Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[S:17]([C:20]1[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=1)(=[O:19])=[O:18])=O)(C)(C)C.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(OCC)C.CCCCCC>C(OCC)(=O)C>[N:27]1([C:23]2[CH:22]=[CH:21][C:20]([S:17]([C:9]3[NH:8][C:16]4[C:11]([CH:10]=3)=[CH:12][CH:13]=[CH:14][CH:15]=4)(=[O:18])=[O:19])=[CH:25][CH:24]=2)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1
Reactant: CC(C)(C)OC(=O)n1c(S(=O)(=O)c2ccc(F)cc2)cc2ccccc21
Reactant: C1CNCCN1
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=S(=O)(c1ccc(N2CCNCC2)cc1)c1cc2ccccc2[nH]1
Temperature: 25 °C
Yield: 31.2 %

Procedure:
The Boc-protecting group on 0.530 g, 1.41 mmol of the 2-(4-Fluorobenzenesulfonyl)-indole-1-carboxylic acid tert-butyl ester from Step 1 was removed by stirring at room temperature in 3 mL of neat TFA. The reaction mixture turned a light burgundy color while stirring. The TFA was removed by adding 25 mL of toluene and removing the solvent/TFA as an azeotrope. This was repeated and the oily residue was then transferred to a sealed tube using 5 mL of DMSO. Solid piperazine (0.61 g, 7.06 mmol, 5 eq.) was added, the tube was sealed, and the reaction mixture heated at 100° C. (bath temp.) for a period of 16 h. The reaction mixture was allowed to cool to room temperature, diluted with 400 mL of ethyl acetate, then washed sequentially with saturated NaHCO3 solution, water, brine, and dried over anhydrous magnesium sulfate. Evaporation of the solvent gave an amber glass which was treated with anhydrous diethyl ether. Hexane (25 mL) was added to the solution, causing a small amount of solid to precipitate out of solution. The mixture cooled was to 0° C. in an ice-water bath, followed by vacuum-filtration of the off-white solid. After drying, 0.150 g, 0.44 mmol, 31.1% yield of 2-(4-Piperazin-1-yl-benzenesulfonyl)-1H-indole was obtained, with a melting point range of 246–248.5° C. and M+H of 342.
Reaction SMILES: CO.C(O)C.[C:6]([OH:16])(=[O:15])[C@@H:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[OH:8]>C(O)(C)C>[C:6]([OH:16])(=[O:15])[CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[OH:8]
Reactant: O=C(O)[C@H](O)c1ccccc1
Solvent: CC(C)O
Solvent: CCO
Solvent: CO
Product: O=C(O)C(O)c1ccccc1

Procedure:
The resolution of a racemic mixture of a compound of the formula I to prepare the (+) enantiomer of such compound is generally carried out using methanol, ethanol, or isopropanol, preferably isopropanol, as the organic reaction inert solvent. Preferably, the resolution is carried out by combining a racemic mixture of a compound of the formula I and (R)-(-)-mandelic acid in isopropanol, and stirring the mixture to form an optically enriched mandelic acid salt precipitate. The optically enriched precipitate is then recrystallized twice from isopropanol, after which the recrystallized precipitate is converted to the free base of the optically pure compound of formula I by partitioning it between dichloromethane and an aqueous base such as sodium hydroxide, sodium bicarbonate or potassium bicarbonate, preferably sodium hydroxide, or by stirring an alcoholic solution of the salt with a basic ion exchange resin. The free base, which is dissolved in the methylene chloride, can then be converted to the corresponding hydrochloric acid salt. Isolation of the mandelate may be conducted at temperatures from about 0° C. to about 40° C. About 25° C. is preferred.
