Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C:9]1([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]3[CH:34]=[C:33]([C:35]4[CH:40]=[CH:39][C:38]([C:41]5[C:42]6[N:46]([C:47]([F:56])([F:55])[N:48]7[C:52]=5[C:51]([CH3:53])=[CH:50][CH:49]7[CH3:54])[C:45]([CH3:57])=[CH:44][C:43]=6[CH3:58])=[CH:37][CH:36]=4)[N:32]=[N:31]3)=[CH:21][CH:20]=2)[CH2:14][O:13]C(C)(C)[O:11][CH2:10]1)=O)(C)(C)C.B(F)(F)F.CCOCC>C(Cl)Cl>[NH2:8][C:9]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]2[CH:34]=[C:33]([C:35]3[CH:40]=[CH:39][C:38]([C:41]4[C:42]5[N:46]([C:47]([F:56])([F:55])[N:48]6[C:52]=4[C:51]([CH3:53])=[CH:50][CH:49]6[CH3:54])[C:45]([CH3:57])=[CH:44][C:43]=5[CH3:58])=[CH:37][CH:36]=3)[N:32]=[N:31]2)=[CH:21][CH:20]=1)([CH2:10][OH:11])[CH2:14][OH:13]
Reactant: CC1=CC(C)N2C1=C(c1ccc(-c3cn(CCCCCc4ccc(CCC5(NC(=O)OC(C)(C)C)COC(C)(C)OC5)cc4)nn3)cc1)c1c(C)cc(C)n1C2(F)F
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CC1=CC(C)N2C1=C(c1ccc(-c3cn(CCCCCc4ccc(CCC(N)(CO)CO)cc4)nn3)cc1)c1c(C)cc(C)n1C2(F)F
Temperature: 0 °C
Yield: 60.8 %

Procedure:
To a cold solution (0° C.) of 21 (40 mg, 50.3 μmol) in dry CH2Cl2 (10 mL) were added 4 Å molecular sieves (0.40 g) and BF3.OEt2 (0.18 g, 1.27 mmol) with vigorous stirring. The mixture was stirred at 0° C., and the reaction was monitored by TLC (hexanes/EtOAc 2:1). On the disappearance of 21 (˜5 h), the reaction was quenched by adding saturated aqueous NaHCO3 solution (10 mL). After the mixture was stirred for 30 min, CH2Cl2 (30 mL) was added. The organic layer was separated and washed with saturated aqueous NaHCO3 solution (20 mL), water (2×20 mL), and brine (2×20 mL). The solution was dried (Na2SO4) and concentrated under vacuum. The residue was purified by chromatography (CH2Cl2/MeOH 9:1) to give 3 (20.1 mg, 61%). 1HNMR δ 7.96 (d, 2H, J=8.4 Hz), 7.84 (s, 1H), 7.34 (d, 2H, J=8.4 Hz), 7.11-7.01 (m, 4H), 5.98 (s, 2H), 4.39 (t, 2H, J=7.2 Hz), 3.85-3.57 (m, 4H), 3.56-3.01 (br s, 4H), 2.61-2.51 (m, 4H), 2.55 (s, 6H), 2.00-1.92 (m, 2H), 1.70-1.56 (m, 2H), 1.43 (s, 6H), 1.46-1.05 (m, 4H); 13C NMR δ 155.6, 147.0, 143.0, 141.2, 139.8, 138.6, 134.7, 131.4, 128.6, 128.5, 128.3, 126.3, 122.5, 121.3, 119.9, 50.4, 35.1, 30.8, 30.3, 29.7, 29.4, 26.0, 14.6, 14.1; 19F NMR δ-146.1 (m). HRMS m/z: calcd for C37H46BF2N6O2 (MH+), 655.3737; found, 655.3746.
Reaction SMILES: P(OP(O)=O)(O)=O.C(C(C(C)C)(C(C)C)C(C)C)(C)C.[C:21]1([P:37]([O:43]C(C)C)(=[O:42])[O:38]C(C)C)([P:27]([O:33]C(C)C)(=[O:32])[O:28]C(C)C)[CH2:26][CH2:25][CH:24]=[CH:23][CH2:22]1.ClC/C=C\CCCl>>[C:21]1([P:37]([OH:43])(=[O:38])[OH:42])([P:27]([OH:32])(=[O:28])[OH:33])[CH2:26][CH2:25][CH:24]=[CH:23][CH2:22]1
Reactant: CC(C)OP(=O)(OC(C)C)C1(P(=O)(OC(C)C)OC(C)C)CC=CCC1
Agent: CC(C)C(C(C)C)(C(C)C)C(C)C
Agent: ClC/C=C\CCCl
Agent: O=[PH](O)O[PH](=O)O
Product: O=P(O)(O)C1(P(=O)(O)O)CC=CCC1

