Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([CH2:17][O:18][C:19]3[CH:51]=[CH:50][C:22]([CH2:23][CH:24]4[S:28][C:27](=[O:29])[N:26](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[C:25]4=[O:49])=[CH:21][CH:20]=3)=[CH:16][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.C(=O)([O-])O.[Na+]>O>[OH2:18].[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([CH2:17][O:18][C:19]3[CH:51]=[CH:50][C:22]([CH2:23][CH:24]4[S:28][C:27](=[O:29])[NH:26][C:25]4=[O:49])=[CH:21][CH:20]=3)=[CH:16][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([CH2:17][O:18][C:19]3[CH:51]=[CH:50][C:22]([CH2:23][CH:24]4[S:28][C:27](=[O:29])[NH:26][C:25]4=[O:49])=[CH:21][CH:20]=3)=[CH:16][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1SC(Cc2ccc(OCc3ccc4c(c3)ncn4Cc3ccccc3)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1NC(=O)C(Cc2ccc(OCc3ccc4c(c3)ncn4Cc3ccccc3)cc2)S1
Temperature: 50 °C
Reaction time: 3 h
Yield: 101.4 %

Procedure:
A mixture of 0.26 g of 5-[4-(1-benzylbenzimidazol-5-ylmethoxy)benzyl]-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 29), 3 ml of acetic acid and 1 ml of water was stirred for 3 hours at 50° C. in oil bath. At the end of this time, the reaction mixture was neutralized with sodium hydrogencarbonate and then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure, and the resulting residue was recrystallized from a mixture of ethanol and methanol, to give 116 mg of the title compound, melting at 185°-187° C.
Reaction SMILES: [CH:1]1([CH:7]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([N:28]([CH3:36])[CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:27])=[CH:22][CH:21]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:37]1[CH:42]=[CH:41][C:40]([CH2:43]O)=[CH:39][CH:38]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH:1]1([CH:7]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([N:28]([CH3:36])[CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:27])=[CH:24][CH:25]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][CH2:43][C:40]4[CH:41]=[CH:42][N:37]=[CH:38][CH:39]=4)=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(O)cc3c2C)C2CCCCC2)cc1
Reactant: OCc1ccncc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(OCc4ccncc4)cc3c2C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66 %

Procedure:
Ethyl 3-{[(4-{[cyclohexyl(5-hydroxy-3-methyl-1-benzofuran-2-yl)methyl]amino}phenyl)carbonyl](methyl)amino}propanoate (0.23 g) synthesized in Example A155(1) was dissolved in tetrahydrofuran (5 mL), and 4-pyridinemethanol (62 mg), tributylphosphine (0.21 mL) and 1,1′-(azodicarbonyl)dipiperidine (0.21 g) were added to the solution under ice-cooling. The ice bath was removed, the reaction mixture was stirred at room temperature for 12 hr, then hexane (5 mL) was added to the mixture, and the precipitate was filtered off through celite. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1, volume ratio) to give the title object compound (0.18 g, 64%) as a pale-yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[CH:4][CH:3]=1.[CH2:14]([Mg]Br)[CH2:15][CH3:16]>C1COCC1>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](=[O:7])[CH2:14][CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)c1ccc(Br)cc1
Reactant: CCC[Mg]Br
Solvent: C1CCOC1
Product: CCCC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 82.1 %

