Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([S:9][C:10](=[NH:12])[NH2:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=O)[CH:21]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)Br)=[CH:16][CH:15]=1.C([O-])(O)=O.[Na+]>CCO>[CH2:2]([S:9][C:10]1[NH:11][C:20]([C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)=[C:21]([C:23]2[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:28]=2)[N:12]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)c1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Reactant: N=C(N)SCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(-c2nc(SCc3ccccc3)[nH]c2-c2ccc(F)cc2)cc1
Yield: 17.5 %

Procedure:
A mixture of S-benzylisothiourea hydrochloride (300 mg, 1.5 mmol), 1-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)-2-bromoethan-1-one (Example 1, Method B, step 1) (500 mg, 1.3 mmol) and NaHCO3 (500 mg, 6 mmol) in EtOH (10 ml) was heated to reflux for 3 hours. After evaporation of the solvent, the residue was treated with water (25 ml) and extracted with methylene chloride (25 ml). After drying (MgSO4), the organic phase was evaporated. The residue was purified by chromatography on silica gel, eluting with ethyl acetate/toluene (25/75). The crude material was recrystallized from toluene and hexane to give 100 mg (17%) of titled product: m.p. 155-156° C. Anal. Calc'd. for C23H19FN2O2S2: C, 62.99; H, 4.37; N, 6.39; S, 14.62. Found: C, 62.93; H, 4.41; N, 5.98; S, 14.33.
Reaction SMILES: [OH-].[Na+].[C:3]([CH2:6][N:7]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14][N:13]([CH2:19][C:20]([OH:22])=[O:21])[CH2:12][CH2:11][N:10]([CH2:23][C:24]([OH:26])=[O:25])[CH2:9][CH2:8]1)([OH:5])=[O:4].O1[CH2:29][CH:28]1[CH2:30][CH2:31][C:32]([OH:34])=[O:33].CC(O)C>O.C(O)CCC>[O:33]=[C:32]1[O:34][CH:28]([CH2:29][N:16]2[CH2:15][CH2:14][N:13]([CH2:19][C:20]([OH:22])=[O:21])[CH2:12][CH2:11][N:10]([CH2:23][C:24]([OH:26])=[O:25])[CH2:9][CH2:8][N:7]([CH2:6][C:3]([OH:5])=[O:4])[CH2:18][CH2:17]2)[CH2:30][CH2:31]1
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Reactant: O=C(O)CCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Solvent: O
Solvent: CC(C)O
Product: O=C(O)CN1CCN(CC(=O)O)CCN(CC2CCC(=O)O2)CCN(CC(=O)O)CC1

Procedure:
8.3 g (207.6 mmol) of sodium hydroxide is added to 12.0 g (34.6 mmol) of 1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (D03A) in 50 ml of water. A solution that consists of 5.02 g (43.25 mmol) of 3-oxiranylpropionic acid (Dakoji et al., J. Am. Chem. Soc., 1996, 10971-10979) in 50 ml of n-butanol/50 ml of 2-propanol is added in drops thereto, and the solution is heated for 24 hours to 80° C. The reaction solution is evaporated to the dry state in a vacuum, the residue is mixed with 300 ml of water, and a pH of 3 is set with 3N hydrochloric acid. Then, it is extracted three times with 200 ml each of n-butanol, the combined butanol phases are evaporated to the dry state in a vacuum, and the residue is purified by chromatography (RP-18; mobile solvent: gradient that consists of water/acetonitrile).
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]2[CH:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH2:12][CH2:13][N:6]2[C:5](=[O:21])[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl.CCOC(C)=O>[O:21]=[C:5]1[CH2:4][CH2:3][C@H:2]([NH:1][S:32]([CH3:31])(=[O:34])=[O:33])[C:8](=[O:9])[N:7]2[C@H:10]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:11][CH2:12][CH2:13][N:6]12
Reactant: CC(C)(C)OC(=O)C1CCCN2C(=O)CCC(N)C(=O)N12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@@H]1CCCN2C(=O)CC[C@H](NS(C)(=O)=O)C(=O)N12
Reaction time: 1 h
Yield: 76.9 %

