Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](I)=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.[CH3:31][C:32]1[CH:37]=[C:36](B(O)O)[CH:35]=[CH:34][N:33]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([C:36]3[CH:35]=[CH:34][N:33]=[C:32]([CH3:31])[CH:37]=3)=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1
Reactant: Clc1cc2c(cn1)c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1cc(B(O)O)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3cc(Cl)ncc23)ccn1
Temperature: 80 °C
Yield: 44.3 %

Procedure:
6-chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridine (2.465 g, 4.72 mmol), 2-methylpyridine-4-boronic acid (0.966 g, 7.05 mmol), PdCl2(dppf)-CH2Cl2Adduct (0.579 g, 0.709 mmol) and K2CO3 (1.959 g, 14.17 mmol) were dissolved in a mixture of 1,4-dioxane (10 mL)/H2O (2.5 mL). The reaction mixture was degassed for 5 min, heated to 80° C. overnight, cooled to RT and diluted with EtOAc. Reaction was filtered through Celite and then partitioned between EtOAc and saturated NaHCO3. The organic layer was extracted with EtOAc (3×) and the combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel over a gradient of 0-75% EtOAc in hexanes to yield 6-chloro-3-(2-methylpyridin-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridine (1.02 g, 2.09 mmol, 44%) as a solid. MS ESI calc'd. for C31H24ClN4 [M+1]+487, found 487.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][CH:3]=1.Cl[C:11]1[CH:21]=[C:15]2[N:16]([CH3:20])[CH2:17][CH2:18][CH2:19][N:14]2[C:13](=[O:22])[N:12]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:11]2[CH:21]=[C:15]3[N:16]([CH3:20])[CH2:17][CH2:18][CH2:19][N:14]3[C:13](=[O:22])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: NCc1ccc(F)cc1
Product: CN1CCCn2c1cc(NCc1ccc(F)cc1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E59 starting from (4-fluorophenyl)methanamine and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: O.O.[Sn](Cl)Cl.[Br:6][C:7]1[C:12]([F:13])=[CH:11][C:10]([OH:14])=[C:9]([N+:15]([O-])=O)[CH:8]=1>C(O)C>[NH2:15][C:9]1[CH:8]=[C:7]([Br:6])[C:12]([F:13])=[CH:11][C:10]=1[OH:14]
Reactant: O=[N+]([O-])c1cc(Br)c(F)cc1O
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1cc(Br)c(F)cc1O
Temperature: 85 °C

Procedure:
Tin(II) chloride dihydrate (16.83 g, 74.6 mmol) was added to a solution of 4-bromo-5-fluoro-2-nitrophenol (4.4 g, 18.64 mmol) in ethanol (180 mL). The mixture was flushed with nitrogen and heated to 85° C. (oil bath temperature) for 1 day. The mixture was diluted with ethyl acetate (500 mL), saturated aqueous sodium bicarbonate (200 mL) was added with vigorous stirring. The mixture was filtered through celite and the celite pad was repeatedly washed with ethyl acetate. The two phases were separated and the organic phase was washed with brine. The combined aqueous phase was extracted with ethyl acetate. The combined organic phase was dried over MgSO4, filtered and concentrated to give 2-amino-4-bromo-5-fluorophenol. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.61 (br. s., 2H) 6.60 (d, J=10.11 Hz, 1H) 6.76 (d, J=7.33 Hz, 1H) 9.69 (br. s., 1 H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]2[O:14][CH2:15][C:16]3([CH2:18][CH2:17]3)[N:7]3[C:8]=2[C:3]=1[C:4](=[O:21])[C:5]([C:19]#[N:20])=[CH:6]3.[NH:22]1[CH:26]=[CH:25][C:24](CCCN)=[N:23]1>>[N:23]1([CH2:4][CH2:3][CH2:2][NH:1][C:10]2[C:9]3[O:14][CH2:15][C:16]4([CH2:17][CH2:18]4)[N:7]4[C:8]=3[C:3]([C:4](=[O:21])[C:5]([C:19]#[N:20])=[CH:6]4)=[C:2]([NH2:1])[C:11]=2[F:12])[CH:24]=[CH:25][CH:26]=[N:22]1
Reactant: NCCCc1cc[nH]n1
Reactant: N#Cc1cn2c3c(c(F)c(F)c(N)c3c1=O)OCC21CC1
Product: N#Cc1cn2c3c(c(NCCCn4cccn4)c(F)c(N)c3c1=O)OCC21CC1

