Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH2:9].N1C=CC=CC=1.Cl[C:17]([O:19][CH3:20])=[O:18]>ClCCl>[CH3:20][O:19][C:17](=[O:18])[NH:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1]
Reactant: Nc1ccc(F)cc1F
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
Into a reaction flask under nitrogen, 2,4-difluoro-phenylamine (1, 50.00 g, 390 mmol) is combined with 550 mL of anhydrous dichloromethane and anhydrous pyridine (61.27 g, 770 mmol). Methyl chloroformate (43.92 g, 460 mmol) is added dropwise while cooling to maintain the temperature in the range of 20-30° C. The reaction is stirred overnight, then concentrated under vacuum. The resulting material is diluted with 250 mL of water, adjusted to pH 2 with 2M hydrochloric acid, and extracted with 3×250 mL of ethyl acetate. The organic layers are combined, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is slurried from hexane and the resulting solid is collected by filtration and dried to provide the desired compound (2, 71.06 g, 98%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[C:6]([NH:8][S:9]([C:12]2[CH:24]=[CH:23][C:15]([C:16]([NH:18][CH2:19][C:20]([OH:22])=O)=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:7]=1.[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)=[C:6]([NH:8][S:9]([C:12]2[CH:24]=[CH:23][C:15]([C:16]([NH:18][CH2:19][C:20](=[O:22])[N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:7]=1
Reactant: O=C(O)CNC(=O)c1ccc(S(=O)(=O)Nc2cc(F)ccc2Oc2ccc(F)cc2)cc1
Reactant: C1CCNCC1
Product: O=C(NCC(=O)N1CCCCC1)c1ccc(S(=O)(=O)Nc2cc(F)ccc2Oc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared from {4-[5-fluoro-2-(4-fluoro-phenoxy)-phenylsulfamoyl]-benzoylamino}-acetic acid and piperidine according to the method described in Example 1.1/f. MS (EI) 533.3 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:31]([Cl:32])=[CH:30][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:33][CH3:34])[CH:3]=1.[CH:35](=O)[CH3:36].C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:31]([Cl:32])=[CH:30][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:35][CH3:36])[CH2:22][C:23]3[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:33][CH3:34])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNCc2ccc(C)cc2)CC1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN(CCCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)CC1)Cc1ccc(C)cc1

Procedure:
4-Amino-5-chloro-2-methoxy-N-((1-(5-(4-methylbenzylamino)pentyl)-piperidin-4-yl)methyl)benzamide (1.5 g) as starting compound, acetaldehyde (0.22 ml) and sodium cyanoborohydride (0.25 g) were reacted and treated in the same manner as in Example 136 to give 0.7 g of 4-amino-5-chloro-N-((1-(5-(N-ethyl-N-(4-methylbenzyl)amino)pentyl)piperidin-4-yl)-methyl)-2-methoxybenzamide.
Reaction SMILES: I(O)(=O)(=O)=[O:2].[CH2:6]([O:9][N:10]1[C:16](=[O:17])[N:15]2[CH2:18][C@H:11]1[C:12]([CH3:21])=[CH:13][C@H:14]2[CH2:19][OH:20])[CH:7]=[CH2:8]>C(#N)C.[O-2].[Cr+6].[O-2].[O-2]>[CH2:6]([O:9][N:10]1[C:16](=[O:17])[N:15]2[CH2:18][C@H:11]1[C:12]([CH3:21])=[CH:13][C@H:14]2[C:19]([OH:2])=[O:20])[CH:7]=[CH2:8]
Reactant: C=CCON1C(=O)N2C[C@H]1C(C)=C[C@H]2CO
Reactant: [O-][I+3]([O-])([O-])O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC#N
Product: C=CCON1C(=O)N2C[C@H]1C(C)=C[C@H]2C(=O)O
Reaction time: 0.5 h

