Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:23](=[O:39])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:27][CH:26]=2)[CH:12]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.C1COCC1>[CH2:16]([O:15][C:13]1[CH:12]=[C:11]([CH:23]([OH:39])[CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:29][CH:30]=2)[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cc1ccc(OCc2ccccc2)cc1)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: OC(Cc1ccc(OCc2ccccc2)cc1)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Reaction time: 1 h
Yield: 99.3 %

Procedure:
2 g (3.9 mmol) of recrystallized 1-(3,5-dibenzyloxyphenyl)-2-(4-benzyloxyphenyl)ethanone prepared according to Example 5 are introduced into a 100 ml round-bottomed flask and are dissolved in 30 ml of methanol and 25 ml of THF. Approximately 0.147 g of sodium borohydride is added in small fractions at ambient temperature over 1 hour. The medium is kept stirred for 1 h and concentrated, 30 ml of water are added and the medium is extracted with 60 ml of MTBE. The MTBE phase is concentrated to produce 2 g of a light yellow oil which crystallizes over time. 5 ml of methanol are added to this product, the mixture is kept stirred for 1 h and then the white precipitate obtained is filtered off. After drying at vacuum at 35° C., 1.3 g of 1-(3,5-dibenzyloxyphenyl)-2-(4-benzyloxyphenyl)ethanol are recovered in the form of a white solid with a melting point of 80-81° C., i.e. a yield of 65% with respect to the starting ketone.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.C([Li])CCC.[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([N:25]=[C:26](Cl)[O:27][CH3:28])(=[O:24])=[O:23]>O1CCCC1.CCCCCC>[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([N:25]=[C:26]([O:27][CH3:28])[NH:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1)(=[O:24])=[O:23]
Reactant: Cc1cc(C)nc(N)n1
Reactant: COC(Cl)=NS(=O)(=O)c1ccccc1C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=NS(=O)(=O)c1ccccc1C)Nc1nc(C)cc(C)n1
Reaction time: 0.25 h

Procedure:
To 1.2 g of 2-amino-4,6-dimethylpyrimidine in 50 ml of tetrahydrofuran is added 6.85 ml of 1.6 molar n-butyl lithium in hexane at 0°. The mixture is stirred for 15 minutes. To this solution is added dropwise, a solution of 2.1 g of methyl N-(2-methylphenylsulfonyl)carbonimidochloridate in 5 ml of tetrahydrofuran at 0°-10°. This reaction mixture is stirred for 30 minutes at 0°-10° and 30 minutes at ambient temperature. The reaction mixture is filtered and the solvent is stripped from the filtrate under reduced pressure to yield a crude product. The crude product is further purified via dry column chromatography on silica gel with ethyl acetate as the eluent. Pure N'-(2-methylphenylsulfonyl)-N-(4,6-dimethylpyrimidin-2-yl)carbamimidic acid, methyl ester is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH:24][CH:25]([CH3:27])[CH3:26])[CH:18]=3)[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][C:3]=1[OH:28].[CH3:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][N:31]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=3)[CH2:23][N:24]([CH:25]([CH3:26])[CH3:27])[C:34](=[O:35])[C:33]3[CH:37]=[CH:38][C:30]([CH3:29])=[N:31][CH:32]=3)[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][C:3]=1[OH:28]
Reactant: CC(C)NCc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1
Reactant: Cc1ccc(C(=O)O)cn1
Product: Cc1ccc(C(=O)N(Cc2cccc(-c3ccnc(NCCc4ccc(O)c(Cl)c4)n3)c2)C(C)C)cn1