Procedure:
Using the same procedure as in Example I, tetraisopropyl methane diphosphonate is converted to tetraisopropyl 3-cyclohexene-1,1-diphosphonate by reaction with 1,5-dichloro-cis-2-pentene. The resulting ester is hydrolyzed as in Example I to yield the 3-cyclohexene-1,1-diphosphonic acid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]Cl)=[C:6]([F:10])[CH:5]=[CH:4][CH:3]=1.[N-:11]=[N+:12]=[N-:13].[Na+]>CS(C)=O>[Cl:1][C:2]1[C:7]([CH2:8][N:11]=[N+:12]=[N-:13])=[C:6]([F:10])[CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cccc(Cl)c1CCl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NCc1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
123 g of (0.687 mole) of 6-chloro-2-fluorobenzyl chloride are added dropwise at 20°-40° C. to a suspension of 47 g (0.722 mole) of sodium azide in 400 ml of dimethylsulfoxide. The mixture is stirred for 4 hours at room temperature, then diluted with ice-water and extracted with cyclohexane. The solvent is removed by distillation and the residue is distilled, affording 6-chloro-2-fluorobenzyl azide; bp15 =99°-100° C.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([S:7]([NH:10][NH2:11])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:13]([O:17][C:18]([N:20]1[C:25]2([CH3:29])[CH2:26][CH2:27][CH2:28][C:21]1([CH3:31])[CH2:22][C:23](=O)[CH2:24]2)=[O:19])([CH3:16])([CH3:15])[CH3:14].O.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[C:13]([O:17][C:18]([N:20]1[C:21]2([CH3:31])[CH2:28][CH2:27][CH2:26][C:25]1([CH3:29])[CH2:24][C:23](=[N:11][NH:10][S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:12])=[CH:6][CH:5]=1)(=[O:8])=[O:9])[CH2:22]2)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1C2(C)CCCC1(C)CC(=O)C2
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: Cc1ccc(S(=O)(=O)NN=C2CC3(C)CCCC(C)(C2)N3C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Yield: 61.8 %

Procedure:
p-Toluenesulfonyl hydrazine (6.37 g, 34.2 mmol) was added to a benzene solution (115 ml) of N-tert-butoxycarbonyl-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-one (3.04 g, 11.4 mmol), and the mixture was heated under reflux for 6 h with a Dean-Stark device. After adding saturated sodium bicarbonate water under ice-cooled condition, the ice-cooled reaction liquid was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography to give N-tert-butoxycarbonyl-1,5-dimethyl-3-(tosylhydrazono)-9-azabicyclo[3.3.1]nonane (3.07 g, 62%).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH3:16])[CH:10]=1)=O>O1CCOCC1>[NH2:1][C:2]1[S:3][CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH3:16])[CH:10]=2)[N:4]=1
Reactant: NC(N)=S
Reactant: Cc1cc(C(=O)CBr)ccc1O
Solvent: C1COCCO1
Product: Cc1cc(-c2csc(N)n2)ccc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.3 %

