Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:19][CH:20]=C)[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].CC[O:24]C(C)=O>CC(O)C.O.O=[Os](=O)(=O)=O>[CH2:1]([O:3][C:4]([C:6]1([CH2:19][CH:20]=[O:24])[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: C=CCC1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCOC(C)=O
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)O
Solvent: O
Product: CCOC(=O)C1(CC=O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
4-Allyl-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (2.97 g, 10 mmol) was dissolved in iPrOH (50.0 mL) and H2O (10.0 mL). To this was added a aqueous solution of NaIO4 (4.68 g, 21.8 mmol) in water (40.0 mL), followed by addition of OsO4 (8.4 mg, crystals, in one portion) at rt. The solution was stirred at rt. After 30 min, milky cloudy formed. Stirring was continued overnight. TLC and LC/MS did not detect the SM, but it is still very milky. The reaction mixture was poured into ice water (20 mL) and EtOAc (30 mL). The two layers were separated and the aqueous layer was extracted with EtOAc (3×15 mL). The combined extracts were washed with brine, and concentrated to dryness to get a liquid. The liquid was subject a reduced distillation to remove isopropanol. The remaining liquid was purified on a 50-g silica gel column, eluted with MeOH in DCM (0-5%). Note: the product is not UV active. Anisaldehyde visualization was used. The product fractions were collected and concentrated to yield 1.03 g (34% yield) of the title compound as a liquid.
Reaction SMILES: [CH3:1][C@H:2]([OH:5])[C:3]#[CH:4].[F:6][C:7]1[C:8](I)=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:19][CH:20]=[CH:21][C:22]=1[O:23][CH3:24]>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.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>[F:6][C:7]1[C:8]([C:4]#[C:3][C@@H:2]([OH:5])[CH3:1])=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:19][CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#C[C@H](C)O
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
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#C[C@H](C)O)c21

Procedure:
Using Method C above, (S)-but-3-yn-2-ol (36 mg, 0.53 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (50 mg, 0.13 mmol) (Starting Material 6) using (Ph3P)4Pd (15 mg, 0.01 mmol) and CuI (2 mg) in a mixture of DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 5 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4 and concentrated. (S)-(Z)-1,3-Dihydro-5-fluoro-4-(3-hydroxy-1-butynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one was obtained after silica gel column chromatography with a 0-70% EtOAc in hexanes gradient and trituration with petroleum ether. (Yield 32 mg, 75%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[C:50]3[O:49][C:48]([NH2:51])=[N:47][C:46]=3[C:45]([O:52][CH3:53])=[CH:44][CH:43]=2)=[CH:38][CH:37]=1>C1COCC1.O1CCOCC1.CN(C=O)C>[F:35][C:36]1[CH:37]=[CH:38][C:39]([C:42]2[C:50]3[O:49][C:48]([NH:51][C:5](=[O:7])[C:4]4[CH:8]=[CH:9][N:10]=[C:2]([CH3:1])[CH:3]=4)=[N:47][C:46]=3[C:45]([O:52][CH3:53])=[CH:44][CH:43]=2)=[CH:40][CH:41]=1
Reactant: Cc1cc(C(=O)O)ccn1
Reactant: COc1ccc(-c2ccc(F)cc2)c2oc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(F)cc2)c2oc(NC(=O)c3ccnc(C)c3)nc12

Procedure:
From 2-methyl-isonicotinic acid, HATU and N-diethylisopropylamine in THF, then treatment with 7-(4-fluoro-phenyl)-4-methoxy-benzooxazol-2-yl-amine in dioxane and DMF. ES-MS m/e (%): 378 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]([S:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[O:8]1[C:12]2([CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)[O:11][CH2:10][CH2:9]1.ClCCl.C1COCC1>[O-]S([O-])(=O)=O.[Cu+2].O1CCOCC1>[O:8]1[C:12]2([CH2:17][CH2:16][C:15](=[N:7][S:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])[CH2:14][CH2:13]2)[O:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)S(N)=O
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)S(=O)N=C1CCC2(CC1)OCCO2

Procedure:
Commercially available 2-methyl-propane-2-sulfinic acid amide is reacted with commercially available 1,4-dioxa-spiro[4.5]decan-8-one in the presence of a coupling agent such as Ti(OEt)4 or CuSO4, in an organic solvent such as dichloromethane, THF or dioxane, at a temperature in the range of about 25° C. to about 80° C., to yield 2-methyl-propane-2-sulfinic acid (1,4-dioxa-spiro[4.5]dec-8-ylidene)-amide.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([Cl:16])[CH:10]=1)[C:5]([O:7]C)=[O:6].[OH-].[Na+]>>[CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([Cl:16])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: CON=C(C(=O)OC)c1ccc(O)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Product: CON=C(C(=O)O)c1ccc(O)c(Cl)c1
Yield: 97.9 %

