Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[CH:6][N:7]([CH2:9][CH2:10][CH2:11][NH:12][C:13]([CH2:22][CH3:23])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][CH3:15])[CH:8]=1.[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>>[CH2:14]([C:13]([NH:12][CH2:11][CH2:10][CH2:9][N:7]1[CH:8]=[C:4]([CH2:3][CH2:2][NH:1][C:30](=[O:31])[C:29]2[CH:33]=[CH:34][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)[N:5]=[CH:6]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:22][CH3:23])[CH3:15]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CCC(CC)(NCCCn1cnc(CCN)c1)c1ccccc1
Product: CCC(CC)(NCCCn1cnc(CCNC(=O)c2ccc(OC)cc2)c1)c1ccccc1

Procedure:
3-[4-(2-Aminoethyl)imidazol-1-yl]-N-(1-ethyl-1-phenylpropyl)propylamine (0.5 g) was reacted with 4-methoxybenzoyl chloride (0.29 g) in a similar manner to Example 55 to give N-(2-{1-[3-(1-ethyl-1-phenylpropylamino)propyl]-imidazol-4-yl}ethyl)-4-methoxybenzamide, as an oil.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]([CH2:5][CH2:6][CH2:7][C:8]#[C:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=O)=[O:4].CCN=C=NCCCN(C)C.C(N(CC)CC)C.[F:38][CH2:39][CH2:40][NH2:41]>ClCCl>[CH3:19][N:2]([CH3:1])[C:3]([CH2:5][CH2:6][CH2:7][C:8]#[C:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([NH:41][CH2:40][CH2:39][F:38])=[O:15])=[O:4]
Reactant: NCCF
Reactant: CN(C)C(=O)CCCC#Cc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)CCCC#Cc1cccc(C(=O)NCCF)c1
Temperature: 25 °C
Yield: 89.5 %

Procedure:
To a solution of 3-(5-dimethylcarbamoyl-pent-1-ynyl)-benzoic acid (0.100 g, 0.38 mmol) in dry dichloromethane (1.5 mL) under a nitrogen atmosphere at room temperature, EDCI (0.0728 g, 0.38 mmol) was added followed by triethylamine (0.162 mL, 1.14 mmol), the resulting mixture was stirred at room temperature for further minutes. 2-Fluoro ethylamine (0.189 g, 1.9 mmol) was then added and the mixture stirred at room temperature for 16 hrs. The reaction mixture was washed with a mixture of saturated brine and saturated sodium bicarbonate (1:1; 2×150 mL) followed by saturated brine solution (100 mL). The organic layer was separated and dried over magnesium sulfate and the solvent evaporated under vacuum. The residue was purified by flash column chromatography on silica gel (DCM:MeOH, 95% to 5% methanol gradient) to afford 3-(5-dimethylcarbamoyl-pent-1-ynyl)-N-(2-fluoro-ethyl)benzamide (26) (0.103 g, 0.34 mmol, 91% yield).
Reaction SMILES: [F:1][S:2]([F:20])([F:19])([F:18])([F:17])[C:3]1[CH:4]=[C:5]([C:14](=[O:16])[CH3:15])[CH:6]=[C:7]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:8]=1.C(OC)(OC)OC.CC1(C)[C@]2(CS(O)(=O)=O)C(C[C@H]1CC2)=O.[Br-:43].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>CO.C1COCC1>[Br:43][CH2:15][C:14]([C:5]1[CH:6]=[C:7]([N:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)[CH:8]=[C:3]([S:2]([F:1])([F:17])([F:18])([F:19])[F:20])[CH:4]=1)=[O:16]
Reactant: [Br-]
Reactant: CC(=O)c1cc(N2CCCC2)cc(S(F)(F)(F)(F)F)c1
Agent: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Agent: C[N+](C)(C)c1ccccc1
Solvent: CO
Solvent: C1CCOC1
Solvent: COC(OC)OC
Product: O=C(CBr)c1cc(N2CCCC2)cc(S(F)(F)(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 17.8 %

