Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[N:3]1([CH:7]2[CH2:10][NH:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1.C(N(CC)CC)C.C1([O:24][C:25](=O)[N:26]([C:36]2[CH:41]=[C:40]([O:42][C:43]3[CH:48]=[CH:47][C:46]([NH:49][C:50]([C:52]4([C:55](=[O:64])[NH:56][C:57]5[CH:62]=[CH:61][C:60]([F:63])=[CH:59][CH:58]=5)[CH2:54][CH2:53]4)=[O:51])=[C:45]([F:65])[CH:44]=3)[CH:39]=[CH:38][N:37]=2)C(OC2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O>[N:3]1([CH:7]2[CH2:10][N:9]([C:25]([NH:26][C:36]3[CH:41]=[C:40]([O:42][C:43]4[CH:48]=[CH:47][C:46]([NH:49][C:50]([C:52]5([C:55]([NH:56][C:57]6[CH:58]=[CH:59][C:60]([F:63])=[CH:61][CH:62]=6)=[O:64])[CH2:54][CH2:53]5)=[O:51])=[C:45]([F:65])[CH:44]=4)[CH:39]=[CH:38][N:37]=3)=[O:24])[CH2:8]2)[CH2:6][CH2:5][CH2:4]1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Reactant: C1CN(C2CNC2)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1)N1CC(N2CCC2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 5.9 %

Procedure:
To a suspension of 3-(azetidin-1-yl)azetidine dihydrochloride (111 mg) in N,N-dimethylformamide (1.5 ml) was added triethylamine (0.167 ml), followed by stirring at room temperature for 15 min. A crude product of [4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (100 mg) was added thereto, followed by stirring at room temperature for 25 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. This was concentrated and the residue was purified by LC-MS. Fractions containing the target compound were concentrated, and the residue was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and to the resultant solid (31.5 mg) was added diethyl ether (2 ml) to suspend. This was collected by filtration and washed with diethyl ether. This was dried under aeration to provide the titled compound as colorless powder (5.0 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]([C:11]2([CH2:24][CH2:25][CH2:26][CH2:27]Br)[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:10])=[CH:5][CH:4]=1.[Cl:31][C:32]1[CH:41]=[CH:40][CH:39]=[C:38]2[C:33]=1[CH:34]=[CH:35][C:36]([N:42]1[CH2:47][C@H:46]([CH3:48])[NH:45][C@H:44]([CH3:49])[CH2:43]1)=[N:37]2>>[CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]([C:11]2([CH2:24][CH2:25][CH2:26][CH2:27][N:45]3[C@H:46]([CH3:48])[CH2:47][N:42]([C:36]4[CH:35]=[CH:34][C:33]5[C:38](=[CH:39][CH:40]=[CH:41][C:32]=5[Cl:31])[N:37]=4)[CH2:43][C@@H:44]3[CH3:49])[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:10])=[CH:5][CH:4]=1
Reactant: C[C@@H]1CN(c2ccc3c(Cl)cccc3n2)C[C@H](C)N1
Reactant: COc1ccc(CNC(=O)C2(CCCCBr)c3ccccc3-c3ccccc32)cc1
Product: COc1ccc(CNC(=O)C2(CCCCN3[C@H](C)CN(c4ccc5c(Cl)cccc5n4)C[C@@H]3C)c3ccccc3-c3ccccc32)cc1

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-methoxy-benzylamide and 5-chloro-2-(cis-3,5-dimethyl-piperazin-1-yl)-quinoline.
Reaction SMILES: [C@@H:1]12[N:8]([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[CH:4]([NH:10][C:11]([C:13]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][N:14]=1)=[O:12])[CH2:3][CH2:2]2.[H-].[Na+].I[CH:25]([CH3:27])[CH3:26]>CN(C)C=O>[C@@H:1]12[N:8]([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[CH:4]([NH:10][C:11]([C:13]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH:25]([CH3:27])[CH3:26])[N:14]=1)=[O:12])[CH2:3][CH2:2]2
Reactant: CN1[C@H]2CCC(NC(=O)c3n[nH]c4ccccc34)[C@@H]1CC2
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1nc(C(=O)NC2CC[C@H]3CC[C@@H]2N3C)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.2 %