Procedure:
Methyl 2-methoxyimino-2-(3-chloro-4-hydroxyphenyl)-acetate (syn isomer) (2.6 g.) and a 2N aqueous solution of sodium hydroxide (10.6 ml.) were treated according to a similar manner to that of Preparation 5-3) (c) to give 2-methoxyimino-2-(3-chloro-4-hydroxyphenyl)acetic acid (syn isomer) (2.4 g.), mp 147° to 150° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:17])=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15])[CH2:8][CH2:7]2.[CH:18]([O-])([O-])OC.Cl.CO>CO>[N:1]1[C:2]2[C:10]3[CH:9]([CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15])[CH2:8][CH2:7][C:6]=3[CH:5]=[CH:4][C:3]=2[O:17][CH:18]=1
Reactant: COC([O-])[O-]
Reactant: CC(=O)NCCC1CCc2ccc(O)c(N)c21
Agent: Cl
Solvent: CO
Product: CC(=O)NCCC1CCc2ccc3ocnc3c21
Temperature: 60 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
To a solution of N-[2-(7-amino-6-hydroxyindan-1-yl)ethyl]acetamide (630 mg, 2.7 mmol.) in methanol (5 mL) were added dropwise, under ice-cooling, methyl orthoformate (7.4 mL, 67.3 mmol.) and a saturated HCl/methanol (1.4 mL) solution. The reaction mixture was stirred for 30 minutes at room temperature and for further one hour at 60° C. The reaction mixture was cooled, which was poured into ice-water, followed by extracting the organic matter with chloroform. The extract solution was washed with a saturated aqueous saline solution and water, which was then dried over anhydrous magnesium sulfate, followed by distilling off the solvent. The residue was purified by means of silica gel column chromatography (chloroform:methanol=20:1) to afford the title compound (yield 520 mg, 79%).
Reaction SMILES: [C:1]([N:4]([CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=1)[CH2:5][C:6]1[N:7]=[N:8][N:9]([CH2:11][Si](C)(C)C)[CH:10]=1)(=[O:3])[CH3:2].C1COCC1.[Li+].[OH-]>CO>[C:1]([N:4]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:25][CH:26]=1)[CH2:5][C:6]1[N:7]=[N:8][N:9]([CH3:11])[CH:10]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(CN(Cc2cn(C[Si](C)(C)C)nn2)C(C)=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)N(Cc1ccc(C(=O)O)cc1)Cc1cn(C)nn1
Reaction time: 8 h

Procedure:
A solution of methyl 4-{[acetyl({1-[(trimethylsilyl)methyl]-1H-1,2,3-triazol-4-yl}methyl)amino]methyl}benzoate (101 mg, 0.270 mmol), THF (809 uL) and MeOH (270 uL) was treated with aqueous LiOH (270 uL, 0.809 mmol, 3M in water). The reaction immediately turned red and was stirred overnight. The reaction was quenched with 2M aq. HCl and extracted with EtOAc 2×. The combined organic layers were washed with brine, dried (MgSO4) and concentrated to afford the protosilylated carboxylic acid as a yellow oil. MS: cal'd 361 (MH+), exp 361 (MH+).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:29])[CH:14]=[CH:13][CH:12]=3)=O)C.[C:40]1([Li])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.CCOCC>O1CCCC1>[C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:29])[CH:14]=[CH:13][CH:12]=3)(=[O:3])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: [Li]c1ccccc1
Reactant: CCOC(=O)c1ncc2c(c1COC)c1c(Cc3ccccc3Cl)cccc1n2S(=O)(=O)c1ccc(C)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COCc1c(C(=O)c2ccccc2)ncc2[nH]c3cccc(Cc4ccccc4Cl)c3c12
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 16 %

