Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([S:18]([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)(=[O:20])=[O:19])[C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15](O)=[O:16])=[CH:11]2.Cl.[C:27]([S:46][CH2:47][CH2:48][NH2:49])([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O.C(N(CC)CC)C>[CH3:1][O:2][CH2:3][CH2:4][N:5]([S:18]([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)(=[O:19])=[O:20])[C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]([NH:49][CH2:48][CH2:47][S:46][C:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:16])=[CH:11]2
Reactant: COCCN(c1cccc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1cccs1
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COCCN(c1cccc2cc(C(=O)NCCSC(c3ccccc3)(c3ccccc3)c3ccccc3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 50 °C
Reaction time: 1 h
Yield: 109.2 %

Procedure:
To a mixture of 7-[(2-methoxyethyl)(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.46 g), 2-(tritylthio)ethylamine hydrochloride (0.47 g), 1H-1,2,3-benzotriazol-1-ol (0.19 g), triethylamine (0.20 mL) and N,N-dimethylformamide (10 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.28 g) at 0° C., and the mixture was stirred at 50° C. for 1 hr. Water was added to the reaction mixture, and the obtained crystals were filtrated, washed with water and dried to give the title compound (0.90 g, quantitative) as colorless crystals. melting point 65-66° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[CH:15]=2)[C:10]1=[O:23].[CH2:24]([Br:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[Br-:31].[CH2:24]([N+:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[CH:15]=3)[C:10]2=[O:23])=[C:2]([Cl:1])[CH:3]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1cc2c(cc1OC)C(=O)C(Cc1ccncc1Cl)CC2
Reactant: BrCc1ccccc1
Product: COc1cc2c(cc1OC)C(=O)C(Cc1cc[n+](Cc3ccccc3)cc1Cl)CC2
Product: [Br-]

Procedure:
The title compound 134 is prepared according to the procedure reported in Example 38.1 with compound 101 (132.4 mg, 0.4 mmol) and benzyl bromide (95 μL, 2 equiv) as reactants. White solid. (Yield 133.4 mg, 79%).
Reaction SMILES: [BrH:1].Cl[C:3]1[CH:8]=[CH:7][C:6](C2(O)CSC(=NC)N2C)=[CH:5][C:4]=1[S:18]([Cl:21])(=[O:20])=[O:19].ClC1C=C[C:26]([C:29](=[O:31])C)=CC=1S(Cl)(=O)=O.BrBr>C(OCC)(=O)C>[Br:1][CH2:26][C:29]([C:7]1[CH:8]=[CH:3][C:4]([S:18]([Cl:21])(=[O:19])=[O:20])=[CH:5][CH:6]=1)=[O:31]
Reactant: Br
Reactant: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)Cl)c2)N1C
Reactant: CC(=O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Agent: BrBr
Solvent: CCOC(C)=O
Product: O=C(CBr)c1ccc(S(=O)(=O)Cl)cc1

Procedure:
4-(4-Chloro-3-chlorosulfonylphenyl-3-methyl-2-methylimino-1,3-thiazolidine-4-ol-hydrobromide. 5.1 g of 4'-chloro-3'-chlorosulfonyl-acetophenone were reacted in the manner described in Example 1a) with 3.2 g bromine in ethyl acetate to yield the 2-bromo-4'-chlorosulfonylacetophenone (melting point: 111° C from chloroform, γC=O 1700 cm-1) which was reacted without further isolation, as described in Example 1b) with 2.1 g of 1.3-dimethylthiourea in 50 ml of acetone. The mixture was stirred for 30 minutes at 30°-35° C, cooled to 10° C and the 4-(4-chloro-3-chlorosulfonylphenyl)-3-methyl-2-methylimino-1,3-thazolidine-4-ol-hydrobromide was filtered. Colorless crystals melting at 162° C (decomposition).
Reaction SMILES: [H-].[Na+].[CH:3]1([N:6]2[C:15]3[C:10](=[CH:11][C:12]([F:24])=[C:13]([N:17]4[CH2:21][CH2:20][CH2:19][C@H:18]4[CH2:22][OH:23])[C:14]=3F)[C:9](=[O:25])[C:8]([C:26]([OH:28])=[O:27])=[CH:7]2)[CH2:5][CH2:4]1.[H][H]>CN(C=O)C>[CH:3]1([N:6]2[C:15]3[C:14]4[O:23][CH2:22][C@@H:18]5[CH2:19][CH2:20][CH2:21][N:17]5[C:13]=4[C:12]([F:24])=[CH:11][C:10]=3[C:9](=[O:25])[C:8]([C:26]([OH:28])=[O:27])=[CH:7]2)[CH2:5][CH2:4]1
Reactant: [H][H]
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCC[C@H]3CO)c(F)cc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1cn(C2CC2)c2c3c(c(F)cc2c1=O)N1CCC[C@H]1CO3

