Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:18]([C:27]([N:29]3[CH2:34][CH2:33][CH:32]([CH2:35]Br)[CH2:31][CH2:30]3)=[O:28])[C:17]([C:37]3[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][C:38]=3[O:47][CH2:48][CH3:49])=[N:16]2)=[CH:11][CH:10]=1>CN(C)C=O>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH:19]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[N:18]([C:27]([N:29]3[CH2:34][CH2:33][CH:32]([CH2:35][N:4]4[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]4)[CH2:31][CH2:30]3)=[O:28])[C:17]([C:37]3[CH:42]=[CH:41][C:40]([C:43]([F:44])([F:45])[F:46])=[CH:39][C:38]=3[O:47][CH2:48][CH3:49])=[N:16]2)=[CH:11][CH:10]=1
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCC(CBr)CC1
Reactant: O=C1CNCCN1
Solvent: CN(C)C=O
Product: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCC(CN2CCNC(=O)C2)CC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Piperazine-2-one (21 mg, 0.21 mmol) was added to a solution [4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-bromomethyl-piperidin-1-yl]-methanone (48 mg, 0.07 mmol) in anhydrous dimethylformamide (2.0 mL). The mixture was stirred overnight at 70° C. The reaction mixture was cooled to ambient temperature and partitioned between methylene chloride and a saturated aqueous solution of ammonium chloride. The aqueous phase was extracted with methylene chloride and the combined organic extracts were washed with brine, and dried over anhydrous sodium sulfate. Evaporation of the solvents and chromatography of the residue over silica gel using 1-5% methanol in methylene chloride gave [4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(piperazin-2-one-4-yl-methyl)-piperidin-1-yl]-methanone, which was dissolved in dilute hydrochloric acid (0.5 N, 1 mL) and lyophilized to give [4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(piperazin-2-one-4-yl-methyl)-piperidin-1-yl]-methanone hydrochloride as an off-white powder (23 mg, 45%). LR-MS (APCI): 702.4 [(M+H)+].
Reaction SMILES: [CH2:1]([N:4]([CH3:9])[CH2:5][C@@H:6]([OH:8])[CH3:7])[CH:2]=[CH2:3].F[C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[C:13]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=3)=[C:24]([CH3:36])[CH:23]=1)=[N:14][CH:15]=[N:16]2>>[CH2:1]([N:4]([CH3:9])[CH2:5][C@H:6]([CH3:7])[O:8][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[C:13]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=3)=[C:24]([CH3:36])[CH:23]=1)=[N:14][CH:15]=[N:16]2)[CH:2]=[CH2:3]
Reactant: C=CCN(C)C[C@H](C)O
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4cccc(F)c34)cc2C)cn1
Product: C=CCN(C)C[C@H](C)Oc1cccc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(C)c3)c12
Yield: 92 %

Procedure:
The procedure described in Example 103, preparation of starting materials, was repeated using (2S)-1-[allyl(methyl)amino]propan-2-ol (obtained as described for the R-antipode in Example 2.3, preparation of starting materials) and 5-fluoro-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine (obtained as described in Example 103, preparation of starting materials) to give 5-{(1S)-2-[allyl(methyl)amino]-1-methylethoxy}-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine in 92% yield as a gum; Mass spectrum: MH+ 470.
Reaction SMILES: N1CCCC1.C(O)(=O)C.[C:10]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:11][CH2:12][C:13]([CH3:15])=[O:14].[CH3:20][C:21]1[O:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1>C(O)C>[CH3:25][C:24]1[O:27][C:21]([CH:20]=[CH:15][C:13](=[O:14])[CH2:12][CH2:11][C:10]([O:17][CH2:18][CH3:19])=[O:16])=[CH:22][CH:23]=1
Reactant: Cc1ccc(C=O)o1
Reactant: CCOC(=O)CCC(C)=O
Solvent: CCO
Solvent: C1CCNC1
Solvent: CC(=O)O
Product: CCOC(=O)CCC(=O)C=Cc1ccc(C)o1
Temperature: 25 °C
Yield: 69.4 %

