Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:37])[C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([NH:15][C:16]3[N:17]=[CH:18][C:19]4[N:25]([CH3:26])[C:24](=[O:27])[C:23]([F:29])([F:28])[CH2:22][N:21]([CH:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[C:20]=4[N:35]=3)=[CH:9][C:8]=2[F:36])[CH2:2]1.C(Cl)Cl.CO.[CH3:43][C:44]([CH3:46])=O>CC(O)=O>[CH:30]1([N:21]2[CH2:22][C:23]([F:28])([F:29])[C:24](=[O:27])[N:25]([CH3:26])[C:19]3[CH:18]=[N:17][C:16]([NH:15][C:10]4[C:11]([O:13][CH3:14])=[CH:12][C:7]([C:6]([NH:5][CH:3]5[CH2:2][N:1]([CH:44]([CH3:46])[CH3:43])[CH2:4]5)=[O:37])=[C:8]([F:36])[CH:9]=4)=[N:35][C:20]2=3)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CC(C)=O
Reactant: COc1cc(C(=O)NC2CNC2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(C(=O)NC2CN(C(C)C)C2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 3 h
Yield: 3.1 %

Procedure:
To a solution of N-(azetidin-3-yl)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzamide (100 mg, 0.19 mmol) in AcOH:DCM:MeOH (2.5 mL, 1:2:2) was added acetone (100 μL, 1.36 mmol), borane-pyridine complex (100 μL, 0.8 mmol), and left to stir for 3 h. The solvent was then removed and the product purified by reverse phase HPLC, free based, and lyophilized to yield a white solid (3.3 mg, 3%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.85 (d, J=6.06 Hz, 4H) 1.05 (d, J=6.57 Hz, 2H) 1.44-1.80 (m, 6H) 1.95 (br. s., 2H) 2.27 (dt, J=12.32, 6.09 Hz, 1H) 2.89 (t, J=7.33 Hz, 2H) 3.50 (t, J=7.33 Hz, 1H) 3.92 (s, 3H) 4.08 (t, J=13.89 Hz, 2H) 4.29-4.42 (m, 1H) 4.72-4.89 (m, 1H) 7.19 (d, J=6.82 Hz, 1H) 8.05 (s, 1H) 8.25 (d, J=13.39 Hz, 1H) 8.29-8.32 (m, 1H) 8.40 (d, J=7.07 Hz, 1H). [M+H] calc'd for C27H34F3N7O3, 562. found 562.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[CH2:9][CH2:8]2)([CH3:4])([CH3:3])[CH3:2].CS(O)(=O)=O.[N-:20]=[N+]=[N-].[Na+]>ClCCl>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[NH:20][CH2:9][CH2:8]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)c1ccc2c(c1)CCC2=O
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)c1ccc2c(c1)CCNC2=O
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 42.6 %

Procedure:
To 5-tert-Butyl-indan-1-one (15.7 g, 83.4 mmol) in dichloromethane (150 mL) was added methanesulfonic acid (100 mL) and the resulting mixture was cooled to 0° C. Then sodium azide (10.83 g, 2 eq) was added carefully portion-wise over 15 minutes. The resulting mixture was stirred at 0° C. for about 2.5 hours. TLC analysis confirmed that all of the 5-tert-Butyl-indan-1-one had been consumed. With stirring at 0° C. was added very carefully a solution of aqueous sodium hydroxide (20%) until pH=14. Then added dichloromethane (1000 mL) and water (500 mL) which results in a large emulsion. The layers were separated and the aqueous layer was further extracted with dicholormethane (2×200 mL). Finally the combined dichloromethane layers were washed with brine (9×200 mL), dried over magnesium sulfate and filtered through a bed of celite. After concentrating and pumping to dryness there was 13.5 g of crude product as a tan solid. Purification on a 400 g Analogix Column eluting with a gradient of 10% to 60% ethyl acetate in hexane provided the correct isomer as a white powder (7.22 g) ((M+H)+=204) and the undesired isomer (1.555 g) as a white powder.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:9]=1.O.[NH2:25][NH2:26]>>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[NH:26][N:25]=2)=[CH:10][CH:9]=1
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1cc(-c2ccc(F)cc2)n[nH]1
Reaction time: 24 h

