Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[C@@:22]2([CH3:23])[C@@H:14]([CH2:15][CH2:16][C@@H:17]2[CH:18]([CH:20]=[O:21])[CH3:19])[C@H:13]2[C@@H:4]([C@:5]3([CH3:25])[C:10]([CH2:11][CH2:12]2)=[CH:9][C:8](=[O:24])[CH:7]=[CH:6]3)[CH2:3]1.[C:26](Cl)(=[O:28])[CH3:27].N1C=CC=CC=1>C(Cl)Cl>[C:26]([O:1][C@@H:2]1[C@@:22]2([CH3:23])[C@@H:14]([CH2:15][CH2:16][C@@H:17]2[CH:18]([CH:20]=[O:21])[CH3:19])[C@H:13]2[C@@H:4]([C@:5]3([CH3:25])[C:10]([CH2:11][CH2:12]2)=[CH:9][C:8](=[O:24])[CH:7]=[CH:6]3)[CH2:3]1)(=[O:28])[CH3:27]
Reactant: CC(C=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)O[C@H]1C[C@H]2[C@@H](CCC3=CC(=O)C=C[C@@]32C)[C@@H]2CC[C@H](C(C)C=O)[C@@]12C
Reaction time: 5 h

Procedure:
12α-Hydroxypregna-1,4-dien-3-one-20-carbaldehyde (34.2 g) was dissolved in 300 ml of methylene chloride. To the solution were added 23.6g of acetyl chloride and 27.7 g of pyridine, and the mixture was stirred atroom temperature for 5 hours. To the reaction mixture was added 300 ml of methylene chloride, the resulting solution was washed in sequence with diluted hydrochloric acid and water, and dried over anhydrous magnesium sulfate. Low-boiling fractions were distilled off from the solution under reduced pressure. There was thus obtained crude 12α-acetoxypregna-1,4-dien-3-one-20-carbaldehyde as a viscous substance. This crude product was dissolved in 300 ml of benzene, 21.3 g of piperidine was added to the solution, and the resulting mixture was refluxed for 3 hours while removing the byproduct water azeotropically with benzene. Low-boiling fractions were distilled off from the thus-obtained reaction mixture. There remained crude 12α-acetoxy-22-(N-peridyl)bisnor-1,4,20(22)-cholatrien-3-one as a viscous substance, which was dissolved in 180 ml of pyridine. To the solution was added gradually at room temperature a mixture of 20.0 g of chromium trioxide and 250 ml of pyridine. After stirring the resulting mixture for one hour, 1 liter of benzene was added to the reaction mixture. The solid matter was filtered off, and diluted hydrochloric acid was added to the filtrate. After effecting benzene extraction to a sufficient extent, the benzene layer was washed in sequence with diluted hydrochloric acid and water. Low-boiling fractions were distilled off under reduced pressure, and the residue was purified by preparative liquidchromatography [column: Waters Associates' Prep LC/System 500, Prep PAK™500/SILICA; solvent system: isopropyl alcohol:n-hexan=20:80, v/v] to give 9.1 g of 12α-acetoxypregna-1,4-diene-3,20-dione as crystals. It has the following physical properties.
Reaction SMILES: [S:1](Cl)([C:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:9]([N:10]([CH3:12])[CH3:11])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH2:18]([O:20][CH:21]([O:26][CH2:27][CH3:28])[CH2:22][CH2:23][CH2:24][NH2:25])[CH3:19].CCN(CC)CC>C(Cl)Cl>[CH2:27]([O:26][CH:21]([O:20][CH2:18][CH3:19])[CH2:22][CH2:23][CH2:24][NH:25][S:1]([C:4]1[C:16]2[C:8](=[C:9]([N:10]([CH3:12])[CH3:11])[CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:6][CH:5]=1)(=[O:3])=[O:2])[CH3:28]
Reactant: CCOC(CCCN)OCC
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(CCCNS(=O)(=O)c1cccc2c(N(C)C)cccc12)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of dansyl chloride (270 mg, 1.00 mmol) in CH2Cl2 (10 mL) was added 4-aminobutyraldehyde diethyl acetal (237 μL, 1.20 mmol) and Et3N (170 μL, 1.20 mmol). The solution was stirred for 1 h at 25° C. and was then evaporated to dryness under reduced pressure. The material left was processed and purified under conditions identical to those described for the processing and purification of 11. Fractions containing the product were collected and evaporated to dryness under low pressure affording 13 (366 mg, 930 μmol) as a solid in a yield of 93%. 1H NMR (300 MHz, DMSO-d6): δ 8.45 (dt, J=8.5, 1.1 Hz, 1H), 8.30 (dt, J=8.8, 0.9 Hz, 1H), 8.09 (dd, J=7.3, 1.2 Hz, 1H), 7.89 (t, J=5.5 Hz, 1H), 7.61 (t, J=8.5 Hz, 1H), 7.58 (t, J=8.5 Hz, 1H), 7.25 (dd, J=7.6, 0.7 Hz, 1H), 4.19 (t, J=5.3 Hz, 1H), 3.36 (m, 2H), 3.23 (m, 2H), 2.81 (s, 6H), 2.77 (t, J=5.5 Hz, 2H), 1.31 (m, 4H), 0.99 (t, J=7.0 Hz, 6H). 13C NMR (75 MHz, DMSO-d6): δ 151.2, 136.1, 129.2, 128.9, 128.1, 127.7, 123.5, 119.1, 114.9, 101.6, 60.2, 44.9, 42.2, 30.1, 24.4, 15.1. +ESI-HRMS: Calcd for C20H30N2O4S [M+H]+ 395.1999. found 395.2000.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][O:10][C:9]2=[O:13])[CH:5]=[CH:4][C:3]=1[N+:14]([O-])=O>[Pd]>[NH2:14][C:3]1[CH:4]=[CH:5][C:6]([N:8]2[CH2:12][CH2:11][O:10][C:9]2=[O:13])=[N:7][C:2]=1[CH3:1]
Reactant: Cc1nc(N2CCOC2=O)ccc1[N+](=O)[O-]
Agent: [Pd]
Product: Cc1nc(N2CCOC2=O)ccc1N
Yield: 89.5 %