Procedure:
To make a starting compound of Formula I, 11.5 mL of pyrrolidine (0.139 mol, 0.2 eq) and 8.0 mL of acetic acid (0.139 mol, 0.2 eq) were added to a solution of 100 g of ethyl levulinate (0.694 mol, 1.0 eq) in 400 mL of ethanol. To this solution, 76.4 g of 5-methyl-furfural (0.694 mol, 1.0 eq) was added over 30 minutes. The reaction was stirred at ambient temperature until complete, as analyzed by gas chromatography-mass spectrometry (GCMS). The reaction mixture was evaporated to dryness and dissolved in a mixture of 400 mL of hexane and 100 mL of ethyl acetate. Activated charcoal (Darco® G-60, Sigma-Aldrich) was added and stirred for 15 minutes. The reaction mixture was filtered over a six inch sintered glass funnel containing a six inch bed of silica and washed with 4:1 hexane/ethyl acetate to collect 7 fractions. Fractions 3 and 4 were combined and evaporated to an oil to give ethyl 6-(5-methylfuran-2-yl)-4-oxohex-5-enoate as an orange oil (114.6 g, 69.4% yield, proton nuclear magnetic resonance (HNMR), GCMS molecular weight=236).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11]([OH:13])=O)[CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1.[NH:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[CH2:26][C@H:15]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[N:14]1([C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:4]=[CH:3][N:2]([CH3:1])[C:6]=3[CH:7]=2)=[O:13])[CH2:19][CH2:18][CH2:17][C@@H:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[CH2:26][C@H:15]12
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Reactant: Cn1cnc2ccc(C(=O)O)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cn1cnc2ccc(C(=O)N3CCC[C@@H]4c5ccccc5C[C@@H]43)cc21
Yield: 94 %

Procedure:
The title compound is prepared from 3-methyl-3H-benzoimidazole-5-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 94% of theory; LC (method 4): tR=1.62 min; Mass spectrum (ESI+): m/z=332 [M+H]+.
Reaction SMILES: [Cu][C:2]#[N:3].[NH2:4][C:5]1[N:10]=[C:9]([CH3:11])[C:8](Br)=[CH:7][CH:6]=1.[C-]#N.[Na+]>CN(C)C=O.O>[NH2:4][C:5]1[N:10]=[C:9]([CH3:11])[C:8]([C:2]#[N:3])=[CH:7][CH:6]=1
Reactant: N#C[Cu]
Reactant: Cc1nc(N)ccc1Br
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(N)ccc1C#N
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Copper(I) cyanide (12 mmol) is added to 10 mmol of 6-amino-3-bromo-2-methylpyridine dissolved in dimethylformamide. The mixture is heated at reflux for 10 hours and then cooled to 80° C. and poured into a solution of sodium cyanide (40 mmol) in water. After stirring for one hour at ambient temperature, the mixture is extracted with ethyl acetate. The organic phase is washed and then dried and evaporated to yield the expected product in the form of an ochre solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[O:9][CH:10]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:11]([NH:13][CH2:14][C:15]#[N:16])=[O:12])=[CH:4][CH:3]=1.[N:27]1([C:33]2[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=2)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[C:15]([CH2:14][NH:13][C:11](=[O:12])[CH:10]([O:9][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([C:36]2[CH:35]=[CH:34][C:33]([N:27]3[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]3)=[CH:38][CH:37]=2)=[CH:3][CH:4]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[CH2:17][CH:18]([CH3:20])[CH3:19])#[N:16]
Reactant: CC(C)CC(OC(c1ccc(Br)cc1)c1ccccn1)C(=O)NCC#N
Reactant: OB(O)c1ccc(N2CCNCC2)cc1
Product: CC(C)CC(OC(c1ccc(-c2ccc(N3CCNCC3)cc2)cc1)c1ccccn1)C(=O)NCC#N

