Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:31]([CH2:32]OCC[Si](C)(C)C)[C:18]4[CH:19]=[N:20][N:21](CC5C=CC=CC=5)[C:22](=[O:23])[C:17]=4[C:16]=3[OH:40])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1.C1(O[C:45]2[CH:46]=[C:47](C3N(COCC[Si](C)(C)C)C4C=NNC(=O)C=4C=3)[CH:48]=[CH:49][C:50]=2OC(F)F)CC1>O>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:31]([CH2:32][C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)[C:18]4[CH:19]=[N:20][NH:21][C:22](=[O:23])[C:17]=4[C:16]=3[OH:40])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OC3CC3)c2)c(O)c2c(=O)n(Cc3ccccc3)ncc21
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OC3CC3)c2)cc2c(=O)[nH]ncc21
Solvent: O
Product: O=c1[nH]ncc2c1c(O)c(-c1ccc(OC(F)F)c(OC3CC3)c1)n2Cc1ccccc1
Yield: 42 %

Procedure:
Reaction was carried out in the same manner as in Example 1-(b) except for using 51 mg (0.090 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-hydroxyphenylmethyl-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo-[2,3-d]pyridazin-4-one obtained in Example 20-(a) in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with a mixed solvent (chloroform:methanol=9:1 (V/V)). The organic layer after separating the liquids was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=9:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 17 mg of the title compound as a white solid. (Yield: 42%)
Reaction SMILES: C([O:3][C:4](=[O:35])[C:5]([CH3:34])([CH3:33])[CH2:6][C:7]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:14]2[C:9](=[N:10][C:11]([O:24][CH3:25])=[CH:12][CH:13]=2)[C:8]=1[C:26](=[O:32])[CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])C.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CC#N.CCOC(C)=O.O>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:15]2[C:14]3[C:9](=[N:10][C:11]([O:24][CH3:25])=[CH:12][CH:13]=3)[C:8]([C:26](=[O:32])[CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[C:7]2[CH2:6][C:5]([CH3:34])([CH3:33])[C:4]([OH:35])=[O:3])=[CH:18][CH:19]=1
Reactant: CCOC(=O)C(C)(C)Cc1c(C(=O)CC(C)(C)C)c2nc(OC)ccc2n1Cc1ccc(Cl)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: COc1ccc2c(n1)c(C(=O)CC(C)(C)C)c(CC(C)(C)C(=O)O)n2Cc1ccc(Cl)cc1
Temperature: 60 °C

Procedure:
3-[1-(4-Chloro-benzyl)-3-(3,3-dimethyl-butyryl)-5-methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl]-2,2-dimethyl-propionic acid ethyl ester (0.020 g, 0.04 mmol) was dissolved in MeCN (1 mL). 1N LiOH (0.16 mL, 0.16 mmol) was added and the reaction was heated to 60° C. overnight. Once no starting material was seen by LCMS, the reaction was cooled to room temperature and diluted with EtOAc and water. The mixture was neutralized with solid citric acid to ˜pH 5, the aqueous layer was extracted three times with EtOAc, the combined organics were washed twice with water, once with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by HPLC to give the desired acid. LCMS (ESI) M+H 471.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16](=[O:17])[C:15]2[C@@H:14]3[C:18]([CH3:20])([CH3:19])[C@@:11]([CH3:21])([CH2:12][CH2:13]3)[C:10]=2[NH:9]1.IC.O.[C:25](=O)(O)[O-].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16](=[O:17])[C:15]2[C@@H:14]3[C:18]([CH3:20])([CH3:19])[C@@:11]([CH3:21])([CH2:12][CH2:13]3)[C:10]=2[N:9]1[CH3:25]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccccc3F)c(=O)c12
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c2c(c(=O)n1-c1ccccc1F)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 98 °C
Reaction time: 5 h
Yield: 41 %