Procedure:
To a solution of 4-bromo-N-methoxy-N-methylbenzamide (13.4 g, 54.2 mmol) in THF (200 ml) was added n-PrMgBr (2M THF solution, 54.0 ml, 108 mmol) at 0° C. The mixture was stirred at room temperature for 45 minutes. Further n-PrMgBr (13.5 ml, 27.0 mmol) was added at 0° C., and the mixture was stirred at room temperature for 30 minutes. The excess reagent was quenched with saturated aqueous NH4Cl (200 ml), and ether (300 ml) was added. The organic layer was separated and the aqueous layer was extracted with ether (300 ml). The combined organic layer was washed with water (200 ml) and brine (200 ml), dried over Na2SO4, and concentrated in vacuo. The obtained residue was chromatographed on a column of silica gel eluting with hexane/ethyl acetate (15:1) to give 10.1 g (82%) of the title compound as a yellow solid.
Reaction SMILES: [OH-].[Na+].[SH:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].Cl[CH2:14][C:15]([F:18])([F:17])[F:16]>CN(C)C=O>[F:16][C:15]([F:18])([F:17])[CH2:14][S:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: FC(F)(F)CCl
Reactant: O=C(O)c1ccccc1S
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1SCC(F)(F)F
Temperature: 100 °C
Yield: 23.1 %

Procedure:
A two-necked flask was charged under nitrogen with 45 ml of dimethylformamide and 16 g of a 50% strength by weight aqueous sodium hydroxide solution. After addition of 15 g of 2-mercaptobenzoic acid, 18 g of chlorotrifluoroethane were passed in at 0° C. and the reaction mixture was then transferred into a stirred autoclave. The mixture was heated at 100° C. for 12 hours (maximum pressure: 2.5 bar), allowed to cool and the crude product was then precipitated by addition of concentrated hydrochloric acid. The dried crude product was recrystallized from hot formic acid, giving 5.3 g of 2-(2',2',2'-trifluoroethylthio)benzoic acid having a melting point of 226°-227° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]#[N:21])=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH:18]=O)[CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]#[N:21])=[C:7]([C:12]3[CH:17]=[C:16]([CH2:18][NH:32][S:29]([C:26]4[CH:25]=[CH:24][C:23]([F:22])=[CH:28][CH:27]=4)(=[O:31])=[O:30])[CH:15]=[N:14][CH:13]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1c(-c2cncc(C=O)c2)c(C#N)c2ccc(Cl)cc21
Reactant: NS(=O)(=O)c1ccc(F)cc1
Product: Cn1c(-c2cncc(CNS(=O)(=O)c3ccc(F)cc3)c2)c(C#N)c2ccc(Cl)cc21

Procedure:
6-Chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile (Example 126) and 4-fluoro-benzenesulfonamide are processed according to the method described in Example 170 to give N-[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-4-fluoro-benzenesulfonamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.74 (s, 3H), 4.23 (s, 2H), 7.33-7.41 (m, 3H), 7.72 (d, J=8.6 Hz, 1H), 7.82-7.88 (m, 2H), 7.95 (d, J=1.5 Hz, 2H), 8.44 (s, 1H), 8.62 (d, J=2.0 Hz, 1H), 8.73 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z 455.0746 [(M+H)+ Calcd for C22H17ClFN4O2S: 455.0745].
Reaction SMILES: [C:1]([C:3]1[C:4]([C:19]2[O:23][C:22]([CH3:24])=[C:21]([C:25]([O:27]C)=[O:26])[CH:20]=2)=[C:5]2[CH:18]=[N:17][NH:16][C:6]2=[N:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)#[N:2].[OH-].[Li+].O.Cl>O1CCOCC1.O>[C:1]([C:3]1[C:4]([C:19]2[O:23][C:22]([CH3:24])=[C:21]([C:25]([OH:27])=[O:26])[CH:20]=2)=[C:5]2[CH:18]=[N:17][NH:16][C:6]2=[N:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)#[N:2]
Reactant: COC(=O)c1cc(-c2c(C#N)c(-c3ccc(O)cc3)nc3[nH]ncc23)oc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1oc(-c2c(C#N)c(-c3ccc(O)cc3)nc3[nH]ncc23)cc1C(=O)O
Reaction time: 5 h
Yield: 8.3 %

