Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:21])=[C:5]([O:11][C:12]2[CH:13]=[C:14]([CH:17]=[C:18]([Cl:20])[CH:19]=2)[C:15]#[N:16])[C:6]([CH2:9][CH3:10])=[CH:7][CH:8]=1.[Cl:22][C:23]1[N:24]=[C:25]([CH3:31])[NH:26][C:27]=1[C:28](O)=[O:29].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C([O-])(O)=O.[Na+]>CN(C=O)C.C(OCC)(=O)C>[Cl:22][C:23]1[N:24]=[C:25]([CH3:31])[NH:26][C:27]=1[C:28]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH3:10])=[C:5]([O:11][C:12]2[CH:13]=[C:14]([C:15]#[N:16])[CH:17]=[C:18]([Cl:20])[CH:19]=2)[C:4]=1[F:21])=[O:29]
Reactant: Cc1nc(Cl)c(C(=O)O)[nH]1
Reactant: CCc1ccc(CN)c(F)c1Oc1cc(Cl)cc(C#N)c1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1ccc(CNC(=O)c2[nH]c(C)nc2Cl)c(F)c1Oc1cc(Cl)cc(C#N)c1
Yield: 47.3 %

Procedure:
A solution of 3-{[3-(aminomethyl)-6-ethyl-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.075 g, 0.246 mmol), 4-chloro-2-methyl-1H-imidazole-5-carboxylic acid (0.040 g, 0.246 mmol), EDC (0.047 g, 0.246 mmol) and HOBT (0.038 g, 0.246 mmol) in DMF (4 ml) was stirred at RT under an atmosphere of nitrogen for 1 h then ethyl acetate (100 mL) and saturated aqueous NaHCO3 solution (100 mL) were added. The organic layer was separated, washed with saturated aqueous NaHCO3 solution (100 mL), water (100 mL), dried over MgSO4, filtered and concentrated. The material was purified by Reverse Phase HPLC (MeCN/water+0.1% TFA). The desired product was washed with saturated NaHCO3 solution and extraced with ethyl acetate. The organic layer was separated, washed with saturated aqueous NaHCO3 solution (50 mL), water (50 mL), dried over MgSO4, filtered and concentrated to give the title compound (0.052 g, 47%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 11.06 (br. s., 1H), 7.29 (s, 1H), 7.20 (d, 1H), 7.03-7.12 (m, 3H), 6.97 (s, 1H), 4.67 (d, 2H), 2.53 (q, 2H), 2.37 (s, 3H), 1.13 (t, 3H). LCMS m/z 447.05 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:18]2[N:19]=[C:20]3[CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22][N:21]3[C:17]=2[C:16]2[C:11](=[CH:12][C:13]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:14][CH:15]=2)[N:10]=1>ClCCl>[CH2:34]([O:33][C:13]1[CH:12]=[C:11]2[C:16]([C:17]3[N:21]4[CH2:22][CH2:23][NH:24][CH2:25][C:20]4=[N:19][C:18]=3[C:9]([NH2:8])=[N:10]2)=[CH:15][CH:14]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)N1CCn2c(nc3c(N)nc4cc(OCc5ccccc5)ccc4c32)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc2cc(OCc3ccccc3)ccc2c2c1nc1n2CCNC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoroacetic acid (10 mL of a 10% solution in dichloromethane) was added to tert-butyl 6-amino-3-benzyloxy-10,11-dihydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinoline-9(8H)-carboxylate (0.550 g, 1.23 mmol), and the reaction was stirred at ambient temperature overnight. The solvent was removed under reduced pressure, and the residue was treated with hydrogen chloride (4 N in 1,4-dioxane). The solvent was removed under reduced pressure, and the residue was dissolved in methanol. Ammonia gas was bubbled through the resulting solution for 15 minutes, and then the solvent was removed under reduced pressure. The residue was dried overnight under vacuum to provide 3-benzyloxy-8,9,10,11-tetrahydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinolin-6-amine in a crude mixture, which was used in the next step without purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=[N:8][CH:9]=1)([O-:3])=[O:2].