Procedure:
A mixture of a (4S,7R)-2-(2-fluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 12; 1.06 g, 3.7 mmol) and iodomethane (450 μL, 7.2 mmol) in N,N-dimethylformamide (20 mL) in a sealed tube was heated to 98° C. and stirred for 5 h. The reaction mixture was allowed to cool and water (20 mL) and saturated sodium bicarbonate solution (200 mL) were added. The solution was extracted with ethyl acetate (200 mL), and the organic layer was washed with brine (200 mL), dried (sodium sulfate), filtered, and evaporated. The residue was triturated with hexanes (4×5 mL) and the solid was recrystallized twice from ethyl acetate/hexanes to give (4S,7R)-2-(2-fluoro-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (451 mg, 41%) as white needles. ES(+)-MS (M+H) 301.
Reaction SMILES: [NH2:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[Cl:29][C:30]1[CH:34]=[CH:33][S:32][C:31]=1[C:35](Cl)=[O:36]>>[Cl:29][C:30]1[CH:34]=[CH:33][S:32][C:31]=1[C:35]([NH:1][C@H:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:12]=2)[CH2:7][CH2:6]1)=[O:36]
Reactant: O=C(Cl)c1sccc1Cl
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=O)c3sccc3Cl)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 3-chloro-2-thiophenecarbonyl chloride: ESMS m/e: 524.2 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].C1N2CN3CN(C2)C[N:14]1C3.C(Cl)[Cl:24]>>[ClH:24].[NH2:14][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:4]
Reactant: ClCCl
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: C1N2CN3CN1CN(C2)C3
Product: COc1ccc(C(=O)CN)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
45.82 g of α-bromo-p-methoxyacetophenone were dissolved in 400 ml of methylene chloride, and 28.04 g of hexamethylenetetramine were added to the solution, which was then stirred at room temperature for 2 hours. The crystals which precipitated were collected by filtration. 200 ml of ethanol and 100 ml of concentrated hydrochloric acid were added to these crystals, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then concentrated by evaporation under reduced pressure, and the residue was dissolved in water. The aqueous solution was made alkaline by the addition of a 20% w/v aqueous solution of potassium carbonate and was then extracted with ethyl acetate. The ethyl acetate extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. A 4N solution of hydrochloric acid in dioxane was then added. The crystals which precipitated were collected by filtration, to give to 30.7 g of the title compound as yellow fine crystals melting at 201° C. (with decomposition).
Reaction SMILES: N1([CH:10]([NH:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)[C:11]([CH3:14])([CH3:13])[CH3:12])C2C=CC=CC=2N=N1.ClC1C=CC(N)=CC=1.[C:33]([O-])([O-])=[O:34].[K+].[K+]>CO.C1COCC1>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([NH:15][CH:10]([O:34][CH3:33])[C:11]([CH3:14])([CH3:13])[CH3:12])=[O:24])=[CH:18][CH:19]=1
Reactant: CC(C)(C)C(NC(=O)c1ccc(Br)cc1)n1nnc2ccccc21
Reactant: O=C([O-])[O-]
Agent: Nc1ccc(Cl)cc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(NC(=O)c1ccc(Br)cc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of N-(1-(1H-benzo[d][1,2,3]triazol-1-yl)-2,2-dimethylpropyl)-4-bromobenzamide 120 as a white solid (2.38 mmol), 4-chloroaniline (0.64 g, 5.0 mmol), and K2CO3 (1 g, 7.23 mmol) in methanol (20 mL) and THF (2 mL) was stirred for 18 h at room temperature. The reaction was quenched with 2M HCl and extracted with ether. The organic solution was concentrated onto silica gel and chromatography (9:1 hexanes:ethyl acetate) and gave 4-bromo-N-(1-methoxy-2,2-dimethylpropyl)benzamide and the title product. The product was titrated with ether to give pure 4-bromo-N-(1-(4-chlorophenylamino)-2,2-dimethylpropyl)benzamide (Compound-38) (104 mg, 11%). 1H NMR (300 MHz, d6-DMSO): δ=8.34 (d, J=8.4 Hz, 1H), 7.76 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.4 Hz, 2H), 7.07 (d, J=8.7 Hz, 2H), 6.71 (J=8.7 Hz, 2H), 5.81 (d, J=6.6 Hz, 1H), 5.19 (t, J=3.9 Hz, 1H), 1.03 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C@@:11]23[CH2:24][CH2:23][C:18]4(OCC[O:19]4)[CH2:17][C@H:16]2[CH2:15][O:14][C:13]2[C:25]([F:30])=[CH:26][CH:27]=[C:28]([F:29])[C:12]3=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1(C)C(S(Cl)(=O)=O)=CC=CC=1>CC(C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C@@:11]23[CH2:24][CH2:23][C:18](=[O:19])[CH2:17][C@H:16]2[CH2:15][O:14][C:13]2[C:12]3=[C:28]([F:29])[CH:27]=[CH:26][C:25]=2[F:30])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)[C@@]12CCC3(C[C@H]1COc1c(F)ccc(F)c12)OCCO3
Agent: Cc1ccccc1S(=O)(=O)Cl
Solvent: O
Solvent: CC(C)=O
Product: O=C1CC[C@@]2(S(=O)(=O)c3ccc(Cl)cc3)c3c(F)ccc(F)c3OC[C@@H]2C1