Procedure:
A solution of t-butyl 9-amino-6,10-dioxo-1,2,3,4,7,8,9,10-octahydro-6H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate (GB 2,128,984; 831 mg, 2.79 mmol) and diisopropylethylamine (1.22 ml, 6.99 mmol, 2.5 equiv) in CH2Cl2 (10 ml) under dry nitrogen was treated with methanesulphonyl chloride (237 μl, 3.07 mmol 1.1 equiv). The mixture was stirred for 1 h, diluted with EtOAc (75 ml) and washed with saturated NaHCO3 (50 ml) and saturated aqueous sodium chloride (30 ml), dried (MgSO4) and concentrated. Flash chromatography (10-35% EtOAc in CH2Cl2) afforded 211b (806 mg, 77%) as a colourless solid: mp 68-70° C.; [α]D23 −109 (c 1.09, CH2Cl2); IR (KBr) 3270, 2980, 2939, 1735, 1677, 1458, 1447, 1418, 1396, 1370, 1328, 1272, 1252, 1232, 1222, 1156, 1131, 991; 1H NMR (CDCl3) δ 6.15 (1H, d), 5.31 (1H, m), 4.65-4.11 (2H, m), 3.47 (1H, m) 2.99 (3H, s), 2.89 (1H, m), 2.72-2.51 (2H, m), 2.34 (1H, m), 2.26 (1H, m), 2.05-1.62 (4H, m), 1.47 (9H, s);
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][O:9][C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])[CH2:4][CH2:3]1.CC1(C)N([O])C(C)(C)CCC1.OOS([O-])=O.[K+]>C(Cl)Cl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][O:9][C:10]([N:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)=[O:11])[CH2:4][CH2:3]1
Reactant: O=C(OCC1CCC(O)CC1)N1CCCC1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S([O-])OO
Solvent: ClCCl
Solvent: O
Product: O=C1CCC(COC(=O)N2CCCC2)CC1
Reaction time: 14 h

Procedure:
To a solution of pyrrolidine-1-carboxylic acid 4-hydroxycyclohexylmethyl ester (2 mmol) in methylene chloride (10 mL) were added TEMPO (0.2 mmol), tetrabutylammonium bromide (0.8 mmol), and oxone (4.4 mmol) and the resulting mixture was stirred for 14 hours. The reaction mixture was diluted with water, followed by few times of extraction with methylene chloride. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane:ethyl acetate=1:2) to provide pyrrolidine-1-carboxylic acid 4-oxo-cyclohexylmethyl ester. To a solution of pyrrolidine-1-carboxylic acid 4-oxo-cyclohexylmethyl ester in 1,2-dichloroethane (10 mL) were added benzyl amine (2 mmol) and sodium triacetoxyborohydride (2 mmol) and the resulting mixture was stirred for 14 hours. The reaction mixture was diluted with water, followed by few times of extraction with methylene chloride. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, ethyl acetate), thereby completing the preparation of a target compound (399 mg, 63% yield). To a solution of the obtained compound in methylene chloride was added a saturated HCl solution in ether to provide a hydrochloride salt.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[C:22]([CH3:23])=[N:21][CH:20]=[CH:19][N:18]=1)=[O:16].[F:24][C:25]([F:38])([F:37])[O:26][C:27]1[CH:32]=[CH:31][C:30](OB(O)O)=[CH:29][CH:28]=1.C(OCC)(=O)C>O.C1(C)C=CC=CC=1>[F:24][C:25]([F:37])([F:38])[O:26][C:27]1[CH:32]=[CH:31][C:30]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15]([C:17]2[C:22]([CH3:23])=[N:21][CH:20]=[CH:19][N:18]=2)=[O:16])=[CH:29][CH:28]=1
Reactant: OB(O)Oc1ccc(OC(F)(F)F)cc1
Reactant: Cc1nccnc1C(=O)Nc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1nccnc1C(=O)Nc1ccccc1-c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Yield: 67 %

