Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([N+:30]([O-:32])=[O:31])=[CH:25][N:24]=1.Cl>O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:23]2[CH:28]=[C:27]([CH3:29])[C:26]([N+:30]([O-:32])=[O:31])=[CH:25][N:24]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)ncc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 71.5 %

Procedure:
A mixture of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (440 mg; 2.2 mmol), triethylamine (420 μL; 3.0 mmol) and 2-chloro-4-methyl-5-nitro-pyridine (346 mg; 2.0 mmol) is irradiated in a mono-mode microwave oven for 10 hours at 120° C. The mixture is then cooled to room temperature, water is added (5 mL) and the pH is adjusted to pH 4-5 by addition of aq. 1N hydrochloric acid. After extraction with dichloromethane (2×10 mL), the combined organic layers are dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. The residue obtained is finally purified by column chromatography on silica gel (dichloromethane:ethyl acetate 1:0; 12:1; 2:1) to afford the desired product (480 mg; 1.43 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([NH:9][CH3:10])[C:3]=1[NH2:11].[Cl:12][CH2:13][C:14](O)=O>>[Cl:12][CH2:13][C:14]1[N:9]([CH3:10])[C:4]2[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[C:3]=2[N:11]=1
Reactant: O=C(O)CCl
Reactant: CNc1cc(F)cc(F)c1N
Product: Cn1c(CCl)nc2c(F)cc(F)cc21
Yield: 21.5 %

Procedure:
The title compound was prepared in accordance with the general method of Example 191(C), from 3,5-difluoro-N1-methylbenzene-1,2-diamine (1.50 g, 9.50 mmol) and 2-chloroacetic acid (1.3 g, 14 mmol). The crude residue was purified over silicagel chromatography (prepacked 25 g silicagel column, Cyclohexane/AcOEt:70/30 as eluent) to afford 443 mg of 2-(chloromethyl)-4,6-difluoro-1-methyl-1H-benzo[d]imidazole (Yield: 22%) as a purple solid.
Reaction SMILES: C[O:2][C:3](=[O:49])[C@H:4]([NH:27][S:28]([C:31]1[CH:48]=[CH:47][C:34]2[N:35]=[C:36]([S:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)[S:37][C:33]=2[CH:32]=1)(=[O:30])=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][N:16]2[C:20](=[O:21])[C:19]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]3[C:17]2=[O:26])=[CH:8][CH:7]=1.[Li+].[OH-]>C1COCC1.O>[CH3:46][O:45][C:42]1[CH:41]=[CH:40][C:39]([S:38][C:36]2[S:37][C:33]3[CH:32]=[C:31]([S:28]([NH:27][C@H:4]([CH2:5][C:6]4[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][N:16]5[C:20](=[O:21])[C:19]6=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]6[C:17]5=[O:26])=[CH:8][CH:7]=4)[C:3]([OH:49])=[O:2])(=[O:29])=[O:30])[CH:48]=[CH:47][C:34]=3[N:35]=2)=[CH:44][CH:43]=1
Reactant: COC(=O)[C@@H](Cc1ccc(OCCCN2C(=O)c3ccccc3C2=O)cc1)NS(=O)(=O)c1ccc2nc(Sc3ccc(OC)cc3)sc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Sc2nc3ccc(S(=O)(=O)N[C@H](Cc4ccc(OCCCN5C(=O)c6ccccc6C5=O)cc4)C(=O)O)cc3s2)cc1

Procedure:
(2R)-2-[(2-(4-Methoxyphenylthio)benzthiazol-6-sulfonyl)amino]-3-(4-(3-phthalimido-1-propyl)oxyphenyl) propionic acid methylester (0.196 g, 0.27 mmol) prepared in Example 61 was dissolved in THF/H2O (2 mL/2 mL), and LiOH(0.057 g, 5 equi.) was added and refluxed for 12 hours. Then, the reaction solution was distilled under reduced pressure to remove the solvent and treated with 1N HCl. The product was extracted with ethylacetate (10 mL). The separated organic phase was washed with NaCl solution, dried over anhydrous MgSO4, distilled under reduced pressure and dried under vacuum to prepare the titled compound, (2R)-2-[(2-(4-methoxyphenylthio)benzthiazol-6-sulfonyl)amino]-3-(4-(3-phthalimido-1-propyl)oxyphenyl) propionic acid (0.15 g, 80%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.[C:13]1([CH:19](O)[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.B(F)(F)F.CCOCC>O1CCOCC1>[C:13]1([CH:19]([C:3]2[C:4](=[O:12])[O:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OC(Cc1ccccc1)c1ccccc1
Reactant: O=c1cc(O)c2ccccc2o1
Agent: FB(F)F
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=c1oc2ccccc2c(O)c1C(Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8058.5 %

