Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:20][CH2:19][O:18]/[C:17](=[N:21]\C(=O)C4C=CC=CC=4)/[NH:16]3)[C:14]3[CH:13]=[C:12]([Cl:30])[N:11]=[C:10]([F:31])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.N.CO>C1COCC1>[Cl:30][C:12]1[N:11]=[C:10]([F:31])[C:9]2[O:8][C:5]3[C:4]([C@@:15]4([CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]4)[C:14]=2[CH:13]=1)=[CH:3][C:2]([NH2:1])=[CH:7][CH:6]=3
Reactant: Nc1ccc2c(c1)[C@@]1(CCO/C(=N\C(=O)c3ccccc3)N1)c1cc(Cl)nc(F)c1O2
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: NC1=N[C@@]2(CCO1)c1cc(N)ccc1Oc1c2cc(Cl)nc1F
Temperature: 50 °C
Yield: 17 %

Procedure:
(S,Z)—N-(7-amino-3-chloro-1-fluorospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazinan]-2′-ylidene)benzamide was dissolved in THF (5 mL) followed by the addition of ammonia, 2.0 m solution in methanol (49.7 ml, 99 mmol) and heated in a sealed tube at 50° C. for 17 h. The mixture was concentrated and chromatographed on silica gel using 0-5% MeOH/DCM to afford a yellow oil as (S)-3-chloro-1-fluoro-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazine]-2′,7-diamine (0.23 g, 0.687 mmol, 17% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[O:12][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: CC(=O)Nc1ccc(Cl)c(O)c1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(=O)Nc1ccc(Cl)c(OCCN2CCOCC2)c1
Yield: 69 %

Procedure:
The compound 23a was prepared by using the general procedure H, as given in Example 9, in 69% yield starting from 17a, with 2.5 eq of cesium carbonate and 1.1 eq of 4-(2-chloroethyl) morpholine hydrochloride.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([CH:25]=O)[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:27]=[C:28]([C:31]([F:34])([F:33])[F:32])[CH:29]=[CH:30][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.[BH3-]C#N.[Na+]>CCO.C([O-])(O)=O.[Na+]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([CH2:25][N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:27]=[C:28]([C:31]([F:33])([F:34])[F:32])[CH:29]=[CH:30][C:16]=3[CH2:15]2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(C=O)cc32)cc1
Reactant: C1COCCN1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(CN4CCOCC4)cc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-[(4-tert-butylphenyl)sulfonyl]-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine-8-carbaldehyde (Step A, Example 453, 10 mg, 0.020 mmol) in EtOH (2 mL) at rt was added morpholine (10 uL, 0.12 mmol) and NaCNBH3 (100 mg). After stirring at rt overnight, the reaction was diluted with sat. NaHCO3, and product was extracted with EtOAc (3×). The combined extracts were washed with brine, dried with MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography (0-100% EtOAc/hexanes) to give the title compound. 1H NMR (500 MHz, (CD3)2CO): δ, 8.31 (s, 1H), 7.71 (d, 1H), 7.46 (s, 1H), 7.27 (s, 2H), 7.20 (d, 2H), 7.12 (d, 1H), 6.97 (d, 2H), 4.82 (br s, 2H), 3.66 (t, 4H), 3.51 (s, 2H), 2.46 (br, 4H), 1.24 (s, 9H). LCMS: m/e 561.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:22][CH3:23])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH2:20][CH3:21])[CH:11]=3)=[CH:4][CH:3]=1.Cl[CH2:25][C:26]([N:28]=[C:29]=[O:30])=[O:27].C1CCN2C(=NCCC2)CC1>O1CCOCC1>[O:30]=[C:29]1[NH:28][C:26](=[O:27])[CH2:25][N:1]1[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH2:22][CH3:23])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH2:20][CH3:21])[CH:11]=3)=[CH:6][CH:7]=1
Reactant: O=C=NC(=O)CCl
Reactant: CCOc1ccc2c(C#N)c(-c3ccc(N)cc3)n(CC)c2c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: CCOc1ccc2c(C#N)c(-c3ccc(N4CC(=O)NC4=O)cc3)n(CC)c2c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
A solution of 2-(4-aminophenyl)-6-ethoxy-1-ethyl-1H-indole-3-carbonitrile (319 mg, 1.04 mmol) in 1,4-dioxane (3 mL) is treated with chloroacetyl isocyanate (0.10 mL, 1.17 mmol), and the resulting solution is warmed to 60° C. overnight. The solution is cooled, and DBU (0.20 mL, 1.31 mmol) is added. This mixture is stirred at ambient temperature overnight, and then is partitioned between water and ethyl acetate (50 mL each). The organic layer is washed with saturated brine, and then dried over anhydrous magnesium sulfate, filtered and evaporated. The residual material is triturated with ether, and the resulting solid is collected by filtration and dried under high vacuum to afford the title product (319 mg, 0.821 mmol, 79%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])/[CH:5]=[C:6](/[O:8][C:9]1[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=1)\[CH3:7])[CH3:2].[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:16])/[CH:5]=[C:6](/[O:8][C:9]1[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=1)\[CH2:7][Br:17])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)/C=C(\C)Oc1cccc(C)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)/C=C(\CBr)Oc1cccc(C)c1
Yield: 43.8 %

