Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:3]([CH2:6][CH3:7])CC)C.[CH2:8]([O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>C1COCC1>[CH2:8]([O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:3][CH2:6][CH:7]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]2[CH3:8])=[O:20])=[CH:17][CH:16]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCOc1ccc(C(=O)Cl)cc1
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCOc1ccc(C(=O)NCC2CCCCC2C)cc1
Reaction time: 0.08 h

Procedure:
To a suspension of title B compound (213 mg, 1.30 mmol) in THF (6 mL) was added triethylamine 0.42 mL, 3.0 mmol). After stirring for 5 minutes, 4-hexyloxybenzoyl chloride (0.223 mL, 1.00 mmol) was added. After stirring for 4 hours, the reaction was filtered through a Celite pad. The pad was rinsed with ether (4×5 mL) and the combined filtrates were concentrated in vacuo. Purification by RP-HPLC (YMC SH-365-10 120A S-110 30×500 mm column, 40 mL/minute, 90:10 methanol/water containing 0.1% TFA)) afforded the title compound as a 1:1 mixture of cis- and trans- isomers (43 mg). MS: (ESI) (m/z) 332.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][C@H:9]([NH:14][S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[CH2:8]2)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:2][CH2:3][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][C@H:9]([NH:14][S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[CH2:8]2
Reactant: COC(=O)c1ccc2c(c1)C[C@@H](NS(=O)(=O)C(C)C)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(CO)cc2C1
Reaction time: 0.17 h
Yield: 102.7 %

Procedure:
(S)-methyl-2-(1-methylethylsulfonamido)-2,3-dihydro-1H-indene-5-carboxylate (2.502 mmol, 744 mg) was dissolved in dry THF (20 mL) and was purged with nitrogen and cooled in an ice bath. Lithium aluminium hydride (7.51 mmol, 7.51 mL) was added dropwise and stirring continued at 0° C. for 10 min. The mixture was quenched by addition of methanol followed by 1:1 THF/water and 1N HCl before concentration to remove organics. The residue was partitioned between dichlormethane/1N HCl. and the phases mixed and separated. The aqueous layer was further extracted with DCM (×2) Combined organics washed with brine and concentrated before purification on silica eluting with 2% MeOH/DCM to give (S)-N-(5-(hydroxymethyl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (0.692 g, 103%). 1H NMR (400 MHz, CDCl3) δ 1.39 (d, 6H) 1.71 (bt, 1H) 2.89 (m, 2H) 3.18 (sept, 1H) 3.30 (m, 2H) 4.28 (m, 1H) 4.41 (m, 1H) 4.66 (d, 2H) 7.18 (m, 2H) 7.24 (m, 1H)
Reaction SMILES: C[NH:2][C:3]1([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH:7]=NC(NC)=N1.Cl.[NH3:20].[CH3:21]O>>[NH3:2].[CH:16]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3[N:20]=[CH:21][CH:7]=[CH:3][C:10]=3[C:18]=2[CH:17]=1
Reactant: CO
Reactant: CNC1=NC(NC)(c2c[nH]c3ccccc23)C=N1
Agent: Cl
Agent: N
Product: c1ccc2c(c1)[nH]c1ncccc12