Procedure:
1-[3-(Pentafluorosulfanyl)-5-pyrrolidin-1-ylphenyl]ethanone (78 mg) was dissolved in methanol (5 ml) and admixed while stirring with trimethyl orthoformate (80 mg) and DL-10-camphorsulfonic acid (57 mg). After stirring at RT for 3 h, THF (5 ml) was added, followed by phenyltrimethylammonium tribromide (83 mg). After stirring at RT for 3 h, the mixture was left to stand overnight. Then the mixture was heated to 50° C. for 3 h and subsequently dried. The residue was taken up in ACN, admixed with 2N sulfuric acid and stirred for 30 min. Then it was admixed with water and concentrated. The residue was purified by means of preparative HPLC. The product-containing fractions were combined, freed of the acetonitrile, admixed with saturated sodium hydrogencarbonate solution and extracted three times with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. 9 mg of the desired compound were obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][CH2:10][O:11][CH3:12])[CH:5]=[CH:4][N:3]=1.[CH3:13][C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([B:21]2[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]2)[CH:20]=1)[NH2:17].CS(O)(=O)=O>O1CCOCC1>[CH3:12][O:11][CH2:10][CH2:9][O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:17][C:16]2[CH:18]=[C:19]([B:21]3[O:25][C:24]([CH3:26])([CH3:27])[C:23]([CH3:29])([CH3:28])[O:22]3)[CH:20]=[C:14]([CH3:13])[CH:15]=2)[N:7]=1
Reactant: COCCOc1ccnc(Cl)n1
Reactant: Cc1cc(N)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: CS(=O)(=O)O
Solvent: C1COCCO1
Product: COCCOc1ccnc(Nc2cc(C)cc(B3OC(C)(C)C(C)(C)O3)c2)n1
Temperature: 100 °C
Yield: 85.6 %

Procedure:
2-Chloro-4-(2-methoxyethoxy)pyrimidine (91 mg, 0.485 mmol) and 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (113 mg, 0.485 mmol) were dissolved in Dioxane (4 ml), and methanesulfonic acid (0.033 ml, 0.509 mmol) was added. The mixture was heated to 100° C. for 18 h. The mixture was allowed to cool to room temperature, quenched with saturated aqueous sodium bicarbonate and extracted with EtOAc (2×). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to obtained 4-(2-methoxyethoxy)-N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrimidin-2-amine (160 mg, 86%) as a brown solid. MS APCI: [M+H]+ m/z 386. 1H NMR (500 MHz, CDCl3) δ 8.08 (d, J=5.8, 1H), 7.93 (s, 1H), 7.48 (s, 1H), 7.34 (s, 1H), 6.26 (d, J=6.0, 1H), 4.58 (m, 2H), 3.77 (m, 2H), 3.42 (s 3H), 2.37 (s, 3H), 1.34 (s, 12H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[CH3:20])[C:5]([NH:21][C:22](=O)[CH3:23])=[C:4]([O:25][CH3:26])[CH:3]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O=P(Cl)(Cl)Cl>CO.ClCCl>[F:1][C:2]1[CH:7]=[C:6]2[C:5]([N:21]=[C:22]([CH3:23])[C:12]3[N:8]2[C:9]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[CH3:20])=[N:10][C:11]=3[CH3:13])=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: COc1cc(F)cc(-n2cc(C)nc2-c2ccncc2C)c1NC(C)=O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: COc1cc(F)cc2c1nc(C)c1c(C)nc(-c3ccncc3C)n12
Temperature: 120 °C
Reaction time: 6 h
Yield: 58.7 %