Procedure:
2-Chloro-4-(2-{4-[3-(isopropylamino-methyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol (compound 132) was coupled with 6-methyl-nicotinic acid following procedure D2. LC-MS showed the product had the expected M+H+ of 516. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 9.3 (s, 1H)) 8.3 (m, 2H) 8.2 (s, 1H) 8.0 (d, 2H) 7.6 (d, 1H) 7.4 (m, 2H) 7.3 (d, 1H) 7.2 (s, 1H) 7.0 (d, 1H) 5.4 (s, br, 1H) 3.9 (s, 2H) 3.7 (m, 2H) 3.1 (m, 1H) 2.9 (m, 2H) 2.7 (s, 3H) 1.3 (d, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11](Cl)[CH:10]=2)=[O:5])[CH3:2].CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[C:48](=[NH:61])([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([N:61]=[C:48]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[CH:10]=2)=[O:5])[CH3:2]
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1cnc2cc(Cl)ccc2c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2cc(N=C(c3ccccc3)c3ccccc3)ccc2c1
Temperature: 100 °C
Yield: 12.3 %

Procedure:
7-Chloro-quinoline-3-carboxylic acid ethyl ester (1 g, 4.24 mmol, 1 equiv), dry sodium t-butoxide (571 mg, 5.94 mmol, 1.4 equiv), tris(dibenzylideneacetone)dipalladium (19.5 mg, 21.2 μmol, 1 mol % equiv), and 2-(dicylcohexylphosphino)biphenyl (30 mg, 84.8 μmol, 4 mol % equiv) were placed in a round bottom flask with a magnetic stir bar. The flask was flushed with nitrogen. Benzophenone imine (783 μL, 4.66 mmol, 1.1 equiv) and toluene (8.5 mL) were added. The flask was fitted with a reflux condenser and the reaction was heated at 100° C. for 12 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (20 mL). The reaction mixture was washed with a saturated sodium bicarbonate solution (25 mL), saturated ammonium chloride solution (25 mL), and brine (25 mL). The organic layer was dried over sodium sulfate and then treated with activated charcoal (Darco G-60®) (1 g). The mixture was filtered through diatomaceous earth and concentrated. The residue was stirred in a minimal amount of isopropanol (about 2 mL) to provide 7-(benzhydrylidene-amino)-quinoline-3-carboxylic acid ethyl ester (199 mg, 12%) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@:8]2([CH2:19][F:20])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[N-:21]=[N+]=[N-].[Na+].C(O)[C@H](O)[C@H]1OC(=O)C(O)=C1[O-].[Na+].CP(C)C.O1CCCC1>[Cu]I.O>[NH2:21][C:2]1[CH:3]=[C:4]([C@:8]2([CH2:19][F:20])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: NC1=N[C@](CF)(c2cccc(Br)c2)C[C@@H](C(F)(F)F)O1
Agent: [Cu]I
Agent: CP(C)C
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Solvent: C1CCOC1
Solvent: O
Product: NC1=N[C@](CF)(c2cccc(N)c2)C[C@@H](C(F)(F)F)O1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
A mixture of (4S,6S)-4-(3-bromophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (0.480 g, 1.352 mmol), sodium azide (0.142 ml, 4.05 mmol), copper(I) iodide (9.16 μl, 11, 0.270 mmol) and L(+)-ascorbic acid sodium salt (0.027 g, 0.135 mmol) was purged with N2 followed by the addition of (1R,2R)-(−)-N,N″-dimethylcyclohexane-1,2-diamine (0.064 ml, 0.405 mmol) and degassed EtOH/water (3/1.5 mL). The resulting mixture was heated at 90° C. for 30 min, then cooled to room temperature, and poured into a mixture of 9:1 saturated NH4Cl solution/NH4OH. The resulting mixture was extracted with EtOAc three times. The combined organic layers were dried over Na2SO4, filtered and concentrated. This product was dissolved in a mixture of THF/water (3/1.5 mL) followed by the addition of trimethylphosphine, 1.0M solution in tetrahydrofuran (1.622 ml, 1.622 mmol) and stirred at room temperature for 30 min. The mixture was worked up with water and extracted with dichloromethane three times. The combined organic layers were dried on sodium sulfate, filtered and concentrated. The crude material was purified by column chromatography using 5-10% MeOH/dichloromethane to give (4S,6S)-4-(3-aminophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (0.322 g, 82% yield). MS m/z=292.0 [M+H]+. Calculated for C12H13F4N3O: 291.2
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:16]1[N:17]=[C:18]([NH2:21])[S:19][CH:20]=1.[Cl:22][C:23]1[C:28]([Cl:29])=[C:27]([Cl:30])[CH:26]=[CH:25][C:24]=1[S:31](Cl)(=[O:33])=[O:32]>>[Cl:22][C:23]1[C:28]([Cl:29])=[C:27]([Cl:30])[CH:26]=[CH:25][C:24]=1[S:31]([NH:21][C:18]1[S:19][CH:20]=[C:16]([C:3]2[CH:4]=[CH:5][C:6]([O:8][C:9]3[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=3)=[CH:7][C:2]=2[Cl:1])[N:17]=1)(=[O:33])=[O:32]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1Cl
Reactant: Nc1nc(-c2ccc(Oc3ccc(Cl)cc3)cc2Cl)cs1
Product: O=S(=O)(Nc1nc(-c2ccc(Oc3ccc(Cl)cc3)cc2Cl)cs1)c1ccc(Cl)c(Cl)c1Cl