Reaction SMILES: [O:1]([CH2:8][C@H:9]1[NH:13][CH2:12][C@H:11]([OH:14])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:15]1[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][CH:16]=1>>[O:1]([CH2:8][C@H:9]1[N:13]([CH2:21][C:18]2[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=2)[CH2:12][C@H:11]([OH:14])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@H]1CN[C@H](COc2ccccc2)C1
Reactant: O=Cc1ccncc1
Product: O[C@@H]1C[C@@H](COc2ccccc2)N(Cc2ccncc2)C1

Procedure:
The title compound was prepared by a similar method to Preparation 35 from (3R,5S)-5-(phenoxymethyl)pyrrolidine-3-ol [see Preparation 37] and 4-pyridinecarboxaldehyde. The crude product was purified by column chromatography on silica gel eluting with a solvent system of 95:5, by volume, chloroform:methanol to afford (3R,5S)-5-(phenoxymethyl)-1-(4-pyridinylmethyl)pyrrolidine-3-ol as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](Cl)=[N:9]2)=[CH:4][CH:3]=1.[I-:13].[Na+].C(Cl)(=O)C.C(=O)([O-])[O-].[K+].[K+].S([O-])([O-])=O.[Na+].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([I:13])=[N:9]2)=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: Clc1ccc2ccc(Br)cc2n1
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: O=S([O-])[O-]
Solvent: CC#N
Solvent: CC(=O)Cl
Product: Brc1ccc2ccc(I)nc2c1
Temperature: 80 °C

Procedure:
To a stirred slurry of 7-bromo-2-chloro-quinoline (obtained from AstaTech, Inc.), (8.10 g, 33.4 mmol) and sodium iodide (50.0 g, 334 mmol) in acetonitrile (27 mL) was slowly added acetyl chloride (3.56 mL, 50.0 mmol). The flask was stoppered and sealed and heated at 80° C. for 3 h before being allowed to cool. The mixture was treated sequentially with 10% w/w aqueous potassium carbonate solution (80 mL), 5% w/w aqueous sodium sulfite solution (80 mL) and saturated aqueous sodium thiosulfate solution (80 mL) and the mixture extracted with dichloromethane (2×). The combined organic extracts were dried over sodium sulfate, filtered and evaporated to give a crude 7-bromo-2-iodo-quinoline. To the quinoline was added tributyl(1-ethoxyvinyl)tin (13.6 mL, 40.1 mmol), 1,4-dioxane (67 mL) and bis(triphenylphosphine)palladium(II) dichloride (2.37 g, 3.34 mmol) and the reaction mixture heated at 100° C. for 5 h before being allowed to cool. 2 M aqueous hydrochloric acid (67 mL) was added and the reaction stirred for 1 h. The mixture was filtered and the solids washed with ethyl acetate and the filtrate evaporated to remove organics. The residue was extracted with ethyl acetate (3×) and the combined organic extracts were dried over sodium sulfate, filtered and evaporated. The product was purified on silica gel doped with 10% w/w potassium carbonate eluting with a gradient of 0% to 6% ethyl acetate in iso-hexanes to afford the title compound (5.5 g, 66%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 2.86 (s, 3H), 7.72-7.80 (m, 2H), 8.21 (ABq, ΔδAB=0.11, JAB=8.5 Hz, 2H), 8.42 (s, 1H). LCMS (m/z) 250.1/252.1 [M+H], Tr=2.90 min.
Reaction SMILES: C([O:8][C:9]1[C:10]([O:36][CH3:37])=[CH:11][C:12]2[CH2:21][CH2:20][N:19]3[CH:14]([CH2:15][C:16]4[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH3:28])=[C:22]([O:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:17]=4[CH2:18]3)[C:13]=2[CH:35]=1)C1C=CC=CC=1>[Ni]>[OH:8][C:9]1[C:10]([O:36][CH3:37])=[CH:11][C:12]2[CH2:21][CH2:20][N:19]3[CH:14]([CH2:15][C:16]4[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH3:28])=[C:22]([O:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:17]=4[CH2:18]3)[C:13]=2[CH:35]=1
Reactant: CCOC(=O)Oc1c(OC)cc(Cl)c2c1CN1CCc3cc(OC)c(OCc4ccccc4)cc3C1C2
Agent: [Ni]
Product: CCOC(=O)Oc1c(OC)cc(Cl)c2c1CN1CCc3cc(OC)c(O)cc3C1C2

Procedure:
A product obtained in Example 20 (0.09 g, 0.17 mmol) was hydrogenated in the present of Raney-Ni. The desired product was obtained following the synthetic procedure described in Example 1, 4 or 7. The crude product was recrystallized with CH2Cl2/hexane to give pink solid (0.044 g, 59.0%). mp 169˜170° C. 1HNMR (CDCl3) δ: 1.39 (3H, t, CH3), 2.59˜2.68 (3H, m, CH2), 3.10˜3.16 (2H, m, CH2), 3.33˜3.56 (3H, m, CH2 and N—CH), 3.82 (3H, s, Ar—OCH3), 3.88 (3H, s, Ar—OCH3), 4.08 (1H, d, CH2), 4.32 (2H, q, CH2), 5.52 (1H, brs, Ar—OH), 6.60 (1H, s, ArH), 6.87 (1H, s, ArH), 6.91 (1H, s, ArH). MS (EI) m/z: 432 (M−1), 344 (base), 183, 176, 91.
