Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[C:3]([CH2:5][C:6]([O:8]C)=[O:7])#[N:4].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:15]=O>Cl>[C:3]([C:5](=[CH:15][C:14]1[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:12]([O:11][CH3:10])[CH:13]=1)[C:6]([OH:8])=[O:7])#[N:4]
Reactant: COc1ccc(C=O)cc1OC
Reactant: COC(=O)CC#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(C=C(C#N)C(=O)O)cc1OC
Temperature: 85 °C
Yield: 55.7 %

Procedure:
To 150 ml of an aqueous solution of 9.19 g of sodium hydroxide, 20.50 g of methyl cyanoacetate was added and, under stirring, 25.38 g of 3,4-dimethoxybenzaldehyde was further added, followed by heating at 85° C. for 40 hours under stirring. After completion of the reaction, the reaction mixture was added to 50 ml of 12 N hydrochloric acid to recover the resultant solid. The solid was repeated twice to recrystallize from ethanol to obtain 19.84 g of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C.CCOCC.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH:5][CH:20]1[CH2:21][CH2:22][N:17]([C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])[CH2:18][CH2:19]1
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Cl)c(Cl)c2)CC1

Procedure:
A solution of 3,4-dichloroaniline (5 g), N-tert-butoxycarbonyl4-piperidone (11.7 g), sodium triacetoxyborohydride (19.7 g) and acetic acid (7 ml) in dichloroethane (150 ml) was stirred for 16 hours. 2M NaOH solution and ether were added, the organic phase separated, dried and concentrated. The residue was triturated under an isohexane:ethyl acetate, 4:1 mixture and the sub-titled product collected as a solid (7.25 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH3:11])[C:3]=1[NH2:12].[CH:13]1([CH2:18][C:19](Cl)=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14]1.O>C(#N)C>[CH:13]1([CH2:18][C:19]([NH:12][C:3]2[C:2]([CH3:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][C:4]=2[CH3:11])=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(Cl)CC1CCCC1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1N
Solvent: O
Solvent: CC#N
Product: Cc1cc([N+](=O)[O-])cc(C)c1NC(=O)CC1CCCC1
Temperature: 150 °C
Yield: 89 %

Procedure:
2,6-Dimethyl-4-nitro-phenylamine (0.98 g) and cyclopentylacetyl chloride (0.99 mL) were dissolved in acetonitrile (10 mL) and heated to 150° C. for 5 minutes in a sealed microwave process vial. Water (10 mL) was added to the reaction mixture, and the product was collected by filtration and washed with water (20 mL) and heptane (20 mL) to furnish 1.45 g (89% yield) of the title compound as a yellow solid. 1H NMR (500 MHz, DMSO-d6): 1.24 (m, 2H), 1.54 (m, 2H), 1.63 (m, 2H), 1.79 (m, 2H), 2.25 (s, 6H), 2.27 (m, 1H), 2.36 (d, 2H), 7.98 (s, 2H), 9.56 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:30]1[CH2:29][CH2:28][N:27]([C:24]3[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=3)[CH2:32][CH2:31]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Nc1nc2ccc(Cl)cc2nc1OC
Product: COc1nc2cc(Cl)ccc2nc1NC(=O)N1CCN(c2ccc(F)cc2)CC1
Yield: 88 %

Procedure:
Ethyl N-(6-chloro-3-methoxyquinoxalin-2-yl)carbamate and 1-(4-fluorophenyl)piperazine were reacted by the same way with the example 106 to obtain the titled compound (yield, 88%). 1H NMR (300 MHz, CDCl3): δ 3.19-3.22 (m, 4H), 3.75-3.78 (m, 4H), 4.16 (s, 3H), 6.89-6.93 (m, 4H), 7.29-7.46 (m, 2H), 7.74-7.76 (m, 1H).
Reaction SMILES: [C:1]1([C:7]2[C:22]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4([NH:33]C(=O)OC(C)(C)C)[CH2:32][CH2:31][CH2:30]4)=[CH:25][CH:24]=3)=[N:21][C:10]3[O:11][CH2:12][CH2:13][N:14]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=4)[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(C(F)(F)F)=O>[C:1]1([C:7]2[C:22]([C:23]3[CH:24]=[CH:25][C:26]([C:29]4([NH2:33])[CH2:32][CH2:31][CH2:30]4)=[CH:27][CH:28]=3)=[N:21][C:10]3[O:11][CH2:12][CH2:13][N:14]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=4)[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(c3cccnc3)CCO4)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(c3cccnc3)CCO4)cc2)CCC1
Reaction time: 0.01 h
Yield: 48.4 %

