Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.Cl.C(O)[N:5]1[C:9](=[O:10])[N:8](CO)[CH:7]2[N:13](CO)[C:14]([N:16](CO)[CH:6]12)=[O:15].C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>>[CH:7]12[NH:13][C:14](=[O:15])[NH:16][CH:6]1[NH:5][C:9]([NH:8]2)=[O:10]
Reactant: O=C1N(CO)C2C(N1CO)N(CO)C(=O)N2CO
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CO
Product: O=C1NC2NC(=O)NC2N1
Reaction time: 0.29 h

Procedure:
Into a suitable reaction vessel equipped with a stirrer, thermometer, and reflux condenser there was introduced 950 parts (30 moles) of methanol and 40 parts of concentrated hydrochloric acid. To this mixture, 262 parts (1 mole of tetramethylol glycoluril) were added and the reaction mixture was stirred at 25°-30° C. In about 15-20 minutes, all the tetramethylol glycoluril went into solution. After half an hour, the reaction mixture was neutralized with 140 parts of sodium bicarbonate and 20 parts of sodium carbonate at 22°-23° C. The pH after neutralization was about 8. The salt was filtered. The filtrate was concentrated at 60° C. under reduced pressure. The yield of the syrupy product after filtration of the salt was 290 parts, which was diluted to 90% solids with cellosolve. The product characteristics were as follows: Foil Solids: 91.4%; Pan Solids: 82.2%; and Gardner-Holdt Viscosity (25° C.): Z1. I.R. of the product indicated that the methylated product has a significant amount of unreacted methylol groups.
Reaction SMILES: O=[C:2]([CH3:13])[CH2:3][NH:4][C:5](=[O:12])[C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1>O=P(Cl)(Cl)Cl>[CH3:13][C:2]1[O:12][C:5]([C:6]2[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=2)=[N:4][CH:3]=1
Reactant: CC(=O)CNC(=O)c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cnc(-c2ccncc2)o1
Temperature: 120 °C
Yield: 58.4 %

Procedure:
20 g N-(2-oxo-propyl)-isonicotinamide was dissolved in 200 mL phosphoroxychloride at 0° C. and the mixture was heated at 120° C. over night. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine and concentrated. The residue was purified by chromatographie on silica to yield 10.5 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH3:11][O:12][CH:13]([CH3:16])[CH2:14][NH2:15]>>[NH2:1][C:2]1[CH:9]=[C:8]([NH:15][CH2:14][CH:13]([O:12][CH3:11])[CH3:16])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: N#Cc1cnc(N)cc1F
Reactant: COC(C)CN
Product: COC(C)CNc1cc(N)ncc1C#N

Procedure:
From intermediate 21 and racemic 2-methoxypropan-1-amine, reacted in an analogous manner to the preparation of intermediate 49. (UPLC-MS 3) tR 0.39 min; ESI-MS 207.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]([F:14])([F:13])[F:12])[N:7]([CH2:15][C:16]([F:19])([F:18])[F:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:20]C.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]([F:14])([F:12])[F:13])[N:7]([CH2:15][C:16]([F:17])([F:18])[F:19])[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:20]
Reactant: COc1ccc2c(nc(C(F)(F)F)n2CC(F)(F)F)c1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc2c(nc(C(F)(F)F)n2CC(F)(F)F)c1Cl
Reaction time: 2 h
Yield: 76.6 %

Procedure:
A CH2Cl2 (15 mL) solution of 4-chloro-5-(methyloxy)-1-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)-1H-benzimidazole (0.14 g, 0.422 mmol) at rt was treated dropwise with BBr3 (1M CH2Cl2, 1.055 ml, 1.055 mmol) and stirred for 2 h. The mixture was quenched with saturated aqueous NaHCO3, adjusted to a pH of 7, and extracted with CH2Cl2. The combined organic portions were washed combined with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification (SiO2; EtOAc/hexanes) afforded the title compound (0.103 g): MS (ESI) m/z 319 (M+1).
Reaction SMILES: ClC1C(C(O)=O)=CC=C2C=1NC=C2.CO.[Cl:16][C:17]1[C:18]([C:32]([OH:34])=[O:33])=[CH:19][CH:20]=[C:21]2[C:25]=1[NH:24][CH:23]=[C:22]2[C:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1>C1COCC1.CO.[OH-].[OH-].[Pd+2]>[Cl:16][C:17]1[C:18]([C:32]([OH:34])=[O:33])=[CH:19][CH:20]=[C:21]2[C:25]=1[NH:24][CH:23]=[C:22]2[CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(O)c1ccc2c(C3=CCCCC3)c[nH]c2c1Cl
Agent: [Pd+2]
Agent: O=C(O)c1ccc2cc[nH]c2c1Cl
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(C3CCCCC3)c[nH]c2c1Cl
Yield: 94.4 %