Procedure:
The title compound was prepared from 4-[2-chloro-4-(4-chlorophenoxy)phenyl]-1,3-thiazol-2-amine (91 mg) and 2,3,4-trichlorobenzenesulfonyl chloride (76 mg) as described in the synthetic METHOD B to give a white solid (49.2 mg) with purity >90%: MS (pos) m/z 579.1, 581.1, 583.1; MS (neg) m/z 577.5, 579.5, 581.5.
Reaction SMILES: [Cl-].[Cl-].[Ca+2].[O-]S([O-])(=O)=O.[Ca+2].[C:10]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)([CH3:12])[CH3:11].[C:27]1([P:33](Cl)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:27]1([P:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([O:26][C:23]2[CH:22]=[CH:21][C:20]([C:10]([C:13]3[CH:14]=[CH:15][C:16]([O:19][P:33]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:34])=[CH:17][CH:18]=3)([CH3:12])[CH3:11])=[CH:25][CH:24]=2)=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: c1ccncc1
Product: CC(C)(c1ccc(OP(=O)(c2ccccc2)c2ccccc2)cc1)c1ccc(OP(=O)(c2ccccc2)c2ccccc2)cc1
Reaction time: 16 h
Yield: 91.6 %

Procedure:
An oven-dried 100 mL 3-necked flask equipped with a magnetic stirring bar, a reflux condenser carrying a CaCl2 -Drierite tuber and a heating mantle, was charged with 4,4'-isopropylidenediphenol (3.6 g, 15.8 mmol), 4-dimethylaminopyridine (0.39 g, 3.2 mmol), and anhydrous pyridine (35 mL), and the stirred solution was treated slowly with diphenylphosphinyl chloride (6.5 mL, 34.1 mmol) via syringe. The resulting mixture was heated at reflux for 7 hours, then was allowed to stand at room temperature for 16 hours. The reaction was monitored periodically by HPLC. After completion of the reaction, the mixture was partitioned between water (100 mL) and CH2Cl2 -Et2O (1:3;250 mL), and the organic phase was washed successively with 50 mL portions of 5 percent NaOH, water, 5 percent HCl water and brine, then it was dried (MgSO4), filtered and concentrated on the rotavap to leave 9.42 g of a faintly yellowish thick oil which set on standing to a brittle glassy material. Crystallization was effected by dissolving the material in a minimum amount of EtOAc with heating then diluting the solution with hexane and allowing it to stand in a freezer at -25° C. overnight. This afforded 9.1 g (92 percent yield) of the title compound as white prisms, m.p. 71-72° C. which had a PDSC (O2) onset/extrap (° C.) of 316/347.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH:13]=[O:14])=[CH:5][C:6]2[O:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:12]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[C:4]([CH:13]=[O:14])=[CH:5][C:6]2[O:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:12]=1
Reactant: COc1cc2c(cc1C=O)OCCC2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1cc2c(cc1O)CCCO2
Reaction time: 3 h
Yield: 67.6 %