Procedure:
Using the same protocol as described in example 21, 2-[(4-bromophenyl)(pyridin-2-yl)methoxy]-N-(cyanomethyl)-4-methylpentanamide from example 7, step 4 (241 mg, 0.58 mmol) was coupled with 4-piperazin-1-ylphenylboronic acid (155 mg, 0.64 mmol). The crude residue obtained was chromatographed on silica gel using 1% NH4OH and 9% MeOH in dichloromethane to afford the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH:20]([C:23]([OH:25])=[O:24])[CH2:19][CH2:18]1.O>CN(C=O)C>[CH2:7]([O:25][C:23]([CH:20]1[CH2:21][CH2:22][CH:17]([CH2:16][OH:15])[CH2:18][CH2:19]1)=[O:24])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)C1CCC(CO)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)C1CCC(CO)CC1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Potassium carbonate (2.61 g, 18.9 mmol) and benzyl bromide (2.24 mL, 18.9 mmol) were added to a solution of 4-hydroxymethyl-cyclohexanecarboxylic acid (cis-trans=2.9:1 mixture) (2.49 g, 15.7 mmol) in DMF (31.5 mL) at room temperature, and the mixture was stirred at 60° C. for one hour. The reaction solution was cooled, and H2O (60 mL) was then added to the reaction solution, followed by extraction with hexane:ethyl acetate (2:1) (300 mL) twice. The organic layers were dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 4-hydroxymethyl-cyclohexanecarboxylic acid benzyl ester (cis-trans=3.5:1 mixture) as a colorless oily substance (3.79 g, 97%).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:19])[CH2:16][CH2:17][NH2:18])=[CH:11][CH:10]=1.C(N(CC)CC)C.O>CN(C)C1C=CN=CC=1.ClCCl>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]([CH3:19])[CH2:16][CH2:17][NH:18][C:5](=[O:7])[CH3:6])=[CH:13][CH:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(CCN)c1ccc(Br)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCC(C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.7 %

Procedure:
At 0° C., acetic anhydride (0.59 g, 5.75 mmol) was added dropwise into a mixture of 3-(4-bromophenyl)butan-1-amine (0.57 g, 2.5 mmol), triethylamine (1.16 g, 11.5 mmol) and 4-dimethylamino-pyridine (1.0 mg, 0.008 mmol) in anhydrous dichloromethane (10 mL) the mixture was stirred at room temperature for 1.5 hours, water (20 mL) was added and extracted with dichloromethane (10 mL×3), combined and concentrated the organic layers, the residue was purified by column chromatography (silica gel, dichloromethane/Methanol=50:1) to give N-(3-(4-bromophenyl)butyl)acetamide (0.66 g, 94.4%). LRMS (M+H+) m/z: calcd for 270.17. found 270.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2C=[CH:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].C1C(=O)N([Cl:30])C(=O)C1.[C:31]([Cl:35])(Cl)(Cl)Cl>C(OOC(C1C=CC=CC=1)=O)(C1C=CC=CC=1)=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:31]([Cl:35])=[CH:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]2=[C:10]([Cl:30])[N:11]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1ncc2c(ccn2Cc2ccccc2)c1O
Reactant: ClC(Cl)(Cl)Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: CCOC(=O)c1nc(Cl)c2c(c(Cl)cn2Cc2ccccc2)c1O

Procedure:
A mixture of 1-benzyl-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (60 mg, 0.202 mmol), NCS (57 mg, 0.424 mmol), and BzOOBz (2.4 mg, 0.01 mmol) in carbontetrachloride was refluxed for 1 hour. Then the reaction was cooled, solvent was removed, and the resulting residue was purified on column to give the title compound (48 mg). The title compound: ESI MS (m/z): 410 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH3:25][N:26]([CH3:32])[CH:27]1[CH2:31][CH2:30][NH:29][CH2:28]1>C(OCC)(=O)C.CO>[CH3:25][N:26]([CH3:32])[CH:27]1[CH2:31][CH2:30][N:29]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]3[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:28]1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1C(=O)C(F)(F)F
Reactant: CN(C)C1CCNC1
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1nc2ccc(N3CCC(N(C)C)C3)cc2c(-c2ccccc2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 37 %

Procedure:
The title compound was prepared from 1-(6-Bromo-2-methyl-4-phenyl-quinolin-3-yl)-2,2,2-trifluoro-ethanone [example 3] and 3-(dimethylamino)pyrrolidine according to the procedure of example 25, except that the reaction time was of 16 h and that ethyl acetate/methanol (9:1) was used. Yield: 37%; MS: m/z=428 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][CH3:22])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:23]#[C:24][CH2:25][CH2:26][CH3:27].Cl>CCN(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:23]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][CH3:22])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)#[C:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCC1CCC(C2CCC(c3ccc(Br)cc3)CC2)CC1
Reactant: C#CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCN(CC)CC
Product: CCCC#Cc1ccc(C2CCC(C3CCC(CCC)CC3)CC2)cc1
Temperature: 0 °C