Procedure:
A solution of 3-(6-methyl-5-nitro-2-pyridinyl)-1,3-oxazolidin-2-one (which may be prepared, for example, according to Intermediate 3) (200 mg, 0.896 mmol) was stirred rapidly over 10% palladium on carbon (30 mg, 0.028 mmol) under an atmosphere of hydrogen at room temperature for 3 hours. The catalyst was then removed by filtration through a pad of celite. The filtrate was evaporated in vacuo to give the title compound (155 mg) as a white solid. LCMS (2 min, formic) Rt 0.38 min, m/z (ES+) 194 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]#[N:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:18][CH2:19]Cl.[OH-].[K+]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3([C:15]#[N:16])[CH2:19][CH2:18]3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: N#CCc1ccc(-c2ccc(F)cc2)cc1
Reactant: ClCCBr
Agent: [K+]
Agent: [OH-]
Product: N#CC1(c2ccc(-c3ccc(F)cc3)cc2)CC1
Reaction time: 18 h

Procedure:
A suspension of 3.1 g (14.7 mmol) of (4′-fluoro-1,1′-biphenyl-4-yl)acetonitrile, prepared in step 7.1., 2.4 ml (29.4 mmol) of 1-bromo-2-chloroethane and 0.067 g (0.294 mmol) of N-triethylbenzylammonium chloride, heated to approximately 50° C., is admixed dropwise with 6.7 g (102.8 mmol) of aqueous 60% potassium hydroxide solution. Stirring is continued at 50° C. for 18 hours.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[S:13][C:14]#[N:15])([O-])=O.NC(N)=S.O>CN(C)C=O>[NH2:15][C:14]1[S:13][C:5]2[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=2[N:1]=1
Reactant: N#CSc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: NC(N)=S
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc2cc([N+](=O)[O-])ccc2s1
Temperature: 150 °C
Reaction time: 2 h
Yield: 108.4 %

