Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Cl)#[N:2].[OH-].[Na+].ClCl.CO>CN(C)C=O>[C:4]1([CH:5]=[CH:5][C:4]2[C:3]([C:1]#[N:2])=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([C:1]#[N:2])=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N#Cc1ccccc1CCl
Agent: ClCl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: N#Cc1ccccc1C=Cc1ccccc1C#N
Temperature: 20 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
30.4 g (0.2 mole) of o-cyanobenzyl chloride are dissolved in 70 g of dimethylformamide, and 24 g (0.6 mole) of sodium hydroxide powder are added at the same time as nitrogen is passed in. The mixture is stirred at 20° C. for about 6-10 hours until all the organically bound chlorine has reacted, 70 g of methanol are added dropwise, and the precipitate is filtered off with suction at 0° C. and is washed with methanol and then with water until no chlorine ions are detectable in the water from the wash. Drying gives 17.8 g of stilbene-2,2'-dicarbonitrile in the form of white crystals.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][C:4]#[CH:5].Cl[Si](C)(C)C.Br[C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1/[C:15](=[CH:23]/[C:24]1[NH:25][CH:26]=[CH:27][C:28]=1[O:29][CH3:30])/[C:16](=[O:22])[NH:17]2>CN(C=O)C.C(N(CC)CC)C>[OH:6][CH2:1][CH2:2][CH2:3][C:4]#[C:5][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1/[C:15](=[CH:23]/[C:24]1[NH:25][CH:26]=[CH:27][C:28]=1[O:29][CH3:30])/[C:16](=[O:22])[NH:17]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: C#CCCCO
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCCCO)c21
Temperature: 70 °C

Procedure:
Using Method I above, 4-pentyn-1-ol (40 mg, 0.57 mmol) (Aldrich) was dissolved, under argon, in 3 mL DMF and 2 mL triethylamine, and to this solution was added chlorotrimethylsilane (0.13 mL, 1 mmol) (Aldrich). The reaction was stirred at room temperature for 1 h, at which time (Z)-4-bromo-1,3-dihydro-3-1(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (110 mg, 0.38 mmol) (Starting Material 1 supra) was added and the solution was degassed for 15 min by bubbling argon through the solution. (Ph3P)2PdCl2 (15 mg) (Aldrich) and Cul (7 mg) (Aldrich) were added and the reaction was heated at 70° C. for 14 h. The reaction mixture was then poured into 25 mL 1 N HCl and the yellow precipitate was filtered off. The product was purified via flash column chromatography to obtain (Z)-1,3-dihydro-4-(5-hydroxy-1-pentynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one as a yellow powder. (Yield 55 mg, 45%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:27][OH:28].C([O-])(O)=O.[Na+].[Cl-].[NH4+]>C(O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9]/[C:10](/[C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[N:27]\[OH:28])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1C(CC(=O)c1ccc(O)cc1)c1ccc(Br)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(O)cc1)c1ccc(Br)cc1
Temperature: 25 °C

Procedure:
A suspension of 3-(4-bromo-phenyl)-1-(4-hydroxy-phenyl)-3-o-tolyl-propan-1-one (16 mg), hydroxylamine hydrochloride (7 mg) and NaHCO3 (6.8 mg) in ethanol (0.455 ml) and water (0.016 ml) was heated to reflux for 2.5 h. After cooling to room temperature, a saturated aqueous solution of ammonium chloride was added and the mixture was extracted with dichloromethane. The organic phase was washed with brine, dried using MgSO4, filtered and concentrated to dryness. The product was purified by preparative TLC (SiO2, dichloromethane/methanol 9:1) to give the title compound containing less than 10% of the corresponding Z isomer (13 mg) as an off-white foam, MS (ESI+): m/z=408.1 [M−H]−.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:16]=[C:15]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[S:14][C:9]=3[N:10]=[C:11]([NH2:13])[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:23][O:24][C:25]1[CH:34]=[CH:33][C:28]([CH2:29][N:30]=[C:31]=[O:32])=[CH:27][CH:26]=1>>[NH2:13][C:11]1[N:12]=[C:7]([N:1]2[CH2:6][CH2:5][N:4]([C:31]([NH:30][CH2:29][C:28]3[CH:33]=[CH:34][C:25]([O:24][CH3:23])=[CH:26][CH:27]=3)=[O:32])[CH2:3][CH2:2]2)[C:8]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[S:14][C:9]=2[N:10]=1
Reactant: Nc1nc(N2CCNCC2)c2nc(-c3cccnc3)sc2n1
Reactant: COc1ccc(CN=C=O)cc1
Product: COc1ccc(CNC(=O)N2CCN(c3nc(N)nc4sc(-c5cccnc5)nc34)CC2)cc1
Yield: 40 %