Procedure:
This example describes the synthesis of compounds 7 and 8 of FIG. 5. A solution of 2-dimethylamino-4-(3-indolyl)imidazole 5.HCl (0.2 g, 0.76 mmol) in 40 mL of methanol saturated with ammonia (MeOH, sat. NH3) was allow to stir in the presence of air at 25° C. for 1 day during which time compound 7 precipitated from the solution as a dark solid and was collected by filtration. Resubjection of 7 to an ammonia saturated methanol solution in air for 7 days at 25° C. produced compound 8 as a orange solid after concentration of the reaction mixture in vacuo followed by Flash silica gel chromatography (CH2Cl2/MeOH(NH3), 19:1). The yield of compound 8 was 60%. Referring to FIGS. 21 and 22, Compound 7: 1H NMR (300 MHz, DMSO-d6) δ 11.98 (bs, 2H), 10.43 (s, 2H), 8.72 (m, 2H), 7.49 (m, 2H), 7.22 (m, 4H), 3.46 (bs, 6H); 13CNMR (100 MHz, DMSO-d6) δ 173.2 (sx2), 172.1 (sx2), 147.2 (sx2), 139.5 (dx2), 137.6 (sx2), 128.2 (sx2), 124.6 (dx2), 123.6 (dx2), 122.0 (dx2), 112.8 (dx2), 111.9 (sx2), 38.9 (qx4); HRFABMS calcd for C26H25N8 449.2202, found 449.2178. Referring to FIGS. 23-25, Compound 8: 1H NMR (300 MHz, DMSO-d6) δ 13.36 (s, 1H), 12.13 (s, 1H), 11.88 (bs, 1H), 11.00 (bs, 1H), 9.03 (d, J=7.7 Hz, 1H), 8.94 (bs, 1H), 7.96 (bs, 1H), 7.68 (dm, J=7.7 Hz, 1H), 7.55 (m, 2H), 7.42-7.28 (m, 3H), 3.37 (s, 6H); 13C NMR (100 MHz, DMSO-d6+D2O) δ 167.5 (s), 155.8 (s), 148.1 (s), 143.3 (d), 141.0 (s), 138.2 (s), 134.4 (s), 130.5 (s), 128.9 (d), 128.3 (d), 125.5 (d), 125.2 (s), 124.9 (d), 124.5 (d), 121.4 (d), 120.6 (d), 118.2 (s), 114.5 (d), 112.0 (d), 108.6 (s), 103.4 (s), 40.4 (qx2); HRFABMS calcd for C23H20N7 394.1780, found 394.1784.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:28](O)=[O:29])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Si:64]([O:71][CH2:72][CH2:73][NH:74][CH2:75][CH:76]1[CH2:78][CH2:77]1)([C:67]([CH3:70])([CH3:69])[CH3:68])([CH3:66])[CH3:65]>CN(C)C=O.CCCCCC.C(OCC)(=O)C>[Si:64]([O:71][CH2:72][CH2:73][N:74]([CH2:75][CH:76]1[CH2:77][CH2:78]1)[C:28]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:14]([OH:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:19][CH2:20][CH2:21]2)[N:11]=1)=[O:29])([C:67]([CH3:70])([CH3:69])[CH3:68])([CH3:66])[CH3:65]
Reactant: CC(C)(C)[Si](C)(C)OCCNCC1CC1
Reactant: O=C(O)c1nc(CC2(c3ccccn3)CCCC2)nc(O)c1OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCN(CC1CC1)C(=O)c1nc(CC2(c3ccccn3)CCCC2)nc(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87 %

Procedure:
To a stirred solution of 5-benzyloxy-6-hydroxy-2-(1-pyridin-2-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (437) (150 mg, 0.37 mmol) in dimethylformamide (5 mL), N,N-diisopropylethylamine (0.184 mL, 1.111 mmol), HATU (211.24 mg, 0.556 mmol), and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclopropylmethyl-amine (8i) were added, then this reaction mixture was allowed to stir for 16 h at room temperature while silica thin layer chromatography was performed (50% ethyl acetate in hexane; Rf=0.5). The reaction mixture was quenched with ice cold water (25 mL) then extracted with ethyl acetate (2×30 mL). The organic part was dried and concentrated. The resulting crude product was purified by normal silica gel (100-200 mesh) column chromatography using 30-40% ethyl acetate in hexane as gradient polarity mobile phase to get 5-benzyloxy-6-hydroxy-2-(1-pyridin-2-yl-cyclopentylmethyl)-pyrimidine-4-carboxylicacid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclopropylmethyl-amide (446) (198 mg, 87%) as a colorless gummy liquid.
Reaction SMILES: [CH2:1]([N:5]1[C:9]([NH:10][C:11](=O)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:8]([C:20]#[N:21])[C:7]([CH3:22])=[N:6]1)[CH2:2][CH2:3][CH3:4].OO.C([OH:27])C.Cl>[OH-].[Na+]>[CH2:1]([N:5]1[C:9]2[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[NH:21][C:20](=[O:27])[C:8]=2[C:7]([CH3:22])=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1nc(C)c(C#N)c1NC(=O)c1ccccc1F
Reactant: CCO
Agent: Cl
Agent: OO
Agent: [Na+]
Product: CCCCn1nc(C)c2c(=O)[nH]c(-c3ccccc3F)nc21
Yield: 32 %