Procedure:
To a solution of N-(tropan-4-yl)-1H-indazole-3-carboxamide (2.98 g, 10 mmol) in 75 mL of dimethylformamide under a nitrogen atmosphere was added, in portions, sodium hydride (60% dispersion in mineral oil, 420 mg, 10 mmol). The resulting solution was allowed to stir for about 1 hour at room temperature before adding 2-iodopropane (1.2 mL, 12 mmol). This resulting solution was allowed to stir at room temperature for about 18 hours. The dimethylformamide was evaporated under reduced pressure and the residue was dissolved in about 100 mL of 1N hydrochloric acid. The acidic solution was washed with ethyl acetate and then cooled before making it basic with saturated aqueous sodium carbonate. The basic mixture was extracted 3 times with methylene chloride. The extracts were washed with brine, dried over sodium sulfate, filtered, then evaporated under reduced pressure to give a viscous oil. The oil was purified by preparative HPLC (gradient methylene chloride:methanol 0-25%, 1% ammonium hydroxide) to give 2.52 g of an oil. Yield: 77%. MS(FD) M+326.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:9]=[C:8]([N:10]2C(C)=CC=C2C)[CH:7]=[C:6]([CH3:17])[CH:5]=1.Cl.NO.[OH-].[K+].Cl>C(O)C.ClCCl.O>[NH2:10][C:8]1[CH:7]=[C:6]([CH3:17])[CH:5]=[C:4]([CH2:3][CH2:2][OH:1])[N:9]=1
Reactant: Cc1cc(CCO)nc(-n2c(C)ccc2C)c1
Agent: Cl
Agent: NO
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: Cc1cc(N)nc(CCO)c1
Temperature: 100 °C
Yield: 66.7 %

Procedure:
6-(2-Hydroxyethyl)-4-methyl-2-(2,5-dimethylpyrrol-1-yl)pyridine (457 mg, 1.98 mmol) was dissolved in 5.0 mL of 95% ethanol and 2.0 mL of water was added followed by 625 mg (8.99 mmol) of hydroxylamine hydrochloride and 350 mg (5.36 mmol) of 86% potassium hydroxide. The mixture was heated in a 100° C. oil bath for 24 h, the cooled to room temperature and partitoned between 15 mL of 2 N aqueous hydrochloric acid and 30 mL of dichloromethane. The aqueous layer was made strongly basic by the addition of solid 86% potassium hydroxide and extracted with 3×30 mL of ethyl ether. The ethyl ether layers were dried (sodium sulfate), decanted, and evaporated. The residue was purified by flash column chromatography on 25 g of silica gel, eluting with 20% isopropanol in dichloromethane to give 201 mg (67% yield) of 2-amino-6-(2-hydroxyethyl)4-methylpyridine as a colorless oil which spontaneously crystallized.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][C:6]([OH:12])([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[Cl:19][C:20]1[CH:25]=[C:24](Cl)[C:23]([N+:27]([O-:29])=[O:28])=[CH:22][N:21]=1.Cl>O1CCOCC1.O>[Cl:19][C:20]1[CH:25]=[C:24]([NH:2][CH:3]2[CH2:8][CH2:7][C:6]([OH:12])([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]2)[C:23]([N+:27]([O-:29])=[O:28])=[CH:22][N:21]=1
Reactant: O=[N+]([O-])c1cnc(Cl)cc1Cl
Reactant: NC1CCC(O)(C(=O)O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)C1(O)CCC(Nc2cc(Cl)ncc2[N+](=O)[O-])CC1
Temperature: 60 °C
Reaction time: 24 h
Yield: 62 %

