Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13](=[O:20])[CH2:14][CH2:15][C:16]([O:18]C)=[O:17])[CH2:8][CH2:7]1.[OH-].[Li+:26]>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:5][N:6]1[CH2:7][CH2:8][CH:9]([NH:12][C:13](=[O:20])[CH2:14][CH2:15][C:16]([O-:18])=[O:17])[CH2:10][CH2:11]1.[Li+:26]
Reactant: COC(=O)CCC(=O)NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C([O-])CCC(=O)NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reaction time: 48 h
Yield: 96.2 %

Procedure:
To a solution of methyl 4-{[1-(3,4-dichlorobenzyl)-4-piperidinyl]amino}-4-oxobutanoate (3.72 g) in methanol (30 ml) was added lithium hydroxide (0.41 g) in water (10 ml) which was stirred under nitrogen for 48 hours. The solvent was removed under reduced pressure, the residue was triturated with ether and filtered to leave lithium 4-{[1-(3,4-dichlorobenzyl)-4-piperidinyl]amino}-4-oxobutanoate (3.50 g).
Reaction SMILES: C[O:2][C:3](=[O:23])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:5]C(C1C(C)=CC=CC=1Cl)=O.Cl[C:25]1C=CC=C(Cl)C=1C(Cl)=O>>[CH3:25][C:21]1[CH:22]=[C:17]([CH:18]=[CH:19][CH:20]=1)[CH2:16][C@@H:4]([C:3]([OH:2])=[O:23])[NH2:5]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)c1c(C)cccc1Cl
Product: Cc1cccc(C[C@H](N)C(=O)O)c1

Procedure:
N-[1-(2-chloro-6-methylphenyl)carbonyl]-4-[[2,6-dichlorophenyl)carbonyl]amino]-3-methyl-L-phenylalanine was prepared from 4-amino-3-methyl-N-[[(2-chloro-6-methylphenyl)carbonyl]-L-phenylalanine methyl ester (87.4 mg, 0.22 mmol) and 2,6-dichlorobenzoyl chloride using the procedures described in examples 1 and 120 to give 56 mg of a white powder. HR MS (C25H21N2O4Cl3): Obs. Mass 519.0656. Calcd. Mass 519.0645 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[C:12]([CH3:24])=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:5]2=[N:6][CH:7]=1.[F:35][C:36]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[CH:38][C:37]=1[C:51]1[CH2:56][CH2:55][N:54]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:53][CH:52]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:35][C:36]1[CH:41]=[C:40]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[C:12]([CH3:24])=[N:13][N:14]([CH2:16][C:17]5[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=5)[CH:15]=4)=[CH:9][N:8]([S:25]([C:28]4[CH:29]=[CH:30][C:31]([CH3:32])=[CH:33][CH:34]=4)(=[O:26])=[O:27])[C:5]3=[N:6][CH:7]=2)[CH:39]=[CH:38][C:37]=1[C:51]1[CH2:56][CH2:55][N:54]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:53][CH:52]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2F)CC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cn(Cc4cccc(F)c4)nc3C)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cn(Cc4cccc(F)c4)nc3C)c3cc(-c4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Yield: 61.8 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-3-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (300 mg, 0.55 mmol) was coupled with tert-butyl 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (intermediate 70) (270 mg, 0.66 mmol) using sodium carbonate (175 mg, 1.65 mmol) and Pd(PPh3)2Cl2 (20 mg, 0.027 mmol) in DME/water (10/2.5 ml) to afford 250 mg (61.2% yield) of the pure product after column purification using 50% ethyl acetate in hexane as eluent. MS: m/z=736.4 (M+1).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([O:9]C)=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1.[Br:17]N1C(=O)CCC1=O.[OH-].[Na+]>O1CCCC1>[Br:17][C:12]1[CH:13]=[N:14][N:15]([CH3:16])[C:11]=1[C:3]1[CH:4]=[C:5]([C:7]([OH:9])=[O:8])[S:6][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(-c2ccnn2C)c(C)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1sc(C(=O)O)cc1-c1c(Br)cnn1C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
A solution of methyl 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (250 mg, 1.058 mmol)[prepared in Example 99] and N-bromosuccinimide (188 mg, 1.06 mmol) in tetrahydrofuran (5.29 ml) was stirred in a sealed tube for 1 h at 70° C. Sodium hydroxide (3.53 ml, 21.16 mmol) was added in one portion and the solution stirred an additional 1 h. The reaction mixture was then partitioned between H2O-DCM and the pH of the aqueous phase was adjusted to ˜4 and washed several times with DCM. The combined organic fractions were dried over Na2SO4 and concentrated yielding 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (289 mg, 0.96 mmol, 91% yield) as a yellow oil: LCMS (ES) m/e 301, 303 (M, M+2)+.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1)C.[C:24]1([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36][O:37]S(C3C=CC(C)=CC=3)(=O)=O)[N:34]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[F:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:5]([CH3:14])([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:37][CH2:36][CH2:35][C:33]3[N:34]=[C:30]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[O:31][C:32]=3[CH3:48])=[CH:11][CH:12]=2)[C:4]([OH:23])=[O:3])=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(F)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC(C)(Oc2ccc(F)cc2)C(=O)O)cc1