[OH:27][C:28]1[CH:29]=[C:30]([CH:34]2[CH2:43][CH:42]([OH:44])[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([OH:45])[CH:40]=3)[O:35]2)[CH:31]=[CH:32][CH:33]=1.Cl[C:47]1[CH:52]=[CH:51][C:50]([N+:53]([O-:55])=[O:54])=[CH:49][N:48]=1>>[N+:53]([C:50]1[CH:51]=[CH:52][C:47]([O:45][C:39]2[CH:40]=[C:41]3[C:36](=[CH:37][CH:38]=2)[O:35][CH:34]([C:30]2[CH:31]=[CH:32][CH:33]=[C:28]([O:27][C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=4)[CH:29]=2)[CH2:43][CH:42]3[OH:44])=[N:48][CH:49]=1)([O-:55])=[O:54]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Oc1cccc(C2CC(O)c3cc(O)ccc3O2)c1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: O=[N+]([O-])c1ccc(Oc2cccc(C3CC(O)c4cc(Oc5ccc([N+](=O)[O-])cn5)ccc4O3)c2)nc1

Procedure:
6-(5-Nitropyridin-2-yloxy)-2-[3-(5-nitropyridin-2-yloxy)phenyl]chroman-4-ol was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1 (b) but starting from 2-(3-hydroxyphenyl)chroman-4,6-diol and using 210 mol-% of 2-chloro-5-nitropyridine. 1H NMR (400 MHz, d6-DMSO) δ: 9.06 (d, 1H, J 2.8 Hz), 9.03 (d, 1H, J 2.8 Hz), 8.64 (dd, 1H, J 2.8, 9.1 Hz), 8.61 (dd, 1H, J 2.8, 9.1 Hz), 7.54 (t, 1H, J 7.9 Hz), 7.43 (d, 1H, J 7.9 Hz), 7.36 (s, 1H), 7.30 (d, 1H, J 9.1 Hz), 7.25-7.21 (m, 3H) 7.01 (dd, 1H, J 2.9, 8.7 Hz), 6.89 (d, 1H, J 8.7 Hz), 5.67 (d, 1H, J 6.4 Hz), 5.36 (d, 1H, J 10.8 Hz), 5.01-4.95 (m, 1H), 2.41-2.36 (m, 1H), 2.02-1.92 (m, 1H).
Reaction SMILES: [CH2:1]([C:8]1[C:9](=[O:19])[NH:10][N:11]([CH:16]([CH3:18])[CH3:17])[C:12]=1[CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O:23][CH2:24][C@H:25]1[O:30][C@H:29](Br)[C@H:28]([O:32]C(C)=O)[C@@H:27]([O:36]C(C)=O)[C@@H:26]1[O:40]C(C)=O)=O.[OH-].[Na+]>ClCCl>[CH2:1]([C:8]1[C:9]([O:19][C@@H:29]2[O:30][C@H:25]([CH2:24][OH:23])[C@@H:26]([OH:40])[C@H:27]([OH:36])[C@H:28]2[OH:32])=[N:10][N:11]([CH:16]([CH3:18])[CH3:17])[C:12]=1[CH:13]([CH3:14])[CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(C)c1c(Cc2ccccc2)c(=O)[nH]n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)c1c(Cc2ccccc2)c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)nn1C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
To a suspension of 4-benzyl-1,5-diisopropyl-1,2-dihydro-3H-pyrazole-3-one (0.078 g), acetobromo-α-D-glucose (0.62 g) and benzyl(n-tributyl)ammonium bromide (0.054 g) in dichloromethane (4 mL) was added a sodium hydroxide aqueous solution (5 mol/L, 0.6 mL) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was purified by column chromatography on aminopropylated silica gel (eluent: tetrahydrofuran). The obtained semi purified 4-benzyl-1,5-diisopropyl-3-(2,3,4,6-tetraacetyl-β-D-glucopyranosyloxy)-1H-pyrazole was dissolved in methanol (3 mL), and sodium methoxide (28% methanol solution, 0.58 mL) was added to the solution. The mixture was stirred at room temperature for 2 hours. The solvent of the reaction mixture was removed under reduced pressure, and the residue was acidified by adding 10% citric acid aqueous solution. The mixture was purified by solid phase extraction on ODS (washing solvent: water, eluent: methanol). Further purification by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) gave the title compound (0.11 g).