Procedure:
A 100 mL round bottom flask was charged with 4-amino-1-hydroxycyclohexanecarboxylic acid hydrochloride (0.28 g, 1.431 mmol), potassium carbonate (0.435 g, 3.15 mmol) and water (1.908 mL). To the mixture was added 2,4-dichloro-5-nitropyridine (0.276 g, 1.431 mmol) as a solution in dioxane (0.954 mL). After the resulting mixture was stirred at 60° C. for 24 hours, it was cooled to RT and treated with 2N aqueous HCl to bring the pH to about 4-5. The aqueous layer was extracted with DCM (3×40 mL). The combined organic portions were dried over sodium sulfate and concentrated to afford 4-(2-chloro-5-nitropyridin-4-ylamino)-1-hydroxycyclohexanecarboxylic acid as a yellow solid (0.28 g, 62.0% yield). MS m/z=316.2 [M+H]. Calc'd for C12H14ClN3O5: 315.1.
Reaction SMILES: [N:1]1([C:6]2[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][OH:13])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[CH3:18][N:19]([CH3:24])[S:20](Cl)(=[O:22])=[O:21].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[N:1]1([C:6]2[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][O:13][S:20](=[O:22])(=[O:21])[N:19]([CH3:24])[CH3:18])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: OCCOc1ccc(-n2ccnc2)cc1
Reactant: CN(C)S(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)S(=O)(=O)OCCOc1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 15.0 g (0.074 mol) of 2-[4-(1H-imidazol-1-yl)phenoxy]ethanol in 100 mL of N,N-dimethylformamide (DMF) was added 3.8 g (0.1 mol) of sodium hydride (60% oil dispersion) portionwise and the mixture was stirred at ambient temperature for 3 h. To this mixture was added 13.7 g (0.1 mol) of dimethylsulfamoyl chloride and the mixture was stirred at ambient temperature overnight. The reaction mixture was poured into 1.2 L of water and its pH was adjusted to 10 with sodium carbonate. The mixture was extracted with three 400-mL portions of ethyl acetate. The combined organic layers were washed twice with 400-mL portions of water, dried (MgSO4), and the solvent was evaporated under reduced pressure to give a viscous residue. The residue was purified by high pressure liquid chromatography (Waters Associates Prep LC/System 500 A; PrepPAK 500 silica; ethyl acetate; flow rate 150 mL/min). Fractions containing the product were combined and the solvent was evaporated under reduced pressure to give the title compound, a viscous oil. The oil was converted to the hydrochloride (2-propanol; ethereal HCl) and the white solid was collected by filtration to yield 5.9 g (26%), mp 120°-123° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[S:12](=[O:15])(=[O:14])[NH2:13])[CH2:8][CH2:7][CH2:6]2.CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[S:12]([N:13]=[CH:18][N:19]([CH3:21])[CH3:20])(=[O:15])=[O:14])[CH2:8][CH2:7][CH2:6]2
Reactant: COC(OC)N(C)C
Reactant: COc1cc2c(cc1S(N)(=O)=O)CCC2
Product: COc1cc2c(cc1S(=O)(=O)N=CN(C)C)CCC2

