Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH2:9][C@H:10]([C:12]1[N:13]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:14](=[O:23])[C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:22])[CH3:11]>O1CCOCC1.C(Cl)Cl.C(O)(=O)C.[Cl-].[Na+].O>[Cl:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[C:14](=[O:23])[N:13]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:12]([C@@H:10]([NH:9][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1)[CH3:11])=[CH:21]2
Reactant: Clc1cc(Cl)ncn1
Reactant: C[C@H](N)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: O
Product: C[C@H](Nc1cc(Cl)ncn1)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Temperature: 60 °C

Procedure:
A mixture of 4,6-dichloropyrimidine (200 mg, 1.34 mmol, 1.6 eq.), compound 1 (250 mg, 0.84 mmol, 1.0 eq.), and TEA (350 μL, 2.5 mmol, 3.0 eq.) in 1,4-dioxane (7.5 mL) was heated at 60° C. for 3 days. The reaction was charged with additional 4,6-dichloropyrimidine (100 mg, 0.67 mmol, 0.8 eq.) and TEA (175 μL, 1.3 mmol, 1.5 eq.) and heated at 80° C. for 16 h. The reaction mixture was diluted with DCM, 5% aqueous acetic acid, and brine (50 mL each), separated, and the organic phase was washed with 0.1 M NaOH and brine (15 mL each), dried on Na2SO4, and concentrated. The residue was purified by flash chromatography eluting with 300 mL each 10/20/30/40/50% EtOAc/hexanes to give (S)-8-chloro-3-(1-(6-chloropyrimidin-4-ylamino)ethyl)-2-phenylisoquinolin-1(2H)-one 77. ESI-MS m/z: 411.14 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:11][C:12]1[CH:46]=[CH:45][C:44]([C:47]2[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=2)=[CH:43][C:13]=1[C:14]([NH:16][C:17]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[N:33](C(OC(C)(C)C)=O)[CH2:34][CH3:35])[CH:24]=[CH:23][C:18]=1[C:19]([O:21]C)=[O:20])=[O:15])(=O)C>>[CH2:34]([NH:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:25]1[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[C:17]([NH:16][C:14](=[O:15])[C:13]2[CH:43]=[C:44]([C:47]3[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=3)[CH:45]=[CH:46][C:12]=2[OH:11])[CH:26]=1)[CH3:35]
Reactant: CCN(C(=O)OC(C)(C)C)c1ccccc1-c1ccc(C(=O)OC)c(NC(=O)c2cc(-c3cccnc3)ccc2OC(C)=O)c1
Solvent: O=C(O)C(F)(F)F
Product: CCNc1ccccc1-c1ccc(C(=O)O)c(NC(=O)c2cc(-c3cccnc3)ccc2O)c1
Temperature: 52.5 °C
Reaction time: 2 h

Procedure:
A trifluoroacetic acid (4.0 mL) solution of the obtained methyl 2-(2-acetoxy-5-(pyridin-3-yl)benzamido)-4-(2-((tert-butoxycarbonyl)(ethyl)amino)phenyl)benzoate was stirred at room temperature for 2 hours and 30 minutes. The solvent was evaporated under reduced pressure, and toluene was added thereto. The solvent was evaporated under reduced pressure, and diisopropyl ether was added to the obtained residue. The solid substance was collected by filtration. Dioxane (4.0 mL) and a 1 mol/L aqueous solution of sodium hydroxide (0.40 mL) were added to the obtained solid substance, followed by stirring at 50 to 55° C. for 2 hours. The reaction mixture was cooled to room temperature and then adjusted to a pH of 7.4 with 1 mol/L hydrochloric acid. The solvent was evaporated under reduced pressure, and water was added to the obtained residue. The solid substance was collected by filtration to obtain 0.032 g of 4-(2-(ethylamino)phenyl)-2-(2-hydroxy-5-(pyridin-3-yl)benzamido)benzoic acid as a white solid.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[N:3]=1.[CH3:16][C:17]1([CH3:24])[O:21][CH:20]([CH2:22][OH:23])[CH2:19][O:18]1.[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[CH3:16][C:17]1([CH3:24])[O:21][CH:20]([CH2:22][O:23][C:2]2[S:6][N:5]=[C:4]([S:7][CH2:8][C:9]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=3)[N:3]=2)[CH2:19][O:18]1
Reactant: Cc1ccc(CSc2nsc(Cl)n2)cc1
Reactant: CC1(C)OCC(CO)O1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(CSc2nsc(OCC3COC(C)(C)O3)n2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 76.5 %