Reaction SMILES: [NH:1]1[C:5]([NH:6][C:7]([C:9]2[S:17][C:16]3[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][C:11]=3[C:10]=2[O:25][CH:26]([CH3:28])[CH3:27])=[O:8])=[N:4][N:3]=[N:2]1.[ClH:29]>CO>[ClH:29].[NH:1]1[C:5]([NH:6][C:7]([C:9]2[S:17][C:16]3[CH2:15][CH2:14][NH:13][CH2:12][C:11]=3[C:10]=2[O:25][CH:26]([CH3:28])[CH3:27])=[O:8])=[N:4][N:3]=[N:2]1
Reactant: CC(C)Oc1c(C(=O)Nc2nnn[nH]2)sc2c1CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CO
Product: CC(C)Oc1c(C(=O)Nc2nnn[nH]2)sc2c1CNCC2

Procedure:
A solution of 0.10 g (0.245 mmol) of 3-isopropoxy-5-tert -butoxycarbonyl-6,7-dihydro-4H-thieno[3,2-c]pyridine-2-carboxylic acid (1H-tetrazol-5-yl) amide (from Example 7) in 15 mL of 5% (w/w) hydrogen chloride in methanol was stirred at 24° C. for 3 days. The reaction solvent was removed by evaporation under reduced pressure to afford an oil. The oil was crystallized from 10 mL of ethyl acetate/diethyl ether (1:1 v/v) to afford 0.089 g of 3-isopropoxy-6,7-dihydro-4H-thieno[3,2-c]pyridine-2-carboxylic acid (1H-tetrazol-5-yl) amide monohydrochloride, mp 237°-238° C.
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5]([CH:7]=O)[N:4]([CH3:9])[N:3]=1.[Cl-].[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[N:15]2[N:19]=[C:20]([CH2:22][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:21]=[C:14]2[N:13]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[Br:1][C:2]1[N:6]=[C:5]([CH:7]=[CH:22][C:20]2[N:21]=[C:14]3[N:13]=[C:12]([CH3:11])[CH:17]=[C:16]([CH3:18])[N:15]3[N:19]=2)[N:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(C)n2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc2n1
Reactant: Cn1nc(Br)nc1C=O
Agent: [Cl-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Cc1cc(C)n2nc(C=Cc3nc(Br)nn3C)nc2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.2 %

Procedure:
A mixture of 3-bromo-1-methyl-1H-1,2,4-triazole-5-carbaldehyde (193 mg, 1.02 mmol, Eq: 1.00), ((5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)triphenylphosphonium chloride (466 mg, 1.02 mmol, Eq: 1.00) and DBU (387 mg, 383 μl, 2.54 mmol, Eq: 2.5) in tetrahydrofuran (12 ml) was stirred for 18 hours at 25° C. under argon atmosphere. Chromatography afforded) 2-[2-(5-bromo-2-methyl-2H-[1,2,4]triazol-3-yl)-vinyl]-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine (161 mg/47.4%) as a white solid. MS: m/z=334336 (M+H+), mp: 277.4° C.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[CH:3]([C:19]1[CH:24]=[C:23]([Cl:25])[C:22]([Cl:26])=[C:21]([Cl:27])[CH:20]=1)/[CH:4]=[CH:5]/[C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[C:8]([C:15]([F:18])([F:17])[F:16])[CH:7]=1.ClCCCl.S(Cl)(Cl)=O.Cl.