Reaction SMILES: [CH2:1]([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@@H:9]1[CH2:14][NH:13][C:12](=[O:15])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23]C(C)([O-])C.[K+].CI.[Na+].[Cl-]>O1CCCC1>[CH2:16]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:9]1[CH2:14][N:13]([CH3:23])[C:12](=[O:15])[CH2:11][CH2:10]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)CN1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CN1C[C@@H](N(Cc2ccccc2)Cc2ccccc2)CCC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
0.500 g (S)-5-dibenzylaminopiperidin-2-one are suspended in 15 ml of tetrahydrofuran. While cooling with the ice bath 0.175 g potassium-tert-butoxide are added. The reaction mixture is then stirred for 30 minutes at ambient temperature. While cooling with the ice bath 0.095 ml methyl iodide are added. The reaction mixture is then stirred for 48 hours at ambient temperature and then combined with a saturated NaCl solution. The product is extracted with ethyl acetate. 0.450 g of the product are obtained as an oil. Analytical HPLC-MS (method A): RT=1.07 min.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([CH:11]=[O:12])[CH:9]=2)[O:4][CH:3]=1.[OH:13]P([O-])(O)=O.[K+]>C1COCC1.CC(O)(C)C.O>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=2)[O:4][CH:3]=1
Reactant: O=P([O-])(O)O
Reactant: O=Cc1cc2c(Br)coc2cn1
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: O=C(O)c1cc2c(Br)coc2cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.9 %

Procedure:
3-Bromofuro[2,3-c]pyridine-5-carbaldehyde (3.26 g, 14.42 mmol) is dissolved in THF (100 mL)/t-BuOH (50 mL)/H2O (50 mL), treated with a single portion of NaOCl2 (4.89 g, 43.3 mmol) and KH2PO4 (3.92 g, 28.8 mmol) and stirred at rt for 18 h. The white solid is collected via filtration and the filtrate is concentrated in vacuo to dryness. The residue is suspended in water (25 mL), acidified to pH 2 with concentrated HCl and the resulting solid collected via filtration. The collected solids are dried in a vacuum oven at 50° C. for 18 h and combined to afford 3.52 g (99%) of 3-bromofuro[2,3-c]pyridine-5-carboxylic acid as a white solid. MS (EI) m/z: 241 (M+).
