Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1)=O>P(Cl)(Cl)(Cl)=O>[CH3:10][C:8]1[CH:7]=[CH:6][C:5]2[N:11]3[CH2:12][CH2:13][C:14]4[C:19]3=[C:18]([CH:17]=[CH:16][CH:15]=4)[CH:1]=[N:3][C:4]=2[CH:9]=1
Reactant: Cc1ccc(N2CCc3ccccc32)c(NC=O)c1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc2c(c1)N=Cc1cccc3c1N2CC3
Temperature: 25 °C
Yield: 88.7 %

Procedure:
1-(2-Formamido-4-methylphenyl)indoline (34 gm) in phosphorous oxychloride (220 ml) was heated at 100° C. (steam bath) for 2.5 hours, during which the product precipitated. The mixture was cooled to room temperature and ether (400 ml) was added and the excess phosphorous oxychloride was removed by filtration. The solids were washed with ether (3×400 ml) and thereafter dissolved in a mixed solvent of 10% triethylamine/dichloromethane (1.2 L). The organic solution was washed with 10% sodium hydroxide solution (350 ml), water (400 ml) and brine (600 ml), and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to leave an oil (28 gm). The oil was purified by flash chromatography over silica gel (320 gm, eluted with dichloromethane, 6 L). The resultant oil turned into crystals on shaking with ether (150 ml). The crystals were collected and dried to afford 25.9 gm, m.p. 77°-78° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([CH:27]=1)[C:7]([NH:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([S:21](=[O:24])(=[O:23])[NH2:22])[CH:19]=2)[O:14][CH2:13][CH2:12]1)=[O:8].[CH2:30]([N:32]=[C:33]=[S:34])[CH3:31]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([CH:27]=1)[C:7]([NH:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([S:21]([NH:22][C:33]([NH:32][CH2:30][CH3:31])=[S:34])(=[O:23])=[O:24])[CH:19]=2)[O:14][CH2:13][CH2:12]1)=[O:8]
Reactant: CCN=C=S
Reactant: COc1ccc(Cl)cc1C(=O)NCC1CCOc2cc(OC)c(S(N)(=O)=O)cc21
Product: CCNC(=S)NS(=O)(=O)c1cc2c(cc1OC)OCCC2CNC(=O)c1cc(Cl)ccc1OC

Procedure:
4-(5-Chloro-2-methoxybenzamidomethyl)-6-(ethylaminothiocarbonylaminosulfonyl)-7-methoxychroman ##STR35## 4-(5-Chloro-2-methoxybenzamidomethyl)-6-(ethylaminothiocarbonylaminosulfonyl)-7-methoxychroman is synthesize as described in Example 4 from 4-(5-chloro-2-methoxybenzamidomethyl)-6-sulfamoyl-7-methoxychroman and ethyl isothiocyanate. Melting point: 196°-197° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14]([NH2:16])=[O:15])[CH:11]=2)[NH:6][CH:5]=1.[CH3:17][C:18]([CH3:20])=O.[BH3-]C#N.[Na+]>CO>[CH3:17][CH2:18][CH2:20][NH:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14]([NH2:16])=[O:15])[CH:11]=2)[NH:6][CH:5]=1
Reactant: NCCc1c[nH]c2ccc(NC(N)=O)cc12
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCNCCc1c[nH]c2ccc(NC(N)=O)cc12
Reaction time: 18 h

Procedure:
A solution of 3.0 g (0.014 mole) of N-[3-(2-aminoethyl)-1H-indol-5-yl]urea, Example 1, in 100 ml MeOH was treated with 1.11 ml of acetone followed by 1.32 g (0.021 mole) of NaBH3CN and stirred for 18 hours. The solvent was removed in vacuo and the residue carefully dissolved in 20 ml of 20% HCl, heated for 15 minutes, cooled and neutralized with 4N NaOH to pH=12. The precipitated oil was extracted into EtOAc, dried over MgSO4, filtered and evaporated to give a glassy white solid. This material was purified by column chromatography (0.75% NH4OH/MeOH on silica gel) followed by recrystallization from acetone to give desired product: m.p. 145.5°-147°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]([CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]4[CH:32]=[CH:31][C:30]([O:33]C)=[CH:29][CH:28]=4)[CH2:21][CH2:20]3)=[N:16][C:15]3[C:10]2=[N:11][CH:12]=[N:13][C:14]=3[OH:35])=[CH:4][CH:3]=1.Br>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:17]([CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]4[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=4)[CH2:21][CH2:20]3)=[N:16][C:15]3[C:10]2=[N:11][CH:12]=[N:13][C:14]=3[OH:35])=[CH:6][CH:7]=1
Reactant: COc1ccc(CCN2CCC(Cc3nc4c(O)ncnc4n3Cc3ccc(F)cc3)CC2)cc1
Agent: Br
Solvent: O
Product: Oc1ccc(CCN2CCC(Cc3nc4c(O)ncnc4n3Cc3ccc(F)cc3)CC2)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 38.6 %