Procedure:
11.71 g of 2,4-dinitrophenyl thiocyanate are added, over the course of 15 minutes, to a solution of 7.6 g of thiourea in 50 ml of dimethylformamide at 150° C. The mixture is stirred at 150° C. for a further 2 hours, and the product is discharged into 500 ml of water, and the solid is filtered off with suction and washed with water. 11 g of crude 2-amino-5-nitrobenzothiazole are obtained, its identity being confirmed by TLC comparison with authentic material.
Reaction SMILES: C([O:8][C:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([CH2:20][CH2:21][CH:22]([CH3:29])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:15][CH:16]=2)[O:11][C:10]=1[C:30]1[CH:35]=[C:34]([O:36]C)[C:33]([O:38]CC2C=CC=CC=2)=[C:32]([O:46]C)[CH:31]=1)C1C=CC=CC=1.B(Br)(Br)Br.CO>ClCCl>[CH3:29][CH:22]([CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:21][CH2:20][C:14]1[CH:13]=[C:12]2[C:17]([C:18](=[O:19])[C:9]([OH:8])=[C:10]([C:30]3[CH:35]=[C:34]([OH:36])[C:33]([OH:38])=[C:32]([OH:46])[CH:31]=3)[O:11]2)=[CH:16][CH:15]=1
Reactant: COc1cc(-c2oc3cc(CCC(C)CCCC(C)C)ccc3c(=O)c2OCc2ccccc2)cc(OC)c1OCc1ccccc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CC(C)CCCC(C)CCc1ccc2c(=O)c(O)c(-c3cc(O)c(O)c(O)c3)oc2c1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a stirring solution of 47 (0.028 g, 0.05 mmol) in dichloromethane (1 ml) under argon at 0° C. was added boron tribromide (1.0M in DCM, 0.7 ml, 14 eq). The reaction was then warmed to room temperature and stirred for 23 hours. The mixture was then cooled to 0° C., methanol (1 ml) added heated to reflux for 2 hours. The reaction was then cooled and concentrated in vacuo to give a solid that was chromatographed (silica gel, DCM:methanol, 19:1) to give 9g* (0.008g, 37%) as a yellow solid.
Reaction SMILES: [F:1][CH:2]([F:39])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH2:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:5]=2[N:4]=1.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>>[F:39][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]([CH:27]3[CH2:32][CH2:31][N:30]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:29][CH2:28]3)[CH2:21][CH2:22][CH2:23][N:24]([CH3:25])[CH3:26])[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCN(C)C)C2CCNCC2)n1
Reactant: CS(=O)(=O)Cl
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCN(C)C)C2CCN(S(C)(=O)=O)CC2)n1
Yield: 99 %

