Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)[N:11]=2)=[CH:6][CH:5]=1)([O-])=O.Cl.C([O-])([O-])=O.[K+].[K+]>[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)[N:11]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc(-c3cccs3)no2)cc1
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Product: Nc1ccc(-c2nc(-c3cccs3)no2)cc1
Yield: 50 %

Procedure:
A suspension of 5-(4-nitrophenyl)-3-(2-thienyl)-1,2,4-oxadiazole (3.1 g, 0.01 mole) in 150 ml of absolute alcohol containing 1.84 ml of concentrated HCl is hydrogenated using 0.4 g of 5% Pd on carbon as catalyst. The solid is slurried with saturated K2CO3 solution and extracted with chloroform. Evaporation of the chloroform in vacuo gives the amine as a yellow solid, 1.4 g (50% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[CH3:11].C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.Cl>CCOC(C)=O.C(#N)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:6][C:5]=1[CH3:11]
Reactant: COC(=O)c1ccc(O)cc1C
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1ccc(OCc2ccccn2)cc1C
Temperature: 90 °C
Reaction time: 4 h
Yield: 89.7 %

Procedure:
To 0.85 g of 4-hydroxy-2-methyl benzoic acid methyl ester were added 12 mL of acetonitrile, 2.12 g of K2CO3 and 0.84 g of 2-(chloromethyl)pyridine hydrochloride, and the mixture was stirred at 90° C. for 4 hours. The reaction mixture was allowed to cool back to room temperature and neutralized by the addition of 5% hydrochloric acid. To this, 150 mL of AcOEt was added, and the organic layer was separated. The obtained organic layer was washed with saturated brine, dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography (hexane/AcOEt system) to give 1.18 g of the title compound (89% yield).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:15][C:16]1[CH:35]=[CH:34][C:19]([CH2:20][C:21]2[O:25][N:24]=[C:23]([C:26]3[C:27]([NH2:33])=[N:28][CH:29]=[C:30]([Cl:32])[CH:31]=3)[CH:22]=2)=[CH:18][CH:17]=1)C1C=CC=CC=1.C1(SC)C=CC=CC=1.C(=O)([O-])O.[Na+]>O>[NH2:33][C:27]1[C:26]([C:23]2[CH:22]=[C:21]([CH2:20][C:19]3[CH:34]=[CH:35][C:16]([OH:15])=[CH:17][CH:18]=3)[O:25][N:24]=2)=[CH:31][C:30]([Cl:32])=[CH:29][N:28]=1
Reactant: Nc1ncc(Cl)cc1-c1cc(Cc2ccc(OCc3ccccc3)cc2)on1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: Nc1ncc(Cl)cc1-c1cc(Cc2ccc(O)cc2)on1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.4 %

Procedure:
To a trifluoroacetic acid (6 mL) solution of 3-(5-(4benzyloxy-benzyl)-isoxazol-3-yl)-5-chloro-pyridin-2-ylamine (304 mg, 0.776 mmol) described in Manufacturing Example 29-2-3 was added thioanisole (364 mL, 3.10 mmol) at 0° C., which was stirred for 3 hours at room temperature. To this reaction mixture were added sodium hydrogencarbonate and water at 0° C., which was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=20:1) to obtain the title compound (146 mg, 62%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([C:8]1[CH:13]=[CH:12][C:11]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C@H:22]([OH:31])[C:23]3[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=3)[C:26]#[N:27])=[CH:18][CH:17]=2)=[C:10]([CH2:32][CH2:33][CH3:34])[C:9]=1[OH:35])(=[O:7])[CH3:6].O>CN1CCCC1=O.[Br-].[Zn+2].[Br-]>[OH:35][C:9]1[C:10]([CH2:32][CH2:33][CH3:34])=[C:11]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C@H:22]([OH:31])[C:23]3[CH:30]=[CH:29][CH:28]=[C:25]([C:26]4[NH:27][N:3]=[N:2][N:1]=4)[CH:24]=3)=[CH:18][CH:17]=2)[CH:12]=[CH:13][C:8]=1[C:5](=[O:7])[CH3:6]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1c(SCc2ccc([C@H](O)c3cccc(C#N)c3)cc2)ccc(C(C)=O)c1O
Agent: [Br-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCc1c(SCc2ccc([C@H](O)c3cccc(-c4nnn[nH]4)c3)cc2)ccc(C(C)=O)c1O
Temperature: 140 °C
Reaction time: 18 h
Yield: 31.2 %