Procedure:
A solution of 6-methoxy-3,4-dihydrobenzopyran-7-carboxaldehyde (30.00 g, 156 mmol) in dry methylene chloride (625 mL) under nitrogen was cooled to an internal temperature of -67°. A solution of boron tribromide (1M in methylene chloride, 67.5 mL, 67.5 mmol) was added dropwise. The cooling bath was removed and the mixture allowed to stir under nitrogen for three hours. The reaction was then quenched by the dropwise addition of methanol (75 mL) and the resulting mixture poured into saturated aqueous sodium chloride (1200 mL). The layers were separated and the organic extract washed with saturated sodium chloride (600 mL), dried (Na2SO4) and concentrated to a dark solid (31.0 g). Purification by preparative HPLC (Waters Prep 500, 9:1 hexane:ethyl acetate as eluant) afforded 6-hydroxy-3,4-dihydrobenzopyran-7-carboxaldehyde (18.80 g, 67.6%), m.p. 97°-100°.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]([OH:12])[CH2:8][CH2:9][CH:10]=[CH2:11])=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=[N:3]1.[I:16]I.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.[O-]S(C(F)(F)F)(=O)=O.[Ag+]>[I:16][CH2:11][CH:10]1[O:12][CH:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][C:5]=2[N+:13]([O-:15])=[O:14])[CH2:8][CH2:9]1
Reactant: C=CCCC(O)c1c([N+](=O)[O-])cnn1C
Reactant: II
Agent: [Ag+]
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: C1CCOC1
Product: Cn1ncc([N+](=O)[O-])c1C1CCC(CI)O1
Reaction time: 0.08 h
Yield: 47.7 %

Procedure:
To a stirred solution of 1-(1-methyl-4-nitro-1H-pyrazol-5-yl)pent-4-en-1-ol (0.84 g, 3.98 mmol, intermediate 59) in dry THF (25 mL) under nitrogen was added iodine (1.52 g, 5.97 mmol). After stirring for 5 min, Na2CO3 (0.63 g, 5.97 mmol) was added followed by silver triflate (3.07 g, 11.94 mmol) and the dark red solution turned yellow. The mixture was stirred at room temperature for 1 hr, diluted with THF (25 mL) and filtered through celite. The yellow solid was washed with THF/DCM and the filtrate concentrated under reduced pressure. Purification via silica gel chromatography (0-40% EtOAc/DCM) gave 5-(5-(iodomethyl)tetrahydrofuran-2-yl)-1-methyl-4-nitro-1H-pyrazole as a pale yellow gum (640 mg, 48%). 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 5.91-5.87 (m, 1H), 4.39-4.35 (m, 1H), 4.02 (s, 3H), 3.37-3.30 (m, 2H), 2.69-2.67 (m, 1H), 2.45-2.41 (m, 1H), 2.05-1.89 (m, 2H).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7](C1CCCCC1NS(C)(=O)=O)[CH:6](C1C=CC(Cl)=CC=1Cl)[CH:5]2[C:32]([NH:34][O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1)=[O:33].C=O.S(=O)(=O)(O)O.[BH4-].[Na+]>C1COCC1>[O:12]=[C:8]1[C:9]2[C:4](=[CH:3][CH:2]=[CH:11][CH:10]=2)[CH:5]([C:32]([NH:34][O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)=[O:33])[CH2:6][NH:7]1
Reactant: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccc(N)cc2C(C(=O)NOCc2ccccn2)C1c1ccc(Cl)cc1Cl
Agent: C=O
Agent: O=S(=O)(O)O
Agent: [BH4-]
Solvent: C1CCOC1
Product: O=C1NCC(C(=O)NOCc2ccccn2)c2ccccc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 300 mg of (3RS,4RS)-6-amino-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-(pyridin-2-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, 213 mg of formaldehyde, and 11 mg of sulfuric acid in 5 ml of THF was added 125 mg of sodium borohydride at 0° C., followed by stirring for 2 hours. The reaction solution was poured into ice water and the organic layer was extracted with ethyl acetate. The solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by reverse-phase silica gel column chromatography (eluent: acetonitrile-water) to obtain 10 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-6-(dimethylamino)-2-(1R,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-(pyridin-2-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][CH:8]1[CH2:12][CH:11]([C:13]([NH:15][NH:16][C:17]2[N:18]=[C:19]3[CH:25]=[CH:24][N:23]([S:26]([C:29]4[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=4)(=[O:28])=[O:27])[C:20]3=[N:21][CH:22]=2)=O)[CH:10]([CH2:36][CH3:37])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].O1CCOCC1.O=S(Cl)Cl.CCOC(C)=O>O>[CH2:36]([C@H:10]1[C@@H:11]([C:13]2[N:18]3[C:19]4[CH:25]=[CH:24][N:23]([S:26]([C:29]5[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=5)(=[O:28])=[O:27])[C:20]=4[N:21]=[CH:22][C:17]3=[N:16][N:15]=2)[CH2:12][C@@H:8]([NH:7][C:6](=[O:38])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:9]1)[CH3:37]
Reactant: CCC1CC(NC(=O)OC(C)(C)C)CC1C(=O)NNc1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)n1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Temperature: 80 °C
Yield: 71.2 %