Procedure:
A mixture of 2.7 parts of 9-[(4-fluorophenyl)methyl]-8-[[1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl]-methyl]-9H-purin-6-ol and 75 parts of a hydrobromic acid solution 48% in water was stirred for 4 hours at 80° C. After evaporation, the residue was taken up in water and treated with sodium carbonate. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from ethanol and acetonitrile. The product was filtered off and dried, yielding 1 part (38.6%) of 9-[(4-fluorophenyl)methyl]-8-[[1-[2-(4-hydroxyphenyl)ethyl]-4-piperidinyl]methyl]-9H-purin-6-ol; mp. 215.7° C. (compound 186).
Reaction SMILES: B.[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][CH2:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=2)=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1>C1COCC1>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C@@H:14]([OH:15])[CH2:13][O:12][S:9]([C:6]2[CH:7]=[CH:8][C:3]([CH3:2])=[CH:4][CH:5]=2)(=[O:10])=[O:11])=[CH:17][C:18]=1[C:23]([F:26])([F:24])[F:25]
Reactant: Cc1ccc(S(=O)(=O)OCC(=O)c2ccc(F)c(C(F)(F)F)c2)cc1
Agent: B
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OC[C@H](O)c2ccc(F)c(C(F)(F)F)c2)cc1
Yield: 96 %