Procedure:
Add sodium azide (66 mg, 0.25 mmol) and zinc bromide (131 mg, 0.50 mmol) to a solution of (S)-3-{[4-(4-Acetyl-3-hydroxy-2-propyl-phenylsulfanylmethyl)-phenyl]-hydroxy-methyl}-benzonitrile (110 mg, 0.25 mmol) in N-methylpyrrolidinone (2.0 ml). Heat the mixture at 140° C. for 12 hours, then cool to room temperature and stir for 18 hours. Pour the mixture into water (25 ml) and stir the solid suspension for 20 minutes. Filter and wash the filtered solid with water. Dissolve the solid in a 1N HCl (25 ml) and ethyl acetate (20 ml) mixture. Extract the aqueous layer with ethyl acetate (25 ml), combine the organic extracts, then wash with water, brine, dry over sodium sulfate and concentrate. Purify the crude product via reverse phase HPLC using a gradient of 90:10 to 20:80 (water/0.1% TFA):acetonitrile as eluent to give the title compound (37 mg, 31%). MS (m/z) 473 (M−H). 1H NMR (400 MHz, DMSO-d6) 12.83 (s, 1H), 8.13-8.11 (m, 1H), 7.89-7.86 (m, 1H), 7.72 (d, 1H), 7.59-7.51 (m, 2H), 7.41-7.37 (m, 4H), 6.96 (d, 1H), 5.60 (s, 1H), 4.30 (s, 2H), 2.65-2.60 (m, 5H), 1.45 (sextet, 2H), 0.90 (t, 3H).
Reaction SMILES: [C:1]12([C:12]3[C:11]([OH:13])=[CH:10][CH:9]=[CH:8][C:7]=3[O:6][CH2:5][CH2:4]1)[CH2:3][CH2:2]2.CN(C=O)C.Cl[C:20]1[N:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][N:21]=1>>[C:1]12([C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[O:13][C:20]3[N:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][N:21]=3)[O:6][CH2:5][CH2:4]1)[CH2:3][CH2:2]2
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Reactant: Oc1cccc2c1C1(CCO2)CC1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc(Oc2cccc3c2C2(CCO3)CC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
To a solution of 2,3-dihydrospiro[chromene-4,1′-cyclopropan]-5-ol (Intermediate 221, 63 mg, 0.358 mmol) in DMF (3 ml) K2CO3 (74.1 mg, 0.536 mmol) and 2-chloro-5-nitropyrimidine (86.0 mg, 0.536 mmol) were added and the reaction mixture was stirred at rt for 1 h. DMF was then evaporated under high vacuum, water was added and the reaction mixture was extracted with AcOEt (three times). Collected organic layers were dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (Biotage system) on silica gel using cyclohexane to cyclohexane/ethyl acetate 9:1 as eluents affording the title compound (91 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].[S-:12][C:13]#[N:14].[Na+].BrBr.[Br-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CO.C(Cl)Cl.O>[S:12]([C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([C:8]([F:9])([F:10])[F:11])[CH:4]=1)[C:13]#[N:14]
Reactant: Nc1ccccc1C(F)(F)F
Reactant: N#C[S-]
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: N#CSc1ccc(N)c(C(F)(F)F)c1
Reaction time: 0.33 h
Yield: 96 %

Procedure:
To a cold (0°-5° C.) stirred solution of 2-aminobenzotrifluoride (6.44 g., 0.04 mole) and sodium thiocyanate (9.72 g., 0.12 mole) in methanol (100 ml) is added dropwise a solution of bromine (6.6 g., 0.42 mole) in methanol (25 ml) saturated with sodium bromide. The solution is stirred for 20 minutes following the addition of bromine and then poured into water (750 ml) and neutralized with sodium carbonate. The resulting oil is taken up in methylene chloride and dried. Removal of the drying agent and solvent gives 4-thiocyano-2-trifluoromethylaniline as an oil that solidifies on standing (8.4 g., 96 percent yield). A purified sample has a melting point of 52°-55° C. and the following analysis:
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:23])[N:15]([CH3:24])[N:14]=2)=[CH:8][C:7]=1[CH3:25])(O)=[O:2].C(N(CC)CC)C.ClC(OC(C)=C)=O.[Si]([O:47][NH2:48])(C(C)(C)C)(C)C>ClCCl>[OH:47][NH:48][C:1]([CH2:4][O:5][C:6]1[C:7]([CH3:25])=[CH:8][C:9]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:23])[N:15]([CH3:24])[N:14]=2)=[CH:10][C:11]=1[CH3:12])=[O:2]
Reactant: Cc1cc(-c2nn(C)c(=O)c3ccccc23)cc(C)c1OCC(=O)O
Reactant: CC(C)(C)[Si](C)(C)ON
Agent: C=C(C)OC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(-c2nn(C)c(=O)c3ccccc23)cc(C)c1OCC(=O)NO
Reaction time: 1 h
Yield: 8.3 %