Procedure:
To a suspension of 0.066 g (0.10 mmol) of methyl 5-(5-cyano-6-(4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine-4-yl)-2-methylfuran-3-carboxylate in 2 ml of dioxane/water (80:20) are added 0.011 g (0.4 mmol) of lithium hydroxide. The mixture is brought to 50° C. for 5 h. After return to room temperature, the mixture is poured onto 20 ml of iced water and adjusted to pH=1-2 with 0.1N hydrochloric acid solution. The solution is left to stand for 18 h at 4° C. The precipitate obtained is filtered. The residue obtained is purified by preparative reverse-phase HPLC (acetonitrile/water eluent) to yield 3 mg (6%) of 5-(5-cyano-6-(4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine-4-yl)-2-methylfuran-3-carboxylic acid in the form of a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[CH:3]=1.[C:13]([OH:21])(=[O:20])[C:14]([CH2:16][C:17](O)=[O:18])=[CH2:15]>C1(C)C(C)=CC=CC=1>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][C:2]([N:1]2[C:17](=[O:18])[CH2:16][CH:14]([C:13]([OH:21])=[O:20])[CH2:15]2)=[CH:3][C:4]=1[CH3:12])=[O:7]
Reactant: COC(=O)c1ccc(N)cc1C
Reactant: C=C(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1C
Product: COC(=O)c1ccc(N2CC(C(=O)O)CC2=O)cc1C
Temperature: 25 °C

Procedure:
10 g (60.5 mmol) methyl 4-amino-2-methyl-benzoate and 7.9 g (60.5 mmol) itaconic acid are suspended in 50 ml xylene and refluxed for seven hours. The reaction mixture is cooled to ambient temperature and evaporated to dryness. The residue is suspended in methanol. The undissolved solid is filtered off and dried until the weight remains constant.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=O.[NH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][CH2:19][NH:18][CH2:13][C:12]1[CH:15]=[CH:16][CH:17]=[C:10]([CH2:9][CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH:11]=1
Reactant: NCCc1ccccn1
Reactant: O=Cc1cccc(CCOC2CCCCO2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(CCNCc2cccc(CCOC3CCCCO3)c2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
To a solution of 3-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-benzaldehyde (Example 50, step A, 6.1 g) and 2-(2-aminoethyl)pyridine (3.18 g, 3.1 ml) in toluene (150 mL) was added p-toluene sulfonic acid (100 mg). The reaction was heated at reflux in a Dean-Stark apparatus for couple of hours. Around 2 mL water were displaced. The mixture was cooled and washed with aqueous bicarbonate and concentrated in vacuo. The residue was taken up in ethanol (100 ml) and cooled. Sodium borohydride (1.0 g) was added slowly and the reaction left 1 hour to warm to room temperature. Water was added (100 mL) and ethanol removed by distillation. The reaction was partitioned between aqueous bicarbonate and ethyl acetate. The organic layers were dried over sodium sulfate and concentrated in vacuo to give yellow oil (6.5 g). The material was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][N+:12]([O-:14])=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[C:22]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][N+:12]([O-:14])=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1ccc(S(=O)(=O)C[N+](=O)[O-])cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(S(=O)(=O)C[N+](=O)[O-])cc1)c1ccccc1
Reaction time: 2 h
Yield: 19.5 %

Procedure:
(4-Aminophenylsulphonyl)nitromethane (0.86 g, 4 mmol) was dissolved in dry tetrahydrofuran (20 ml) under an atmosphere of argon. Triethylamine (0.61 g, 6 mmol) was added, followed by benzoyl chloride (0.62 g, 4.4 mmol). The mixture was then stirred for 2 hours. The precipitated triethylamine hydrochloride was removed by filtration and the filtrate concentrated in vacuo. The orange oil obtained was purified by MPLC, eluting with dichloromethane/ethyl acetate (9:1 v/v) to give (4-benzamidophenylsulphonyl)nitromethane (0.25 g, 20% yield) as a solid, m.p. 211°-212° C.; microanalysis, found: C, 52.3; H, 3.7; N, 8.4%; C14H12N2O5S requires: C, 52.5; H, 3.75; N, 8.75%.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][NH2:17]>>[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][NH:17][C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CN(C)CCN
Product: CCCCCCC/C=C/C(=O)NCCN(C)C