Procedure:
A solution of sodium carbonate (0.31 g: 1.5 mmole) in 5 mL of water was added to a solution of N-(2-bromophenyl)-3-methylpyrazine-2-carboxamide (0.4 g: 1.4 mmole) and 4-trifluoromethoxyphenyl boric acid (0.31 g: 1.5 mmole) in 10 mL of toluene, followed by addition of tetrakis(triphenyl-Phosphine)palladium (0) (0.1 g: 0.09 mmole). After heating under reflux condition for 6 hours under argon atmosphere, the reaction mixture was cooled to room temperature, and admixed with ethyl acetate and water, followed by separation. The organic layer was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the subject compound (0.35 g).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][C:11]([O:16][CH3:17])([O:14][CH3:15])[CH:10]([OH:18])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:21]I>CN(C)C=O>[C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][C:11]([O:14][CH3:15])([O:16][CH3:17])[CH:10]([O:18][CH3:21])[CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC1(OC)CCN(Cc2ccccc2)CC1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1CN(Cc2ccccc2)CCC1(OC)OC
Temperature: 60 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
1-Phenylmethyl-3-hydroxy-4,4-dimethoxypiperidine (3b, 5.5g, 22 mmol) from Example 1 in 30ml of dimethylformamide was added slowly to a stirred suspension of sodium hydride (0.81g, 27 mmol, 80% oil suspension) in 100ml of dimethylformamide. The reaction mixture was warmed to 60° C. for 2 hours, then cooled to 0° C. whereupon methyl iodide (3.8g, 27 mmol) was slowly added to the mixture. The reaction mixture was stirred overnight at room temperature then quenched with 10ml of 10% sodium hydroxide solution. The reaction mixture was concentrated under vacuum, the residue slurried in 300ml of water and the aqueous mixture extracted with 3×100ml of ether. The combined organic layers were dried over magnesium sulfate, concentrated under vacuum, then purified by column chromatography (alumina; ethyl acetate/hexane; 2.5:1) to yield the intermediate 1-phenylmethyl-3-methoxy-4,4-dimethoxypiperidine (4b, 3.77g, 64.6%, Rf 0.63).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([N+:14]([O-:16])=[O:15])=[C:12]([CH3:17])[NH:11][C:10]([CH3:18])=[C:9]2[C:19](O)=[O:20])[CH:5]=[CH:6][CH:7]=1.[CH2:22]([NH2:31])[CH:23]=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[I-].ClC1C=CC=C[N+]=1C.C(N(CC)CC)C>CN(C=O)C>[C:25]1([CH:24]=[CH:23][CH2:22][NH:31][C:19]([C:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:13]([N+:14]([O-:16])=[O:15])=[C:12]([CH3:17])[NH:11][C:10]=2[CH3:18])=[O:20])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCC=Cc1ccccc1
Reactant: CC1=C(C(=O)O)C(c2cccc(Cl)c2)C([N+](=O)[O-])=C(C)N1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1=C(C(=O)NCC=Cc2ccccc2)C(c2cccc(Cl)c2)C([N+](=O)[O-])=C(C)N1