Procedure:
To a solution of periodic acid (2 g, 10.42 mmol) in wet acetonitrile (20 mL) (0.75% water by volume) at room temperature was added chromium(VI) oxide (4 mg, 0.04 mmol). The mixture was stirred until complete dissolution was achieved. This solution (5.47 mL, 3 eq) was added dropwise at 0° C. to a solution of (2S,5R)-6-(allyloxy)-2-(hydroxymethyl)-4-methyl-1,6-diazabicyclo[3.2.1]oct-3-en-7-one (Intermediate 14, 0.212 g, 0.95 mmol) in wet acetonitrile (10 mL) (0.75% by volume). The reaction mixture went from clear orange to cloudy brownish color to cloudy green suspension. After 30 minutes, LC/MS showed desired product mass and some remaining starting material. Another equivalent of the oxidizing agent solution (1.82 mL) was added. After 30 minutes, the reaction mixture was diluted with ethyl acetate and washed with 1 to 1 brine/water. The organics were dried over magnesium sulfate, filtered and concentrated to afford a green foam (0.193 g, 86%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:27]=[CH:26][C:6]([C:7]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:10]=2)=[O:8])=[CH:5][C:4]=1[O:28][CH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[O:44][CH3:45])[CH2:34][CH2:33]1.[C:46]1([CH:52](Cl)[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:46]1([CH:52]([NH:2][C:3]2[CH:27]=[CH:26][C:6]([C:7]([C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]([CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:10]=3)=[O:8])=[CH:5][C:4]=2[O:28][CH2:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][N:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[O:44][CH3:45])[CH2:34][CH2:33]2)[C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CCOC(=O)CCCn1cc(C(=O)c2ccc(N)c(OCCCN3CCN(c4ccccc4OC)CC3)c2)c2ccccc21
Reactant: ClC(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1cc(C(=O)c2ccc(NC(c3ccccc3)c3ccccc3)c(OCCCN3CCN(c4ccccc4OC)CC3)c2)c2ccccc21
Temperature: 90 °C
Reaction time: 5 h

Procedure:
Ethyl 4-{3-{4-amino-3-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propoxy}benzoyl}indol-1-yl}butanoate hydrochloride (2.0 g) was dissolved in N,N-dimethylformamide (10 ml), and diphenylmethyl chloride (1.2 ml) and potassium carbonate (1.3 g) were added to the solution. The mixture was stirred at 90° C. for five hours. The reaction mixture was cooled and diluted with ethyl acetate (200 ml). The resultant mixture was sequentially washed with water and saturated brine, and dried and evaporated under reduced pressure. The resultant residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1), to thereby obtain 1.13 g of ethyl 4-{3-{4-diphenylmethylamino-3-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propoxy}benzoyl}indol-1-yl}butanoate as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1([C:19]([NH2:21])=[O:20])[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([CH3:18])=O)=[CH:11][CH:10]=2)[O:3]1.[OH:22][CH:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=1)[CH2:24][NH2:25]>>[CH3:1][C:2]1([C:19]([NH2:21])=[O:20])[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:25][CH2:24][CH:23]([OH:22])[C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)[CH3:18])=[CH:11][CH:10]=2)[O:3]1
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: CC(=O)Cc1ccc(OCC2CCC(C)(C(N)=O)O2)cc1
Product: CC(Cc1ccc(OCC2CCC(C)(C(N)=O)O2)cc1)NCC(O)c1cccc(Cl)c1

Procedure:
Methyl 5-[4-[2-[(3-chloro-β-hydroxyphenethyl)amino] propyl]phenoxymethyl]tetrahydrofuran-2-carboxamide was prepared from methyl 5-[4-acetonylphenoxymethyl]tetrahydrofuran-2-carboxamide and 2-hydroxy-2-(3-chlorophenyl)ethanamine in an analogous manner to the compound described in Example 50.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]2[CH3:14])=[CH:4][C:3]=1[O:15][CH3:16].[NH:17]1[CH:21]=[CH:20][N:19]=[C:18]1[C:22]1[C:30]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[N:24]([CH2:31][C:32](O)=[O:33])[N:23]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:32](=[O:33])[CH2:31][N:24]3[C:25]4=[N:26][CH:27]=[CH:28][CH:29]=[C:30]4[C:22]([C:18]4[NH:17][CH:21]=[CH:20][N:19]=4)=[N:23]3)[CH2:10][C@H:9]2[CH3:14])=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COc1cc(N2CCNC[C@H]2C)ccc1Cl
Reactant: O=C(O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Product: COc1cc(N2CCN(C(=O)Cn3nc(-c4ncc[nH]4)c4cccnc43)C[C@H]2C)ccc1Cl