Procedure:
8.0 g (22.0 mmol) of 4′-(4-bromophenyl)-4-propylbicyclohexyl are stirred at 60° C. for 60 h in 80 ml of NEt3 together with 4.4 ml (44.0 mmol) of 1-pentyne in the presence of 309 mg (0.44 mmol) of bis(triphenylphosphine)palladium(II) chloride and 42 mg (0.22 mmol) of copper(I) iodide. The batch is added to ice-water and acidified using hydrochloric acid. The mixture is extracted with MTBE, and the combined organic phases are washed with water and sat. sodium chloride solution. The solution is concentrated to completion, and the crude product is purified by column chromatography (SiO2, n-heptane). The further purification is carried out by recrystallisation from n-heptane (−20° C.). This gives 4′-(4-pent-1-ynylphenyl)-4-propylbicyclohexyl as a colourless solid (m.p. 47° C.).
Reaction SMILES: [Na].[C:2]1([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][C:12](=[O:17])[C:11]=3[CH:10]=[N:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:18](OCC)=[O:19].C(O)C>C1(C)C=CC=CC=1.O>[O:17]=[C:12]1[CH:13]([CH:18]=[O:19])[CH2:14][CH2:15][C:16]2[N:8]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[N:9]=[CH:10][C:11]1=2
Reactant: O=C1CCCc2c1cnn2-c1ccccc1
Reactant: CCOC=O
Agent: [Na]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=CC1CCc2c(cnn2-c2ccccc2)C1=O
Reaction time: 0.5 h
Yield: 3.7 %

Procedure:
To a stirred suspension of sodium (0.75 g, 33 mmol) in toluene (200 mL) was added 1-phenyl-6,7-dihydro-1H-indazol-4(5H)-one (2.6 g, 123 mmol). The reaction mixture was stirred for 30 minutes and a solution of ethyl formate (2.22 mL, 276 mmol) in toluene (10 mL) was added over 10 minutes followed by absolute ethanol (1 mL). The reaction was stirred at room temperature for 40 hours. The reaction mixture was cautiously poured into ice-cooled water (100 mL). The organic layer was separated. The aqueous layer was extracted with diethylether (100 mL) and acidified with 6N HCl to a pH between 5 and 6. The aqueous layer was then extracted with dichloromethane (3×75 mL). The combined organic layer was dried using sodium sulfate and concentrated under reduced pressure to give a residue which on trituration with hexane gave the desired product (1.1 g, 32%) as a solid. 1H NMR (CDCl3, 400 MHz): δ 10.75 (s, 1H), 8.00 (s, 1H), 7.61-7.54 (m, 5H), 7.48-7.45 (m, 1H), 3.00-2.96 (m, 2H), 2.76-2.70 (m, 2H); LCMS [M+H]: 241.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][O-].[Na+].[C:13]([OH:16])(=[O:15])C>COC(=O)OC>[CH3:10][O:16][C:13](=[O:15])[NH:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: CC(=O)O
Reactant: C[O-]
Reactant: Cc1cc(C)nc(N)n1
Agent: [Na+]
Solvent: COC(=O)OC
Product: COC(=O)Nc1nc(C)cc(C)n1