Procedure:
93 mg (0.30 mmol) of 4-(3-chlorophenyl)-2,6-dimethyl-5-nitro-1,4-dihydropyridine-3-carboxylic acid, 100 mg (0.75 mmol) of cinnamylamine, 138 mg (0.54 mmol) of 2-chloro-1-methylpyridinium iodide and 0.15 ml (1.08 mmol) of triethylamine were stirred in 5 ml of DMF at room temperature for 2 days. DMF was evaporated under reduced pressure. Ethyl acetate was added to the reaction mixture. After washing with 1 N hydrochloric acid, the organic layer was dried over anhydrous sodium sulfate. After the concentration under reduced pressure, the residue was purified by the silica gel chromatography (hexane/ethyl cetate=4/1) to obtain the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[C:19]([N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=2)[NH2:32])[CH2:24][CH2:23]1)(=[O:21])[CH3:20].C(N(CC)C(C)C)(C)C>CS(C)=O>[C:19]([N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:30]=[C:31]([NH:32][C:2]3[N:7]=[C:6]([N:8]4[CH:12]=[CH:11][N:10]=[C:9]4[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH:5]=[CH:4][N:3]=3)[CH:33]=[CH:34][CH:35]=2)[CH2:24][CH2:23]1)(=[O:21])[CH3:20]
Reactant: Clc1nccc(-n2ccnc2-c2ccccc2)n1
Reactant: CC(=O)N1CCN(Cc2cccc(N)c2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(=O)N1CCN(Cc2cccc(Nc3nccc(-n4ccnc4-c4ccccc4)n3)c2)CC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
2-Chloro-4-(2-phenyl-1H-imidazol-1-yl)pyrimidine (56 mg, 0.22 mmol) and 3-[(4-acetylpiperazin-1-yl)methyl]aniline (142 mg, 0.61 mmol) were mixed and heated neat to 100° C. After 2 hours the reaction was heated to 120° C. for 1 hour then to 140° C. for 1 hour. N,N-di-iso-propylethylamine (0.076 ml, 0.44 mol) was added and the reaction was heated for an additional 1.5 hours. The reaction was cooled, diluted with DMSO and directly purified by reverse phase HPLC (5-100% CH3CN/H2O+0.1% TFA) to afford the title compound. 1H NMR (300 MHz, CDCl3) δ 8.29 (d, J=5.2 Hz, 1H), 7.67 (d, J=1.5 Hz, 1H), 7.52 (m, 3H), 7.41 (m, 4H), 7.25 (m, 2H), 7.02 (d, J=7.8 Hz, 1H), 6.30 (d, J=5.1 Hz, 1H), 3.63 (t, J=5.5 Hz, 2H), 3.52 (s, 2H), 3.47 (m, 2H), 2.45 (m, 4H), 2.08 (s, 3H).
Reaction SMILES: [Mg].C(Br)Br.Cl[CH:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1.[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[C:23](=[O:24])[C:22]3[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=3[CH2:20][O:19][C:18]=2[CH:29]=1>C1COCC1>[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[C:23]([CH:6]3[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]3)([OH:24])[C:22]3[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=3[CH2:20][O:19][C:18]=2[CH:29]=1
Reactant: O=C1c2ccccc2COc2cc(Br)ccc21
Reactant: CN1CCC(Cl)CC1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCBr
Product: CN1CCC(C2(O)c3ccccc3COc3cc(Br)ccc32)CC1

Procedure:
Magnesium turnings (3.42 g, 143 mmol) were suspended in 15 mL of dry THF under nitrogen. To this was added CH2Br2 (1.25 mL, 14.5 mmol) and a vigorous reaction was observed. The reaction was heated to reflux, and 4-chloro-1-methyl-piperidine (21 mL, 128 mmol) was added. The reaction was refluxed for 1 h. The reaction was allowed to cool, and the supernatant was transferred via cannula to a stirring solution of compound 2c (8 g, 128 mmol) in THF at room temperature. The slurry was rinsed with 2×20 mL THF and the supernatant was transferred. At that time, all of the starting ketone had been consumed. To the reaction was added saturated sodium bicarbonate, and the mixture was extracted with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered, and concentrated. The crude product Compound 1d was used without further purification. MS m/z (MH+) 388.14.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23](=[O:24])[C:22]4[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=4[O:20][C:19]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH2:36]C1C=CC2C(=O)C(Br)=C(C3C=CC=CC=3)OC=2C=1>>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23](=[O:24])[C:22]4[CH:25]=[CH:26][C:27]([NH2:36])=[CH:28][C:21]=4[O:20][C:19]=3[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:14][CH:13]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Nc1ccc2c(=O)c(Br)c(-c3ccccc3)oc2c1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccccc4c3=O)cc2)CCC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4cc(N)ccc4c3=O)cc2)CCC1
Yield: 19 %

Procedure:
Following the procedure used for {1-[4-(4-oxo-2-phenyl-4H-1-benzopyran-3-yl)phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 7-amino-3-bromo-2-phenyl-1-benzopyran-4-one (28.4 mg, 0.09 mmol) was reacted to give the title compound as a yellow solid (6.3 mg, 19%). 1H-NMR (400 MHz, CDCl3) δ 8.05 (d, 1H), 7.64 (d, 2H), 7.50 (d, 2H), 7.45 (d, 2H), 7.35 (dd, 1H), 7.31 (dd, 2H), 6.82 (d, 1H), 6.74 (s, 1H), 5.28 (bs, 1H), 4.11 (bs, 2H), 2.62-2.65 (m, 4H), 2.15-2.19 (m, 1H), 1.90-1.97 (m, 1H) 1.33 (bs, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH2:12])=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH2:12]
Reactant: NC(=O)Cc1ccc(F)cc1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCc1ccc(F)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 16.2 %