Procedure:
To a mixture of 7-chloro-1H-indole-6-carboxylic acid (3.8 g, about 19.4 mmol) in MeOH (50 ml) at r.t. under N2 was added cyclohexanone (6.13 ml, 59.1 mmol), followed by a solution of NaOMe in MeOH (17.5 ml, 76.6 mmol, 25% wt). The reaction mixture was stirred at reflux for 16 hr. After cooling to r.t., the mixture was added another bath of cyclohexanone (6.13 ml, 59.1 mmol), followed by another solution of NaOMe in MeOH (17.5 ml, 76.5 mmol, 25% wt), and then re-stirred at reflux for another 7 hr. After cooling to r.t., the mixture was evaporated, added with water (100 ml), acidified with hydrochloric acid (5N) and left standing at r.t. overnight. The aqueous mixture was decanted, and the residue washed twice with hydrochloric acid (30 ml, 1N) and twice with water (30 ml). The residue was further washed three times with hexane, and then dried to give 5.5 g of 7-chloro-3-cyclohexenyl-1H-indole-6-carboxylic acid. Another 2.6 g of the product was obtained from another reaction using 2.27 g of 7-chloro-1H-indole-6-carboxylic acid. Analytical HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Flow Rate=5 ml/min, Column: Xterra MS C18 S7 3.0×50 mm; LC/MS: (ES+) m/z (M+H)+=275.94, 277.94, HPLC Rt=1.750 min. To a mixture of the 7-chloro-3-cyclohexenyl-1H-indole-6-carboxylic acid (8.1 g) obtained from above in a mixture of THF/MeOH (25 ml/25 ml) at r.t. under N2 was added Pd(OH)2/C (764 mg, 20%). The mixture was then flushed with a stream of hydrogen gas using a balloon, and then stirred under hydrogen (using a balloon) for 27 hr. After removing the hydrogen balloon, the mixture was then flushed with a stream of N2, and then filtered through a cake of celite. The filtrate was evaporated to give 7-chloro-3-cyclohexyl-1H-indole-6-carboxylic acid (7.7 g). Analytical HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Flow Rate=5 ml/min, Column: Xterra MS C18 S7 3.0×50 mm; LC/MS: (ES+) m/z (M+H)+=278.01, 280.00, HPLC Rt=1.773 min.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]2[NH:14][CH2:13][C:12]3([CH2:18][CH2:17][CH2:16][CH2:15]3)[S:11]2)=[C:5]([CH3:19])[CH:4]=1)#[N:2].[CH2:20](Br)[CH:21]([CH3:23])[CH3:22]>>[CH2:20]([N:14]1[CH2:13][C:12]2([CH2:15][CH2:16][CH2:17][CH2:18]2)[S:11][C:10]1=[N:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[CH3:19])[CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)CBr
Reactant: Cc1cc(C#N)ccc1N=C1NCC2(CCCC2)S1
Product: Cc1cc(C#N)ccc1N=C1SC2(CCCC2)CN1CC(C)C

Procedure:
1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7a to give 1-amino-1-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 4-cyano-2-ethylphenyl isothiocyanate according to Method C1a to give 2-(4-cyano-2-methylphenylimino)-1-thia-3-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2b to give 3-isobutyl-2-(4-cyano-2-methylphenylimino)-1-thia-3-azaspiro[4.4]nonane.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.[O:11]=[C:12]([N:17]1[CH2:22][CH2:21][N:20]([C:23](=[O:33])[C:24]2[CH:29]=[C:28]([F:30])[C:27]([F:31])=[C:26]([F:32])[CH:25]=2)[CH2:19][CH2:18]1)[CH2:13][C:14](O)=[O:15].CCN=C=NCCCN(C)C.Cl.[C:46]1([C:52]2[N:57]=[CH:56][C:55]([NH2:58])=[CH:54][CH:53]=2)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[O:11]=[C:12]([N:17]1[CH2:22][CH2:21][N:20]([C:23](=[O:33])[C:24]2[CH:25]=[C:26]([F:32])[C:27]([F:31])=[C:28]([F:30])[CH:29]=2)[CH2:19][CH2:18]1)[CH2:13][C:14]([NH:58][C:55]1[CH:56]=[N:57][C:52]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[CH:53][CH:54]=1)=[O:15]
Reactant: O=C(O)CC(=O)N1CCN(C(=O)c2cc(F)c(F)c(F)c2)CC1
Reactant: Nc1ccc(-c2ccccc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CC(=O)N1CCN(C(=O)c2cc(F)c(F)c(F)c2)CC1)Nc1ccc(-c2ccccc2)nc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 36.5 %