Procedure:
To a flame-dried flask containing a near-solution of 810 mg of 4-hydroxycoumarin and 1.20 mg of 1,2-diphenylethanol of Preparation 15 in 30 mL of dioxane under an argon atmosphere is added 3.0 mL of boron trifluoride etherate. The resulting yellow solution is left to stir at room temperature overnight; the reaction is then heated to reflux for 48 hours. The volatiles are removed and the residue is partioned between diethyl ether and 1N sodium hydroxide. The basic aqueous phase is washed with diethyl ether and acidified to pH=1 with 6N hydrochloric acid. The resulting precipitant is repeatedly extracted with dichloromethane (methanol-chloroform co-solvents). The combined dichloromethane extracts are washed once with dilute sodium bicarbonate to remove most of the unreacted 4-hydroxycoumarin, then brine, dried (magnesium sulfate), and finally concentrated under reduced pressure. The residue is adsorbed onto silica and flash column chromatographed with 40% to 50% ethyl acetate in hexanes to yield 167 mg of the title product as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8](=[O:17])[CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:11][C:6]=2[C:5]([CH2:18][CH2:19][CH3:20])=[CH:4][CH:3]=1.[OH:21][CH:22]([CH3:25])[CH2:23]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[OH:21][CH:22]([CH3:25])[CH2:23][O:1][C:2]1[C:7]2[C:8](=[O:17])[CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:11][C:6]=2[C:5]([CH2:18][CH2:19][CH3:20])=[CH:4][CH:3]=1
Reactant: CC(O)CBr
Reactant: CCCc1ccc(O)c2c(=O)cc(C(=O)OCC)oc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1ccc(OCC(C)O)c2c(=O)cc(C(=O)OCC)oc12

Procedure:
A mixture of ethyl 5-hydroxy-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylate (2.2 g), 2-hydroxy propyl bromide (5 g), anhydrous potassium carbonate (5 g) and acetone (200 ml) was heated at reflux for 3 days. After cooling, the reaction mixture was filtered and the acetone removed from the filtrate in vacuo. The oily residue was dissolved in chloroform (100 ml) and the chloroform solution washed with 1 N aqueous sodium hydroxide solution (50 ml) and water (50 ml) and then dried. Removal of the chloroform in vacuo gave a brown solid which on crystallisation from ethanol gave ethyl 5-(2-hydroxypropoxy)-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylate identical in all respects with authentic material.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3=[N:10][CH:11]=[C:12]([NH:14][CH3:15])[CH:13]=[C:8]3[N:7]=[C:6]2[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH3:25])=[CH:19][CH:18]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:33]1([S:39](Cl)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CC(O)=O>C(#N)C>[CH:1]1([CH2:4][N:5]2[C:9]3=[N:10][CH:11]=[C:12]([N:14]([CH3:15])[S:39]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)(=[O:41])=[O:40])[CH:13]=[C:8]3[N:7]=[C:6]2[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH3:25])=[CH:19][CH:18]=2)[CH2:3][CH2:2]1
Reactant: CCOc1ccc(Cc2nc3cc(NC)cnc3n2CC2CC2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CC(=O)O
Product: CCOc1ccc(Cc2nc3cc(N(C)S(=O)(=O)c4ccccc4)cnc3n2CC2CC2)cc1
Reaction time: 8 h
Yield: 17 %