Procedure:
To 2-Amino-4,6-dimethylpyrimidine (10 g) dissolved in dimethylcarbonate (80 ml) was added sodium methoxide (4.4 g) and the mixture refluxed for four hours. The mixture was cooled and acetic acid (5 ml) was added. The mixture was then partitioned between water (100 ml) and methylene chloride (300 ml). A second methylene chloride extraction of the aqueous phase was made and the combined methylene chloride phase washed with water (50 ml) containing NH4Cl. The solvent was evaporated and the residue triturated with a methylene chloride/1-chlorobutane mixture. The filtrate, on concentration and addition of hexane gave 6.7 g of the pure carbamate, m.p. 80°-85° C. IR: NH at 3200; carbonyl at 1745 cm-1. NMR: 2.4 ppm, 2×CH3, singlet; ArH 6.75 ppm 1H, singlet 8.9 ppm, NH, broad.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[S:15][CH:14]=[N:13][C:12]=3[CH:11]=[C:10](C)[C:9]=2C=C)=[CH:4][CH:3]=1.S([O-])([O-])=[O:21].[Na+].[Na+].[C:26]([OH:30])(C)([CH3:28])[CH3:27]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[S:15][CH:14]=[N:13][C:12]=3[CH:11]=[C:10]([CH3:9])[C:27]=2[C@H:26]([OH:30])[CH2:28][OH:21])=[CH:4][CH:3]=1
Reactant: O=S([O-])[O-]
Reactant: C=Cc1c(C)cc2ncsc2c1-c1ccc(Cl)cc1
Reactant: CC(C)(C)O
Agent: [Na+]
Solvent: O
Product: Cc1cc2ncsc2c(-c2ccc(Cl)cc2)c1[C@H](O)CO
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A biphasic mixture of AD mix-α (1.5 g) in tert-butanol (5 mL)/H2O (5 mL) was cooled to 0° C. and 7-(4-chlorophenyl)-5-methyl-6-vinylbenzo[d]thiazole (5G) (0.050 g, 0.175 mmol) was added. Reaction mixture was stirred overnight at 0° C. Sodium sulfite (1.5 g) was added at 0° C., then warmed to room temperature and stirred for 30 min to give a white mixture. Mixture was diluted with ethyl ecetate and H2O. Extracted with ethyl ecetate (3×) and combined organic layer was dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give the product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[S:16]([CH3:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]([N-]C(C)C)(C)C.[Li+].CI.CO>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[S:16]([CH2:18][CH3:19])=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)c1cc(O)ccc1OCc1ccccc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CI
Product: CCS(=O)c1cc(O)ccc1OCc1ccccc1
Reaction time: 0.25 h

Procedure:
A solution of 0.4 g of 4-benzyloxy-3-methylsulfinylphenol pmb (1.05 mmol) in 40 ml of tetrahydrofuran is cooled to −50° C. and 0.784 ml of a dimolar solution of lithium diisopropylamide (1.57 mmol) in tetrahydrofuran is then added. The reaction mixture is stirred for 15 minutes and 0.13 ml of methyl iodide (1.1 mmol) is added. After stirring for 15 minutes, methanol is added and the solvents are evaporated off under reduced pressure. The 4-benzyloxy-3-ethylsulfinylphenol pmb is obtained in the form of a white solid (0.3 g, 72%) after purification on silica gel (40 g SiO2, eluent: 4/1 heptane/ethyl acetate)
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:10]=[N:11][N:12]([CH:14]([O:16][CH2:17][CH3:18])[CH3:15])[CH:13]=2)[C:5]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=2)=[C:4]([C:27](=O)[CH3:28])[CH:3]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:36].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:10]=[N:11][N:12]([CH:14]([O:16][CH2:17][CH3:18])[CH3:15])[CH:13]=2)[C:5]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=2)=[C:4]([CH:27]([NH2:36])[CH3:28])[CH:3]=1
Reactant: [BH3-]C#N
Reactant: CCOC(C)n1cc(-c2c(C)c(Cl)cc(C(C)=O)c2-c2cc(F)cc(F)c2)cn1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Solvent: C1CCOC1
Product: CCOC(C)n1cc(-c2c(C)c(Cl)cc(C(C)N)c2-c2cc(F)cc(F)c2)cn1
Temperature: 25 °C

Procedure:
A mixture of 1-[4-chloro-6-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]-3′,5′-difluoro-5-methylbiphenyl-2-yl]ethanone (0.094 g, 0.22 mmol), ammonium acetate (0.17 g, 2.2 mmol) and 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.56 mL, 0.56 mmol) in methanol (0.6 mL) and acetonitrile (0.6 mL) was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic layers were dried over MgSO4, filtered and concentrated to give the desired product. LCMS calculated for C22H25ClF2N3O (M+H)+: m/z=420.2. found: 420.1.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[F:12].[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.[BH4-].[Na+]>C(O)C>[F:12][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[NH:1][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([F:13])=[CH:15][CH:16]=1)[NH:8][C:7](=[O:11])[CH2:6]2
Reactant: Nc1cc2c(cc1F)CC(=O)N2
Reactant: O=Cc1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C1Cc2cc(F)c(NCc3ccc(F)cc3)cc2N1
Temperature: 25 °C
Yield: 44.8 %