Procedure:
Standard Procedure (B) was utilized to prepare the title compound from 2-(4-fluorophenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-phenyl-5-methyl-oxazol-4-yl)-ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH:14]=[C:15](Br)Br)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.CCCCCC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]#[CH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(C=C(Br)Br)C1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C#CC1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of 3-(2,2-Dibromo-vinyl)-piperidine-1-carboxylic acid tert-butyl ester (0.15 g, 0.42 mmol) in THF (1 ml) wad added at −78° C., 0.5 ml of n-BuLi 2.5 M in hexane (1.23 mmol). After 1 h at −78° C., the reaction mixture was quenched with 1 ml of water and the aqueous phase was extracted with AcOEt. The combined organic phase was dried over K2CO3, filtered and evaporated to give 80 mg (93%) of 3-Ethynyl-piperidine-1-carboxylic acid tert-butyl ester as a white solid.
Reaction SMILES: [Si](C=[N+]=[N-])(C)(C)C.[Li][CH2:9][CH2:10][CH2:11][CH3:12].[CH:13]([Si:16]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[O:17][CH2:18][CH2:19][CH:20]1CC(C=O)=[CH:23][CH2:22][CH2:21]1)([CH3:15])[CH3:14]>C1COCC1>[C:11]([C:10]1[CH2:9][CH:20]([CH2:19][CH2:18][O:17][Si:16]([CH:31]([CH3:32])[CH3:33])([CH:28]([CH3:30])[CH3:29])[CH:13]([CH3:14])[CH3:15])[CH2:21][CH2:22][CH:23]=1)#[CH:12]
Reactant: CC(C)[Si](OCCC1CCC=C(C=O)C1)(C(C)C)C(C)C
Reactant: [Li]CCCC
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Product: C#CC1=CCCC(CCO[Si](C(C)C)(C(C)C)C(C)C)C1