Procedure:
Thiourea (79.8 mg, 1.05 mmol) was added to a solution of 2-bromo-1-(4-hydroxy-3-methylphenyl)ethanone (200 mg, 0.87 mmol) in 1,4-dioxane (15 mL). The reaction mixture was stirred at 25° C. for 24 h. The resulting suspension was filtered and the solid was washed with 1,4-dioxane and dried under reduced pressure. The solid was suspended in water (30 mL), pH 7 buffer solution (15 mL) was added and the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were successively washed with water (20 mL) and brine (20 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Hexane:EtOAc, 1:1) to give the title compound (180 mg, 100% yield).
Reaction SMILES: [CH2:1]([NH:9][S:10]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]([OH:23])=O)[CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:24]CCl>CN(C)C=O>[CH2:1]([NH:9][S:10]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]([Cl:24])=[O:23])[CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClCCl
Reactant: O=C(O)C=Cc1cccc(S(=O)(=O)NCCc2ccccc2)c1
Solvent: CN(C)C=O
Product: O=C(Cl)C=Cc1cccc(S(=O)(=O)NCCc2ccccc2)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 101.6 %

Procedure:
To a suspension of 3-(3-phenethylsulfamoyl-phenyl)-acrylic acid (5h) (0.15 g, 0.45 mmol) in dichloromethane (2.0 ml) oxalyl chloride (0.14 ml, 1.57 mmol) and one drop of dimethylformamide were added. The reaction mixture was stirred at 40° C. for one hour and concentrated under reduced pressure to give crude title compound (0.16 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].[CH2:15](OC(OCC)OCC)C>C(O)(=O)C>[F:13][C:11]([F:12])([F:14])[CH2:10][C:4]1[S:3][C:2]2[N:1]=[CH:15][NH:9][C:7](=[O:8])[C:6]=2[CH:5]=1
Reactant: CCOC(OCC)OCC
Reactant: NC(=O)c1cc(CC(F)(F)F)sc1N
Solvent: CC(=O)O
Product: O=c1[nH]cnc2sc(CC(F)(F)F)cc12

Procedure:
8.4 g of 2-amino-5-(2,2,2-trifluoroethyl)thiophene-3-carboxamide was refluxed in a mixture of 28 mL of triethylorthoformate and 20 mL of acetic acid for 4 hs. Solvents were removed under reduced pressure and the residue was triturated hexane-ethyl acetate mixture (1:1). The solid was filtered off to afford 5.7 g of 6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4(3H)-one. 1H NMR MeOH-d4 (300 MHz): 12.6 (br, 1H), 8.14 (s, 1H), 7.42 (s, 1H), 4.07 (q, 2H, J 11.0 Hz). 13C NMR MeOH-d4 (75 MHz): 164.5, 157.01, 146.1, 128.4, 124.6, 123.5, 33.6 (q, J31.5 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[S:14][CH:15]=[CH:16][C:11]3=[CH:10][C:9]=2[C@@H:17]([NH2:19])[CH3:18])[CH:5]=[CH:6][CH:7]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[NH:23][CH:24]=[N:25]2.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[S:14][CH:15]=[CH:16][C:11]3=[CH:10][C:9]=2[C@@H:17]([NH:19][C:21]2[N:29]=[CH:28][N:27]=[C:26]3[C:22]=2[N:23]=[CH:24][NH:25]3)[CH3:18])[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](N)c1cc2ccsc2nc1-c1cccc(F)c1
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2ccsc2nc1-c1cccc(F)c1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
In a reaction flask was combined (1S)-1-(6-(3-fluorophenyl)thieno[2,3-b]pyridin-5-yl)ethanamine (39 mg, 143 μmol), 6-chloropurine (24 mg, 158 μmol), Hunig's Base (38 μL, 215 μmol) and n-butanol (1.5 mL). The solution was heated to 110° C. After 24 h, the solvent was removed and the residue purified by column chromatography using a 0-70% gradient of (90:9:1 CH2Cl2:MeOH:NH4OH) in CH2Cl2 to afford N—((S)-1-(6-(3-fluorophenyl)thieno[2,3-b]pyridin-5-yl)ethyl)-9H-purin-6-amine. 1H NMR (400 MHz, DMSO-d6) δ 12.90 (br s, 1H), 8.51 (br s, 1H), 8.34 (br s, 1H), 8.10 (m, 2H), 7.88 (d, J=5.9 Hz, 1H), 7.59 (m, 3H), 7.45 (d, J=5.9 hz, 1H), 7.30 (br t, J=6.3 Hz, 1H), 5.60 (br s, 1H), 1.44 (br d, J=5.1 Hz, 3H) ppm. LC/MS (M+1, found=391.1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]([OH:24])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=3[O:24]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COc1ccc(CC(O)COS(=O)(=O)c2ccc(C)cc2)c(O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)OC(COS(=O)(=O)c1ccc(C)cc1)C2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 73.2 %