Procedure:
To a solution of 1.2 g (0.0021 mol) of 5-(2-chlorobenzyl)-4-methoxymethyl-9-tosyl-β-carboline-3-carboxylic acid ethyl ester in 60 ml of absolute tetrahydrofuran is slowly added 2.4 ml of a 2-molar solution of phenyllithium in bezene/ether at -70° C. under argon protection. The reaction mixture is stirred for another 15 minutes at -70° C. then for 3 hours at room temperature and finally for one hour at 35° C. The it is concentrated by evaporation. The residue is taken up in 150 ml of ethyl acetate. The solution in succession is washed with citric acid solution, water, sodium bicarbonate solution, water, saturated common salt solution and once more with water, dried and concentrated by evaporation. After chromatography on silica gel with equal parts of toluene and ethyl acetate and recrystallization from ethanol, 0.15 g (16% of theory) of 3-benzoyl-5-(2-chlorobenzyl)-4-methoxymethyl-β-carboline is obtained, melting point 147°-148° C.
Reaction SMILES: [CH:1]1([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[Br-].[CH2:16]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:17][CH3:18].[CH3:38][C:39](C)([O-])[CH3:40].[K+]>C1COCC1>[CH:16](=[C:4]1[CH2:5][CH2:6][CH:1]([CH:8]2[CH2:13][CH2:12][C:11](=[CH:38][CH2:39][CH3:40])[CH2:10][CH2:9]2)[CH2:2][CH2:3]1)[CH2:17][CH3:18]
Reactant: CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[O-]
Reactant: O=C1CCC(C2CCC(=O)CC2)CC1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCC=C1CCC(C2CCC(=CCC)CC2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
29.1 g of bicyclohexyl-4,4'-dione and 123 g of propyl-triphenylphosphonium bromide were suspended in 300 ml of THF. The solution was cooled to 0° C., and a solution of 36 g of potassium tert-butoxide in 100 ml of THF was added dropwise, and the mixture was stirred at RT overnight. Conventional work-up gave 4,4'-dipropylidenebicyclohexyl.
Reaction SMILES: Cl.[F:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]3[C:18]([C:19]4[CH2:20][CH2:21][NH:22][CH2:23][CH:24]=4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)=[O:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:36](OC(=O)C)(=[O:38])[CH3:37].C(=O)(O)[O-].[Na+]>C1COCC1.O>[C:36]([N:22]1[CH2:21][CH:20]=[C:19]([C:18]2[C:12]3[S:11][C:10]([NH:9][C:7](=[O:8])[C:6]4[CH:5]=[CH:4][C:3]([F:2])=[CH:28][CH:27]=4)=[N:14][C:13]=3[C:15]([O:25][CH3:26])=[CH:16][CH:17]=2)[CH2:24][CH2:23]1)(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C2=CCNCC2)c2sc(NC(=O)c3ccc(F)cc3)nc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C2=CCN(C(C)=O)CC2)c2sc(NC(=O)c3ccc(F)cc3)nc12
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
To a solution of 0.12 g (0.28 mMol) 4-fluoro-N-[4-methoxy-7-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzothiazol-2-yl]-benzamide hydrochloride in 3 ml THF were added 0.043 ml triethyl amine. At 0° C. 0.029 ml (0.31 mMol) acetic anhydride was added dropwise and stirred for 30 min. Then a mixture of 5 ml sat. aqueous sodium bicarbonate and 15 ml water were added. After extracting with four times 25 ml ethyl acetate the combined organic phases were dried over sodium sulfate and concentrated to dryness in vacuo to yield 0.088 g (73%) N-[7-(1-acetyl-1,2,3,6-tetrahydro-pyridin-4-yl)-4-methoxy-benzothiazol-2-yl]-4-fluoro-benzamide as an off-white solid; F.p.: 264-265° C.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[N:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1.O[C:27]1[CH:38]=[CH:37][C:30]([O:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:29][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[N:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][CH:22]([O:25][C:27]3[CH:38]=[CH:37][C:30]([O:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:29][CH:28]=3)[CH2:21][CH2:20]2)=[CH:15][CH:14]=1
Reactant: COC(=O)COc1ccc(O)cc1
Reactant: OC1CCN(c2ccncc2)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC2CCN(c3ccncc3)CC2)cc1
Temperature: 4 °C
Reaction time: 1 h

Procedure:
Diethylazodicarboxylate (0.47 ml) was added dropwise over 30 minutes to a stirred mixture of 1-(4-pyridyl)-4-piperidinol (534 mg), methyl 4-hydroxyphenoxyacetate (546 mg), triphenylphosphine (787 mg) and dry THF (30 ml) in an atmosphere of argon and cooled to 4° C. After 1 hour at 4° C., the mixture was allowed to reach ambient temperature and stirred for 48 hours. The solvent was removed by evaporation and the residue purified by flash chromatography on silica eluting with 5% v/v methanol/dichloromethane. Recrystallisation from ethyl acetate/hexane gave the title compound, 532 mg, as a white solid: m.p. 74°-76° C.; NMR (d6DMSO) δ 8.15(2H, bd), 6.89(6H, m), 4.71(2H, s), 4.50(1H, m), 3.70(2H, m), 3.69(3H, s), 3.23(2H, m), 1.96(2H, m), 1.62(2H, m); m/e 343 (M+H)+ ; calculated for C19H22N2O4 : C, 66.7; H, 6.5; N, 8.2. found: C, 66.2; H, 6.7; N, 8.2%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:18][O:19][C:20](=[O:38])[C@H:21]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[O:36][CH3:37])=[CH:26][CH:25]=1)[NH2:22]>>[CH3:18][O:19][C:20](=[O:38])[C@H:21]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[O:36][CH3:37])=[CH:26][CH:25]=1)[NH:22][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:10][C:2]=1[Cl:1]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2OC)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(C(=O)O)c(Cl)c1
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2OC)cc1)NC(=O)c1ccc(C(=O)OC(C)(C)C)cc1Cl

