Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[S:2]([C:5]1[N:13]=[C:12]2[N:7]([C:8]([O:18][CH3:19])=[N:9][C:10]3[N:17]=[CH:16][CH:15]=[CH:14][C:11]=32)[N:6]=1)(=[O:4])=[O:3].[Cl:20][C:21]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:22]=1[NH2:23].N1C=CC=CC=1.CS(C)=O>C(#N)C>[Cl:20][C:21]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:22]=1[NH:23][S:2]([C:5]1[N:13]=[C:12]2[N:7]([C:8]([O:18][CH3:19])=[N:9][C:10]3[N:17]=[CH:16][CH:15]=[CH:14][C:11]=32)[N:6]=1)(=[O:4])=[O:3]
Reactant: COc1nc2ncccc2c2nc(S(=O)(=O)Cl)nn12
Reactant: Nc1c(Cl)cccc1Cl
Solvent: c1ccncc1
Solvent: CS(C)=O
Solvent: CC#N
Product: COc1nc2ncccc2c2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nn12
Yield: 8.8 %

Procedure:
A mixture of 2.0 g (6.7 mmol) of 2-chlorosulfonyl-5-methoxypyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine, 2.2 g (13.3 mmol) of 2,6-dichloroaniline, 0.50 g (67 mmol) of pyridine, and 30 mL of dry acetonitrile was prepared and to this was added with stirring at ambient temperature 95 microliters (1.3mmol) of dimethyl sulfoxide. The mixture was allowed to react overnight and was then concentrated by evaporation under reduced pressure. The residue was diluted with dichloromethane and water and the resulting mixture was filtered to remove the insoluble solids. The organic phase was recovered and the dichloromethane was removed by evaporation under reduced pressure. The residue was diluted with hexane, recovered by filtration, and redissolved in dichloromethane. The resulting solution was filtered through silica gel and concentrated by evaporation under reduced pressure. The residue was diluted with hexane, recovered by filtration, and dried to obtain 0.25 g of the title compound as a light tan powder melting at 290°-293° C. with decomposition. The proton NMR spectrum of this was compatible with the assigned structure.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:14][S:15][CH3:16].O.NN>C(O)C>[NH2:3][CH2:12][CH:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:14][S:15][CH3:16]
Reactant: CSCC(CN1C(=O)c2ccccc2C1=O)NC(=O)OC(C)(C)C
Agent: NN
Solvent: O
Solvent: CCO
Product: CSCC(CN)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl [1-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-(methylsulfanyl)propan-2-yl]carbamate (from Step 3 of PrepEx 4.11) (10.0 g, 28.6 mmol) in ethanol (150 mL) was added dropwise hydrazine hydrate (15.7 g, 286 mmol) at 0° C. and then the reaction mixture was allowed to warm to ambient temperature. After 30 minutes, the reaction mixture was heated to reflux. After two hours, the reaction mixture was cooled, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel to give tert-butyl [1-amino-3-(methylsulfanyl)propan-2-yl]carbamate. MS ESI calc'd. for C9H21N2O2S [M+H]+ 221. found 221. 1H NMR (400 MHz, CD3OD) δ 3.66-3.63 (m, 1H), 2.83-2.79 (m, 1H), 2.64-2.50 (m, 3H), 2.12 (s, 3H), 1.45 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.N[CH:19]1C2C(=CC=CC=2)[CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[NH:21][C:20]1=[O:35]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:30][CH:31]2[CH2:32][CH2:33][CH2:34][CH2:29][CH2:22][NH:21][C:20](=[O:35])[CH2:19]2)=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: NC1C(=O)NC(c2ccccn2)c2ccccc21
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1CCCCCNC(=O)C1