Procedure:
2-(2-chloro-4-fluorophenyl)acetamide (400 mg, 2.13 mmol) was diluted with THF (2 mL), placed under nitrogen and cooled to 0° C. LAH (4264 μL, 4.26 mmol) was added dropwise and the reaction was refluxed for 3 hours. The reaction was cooled to 0° C. and quenched with 160 μL of water, 160 μL, of 15% NaOH, and 530 μL of water. After stirring for 30 minutes the reaction was filtered and concentrated. The material was purified using a biotage 25 column eluting with 2% NH4OH/10% methanol/DCM to yield 2-(2-chloro-4-fluorophenyl)ethanamine (60 mg, 0.346 mmol, 16.2% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][CH2:9][CH2:10][NH2:11])=[CH:5][CH:4]=1.[OH:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O.O.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[C:15]([OH:14])[CH:16]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1cccc(O)c1
Reactant: COc1ccc(OCCCN)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(OCCCNCc2cccc(O)c2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
3-(4-Methoxyphenoxy)propylamine (10.0 g) was dissolved in methanol (50 mL) at room temperature, a solution of 3-hydroxybenzaldehyde (6.7 g) in methanol (50 mL) was added dropwise within 5 minutes at water temperature (about 20° C.), and then the resulting mixture was stirred at room temperature for 20 hours. Then, sodium borohydride (2.1 g)/water (100 mL) was added dropwise at water temperature (about 20° C.) for 5 minutes, and the mixture was stirred at room temperature for 12 hours. Precipitates were removed, washed with water and then dried under reduced pressure at 80° C. for 5 hours. Pale yellow crystals were obtained (13.9 g, 87.4%).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]([OH:16])=O)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[C:19]([NH:26][C:27]([S:29][CH3:30])=[NH:28])([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]([N:28]=[C:27]([S:29][CH3:30])[NH:26][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[O:16])[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: CSC(=N)NC(=O)OC(C)(C)C
Reactant: O=C(O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
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: ClCCl
Product: CSC(=NC(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
9-Bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylic acid (3.2 g, 10.4 mmol), methyl N-Boc-carbamimidothioate (4.7 g, 12.4 mmol), HATU (5.0 g, 26.0 mmol) and DIPEA (6.7 g, 52.1 mmol) were dissolved in DCM (200 mL). After the resulting mixture was stirred at room temperature for 2 h, the reaction mixture was concentrated and methanol (50 mL) was added and filtered. The solid was collected to give methyl N′-9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carbonyl-N-Boc-carbamimidothioate (3.0 g, 60%). 1H NMR (DMSO, 400 MHz) δ 12.84 (s, 1H), 8.31 (s, 1H), 8.18 (s, 1H), 7.32-7.27 (m, 2H), 5.72 (s, 1H), 4.49 (s, 4H), 2.30 (s, 3H), 1.49 (s, 9H)
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:31]([NH2:34])[CH2:32][CH3:33]>>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([NH:34][CH2:31][CH2:32][CH3:33])=[O:16])[CH2:6][CH2:5]2
Reactant: CCCN
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Agent: O=C(n1ccnc1)n1ccnc1
Product: CCCNC(=O)C1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Yield: 63.3 %

Procedure:
Following the amide coupling procedure described in protocol A, 502.3 mg 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.01 mmol), 358 mg CDI (2.21 mmol) and 130 mg propylamine (2.20 mmol) produced 371 mg of 6-hydroxy-2,5,7,8-tetramethyl-N-propylchroman-2-carboxamide as an off white syrup.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:23][S:24]([N:27]1[CH2:32][CH2:31][C:30]2[N:33]([CH2:46][CH2:47][CH2:48][OH:49])[N:34]=[C:35]([C:36]3[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=3)[C:29]=2[CH2:28]1)(=[O:26])=[O:25].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl.CCOCC.C([O-])(O)=O.[Na+]>[CH3:23][S:24]([N:27]1[CH2:32][CH2:31][C:30]2[N:33]([CH2:46][CH2:47][CH:48]=[O:49])[N:34]=[C:35]([C:36]3[CH:37]=[CH:38][C:39]([C:42]([F:43])([F:44])[F:45])=[CH:40][CH:41]=3)[C:29]=2[CH2:28]1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCO)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: CCOCC
Product: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCC=O)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.2 %