Procedure:
A solution of example 108 (1.15 g) in dichloromethane (30 ml) at 0° C. was treated with triethylamine (0.52 g) followed by isopropenyl chloroformate (0.41 g), and the mixture was stirred for 1 h. O-tert-butyldimethylsilylhydroxylamine (0.50 g) was then added and the mixture was stirred for a further 18 h. The reaction mixture was washed with 10% citric acid (20 ml), saturated sodium bicarbonate (20 ml) and the concentrated to dryness in vacuo. A solution of the residual solid in tetrahydrofuran (30 ml) and water (5 ml) was then treated with a 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (1 ml) and stirred 1 h. the resultant crude mixture was concentrated on to silica and purified by chromatography, eluting with 5% methanol in dichloromethane, to provide the title compound as a white solid (0.10 g).
Reaction SMILES: Cl.[Br:2][C:3]1[C:4]([C:9]2([CH2:21][NH2:22])[CH2:14][CH2:13][N:12]([S:15]([CH2:18][CH2:19][CH3:20])(=[O:17])=[O:16])[CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C(N(CC)C(C)C)(C)C.[Cl:32][C:33]1[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Br:2][C:3]1[C:4]([C:9]2([CH2:21][NH:22][C:35](=[O:36])[C:34]3[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:33]=3[Cl:32])[CH2:14][CH2:13][N:12]([S:15]([CH2:18][CH2:19][CH3:20])(=[O:16])=[O:17])[CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: CCCS(=O)(=O)N1CCC(CN)(c2ncccc2Br)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCS(=O)(=O)N1CCC(CNC(=O)c2ccc(Cl)cc2Cl)(c2ncccc2Br)CC1

Procedure:
{[4-(3-Bromopyridin-2-yl)-1-(propylsulfonyl)piperidin-4-yl]methyl}amine hydrochloride salt (100 mg, 0.24 mmol) was dissolved in dichloromethane (5 mL) with N,N-diisopropylethylamine (0.13 mL, 0.72 mmol). 2,4-dichlorobenzoyl chloride (34 μL, 0.24 mmol) was added and the mixture stirred over night. The mixture was poured into aqueous sodium carbonate (10 mL, 2 M) and extracted with dichloromethane (10 mL x 2). The combined organic phases were dried over magnesium sulphate (anhydrous), filtered and evaporated. The reside was purified by flash column chromatography on silica gel using dichloromethane containing 10% ethyl acetate as eluent to afford the desired product: N-{[4-(3-bromopyridin-2-yl)-1-(propylsulfonyl)piperidin-4-yl]methyl}-2,4-dichlorobenzamide: 1H NMR δ (ppm)(CDCl3): 8.50 (1 H, dd, J=1.4, 4.5 Hz), 7.94 (1 H, dd, J=1.4, 7.9 Hz), 7.58 (1 H, d, J=8.3 Hz), 7.36(1 H, d, J=1.9 Hz), 7.29 (1 H, dd, J=8.3, 1.9 Hz), 7.10 (1 H, dd, J=4.5, 7.9 Hz), 6.87 (1 H, m), 5.30 (1 H, s), 4.15 (2 H, d, J=6.2 Hz), 3.46-3.44 (4 H, m), 3.14-3.08 (2 H, m), 2.90-2.88 (2 H, m), 1.90-1.76 (4 H, m), 1.06 (3 H, t, J=7.4 Hz); m/z (ES) 548, 550 (M+H).
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][OH:5])[CH3:2].[H-].[Na+].[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:24](=[O:25])[C:23](OS(C3C=CC(C)=CC=3)(=O)=O)=[C:22]([C:37]3[CH:42]=[CH:41][C:40]([S:43]([CH3:46])(=[O:45])=[O:44])=[CH:39][CH:38]=3)[CH:21]=[N:20]2)=[CH:15][CH:14]=1>C1COCC1>[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:24](=[O:25])[C:23]([O:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:6][CH2:7][CH2:8][CH3:9])=[C:22]([C:37]3[CH:42]=[CH:41][C:40]([S:43]([CH3:46])(=[O:44])=[O:45])=[CH:39][CH:38]=3)[CH:21]=[N:20]2)=[CH:15][CH:14]=1
Reactant: CCCCC(CC)CO
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)cc3)c2=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCC(CC)COc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.3 %