Procedure:
To a solution of (R)-(3aR)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole (295 mg, 1.06 mmol) in THF (10 mL) was added borane in THF (1M, 11 mL, 11 mmol). The resulting solution was stirred and 2-(4-fluoro-3-(trifluoromethyl)phenyl)-2-oxoethyl 4-methylbenzenesulfonate (4.0 g, 10.6 mmol) in THF (30 mL) was added through a dropping funnel over 45 min. The solution was stirred at room temperature for 45 min. The mixture was quenched with methanol (5 mL) and concentrated. The resulting residue was extracted with ethyl acetate and 0.5N hydrochloric acid. The organic layer was dried and concentrated to give toluene-4-sulfonic acid (R)-2-(4-fluoro-3-trifluoromethyl-phenyl)-2-hydroxyethyl ester (3.85 g). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.46 (s, 3H) 3.99-4.19 (m, 2H) 5.03 (dd, J=8.08, 3.54 Hz, 1H) 7.11-7.22 (m, 1H) 7.35 (dd, J=8.59, 0.76 Hz, 2H) 7.49-7.55 (m, 1H) 7.57 (dd, J=6.69, 1.89 Hz, 1H) 7.76 (d, J=8.34 Hz, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:19])([CH:16]([CH3:18])[CH3:17])[CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[CH:5][CH:4]=1)#[CH:2].CO.[I:22]I.[OH-].[Na+]>O>[I:22][C:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:19])([CH:16]([CH3:17])[CH3:18])[CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[CH:5][CH:4]=1
Reactant: C#Cc1ccc(C(O)(Cn2cncn2)C(C)C)cc1
Reactant: II
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)C(O)(Cn1cncn1)c1ccc(C#CI)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5.1 g 2-(4-ethynylphenyl)-3-methyl-1-(1H-1,2,4-triazole-1-yl)butan-2-ol in 100 ml abs. CH3OH are simultaneously added, with stirring at 20°-25°, 2.6 g iodine and 10 ml 30% NaOH solution. The reaction mixture is maintained at room temperature for 24 hours, with stirring, then poured into 500 ml H2O and extracted with CH2Cl2. The organic phase is washed, dried and evaporated. The residue is stirred in hexane fraction and kept over 16 hours at rest. The precipitate is sucked off and dried to give the title compound m.p. 122° as colourless crystals.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[NH:5][CH:6]=1.[C:15](N1C=CN=C1)(N1C=CN=C1)=[O:16]>C(Cl)Cl>[CH3:1][C:2]1[N:3]=[C:4]2[CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:14][C:15](=[O:16])[N:5]2[CH:6]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1c[nH]c(Cc2ccccc2N)n1
Solvent: ClCCl
Product: Cc1cn2c(n1)Cc1ccccc1NC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 18.61 g of 4-methyl-2-(2-aminobenzyl)imidazole, 16.12 g of 1,1'-carbonyldiimidazole and 375 ml of methylene chloride is stirred at room temperature overnight. The methylene chloride is evaporated to a small volume, the mixture is cooled to 0° and the solids are filtered and washed with ether to give 2-methyl-11H-imidazo[1,2-c][1,3]benzodiazepine-5(6H)-one, m.p. 234.5°-236.5°.
Reaction SMILES: CO[C:3]([C:5]1[CH:9]=[CH:8][N:7]([S:10](=[O:15])(=[O:14])[N:11]([CH3:13])[CH3:12])[N:6]=1)=[O:4].Cl.[CH3:17][NH:18][O:19][CH3:20].C([Mg]Cl)(C)C>C(Cl)Cl>[CH3:20][O:19][N:18]([CH3:17])[C:3]([C:5]1[CH:9]=[CH:8][N:7]([S:10](=[O:14])(=[O:15])[N:11]([CH3:12])[CH3:13])[N:6]=1)=[O:4]
Reactant: CNOC
Reactant: COC(=O)c1ccn(S(=O)(=O)N(C)C)n1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)c1ccn(S(=O)(=O)N(C)C)n1
Temperature: -78 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
1-Dimethylsulfamoyl-1H-pyrazole-3-carboxylic acid methyl ester (4 g, 17.15 mmol) and N,O-dimethylhydroxylamine hydrochloride (2.18 g, 22.29 mmol) were slurried in DCM (20 mL). The mixture was flushed with nitrogen and cooled to −78° C. Then a solution of isopropylmagnesium chloride (2M in THF) (24.01 mL, 48.02 mmol) was added dropwise. When the addition was completed the mixture was allowed to warm to room temperature and stirred overnight. The mixture was quenched with NH4Cl (aq. sat. solution) and the product was extracted with AcOEt. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; AcOEt in DCM 0/100 to 100/0). The desired fractions were collected and concentrated in vacuo to yield 1-dimethylsulfamoyl-1H-pyrazole-3-carboxylic acid methoxy-methyl-amide (3.2 g, 71% yield) as a pale yellow oil.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C.S(=O)(=O)(O)O>O1CCCC1>[C:8]1([CH2:7][O:6][CH2:5][CH:4]=[O:3])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(COCc1ccccc1)OCC
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: O=CCOCc1ccccc1
Temperature: 25 °C

Procedure:
A stirring mixture of 100 g of benzyloxyacetaldehyde diethyl acetal, 500 mlof tetrahydrofuran and 400 ml of 2N sulfuric acid is heated at reflux temperature for 45 minutes. The resulting solution is cooled to room temperature, concentrated in vacuo to 400 ml volume and diluted with 1000 ml of chloroform. The organic layer is washed with water, cold saturated sodium bicarbonate, saturated sodium chloride and dried. The filtrate is evaporated in vacuo to give the product as an oil. The crude oil is purified by Kugelrohr distillation (bath temperature 100° C.) to give 59.0 g of the desired product as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH2:25][CH2:26][CH3:27])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]3=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:10]3[N:9]=2)[CH:7]=1.[Cl:28][C:29]1[S:30][C:31]([Cl:38])=[CH:32][C:33]=1[S:34](Cl)(=[O:36])=[O:35].N1C=CC=CC=1>O1CCCC1>[Cl:28][C:29]1[S:30][C:31]([Cl:38])=[CH:32][C:33]=1[S:34]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH2:25][CH2:26][CH3:27])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]3=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:10]3[N:9]=2)[CH:7]=1)(=[O:36])=[O:35]
Reactant: O=S(=O)(Cl)c1cc(Cl)sc1Cl
Reactant: CCCOc1ccc(N)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCOc1ccc(NS(=O)(=O)c2cc(Cl)sc2Cl)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1