Procedure:
Dess-Martin periodinane (3.45 g, 8.2 mmol) was added to a solution of 3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-1-ol (3.0 g, 7.4 mmol) in CH2Cl2 (20 mL) at 0° C. under N2. After 15 min, the reaction was allowed to warm to room temperature and stirred for another 1.5 h. The reaction was diluted with Et2O (60 mL) and 20% aq. NaHCO3 (35 mL) was added slowly (caution! rapid gas evolution). Then Na2S2O3 was added and stirred at room temperature for 30 min. The layers were separated and the aqueous portion was extracted with Et2O (2×30 mL). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. MPLC (silica, 1-10% MeOH/CH2Cl2) afforded 2.53 g of the desired aldehyde in 85% yield. MS (electrospray): exact mass calculated for C17H18F3N3O3S, 401.11; m/z found, 402.1 [M+H]. 1H NMR (400 MHz, CDCl3): 9.82 (s, 1H), 7.63 (d, J=8.4 Hz, 2H), 7.58 (d, J=8.4 Hz, 2H), 4.68 (s, 2H), 4.25 (t, J=6.1 Hz, 2H), 3.63 (t, J=5.8 Hz, 4H), 3.14 (t, J=6.1 Hz, 2H), 2.92 (t, J=5.8 Hz, 2H), 2.81 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C=O)C>[Br:1][C:2]1[C:3]([CH:4]=[O:5])=[CH:6][CH:7]=[CH:8][C:9]=1[O:10][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)CBr
Reactant: O=Cc1cccc(O)c1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(C=O)c1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-bromo-3-hydroxybenzaldehyde (1 eq.) in DMF (0.4 M) was added cesium carbonate (1.2 eq.) and ethyl bromoacetate (1 eq.). The resulting suspension was stirred at RT for 16 h. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic extracts were washed with water and brine. Drying over MgSO4, filtration and concentration of the filtrate in vacuo afforded the crude product as a red oil. Purification by way of column chromatography (SiO2, 5:1 (v/v) Hex:EtOAc→1:1 (v/v) Hex:EtOAc) afforded the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][NH:21]3)=[CH:16][CH:15]=2)=[O:13])=[CH:7][CH:6]=1)[CH3:2].[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([O:36][CH3:37])=[C:30]([S:32](Cl)(=[O:34])=[O:33])[CH:31]=1>ClCCl.N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][N:21]3[S:32]([C:30]3[CH:31]=[C:26]([Cl:25])[CH:27]=[CH:28][C:29]=3[O:36][CH3:37])(=[O:33])=[O:34])=[CH:16][CH:15]=2)=[O:13])=[CH:9][CH:10]=1)[CH3:2]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)NCCC3)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CCC3)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of 4-[(1,2,3,4-tetrahydro-quinoline-7-carbonyl)-amino]-benzoic acid ethyl ester (140 mg, 0.43 mmol) in dichloromethane (5 ml) and pyridine (0.15 ml) was treated with 5-chloro-2-methoxy-benzenesulfonyl chloride (159 mg, 0.66 mmol, 1.5 equiv.) and stirred at room temperature for 17 hours. The solvent was then evaporated and the residue purified by flash chromatography (dichloromethane/ether 9:1) to yield 4-{[1-(5-chloro-2-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid ethyl ester as a white foam, 227 mg (100%). MS (ISP): m/e=527.2 (M−H); δH (300 MHz; d6-DMSO) 10.5 (1H, s), 8.02 (1H, d), 7.96 (2H, d), 7.93 (2H, d), 7.85 (1H, d), 7.72 (1H, dd), 7.67 (1H, dd), 7.30 (1H, d), 7.23 (1H, d), 4.30 (2H, q), 3.78 (2H, m), 2.75 (2H, t), 1.74 (2H, m), 1.32 (3H, t).