Procedure:
A round-bottomed flask was charged with tert-butyl-3-ethyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentylcarbamate (2.45 g, 4.55 mmol) and 1,4-dioxane (24 mL) to give a brown solution. TEA (2.54 mL, 18.2 mmol) was added followed by the addition of SOCl2 (0.50 mL, 6.8 mmol). The reaction mixture was heated at about 80° C. for about 5 h. The mixture was cooled to ambient temperature and EtOAc (100 mL) and water (30 mL) were added. The layers were partitioned and the organic layer was washed with water (2×30 mL) and brine (2×30 mL), dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure to give a brown residue. The crude material was purified by silica gel chromatography eluting with a gradient of 0-10% MeOH/DCM. The product-containing fractions were combined and concentrated to give tert-butyl (1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylcarbamate (1.7 g, 71%): LC/MS (Table 2, Method a) Rt=2.50 min; MS m/z: 525 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][C:7]2[N:8]=[C:9](OS(C(F)(F)F)(=O)=O)[C:10]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12][C:11]=3[N:24]=2)=[CH:4][CH:3]=1.[CH3:35][NH2:36].C1COCC1>CC(N(C)C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:8]=[C:9]([NH:36][CH3:35])[C:10]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12][C:11]=3[N:24]=2)=[CH:33][CH:34]=1
Reactant: CN
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Cc3ccc(F)cc3)nc(OS(=O)(=O)C(F)(F)F)c2CC1
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: CNc1nc(Cc2ccc(F)cc2)nc2c1CCN(C(=O)OC(C)(C)C)CC2
Reaction time: 48 h

Procedure:
To a solution of the triflate from Step C (90.0 mg, 0.18 mmol) in DMA (2 mL) was added methylamine solution in THF (0.45 mL, 2.0M, 0.89 mmol) and the reaction was stirred for 48 h. The reaction mixture was concentrated in vacuo and the material was used without further purification. A quantitative yield was assumed. LRMS ES+ and AP+ m/z 387 [MH]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:2]1.Cl.[CH3:16]O>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([O:14][CH3:16])=[O:13])=[CH:2]1
Reactant: CO
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Agent: Cl
Product: COC(=O)CCc1c[nH]c2ccccc12
Reaction time: 8 h