Procedure:
2-Chloro-4-(tert-butoxycarbonyl)benzoic acid was coupled with 4-(2-methoxyphenyl)-L-phenylalanine methyl ester (free amine from Example 1-3)) using a similar procedure as described in Example 2-1) to give N-[2-chloro-4-(tert-butoxycarbonyl)benzoyl]-4-(2-methoxyphenyl)-L-phenylalanine methyl ester (0.332 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([CH:22]=O)=[CH:12]2)(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1.[CH3:24][NH2:25].[BH4-].[Na+].[C:28](=[O:31])([O-])[OH:29].[Na+]>O1CCCC1.CO.O>[C:13]([O:29][C:28](=[O:31])[N:25]([CH2:22][C:13]1[CH:14]=[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]([S:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=2)(=[O:10])=[O:9])[CH:12]=1)[CH3:24])([CH3:22])([CH3:14])[CH3:12]
Reactant: CN
Reactant: O=C([O-])O
Reactant: O=Cc1cc(-c2ccccc2)n(S(=O)(=O)c2cncc(Br)c2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cc(-c2ccccc2)n(S(=O)(=O)c2cncc(Br)c2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 48 %

Procedure:
1-[(5-Bromopyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde (1.18 g) was dissolved in absolute tetrahydrofuran (15 mL), a 2 mol/L solution (4.6 mL) of methylamine in tetrahydrofuran was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was added to a solution of sodium borohydride (341 mg) in methanol (6 mL), and the mixture was stirred at the same temperature for 5 min. di-tert-Butyl bicarbonate (3.87 g) was added, and water (15 mL) and sodium hydrogencarbonate (1.26 g) were added 5 min later. The mixture was further stirred at room temperature for 30 min, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→1:1), and fractions showing Rf values of 0.63, 0.30 and 0.075 (eluent: hexane-ethyl acetate=3:1) by TLC analysis were collected and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (30 mL), manganese dioxide (75% chemically treated product, 3.0 g) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was filtered through celite, and celite was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→1:1) to give the title compound as a colorless oil (yield 733 mg, 48%).
Reaction SMILES: [C:1]1([C:7]2O[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:10][C:11](=[O:17])[C:12]=2[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[CH3:26][NH2:27].C(O)(=O)C>O>[C:1]1([C:7]2[N:27]([CH3:26])[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:10][C:11](=[O:17])[C:12]=2[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN
Reactant: COC(=O)c1c(-c2ccccc2)oc(-c2ccccc2)cc1=O
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1c(-c2ccccc2)n(C)c(-c2ccccc2)cc1=O

Procedure:
3.0 gms of 2,6-diphenyl-3-methoxycarbonyl-pyr-4-one, 33 mls of methanol, 13.3 mls of 40% aqueous methylamine and 2 mls of glacial acetic acid were mixed at room termperature. The next day the mixture was diluted with water. Filtration of the resulting suspension yielded 2.5 gms of methyl 2,6-diphenyl-1-methyl-4-oxonicotinate. Recrystallization from methanol provided material at 255°-7°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[CH:22])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.Br[C:24]1[C:25]([F:35])=[CH:26][C:27]([F:34])=[C:28]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:29]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[C:22][C:24]4[C:25]([F:35])=[CH:26][C:27]([F:34])=[C:28]([S:30]([NH2:33])(=[O:31])=[O:32])[CH:29]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1cc(Br)c(F)cc1F
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Product: NS(=O)(=O)c1cc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)cc4)nc23)c(F)cc1F