Procedure:
This compound was prepared from 7-(piperazin-1-yl)-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-5-amine using 4-methoxybenzyl isocyanate in a yield of 40%, according to the procedure for the synthesis of example 42.
Reaction SMILES: [Cl:1][C:2]([Cl:17])([C:13]([F:16])([F:15])[F:14])[CH2:3][CH:4]1[CH:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]1([CH3:12])[CH3:11]>ClCCl>[Cl:1][C:2]([Cl:17])([C:13]([F:14])([F:16])[F:15])[CH2:3][C@@H:4]1[C@H:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]1([CH3:12])[CH3:11]
Reactant: COC(=O)C1C(CC(Cl)(Cl)C(F)(F)F)C1(C)C
Solvent: ClCCl
Product: COC(=O)[C@H]1[C@@H](CC(Cl)(Cl)C(F)(F)F)C1(C)C

Procedure:
Polarimetry of the methyl 3-(2,2-dichloro-3,3,3-trifluoropropyl)-2,2-dimethyl-cyclopropane carboxylate in dichloromethane (5.84 gm/liter at 20° C.) gave an ∝D=+10.3°.
Reaction SMILES: [CH2:1]([CH:6]([CH2:9][OH:10])[CH2:7][OH:8])[CH2:2][CH2:3][CH2:4][CH3:5].[C:11]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)([OH:13])=[O:12].C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH2:1]([CH:6]1[CH2:9][O:10][CH:18]([C:17]2[CH:20]=[CH:21][C:14]([C:11]([OH:13])=[O:12])=[CH:15][CH:16]=2)[O:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC(CO)CO
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCCCCC1COC(c2ccc(C(=O)O)cc2)OC1
Yield: 80.9 %

Procedure:
A mixture of 2-n-pentylpropane-1, 3-diol (8 g, 0.054 m), 4-carboxybenzaldehyde (8 g, 0.053 m), benzene (200 ml) and a catalytic amount of 4-toluenesulfonic acid was azeotropically refluxed until no more water was collected. The cold reaction mixture was washed with saturated NaHCO3 solution and water and then dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was crystallized from ethanol to yield 4-(5-n-pentyl-1, 3-dioxan-2-yl) benzoic acid (12 g, 80%)
Reaction SMILES: Br[C:2]1[C:6]([N+:7]([O-])=O)=[C:5]([NH:10][CH3:11])[N:4]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:3]=1.S(=O)(=O)(O)O>>[NH2:7][C:6]1[CH:2]=[N:3][N:4]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:5]=1[NH:10][CH3:11]
Reactant: CNc1c([N+](=O)[O-])c(Br)nn1Cc1ccc(OC)cc1
Agent: O=S(=O)(O)O
Product: CNc1c(N)cnn1Cc1ccc(OC)cc1
Yield: 87 %

Procedure:
1.04 g (3.00) mmoles) of 3-bromo-1 -(4'-methoxybenzyl)-5-methylamino-4-nitropyrazole are hydrogenated for 2 hours according to General Directions A. 0.30 g (2.80 mmoles) of concentrated sulfuric acid (97%) are added. After reduction, 0.86 g (87 percent of theory) of 4-amino-1-(4'-methoxybenzyl)-5-methylaminopyrazole hydrosulfate are obtained in the form of an oil.
Reaction SMILES: [C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O-:6])=[O:5].[NH4+:9].[NH4+].P([O-])(O)(O)=O.[K+].O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Mg+2]>>[NH2:9][C@H:2]([C:1]([OH:8])=[O:7])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: O=C([O-])/C=C/C(=O)[O-]
Reactant: [NH4+]
Agent: O=P([O-])(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: O
Product: N[C@@H](CC(=O)O)C(=O)O
Temperature: 37 °C
Reaction time: 24 h