Procedure:
HOBt (40 mg, 0.3 mmol) and DMAP (46 mg, 0.37 mmol) were added to a stirred solution of 3-oxo-3-[4-(3,4,5-trifluoro-benzoyl)-piperazin-1-yl]-propionic acid (83 mg, 0.25 mmol) in DMF (2 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (58 mg, 0.3 mmol) followed by 6-phenyl-pyridin-3-ylamine (51 mg, 0.3 mmol) were added. The reaction mixture was stirred at room temperature overnight, diluted with water and the product was extracted with ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated to afford 44 mg (36%) of 3-oxo-N-(6-phenyl-pyridin-3-yl)-3-[4-(3,4,5-trifluoro-benzoyl)-piperazin-1-yl]-propionamide. LCMS: 483.16 (M+1)+, 97.0%, 1H NMR: (DMSO-d6): δ 10.5 (s, 1H), 8.8 (d, 1H), 8.2-8.1 (m, 1H), 8.1 (d, 2H), 8.0 (d, 1H), 7.6-7.4 (m, 5H), 3.4-3.2 (m. 10H).
Reaction SMILES: [CH:1]1([CH2:4][C:5]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])SCCCS2)[CH2:3][CH2:2]1.BrN1C(=[O:22])CCC1=O>>[CH:1]1([CH2:4][C:5](=[O:22])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C1(CC2CC2)SCCCS1
Reactant: O=C1CCC(=O)N1Br
Product: CCOC(=O)C(=O)CC1CC1

Procedure:
A fifth aspect of this invention is a process for the preparation of ethyl 3-cyclopropyl-2,2-difluoropropanoate, which process comprises: (a) reacting bromomethylcyclopropane with 2-carboethoxy-1,3-dithiane in the presence of strong base to give ethyl 2-(cyclopropylmethyl)-1,3-dithiane-2-carboxylate; (b) reacting the ethyl 2-(cyclopropylmethyl)-1,3-dithiane-2-carboxylate with N-bromosuccinimide to give ethyl 3-cyclopropyl-2-oxopropanoate; and (c) reacting the ethyl 3-cyclopropyl-2-oxopropanoate with a fluorinating agent.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](O)=[O:25])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.Cl.[CH3:34][O:35][C:36](=[O:51])[C@@H:37]([NH:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])[CH2:38][NH2:39].C[Si](C)(C)NC(=O)C>ClCCl.CN(C)C=O>[CH3:34][O:35][C:36](=[O:51])[C@@H:37]([NH:40][C:41]([O:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)=[O:42])[CH2:38][NH:39][C:24]([C@@H:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])[CH2:15][CH2:14][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9][CH2:10]2)[CH2:19]1)=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)N2CCC[C@@H](C(=O)O)C2)CC1
Reactant: COC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Agent: CC(=O)N[Si](C)(C)C
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CNC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 54.4 %