Procedure:
To 2 g of N,N-dimethylformamide, 0.257 g of 5-chloro-3-(4-methylbenzyl)thio-1,2,4-thiadiazole and 0.145 g of 2,2-dimethyl-1,3-dioxolane-4-methanol were dissolved, and added 48 mg of sodium hydride (60% in oil) at about 0° C., followed by stirring at about 0° C. for 30 minutes and at room temperature for 4 hours. Then, the reaction mixture was added to saturated sodium chloride aqueous solution, and extracted with tert-butylmethylether. The organic layer was concentrated, and the residue obtaind was subjected to silica gel column chromatography to obtain 0.27 g of 5-(2,2-dimethyl-1,3-dioxolane-4-yl)methoxy-3-(4-methylbenzyl)thio-1,2,4-thiadiazole.
Reaction SMILES: CS(OCC1C(C2C=CC(Cl)=CC=2)=CSC=1C(F)(F)F)(=O)=O.FC1C(F)=C(O)C(F)=CC=1CCC(OCC)=O.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]2[C:48]([CH2:56][O:57][C:58]3[C:63]([F:64])=[CH:62][C:61]([CH2:65][CH2:66][C:67]([O:69]CC)=[O:68])=[C:60]([F:72])[C:59]=3[F:73])=[C:49]([C:52]([F:55])([F:54])[F:53])[S:50][CH:51]=2)=[CH:43][CH:42]=1>>[Cl:40][C:41]1[CH:42]=[CH:43][C:44]([C:47]2[C:48]([CH2:56][O:57][C:58]3[C:63]([F:64])=[CH:62][C:61]([CH2:65][CH2:66][C:67]([OH:69])=[O:68])=[C:60]([F:72])[C:59]=3[F:73])=[C:49]([C:52]([F:53])([F:54])[F:55])[S:50][CH:51]=2)=[CH:45][CH:46]=1
Reactant: CCOC(=O)CCc1cc(F)c(OCc2c(-c3ccc(Cl)cc3)csc2C(F)(F)F)c(F)c1F
Agent: CCOC(=O)CCc1cc(F)c(O)c(F)c1F
Agent: CS(=O)(=O)OCc1c(-c2ccc(Cl)cc2)csc1C(F)(F)F
Product: O=C(O)CCc1cc(F)c(OCc2c(-c3ccc(Cl)cc3)csc2C(F)(F)F)c(F)c1F

Procedure:
The title compound was prepared according to the procedure described in Example 183 by coupling of [4-(4-chlorophenyl)-2-(trifluoromethyl)thiophen-3-yl]methyl methanesulfonate and ethyl 3-(2,3,5-trifluoro-4-hydroxyphenyl)propanoate followed by hydrolysis of ethyl 3-(4-((4-(4-chlorophenyl)-2-(trifluoromethyl)thiophen-3-yl)methoxy)-2,3,5-trifluorophenyl)propanoate to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J=7.3 Hz, 2H), 7.41 (s, 1H), 7.40 (d, J=7.0 Hz, 2H), 6.75 (m, 1H), 5.07 (s, 2H), 2.95 (t, J=8.1 Hz, 2H), 2.73 (t, J=8.0 Hz, 2H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[OH:7][C@@:8]([CH3:16])([C:12]([F:15])([F:14])[F:13])[C:9](O)=[O:10].[Cl:17][C:18]1[CH:24]=[C:23]([I:25])[CH:22]=[CH:21][C:19]=1[NH2:20].C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C>ClCCl.CN(C=O)C>[Cl:17][C:18]1[CH:24]=[C:23]([I:25])[CH:22]=[CH:21][C:19]=1[NH:20][C:9](=[O:10])[C@:8]([OH:7])([CH3:16])[C:12]([F:15])([F:14])[F:13]
Reactant: C[C@@](O)(C(=O)O)C(F)(F)F
Reactant: Nc1ccc(I)cc1Cl
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@@](O)(C(=O)Nc1ccc(I)cc1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.4 %

