Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([CH3:23])([CH3:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].CC(C)[O-].[Al+3:28].CC(C)[O-].CC(C)[O-].O>C(O)(C)C>[Cl:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([CH3:23])([CH3:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)[C:3]([O-:5])=[O:4].[Al+3:28].[Cl:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([CH3:23])[CH3:22])=[CH:9][CH:8]=1)[C:3]([O-:5])=[O:4].[Cl:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([CH3:23])[CH3:22])=[CH:9][CH:8]=1)[C:3]([O-:5])=[O:4]
Reactant: CC(C)(COc1ccc(CC(Cl)C(=O)O)cc1)c1ccccc1
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: O
Solvent: CC(C)O
Product: CC(C)(COc1ccc(CC(Cl)C(=O)[O-])cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.4 %

Procedure:
In 30 ml of isopropanol is dissolved 3.05 g of 2-chloro-3-[4-(2,2-dimethyl-2-phenylethyloxy)phenyl]propionic acid, and 0.62 g of aluminum isopropoxide is added to the solution. The mixture is stirred at room temperature for 3 hours. Then, 0.5 ml of water is added to the mixture and the mixture is further stirred for 1 hour. The resulting precipitates are collected by filtration, washed with water and isopropanol and dried. The procedure gives 2.0 g of Aluminum 2-chloro-3-[4-(2,2-dimethyl-2-phenylethyloxy)-phenyl]propionate.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:28]([O:30][CH3:31])=[O:29])=[CH:12][C:13]=3[N:14]3[CH2:21][C:20](=O)[NH:19][CH2:18][C:17]4[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B.C1COCC1.Cl>C1COCC1.CO.CCOC(C)=O>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:28]([O:30][CH3:31])=[O:29])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][NH:19][CH2:18][C:17]4[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(=O)NCc1cc(F)ccc1-3
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCNCc1cc(F)ccc1-3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 14-cyclohexyl-3-fluoro-7-oxo-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylate (from Step 4) in THF (0.02 M), BH3.THF (5 eq, 1 M solution in THF) was added and the solution stirred at RT for 2 h. MeOH (0.02 M) and a 1.25 M solution HCl in MeOH (0.24 M) were added carefully and left overnight to stir at RT before reducing the volume of the volatiles in vacuo and diluting with EtOAc. The organic phase was washed with aqueous NaHCO3 solution and brine, before being dried over Na2SO4, filtered and the solvent evaporated in vacuo to afford the title compound. The crude was used in the next step without further purification (quant); MS (ES+) m/z 407 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:24][C:25]2[C:34]3[C:29](=[C:30]([C:35]([O:37]C)=O)[CH:31]=[CH:32][CH:33]=3)[N:28]=[C:27]([CH3:39])[N:26]=2)[CH2:9][N:10]([CH3:23])[S:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[NH3:40]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:24][C:25]2[C:34]3[C:29](=[C:30]([C:35]([NH2:40])=[O:37])[CH:31]=[CH:32][CH:33]=3)[N:28]=[C:27]([CH3:39])[N:26]=2)[CH2:9][N:10]([CH3:23])[S:11]([C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: N
Reactant: COC(=O)c1cccc2c(N[C@H](CN(C)S(=O)(=O)c3ccc([N+](=O)[O-])cc3)c3ccc(F)cc3)nc(C)nc12
Product: Cc1nc(N[C@H](CN(C)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c2ccc(F)cc2)c2cccc(C(N)=O)c2n1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Crude methyl 4-[((1S)-1-(4-fluorophenyl)-2-{methyl[(4-nitrophenyl)sulfonyl]-amino}ethyl)amino]-2-methylquinazoline-8-carboxylate (177 mg; 0.32 mmol) was treated with methanolic ammonia (10 ml, 7M), and stirred at 70° C. overnight. The reaction mixture was concentrated to provide the desired crude intermediate. (M+H) 539.1
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[C:6]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:5]=2[N:4]([CH3:20])[C:3]1=[O:21].[C:22](=S)=[S:23].CCN=C=NCCCN(C)C.CCN(CC)CC>C1COCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:5]2[N:4]([CH3:20])[C:3](=[O:21])[CH:2]([N:1]=[C:22]=[S:23])[N:8]=[C:7]([C:9]3[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=3)[C:6]=2[CH:15]=1
Reactant: CN1C(=O)C(N)N=C(c2cccnc2)c2cc(Cl)ccc21
Reactant: S=C=S
Agent: CCN=C=NCCCN(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1C(=O)C(N=C=S)N=C(c2cccnc2)c2cc(Cl)ccc21
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 42.1 %