Procedure:
To a solution of (±)-2-hydroxy-3-(2-hydroxy-4-methoxyphenyl)propyl 4-methylbenzenesulfonate (32.27 g, 0.092 mol) in toluene (1000 mL) cooled to 0° C. was added triphenylphosphine (27.62 g, 0.105 mol) followed by dropwise addition of diethylazodicarboxylate (18.34 g, 0.105 mol) and the reaction mixture was allowed to stir at 0° C. for 15 min. The reaction mixture was quenched by the addition of water (10 mL). The solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:19) provided 22.53 g (74%) of (±)-(6-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a colorless oil. Rf=0.67 (silica, ethyl acetate:hexanes 1:9); Anal. calcd. for C17H18O5S: C, 61.06; H, 5.43. Found: C, 60.70; H, 5.37.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]3[C:15](=[CH:16][C:17]4[O:23][CH2:22][O:21][C:18]=4[CH:19]=3)[CH:14]([CH2:24][CH3:25])[N:13]([C:26](=[O:29])[NH:27][CH3:28])[N:12]=2)=[CH:7][CH:6]=1)(=O)C>[OH-].[Na+].CO.CCOC(C)=O>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]3[C:15](=[CH:16][C:17]4[O:23][CH2:22][O:21][C:18]=4[CH:19]=3)[CH:14]([CH2:24][CH3:25])[N:13]([C:26](=[O:29])[NH:27][CH3:28])[N:12]=2)=[CH:7][CH:6]=1
Reactant: CCC1c2cc3c(cc2C(c2ccc(NC(C)=O)cc2)=NN1C(=O)NC)OCO3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCC1c2cc3c(cc2C(c2ccc(N)cc2)=NN1C(=O)NC)OCO3
Temperature: 25 °C
Yield: 90.3 %

Procedure:
A solution of 4-(4-acetylaminophenyl)-1,2-dihydro-1-ethyl-2-methylcarbamoyl-6,7-methylendioxyphthalazine (45 mg, 0.11 mmole) in 1N sodium hydroxide (4 mL) and methanol (6 mL) was heated to reflux for 72 hours. The mixture was cooled to ambient temperature, diluted with EtOAc (30 mL), washed with water (25 mL), dried (MgSO4) and evaporated in vacuo. The residue was chromatographed on silica gel with 25% hexanes/EtOAc to afford the product as a light yellow foamy solid (35 mg, 90%). 200 MHz 1H NMR (CDCl3); δ7.42 (d, 2H, J=8.1 Hz, ArH), 6.82 (s, 1H, ArH), 6.76 (d, 2H, J=8.1 Hz, ArH), 6.70 (s, 1H, ArH), 6.50 (brq, 1H, J=5.4 Hz, NHCH3), 5.59 (d, 2H, J=2.7 Hz, OCH2O), 5.48 (t, 1H, J=6.8 Hz, CHCH2), 2.93 (d, 3H, J=5.4 Hz, NHCH3), 1.64 (m, 2H, CHCH2 CH3), 0.87 (t, 3H, J=8.1 Hz, CH2CH3).
Reaction SMILES: [Br:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[CH:8]=[O:9].[Cl:10][C:11]1[C:16](C(C2C=NN(C)C=2C2C=CC(C)=CC=2)O)=[C:15]([Cl:32])[N:14]=[CH:13][N:12]=1>>[Br:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[CH:8]([C:16]1[C:11]([Cl:10])=[N:12][CH:13]=[N:14][C:15]=1[Cl:32])[OH:9]
Reactant: Cc1ccc(-c2c(C(O)c3c(Cl)ncnc3Cl)cnn2C)cc1
Reactant: Cn1ncc(C=O)c1Br
Product: Cn1ncc(C(O)c2c(Cl)ncnc2Cl)c1Br