Procedure:
Oxalyl chloride (1.07 ml) was added dropwise to a stirred suspension of (R)-(+)-2-hydroxy-2-methyl-3,3,3-trifluoropropanoic acid (Method 9) (1.95 g) in dichloromethane (42 ml) and DMF (0.8 ml). The mixture was stirred at ambient temperature for 2 hours and was then added over 35 minutes to a solution of 2-chloro-4-iodoaniline (2.5 g) and 2,6-di-tert-butylpyridine (2.94 ml) in dichloromethane (40 ml) and stirred a further 18 hours. Volatile material was removed by evaporation and the residue was purified by flash chromatography on silica gel eluting with dichloromethane to give the title compound (2.85 g) as a solid. NMR: 1.6 (s, 3H), 7.7 (m, 2H), 7.8 (d, 1H), 7.9 (br s, 1H); MS: 392 (M−H)−.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]([C:6]1[CH:7]=[C:8]([CH:29]=[CH:30][CH:31]=1)[CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:5].CC(C)([O-])C.[K+].[N:38]1([C:44]2[N:49]=[CH:48][C:47]([CH:50]=O)=[CH:46][N:45]=2)[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>CN(C=O)C>[N:38]1([C:44]2[N:45]=[CH:46][C:47]([CH:50]=[CH:9][C:8]3[CH:7]=[C:6]([CH:31]=[CH:30][CH:29]=3)[C:4]([O:3][CH3:2])=[O:5])=[CH:48][N:49]=2)[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1
Reactant: O=Cc1cnc(N2CCOCC2)nc1
Reactant: COC(=O)c1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C=Cc2cnc(N3CCOCC3)nc2)c1
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
[3-(Methoxycarbonyl)benzyl](triphenyl)phosphonium bromide (930 mg) was mixed with DMF (6 ml), and potassium tert-butoxide (300 mg) was added thereto at 0° C., followed by stirring for 30 minutes. 2-(Morpholin-4-yl)pyrimidine-5-carboaldehyde (300 mg) was added to the reaction mixture, followed by stirring at 0° C. for 1 hour, and stirring again at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and EtOAc and a saturated aqueous sodium hydrogen carbonate solution were then added thereto. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain methyl 3-{2-[2-(morpholin-4-yl)pyrimidin-5-yl]vinyl}benzoate (377 mg).
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10]2[CH:15]=[C:14]([NH:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[C:13]([C:31]3[O:35][N:34]=[C:33]([CH3:36])[N:32]=3)=[CH:12][N:11]=2)=[N:7][CH:8]=1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[CH3:36][C:33]1[N:32]=[C:31]([C:13]2[C:14]([NH:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[CH:15][C:10]([NH:9][C:6]3[N:7]=[CH:8][C:3]([C:1]#[N:2])=[N:4][CH:5]=3)=[N:11][CH:12]=2)[O:35][N:34]=1
Reactant: Cc1noc(-c2cnc(Nc3cnc(C#N)cn3)cc2NCC2CCN(C(=O)OC(C)(C)C)CC2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1noc(-c2cnc(Nc3cnc(C#N)cn3)cc2NCC2CCNCC2)n1
Reaction time: 3 h
Yield: 56.8 %

Procedure:
To a solution of tert-butyl 4-((2-(5-cyanopyrazin-2-ylamino)-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyridin-4-ylamino)methyl)piperidine-1-carboxylate (9 mg, 0.018 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.15 mL) at r.t. After 3 hr, the solution was evaporated to dryness and purified by ion exchange on SCX-II acidic resin (500 mg) eluting with methanol, then 2M ammonia-methanol. The basic fractions were combined and the solvent was removed in vacuo to give the title compound as a yellow solid (4 mg, 56%).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:5](=[C:7]3[N:39]=[C:38]4[N:40]=[C:31]([C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][C:37]=54)[N:30]=[C:28]4[NH:29][C:21]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=54)=[N:20][C:18]4=[N:19][C:11]([C:12]5[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=54)=[N:10][C:9]=2[NH:8]3)[CH:6]=1.C1C=C2C3[N-]C(C2=CC=1)=NC1=NC(C2C1=CC=CC=2)=NC1=NC(C2C1=CC=CC=2)=NC1[N-]C(=C2C=1C=CC=C2)N=3.[O-2].[Ti+4:82]>S(=O)(=O)(O)O>[Ti:82].[CH:2]1[CH:1]=[CH:6][C:5]2[C:4](=[C:9]3[N:10]=[C:11]4[N:19]=[C:18]([C:17]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=54)[N:20]=[C:21]4[NH:29][C:28]([C:27]5[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=54)=[N:30][C:31]4=[N:40][C:38]([C:37]5[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=54)=[N:39][C:7]=2[NH:8]3)[CH:3]=1
Reactant: [Ti+4]
Agent: O=S(=O)(O)O
Agent: [O-2]
Agent: c1ccc2c(c1)-c1nc-2nc2[nH]c(nc3nc(nc4[nH]c(n1)c1ccccc41)-c1ccccc1-3)c1ccccc21
Product: [Ti]
Temperature: 5 °C
Reaction time: 1 h