Procedure:
To a mixture of intermediate N-(4-fluoro-2-methoxy-6-(4-methyl-2-(3-methylpyridin-4-yl)-1H-imidazol-1-yl)phenyl)acetamide (1.58 g, 4.46 mmol) and P2O5 (3.16 g, 22.3 mmol) was added 60 mL of POCl3 under nitrogen. The resulting mixture was stirred at 120° C. for 6 hours and cooled to room temperature. Majority of solvent was removed under vacuum and the residue was diluted with ethyl acetate. The mixture was transferred very carefully into iced-50% NaOH solution. The mixture was stirred for 10 minutes (make sure pH>7) and extracted with ethyl acetate (3×). Condensation and column purification using 4-8% MeOH in dichloromethane as eluent provided 880 mg (60% yield) of 8-fluoro-6-methoxy-3,4-dimethyl-1-(3-methylpyridin-4-yl)imidazo[1,5-a]quinoxaline as an offwhite powder. 1H NMR (400 MHz, DMSO) δ ppm 8.68 (s, 1H), 8.60 (d, 1H), 7.48 (d, 1H), 7.00 (dd, 1H), 6.16 (dd, 1H), 3.88 (s, 3H), 2.75 (s, 3H), 2.69 (s, 3H), 1.98 (s, 3H). EIMS 337.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:39]=[CH:38][C:12]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:33][CH2:34][CH3:35])=[C:21]([NH:24][C:25](=[O:32])/[CH:26]=[CH:27]/[CH2:28][N:29]([CH3:31])[CH3:30])[CH:22]=3)[N:17]=[CH:16][C:15]=2[C:36]#[N:37])=[CH:11][C:10]=1[Cl:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:41][NH:42][CH3:43]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:39]=[CH:38][C:12]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:33][CH2:34][CH3:35])=[C:21]([NH:24][C:25](=[O:32])[CH2:26][CH:27]([N:42]([CH3:43])[CH3:41])[CH2:28][N:29]([CH3:31])[CH3:30])[CH:22]=3)[N:17]=[CH:16][C:15]=2[C:36]#[N:37])=[CH:11][C:10]=1[Cl:40])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccc4)c(Cl)c3)c2cc1NC(=O)/C=C/CN(C)C
Reactant: CNC
Solvent: C1CCOC1
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccc4)c(Cl)c3)c2cc1NC(=O)CC(CN(C)C)N(C)C
Temperature: 36 °C
Yield: 60 %

Procedure:
A solution of (E)-N-{4-[4-(benzyloxy)-3-chloroanilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide (400 mg, 0.719 mmol) and 1.5 mL of 2N dimethylamine in THF was heated at 36° C. in a sealed tube for 20 hours. After the volatile solvents were stripped off, the residue was treated with 1.5 mL of 2N dimethylamine in THF, and heated again at 36° C. in a sealed tube for 20 hours. After the solvent was removed, the residue was purified by preparatory TLC (developed in ethyl acetate:methanol:triethylamine=10:1:1) to yield 260 mg of the title compound as a yellow solid (yield: 60%), mp 102-104° C.; MS (ES) 601.3 (M+1).
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[C:2]([NH2:4])=[NH:3].CS[C:17]1[NH:18][CH2:19][CH:20]([CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:21][C:22]=1[N+:23]([O-:25])=[O:24]>>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:17]2[NH:18][CH2:19][CH:20]([CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:21][C:22]=2[N+:23]([O-:25])=[O:24])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: CSC1=C([N+](=O)[O-])CC(CCc2ccccc2)CN1
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Product: N=C(N)Nc1nc(CSCCNC2=C([N+](=O)[O-])CC(CCc3ccccc3)CN2)cs1

Procedure:
The title compound is prepared from 2-(2-guanidino-4-thiazolylmethylthio)ethylamine and 2-methylthio-3-nitro-5-(2-phenylethyl)-1,4,5,6-tetrahydropyridine by a process analogous to that given in Example 1.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7](=[O:19])[N:8]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18].C(N(CC)CC)C.C([O:29][C:30](=O)[C:31]([F:34])([F:33])[F:32])C>C(#N)C>[CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7](=[O:19])[N:8]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:30](=[O:29])[C:31]([F:34])([F:33])[F:32]
Reactant: CCOC(=O)C(F)(F)F
Reactant: Cc1nc2cccc3n(CCCCCN)c(=O)c1n23
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1nc2cccc3n(CCCCCNC(=O)C(F)(F)F)c(=O)c1n23