Procedure:
The title compound was prepared from 8-amino-9,10-difluoro-7-oxo-2,7-dihydrospiro[[1,4]oxazino[2,3,4-ij]quinoline-3,1′-cyclopropane]-6-carbonitrile and pyrazolepropylamine using synthetic procedures similar to those described in the examples above. 1H-NMR (400 MHz, DMSO-d6) δ 1.16 (2H, t), 1.58 (2H, t), 1.99 (2H, m), 3.65 (2H, m), 4.16 (2H, s), 4.26 (2H, m), 6.29 (1H, s), 7.49 (1H, s), 7.63 (1H, s), 8.04 (1H, s). MS (EP) m/z: 395 (M++1). (Calcd for C20H19FN6O2, 394.40).
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9](C(F)(F)F)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].NC1C(I)=CC([O:29][C:30]([F:33])([F:32])[F:31])=CC=1C(OC)=O>>[NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(C(F)(F)F)cc(C)c1N
Reactant: COC(=O)c1cc(OC(F)(F)F)cc(I)c1N
Product: COC(=O)c1cc(OC(F)(F)F)cc(C)c1N

Procedure:
The title compound was prepared as in the method of compound 3 from methyl 2-amino-3-iodo-5-(trifluoromethoxy)benzoate to give an orange oil (0.413 g, 89%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)C1C=CC=CC=1.[CH3:24][O:25][C:26]1[CH:35]=[CH:34][C:29]2[C:30](=O)[CH2:31][O:32][C:28]=2[CH:27]=1>>[OH:8][C:9]1[CH:14]=[C:13]([C:30]2[C:29]3[CH:34]=[CH:35][C:26]([O:25][CH3:24])=[CH:27][C:28]=3[O:32][CH:31]=2)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:21])(=[O:22])[NH:19][C:18](=[O:23])[CH2:17]1
Reactant: COc1ccc2c(c1)OCC2=O
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Product: COc1ccc2c(-c3ccc(N4CC(=O)NS4(=O)=O)c(O)c3)coc2c1

Procedure:
The title compound is prepared from 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one and 6-methoxybenzofuran-3-one analogous to Example 274: (M−1)−=373; HPLC retention time=1.09 min. (Method A).
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[N:7]([C:15]1[C:16]([CH3:37])([CH3:36])[S:17](=[O:35])(=[O:34])[CH2:18][C@:19]([C:22]2[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=2[CH2:31][CH:32]=[CH2:33])([CH3:21])[N:20]=1)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:4])([CH3:3])[CH3:2].[OH:39]O.[OH-].[Na+]>C1COCC1>[C:1]([O:5][C:6](=[O:38])[N:7]([C:15]1[C:16]([CH3:37])([CH3:36])[S:17](=[O:35])(=[O:34])[CH2:18][C@:19]([C:22]2[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=2[CH2:31][CH2:32][CH2:33][OH:39])([CH3:21])[N:20]=1)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: OO
Reactant: C=CCc1ccc([N+](=O)[O-])cc1[C@]1(C)CS(=O)(=O)C(C)(C)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=N1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@](C)(c2cc([N+](=O)[O-])ccc2CCCO)CS(=O)(=O)C1(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 59.9 %