Reaction SMILES: [Li+].CC([N-][CH:6]([CH3:8])[CH3:7])C.[CH:9]([O:12][C:13](=[O:17])C(C)C)([CH3:11])[CH3:10].Br[CH2:19][C:20]#[CH:21].O>C1COCC1>[CH:9]([O:12][C:13](=[O:17])[C:6]([CH3:7])([CH3:8])[CH2:21][C:20]#[CH:19])([CH3:11])[CH3:10]
Reactant: C#CCBr
Reactant: CC(C)OC(=O)C(C)C
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C#CCC(C)(C)C(=O)OC(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of LDA (2M in THF, 5 mL) in THF (5 mL), at −78° C. is added a solution of isobutyric acid isopropyl ester (1.3 g, 10 mmol) in THF (3 mL) dropwise. After the addition is complete, the solution is slowly warmed to 0° C. and stirred there for 1 h. The temperature is reduced to −78° C. and a solution of 3-bromo-propyne (1.2 g, 10 mmol) in THF (3 mL) is added dropwise then the solution is allowed to warm to RT and stirred for 18 h. The mixture is poured into water and extracted with EtOAc. The organic layer is dried, filtered and the solvent is removed under reduced pressure. The residue is purified by flash chromatography using hexane/EtOAc (10:1) as eluent to give the product as a colorless liquid.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@H:7]([C@@H:8]([CH2:42][CH3:43])[C@@H:9]([O:32][C:33](=[O:41])[C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([I:40])[CH:35]=3)[C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:6]1)(=[O:3])[CH3:2].CC(O)(C)C.[Cl:49]C1C(Cl)=C(I)C=CC=1>C(Cl)Cl>[C:1]([O:4][C@@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@H:7]([C@@H:8]([CH2:42][CH3:43])[C@@H:9]([O:32][C:33](=[O:41])[C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([I:40])[CH:35]=3)[C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@:14]2([Cl:49])[C@H:15]([CH3:22])[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: Clc1cccc(I)c1Cl
Reactant: CC[C@H]1[C@@H](OC(=O)c2cccc(I)c2)[C@@H]2[C@H](CC[C@]3(C)[C@@H]([C@H](C)CCC(=O)OC)CC[C@@H]23)[C@@]2(C)CC[C@@H](OC(C)=O)C[C@@H]12
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: CC[C@H]1[C@@H](OC(=O)c2cccc(I)c2)[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC[C@]3(Cl)[C@H](C)CCC(=O)OC)[C@@]2(C)CC[C@@H](OC(C)=O)C[C@@H]12
Yield: 91.3 %

Procedure:
To a solution of 4 (3.5 g, 4.95 mmol) in CH2Cl2 (280 ml) containing 0.3 M tBuOH (8.2 ml), dichloroiodobenzene (3.38 g, 12.4 mmol) was added. The mixture was deoxygenated for 3 min by bubbling dry N2. Then the mixture was photolyzed at 0° C. using a tungsten lamps (200 W) for 1 h. The solvent was then evaporated under reduced pressure and the residue was quickly purified by flash chromatography eluting with petroleum ether/EtOAc (8:2, v/v) to yield 3.35 g (4.52 mmol, 92%) of the 17-chloro derivative 5 as white solid.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[Br:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>C(Cl)Cl>[Br:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([S:23]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:25])=[O:24])=[CH:21][CH:22]=1
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NS(=O)(=O)c1ccc(CBr)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 79.3 %

Procedure:
t-Butyl amine (5.9 mL, 56 mmol, 1.0 eq) and DIPEA (9.7 mL, 56 mmol, 1.0 eq) were added to 350 ml DCM. The solution was cooled to 0° C. and a solution of 4-bromomethylbenzenesulfonyl chloride (15.1 g, 56 mmol, 1.0 eq) in 100 mL DCM was added drop-wise via an addition funnel. The mixture was then slowly warmed to room temperature and stirred for 3 hours. The mixture was concentrated under reduced pressure and the residue was dissolved into 350 mL EtOAc. The organic was washed with 1N aq. HCl, saturated bicarbonate, water, saturated aqueous NaCl, dried over MgSO4, and filtered. The filtrate was concentrated to yield intermediate (2a) (13.6 g).
