Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:32])([CH3:31])[NH:9][C:10](=[O:30])[C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)=[CH:14][CH:13]=1)(=O)=O.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([C:7]2[C:8]([CH3:32])([CH3:31])[NH:9][C:10](=[O:30])[C:11]=2[C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)=[CH:16][CH:17]=2)=[CH:39][CH:38]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC1(C)NC(=O)C(c2ccc(OCc3ccc4ccccc4n3)cc2)=C1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(C2=C(c3ccc(OCc4ccc5ccccc5n4)cc3)C(=O)NC2(C)C)cc1
Reaction time: 0.5 h
Yield: 6.6 %

Procedure:
To a stirred solution of 2,2-dimethyl-5-oxo-4-(4-(quinolin-2-ylmethoxy)phenyl)-2,5-dihydro-1H-pyrrol-3-yl trifluoromethanesulfonate (500 mg, 1.01 mmol) in 1,4-dioxane (20 mL) were added 4-methoxyphenylboronic acid (185 mg, 1.2 mmol), Na2CO3 (256 mg, 3.04 mmol) and water (4 mL) at RT under an inert atmosphere. The mixture was stirred for 30 min and then Pd(PPh3)4 (117 mg, 0.1 mmol) was added. Stirring was continued at 80° C. for 16 h. The reaction mixture was then diluted with water and extracted with EtOAc (2×200 mL). The combined organic layers were washed with water and brine, and then dried over Na2SO4 and concentrated in vacuo to afford 4-(4-methoxyphenyl)-5,5-dimethyl-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrol-2(5H)-one (30 mg, 7%) as a white solid. 1H NMR (500 MHz, CDCl3): δ 8.20-8.01 (m, 2 H), 7.87-7.62 (m, 2 H), 7.61-7.51 (m, 2 H), 7.38-7.30 (m, 2 H), 7.16-7.09 (m, 2 H), 6.91 6.80 (m, 4 H), 5.96 (bs, 1 H), 5.39 (s, 2 H), 3.81 (s, 3 H), 1.43 (s, 6 H). MS: M+H: m/z=451.2 and HPLC: 94%, (Condition-I).
Reaction SMILES: [S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[C:6]([N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)(=[NH:8])[NH2:7].[C:15]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)(=[NH:17])[NH2:16].[C:24](O[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>O1CCCC1.O>[S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[C:6]([N:9]1[CH2:14][CH2:13][N:12]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:11][CH2:10]1)(=[NH:7])[NH2:8].[C:15]([N:18]1[CH2:23][CH2:22][N:21]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[CH2:20][CH2:19]1)(=[NH:16])[NH2:17]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: N=C(N)N1CCNCC1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=N)N)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 63.4 %

Procedure:
2.50 g of 1-amidinopiperazine hemisulfate were dissolved in 60 ml of a 1:1 by volume mixture of tetrahydrofuran and water, and a solution of 3.40 g of di-t-butyl dicarbonate in 10 ml of tetrahydrofuran was added to the resulting solution, after which the mixture was stirred at room temperature for 2.5 hours. At the end of this time, the tetrahydrofuran was removed from the reaction mixture by distillation under reduced pressure, the insolubles were filtered off and the filtrate was evaporated to dryness under reduced pressure. The resulting residue was extracted with ethanol (twice, each time with 50 ml) and methanol (twice, each time with 50 ml). The extract was evaporated to dryness to obtain 2.48 g of the title compound, as crystals, melting at 278° C. (with decomposition).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[Si:17]([O:34][CH2:35][C:36]1[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[N:39]=[C:38](Cl)[CH:37]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1>[Si:17]([O:34][CH2:35][C:36]1[CH:41]=[C:40]([C:42]([F:45])([F:43])[F:44])[N:39]=[C:38]([O:3][CH:4]2[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]2)[CH:37]=1)([C:30]([CH3:33])([CH3:31])[CH3:32])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)[Si](OCc1cc(Cl)nc(C(F)(F)F)c1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(F)(F)F)n2)CC1
Reaction time: 0.75 h

