Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1](=[CH:3][CH2:4][CH3:5])=[N-].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[S:19][C:18](=[S:20])N[C:16](=[O:21])[N:15]=2)=[CH:9][CH:8]=1>CCOCC.O1CCCC1>[CH2:3]([N:1]1[C:16](=[O:21])[N:15]=[C:14]([S:13][C:10]2[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=2)[S:19][C:18]1=[S:20])[CH2:4][CH3:5]
Reactant: CCC=[N+]=[N-]
Reactant: O=c1nc(Sc2ccc(Cl)cc2)sc(=S)[nH]1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCn1c(=O)nc(Sc2ccc(Cl)cc2)sc1=S
Yield: 66.4 %

Procedure:
A solution of 7.7 g of diazopropane in ether is added in portions to a solution of 28.8 g of 2,3-dihydro-6-(4-chlorophenylthio)-2-thioxo-4H-1,3,5-thiadiazin-4-one in 250 ml of tetrahydrofuran at 22° C. The solvent is distilled off, the residue is taken up in a small amount of methanol, and the precipitate is filtered off under suction, washed with methanol and dried. 21.9 g of 3-propyl-6-(4-chlorophenylthio)-2-thioxo-1,3,5-thiadiazin-4-one are obtained in the form of yellow crystals of melting point 151°-152° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](O)=[O:5].[Cl:12]CCl.C(Cl)(=O)C(Cl)=O>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([Cl:12])=[O:5]
Reactant: ClCCl
Reactant: O=C(O)c1cc(I)ccc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(I)ccc1Cl
Temperature: 25 °C
Reaction time: 18.75 h

Procedure:
A 2 L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and pressure-equalized addition funnel with gas bubbler was charged with 2-chloro-5-iodobenzoic acid (199.41 g, 0.706 mol), dichloromethane (1.2 L, KF=0.003 wt % water) and the suspension was set stirring at ambient temperature. Then N,N-dimethylformamide (0.6 mL, 1.1 mol %) was added followed by oxalyl chloride (63 mL, 0.722 mol, 1.02 equiv) which was added over 11 min. The reaction was allowed to stir at ambient overnight and became a solution. After 18.75 hours, additional oxalyl chloride (6 mL, 0.069 mol, 0.10 equiv) was added to consume unreacted starting material. After 2 hours, the reaction mixture was concentrated in vacuo to afford crude 2-chloro-5-iodobenzoyl chloride as a pale yellow foam which will be carried forward to the next step.
Reaction SMILES: Br[C:2]1[C:3]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[N:4][CH:5]=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[O:15][N:14]=[C:13]([C:16]([F:19])([F:18])[F:17])[N:12]=1)=[O:8].[Cl:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][C:33]=1[CH3:34]>>[Cl:27][C:28]1[CH:29]=[C:30]([C:2]2[C:3]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[N:4][CH:5]=[C:6]([CH:20]=2)[C:7]([NH:9][CH2:10][C:11]2[O:15][N:14]=[C:13]([C:16]([F:19])([F:18])[F:17])[N:12]=2)=[O:8])[CH:31]=[CH:32][C:33]=1[CH3:34]
Reactant: O=C(NCc1nc(C(F)(F)F)no1)c1cnc(OCC(F)(F)F)c(Br)c1
Reactant: Cc1ccc(B(O)O)cc1Cl
Product: Cc1ccc(-c2cc(C(=O)NCc3nc(C(F)(F)F)no3)cnc2OCC(F)(F)F)cc1Cl

Procedure:
The title compound was synthesized in analogy to Example 83 using 5-bromo-6-(2,2,2-trifluoroethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide (example BP) and B-(3-chloro-4-methylphenyl)-boronic acid, (CAN 175883-63-3) as starting materials; LC-MS (UV peak area/ESI) 100%, 493.0516 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])CCC2)[CH2:6]C)[CH3:2].C([O:24][C:25](=[O:42])C(OC1C([N+]([O-])=O)=C2C(=CC=1)CCC2)CC)C>>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([O:8][C:9]1[CH:10]=[C:11]2[O:24][CH2:25][O:42][C:15]2=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(CC)Oc1cc2c(cc1[N+](=O)[O-])CCC2
Reactant: CCOC(=O)C(CC)Oc1ccc2c(c1[N+](=O)[O-])CCC2
Product: CCOC(=O)C(C)Oc1cc2c(cc1[N+](=O)[O-])OCO2