Procedure:
The phthalocyanine derivative prepared in Referential Example or the other material was added, in a proportion shown in Table 9, to 10 parts of the TiOPc crude prepared in Example 1 and mixed together, and then the mixture was gradually dissolved in 200 parts of 97% sulfuric acid at 2°. The resulting mixture was stirred for 1 hour with maintaining its temperature at not higher than 5° C. And then this sulfuric acid solution was poured slowly into 2000 parts of ice water with stirring at a high speed, and crystals precipitated were filtrated. The crystals were washed with distilled water until the acid did not remain, and dried to give a titanium phthalocyanine compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[F:14])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: Nc1ccccc1F
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Product: O=C(Nc1ccccc1F)c1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
A mixture of 4-chloro-3-nitrobenzoyl chloride was reacted with 2-Fluoro-phenylamine to produce 4-Chloro-N-(2-fluoro-phenyl)-3-nitro-benzamide according to the procedure of Example 10A, which was treated sequentially using the procedures from Examples 22A and 22B to provide the title product.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([Cl:15])=[C:8]([CH2:10][NH:11][C:12](=[O:14])[CH3:13])[CH:9]=1)(=[O:3])[CH3:2].CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>C1(C)C=CC=CC=1>[Cl:15][C:7]1[CH:6]=[CH:5][C:4]([C:1](=[O:3])[CH:2]=[CH:18][N:19]([CH3:21])[CH3:20])=[CH:9][C:8]=1[CH2:10][NH:11][C:12](=[O:14])[CH3:13]
Reactant: CC(=O)NCc1cc(C(C)=O)ccc1Cl
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CC(=O)NCc1cc(C(=O)C=CN(C)C)ccc1Cl
Temperature: 105 °C

Procedure:
A mixture of N-[(5-acetyl-2-chlorophenyl)methyl]acetamide (13.0 g, 57.8 mmol; prepared according to a procedure described in EP 1586552-A1) and N,N-dimethylformamide dimethyl acetal (13.8 g, 115.8 mmol) in toluene (130 mL) was heated at 105° C. overnight. The reaction mixture was then concentrated, and the resulting solid was washed with diethyl ether and n-pentane to yield the title product as a solid (10.0 g).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:19](=[O:39])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([CH2:35][CH:36]([CH3:38])[CH3:37])[CH:30]=2)[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:35]([C:31]1[CH:30]=[C:29]([C:25]2[CH:24]=[C:23]([C:21]3[CH2:20][C:19](=[O:39])[NH:18][C:9]4[CH:10]=[C:11]([C:14]([F:16])([F:15])[F:17])[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:28]=[CH:27][CH:26]=2)[CH:34]=[CH:33][N:32]=1)[CH:36]([CH3:37])[CH3:38]
Reactant: CC(C)Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)ccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cc1cc(-c2cccc(C3=Nc4ccc(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from (2-{3-[3-(2-isobutyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M258) (0.25 g, 0.45 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (180 mg, 91%).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][O:7][C:8]1[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[CH:10]2[S:16][C:17]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:18][C:9]=12)(=O)[CH3:2].CSC.B.CSC.C(O)(=O)C(O)=O>C1COCC1.C(O)C.CCOCC>[CH2:1]([NH:4][CH2:5][CH2:6][O:7][C:8]1[CH2:13][CH2:12][S:11](=[O:14])(=[O:15])[CH:10]2[S:16][C:17]([S:19]([NH2:22])(=[O:20])=[O:21])=[CH:18][C:9]=12)[CH3:2]
Reactant: CC(=O)NCCOC1=C2C=C(S(N)(=O)=O)SC2S(=O)(=O)CC1
Agent: B
Agent: O=C(O)C(=O)O
Solvent: CCO
Solvent: C1CCOC1
Solvent: CSC
Product: CCNCCOC1=C2C=C(S(N)(=O)=O)SC2S(=O)(=O)CC1
Reaction time: 0.5 h