Procedure:
tert-Butyl 1-(4-(7-phenyl-1-(pyridin-3-yl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (10 mg, 0.019 mmol) was dissolved in TFA (2 mL) and stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜2 mL) and concentrated to dryness under reduced pressure three times. The residue was then slurried in diethyl ether (2 mL) and after settling the supernatant solvent removed by pipette. This was repeated three times. The remaining solvent was removed by freeze drying overnight to give the desired compound as an off-white solid (4 mg, 32% yield). 1H-NMR (500 MHz, MeOD) δ 8.57 (1H, br s), 8.28 (1H, br s), 7.80 (1H, d), 7.43 (1H, br s), 7.26 (2H, d), 7.24 (2H, d), 7.04-7.16 (4H, m), 6.90-7.00 (2H, m), 4.51 (2H, t), 3.80 (2H, t), 2.56-2.70 (2H, m), 2.37-2.52 (2H, m), 2.02-2.16 (1H, m), 1.74-1.90 (1H, m). LCMS (Method D) RT=0.77 min, M+H+=435.20.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][C@H:14]([C:19]([NH:21][CH:22]1[N:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:26]2[CH:35]=[CH:36][CH:37]=[CH:38][C:25]=2[N:24]([CH3:39])[C:23]1=[O:40])=[O:20])[C:15]([CH3:18])([CH3:17])[CH3:16]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:13][C@H:14]([C:19]([NH:21][CH:22]2[N:28]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:26]3[CH:35]=[CH:36][CH:37]=[CH:38][C:25]=3[N:24]([CH3:39])[C:23]2=[O:40])=[O:20])[C:15]([CH3:18])([CH3:17])[CH3:16])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: CN1C(=O)C(NC(=O)[C@@H](N)C(C)(C)C)N=C(c2ccccc2)c2ccccc21
Product: CN1C(=O)C(NC(=O)[C@@H](NC(=O)Cc2cc(F)cc(F)c2)C(C)(C)C)N=C(c2ccccc2)c2ccccc21

Procedure:
Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(L-tert-leucinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (Example 8-Z), the title compound was prepared as a solid (mp.=221–222° C.). The product was purified by slurrying in ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH2:10][C:11]#N)=[C:5]([N+:13]([O-])=O)[CH:4]=1.O1CCCC1>[C].[Pd].C(O)CCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6]([CH:10]=[CH:11][NH:13]2)=[CH:7][C:8]=1[CH3:9]
Reactant: COc1cc([N+](=O)[O-])c(CC#N)cc1C
Agent: [Pd]
Solvent: CCCCO
Solvent: C1CCOC1
Product: COc1cc2[nH]ccc2cc1C
Temperature: 60 °C
Reaction time: 36 h
Yield: 69.3 %

Procedure:
To a solution of (4-methoxy-5-methyl-2-nitrophenyl)acetonitrile (0.24 g) in a mixed solvent of tetrahydrofuran (2 mL) and n-butanol (2 mL) was added palladium-carbon powder (0.043 g) under an argon atmosphere and this mixture was stirred at 60° C. under a hydrogen atmosphere for 36 hours. The insoluble material was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (0.13 g).
Reaction SMILES: Cl.[I:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[N:9][C:10]=2[NH2:12])[N:5]([CH:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[N:4]=1.C=O.[C:20](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[I:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[N:9][C:10]=2[NH2:12])[N:5]([CH:13]2[CH2:17][CH2:16][N:15]([CH3:20])[CH2:14]2)[N:4]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Nc1ncnc2c1c(I)nn2C1CCNC1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CN1CCC(n2nc(I)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 170.3 %