Procedure:
2-(6-nitro-5-indanoxy)-butyric acid ethyl ester and 2-(4-nitro-5-indanoxy)-butyric acid ethyl ester
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=O)=[N:2]1.[N:12]1([C:18]2[CH:19]=[CH:20][C:21]3[N:22]([C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][N:26]=3)[N:23]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(O)(=O)C>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][N:15]2[CH2:14][CH2:13][N:12]([C:18]3[CH:19]=[CH:20][C:21]4[N:22]([C:24]([C:27]([F:28])([F:29])[F:30])=[N:25][N:26]=4)[N:23]=3)[CH2:17][CH2:16]2)=[N:2]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: ClCCl
Solvent: CC(=O)O
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4n[nH]c5ccccc45)CC3)nn12
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.8 %

Procedure:
1H-Indazole-3-carboxaldehyde (75 mg, 0.51 mmol) and (polystyrylmethyl)trimethylammonium cyanoborohydride (125 mg, 0.51 mmol) were added to a solution of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (100 mg, 0.37 mmol) in DCM (2 mL)/acetic acid (0.2 mL). The mixture was stirred at ambient temperature for 18 hours. The resin was filtered off and the filtrate was evaporated. The crude product was purified by preparative HPLC (Waters XTerra C18 column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 6-[4-(1H-indazol-3-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (89 mg, 60%) as a white solid.
Reaction SMILES: Br[C:2]1([CH2:10][C:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])=[O:12])[C:6](=[O:7])[O:5][C:4]([CH3:9])([CH3:8])[O:3]1>C(Cl)(Cl)(Cl)Cl.O1CCCC1>[CH3:8][C:4]1([CH3:9])[O:5][C:6](=[O:7])/[C:2](=[CH:10]/[C:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])=[O:12])/[O:3]1
Reactant: CC1(C)OC(=O)C(Br)(CC(=O)O[Si](C)(C)C(C)(C)C)O1
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CC1(C)OC(=O)/C(=C/C(=O)O[Si](C)(C)C(C)(C)C)O1
Reaction time: 1 h

Procedure:
The solution of crude 4-bromo-2,2-dimethyl-5-oxo-1,3-dioxolane-4-acetic acid, tert-butyldimethylsilyl ester (72.4 mmol) in carbon tetrachloride (˜220 ml) was cooled to 0-5° C. and treated dropwise over 10 min. and under good stirring with a solution of 1,8-diazabcyclo 5,4,0 undec-7-ene (12.1 g, 79.6 mmol) in dry tetrahydrofuran (125 ml). A heavy precipitate was formed which gradually became a granular solid. After 1 h, the solid obtained was filtered and washed with a small amount of tetrahydrofuran. The filtrate was concentrated under reduced pressure to give a light orange oil which was used as such for the next step.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[N:44]=[CH:43][CH:42]=[CH:41][C:38]=1[C:39]#[N:40]>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[N:44]=[CH:43][CH:42]=[CH:41][C:38]=3[C:39]#[N:40])=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: N#Cc1cccnc1Br
Product: C[C@@H](c1ccc(-c2ncccc2C#N)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 2-bromonicotinonitrile following a procedure analogous to that described in Example 138 Method 1. LC-MS Method 2 tR=1.23 min, m/z=398.1; 1H NMR (CD3OD) 0.93 (s, 3H), 1.26 (s, 3H), 1.57 (d, 3H), 2.17 (s, 2H), 2.28 (m, 1H), 2.50 (m, 2H), 3.09 (m, 1H), 5.58 (m, 1H), 7.08 (d, 2H), 7.22-7.41 (m, 5H), 7.50 (m, 1H), 7.62 (d, 2H), 8.23 (d, 1H), 8.81 (m, 1H). Mass spectrum (ESI−): m/z=500 [M+HCOO]−
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=2)[O:30][CH2:31][CH2:32][CH2:33][C:34](O)=[O:35])=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C[O:44][C:45](=[O:52])[C@H:46]([CH2:48][CH:49]([CH3:51])[CH3:50])[NH2:47]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=2)[O:30][CH2:31][CH2:32][CH2:33][C:34]([NH:47][C@H:46]([C:45]([OH:44])=[O:52])[CH2:48][CH:49]([CH3:51])[CH3:50])=[O:35])=[CH:40][CH:41]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCCC(=O)O)c2)cc1
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCCC(=O)N[C@@H](CC(C)C)C(=O)O)c2)cc1