Procedure:
N-(2-Butyl-4-cyano-5-methyl-2H-pyrazol-3-yl)-2-fluoro-benzamide (4.0 g, 13.3 mmole) was suspended in 26 ml 1M sodium hydroxide, and 30% hydrogen peroxide (10 ml) and ethanol (5 ml) were added. The reaction mixture was heated to reflux for 4 hours, then more 30% hydrogen peroxide (10 ml) was added and heated to reflux overnight. The reaction mixture was cooled and acidified with diluted hydrochloric acid to pH 6.0. The product was collected by filtration and dried under vacuum to obtain 1.29 g of product (yield: 32%).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=1>CN(C)C=O.C1(C)C=CC=CC=1>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([Cl:3])=[O:14])=[N:10][CH:11]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Cl)cn1
Temperature: 25 °C

Procedure:
N,N-Dimethylformamide (one drop) and thionyl chloride (1 mL) were added to a suspension of 5-chloropyridinecarboxylic acid (55.2 mg) in toluene (5 mL). The mixture was heated under reflux for one hour. The reaction solution was cooled to room temperature and then the solvent was evaporated under reduced pressure to obtain 5-chloropyridinecarboxylic acid chloride. A solution of 5-chloropyridinecarboxylic acid chloride in THF (5 mL) and pyridine (115 μL) were sequentially added to a solution of the compound of Preparation Example 2-(2) (111 mg) in THF (10 mL) under ice-cooling. The mixture was warmed to room temperature and stirred for 30 minutes. After confirming completion of the reaction, a saturated sodium bicarbonate solution was added to the mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain an amide compound of a synthetic intermediate. The resulting amide was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (2 mL) was added and the mixture was stirred at room temperature for three hours. The reaction solution was diluted with diethyl ether. Then, the reaction mixture was neutralized with a sodium bicarbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by NH-silica gel column chromatography to obtain the title compound (115 mg; >99% ee).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](SC)[N:19]=3)[C:10]3[C:11]([N:17]=2)=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=3)=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.C([O-])([O-])=O.[Na+].[Na+].[C:43]1([C@@H:49]([NH2:51])[CH3:50])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(Cl)Cl.CC(O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:51][C@H:49]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[CH3:50])[N:19]=3)[C:10]3[C:11]([N:17]=2)=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=3)=[CH:4][CH:3]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: CSc1nccc(-n2c(-c3ccc(F)cc3)nc3nc(N)ccc32)n1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: C[C@H](Nc1nccc(-n2c(-c3ccc(F)cc3)nc3nc(N)ccc32)n1)c1ccccc1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
2-(4-Fluorophenyl)-1-(2-methylthio-4-pyrimidinyl)-5-aminoimidazo[4,5-b]pyridine (110 mg, 0.31 mmol) is dissolved in CH2Cl2/HOAc 1:1 (6.2 ml), combined at 0° C. with mCPBA (84 mg 70% 0.34 mmol) and stirred for 30 min. The reaction mixture is poured on 2N Na2CO3 and extracted with ethyl acetate three times. The combined organic phases are dried over Na2SO4, filtered and evaporated to dryness to yield the crude sulfoxide (110 mg). 50 mg are dissolved in 1-(S)-phenylethylamine (0.5 ml) and heated to 120° C. for 1 h. Purification over RP18 (CH3CN/Water 70/30 to 10/90) yielded the title compound as light brown foam (30 mg 52%)
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:29]2[NH:30][CH2:31][CH2:32][N:33]=2)=[N:4][N:5]([CH:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:14]=[N:15][N:16]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:17]=3[CH:18]([CH3:20])[CH3:19])[C:9]2=[O:28])[C:6]=1[CH3:7].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>CS(C)=O>[Cl:1][C:2]1[C:3]([C:29]2[NH:33][CH:32]=[CH:31][N:30]=2)=[N:4][N:5]([CH:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:14]=[N:15][N:16]([C:21]4[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=4)[C:17]=3[CH:18]([CH3:20])[CH3:19])[C:9]2=[O:28])[C:6]=1[CH3:7]
Reactant: Cc1c(Cl)c(C2=NCCN2)nn1C1CCN(c2cnn(-c3ccc(F)cc3)c2C(C)C)C1=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CS(C)=O
Product: Cc1c(Cl)c(-c2ncc[nH]2)nn1C1CCN(c2cnn(-c3ccc(F)cc3)c2C(C)C)C1=O
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 61.4 %