Procedure:
The title compound was prepared following Protocol A. (R)-1-(4-Chloro-3-methoxyphenyl)-2-methylpiperazine and [3-(1H-imidazol-2-yl)pyrazolo[3,4-b]pyridin-1-yl]acetic acid were used as the coupling components. The crude product was purified by silica gel chromatography (1% to 7.5% MeOH in CH2Cl2) to provide 1-[(R)-4-(4-chloro-3-methoxyphenyl)-3-methylpiperazin-1-yl]-2-[3-(1H-imidazol-2-yl)-pyrazolo[3,4-b]pyridin-1-yl]ethanone as a tan solid: 1H NMR (CDCl3, 400 MHz) δ□ 8.76 (d, 0.6H), 8.66 (dd, 0.3H), 8.57-8.54 (m, 1H), 7.29-7.19 (m, 4H), 6.48-6.40 (m, 2H), 5.53-5.40 (m, 2H), 4.26 (br. d, 0.6H), 4.00 (br. d, 0.6H), 3.88 (s, 1.3H), 3.86 (s, 1.7H), 3.80-3.49 (m, 3.2H), 3.33 (br. s, 0.6H), 3.17-3.14 (m, 2H), 1.51-1.42 (m, 3H); LC/MS m/z (M+H)+ 466.4.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([O:33][CH3:34])=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11](=[O:32])[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[C:21](=[O:31])[C:22](=[O:30])[C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:16][CH2:15]1)=[O:13].C([Sn](CCCC)(CCCC)[C:40]1[CH:45]=[N:44][CH:43]=[CH:42][N:41]=1)CCC>O1CCOCC1.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>[N:41]1[CH:42]=[CH:43][N:44]=[CH:45][C:40]=1[C:2]1[N:3]=[CH:4][C:5]([O:33][CH3:34])=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11](=[O:32])[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[C:21](=[O:31])[C:22](=[O:30])[C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:16][CH2:15]1)=[O:13]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: COc1cnc(Br)c2[nH]cc(C(=O)C(=O)N3CCN(c4c(-c5ccccc5)c(=O)c4=O)CC3)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cnc(-c2cnccn2)c2[nH]cc(C(=O)C(=O)N3CCN(c4c(-c5ccccc5)c(=O)c4=O)CC3)c12
Temperature: 90 °C
Yield: 6.7 %

Procedure:
A solution of 3-[4-[2-(7-bromo-4-methoxy-6-azaindol-3-yl)-2-oxoacetyl]piperazin-1-yl]-4-phenyl-cyclobut-3-ene-1,2-dione (0.030 g, 0.057 mmol) and 2-tributylstannylpyrazine (0.025 g, 0.069 mmol) in dioxane (3 mL) was purged with Ar and then Pd(PPh3)4 (0.020 g, 0.017 mmol) was added, the reactor was sealed and the mixture was heated at 90° C. for 16 h. The cooled reaction mixture was diluted with EtOAc, washed (1M aqueous KF, brine), dried (Na2SO4) and evaporated to give a solid. Purification of this material by preparative HPLC (C-18/10-90% MeCN-5 mmolar aqueous NH4OAc) gave the title compound (0.002 g, 7%) as a yellow solid:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19](N)[CH:20]=2)[CH:15]=[N:14]1.N([O-])=[O:24].[Na+]>S(=O)(=O)(O)O.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([OH:24])[CH:20]=2)[CH:15]=[N:14]1
Reactant: Nc1ccc2cnn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)c2c1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Oc1ccc2cnn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)c2c1
Reaction time: 1 h
Yield: 59.8 %