Procedure:
A solution of (R)-tert-butyl-N-(5-(2-allyl-5-nitrophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)-N-tert-butoxycarbonyl-carbamate (623 mg, 1.129 mmol), in THF (11 ml) was cooled to 0° C. and borane tetrahydrofuran complex, 1.0 M in THF (1.13 ml, 1.13 mmol) was added dropwise. The mixture was stirred for 1.5 h at 0° C., then quenched with water (1 ml) and allowed to warm up to rt. The mixture was recooled to 0° C. and hydrogen peroxide (30% solution) (1.15 ml, 11.29 mmol) and sodium hydroxide (2N solution) (1.129 ml, 2.259 mmol) then were added and stirred at rt for 30 min. The mixture was partitioned between EtOAc (20 ml) and water (10 ml), organic layer was washed with brine and concentrated. The residue was purified by FC on 12 g RediSep Gold column using 20-100% EtOAc in heptane to afford (R)-tert-butyl-N-(5-(2-(3-hydroxypropyl)-5-nitrophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)-N-tert-butoxycarbonyl-carbamate (385 mg, 0.676 mmol, 60% yield). LC/MS (ESI+) m/z=592 (M+Na).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([CH:21]3[CH2:23][CH:22]3[C:24]([OH:26])=O)[CH:19]=2)[NH:14][CH:13]=1)=[O:11].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:60][N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1>CN(C=O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C@@H:21]3[CH2:23][C@H:22]3[C:24]([N:64]3[CH2:65][CH2:66][N:61]([CH3:60])[CH2:62][CH2:63]3)=[O:26])[CH:19]=2)[NH:14][CH:13]=1)=[O:11]
Reactant: CN1CCNCC1
Reactant: O=C(Cc1cccc(F)c1F)c1c[nH]c2ncc(C3CC3C(=O)O)cc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)[C@@H]2C[C@H]2c2cnc3[nH]cc(C(=O)Cc4cccc(F)c4F)c3c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-{3-[(2,3-Difluoro-phenyl)-acetyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-cyclopropanecarboxylic acid, (93 mg, 0.26 mmol), was combined with DIEA, (67 mg, 0.52 mmol), and HBTU, (113 mg, 0.3 mmol) in 1 mL DMF and stirred at rt for ˜15 min. Then N-methyl piperazine, (26 mg, 0.26 mmol), was added and the reaction stirred at rt for 4 hours. The DMF was evaporated under vacuum, water added and the suspension extracted with dichloromethane. The solvent was evaporated under vacuum and the residue purified by silica chromatography, (eluent: 5% methanol/DCM), affording trans-2-(2,3-Difluoro-phenyl)-1-{5-[2-(4-methyl-piperaz ine-1-carbonyl)-cyclopropyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-ethanone, (35 mg, Rf 0.5) and the cis isomer (16 mg, Rf 0.3).
Reaction SMILES: CO[C:3](=[O:21])[CH2:4][C:5]1[CH2:6][CH2:7][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:9][CH:10]=1.[NH2:22][C:23]1[C:28]([Br:29])=[CH:27][CH:26]=[CH:25][N:24]=1>ClCCCl>[Br:29][C:28]1[C:23]([NH:22][C:3](=[O:21])[CH2:4][C:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:12])[CH2:9][CH:10]=2)=[N:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)CC1=CCN(C(=O)OCc2ccccc2)CC1
Reactant: Nc1ncccc1Br
Solvent: ClCCCl
Product: O=C(CC1=CCN(C(=O)OCc2ccccc2)CC1)Nc1ncccc1Br
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 189 %

Procedure:
Timethylaluminum (2.0 M, 2.05 mL, 4.10 mol) was added slowly to a 0° C. solution of benzyl 4-(2-methoxy-2-oxoethyl)-3,6-dihydropyridine-1(2H)-carboxylate (0.79 g, 2.73 mol) and 2-amino-3-bromopyridine (0.520 g, 3.00 mmol) in 1,2-dichloroethane (15 mL). After 30 min, the reaction was heated to 55° C. for 48 h. The reaction was quenched by the careful addition of saturated aqueous sodium bicarbonate and the mixture extracted with dichlormethane (4×). The combined organic layers were washed with 1N sodium potassium tartrate, brine, dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel chromatography, eluting with a gradient of 50 to 100% ethyl acetate:hexanes to give the title compound (2.44 g). MS: m/z=430.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([CH2:10][CH2:11][OH:12])[S:7][C:6]=2[CH:13]=1.[CH3:14][S:15](Cl)(=[O:17])=[O:16].CCN(C(C)C)C(C)C>ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([CH2:10][CH2:11][O:12][S:15]([CH3:14])(=[O:17])=[O:16])[S:7][C:6]=2[CH:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc2cc(CCO)sc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc2cc(CCOS(C)(=O)=O)sc2c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a cooled (0° C.) solution of 2-(6-methyl-benzo[b]thiophen-2-yl)-ethanol (3.22 g, 16.8) mmol) in dichloromethane (100 mL), methanesulfonylchloride (1.56 mL, 20.1 mmol) and DIEA (5.96 mL, 33.5 mmol) were added. The mixture was stirred for 15 min at 0° C. and then allowed to reach room temperature and stirred for an additional 2.5 hrs. It was washed with sat. NaHCO3 (2×) and brine (1×), dried (Na2SO4), filtered and concentrated in vacuo. Methanesulfonic acid 2-(6-methyl-benzo[b]thiophen-2-yl)-ethyl ester was obtained as a solid and used without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1.[C:19]1([N:25]=[C:26]=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)C>O1CCCC1>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:26]([NH:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:27])[CH2:6][CH2:7]2)=[CH:17][CH:16]=1
Reactant: O=C=Nc1ccccc1
Reactant: NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(NCCCN1CCN(Cc2ccc(Cl)cc2)CC1)Nc1ccccc1
Reaction time: 3 h
Yield: 21.4 %

