Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[C:8]([CH2:10][C@H:11]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:12]([OH:14])=O)[CH:7]=[CH:6][C:5]=1[O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26].C(Cl)CCl.[CH3:34][O:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[CH:38][CH:37]=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[C:8]([CH2:10][C@H:11]([NH:15][C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[C:12](=[O:14])[NH:41][CH2:40][C:39]2[CH:42]=[CH:43][C:36]([O:35][CH3:34])=[CH:37][CH:38]=2)[CH:7]=[CH:6][C:5]=1[O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26]
Reactant: COc1ccc(CN)cc1
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)NCc2ccc(OC)cc2)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5-((2S)-2-tert-Butoxycarbonylamino-2-carboxy-ethyl)-2-methoxycarbonylmethoxy-benzoic acid methyl ester of Step F (51 mg, 0.12 mmol) is stirred in CH2Cl2 (1.2 mL) at 0° C. under N2. EDC (24 mg, 0.12 mmol) is added and the reaction mixture is stirred for and additional 10 minutes. 4-Methoxybenzyl amine (0.18 μl, 0.14 mmol) is then added and the reaction is allowed to warm to RT overnight. The reaction is diluted with CH2Cl2 (25 mL) and is subsequently washed with 2N HCl (2×25 mL) and then saturated NaHCO3 (2×25 mL). The organics are then dried over MgSO4, filtered and and purified by flash column chromatography to provide 5-[(2S)-2-tert-butoxycarbonylamino-2-(4-methoxy-benzylcarbamoyl)-ethyl]-2-methoxycarbonylmethoxy-benzoic acid methyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[NH2:1][C:2]1[CH:7]=[C:6]([S:19][C:16]2[CH:17]=[CH:18][C:13]([CH3:12])=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1ccc(S)cc1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Sc2ccc([N+](=O)[O-])c(N)c2)cc1

Procedure:
A mixture of 2.5 g. 2-amino-4-chloro-1-nitrobenzene, 3.6 g. p-thiocresol, 4.2 g. potassium carbonate in 20 ml. dimethylformamide is stirred overnight at room temperature, then poured into water. The crude product, recrystallized from methanol, gives 2-amino-4-(p-methylphenylthio)-1-nitrobenzene.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C@@H:11](O)[CH:12]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=1)[N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:15][OH:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[Si:1]([O:8][CH2:9][CH2:10][C@H:11]1[O:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[CH:12]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CCO)C(c1ccc(Cl)c(Cl)c1)[C@H](O)CCO[Si](C)(C)C(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCO[C@H](CCO[Si](C)(C)C(C)(C)C)C1c1ccc(Cl)c(Cl)c1
Reaction time: 2 h
Yield: 89.8 %

Procedure:
49.9 g (98.1 mmole) of 4-t-butyldimethylsilyloxy-(2 R)-(3,4-dichlorophenyl)-1-[N-(t-butoxycarbonyl)-N-(2-hydroxyethyl)amino]-2-butanol [prepared as described in step (a) above] and 30.9 g (118 mmole) of triphenylphosphine were dissolved in 600 ml of dried toluene. 51.3 g of a 40% w/v toluene solution containing 118 mmole of diethyl azodicarboxylate were added dropwise to the resulting solution at room temperature under a nitrogen atmosphere, and the mixture was stirred for 2 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography, using a gradient elution method, with mixtures of hexane and ethyl acetate ranging from 47:3 to 23:2 by volume as the eluent, to give 43.2 g of the title compound.
Reaction SMILES: [NH2:1][CH:2]([C:5]([F:12])([F:11])[CH2:6][CH2:7][CH2:8][O:9][CH3:10])[CH:3]=[CH2:4].C(N1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28])(OCC)=O>C1C=CC=CC=1>[C:19]1(=[O:28])[N:1]([CH:2]([C:5]([F:11])([F:12])[CH2:6][CH2:7][CH2:8][O:9][CH3:10])[CH:3]=[CH2:4])[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]12
Reactant: C=CC(N)C(F)(F)CCCOC
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Solvent: c1ccccc1
Product: C=CC(N1C(=O)c2ccccc2C1=O)C(F)(F)CCCOC
Reaction time: 8 h
Yield: 85.7 %