Procedure:
Reaction of N1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N3,N3-dimethyl-N1-(4-piperidinyl)-1,3-propanediamine with methanesulfonyl chloride gave N1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N3,N3-dimethyl-N1-[1-(methylsulfonyl)-4-piperidinyl]-1,3-propanediamine in 99% yield.
Reaction SMILES: C(OC([N:11]1[CH2:16][C@H:15]([NH:17][C:18]([NH:20][C:21]2[N:22]=[C:23]3[CH:29]=[CH:28][N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:24]3=[N:25][CH:26]=2)=[O:19])[CH2:14][C@@H:13]([CH3:38])[CH2:12]1)=O)C1C=CC=CC=1>CCO.[OH-].[Pd+2].[OH-]>[CH3:38][C@H:13]1[CH2:12][NH:11][CH2:16][C@H:15]([NH:17][C:18]([NH:20][C:21]2[N:22]=[C:23]3[CH:29]=[CH:28][N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:35])([CH3:37])[CH3:36])[C:24]3=[N:25][CH:26]=2)=[O:19])[CH2:14]1
Reactant: C[C@@H]1C[C@@H](NC(=O)Nc2cnc3c(ccn3COCC[Si](C)(C)C)n2)CN(C(=O)OCc2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: C[C@H]1CNC[C@H](NC(=O)Nc2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
A mixture of (3R,5R)-3-methyl-5-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-ureido}-piperidine-1-carboxylic acid benzyl ester (1.04 g, 1.93 mmol) and palladium hydroxide 20% on carbon (0.15 g) in 20 mL of EtOH was stirred at RT under hydrogen (1 atm) for 2 hours before being filtered. The dark brown filtrate was evaporated to give 0.76 g of 1-((3R,5R)-5-methyl-piperidin-3-yl)-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea (>95%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:28]=[CH:27][C:10]2[C:11]3[N:12]([CH:16]=[C:17]([C:19]4[N:23]([CH:24]([CH3:26])[CH3:25])[N:22]=[CH:21][N:20]=4)[N:18]=3)[CH2:13][CH2:14][O:15][C:9]=2[CH:8]=1)(=O)=O.[NH:31]1[CH2:35][CH:34]=[CH:33][C@H:32]1[C:36]([NH2:38])=[O:37]>>[CH:24]([N:23]1[C:19]([C:17]2[N:18]=[C:11]3[C:10]4[CH:27]=[N:28][C:7]([N:31]5[CH2:35][CH:34]=[CH:33][C@H:32]5[C:36]([NH2:38])=[O:37])=[CH:8][C:9]=4[O:15][CH2:14][CH2:13][N:12]3[CH:16]=2)=[N:20][CH:21]=[N:22]1)([CH3:25])[CH3:26]
Reactant: NC(=O)[C@@H]1C=CCN1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(OS(=O)(=O)C(F)(F)F)cc1OCC2
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CC=C[C@H]3C(N)=O)cc1OCC2

Procedure:
Following the procedures in Example 388, 2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl trifluoromethanesulfonate and (S)-2,5-dihydro-1H-pyrrole-2-carboxamide were reacted to give 389. M/z 407.2, calc. 406.19. 1H NMR (400 MHz, DMSO) δ 9.08 (s, 1H), 7.88 (s, 1H), 7.84 (s, 1H), 7.38 (s, 1H), 6.98 (s, 1H), 6.13 (dd, J=6.2, 1.9, 1H), 6.02-5.88 (m, 3H), 4.97 (s, 1H), 4.52 (dd, J=9.3, 7.1, 4H), 4.39-4.18 (m, 2H), 1.48 (dd, J=6.6, 2.5, 6H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[O:21]1[CH2:24][CH:23]([CH2:25]O)[CH2:22]1.C(P(CCCC)(CCCC)=CC#N)CCC>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][N:13]=2)[CH2:25][CH:23]2[CH2:24][O:21][CH2:22]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(NS(=O)(=O)c2ccc(F)cc2)nc1
Reactant: OCC1COC1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(C)c1ccc(N(CC2COC2)S(=O)(=O)c2ccc(F)cc2)nc1
Temperature: 20 °C
Reaction time: 16 h
Yield: 72.6 %

Procedure:
To a solution of 4-fluoro-N-(5-isopropylpyridin-2-yl)benzenesulfonamide (100 mg, 0.340 mmol) and oxetan-3-ylmethanol (20.95 mg, 0.238 mmol) in toluene (1.5 mL) stirred in air at room temperature was added a solution of 2-(tributylphosphoranylidene)acetonitrile (82 mg, 0.340 mmol) in toluene (0.5 mL). The reaction mixture was stirred at 20° C. for 16 hours. Additional 2-(tributylphosphoranylidene)acetonitrile (82 mg, 0.340 mmol) and oxetan-3-ylmethanol (20.95 mg, 0.238 mmol) were added and the solution stirred for a further 24 hours. The reaction solution was then purified on an aminopropyl (NH2) solid phase extraction (SPE) cartridge eluting with a 0-50% ethyl acetate-cyclohexane gradient, to give the title product (63 mg) as a colourless gum. LCMS (2 min, formic) Rt 1.12 min, m/z (ES+) 365 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:7]2([CH2:12][CH:11]([CH:13]=[O:14])[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH2:4][CH2:3]1.[BH4-].[Na+].[OH-].[Na+]>CO>[CH3:1][C:2]1([CH3:15])[C:7]2([CH2:12][CH:11]([CH2:13][OH:14])[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH2:4][CH2:3]1
Reactant: CC1(C)CCC=CC12CCCC(C=O)C2
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCC=CC12CCCC(CO)C2
Yield: 96.5 %