Procedure:
A solution of 1-(3-aminopropyl)-4-(4-chlorobenzyl)piperazine (2.0 g; 7.5 mmole) and phenyl isocyanate (1.6 g; 13.4 mmole) in tetrahydrofuran (5 ml) was stirred at room temperature for 30 minutes. Ethanol (5 ml) was added, and the reaction mixture was stirred for 3 hours and then concentrated under reduced pressure. The residue was crystallized from aqueous ethanol to provide crude product (2.7 g). Recrystallization from the same solvent yielded the title compound as colorless crystals (0.62 g; 21% yield), m.p. 135°-137° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])([OH:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.[F:19][C:20]([F:32])([F:31])[C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[C:3]([OH:10])([CH2:2][NH:1][S:27]([C:24]1[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:31])[F:32])=[CH:26][CH:25]=1)(=[O:29])=[O:28])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: NCC(O)(Cn1cncn1)c1ccc(F)cc1F
Product: O=S(=O)(NCC(O)(Cn1cncn1)c1ccc(F)cc1F)c1ccc(C(F)(F)F)cc1

Procedure:
Following the procedure described in the preceeding examples but using 3-amino-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol and 4-trifluoromethylbenzenesulfonylchloride, the title compound was obtained in a similar yield:
Reaction SMILES: [CH3:1][S:2]([C:5]([CH3:11])([CH3:10])[CH2:6][C:7]([OH:9])=[O:8])(=[O:4])=[O:3].I[CH2:13]C>>[CH2:1]([S:2]([C:5]([CH3:11])([CH3:10])[CH2:6][C:7]([OH:9])=[O:8])(=[O:3])=[O:4])[CH3:13]
Reactant: CC(C)(CC(=O)O)S(C)(=O)=O
Reactant: CCI
Product: CCS(=O)(=O)C(C)(C)CC(=O)O

Procedure:
The starting material 3-(ethanesulfonyl)-3-methylbutyric acid was prepared in a manner analogous to that described for the preparation of 3-(methanesulfonyl)-3-methylbutyric acid, the starting material usedfor Example 95, using iodoethane in place of iodomethane.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=2)[CH:3]=[CH:2]1.CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)=[O:41])([CH3:38])([CH3:37])[CH3:36]>CN(C=O)C>[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][N:45]([C:10]([C:7]2[CH:8]=[C:9]3[C:4]([CH:3]=[CH:2][NH:1]3)=[CH:5][CH:6]=2)=[O:12])[CH2:44][CH2:43]1)=[O:41])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc3cc[nH]c3c2)CC1
Yield: 129.5 %