Procedure:
To sodium hydride (36 mg, 0.89 mmol, 60% in mineral oil) in tetrahydrofuran (1.0 mL) was added tert-butyl 4-hydroxypiperidine-1-carboxylate (0.18 g, 0.89 mmol, Aldrich). After stirring for 45 minutes, 4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-chloro-6-(trifluoromethyl)pyridine (0.20 g, 0.44 mmol, from Step B) in tetrahydrofuran (0.60 mL) was added and the mixture was stirred overnight. The reaction was quenched and diluted with water and extracted with ether. The extract was washed with water, brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography on silica gel, eluting with a gradient from 0-5% EtOAc in hexanes afforded product as an oil (0.19 g, 52%). LCMS (M-tBu+H)+: 559.2
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16](OCC)=[O:17])=[N:4][C:5]([C:12]([F:15])([F:14])[F:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.O.[NH2:22][NH2:23].Cl>CO.O>[NH2:1][C:2]1[C:3]([C:16]([NH:22][NH2:23])=[O:17])=[N:4][C:5]([C:12]([F:14])([F:15])[F:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1
Reactant: NN
Reactant: CCOC(=O)c1nc(C(F)(F)F)c(C(F)(F)F)nc1N
Agent: Cl
Solvent: CO
Solvent: O
Product: NNC(=O)c1nc(C(F)(F)F)c(C(F)(F)F)nc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of ethyl 3-amino-5,6-bis(trifluoromethyl)pyrazine-2-carboxylate (Int. G1)(455 mg, 1.501 mmol) in MeOH (10 ml) was treated with hydrazine monohydrate (0.147 ml, 3.00 mmol) and stirred at RT overnight. The reaction mixture was diluted with water (50 ml) and the pH was adjusted to pH4-5 using 1M HCl. A yellow precipitate formed which was filtered under vacuum, washed with water and air dried to afford the title compound which was used without further purification;
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[N+:29]([C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34]Br)([O-:31])=[O:30]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:34][C:33]2[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=2[N+:29]([O-:31])=[O:30])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2ccccc2[N+](=O)[O-])CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
To a cold (−78° C.) solution of ethyl N-tert-butoxycarbonylpiperidine-4-carboxylate (7.5 g, 29 mmol) in anhydrous THF (75 mL), a solution of sodium bis(trimethylsilyl)amide (40 mL, 1M, 40 mmol) was added over a period of 30 min. The resultant mixture was stirred at −78° C. for 1 h., and a solution of 2-nitrobenzyl bromide (7.6 g, 35) in THF (10 mL) was added. The reacting mixture was allowed to warm up to room temp. and stirred overnight. The product mixture was concentrated, and the residue partition between water and ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 20% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:8][C:9]1=[C:10]([Br:16])[C:11]([O:13][C:14]1=O)=[O:12]>CC(O)=O>[C:2]1([N:1]2[C:14](=[O:13])[C:9]([Br:8])=[C:10]([Br:16])[C:11]2=[O:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C1OC(=O)C(Br)=C1Br
Solvent: CC(=O)O
Product: O=C1C(Br)=C(Br)C(=O)N1c1ccccc1
Temperature: 130 °C
Reaction time: 1.5 h
Yield: 63.7 %