Procedure:
To a stirred mixture of (E)-3-m-tolyloxy-but-2-enoic acid ethyl ester (6.41 g, 0.029 mol) in carbon tetrachloride (30 mL) under a nitrogen atmosphere was added N-bromosuccinimide (7.78 g, 0.044 mol) and benzoyl peroxide (704 mg, 0.003 mol). Nitrogen gas was bubbled through the mixture for 5 min, and the resulting mixture was heated to reflux for 4 h. The reaction mixture was then placed in the refrigerator overnight. The solids formed were removed by filtration and the filtrate concentrated in vacuo. The crude product obtained was purified using flash column chromatography (silica gel (100-200 mesh), ethyl acetate/hexanes) to afford (E)-4-bromo-3-m-tolyloxy-but-2-enoic acid ethyl ester (3.80 g, 44%) as a yellow oil.
Reaction SMILES: [C:1]([C:11]1[CH:19]=[CH:18][C:14]2[S:15][CH:16]=[CH:17][C:13]=2[CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C([Li])CCC.CN(C)[CH:27]=[O:28]>CCOCC>[C:1]([C:11]1[CH:19]=[CH:18][C:14]2[S:15][C:16]([CH:27]=[O:28])=[CH:17][C:13]=2[CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCC#Cc1ccc2sccc2c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCCCCCCC#Cc1ccc2sc(C=O)cc2c1
Temperature: 25 °C
Yield: 52.1 %

Procedure:
To a solution of 5-(1-decynyl)benzo[b]thiophene (20.0 g) in dry ether (150 ml), under nitrogen, was added n-butyllithium (2.5M in hexanes) (32.6 ml) dropwise, with stirring at room temperature. The solution was stirred at room temperature, under nitrogen, for 2.5 hrs and then cooled to -60° C. A solution of dry dimethylformamide (5.95 g) in dry ether (15 ml) was added dropwise, and the reaction mixture was allow to warm to room temperature. The reaction mixture was quenched with ammonium chloride solution and the layers separated. The aqueous phase was extracted with ether, the organic extracts combined, dried over anhydrous sodium sulfate, filtered, and the titrate was evaporated. The residue was flash chromatographed (silica: 3-4%, ethyl acetate:heptane). The appropriate fractions were collected and evaporated. The residue was recrystallized from I heptane to give 11.5 g (52.0%) of product, mp 45°-47° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:17]([C:18]3[N:26]=[C:25]([CH3:27])[N:24]=[C:23]4[C:19]=3[N:20]=[CH:21][N:22]4[CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][O:29]3)=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][N:11]=2)=[CH:5][CH:4]=1.[C:34]([Mg]Cl)([CH3:37])([CH3:36])[CH3:35].Cl>C1COCC1.CO>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[CH:12][C:13]([CH:14]([OH:15])[C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:16][C:17]=2[C:18]2[N:26]=[C:25]([CH3:27])[N:24]=[C:23]3[C:19]=2[N:20]=[CH:21][N:22]3[CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)[Mg]Cl
Reactant: COc1ccc(Nc2ncc(C=O)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Nc2ncc(C(O)C(C)(C)C)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.8 %