Procedure:
To a suspension of 1-(2,6-dichloro-4-trifluoromethylphenyl)-6-aminoindazole [Compound No. 47] (10 g) in 50% sulfuric acid (30 g), a solution of sodium nitrite (3 g) in water (10 g) was added dropwise while cooling with ice, and the resultant mixture was stirred. After 1 hour, the mixture was added dropwise for 1 hour to 10% sulfuric acid heated at 100° C. to 110° C., and the resultant mixture was refluxed for 30 minutes. After completion of the reaction, the reaction mixture was cooled and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with hexaneethyl acetate (4:1) to give 1-(2,6-dichloro-4-trifluoromethylphenyl)-6-hydroxyindazole (6 g).
Reaction SMILES: [N:1]#[C:2][NH2:3].Cl.C([NH:9][C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)=[O:11])(C)(C)C>O>[C:14]([N:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:2]([NH2:3])=[NH:1])=[CH:18][CH:19]=1)[C:10]([NH2:9])=[O:11])([CH3:19])([CH3:15])[CH3:13]
Reactant: CC(C)(C)NC(=O)NCc1ccc(N)cc1
Reactant: N#CN
Agent: Cl
Solvent: O
Product: CC(C)(C)N(Cc1ccc(NC(=N)N)cc1)C(N)=O
Temperature: 62.5 °C
Reaction time: 2 h
Yield: 142.1 %

Procedure:
Cyanamide (100 g, 2.4 mol) was placed in a 500 mL round bottom flask and heated to 60-65° C. until the material completely melted. N-tert-butyl-N′-4-aminobenzylurea hydrochloride, (25.3 g, 97.8 mmol) was then added directly to the liquid cyanamide and the resulting yellow solution was stirred at 60-65° C. an additional two hours. Water (100 mL) was subsequently added to the solution followed by cooling to room temperature. The aqueous solution was washed with ethyl ether (1 L) followed by back extraction of the organic phase with water (2×, 100 mL). The combined aqueous layers were again washed with ethyl ether (500 mL) and the aqueous solution cooled in an ice water bath followed by basification with aqueous sodium hydroxide (10M, 100 mL). The resulting insoluble oil slowly crystalized and was collected by filtration. The material then was washed with water and dried in vacuo to give N-tert-butyl-N-4-guanidinobenzylurea (18.3 g, 70.8%) as a colorless crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[N:10]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:9]2[C:4](=[N:5][C:6]([N:20](C(OC(C)(C)C)=O)[NH:21][C:22](OC(C)(C)C)=O)=[CH:7][CH:8]=2)[CH:3]=1.[C:36](O)(=O)C>>[CH3:36][C:22]1[N:5]2[C:4]3[CH:3]=[C:2]([CH3:1])[N:10]([S:11]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)(=[O:12])=[O:13])[C:9]=3[CH:8]=[CH:7][C:6]2=[N:20][N:21]=1
Reactant: CC(=O)O
Reactant: Cc1cc2nc(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc2n1S(=O)(=O)c1ccccc1
Product: Cc1cc2c(ccc3nnc(C)n32)n1S(=O)(=O)c1ccccc1
Temperature: 120 °C