Procedure:
To a solution of 2-ethyl-1-hexanol (65 mg, 0.5 mmol) in THF (15 mL) at room temperature was added NaH (60% oil suspension) (20 mg, 0.5 mmol) and after 10 minutes 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (193 mg, 0.5 mmol) was added. The resulting mixture was stirred at room temperature for the next 2 hours. The mixture was quenched with 10% citric acid and extracted with ethyl acetate. The extract was washed with water, brine, dried with MgSO4, and purified by chromatography (silica gel, 2:1 hexanes-ethyl acetate) to provide the desired product (yield: 140 mg, 60%). mp 120-122° C. 1H NMR (300 MHz, DMSO-d6) δ 0.75 (m, 6H), 1.1 (m, 6H), 1.20 (quintet, J=7 Hz, 2H), 1.44 (m, 1H), 3.27 (s, 3H), 4.30 (d, J=6 Hz, 2H), 7.37 (t, J=9 Hz, 2H), 7.65 (m, 2H), 7.89 (d, J=9 Hz, 2H), 8.06 (d, J=9 Hz, 2H), 8.18 (s, 1H). MS (APCI+) m/z 473 (M+H)+; (APCI−) m/z 507 (M+Cl)−. Anal. calc. for C25H29FN2O4S.0.5H2O: C, 62.35; H, 6.27; N, 5.87. Found: C, 62.22; H, 6.14; N, 6.22.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:14][C@@H:13]([O:25][Si](C(C)(C)C)(C)C)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][C@H:13]([OH:25])[CH2:14][C@@H:15]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:20])[CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN(C(=O)OCc2ccccc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](O)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Yield: 16.7 %

Procedure:
To a solution of 8.7 g (18 mmol) (3R,5R)-3,5-bis-(tert-butyl-dimethyl-silanyloxy)-piperidine-1-carboxylic acid benzyl ester in 200 ml THF were added 18 ml (18 mmol) of a 1M solution of tetrabutyl ammoniumfluoride in THF at 0° C. After completed addition, the mixture was allowed to warm to room temperature over night. Addition of water was followed by extraction with three portions of tert-butyl methyl ether. The combined organic extracts were dried over sodium sulfate. Flash chromatography gave 1.1 g (16%) of the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[C:5](=[O:15])[NH:4][CH2:3]1.[H-].[Na+].[CH:18]1([CH2:21]Br)[CH2:20][CH2:19]1.O>CN(C=O)C>[CH:18]1([CH2:21][N:4]2[CH:3]=[C:2]([CH3:1])[C:11]3[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=3)[C:5]2=[O:15])[CH2:20][CH2:19]1
Reactant: CC1CNC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cn(CC2CC2)c(=O)c2cc([N+](=O)[O-])ccc12
Reaction time: 1 h
Yield: 19.5 %

Procedure:
To 4-methyl-7-nitro-3,4-dihydro-2H-isoquinolin-1-one (0.90 g) in DMF (30 ml), sodium hydride (0.212 g, 60% suspension in oil) was added in portions. The mixture was stirred for 1 h then treated with cyclopropylmethyl bromide (0.72 g). The mixture was stirred for 4 h, poured into water and extracted with ethyl acetate. The organic phase was washed with water, dried (Na2SO4) and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, DCM) to give the sub-title compound (0.22 g) as a yellow solid. 1H NMR δ: 0.43-0.54 (4H, m), 1.26 (1H, m), 2.30 (3H, s), 3.84 (2H, d, J 7.2 Hz), 7.70 (1H, s), 7.91 (1H, d, J=9.0 Hz), 8.50 (1H, dd, J=2.5, 8.9 Hz), 8.98 (1H, d, J=2.5 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:44])[CH2:7][CH:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH2:26][CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1[O:38][CH2:39][CH2:40][N:41]([CH3:43])[CH3:42])(=[O:18])=[O:17])[C:9](N(OC)C)=[O:10])([CH3:4])([CH3:3])[CH3:2].C1COCC1.CCOCC.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CO.C(Cl)Cl.C(Cl)Cl.C(#N)C>[C:1]([O:5][C:6](=[O:44])[CH2:7][CH:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH2:26][CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1[O:38][CH2:39][CH2:40][N:41]([CH3:43])[CH3:42])(=[O:18])=[O:17])[CH:9]=[O:10])([CH3:2])([CH3:4])[CH3:3]
Reactant: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccccc1OCCc1c(OCCN(C)C)ccc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCOCC
Product: CN(C)CCOc1ccc2ccccc2c1CCOc1ccccc1S(=O)(=O)NC(C=O)CC(=O)OC(C)(C)C
Temperature: -65 °C
Reaction time: 1.25 h
Yield: 95.6 %