Procedure:
A mixture of 3-amino-4,4-difluoro-7-methoxy-1-heptene (420 mg, 2.3 mmoles) and N-carbetoxyphthalimide (506 mg, 2.3 mmoles) in benzene (9 ml) is kept at 25° C. overnight. After concentration under reduced pressure, the residue is dissolved in dichloromethane (5 ml) and treated with triethylamine (0.7 ml) for 41/2 hours. After addition of dichloromethane, the solution is washed with 1N HCl and water. Usual work-up affords an oil (610 mg) which is purified by chromatography on silica (ethyl acetate/petroleum ether: 20/80 RF: 0.4): 440 mg (62%).
Reaction SMILES: NO.[CH:3]1([CH:6]=[O:7])[CH2:5][CH2:4]1.C([Zn][CH2:11][CH3:12])C.[C:13](OC(=O)C)(=[O:15])[CH3:14]>CCCCCC.CCOCC.C1(C)C=CC=CC=1>[C:13]([O:7][CH:6]([CH:3]1[CH2:5][CH2:4]1)[CH2:11][CH3:12])(=[O:15])[CH3:14]
Reactant: CC[Zn]CC
Reactant: O=CC1CC1
Reactant: CC(=O)OC(C)=O
Agent: NO
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCC(OC(C)=O)C1CC1
Reaction time: 72 h
Yield: 54 %

Procedure:
To a vial containing aminoalcohol A (0.05 g, 0.21 mmol) prepared as in Example 13 was added a solution containing cyclopropanecarboxaldehyde (0.21 g, 3.0 mmol), toluene (3.0 mL), and 1 M diethylzinc in hexane (6.0 mL). After 3 days at room temperature, acetic anhydride (1.2 mL, 13 mmol) was added. After 2 additional days the mixture was diluted in ether (50 mL) and the reaction was quenched by dropwise addition of half-saturated aqueous ammonium chloride (50 mL). The ether layer was separated and the aqueous layer was further extracted with ether (2×50 mL). The combined ether layers were dried over magnesium sulfate whereupon the solvent was removed at reduced pressure. The residue was purified by flash chromatography on 220-400 mesh silica with 90% hexane and 10% ether as eluant. The product (+)-1-(cyclopropyl)propyl acetate (0.23 g, 54%) was isolated as a colorless liquid by distillation at reduced pressure. Anal. for C11H20O2. Calcd: C, 71.70; H, 10.94; found: C, 71.41; H, 10.69. 1H NMR (CDCl3/TMS): δ 0.23 (m, 1 H), 0.36 (m, 1 H), 0.43 (m, 1 H), 0.52 (m, 1 H), 1.00-1.09 (m+t, 4 H total), 1.69 (m, 2 H), 2.05 (s, 3 H), 4.20 (m, 1 H); 13C NMR (CDCl3/TMS): δ 2.66, 2.82, 9.57, 14.57, 21.03, 27.45, 79.62, 170.66. [α]D25=+26.2, c=1.04 g/100 mL chloroform. Chiral capillary gas chromatographic analysis at 55° C. on Cyclodex B stationary phase (J & W Scientific) indicated that the enantiomeric excess of the product was 96%.
Reaction SMILES: [C:1]([CH:3]=[C:4]([NH:13][C:14](=O)[O:15]CC)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])#[N:2].[NH:19]([C:21](=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[NH2:20].C(OCC)(=O)C.O>CN1C(=O)CCC1>[Cl:12][C:6]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=1[C:4]1[N:13]=[C:14]([OH:15])[N:20]2[N:19]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:2]=[C:1]2[CH:3]=1
Reactant: CCOC(=O)C(=O)NN
Reactant: CCOC(=O)NC(=CC#N)c1ccc(Cl)cc1Cl
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc2cc(-c3ccc(Cl)cc3Cl)nc(O)n2n1
Temperature: 160 °C
Reaction time: 4 h