Procedure:
Escherichia coli TA 5004 was inoculated into a medium (500 ml, pH 7.0) containing ammonium fumarate (3%), potassium dihydrogen phosphate (0.2%), magnesium sulfate heptahydrate (0.05%), corn steep liquor (4%) and yeast extract (2%) and incubated with shaking at 37° C. for 24 hours. The resulting culture was adjusted to pH 8.5 with aqueous ammonia. Ammonium fumarate (65 g) and Triton X-100 (500 mg) were added to the culture and incubation was further continued at 37° C. for 6 hours to conduct the enzymatic reaction. The reaction mixture was filtered, concentrated and adjusted to pH 2.8 to precipitate crude crystals of L-aspartic acid. The crude crystals were filtered off and recrystallized from water to give L-aspartic acid (47.0 g).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:9]=[CH:8][NH:7][C:6](=[O:10])[C:5]=2[N:11]=1.[I:12]N1C(=O)CCC1=O>C(#N)C>[I:12][C:9]1[C:4]2[S:3][C:2]([CH3:1])=[N:11][C:5]=2[C:6](=[O:10])[NH:7][CH:8]=1
Reactant: Cc1nc2c(=O)[nH]ccc2s1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: Cc1nc2c(=O)[nH]cc(I)c2s1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
2-Methyl-5H-thiazolo[4,5-c]pyridin-4-one (770 mg, 4.6 mmol) was suspended in 25 ml acetonitrile and N-iodosuccinimide (1.04 g, 4.6 mmol) was added. The reaction mixture was refluxed for 3 hrs. The brown suspension was cooled to 5° C. and stirred for 15 min. The solid was filtered, washed with cold acetonitrile and dried for 1 hour at 50° C. and <30 mbar. The crude product (830 mg, 61%) [MS: m/e=292.9 (M+H+)] was used without any further purification for the next step.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:4](=[O:24])[C:5]2[N:6]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:7]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[N:8][C:9]=2[N:10]=1.CN1CCCC1.C(=O)([O-])[O-].[K+].[K+].[CH3:41][C:42]1[C:47]([OH:48])=[CH:46][CH:45]=[CH:44][N:43]=1>O>[CH:11]1([C:7]2[N:6]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:5]3[C:4](=[O:24])[N:3]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:2]([O:48][C:47]4[C:42]([CH3:41])=[N:43][CH:44]=[CH:45][CH:46]=4)=[N:10][C:9]=3[N:8]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(C)Cn1c(Cl)nc2nc(C3CCCC3)n(COCC[Si](C)(C)C)c2c1=O
Reactant: Cc1ncccc1O
Agent: CN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1ncccc1Oc1nc2nc(C3CCCC3)n(COCC[Si](C)(C)C)c2c(=O)n1CC(C)C
Temperature: 87.5 °C
Yield: 85.3 %

Procedure:
A mixture of 2-chloro-8-cyclopentyl-1-isobutyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (0.11 g, 0.259 mmol), N-methylpyrrolidine (1 ml), potassium carbonate (0.11 g, 0.778 mmol) and 2-methyl 3-hydroxy pyridine (0.034 g, 0.31 mmol), was heated at 85-90° C. overnight. Reaction mixture was cooled room temperature, diluted with water (10 ml), extracted with ethyl acetate. The ethyl acetate layer was washed with brine and water, dried over sodium sulphate, filtered and concentrated to obtain 8-cyclopentyl-1-isobutyl-2-(2-methyl-pyridin-3-yloxy)-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (0.11 g, 75%) as crude oil.
Reaction SMILES: [CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([C:23]3[N:27]([CH3:28])[CH:26]=[N:25][CH:24]=3)([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[OH:16])[CH:13]=2)[N:8]=[C:7](Cl)[C:6]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:2][CH2:3][CH3:4].[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37].O(C(C)C)[Na]>CC(O)C>[CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([C:23]3[N:27]([CH3:28])[CH:26]=[N:25][CH:24]=3)([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[OH:16])[CH:13]=2)[N:8]=[CH:7][C:6]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:2][CH2:3][CH3:4].[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]
Reactant: CCCCc1c(-c2ccccc2)c(Cl)nc2ccc(C(O)(c3ccncc3)c3cncn3C)cc12
Agent: CC(C)O[Na]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: CCCCc1c(-c2ccccc2)cnc2ccc(C(O)(c3ccncc3)c3cncn3C)cc12
Temperature: 80 °C