Procedure:
The product from Example 116B (57 mg, 0.10 mmole) and L-leucine methyl ester hydrochloride (36 mg, 0.20 mmole) were processed as in Example 279A and B to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ12.22-12.61 (br.s, 1 H), 8.95 (s, 1 H), 8.06 (d, 1 H), 7.24 (m, 8 H), 7.03 (m, 1 H), 6.94 (m, 4 H), 6.67 (dd, 1 H), 6.49 (m, 2 H), 4.22 (m, 1 H), 4.06 (s, 2 H), 4.03 (s, 2 H), 3.91 (m, 2 H), 2.91 (s, 3 H), 2.40 (s, 3 H), 2.26 (m, 2 H), 1.90 (m, 2 H), 1.60 (m, 1 H), 1.47 (m, 2 H), 0.85 (d, 3 H), 0.81 (d, 3 H); MS (APCI+) m/z 688.7 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:27]=[C:8]2[NH:9][C:10]([C:20]3[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=3)=[C:11]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:12](=[O:13])[N:7]2[N:6]=1)=[O:4].[CH3:28][C:29]1(B(O)O)[CH:33]=[C:32]([CH3:34])[O:31][NH:30]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Pd].O1CCOCC1.ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:27]=[C:8]2[NH:9][C:10]([C:20]3[CH:25]=[CH:24][C:23]([C:33]4[C:29]([CH3:28])=[N:30][O:31][C:32]=4[CH3:34])=[CH:22][CH:21]=3)=[C:11]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:12](=[O:13])[N:7]2[N:6]=1)=[O:4]
Reactant: CC1=CC(C)(B(O)O)NO1
Reactant: COC(=O)c1cc2[nH]c(-c3ccc(Br)cc3)c(C3CCCCC3)c(=O)n2n1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)c1cc2[nH]c(-c3ccc(-c4c(C)noc4C)cc3)c(C3CCCCC3)c(=O)n2n1
Temperature: 95 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
A mixture of 42 mg (0.1 mmol) of 5-(4-bromo-phenyl)-6-cyclohexyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid methyl ester, 21 mg (0.15 mmol) of 3,5-dimethyl-isoxazoleboronic acid, 7.3 mg (0.01 mmol) of Pd catalyst, and 63 mg (0.3 mmol) of potassium phosphate in 1 mL of 1,4-dioxane was shaken at 95° C. in a sandbath overnight. The reaction mixture was then diluted with dichloromethane, filtered through a small pad of Celite, dried over sodium sulfate and evaporated to give a residue, which was purified via reverse-phase chromatography (Gilson) to afford desired 6-cyclohexyl-5-[4-(3,5-dimethyl-isoxazol-4-yl)-phenyl]-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid methyl ester as a solid as indicated by LC-MS—calcd for C25H26N4O4 [M++H]+: 447.19, found: 447.3. This material was then converted to 6-cyclohexyl-5-[4-(3,5-dimethyl-isoxazol-4-yl)-phenyl]-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (591) via the well known LiOH saponification protocol (37% yield over 2 steps); LC-MS—calcd for C24H24N4O4 [M++H]+: 433.18, found: 433.1.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH3:15])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.Br[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1>>[CH3:15][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)[C:6]=1[C:4]([OH:3])=[O:5]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1C
Reactant: BrCc1cccc2ccccc12
Product: Cc1c(C(=O)O)n(Cc2cccc3ccccc23)c2ccccc12

Procedure:
Using general procedure B, 3-methyl-1H-indole-2-carboxylic acid ethyl ester was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 314.1 ([M−H]−).
Reaction SMILES: [C:1](=[S:3])=S.[NH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.C(N(CC)CC)C.BrBr.Cl.S([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.O.CN(C)C=O>[N:4]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)=[C:1]=[S:3]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: S=C=S
Agent: BrBr
Agent: Cl
Agent: O=S([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(N=C=S)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 25 %

Procedure:
Carbon disulfide (0.67 mL, 11 mmol) was added to a mixture comprising 4-aminobenzoic acid (0.50 g, 3.6 mmol), N,N-dimethylformamide (6.3 mL) and triethylamine (1.3 mL, 9.3 mmol), followed by stirring at room temperature for 4 hours. To the obtained reaction mixture, bromine (0.20 mL, 3.8 mmol) was dropwise added over a period of 20 minutes at 0° C., followed by stirring at 0° C. for further two hours. Thereafter, 1M hydrochloric acid (3.6 mL), sodium sulfite (0.092 g, 0.72 mmol) and water (5.0 mL) were added and mixed. Then, ethyl acetate (15 mL) was added, and the solid was collected by filtration and washed with ethyl acetate (1.0 mL). Obtained crystals were dried under reduced pressure at 50° C. to obtain 4-isothiocyanatobenzoic acid as a slightly yellow solid (0.16 g, yield: 25%, HPLC purity: 94%, HPLC retention time: 3.7 min).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][O:7][C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([C:18](=[O:20])[CH3:19])[CH:14]=[N:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].[Li+].[BH4-]>C1COCC1>[F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][O:7][C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([CH:18]([OH:20])[CH3:19])[CH:14]=[N:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)c1cnc2cc(OCc3ccc(F)cc3)ccc2c1
Agent: [BH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(O)c1cnc2cc(OCc3ccc(F)cc3)ccc2c1
Reaction time: 1 h
Yield: 37.4 %