Procedure:
To a solution of 2.58 g (10.0 mmol) of 3-methyl-1-[5-(amino)pentyl]-1,4,7b-triazacyclopent[cd]inden-2-one and 1.81 ml (13.0 mmol) of triethylamine in 100 ml of acetonitrile was added, while stirring under ice-cooling, 1.43 ml (12.0 mmol) of trifluoroacetic acid ethyl ester. The mixture was stirred for one hour at the same temperature. The solvent was distilled off. To the residue was added ethyl acetate—tetrahydrofuran. The mixture was washed with an aqueous saline solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate), which was recrystallized from ethyl acetate—n-hexane to afford 2.57 g (72.6%, a pale yellow crystals) of the desired compound.
Reaction SMILES: Cl.N1(CCC2CCCC3C(C(O)=O)=CC=CC2=3)C=CN=C1.IC.[OH:24][CH2:25][CH2:26][C:27]1[C:28]2[CH:29]=[CH:30][C:31]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:32][C:33]=2[CH2:34][CH2:35][CH:36]=1>C(O)C.[C].[Pd]>[OH:24][CH2:25][CH2:26][CH:27]1[CH2:36][CH2:35][CH2:34][C:33]2[CH:32]=[C:31]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH:30]=[CH:29][C:28]1=2
Reactant: CCOC(=O)c1ccc2c(c1)CCC=C2CCO
Agent: [Pd]
Agent: Cl
Agent: O=C(O)c1cccc2c1CCCC2CCn1ccnc1
Solvent: CCO
Solvent: CI
Product: CCOC(=O)c1ccc2c(c1)CCCC2CCO

