Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(C1C=NN([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)C=1)=O)C.[CH3:30][O:31][C:32]([C:34]1[CH:38]=[C:37]([C:39]([O:41][CH3:42])=[O:40])[NH:36][N:35]=1)=[O:33].[H-].[Na+].C(Cl)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>CN(C)C=O>[C:11]([N:36]1[C:37]([C:39]([O:41][CH3:42])=[O:40])=[CH:38][C:34]([C:32]([O:31][CH3:30])=[O:33])=[N:35]1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)c1cc(C(=O)OC)[nH]n1
Reactant: CCOC(=O)c1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(=O)OC)n(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 98 %

Procedure:
This compound is a white microcrystalline solid that has been isolated following the methodology described in 2b for ethyl-1-tritylpyrazole-4-carboxylate, by reaction of with dimethyl-3,5-pyrazoledicarboxylate (1.411 g, 7.66 mmol) with sodium hydride (250 mg, 10.41 mmol) in dry dimethylformamide (20 mL), followed by treatment with trityl chloride (2.135 g, 7.66 mmol). Yield: 98% (3.200 g, 7.50 mmol).
Reaction SMILES: [N+:1]([C:4]1[CH:43]=[CH:42][C:7]([C:8]([O:10][C@@H:11]2[C@H:15]([O:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)[C@@H:14]([CH2:28][O:29][C:30](=[O:40])[C:31]3[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=3)[O:13][C@H:12]2Br)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1C=CC=CC=1.CC(C)=[O:52]>ClCCl.O.C(=O)([O-])[O-].[Ag+2]>[N+:1]([C:4]1[CH:43]=[CH:42][C:7]([C:8]([O:10][C@@H:11]2[C@H:15]([O:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)[C@@H:14]([CH2:28][O:29][C:30](=[O:40])[C:31]3[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=3)[O:13][CH:12]2[OH:52])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(OC[C@H]1O[C@@H](Br)[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)[C@@H]1OC(=O)c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)=O
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: c1ccccc1
Solvent: ClCCl
Product: O=C(OC[C@H]1OC(O)[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)[C@@H]1OC(=O)c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 65 %

Procedure:
3 g of 2,3,5-tri-O-(p-nitrobenzoyl)-β-D-ribofuranosyl bromide prepared by the procedure described in Example 2 were dissolved in a mixture of 25 ml of acetone and 25 ml of dichloromethane. This solution was cooled to 5° C. and treated with a suspension of silver carbonate (1.25 g) in water (5 ml) with vigorous stirring. Stirring was continued for 90 minutes while the mixture was maintained at 5° C. The mixture was filtered and the filtrate evaporated under reduced pressure to yield a syrup. This syrup was redissolved in 50 ml of dichloromethane, dried over anhydrous MgSO4 and evaporated to yield a syrup which solidified on slow coevaporation with benzene. This yielded 1.76 g (65% yield) of 2,3,5-tri-O-(p-nitrobenzoyl)-D-ribofuranose. Recrystallization of this product from nitromethane yielded colorless needles which had a melting point of 177° to 178° C.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16]OS(C)(=O)=O)[CH2:10][C@H:9]1[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=[O:7].[CH2:41]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44][CH2:43][NH:42]1>CO>[F:39][C:2]([F:40])([F:1])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:34]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:42]2[CH2:43][CH2:44][C:45]3[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:41]2)[CH2:10][C@H:9]1[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=[O:7]
Reactant: CS(=O)(=O)OCCCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Reactant: c1ccc2c(c1)CCNC2
Solvent: CO
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CCCN2CCc3ccccc3C2)C[C@H]1Cc1c[nH]c2ccccc12
Reaction time: 1.5 h
Yield: 78.6 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(3-methylsulfonyloxypropyl) piperazine (200 mg) and 1,2,3,4-tetrahydroisoquinoline (90 mg) in methanol (3 ml) was stirred for 1.5 hours at reflux temperature. The reaction mixture was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using ethyl acetate-methanol (10:1) as an eluent to give (2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(1H-indol-3-ylmethyl)-4-[3-[1,2,3,4-tetrahydroisoquinolin-2-yl]propyl]piperazine (167 mg) as a powder.
Reaction SMILES: [CH3:1][C:2]([C:6]1[N:10]([CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[CH:18]=[CH:19][C:20]([S:22](Cl)(=[O:24])=[O:23])=[CH:21][C:8]=2[N:7]=1)([CH3:5])[CH2:3][CH3:4].[NH:26]1[CH:30]=[C:29]([CH:31]=[O:32])[CH:28]=[N:27]1>CN(C1C=CN=CC=1)C.CC#N>[CH3:1][C:2]([C:6]1[N:10]([CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[CH:18]=[CH:19][C:20]([S:22]([N:26]3[CH:30]=[C:29]([CH:31]=[O:32])[CH:28]=[N:27]3)(=[O:24])=[O:23])=[CH:21][C:8]=2[N:7]=1)([CH3:5])[CH2:3][CH3:4]
Reactant: CCC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Reactant: O=Cc1cn[nH]c1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CCC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C=O)cn3)ccc2n1CC1CCOCC1
Yield: 23.8 %