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and N,N-dimethylethane-1,2-diamine as starting materials to give the aimed compound.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-:3])=[O:2].[H-].[Na+].S(O[CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28]1)(C1C=CC(C)=CC=1)(=O)=O>CC(N(C)C)=O.O>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2[CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])[CH2:28]1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCN(C(=O)OC(C)(C)C)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCCC(Cn2ncc3c([N+](=O)[O-])cccc32)C1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 39.7 %

Procedure:
To a solution of 4-nitro-1H-indazole (0.200 g, 1.23 mmol) in DMA (3 mL) was added 60% sodium hydride (0.074 g, 1.84 mmol) at ambient temperature. After 30 minutes, tert-butyl 3-(tosyloxymethyl)piperidine-1-carboxylate (0.544 g, 1.47 mmol) was added. The mixture was heated at 100° C. overnight, diluted with water, extracted with DCM, dried (phase separator silicone treated filter paper), concentrated and the residue purified on silica gel (10-50% EtOAc in DCM) to provide tert-butyl 3-((4-nitro-1H-indazol-1-yl)methyl)piperidine-1-carboxylate (0.176 g, 40% yield) as a yellow gum.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[O:12][CH2:11][C@@H:10]([CH3:13])[N:9]([C:14]2[CH:19]=[C:18]([Cl:20])[N:17]=[C:16]([NH2:21])[N:15]=2)[CH2:8]1)(=O)=O.[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C=O)C.CCOC(C)=O>[N:22]([CH2:6][C@H:7]1[O:12][CH2:11][C@@H:10]([CH3:13])[N:9]([C:14]2[CH:19]=[C:18]([Cl:20])[N:17]=[C:16]([NH2:21])[N:15]=2)[CH2:8]1)=[N+:23]=[N-:24]
Reactant: C[C@@H]1CO[C@H](COS(C)(=O)=O)CN1c1cc(Cl)nc(N)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H]1CO[C@H](CN=[N+]=[N-])CN1c1cc(Cl)nc(N)n1
Temperature: 80 °C
Reaction time: 20.5 h
Yield: 80.8 %

Procedure:
A mixture of crude [(2S,5R)-4-(2-amino-6-chloro-4-pyrimidinyl)-5-methyl-2-morpholinyl]methyl methanesulfonate (1.53 g, about 85% pure, 3.88 mmol) and sodium azide (0.382 g, 5.88 mmol) in DMF (75 mL) was stirred at 80° C. under nitrogen for 20.5 hours. Another portion of sodium azide (0.094 g, 1.45 mmol) was then added and stirring continued at 80° C. for an additional 6.5 hours. The mixture was then cooled, diluted with EtOAc (200 mL), washed with water (2×150 mL) and brine (1×150 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (60 g SiO2, 1:1 hexanes/CH2Cl2 to 45:45:10 hexanes/CH2Cl2/CH3CN gradient) to give the title compound (890 mg) as a thick colorless oil. LC-MS (ES) m/z=284, 286 [M+H]+.
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:35]=[CH:34][C:33]([N:36]2[CH:40]=[N:39][N:38]=[N:37]2)=[CH:32][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][C:16]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([CH2:19][CH2:20]OS(C)(=O)=O)[CH2:15]1)=[O:13])([O:3][CH2:4][CH3:5])=[O:2].[CH2:41]([O:43][CH2:44][CH2:45][N:46]1[C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=2[N:48]=[C:47]1[NH:55][CH:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1)[CH3:42]>>[C:1]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:35]=[CH:34][C:33]([N:36]2[CH:40]=[N:39][N:38]=[N:37]2)=[CH:32][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][C:16]([CH2:19][CH2:20][N:59]2[CH2:58][CH2:57][CH:56]([NH:55][C:47]3[N:46]([CH2:45][CH2:44][O:43][CH2:41][CH3:42])[C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=4[N:48]=3)[CH2:61][CH2:60]2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:15]1)=[O:13])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Reactant: CCOC(=O)CCCOc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCOS(C)(=O)=O)(c2ccccc2)C1
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(-n5cnnn5)ccc4OCCCC(=O)OCC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.6 using 1-(2-(3-carboethoxypropyloxy)-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine and (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine to give the title compound.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].Cl.[OH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[CH2:14][NH:13][CH2:12][CH2:11]2.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>O>[OH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[CH2:14][N:13]([C:1](=[O:4])[CH2:2][CH3:3])[CH2:12][CH2:11]2
Reactant: COc1cc2c(cc1O)CCNC2
Reactant: CCC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCC(=O)N1CCc2cc(O)c(OC)cc2C1
Reaction time: 18 h
Yield: 69.9 %