Procedure:
A mixture of 3-[4-chloro-3-(4,5-dihydro-1H-imidazol-2-yl)-5-methylpyrazol-1-yl]-1-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-yl]pyrrolidin-2-one (0.041 g, 0.087 mmol) and Dess-Martin periodinane (0.150 g, 0.35 mmol) in DMSO (2.0 mL) was stirred at 80° C. for 1.5 hr. The mixture was then cooled to room temperature, quenched with sat. aq. NaHCO3 (50 mL), and extracted with EtOAc (50 mL). The organic layer was separated, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to yield the title compound (0.025 g, TFA salt, 50%). 1H NMR (TFA salt) (400 MHz, CDCl3) δ 7.62 (s, 1H), 7.35 (dd, J=8.4, 4.8 Hz, 2H), 7.16 (m, 4H), 5.15 (dd, J=8.6, 8.6 Hz, 1H), 4.02 (m, 1H), 3.82 (m, 1H), 3.05 (m, 1H), 2.97 (septet, J=7.0 Hz, 1H), 2.35 (s, 3H), 2.70 (m, 1H), 1.18 (d, J=6.8 Hz, 3H), 1.14 (d, J=6.8 Hz, 3H); MS: (ES) m/z calculated for C23H23ClFN7O (free form) [M+H]+ 468.1. found 468.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][N:12]([CH2:14][CH2:15][CH3:16])[C:11](=O)[CH2:10][O:9]2)=[CH:4][C:3]=1[O:18][CH3:19]>Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:9][CH2:10][CH2:11][N:12]([CH2:14][CH2:15][CH3:16])[CH2:13]2)=[CH:4][C:3]=1[O:18][CH3:19]
Reactant: CCCN1CC(c2ccc(F)c(OC)c2)OCC1=O
Agent: Cl
Product: CCCN1CCOC(c2ccc(F)c(OC)c2)C1
Yield: 92 %

Procedure:
Prepared following the same method as for example 6 starting with the morpholin-3-one from example 21 (633 mg, 2.37 mmol). After refluxing in 6M HCl (aq) the reaction mixture was cooled and extracted with diethyl ether (2×20 ml). The organic layers were discarded and the aqueous layer basified by the addition of potassium carbonate. The aqueous residue was then extracted with ethyl acetate (3×20 ml). The organic extracts were combined and dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give the title compound as a yellow oil (552 mg, 2.18 mmol, 92%). 1H NMR (CD3OD, 400 MHz) δ: 0.95 (t, 3H), 1.58 (m, 2H), 2.02 (t, 1H), 2.22 (dt, 1H), 2.38 (t, 2H), 2.85 (d, 1H), 2.93 (d, 1H), 3.80 (m, 1H), 3.84 (s, 3H), 4.01 (dd, 1H), 4.50 (dd, 1H), 6.88 (m, 1H), 7.02 (t, 1H), 7.09 (d, 1H). LRMS: m/z 254 (M-H+).
Reaction SMILES: [CH2:1]([O:3][P:4]([N:9]1[CH2:22][CH2:21][CH2:20][N:19](P(OCC)(OCC)=O)[CH2:18][CH2:17][N:16](P(OCC)(OCC)=O)[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].BrCC1C=CC(CBr)=CC=1>CC#N>[CH2:7]([O:6][P:4]([N:9]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOP(=O)(OCC)N1CCCN(P(=O)(OCC)OCC)CCN(P(=O)(OCC)OCC)CCCNCC1
Agent: BrCc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOP(=O)(OCC)N1CCCNCCNCCCNCC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 139.7 %