Procedure:
This compound is prepared analogously to Example 1c from 5-methoxy-6-sulfamoylindane and dimethylformamide dimethylacetal.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:14])[C:4]([CH3:13])([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[CH2:5][CH2:6][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH3:1][C:2]1[CH:3]([OH:14])[C:4]([CH3:13])([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[CH2:5][CH2:6][CH:7]=1
Reactant: CC(C)=CCC1(C)CCC=C(C)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)=CCC1(C)CCC=C(C)C1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
2,6-Dimethyl-6-(3-methyl-but-2-enyl)-cyclohex-2-enone (5.00 g, 26.04 mmol) was added dropwise to a suspension of lithium aluminium hydride (0.73 g, 18.2 mmol) in diethyl ether at 0° C. The mixture was stirred at room temperature for 1 h. The resulting suspension was quenched with water, aqueous sodium hydroxide solution and again water, was then filtered and concentrated in vacuo. The residue was distilled (bp. 110° C./0.1 Torr) to yield 4.93 g (98%) of the alcohol as a mixture of 2 diastereomers. 1H-NMR (200 MHz, CDCl3): 5.49 (bs, 1H, 3-H), 5.34-5.15 (m, 1H, 2′-H), 3.57/3.44 (2d, J=4.5, 5.5 Hz, 1H, 1-H), 2.25-1.82 (m, 4H), 1.81-1.71 (m, 6H), 1.65/1.61 (2s, 3H), 1.62-1.19 (m, 3H), 0.93/0.82 (2s, 3H, 6-CH3) ppm. GC/MS (EI) isomer a: 194 (M+, 4), 176 (44), 161 (42), 125 (12), 107 (94), 84 (70), 69 (38), 55 (50), 43 (100). IR (ATR): 3365s, 2966s, 2916vs, 1450s, 1375s, 1239m, 1030m, 1007 s cm−1.
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH:14]2[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[CH2:16][CH2:15]2)[CH2:10][C@H:9]1[C:22]([O:24][CH3:25])=[O:23])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:26][C:27](OC(C)=O)=[O:28]>N1C=CC=CC=1>[C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([C:27](=[O:28])[CH3:26])[CH:14]2[CH2:19][CH2:18][C:17]([CH3:20])([CH3:21])[CH2:16][CH2:15]2)[CH2:10][C@H:9]1[C:22]([O:24][CH3:25])=[O:23])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)[C@@H]1C[C@H](NC2CCC(C)(C)CC2)CN1C(=O)OC(C)(C)C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COC(=O)[C@@H]1C[C@H](N(C(C)=O)C2CCC(C)(C)CC2)CN1C(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
Methyl(2S,4S)-1-BOC-4-[(4,4-dimethylcyclohexyl)amino]pyrrolidine-2-carboxylate (1.01 g, 2.84 mmol) obtained in Step A, was dissolved in pyridine (5 mL), and Ac2O (1.34 mL, 14.20 mmol) was added thereto at room temperature. The reaction solution was heated to 90° C. and was stirred for 2 hours. After the reaction was completed, CuSO4.5H2O aqueous solution was added and the solution was extracted with EtOAc. The extracted organic solution was dried over MgSO4 and concentrated in vacuo. The obtained residue was purified by column chromatography (eluent: EtOAc/Hex=1/1) to give the title compound (0.98 g, 87%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:7])=[CH:5][N:6]=1.Br[CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][O:11]1>>[CH3:7][C:4]1[S:3][C:2](=[NH:1])[N:6]([CH2:9][CH:10]2[CH2:14][CH2:13][CH2:12][O:11]2)[CH:5]=1
Reactant: BrCC1CCCO1
Reactant: Cc1cnc(N)s1
Product: Cc1cn(CC2CCCO2)c(=N)s1
Temperature: 85 °C
Reaction time: 24 h
Yield: 86.2 %

Procedure:
A mixture of 2-amino-5-methylthiazole (1.0 g, 8.7 mmol) and 2-(bromomethyl)tetrahydrofuran (Maybridge, 1.1 mL, 10 mmol) was warmed to 85° C. and allowed to stir for 24 hours. The mixture was then cooled to ambient temperature and purified via column chromatography (SiO2, 9:1:0.1 CH2Cl2:CH3OH:NH4OH) to afford the title compound (1.5 g, 7.5 mmol, 86% yield). 1H NMR (300 MHz, CD3OD) δ ppm 1.55-1.70 (m, 1H) 1.89-2.01 (m, 2H) 2.07-2.20 (m, 1H) 2.28 (d, J=1.36 Hz, 3H) 3.72-3.82 (m, 1H) 3.86-4.00 (m, 2H) 4.08-4.24 (m, 2H) 6.98-7.04 (m, 1H); MS (DCI/NH3) m/z 199 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[NH:9][C:8](=[O:15])[CH2:7]2)([O-])=O>CO.CN(C)C=O.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[NH:9][C:8](=[O:15])[CH2:7]2
Reactant: O=C1Cc2cc([N+](=O)[O-])ccc2C(=O)N1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1ccc2c(c1)CC(=O)NC2=O
Yield: 102.2 %

Procedure:
A solution of 6.19 g (30 mmol) of 6-nitroisoquinoline-1,3(2H,4H)-dione in 15 ml of MeOH and 150 ml of N,N-DIMETHYLFORMAMIDE is hydrogenated at 1 atmosphere of H2 at 250 in the presence of 1.5 g of 10% Pd/C for 7 h. The catalyst is removed by filtration through Celite. The filtrate is evaporated to give 5.4 g (100%) of a tan solid, mp 200-2200 (dec); MS (ES+) m/z 177.2 (M+H)+1.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([CH3:17])([CH3:16])[CH2:8][C:9](=[O:15])[NH:10]2)C=C.CN(C)[C:20]1[CH:25]=CC=C[CH:21]=1>>[CH2:25]([C:14]1[C:5]([OH:4])=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:15])[CH2:8][C:7]2([CH3:16])[CH3:17])[CH:20]=[CH2:21]
Reactant: C=CCOc1cccc2c1C(C)(C)CC(=O)N2
Reactant: CN(C)c1ccccc1
Product: C=CCc1ccc2c(c1O)C(C)(C)CC(=O)N2
Yield: 86.9 %