Procedure:
5-Bromo-1-methyl-1H-pyrazole-4-carbaldehyde (C24) was converted to the product using a procedure analogous to that described for the synthesis of (4,6-dichloropyrimidin-5-yl)[1-methyl-5-(4-methylphenyl)-1H-pyrazol-4-yl]methanol (C4) in Example 1, step 4. In this case the product was purified not by recrystallization, but using silica gel chromatography (Eluent: 10:1 heptane/ethyl acetate, then 2:1 heptane/ethyl acetate). Yield: 1.26 g, 3.73 mmol, 70%. LCMS m/z 339.1 (M+1). 1H NMR (400 MHz, CDCl3) δ 2.4-3.0 (v br s, 1H), 3.88 (s, 3H), 6.36 (s, 1H), 7.56 (s, 1H), 8.74 (s, 1H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH:24]4[CH2:31][C@@H:27]5[CH2:28][NH:29][CH2:30][C@@H:26]5[CH2:25]4)=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[Cl:9].C=O.Cl.O1CCOC[CH2:36]1>C(O)=O>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH:24]4[CH2:31][C@@H:27]5[CH2:28][N:29]([CH3:36])[CH2:30][C@@H:26]5[CH2:25]4)=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: C1COCCO1
Reactant: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OC1C[C@H]2CNC[C@H]2C1
Agent: C=O
Agent: Cl
Solvent: O=CO
Product: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OC1C[C@@H]2CN(C)C[C@@H]2C1
Temperature: 95 °C
Yield: 56 %

Procedure:
N-(3,4-Dichloro-phenyl)-6-(methyloxy)-7-{[(3aR,6aS)-octahydrocyclopenta-[c]pyrrol-5-yl]oxy}quinazolin-4-amine hydrochloride (0.20 g, 0.42 mmol) was solubilized in formic acid (5.0 mL) and 37% aqueous formaldehyde (1 mL) was added. The solution was heated to 95° C. for 12 h. The reaction mixture was concentrated in vacuo. The residue was taken up in a mixture of 10% methanol in ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate (2×30 mL) and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by HPLC (reverse-phase, acetonitrile/water/0.1% TFA). Upon removal of solvent the product was taken up in a mixture of 10% methanol in ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate (2×30 mL) and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated then the product was taken up in methanol and treated with 4.0 M hydrogen chloride in dioxane (1 eq.). Removal of solvent in vacuo provided 116 mg (56%) of N-(3,4-dichlorophenyl)-7-({[(3aR,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]}oxy)-6-(methyloxy)quinazolin-4-amine hydrochloride. 1H NMR (400 MHz, d6-DMSO): 11.05 (bs, 1H), 8.90 (s, 1H), 8.44 (s, 1H), 8.18 (d, 1H), 7.84 (dd, 1H), 7.76 (s, 1H), 7.48 (s, 1H), 5.30 (m, 1H), 4.00 (s, 3H), 3.35 (m, 2H), 2.90 (m, 2H), 2.24 (m, 5H), 2.10 (m, 2H), 1.24 (m, 2H). MS (EI) for C23H24Cl2N4O2: 459, 461 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:14])[CH:12]=2)[N:7]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:6]=1[CH3:23].ClC1C=CC(CN2C3C(=CC(OC)=CC=3)C(CC(O)=O)=C2C)=CC=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][N:7]2[C:8]3[C:13](=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=3)[C:5]([CH2:4][C:3]([OH:24])=[O:2])=[C:6]2[CH3:23])=[CH:21][CH:20]=1
Reactant: COC(=O)Cc1c(C)n(Cc2ccc(Cl)cc2)c2ccc(O)cc12
Agent: BrB(Br)Br
Agent: COc1ccc2c(c1)c(CC(=O)O)c(C)n2Cc1ccc(Cl)cc1
Solvent: ClCCl
Product: Cc1c(CC(=O)O)c2cc(O)ccc2n1Cc1ccc(Cl)cc1

