Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[CH2:18]1[O:28][C:27]2[C:20](=[C:21]([CH:24]=[CH:25][CH:26]=2)[CH2:22]Br)[O:19]1>>[O:28]1[C:27]2[CH:26]=[CH:25][CH:24]=[C:21]([CH2:22][N:12]3[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]3[CH:2]3[CH:3]4[CH2:4][CH:5]5[CH2:6][CH:7]([CH2:8][CH:1]3[CH2:10]5)[CH2:9]4)[C:20]=2[O:19][CH2:18]1
Reactant: BrCc1cccc2c1OCO2
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1cccc2c1OCO2

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2,3-(methylenedioxy)benzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[NH2:11][CH2:12][CH:13]([OH:15])[CH3:14].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>ClCCl.C(Cl)(Cl)Cl>[OH:15][CH:13]([CH3:14])[CH2:12][NH:11][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=1
Reactant: CC(O)CN
Reactant: O=C(O)c1cccc(I)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(O)CNC(=O)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.5 %

Procedure:
3-Iodobenzoic acid (2.00 g, 8.06 mmol) was dissolved in dichloromethane (80 mL), and the mixture was stirred at room temperature for 2 hours after adding 1-amino-2-propanol (1.25 mL, 16.1 mmol), 1-ethyl-3-(3dimethylaminopropyl)carbodiimide hydrochloride (1.86 g, 9.67 mmol), and 1-hydroxybenzotriazole.monohydrate (1.23 g, 8.06 mmol). The mixture was diluted with chloroform, and washed with a saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and crystallized from diethyl ether to give N-(2-hydroxypropyl)-3-iodobenzamide (1.71 g, 70%).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:27][OH:28])=[C:4]([CH2:9][NH:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)=[O:12])[CH:5]=[N:6][C:7]=1[CH3:8].Br[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][CH:32]=1>>[C:37]([C:34]1[CH:35]=[CH:36][C:31]([CH2:30][O:1][C:2]2[C:3]([CH2:27][OH:28])=[C:4]([CH2:9][NH:10][C:11]([C:13]3[CH:14]=[CH:15][C:16]([C:19]4[CH:20]=[CH:21][C:22]([C:25]#[N:26])=[CH:23][CH:24]=4)=[CH:17][CH:18]=3)=[O:12])[CH:5]=[N:6][C:7]=2[CH3:8])=[CH:32][CH:33]=1)#[N:38]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: Cc1ncc(CNC(=O)c2ccc(-c3ccc(C#N)cc3)cc2)c(CO)c1O
Product: Cc1ncc(CNC(=O)c2ccc(-c3ccc(C#N)cc3)cc2)c(CO)c1OCc1ccc(C#N)cc1
Yield: 75.5 %

Procedure:
The coupling of 4′-cyano-biphenyl-4-carboxylic acid (5-hydroxy-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl)-amide (64) (650 mg, 1.7 mmol) and α-bromo-p-tolunitrile (375 mg, 1.9 mmol), as described in Example 3, gave 4′-cyano-biphenyl-4-carboxylic acid (5-(4-cyano-benzyloxy)-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl)-amide (65) (627 mg, 74% yield).
Reaction SMILES: B(Br)(Br)Br.C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:23][CH:22]=3)=[N:19][CH:20]=2)=[CH:11][CH:10]=1)(C)C>ClCCl>[CH2:27]([C:24]1[CH:23]=[CH:22][C:21]([C:18]2[N:17]=[CH:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)=[CH:20][N:19]=2)=[CH:26][CH:25]=1)[CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCc1ccc(-c2ncc(-c3ccc(OC(C)C)cc3)cn2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCCc1ccc(-c2ncc(-c3ccc(O)cc3)cn2)cc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 90.6 %