Procedure:
Following General Procedure B above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 3-amino-8-octanelactam (i.e., 2-oxo-1-azacyclononane prepared as described in General Procedure 5-C), the title compound was prepared as a solid having a melting point of >220° C.
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6](=[O:18])[N:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N+:15]([O-:17])=[O:16])[N:8]=2)[CH2:3][CH2:2]1.N([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]2[N:39]([C:40]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:38]=[N:37][N:36]=2)=[CH:25][CH:24]=1)=[N+]=[N-].[H-].[Na+]>>[CH:1]1([C:4]2[N:5]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]4[N:39]([C:40]([C:53]5[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=5)([C:47]5[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=5)[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)[N:38]=[N:37][N:36]=4)=[CH:27][CH:28]=3)[C:6](=[O:18])[N:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N+:15]([O-:17])=[O:16])[N:8]=2)[CH2:3][CH2:2]1
Reactant: O=c1[nH]c(C2CC2)nn1-c1ccccc1[N+](=O)[O-]
Reactant: [N-]=[N+]=NCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Product: O=c1n(-c2ccccc2[N+](=O)[O-])nc(C2CC2)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 59 %

Procedure:
The alkylation of 5-cyclopropyl-2,4-dihydro-2-(2-nitrophenyl)-3H-1,2,4-triazol-3-one with 5-[4'-bromomethyl)biphenyl-2-yl]-N-trityltetrazole (see Example 2, Step B) was carried out as described in Example 4, Step D, except that a 20% excess of sodium hydride and 20% excess of the alkylating agent were used. After work-up, the crude product mixture was flash chromatographed on silica gel (124 mL for 0.467 mmole, eluted with 0.5% MeOH/CH2Cl2) to give a 59% yield of the desired material as a yellow foam, homogeneous by TLC in 2% MeOH/CH2Cl2, mass spectrum (FAB) m/e 723 (M+1)+.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]([F:26])([F:25])[O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][CH2:17][C:16]3([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:15]2=[O:24])=[CH:10][CH:9]=1.[Cl:27][C:28]1[N:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>>[Cl:27][C:28]1[N:33]=[CH:32][C:31]([S:34]([N:21]2[CH2:20][CH2:19][C:16]3([C:15](=[O:24])[N:14]([C:11]4[CH:12]=[CH:13][C:8]([O:7][C:6]([F:5])([F:25])[F:26])=[CH:9][CH:10]=4)[CH2:18][CH2:17]3)[CH2:23][CH2:22]2)(=[O:36])=[O:35])=[CH:30][CH:29]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Solvent: CC(=O)O
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1ccc(Cl)nc1)CC2

Procedure:
The title compound was prepared in analogy to example 180 step D from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one acetic acid salt (described in example 180 step C) and 6-chloro-pyridine-3-sulfonyl chloride. White solid. MS (ESI): 490.2 (MH+).
Reaction SMILES: [Cl-].[NH4+].O.[Cl:4][C:5]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([N+:15]([O-])=O)=[CH:7][N:6]=1>CO>[Cl:4][C:5]1[N:6]=[CH:7][C:8]([NH2:15])=[CH:9][C:10]=1[C:11]([F:14])([F:12])[F:13]
Reactant: O=[N+]([O-])c1cnc(Cl)c(C(F)(F)F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Nc1cnc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 64 %

Procedure:
Reduced iron (1.3 g) and ammonium chloride (2.1 g) were added to water (40 mL), and the mixture was stirred at room temperature for 5 min. A solution of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (1.8 g) in methanol (40 mL) was added, and the mixture was stirred at room temperature for 1 hr. Reduced iron (2.3 g) was added, and the mixture was further stirred at the same temperature for 3 hr. The reaction mixture was filtered through celite, and celite was washed with ethyl acetate. The filtrate was extracted with ethyl acetate, and the extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→1:1) to give the title compound as a solid (yield 1.0 g, 65%).
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[CH3:6].[CH:17]1([C:22]([OH:24])=[O:23])[CH2:21][CH:20]=[CH:19][CH2:18]1>C1CCCCC1.C(Cl)Cl>[CH:17]1([C:22]([O:24][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([CH3:7])[CH3:6])=[O:23])[CH2:21][CH:20]=[CH:19][CH2:18]1
Reactant: CC(C)(OC(=N)C(Cl)(Cl)Cl)c1ccccc1
Reactant: O=C(O)C1CC=CC1
Solvent: C1CCCCC1
Solvent: ClCCl
Product: CC(C)(OC(=O)C1CC=CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.4 %