Procedure:
To a solution of 11,11-dimethyl-spiro[5.5]undec-7-ene-2-carbaldehyde (195 mg) obtained in Step 7 in methanol (5 mL) was added sodium borohydride (55 mg) under ice-cooling, followed by stirring the reaction mixture under ice-cooling for 15 minutes. Then, after addition of 0.5N aqueous sodium hydroxide solution (10 mL), the reaction mixture was extracted with diethyl ether. The organic layer was washed with water, dried and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate (volume ratio)=10:1 to 5:1) to give (11,11-dimethyl-spiro[5.5]undec-7-en-2-yl)-methanol (190 mg).
Reaction SMILES: [C:1]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:15][CH:16]=O)[CH:13]=2)[N:8]([CH3:18])[CH:7]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[H-].[Na+].[Cl:21][C:22]1[CH:27]=[CH:26][N:25]=C(S(C)(=O)=O)[N:23]=1.[OH-].[Na+]>C1COCC1.CN(C=O)C>[Cl:21][C:22]1[CH:27]=[CH:26][N:25]=[C:16]([NH:15][C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[N:8]([CH3:18])[CH:7]=[C:6]3[C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[N:23]=1
Reactant: CC(C)C(=O)c1cn(C)c2ccc(NC=O)cc12
Reactant: CS(=O)(=O)c1nccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)C(=O)c1cn(C)c2ccc(Nc3nccc(Cl)n3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
To a solution of N-(3-isobutyryl-1-methyl-1H-indol-5-yl)formamide (450 mg, 1.84 mmol) in anhydrous THF (3 mL) and anhydrous DMF (3 mL) was added 60% NaH (228 mg, 5.52 mmol) at 0° C. After being stirred for 30 min at room temperature, it was cooled to 0° C. To this, was added 4-chloro-2-(methylsulfonyl)pyrimidine (466 mg, 2.43 mmol) and then stirred for 2 hours. Quenching the reaction by addition of ice and 2N solution of sodium hydroxide (2 mL) resulted precipitation of brown solids. Additional 20 mL of water was added to complete of solid formation. The resulted solids were collected by filtration, rinsed with water and the dried in vacuo to provide the desired intermediate 5 as a brown solid (542 mg, 89%); MS (ESI) m/z 329 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]12[CH2:24][CH:23]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[C:14](=[O:34])[N:13]1[CH:9]([CH2:10][CH:11]([O:35][C:36]3[C:45]4[C:40](=[C:41]([CH3:48])[C:42]([O:46][CH3:47])=[CH:43][CH:44]=4)[N:39]=[C:38]([C:49]4[S:50][CH:51]=[C:52]([CH:54]([CH3:56])[CH3:55])[N:53]=4)[CH:37]=3)[CH2:12]1)[C:8](=[O:57])[NH:7]2)=[O:5])C.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO.O>[CH:54]([C:52]1[N:53]=[C:49]([C:38]2[CH:37]=[C:36]([O:35][CH:11]3[CH2:10][CH:9]4[N:13]([C:14](=[O:34])[N:15]([CH2:25][C:26]5[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=5)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH:22][CH:23]5[C:6]([C:4]([OH:5])=[O:3])([NH:7][C:8]4=[O:57])[CH2:24]5)[CH2:12]3)[C:45]3[C:40](=[C:41]([CH3:48])[C:42]([O:46][CH3:47])=[CH:43][CH:44]=3)[N:39]=2)[S:50][CH:51]=1)([CH3:56])[CH3:55]
Reactant: CCOC(=O)C12CC1C=CCCCCCN(Cc1ccc(OC)cc1)C(=O)N1CC(Oc3cc(-c4nc(C(C)C)cs4)nc4c(C)c(OC)ccc34)CC1C(=O)N2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN2CCCCCC=CC3CC3(C(=O)O)NC(=O)C3CC(Oc4cc(-c5nc(C(C)C)cs5)nc5c(C)c(OC)ccc45)CN3C2=O)cc1
Reaction time: 8 h
Yield: 60 %