Procedure:
To a stirred solution of 4,8,11-Tris(diethoxyphosphoryl)-1,4,8,11-tetraazacyclotetradecane (see Bridger et. al. J Med. Chem. 1995, 38, 366-378) (6.1 g, 0.01 mol) and K2CO3 (1.89 g, 0.013 mol) in CH3CN (150 ml) was added α,α'-dibromo-p-xylene (13.2 g, 0.05 mol) and the reaction mixture stirred at 70° C. for 1 hour. The solution was cooled to room temperature and the solvent removed under reduced pressure. The residue was partitioned between brine (50 ml) and CH2Cl2 (100 ml). The organic phase was separated, dried (Na2SO4) and concentrated to a minimum volume. The solid was filtered off and the solvent evaporated under reduced pressure to give the crude product as a pale yellow oil. Purification by column chromatography in silica gel (CH2Cl2CH3OH, 25:1) gave 1-[1-methylene-4-(bromo-methylene)phenylene]-4,8,11-tris(diethoxyphosphoryl-1,4,8,11-tetraazacyclotetra-decane (4.7 g, 59%) as a pale yellow oil. 1H NMR (CDCl3) δ 1.21-1.37 (m, 18 H), 1.66-1.74 (m, 2 H), 1.82-1.91 (m, 2 H), 2.30-2.35 (m, 2 H), 2.58-2.63 (m, 2 H), 2.99-3.16 (m, 12 H), 3.48 (s, 2 H), 3.95-4.07 (m, 12 H), 4.48 (s, 2 H), 7.21-7.35 (4 H).
Reaction SMILES: [CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([I:15])[CH:9]=1)(=[O:5])=[O:4].[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH4-].[Na+].C(O)(C)C>CO>[CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:10]([I:15])[CH:9]=1)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)CCc1ccc(N)c(I)c1
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CO
Product: CNS(=O)(=O)CCc1ccc(NCc2ccccc2)c(I)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 2-(4-amino-3-iodo-phenyl)-ethanesulfonic acid methylamide (100 g) in anhydrous methanol (500 ml), a solution of benzaldehyde (46 g) in methanol (100 ml) was added dropwise maintaining temperature below 30° C. The reaction mass was stirred for 2-3 hours at 25° C. and sodium borohydride (12 g) was added over a period of 2 hours maintaining the temperature below 30° C. The reaction mass was stirred for about 2 hours at 25° C. Methanol was evaporated from the mixture and water (1000 ml) was added. The solution was extracted with dichloromethane (2000 ml). The organic layer was washed with water and distilled under vacuum to obtain a solid. The solid was treated with isopropyl alcohol (500 ml), filtered and dried under vacuum at 50-55° C. to obtain the title compound. (Yield: 116 g, HPLC Purity: 99%)
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:16]=[C:15]3[C:11]([CH:12]=[CH:13][N:14]3COCC[Si](C)(C)C)=[C:10]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35]C)=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH:9]=2)=[C:6]([NH:37][C@H:38]([C:40]2[N:45]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:44](=[O:52])[C:43]3=[C:53]([CH3:56])[CH:54]=[CH:55][N:42]3[N:41]=2)[CH3:39])[N:5]=[CH:4][N:3]=1.B(Br)(Br)Br.CO>ClCCl>[NH2:1][C:2]1[C:7]([C:8]2[CH:16]=[C:15]3[C:11]([CH:12]=[CH:13][NH:14]3)=[C:10]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH:9]=2)=[C:6]([NH:37][C@H:38]([C:40]2[N:45]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:44](=[O:52])[C:43]3=[C:53]([CH3:56])[CH:54]=[CH:55][N:42]3[N:41]=2)[CH3:39])[N:5]=[CH:4][N:3]=1
Reactant: COc1ccc(S(=O)(=O)Nc2cc(-c3c(N)ncnc3N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)cc3c2ccn3COCC[Si](C)(C)C)cc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cc(NS(=O)(=O)c4ccc(O)cc4)c4cc[nH]c4c3)n(-c3ccccc3)c(=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.2 %