Procedure:
A mixture of (4-butyl-2-chloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)pyridin-4-ylmethanol•TFA (16 mg, 0.023 mmol, Example 78) and NaOiPr (19 mg, 0.23 mmol) in iPrOH (0.4 mL) was heated in a sealed tube at 80° C. for 17 hours, and more NaOiPr (7 mg, 0.085 mmol) was added. The mixture was heated for 64 hours and purified by reverse phase HPLC (water/acetonitrile/0.1% TFA) to provide the title compound. 1H NMR (400 MHz, MeOH-d4) δ 9.08 (s, 1H), 8.90 (s, 1H), 8.77 (d, J=6.57 Hz, 3H), 8.29 (d, J=2.02 Hz, 1H), 8.24 (d, J=8.59 Hz, 1H), 8.03 (dd, J=2.02, 9.09 Hz, 1H), 7.83 (d, J=6.57 Hz, 2H), 7.53-7.58 (m, 2H), 7.43 (d, J=6.06 Hz, 2H), 7.18 (s, 1H), 3.72 (s, 3H), 3.06-3.12 (m, 2H), 1.45-1.55 (m, 2H), 1.19-1.28 (m, 2H), 0.78 (t, J=7.33 Hz, 3H); MS m/e 449.2 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[CH:8][C:9]3[N:10]([C:12]([CH2:15][C:16]4[CH:17]=[C:18]5[C:23](=[CH:24][CH:25]=4)[N:22]=[CH:21][CH:20]=[CH:19]5)=[N:13][N:14]=3)[N:11]=2)[CH:3]=[N:2]1.C([O-])([O-])=O.[K+].[K+].[CH3:32][O:33][CH2:34][CH2:35]Br>CCO>[CH3:32][O:33][CH2:34][CH2:35][N:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[CH:8][C:9]3[N:10]([C:12]([CH2:15][C:16]4[CH:17]=[C:18]5[C:23](=[CH:24][CH:25]=4)[N:22]=[CH:21][CH:20]=[CH:19]5)=[N:13][N:14]=3)[N:11]=2)[CH:3]=[N:2]1
Reactant: c1cnc2ccc(Cc3nnc4ccc(-c5cn[nH]c5)nn34)cc2c1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COCCn1cc(-c2ccc3nnc(Cc4ccc5ncccc5c4)n3n2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
To a solution of 6-[6-(1H-Pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl]-quinoline as prepared in Example 3 (19 mg, 0.06 mmol) and K2CO3 (12 mg, 0.09 mmol) in EtOH (2 mL) was added 2-bromoethyl methyl ether (8 μL, 0.09 mmol). The reaction was stirred at rt overnight. The reaction was concentrated in vacuo followed by purification by HPLC (5-65% CH3CN over 35 min) resulting in the title compound (2.8 mg, 15%) as a clear glass. 1H-NMR (CD3OD): δ 9.05-9.03 (1H, dd, J=3.7, 5.3 Hz), 9.02-8.99 (1H, d, J=7.8 Hz), 8.32 (1H, s), 8.27 (1H, s), 8.18-8.08 (4H, m), 7.95-7.91 (1H, q, J=3.0, 5.5 Hz), 7.66-7.63 (1H, d, J=9.8 Hz), 4.84 (2H, s), 4.30-4.28 (2H, t, 4.8 Hz), 3.70-3.76 (2H, t, J=5.3 Hz), 3.23 (2H, br s). ESI-MS (m/z): Calcd. For C21H19N7O: 385.17; found: 386.2 (M+H).
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.C([Li])CCC.CCCCCC.[CH3:21][N:22](C=O)[CH3:23]>C1COCC1>[CH3:21][NH:22][CH2:23][C:2]1[S:1][C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=1
Reactant: CN(C)C=O
Reactant: c1cc2sccc2cn1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CNCc1cc2cnccc2s1
Reaction time: 0.08 h
Yield: 41.5 %