Procedure:
14.3 g of the above product was allowed to react using procedures analogous to those described in steps (5) and (6) of Referential Example 1 but using iodomethane instead of bromoethane to give an oily product containing a small amount of ethyl 5-(2-hydroxyethyl)-7,8-dihydro-2-naphthalenecarboxylate as a by-product. The product was dissolved in 10 ml of ethanol and 0.5 g of 10% palladium carbon was added thereto. The mixture was catalytically reduced. After absorption of hydrogen gas was completed, the catalyst was removed by filtration. The filtrate was concentrated in vacuo to give 1.4 g of ethyl 5-(2-hydroxyethyl)-5,6,7,8-tetrahydro-2-naphthalenecarboxylate as an oil.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:11][CH2:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[C@@H:22]2[O:26][C@H:25]([C:27]([NH:29][CH2:30][CH3:31])=[O:28])[C@@H:24]([OH:32])[C@H:23]2[OH:33])=[C:15]([NH:34][CH2:35][CH:36]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:14]=1>ClCCl>[CH2:1]([NH:8][C:9]([NH:11][CH2:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[C@@H:22]2[O:26][C@H:25]([C:27]([NH:29][CH2:30][CH3:31])=[O:28])[C@@H:24]([OH:32])[C@H:23]2[OH:33])=[C:15]([NH:34][CH2:35][CH:36]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[N:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Reactant: O=C=NCc1ccccc1
Solvent: ClCCl
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNC(=O)NCc4ccccc4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Benzylisocyanate (26 mg, 0.30 mmol) was added to a solution of (2S,3S,4R,5R)-5-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide (Preparation 11) in dichloromethane (2 ml). The reaction mixture was stirred for 16 hours at room temperature and allowed to evaporate. Ethanol (2 ml) was added and then aqueous hydrochloric acid (1 M, 1 ml) was added. The reaction mixture was stirred at 60° C. for 6 hours, then allowed to cool to room temperature and left for a further 16 h. More aqueous hydrochloric acid (1M, 0.5 ml) was added and the reaction mixture was stirred at room temperature for a further 4 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol (95:5 by volume) increasing in polarity to dichloromethane:methanol (90:10 by volume). The material obtained was impure and hence was repurified by column chromatography on silica gel eluting with dichloromethane:methanol (95:5 by volume) increasing in polarity to dichloromethane:methanol (90:10 by volume) to give the title compound as a solid (85 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[F:32][C:33]([F:46])([F:45])[O:34][C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:41]([C:38]4[CH:37]=[CH:36][C:35]([O:34][C:33]([F:32])([F:45])[F:46])=[CH:40][CH:39]=4)(=[O:43])=[O:42])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4ccc(OC(F)(F)F)cc4)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 4-(trifluoromethoxy)-benzenesulfonyl chloride. Purity (ELSD, based on MW=645.6)=87%.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH:10]1[CH:14]=[C:13]([CH2:15][OH:16])[N:12]=[CH:11]1.[C:17]1([C:23](Cl)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC#N>[C:17]1([C:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:10]2[CH:14]=[C:13]([CH2:15][OH:16])[N:12]=[CH:11]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCc1c[nH]cn1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
Diisopropylethylamine (14 mL, 80 mmol) was added dropwise to a suspension of 4-imidazole methanol (5.4 g, 40 mmol) in CH3CN (15 mL) at 0° C. A homogeneous yellow solution was formed. To this solution was added triphenylmethyl chloride (11.2 g, 40 mmol). The reaction mixture was stirred at room temperature for 2 h. The resultant white precipitate was filtered and washed successively with saturated NaHCO3 aqueous solution (2×20 mL) and water (2×20 mL), then dried in a vacuum oven (45° C.) for 12 h to afford a white solid 11.2 g (82%) which was used in next step without further purification.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@H:11]([CH3:12])[C@H:10]2[NH:13]C(=O)OC(C)(C)C)=[CH:5][CH:4]=1>O1CCOCC1.ClCCl>[ClH:2].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH:11]([CH3:12])[CH:10]2[NH2:13])=[CH:7][CH:8]=1
Reactant: C[C@@H]1[C@@H](NC(=O)OC(C)(C)C)[C@H]1c1ccc(Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC1C(N)C1c1ccc(Cl)cc1
Reaction time: 3 h
Yield: 83 %

Procedure:
A solution of HCl in dioxane (0.6 ml) was added to a solution of racemic tert-butyl N-[(1R,2R,3S)-2-(4-chlorophenyl)-3-methyl-cyclopropyl]carbamate. (84.5 mg) in dichloromethane (1.2 ml). The solution was left for 3 hours during which time a white precipitate had formed. The solvent was evaporated and the solid was stirred with diethyl ether, filtered off, and washed with more ether to yield 43.4 mg (83%) of racemic (1R,2R,3S)-2-(4-chlorophenyl)-3-methyl-cyclopropanamine hydrochloride
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]3[O:17][C:16]([CH:18]([NH:20][C:21](=[O:23])[CH3:22])[CH3:19])=[CH:15][C:14]=3[CH:24]=2)=[CH:4][CH:3]=1.Br[CH2:26][CH2:27][CH3:28].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:26]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]3[O:17][C:16]([CH:18]([NH:20][C:21](=[O:23])[CH3:22])[CH3:19])=[CH:15][C:14]=3[CH:24]=2)=[CH:4][CH:3]=1)[CH2:27][CH3:28]
Reactant: CC(=O)NC(C)c1cc2cc(CCc3ccc(O)cc3)ccc2o1
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1ccc(CCc2ccc3oc(C(C)NC(C)=O)cc3c2)cc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 78.1 %