Procedure:
150 mg (0.408 mmol) of the compound from example 44A are reacted with 308 mg (1.224 mmol) of 2,5-dichlorothiophene-3-sulfonyl chloride and 0.33 ml (4.08 mmol) of pyridine in tetrahydrofuran for 4 hours.
Reaction SMILES: [CH3:1][C:2]1([C:5]2[CH:6]=[C:7]([NH2:17])[N:8]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)[N:9]=2)[CH2:4][CH2:3]1.N1C=CC=CC=1.Cl[C:25]([O:27][CH2:28][C:29]([Cl:32])([Cl:31])[Cl:30])=[O:26].ClC([O-])=O>C1COCC1.O>[Cl:30][C:29]([Cl:32])([Cl:31])[CH2:28][O:27][C:25](=[O:26])[NH:17][C:7]1[N:8]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[N:9]=[C:5]([C:2]2([CH3:1])[CH2:3][CH2:4]2)[CH:6]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Cc1ccc(-n2nc(C3(C)CC3)cc2N)cc1
Agent: O=C([O-])Cl
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1ccc(-n2nc(C3(C)CC3)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
Treat a cooled (0° C.) solution of the 5-(1-methyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-ylamine (5.68 g, 25 mmol) and pyridine (2.2 mL, 27.5 mmol) in THF (3 mL/mmol) with 2,2,2-trichloroethyl chloroformate (3.7 mL, 27.5 mmol). Maintain the reaction temperature at 0° C., and after 2 hours, add small portions of chloroformate (0.3 mL) and pyridine (0.2 mL). One hour later, dilute the reaction with water (150 mL) and extract with EtOAc (3×100 mL). Wash the combined organic phases with water (100 mL), saturated aq. NaHCO3 (50 mL), and saturated aq. sodium chloride (50 mL). Recrystallize the crude syrup from ethyl acetate/hexanes to provide the title compound as a white solid (8.18 g, 20.3 mmol; 81%). LCMS (ES+): m/z=402.2/404.2 [M+H].
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.S(=O)(O)[O-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+].O.[Br:42][CH2:43][CH2:44]Br>ClCCl>[Br:42][CH2:43][CH2:44][O:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Reactant: BrCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)[C@@H]1C[C@H](OCCBr)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.98 g (4 mmol) of 1-tert-butyl 2-methyl (2S,4S)-4-hydroxypyrrolidine-1,2-dioate (ALDRICH) was dissolved in 36 ml of 1,2-dibromoethane and cooled in an ice-bath. After addition of 1.36 g (4 mmol) of tetrabutylammonium bisulphite, 18 ml of 50% strength aqueous sodium hydroxide solution are added, and the mixture is stirred on ice for 2 hours and at room temperature overnight. After addition of 200 ml of water and 200 ml of dichloro-methane, the organic phase was washed once more with water, dried over sodium sulphate and filtered, and the filtrate was concentrated. The resulting crude product is chromatographed on silica gel using a dichloromethane/ethyl acetate gradient, and the appropriate fractions are combined and concentrated. Yield: 60 mg (4.3%)
Reaction SMILES: C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.Cl[C:36]1[C:45]2[C:40](=[CH:41][C:42]([F:47])=[CH:43][C:44]=2[F:46])[N:39]=[C:38]([N:48]2[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2)[C:37]=1[CH3:54].[CH3:55][C:56]1([CH3:71])[C:64]2[C:59](=[CH:60][C:61]([N:65]3[CH2:70][CH2:69][O:68][CH2:67][CH2:66]3)=[CH:62][CH:63]=2)[NH:58][CH2:57]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:55][C:56]1([CH3:71])[C:64]2[C:59](=[CH:60][C:61]([N:65]3[CH2:70][CH2:69][O:68][CH2:67][CH2:66]3)=[CH:62][CH:63]=2)[N:58]([C:36]2[C:45]3[C:40](=[CH:41][C:42]([F:47])=[CH:43][C:44]=3[F:46])[N:39]=[C:38]([N:48]3[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]3)[C:37]=2[CH3:54])[CH2:57]1
Reactant: Cc1c(N2CCCCC2)nc2cc(F)cc(F)c2c1Cl
Reactant: CC1(C)CNc2cc(N3CCOCC3)ccc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)C1=CC(C(C)C)=C(c2ccccc2)C(C(C)C)(P(C2CCCCC2)C2CCCCC2)C1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(N2CCCCC2)nc2cc(F)cc(F)c2c1N1CC(C)(C)c2ccc(N3CCOCC3)cc21
Temperature: 110 °C