Procedure:
As illustrated in the scheme above, a solution of 3-amino-7-chloro-1,3-dihydro-1-methyl-5-(3-pyridinyl)-2H-1,4benzodiazepin-2-one (1.36 g, 4.52 mmol) in dry THF (55 mL) was cooled to −15° C. Carbon disulfide (2.7 mL, 45 mmol) was added, followed by EDCI (1.73 g, 9.03 mmol). The mixture was stirred for 10 min., and then Et3N (1.26 mL, 9.04 mmol) was added. The reaction was stirred for 16 h while it was allowed to slowly warm to room temperature. The precipitated solid was removed by filtration and was washed well with CH2Cl2 and then discarded. The filtrate was concentrated in vacuo, and the residue was dissolved in CH2Cl2. The organic phase was washed with water, saturated NaHCO3, and brine, and was then dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the crude product by silica gel column chromatography (3:1 CH2Cl2:EtOAc) provided the title compound as a solid (0.652 g, 42%). 1H-NMR (CDCl3): δ 8.75 (s, 2H), 8.12 (dt, J=2.0 Hz, J=8.0 Hz, 1H), 7.63 (dd, J=2.0 Hz, J=8.8 Hz, 1H), 7.43 (dd, J=4.8 Hz, J=8.0 Hz, 1H), 7.39 (d, J=8.8 Hz, 1H), 7.33 (d, J=2.4 Hz, 1H), 5.22 (s, 1H), 3.50 (s, 3H). MS (ESI) (M+H)+=343.
Reaction SMILES: [C:1]12([CH:11]3[C:20]4[C:15](=[CH:16][C:17]([O:21]C)=[CH:18][CH:19]=4)[CH2:14][CH2:13][N:12]3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(Cl)Cl>CO.C(Cl)Cl>[C:1]12([CH:11]3[C:20]4[C:15](=[CH:16][C:17]([OH:21])=[CH:18][CH:19]=4)[CH2:14][CH2:13][N:12]3[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: COc1ccc2c(c1)CCN(c1ccccc1)C2C12CC3CC(CC(C3)C1)C2
Solvent: ClCCl
Solvent: CO
Product: Oc1ccc2c(c1)CCN(c1ccccc1)C2C12CC3CC(CC(C3)C1)C2

Procedure:
The title compound was prepared by analogy to Example 48 except that 1-adamantan-1-yl-6-methoxy-2-phenyl-1,2,3,4-tetrahydroisoquinoline was used instead of 6-methoxy-1-(4-methoxy-phenyl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline, and neat CH2Cl2 to 10% MeOH/CH2Cl2 was used as eluent for flash chromatography purification.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29]([CH2:36][C:37]([O-])=[O:38])=[CH:30][C:31](=[O:35])[O:32]2)=[CH:27][CH:26]=1)(=O)C.[CH2:40]([CH2:42][NH2:43])[OH:41]>C(Cl)Cl.CO.CCOCC>[OH:41][CH2:40][CH2:42][NH:43][C:37](=[O:38])[CH2:36][C:29]1[C:28]2[C:33](=[CH:34][C:25]([O:24][C@@H:6]3[O:7][C@H:8]([CH2:19][OH:20])[C@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]3[OH:4])=[CH:26][CH:27]=2)[O:32][C:31](=[O:35])[CH:30]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2ccc3c(CC(=O)[O-])cc(=O)oc3c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: NCCO
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: O=C(Cc1cc(=O)oc2cc(O[C@@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)ccc12)NCCO
Temperature: 25 °C
Reaction time: 60 h
Yield: 37.1 %

Procedure:
43 g (0.076 moles) of 7-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)coumarin-4-acetate (i.e. compound 1 prepared as described in Scheme 1) was dissolved in 430 ml of methylene chloride in a 1 liter RB flask. 43 ml (0.712 moles) of ethanolamine was dissolved in 43 ml of methanol and added to the above solution. The solution was stirred at room temperature for 60 hrs and the resulting solid residue was filtered and washed with 50 ml of methylene chloride. The solid was suspended in 250 ml of methanol and stored in the freezer for 12 hrs. The solid was filtered again and suspended in 700 ml of methanol and refluxed for 30 min. The cloudy suspension was cooled to room temperature, then further cooled in an ice bath and filtered. The wet solid thus obtained was suspended in 200 ml of ether and stirred for 30 min., then filtered and vacuum dried at room temperature to give 12 g of an off-white solid. The yield was 37%. The structure was confirmed by 1H NMR and MS (as in Example 1).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14](Br)[N:15]=2)[N:10]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26]([SiH2:30][O:31][C:32]([CH3:56])([CH3:55])[C:33]1[CH:34]=[CH:35][CH:36]=[C:37]2[C:41]=1[NH:40][N:39]=[C:38]2[Sn](CCCC)(CCCC)CCCC)([CH3:29])([CH3:28])[CH3:27]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:38]3[C:37]4[C:41](=[C:33]([C:32]([CH3:56])([CH3:55])[O:31][SiH2:30][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:34]=[CH:35][CH:36]=4)[NH:40][N:39]=3)[N:15]=2)[N:10]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2c(C(C)(C)O[SiH2]C(C)(C)C)cccc12
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4c(C(C)(C)O[SiH2]C(C)(C)C)cccc34)nc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 33.6 %