Procedure:
9.2 mg of a 55% sodium hydride dispersion were added to a solution of 0.364 g (1 mmol) of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-[(S)-2-hydroxymethyl-1-pyrrolidinyl]-4-oxoquinoline-3-carboxylic acid in 8 ml of DMF. After completion of the hydrogen evolution, the mixture was stirred at 140° C. for 35 minutes, the solvent was evaporated, the residue was taken up in water, adjusted to pH 6 with glacial acetic acid and suction filtered. Crystallization from ethanol gave (S)-4-cyclopropyl-11-fluoro-1,4,6a,7,8,9-hexahydro-1-oxo-6H-pyrrolo-[1',2':4,5][1,4]oxazino[3,2-h]quinoline-2-carboxylic acid, m.p. >275° C. (dec.), MS: 344 (M+, 58%), 300 (100), 271 (12), 245 (8), 216 (17), 189 (4), 158 (4), 41 (24).
Reaction SMILES: [C:1]1([C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[CH2:8][C:9]([N:11]2[CH2:16][CH:15]3[CH2:17][CH2:18][CH:12]2[CH2:13][CH2:14]3)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[C:24]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[CH2:8][CH2:9][N:11]2[CH2:16][CH:15]3[CH2:17][CH2:18][CH:12]2[CH2:13][CH2:14]3)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(CC(c1ccccc1)(c1ccccc1)c1cccs1)N1CC2CCC1CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: c1ccc(C(CCN2CC3CCC2CC3)(c2ccccc2)c2cccs2)cc1

Procedure:
1 Part of 3,3-(diphenyl)-3-(2-thienyl)propionyl chloride (Martenson and Nilson Acta Chem. Scand. 19 711, (1965) is reacted with 20 parts of 2-azabicyclo[2.2.2]octane in 50 parts of benzene. The precipitated amide is filtered and the benzene solution washed with water, dried with magnesium sulfate, and the benzene evaporated. The remaining oil is crystallized to provide 2-[3,3-diphenyl-3-(2-thienyl)propionyl]2-azabicyclo[2.2.2]octane. This amide is reduced with lithium aluminum hydride as described in Example 1 to provide 2-[3,3-diphenyl-3-(2-thienyl)propyl]2-azabicyclo[2.2.2]octane. This compound has the following structural formula ##STR34##
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])/[CH:5]=[CH:6]/[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2].[CH2:13]([NH:20][CH2:21]C(O)=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:25]=O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C@H:5]1[C@H:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:21][N:20]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:25]1)=[O:12])[CH3:2]
Reactant: C=O
Reactant: CCOC(=O)/C=C/C(=O)OCC
Reactant: O=C(O)CNCc1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1C(=O)OCC
Temperature: 105 °C