Procedure:
A solution of 5.5 g of boron tribromide in 50 ml of absolute dichloromethane is treated dropwise at 0° C. with a solution of 6.5 g of 5-(4-isopropyloxyphenyl)-2-(4-pentylphenyl)pyrimidine in 50 ml of absolute dichloromethane. The mixture is stirred for 24 hours and then poured on to ice-water. The organic phase is separated and the aqueous phase is back-extracted three times with 50 ml of dichloromethane each time. The combined organic phases are washed with 50 ml of 2N sodium carbonate solution and several times with water, dried over magnesium sulphate and concentrated. Chromatography of the residue on silica gel with dichloromethane/methanol (vol. 99:1 ) and recrystallization from hexane give 5.2 g of 4-(2-[4-pentylphenyl]-5-pyrimidinyl)phenol with m.p. 152°-153° C.
Reaction SMILES: [CH2:1]([C@H:9]1[CH2:11][C@H:10]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(N(CC)CC)C.C(OC(Cl)=O)C.[CH2:35]([CH:42]([NH2:50])[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl>[CH2:43]([CH:42]([NH:50][C:19](=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C@@H:10]1[CH2:11][C@@H:9]1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: NC(Cc1ccccc1)Cc1ccccc1
Reactant: CCCCCCCC[C@H]1C[C@H]1CCCCCCCC(=O)O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCC[C@H]1C[C@H]1CCCCCCCC(=O)NC(Cc1ccccc1)Cc1ccccc1
Reaction time: 1 h

Procedure:
To a cooled solution of 2.0 g (cis)-2-octylcyclopropanoctanoic acid in 70 ml methylene chloride at -20° is added first 0.707 g triethylamine and then dropwise 0.732 g ethylchloroformate. The reaction mixture is then allowed to come to room temperature and stirred for 1 hours. Then 1.5 g of 1-benzyl-2-(phenyl)ethylamine is added, and the reaction mixture stirred for 16 hours. The reaction mixture is then extracted a few times with 2 N hydrochloric acid, then with 2 N aq. sodium hydroxide sol. and washed several times with saturated aq. sodium chloride. The organic phase is then dried over anh. sodium sulphate filtered and evaporated i.v. to dryness to obtain a residue, which upon crystallization from pentane yields the title product (m.p. 40°-45°).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[NH2:21][CH2:22][CH2:23][C:24]([N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:21][CH2:22][CH2:23][C:24](=[O:25])[N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: NCCC(=O)N1CCCC1
Product: O=C(NCCC(=O)N1CCCC1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 70 from 5-((3,5-dichloropyridin-4-yl)thio)-4-nitrothiophene-2-carboxylic acid (500 mg, 1.4 mmol) and 3-amino-1-(pyrrolidin-1-yl)propan-1-one (240 mg, 1.7 mmol). The title compound was obtained as a solid (22.0 mg, 3% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.99 (2H, m), 8.92 (1H, m), 8.43 (1H, s), 3.40 (2H, m), 3.34 (2H, m), 3.26 (2H, m), 2.47 (2H, m), 1.84 (2H, m), 1.73 (2H, m). MS m/z: 475.10, 477.11 [M+H]+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:28]=[CH:27][C:10]2[C:11]3[CH:12]=[N:13][N:14]([C:18]4[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH3:26])=[CH:20][CH:19]=4)[C:15]=3[CH2:16][CH2:17][C:9]=2[CH:8]=1)(=O)=O.[CH2:31]([Sn](CCCC)(CCCC)C=C)[CH2:32]CC.[Cl-].[Li+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:24]([C:21]1[CH:22]=[CH:23][C:18]([N:14]2[C:15]3[CH2:16][CH2:17][C:9]4[CH:8]=[C:7]([CH:31]=[CH2:32])[CH:28]=[CH:27][C:10]=4[C:11]=3[CH:12]=[N:13]2)=[CH:19][CH:20]=1)[CH2:25][CH3:26]
Reactant: CCCc1ccc(-n2ncc3c2CCc2cc(OS(=O)(=O)C(F)(F)F)ccc2-3)cc1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C=Cc1ccc2c(c1)CCc1c-2cnn1-c1ccc(CCC)cc1
Temperature: 100 °C

Procedure:
To 3-(4-propylphenyl)-4,5-dihydro-3H-benzo[e]indazol-7-yl trifluoromethanesulfonate (Preparation 136D, 240 mg, 0.550 mmol) in dioxane was sequentially added tributyl(vinyl)stannane (0.178 mL, 0.605 mmol), lithium chloride (69.9 mg, 1.650 mmol) and tetrakis(triphenylphosphine)palladium(0) (38.1 mg, 0.033 mmol). Contents were purged with nitrogen gas for 5 min. and heated at 100° C. for 16 h.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[OH:11].[NH2:12][C:13]1[N:18]=[C:17]([NH2:19])[C:16]([CH2:20]C2C=C(OC)C(O)=C(OC)C=2)=[CH:15][N:14]=1>>[NH2:12][C:13]1[N:18]=[C:17]([NH2:19])[C:16]([CH2:20][C:8]2[CH:7]=[CH:6][C:5]([O:9][CH3:10])=[C:4]([OH:11])[C:3]=2[O:2][CH3:1])=[CH:15][N:14]=1
Reactant: COc1cccc(OC)c1O
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(OC)c1O
Product: COc1ccc(Cc2cnc(N)nc2N)c(OC)c1O