Procedure:
In a further embodiment, a pyrazole cyclization reaction is provided in Scheme 14A. In this embodiment, 1-(4-fluorophenyl)ethanone is reacted with diethyl oxalate to provide ethyl 4-(4-fluorophenyl)-2,4-dioxobutanoate. In one embodiment, this reaction is performed in the presence of a base such as potassium tert-butoxide. In another embodiment, this reaction is performed at about room temperature for about 24 hours. The pyrazole ring is then generated by reaction of ethyl 4-(4-fluorophenyl)-2,4-dioxobutanoate with hydrazine hydrate to provide ethyl 3-(4-fluorophenyl)-1H-pyrazole-5-carboxylate. In one embodiment, this reaction is performed in at elevated temperatures. In another embodiment, this reaction is performed in ethanol and glacial acetic acid for about 2 to 16 hours. Ethyl 3-(4-fluorophenyl)-1H-pyrazole-5-carboxylate is then reduced with lithium aluminum hydride to provide 3-(4-fluorophenyl)-1H-pyrazol-5-yl-methanol. In one embodiment, the reduction is performed in THF at a temperature of about 0° C. to about room temperature overnight. 3-(4-Fluorophenyl)-1H-pyrazole-5-carbaldehyde is then formed by oxidizing 3-(4-fluorophenyl)-1H-pyrazole-5-methanol. In one embodiment, the oxidation is performed using PCC. In another embodiment, the oxidation is performed in dichloromethane at about room temperature overnight. 3-(4-Fluorophenyl)-1H-pyrazole-5-carbaldehyde may then converted to a compound of Formula (I-A) using the methods described herein.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]([O:22][CH3:23])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][C:8]=1[Cl:21])[CH3:2]>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:24])[CH:5]([O:22][CH3:23])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[Cl:21])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1Cl)OC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1ccc(O)cc1Cl)OC

Procedure:
3-(4-Benzyloxy-2-chloro-phenyl)-2-methoxy-propionic acid ethyl ester in ethyl acetate was treated with Pd(C) and H2 under balloon pressure. Then filtered through celite and concentrated to give the title compound.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1/[CH:12]=[C:13](\[CH3:58])/[C:14](=O)[CH2:15][C@H:16]1[N:19]([C:20](=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22])[C:18](=[O:46])[C@@H:17]1[C@H:47]([O:49][Si:50]([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:52])[CH3:51])[CH3:48])=[O:6])[CH:2]=[CH2:3]>C1(C)C(C)=CC=CC=1>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1/[CH:12]=[C:13](/[C:14]1[CH2:15][C@H:16]2[N:19]([C:18](=[O:46])[C@@H:17]2[C@H:47]([O:49][Si:50]([C:53]([CH3:54])([CH3:56])[CH3:55])([CH3:51])[CH3:52])[CH3:48])[C:20]=1[C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22])\[CH3:58])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)C(N1C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]1CC(=O)/C(C)=C/[C@@H]1CCCN1C(=O)OCC=C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1C
Product: C=CCOC(=O)C1=C(/C(C)=C/[C@@H]2CCCN2C(=O)OCC=C)C[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Temperature: 150 °C
Yield: 82.8 %

Procedure:
Allyl 2-[(3S,4R)-4-[(E)-4-{(2S)-1-allyloxycarbonylpyrrolidin-2-yl}-3-methyl-2-oxo-3-butenyl]-3-{(1R)-1-t-butyldimethylsilyloxyethyl}-2-oxoazetidin-1-yl]-2-triphenylphosphoranylideneacetate (9.78 g) was dissolved in degassed xylene (150 ml) and the solution was heated to 150° C. for 10 hours. Evaporation of the mixture gave a residue, which was chromatographed on silica gel (250 ml) eluting with a mixture of n-hexane and ethyl acetate (2:8-7:3 V/V) to give allyl (5R,6S)-3-[(E)-2-{(2S)-1-allyloxycarbonylpyrrolidin-2-yl}-1-methylethenyl]-6-{(1R)-1-t-butyldimethylsilyloxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (5.36 g).
Reaction SMILES: [O:1]1[C:7]2[C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:15]N1C(=O)CCC1=O>CN(C=O)C.C(OCC)(=O)C>[Cl:15][C:10]1[CH:9]=[C:8]([C:12]([OH:14])=[O:13])[C:7]2[O:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]=2[CH:11]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(O)c1cccc2c1OCCCC2
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(Cl)cc2c1OCCCC2
Reaction time: 8 h