Procedure:
A solution of 2-phenylpropan-2-yl 2,2,2-trichloroacetimidate (23.85 g, 85 mmol) in cyclohexane (85 mL) was treated with a solution of cyclopent-3-enecarboxylic acid (4.77 g, 42.5 mmol) in methylene chloride (43 mL), and the mixture was stirred for about 16 hours at room temperature during which time a colorless solid precipitated. The precipitate was collected by filtration and rinsed with hexanes. The combined filtrates were concentrated in vacuo to yield a residue. The residue was purified over a 330 g silica gel column, eluting at 100 mL/min with a 0-5% ethyl acetate/hexanes gradient over 2 column volumes, then 5% ethyl acetate/hexanes for 2 column volumes, then a 5-40% ethyl acetate/hexanes gradient over 10 column volumes to yield 2-phenylpropan-2-yl cyclopent-3-enecarboxylate (8.84 g, 38.4 mmol, 90% yield) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[N:19]3[CH2:20][CH2:21][CH2:22][C:23]([CH3:27])([C:24](O)=[O:25])[C:18]3=[N:17][N:16]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][C:12]([CH3:14])=[N:11][CH:10]=1.Cl.[Cl:29][C:30]1[CH:31]=[C:32]([CH:37]=[CH:38][C:39]=1[Cl:40])[C:33]([NH:35][NH2:36])=O.C(N(CC)CC)C.O>CN(C=O)C>[Cl:29][C:30]1[CH:31]=[C:32]([C:33]2[O:25][C:24]([C:23]3([CH3:27])[CH2:22][CH2:21][CH2:20][N:19]4[C:15]([C:5]5[CH:6]=[CH:7][C:8]([C:9]6[O:13][C:12]([CH3:14])=[N:11][CH:10]=6)=[C:3]([O:2][CH3:1])[CH:4]=5)=[N:16][N:17]=[C:18]34)=[N:36][N:35]=2)[CH:37]=[CH:38][C:39]=1[Cl:40]
Reactant: NNC(=O)c1ccc(Cl)c(Cl)c1
Reactant: COc1cc(-c2nnc3n2CCCC3(C)C(=O)O)ccc1-c1cnc(C)o1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(-c2nnc3n2CCCC3(C)c2nnc(-c3ccc(Cl)c(Cl)c3)o2)ccc1-c1cnc(C)o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 26.6 %

Procedure:
A mixture of 3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-8-methyl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid (100 mg), 3,4-dichlorobenzohydrazide hydrochloride (79 mg) and triethylamine (114 μL) in DMF (1.5 ml) was stirred at room temperature for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in acetonitrile (1.5 ml), trichloroacetonitrile (114 μL) and triphenylphosphine (286 mg) were added, and the mixture was stirred at 70° C. for 2 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (38.8 mg).
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:25](O)=[O:26].Cl.[NH2:33][C:34]1([C:45]2[N:50]=[CH:49][CH:48]=[CH:47][N:46]=2)[CH2:37][N:36]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:35]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:25]([NH:33][C:34]1([C:45]2[N:46]=[CH:47][CH:48]=[CH:49][N:50]=2)[CH2:35][N:36]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:37]1)=[O:26]
Reactant: CC(C)(C)OC(=O)N1CC(N)(c2ncccn2)C1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)c(F)c12
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncccn5)CN(C(=O)OC(C)(C)C)C4)ccc3C)c(F)c12
Reaction time: 8 h
Yield: 59.3 %