Procedure:
Following the same procedure in Example 1, Step A, using 2-(1,1-dimethylpropyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (2.12 g, 5.5 mmol), 1H-pyrazole-4-carbaldehyde (0.48 g, 5.0 mmol) and DMAP (0.73 g, 6.0 mmol) in MeCN (20 mL). The crude product was purified by MPLC using CH2Cl2/EtOAc (1:1) on silica gel to give 0.53 g (24%) of a white solid as the title compound. MS (ESI) (M+H)+=444.92.
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]2[C@H:11]([CH2:12][CH2:13][CH3:14])[N:10]([O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[C:9]2=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].S(=O)(=O)(O)[O-:26].[Na+]>O1CCOCC1.CCOCC>[O:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]1[O:15][NH:10][C@@H:11]([CH2:12][CH2:13][CH3:14])[C@@H:8]([CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]([OH:22])=[O:26]
Reactant: CCC[C@H]1[C@@H](CC2CCCCC2)C(=O)N1OC1CCCCO1
Reactant: O=S(=O)([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCC[C@H](NOC1CCCCO1)[C@@H](CC1CCCCC1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
(3R,4S)-3-Cyclohexylmethyl-4-propyl-1-(2-tetrahydropyranyloxy)azetidin-2-one (2.25 g, 7.27 mmol) is dissolved in 10 mL of 1,4-dioxane. 2.5 N Aqueous sodium hydroxide solution (8.73 mL, 21.8 mmol) is added and the reaction stirred for 18 h at 25° C. The solution is diluted with 50 mL of ether and shaken. The organic phase is discarded and the aqueous layer is acidified with solid sodium bisulfate and then extracted with two 25-mL portions of ether. The combined organic phases are dried over sodium sulfate and concentrated in vacuo giving (2R,3S)-3-(2-tetrahydropyranyloxyamino)-2-(cyclohexylmethyl)hexanoic acid as an oil (2.02 g, 85% yield).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1.CCN(CC)CC.[C:43](#[N:46])[CH:44]=[CH2:45].CO>ClCCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:43]([CH2:44][CH2:45][N:23]1[CH2:22][CH2:21][CH:20]([C:18]2[CH:17]=[CH:16][C:15]([NH:26][C:27]([C:29]3[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=3)=[O:28])=[C:14]([C:8]3[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=3)[CH:19]=2)[CH2:25][CH2:24]1)#[N:46]
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCNCC3)cc2C2=CCCCC2)n1
Reactant: C=CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CO
Product: N#CCCN1CCC(c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCCCC3)c2)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