Procedure:
To a solution of 1.7 g (8.9 mmol) of 2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid in 5 ml of DMF is added 1.41 g (10.6 mmol) of N-chlorosuccinimide (NCS) in one portion at room temperature. The solution is stirred overnight and then diluted with ethyl acetate and washed with water. The organic layer is then dried (MgSO4), filtered and concentrated to obtain 7-chloro-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.N1C=CC=CC=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20].O>C1(C)C=CC=CC=1>[C:8]([C:6]1[CH:7]=[C:2]([NH:1][S:19]([CH3:18])(=[O:21])=[O:20])[CH:3]=[CH:4][C:5]=1[Cl:11])(=[O:10])[CH3:9]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)c1cc(N)ccc1Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)c1cc(NS(C)(=O)=O)ccc1Cl
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
1-(5-Amino-2-chlorophenyl)ethanone (411 mg; synthesized by the process reported by Radziejewski et al., Heterocycles, vol. 26, pp. 1227-1238, 1987) was dissolved in toluene (5 mL), and pyridine (235 μL) and methanesulfonyl chloride (225 μL) were added. The resulting mixture was stirred at room temperature for 50 minutes. After adding water (50 mL), the reaction mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with an aqueous 1 N hydrochloric acid solution (50 mL) and saturated brine (50 mL) and then dried over anhydrous sodium sulfate (5 g). The solvent was distilled off under reduced pressure to yield N-(3-acetyl-4-chlorophenyl)methanesulfonamide (595 mg) as a colorless crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([SH:14])=[N:10]2)=[CH:5][CH:4]=1.[OH-].[Na+].CO.S(OC)(O[CH3:23])(=O)=O>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:13]=[N:12][C:11]([S:14][CH3:23])=[N:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-n2cnc(S)n2)cc1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(-n2cnc(SC)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
A mixture of 8 parts of 1-(4-methoxyphenyl)-1H-1,2,4-triazole-3-thiol, 3.1 parts of sodium hydroxide and 40 parts of methanol is stirred for 30 minutes at room temperature. Then there are added 4.9 parts of dimethyl sulfate and stirring at room temperature is continued for 3 hours. Water is added to the reaction mixture and the product is extracted twice with 1,1'-oxybisethane. The combined extracts are dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using trichloromethane as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2,2'-oxybispropane, yielding 5.6 parts (65%) of 1-(4-methoxyphenyl)-3-(methylthio)-1H-1,2,4-triazole; mp. 54.9° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:8][CH3:9])[O:6][CH3:7].[CH2:12]([O:14][C:15](=[O:23])/[CH:16]=[CH:17]\[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:13]>>[CH2:12]([O:14][C:15](=[O:23])[C@H:16]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:1][CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:6][CH3:7])[O:8][CH3:9])[CH3:13]
Reactant: CO[Si](CCCN)(OC)OC
Reactant: CCOC(=O)/C=C\C(=O)OCC
Product: CCOC(=O)C[C@H](NCCC[Si](OC)(OC)OC)C(=O)OCC

Procedure:
179.0 g (1.0 mol) of 3-aminopropyl-trimethoxysilane and 172.0 g (1.0 mol) of maleic acid diethyl ester were reacted by the same procedure used Example 1. A clear, colorless product having a viscosity of about 30 mPa.s (23° C.) was obtained. The amine equivalent weight determined by base titration was about 359 g (theory: 351 g).
Reaction SMILES: Cl[C:2]1[C:3]([C:15]#[N:16])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:6]([CH3:8])[N:7]=1.Cl.[CH2:18]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH2:22][CH2:21][NH:20][CH2:19]1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH3:8][C:6]1[N:7]=[C:2]([N:20]2[CH2:19][CH2:18][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][CH2:21]2)[C:3]([C:15]#[N:16])=[N:4][C:5]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1nc(Cl)c(C#N)nc1-c1ccccc1
Reactant: c1ccc2c(c1)CCNCC2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(N2CCc3ccccc3CC2)c(C#N)nc1-c1ccccc1