Procedure:
Ethyl ester 137 (366 mg, 0.460 mmol) was dissolved in THF/MeOH/H2O 2:1:1 (30 mL) and 1M LiOH (4.6 mL, 4.40 mmol) was added dropwise at room temperature during 5 minutes after which the solution was stirred overnight. The mixture was acidified to pH 3-4 by addition of solid citric acid and the organic solvents were evaporated. The water phase was diluted with brine (50 mL) and was then extracted trice with DCM. The combined organic phase was washed twice with brine and was thereafter dried, filtered and concentrated. The crude was then purified by flash column chromatography (ethyl actetate/methanol 7:1) to give the title compound (212 mg, 60%). (M+H)+ calcd: 768.3. found: 768.7.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1.[I:23][CH2:24]I.[NH4+].[Cl-]>O1CCCC1>[I:23][CH2:24][C:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1
Reactant: ICI
Reactant: CC(C)(C)OC(=O)C1CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1(CI)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 14.6 %

Procedure:
To a stirred solution of diisopropylamine (7.7 mL, 0.055 mol) in tetrahydrofuran (80 mL), n-butyl lithium (1.59 M in cyclohexane, 34 mL, 0.055 mol) was added slowly at −70° C. and the mixture was stirred for 20 min at 0° C. The mixture was cooled to −78° C. and tert-butyl cyclopropanecarboxylate (6.5 g, 0.046 mol, Kohlrausch et al., Z. Elektrochem. Angew. Phys. Chem., 1937, 70, 392) in tetrahydrofuran (10 mL) was added dropwise, and the mixture was stirred for 3 h. Then, diiodomethane (4.0 mL, 0.050 mol) in tetrahydrofuran (10 mL) was added dropwise, and the mixture was allowed to warm up to room temperature overnight. Saturated aqueous NH4Cl (80 mL) was added to the solution and it was extracted with diethyl ether (50 mL), washed with brine (20 mL), dried over MgSO4, filtered and concentrated to give brown oil. The oil was chromatographed on a column of silica gel eluting with hexane/diethyl ether (40:1) to give 1.9 g of the title compound as a crude product. The crude product was used without further purification. Rf: 0.3 (hexane/diethyl ether (40:1))
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[S:15][C:14]3[C:9](=[N:10][CH:11]=[CH:12][C:13]=3[O:16][C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[CH:8]=2)[CH:6]=1.[C:24]1([CH2:30][C:31]([N:33]=[C:34]=[S:35])=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[S:15][C:14]3[C:9](=[N:10][CH:11]=[CH:12][C:13]=3[O:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:34]([NH:33][C:31](=[O:32])[CH2:30][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[S:35])=[CH:19][CH:18]=3)[CH:8]=2)[CH:6]=1
Reactant: Cc1cnn(-c2cc3nccc(Oc4ccc(N)cc4)c3s2)c1
Reactant: O=C(Cc1ccccc1)N=C=S
Solvent: C1CCOC1
Product: Cc1cnn(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4)c3s2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.8 %