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-3-ethynyl-7-trifluoromethyl pyrazolo[1,5-a]pyrimidine (example C.4) (161 mg, 0.5 mmol) and 5-bromo-2,4-difluoro-benzenesulfonamide (136 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (146 mg, 57%). MS (ISP) 513.3 [(M+H)+]; mp 292-293° C.
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH2:19][CH2:18][C@H:17]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:16]2=[O:31])[C@H:11]([CH:32]([CH3:34])[CH3:33])[CH2:10]1)(C(C)(C)C)(C)C>CC(O)=O.C1COCC1.O>[OH:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH2:19][CH2:18][C@H:17]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:16]2=[O:31])[C@H:11]([CH:32]([CH3:34])[CH3:33])[CH2:10]1
Reactant: CC(C)[C@@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)[C@@H]1C[C@H](O)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Reaction time: 72 h
Yield: 97.9 %

Procedure:
Benzyl (S)-1-((1S,2S,4R)-4-(tert-butyldimethylsilyloxy)-2-isopropylcyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (1.0 g) was dissolved in a 4/1/1 mixture of AcOH/THF/H2O (60 mL). After 72 h, additional 4/1/1 mixture of AcOH/THF/H2O (30 mL) was added. This solution was stirred an additional 24 h before it was concentrated. The residue was dissolved in EtOAc and washed with saturated NaHCO3, dried (MgSO4), filtered, and concentrated in vacuo to afford benzyl (S)-1-((1S,2S,4R)-4-hydroxy-2-isopropylcyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (750 mg). MS found: (M+H)+=375.3.
Reaction SMILES: O.[CH3:2][N:3]([CH3:23])[C@H:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[N+:20]([O-])=O)[CH2:5]1>CO.[Pd]>[NH2:20][C:11]1[CH:12]=[C:13]([C:16]([F:17])([F:18])[F:19])[CH:14]=[CH:15][C:10]=1[N:6]1[CH2:7][CH2:8][CH2:9][C@H:4]([N:3]([CH3:23])[CH3:2])[CH2:5]1
Reactant: CN(C)[C@H]1CCCN(c2ccc(C(F)(F)F)cc2[N+](=O)[O-])C1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CN(C)[C@H]1CCCN(c2ccc(C(F)(F)F)cc2N)C1
Reaction time: 8 h

Procedure:
A 500 mL parr pressure bottle was charged with palladium, 10 wt. % on activated carbon, 50% water wet (9.1 g, 8.6 mmol) under nitrogen. (S)—N,N-dimethyl-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-amine (13.6 g, 43 mmol) was added as a solution in methanol via syringe, rinsing in with multiple methanol washes until the final volume was approximately 100 mL. The vessel was placed in a parr shaker, and treated with 2 atm H2 and shaken overnight. The reaction was flushed with nitrogen, and filtered through a pad of celite rinsing with 1.3 L of methanol and concentrated in vacuo. The oil was taken up in CH2Cl2, dried over Na2SO4, filtered, and concentrated in vacuo to give (S)-1-(2-amino-4-(trifluoromethyl)phenyl)-N,N-dimethylpiperidin-3-amine as a red oil. MS m/z=288 [M+H]+. Calc'd for C14H20F3N3: 287.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]([C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]([CH2:30][CH2:31][CH:32]=O)[CH:22]=1)([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[N:9]=[CH:8]2)[OH:4].C(O)(=O)C.[NH:40]1[CH2:45][CH2:44][CH:43]([CH2:46][OH:47])[CH2:42][CH2:41]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.O>[F:34][C:2]([F:1])([F:35])[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)[N:9]=[CH:8]2)([C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]([CH2:30][CH2:31][CH2:32][N:40]2[CH2:45][CH2:44][CH:43]([CH2:46][OH:47])[CH2:42][CH2:41]2)[CH:22]=1)[OH:4]
Reactant: O=CCCn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c2ccccc21
Reactant: OCC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: OCC1CCN(CCCn2cc(C(O)(c3ccc4c(cnn4-c4ccc(F)cc4)c3)C(F)(F)F)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.4 %

Procedure:
To a chilled (0° C.) solution of 100 mg (0.21 mmol) of 3-(3-{2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-1-hydroxyethyl}indol-1-yl)propionaldehyde (prepared according to methods described in Examples 34 and 35) in dichloroethane was added 160 mg (2.6 mmol) acetic acid and 300 mg (2.6 mmol) 4-piperidinemethanol. The solution was warmed to room temperature, stirred for 30 minutes, and 0.1 g (0.5 mmol) of sodium triacetoxyborohydride was added. The solution was stirred at room temperature overnight. The reaction was diluted with water and extracted with ethyl acetate, the aqueous layer was separated and the organic layers were combined and washed with saturated sodium bicarbonate, brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by prep-HPLC to afford 42 mg (34.8%) of the title compound. MS m/z 581.6 (MH+).