Procedure:
To a mixture of 3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (60 mg, 0.142 mmol) and tert-butyl 3-amino-3-(pyrimidin-2-yl)azetidine-1-carboxylate hydrochloride (40.8 mg, 0.142 mmol) in DMF (1 ml) was added PyBOP (74.1 mg, 0.142 mmol) and triethylamine (0.020 ml, 0.142 mmol). The reaction mixture was stirred overnight, and then diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The crude product was then purified by column chromatography (2% methanol in chloroform) to afford tert-butyl 3-(3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzamido)-3-(pyrimidin-2-yl)azetidine-1-carboxylate Yield: 55 mg (59%). LCMS: (ES+) m/z observed=554.2 (M+H)+ of 4-fluoro-2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(3-(pyrimidin-2-yl)azetidin-3-ylcarbamoyl)phenyl)benzofuran-3-carboxamide.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[NH:11][C:12]1[N:17]=[C:16]([N:18]2[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]2)[CH:15]=[CH:14][N:13]=1.[CH3:24][C:25]1[N:26]([C:30]2[CH:31]=[C:32]([NH2:40])[CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=2)[CH:27]=[CH:28][N:29]=1>>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:40][C:32]2[CH:33]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:35]=[C:30]([N:26]3[CH:27]=[CH:28][N:29]=[C:25]3[CH3:24])[CH:31]=2)=[O:8])=[CH:4][C:3]=1[NH:11][C:12]1[N:17]=[C:16]([N:18]2[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]2)[CH:15]=[CH:14][N:13]=1
Reactant: Cc1cn(-c2ccnc(Nc3cc(C(=O)O)ccc3C)n2)cn1
Reactant: Cc1nccn1-c1cc(N)cc(C(F)(F)F)c1
Product: Cc1cn(-c2ccnc(Nc3cc(C(=O)Nc4cc(-n5ccnc5C)cc(C(F)(F)F)c4)ccc3C)n2)cn1

Procedure:
4-methyl-3-[4-(4-methylimidazol-1-yl)pyrimidin-2-yl-amino]benzoic acid and 3-(2-methylimidazol-1-yl)-5-trifluoromethyl-phenylamine prepared in Preparation 31 were used according to the similar procedure to Example 1 to give the titled compound as yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]2[C:9]([CH:10]=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2.O.[CH2:18]([OH:20])[CH3:19]>>[CH2:18]([O:20][CH2:2][C:3]1[C:4]2[C:9]([CH:10]=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH3:19]
Reactant: CCO
Reactant: ClCc1c2ccccc2cc2ccccc12
Solvent: O
Product: CCOCc1c2ccccc2cc2ccccc12
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A solution of 9-chloromethylanthracene (5.2 g, 23 mmole) obtained in Synthesis Example 2-(1) in ethanol (700 ml) was reacted with stirring for 10 hours at room temperature, poured into H2O (700 ml), and extracted with methylene chloride (500 ml×1). The resulting organic layer was dried over anhydrous MgSO4 and evaporated. The residual crude solid (4.25 g) was recrystallized from 50% THF/H2O to give 4.02 g of 9-ethoxymethylanthracene as orange yellow crystals, mp. 74°-75° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9]OCCCC)=[C:4]([O:15][CH2:16][O:17][CH3:18])[C:3]=1[C@H:19]1[CH2:21][C@H:20]1[NH:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1)=[O:24].[OH2:33]>O1CCOCC1.Cl>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C@H:19]2[CH2:21][C@H:20]2[NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=2)=[O:24])[C:4]=1[O:15][CH2:16][O:17][CH3:18])(=[O:33])[CH3:9]
Reactant: O
Reactant: CCCCOC=Cc1ccc(F)c([C@H]2C[C@H]2NC(=O)Nc2ccc(Cl)cn2)c1OCOC
Agent: Cl
Solvent: C1COCCO1
Product: COCOc1c(C(C)=O)ccc(F)c1[C@H]1C[C@H]1NC(=O)Nc1ccc(Cl)cn1
Reaction time: 0.25 h