Procedure:
A suspension of N-(1-{5-[2-(4-hydroxyphenyl)ethyl]-1-benzofuran-2-yl}ethyl)acetamide (333 mg, 1.03 mmol) obtained in Example 157, bromopropane (1.08 g, 6.37 mmol) and potassium carbonate (924 mg, 6.68 mmol) in DMF (10 mL) was stirred at 80° C. for 2 days. Water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solution was applied to silica gel column chromatography (hexane:ethyl acetate=9:11 to 0:1), and recrystallized from hexane-ethyl acetate to give the title compound (294 mg, yield 78%) as colorless crystals.
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([C:31]([OH:33])=O)[C:20]([CH2:34][CH3:35])=[CH:19]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].C(O[N:40]([C@H]1CN(C(OC(C)(C)C)=O)[C@H](C(=O)N)C=C1C)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C>>[CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([C:31](=[O:33])[NH2:40])[C:20]([CH2:34][CH3:35])=[CH:19]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(N)=O)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: C=CCON([C@@H]1C=C(CC)[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: C=CCON([C@@H]1C=C(CC)[C@@H](C(N)=O)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 77 %

Procedure:
The title compound was prepared from (2S,5R)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-1-(tert-butoxycarbonyl)-3-ethyl-1,2,5,6-tetrahydropyridine-2-carboxylic acid (Intermediate 211, 1.89 g, 3.69 mmol) following the procedure described for Intermediate 20. Silica gel chromatography (0%-80% ethyl acetate/hexanes) afforded the title compound (1.445 g, 77%) as a beige foam.
Reaction SMILES: I[C:2]1[C:6]([CH:7]=[O:8])=[CH:5][N:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[N:3]=1.[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[CH2:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.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>[F:23][C:20]1[CH:21]=[CH:22][C:17](/[CH:15]=[CH:16]/[C:2]2[C:6]([CH:7]=[O:8])=[CH:5][N:4]([CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][O:10]3)[N:3]=2)=[CH:18][CH:19]=1
Reactant: C=Cc1ccc(F)cc1
Reactant: O=Cc1cn(C2CCCCO2)nc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cn(C2CCCCO2)nc1/C=C/c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 28.1 %

Procedure:
A mixture of (R/S) 3-iodo-1-(oxan-2-yl)-1H-pyrazole-4-carbaldehyde (800 mg, 2.61 mmol, 1.00 equiv), 1-ethenyl-4-fluorobenzene (957 mg, 7.84 mmol, 3.00 equiv), Pd(PPh3)4 (302 mg, 0.26 mmol, 0.10 equiv) and potassium carbonate (1082 mg, 7.83 mmol, 3.00 equiv) in N,N-dimethylformamide (10 mL) was stirred under nitrogen at 100° C. overnight. The reaction was cooled to room temperature then quenched by the addition of 100 mL of water. The resulting mixture was extracted with 3×100 mL of ethyl acetate. The combined organic layers was washed with 3×100 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 1-15% ethyl acetate in petroleum ether to give 220 mg (28%) of (E)-3-(4-fluorostyryl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carbaldehyde as a yellow oil. LCMS (method D, ESI): RT=1.49 min, m/z=301.0 [M+H]+.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[NH:16][C:17](=[O:35])[C:18]([C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1)([CH3:20])[CH3:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:38]I>CN(C)C=O>[C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]([CH3:38])[C:17](=[O:35])[C:18]([C:21]1[CH:22]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:26]=1)([CH3:20])[CH3:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C(=O)Nc1ccc(Cl)cc1C(=O)c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccc(Cl)cc1C(=O)c1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
To a solution of 154 mg (0.3 mmol) of N-(2-benzoyl-4-chloro-phenyl)-2-(3,5-bis-trifluoromethyl-phenyl)-isobutyramide in 1 ml dimethylformamide were added 26 mg (0.6 mmol) sodium hydride (55% suspension in mineral oil). After 30 min stirring at room temperature 85 mg of methyl iodide (0.6 mmol) were added and the reaction mixture was stirred at 80° C. overnight. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography to yield 51 mg (32%) of the title compound as white crystals. M.p. 89-91° C.