Procedure:
3.0 g (10.5 mmol) of ethyl [2-cyano-1-(2,4-dichlorophenyl)ethenyl]carbamate (Example 128A) and 1.39 g (10.5 mmol) of ethyl hydrazino(oxo)acetate are dissolved in NMP (16 ml) and stirred in a flask with a calcium chloride drying tube at an oil-bath temperature of 160° C. for 4 h. The reaction mixture is cooled to RT and ethyl acetate (150 ml) and water (100 ml) are added. The organic phase is separated off, dried with magnesium sulphate and concentrated. The residue is chromatographed on silica gel (mobile phase cyclohexane/ethyl acetate 10:1 to 1:1, then with dichloromethane/methanol 100:1). The crude product is concentrated, mixed with water and stirred for 1 h. The solid is filtered off with suction and dried; 1.31 g (35% of theory) of the product are obtained.
Reaction SMILES: [Mo:1](=O)(=O)=[O:2].[OH-:5].[NH4+:6]>O>[NH3:6].[NH3:6].[NH3:6].[NH3:6].[NH3:6].[NH3:6].[OH2:2].[OH2:5].[OH2:2].[OH2:2].[OH2:2].[OH2:2].[OH2:2].[OH2:2].[OH2:2].[OH2:2].[OH2:2].[OH2:2].[OH2:2].[OH2:2].[OH2:2].[OH2:2].[OH2:2].[OH2:2].[OH2:2].[OH2:2].[OH2:2].[OH2:2].[OH2:2].[OH2:2].[Mo:1].[Mo:1].[Mo:1].[Mo:1].[Mo:1].[Mo:1].[Mo:1]
Reactant: [NH4+]
Reactant: O=[Mo](=O)=O
Reactant: [OH-]
Solvent: O
Product: N
Product: [Mo]

Procedure:
About 100 parts of impure molybdenum trioxide are slurried in about 40 parts of water and enough reagent grade ammonium hydroxide to completely dissolve the molybdenum trioxide. The resulting solution is filtered to remove the hydroxides of iron. About 16 parts of nicotine are added to the filtered solution and the pH is adjusted to about 2.0 with hydrochloric acid. The resulting white precipitate of nicotine-molybdenum is filtered off and washed with about 1000 parts of hot water. The nicotine-molybdenum precipitate is again dissolved in ammonium hydroxide, reslurried, and the pH of the nicotine-treated solution is adjusted to about 2.0 with hydrochloric acid to reprecipitate the nicotine-molybdenum compound which is then filtered off and washed with about 1000 parts of hot water. The resulting nicotine-molybdenum precipitate is again dissolved in ammonium hydroxide. The nicotine phase comes to the top of the reaction vessel and is separated for reuse. The molybdenum containing phase is then evaporated to dryness to produce ammonium paramolybdate crystals. The ammonium paramolybdate is reduced to molybdenum powder.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH:7]2[C:14]3[CH:13]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[NH:11][C:10]=3[C:9](=O)[CH2:8]2)=[CH:4][CH:3]=1.[B][B][B][B][B][B][B][B][B][B]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[C:14]3[CH:13]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[NH:11][C:10]=3[CH2:9][CH2:8]2)=[CH:20][CH:21]=1
Reactant: COC(=O)c1cc2c([nH]1)C(=O)CC2Cc1ccc(Br)cc1
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: COC(=O)c1cc2c([nH]1)CCC2Cc1ccc(Br)cc1