Procedure:
To a solution of rac-3-iodo-1-tetrahydro-1H-3-pyrrolyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine monohydrochloride (0.400 g, 1.09 mmol) in dichloroethane (10 mL) was added formaldehyde (37% in water, 0.12 mL, 1.63 mmol), sodium triacetoxyborohydride (0.578 g, 2.73 mmol), and acetic acid (0.37 mL, 6.55 mmol). The reaction mixture was stirred at room temperature for 3 days and then additional formaldehyde (37% in water, 0.12 mL, 1.63 mmol), sodium triacetoxyborohydride (0.578 g, 2.73 mmol), and acetic acid (0.37 mL, 6.55 mmol) were added. The reaction mixture stirred for an additional 3 h and was then concentrated to afford rac-3-iodo-1-(1-methyltetrahydro-1H-3-pyrrolyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a pale yellow solid (0.639 g) which was used in subsequent reactions without further purification. RP-HPLC Rt 4.226 min, 96% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); m/z 345 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][C:16]2[CH:17]=[C:18]([N:26]([CH2:33][CH3:34])[CH:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[C:19]([CH3:25])=[C:20]([CH:24]=2)[C:21](O)=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl-].[CH3:43][C:44]1[CH:49]=[C:48]([CH3:50])[NH:47][C:46](=[O:51])[C:45]=1[CH2:52][NH3+:53].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CS(C)=O>[CH3:43][C:44]1[CH:49]=[C:48]([CH3:50])[NH:47][C:46](=[O:51])[C:45]=1[CH2:52][NH:53][C:21]([C:20]1[CH:24]=[C:16]([C:15]#[C:14][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9][CH2:10]2)[CH:17]=[C:18]([N:26]([CH2:33][CH3:34])[CH:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:19]=1[CH3:25])=[O:22]
Reactant: Cc1cc(C)c(C[NH3+])c(=O)[nH]1
Reactant: CCN(c1cc(C#CC2CCN(C(=O)OC(C)(C)C)CC2)cc(C(=O)O)c1C)C1CCOCC1
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCN(c1cc(C#CC2CCN(C(=O)OC(C)(C)C)CC2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
To a solution of 5-((1-(tert-butoxycarbonyl)piperidin-4-yl)ethynyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzoic acid (1.06 g, 2.25 mmol) in DMSO (5.8 mL) at rt was added triethylamine (0.90 mL, 6.44 mmol) and (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methanaminium chloride (0.405 g, 2.15 mmol). The clear solution become heterogenous. Then HOBT (0.493 g, 3.22 mmol) and EDC (0.617 g, 3.22 mmol) were added and the resulting reaction mixture was stirred at rt overnight. The reaction was quenched with water (80 mL) and the slurry was stirred for 1 h at rt. The slurry was filtrated and the cake was washed with water (2×20 mL). The collected solid was dried under vacuum to give the titled compound (1.27 g, 98% yield). 1H-NMR (500 MHz, CD3OD) 8 ppm; 7.22 (s, 1H), 7.08 (d, J=1.0 Hz 1H), 6.11 (s, 1H), 4.45 (s, 2H), 3.92 (brd, J=10.8 Hz, 2H), 3.78 (dd, J=4.4, 5.4 Hz, 1H), 3.75 (dd, J=4.4, 5.4 Hz, 1H), 3.36 (t, J=11.7 Hz, 2H), 3.21 (br t, J=8.3 Hz, 2H), 3.07 (q, J=7.3 Hz, 2H), 3.01 (dddd, J=3.9, 3.9, 11.3, 11.3 Hz, 1H), 2.84 (dddd, J=3.4, 3.4. 3.9, 3.9 Hz, 1H), 2.38 (s, 3H), 2.28 (s, 3H), 2.25 (s, 3H), 1.88 (m, 2H), 1.70 ((brd, J=12.2 Hz, 2H), 1.60 (m, 4H), 1.47 (s, 9H), 0.87 (t, J=7.3 Hz, 3H); MS (ESI) [M+H]+605.6.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[CH:10]=[C:11]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.O1CCCC1.[Pt]=O>[C:1]1([CH2:7][CH2:8][C:9]2[CH:10]=[C:11]([CH2:15][O:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:22]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CCc1ccc(OCc2cccc(/C=C/c3ccccc3)c2)cc1
Agent: O=[Pt]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(OCc2cccc(CCc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59 %