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[C:5]([NH:12][C@H:13]([C:22]([OH:24])=O)[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]>ClCCl.CN(C)C=O>[C:8]([O:7][C:5](=[O:6])[NH:12][C@H:13]([C:22](=[O:24])[N:3]([CH3:4])[CH3:2])[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=1)([CH3:9])([CH3:10])[CH3:11]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(N)cc1)C(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)C(=O)[C@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C

Procedure:
Dimethylamine hydrochloride (2.04 mmol) and Boc-p-amino-L-phenylalanine (1.7 mmol) were coupled according to Procedure A (0-25° C. reaction temperature, 4:1 dichloro-methane/dimethylformamide reaction solvent, washed with base only). The product was purified by chromatography on silica gel eluted with 50, 60, 70 and 100% ethyl acetate in hexanes. Yield 226 mg, 42%; HPLC (70/30) 2.45 minutes (100%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:3]([NH:5][C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[N:8][CH:7]=1)=[O:4].[S:24]1[CH:28]=[C:27]([CH:29]=O)[N:26]=[CH:25]1.CN(C)C=O.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:18]1([CH2:17][C@H:2]([NH:1][CH2:29][C:27]2[N:26]=[CH:25][S:24][CH:28]=2)[C:3]([NH:5][C:6]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[N:8][CH:7]=2)=[O:4])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)Nc1cnc(-c2ccncc2)s1
Reactant: O=Cc1cscn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Nc1cnc(-c2ccncc2)s1)[C@H](Cc1ccccc1)NCc1cscn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 10.3 %

Procedure:
To a mixture of (S)-2-amino-3-phenyl-N-(2-(pyridin-4-yl)thiazol-5-yl)propanamide (0.075 g, 0.23 mmol), thiazole-4-carbaldehyde (0.026 g, 0.23 mmol) and N,N-dimethylformamide (0.500 ml, 0.23 mmol) in 1,2-dichloroethane (1.000 ml, 0.23 mmol) was added sodium triacetoxyborohydride (0.17 g, 0.81 mmol). The resulting mixture was allowed to stir at room temperature for 4 hours. Upon completion, the mixture was directly subjected to HPLC purification give 10 mg of (S)-3-phenyl-N-(2-(pyridin-4-yl)thiazol-5-yl)-2-(thiazol-4-ylmethylamino)-propanamide 5.3. 400 MHz 1H NMR (CD3OD) δ: 9.30 (d, 1H), 8.81 (d, 2H), 8.07 (d, 2H), 7.95 (d, 1H), 7.76 (s, 1H), 7.28-7.37 (m, 3H), 7.24 (dd, J=8.0, 4.0 Hz, 2H), 4.49 (d, J=16 Hz, 1H), 4.44 (d, J=16 Hz, 1H), 4.43 (dd, J=12, 8.0 Hz, 1H), 3.49 (dd, J=12, 4.0 Hz, 1H), 3.23 (dd, J=12, 8.0 Hz, 1H). LCMS (ES+) m/z 422.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([S:13][C:14]3[CH:15]=[C:16]([C:20]4([C:26]([OH:28])=O)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH:17]=[CH:18][CH:19]=3)=[CH:9][CH:8]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.C(=O)(O)[O-].[NH4+].C(OC1C=CC2C(=CC=CC=2)[N:38]1C(OCC)=O)C>ClCCl>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([S:13][C:14]3[CH:15]=[C:16]([C:20]4([C:26]([NH2:38])=[O:28])[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[CH:17]=[CH:18][CH:19]=3)=[CH:9][CH:8]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: CCOC(=O)N1c2ccccc2C=CC1OCC
Reactant: O=C(O)C1(c2cccc(Sc3ccc(Cn4cccc4)cc3)c2)CCOCC1
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: ClCCl
Product: NC(=O)C1(c2cccc(Sc3ccc(Cn4cccc4)cc3)c2)CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
