93 Hz, 5 H) 1.48 (br. s., 2 H) 1.67 (br. s., 2 H) 1.97-2.08 (m, 1 H) 2.17 (br. s., 1 H) 2.74 (t, J=7.07 Hz, 2 H) 3.01 (m, J=7.07, 5.81 Hz, 2 H) 3.43 (t, J=7.20 Hz, 2 H) 4.12 (d, J=5.56 Hz, 2 H) 4.17-4.30 (m, 1 H) 7.61 (t, J=5.56 Hz, 1 H) 7.88 (d, J=8.59 Hz, 1 H) 8.05 (dd, J=8.97, 1.39 Hz, 1 H) 8.44 (d, J=7.33 Hz, 1 H) 8.55 (s, 1 H) 8.81 (s, 1 H) 9.05 (t, J=5.43 Hz, 1 H); ESI-MS (m/z): Calcd. For C23H29F3N6O2: 478.23. found: 479 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.Br[CH2:40][CH2:41][CH2:42][CH2:43][O:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[F:51]>>[F:51][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=1[O:44][CH2:43][CH2:42][CH2:41][CH2:40][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1
Reactant: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(O)cc3)cc21
Reactant: Fc1ccccc1OCCCCBr
Product: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCCOc4ccccc4F)cc3)cc21

Procedure:
Analogously to Method I, 0.160 g of tert-butyl 4-(4-hydroxyphenyl)-3-[1-(3-methoxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethoxy]piperidine-1-carboxylate (Example 44d) and 0.093 g of 1-(4-bromobutoxy)-2-fluorobenzene are reacted. The title compound is obtained as a colourless oil. Rf=0.28 (2:1 EtOAc-heptane); Rt=6.00.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[NH2:19][C:20]1[S:21][CH:22]=[C:23]([C:25](O)=[O:26])[N:24]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>>[NH2:19][C:20]1[S:21][CH:22]=[C:23]([C:25]([NH:1][C@@H:2]([CH3:18])[CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=3)=[N:5]2)=[O:26])[N:24]=1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: Nc1nc(C(=O)O)cs1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(N)n1
Yield: 62.6 %

Procedure:
The compound was prepared using the method of Example 34(d). (S)-4-(1-(2-amino-propyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (1.00 g; 3.84 mmol), 2-aminothiazole-4-carboxylic acid (0.66 g; 4.66 mmol), 1.00 ml of DIPEA, HOBt (0.26 g; 1.9 mmol) and EDCI (1.10 g; 5.75 mmol) were used as starting materials. Purification by isopropanol:toluene crystallization afforded 0.93 g (63%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.10 (d, 3H), 4.22-4.45 (m, 3H), 6.96 (d, 1H), 7.04 (broad s, 2H), 7.15 (s, 1H), 7.82 (d, 1H), 7.90 (d, 1H), 7.97 (s, 1H), 8.08 (s, 1H).
Reaction SMILES: [C:1]1([CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[CH:14][C:15]([OH:17])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[SH:25]>CN(C)C=O.C(OCC)(=O)C>[C:1]1([CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]32[CH2:14][C:15](=[O:17])[NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[S:25]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C=C1CCCCC1Cc1ccccc1
Reactant: Nc1ccccc1S
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1CC2(CCCCC2Cc2ccccc2)Sc2ccccc2N1
Temperature: 0 °C
Yield: 50 %

Procedure:
A mixture of 2-phenylmethyl-1-carboxymethylenecyclohexane (3.0 g) and 2-aminothiophenol (5.0 g) in N,N-dimethylformamide (3 ml) was refluxed for 20 hours under nitrogen atmosphere. The mixture was cooled to 0° C. and diluted with ethyl acetate (30 ml) and the mixture was washed with 1N hydrochloric acid (30 ml), water (30 ml), a saturated aqueous solution of sodium bicarbonate (30 ml) and brine (30 ml). The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with diethyl ether to give 2'-phenylmethyl-4,5-dihydro-4-oxospiro[1,5-benzothiazepine-2(3H), 1'-cyclohexane] (2.2 g).
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]([O:17][CH3:18])[C:13](OC)=[O:14].[CH3:24][NH2:25].CO>CO>[CH3:1][C:2]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]([O:17][CH3:18])[C:13]([NH:25][CH3:24])=[O:14]
Reactant: CN
Reactant: COC(=O)C(OC)c1ccccc1COc1cc(C)ccc1C
Solvent: CO
Product: CNC(=O)C(OC)c1ccccc1COc1cc(C)ccc1C
Reaction time: 22 h
Yield: 82.1 %

Procedure:
A solution of methyl 2-[2-(2,5-dimethylphenoxymethyl)phenyl)-2-methoxyacetate (0.44 g, 1.40 mmol) in methanol (5 ml) was stirred at room temperature. 40% methylamine/methanol solution (0.33 g, 4.2 mmol) was added thereto. After 22 hours, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=2/1) to give the desired compound 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxy-N-methylacetamide (0.36 g, 82%) as white crystals.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].O>N1C=CC=CC=1>[C:1]1([NH:7][NH:8][C:12](=[O:13])[C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[F:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNc1ccccc1
Reactant: O=C(Cl)c1ccccc1F
Solvent: O
Solvent: c1ccncc1
Product: O=C(NNc1ccccc1)c1ccccc1F
Reaction time: 2 h
Yield: 77 %

Procedure:
To a stirred solution of 50.0 g of phenylhydrazine in 280 ml of dry pyridine, cooled to about 5° was added, dropwise, 80.0 g of o-fluorobenzoyl chloride. After coming to ambient temperature, the reaction mixture was stirred for about 2 hours, and then poured into water. The resultant precipitate was recrystallized from toluene to yield 82 g (77.5%) of 2-fluorobenzoic acid, 2-phenylhydrazide.