Procedure:
To a solution of methyl 4-[[3-((E)-2-phenylethenyl) phenyl]methoxy]benzenepropanoate (0.35 g, 0.95 mmol) in methanol (15 mL) and tetrahydrofuran (25 mL) was added platinum oxide (0.018 g, 0.078 mmol), and the mixture was stirred under a hydrogen atmosphere at room temperature for 18 hrs. The catalyst was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=15:1) to give the title compound (0.21 g, yield 58%). oil.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7](Cl)[S:8][C:4]=2[CH:3]=1.FC(F)(F)C(O)=O.[NH:19]1[CH2:24][CH2:23][CH:22]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[NH:32][S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)(=[O:35])=[O:34])[CH2:21][CH2:20]1>>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([N:19]3[CH2:24][CH2:23][CH:22]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[NH:32][S:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=4)(=[O:35])=[O:34])[CH2:21][CH2:20]3)[S:8][C:4]=2[CH:3]=1
Reactant: O=S(=O)(Nc1ccccc1OC1CCNCC1)c1ccccn1
Reactant: Clc1nc2ccc(Br)cc2s1
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1ccccc1OC1CCN(c2nc3ccc(Br)cc3s2)CC1)c1ccccn1

Procedure:
Compound 27 is prepared using synthesis method 3 using intermediates 2d and 6a (yield: 14%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.Br[CH2:12][C:13]#[CH:14].CC1C=CC=C(C)N=1>C1(C)C=CC=CC=1.CC(N(C)C)=O>[CH2:14]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1)[C:13]#[CH:12]
Reactant: C#CCBr
Reactant: NC(=O)c1ccc(N)cc1
Solvent: Cc1ccccc1
Solvent: Cc1cccc(C)n1
Solvent: CC(=O)N(C)C
Product: C#CCNc1ccc(C(N)=O)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A suspension of 13.62 g (0.1 mol) of 4-aminobenzamide, 17.85 g (0.12 mol) of an 80% solution of 3-bromo-1-propyne in toluene, and 13.98 ml (0.12 mol) of 2,6-dimethylpyridine in 140 ml of dimethylacetamide (DMA) is stirred at 60° C. for two hours and then at 90° C. for one hour. The solution is cooled and the precipitated solid is collected and discarded. The filtrate is poured into a water-ice mixture and stirred. The suspension is extracted with ethyl acetate. The ethyl acetate solution is separated, dried (magnesium sulfate), and concentrated to give 20.7 g of a brown liquid. This is applied to a column of 1 kg of flash silica gel packed in dichloromethane-methanol (50:1). Elution with the same solvent gives 6.73 g (38.7%) of the product as a yellow solid, mp 139°-141° C.
Reaction SMILES: [F:1][CH:2]([F:23])[C@:3]12[CH2:20][CH2:19][C@H:18]3[C@@H:8]([CH2:9][CH2:10][C:11]4[C@:16]3([CH3:17])[CH2:15][CH2:14][C:13](=[O:21])[CH:12]=4)[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:22].[CH2:24](OC(O)O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.CI>O1CCOCC1.CO.O>[F:1][CH:2]([F:23])[C@:3]12[CH2:20][CH2:19][C@H:18]3[C@@H:8]([CH2:9][CH2:10][C:11]4[C@:16]3([CH3:17])[CH2:15][CH2:14][C:13](=[O:21])[CH:12]=4)[C@@H:7]1[CH2:6][CH2:5][C@@:4]2([OH:22])[CH3:24]
Reactant: CCOC(O)O
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C(F)F)C(=O)CC[C@@H]12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CI
Solvent: O
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@@]2(C(F)F)[C@H]1CC[C@]2(C)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
500 mg of 18,18-difluoro-androst-4-ene-3,17-dione are dissolved in 20 ml of dioxane and, after adding 1 ml of orthoformic acid ethyl ester and 30 mg of p-toluenesulphonic acid, the mixture is stirred for 8 hours at room temperature. The reaction mixture is then poured into water (containing traces of pyridine) and extracted twice with ethyl acetate and the extracts are washed until neutral, dried and evaporated in an aspirator vacuum. The crude amorphous enol ether (3-ethoxy-18,18-difluoro-androsta-3,5-dien-17-one) is dissolved direct in 30 ml of absolute ether and the solution is added dropwise to an ethereal solution of methyl magnesium iodide prepared from 300 mg of magnesium turnings and an equivalent amount of methyl iodide, whilst stirring and cooling. The reaction mixture is refluxed for 2 hours and then worked up in the customary manner. The crude carbinol is subjected to hydrolysis direct, without purification. For this purpose, the compound is dissolved in 10 ml of 66% strength acetic acid and the solution is stirred for 2 hours at 30° C. It is then diluted with water and extracted with ethyl acetate and the extracts are washed until neutral (twice with saturated sodium bicarbonate solution and with water), dried and evaporated in an aspirator vacuum. Chromatography of the crude product over 100 times the amount by weight of silica gel (system: hexane/ethyl acetate, 3:1) gives 18,18-difluoro-17β-hydroxy-17-methyl-androst-4-en-3-one.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].CO.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1.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>[C:23]1([C:2]2[N:7]3[CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1cn2c(Br)cccc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn2c(-c3ccccc3)cccc2n1
Temperature: 80 °C
Yield: 95 %