Procedure:
Trans-10a-[(4-chlorophenyl)sulfonyl]-1,4-difluoro-6a,9,10,10a-tetrahydrospiro[6H-dibenzo[b,d]pyran-8(7H), 2′-[1,3]dioxolane] (3.1 g, 6.8 mmole) was dissolved in 200 ml acetone and 10 ml water. Toluenesulfonyl chloride (1 g) was added and the mixture was refluxed overnight. Acetone was removed. 100 water and 100 ml EtOAc were added. The organic layer washed with water (50 ml), dried over Na2SO4 and concentrated. The residue was pure enough for next step. Yield: 2.8 g, 100%. 1H NMR (CDCl3 400 MHz δ 7.63 (d, J=8.1 Hz, 2H), 7.52 (d, J=8.8 Hz, 2H), 7.14 (m, 1H), 6.64 (m, 1H), 5.27 (dd, J=11.7 and 2.9 Hz, 1H), 4.13 (d, J=11.7 Hz, 1H), 3.18 (d, J=12.4 Hz, 1H), 2.79 (dt, J=12.4 and 3.7 Hz, 1H), 2.4-2.57 (m, 4H), 2.04-2.17 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:23]OS(C)(=O)=O)[C:13]([NH:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH:12]([CH2:23][N:29]2[CH:33]=[CH:32][N:31]=[CH:30]2)[C:13]([NH:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[O:14])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)CCCNC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c1ccc(Cl)cc1
Reactant: c1c[nH]cn1
Product: COC(=O)CCCNC(=O)C(Cn1ccnc1)NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
The procedure described in Example 79 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(3-methoxycarbonylpropyl)propanamide (107.6 mg) was reacted with imidazole to obtain the desired (RS)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)-N-(3-methoxycarbonylpropyl)propanamide (16.3 mg) together with a less polar by-product. The by-product was not investigated further.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[CH:3]=1.[OH-].[Na+].[C:14](=[S:16])=[S:15].S(OC)(O[CH3:21])(=O)=O>CS(C)=O.O>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[C:3]=1[C:14]([S:16][CH3:21])=[S:15]
Reactant: Cn1c(N)cc(=O)n(C)c1=O
Reactant: S=C=S
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CSC(=S)c1c(N)n(C)c(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.8 %