Procedure:
A solution of TMS-diazomethane (4.61 mL, 9.22 mmol) in THF (60 mL) was reacted with n-BuLi (5.0 mL, 7.99 mmol) at −78 EC for 0.5 h. 5-(2-triisopropylsilanyloxy-ethyl)-cyclohex-1-enecarbaldehyde (Intermediate R13) was added via cannula. The mixture was reacted at −78 EC for 1 h and at 0 EC for 1 h. After work-up and chromatographic purification, [2-(3-ethynyl-cyclohex-3-enyl)-ethoxy]-triisopropyl-silane (Intermediate R14) was isolated, 1.44 g (77%). To Intermediate R14 in THF (70 mL) at 0 EC was injected tetrabutyl ammonium fluoride (TBAF). After 2 h at rt the mixture was subjected to an aqueous work-up. The material was purified by chromatography to give the alcohol, 2-(3-ethynyl-cyclohex-3-enyl)-ethanol 0.68 g, (98%). The alcohol was oxidized by a Swern reaction to the aldehyde stage and aldehyde was subjected to the applicable step of Method A to yield 4-(3-ethynyl-cyclohex-3-enylmethyl)-1H-imidazole (Intermediate R15).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:41])[CH:13]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][O:30][Si](C(C)C)(C(C)C)C(C)C)=[CH:25][CH:24]=3)[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].CCOC(C)=O>C1COCC1>[OH:30][CH2:29][C:26]1[CH:25]=[CH:24][C:23]([CH:13]([C:12]([NH:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[CH:1]=[N:2][CH:3]=[CH:4]3)=[O:41])[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[CH:28][CH:27]=1
Reactant: CC(C)[Si](OCc1ccc(C(CNC(=O)OC(C)(C)C)C(=O)Nc2ccc3cnccc3c2)cc1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(CO)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To tert-butyl 3-(isoquinolin-6-ylamino)-3-oxo-2-(4-((triisopropylsilyloxy)methyl)phenyl)propylcarbamate (E138) in THF at 0° C. was added TBAF, and the solution was stirred for 45 min at 0° C. The compound was poured into EtOAc and washed with NH4Cl(sat), dried (MgSO4), filtered, and evaporated. Column chromatography (SiO2, 6% MeOH/CH2Cl2) gave pure tert-butyl 2-(4-(hydroxymethyl)phenyl)-3-(isoquinolin-6-ylamino)-3-oxopropylcarbamate (E139).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[CH:6][C:7]=1Cl.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>C(O)C>[Cl:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[CH:6][C:7]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: C1CNCCN1
Reactant: Cn1ncc(Cl)c(Cl)c1=O
Solvent: CCO
Product: Cn1ncc(N2CCNCC2)c(Cl)c1=O
Yield: 60.2 %

Procedure:
A solution of 4.48 g (25 mmoles) of 4,5-dichloro-2-methyl-3(2H)-pyridazinone and 17.2 g (200 mmoles) of piperazine in 45 ml of anhydrous ethanol is boiled for 4 hours under stirring and reflux cooling. The solvent is evaporated in vacuo and the residue is dissolved in a mixture of water and dichloromethane. The organic phase is washed with water, dried and evaporated. The residue is triturated with ether. Thus 3.44 g (60%) of the desired compound are obtained. M.p.: 83°-87° C.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([S:26][CH3:27])[N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[N:20]=4)=[CH:15][CH:14]=3)[N:11]=[C:5]2[N:4]2[C@H:28]3[CH2:33][CH2:32][CH2:31][C@H:29]3[N:30]=[C:3]12.[OH:34]OS([O-])=O.[K+]>CC#N.CO>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([S@@:26]([CH3:27])=[O:34])[N:10]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[N:20]=4)=[CH:17][CH:18]=3)[N:11]=[C:5]2[N:4]2[C@H:28]3[CH2:33][CH2:32][CH2:31][C@H:29]3[N:30]=[C:3]12
Reactant: CSc1c2c(nn1Cc1ccc(-c3cccc(F)n3)cc1)N1C(=N[C@@H]3CCC[C@@H]31)N(C)C2=O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: CN1C(=O)c2c(nn(Cc3ccc(-c4cccc(F)n4)cc3)c2[S@@](C)=O)N2C1=N[C@@H]1CCC[C@@H]12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(methylthio)-2-(4-(6-fluoropyridin-2-yl)benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one (35.2 mg, 0.076 mmol) is dissolved in CH3CN (0.5 mL) and CH3OH (2 mL), and then an aqueous solution of oxone (93.7 mg, 0.152 mmol) is added. The reaction mixture is stirred at room temperature for 20 h, and then purified by a semi-preparative HPLC to give pure product as white solids. MS (ESI) m/z 479.2 [M+H]+.
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[C:13]([C:15]1[C:16]([NH:33][C:34]2[CH:39]=[C:38]([O:40][CH3:41])[C:37]([Cl:42])=[CH:36][C:35]=2[Cl:43])=[C:17]2[S:23][C:22]([C:24]3[CH:32]=[CH:31][C:27]([C:28]([OH:30])=O)=[CH:26][CH:25]=3)=[CH:21][C:18]2=[N:19][CH:20]=1)#[N:14]>CN(C)C=O>[C:13]([C:15]1[C:16]([NH:33][C:34]2[CH:39]=[C:38]([O:40][CH3:41])[C:37]([Cl:42])=[CH:36][C:35]=2[Cl:43])=[C:17]2[S:23][C:22]([C:24]3[CH:32]=[CH:31][C:27]([C:28]([NH2:3])=[O:30])=[CH:26][CH:25]=3)=[CH:21][C:18]2=[N:19][CH:20]=1)#[N:14]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1cc(Nc2c(C#N)cnc3cc(-c4ccc(C(=O)O)cc4)sc23)c(Cl)cc1Cl
Solvent: CN(C)C=O
Product: COc1cc(Nc2c(C#N)cnc3cc(-c4ccc(C(N)=O)cc4)sc23)c(Cl)cc1Cl
Temperature: 60 °C
Reaction time: 2 h
Yield: 9.4 %