[NH2:39][C:40]1([C:43]([N:45]([O:51][CH3:52])[CH2:46][C:47]([F:50])([F:49])[F:48])=[O:44])[CH2:42][CH2:41]1>C(Cl)Cl>[CH3:52][O:51][N:45]([CH2:46][C:47]([F:48])([F:49])[F:50])[C:43]([C:40]1([NH:39][C:10](=[O:11])[C:9]2[CH:13]=[CH:14][C:6](/[CH:5]=[CH:4]/[CH:3]([C:19]3[CH:20]=[C:21]([Cl:27])[C:22]([Cl:26])=[C:23]([Cl:25])[CH:24]=3)[C:2]([F:28])([F:29])[F:1])=[CH:7][C:8]=2[C:15]([F:18])([F:16])[F:17])[CH2:42][CH2:41]1)=[O:44]
Reactant: O=C(O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1C(F)(F)F
Reactant: CON(CC(F)(F)F)C(=O)C1(N)CC1
Agent: Cl
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Product: CON(CC(F)(F)F)C(=O)C1(NC(=O)c2ccc(/C=C/C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 8.2 %

Procedure:
A 25 mL rb flask was charged with (E)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzoic acid (150 mg, 0.31 mmol) and DCE (5 mL). Thionyl chloride (41.1 mg, 0.35 mmol) was added neat in one portion and the resulting reaction mixture was heated at reflux for 1.5 h. After which time, reaction mixture was allowed to cool and concentrated to give a brown oil which was used without further purification. The crude acid chloride was taken up in anhydrous DCM (2 mL) and was added drop wise to a cold solution containing crude 1-amino-N-methoxy-N-(2,2,2-trifluoroethyl)cyclopropanecarboxamide hydrochloride (78 mg, 0.31 mmol), TEA (66.7 mg, 0.66 mmol) and DCM (10 mL). The reaction mixture was stirred at RT for 18 h. The reaction mixture was diluted with DCM and washed with 0.1N HCl, aqueous NaHCO3, dried over MgSO4, filtered and evaporated to give an oil. The residue was chromatographed on a silica gel column eluting with 10% EtOAc/hex to afford the title compound (17 mg, 8.%): 1H NMR (400 MHz, CDCl3) δ 7.66 (dd, J=14.1, 1.6 Hz, 1H), 7.59 (dd, J=8.0, 1.8 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.41 (s, 2H), 6.62 (d, J=15.9 Hz, 1H), 6.53 (s, 1H), 6.44 (m, 1H), 4.29 (q, J=8.5 Hz, 2H), 4.12 (m, 1H), 3.78 (s, 3H), 1.62 (m, 2H), 1.29 (m, 2H); 19F NMR (376 MHz, CDCl3) δ −58.81, −68.59, −69.22; ESIMS m/z 671.3 ([M−H]−).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][S:10]([CH2:13][Cl:14])(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].[Cl:15]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([Cl:15])=[C:4]([NH:9][S:10]([CH2:13][Cl:14])(=[O:11])=[O:12])[CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1cc(NS(=O)(=O)CCl)ccc1F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Temperature: 50 °C
Yield: 82.1 %

Procedure:
A mixture of N-(3-amino-4-fluorophenyl)-1-chloromethanesulfonamide (4.42 g, 18.5 mmol), N-chlorosuccinimide (2.47 g) in 50 mL of anhydrous dimethylformamide was heated to 50° C. for 1.5 hours. The reaction mixture was diluted with 200 mL of ethyl acetate and washed with water (twice with 50 mL). The organic phase was separated, dried (MgSO4), and concentrated under reduced pressure to yield 4.15 g (82%) of the title compound. Purification by flash chromatography provided a solid melting at 107-108° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:32][CH3:33])=[CH:5][C:6]2[C:15]3[C:14](=O)[NH:13][C:12]4[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=4[C:10]=3[N:9]([CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:8](=[O:30])[C:7]=2[CH:31]=1.O=P(Cl)(Cl)[Cl:36].P(Cl)(Cl)(Cl)(Cl)Cl>>[Cl:36][C:14]1[N:13]=[C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]2=[C:10]2[C:15]=1[C:6]1[CH:5]=[C:4]([O:32][CH3:33])[C:3]([O:2][CH3:1])=[CH:31][C:7]=1[C:8](=[O:30])[N:9]2[CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2c(=O)n(CCCN3CCOCC3)c3c4ccccc4[nH]c(=O)c3c2cc1OC
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: COc1cc2c(=O)n(CCCN3CCOCC3)c3c4ccccc4nc(Cl)c3c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
Precursor 29 (22.5 mg, 0.05 mmol) was mixed with POCl3 (3 mL) and phosphorus pentachloride (100 mg, 10 equiv) was added slowly at room temperature. Starting material dissolved upon PCl5 addition, forming a clear yellow solution. The reaction mixture was stirred for 1 h and then heated at reflux for 1.5 h. After disappearance of starting material, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The brown oily residue was dissolved completely in ice-cold water (3 mL) and concentrated ammonium hydroxide solution was added dropwise to neutral pH. The cloudy aqueous solution was extracted with ethyl acetate (3×30 mL). The combined extracts were washed with concentrated ammonium hydrochloride solution, dried with sodium sulfate and evaporated to dryness under reduced pressure to yield 32 as an amorphous solid (15 mg, 66%): mp 185-190° C. (dec.), IR (KBr) 1651, 1606 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.52 (s, 1 H), 8.17 (d, J=8.5 Hz, 1 H), 7.95 (d, J=7.6 Hz, 1 H), 7.82 (t, J=7.6 Hz, 1 H), 7.77 (s, 1 H), 7.71 (t, J=7.4 Hz, 1 H), 4.56-4.28 (m, 2 H), 3.97 (s, 3 H), 3.96-3.88 (m, 5 H), 3.76 (t, J=12.0 Hz, 2 H), 3.42 (d, J=11.9 Hz, 2 H), 3.18 (s, 2 H), 3.05 (d, J=11.1 Hz, 2 H), 2.42 (s, 2 H); 13C NMR (126 MHz, CDCl3) δ 161.90, 152.44, 149.88, 145.75, 144.76, 144.57, 130.45, 127.92, 126.50, 125.47, 124.66, 119.34, 117.80, 110.25, 108.06, 107.89, 63.23, 55.91, 55.78, 53.12, 50.89, 48.68, 22.93; positive ESIMS m/z (rel intensity) 468/470 (MH+, 100/32), 381/383 (97/30). Anal. Calcd for C25H28Cl3N3O4.1.2H2O: C, 53.38; H, 5.45; N, 7.47. Found: C, 53.36; H, 5.45; N, 7.10.