Procedure:
(+,−)-N-(cis-2-(2-fluoro-5-butoxyvinyl-6-methoxymethoxy)-cyclopropyl)-N′-(5-chloropyrid-2-yl)-urea (Example 55) was dissolved in dioxane and a few drops of dilute hydrochloric acid was added. The solution was stirred for 15 minutes, was diluted water and evaporated. The residue was co-evaporated with water to yield the title product as a solid. 1H-NMR CDCl3 1.3 (q, 1H) 1.5 (q, 1H) 2.1 (q, 1H) 2.5 (s, 3H) 3.4 (m, 1H) 3.5 (s, 3H) 5.1 (m, 2H) 6.8 (m, 2H) 7.4-7.6 (m, 2H) 7.8 (d, 1H) 9.1 (bs, 1H) 9.8 (bs, 1H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:13]=[C:12]([NH:14][C:15](=[O:24])[C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])[C:6]2[O:7][C:8]([CH3:11])=[C:9]([CH3:10])[C:5]=2[CH:4]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].O>C(O)(=O)C>[C:25]([NH:2][C:3]1[CH:13]=[C:12]([NH:14][C:15](=[O:24])[C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])[C:6]2[O:7][C:8]([CH3:11])=[C:9]([CH3:10])[C:5]=2[CH:4]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1oc2c(NC(=O)c3c(Cl)cccc3Cl)cc(N)cc2c1C
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1cc(NC(=O)c2c(Cl)cccc2Cl)c2oc(C)c(C)c2c1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 82.4 %

Procedure:
A mixture of 5-amino-7-(2,6-dichlorobenzoylamino)-2,3-dimethylbenzo[b]furan hydrochloride (116 mg) and acetic anhydride (74 mg) in acetic acid (1 ml) was stirred at 80° C. for 1.5 hours. The reaction mixture was cooled and to the mixture was added water. The separated solid was collected, washed with water and dried to give 5-acetylamino-7-(2,6-dichlorobenzoylamino)-2,3-dimethylbenzo[b]furan (97 mg).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:19]=[CH:18][C:6]([CH2:7][CH:8]2[CH2:13][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:11][CH2:10][NH:9]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[C:31](Cl)(=[O:34])[O:32][CH3:33]>ClCCl.CCOCC>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]2[CH2:13][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:11][CH2:10][N:9]2[C:31]([O:32][CH3:33])=[O:34])=[CH:18][CH:19]=1
Reactant: COC(=O)C1CCNC(Cc2ccc(C(F)(F)F)cc2)C1
Reactant: COC(=O)Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(Cc2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
Methyl 2-(4-(trifluoromethyl)benzyl)piperidine-4-carboxylate (9.5 g, 31.53 mmol) was dissolved in DIPEA (8.24 mL, 47.29 mmol) and dichloromethane (150 mL). Methyl carbonochloridate (3.58 g, 37.50 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 1 h, diluted with ether and washed with 1 M HCl. The organic layer was washed with Na2CO3 (aq), dried MgSO4, filtered through celite and the solvent was evaporated to yield dimethyl 2-(4-(trifluoromethyl)benzyl)piperidine-1,4-dicarboxylate (10.9 g, 96%).
Reaction SMILES: [Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21].[NH2:22][C:23]1[N:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][CH:32]([OH:35])[CH2:31][CH2:30]2)=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7]([NH:22][C:23]3[N:28]=[CH:27][C:26]([N:29]4[CH2:34][CH2:33][CH:32]([OH:35])[CH2:31][CH2:30]4)=[CH:25][CH:24]=3)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21]
Reactant: Nc1ccc(N2CCC(O)CC2)cn1
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(S(C)=O)ncc12
Solvent: Cc1ccccc1
Product: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCC(O)CC4)cn3)ncc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.7 %