Procedure:
(S)—N-(6-(4-Amino-6-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidin-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-4-yl)-4-methoxybenzenesulfonamide (56 mg, 0.07 mmol) was dissolved in dichloromethane (1 ml). A solution of boron tribromide (1M in dichloromethane, 707 μl, 0.71 mmol) was added dropwise and the reaction was stirred at room temperature overnight. Methanol was added and the solvents were removed. Then ammonia (7N in methanol) (1.5 ml) was added and the mixture was stirred at room temperature overnight. The solvent was removed and the residue was purified by reverse phase chromatography using SP1® Purification System to give 6 mg (20% yield) of the title compound as a white solid. Purity 97%.
Reaction SMILES: F[C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[NH3:10]>CS(C)=O.C(Cl)(Cl)Cl>[NH2:10][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ncccc1F
Reactant: N
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: N#Cc1ncccc1N
Temperature: 70 °C

Procedure:
A solution of 3-fluoro-2-cyanopyridine (Sakamoto et. al., Chem. Pharm. Bull. 1985, 33: 565-571) (10 g, 82 mmol) in DMSO (30 mL) was placed in a pressure vessel and saturated with ammonia gas. The reaction was capped and heated to 70 degrees C. overnight. The reaction was cooled, vented and re-saturated with ammonia, then sealed and re-heated for several hours. The reaction was cooled, vented, diluted with CHCl3 and the solids that had formed were filtered off. The solution was added to the top of a silica gel column (150 mm×7 inches) saturated with CHCl3 and the column was eluted with a gradient of 100% CHCl3 to 100% CHCl3 saturated with NH3. The fractions were collected and concentrated to give the product which contained some residual DMSO. This was used a in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:16][O:15][C@H:14]([CH3:17])[C@H:13]1[C@@H:12]([C:18]([F:21])([F:20])[F:19])[O:11][C:10]([NH2:22])=[N:9]2.[N+:23]([O-])([OH:25])=[O:24]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:23]([O-:25])=[O:24])=[CH:4][C:3]=1[C@:8]12[CH2:16][O:15][C@H:14]([CH3:17])[C@H:13]1[C@@H:12]([C:18]([F:19])([F:20])[F:21])[O:11][C:10]([NH2:22])=[N:9]2
Reactant: O=[N+]([O-])O
Reactant: C[C@H]1OC[C@]2(c3ccccc3F)N=C(N)O[C@H](C(F)(F)F)[C@H]12
Product: C[C@H]1OC[C@]2(c3cc([N+](=O)[O-])ccc3F)N=C(N)O[C@H](C(F)(F)F)[C@H]12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.5 %

Procedure:
(4S,4aS,5R,7aS)-7a-(2-fluorophenyl)-5-methyl-4-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]oxazin-2-amine (Preparation Example 30-(7)) (226 mg, 0.71 mmol) was dissolved in nitric acid (4.80 g, 76.20 mmol). The reaction was then stirred at RT for 90 min. LCMS (Agilent Method A) retention time 3.25 min, ES+: 364 [MH]+. The reaction was concentrated and purified by flash chromatography (Hexane/EtOAc 20-100%). 218 mg (84% yield) of the title compound (85%) and its isomer (15%) were isolated as a mixture.
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].CC(C)([O-])C.[K+].Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl>C1COCC1.CCOCC>[CH3:1][C:2]([O:6][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])([CH3:3])[C:4]#[CH:5]
Reactant: C#CC(C)(C)O
Reactant: CCOC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#CC(C)(C)OCC(=O)OCC
Reaction time: 0.17 h
Yield: 82.5 %

Procedure:
A solution of 0.87 g (10.32 mmol) of 2-methylbut-3-yn-2-ol in 20 ml of anhydrous THF is cooled to 0-5° C. with an ice bath and then 10.32 ml (10.32 mmol) of 1.0M potassium t-butoxide in THF (Aldrich) are added. Stirring is carried out under cold conditions for 10 minutes and then 1.89 g (11.35 mmol) of ethyl bromoacetate are added. The reaction mixture is stirred at ambient temperature for 45 minutes and then 0.1 N aqueous HCl and ether are added. The organic phase is dried over sodium sulfate, filtered and concentrated under vacuum. 1.45 g of the expected product are obtained in the form of a yellow oil which is used without subsequent purification. Yield=83%.