Procedure:
A mixture of di-tert-butyl 1-[2-methyl-1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridin-5-yl]hydrazine-1,2-dicarboxylate (19.53 g, 38.86 mmol, from Step 3) in acetic acid (200 mL) was heated at 120° C. overnight. Precipitate was filtered off, and the filtrate was concentrated in vacuo. Dichloroethane (15 mL) was added, and the suspension was heated at reflux for 15 minutes. Upon cooling to 0° C., the solid product was isolated by filtration and dried at 40° C. under vacuum to give an off-white solid (5.94 g). Solvent was removed from the filtrate in vacuo and the above procedure was repeated using DCE (6 mL) to afford additional solid (3.6 g). Additional product was obtained by flash chromatography of the filtrate, (eluting with a gradient of 0-1% MeOH/DCM containing 1% NH4OH). The chromatography afforded product as a glass, which was recrystallized from MeOH (6 mL). Upon recrystallization, product was isolated as white crystals and air dried (2.19 g). Yield: (11.7 g, 92%).
Reaction SMILES: [CH:1]1([C@H:4]([C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[NH:5][S@@](C(C)(C)C)=O)[CH2:3][CH2:2]1.C(O)C.Cl>O1CCOCC1>[CH:1]1([C@H:4]([C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:16][CH:17]=2)[NH2:5])[CH2:3][CH2:2]1
Reactant: CC(C)(C)[S@@](=O)N[C@@H](c1ccc(C(F)(F)F)nc1)C1CC1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: N[C@@H](c1ccc(C(F)(F)F)nc1)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-N-((R)-Cyclopropyl(6-(trifluoromethyl)pyridin-3-yl)methyl)-2-methylpropane-2-sulfinamide (0.245 g, 0.765 mmol), ethanol (2.7 mL), and 4.0 M of hydrogen chloride in dioxane (2.7 mL) were combined and the mixture was stirred at rt overnight. Reaction was concentrated down to an oil and then redissolved and washed with ethanol 3 times, and concentrated. The residue was dried on the high vacuum overnight to obtain a white solid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][OH:9])[CH:5]=[N:4][CH:3]=[N:2]1.[C:10]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])([CH3:12])[CH3:11].N1C=CN=C1>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:10]([Si:14]([CH3:16])([CH3:15])[O:9][CH2:8][CH2:7][CH2:6][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCn1cncn1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCn1cncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
To a solution of 3-(1,2,4-triazol-1-yl)propan-1-ol (7 g, 55 mmol) in DMF (70 ml) was added tertbutyldimethylsilyl chloride (9.1 g, 60 mmol) followed by DMAP (336 mg, 2.7 mmol) followed by imidazole (4.5gr, 66 mmol). After stirring overnight at ambient temperature, the volatiles were removed under vacuum and the residue was partitioned between water and ethyl acetate/ether. The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography eluting with methylene chloride/ether (6/4) to give 3-(tertbutyldimethylsilyloxy)-1-(1,2,4-triazol-1-yl)propane (11.1 gr, 84%).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]#[N:25])[CH2:20][CH2:19]3)=[N:10]2)=[CH:5][CH:4]=1.[CH3:28][O-:29].[Na+].O>CO>[CH3:28][O:29][C:24]([N:21]1[CH2:20][CH2:19][CH:18]([C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:26])[F:27])=[CH:4][CH:5]=3)[N:10]=2)[CH2:23][CH2:22]1)=[NH:25]
Reactant: N#CN1CCC(c2nn(-c3ccc(C(F)(F)F)cc3)c3ccccc23)CC1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=N)N1CCC(c2nn(-c3ccc(C(F)(F)F)cc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.4 %

Procedure:
A mixture of 4-[1-(4-trifluoromethylphenyl)-1H-indazol-3-yl]-piperidine-1-carbonitrile of Example 101 (20.0 g, 0.054 moles) and sodium methoxide (12.4 ml of 25% sodium methoxide in methanol 0.054 moles) in methanol (120 ml) was warmed to effect solution and then stirred at ambient temperature for 3 hours. The mixture was poured into H2O, extracted (CHCl3), dried (MgSO4), and concentrated to yield an oil. The oil was triturated with hexane which produced 19 g of a solid. The solid was recrystallized twice from toluene-hexane which yielded 14.2 g (65%) of 4-[1-[4-trifluoromethyl)phenyl]-1H-indazol-3-yl]piperidine-1-carboximidic acid methyl ester, m.p. 113°-115° C..
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[N:9]([CH3:25])[C:10](=[O:24])[CH2:11][C@@:12]([CH3:23])([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[Li+].[CH3:28][CH:29]([N-]C(C)C)C.ICC>C1COCC1>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[N:9]([CH3:25])[C:10](=[O:24])[C@H:11]([CH2:28][CH3:29])[C@@:12]([CH3:23])([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[N:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1C(=O)C[C@@](C)(c2cccc([N+](=O)[O-])c2)N=C1NC(=O)OC(C)(C)C
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCI
Product: CC[C@H]1C(=O)N(C)C(NC(=O)OC(C)(C)C)=N[C@]1(C)c1cccc([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
To a solution of [(S)-1,4-dimethyl-4-(3-nitro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (165 mg, intermediate E1) in THF (3.0 ml) was added at −78° C. a solution of LDA (3 eq., 2.8 ml) and stirring was continued for 1 h. The mixture was treated at −78° C. with a solution of iodoethane (67 μl) in THF (2.0 ml) and stirring was continued at the same temperature for 1.5 h and at −20° C. for 16 hours. The mixture was quenched with saturated aqueous NH4Cl, extracted with diethyl ether, the organic layer was dried and evaporated. The residue was chromatographed on silica using n-heptane/ethyl acetate (4:1) to give [(4S,5R)-5-ethyl-1,4-dimethyl-4-(3-nitro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (96 mg) as a colorless foam. MS (ESI): m/z=391.3 [ M+H]+. The hydrogenation of the nitro group to give the aniline (intermediate F) was carried out as described in Scheme 1.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[CH:12]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.ClCCl.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:17][C:13]1[CH:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([CH3:1])=[N:3][N:4]=3)[N:7]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Cc1nnc2ccc(-c3cccc([N+](=O)[O-])c3)nn12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: Cc1nnc2ccc(-c3cccc(N)c3)nn12
Temperature: 20 °C