Procedure:
6-(6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)nicotinaldehyde (95.0 mg, 0.213 mmol) was dissolved in THF (2.5 mL) and the flask was cooled in an ice water bath. Then, tert-butylmagnesium chloride (1.0 M solution in tetrahydrofuran, 0.60 mL, 0.60 mmol) was added via syringe, turning the reaction red. The reaction was stirred under nitrogen while being warmed to room temperature, and after 70 min the reaction was treated with MeOH (1.0 mL) and 5 N HCl (0.50 mL). The flask was fitted with a reflux condenser and put in a preheated oil bath (about 50° C.), and stirring was continued for 1 h. Then, the reaction was cooled to room temperature, diluted with MeOH, concentrated, and purified by prep HPLC (10% to 100% MeCN/water with 0.1% TFA over 28 min using a total flow rate of 100 mL/min) to give 1-(6-(6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)-2,2-dimethylpropan-1-ol (45.9 mg, 97.4% purity, 52% yield). 1H NMR (d6-DMSO, 400 MHz) δ 12.62 (br s, 1H), 9.61 (s, 1H), 8.63 (s, 1H), 8.53 (d, J=2.74 Hz, 1H), 8.21-8.14 (m, 2H), 6.88 (d, J=9.0 Hz, 1H), 4.31 (s, 1H), 3.86 (s, 3H), 2.85 (s, 3H), 0.91 (s, 9H). m/z (ESI, pos. ion) 420 (M+H)+.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1.[BH4-].[Na+].O>C(O)C>[F:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=1
Reactant: O=Cc1ccc(OCCF)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OCc1ccc(OCCF)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
The crude 4-(2-fluoroethoxy)benzaldehyde (35.6 g) was dissolved in 140 ml of ethanol, and 11.0 g of sodium borohydride was carefully added to the solution at 47° to 50° C. After adding sodium borohydride, the reaction was carried out at 50° C. for 2 hours. After the reaction, the reaction mixture was cooled to room temperature and water was added. The mixture was extracted with toluene. The toluene layer was washed with water and dried over anhydrous sodium sulfate. Toluene was evaporated under reduced pressure to give 32.4 g of 4-(2-fluoroethoxy)benzyl alcohol as crystals (m.p. 37.3°-38.0° C.).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:32]O.Cl>CO.O>[O:3]=[C:4]1[CH:5]=[C:6]([C@H:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[CH2:9]2)[O:7][NH:32]1
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](Cc2ccc(C(F)(F)F)cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(C(F)(F)F)cc1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 93.4 %

Procedure:
Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-(trifluoromethyl)benzyl)piperidine-1-carboxylate (14.9 g, 35.87 mmol) was dissolved in MeOH (120 mL) and cooled to −40° C. Sodium hydroxide (1.495 g, 37.38 mmol) dissolved in water (14.4 mL) was added over 2 min and the resulting solution stirred at −40° C. for 20 min. Then hydroxylamine (50% by weight in water, 2.2 mL, 35.90 mmol) was added over 1 min and stirring continued between −40° C. and −45° C. for 80 min. The reaction mixture was then poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (400 mL, 2400.00 mmol) and the mixture was continued to be stirred at 80° C. for 1 h. Then cooled to room temperature. Methanol was evaporated, then water was added. Extracted three times with DCM. Combined organic layers dried over Na2SO4 and evaporated. Crude cis-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(4-(trifluoromethyl)benzyl)piperidine-1-carboxylate (12.88 g, 94%) was isolated. MS m/z 385 (M+H)+
Reaction SMILES: [CH3:1][C:2]1([CH2:9][CH2:10][OH:11])[CH2:5][CH2:4][CH:3]1[C:6]([CH3:8])=[CH2:7].CC1(CC=[O:22])CCC1C(C)=C.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>>[CH3:1][C:2]1([CH2:9][C:10]([OH:22])=[O:11])[CH2:5][CH2:4][CH:3]1[C:6]([CH3:8])=[CH2:7]
Reactant: C=C(C)C1CCC1(C)CCO
Reactant: C=C(C)C1CCC1(C)CC=O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Product: C=C(C)C1CCC1(C)CC(=O)O