Procedure:
In a 25 ml round-bottomed flask, 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (180 mg, 0.42 mmol) and 7-(tert-butyldimethyl-silanyloxymethyl)-3-tributylstannanyl-1H-indazole (crude from Step 4, 462 mg, 0.50 mmol) were dissolved in DMF (2.8 ml). The reaction mixture was evacuated and backfilled with argon and tetrakis(triphenylphosphine)palladium (0) (25 mg, 0.022 mmol) and copper (I) iodide (16 mg, 0.084 mmol) were added. The reaction mixture was stirred at 80° C. overnight then cooled to room temperature, quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then concentrated. The residue was chromatographed over 25 g silica gel with EtOAc/hexanes (gradient: 0-30% EtOAc) to afford 86 mg (34%) of 2-[7-(tert-butyl-dimethyl-silanyloxymethyl)-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[NH:6][C:5](=[O:10])[C:4]=1[CH2:11][NH:12][C:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH:24]([CH:26]2[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]2)[CH3:25])[C:16]=1[CH3:32])=[O:14].C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[NH:6][C:5](=[O:10])[C:4]=1[CH2:11][NH:12][C:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH:24]([CH:26]2[CH2:31][CH2:30][CH2:29][N:28]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:27]2)[CH3:25])[C:16]=1[CH3:32])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C)[nH]c(=O)c1CNC(=O)c1c(C)n(C(C)C2CCCNC2)c2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C)[nH]c(=O)c1CNC(=O)c1c(C)n(C(C)C2CCCN(S(C)(=O)=O)C2)c2ccccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 19.8 %

Procedure:
To a solution of N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(piperidin-3-yl)ethyl)-1H-indole-3-carboxamide (20 mg, 45.81 mol) in dichloromethane (3 mL) was added triethylamine (9.27 mg, 91.63 μmol) and methanesulfonyl chloride (7.87 mg, 68.72 μmol). The mixture was stirred at room temperature for 12 hours. The mixture was evaporated and purified by preparative-HPLC (Instrument: Gilson GX281 Column: Phenomenex Gemini C18 250*21.2 mm Mobile phase A: water with 0.01 mol/1NH4HCO3; Mobile phase B: MeCN Column temperature: 30° C. Gradient: 23-53% B 10 min) to afford the title compound (7 mg, yield: 29.69%). LRMS (M+H+) m/z: calc'd 515.22. found 515.2. 1H NMR (400 MHz, METHANOL-d4) δ 0.94-1.12 (m, 2 H) 1.39 (br. S., 2 H) 1.57-1.70 (m, 4 H) 2.33 (s, 3 H) 2.63 (s, 3 H) 2.83 (d, J=9.54 Hz, 2 H) 2.88 (s, 3 H) 3.48 (br. S., 1 H) 3.79-3.87 (m, 1 H) 3.95 (s, 3 H) 4.38 (br. S., 1 H) 4.54 (s, 2 H) 6.28 (s, 1 H) 7.07-7.17 (m, 2 H) 7.58 (d, J=8.03 Hz, 1 H) 7.72 (d, J=7.53 Hz, 1 H).
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9])(=[O:3])[CH3:2].Br[C:11]1[CH:12]=[CH:13][C:14]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[C:27]([CH3:33])[N:26]=3)[CH2:21][CH2:20]2)=[O:18])=[N:15][CH:16]=1>>[C:1]([N:4]1[CH2:8][CH2:7][N:6]([C:11]2[CH:16]=[N:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[C:27]([CH3:33])[N:26]=4)[CH2:21][CH2:20]3)=[O:18])=[CH:13][CH:12]=2)[C:5]1=[O:9])(=[O:3])[CH3:2]
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)cn3)CC2)nc1C
Reactant: CC(=O)N1CCNC1=O
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4nc(C)c(C)cc4C)CC3)nc2)C1=O
Yield: 53.2 %