Procedure:
The title compound was synthesized in six steps. First, methyl 1H-pyrrole-2-carboxylate (1.0 g, 8 mmol, 1 equiv) in DCE (15 mL) was reacted with 4-bromophenylacetic acid (2.06 g, 9.6 mmol, 1.2 equiv) according to General Procedure 1.2.A to afford methyl 4-(2-(4-bromophenyl)acetyl)-1H-pyrrole-2-carboxylate, which was then BOC-protected according to General Procedure 1.2.B to provide 1-tert-butyl 2-methyl 4-(2-(4-bromophenyl)acetyl)-1H-pyrrole-1,2-dicarboxylate, which was next reacted with 2-tert-butoxy-2-oxoethylzinc chloride (3.0 g, 28.2 mL, 0.5M in ether, 14 mmol, 3.5 equiv) according to General Procedure 1.2.C to afford 1-tert-butyl 2-methyl 4-(1-(4-bromophenyl)-4-tert-butoxy-2-hydroxy-4-oxobutan-2-yl)-1H-pyrrole-1,2-dicarboxylate, which was reacted with trifluoroacetic acid (8.25 mL, 0.45 M) and triethylsilane (1.25 g, 1.72 mL, 2.9 equiv) according to General Procedure 1.2.D to provide 4-(4-bromophenyl)-3-(5-(methoxycarbonyl)-1H-pyrrol-3-yl)butanoic acid. This product was then cyclized by reaction with PPA (3.16 g) according to General Procedure 1.2.E to achieve methyl 4-(4-bromobenzyl)-6-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate. Reduction with decaborane (0.34 g, 3 mmol, 5 equiv) according to Procedure 5b afforded the title compound, which was purified by purified by column chromatography (Isco CombiFlash) using a 0-30% gradient (EtOAc/Heptane). 0.0998 g. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.03-2.16 (m, 1H) 2.58 (dt, J=12.39, 6.88 Hz, 1H) 2.66 (t, J=6.99 Hz, 2H) 2.76 (d, J=7.39 Hz, 2H) 3.28 (dq, J=7.18, 6.92 Hz, 1H) 3.81 (s, 3H) 6.38 (d, J=1.48 Hz, 1H) 7.07 (d, J=8.31 Hz, 2H) 7.42 (q, J=4.17 Hz, 2H) 8.82 (br. s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[CH3:11][N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:15]1[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH:14]=1
Reactant: CN1CCC(=O)CC1
Reactant: Fc1cccc2cc[nH]c12
Product: CN1CC=C(c2c[nH]c3c(F)cccc23)CC1
Yield: 75.1 %

Procedure:
Beginning with 0.50 gm (3.70 mMol) 7-fluoro-1H-indole and 0.91 mL (7.4 mMol) 1-methyl-4-piperidone, 0.64 gm (75%) of the title compound were recovered as a white solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:18]([F:19])=[C:17]2[C:9]([C:10]3[CH:11]=[CH:12][C:13](B(O)O)=[C:14]([F:20])[C:15]=3[CH2:16]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[OH:24]O>COC(C)(C)C>[CH2:1]([O:5][C:6]1[C:18]([F:19])=[C:17]2[C:9]([C:10]3[CH:11]=[CH:12][C:13]([OH:24])=[C:14]([F:20])[C:15]=3[CH2:16]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc2c(c1F)Cc1c-2ccc(B(O)O)c1F
Reactant: OO
Solvent: COC(C)(C)C
Product: CCCCOc1ccc2c(c1F)Cc1c-2ccc(O)c1F