Procedure:
In a similar manner to Step 1 of Reference Example 2, indole-6-carboxylic acid (200 mg, 1.24 mmol) was dissolved in DMF (2 mL), and the solution was treated with EDCI (475 mg, 2.48 mmol), HOBT monohydrate (168 mg, 1.24 mmol) and 1-(tert-butoxycarbonyl)piperazine (461 mg, 2.48 mmol) to obtain 6-[4-(tert-butoxycarbonyl)piperazin-1-ylcarbonyl]indole (529 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:29][CH2:30][NH2:31])[O:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.[C:41]([C:45]1[CH:50]=[CH:49][C:48]([N:51]=[C:52]=[O:53])=[CH:47][CH:46]=1)([CH3:44])([CH3:43])[CH3:42]>C(Cl)Cl>[C:41]([C:45]1[CH:50]=[CH:49][C:48]([NH:51][C:52]([NH:31][CH2:30][CH2:29][CH2:28][N:27]([CH2:26][C@@H:18]2[C@@H:19]3[C@@H:20]([O:21][C:22]([CH3:24])([CH3:25])[O:23]3)[C@H:16]([N:13]3[C:9]4[N:10]=[CH:11][N:12]=[C:7]([NH:6][CH2:5][C:4]5[CH:35]=[CH:36][C:37]([O:39][CH3:40])=[CH:38][C:3]=5[O:2][CH3:1])[C:8]=4[CH:15]=[CH:14]3)[O:17]2)[CH:32]([CH3:34])[CH3:33])=[O:53])=[CH:47][CH:46]=1)([CH3:44])([CH3:42])[CH3:43]
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN(CCCN)C(C)C)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Solvent: ClCCl
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN(CCCNC(=O)Nc3ccc(C(C)(C)C)cc3)C(C)C)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
A suspension of N1-(((3aR,4R,6R,6aR)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-N1-isopropylpropane-1,3-diamine (1.11 g, 2.00 mmol, crude from step 6) in methylene chloride (40 mL) was treated dropwise with a solution of 1-tert-butyl-4-isocyanatobenzene (0.36 mL, 2.0 mmol) in methylene chloride (3.5 mL) and allowed to stir at room temperature. After 1 h, reaction was complete by HPLC. The reaction mixture was concentrated to yield a glass. The crude material was purified by flash chromatography (100 g silica gel, 2-4% 7N NH3 in CH3OH/CH2Cl2 to yield the title compound (1.07 g, 73%) as a foam: MS (ESI+) for C10H55N7O6 m/z 730.4 (M+H)+; (ESI−) for C40H55N7O6 m/z 728.5 (M−H)−; HPLC purity, 89% (ret. time, 3.78 min).
Reaction SMILES: Cl.[SH:2][CH:3]1[CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.Cl[CH2:15][CH2:16][N:17]=[C:18]=[S:19].[CH3:20][S:21]([OH:24])(=[O:23])=[O:22]>O1CCCC1>[CH3:20][S:21]([OH:24])(=[O:23])=[O:22].[SH:2][CH:3]1[CH2:6][N:5]([C:18]2[S:19][CH2:15][CH2:16][N:17]=2)[CH2:4]1
Reactant: SC1CNC1
Reactant: S=C=NCCCl
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: SC1CN(C2=NCCS2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 39.2 %

Procedure:
To a solution of 63.3 mg of 3-mercaptoazetidine hydrochloride (12) obtained in the above Example 10 dissolved in 1.0 ml of dried tetrahydrofuran, there was added 0.07 ml of triethylamine in the stream of nitrogen at a room temperature, and the resulting solution was stirred for 30 minutes. To this solution, there was added dropwise a solution of 70.3 mg of 2-chloroethylisothiocyanate dissolved in dried tetrahydrofuran, and the resulting solution was further stirred for one hour. After the reaction liquid was cooled to 0° C., 0.04 ml of methanesulfonic acid was added dropwise, and the resulting solution was stirred for 30 minutes, and, then, the solvent was evaporated in a vacuum. To the obtained residue, there was added 1.0 ml of dried methanol, and the resulting solution was subjected to heating and reflux for one hour, and, then, the solvent was evaporated in a vacuum. The obtained residue was separated and purified by thin-layer chromatography, and, thus, there was obtained 53.4 mg (yield: 39.2%) of 3-mercapto-1-(1,3-thiazolin-2-yl)azetidine methanesulfonate (13) in the form of colorless oily matter.
Reaction SMILES: Cl[C:2]1[N:22]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[S:18]([CH3:21])(=[O:20])=[O:19])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[N:23]1([CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:21][S:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:37][C:34]3[CH:35]=[CH:36][C:31]([O:30][CH2:29][CH2:28][N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)=[CH:32][CH:33]=3)[N:22]=2)[CH:9]=[CH:8][CH:7]=1)(=[O:20])=[O:19]
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Reactant: CS(=O)(=O)c1ccccc1CNc1cccn2nc(Cl)nc12
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CS(=O)(=O)c1ccccc1CNc1cccn2nc(Nc3ccc(OCCN4CCCC4)cc3)nc12