Reaction SMILES: CB1N2CCC[C@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.[C:22]([C:25]1[C:26]([O:45][CH2:46][CH3:47])=[C:27]([CH:34]2[CH2:37][N:36]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:35]2)[C:28]([C:32]#[N:33])=[C:29]([Cl:31])[CH:30]=1)(=[O:24])[CH3:23]>O1CCCC1>[Cl:31][C:29]1[C:28]([C:32]#[N:33])=[C:27]([CH:34]2[CH2:35][N:36]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:37]2)[C:26]([O:45][CH2:46][CH3:47])=[C:25]([CH:22]([OH:24])[CH3:23])[CH:30]=1
Reactant: CCOc1c(C(C)=O)cc(Cl)c(C#N)c1C1CN(C(=O)OC(C)(C)C)C1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Solvent: C1CCOC1
Product: CCOc1c(C(C)O)cc(Cl)c(C#N)c1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 78 %

Procedure:
A solution of (3aS)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole (9.7 g, 35 mmol) in tetrahydrofuran (100 mL) was treated with 1.0 M borane-THF complex in tetrahydrofuran (42 mL, 42 mmol) and stirred at 20° C. for 15 min. The reaction mixture was cooled to −30° C. and treated with a solution of tert-butyl 3-(3-acetyl-5-chloro-6-cyano-2-ethoxyphenyl)azetidine-1-carboxylate (13 g, 35 mmol) in tetrahydrofuran (110 mL) slowly. The flask containing the starting material ketone was rinsed with additional tetrahydrofuran (20 mL) and added to the reaction mixture. The reaction mixture was warmed to 0° C. over a period of 30 min and stirred at 0° C. for 15 min. The reaction mixture was quenched with water at 0° C., poured into saturated sodium bicarbonate solution, and extracted with ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried with magnesium sulfate, filtered, and concentrated to a crude dark oil. The crude material was purified by flash column chromatography using ethyl acetate in hexanes (0%-70%) to give the desired product (10.4 g, 78%) as a yellow foam as a 98:2 mixture of enantiomers (Retention times=7.73 min and 9.41 min; ChiralPak AD-H column, 4.6×150 mm, 5 micron particle size, eluting with 5% ethanol in hexanes at 1 ml/min). 1H NMR (300 MHz, CDCl3) δ 7.56 (s, 1H), 5.15-5.07 (m, 1H), 4.41-4.17 (m, 5H), 3.74 (q, J=7.0 Hz, 2H), 2.12 (d, J=3.7 Hz, 1H), 1.49-1.37 (m, 15H). LCMS for C15H18ClN2O4 ([M-(t-Bu)+H]+H)+: m/z=325.1; Found: 325.1.
Reaction SMILES: [OH:1]/[N:2]=[C:3]1\[CH2:4][CH2:5][CH2:6][C:7]2[O:11][CH:10]=[C:9]([C:12]([OH:14])=[O:13])[C:8]\1=2.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>N1C=CC=CC=1.Cl>[CH3:25][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O:1][N:2]=[C:3]2[C:8]3[C:9]([C:12]([OH:14])=[O:13])=[CH:10][O:11][C:7]=3[CH2:6][CH2:5][CH2:4]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)c1coc2c1/C(=N/O)CCC2
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)ON=C2CCCc3occ(C(=O)O)c32)cc1
Reaction time: 1 h
Yield: 95.4 %

Procedure:
To a partial solution of 2.8 g of (E)-4,5,6,7-tetrahydro-4-(hydroxyimino)-3-benzofurancarboxylic acid in 7 ml of pyridine is added portionwise at 0° C., 3.01 g of p-toluene sulfonyl chloride under argon. The mixture is stirred for 1 hour then diluted with 40 ml of cold 1N HCl, filtered, washed with water and dried with Na2SO4. The filtrate is concentrated in vacuo to give 4.78 g of the desired product as an off-white solid, m.p. 155°-165° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:21][C:22]([OH:24])=O)=[C:4]([F:20])[C:5]([NH:8][CH2:9][C:10]([F:19])([F:18])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=2[O-])=[N:6][CH:7]=1.[NH2:25][CH2:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[CH2:34][CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O>[Cl:33][C:31]1[CH:30]=[CH:29][C:28]([CH2:34][CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:41])([CH3:42])[CH3:40])=[C:27]([CH2:26][NH:25][C:22](=[O:24])[CH2:21][C:3]2[C:2]([Cl:1])=[CH:7][N:6]=[C:5]([NH:8][CH2:9][C:10]([F:18])([F:19])[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[C:4]=2[F:20])[CH:32]=1