Procedure:
In analogy to the procedure described in example 12 1-phenyl-1,2-propanedione and 2-aminomalonamide were heated in an aqueous solution to give 5-methyl-3-oxo-6-phenyl-3,4 -dihydro-pyrazine-2-carboxylic acid amide. Then, the 5-methyl-3-oxo-6-phenyl-3,4-dihydro-pyrazine-2-carboxylic acid amide was treated with triethylamine and phosphorus pentachloride in phosphorus oxychloride at reflux to give the 3-chloro-5-methyl-6-phenyl-pyrazine-2-carbonitrile. The 3-chloro-5-methyl-6-phenyl-pyrazine-2-carbonitrile was finally treated with 2,3,4,5-tetrahydro-1H-benzo[d]azepine hydrochloride (J. Heterocycl. Chem. 1971, 8(5), 779-83) and N-ethyldiisopropylamine in N,N-dimethylformamide at room temperature to yield the 5-methyl-6-phenyl-3-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-pyrazine-2-carbonitrile as yellow amorphous solid; MS: 341 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[S:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[CH:6]=[CH:5][CH:4]=1.[N+:16]([O-])([OH:18])=[O:17].O>C(O)(=O)C>[CH3:1][O:2][C:3]1[C:8]2[S:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[C:6]([N+:16]([O-:18])=[O:17])=[CH:5][CH:4]=1
Reactant: COc1cccc2c1sc1ccccc12
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc([N+](=O)[O-])c2c1sc1ccccc12
Reaction time: 0.75 h

Procedure:
4-Methoxy-dibenzothiophene (ii)(4.3 g, 20.0 mmol) was dissolved in glacial acetic acid (60 ml) and to this solution was added fuming nitric acid (3.37 ml) in a dropwise fashion ensuring that the temperature of the mixture did not rise above 25° C. The yellow suspension was stirred for a further 45 minutes before being poured carefully into water (200 ml) and stirred for 15 minutes. The yellow solid was removed by filtration and washed thoroughly with copious amounts of water and then hexanes. The residue thus obtained was then dried in a vacuum oven to give the title compound as a yellow solid which was used without any further purification. (5.19 g, 97%) m/z (LC-MS, ESP), RT=4.15 min, (M+H)=260.1.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:17]([CH2:18][CH2:19][CH2:20][CH3:21])[C@H:16]([CH3:22])[O:15][C:14](=[O:23])[C@@H:13]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:12][CH2:11][CH2:10]1)C1C=CC=CC=1.[H][H]>CCOC(C)=O.[Pd]>[CH2:18]([C@H:17]1[C@H:16]([CH3:22])[O:15][C:14](=[O:23])[C@@H:13]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:12][CH2:11][CH2:10][C@@H:9]1[OH:8])[CH2:19][CH2:20][CH3:21]
Reactant: CCCC[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)CCC[C@@H]1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCC[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)CCC[C@@H]1O
Reaction time: 72 h
Yield: 85.5 %