Procedure:
The 2-(dicyclohexylphosphino)-2,4,6-tri-i-propyl-1,1-biphenyl (9.85 mg, 0.021 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(piperidin-1-yl)quinoline (38.3 mg, 0.129 mmol), 4-(3,3-dimethylindolin-6-yl)morpholine (30.0 mg, 0.129 mmol), sodium tert-butoxide (31.0 mg, 0.323 mmol) and Pd2(dba)3 (4.73 mg, 5.17 μmol) were slurried in toluene (1.00 mL) in a sealed tube and heated to 110° C. for 45 minutes. The reaction was cooled to rt and diluted with water (˜20 mL). This mixture was extracted with EtOAc (1×50 mL) and DCM (1×50 mL). The combined organic layers were dried over magnesium sulfate and the crude product was purified by medium pressure chromatography (silica, 0 to 100% EtOAc:hexane) to give 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-indol-1-yl)-5,7-difluoro-3-methyl-2-(1-piperidinyl)quinoline. 1H NMR (CDCl3) δ ppm 7.31 (1H, br. s.), 7.02 (1H, d, J=8.1 Hz), 6.68 (1H, ddd, J=11.7, 9.1, 2.4 Hz), 6.26 (1H, d, J=7.3 Hz), 5.46 (1H, br. s.), 3.67-3.80 (5H, m), 3.59 (1H, d, J=8.8 Hz), 3.32 (4H, br. s.), 2.94 (4H, d, J=3.7 Hz), 2.24 (3H, s), 1.65-1.86 (6H, m), 1.45 (3H, s), 1.42 (3H, s). Mass Spectrum (ESI) m/e=493.3 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[CH2:11][C:10]([CH3:15])([CH3:14])[NH:9]2)=[N:6][CH:7]=1.[C:16]1([C:22]#[CH:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:14][C:10]1([CH3:15])[NH:9][N:8]([C:5]2[CH:4]=[CH:3][C:2]([C:23]#[C:22][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:7][N:6]=2)[C:12](=[O:13])[CH2:11]1
Reactant: C#Cc1ccccc1
Reactant: CC1(C)CC(=O)N(c2ccc(Br)cn2)N1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)CC(=O)N(c2ccc(C#Cc3ccccc3)cn2)N1
Temperature: 65 °C
Reaction time: 16 h
Yield: 45.5 %

Procedure:
Bis-(triphenylphosphine)-palladium(II)dichloride (27 mg, 39 μmol, 0.05 equiv.) was dissolved in 2 ml THF. (210 mg, 770 μmol) 2-(5-Bromo-pyridin-2-yl)-5,5-dimethyl-pyrazolidin-3-one (Example 1, step 2) and phenylacetylene (130 mg, 1.24 mmol, 1.6 equiv.) were added at room temperature. Triethylamine (325 μl, 2.33 mmol, 3 equiv.), triphenylphosphine (6 mg, 23.3 μmol, 0.03 equiv.) and copper(I)iodide (4 mg, 23.3 μmol, 0.03 equiv.) were added and the mixture was stirred for 16 hours at 65° C. The reaction mixture was cooled and extracted with saturated NaHCO3 solution and two times with a small volume of dichloromethane. The crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a silica gel column eluting with an ethyl acetate:heptane gradient 0:100 to 100:0. The desired 5,5-dimethyl-2-(5-phenylethynyl-pyridin-2-yl)-pyrazolidin-3-one (102 mg, 45% yield) was obtained as a white solid, MS: m/e=292.1 (M+H+).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([CH3:9])[C:6]([CH2:10][O:11][CH2:12]Cl)=[CH:5][N:4]=1.Cl.[Cl:15][C:16]1[CH:17]=[N:18][C:19](=[O:22])[NH:20][CH:21]=1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2][C:3]1[N:8]=[C:7]([CH3:9])[C:6]([CH2:10][O:11][CH2:12][N:20]2[CH:21]=[C:16]([Cl:15])[CH:17]=[N:18][C:19]2=[O:22])=[CH:5][N:4]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: CSc1ncc(COCCl)c(C)n1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1ncc(COCn2cc(Cl)cnc2=O)c(C)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-Methylthio-4-methyl-5-(chloromethyloxymethyl)pyrimidine (see Preparation 11) (2.7 mmol) in dichloromethane (5 ml) was added dropwise with stirring at room temperature to a solution of 5-chloropyrimidin-2-one hydrochloride (2.7 mmol) and triethylamine in dichloromethane (0.76 ml). The mixture was stirred for 24 hours at room temperature before the solvent was distilled off. The residue was triturated with water, extracted into chloroform and the dried (MgSO4) solution evaporated. yield 0.55 g (65%). 1H NMR (CDCl3): δ2.42 (4-Me), 2.55 (SMe), 4.65 (CH2Pyr), 5.32 (CH2O), 7.80 and 8.42 (H-4, H-6, J 3 Hz), 8.20 (H-6').
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=3[F:31])=[O:19])=[CH:13][CH:12]=2)=[C:5]([C:8]([NH2:10])=[O:9])[NH:6][CH:7]=1.Cl.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[N:36][CH:35]=1.C(N(CC)CC)C>O1CCCC1.CN(C)C1C=CN=CC=1.ClCCl>[C:33]([NH:2][C:3]1[C:4]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:24]=[CH:23][C:22]=3[F:31])=[O:19])=[CH:13][CH:12]=2)=[C:5]([C:8]([NH2:10])=[O:9])[NH:6][CH:7]=1)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[N:36][CH:35]=1
Reactant: NC(=O)c1[nH]cc(N)c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Reactant: O=C(Cl)c1cccnc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)c1[nH]cc(NC(=O)c2cccnc2)c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Reaction time: 16 h
Yield: 86.3 %