Procedure:
To a stirred solution of (R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl]-3-piperidine carboxylic acid (1.0 g) and N,N-dimethylformamide (210 μl) in dichloromethane (10 ml) was added dropwise oxalyl chloride (240 μl) at 4° C. under a nitrogen atmosphere. To an ice cooled solution of 2(S)-benzyloxycarbonylamino-β-alanine methyl ester hydrochloride (940 mg) and N-(trimethylsilyl)-acetamide (2.85 g) in N,N-dimethylformamide (10 ml) was added dropwise the above solution with stirring under a nitrogen atmosphere. The reaction mixture was allowed to warm to ambient temperature, and stirred for 2 hours, which was partitioned between a mixture of ethyl-acetate and n-hexane and water. The organic layer was separated, washed in turn with water, aqueous 5% NaHCO3 solution and brine, and dried over MgSO4. Evaporation of the solvent gave a residue, which was purified by silica-gel column chromatography eluting with n-hexane-ethyl acetate (from 1:6 to ethyl acetate only) to give N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(S)-benzyloxycarbonylamino-β-alanine methyl ester (0.89 g) as a foam, which is the same compound obtained in Preparation 15.
Reaction SMILES: Cl[C:2]1[C:3]([CH:8]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:19][CH:20]1[CH2:24][CH2:23][NH:22][CH2:21]1.CCN(CC)CC>CS(C)=O.O>[C:15]([O:14][C:12]([N:10]1[CH2:11][CH:8]([C:3]2[C:2]([N:22]3[CH2:23][CH2:24][CH:20]([CH3:19])[CH2:21]3)=[N:7][CH:6]=[CH:5][N:4]=2)[CH2:9]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC1CCNC1
Reactant: CC(C)(C)OC(=O)N1CC(c2nccnc2Cl)C1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC1CCN(c2nccnc2C2CN(C(=O)OC(C)(C)C)C2)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
To a solution of 3-(3-chloro-pyrazin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester (7) (200 mg, 0.74 mmol, Preparation 2) and 3-methyl-pyrrolidine (42) (69.2 mg, 0.84 mmol) in DMSO (5 mL) was added Et3N (149.5 mg, 1.48 mmol). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was diluted with water, extracted with EtOAc (30 mL×3). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel to give 3-[3-(3-methyl-pyrrolidin-1-yl)-pyrazin-2-yl]-azetidine-1-carboxylic acid tert-butyl ester (43) (194 mg, 0.56 mmol, yield 75.99%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][O:39]2)=[C:6]([N:8]2[C:20]3[CH:19]=[CH:18][C:17]([C:21]([CH3:28])([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:22])=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[C:12]([C:29]([CH3:36])([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH3:30])[CH:13]=3)[CH:7]=1.[Li]CCCC.C([O:52][B:53](OC(C)C)[O:54]C(C)C)(C)C>C1COCC1.CCCCCC>[CH3:28][C:21]([C:17]1[CH:18]=[CH:19][C:20]2[N:8]([C:6]3[C:5]([O:37][CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][O:39]4)=[C:4]([B:53]([OH:54])[OH:52])[CH:3]=[C:2]([CH3:1])[CH:7]=3)[C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][C:12]([C:29]([CH3:30])([CH2:31][C:32]([CH3:33])([CH3:35])[CH3:34])[CH3:36])=[CH:11][CH:10]=3)([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH3:22]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1ccc(OC2CCCCO2)c(-n2c3ccc(C(C)(C)CC(C)(C)C)cc3c3cc(C(C)(C)CC(C)(C)C)ccc32)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(B(O)O)c(OC2CCCCO2)c(-n2c3ccc(C(C)(C)CC(C)(C)C)cc3c3cc(C(C)(C)CC(C)(C)C)ccc32)c1
Reaction time: 3 h
Yield: 78.1 %

Procedure:
The 9-(5-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-3,6-bis(2,4,4-trimethylpentan-2-yl)-9H-carbazole (5.00 g, 8.6 mmol) is dissolved in 50 mL THF in a 250 mL round bottom flask in an ice water bath. n-BuLi (7.0 ml of a 1.6 M solution in hexane, 11.2 mmol) is added dropwise via syringe (soln turns yellow in color) and the brown solution stirred for 3 hours. Triisopropylborate (2.37 mL, 11.2 mmol) is added dropwise via syringe and the solution stirred for one hour, during which time the mixture became turbid and darkened in color. The mixture is quenched with 100 mL ice water. The solution is extracted with 2×100 mL Et2O. The combined organic portions are dried with MgSO4, filtered and rotovapped down to a white solid (5.1 g). This solid is added to 200 mL water and stirred for 1.5 hrs. The mixture is extracted with 150 and 100 mL Et2O. The combined organic extract is dried with MgSO4, filtered and rotovapped down to yield 4.2 g (78% yield) of a white powder. 1H NMR (CDCl3): δ 8.07 (d, JH—H=1.4 Hz, 1H, CBZ), 8.04 (d, JH—H=1.4 Hz, 1H, CBZ), 7.69 (d, JH—H=2.3 Hz, 1H, aryl), 7.42 (dd, JH—H=8.6, 1.8 Hz, 2H, CBZ), 7.40 (dd, JH—H=8.6, 1.7 Hz, 1H, CBZ), 7.37 (d, JH—H=2.3 Hz, 1H, aryl), 7.18 (d, JH—H=8.6 Hz, 1H, CBZ), 6.99 (d, JH—H=8.6 Hz, 1H, CBZ), 6.34 (s, 2H, OH), 3.80 (m, 2H, THP), 2.91 (m, 1H, THP), 2.39 (s, 3H, aryl Me), 1.89 (dd, JH—H=12.8, 4.2 Hz, 2H, tOCT CH2), 1.82 (d, JH—H=14.5 Hz, 2H, tOCT CH2), 1.55 (s, 3H, tOCT CMe2), 1.52 (s, 3H, tOCT CMe2), 1.48 (s, 3H, tOCT CMe2), 1.45 (s, 3H, tOCT CMe2), 0.71 (s, 9H, tOCT tBu), 0.70 (s, 9H, tOCT tBu).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:12][CH2:11][CH2:10][S:9]2)=[CH:4][N:3]=1.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:12][CH2:11][CH2:10][SH:9])=[CH:4][N:3]=1
Reactant: Clc1ccc(C2NCCS2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: SCCNCc1ccc(Cl)nc1
Yield: 82.2 %