Procedure:
N(8)-(2-Methanesulfonyl-benzyl)-N(2)-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonyl-benzyl)-amine (75.0 mg, 0.223 mmol) and 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (51.0 mg, 0.247 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.037 g, 33%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.11 (d, J=7.8 Hz, 1H), 7.84 (d, J=6.6 Hz, 1H), 7.67-7.58 (m, 2H), 7.52 (t, J=6.9 Hz, 1H), 7.46 (d, J=8.8 Hz, 2H), 6.92 (d, J=8.8 Hz, 2H), 6.68 (t, J=7.5 Hz, 1H), 6.52 (s, 1H), 6.42 (d, J=7.6 Hz, 1H), 5.28 (t, J=6.0 Hz, 1H), 4.96 (d, J=6.2 Hz, 2H), 4.12 (t, J=5.6 Hz, 2H), 3.16 (s, 3H), 2.96-2.88 (m, 2H), 2.67 (br s, 4H), 1.89-1.76 (m, 4H). MS=507 (MH)+.
Reaction SMILES: [F:1][C:2]([F:52])([F:51])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=3[C:31]3[CH:32]=[C:33]([C:39]4[CH:44]=[CH:43][C:42]([C:45]([O:47]C)=[O:46])=[CH:41][C:40]=4[CH3:49])[CH:34]=[CH:35][C:36]=3[O:37][CH3:38])[C@@H:15]([CH3:50])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[K+]>CO>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=3[C:31]3[CH:32]=[C:33]([C:39]4[CH:44]=[CH:43][C:42]([C:45]([OH:47])=[O:46])=[CH:41][C:40]=4[CH3:49])[CH:34]=[CH:35][C:36]=3[O:37][CH3:38])[C@@H:15]([CH3:50])[CH2:14]2)[CH:4]=[C:3]([C:2]([F:1])([F:52])[F:51])[CH:8]=1
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)C[C@@H]3C)c2)c(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(-c2ccc(C(=O)O)cc2C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of methyl 2″-({(4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazinan-3-yl}methyl)-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (Step A; 48 mg; 0.065 mmol) in MeOH (5 mL), was added 4 M KOH (800 μL). The reaction was stirred at room temperature for 4 h, quenched with saturated citric acid and partitioned between EtOAc (25 mL) and water (25 mL). The aqueous layer was extracted with EtOAc (3×25 mL) and the combined extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by preparatory thin layer chromatography, eluting with 2:1 hexanes:EtOAc+1% AcOH to afford 2″-({(4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazinan-3-yl}methyl)-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylic acid as a white solid. LCMS=725.9 (M+1)+. 1H NMR (CDCl3, 500 MHz, mixture of atropisomers) δ 7.97-7.94 (m, 1H), 7.86-7.82 (m, 2H), 7.78 (d, J=8 Hz, 1H), 7.68-7.66 (m, 1H), 7.63-7.61 (m, 1H), 7.45-7.39 (m, 2H), 7.34 (d, J=8 Hz, 1H), 7.25-7.20 (m, 2H), 7.12-7.09 (m, 1H), 5.37 (d, J=15.5 Hz, 1H), 4.67 (d, J=11.4 Hz, 1H), 4.34 (d, J=15.6 Hz, 1H), 3.91 (s, 3H), 3.32-3.26 (m, 1H), 2.36 (s, 3H), 2.19-2.13 (m, 1H), 1.75-1.67 (m, 1H), 1.09 (d, J=6.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[N:9][OH:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:11]N1C(=O)CCC1=O.Cl>CN(C)C=O>[Cl:11][C:8]([C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=1)=[N:9][OH:10]
Reactant: ON=Cc1cccnc1Cl
Reactant: O=C1CCC(=O)N1Cl
Agent: Cl
Solvent: CN(C)C=O
Product: ON=C(Cl)c1cccnc1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 98.2 %

Procedure:
Dissolve 2-chloropyridine-3-carboxaldehyde oxime (2.50 g, 0.016 mol) in N,N-dimethylformamide (20 mL). Add N-chlorosuccinimide (2.14 g, 0.016 mol) in small portions along with a small amount of gaseous hydrochloric acid. Stir for 3 hours. When TLC analysis indicates the reaction to be complete, pour into ice/water. Extract with diethyl ether and wash the combined extracts with water and dry over sodium sulfate. Concentrate the extracts to give 3.00 g (98%) of crude product as an off white solid. MS(FD): (M)+ 190.0, 192.0 m/z.