Procedure:
Fumaric acid diethylester (21.6 g; 0.126 mol) is dissolved in toluene (900 ml) and heated at 105° C. A mixture of N-benzylglycine (25 g; 0.151 mol) and paraformaldehyde (25.36 g; 0.844 mol) is added in 4 g portions to the refluxing solution. After completion of the addition the mixture is heated for 18 h at 105° C. The mixture is then evaporated to dryness and suspended in n-hexane. The insoluble material is filtered off and the remaining solution is evaporated to dryness. The crude product is used for the next step without further purification. Yield: 32.5 g (70.3%), ESI-MS: m/z=306 [M+H]+
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:12](=[O:13])[C:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[N:10][C:9]3[CH:19]=[CH:20][CH:21]=[N:22][C:8]2=3)[CH:2]=1.IC.[C:31](=O)([O-])[O-].[K+].[K+].[Na]>CN(C)C=O.C(OCC)(=O)C>[C:1]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:12](=[O:13])[C:11]([CH2:14][CH2:15][C:16]([O:18][CH3:31])=[O:17])=[N:10][C:9]3[CH:19]=[CH:20][CH:21]=[N:22][C:8]2=3)[CH:2]=1
Reactant: O=C(O)CCc1nc2cccnc2n(-c2cccc(-c3ccccc3)c2)c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: COC(=O)CCc1nc2cccnc2n(-c2cccc(-c3ccccc3)c2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
A mixture of 4-(3-biphenylyl)-2-(2-carboxyethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (80 mg), iodomethane (0.04 ml) and potassium carbonate (90 mg) in N,N-dimethylformamide (2 ml) was stirred at room temperature for 1 hour. Then the mixture was poured into a mixture of ethyl acetate and aqueous sodium bicarbonte. The organic phase was separated, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was crystallized from methanol to give 4-(3-biphenylyl)-2-(2-methoxycarbonylethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (71 mg).
Reaction SMILES: [Br:1][C:2]([Br:12])=[CH:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8].[C-:13]#[N:14].[K+].[Cl:16][C:17]([Cl:27])=[CH:18][CH:19]1[CH:21]([C:22](Cl)=[O:23])[C:20]1([CH3:26])[CH3:25]>CCOCC.O.[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C>[Cl:16][C:17]([Cl:27])=[CH:18][CH:19]1[CH:21]([C:22]([O:8][CH:7]([C:13]#[N:14])[C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([CH:3]=[C:2]([Br:12])[Br:1])[CH:5]=2)=[O:23])[C:20]1([CH3:26])[CH3:25]
Reactant: [C-]#N
Reactant: CC1(C)C(C=C(Cl)Cl)C1C(=O)Cl
Reactant: O=Cc1cccc(C=C(Br)Br)c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)OC(C#N)c1cccc(C=C(Br)Br)c1
Reaction time: 8 h

Procedure:
In a two-phase reaction mixture, 6.1 g (0.021 mole) of 3-(2,2-dibromovinyl)-benzaldehyde in 50 ml of ether, 1.5 g (0.023 mole) of KCN in 20 ml of water, 5.0 g (0.022 mole) of 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid chloride and 0.5 g of triethylbenzylammonium chloride are stirred at room temperature, and thorough mixing is continued overnight at 25° C. The phases are separated and the aqueous phase is extracted twice by shaking with ether. The ether solution is washed with sodium bisulfite, NaHCO3 and water, dried over Na2SO4 and evaporated down.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][N:24]=2)[CH2:19][C:18]1=[O:26]>>[CH3:1][O:2][C:3]1[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][C:6]([CH:7]=[C:19]2[C:20]3[C:25](=[N:24][CH:23]=[CH:22][CH:21]=3)[NH:17][C:18]2=[O:26])=[CH:9][CH:10]=1
Reactant: COc1ccc(C=O)cc1-c1ccccc1
Reactant: O=C1Cc2cccnc2N1
Product: COc1ccc(C=C2C(=O)Nc3ncccc32)cc1-c1ccccc1

Procedure:
4-Methoxy-3-phenylbenzaldehyde was condensed with 7-aza-2-oxindole to give 0.25 g of 3-(6-methoxybiphenyl-3-ylmethylene)-1,3-dihydropyrrolo[2,3-b]pyridin-2-one as a yellow-orange solid.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[N:7]2[CH:8]=[C:9]([C:12]3[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.Cl.[F:24][C:25]1([F:29])[CH2:28][NH:27][CH2:26]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:24][C:25]1([F:29])[CH2:28][N:27]([C:16]([C:15]2[CH:19]=[CH:20][C:12]([C:9]3[CH:10]=[CH:11][C:6]4[N:7]([C:3]([C:2]([F:1])([F:21])[F:22])=[N:4][N:5]=4)[CH:8]=3)=[CH:13][CH:14]=2)=[O:17])[CH2:26]1
Reactant: O=C(O)c1ccc(-c2ccc3nnc(C(F)(F)F)n3c2)cc1
Reactant: FC1(F)CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(-c2ccc3nnc(C(F)(F)F)n3c2)cc1)N1CC(F)(F)C1
Reaction time: 24 h
Yield: 57.2 %