Procedure:
1-[(4-Chlorophenyl)methyl]-5-hydroxy-2-methyl-1H-indole-3-acetic acid methyl ester. Using the methods in Example 63, Part C, 1.2 g (3.5 mmol) of 1-[(4-chlorophenyl)methyl]-5-methoxy-2-methyl-1H-indole-3-acetic acid was treated with 15 mL of 1M BBr3 in CH2Cl2 to give crude 1-[(4-chlorophenyl)-methyl]-5-hydroxy-2-methyl-1H-indole-3-acetic acid which was treated with sulfuric acid in MeOH to give 1.2 g of 1-[(4-chlorophenyl)methyl]-5-hydroxy-2-methyl-1H-indole-3-acetic acid methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:13][CH2:14][C:15](Cl)=[O:16].Cl>C(OCC)(=O)C.O>[Cl:13][CH2:14][C:15]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([F:8])[CH:4]=1)=[O:16]
Reactant: O=C(Cl)CCl
Reactant: Fc1ccccc1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CCl)c1ccc(F)c(F)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
1,2-Difluorobenzene (150 g) and aluminium chloride (156 g) were charged in a round bottom flask. The reaction mixture is heated to about 60° C. followed by slow addition of chloroacetyl chloride (105 mL) over a period of 1 hour at the same temperature. The reaction mixture was stirred for another 3 hours followed by cooling to about 10° C. The reaction mass was poured into precooled water (1500 mL) followed by addition of hydrochloric acid (36%, 225 mL) at the same temperature and stirring. To this mixture ethyl acetate (750 mL) was charged and layers were separated. The aqueous layer is extracted with ethyl acetate (750 mL). The organic layers were combined and washed with water (750 mL) followed by complete evaporation of organic layer under vacuum at 50-55° C. The residue obtained is cooled to 25-35° C. followed by purification with column chromatography using 0-5% ethyl acetate in petroleum ether to afford the title compound in about 70% yield having HPLC purity of 99.51%.
Reaction SMILES: [F:1][C:2]1[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)(=[O:15])=[O:14])[CH:9]=[C:8]([O:29][CH2:30][CH2:31][CH2:32][OH:33])[N:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)(=[O:15])=[O:14])[CH:9]=[C:8]([O:29][CH2:30][CH2:31][CH2:32][OH:33])[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)Nc2cc(OCCCO)nc(SCc3cccc(F)c3F)n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1cc(OCCCO)nc(SCc2cccc(F)c2F)n1)N1CCNCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl 4-({[2-[(2,3-difluorobenzyl)thio]-6-(3-hydroxypropoxy)pyrimidin-4-yl]amino}sulfonyl)piperazine-1-carboxylate (the product from step ii), 0.83 g) in DCM (5 ml) was added TFA (5 ml) slowly. The reaction was then stirred at room temperature for 18 h. The reaction was reduced in vacuo and the residue purified by prep HPLC to give the title compound as a white solid. Yield 160 mg
Reaction SMILES: [C:1]([O:4][C@:5]1([C@:29]2([CH3:30])[C@H:15]([C@H:16]3[C@H:26]([CH2:27][CH2:28]2)[C@:24]2([CH3:25])[C:19](=[CH:20][C:21](=[O:31])[CH2:22][CH2:23]2)[CH2:18][CH2:17]3)[CH2:14][CH2:13]1)[C:6](=[O:12])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2].[C:32]([O-])(=O)C.[Na+].P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)Cl.COCOC>[C:1]([O:4][C@:5]1([C@:29]2([CH3:30])[C@H:15]([C@H:16]3[C@H:26]([CH2:27][CH2:28]2)[C@:24]2([CH3:25])[C:19](=[CH:20][C:21](=[O:31])[CH2:22][CH2:23]2)[C:18](=[CH2:32])[CH2:17]3)[CH2:14][CH2:13]1)[C:6](=[O:12])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CC(=O)OCC(=O)[C@@]1(OC(C)=O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Solvent: COCOC
Solvent: ClCCl
Product: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC[C@]3(OC(C)=O)C(=O)COC(C)=O)[C@@]2(C)CCC(=O)C=C12
Yield: 58.9 %