Procedure:
1,1′-Carbonyldiimidazole (100 mg, 0.61 mmol) is added to a suspension of 4-{6-cyano-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridine-2-yl}benzoic acid (130 mg, 0.28 mmol) in 10 mL of N,N-dimethylformamide. After stirring at 60° C. for 2 hours the reaction mixture is allowed to cool to room temperature and ammonia gas is bubbled through the mixture for 15 minutes. The mixture is stirred at room temperature for an additional 60 minutes and poured into 50 g of ice and stirred for 30 minutes. The mixture is adjusted to pH 4 with concentrated hydrochloric acid and stirred for 60 minutes. The resulting precipitate is collected by filtration washing with water and dried under reduced pressure. The resulting solid is purified by flash column chromatography eluting with a gradient of ethyl acetate to 20% methanol in ethyl acetate to provide 12.3 mg of 4-{6-cyano-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridine-2-yl}benzamide as a gray solid, mp>300° C.; 1H NMR (DMSO-d6) δ 3.86 (s, 3H), 7.40 (s, 1H), 7.48 (s, 1H), 7.78 (s, 1H), 7.82 (d, J=8 Hz, 2H), 7.97 (d, J=8 Hz, 2H), 8.06 (s, 2H), 8.08 (s, 1H), 8.63 (s, 1H), 9.78 (s, 1H); MS 468.9, 471.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2.[N+:12]([O-])([O-:14])=[O:13].[K+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2
Reactant: Clc1cccc2ccncc12
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1ccc(Cl)c2cnccc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 8-chloroisoquinoline (1 mmol) in concentrated sulfuric acid at 0° C. was added potassium nitrate (1.1 mmol). The reaction mixture was warmed to room temperature and stirred at room temperature for 5 hours. The reaction mixture was basified Solid precipitated was column purified to afford a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1.[ClH:25]>C(Cl)Cl.CCOCC>[ClH:25].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:9])([F:10])[F:11])[C:3]=1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c(F)cccc2C(F)(F)F)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Fc1cccc(C(F)(F)F)c1C1CCNCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl 4-(2-fluoro-6-(trifluoromethyl)phenyl)piperidine-1-carboxylate (22, 0.219 g, 0.63 mmol) in CH2Cl2 (4 mL) was added 2 N HCl (2.0 N solution in Et2O, 4 mL), and the mixture was stirred at ambient temperature for 4 h. The reaction mixture was diluted with Et2O (50 mL) and the solids were collected by filtration to give 4-(2-fluoro-6-(trifluoromethyl)phenyl)piperidine hydrochloride (23) as an offwhite solid (158 mg, 88%): 1H NMR (300 MHz, DMSO-d6) δ 8.82 (br s, 1H), 8.50 (br s, 1H), 7.66-7.48 (m, 3H), 3.42-3.33 (m, 2H), 3.24-2.95 (m, 3H), 2.35-2.15 (m, 2H), 1.87-1.74 (m, 2H); ESI MS m/z 248 [M+H]+.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[F:27][C:28]1([F:34])[CH2:30][CH:29]1[C:31](O)=[O:32]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:31]([CH:29]3[CH2:30][C:28]3([F:34])[F:27])=[O:32])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: O=C(O)C1CC1(F)F
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)C1CC1(F)F