Procedure:
To a suspension of the 257 (134.6 mg, 0.418 mmol) in THF (4.2 mL) was added 2-phenylacetyl isothiocyanate (111 mg, 0.627 mmol). The reaction mixture was stirred for 1 hr at room temperature, transferred onto a chromatography column and eluted wit a gradient of gradient EtOAc/hexane, 1:1 to 2:1, to provide a beige solid which was triturated with diethyl ether to afford title compound 258a (31 mg, 15% yield) as a white solid. Characterization of 258a is provided in the table 23.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:12][C:13]1[C:18]([CH3:19])=[C:17]([CH3:20])[N:16]=[C:15]([Cl:21])[C:14]=1[N+:22]([O-])=O)[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>[Pt].C1(C)C=CC=CC=1>[Si:1]([O:8][CH2:9][C@@H:10]([NH:12][C:13]1[C:18]([CH3:19])=[C:17]([CH3:20])[N:16]=[C:15]([Cl:21])[C:14]=1[NH2:22])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(N[C@@H](C)CO[Si](C)(C)C(C)(C)C)c1C
Agent: [Pt]
Solvent: Cc1ccccc1
Product: Cc1nc(Cl)c(N)c(N[C@@H](C)CO[Si](C)(C)C(C)(C)C)c1C
Reaction time: 6 h
Yield: 99.7 %

Procedure:
A pressure bottle was charged with platinum on carbon (5%, 1.16 g) followed by a solution of N-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl)-2-chloro-5,6-dimethyl-3-nitropyridin-4-amine (4.79 g, 12.8 mmol) dissolved in 125 mL of toluene. The reaction mixture was shaken under H2 at 48 PSI (3.3×105 Pa). After 6 hours, the reaction mixture was filtered through a pad of CELITE filter agent. The pad was rinsed with toluene and CH2Cl2. The combined filtrates were concentrated under reduced pressure to give N4-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl)-2-chloro-5,6-dimethylpyridine-3,4-diamine (4.39 g) as an orange oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[N:31]1[CH:35]=[N:34][CH:33]=[N:32]1)[C:5]([NH:7][C:8]1[C:13]([CH2:14][CH3:15])=[CH:12][C:11]([C:16]([F:25])([C:21]([F:24])([F:23])[F:22])[C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[CH2:26][CH3:27])=[O:6].C(N(CC)CC)C.[F:43][C:44]1[CH:52]=[CH:51][C:47]([C:48](Cl)=[O:49])=[CH:46][CH:45]=1>ClCCl>[F:43][C:44]1[CH:52]=[CH:51][C:47]([C:48]([NH:1][C:2]2[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=2[N:31]2[CH:35]=[N:34][CH:33]=[N:32]2)[C:5]([NH:7][C:8]2[C:13]([CH2:14][CH3:15])=[CH:12][C:11]([C:16]([F:25])([C:17]([F:19])([F:20])[F:18])[C:21]([F:22])([F:23])[F:24])=[CH:10][C:9]=2[CH2:26][CH3:27])=[O:6])=[O:49])=[CH:46][CH:45]=1
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(CC)c1NC(=O)c1ccc(-n2cncn2)c(N)c1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(CC)c1NC(=O)c1ccc(-n2cncn2)c(NC(=O)c2ccc(F)cc2)c1
Temperature: 25 °C
Yield: 82 %

Procedure:
To a solution of 3-amino-N-[2,6-diethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)phenyl]-4-(1,2,4-triazol-1-yl)benzamide (75 mg, 0.15 mmol) (Example I4) in dichloromethane (3 ml) was added triethylamine (63 μl, 0.45 mmol) and 4-fluorobenzoyl chloride (21.3 μl, 0.18 mmol). The reaction mixture was heated to reflux for 15 hours. The reaction mixture was cooled to ambient temperature and quenched by addition of saturated aqueous sodium hydrogen carbonate (5 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (2×5 ml). The combined organic phases were dried over sodium sulfate and concentrated. The residue was purification by column chromatography on silica gel (eluent: hexane/ethyl acetate 1:4) to give Compound No. D2 of Table D (76 mg, 82% yield).