A flask was charged with 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (77 mg, 0.16 mmol) (as prepared in Example 14, step (b)), NEt3 (24 μL, 0.16 mmol), acrylonitrile (12 μL, 0.18 mmol), 0.1 mL MeOH and 1.0 mL of 1,2-dichloroethane and stirred for 1 h at 80° C. The reaction was concentrated and the title compound was purified by RP-HPLC (C18), eluting with 30-50% CH3CN in 0.1% TFA/H2O over 12 min to give 83 mg (95%) of a white solid. 1H-NMR (400 MHz, CD3OD): δ 8.18 (d, 1H), 8.06 (m, 1H), 7.22 (dd, 1H), 7.12 (d, 1H), 5.82 (m, 1H), 3.76 (m, 2H), 3.60 (m, 2H), 3.28 (t, 2H), 3.12 (t, 2H), 2.92 (m, 1H), 2.30 (m, 4H), 2.18-1.98 (m, 4H), 1.92-1.74 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C25H28N6O, 429.2 (M+H), found 429.2.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5](/[CH:6]=[CH:7]/[C:8]2[S:9][CH:10]=[CH:11][C:12]=2[S:13](Cl)(=[O:15])=[O:14])=[CH:4][CH:3]=1.[NH2:19][C:20]1[O:24][N:23]=[C:22]([CH3:25])[C:21]=1[Br:26]>>[Br:26][C:21]1[C:22]([CH3:25])=[N:23][O:24][C:20]=1[NH:19][S:13]([C:12]1[CH:11]=[CH:10][S:9][C:8]=1/[CH:7]=[CH:6]/[C:5]1[CH:17]=[CH:18][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:15])=[O:14]
Reactant: Cc1noc(N)c1Br
Reactant: Cc1ccc(/C=C/c2sccc2S(=O)(=O)Cl)cc1
Product: Cc1ccc(/C=C/c2sccc2S(=O)(=O)Nc2onc(C)c2Br)cc1
Yield: 34 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-(4-methyl-trans-styryl)thiophene-3-sulfonamide was prepared in the same manner as described in Example 2 by reaction of 2-(4-methyl-trans-styryl)thiophene-3-sulfonyl chloride with 5-amino-4-bromo-3-methylisoxazole. The crude product was purified by HPLC followed by crystallization resulting in a 34% yield, m.p. 101-105° C.
Reaction SMILES: C(O[C:6]([N:8]([C:41](OC(C)(C)C)=O)[C:9](=[O:40])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][S:17]2(=[O:22])=[O:21])[CH:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[C:36]([CH3:37])=[CH:35][C:34]([CH2:38][CH3:39])=[CH:33][N:32]=2)[CH2:27][CH2:26]1)=[O:24])=O)(C)(C)C>O1CCCC1.CNC>[O:22]=[S:17]1(=[O:21])[CH2:18][CH2:19][CH2:20][N:16]1[C:14]1[CH:13]=[CH:12][C:11]([C:23]([N:25]2[CH2:30][CH2:29][N:28]([C:31]3[C:36]([CH3:37])=[CH:35][C:34]([CH2:38][CH3:39])=[CH:33][N:32]=3)[CH2:27][CH2:26]2)=[O:24])=[C:10]([CH:15]=1)[C:9]([N:8]([CH3:41])[CH3:6])=[O:40]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC2)c(C)c1
Agent: CNC
Solvent: C1CCOC1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3C(=O)N(C)C)CC2)c(C)c1
Yield: 53.9 %