Procedure:
The title compound, light brown solid (81 mg, 75%), MS (ISP) m/z=431.4 [(M+H)+], mp 189° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 2,2-difluoro-cyclopropane-carboxylic acid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:55]([C:58]1[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[CH:60][CH:59]=1)=[C:56]=[O:57]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:56]([NH:55][C:58]2[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[CH:60][CH:59]=2)=[O:57])[CH2:49][CH2:48]1
Reactant: COc1ccc(N=C=O)cc1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(NC(=O)N2CCC(CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)cc1
Yield: 26 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 1-isocyanato-4-methoxybenzene as starting materials in 26% yield. LCMS for C32H34ClN8O3 (M+H)+: m/z=613.2.
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([O:7][C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[C:21]([C:22]2[CH:27]=[CH:26][C:25]([O:28]C)=[CH:24][CH:23]=2)=[C:20]([C:30]2[CH:35]=[CH:34][C:33]([O:36]C)=[CH:32][CH:31]=2)[N:19]=[CH:18]1)=[O:9])[CH3:6].O>ClCCl>[CH2:5]([O:7][C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[C:21]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[C:20]([C:30]2[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=2)[N:19]=[CH:18]1)=[O:9])[CH3:6]
Reactant: CCOC(=O)CCCCCCCn1cnc(-c2ccc(OC)cc2)c1-c1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CCCCCCCn1cnc(-c2ccc(O)cc2)c1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.5 %

Procedure:
Boron tribromide (1.3 ml) was added to a solution of 1-(7-ethoxycarbonylheptyl)-4,5-bis(4-methoxyphenyl)-imidazole (1.25 g) in dry dichloromethane (30 ml). The reaction was stirred at room temperature for 4 h, cooled and water (20 ml) was carefully added. The resulting purple precipitate was collected and column chromatography on silica gel eluted with a dichloromethane:methanol gradient, followed by recrystallisation from ethanol and water gave 1-(7-ethoxycarbonylheptyl)-4,5-bis(4-hydroxyphenyl)-imidazole as a white solid (0.58 g, 50%), m.p. 186°-187°.
Reaction SMILES: C1(C(C2C=CC=CC=2)CCO[C:11](=[S:15])[CH:12]([F:14])[F:13])C=CC=CC=1.[NH2:22][CH2:23][CH:24]1[O:28][C:27](=[O:29])[N:26]([C:30]2[CH:35]=[CH:34][C:33]([N:36]3[CH:41]=[CH:40][C:39](=[O:42])[CH2:38][CH2:37]3)=[C:32]([F:43])[CH:31]=2)[CH2:25]1>CC#N.CN(C=O)C>[F:13][CH:12]([F:14])[C:11]([NH:22][CH2:23][CH:24]1[O:28][C:27](=[O:29])[N:26]([C:30]2[CH:35]=[CH:34][C:33]([N:36]3[CH:37]=[CH:38][C:39](=[O:42])[CH2:40][CH2:41]3)=[C:32]([F:43])[CH:31]=2)[CH2:25]1)=[S:15]
Reactant: FC(F)C(=S)OCCC(c1ccccc1)c1ccccc1
Reactant: NCC1CN(c2ccc(N3C=CC(=O)CC3)c(F)c2)C(=O)O1
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=C1C=CN(c2ccc(N3CC(CNC(=S)C(F)F)OC3=O)cc2F)CC1
Reaction time: 36 h

Procedure:
Difluoro-thioacetic acid-O-(3,3-diphenyl-propyl)ester (84 mg, 0.25 mmol) is added to a solution of 1-[4-(5-aminomethyl-2-oxo-oxazolidin-3-yl)-2-fluoro-phenyl]-2,3-dihydro-1H-pyridin-4-one in MeCN (1.2 mL) and DMF (0.2 mL). This solution is stirred for 36 h at which time the reaction is concentrated under reduced pressure and the title compound is purified by silica gel column chromatography (eluent: 1% MeOH in EtOAc). Yield 45 mg (41%). MS (m/z) 400 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ 11.32 (s, 1H), 7.83–7.51 (m, 4H), 6.69 (t, J=55.2 Hz, 1H), 5.25–5.17 (m, 2H), 4.39 (t, J=9.1 Hz,1H), 4.22–4.03 (m, 6H), 3.55–3.49 (m, 2H).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][C:6]1[S:10][C:9]2=[N:11][C:12]([Cl:14])=[CH:13][N:8]2[CH:7]=1.Cl[CH2:16][N:17]1[CH2:21][CH:20]([CH2:22][CH2:23][CH3:24])[CH2:19][C:18]1=[O:25].O>O1CCOCC1>[Cl:5][C:6]1[S:10][C:9]2=[N:11][C:12]([Cl:14])=[C:13]([CH2:16][N:17]3[CH2:21][CH:20]([CH2:22][CH2:23][CH3:24])[CH2:19][C:18]3=[O:25])[N:8]2[CH:7]=1
Reactant: Clc1cn2cc(Cl)sc2n1
Reactant: CCCC1CC(=O)N(CCl)C1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: C1COCCO1
Product: CCCC1CC(=O)N(Cc2c(Cl)nc3sc(Cl)cn23)C1
Yield: 74 %