Procedure:
A solution composed of 6 chloronicotinaldehyde (14.2 g), 2-aminoethanethiol (7.7 g) and benzene (80 ml) was heated with stirring for 5 hours while removing water as an azeotrope. After the reaction, benzene was distilled off under reduced pressure, and further volatile materials were removed at 1 mmHg and 70° C. to give 2-(2-chloro-5 pyridyl)thiazolidine (18 g) as a residue. Ten grams of 2-(2-chloro-5-pyridyl)thiazolidine was dissolved in 100 ml of ethanol, and sodium borohydride was added. With stirring, the mixture was gradually heated and thereafter refluxed for 1 hour. Ethanol was distilled off under reduced pressure, and chloroform was added to the residue. Insoluble materials were separated by filtration and the chloroform layer was washed with water and dehydrated. Chloroform was distilled off under reduced pressure to give the desired N-(2-chloro-5-pyridylmethyl)2-aminoethanethiol (8.3 g).
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[N:6]1([C:15]2[O:20][C:19](=[O:21])[C:18]3[C:22]([CH2:26][CH3:27])=[CH:23][CH:24]=[CH:25][C:17]=3[N:16]=2)[C:10]2C=C[CH:13]=[CH:14][C:9]=2N=N1.C(OCC)(=O)C>C(Cl)Cl.C1(C)C=CC=CC=1>[CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[CH2:10]([NH:6][C:15]1[O:20][C:19](=[O:21])[C:18]2[C:22]([CH2:26][CH3:27])=[CH:23][CH:24]=[CH:25][C:17]=2[N:16]=1)[CH2:9][CH2:14][CH3:13]
Reactant: CCc1cccc2nc(-n3nnc4ccccc43)oc(=O)c12
Solvent: CCCCN
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCCNc1nc2cccc(CC)c2c(=O)o1
Reaction time: 0.33 h