Procedure:
Using N,N-di-tert-butyloxycarbonyl-5-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-[4-(5-ethyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]benzamide (202 mg) described in Example 785 and 2M dimethylamine tetrahydrofuran solution (180 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (81 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:25])=[C:4]([CH:14]2[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]2)[C:5]([O:11][CH2:12][CH3:13])=[C:6]([CH:8](Cl)[CH3:9])[CH:7]=1.[I:26][C:27]1[C:35]2[C:30](=[N:31][CH:32]=[N:33][C:34]=2[NH2:36])[NH:29][N:28]=1>>[NH2:36][C:34]1[N:33]=[CH:32][N:31]=[C:30]2[N:29]([CH:8]([C:6]3[C:5]([O:11][CH2:12][CH3:13])=[C:4]([CH:14]4[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]4)[C:3]([F:25])=[C:2]([Cl:1])[CH:7]=3)[CH3:9])[N:28]=[C:27]([I:26])[C:35]=12
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: CCOc1c(C(C)Cl)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Product: CCOc1c(C(C)n2nc(I)c3c(N)ncnc32)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1

Procedure:
This compound was prepared using procedures analogous to those for Example 139 step 5, with racemic tert-butyl 3-[3-chloro-5-(1-chloroethyl)-6-ethoxy-2-fluorophenyl]azetidine-1-carboxylate from Example 139 Step 4 and 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine as starting materials. LCMS calculated for C23H28ClFIN6O3 (M+H)+: m/z=617.1; Found:617.1
Reaction SMILES: [O:1]=[C:2]([N:16]1[CH2:21][CH2:20][N:19]2[C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=[C:18]2[CH2:17]1)[CH:3]=[C:4]([NH2:15])[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:7]=1[F:14].C([BH3-])#N.[Na+].Cl>CO>[O:1]=[C:2]([N:16]1[CH2:21][CH2:20][N:19]2[C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=[C:18]2[CH2:17]1)[CH2:3][CH:4]([NH2:15])[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:7]=1[F:14]
Reactant: NC(=CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: NC(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: 30 °C
Reaction time: 5 h
Yield: 99.9 %

Procedure:
A mixture of methanol (135 ml), 7-(1-oxo-3-amino-4-(2,4,5-trifluorophenyl)-but-2-enyl)-3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine (13.5 gm), sodium cyano borohydride (2.5 g), and methanolic hydrogen chloride (35 mL) at about 4.5 pH is stirred for about 5 hours at about 30° C. The solvent is distilled off completely and water (50 mL) is added to the residue. The extraction is carried out with ethylacetate (150 mL). The obtained organic layer is distilled off completely to afford the title compound. (Yield: 99.9%; purity by HPLC: 92.25%)
Reaction SMILES: [O:1]1[CH:3]2[C:4](=[O:30])[CH2:5][CH:6]3[C@:27]([CH3:28])([CH:2]12)[C@@H:26]1[C@H:9]([C@H:10]2[C@:23]([CH3:29])([CH2:24][CH2:25]1)[C@@H:13]([C:14]([CH3:22])=[CH:15][CH:16]=[CH:17][C:18]([F:21])([CH3:20])[CH3:19])[CH2:12][CH2:11]2)[CH2:8][CH2:7]3.O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)(=O)C>[F:21][C:18]([CH2:17][CH2:16][CH2:15][C@H:14]([C@@H:13]1[C@:23]2([CH3:29])[C@H:10]([C@H:9]3[C@H:26]([CH2:25][CH2:24]2)[C@:27]2([CH3:28])[C:6](=[CH:5][C@@H:4]([OH:30])[CH2:3][C@@H:2]2[OH:1])[CH:7]=[CH:8]3)[CH2:11][CH2:12]1)[CH3:22])([CH3:19])[CH3:20]
Reactant: CC(=CC=CC(C)(C)F)[C@H]1CC[C@H]2[C@@H]3CCC4CC(=O)C5OC5[C@]4(C)[C@H]3CC[C@]12C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@H](CCCC(C)(C)F)[C@H]1CC[C@H]2[C@@H]3C=CC4=C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C

Procedure:
1,2-Epoxy-25-fluorocholestadien-3-one (0.01 mole) prepared according to 3A above is dissolved in 100 ml. of dry tetrahydrofuran under a nitrogen blanket at 0° C. and fresh lithium aluminum hydride (0.005 mole) is slowly added over 10 minutes with stirring. The mixture is stirred for 1.0 hour and 1.0 ml. of ethyl acetate is added to destroy the excess lithium aluminum hydride. Concentrated aqueous ammonium chloride (20 ml.) is added to the reaction mixture and the mixture is stirred for 5 minutes. Diethyl ether (200 ml.) is added to the reaction mixture, the mixture is well shaken and the organic layer separated. The organic layer is washed with water, dried with magnesium sulfate and the solvent is evaporated to give crude 25-fluoro-4,6-cholestadiene-1α,3β-diol. 25-Fluoro-4,6-cholestadiene-1α,3β-diol can be purified by chromatographing the crude product on a silica gel column using a solvent of petroleum ether and diethyl ether.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH2:22][C:23]([O:25]C)=[O:24])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.O[Li].O.O>C1COCC1>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:12][C:13]=2[F:14])=[N:6][CH:7]=1
Reactant: COC(=O)COc1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Nc1cnc(-c2ccc(-c3ccccc3OCC(=O)O)cc2F)cn1
Temperature: 25 °C
Reaction time: 14 h
Yield: 84.2 %