Procedure:
To a stirred solution of 6-amino-1,3-dimethyl uracil (50.0 g, 322.24 mmol) in DMSO (488 ml) was added dropwise a solution of 8 N sodium hydroxide (96.6 ml) and carbon disulphide (12.53 ml, 209.45 mmol) at 0° C. The resulting reaction mixture was vigorously stirred at room temperature for 30 min. The reaction mixture was cooled to 0-5° C. and dimethyl sulphate (31 ml, 418 mmol) was added dropwise over a period of 30 min. The reaction mixture was then slowly warmed to room temperature and stirred further for 3 h. The mixture was then diluted with water (500 ml) and precipitated solid was collected by filtration to give 30.2 g of the product as a yellow solid; 1H NMR (300 MHz, CF3COOD) δ 2.73 (s, 3H), 3.51 (s, 3H), 3.62 (s, 3H).
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:10]([C:12]([C:14]3[NH:18][C:17]4[CH:19]=[CH:20][C:21]([C:23]#[N:24])=[CH:22][C:16]=4[N:15]=3)=[O:13])=[C:9]([CH3:25])[CH:8]=[C:7]([CH3:26])[C:6]=2[NH:5][CH:4]=1)=O.[BH4-].[Na+]>CO.CCOC(C)=O.FC(F)(F)CO>[CH3:1][C:3]1[C:11]2[C:10]([C:12]([C:14]3[NH:18][C:17]4[CH:19]=[CH:20][C:21]([C:23]#[N:24])=[CH:22][C:16]=4[N:15]=3)=[O:13])=[C:9]([CH3:25])[CH:8]=[C:7]([CH3:26])[C:6]=2[NH:5][CH:4]=1
Reactant: Cc1cc(C)c2[nH]cc(C=O)c2c1C(=O)c1nc2cc(C#N)ccc2[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: OCC(F)(F)F
Solvent: CO
Product: Cc1cc(C)c2[nH]cc(C)c2c1C(=O)c1nc2cc(C#N)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(3-formyl-5,7-dimethyl-1H-indole-4-carbonyl)-1H-benzo[d]imidazole-5-carbonitrile (20 mg, 0.058 mmol) in MeOH (2 mL) was added NaBH4 (11.05 mg, 0.292 mmol), and then the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with EtOAc/2,2,2-trifluoroethanol (c.a. 9/1). The organic phase was successively washed by H2O and brine, dried over Na2SO4, and filtered. Concentration of the filtrate gave the title compound, which was used in the next reaction without any further purification. MS (ESI+) m/z 329.1 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Br>CN(C=O)C.C(OCC)(=O)C>[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][N:13]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=2[C:6]2[C:14]1=[CH:15][CH:16]=[CH:17][C:5]=2[C:1]([O:3][CH3:4])=[O:2]
Reactant: Clc1ccccc1CBr
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2ccccc2Cl)CCCC1=O
Reaction time: 0.08 h
Yield: 53.5 %

Procedure:
40% Methanolic Triton B (2.42 mL, 5.3 mM) was slowly added dropwise to a solution of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (873.7 mg, 3.59 mM) in 10 mL of DMF at 25° C. After 5 minutes, 2-chlorobenzyl bromide (1.11 g, 5.39 mM) was added and the resultant mixture stirred at room temperature for 72 hours. The mixture was diluted with ethyl acetate, washed five times with H2O, once with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by crystallization from ethyl acetate to afford 706.3 mg (53%) of the 9-[(2-chlorophenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a yellow solid. 1H NMR (DMSO-d6) δ 7.6 (m, 2H), 7.4-7.1 (m, 4H), 6.5 (d, 1H, J=8 Hz), 5.6 (s, 2H), 3.8 (s, 3H), 2.9 (t, 2H, J=6 Hz), 2.4 (t, 2H, J=6 Hz), and 2.1 (m, 2H). IR (CHCl3, cm−1) 3050, 2950, 1725, 1655, 1462, 1446, 1435, 1288 and 1120. MS (ES) m/e 368, 370.
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Br[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1)=[O:30]>C(O)(C)C>[C:14]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:9][CH2:10][N:11]([CH2:28][C:29]([C:31]3[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=3)=[O:30])[CH2:12][CH2:13]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=C(CBr)c1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: O=C(CN1CCN(C(c2ccccc2)c2ccccc2)CC1)c1ccc(O)cc1
Reaction time: 8 h
Yield: 84.6 %