Reactant: O=C(O)Cc1c(Cl)cnc(NCC(F)(F)c2cccc[n+]2[O-])c1F
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Cl)cc1CN
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCc1ccc(Cl)cc1CNC(=O)Cc1c(Cl)cnc(NCC(F)(F)c2ccccn2)c1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 0.035 g (0.1 mmol) (5-chloro-2-{[2,2-difluoro-2-(2-pyridinyl)ethyl]amino}-3-fluoro-4-pyridinyl)acetic acid 1-9 (mixed with LiCl) in 1 mL DMF was added 0.029 g (0.1 mmol) tert-butyl 2-[2-(aminomethyl)-4-chlorophenyl]ethylcarbamate, 0.03 g (0.15 mmol) EDC and 0.014 g (0.1 mmol) HOAt and the reaction mixture stirred at room temperature 4 h, then diluted with 50 mL EtOAc, washed with 50 mL saturated aqueous sodium bicarbonate solution, brine, then dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography (2×12 cm silica gel, linear gradient 2-6% MeOH (containing 10% saturated ammonium hydroxide solution)/CH2Cl2 afforded tert-butyl 2-[4-chloro-2-({[(5-chloro-2-{[2,2-difluoro-2-(2-pyridinyl)ethyl]amino}-3-fluoro-4-pyridinyl)acetyl]amino}methyl)phenyl]ethylcarbamate 1-10. 1H NMR (400 mHz, CD3OD) δ8.60 (d, 1H, J=4.58 Hz); 7.89 (ddd, J=7.7, 7.7, and 1.47 Hz); 7.72 (s, 1H); 7.67 (d, 1H, J=7.87 Hz); 7.46 (dd, 1H, J=7.51 and 4.58); 7.29(d, 1H, J=1.83 Hz); 7.18 (m, 2H); 4.42 (s, 2H); 4.32 (t, 2H, J=13.9 Hz); 3.74 (d, 2H, J=1.46 Hz); 3.21 (t, 2H, J=7.14 Hz); 2.80 (t, 2H, J=7.4 Hz); 1.40 (s, 9H). Mass Spectrum (electrospray) M+H=612.3.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:16][CH2:15][C:14]2[C:10](=[CH:11][N:12]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[N:25]=4)[N:20]=[CH:19][CH:18]=3)[N:13]=2)[CH2:9]1)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl.CO>[CH3:28][O:27][C:24]1[N:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][CH:18]=[C:17]2[N:12]1[CH:11]=[C:10]2[C:14]([CH2:15][CH2:16][CH:8]([NH2:7])[CH2:9]2)=[N:13]1
Reactant: COc1ccc2nccc(-n3cc4c(n3)CCC(NC(=O)OC(C)(C)C)C4)c2n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc2nccc(-n3cc4c(n3)CCC(N)C4)c2n1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of [2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-carbamic acid tert-butyl ester (317 mg, 0.800 mmol) in CH2Cl2 (3.6 mL) was added 4 M HCl in dioxane (3.40 mL, 13.7 mmol), and the solution was stirred at RT for 3.5 h. The solution was concentrated to afford a crude solid, which was dissolved in CH3OH (10 mL). Anionic exchange resin (550 Å OH, 100 mg) was added and the mixture was stirred for 20 min. The mixture was filtered, and the resin was washed with CH3OH (30 mL). The filtrate was concentrated to afford 234 mg (99% crude) of the title compound as a brown oil. MS (ESI): exact mass calculated for C16H17N5O, 295.14; m/z found, 296.3 [M+H]+. 1H NMR (400 MHz, CDCl3): 9.08 (s, 1H), 8.76 (d, J=5.1, 1H), 8.26 (d, J=9.1, 1H), 8.15 (d, J=5.1, 1H), 7.18 (d, J=9.1, 1H), 4.10 (s, 3H), 3.29-3.27 (m, 1H), 3.01-2.96 (m, 2H), 2.87-2.80 (m, 1H), 2.48-2.39 (m, 1H), 2.11-2.05 (m, 1H), 1.82-1.64 (m, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:16]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCC(C(=O)N2CCN(Cc3ccccc3)CC2)(c2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCC(CN2CCN(Cc3ccccc3)CC2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.2 %

Procedure:
To a solution of (4-benzylpiperazin-1-yl)(1-methyl-4-phenylpiperidin-4-yl)methanone (1.5 g, 4 mmol) in THF (30 ml) was added LiAlH4 (8 mmol) in portions. The resulting mixture was stirred at room temperature overnight. The mixture was quenched with ethyl acetate and methanol then made alkaline with 10% NaOH solution and extracted with ethyl acetate (3×40). The combined organic solution was dried and concentrated to give 1.5 g of desired product.