Procedure:
3-(2-{2-[2-(2-Dimethylamino-ethoxy)-naphthalen-1-yl]-ethoxy}-benzenesulfonylamino)-N-methoxy-N-methyl-succinamic acid tert-butyl ester (230 mg, 0.366 mmol) was dissloved in a mixture of freshly distilled THF (0.85 mL) and ether (1.35 mL). The mix was chilled to −65° C. in a dry-ice/chlorofrom bath. LiAlH4 solution (1.23 mL of 1.0 M solution in ether, 1.23 mmol) was added via syringe. The reaction became heterogeneous. Acetonitrile (0.2 mL) and CH2Cl2 (0.2 mL) were added to aid dissolution. The reaction was stirred at −65° C. for 1.25 hours. TLC analysis (5% MeOH/CH2Cl2, silca) indicated the reaction was complete. The reaction was carefully quenched with saturated aqueous KHSO4 (2 mL) and was allowed to warm to room temperature. The reaction was diluted with saturated aqueous NaHCO3 and was extracted three times with EtOAc. The organic extracts were combined, dried over Na2SO4, decanted, and concentrated to give 3-(2-{2-[2-(2-dimethylamino-ethoxy)-naphthalen-1-yl]-ethoxy}-benzenesulfonylamino)-4-oxo-butyric acid tert-butyl ester (202 mg, 0.35 mmol) in 97% yield. MS (APCI) m/z 571.1 (M+1).
Reaction SMILES: CS(Cl)(=O)=O.[Cl:6][C:7]1[C:15]2[N:14]=[C:13]([NH:16][C:17]3[C:18]([O:26][CH3:27])=[N:19][C:20]([CH3:25])=[N:21][C:22]=3[O:23][CH3:24])[N:12]([CH2:28][CH2:29][CH2:30]O)[C:11]=2[C:10]([C:32]([O:34][CH3:35])=[O:33])=[CH:9][CH:8]=1.S([O-])(=O)(=O)C.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.CN(C)C=O.O.C(N(CC)CC)C>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:32]([O:34][CH3:35])=[O:33])=[C:11]2[C:15]=1[N:14]=[C:13]1[N:16]([C:17]3[C:22]([O:23][CH3:24])=[N:21][C:20]([CH3:25])=[N:19][C:18]=3[O:26][CH3:27])[CH2:30][CH2:29][CH2:28][N:12]21
Reactant: COC(=O)c1ccc(Cl)c2nc(Nc3c(OC)nc(C)nc3OC)n(CCCO)c12
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(OC)nc(C)nc1OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
Methanesulfonyl chloride (0.11 mL, 1.43 mmol) was added to a stirred solution of methyl 4-chloro-2-[(4,6-dimethoxy-2-methylpyrimidin-5-yl)amino]1-(3-hydroxypropyl)-1H-benzimidazole-7-carboxylate (Reference example 124, 208 mg, 0.477 mmol) and triethylamine (0.27 mL) in tetrahydrofuran (4.0 mL) at 0° C. The mixture was stirred at 0° C. for 2 hr, and concentrated in vacuo. A mixture of the resulting mesylate and potassium carbonate (264 mg, 1.91 mmol) in N,N-dimethylformamide (5.0 mL) was stirred at 80° C. for 2 hr. The mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was washed with diisopropyl ether to give the title compound as a colorless powder (160 mg, 0.383 mmol, 80% in 2 steps).
Reaction SMILES: [CH:1]1([C:4]2[CH:12]=[C:11]3[C:7]([CH:8]=[N:9][N:10]3COCC[Si](C)(C)C)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.C(N)CN>ClCCl>[CH:1]1([C:4]2[CH:12]=[C:11]3[C:7]([CH:8]=[N:9][NH:10]3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1ncc2ccc(C3CC3)cc21
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc2cn[nH]c2cc1C1CC1
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 91.1 %