Procedure:
To 0.15 g (0.328 mmol) 4-amino-3-{4-[3-(2-fluoro-5-trifluoromethylphenyl)-ureido]phenyl}-1H-pyrrole-2-carboxamide hydrochloride dissolved in 4.5 cm3 of tetrahydrofuran are added, at a temperature in the region of 20° C. under an argon atmosphere, 0.058 g of nicotinoyl chloride hydrochloride, 0.091 cm3 of triethylamine and 8 mg of 4-dimethylaminopyridine. After stirring for 16 hours at reflux, the reaction mixture is diluted with 15 cm3 of dichloromethane and then washed with twice 10 cm3 of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 148 mg of a beige-coloured solid, which is purified by flash chromatography [eluent: dichloromethane/methanol/acetonitrile (82/9/9 by volume)]. After concentrating the fractions under reduced pressure, 0.01 g of 4-nicotinoyl-amino-3-{4-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]phenyl}-1H-pyrrole-2-carboxamide is obtained in the form of a yellow solid; ES+: m/z=527: [M+H]+.
Reaction SMILES: C(O[C:4](=[O:23])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[CH:8][CH:7]=1)C.[CH3:24][O:25][CH:26]([O:30][CH3:31])[CH2:27][NH:28][CH3:29]>>[F:22][C:19]([F:20])([F:21])[C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[O:12][C:9]1[CH:8]=[CH:7][C:6]([NH:5][C:4]([N:28]([CH2:27][CH:26]([O:30][CH3:31])[O:25][CH3:24])[CH3:29])=[O:23])=[CH:11][CH:10]=1
Reactant: CCOC(=O)Nc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Reactant: CNCC(OC)OC
Product: COC(CN(C)C(=O)Nc1ccc(Oc2cccc(C(F)(F)F)c2)cc1)OC
Temperature: 120 °C

Procedure:
Ethyl[4-[3-(trifluoromethyl)phenoxy]-phenyl]carbamate (7.1 grams; 0.02 mol) and N-(2,2-dimethoxyethyl) methanamine (15 ml) were charged into a glass reaction vessel equipped with mechanical stirrer, thermometer and reflux condenser. The mixture was refluxed for about 36 hours at a temperature of about 120° C. The product was recrystallized from ethyl acetate, then recrystallized from hexane giving the desired product having a melting point of 86°-88° C.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[O-2].[Zn+2:22]>P(=O)(O)(O)O.CCCCC(CCC(OS([O-])(=O)=O)CC(C)C)CC.[Na+].O>[C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Zn+2:22].[C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: CCCCC(CC)CCC(CC(C)C)OS(=O)(=O)[O-]
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)[O-]
Temperature: 65 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
A molten stearic acid (29.5 grams, Hystrene 7018) was added gradually to a stirred mixture of zinc oxide (4.9 grams), phosphoric acid (0.1 gram), Tergitol 15-S-7 (0.2 gram), and water (66 grams) at 65° C. The reaction mixture was stirred at 60-70° C. for one hour, cooled to 25° C., filtered, and dried to afford 32.4 grams (98.8% yield) of zinc stearate white powder having 0.1% water, 14.3% ash, 0.44% by weight of free fatty acid, and a melting point of 126° C.