Procedure:
Under nitrogen, a suspension of 5,6-dihydro-4-[2-(acetamido)ethoxy]thieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide (2.0 g, 0.0054 mole) in THF (50 ml) was heated to just barely refluxing. Borane methyl sulfide (1.6 ml of 10M solution) was introduced dropwise while methyl sulfide was distilled. Heating was continued for 30 minutes with slow distillaion of THF. The mixture then was evaporated to dryness in vacuo. The residue was treated cautiously with 6N HCl (25 ml). The resulting solution was heated at reflux for 1 hour and then evaporated to dryness in vacuo. The residual oily product was chromatographed on a column of silica gel, the product being eluted with 80 chloroform: 20 methanol: 2 conc. NH4OH (v/v/v). Evaporation of the eluant left the product as a colorless glass that was dried at 46° C. under high vacuum for 20 hours; 1.2 g (63%). The product was converted to the hydrogen oxalate salt by treatment of a solution in absolute ethanol (12 ml) with a solution of oxalic acid (1 equiv.) in ether (25 ml), yield, 1.2 g, m.p. dec. 219°-221° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=O)[CH:10]=1>C(OC(=O)C)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]=[CH:15][C:11]2[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=2)[N:3]=1
Reactant: Cc1cccc(C)n1
Reactant: O=Cc1cccnc1
Solvent: CC(=O)OC(C)=O
Product: Cc1cccc(C=Cc2cccnc2)n1

Procedure:
A solution of 2,6-dimethyl pyridine (5.8 ml, 50 mMol), pyridine-3-carbaldehyde (4.9 ml, 52 mMol) in acetic anhydride (9.5 ml) is heated under reflux for 10 hours. The acetic anhydride is then evaporated in vacuo and the residue purified on column chromatography (silica gel 900 g). The column is first eluted with toluene/acetone 9:1 (7 L), then with toluene/acetone 4:1 (5 L) and finally with toluene/acetone 2:1 (5 L). The fractions containing the desired compound are combined, and evaporated in vacuo. The solid residue is recrystallized from methylene chloride/diisopropyl ether and 4.28 g of a colorless oil which solidify upon standing at 6-8° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[C:6]([N+:15]([O-])=O)=[CH:5][CH:4]=1>[Pt]=O.C(O)C>[NH2:15][C:6]1[C:7]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COC(=O)COc1nc(OC)ccc1[N+](=O)[O-]
Agent: O=[Pt]
Solvent: CCO
Product: COC(=O)COc1nc(OC)ccc1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 6-methoxy-2-(methoxycarbonyl)methoxy-3-nitropyridine, platinum oxide and ethanol is stirred for 3 hours at room temperature under hydrogen atmosphere. The reaction system is purged with nitrogen, then, the reaction solution is filtrated through Celite, and the filtrate is concentrated. The residue is subjected to silica gel column chromatography to obtain 3-amino-6-methoxy-2-(methoxycarbonyl)methoxypyridine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH2:11]2)=[C:7]([NH2:9])[CH:8]=1.Cl.[N:23]1([CH2:30][CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36]([CH2:39][C:40](O)=O)=[CH:35][CH:34]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[N:23]1([CH2:30][CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][NH:9][C:7]3[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[CH:10]3[CH2:19][CH2:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=4)[CH2:11]3)=[CH:35][CH:34]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(O)Cc1ccc(OCCN2CCCCCC2)cc1
Reactant: COc1ccc(C2CCc3cc(OC)ccc3C2)c(N)c1
Agent: Cl
Product: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NCCc1ccc(OCCN3CCCCCC3)cc1)C2
Yield: 17.7 %