Procedure:
To a solution of tert-butyl ((3S,7S,8S,9S)-7-(benzyloxy)-8-butyl-9-methyl-2-oxooxonan-3-yl)carbamate (0.600 g, 1.38 mmol) in EtOAc (15 mL) was added 10% Pd/C (0.0740 g, 0.0690 mmol). The reaction flask was placed under 1 atm. of hydrogen (balloon) and stirred vigorously for 72 h. The reaction was filtered through a pad of celite and the pad was washed with EtOAc. The filtrate was concentrated and the residue purified by flash chromatography (SiO2; EtOAc/hexanes) to give the title compound as a colorless oil (0.405 g, 1.18 mmol, 85%): 1H NMR (400 MHz, CDCl3) δ 5.11 (d, J=8.3 Hz, 1H), 4.71 (dq, J=10.0, 6.4 Hz, 1H), 4.26-4.15 (m, 1H), 3.69 (ddd, J=8.7, 5.7, 2.2 Hz, 1H), 2.34-2.22 (m, 1H), 1.97 (dddd, J=15.5, 10.1, 7.7, 5.2 Hz, 1H), 1.87-1.76 (m, 1H), 1.75-1.53 (m, 5H), 1.52-1.46 (m, 1H), 1.44 (s, 9H), 1.40-1.34 (m, 1H), 1.33 (d, J=6.3 Hz, 3H), 1.30 (d, J=7.1 Hz, 1H), 1.23-1.13 (m, 2H), 1.10-1.00 (m, 1H), 0.90 (t, J=7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 173.03, 154.09, 79.78, 73.54, 72.41, 52.43, 48.04, 34.24, 33.60, 28.31, 28.26, 27.61, 23.41, 19.21, 17.61, 13.97; ESIMS m/z 407 ([M+Na+CH3CN]+).
Reaction SMILES: [BH4-].[Na+].[NH2:3][C:4]([NH:6][C:7]1[NH:8][C:9]2[C:14]([C:15]=1[C:16]([NH2:18])=[O:17])=[CH:13][CH:12]=[C:11]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]=[O:26])[CH:20]=1)[CH:10]=2)=[O:5]>CO.O1CCCC1>[NH2:3][C:4]([NH:6][C:7]1[NH:8][C:9]2[C:14]([C:15]=1[C:16]([NH2:18])=[O:17])=[CH:13][CH:12]=[C:11]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][OH:26])[CH:20]=1)[CH:10]=2)=[O:5]
Reactant: NC(=O)Nc1[nH]c2cc(-c3cccc(C=O)c3)ccc2c1C(N)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)Nc1[nH]c2cc(-c3cccc(CO)c3)ccc2c1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
Sodium borohydride (0.23 g, 6.2 mmol) was added to a solution mixture of 2-aminocarbonylamino-6-(3-formylphenyl)indole-3-carboxamide (Compound 4-69, 1.0 g, 3.1 mmol) in anhydrous methanol and anhydrous tetrahydrofuran (methanol/tetrahydrofuran=1/1, 60 mL) under ice-cooling, and the mixture was stirred at room temperature overnight. After the reaction mixture was concentrated under reduced pressure, the precipitated solid was washed with water (30 mL), ethyl acetate (30 mL), and dried under reduced pressure to give the title compound (0.59 g) as a brown solid (yield 58%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][N:14]([S:16]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)(=[O:18])=[O:17])[CH2:13][CH2:12][N:11]1[C:24]1[CH:29]=[CH:28][C:27]([C:30]([OH:36])([CH3:35])[C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=1)[C:2]1[CH:7]=C[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl.ClCC1C=[N:44]C=CC=1.[NH4+].[Cl-]>CN(C=O)C>[F:32][C:31]([F:34])([F:33])[C:30]([C:27]1[CH:28]=[CH:29][C:24]([N:11]2[CH2:12][CH2:13][N:14]([S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:18])=[O:17])[CH2:15][CH:10]2[CH2:9][O:8][CH2:1][C:2]2[CH:7]=[N:44][CH:5]=[CH:4][CH:3]=2)=[CH:25][CH:26]=1)([OH:36])[CH3:35]
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)CC2COCc2ccccc2)cc1)C(F)(F)F
Reactant: ClCc1cccnc1
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)CC2COCc2cccnc2)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 67.1 %

Procedure:
A 25 ml, round-bottomed flask was charged with 1,1,1-trifluoro-2-(4-(2-(hydroxymethyl)-4-(thiophen-2-ylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (25 mg, 0.055 mmol, Example 44) and DMF (5 mL) was cooled to 0° C. To this solution was added sodium hydride (7.3 mg, 60% by weight in mineral oil, 0.18 mmol). The mixture was warmed to room temperature and stirred for 20 min. After cooling to 0° C., 3-(chloromethyl)pyridine hydrochloride (9.1 mg, 0.055 mmol, Sigma-Aldrich, St. Louis, Mo.) was added. The reaction was warmed to room temperature and stirred for 2 h. Saturated aqueous NH4Cl (0.1 mL) was added and the mixture was then purified by silica gel preparatory TLC (2:1 (5% MeOH-EtOAc) in hexanes) to yield 1,1,1-trifluoro-2-(4-(2-((3-pyridinylmethoxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (20 mg) as a mixture of four isomers.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([O:12][CH2:13][CH3:14])(=[O:11])[CH3:10].CN1C(=O)N(C)CCC1.I[CH2:25][C:26]1[N:30]([CH3:31])[N:29]=[C:28]([C:32]2[CH:37]=[CH:36][C:35]([O:38][C:39]([F:42])([F:41])[F:40])=[CH:34][CH:33]=2)[CH:27]=1>O1CCCC1.CCCCCCC.C(C1C=CC=CC=1)C.O1CCCC1>[CH2:13]([O:12][C:9](=[O:11])[CH2:10][CH2:25][C:26]1[N:30]([CH3:31])[N:29]=[C:28]([C:32]2[CH:33]=[CH:34][C:35]([O:38][C:39]([F:41])([F:40])[F:42])=[CH:36][CH:37]=2)[CH:27]=1)[CH3:14]
Reactant: Cn1nc(-c2ccc(OC(F)(F)F)cc2)cc1CI
Reactant: CCOC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: CN1CCCN(C)C1=O
Solvent: CCCCCCC
Product: CCOC(=O)CCc1cc(-c2ccc(OC(F)(F)F)cc2)nn1C
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 40 %