Procedure:
The oxidation of 24 mmol of 7-butoxy-1,8-difluorofluorene-2-boronic acid with 22 ml of hydrogen peroxide (35 percent) in 60 ml of tert-butyl methyl ether is effected in a similar manner to the procedure described in Example 1. 7-Butoxy-1,8-difluorofluoren-2-ol is obtained.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:23]=[N:24][NH:25][CH:26]=4)=[CH:18][CH:17]=3)[CH:11]=[C:12]([C:13]([OH:15])=O)[C:7]=2[CH:6]=[N:5]1)[CH3:3].[NH2:27][CH2:28][C:29]1[C:30](=[O:37])[NH:31][C:32]([CH3:36])=[CH:33][C:34]=1[CH3:35].CN1CCOCC1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CS(C)=O>[CH3:35][C:34]1[CH:33]=[C:32]([CH3:36])[NH:31][C:30](=[O:37])[C:29]=1[CH2:28][NH:27][C:13]([C:12]1[C:7]2[CH:6]=[N:5][N:4]([CH:2]([CH3:3])[CH3:1])[C:8]=2[N:9]=[C:10]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:26]=[N:25][NH:24][CH:23]=3)=[CH:18][CH:17]=2)[CH:11]=1)=[O:15]
Reactant: CC(C)n1ncc2c(C(=O)O)cc(-c3ccc(-c4cn[nH]c4)cc3)nc21
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CS(C)=O
Solvent: ClCCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(-c4cn[nH]c4)cc3)nc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described in example 109 using 1-(1-methylethyl)-6-[4-(1H-pyrazol-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (20 mg, 0.058 mmol), DMSO (1 mL), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (16.29 mg, 0.086 mmol), N-methylmorpholine (0.025 mL, 0.230 mmol), 1-hydroxy-7-azabenzotriazole (15.67 mg, 0.115 mmol) and EDC (22.07 mg, 0.115 mmol). The final product was collected as 12 mg (43%). LCMS E-S (M+H)=482.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.56 (d, J=6.4 Hz, 6H), 2.14 (s, 3H), 2.24 (s, 3H), 4.42 (d, J=4.8 Hz, 2H) 5.27-5.47 (m, 1H), 5.91 (s, 1H), 7.79 (d, J=8.3 Hz, 2H), 8.04 (br. s., 1H), 8.15-8.21 (m, 1H), 8.27 (d, J=8.3 Hz, 2H), 8.35-8.42 (m, 1H), 8.99 (t, J=4.8 Hz, 1H), 11.58 (br. s., 3H).
Reaction SMILES: C([O-])(=O)/C=C\C([O-])=[O:5].[F:9][C:10]([F:32])([CH:29]([F:31])[F:30])[CH2:11][N:12]=[C:13]([NH2:28])[NH:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17](OCCCC(N)=N)[N:16]=1.FC(F)(C(F)F)CN=[C:37]=[S:38]>>[F:9][C:10]([F:32])([CH:29]([F:31])[F:30])[CH2:11][N:12]=[C:13]([NH2:28])[NH:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([S:38]([CH3:37])=[O:5])[N:16]=1
Reactant: N=C(N)CCCOc1nccc(NC(N)=NCC(F)(F)C(F)F)n1
Reactant: O=C([O-])/C=C\C(=O)[O-]
Reactant: FC(F)C(F)(F)CN=C=S
Product: CS(=O)c1nccc(NC(N)=NCC(F)(F)C(F)F)n1
Yield: 25 %

Procedure:
maleate, m.p. 182°-184° (yield 25%). The 4-[4-(2-[2,2,3,3-tetrafluoropropyl]guanidino)pyrimid-2-yloxy]butyramidine used as starting material may be prepared as follows. The second, third and fourth parts of Example 34 in European Patent Publication No.30092 were repeated, using 2,2,3,3-tetrafluoropropylisothiocyanate in place of 2,2,2-trifluoroethylisothiocyanate, to give 4-[2-(2,2,3,3-tetrafluoropropyl)guanidino]-2methylsulphinylpyrimidine. Using this intermediate, and 3-cyanopropanol in place of 4-cyanobutanol, the second, third and fourth parts of Example 24 were repeated to give the required starting material.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Br[CH2:29][C:30]1[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=1>CN(C=O)C.C(OCC)C>[CH2:1]([N:8]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:38][CH:39]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NCc2ccccc2)cccc1[N+](=O)[O-]
Reactant: COC(=O)c1ccc(CBr)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: COC(=O)c1ccc(CN(Cc2ccccc2)c2cccc([N+](=O)[O-])c2C)cc1
Temperature: 90 °C
Yield: 84.9 %