Procedure:
Synthesized from 5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine (425 mg) and [4-(2-azepan-1-ylethoxy)phenyl]acetic acid hydrochloride (700 mg) was used according to an analogous synthetic method to Example 337 to provide the title compound (140 mg).
Reaction SMILES: [Na].[C:2]([CH:5]([C:11]([CH3:20])([CH3:19])[CH:12](Cl)[CH2:13][C:14]([Cl:17])([Cl:16])Cl)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:4])[CH3:3].Cl>C(O)C>[C:2]([C:5]1([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11]([CH3:19])([CH3:20])[CH:12]1[CH:13]=[C:14]([Cl:16])[Cl:17])(=[O:4])[CH3:3]
Reactant: CCOC(=O)C(C(C)=O)C(C)(C)C(Cl)CC(Cl)(Cl)Cl
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C1(C(C)=O)C(C=C(Cl)Cl)C1(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
Sodium (0.5 g) was dissolved in 37 ml of absolute ethanol, and 2.9 g of ethyl 2-acetyl-4,6,6,6-tetrachloro-3,3-dimethylhexanoate was added thereto. The mixture was stirred at room temperature for 30 minutes and then heated at a temperature of 50° C. for 24 hours with stirring. The mixture was rendered neutral with an ethereal solution of hydrogen chloride, while cooled with ice and the solvent was distilled off. The resulting residue was dissolved in diethyl ether, and the solution was washed with water, dried over anhydrous magnesium sulfate, and distilled to give 2.01 g (88% yield) of ethyl 1-acetyl-2-(2,2-dichlorovinyl)3,3-dimethylcyclopropanecarboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:15][NH:16][C:17](=O)[CH:18]([CH3:20])[CH3:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B.O1CCCC1.CCN(C(C)C)C(C)C.II>C1COCC1.CCOC(C)=O.CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH:14]([CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[CH2:15][NH:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)C(=O)NCC(C1CCCCC1)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: B
Agent: II
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CNCC(C1CCCCC1)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
A solution of the product from Step I (1.23 g, 3.21 mmol) and borane-tetrahydrofurane complex (9.6 mL, 9.63 mmol, 1 M in THF) in THF (20 mL) was heated at 60° C. for 1 hour. The mixture was allowed to cool to ambient temperature followed by addition of MeOH (5 mL) and DIPEA (7.5 mL). Next, iodine (1.62 g, 6.42 mmol) in THF (10 mL) was added and the mixture stirred for 30 min. The mixture was diluted with EtOAc and successively washed with 10% aqueous Na2S2O5 and brine, dried (Na2SO4), and evaporated. The residue was purified by flash chromatography (hexane:EtOAc 1:1→EtOAc→EtOAc:MeOH:NEt3 90:5:5) to afford the title compound (904 mg) as a yellow oil. MS m/z 368.3 (M++1).
Reaction SMILES: ClC1C=CC=CC=1CN1CCN(CCC2C=CC([C:17]([O:19][CH2:20][CH2:21]CC)=[O:18])=CC=2)CC1.ClC1C=CC=CC=1C[N:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][C:42]2[CH:50]=[CH:49][C:45]([C:46](O)=O)=[CH:44][CH:43]=2)[CH2:36][CH2:35]1>C(O)CCC>[N:37]1([CH2:40][CH2:41][C:42]2[CH:43]=[CH:44][C:45]([CH2:46][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:49][CH:50]=2)[CH2:36][CH2:35][NH:34][CH2:39][CH2:38]1
Reactant: O=C(O)c1ccc(CCN2CCN(Cc3ccccc3Cl)CC2)cc1
Reactant: CCCCOC(=O)c1ccc(CCN2CCN(Cc3ccccc3Cl)CC2)cc1
Solvent: CCCCO
Product: CCOC(=O)Cc1ccc(CCN2CCNCC2)cc1

Procedure:
n-butyl 4-{2-[1-(2-chlorobenzyl)-piperazin-4-yl]-ethyl}-benzoate from 4-{2-[1-(2-chlorobenzyl)-piperazin-4-yl]-ethyl}-benzoic acid and n-butanol.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12]2[N:13]([N:17]=[C:18]([NH2:20])[N:19]=2)[CH:14]=[CH:15][CH:16]=1)(=[O:4])=[O:3].Br[C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12]2[N:13]([N:17]=[C:18]([NH:20][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)[CH:23]=3)[N:19]=2)[CH:14]=[CH:15][CH:16]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccccc1-c1cccn2nc(N)nc12
Reactant: CN1CCN(c2cccc(Br)c2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2cccc(Nc3nc4c(-c5ccccc5S(C)(=O)=O)cccn4n3)c2)CC1

Procedure:
[8-(2-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 8-(2-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.260 mmol) and 1-(3-bromo-phenyl)-4-methyl-piperazine (80.0 mg, 0.314 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (30.0 mg, 0.0549 mmol) as the ligand in a manner analogous to Step 2d and was isolated as a yellow foam (0.074 g, 62%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.49m (d, J=6.6 Hz, 1H), 8.24 (d, J=7.9 Hz, 1H), 7.74 (t, J=6.8 Hz, 1H), 7.67 (t, J=7.8 Hz, 1H), 7.49 (d, J=7.3 Hz, 2H), 7.29-7.25 (m, 1H), 7.19 (t, J=7.8 Hz, 1H), 6.99 (t, J=6.9 Hz, 1H), 6.90 (d, J=7.9 Hz, 1H), 6.73 (s, 1H), 6.57 (d, J=8.2 Hz, 1H), 3.24-3.19 (m, 4H), 2.96 (s, 3H), 2.59-2.54 (m, 4H), 2.36 (s, 3H). MS=463 (MH)+.