Procedure:
A solution of 2.0 g of 17,21-diacetoxy-4-pregnene-3,20-dione in 60 ml of methylene chloride and 60 ml of formaldehyde dimethylacetal is refluxed for 30 hours with 2.0 g of sodium acetate and 12.6 g of phosphorus pentachloride. The mixture is worked up analogously to Example 9, thus isolating 1.21 g of 17,21-diacetoxy-6-methylene-4-pregnene-3,20-dione, mp 227°-228° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:27])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:3]1.C(O[AlH-](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+]>O1CCCC1>[CH3:18][C@@H:12]([C@@H:11]1[C@@:19]2([CH3:27])[CH2:20][CH2:21][C@@H:22]3[C@@:23]4([CH3:26])[CH2:24][CH2:25][C@@H:2]([OH:1])[CH2:3][C@H:4]4[CH2:5][CH2:6][C@H:7]3[C@@H:8]2[CH2:9][CH2:10]1)[CH2:13][CH2:14][C:15]([OH:17])=[O:16]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)(C)O[AlH-](OC(C)(C)C)OC(C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.25 h
Yield: 99.5 %

Procedure:
3-Oxo-5β-cholan-24-oic acid (3.0 g) was dissolved in dry tetrahydrofuran (40 ml), cooled on an ice-bath, and over 15 min. 17.5 ml of 1.1 M solution of Lithium tri-tert-butoxyaluminohydride was added with stirring. Further 10 ml of tetrahydrofuran was added and stirring was continued for 15 min on an ice-bath and 1.5 hours at room temperature. After cooling the mixture on an ice-bath, the reaction was quenched by addition of 16 ml of water, followed by 20 ml of 6M HCl. The mixture was extracted with dichloromethane and the combined organic phases were washed with 1 M HCl and water and dried (Na2SO4). Removal of the solvent under reduced pressure gave 3.0 g of crude lithocholic acid. NMR analysis (CDCl3, 300 MHz) of the product showed characteristic signal at 0.66 (3H,s); 0.93 (6H, s and d); 2.15-2.49 (2H, m); 3.63 (1H, m), in accordance with the 1H-NMR spectrum of reference lithocholic acid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:22])[N:9]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:4][CH:3]=1.[CH2:23]([O:25][C:26]([C:28]1[N:29]=[C:30]([SH:33])[NH:31][CH:32]=1)=[O:27])[CH3:24]>>[CH2:23]([O:25][C:26]([C:28]1[N:29]=[C:30]([S:33][C:2]2[S:6][C:5]([NH:7][C:8]([N:9]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)=[O:22])=[N:4][CH:3]=2)[NH:31][CH:32]=1)=[O:27])[CH3:24]
Reactant: O=C(Nc1ncc(Br)s1)N(C1CCCCC1)C1CCCCC1
Reactant: CCOC(=O)c1c[nH]c(S)n1
Product: CCOC(=O)c1c[nH]c(Sc2cnc(NC(=O)N(C3CCCCC3)C3CCCCC3)s2)n1

Procedure:
Prepared as described in general procedure (E) using 3-(5-bromo-thiazol-2-yl)-1,1-dicyclohexyl-urea and ethyl-2-mercapto-1H-imidazole-4-carboxylate.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([B:10]([OH:12])[OH:11])[CH:7]=[CH:8][CH:9]=1.[CH3:15][C:16]([CH2:20]O)([CH2:18]O)[CH3:17]>>[CH3:15][C:16]1([CH3:20])[CH2:18][O:12][B:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:1])([F:13])[F:14])[CH:5]=2)[O:11][CH2:17]1
Reactant: CC(C)(CO)CO
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Product: CC1(C)COB(c2cccc(OC(F)(F)F)c2)OC1
Yield: 64 %

Procedure:
The title compound (64%, oil) was prepared from 3-trifluoromethoxyphenylboronic acid and neopentylglycol.