Procedure:
Aniline (72 μL, 0.788 mmol) was added to a solution of dibromomaleic anhydride (200 mg, 0.788 mmol) in AcOH (10 mL). The mixture was stirred for 3 h at RT and at 130° C. for 90 mins. After cooling, the mixture was concentrated to dryness and traces of AcOH removed by azeotrope with toluene. The tan residue was purified using silica flash chromatography (5% EtOAc/95% petroleum ether) to yield the desired compound as a pale yellow solid (166 mg, 60%). δH (600 MHz, CDCl3) 7.48 (m, 2H, ArH), 7.41 (tt, 1H, J=7.4 and 1.1 Hz, ArH), 7.33 (m, 2H, ArH); δC (150 MHz, CDCl3) 163.0, 131.0, 130.0, 129.5, 128.8, 126.2.
Reaction SMILES: P([N:17]=[N+:18]=[N-:19])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1.N12CCCN=C1CCCCC2.[Br:31][C:32]1[C:33]([O:40][CH3:41])=[C:34]([CH2:38]O)[CH:35]=[CH:36][CH:37]=1>C1(C)C=CC=CC=1>[N:17]([CH2:38][C:34]1[CH:35]=[CH:36][CH:37]=[C:32]([Br:31])[C:33]=1[O:40][CH3:41])=[N+:18]=[N-:19]
Reactant: COc1c(Br)cccc1CO
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1c(Br)cccc1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6.00 g of diphenyl phosphorazidate and 4.1 g of 1,8-diazabicyclo[5.4.0]undec-7-ene were added to 4.0 g of 3-bromo-2-methoxy-phenyl-methanol 6 in 100 mL of toluene at 0° C. The mixture was stirred at room temperature overnight. The reaction mixture was quenched with aqueous ammonium chloride. The aqueous layer was extracted with ethyl acetate/THF. The pooled organic extracts were washed with brine and dried over magnesium sulfate. The mixture was filtered. The solvents were removed under vacuum. The residue was purified by chromatography on silica gel to give 1-azidomethyl-3-bromo-2-methoxy-benzene 7.
Reaction SMILES: C(=O)(O)[O-].[Na+].[Br:6][C:7]1[C:16]([O:17][CH3:18])=[C:15]2[C:10]([C:11](=[O:28])[C:12]([C:23](OCC)=[O:24])=[C:13]([SH:22])[N:14]2[CH:19]2[CH2:21][CH2:20]2)=[CH:9][CH:8]=1.[NH2:29]OS(O)(=O)=O>O.O1CCCC1>[Br:6][C:7]1[C:16]([O:17][CH3:18])=[C:15]2[C:10]([C:11](=[O:28])[C:12]3[C:23](=[O:24])[NH:29][S:22][C:13]=3[N:14]2[CH:19]2[CH2:21][CH2:20]2)=[CH:9][CH:8]=1
Reactant: NOS(=O)(=O)O
Reactant: CCOC(=O)c1c(S)n(C2CC2)c2c(OC)c(Br)ccc2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1c(Br)ccc2c(=O)c3c(=O)[nH]sc3n(C3CC3)c12
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of sodium bicarbonate (316.9 mg, 3.77 mmol) in water (7.5 mL) is added to a solution of ethyl 7-bromo-1-cyclopropyl-2-mercapto-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (from above, ˜0.37 mmol) in tetrahydrofuran (7.5 mL) at room temperature. Hydroxylamine-O-sulfonic acid (214.7 mg, 1.90 mmol) is added as a solid and in one portion to this mixture. The resulting amber solution is stirred at room temperature for 2.5 h and quenched by addition of an aqueous solution of 5% hydrochloric acid (50 mL). The solid that formed is collected by filtration, washed with an aqueous solution of 5% hydrochloric acid (3×10 mL), washed with distilled water (3×10 mL), and dried in vacuo to give 17 as a tan solid. This product ids of sufficient purity (≧95% by 1H NMR spectroscopy) to use directly in the next synthetic step. 1H NMR (DMSO-d6): δ 1.00 (m, 2H, c-Pr CH2), 1.20 (m, 2H, c-Pr CH2), 3.79 (s, 3H, OCH3), 3.85 (m, 1H, c-Pr CH), 7.66 (d, J=8.5 Hz, 1H, aromatic H-6), 7.93 (d, J=8.5 Hz, 1H, aromatic H-5), 11.67 (br, 1H). 13C{1H} NMR (DMSO-d6): δ 11.5 (c-Pr CH2), 35.1 (c-Pr CH), 61.9 (OCH3), 107.7, 122.9 (CH, C-5), 123.5 (C—Br, C-7), 127.9 (CH, C-6), 128.0 (C-4a), 136.5 (C-8a), 146.6 (C—OCH3), 164.5, 171.1 (C═O, C-4), 171.2 (br). LCMS m/z calcd for C14H1179BrN2O3S ([M]+) 366. Found 367 ([M+H]+). HRMS m/z calcd for C14H1179BrN2NaO3S 388.9571 ([M+Na]+). Found 388.9577.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C)C=O>[CH2:16]([N:6]1[CH:7]=[C:2]([Br:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=c1[nH]cc(Br)c(=O)[nH]1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]c(=O)n(Cc2ccccc2)cc1Br
Reaction time: 72 h

Procedure:
To a suspension of 5-bromouracil (5.0 g, 26 mmol) and potassium carbonate (7.2 g, 52 mmol) in N,N-dimethylformamide (25 mL) was added benzyl bromide (3.1 mL, 26 mmol) and the reaction mixture stirred 72 h. The reaction was treated with water (50 mL) and then extracted into ethyl acetate (3×75 mL). The aqueous layer was further extracted with dichloromethane (3×100 mL), the dichloromethane layers were combined, washed with water (2×50 mL), brine (1×50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting mixture of products was purified by pressurized silica gel chromatography (25% ethyl acetate in hexane) to provide 1-benzyl-5-bromo-1H-pyrimidine-2,4-dione.
Reaction SMILES: N(C(C)C)C(C)C.[Li]CCCC.[Br:13][C:14]1[CH:15]=[C:16]([F:22])[C:17]([F:21])=[C:18]([F:20])[CH:19]=1.[C:23](=[O:25])=[O:24].Cl>C1COCC1>[Br:13][C:14]1[C:19]([C:23]([OH:25])=[O:24])=[C:18]([F:20])[C:17]([F:21])=[C:16]([F:22])[CH:15]=1
Reactant: O=C=O
Reactant: Fc1cc(Br)cc(F)c1F
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)c1c(Br)cc(F)c(F)c1F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 84 %