Procedure:
A four gram sample of racemic 1-methyl-2-(1-methylethenyl)-cyclobutaneethanol (grandisol I) [2] (Bedoukian, Inc.) was oxidized to the corresponding racemic aldehyde, 1-methyl-2-(1-methylethenyl)-cyclobutaneacetaldehyde (grandisal) using pyridinium chlorochromate (Webster) (3.4 g, % yield 86.1). The racemic aldehyde was distilled under vacuum and a 3 gram sample was subsequently oxidized to racemic 1 using AgNO3 and NaOH (Pickett): nearly colorless oil (1.23 g, % yield 32.2); eims m/z (rel. int. %) 168 (1), 125 (12), 109 (14), 108 (35), 93 (9), 91 (3), 81 (6), 79 (11), 77 (10), 69 (11), 68 (100), 67 (86), 55 (11), 53 (30), 43 (35), 41 (41); H NMR (CDCl3) δ 2.61 (1H, m, H-2), 1.83 (1H, m, H-3a), 1.95 (1H, m, H-3b), 1.71 (1H, m, H-4a), 1.95 (1H, m, H-4b), 1.31 (3H, s, Me-5), 2.03 (1H, dd, J=14.6,H-6a), 2.54 (1H, d, J=14.6, H-6b), 4.85 (1H, m, H-9a), 4.65 (1H, m, H-9b), 1.64 (3H, s, Me-10); 13C NMR (CDCl3) δ 41.1 (C-1), 51.9 (C-2), 18.7 (C-3), 29.0 (C-4), 27.9 (C-5), 38.5 (C-6), 179.7 (C-7), 144.1 (C-8), 110.3 (C-9), 22.8 (C-10).
Reaction SMILES: [OH:1][CH:2]([C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[N:27]([CH3:31])[CH:26]=[C:25]2[CH2:32][CH2:33][CH2:34][O:35][CH3:36])[CH:3]([CH:19]([CH3:21])[CH3:20])[CH2:4][CH:5]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].N1C=CC=CC=1.[CH3:43][O:44][CH2:45][C:46](Cl)=[O:47].Cl>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:43][O:44][CH2:45][C:46]([O:1][CH:2]([C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[N:27]([CH3:31])[CH:26]=[C:25]2[CH2:32][CH2:33][CH2:34][O:35][CH3:36])[CH:3]([CH:19]([CH3:21])[CH3:20])[CH2:4][CH:5]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[N:6]1[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[O:47]
Reactant: COCCCc1cn(C)c2ccc(C(O)C(CC3COC(C)(C)N3C(=O)OC(C)(C)C)C(C)C)cc12
Reactant: COCC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COCCCc1cn(C)c2ccc(C(OC(=O)COC)C(CC3COC(C)(C)N3C(=O)OC(C)(C)C)C(C)C)cc12
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
A solution of 2.48 g of tert-butyl 4-(2-{hydroxy-[3-(3-methoxypropyl)-1-methyl-1H-indol-5-yl]methyl}-3-methylbutyl)-2,2-dimethyloxazolidine-3-carboxylate (diastereomer mixture) in 70 ml of toluene is admixed at 0° C. successively with 1.04 ml of pyridine, 1.11 ml of methoxyacetyl chloride and 0.62 g of 4-dimethylaminopyridine. The reaction mixture is stirred at 0° C. over 3.5 hours. The resulting mixture is poured onto 0.1N HCl (cold) and extracted with tert-butyl methyl ether (2×). The combined organic phases are washed successively with water, 1M sodium hydrogencarbonate solution and brine, dried over sodium sulphate and filtered, and the filtrate is concentrated by evaporation. The title compound (diastereomer mixture) is obtained as a white foam from the residue by means of flash chromatography (SiO2 60F). Rf=0.32 (1:1 EtOAc-heptane). Rt=26.14 (gradient II).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[C:28]([F:34])[C:27]=1[O:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1.[Cl:46][C:47]1[N:48]=[C:49]([CH2:55][CH3:56])[NH:50][C:51]=1[C:52](O)=[O:53].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:46][C:47]1[N:48]=[C:49]([CH2:55][CH3:56])[NH:50][C:51]=1[C:52]([NH:33][CH2:32][C:29]1[CH:30]=[CH:31][C:26]([Cl:25])=[C:27]([O:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:39]=[CH:38][CH:37]=2)[C:28]=1[F:34])=[O:53]
Reactant: NCc1ccc(Cl)c(Oc2cccc3ccccc23)c1F
Reactant: CCc1nc(Cl)c(C(=O)O)[nH]1
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: CN(C)C=O
Product: CCc1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cccc4ccccc34)c2F)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.5 %