Procedure:
To a cooled solution, 0° C., of 1-(7-((4-fluorobenzyl)oxy)quinolin-3-yl)ethanone (Example 42, 53 mg, 0.18 mmol) in THF was added NaBH4 (8 mg, 0.24 mmol). The reaction mixture was stirred for 1 hour. A further portion of NaBH4 (20 mg, 0.59 mmol) was added and stirred for 30 minutes at 0° C. LiBH4 (50 mg, 2.30 mmol) was added and the reaction was stirred for 15 minutes before being quenched with sat. NH4Cl (aq.) solution. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and concentrated under reduced pressure onto silica. Purification (FCC, SiO2, 0-5%, MeOH/DCM) afforded the title compound as a white solid (20 mg, 38%). 1H NMR (400 MHz, CDCl3) δ 8.85 (d, J=1.6 Hz, 1H), 8.10 (s, 1H), 7.73 (d, J=9.0 Hz, 1H), 7.53-7.43 (m, 3H), 7.31-7.26 (m, 1H), 7.09 (t, J=8.6 Hz, 2H), 5.17 (s, 2H), 5.12 (q, J=6.5 Hz, 1H), 1.62 (d, J=6.7 Hz, 3H). [M+H]=298.3.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([NH:21][C:22]1[CH:23]=[N:24][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:32][C:33]1[CH:34]=[N:35][N:36]([CH2:38][C:39]([F:42])([F:41])[F:40])[CH:37]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:22]1[CH:23]=[N:24][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:26][CH:27]=1)[CH2:32][C:33]1[CH:34]=[N:35][N:36]([CH2:38][C:39]([F:42])([F:40])[F:41])[CH:37]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc(NC(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: FC(F)(F)Cn1cc(CCl)cn1
Product: CC(C)c1ccc(N(Cc2cnn(CC(F)(F)F)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 59 %

Procedure:
By the reaction and treatment in the same manner as in Example 132 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (2.05 g) and 4-chloromethyl-1-(2,2,2-trifluoroethyl)pyrazole (1.02 g) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.70 g) was obtained.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:26])[CH2:14][C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])=[N:16]2)=[CH:11][C:10]=1[O:27][CH3:28])C1C=CC=CC=1.FC1C=CC=CC=1C1CC(=O)C2C(=CC=C(O)C=2O)N=1>>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:15]1[CH2:14][C:13](=[O:26])[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[C:10]([O:27][CH3:28])[CH:11]=2)[N:16]=1
Reactant: COc1cc2c(cc1OCc1ccccc1)N=C(c1ccccc1F)CC2=O
Agent: O=C1CC(c2ccccc2F)=Nc2ccc(O)c(O)c21
Product: COc1cc2c(cc1O)N=C(c1ccccc1F)CC2=O
Yield: 61.3 %