Procedure:
55.5 g of propionyl chloride are added dropwise at room temperature over a period of one hour to a mixture of 86.3 g of 1,2,3,4-tetrahydro-6-hydroxy-7-methoxy-isoquinoline-hydrochloride, 138,2 g of potassium carbonate, 600 ml of methylene chloride, and 480 ml of water. The mixture is stirred for an additional 18 hours, the organic phase is separated, and the aqueous phase is extracted twice with methylene chloride. The methylene chloride extracts are dried and evaporated. 65.8 g of 1,2,3,4-tetrahydro-6-hydroxy-7-methoxy-2-propionyl-isoquinoline are obtained. m.p. = 116° - 118° C. (ethyl acetate - diisopropyl ether).
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[N:13][CH:14]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:17]1[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:23])[CH2:18]1>>[OH:1][C:2]1([C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[N:13][CH:14]=2)[CH2:7][CH2:6][CH:5]([N:17]2[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=3)=[O:23])[CH2:18]2)[CH2:4][CH2:3]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: COc1ncc(C2(O)CCC(=O)CC2)cn1
Product: COc1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cn1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-hydroxy-4-(2-methoxy-pyrimidin-5-yl)-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([CH2:10][O:11][C:12]2[CH:17]=[C:16]([CH:18]([CH3:20])[CH3:19])[CH:15]=[CH:14][C:13]=2[CH3:21])=[C:4]([CH3:22])[N:3]=1.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([CH2:10][O:11][C:12]2[CH:17]=[C:16]([CH:18]([CH3:20])[CH3:19])[CH:15]=[CH:14][C:13]=2[CH3:21])=[C:4]([CH3:22])[N:3]=1
Reactant: Cc1cccc(C)c1B(O)O
Reactant: COc1nc(Cl)nc(C)c1COc1cc(C(C)C)ccc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1nc(-c2c(C)cccc2C)nc(C)c1COc1cc(C(C)C)ccc1C
Temperature: 90 °C
Reaction time: 24 h