Procedure:
At room temperature, AlCl3 (0.237 g, 1.78 mmol, 2 eq) is added to a solution of 2,6-dichloroimidazo[2,1-b][1,3]thiazole x172 (0.171 g, 0.89 mmol, 1 eq) and 1-(chloromethyl)-4-propylpyrrolidin-2-one x63 (0.185 g, 1.06 mmol, 1.2 eq) in 1,4-dioxane (25 ml). The mixture is heated at reflux during 2 hours. After cooling, water (20 ml) is added and the aqueous layer is extracted with CH2Cl2 (3×20 ml). The combined organic layers are dried on anhydrous MgSO4, filtered and evaporated under reduced pressure. The crude is purified on silicagel (CH2Cl2/AcOEt: 9/1) yielding 200 mg of 1-[(2,6-dichloroimidazo[2,1-b][1,3]thiazol-5-yl)methyl]-4-propylpyrrolidin-2-one 93 as a white solid.
Reaction SMILES: Br[CH:2]([CH3:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])=O.[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[C:22]1([C:25]([NH2:27])=[NH:26])[CH2:24][CH2:23]1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:12][C:6]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=1[C:3]1[N:27]=[C:25]([C:22]2([C:16]3[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=3[Cl:14])[CH2:24][CH2:23]2)[NH:26][C:2]=1[CH3:13]
Reactant: N=C(N)C1(c2ccc(Cl)cc2Cl)CC1
Reactant: CC(Br)C(=O)c1ccc(Cl)cc1Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1[nH]c(C2(c3ccc(Cl)cc3Cl)CC2)nc1-c1ccc(Cl)cc1Cl
Temperature: 85 °C
Reaction time: 12 h

Procedure:
2-Bromo-1-(2,4-dichloro-phenyl)-propane-1-one (28.2 mg, 0.1 mmol), (1-(2,4-Dichloro-phenyl)-cyclopropanecarboxamidine (22.9 mg, 0.1 mmol) and Huenigs Base (20 μl, 0.1 mmol) were dissolved in 1 mL dry DMF and stirred for 12 hours at 85° C. The crude reaction mixture was purified by reversed phase chromatography to provide 4-(2,4-Dichloro-phenyl)-2-[1-(2,4-dichloro-phenyl)-cyclopropyl]-5-methyl-1H-imidazole. (3.9 mg, 9.5%). ESI MS m/z=411.2, 413.2.
Reaction SMILES: [CH3:1][S:2][CH:3]([CH2:6][CH:7]=[CH2:8])[C:4]#[N:5].C(Cl)[Cl:10]>>[Cl:10][C:3]([S:2][CH3:1])([CH2:6][CH:7]=[CH2:8])[C:4]#[N:5]
Reactant: C=CCC(C#N)SC
Reactant: ClCCl
Product: C=CCC(Cl)(C#N)SC

Procedure:
2×10-2 moles of 2-methylthio-4-pentenenitrile are then dissolved in 50 ml of dry CH2Cl2. 2×10-2 moles of SO2Cl2 dissolved in 10 ml of CH2Cl2 are added dropwise. The mixture is stirred until gas evolution has ceased (silicone oil trap). The solvent is evaporated off and distillation is carried out at 82° C. at a pressure of 12 mm of mercury. 2-Chloro-2-methylthio-4-pentene-nitrile is obtained in a yield of over 95%.