Procedure:
A solution of thieno[3,2-c]pyridine (500 mg, 3.70 mmol) in anhydrous THF (10 mL) was stirred under argon and maintained at −78° C. while a solution of 1.6 M n-butyllithium in hexane (2.5 mL, 4.07 mmol) was added dropwise. The resulting wine red solution was stirred for 5 min. then DMF (573 μL, 7.4 mmol) was added. The cooling bath was removed and the reaction mixture was stirred at room temperature for 16 hr. The reaction mixture was treated with 10% aqueous HCl, made alkaline with saturated aqueous NaHCO3 and extracted with CH2Cl2 (2×50 mL) The combined organic fractions were concentrated in vacuo to give an oily residue which was subjected to flash chromatography on silica gel (70% ethyl acetate:hexanes) to give the title compound as a white solid (41.5%): 1H-NMR (300 MHz, DMSO-d6) δ 10.20 (s, 1H), 9.39 (s, 1H), 8.60 (s, 1H), 8.59 (d, J=5.5 Hz, 1H), 8.19 (d, J=5.6 Hz, 1H); MS (ES) m/e 164 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:22]2[C@@H:21]3[C@H:8]([C@H:9]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:12]3([CH:16]=[CH:15][CH2:14][O:13]3)[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.B.[OH-:26].[Na+].OO.Cl>O.O1CCCC1>[CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:22]2[C@@H:21]3[C@H:8]([C@H:9]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:12]3([CH2:16][CH:15]([OH:26])[CH2:14][O:13]3)[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: [OH-]
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CCC21C=CCO1
Agent: B
Agent: Cl
Agent: OO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CCC21CC(O)CO1
Temperature: 0 °C

Procedure:
To a solution of 116 parts of 3-methoxyspiro[estra-1,3,5(10)-triene-17,2'(5'H)-furan] in 1100 parts of tetrahydrofuran at 5°-10° under nitrogen is added, with stirring, a solution of approximately 5 parts of borane in 325 parts of tetrahydrofuran. Stirring at 5°-10° is continued for 21/4 hours, whereupon a solution of 26 parts of sodium hydroxide in 213 parts of water followed -- cautiously -- by 131 parts of 30% hydrogen peroxide is mixed in. The resultant mixture is acidified with 20% hydrochloric acid and then poured into 7000 parts of ice water. The precipitate which forms is isolated by filtration, washed with water, dried in air, and taken up in benzene. The benzene solution is chromatographed on silica gel, using benzene and mixtures thereof with increasing amounts of ethyl acetate as developing solvents. From an eluate comprising 10% ethyl acetate in benzene, on evaporation of solvent and recrystallization of the residue from ethyl acetate, 4' ,5'-dihydro-3-methoxyspiro[estra-1,3,5(10)-triene-17,2'(3'H)-furan]-4'-ol melting at 95°-97° is obtained.
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH2:5][CH:6]=[CH2:7])[CH:3]=[O:4].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][C:2]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH2:5][CH:6]=[CH2:7])[CH2:3][OH:4]
Reactant: C=CCC(C)(C=O)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC(C)(CO)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.8 %

Procedure:
To a solution of 2-methyl-2-phenylpent-4-enal (4.6 g, 26.4 mmol) in 100 mL of THF was added of lithium aluminum hydride (LAH) (2.6 g, 68.51 mmol) in several portions. The mixture stirred for 3 hours at room temperature and was then refluxed for 2 hours. The reaction was monitored by TLC with ethyl acetate-hexanes (1:9) indicating a new more polar product. The reaction was cooled and the excess LAH was cautiously quenched with water dropwise. The mixture was then diluted with 1N aqueous HCl and extracted with 100 mL of hexanes and two 100 mL portions of ethyl acetate. The combined organic layers were washed with 50 mL of 1 N aqueous HCl, two 50 mL portions of brine, two 50 mL portions of saturated aqueous sodium bicarbonate, 50 mL of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was chromatographed on silica gel using hexanes to load the sample and then eluting with 1% to 15% ethyl acetate-hexanes to afford 3.2 g (68.8) of 2-methyl-2-phenylpent-4-en-1-ol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[Mg].II.[CH2:13]([N:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1)[CH2:14][CH3:15]>C(OCC)C>[CH3:9][S:8][C:4]1[CH:3]=[C:2]([C:19]2([OH:22])[CH2:20][CH2:21][N:16]([CH2:13][CH2:14][CH3:15])[CH2:17][CH2:18]2)[CH:7]=[CH:6][CH:5]=1
Reactant: CSc1cccc(Br)c1
Reactant: CCCN1CCC(=O)CC1
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: CCCN1CCC(O)(c2cccc(SC)c2)CC1
Temperature: 25 °C