Procedure:
A mixture containing 2-chloro-5-[(5-isopropyl-2-methylphenoxy)methyl]-4-methoxy-6-methylpyrimidine (˜3.91 mmol), 2,6-dimethylphenylboronic acid (1.17 g, 7.82 mmol), 15.6 mL of 1 M aqueous sodium carbonate and dioxane (56 mL) is degassed by bubbling with argon for 20 min. To this mixture is added Pd(PPh3)4 (226 mg, 0.05 mol %). The resulting yellow mixture is heated at 90° C. under nitrogen with magnetic stirring for 24 h. Another 50 mg of Pd(PPh3)4 is added and heating is continued for another 18 h until the reaction is complete by LC/MS analysis. The reaction mixture is allowed to cool to ambient temperature and partitioned between EtOAc (200 mL) and water (70 mL). The organic layer is separated, extracted with water (70 mL×2), brine (70 mL), dried over anhydrous sodium sulfate, filtered and evaporated to obtain a yellow oil. Purification by chromatography on silica gel (5-50% EtOAc/Hexanes) provides the title compound as a colorless solid. LC-MS found 391.4 (MH+), rt=1.93 min.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5](N)=[C:4]([O:9][CH3:10])[CH:3]=1.[N+:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-:13])=[O:12].N(OCCC(C)C)=O>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([C:17]2[CH:18]=[CH:19][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=2)=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: O=[N+]([O-])c1ccccc1
Reactant: COc1cc(F)ccc1N
Agent: CC(C)CCON=O
Product: COc1cc(F)ccc1-c1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of 7.7 grams of 4-fluoro-2-methoxyaniline, 200 ml. of nitrobenzene, and 9.0 grams of isoamyl nitrite, is warmed on the steam bath until a vigorous reaction with evolution of gas sets in. This evolution is allowed to proceed without heating until it has subsided, and the mixture is then heated on the steam bath for an additional 3 hours. The excess of nitrobenzene is removed in vacuo. The residue is purified for the desired isomer by elution from a silica gel column using petroleum-benzin to yield 4'-fluoro-2'-methoxy-4-nitrobiphenyl.
Reaction SMILES: C(Cl)[Cl:2].[F:4][C:5]([F:23])([F:22])[C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1)=[O:7].Cl>O1CCOCC1>[ClH:2].[F:23][C:5]([F:4])([F:22])[C:6]([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=[O:7]
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)C(F)(F)F)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NC1CCNCC1)C(F)(F)F
Reaction time: 6 h
Yield: 96 %

Procedure:
To a stirred DCM solution of the title compound of Example 1 (100 mL) was added dropwise a solution of hydrogen chloride (250 mL, 1.0 mol) in 1,4-dioxane (4 M). Stirring was continued for 6 hours, then the suspension was filtered, and the solid washed with diethyl ether (500 mL) to afford the title compound (54.2 g, 96% yield) as a white solid. APCI/MS calcd. for C7H11F3N2O 196.1. found m/z=196.9 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[C:6]([Cl:15])[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[N:3]=1.[K+].[CH:23]([C:26]1[CH:27]=[CH:28][C:29]([S:32]([NH-:35])(=[O:34])=[O:33])=[N:30][CH:31]=1)([CH3:25])[CH3:24]>CN(C=O)C>[CH:23]([C:26]1[CH:27]=[CH:28][C:29]([S:32]([NH:35][C:2]2[C:7]([C:8]3[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=3)=[C:6]([Cl:15])[N:5]=[C:4]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[N:3]=2)(=[O:34])=[O:33])=[N:30][CH:31]=1)([CH3:25])[CH3:24]
Reactant: Cc1ccc(-c2c(Cl)nc(-c3ccncc3)nc2Cl)cc1
Reactant: CC(C)c1ccc(S([NH-])(=O)=O)nc1
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(Cl)nc(-c3ccncc3)nc2NS(=O)(=O)c2ccc(C(C)C)cn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.6 %

Procedure:
A mixture of 654 mg of 4,6-dichloro-2-(4-pyridyl)-5-(p-tolyl)-pyrimidine and 1051 mg of 5-isopropyl-2-pyridine sulfonamide potassium salt (Example 1e) in 20 ml of DMF was stirred for 16 h at room temperature. Eventually, the solvent was distilled off under reduced pressure and the resulting residue was treated with 100 ml of 10% aqueous acetic acid and 100 ml of DCM. The layers were separated. The aqueous layer was extracted two more times with DCM. The combined organic layers were washed once with water, dried over MgSO4 and evaporated. The remaining residue was crystallised from isopropanol:diethyl ether. The yellow crystals were collected, washed with cold isopropanol and diethyl ether, and dried under high vacuum to furnish 870 mg of 5-isopropyl-N-[6-chloro-5-(p-tolyl)-2-(4-pyridyl)4-pyrimidinyl]-2-pyridine sulfonamide. LC-MS: tR=5.06 min, [M+1]+=480.40, [M−1]−=478.48.