Procedure:
HATU (0.113 g, 0.298 mmol) was added to a solution of {[4-chloro-2-fluoro-3-(1-naphthalenyloxy)phenyl]methyl}amine (0.060 g, 0.199 mmol) and 4-chloro-2-ethyl-1H-imidazole-5-carboxylic acid (0.035 g, 0.199 mmol) and diisopropylethylamine (0.052 mL, 0.298 mmol) in DMF (1 mL). The mixture was stirred at room temperature for 1 hr. The reaction mixture was extracted with ethyl acetate and water. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by reverse phase HPLC (acetonitrile:water with 0.1% TFA) to give the title compound (0.026 g, 26%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.28-8.39 (m, 1H), 8.09-8.22 (m, 1H), 7.98 (dd, 1H), 7.57-7.69 (m, 3H), 7.51 (dd, 1H), 7.27-7.40 (m, 2H), 6.52 (d, 1H), 4.52 (d, 2H), 2.59 (q, 2H), 1.16 (t, 3H). ES MS: m/z 458 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([NH2:12])[C:6]=2[CH:5]=[C:4]([CH2:13][CH3:14])[N:3]=1.[F:15][C:16]([F:28])([F:27])[C:17]1[CH:26]=[CH:25][C:20]([CH2:21][N:22]=[C:23]=[O:24])=[CH:19][CH:18]=1>>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([NH:12][C:23]([NH:22][CH2:21][C:20]3[CH:19]=[CH:18][C:17]([C:16]([F:15])([F:28])[F:27])=[CH:26][CH:25]=3)=[O:24])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH2:13][CH3:14])[N:3]=1
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Reactant: CCc1cc2c(N)cccc2c(Cl)n1
Product: CCc1cc2c(NC(=O)NCc3ccc(C(F)(F)F)cc3)cccc2c(Cl)n1

Procedure:
Prepared from 1-chloro-3-ethylisoquinolin-5-amine (Description 66) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to the procedure of Description 61. m/z (ES+) 408, 410 (M+H)+.
Reaction SMILES: [CH:1]1([N:4]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1>CN(C=O)C>[CH:1]1([N:4]([CH:14]2[CH2:19][CH2:18][N:17]([CH2:28][C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=3)[CH2:16][CH2:15]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: O=S(=O)(c1ccccc1)N(C1CCNCC1)C1CC1
Reactant: BrCc1ccc2ccccc2c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccccc1)N(C1CC1)C1CCN(Cc2ccc3ccccc3c2)CC1
Temperature: 80 °C
Reaction time: 12 h
Yield: 15.2 %

Procedure:
N-Cyclopropyl-N-piperidin-4-yl-benzenesulfonamide (56 mg, 0.2 mmol) was dissolved in DMF (2.5 ml) and triethylamine (75 μL, 54 mg, 0.54 mmol) added, followed by 2-bromomethyl-naphthalene (88 mg, 0.4 mmol). The reaction mixture was stirred for 12 hours at 80° C. and then the solvent was evaporated. The residue was purified by flash chromatography to give 12.8 mg of the desired product N-cyclopropyl-N-[1-(naphth-2-ylmethyl)-piperidin-4-yl]benzenesulfonamide (15). 1H NMR (CDCl3): δ 8.06-7.71 (m, 7H), 7.61-7.44 (m, 5H), 3.94-3.84 (m, 1H), 3.68 (S, 2H), 3.01-2.94 (m, 2H), 2.18-1.94 (m, 5H), 1.58-1.49 (m, 2H), 1.02-0.96 (m, 2H), 0.81-0.74 (m, 2H). MS (EI): m/z 421 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][CH2:7][CH2:8][N:9]([C:10]3[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][C:11]=3[O:18][CH3:19])[C:4]=2[CH:3]=1.[Cl:22][S:23](O)(=[O:25])=[O:24]>C(Cl)Cl>[C:14]([C:13]1[CH:16]=[CH:17][C:10]([N:9]2[CH2:8][CH2:7][O:6][C:5]3[CH:20]=[C:21]([S:23]([Cl:22])(=[O:25])=[O:24])[C:2]([F:1])=[CH:3][C:4]2=3)=[C:11]([O:18][CH3:19])[CH:12]=1)#[N:15]
Reactant: O=S(=O)(O)Cl
Reactant: COc1cc(C#N)ccc1N1CCOc2ccc(F)cc21
Solvent: ClCCl
Product: COc1cc(C#N)ccc1N1CCOc2cc(S(=O)(=O)Cl)c(F)cc21
Temperature: -78 °C