Procedure:
The procedure of Example 1 was repeated using 2,6-dimethoxyphenol in place of the 2,6-diethylphenol. A good yield of a mixture of 2,4-diamino-5-(3,5-dimethoxy-4-hydroxybenzyl)pyrimidine and 2,4-diamino-5-(2,4-dimethoxy-3-hydroxybenzyl)pyrimidine was obtained. These components of the mixture could be separated by fractional crystallisation. The latter melting at between 246° and 248° C. (free base).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:7]=2[CH:6]=1)=[O:4].[CH:15]([N:18]1[CH2:23][CH2:22][CH:21](O)[CH2:20][CH2:19]1)([CH3:17])[CH3:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][C:12]([O:14][CH:21]3[CH2:22][CH2:23][N:18]([CH:15]([CH3:17])[CH3:16])[CH2:19][CH2:20]3)=[CH:13][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2cc(O)ccc2s1
Reactant: CC(C)N1CCC(O)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc2cc(OC3CCN(C(C)C)CC3)ccc2s1
Reaction time: 2 h

Procedure:
The above prepared 5-hydroxy-benzo[b]thiophene-2-carboxylic acid methyl ester (0.143 g, 0.687 mmol) was dissolved in 3.4 mL of THF and treated successively at 10° C. with 1-isopropyl-piperidin-4-ol (0.197 g, 2 eq.), triphenylphosphine (0.360 g, 2 eq.) and DIAD (0.267 mL, 2 eq.), and the mixture then kept at ambient temperature for another 2 h. Pouring onto crashed ice, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, NEt3/AcOEt=5/95), delivered 0.222 g of the title compound as light yellow oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[N:8][CH:9]=[CH:10][C:2]1=2.[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:15](Cl)=[O:16].C(N(CC)CC)C.Cl>ClCCl>[Cl:11][C:12]1[CH:13]=[C:14]([C:15]([N:4]2[CH2:5][CH2:6][O:1][C:2]3[CH:10]=[CH:9][N:8]=[CH:7][C:3]2=3)=[O:16])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: c1cc2c(cn1)NCCO2
Reactant: COc1ccc(C(=O)Cl)cc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N2CCOc3ccncc32)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.9 %

Procedure:
To a 10 ml flask, 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine (150 mg, 1.102 mmol) and 3-chloro-4-methoxy-benzoyl chloride (249 mg, 1.212 mmol) were dissolved in dichloromethane. Triethylamine (0.77 ml, 5.510 mmol) was added thereto and then stirred at room temperature for 2 hours. The reaction mixture was neutralized with 1N hydrochloric acid solution and extracted with dichloromethane. And the combined organic layer was dried over anhydrous magnesium sulfate (MgSO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of ethyl acetate. The fractions containing the product were collected and evaporated to obtain ivory-colored solid (238 mg, 71%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:9]([OH:10])=[C:8]([Cl:11])[CH:7]=[C:6]([Cl:12])[CH:5]=1)=[O:3].[BH4-].[Na+]>C(O)C>[Cl:11][C:8]1[CH:7]=[C:6]([Cl:12])[CH:5]=[C:4]([CH:2]([OH:3])[CH3:1])[C:9]=1[OH:10]
Reactant: CC(=O)c1cc(Cl)cc(Cl)c1O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)c1cc(Cl)cc(Cl)c1O
Yield: 79.2 %