Procedure:
An 11.0 g portion of 3-methyl-6-(3-nitrophenyl)-1,2,4-triazolo[4,3-b]pyridazine and 41.0 g portion of anhydrous stannous chloride were dissolved in 500 ml of anhydrous ethanol and heated to reflux for 3 hours. The solution was cooled to 20° C. and poured onto 200 g of crushed ice and 500 ml of dichloromethane. A saturated aqueous solution of sodium bicarbonate was added until pH=7. The mixture was filtered and the salts washed with five 100 ml portions of hot ethyl acetate. The organic layers were combined, dried over magnesium sulfate and the volatiles removed in vacuo. The residue was passed through a short column (50 g) of anhydrous magnesium silicate with dichloromethane-methanol (95:5) as eluent. The fractions containing product were collected, evaporated and recrystallized from dichloromethane-hexane to afford 8 g of the desired compound as yellow needles, mp 206°-208° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][CH2:44]O)=[CH:38][CH:37]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:44][CH2:43][CH2:42][C:39]3[CH:40]=[CH:41][C:36]([F:35])=[CH:37][CH:38]=3)=[CH:30][CH:31]=2)[C:17]=1[N:18]1[CH2:19][CH2:20][C:21]([CH3:24])([CH3:25])[CH2:22][CH2:23]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: OCCCc1ccc(F)cc1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(O)cc2)c1N1CCC(C)(C)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCCCc3ccc(F)cc3)cc2)c1N1CCC(C)(C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
To a stirred solution of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-hydroxyphenyl)-2,6-dimethylpyridin-3-yl)acetate (0.04 g, 0.085 mmol), 3-(4-fluorophenyl)propan-1-ol (0.066 g, 0.427 mmol) and Ph3P (0.067 g, 0.256 mmol) in THF (5 mL) was added DEAD (0.041 ml, 0.256 mmol) at 0° C. After 1 h, cold bath was removed and stirred overnight (13 h) at rt. LCMS at this point showed presence of about 50% unreacted phenol. So, added additional 3-(4-fluorophenyl)propan-1-ol (0.066 g, 0.427 mmol), Ph3P (0.067 g, 0.256 mmol) and DEAD (0.041 ml, 0.256 mmol) at r. After stirring for 5 h, reaction mixture was concentrated and purified by prep-HPLC to afford (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-(3-(4-fluorophenyl)propoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate (0.0351 g, 0.058 mmol, 68.0% yield) as glassy solid. 1H NMR (500 MHz, CDCl3) δ 7.14-7.23 (m, 3H), 7.06-7.09 (m, 1H), 6.95-7.03 (m, 4H), 6.09 (s, 1H), 4.27 (qd, J=7.1, 10.8 Hz, 1H), 4.18 (qd, J=7.1, 10.7 Hz, 1H), 3.99-4.07 (m, 2H), 3.19 (d, J=12.0 Hz, 1H), 2.88 (t, J=12.3 Hz, 1H), 2.82-2.91 (t, J=7.6 Hz, 2H), 2.61 (s, 3H), 2.28 (d, J=12.0 Hz, 1H), 2.21 (s, 3H), 2.11-2.18 (m, 2H), 2.06 (t, J=11.5 Hz, 1H), 1.56 (dt, J=3.9, 12.6 Hz, 1H), 1.38 (dt, J=3.6, 12.7 Hz, 1H), 1.26 (t, J=7.1 Hz, 3H), 1.21 (s, 9H), 1.18-1.21 (m, 1H), 1.08 (d, J=12.1 Hz, 1H), 0.91 (s, 3H), 0.66 (s, 3H). LCMS (M+H)=605.3.