Procedure:
The product from Example 6A (0.92 g, 3.8 mmoles) and diisopropylethylamine (1.7 mL, 9.5 mmoles) in DMF (9.5 mL) were treated with methyl 4-(bromomethyl)benzoate (0.74 g, 7.6 mmoles) and heated for 18 hours at 90° C. After cooling to room temperature, the mixture was diluted with diethyl ether (200 mL). The mixture was washed with saturated ammonium chloride (200 mL), water (2×200 mL), brine (150 mL), dried (Na2SO4), filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 10:1→4:1 hexanes:ethyl acetate) to provide the title compound as a yellow solid (1.26 g, 85%).
Reaction SMILES: [CH2:1]([N:3]([CH2:33][CH3:34])[C:4]([C:6]1[CH:7]=[N:8][C:9]([C:12]2([C:24]3[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=3)C(O)=O)[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([CH3:23])[CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13]2)=[N:10][CH:11]=1)=[O:5])[CH3:2].C([N:37](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C1(C)C=CC=CC=1.C(O)(C)(C)C>[CH2:1]([N:3]([CH2:33][CH3:34])[C:4]([C:6]1[CH:7]=[N:8][C:9]([C:12]2([C:24]3[CH:32]=[CH:31][CH:30]=[C:26]([NH2:37])[CH:25]=3)[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([CH3:23])[CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13]2)=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CCCC(C)CN1CCC(c2cccc(C(=O)O)c2)(c2ncc(C(=O)N(CC)CC)cn2)CC1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: CCCC(C)CN1CCC(c2cccc(N)c2)(c2ncc(C(=O)N(CC)CC)cn2)CC1
Temperature: 120 °C
Reaction time: 22 h
Yield: 63.5 %

Procedure:
To a stirring solution of 3-[4-(5-Diethylcarbamoyl-pyrimidin-2-yl)-1-(2-methyl-pentyl)-piperidin-4-yl]-benzoic acid (210 mg, 0.45 mmol) in 8 mL Toluene and 2 mL tert-butyl alcohol at room temperature was added triethylamine (0.066 mL, 0.48 mmol) and diphenylphosphoryl azide (0.07 mL, 0.45 mmol). The resulting mixture was heated at 120° C. for 20 hours, cooled to room temperature, washed with water, dried and concentrated. The resulting residue was taken up in EtOH/5N HCl (1:1) and stirred at room temperature for 22 hours. The resulting mixture was basified (pH=9) with NaOH and extracted with EtOAc (3×20 mL). The combined organic layers were dried and concentrated. Purification of the crude material was accomplished by flash chromatography with a solvent gradient of 5% and 10% MeOH/CH2Cl2 to yield 125 mg of the desired product. 1HNMR (400 MHz, CDCl3) δ 8.71 (s, 2H), 7.02 (t, 1H), 6.76 (d, 1H), 6.71 (s, 1H), 6.45 (d, 1H), 3.57-3.52 (comp, 4H), 3.28-3.26 (comp, 2H), 2.93-2.89 (comp, 2H), 2.71 (br s, 2H), 2.33 (br s, 2H), 2.15-1.96 (comp, 4H), 1.61 (br s, 1H), 1.38-1.17 (comp, 10H), 1.03-0.96 (comp, 1H), 0.86-0.83 (comp, 6H); MS (M+1) 438.6.
Reaction SMILES: [F:1][CH2:2][C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:4].[Cl:11][S:12](O)(=[O:14])=[O:13]>ClCCl>[F:1][CH2:2][C@H:3]([C:5]1[CH:10]=[CH:9][C:8]([S:12]([Cl:11])(=[O:14])=[O:13])=[CH:7][CH:6]=1)[CH3:4]
Reactant: O=S(=O)(O)Cl
Reactant: C[C@H](CF)c1ccccc1
Solvent: ClCCl
Product: C[C@H](CF)c1ccc(S(=O)(=O)Cl)cc1
Temperature: 30 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
3.5 g of ((S)-2-fluoro-1-methyl-ethyl)-benzene (25.32 mmol) were dissolved in 80 ml of dichloromethane. At 0-5° C., 11.81 g of chlorosulfonic acid (101.31 mmol), dissolved in 20 ml of dichloromethane, were added dropwise. The reaction mixture was stirred for 30 min at room temperature and 2 h at 30° C. The solvent was evaporated. 150 ml of diethyl ether were added to the residue, washed once with 150 ml of water, and the organic layer was dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure. The crude product was purified via silica gel chromatography with n-heptane-dichloromethane (6:4) as eluent to give 1.5 g of the title compound.
Reaction SMILES: [C:1](=[O:12])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.[CH:13]1([NH2:16])[CH2:15][CH2:14]1.[C@H:17]1([NH:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[C:32]([NH2:37])[CH:33]=3)[N:28]=2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18]1>>[CH:13]1([NH:16][C:1]([NH:37][C:32]2[CH:33]=[C:34]3[C:29](=[CH:30][CH:31]=2)[N:28]=[C:27]([NH:26][C@H:17]2[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18]2)[CH:36]=[CH:35]3)=[O:12])[CH2:15][CH2:14]1
Reactant: NC1CC1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: O=C(Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)NC1CC1