Procedure:
Using 1-acetyl-2-imidazolidinone (655 mg) and (5-bromopyridin-2-yl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (1.81 g) described in Preparation Example 147 and by the reaction and treatment in the same manner as in Example 1, the title compound (1.08 g) was obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([C:18]#[N:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[Na+].[Na+].C(O)CCC>[I-].[K+].O>[N:20]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3([C:18]#[N:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[CH:8][CH:7]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: N#CC1(c2ccc(OCCCBr)cc2)CCCCC1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Solvent: O
Product: N#CC1(c2ccc(OCCCN3CCCCC3)cc2)CCCCC1
Temperature: 100 °C
Yield: 67.4 %

Procedure:
A mixture of 1-[4-(3-bromo-propoxy)-phenyl]-cyclohexanecarbonitrile (0.660 g, 2.0 mmol), piperidine (0.260 g, 3.0 mmol), sodium carbonate (0.320 g, 3 mmol), potassium iodide (20 mg) and 20 mL of butanol was heated for 4 h at 100° C. according to general procedure G. After cooling, water was added to quench the reaction and the mixture was extracted with DCM. The organics extracts were washed with a saturated aqueous solution of NaHCO3, water and dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (DCM and DCM/MeOH (10% NH3) to provide the title compound (0.440 g, 67%). 1H NMR (400 MHz, CDCl3) δ7.37 (d, 2H), 6.90 (d, 2H), 4.00 (t, 2H), 2.49-2.36 (m, 6H), 2.17-2.09 (m, 2H), 1.97 (qt, 2H), 1.88-1.67 (m, 7H), 1.62-1.55 (m, 4H), 1.47-1.40 (m, 2H), 1.32-1.20 (m, 1H).
Reaction SMILES: [Cl:1]/[C:2](/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:3](\Cl)/[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH3:15]>CN(C)C=O.C(O)(=O)C>[NH2:15]/[C:3](/[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2](\[Cl:1])/[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)/C(Cl)=C(/Cl)C(=O)OCC
Reactant: N
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOC(=O)/C(N)=C(/Cl)C(=O)OCC
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
48.2 g (0.2 mol) of diethyl dichloromaleate were dissolved in 80 ml of dimethylformamide and 2 ml of glacial acetic acid, and the mixture was warmed to 100° C. Ammonia gas was then passed in. During this operation, the temperature increased to about 120° C. After 30 minutes, the temperature dropped back to 100° C.; the reaction was then complete. The solvent was then removed by vacuum distillation. The residue was taken up in methylene chloride, and the solution was washed with water. The methylene chloride solution was evaporated in a rotary evaporator. 38.9 g (87.8% yield) of diethyl aminochloromaleate were obtained as a yellow oil which solidified on trituration to form needle-shaped crystals (m.p. 84° C.-86° C.).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:50][CH:51]([CH3:53])[CH3:52])[CH2:14][C@@H:15]([OH:49])[C@@H:16]([NH:37][C:38](=[O:48])[O:39][C@@H:40]3[C@H:47]4[C@H:43]([O:44][CH2:45][CH2:46]4)[O:42][CH2:41]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][Si](C(C)(C)C)(C)C)=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.C(O)(=O)C>O1CCCC1.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:50][CH:51]([CH3:53])[CH3:52])[CH2:14][C@@H:15]([OH:49])[C@@H:16]([NH:37][C:38](=[O:48])[O:39][C@@H:40]3[C@H:47]4[C@H:43]([O:44][CH2:45][CH2:46]4)[O:42][CH2:41]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCCO[Si](C)(C)C(C)(C)C)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCCO)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.2 %