Procedure:
To a solution of methyl 2-(4′-(5-aminopyrazin-2-yl)-5′-fluorobiphenyl-2-yloxy)acetate (50 mg, 0.14 mmol) in THF (2 mL) were added LiOH.H2O (63 mg, 1.5 mmol) and H2O (2 mL). The mixture was stirred at rt for 14 hours. The THF was removed under reduced pressure, and the residue diluted with 15 mL of water, washed with DCM (5 mL×2), and then acidified with 1 N HCl to pH=7. The precipitate was collected and washed with water and dried under high vacuum to give the title compound (40 mg, 95% yield). MS (ESI): mass calcd. for C18H14FN3O3, 339.10; m/z found, 340.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 13.02 (s, 1H), 8.36 (s, 1H), 8.01 (s, 1H), 7.88 (m, 1H), 7.55 (d, J=13.0, 1H), 7.48 (d, J=9.2, 1H), 7.40 (d, J=7.4, 1H), 7.33 (m, 1H), 7.08-7.00 (m, 2H), 6.69 (s, 2H), 4.76 (s, 2H).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:17]([O:21][C:22]([NH:24][C@@H:25]1[CH2:29][CH2:28][C@:27]([CH:33]([CH3:35])[CH3:34])([C:30](O)=[O:31])[CH2:26]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[CH:33]([C@:27]1([C:30]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:12]=[C:11]([C:13]([F:16])([F:14])[F:15])[N:10]=[CH:9][N:8]=3)[CH2:2][CH2:3]2)=[O:31])[CH2:28][CH2:29][C@@H:25]([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:26]1)([CH3:35])[CH3:34]
Reactant: FC(F)(F)c1cc(N2CCNCC2)ncn1
Reactant: CC(C)[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ncn3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Yield: 38.2 %

Procedure:
A solution of 4-piperazin-1-yl-6-(trifluoromethyl)pyrimidine (1.0 g, 4.31 mmol), (1S,3R)-3-[(tert-butoxycarbonyl)amino]-1-isopropylcyclopentanecarboxylic acid (1.75 g, 6.46 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (2.86 g, 6.46 mmol), and triethylamine (1.20 mL, 8.61 mmol) in methylene chloride (10 mL) was stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride, washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (800 mg, 38.3%). LCMS calculated for C23H35F3N5O3: (M+1) 486.2; found 486.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].[Br-].[CH2:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C1CCCC1
Reactant: CCOC(=O)CCc1ccc(O)c(Br)c1
Agent: [Br-]
Product: CCOC(=O)CCc1ccc(OC2CCCC2)c(Br)c1