Procedure:
6-Amino-5-fluoro-1,3-dihydro-indol-2-one 3d (2.26 g, 13.6 mmol) was dissolved in 40 ml of ethanol under stirring at room temperature, the resulting solution was cooled down to 0° C. in an ice-water bath, and added with 4-fluoro-benzaldehyde (1.5 ml, 13.6 mmol) to the solution. Upon completion of the addition, the resulting solution was stirred for 1 hour at room temperature, added with sodium borohydride (1.08 g, 28.5 mmol) and heated to reflux for 18 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled down to room temperature, added with ice water and lots of precipitates were formed, filtered and washed with water (50 ml×3). The residue was purified by silica gel column chromatography to obtain the title compound 5-fluoro-6-(4-fluoro-benzylamino)-1,3-dihydro-indol-2-one 3e (1.67 g, yield 45%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.C(O[CH:18]=[C:19]([C:22]#[N:23])[C:20]#[N:21])C>C(O)C>[C:20]([C:19]([C:22]#[N:23])=[CH:18][NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)#[N:21]
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1
Reactant: CCOC=C(C#N)C#N
Solvent: CCO
Product: N#CC(C#N)=CNc1ccc(C2=NNC(=O)CC2)cc1

Procedure:
A solution containing 0.38 g of 6-(4-aminophenyl)-4,5-dihydropyridazin-3(2H)one and 0.3 g of ethoxymethylenemalononitrile in 5 ml of ethanol was refluxed for 1 h. Yield 0.25 g, mp 290°-295° C.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@:4]3([O:22][C@H:5]3[CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1.[OH:23][C@H]1CC[C@@]2(C)[C@@]3(O[C@@H]3C[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CCC2=O)C1.CC(O)C>CC(C)=O.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>[OH:22][C@:4]12[CH2:3][C:2](=[O:1])[CH2:19][CH2:18][C@:17]1([CH3:20])[C@@H:16]1[C@H:7]([C@H:8]3[C@@:12]([CH2:14][CH2:15]1)([CH3:13])[C:11](=[O:21])[CH2:10][CH2:9]3)[CH2:6][C:5]2=[O:23]
Reactant: C[C@]12CC[C@H]3[C@@H](C[C@H]4O[C@]45C[C@@H](O)CC[C@]35C)[C@@H]1CCC2=O
Reactant: C[C@]12CC[C@H]3[C@@H](C[C@@H]4O[C@@]45C[C@@H](O)CC[C@]35C)[C@@H]1CCC2=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: CC(C)O
Product: C[C@]12CC[C@H]3[C@@H](CC(=O)[C@@]4(O)CC(=O)CC[C@]34C)[C@@H]1CCC2=O
Yield: 75 %

Procedure:
To a solution of a 1/1 mixture of 3β-hydroxy-5α,6α-epoxyandrostan-17-one and 3β-hydroxy-5β,6β-epoxyandrostane-17-one (2.10 g, 6.90 mmol) in acetone (38 mL), Jones reagent (8.35 mL) was added dropwise, maintaining the temperature below 40° C. 5 min after completion of the addition, i-PrOH (10 mL) was added and, after further 10 min, the suspension was filtered and the filtrate evaporated to dryness. The residue was treated with H2O (300 mL) and extracted with EtOAc (3×100 mL). The combined organic extracts were washed with H2O (100 mL), 5% aqueous NaHCO3 solution (100 mL), H2O (100 mL), dried over Na2SO4 and evaporated to dryness to give 5α-hydroxyandrostane-3,6,17-trione as a white solid (1.65 g, 75%). 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 5.00 (s, 1H), 2.85 (m, 2H), 2.45-1.25 (m, 17H), 1.06 (s, 3H), 0.88 (s, 3H).