Procedure:
To a solution of (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)-amino]-1-[4-(4-{[tert-butyl(dimethyl)silyl]oxy}butoxy)benzyl]-2-hydroxypropylcarbamate (0.38 g, 0.48 mmol) in tetrahydrofuran (5 mL) at 0° C. was added a 1:1 mixture of 1M tetra-n-butyl ammonium fluoride/tetrahydrofuran and acetic acid (1.2 mL) and the mixture was stirred at ambient temperature for 18 h. The mixture was diluted with ethyl acetate and washed with water (4×), dried (sodium sulfate) and evaporated. The resulting solid was triturated with diethyl ether and filtered to afford the title compound as a white solid (0.24 g) 1H NMR (DMSO-d6: δ 0.78 (3H, d), 0.82 (3H, d), 1.2 (1H, dd), 1.38 (1H, quintuplet), 1.5 (2H, quintuplet), 1.65 (2H, quintuplet), 1.9-2.0 (1H, m), 2.18 (1H, t), 2.7-2.8 (3H, m), 2.9 (1H, d), 2.97 (1H, dd), 3.20-3.25 (1H, m), 3.38 (2H, t), 3.4-3.5 (1H, m), 3.52-3.62 (3H, m), 3.7 (1H, t), 3.8 (1H, dd), 3.93 (2H, t), 4.2 (1H, br s), 4.8 (1H, dt), 5.0 (1H, d), 5.5 (1H, d), 6.18 (2H, s), 6.78 (2H, d), 7.0-7.1 (3H, m), 7.2 (1H, d), 7.26 (1H, s), 7.3 (1H, d); MS: 665 (MH+)
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[C:8]2[C:25]([C:29]([O:31]C)=[O:30])=[CH:26][CH:27]=[CH:28][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[N-:33]=[N+:34]=[N-:35].[Na+].[Cl-].[NH4+].Cl>CN(C=O)C.O>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:24][N:35]=[N:34][N:33]=3)=[CH:15][CH:16]=2)[C:8]2[C:25]([C:29]([OH:31])=[O:30])=[CH:26][CH:27]=[CH:28][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 115 °C
Reaction time: 96 h
Yield: 66.4 %

Procedure:
A mixture of methyl 2-butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]benzimidazole-7-carboxylate (3.2 g), sodium azide (7.4 g) and ammonium chloride (6.1 g) in DMF (30 ml) was stirred for 4 days at 115° C. To the reaction mixture was added water, which was adjusted to pH 3-4 with 1N-HCl. Resulting crude crystals (1) were purified by column chromatography on silica gel. The crystals thus obtained were recrystallized from ethyl acetate-methanol to afford colorless prisms (2.27 g, 63%), m p. 168-169° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N:15]1[C:19]([NH:20][CH2:21][C:22]#[CH:23])=[CH:18][C:17]([O:24][CH2:25][C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28])=[N:16]1.ClC1C=CC=C(C(OO)=[O:41])C=1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9]([CH2:10][C:11]([F:12])([F:13])[F:14])=[O:41])=[CH:4][C:3]=1[N:15]1[C:19]([NH:20][CH2:21][C:22]#[CH:23])=[CH:18][C:17]([O:24][CH2:25][C:26]([F:31])([F:32])[C:27]([F:28])([F:29])[F:30])=[N:16]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C#CCNc1cc(OCC(F)(F)C(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Solvent: ClC(Cl)Cl
Product: C#CCNc1cc(OCC(F)(F)C(F)(F)F)nn1-c1cc(S(=O)CC(F)(F)F)c(C)cc1F
Reaction time: 1 h
Yield: 74.1 %

Procedure:
0.51 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(2,2,3,3,3-pentafluoropropoxy)-5-(2-propynylamino)pyrazole was dissolved in 10 mL of chloroform, and 240 mg of m-chloroperbenzoic acid (purity: 75%) was added under cooling with ice. After stirring for 1 hour under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous sodium hydrogen carbonate solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:2) to obtain 0.39 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-3-(2,2,3,3,3-pentafluoropropoxy)-5-(2-propynylamino)pyrazole.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH3:30])=[C:6]([C:8]([CH3:28])([CH3:27])[CH2:9][C:10]([OH:26])([C:22]([F:25])([F:24])[F:23])[CH2:11][NH:12][C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15]([NH2:17])=[O:16])[CH:7]=1.F[C:32](F)(F)C(O)=O>COC(OC)OC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH3:30])=[C:6]([C:8]([CH3:27])([CH3:28])[CH2:9][C:10]([OH:26])([C:22]([F:25])([F:23])[F:24])[CH2:11][N:12]2[C:13]3[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:15](=[O:16])[N:17]=[CH:32]2)[CH:7]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1ccccc1C(N)=O)C(F)(F)F
Solvent: COC(OC)OC
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cn1cnc(=O)c2ccccc21)C(F)(F)F
Reaction time: 1.5 h

Procedure:
To a solution of 2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentylamino]benzamide (106 mg) in trimethylorthoformate (6 mL) was added trifluoroacetic acid (0.1 mL). After 1.5 hours, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography with silica gel (eluted with 70% ethyl acetate-hexanes) to give the title compound as a white solid (82 mg), m.p. 118° C.-121° C.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([C:34]3[NH:38][C:37]4[CH:39]=[CH:40][CH:41]=[CH:42][C:36]=4[N:35]=3)[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([C:34]3[NH:35][C:36]4[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=4[N:38]=3)[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(-c3nc4ccccc4[nH]3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(-c3nc4ccccc4[nH]3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[(2-n-butyl-6-(1H-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.