Procedure:
3,5-Dichloro-2-hydroxyacetophenone (40 g) was treated in ethanol with sodium borohydride (4 g). The solid reaction product was recrystallized from benzene to give 2,4-dichloro-6-(1'-hydroxy ethyl) phenol (32 g, m.p. 70°).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=2)[NH2:11])[N:4]=1.[C:17]([C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:29][CH2:28][CH:27]([C:30](O)=[O:31])[CH2:26]2)=[N:23][CH:24]=1)#[N:18]>>[C:17]([C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:29][CH2:28][CH:27]([C:30]([NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[C:8]([C:5]4[N:4]=[C:3]([C:2]([F:15])([F:1])[F:16])[O:7][N:6]=4)[CH:9]=3)=[O:31])[CH2:26]2)=[N:23][CH:24]=1)#[N:18]
Reactant: N#Cc1ccc(N2CCC(C(=O)O)C2)nc1
Reactant: Nc1cccc(-c2noc(C(F)(F)F)n2)c1
Product: N#Cc1ccc(N2CCC(C(=O)Nc3cccc(-c4noc(C(F)(F)F)n4)c3)C2)nc1
Yield: 58 %

Procedure:
This compound was synthesized from 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)aniline and 1-(5-cyanopyridin-2-yl)pyrrolidine-3-carboxylic acid as described for example 37 step 3 (65 mg, yield 58%). 1H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 8.48-8.47 (m, 2H), 7.85-7.81 (m, 2H), 7.75 (d, J=7.8 Hz, 1H), 7.58-7.54 (m, 1H), 6.59 (d, J=8.9 Hz, 1H), 3.77-3.66 (m, 3H), 3.52 (m, 1H), 3.33 (m, 1H), 2.35-2.29 (m, 1H), 2.23 (m, 1H). MS (ESI) m/z: Calculated for C20H15F3N6O2: 428.12. found: 429.0 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:12][CH:13]=[C:14]([CH2:16]Cl)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.[H-].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:12][CH:13]=[C:14]([CH2:16][N:22]3[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2nc(CCl)cs2)cc1OC
Reactant: CN1CCNCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(CN3CCN(C)CC3)cs2)cc1OC
Temperature: 25 °C
Reaction time: 14 h
Yield: 77.1 %

Procedure:
In 10 ml of dimethylformamide were dissolved 860 mg of 2-(3,4-dimethoxyphenyl)-4-chloromethylthiazole and 320 mg of N-methylpiperazine. Thereto was added 130 mg of sodium hydride. The mixture was stirred at room temperature for 14 hours. The solvent was removed by distillation. The residue was extracted with chloroform. The extract was water-washed, dried and subjected to distillation to remove the solvent. The residue was dissolved in ethanol. To the solution was added ethanol saturated with hydrogen chloride gas, and the mixture was allowed to stand. The resulting crystals were collected by filtration, washed with a small amount of ethanol, dried and recrystallized from ethanol to obtain 820 mg of 2-(3,4-dimethoxyphenyl)-4-(4-methylpiperazinylmethyl)thiazole.
Reaction SMILES: [Cl:1][C:2]1([Cl:18])[C@@H:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C@@H:3]1[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.[C:19](Cl)(=[O:21])[CH3:20]>CCO>[Cl:1][C:2]1([Cl:18])[C@@H:4]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@H:3]1[C:11]1[CH:12]=[CH:13][C:14]([O:17][C:19](=[O:21])[CH3:20])=[CH:15][CH:16]=1
Reactant: CC(=O)Cl
Reactant: Oc1ccc([C@H]2[C@H](c3ccccc3)C2(Cl)Cl)cc1
Solvent: CCO
Product: CC(=O)Oc1ccc([C@H]2[C@H](c3ccccc3)C2(Cl)Cl)cc1

Procedure:
The reaction of 1,1-dichloro-trans-2-(p-hydroxyphenyl)-3-phenylcyclopropane (Compound 17) (0.005 mol) and 0.4 mL of acetyl chloride yielded off-white needles (0.37 g, 22%) from EtOH, mp 124.5°-125.5° C. 1H NMR (CDCl3) δ 2.32 (s, 3H, OCOCH3), 3.20 (s, 2H, ArCH), 6.80-7.58 (m, 9H, ArH).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]3[C:18]([CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:29][O:30][CH2:31][CH2:32][NH:33][CH3:34]>C1COCC1>[CH:19]1([C:18]2[C:12]3[S:11][C:10]([NH:9][C:7](=[O:8])[C:6]4[CH:27]=[CH:28][C:3]([CH2:2][N:33]([CH2:32][CH2:31][O:30][CH3:29])[CH3:34])=[CH:4][CH:5]=4)=[N:14][C:13]=3[C:15]([O:25][CH3:26])=[CH:16][CH:17]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CNCCOC
Reactant: COc1ccc(C2CCCCC2)c2sc(NC(=O)c3ccc(CCl)cc3)nc12
Solvent: C1CCOC1
Product: COCCN(C)Cc1ccc(C(=O)Nc2nc3c(OC)ccc(C4CCCCC4)c3s2)cc1
Temperature: 70 °C
Yield: 80.9 %