A suspension of 4-[3-[4-(pyrrol-1-ylmethyl)phenylthio]phenyl]-3,4,5,6-tetrahydro-2H-pyran-4-carboxylic acid (0.36 g, 0.93 mmol), ammonium bicarbonate (0.44 g, 5.58 mmol) and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (0.28 g, 1.12 mmol) in dichloromethane (20 ml) were stirred at room temperature overnight. Ammonium bicarbonate and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added until the acid was consumed. The reaction mixture was diluted with dichloromethane (50 ml) and washed with water (50 ml). The organic extract was washed with cold 1N hydrochloric acid (50 ml), water (50 ml) and saturated aqueous sodium bicarbonate (5 ml), water (50 ml) and brine (50 ml), dried (magnesium sulfate) and concentrated to dryness. Recrystallization of the residue from ethyl acetate afforded the titled compound (198 mg, 54%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]([S:15][CH3:16])SC)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:17]([N:24]1[CH2:33][CH2:32][C:27]2([CH2:31][N:30]=[N:29][CH2:28]2)[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>N1C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]=[C:12]([N:30]2[N:29]=[CH:28][C:27]3([CH2:32][CH2:33][N:24]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:25][CH2:26]3)[CH2:31]2)[S:15][CH3:16])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCC3(CC2)CN=NC3)cc1
Reactant: CSC(=NS(=O)(=O)c1ccc(N)cc1)SC
Solvent: c1ccncc1
Product: CSC(=NS(=O)(=O)c1ccc(N)cc1)N1CC2(C=N1)CCN(Cc1ccccc1)CC2
Temperature: 180 °C

Procedure:
In a 25 mL microwave vial, 1.50 g 4-amino-N-(bis-methylsulfanyl-methylene)benzene-sulfonamide and 1.37 g 8-benzyl-2,3,8-triaza-spiro[4.5]dec-2-ene were suspended in 20 mL pyridine. The vial was capped and heated for 1 hour at 180° C. (6 bar) in the microwave. The reaction mixture was concentrated on silica. Purification with flash column chromatography (DCM→DCM/MeOH 99:1→DCM/MeOH 98:2) yielded 1.03 g (41%) of a beige amorph. 1H NMR (400 MHz, CDCl3) δ 1.57-1.72 (m, 2H), 1.78-1.92 (m, 2H), 2.17-2.32 (m, 5H), 2.66-2.81 (m, 2H), 3.51 (s, 2H), 4.04 (s, 2H), 4.28 (s, 2H), 6.64-6.71 (m, 2H), 6.98 (s, 1H), 7.20-7.37 (m, 5H), 7.72-7.79 (m, 2H).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([Cl:9])[C:5]([Cl:8])=[N:6][CH:7]=1.B(F)(F)[F:11].CCOCC.C(ON=O)(C)(C)C.CCCCCC>ClCCl>[Cl:8][C:5]1[C:4]([Cl:9])=[CH:3][C:2]([F:11])=[CH:7][N:6]=1
Reactant: Nc1cnc(Cl)c(Cl)c1
Reactant: FB(F)F
Agent: CC(C)(C)ON=O
Solvent: CCOCC
Solvent: CCCCCC
Solvent: ClCCl
Product: Fc1cnc(Cl)c(Cl)c1
Temperature: -5 °C
Reaction time: 0.25 h

Procedure:
5-Amino-2,3-dichloropyridine (0.80 g) in dichloromethane (10 ml) was added to boron trifluoride etherate (0.92 ml) at -15° C. under nitrogen. Dichloromethane (15 ml) was added followed by t-butylnitrite (0.71 ml) in dichloromethane (5 ml). After 15 minutes the mixture was allowed to warm to -5° C. over 20 minutes. Hexane was added and the resulting solid was filtered, air-dried and washed with ether and stored at approximately -20° C. overnight. The solid was then heated until gas evolution had ceased and the product kugelrohr distilled to give 2,3-dichloro-5-fluoropyridine (0.104 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][C:16]2[CH:15]=[N:14][CH:13]=[C:12]([C:18]#N)[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:20].[Na+].[CH2:22]([OH:24])C>O>[CH3:22][O:24][C:18]([C:12]1[C:11]2[CH2:10][CH2:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:17][C:16]=2[CH:15]=[N:14][CH:13]=1)=[O:20]
Reactant: N#Cc1cncc2c1CCN(Cc1ccccc1)C2
Reactant: [OH-]
Reactant: CCO
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cncc2c1CCN(Cc1ccccc1)C2