Procedure:
5-Allyloxy-4,4-dimethyl-3,4-dihydrocarbostyril (817 mg, 3.73 mmol) was dissolved in dimethylaniline (15 ml), and the resultant solution was stirred in a bath at 205° C. for 5 hours. The reaction solution was condensed under reduced pressure, followed by extracting with chloroform and 2N-aqueous caustic soda solution. The aqueous phase was neutralized with conc. HCl. Subsequently, the neutralized phase was extracted with a mixture of chloroform-methanol (10:1), dried, and condensed under reduced pressure. Recrystallization from a mixture of chloroform-methanol-ether yielded 710 mg of the title compound as pale yellow needles (86.9%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[N:3]=1.[Cl:12][CH:13]([CH3:21])[CH2:14][S:15]([N:18]=[C:19]=[O:20])(=[O:17])=[O:16].CCCCCC>ClCCl>[CH3:9][O:8][C:6]1[N:5]=[C:4]([O:10][CH3:11])[N:3]=[C:2]([NH:1][C:19]([NH:18][S:15]([CH2:14][CH:13]([Cl:12])[CH3:21])(=[O:17])=[O:16])=[O:20])[N:7]=1
Reactant: CC(Cl)CS(=O)(=O)N=C=O
Reactant: COc1nc(N)nc(OC)n1
Solvent: ClCCl
Solvent: CCCCCC
Product: COc1nc(NC(=O)NS(=O)(=O)CC(C)Cl)nc(OC)n1
Temperature: 0 °C
Yield: 90.4 %

Procedure:
15.6 g (0.1 mole) of 2-amino-4,6-dimethoxy-1,3,5-triazine were suspended in 150 ml of dichloromethane, and a solution of 19.5 g (0.106 mole) of 2-chloro-n-prop-1-yl-sulfonyl isocyanate in 100 ml of dichloromethane was added at 0° C., while stirring. The mixture was further stirred for 12 hours at room temperature and cooled to 0° C., and 300 ml of n-hexane were added. The precipitated reaction product was filtered off under suction, washed with n-hexane and dried. 30.7 g (90.5% of theory) of N-(4,6-dimethoxy-1,3,5-triazin-2-yl)-N'-(2-chloro-n-prop-1-yl-sulfonyl)-urea of melting point 139°-41° C. were obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[NH:38]1[CH:42]=[CH:41][N:40]=[CH:39]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:38]3[CH:42]=[CH:41][N:40]=[CH:39]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Reactant: c1c[nH]cn1
Product: O=C(Nc1ccc(Oc2ccnc(-n3ccnc3)n2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and imidazole according to conditions described in general procedure C. Mp: 153-154° C.; 1H NMR (400 MHz, CDCl3) δ 3.29 (s, 4 H), 3.89 (s, 4 H), 6.79-6.85 (m, 2 H), 7.01 (d, J=1.5 Hz, 1 H), 7.12 (d, J=8.2 Hz, 1 H), 7.35 (d, J=2.7 Hz, 1 H), 7.38 (d, J=2.3 Hz, 1 H), 7.53-7.64 (m, 3 H), 7.91-7.93 (m, 1 H), 7.97 (d, J=7.4 Hz, 1 H), 8.05 (d, J=8.2 Hz, 1 H), 8.25-8.27 (m, 2 H), 8.53-8.56 (m, 1 H).
Reaction SMILES: [CH:1]1([C:5]([CH2:10][OH:11])([CH2:8][OH:9])[CH2:6][OH:7])[CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)(Cl)Cl>[CH3:18][S:19]([OH:21])(=[O:7])=[O:20].[CH3:18][S:19]([OH:21])(=[O:7])=[O:20].[CH3:18][S:19]([OH:21])(=[O:7])=[O:20].[CH:1]1([C:5]([CH2:6][OH:7])([CH2:8][OH:9])[CH2:10][OH:11])[CH2:2][CH2:3][CH2:4]1
Reactant: CS(=O)(=O)Cl
Agent: OCC(CO)(CO)C1CCC1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-cyclobutyl-2-hydroxymethylpropane-1,3-diol (10 g, 62.5 mmol) and pyridine (21 ml, 0.25 mol) in dry chloroform (200 ml) at 0° C. under nitrogen atmosphere was added methanesulphonyl chloride (25 g, 18 ml, 0.22 mmol). The solution was stirred overnight, poured into ice/water and extracted with chloroform. The extracts were dried over anhydrous magnesium sulphate. Evaporation afforded 2-cyclobutyl-2-hydroxymethyl-propane-1,3-diol trimethanesulphonate which was not purified further. Nmr δ 4.20[6H, s], 3.05[9H,s], 2.60[1H, m], 2.10-1.70 [6H,m].
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][N:4]=1.CN(C=O)C.C(Cl)(=O)C([Cl:22])=O>ClCCl>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:22])=[O:8])=[CH:5][N:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 1 L 3-neck flask equipped with an overhead stirrer, Claisen adaptor, nitrogen bubbler, 60 mL addition funnel, and thermocouple was added 6-(trifluoromethyl)nicotinic acid (45.0 g, 236 mmol), dichloromethane (540 mL) and DMF (0.910 mL, 11.8 mmol) via syringe. To this solution was added oxalyl chloride (24.5 mL, 283 mmol) and the reaction was allowed to stir at ambient temperature overnight. The reaction was then filtered and the clear filtrate was concentrated in vacuo to afford the title compound as a brownish semisolid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:29]1(B(O)O)[CH2:31][CH2:30]1.C(=O)([O-])O.[Na+]>C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.[Cl-].[Cl-].[Pd+2].C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH:29]3[CH2:31][CH2:30]3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)cn2)CC1
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C3CC3)cn2)CC1
Yield: 71.6 %