Procedure:
To a suspension of ethyl 5-bromo-imidazo[1,2-a]pyridine-2-carboxylate (1.50 g, 5.6 mmol), Pd(PPh3)4 (322 mg, 0.279 mmol) in a mixture of toluene (17 mL), NaHCO3 1M (6 mL) and MeOH (4 mL) was added phenylboronic acid at room temperature. The resulting reaction mixture was heated at 80° C. for 12 h, cooled, and diluted with water (50 mL). The insoluble matter was filtered off, and the phases were separated. The aqueous phase was extracted with ethyl acetate, the combined organic layers were washed with water and the solvent was removed under reduced pressure. The crude product was purified by chromatography (prepacked 25 g silicagel column, DCM/MeOH from 100/0 to 99/1 as eluent) to afford 1.41 g of ethyl 5-phenyl-imidazo[1,2-a]pyridine-2-carboxylate (Yield: 95%) as a yellowish solid (M.P.: 123-123.8° C.)
Reaction SMILES: [CH3:1][C:2]([O:10][Si:11]([CH3:14])([CH3:13])[CH3:12])([CH2:6][CH2:7][CH:8]=[CH2:9])[CH2:3][C:4]#[CH:5].[CH2:15]([SnH:19]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH3:18].N(C(C)(C)C#N)=NC(C)(C)C#N>>[CH2:24]([Sn:19]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:20][CH2:21][CH2:22][CH3:23])/[CH:5]=[CH:4]/[CH2:3][C:2]([CH3:1])([O:10][Si:11]([CH3:13])([CH3:14])[CH3:12])[CH2:6][CH2:7][CH:8]=[CH2:9])[CH2:25][CH2:26][CH3:27]
Reactant: C#CCC(C)(CCC=C)O[Si](C)(C)C
Reactant: CCCC[SnH](CCCC)CCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: C=CCCC(C)(C/C=C/[Sn](CCCC)(CCCC)CCCC)O[Si](C)(C)C
Temperature: 140 °C
Reaction time: 1.5 h