Procedure:
4-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzoic acid (52 mg) was dissolved in DMF (2 mL). 3,3-difluoroazetidine hydrochloride (26 mg), diisopropylethylamine (35 μL) and HATU (93 mg) were added sequentially. After 24 h, added additional amounts of Diisopropylethylamine (105 μL) and HATU (279 mg). When the reaction was mostly complete, quenched with ethyl acetate/water, washed with 0.1N HCl, and concentrated NaHCO3. Purified on prep-TLC plate using 5% MeOH/dichloromethane. Isolated 37 mg of (3,3-difluoroazetidin-1-yl)(4-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)phenyl)methanone (57%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:20]1([C:26]2([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:34]3[CH:30]([CH2:31][NH:32][CH2:33]3)[C:29](=[O:35])[CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([N:32]1[CH2:31][CH:30]2[CH:34]([C:26]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:27][CH2:28][C:29]2=[O:35])[CH2:33]1)=[O:18])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reactant: CC(C)(C)OC(=O)Nc1ccccc1CC(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1ccccc1CC(=O)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Reaction time: 0.75 h
Yield: 28.7 %

Procedure:
N,N'-Carbonyldiimidazole (1.62 g) is added to a solution of (2-tert-butoxycarbonylaminophenyl)acetic acid (2.51 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 45 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (3.27 g) and triethylamine (2.8 cc) in dichloromethane (30 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, then washed with water (3×100 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.2-0.063 mm, diameter 4 cm, height 40 cm), eluting under a nitrogen pressure of 0.7 bar with a mixture of cyclohexane and ethyl acetate (60/40 by volume) and collecting 125 cc fractions. Fractions 22 to 34 are combined and concentrated to dryness under reduced pressure (2.7 kPa) to give (3aRS,7aRS)-2-[(2-tert-butoxycarbonylaminophenyl)acetyl]-7,7-diphenyl-4-perhydroisoindolone (1.5 g) in the form of a yellow meringue.
Reaction SMILES: [C:1]([OH:6])(=O)[C:2](O)=[O:3].C1CO[C:14]23OCCO[C:9]2([C@:10]2([CH2:32][C@H:31]([C:33]4[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=4)[C@H:30]4[C@@H:21]([CH2:22][CH:23]=[C:24]5[C@@H:29]4[CH2:28][CH2:27][CH2:26][CH2:25]5)[C@@H:12]2[CH2:13]3)[CH3:11])[O:8]1.CO.C(Cl)Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:2]1[CH2:1][O:6][C:26]2([CH2:27][CH2:28][C@H:29]3[C:24](=[CH:23][CH2:22][C@@H:21]4[C@@H:30]3[C@@H:31]([C:33]3[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=3)[CH2:32][C@@:10]3([CH3:11])[C@H:12]4[CH2:13][CH2:14][C:9]3=[O:8])[CH2:25]2)[O:3]1
Reactant: O=C(O)C(=O)O
Reactant: COc1ccc([C@H]2C[C@@]3(C)[C@@H](CC45OCCOC43OCCO5)[C@@H]3CC=C4CCCC[C@@H]4[C@H]32)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc([C@H]2C[C@]3(C)C(=O)CC[C@H]3[C@@H]3CC=C4CC5(CC[C@@H]4[C@H]32)OCCO5)cc1