Procedure:
2.52 g (10 mmol) of 1-diphenylmethylpiperazine and 1.11 g (11 mmol) of triethylamine were dissolved in 30 ml of isopropanol, followed by addition of a solution obtained by dissolving 2.15 g (10 mmol) of α-bromo-p-hydroxyacetophenone in 20 ml of isopropanol. The mixture was allowed to stand overnight at room temperature. Precipitated crystals were collected by filtration. The crystals were successively washed with isopropanol, water and isopropanol and then dried to give 3.27 g of crude crystals of 2-(4-diphenylmethylpiperazinyl)-1-(4-hydroxyphenyl)ethanone (yield: 84.6%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N:12]([O-])=O.[Na+].Cl>O>[CH:3]1[C:2]([NH:1][NH2:12])=[CH:7][CH:6]=[C:5]([S:8]([NH2:11])(=[O:9])=[O:10])[CH:4]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(S(N)(=O)=O)cc1
Temperature: 5 °C
Reaction time: 0.67 h

Procedure:
4-Aminobenzenesulfonamide (52 g, 0.3 mol) was dissolved in 200 ml H2O containing 30 ml 30% NaOH and added to 75 ml 4N NaNO2. The resulting solution was poured over 100 g crushed ice containing 100 ml 30% HCl at a rate needed to maintain a reaction temperature of 5° C. The diazotization step was carried out for 40 min and the resultant diazonium salt was then added slowly to a stirred solution of 99.95 g Na2 SO3 in 250 ml water at 10° C., and the reaction was continued for 1 h. At this point, the reaction temperature was raised to 70° C. and 300 ml 30% HCl was added over 30 min. The precipitated product was stirred overnight, collected by filtration, washed with cold water and dried. The phenylhydrazine-4-sulfonamide obtained (47 g) was dissolved in 600 ml H2O containing 40 ml 30% NaOH, and to this solution 27.5 g (0.26 mol) of benzaldehyde was added at 50°-55° C. After stirring for 1 h, the temperature was reduced to 30° C. and 24 ml 30% HCl was added. The precipitated product was collected by filtration, washed with cold water and dried, to give 47.2 g of benzaldehyde phenylhydrazone-4-sulfonamide (m.p. 199° C.).
Reaction SMILES: [OH:1][C@H:2]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[CH:4]([CH2:5][CH2:6][C:7]3[C:8]4[C@:17]([CH3:25])([CH2:18][CH2:19][C:20]=32)[C@@H:11]([C@@H:12]([CH3:16])[CH2:13][CH:14]=O)[CH2:10][CH:9]=4)[C:3]1([CH3:27])[CH3:26].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[N:28]1([CH2:14][CH2:13][C@@H:12]([C@@H:11]2[C@:17]3([CH3:25])[C:8]([C:7]4[CH2:6][CH2:5][C@@H:4]5[C@:21]([C:20]=4[CH2:19][CH2:18]3)([CH3:24])[CH2:22][CH2:23][C@H:2]([OH:1])[C:3]5([CH3:27])[CH3:26])=[CH:9][CH2:10]2)[CH3:16])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: C[C@@H](CC=O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)C1CC3
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: C[C@@H](CCN1CCOCC1)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3

Procedure:
(20S)-3β-hydroxy-4,4,20-trimethyl-pregna-8,14-dien-21-carbaldehyde was treated with morpholine and sodium tris(acetoxy)borohydride as described in Example 9d). (20S)-20-[(morpholin-4-yl)ethyl]-4,4-dimethyl-5α-pregna-8,14-dien-3β-ol was isolated as a white solid.
Reaction SMILES: [C:1](Cl)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[NH2:16][C:17]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:18]=1[C:19]([OH:21])=[O:20].O>C1COCC1>[Cl:26][C:23]1[CH:24]=[CH:25][C:17]2[N:16]=[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[O:20][C:19](=[O:21])[C:18]=2[CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc(Cl)cc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=c1oc(-c2ccccc2)nc2ccc(Cl)cc12
Reaction time: 16 h
Yield: 92.7 %