Procedure:
A solution of lithium diisopropylamide (16.5 ml of a 2 M solution in tetrahydrofuran/heptane/ethylbenzol, 33 mmol) in tetrahydrofuran (25 ml) was cooled to −78° C. Within 30 min a solution of ethyl acetate (3.77 ml, 38 mmol) in tetrahydrofuran (10 ml) was added. The solution was stirred for 45 min at −78° C., DMPU (6.63 ml, 55 mmol) was added within 20 min and the mixture was kept for additional 30 min at −78° C. Within 20 min a solution of 5-iodomethyl-1-methyl-3-(4-trifluoromethoxy-phenyl)-1H-pyrazole (4.2 g, 11 mmol) in tetrahydrofuran (25 ml) was added. The solution was stirred for 40 min at −78° C., the cooling bath was removed and stirring was continued for 1 h. The reaction mixture was poored onto aqueous NH4Cl solution/ice water and extracted two times with ethyl acetate. The combined extracts were washed three times with ice water/brine and dried over sodium sulfate. The solvent was removed under reduced pressure to give an orange oil which was purified by column chromatography (silica gel, heptane/AcOEt) to give 1.5 g (4.4 mmol, 40%) of the title compound as yellow oil.
Reaction SMILES: [F:1][C:2]([F:55])([CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]/[C@H:11]([C:25](N1[C@@H](C(C)C)C(C2C=CC=CC=2)(C2C=CC=CC=2)SC1=O)=[O:26])[C@@:12]([OH:24])([CH2:20][CH2:21][O:22][CH3:23])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[NH2:56][C@@H:57]([CH2:62][C:63]1[CH:68]=[CH:67][C:66]([O:69][CH2:70][C:71]#[C:72][CH3:73])=[CH:65][CH:64]=1)[C:58]([O:60][CH3:61])=[O:59]>ClCCl>[CH2:70]([O:69][C:66]1[CH:65]=[CH:64][C:63]([CH2:62][C@H:57]([NH:56][C:25]([C@@H:11](/[CH:10]=[CH:9]/[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([F:1])([F:55])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[C@@:12]([OH:24])([CH2:20][CH2:21][O:22][CH3:23])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:26])[C:58]([O:60][CH3:61])=[O:59])=[CH:68][CH:67]=1)[C:71]#[C:72][CH3:73]
Reactant: CCCCCCCC(F)(F)CCCCCC/C=C/[C@H](C(=O)N1C(=O)SC(c2ccccc2)(c2ccccc2)[C@@H]1C(C)C)[C@@](O)(CCOC)C(=O)OC(C)(C)C
Reactant: CC#CCOc1ccc(C[C@H](N)C(=O)OC)cc1
Solvent: ClCCl
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(F)(F)CCCCCCC)[C@@](O)(CCOC)C(=O)OC(C)(C)C)C(=O)OC)cc1
Temperature: 45 °C
Reaction time: 96 h
Yield: 80 %

Procedure:
tert-Butyl (E)-(2S,3S)-12,12-difluoro-2-hydroxy-3-((S)-4-isopropyl-2-oxo-5,5-diphenyl-thiazolidine-3-carbonyl)-2-(2-methoxy-ethyl)-nonadec-4-enoate (No. 5552816; 38.8 mg, 0.0494 mmol) synthesized in Steps B1 to B6 and methyl (S)-2-amino-3-(4-but-2-ynyloxy-phenyl)-propionate (18.3 mg, 0.074 mmol) were dissolved in dichloromethane, and the solvent was distilled off under reduced pressure. The obtained mixture was stirred at 45° C. for 4 days, cooled to room temperature, and then extracted by adding ethyl acetate and water. The organic layer was washed with a saturated brine, dried over anhydrous sodium sulfate, and then filtered. The solvent was distilled out of the filtrate under reduced pressure and the residue was purified with SP1 (SiO2 cartridge, 25% ethyl acetate/n-hexane, Rf=0.1) to obtain tert-butyl (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-12,12-difluoro-2-hydroxy-2-(2-methoxy-ethyl)-nonadec-4-enoate (No. 6804236; 28.9 mg, 80% yield).