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate, cyclopropylamine and (R)—N2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=359.5 (M+H+).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC.[C:27](O)([C:29]([F:32])([F:31])[F:30])=O.[NH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(Cl)(Cl)(Cl)[Cl:42]>>[F:30][C:29]([F:32])([F:31])[C:27]([Cl:42])=[N:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Nc1ccccc1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: FC(F)(F)C(Cl)=Nc1ccccc1
Reaction time: 0.17 h

Procedure:
A mixture of Ph3P (138.0 g, 526 mmol), Et3N (21.3 g, 211 mmol), CCl4 (170 mL) and TFA (20 g, 175 mmol) was stirred for 10 min in an ice-bath. Aniline (19.6 g, 211 mmol) was dissolved in CCl4 (20 mL) was added. The mixture was stirred at reflux for 3 h. The solvent was removed under vacuum and hexane was added. The precipitates (Ph3PO and Ph3P) were filtered off and washed with hexane. The filtrate was distilled under reduced pressure to yield 2,2,2-trifluoro-N-phenyl-acetimidoyl chloride (19 g), which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][C@@H:23]2[CH2:25][O:24]2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[CH:26]([NH2:29])([CH3:28])[CH3:27].CN1CCCC1=O.Cl>[Cl-].[Na+].O.ClCCl>[ClH:1].[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][C@@H:23]([OH:24])[CH2:25][NH:29][CH:26]([CH3:28])[CH3:27])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:15][CH:14]3[CH2:16][CH:10]([CH2:11][CH:12]([CH2:13]3)[CH2:17]1)[CH2:9]2)=[O:5]
Reactant: CC(C)N
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(C[C@@H]2CO2)ccc1Cl
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CC(C)NC[C@H](O)Cc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1

Procedure:
2-Chloro-5-[(2R)-2-oxiranylmethyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (Example 5c) (133 mg), isopropylamine (3 mL) and 1-methyl-2-pyrrolidinone (5 mL) were heated together at 80° C. in a sealed tube for 22 hours, cooled and poured into brine (50 mL), extracted into ethyl acetate (3×50 mL), washed with brine (3×50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to give an oil. This was purified by Waters' MCX resin and then by column chromatography eluting with 19:1:0.1 dichloromethane/methanol/ammonia. The oil obtained was dissolved in dichloromethane (5 mL) and 1M ethereal hydrogen chloride (4 mL) was added. The mixture was concentrated to give the titled compound as a solid (85 mg).