Procedure:
To a vial charged with 4-(6-fluoro-2H-benzo[b][1,4]oxazin-4(3 H)-yl)-3-methoxybenzonitrile (0.234 g, 0.823 mmol) was added DCM (3.29 ml). The resulting solution was cooled to −78° C. and chlorosulfonic acid (0.137 ml, 2.058 mmol) was added faster than dropwise. After 30 min the mixture was warmed to 0° C. and the mixture was allowed to stir and warm to rt over 3 hr. LC-MS indicated conversion to the desired product mass (M+23). The reaction mixture was added to ice carefully and EtOAc was used to wash reaction vial. The resulting mixture was extracted with EtOAc (2×). The layers were separated and the cloudy aqueous phase was diluted with brine and extracted once more with EtOAc. The combined organics were dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified with a 40 g silicycle HP column ramping EtOAc in heptane (0-50%) providing product 4-(4-cyano-2-methoxyphenyl)-6-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride (0.093 g, 0.243 mmol, 29.5% yield) as a light yellow solid. m/z (ESI) 405.2 (M+Na)+.
Reaction SMILES: Br[C:2]1[C:3]([O:21][CH3:22])=[C:4]([C:16]([O:19][CH3:20])=[CH:17][CH:18]=1)[C:5]([NH:7][CH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[CH2:14][CH3:15])=[O:6].Cl.[OH-:24].[K+]>CS(C)=O.O>[CH2:14]([N:10]1[CH2:11][CH2:12][CH2:13][C@H:9]1[CH2:8][NH:7][C:5](=[O:6])[C:4]1[C:3]([O:21][CH3:22])=[C:2]([OH:24])[CH:18]=[CH:17][C:16]=1[O:19][CH3:20])[CH3:15]
Reactant: [OH-]
Reactant: CCN1CCC[C@H]1CNC(=O)c1c(OC)ccc(Br)c1OC
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCN1CCC[C@H]1CNC(=O)c1c(OC)ccc(O)c1OC

Procedure:
(S)-(-)-3-Bromo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2,6-dimethoxybenzamide ×HCl×H2O (1.0 g, 0.0026 mol) was dissolved in 25 ml dimethylsulphoxide. A suspension of crushed potassium hydroxide (1.0 g, 0.018 mol) in 5 ml water was added and the mixture was heated at reflux for 2 h. After cooling 200 ml of water was added and the reaction mixture was neutralized and extracted with chloroform. Drying and evaporation of the solvent gave a residue containing a mixture of several products including the starting material. Separation on silica column with CH2Cl2 -C2H5OH-NH3 (90:9:1) gave 0.05 g of the title compound as a oil.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1)=[O:2].[CH2:12]=[O:13].C(N(CC)CC)C>CC(C)=O>[CH:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][OH:13])[CH:4]=1)=[O:2]
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: C=O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=Cc1cn(CO)c2ccccc12
Temperature: 120 °C
Reaction time: 3 h
Yield: 43.9 %

Procedure:
The mixture of 5.81 g of 3-formyl-1H-indole, 1.80 g of paraformaldehyde and 0.40 g of triethylamine was stirred at 120 ° C. for 3 hours. After the reaction mixture was cooled to room temperature, acetone was added to the reaction mixture. The mixture was filtered, and then the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 3.08 g of 3-formyl-1H-indole-1-ylmethanol.