Procedure:
Benzoyl chloride (5.3 mL, 45 mmol) was added dropwise to a suspension of Na2CO3 (3.8 g, 36 mmol) and 2-amino-5-chloro-benzoic acid (3.1 g, 18 mmol) in THF (60 mL). The mixture was allowed to stir for 16 h and then H2O (200 mL) was added. The resulting precipitate was collected by filtration, washed with MeOH/H2O (1/1, 100 mL) and then dried in vacuo to provide 6-chloro-2-phenyl-benzo[d][1,3]oxazin-4-one (4.3 g, 92%). To a suspension of the benzoxazinone (5.0 g, 19 mmol) in CH2Cl2 (100 mL) at −78° C. was added o-tolylmagnesium chloride (2 M in THF, 48 mmol) dropwise. The mixture was allowed to warm to −30° C. and stir for 1 h. 1N HCl (100 mL) was then added. The organic phase was collected and the aqueous phase was washed with CH2Cl2 (2×50 mL). The combined organic portions were washed with 0.1N NaOH (2×50 mL), dried over MgSO4, filtered and concentrated in vacuo to provide N-[4-chloro-2-(2-methyl-benzoyl)-phenyl]-benzamide (6.3 g, 93%). The acylated amino-benzophenone (3.5 g, 10 mmol) was dissolved in MeOH (50 mL) containing KOH (3 M, 30 mmol) and was refluxed for 16 h. The solution was then cooled to room temperature and diluted with H2O (50 mL) and EtOAc (100 mL). The organic phase was collected, washed with H2O (3×50 mL), dried over MgSO4, filtered and evaporated to dryness in vacuo to provide 1m (2.4 g, 98%) MS m/z=246 (M+H).
Reaction SMILES: [C:1]([N:4]([CH2:32][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1)[C:5](=[O:31])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[C:8]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:7]=1)(=[O:3])[CH3:2].[CH3:39][I:40]>>[I-:40].[C:1]([N:4]([CH2:32][C:33]1[CH:34]=[CH:35][N+:36]([CH3:39])=[CH:37][CH:38]=1)[C:5](=[O:31])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[C:8]([C:27]([CH3:28])([CH3:29])[CH3:30])[CH:7]=1)(=[O:3])[CH3:2]
Reactant: CI
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)N(Cc2ccncc2)C(C)=O)cc1C(C)(C)C
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)N(Cc2cc[n+](C)cc2)C(C)=O)cc1C(C)(C)C
Product: [I-]
Reaction time: 18 h
Yield: 97.5 %

Procedure:
A mixture of 0.225 g of product from Example 138 and 6.11 g of methyl iodide is heated in a sealed tube, in the dark, at 105° C. for 18 hours. The reaction is concentrated in vacuo to give 0.279 g of the desired product as orange crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:16](Br)[CH:17]=[CH2:18].C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[CH2:18]([O:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)[CH:17]=[CH2:16]
Reactant: Oc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: C=CCOc1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 100.8 %

Procedure:
42 g of 4(4-chlorophenoxy)-phenol and 48 g of allyl bromide were heated at the boil at a reflux condenser, while stirring and adding 50 g of potassium carbonate, in 500 ml of butanol for 4 hours. Inorganic salts were then separated from the reaction solution by suction-filtration, the solvent was vaporized and the residue was distilled under greatly reduced pressure. 50 g of 4(4-chlorophenoxy)-phenyl allyl ether were obtained, boiling point: 173°-175° C. under a pressure of 2--3 mm mercury.