Procedure:
In a round-bottomed flask, 6-cyclopropyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole (668 mg, 2.2 mmol) was dissolved in dichloromethane (12 ml) and trifluoroacetic acid (6.5 ml, 84.4 mmol) was added. The yellow reaction mixture was stirred at room temperature for 2.25 h then concentrated. The residue was redissolved in dichloromethane (12 ml) and ethylenediamine (9.0 ml, 133 mmol) was added. The solution was stirred at room temperature for 1 h then quenched with water and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/Hexanes (gradient 0-25% EtOAc) to provide 317 mg (91%) of 6-cyclopropyl-1H-indazole as a light yellow solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.99-8.08 (m, 1H), 7.59-7.70 (m, 1H), 7.16-7.25 (m, 1H), 6.88-7.01 (m, 1H), 1.94-2.14 (m, 1H), 0.96-1.11 (m, 2H), 0.71-0.84 (m, 2H).
Reaction SMILES: [H-].[Na+].[C:3]([C:6]1[C:7]2[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=2[S:9][C:10]=1[NH:11][S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])(=[O:5])[CH3:4].[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][C:23]=1[C:30]([F:33])([F:32])[F:31].C1OCCOCCOCCOCCOC1>CN(C=O)C.O>[C:3]([C:6]1[C:7]2[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=2[S:9][C:10]=1[N:11]([CH2:26][C:25]1[CH:28]=[CH:29][C:22]([F:21])=[C:23]([C:30]([F:33])([F:31])[F:32])[CH:24]=1)[S:12]([CH2:15][CH3:16])(=[O:13])=[O:14])(=[O:5])[CH3:4]
Reactant: CCS(=O)(=O)Nc1sc2ccccc2c1C(C)=O
Reactant: Fc1ccc(CBr)cc1C(F)(F)F
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCS(=O)(=O)N(Cc1ccc(F)c(C(F)(F)F)c1)c1sc2ccccc2c1C(C)=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (60% in oil, 46 mg, 1.15 mmol) was added to a solution of N-(3-acetyl-benzo[b]thiophen-2-yl)-ethanesulfonamide (310 mg, 1.09 mmol) in DMF (4 mL), at 0° C. The resulting mixture was stirred at 0° C. for 15 min, to which was added 4-fluoro-3-trifluoromethylbenzyl bromide (253 μL, 1.33 mmol) and the resulting mixture stirred at ambient temperature for 2 h. 15-Crown-5 ether (220 μL, 1.33 mmol) and an additional equivalent of 4-fluoro-3-trifluoromethylbenzyl bromide was then added. The resulting solution was stirred at ambient temperature overnight, water was then added, and the desired product extracted into ethyl acetate. The organic phase was washed with water (3×), brine, dried over sodium sulfate, filtered, and the solvent evaporated in vacuo to yield a residue. The residue was purified by flash column chromatography (SiO2), eluting with an ethyl acetate-heptane gradient to yield N-(3-acetyl-benzo[b]thiophen-2-yl)-N-(4-fluoro-3-trifluoromethyl-benzyl)-ethanesulfonamide as an off-white solid. 1H-NMR (DMSO-d6): δ 1.32 (t, 3H), 2.29 (s, 3H), 3.49 (q, 2H), 5.08 (s, 2H), 7.41-7.52 9m, 3H), 7.70-7.77 (m, 2H), 7.93-8.03 (m, 2H); MS: m/z 460.2 (MH+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].[C-:12]#[N:13].[Na+]>CO>[C:12]([CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])#[N:13]
Reactant: O=C(O)c1cccc(CBr)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CO
Product: N#CCc1cccc(C(=O)O)c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of 3-bromomethylbenzoic acid (2.29 g, 10 mmol) in methanol (30 mL) is added sodium cyanide (0.49 g, 10 mmol) and the mixture is stirred at 70° C. for 2 hrs. The solvent is removed under reduced pressure and water is added to the residue. The mixture is extracted with ether and the organic phase is dried over sodium sulfate. The solvent is removed under reduced pressure and the residue purified by column chromatography using CH2Cl2 as eluent to give 3-cyanomethylbenzoic acid.