Procedure:
A mixture of 30 g. of 4-methyl-4-trimethylsilyloxy-oct-1-yn-7-ene, 58.66 g. of tri-n-butylstannane and 200 mg. of azobisisobutyronitrile is placed in a bath at 95° C. and stirred under argon. The mixture is heated at 140° C. for one hour and then at 140° C. under vacuum for 1.5 hours. The mixture is distilled via a Kugelrohr at 140° C., 0.06 mm. to give the product as a colorless liquid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]([NH:19][C:20]1[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=1)=[O:18].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O.[CH3:39][N:40]([CH:42]=O)C>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>[F:27][C:26]1[CH:23]=[C:24]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:6]=[C:5]3[C:17]([NH:19][C:20]2[CH:21]=[N:22][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:24][CH:25]=2)=[O:18])[CH:39]=[N:40][CH:42]=1
Reactant: O=C(Nc1ccc(C(F)(F)F)nc1)c1nn(C2CCCCO2)c2ccc(Br)cc12
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(Nc1ccc(C(F)(F)F)nc1)c1nn(C2CCCCO2)c2ccc(-c3cncc(F)c3)cc12
Temperature: 90 °C
Yield: 88 %

Procedure:
A solution of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)-1H-indazole-3-carboxamide (CXXVIII) (0.469 g, 1 mmol), 5-fluoro-pyridyl-3-boronic acid (CXXIX) (0.156 g, 1.1 mmol), potassium phosphate tribasic (0.318 g, 1.5 mmol) and water (degassed, 1 mL) in DMF (10 mL) was purged with argon. Tetrakis(triphenylphosphine)palladium(0) (0.034 g, 0.03 mmol) was added and the solution was purged again with argon. The reaction was heated to 90° C. for 3 h when TLC showed disappearance of starting material. The solution was cooled to room temperature and excess solvent was removed under vacuum. The residue was treated with water, sonicated briefly and the solids formed were filtered. The solids were washed with cold water and dried under vacuum at room temperature which was purified by silica gel column chromatography (2:8 EtOAc:hexanes→3:7 EtOAc:hexanes) to afford 5-(5-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)-1H-indazole-3-carboxamide (CXXX) as a white solid (427 mg, 0.88 mmol, 88% yield). 1H NMR (DMSO-d6) δ ppm 10.95 (s, 1H), 9.25 (d, J=1.8 Hz, 1H), 8.85 (m, 1H), 8.63 (d, J=1.8 Hz, 1H), 8.61 (d, J=2.1 Hz, 1H), 8.53 (m, 1H), 8.16-8.13 (m, 1H), 8.08 (d, J=7.1 Hz, 1H), 7.97-7.94 (m, 2H), 6.11 (dd, J=8.1, 1.8 Hz, 1H), 4.01 (m, 1H), 3.88-3.83 (m, 1H), 2.63-2.60 (m, 1H), 2.11-2.07 (m, 2H), 1.83-1.80 (m, 1H). 1.69-1.65 (m, 2H); ESIMS found for C24H19F4N5O2 m/z 486.0 (M+H).
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9](=[O:12])[NH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]#[CH:21]>CC(C)=O>[C:1]1([C:7]2[S:8][C:9](=[O:12])[N:10]([CH2:21][C:20]#[CH:19])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1[nH]nc(-c2ccccc2)s1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCn1nc(-c2ccccc2)sc1=O
Temperature: 25 °C
Yield: 54.9 %

Procedure:
To the solution of 2-phenyl-1,3,4-thiadiazolin-5-one (3 g, 16.85 mmole) in dry acetone (30 ml) under nitrogen with magnetic stirring was added potassium carbonate (3 g, 22 mmole), followed by propargyl bromide (3 g, 80% in toluene, 20 mmole) at room temperature. The mixture was refluxed for one hour. The reaction mixture was cooled down to room temperature and the solid was filtered off by suction-filtration. The filtrate was diluted with ether (200 ml) and washed with water (2×50 ml) and brine. The organic layer was dried over sodium sulfate. After the drying agent was filtered off the filtrate was concentrated to about 5 ml. Hexane was added to precipitate out the product. The product was collected by suction-filtration and washed with a little hexane to afford 2 g of 2-phenyl-4-propargyl-1,3,4-thiadiazolin-5-one as a powder. m.p.=73°-75° C.