Procedure:
6-Bromo-8-cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (2.50 g, 6.76 mmol) and 6′-amino-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-ol (1.96 g, 10.13 mmol) were combined in toluene (10.0 ml) under nitrogen. The reaction mixture was heated to reflux and stirred for 4 h. The reaction mixture was cooled to RT and filtered. The solids were washed with additional toluene (75 mL total) and dried in vacuo to produce a yellow powder (566 mg, 1.13 mmol). MS (APCI+) 499, 501 (M+2, 100); 1H NMR δ(400 MHz, DMSO-d6) 10.06 (s, 1H), 8.96 (s, 1H), 8.04 (s, 1H), 7.83 (d, J=9.3 Hz, 1H), 7.46 (d, J=7.3 Hz, 1H), 5.93-5.89 (m, 1H), 4.71 (s, 1H), 3.65-3.60 (m, 1H), 3.53-3.51 (m, 2H), 2.88-2.83 (m, 2H), 2.57 (s, 3H), 2.18 (br, 2H), 1.90-1.81 (m, 5H), 1.59-1.48 (m, 3H); Anal. Calc'd for C23H27Br1N6O2, 0.45H2O: C, 54.43; H, 5.54; N, 16.56. Found: C, 54.04; H, 5.23; N, 16.33.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl-].[Al+3].[Cl-].[Cl-].[C:19](Cl)(=[O:21])[CH3:20].Cl>ClCCl>[F:1][CH:2]1[C:7]([F:8])([C:19](=[O:21])[CH3:20])[CH:6]=[CH:5][C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:3]1
Reactant: CC(=O)Cl
Reactant: Fc1ccc(-c2ccccc2)cc1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)C1(F)C=CC(c2ccccc2)=CC1F
Temperature: 20 °C
Reaction time: 10 h
Yield: 106.3 %

Procedure:
To one liter of dichloromethane were added 191 g of 3,4-difluorobiphenyl and 160 g of aluminum chloride, and maintaining the temperature to about 20° C., 86 g of acetyl chloride was gradually added dropwise under stirring. After completion of the dropwise addition, stirring was continued for 10 hours, and then 100 ml of hydrochloric acid was added to the mixture and the mixture was stirred well and washed. The mixture was further washed with water and the solvent was removed under reduced pressure. The residue was purified by distillation under reduced pressure (164° C./1 mmHg) to obtain 250 g of 3,4-difluoro-4-acetylbiphenyl.
Reaction SMILES: [CH3:1][C:2]([NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:7])([CH3:4])[CH3:3].[Br-].[Na+].C([Li])CCC.[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1.O>[C:23]1([CH2:22][CH2:14][C:13]2[C:8]([C:6]([NH:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: ClCc1ccccc1
Reactant: Cc1cccnc1C(=O)NC(C)(C)C
Agent: [Br-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)NC(=O)c1ncccc1CCc1ccccc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
Tetrahydrofuran (125 mL), N-(1,1-dimethylethyl)-3-methyl-2-pyridine carboxamide (1 equivalent) and sodium bromide (1.3 g) are charged and cooled to -40° C. under nitrogen. Two equivalents of n-butyllithium are then added over 40 minutes. When half the n-butyllithium is added the mixture turns purple. Benzyl chloride (1.05 equivalents) is then added dropwise (1:1 solution in tetrahydrofuran) over 40-50 minutes while the temperature is maintained at -40° C. After 30 minutes at -40° C., the mixture is diluted with water (250 ml) and the organic phase separated. This phase is dried over sodium sulphate and the solvent removed yielding an oil from which solid product may crystallize. Product yield of 94% determined by internal standard assay on gas chromatograph.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[O:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[C:32](O)=[O:33]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:32]([CH:28]5[CH2:29][CH2:30][CH2:31][O:27]5)=[O:33])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: O=C(O)C1CCCO1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)C1CCCO1

Procedure:
The title compound, white solid (87 mg, 82%), MS (ISP) m/z=427.4 [(M+H)+], mp 160° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydro chloride (intermediate B) (100 mg, 0.25 mmol) and (RS)-tetrahydro-furan-2-carboxylic acid.