Procedure:
14 g of silica gel is suspended in 30 ml of methylene chloride, mixed with 1.4 ml of saturated oxalic acid solution and stirred for 15 more minutes. 4.67 g (10 mmol) of 3,3;17,17-bis-(ethylenedioxy)-11β-(4-methoxyphenyl)-5-estrene is added to this suspension and the reaction mixture is stirred at room temperature for 4 more hours. Then, it is suctioned off on a frit, the frit residue is rewashed with methanol/methylene chloride and the thus obtained filtrate is shaken out with saturated sodium bicarbonate solution. The organic phase is dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel with a mixture of ethyl acetate/hexane. 3.28 g of 3,3-(ethylenedioxy)-11β-(4-methoxyphenyl)-5-estren-17-one is obtained as white foam.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[C:14]([C:17]([CH3:19])=O)[C:15]=2[OH:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:20]([C:22]([NH:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=1)=[S:23])[NH2:21].Cl>CN(C)C=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[C:14]([C:17](=[N:21][NH:20][C:22]([NH:24][C:25]3[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=3)=[S:23])[CH3:19])[C:15]=2[OH:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)c1csc(-c2ccc(C(C)(C)C)cc2)c1O
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)cc1)c1csc(-c2ccc(C(C)(C)C)cc2)c1O
Yield: 52.5 %

Procedure:
2-(4-t-Butylphenyl)-3-hydroxy-4-methylcarbonylthiophene (31 mg, 0.11 mmol) synthesized in Reference Synthetic Example 33 and 4-hydrazinocarbonothioylaminobenzoic acid (23 mg, 0.11 mmol) were stirred with dimethylformamide (1.1 mL) and concentrated hydrochloric acid (0.05 mL) at room temperature for 30 hours. The reaction solution was partitioned between ethyl acetate and water, and the organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The resulting organic layer was concentrated and purified by silica gel column chromatography (chloroform) to give the desired product as a light brown solid (27 mg, yield 52%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][NH:20][C:21]([NH:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=[C:26]([CH3:34])[CH:25]=3)=[O:22])[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:35](I)[CH3:36]>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:35][CH3:36])[CH:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][NH:20][C:21]([NH:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=[C:26]([CH3:34])[CH:25]=3)=[O:22])[CH2:16][CH2:17]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CCI
Reactant: Cc1cc(NC(=O)NCCN2CCC(NS(=O)(=O)c3ccc(Br)cc3)CC2)c2ccccc2n1
Solvent: CS(C)=O
Product: CCN(C1CCN(CCNC(=O)Nc2cc(C)nc3ccccc23)CC1)S(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-bromo-N-(1-{2-[3-(2-methyl-quinolin-4-yl)-ureido]-ethyl}-piperidin-4-yl)-benzenesulfonamide (Example 109., 27.3 mg, 0.05 mmol) in DMSO (1 mL) are added ethyliodide (7.8 mg, 0.05 mmol) and CsCO3 (40 mg, 12 mmol). The reaction mixture is stirred at room temperature for 3 h and then quenched with formic acid (0.25 mL). The reaction mixture is purified by preparative HPLC to provide the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]O)=[CH:4][C:3]=1[O:10][CH3:11].[C-:12]#[N:13].[Na+].Br[CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1.O>CN(C)C=O>[F:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH2:16][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH2:6][C:12]#[N:13])=[CH:4][C:3]=2[O:10][CH3:11])=[CH:20][CH:21]=1
Reactant: COc1cc(CO)ccc1O
Reactant: Fc1ccc(OCCBr)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(CC#N)ccc1OCCOc1ccc(F)cc1
Reaction time: 3 h