Procedure:
To a solution of i-Pr2NH (3.65 mL, 25.8 mmol) in THF (50 mL) was added n-BuLi (10.3 mL, 25.8 mmol, 2.50 M solution in hexanes) at 0° C. After stirring for 15 minutes, the reaction mixture was cooled to −78° C. A solution of 5-bromo-1,2,3-trifluorobenzene (5.00 g, 23.7 mmol) in THF (5 mL) was added. The resulting mixture was stirred for 2 hours at −78° C., poured into an excess of freshly crushed dry ice, and stirred for 30 minutes To this mixture was added 10% aqueous HCl to adjust its pH to 1. The resulting mixture was extracted with ether (3×). The combined organic layers were washed with 5% aqueous NaOH (2×). The combined basic aqueous layers were acidified to pH 1 with concentrated HCl, and extracted with ether (2×). The combined organic layers were washed with water, dried over MgSO4, filtered, and concentrated in vacuo to give the desired product (5.06 g, 84%) that was used directly without further purification.
Reaction SMILES: CO[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[C:18]([F:20])[C:17]([O:21][CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])=[CH:16][C:15]=3[CH2:30][CH3:31])=[CH:11][CH:12]=2)[N:7]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[N:6]=1)=[NH:4].[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][C:48]([O:54][CH2:55][CH3:56])([O:51][CH2:52][CH3:53])[CH:47]([NH2:57])[CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39].C(O)(=O)C>C(O)C>[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][C:48]([O:54][CH2:55][CH3:56])([O:51][CH2:52][CH3:53])[CH:47]([NH:57][C:3]([C:5]2[C:13]3[C:8](=[CH:9][C:10]([C:14]4[CH:19]=[C:18]([F:20])[C:17]([O:21][CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:27])[CH3:28])=[CH:16][C:15]=4[CH2:30][CH3:31])=[CH:11][CH:12]=3)[N:7]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[N:6]=2)=[NH:4])[CH2:46]1)=[O:44])([CH3:39])([CH3:41])[CH3:40]
Reactant: CCOC1(OCC)CCN(C(=O)OC(C)(C)C)CC1N
Reactant: CCc1cc(OCOCC[Si](C)(C)C)c(F)cc1-c1ccc2c(C(=N)OC)nn(C3CCCCO3)c2c1
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC1(OCC)CCN(C(=O)OC(C)(C)C)CC1NC(=N)c1nn(C2CCCCO2)c2cc(-c3cc(F)c(OCOCC[Si](C)(C)C)cc3CC)ccc12
Temperature: 50 °C
Yield: 117.3 %