Temperature: 25 °C
Yield: 77 %

Procedure:
In a 1 L copper flask was placed 7-benzyl-5,6,7,8-tetrahydro-[2,7]-naphthyridine-4-carbonitrile (44.8 g, 0.18 mol) in ethanol (200 mL). A solution of sodium hydroxide (36 g, 0.9 mol) in water (200 mL) was added and the resulting mixture was refluxed for 8 hr. The reaction mixture was concentrated under reduced pressure. To the residue was added ethanol (150 mL) and toluene (150 mL) and concentrated under reduced pressure. This process was repeated three times. Finally methanol (150 mL) and toluene (150 mL) were added and concentrated under reduced pressure. The solid residue was further dried under high vacuum line overnight. To the residue was added a solution of 30% sulfuric acid in methanol (w/w, 800 mL) and refluxed for 24 hr. The reaction mixture was cooled to room temperature and filtered to remove white solid (inorganic salt). The solid on filter paper was washed with methanol (100 mL) and the filtrate was concentrated under reduced pressure. To the residue was added ice (300 g) and basified with ammonium hydroxide (175 mL. 28-38% ammonia). The mixture was extracted with dichloromethane (2×250 mL). The combined organic layers were washed with brine (150 mL), filtered through 1 PS filter paper and concentrated to give a brown oil. The oil was purified by flash chromatography on silica gel (500 g) with anhydrous sodium sulfate (50 g) on top packed with hexane. The column was eluted with 200 mL portions of 25% ethyl acetate in hexane followed by 50% ethyl acetate in hexane. The eluent containing product was concentrated to give the title compound (39.1 g, 77%) as an oil which solidified on standing. 1H NMR 60 MHz, (CDCl3), δ 8.8 (s, 1H), 8.2 (s, 1H), 7.3 (s, 5H), 3.8 (s, 3H), 3.6 (s, 2H), 3.5 (s, 2H), 3.2 (m, 2H), 2.6 (m, 2H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[H-].[Na+].F[C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][C:13]=1[N+:22]([O-:24])=[O:23].Cl>O1CCCC1.O>[N+:22]([C:13]1[CH:14]=[C:15]([S:18]([NH2:21])(=[O:19])=[O:20])[CH:16]=[CH:17][C:12]=1[O:8][CH2:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)([O-:24])=[O:23]
Reactant: OCC1CCOCC1
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: NS(=O)(=O)c1ccc(OCC2CCOCC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(Tetrahydro-2H-pyran-4-yl)methanol (2.0 g) in tetrahydrofuran (20 mL) was treated with 60% NaH (1.377 g). The solution was stirred for 20 minutes at the room temperature. To this solution was added 4-fluoro-3-nitrobenzenesulfonamide (2.84 g) portion-wise. The reaction was stirred for another 2 hours. The mixture was poured into water, neutralized with 10% HCl, and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified with flash column chromatography on silica gel eluting with 20-60% ethyl acetate in hexanes.
Reaction SMILES: [N-:1]=[C:2]=[O:3].[C:4]1([CH2:10][CH2:11][CH2:12][CH2:13]N)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>>[N:1]([CH2:13][CH2:12][CH2:11][CH2:10][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[C:2]=[O:3]
Reactant: NCCCCc1ccccc1
Reactant: [N-]=C=O
Product: O=C=NCCCCc1ccccc1
Yield: 84 %

Procedure:
Following the synthetic procedure of 4b′ as described in Example 17, isocyanate 4c′ (84% yield) was synthesized from 4-(phenyl)butylamine as an oil. 1H-NMR (CDCl3) δ1.61-1.78 (m, 4H), 2.66 (t, J=7.5 Hz, 2H), 3.32 (t, J=6.5 Hz, 2H), 7.17-7.23 (m, 3H), 7.26-7.32 (m, 2H).