Procedure:
To a solution of 0.095 g (0.23 mMol) 4-chloromethyl-N-(7-cyclohexyl-4-methoxy-benzothiazol-2-yl)-benzamide in 1 ml THF were added 0.16 g (1.83 mMol) N-(2-methoxyethyl)-methyl amine. The reaction mixture was heated to 70° C. for 2 h. The solvent was evaporated to dryness, the residue taken up in ethyl acetate and washed with water and brine. The organic phase was dried over sodium sulfate and evaporated to dryness in vacuo. The residue was subjected to column chromatography (dichloro methane/methanol 19:1) to yield (0.087 g (81%) of N-(7-cyclohexyl-4-methoxy-benzothiazol-2-yl)-4-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-benzamide as a light yellow foam. ES-MS m/e (%): 468 ([M+H]+, 100).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]([F:16])[F:15])[C:7]=12.[CH2:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]([F:16])[F:15])[C:7]=12)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1c(C)n(CC(F)F)c2c(Cl)nncc12
Reactant: OCc1ccccc1
Product: Cc1c(C)n(CC(F)F)c2c(OCc3ccccc3)nncc12
Yield: 71.6 %

Procedure:
The title compound was prepared as a white powder in 71.6% yield in a similar procedure to that described in Example 1 by using 7-chloro-1-(2,2-difluoroethyl)-2,3-dimethylpyrrolo[2,3-d]pyridazine and benzyl alcohol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([N+:17]([O-])=O)[CH:13]=[CH:14][CH:15]=2)[CH:10]([CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[NH2:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]([CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:9][N:8]2[CH2:7][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:28]
Reactant: CCOC(=O)CCCC1CN(CC(=O)OC(C)(C)C)c2cccc([N+](=O)[O-])c21
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCCC1CN(CC(=O)OC(C)(C)C)c2cccc(N)c21
Reaction time: 18 h

Procedure:
A mixture of ethyl 4-[1-(2-tert-butoxy-2-oxoethyl)-4-nitro-2,3-dihydro-1H-indol-3-yl]butanoate from Step C (1.10 g, 2.80 mmol) and 10% Pd/C (150 mg) in EtOH (50 mL) was stirred under an atmosphere of hydrogen (ca. 1 atm). After 18 h, the reaction was filtered through a Celite pad and concentrated in vacuo to give the title compound. MS: m/z=363 (M+1).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:18][C:17]2[C:16]([NH:19][C:20]3[O:21][C:22]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)=[CH:23][N:24]=3)=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].IC.[C:39](OCC)(=O)C>CN(C)C=O>[Si:1]([O:8][CH:9]1[CH2:18][C:17]2[C:16]([N:19]([CH3:39])[C:20]3[O:21][C:22]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][CH:26]=4)=[CH:23][N:24]=3)=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)[Si](C)(C)OC1CCc2cccc(Nc3ncc(-c4ccc(C(F)(F)F)cc4)o3)c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(c1ncc(-c2ccc(C(F)(F)F)cc2)o1)c1cccc2c1CC(O[Si](C)(C)C(C)(C)C)CC2
Reaction time: 0.08 h
Yield: 18 %

Procedure:
The product of Example 18D (300 mg, 0.615 mmol) in 5 mL N,N-dimethylformamide was treated with NaH (60% dispersion, 32 mg, 0.8 mmol) at rt. After stirring for 5 minutes, iodomethane (0.15 mL, 2.4 mmol) was added. The reaction was stirred at rt for 24 h, then it was poured into ethyl acetate and washed several times with water and once with brine. The organic layer was dried over Na2SO4 and was concentrated. The concentrate was purified on silica gel, eluting with 5% ethyl acetate-hexane and afforded the title compound as a brown oil (56 mg, 18%).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH:10]=[C:9]([C:23]([F:26])([F:25])[F:24])[N:8]=2)[CH:6]=1.[C:27]([NH:31][S:32]([C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)(=[O:34])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([NH:31][S:32]([C:35]1[CH:36]=[CH:37][CH:38]=[C:39]([C:2]2[N:3]=[CH:4][N:5]([C:7]3[CH:12]=[C:11]([C:13]4[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:22])[F:21])=[CH:17][CH:18]=4)[CH:10]=[C:9]([C:23]([F:26])([F:25])[F:24])[N:8]=3)[CH:6]=2)[CH:40]=1)(=[O:34])=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: FC(F)(F)c1ccc(-c2cc(-n3cnc(I)c3)nc(C(F)(F)F)c2)cc1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cn(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)c1