Procedure:
3-Indolepropionic acid (5 g) was dissolved in MeOH (50 mL) and treated with conc. HCl (5 mL). The solution was stirred overnight before the solvent was removed under reduced pressure to provide methyl 3-indolepropionate in quantitative yield. Crude methyl 3-indolepropionate (4.70 g, 23.2 mmol) was dissolved in THF (50 mL), cooled to 0° C., and treated with DIBAL-H (69.5 mL, 69.5 mmol). The reaction mixture was stirred for 2 h at 0° C. and then quenched by the slow addition of a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate, the combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with 1:1 ethyl acetate/hexane, afforded the 3-(3-hydroxypropyl)indole as a yellow solid. 1H NMR (200 MHz, DMSO-d6) δ 7.48 (d, J=8.0 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.15–6.92 (m, 4H), 4.40 (t, J=6.0 Hz, 1H), 3.55 (t, J=6.0 Hz, 2H), 2.80 (t, J=8.0 Hz, 2H), 1.92–1.76 (m, 2H).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[NH:19])[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[CH2:2][CH3:3].C([Li])CCC.Cl[P:26]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[N:19][P:26]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccccc1NC(=N)c1ccc(C)cc1
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Product: CCCc1ccccc1NC(=NP(c1ccccc1)c1ccccc1)c1ccc(C)cc1

Procedure:
Procedure as described for NP Amidine XVII using the following amounts: 1.26 g of N1-(2-n-propylphenyl)-4-methylbenzamidine (5.0 mmol), 2.50 mL of 2.0 M butyllithium (5.0 mmol), 0.90 mL of chlorodiphenylphosphine (5.0 mmol). 1.76 g (74%) of light yellow solid was collected.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.Cl.[CH:16]1([CH2:19][O:20][C:21]2[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=2[C:23]([NH2:25])=[NH:24])[CH2:18][CH2:17]1.C(N(CC)CC)C>C(#N)C>[CH3:14][S:13][C:4]1[N:3]=[C:2]2[N:24]=[C:23]([C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[O:20][CH2:19][CH:16]3[CH2:18][CH2:17]3)[NH:25][C:8](=[O:10])[C:7]2=[CH:6][N:5]=1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: N=C(N)c1ccccc1OCC1CC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CSc1ncc2c(=O)[nH]c(-c3ccccc3OCC3CC3)nc2n1
Yield: 54.2 %

Procedure:
In a similar manner to Example 29 reaction of ethyl 4-chloro-2-methylthio-5-pyrimidine carboxylate (1.50 g) with 2-cyclopropylmethoxybenzamidine hydrochloride (1.45 g) and triethylamine (1.30 g) in acetonitrile (50 ml) yielded a white solid (1.18 g) which was collected, dissolved in chloroform and the chloroform solution was extracted twice with 2 Normal hydrochloric acid. The chloroform solution was evaporated under reduced pressure and the residue was recrystallized from ethanol to yield the title compound, 0.52 g, m.p. 186-187° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@@H:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])[CH2:11][N:12]2C(=O)C3C(=CC=CC=3)C2=O)=[O:8])=[CH:4][C:3]=1[C:34]1[N:38]([CH3:39])[N:37]=[N:36][CH:35]=1.NN>CO.O>[NH2:12][CH2:11][C@@H:10]([NH:9][C:7]([C:5]1[S:6][C:2]([Cl:1])=[C:3]([C:34]2[N:38]([CH3:39])[N:37]=[N:36][CH:35]=2)[CH:4]=1)=[O:8])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([F:33])([F:32])[F:31]
Reactant: Cn1nncc1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)sc1Cl
Agent: NN
Solvent: O
Solvent: CO
Product: Cn1nncc1-c1cc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)sc1Cl
Yield: 90.5 %

Procedure:
A solution of 5-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide (700 mg, 1.22 mmol) and hydrazine (0.19 mL, 6.1 mmol) in 5 mL of MeOH was stirred at rt overnight, diluted with 200 ml of H2O and extracted with DCM (100 ml×2). The combined organic layers were concentrated and the resulting solid was dissolved in 6N HCl (50 ml). The aqueous layer was washed with DCM (50 ml×2). The organic layers were discarded and the remaining aqueous solution was concentrated to give the product as an HCl salt (490 mg, 75%): LCMS (ES) m/z 444.0 (M+H)+, 1H NMR (400 MHz, METHANOL-d4) ppm 8.10 (m, 1H), 7.92 (m, 1H), 7.73 (m, 1H), 7.57 (m, 1H), 7.44 (m, 1H), 4.65 (m, 1H), 4.17 (s, 3H), 3.25-3.11 (m, 4H).