Procedure:
To a mixture of 4-(5-bromopyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (5.37 g), bis(tricyclohexylphosphine)palladium (II) dichloride (347 mg), tripotassium phosphate (9.99 g) and cyclopropylboronic acid (2.02 g) were added toluene (49 mL) and water (2.5 mL), and the mixture was refluxed. After cooling, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (3.41 g).
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]([F:26])([F:25])[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]([C:22](O)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:11]=1.S(Cl)([Cl:29])=O>CN(C=O)C>[F:8][C:9]([F:26])([F:25])[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]([C:22]([Cl:29])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a nitrogen purged 3 liter 4-neck flask fitted with a condenser, mechanical stirrer, temperature probe, and connected to a 2M aqueous NaOH scrubber was added toluene (1 L), 4′-trifluoromethyl-biphenyl-2-carboxylic acid (250 g, 0.94 mol, 1 equiv), and DMF (5 mL). 4′-Trifluoromethyl-biphenyl-2-carboxylic acid can be obtained from Aldrich, Milwaukee, Wis. The solution was heated to 60° C. and thionyl chloride (110 mL, 1.5 mol, 1.6 equiv) was added at such a rate as to maintain the temperature below 65° C. The addition was complete after 30 minutes and the reaction was heated to reflux. After 4 hours, the heating was stopped and the reaction was allowed to stir overnight at room temperature. The reaction mixture was concentrated in vacuo and the residue was used in the next step without further purification. The material crystallized to a solid at room temperature.
Reaction SMILES: Cl.[NH2:2][NH:3][C:4](=[NH:7])[NH:5][NH2:6].C(N[C:12](=[O:19])[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=O)(=O)C>O>[NH2:7][C:4]1[N:5]([NH2:6])[C:12](=[O:19])[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[N:2][N:3]=1
Reactant: N=C(NN)NN
Reactant: CC(=O)NC(=O)C(=O)C(C)(C)C
Agent: Cl
Solvent: O
Product: CC(C)(C)c1nnc(N)n(N)c1=O

Procedure:
3.8 g (0.03 mole) of diaminoguanidine hydrochloride are dissolved in 35 ml of water. To this solution are added 5.1 g (0.03 mole) of N-acetyl-3,3,3-trimethylpyruvamide and the reaction mixture is heated for 15 minutes to 90° C. The reaction mixture is filtered and the filtrate is neutralised by addition of crystalline sodium bicarbonate. At pH 7, 3.6 g (66.7% of theory) of 3,4-diamino-6-(1,1-dimethylethyl)-4H-1,2,4-triazin-5-one precipitate in the form of a yellowish crystalline solid with a melting point of 223°-224° C.