Procedure:
Compound 22 (0.3 g, 0.80 mmol) was allowed to react in the same manner as described in the preparation of compound 40 to give 43. White solid; yield: 61.3%; mp 277-279° C.; MS (EI, 70 eV): m/z 285 (M+); IR (KBr): 1622.13 (C═O) cm−1; 1H-NMR (DMSO-d6 200 MHz): δ 3.82 (s, 3H), 6.04 (s, 1H), 7.01 (s, 1H), 7.32-7.50 (m, 3H), 7.50-7.67 (m, 2H), 10.22 (s, 1H), 11.68 (s, 1H); 13C-NMR (DMSO-d6, 50 MHz): δ 55.52, 102.72, 105.37, 108.20, 116.28 (d, J=22.5 Hz), 118.07, 122.94, 124.92, 130.75, 131.99 (d, J=7.95 Hz), 136.45, 143.61, 146.58, 151.59, 158.98 (d, J=246.9 Hz), 175.30; Anal. calcd for C16H12FNO3: C, 67.36; H, 4.24; N, 4.91. Found: C, 67.37; H, 4.26; N, 4.90.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:38])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([C:33]#[N:34])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[N:41]1([CH2:47][C:48]([NH2:50])=[O:49])[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:38])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:44]3[CH2:45][CH2:46][N:41]([CH2:47][C:48]([NH2:50])=[O:49])[CH2:42][CH2:43]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([C:33]#[N:34])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1
Reactant: NC(=O)CN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C#N)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(N)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 2-piperazin-1-yl-acetamide dihydrochloride (Matrix Scientific) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 35% methanol in carbon dioxide). LR-MS: 675.2 [(M+H)+]
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[Cl:26]C(Cl)(Cl)C(Cl)(Cl)Cl.C(O)(C(F)(F)F)=O>C(OCC)C.O.CC#N>[Cl:26][C:13]1[C:8]([NH:7][C:6](=[O:20])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[C:9]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1-c1ccccc1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Li]C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Nc1c(Cl)cccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of tert-butyl[1,1′-biphenyl]-2-ylcarbamate (synthesized according to Tsang et al., J. Org. Chem., 7603 (2008)) (12.5 g, 46.4 mmol) in diethyl ether (125 mL) at −30° C. was added tert-butyllithium (1.6 M in pentane, 174 mL, 278 mmol) slowly over 15 minutes. The reaction mixture was stirred for 6 h, then a solution of perchloroethane (43.9 g, 186 mmol) in diethyl ether (125 mL) was added over 10 minutes. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with saturated aqueous ammonium chloride and extracted twice with EtOAc. The organic layers were washed with brine, dried with sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (EtOAc/petroleum ether) to give Preparation 8A (8.5 g, 60%). HPLC: RT=2.432 min (H2O/MeCN with TFA, SunFire C18 3.5 μm, 4.6×150 mm, gradient=30 min, wavelength=220 and 254 nm).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]([O:27]C)=O)[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:29]=[C:30]([C:33]([F:36])([F:35])[F:34])[CH:31]=[CH:32][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[NH2:38][NH2:39]>C(O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]([NH:38][NH2:39])=[O:27])[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:29]=[C:30]([C:33]([F:34])([F:35])[F:36])[CH:31]=[CH:32][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: NN
Reactant: COC(=O)c1ccc2c(c1)N(S(=O)(=O)c1ccc(C(C)(C)C)cc1)Cc1ccc(C(F)(F)F)nc1N2
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(C(=O)NN)cc32)cc1
Temperature: 80 °C

Procedure:
To a solution of methyl 6-[(4-tert-butylphenyl)sulfonyl]-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido-[2,3-b][1,5]benzodiazepine-8-carboxylate (intermediate 56, 0.11 g, 0.21 mmol) in ethanol (1.0 mL) at rt was added hydrazine hydrate (0.460 mL). The mixture was heated at 80° C. for 18 h, cooled to rt, and the precipitate was collected by filtration to provide the title compound. LC/MS: m/e 520.1 (M+H)+. 1H NMR (500 MHz, CD3OD): δ 8.00 (1H, s), 7.78 (1H, d, J=8.3 Hz), 7.65 (1H, d, J=7.5 Hz), 7.10-7.16 (3H, m), 6.90-6.95 (3H, m), 4.45-4.70 (2H, br), 1.24 (9H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:31][C:32](=[O:38])[C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:5]=[C:6]([CH3:30])[C:7]=1[O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14](C(OC(C)(C)C)=O)[N:13]=[C:12]2[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:36]([O:35][C:33](=[O:34])[C:32]([NH:31][C:4]1[CH:5]=[C:6]([CH3:30])[C:7]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][N:13]=[C:12]3[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[C:2]([CH3:1])[CH:3]=1)=[O:38])[CH3:37]
Reactant: CCCCCc1nn(C(=O)OC(C)(C)C)c2ccc(Oc3c(C)cc(NC(=O)C(=O)OCC)cc3C)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCc1n[nH]c2ccc(Oc3c(C)cc(NC(=O)C(=O)OCC)cc3C)cc12
Yield: 99 %

Procedure:
A solution of 474 mg (0.905 mmol) of ethyl ({3,5-dimethyl-4-[(1-tert-butoxycarbonyl-3-pentylindazol-5-yl)oxy]phenyl]}amino)(oxo) acetate (Example 13) and 2.58 g (22.63 mmol) of trifluoroacetic acid in 30 ml of methylene chloride is stirred at room temperature overnight. The mixture is subsequently concentrated in vacuo and the residue obtained is purified on silica gel using cyclohexane/ethyl acetate 3:2. 391 mg (99% of theory) of ethyl-({3,5-dimethyl-4-[(3-pentyl-1H-indazol-5-yl)oxy]phenyl}amino)(oxo)acetate are obtained.