Procedure:
The title compound was prepared from 2-(4-iodo-imidazol-1-yl)-6-trifluoromethyl-4-(4-trifluoromethyl-phenyl)-pyridine (example E.93) (0.200 g, 0.41 mmol) and commercially available 3-(tert-butylsulfamoyl)-benzeneboronic acid (0.117 g, 0.46 mmol) according to the general procedure VI. Obtained as a white solid (0.120 g, 51%). MS (ISP) 569.2 [(M+H)+].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].[Li]CCCC.CCCCCC.[CH2:20]([N:22]([CH2:41][CH3:42])[CH2:23][CH2:24][N:25]1[C:35]2[C:30](=[C:31]([C:37]([F:40])([F:39])[F:38])[CH:32]=[C:33]([I:36])[CH:34]=2)[C:28](=[O:29])[C:26]1=[O:27])[CH3:21]>C1COCC1>[CH2:41]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][N:25]1[C:35]2[C:30](=[C:31]([C:37]([F:38])([F:40])[F:39])[CH:32]=[C:33]([I:36])[CH:34]=2)[C:28]([OH:29])([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[F:8])[C:26]1=[O:27])[CH3:42]
Reactant: Fc1ccccc1Br
Reactant: CCN(CC)CCN1C(=O)C(=O)c2c1cc(I)cc2C(F)(F)F
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCN(CC)CCN1C(=O)C(O)(c2ccccc2F)c2c1cc(I)cc2C(F)(F)F
Reaction time: 0.17 h
Yield: 8.9 %

Procedure:
To a solution of 1-bromo-2-fluorobenzene (0.09 mL, 0.823 mmol) in THF (4 mL) was added dropwise 1.53 N BuLi in hexane (0.54 mL, 0.826 mmol) over 10 min at −78° C. and the mixture was stirred for 10 min. The resulting solution was then transferred into the cooled solution of 1-(2-diethylaminoethyl)-4-trifluoromethyl-6-iodoisatin (330 mg, 0.75 mmol) in THF (2 mL) at −78° C. via a cannula. The mixture was stirred for 30 min at the same temperature and the reaction was quenched with aqueous NaHCO3. The mixture was extracted with ethyl acetate and the extracts were dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography with 50:1 to 30:1 chloroform/methanol to give the title compound (35.9 mg, 9%).
Reaction SMILES: Cl[C:2]1[C:11]2=[N:12][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14]([CH3:15])=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.C([O-])=O.[NH4+].C(O)C>[Pd].C(#N)C>[CH3:15][C:14]1[N:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]=[C:11]2[C:10]=1[C:9]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:3]=[CH:2]2
Reactant: Cc1c2c(nn1-c1ccccc1)c(Cl)nc1ccccc12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CC#N
Product: Cc1c2c(cnc3ccccc32)nn1-c1ccccc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 18.1 %

Procedure:
4-Chloro-1-methyl-2-phenyl-2H-pyrazolo[3,4-c]quinoline (250 mg, 0.85 mmol) was combined with ammonium formate (268 mg, 4.25 mmol), ethanol (4 mL), and palladium on carbon (10%, 25 mg). The resulting gray suspension was warmed to 60° C. and stirred at this temperature for 18 hours. The reaction was cooled to ambient temperature and filtered through CELITE filter agent. The methanol was removed under reduced pressure and the resulting material was purified by automated flash chromatography (AnaLogix, eluted with a gradient of 0-30% CMA in chloroform) to provide material that was stirred in acetonitrile. A solid was isolated by filtration to provide 40 mg of 1-methyl-2-phenyl-2H-pyrazolo[3,4-c]quinoline as a white powder, mp 128-130° C. MS (APCI) m/z 260 (M+H)+; Anal. calcd for C17H13N3.0.15H2O: C, 77.93; H, 5.12; N, 16.04. Found: C, 78.09; H, 5.51; N, 16.27.