Procedure:
To a solution of 6-[2-ethyl-5-fluoro-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-(tetrahydro-pyran-2-yl)-1H-indazole-3-carboximidic acid methyl ester (Preparation 7, 31.4 g, 59.5 mmol) in ethanol (140 mL) was added a solution of 3-amino-4,4-diethoxy-piperidine-1-carboxylic acid tert-butyl ester (US-2004/0229862, 18.02 g, 62.48 mmol) in ethanol (100 mL). Acetic acid (6.81 mL, 119 mmol) was added and the reaction mixture was heated at 50° C. for 18 hours. The reaction mixture was concentrated in vacuo and azeotroped with toluene (100 mL) to give the title compound as a foam (54.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[CH:21]=3)=[O:18])[CH2:14][OH:15])[CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:39](OC(=O)C)(=[O:41])[CH3:40]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH2:8][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[CH:21]=3)=[O:18])[CH2:14][O:15][C:39](=[O:41])[CH3:40])[CH2:10]2)=[CH:30][CH:31]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(NC(=O)N[C@H](CO)CCN2CC(Oc3ccc(Cl)cc3)C2)cc(OC)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(NC(=O)N[C@@H](CCN2CC(Oc3ccc(Cl)cc3)C2)COC(C)=O)cc(OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1-{(S)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(3,5-dimethoxy-phenyl)-urea (0.05 g, 0.111 mmol) and triethylamine (0.031 ml, 0.222 mmol) in DCM (3 ml) is treated with acetic anhydride and left to stir at room temperature for 3 hours. The reaction mixture is partitioned between DCM and water. The organic phase is washed with sodium bicarbonate solution, dried over magnesium sulphate and evaporated to afford acetic acid (S)-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-2-[3-(3,5-dimethoxy-phenyl)-ureido]-butyl ester. [M+H] 492.08
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH:15]1[C:23]([O:25][CH3:26])=[O:24].O>C(Cl)Cl>[C:5]([C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[CH2:14][CH:15]([C:23]([O:25][CH3:26])=[O:24])[CH2:16]2)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)C1Cc2ccccc2C1
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COC(=O)C1Cc2ccc(C(=O)c3ccccc3)cc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 250 cm3 reaction vessel fitted with a stirrer, a cooler, a dropping funnel and a thermometer, is placed 23.2 g (0.173 mole) of anhydrous aluminum chloride in suspension in 40 ml of methylene chloride. 35.3 g (0.252 mole) of benzoyl chloride dissolved in 40 cm3 of methylene chloride is then slowly added at ambient temperature. The aluminum chloride tends to pass into solution while the temperature gradually rises several degrees. The mixture is cooled to hold the temperature close to 20° C. and a solution of 11.1 g (0.063 mole) of methyl indane-2-carboxylate dissolved in 50 cm3 of methylene chloride is added. The temperature gradually rises during the course of the addition and the mixture turns a light brown color. The mixture is stirred for one hour at ambient temperature and is then heated to reflux for 3 hours. After cooling, the mixture is poured into acidified iced water and the resulting mixture is extracted with chloroform. The chloroform extract is then washed with water containing caustic soda, then with slightly acidified water and finally with water. It is dried over anhydrous sodium sulphate. The product is then filtered and the filtrate concentrated to an oily residue which is distilled and a fraction is collected boiling at 178°-184° C. at 0.6 to 0.8 torr.
Reaction SMILES: Cl.[F:2][C:3]([F:32])([F:31])[C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][C@H:12]([NH:16][C@@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]3[NH:23]C(=O)OC(C)(C)C)[CH2:11]2)=[CH:6][N:5]=1>O1CCOCC1.CO>[F:32][C:3]([F:2])([F:31])[C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][C@H:12]([NH:16][C@@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]3[NH2:23])[CH2:11]2)=[CH:6][N:5]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1N[C@H]1CCCN(c2cnc(C(F)(F)F)nc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: N[C@@H]1CCCC[C@H]1N[C@H]1CCCN(c2cnc(C(F)(F)F)nc2)C1
Reaction time: 1 h
Yield: 98.5 %

Procedure:
4 N HCl in dioxane (2.29 mL, 9.15 mmol) was slowly added to a solution of tert-butyl (1R,2R)-2-((S)-1-(2-(trifluoromethyl)pyrimidin-5-yl)piperidin-3-ylamino)cyclohexylcarbamate (0.58 gm, 1.31 mmol) in dioxane (3.52 mL) and MeOH (0.44 mL). After 1 h of stirring the reaction mixture was concentrated and the residue was partitioned between EtOAc and sat. NaHCO3. The aqueous phase was isolated and extracted with EtOAc. All organic phases were combined, washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated to give the product (1R,2R)—N1—((S)-1-(2-(trifluoromethyl)pyrimidin-5-yl)piperidin-3-yl)cyclohexane-1,2-diamine (0.44 gm, 1.29 mmol, 99% yield) as a syrup. Anal. Calcd. for C16H24F3N5 m/z 343.2, found: 344.2 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:31])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:27]=[CH:28][CH:29]=[CH:30][C:5]=2[N:4]=1.[CH3:32][N:33]([CH3:38])[CH2:34][C:35](O)=[O:36].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O>[F:31][CH:2]([F:1])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20][CH:21]3[CH2:26][CH2:25][N:24]([C:35](=[O:36])[CH2:34][N:33]([CH3:38])[CH3:32])[CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:27]=[CH:28][CH:29]=[CH:30][C:5]=2[N:4]=1
Reactant: FC(F)c1nc2ccccc2n1-c1cc(N2CCOCC2)nc(NC2CCNCC2)n1
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CC(=O)N1CCC(Nc2nc(N3CCOCC3)cc(-n3c(C(F)F)nc4ccccc43)n2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 41.7 %

Procedure:
To a mixture of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-morpholin-4-yl-N-piperidin-4-ylpyrimidin-2-amine (18 mg) and N,N-dimethylformamide (0.36 mL) were added N,N-dimethylglycine (4.8 mg), 1-hydroxybenzotriazole (6.2 mg), and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (8.8 mg), and the mixture was stirred at room temperature for 6 hours. To the reaction mixture was added water, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by amino silica gel column chromatography (ethyl acetate, and subsequently chloroform:methanol=96:4). Desired fractions were combined and concentrated under reduced pressure. The residue was solidified by the addition of a small amount of diisopropyl ether to obtain 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-N-{1-[(dimethylamino)acetyl]piperidin-4-yl}-6-morpholin-4-ylpyrimidin-2-amine (9 mg) as a white powder.