Procedure:
A standard solution of n-butylamine was prepared by adding 0.5 ml of n-butylamine to a 10 ml volumetric flask containing 10 ml dry methylene chloride. The n-butylamine solution (0.85 ml) was then added to 2-(1-benzotriazolyl)-5-ethyl-4H-3,1-benzoxazin-4-one (150 mg), prepared as described in Preparation VII above, in 21 mg of dry methylene chloride, and the mixture was stirred for 20 minutes. Analysis by TLC (20% ethyl acetate in toluene) indicated that the reaction was complete. The methylene chloride was then removed under reduced pressure and the remaining residue chromatographed over silica gel (10% ethyl acetate in toluene, flash column chromatography). All product fractions were combined and evaporated to give a solid that was recrystallized from pentane, yielding 40 mg of 2-n-butylamino-5-ethyl-4H-3,1-benzoxazin-4-one, m.p. 136°-137° C., IR, 330, 1725-1740 (broad), 1635, 1590, 1570 cm-1); 'H NMR(delta CDCl3): 1.0 (t, 3H, CH 3); 1.3 (t, 3H, CH3); 1.5 (m, 4H, CH2CH2); 3.2 (q, 2H, PhCH2); 3.4 (q, 2H, CH2NH); 4.8 (broad, s, 1H, NH); 6.9-7.6 (m, 3H, ArH).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.O[CH2:12][C@H:13]1[CH2:18][O:17][CH2:16][C@@H:15]([C:19]2[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=2)[N:14]1C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O.[Cl-].[NH4+].[C:47]([O:50][CH2:51]C)(=[O:49])[CH3:48]>ClCCl.C(N(CC)CC)C>[F:25][C:23]1[CH:24]=[C:19]([C@H:15]2[NH:14][C@@H:13]([CH:12]=[CH:48][C:47]([O:50][CH3:51])=[O:49])[CH2:18][O:17][CH2:16]2)[CH:20]=[C:21]([F:27])[C:22]=1[F:26]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N1[C@@H](CO)COC[C@H]1c1cc(F)c(F)c(F)c1
Reactant: CCOC(C)=O
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: COC(=O)C=C[C@H]1COC[C@@H](c2cc(F)c(F)c(F)c2)N1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
DMSO (0.14 mL) was added to a solution of oxalyl chloride (0.16 mL) in dichloromethane (10 mL) in a nitrogen atmosphere at −78° C. over five minutes, and the reaction solution was stirred at −78° C. for five minutes. A solution of 9H-fluoren-9-ylmethyl (3S,5R)-3-hydroxymethyl-5-(3,4,5-trifluorophenyl)morpholine-4-carboxylate (470 mg) in dichloromethane (2 mL) was added to the reaction solution at −78° C., and the reaction solution was stirred at −78° C. for 30 minutes. Triethylamine (0.86 mL) was added to the reaction solution at −78° C., and the reaction solution was stirred at −78° C. for 20 minutes. A saturated ammonium chloride solution was added to the reaction solution at −78° C., and the reaction solution was heated to room temperature. Then, dichloromethane was added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. Trimethyl phosphonoacetate (0.28 mL) was added to a mixed solution of sodium hydride (containing 60% mineral oil, 58 mg) in THF (10 mL)-DMF (2 mL) at 0° C., and the reaction solution was stirred at 0° C. for 30 minutes. A solution of the residue obtained above in THF (2 ml) was added to the reaction solution at 0° C., and the reaction solution was stirred at 0° C. for 30 minutes. A saturated ammonium chloride solution and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. Diethylamine (1 mL) was added to a solution of the residue in acetonitrile (4 mL), and the reaction solution was stirred for 30 minutes. Toluene was added to the reaction solution, which was then concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: heptane->heptane:ethyl acetate=1:1) to obtain 227 mg of an E/Z isomer mixture of the title compound. The property values of the compound are as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[CH:22]([OH:39])[C:23]2[CH:28]=[CH:27][N:26]=[C:25]3[N:29]([Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH:30]=[CH:31][C:24]=23)[CH2:12][O:13][CH3:14])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:40]([F:43])([F:42])[F:41].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[C:22]([C:23]2[C:24]3[CH:31]=[CH:30][N:29]([Si:32]([C:35]([CH3:37])([CH3:38])[CH3:36])([CH3:33])[CH3:34])[C:25]=3[N:26]=[CH:27][CH:28]=2)=[O:39])[CH2:12][O:13][CH3:14])(=[O:9])=[O:10])=[CH:4][C:3]=1[C:40]([F:43])([F:42])[F:41]
Reactant: COCN(c1cc(Cl)ccc1C(O)c1ccnc2c1ccn2[Si](C)(C)C(C)(C)C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: COCN(c1cc(Cl)ccc1C(=O)c1ccnc2c1ccn2[Si](C)(C)C(C)(C)C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.5 %

Procedure:
To a solution of 4-chloro-N-{5-chloro-2-[hydroxy-(1-(tert-butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-methyl]-phenyl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (88 mg, 0.13 mmol) in CH2Cl2 (3 mL) was added Dess-Martin periodinane (99.8 mg, 0.235 mmol) and stirred for 5 h at room temperature. 10% Na2S2O3 (3 mL) and saturated aqueous NaHCO3 solution (3 mL) was added and stirred for 30 min. Aqueous layer was separated and extracted with EtOAc (2×25 mL). Combined organic layers were washed with saturated aqueous NaHCO3 solution (20 mL), brine (20 mL), dried (anhydrous Na2SO4), concentrated and column purified (SiO2, 30% EtOAc-hexanes) to obtain 4-chloro-N-[5-chloro-2-(1-(tert-butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridine-4-carbonyl)-phenyl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (80 mg) in 92% yield. ESMS m/z (relative intensity): 672 (M+H)+ (100).