Procedure:
A mixture of 4-hydroxy-3-methoxy-benzyl alcohol (14.7 g) and sodium cyanide (5 g) in dimethylformamide (200 ml) is stirred under an atmosphere of nitrogen for 3 hours at +120° C. The mixture is then cooled to +100° C. and 1-(2-bromo-ethoxy)-4-fluoro-benzene (25 g) is added in one portion. The mixture is stirred at +100° C. for another 4 hours. Upon cooling water (800 ml) is added. The mixture is extracted with ethyl acetate (2×500 ml). The organic phases are washed with brine (2×500 ml), dried (MgSO4) and evaporated. The residue is recrystallised from ethyl acetate/hexane. {4-[2-(4-Fluoro-phenoxy)-ethoxy]-3-methoxy-phenyl}-acetonitrile is obtained, m.p. 126-128° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:13]=O)=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][O:11][CH3:12])=[N:6][CH:7]=1.[CH:15]1([NH2:18])[CH2:17][CH2:16]1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[C:3]([CH2:13][NH:18][CH:15]2[CH2:17][CH2:16]2)=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][O:11][CH3:12])=[N:6][CH:7]=1.[Cl:1][C:2]1[C:3]([CH:13]=[N:18][CH:15]2[CH2:17][CH2:16]2)=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][O:11][CH3:12])=[N:6][CH:7]=1
Reactant: NC1CC1
Reactant: COCCCc1cc(C=O)c(Cl)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COCCCc1cc(C=NC2CC2)c(Cl)cn1
Product: COCCCc1cc(CNC2CC2)c(Cl)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-chloro-2-(3-methoxy-propyl)-pyridine-4-carbaldehyde (21.0 g, 98.2 mmol) and cyclopropylamine (13.8 mL, 196 mmol) in MeOH (450 mL) was stirred at rt overnight. NaBH4 (4.83 g, 128 mmol) was added at 0° C., and the mixture was stirred at rt overnight. Ice was added, and the mixture was concentrated under reduced pressure. The crude product was dissolved in EtOAc, and this mixture was washed with aq. 1M NaOH. The aq. layer was extracted back with EtOAc. The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 1:5→1:4→1:3→1:1→3:1→EtOAc) yielded the title compound (11.8 g) and [5-chloro-2-(3-methoxy-propyl)-pyridin-4-ylmethylene]-cyclopropyl-amine (10.7 g). This unreacted imine was dissolved in MeOH (20 mL), and this sol. was cooled to 0° C. NaBH4 (3.20 g, 84.6 mmol) was added, and the mixture was stirred at rt overnight. NaBH4 (3.20 g, 84.6 mmol) was added again, and the mixture was stirred for 3 days. Ice was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The crude product was dissolved in EtOAc and the resulting mixture was washed with aq. 1M NaOH. The aq. phase was extracted back with EtOAc. The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 1:3→1:2→1:1→EtOAc) yielded the title compound (9.40 g). The fractions of the title compounds were mixed together (21.2 g, 85%). LC-MS: tR=0.55 min; ES+: 296.16.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(#N)C.C(N(CC)CC)C>N1C=CC=CC=1>[Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[C:6]([NH:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[CH:4][N:3]=1
Reactant: FC(F)(F)c1c(Cl)ccnc1Cl
Reactant: NCCCc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: FC(F)(F)c1c(NCCCc2ccccc2)ccnc1Cl
Temperature: 80 °C

Procedure:
To a mixture of 2,4-dichloro-3-(trifluoromethyl)pyridine (197 mg, 0.912 mmol) and 3-aminopropylbenzene (0.136 mL, 0.925 mmol) was added acetonitrile (8.0 mL) and triethylamine (0.153 mL, 1.095 mmol). The mixture was heated to 80° C. After five hours the mixture was removed from heat and concentrated. This material was purified on silica gel (25 g) equilibrated in hexane, loaded in dichloromethane and eluted using hexane (96 mL) 0 to 30% EtOAc/hexane (600 mL, linear gradient). Early eluting fractions gave 51 mg of a pale yellow film as a 1:1 mixture of the minor 2-isomer and pyridine starting material by 1H NMR. Later eluting fractions gave 172 mg of a pale yellow film. This was consistent with the desired product by 1H NMR (400 MHz, CHLOROFORM-d) δ 8.02 (d, J=6.0 Hz, 1H), 7.37-7.29 (m, 2H), 7.27-7.17 (m, 3H), 6.45 (d, J=6.0 Hz, 1H), 5.52-5.31 (m, 1H), 3.27-3.16 (m, 2H), 2.75 (t, J=7.4 Hz, 2H), 2.02 (quin, J=7.3 Hz, 2H).