Procedure:
According to the procedure described in the synthesis method of Intermediate 8 in Reference Example 2 (Step e-1), ethyl 3-(3-bromo-4-hydroxyphenyl)propionate and cyclopentane bromide were reacted and treated to obtain ethyl 3-(3-bromo-4-cyclopentyloxyphenyl)propionate (410 mg). According to the procedure described in the synthesis method of Compound of Example 001 (Preparation Method 4, Step d-1) with the modifications that the reaction was carried out for 18 hours, and the purification was performed by flash column chromatography (hexane:ethyl acetate=8:1), the above product was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (396 mg), 2 M aqueous sodium carbonate (1.0 ml) and (Ph3P)4Pd (110 mg) and treated to obtain the title compound (Intermediate 67, 313 mg).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]([O:17][C:18]([NH:20][C@@H:21]([C:25]([OH:27])=O)[CH:22]([CH3:24])[CH3:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(C(C)C)CC)(C)C.[CH2:37]([O:44][NH2:45])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)Cl>[CH3:24][CH:22]([CH3:23])[C@@H:21]([NH:20][C:18](=[O:19])[O:17][C:13]([CH3:14])([CH3:15])[CH3:16])[C:25]([NH:45][O:44][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:27]
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NOCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)NOCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
CDI (2.45 g, 15.1 mmol) is added to a solution of N-(tert-butoxycarbonyl)-D-valine (3.28 g, 15.1 mmol) and CH2Cl2 (60 mL). The solution is stirred for 1 hour at room temperature. Diisopropylethylamine (2.90 mL, 16.6 mmol) and O-benzylhydroxylamine (2.64 g, 16.5 mmol) are added and the solution stirred for 16 hours at room temperature. The solution is concentrated, diluted with EtOAc, and washed with 5% HCl (2×50 mL), NaHCO3 (50 mL) and brine (50 mL). The organic solution is dried (MgSO4), filtered, and concentrated to give 4.42 g (91%) of the title compound as a white solid which is carried on crude.
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:38])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([N:26]2[CH2:30][CH2:29][CH2:28][C@@H:27]2[C:31]([O:33]C(C)(C)C)=[O:32])=[O:25])=[CH:18][CH:17]=1)=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:31]([C@H:27]1[CH2:28][CH2:29][CH2:30][N:26]1[C:24](=[O:25])[CH2:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][C:13]([N:9]2[CH2:10][CH2:11][CH2:12][C@@H:8]2[C:6]([OH:7])=[O:5])=[O:38])=[CH:21][CH:20]=1)([OH:33])=[O:32]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)COc1ccc(OCC(=O)N2CCC[C@@H]2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@H]1CCCN1C(=O)COc1ccc(OCC(=O)N2CCC[C@@H]2C(=O)O)cc1
Reaction time: 8 h
Yield: 95.5 %

Procedure:
A solution of 350 mg (0.66 mmol) (R)-1-[[4-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-phenoxy]-acetyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 4 ml trifluoroacetic acid was stirred for 3 h at room temperature. The solvent was removed in vacuo and the residue suspended in 10 ml ether. The resulting suspension was stirred overnight. Filtration and drying gave 265 mg (96%) of the title compound as a white powder. MS m/e (%): 443 (M+Na+, 48), 438 (M+NH4+, 39), 421 (M+H+, 100).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=1.O=P(Cl)(Cl)Cl.CN([CH:20]=[O:21])C>>[Br:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([O:8][CH3:9])[C:7]=1[CH:20]=[O:21]
Reactant: COc1cc(Br)cc(OC)c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(Br)c(C=O)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a mixture of 1-bromo-3,5-dimethoxybenzene (21.7 g, 100.0 mmol) in DMF (80 mL) was added POCl3 (15 mL, 150 mmol) at 0° C. The mixture was stirred at room temperature for 30 min and then heated at 100° C. for an additional 30 min. The reaction mixture was cooled to room temperature and poured onto ice. The precipitate was collected by filtration and dried under high vacuum to give the title compound as a yellow solid. (19.4 g, Yield: 79%). 1H NMR (400 MHz, DMSO-d) δ10.18 (s, 1H), 6.91-6.91 (d, J=2.0 Hz, 1H), 6.74-6.73 (d, J=2.0 Hz, 1H), 3.90 (s, 3H), 3.89 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([O:4][CH:5]([Cl:9])[CH:6]([CH3:8])[CH3:7])=O.C[S-:11].[Na+]>ClCCl.O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][C:2]([O:4][CH:5]([Cl:9])[CH:6]([CH3:8])[CH3:7])=[S:11]
Reactant: CC(=O)OC(Cl)C(C)C
Reactant: C[S-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(=S)OC(Cl)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1-chloro-2-methylpropyl methylformate in dichloromethane (DCM) was added a solution of sodium methanethiolate (CH3—SNa) (1.0 eq.) in water at 0° C. and 0.02 eq. of tetrabutylammonium bromide. The reactants were stirred at 0° C. for 30 min and then diluted with dichloromethane (DCM). The dichloromethane layer was allowed to separate, then washed with water and brine, and dried with anhydrous sodium sulfate (Na2SO4). After rotary evaporation to remove the solvent, the title compound (6a) was obtained. 1H-NMR (CDCl3): δ 1.05 (d, J=5.6 Hz, 3H), 1.07 (d, J=5.6 Hz, 3H), 2.18 (m, 1H), 2.38 (s, 3H), 6.34 (d, J=5.6 Hz, 1H) ppm.