Procedure:
3-Bromothioanisole (960 mg, 4.73 mmol) was dissolved in 10 mL of diethyl ether dried on Na. 1-Propyl-4-piperidone was dissolved in 8 mL of dry diethyl ether. Approximately 10% of the solution of 3-bromothioanisole in dry diethyl ether was added to magnesium (344 mg, 14.15 mmol) and a few iodine crystals in a dried 250 mL three-necked flask in a nitrogen atmosphere. When the brown mixture turned colourless, the remaining solution of 3-bromothioanisole in dry diethyl ether was added drop wise, while refluxing on a hot water bath in a nitrogen atmosphere. When all the solution was added, the reaction mixture was left to reflux for twenty minutes. Then, 10 mL of dry diethyl ether was added because of evaporation. It was left to reflux for 30 minutes. The reaction mixture turned yellow and then green. Gas forming was noticed even before refluxing. Then the reaction mixture was left to cool to room temperature. The solution of 1-propyl-4-piperidone in dry diethyl ether was added drop wise to the reaction mixture. The reaction mixture then consisted of a dark oil, white precipitation and some clear solution. The reaction mixture was worked up with saturated NH4Cl solution (30 mL). The organic layer was separated. The aqueous layer was extracted twice with diethyl ether. The organic layers were collected and washed with brine and dried on MgSO4 during the night. The solution was filtered and the solvent evaporated in vacuo on a rotavapor. No further purification. Yield: 460 mg (56%). IR (KBr): 3113, 2956, 2917, 2828, 2772, 2365, 1583, 1444, 1375, 1148, 1104, 1044, 780, 696 cm−1; 1H-NMR (CDCl3, 300 MHz): δ 7.280 (d), 7.159 (m), 2.820 (d), 2.484 (s), 2.433 (t), 2.195 (t), 1.761 (d), 1.588 (t), 0.924 (t) ppm; 13C-NMR (CDCl3, 300 MHz): δ 127.291, 123.521, 121.359, 119.865, 69.826, 59.311, 47.947, 36.864, 18.573, 14.310, 10.524 ppm; GCMS (EI): m/z 265 (M+), 236 (M−29), 218, 206, 118; GC (100-320° C., 15° C./min): 7.6 min.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7](B(O)O)[N:8]2[CH3:11])=[CH:4][CH:3]=1.[C:15]([C:18]1[CH:19]=[C:20](Br)[CH:21]=[N:22][CH:23]=1)(=[O:17])[CH3:16]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:20]3[CH:19]=[C:18]([C:15](=[O:17])[CH3:16])[CH:23]=[N:22][CH:21]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1c(B(O)O)cc2ccc(Cl)cc21
Reactant: CC(=O)c1cncc(Br)c1
Product: CC(=O)c1cncc(-c2cc3ccc(Cl)cc3n2C)c1

Procedure:
6-Chloro-1-methyl-indole-2-boronic acid and 5-acetyl-3-bromo-pyridine are processed according to the method described in Example 100 to give 1-[5-(6-chloro-1-methyl-1H-indol-2-yl)-pyridin-3-yl]-ethanone. MS (ESI) m/z 284.98 (M+H)+.
Reaction SMILES: C(=N[OH:9])C1C=CC=CC=1.[H-].[Na+].[C:12]([C:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]#[C:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])([CH3:20])[C:15]([O:17]CC)=O)#[N:13]>CN(C=O)C.O1CCOCC1>[C:12]([C:14]1([CH3:20])[C:21]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:27]([OH:9])=[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:15]1=[O:17])#[N:13]
Reactant: CCOC(=O)C#Cc1ccccc1C(C)(C#N)C(=O)OCC
Reactant: ON=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(O)c2ccccc2C(C)(C#N)C1=O
Reaction time: 0.5 h

Procedure:
A solution of benzaldehyde oxime (0.37 mL, 3.7 mmol) in dry DMF (4 mL) was added to a stirred suspension of NaH (0.16 mL, 3.7 mmol) in dry dioxane (50 mL) in a nitrogen atmosphere at room temperature. After 30 minutes, a solution of ethyl 3-(2-(2-cyano-1-ethoxy-1-oxopropan-2-yl)phenyl)propiolate (1.12 g, 3.7 mmol) was added in dry DMF (5 mL), and the solution was stirred overnight. The solvent was removed under vacuum, and water was added to the residue. The product was extracted with EtOAc. The organic layer was washed with water, dried with MgSO4, concentrated in vacuo, and purified by silica flash chromatography eluting with 0-30% EtOAc/hexane. MS (m/z)=272 (M+H)+.