Procedure:
To a solution of 3-(cyclopropylmethyl)-2-[(4-ethoxyphenyl)methyl]-N-methyl-3H-imidazo[4,5-b]pyridin-6-amine (237.0 mg, 0.70 mmol) in acetonitrile (5 mL) at room temperature was added triethylamine (196 μL, 1.41 mmol) followed by benzenesulfonyl chloride (156 mL, 0.92 mmol). The mixture was stirred overnight. The reaction mixture was concentrated in vacuo. The residue was dissolved into EtOAc (10 ml) and Na2CO3 saturated aqueous solution (10 mL). The phases were separated and the aqueous phase was back-extracted with additional EtOAc (10 mL). The organic phases were combined, dried with MgSO4, filtered and concentrated in vacuo. The residue was purified using preparative HPLC (C-18 column, 20 to 80% [0.1% AcOH in AcCN solution] in 0.1% AcOH aqueous solution) to provide 63 mg of the AcOH salt of the title compound N-[3-(cyclopropylmethyl)-2-[(4-ethoxyphenyl)methyl]-3H-imidazo[4,5-b]pyridin-6-yl]-N-methyl-benzenesulfonamide (17% yield from 3-(cyclopropylmethyl)-2-[(4-ethoxyphenyl)methyl]-N-methyl-3H-imidazo[4,5-b]pyridin-6-amine). 1H-NMR (400 MHz, d3-MeOD): δ 0.37 (m, 2H), 0.42 (m, 2H), 1.10 (m, 1H), 1.35 (t, J=7.0 Hz, 3H), 3.31 (s, 3H), 3.99 (t, J=7.0 Hz, 2H), 4.10 (d, J=7.2 Hz, 2H), 4.32 (s, 2H), 6.86 (d, J=8.6 Hz, 2H), 7.17 (d, J=8.6 Hz, 2H), 7.55 (m, 2H), 7.57 (m, 2H), 7.59 (m, 1H), 7.70 (m, 1H), 8.11 (d, J=2.2 Hz, 1H). MS (ESI) (M+H)+: 477.
Reaction SMILES: [CH2:1]([CH:3]1[C:8]([C:9]2[CH:24]=[CH:23][C:12]3[N:13]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=4)[O:15][C:11]=3[CH:10]=2)=[N:7][NH:6][C:5](=[O:25])[CH2:4]1)[CH3:2].Br[CH:27]([CH3:33])[CH:28]([O:31][CH3:32])[O:29][CH3:30].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>CC(=O)OCC>[CH3:30][O:29][CH:28]([O:31][CH3:32])[CH:27]([CH3:33])[O:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]2[O:15][C:11]3[CH:10]=[C:9]([C:8]4[CH:3]([CH2:1][CH3:2])[CH2:4][C:5](=[O:25])[NH:6][N:7]=4)[CH:24]=[CH:23][C:12]=3[N:13]=2)=[CH:17][CH:18]=1
Reactant: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(O)cc3)oc2c1
Reactant: COC(OC)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(OC(C)C(OC)OC)cc3)oc2c1

Procedure:
146 mg (435 μmol) 5-ethyl-6-[2-(4-hydroxy-phenyl)-benzoxazol-6-yl]-4,5-dihydro-2H-pyridazin-3-one, 910 mg (4.89 mmol) 2-bromo-1,1-dimethoxy-propane, 720 mg (5.21 mmol) potassium carbonate and 5 ml DMF are stirred overnight at 150° C. under protective gas. Then the mixture is diluted with EA, and extracted with 10% sodium carbonate solution and then with sat. saline solution. The solv. of the org. phase is eliminated i.V. The residue is purified on silica gel (eluant: DCM/methanol)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C[Al](C)C.C[O:13][C:14]([C:16]1[C:25]2[C:24]3[N:26]=[CH:27][CH:28]=[CH:29][C:23]=3[CH2:22][N:21]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:20][C:19]=2[NH:18][CH:17]=1)=O>C(Cl)Cl>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:14]([C:16]1[C:25]2[C:24]3[N:26]=[CH:27][CH:28]=[CH:29][C:23]=3[CH2:22][N:21]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:20][C:19]=2[NH:18][CH:17]=1)=[O:13]
Reactant: COC(=O)c1c[nH]c2c1-c1ncccc1CN(Cc1ccccc1)C2
Reactant: Nc1ccccn1
Agent: C[Al](C)C
Solvent: ClCCl
Product: O=C(Nc1ccccn1)c1c[nH]c2c1-c1ncccc1CN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 110 mg (1.2 mmol) of 2-aminopyridine in 2 mL of methylene chloride is added dropwise 0.5 mL (1.0 mmol) of trimethyl aluminum (2M solution in toluene). This mixture is stirred at room temperature for ½ hour. The resulting solution is then added dropwise to a 68 mg (0.2 mmol) solution of 5-Benzyl-3,4,5,6-tetrahydro-3,5,10-triaza-benzo[e]azulene-1-carboxylic acid methyl ester dissolved in 8 mL of methylene chloride and the mixture heated to 40° C. for 4 hours. The reaction mixture is quenched with the dropwise addition of 0.75 mL of 1N NaOH and then dried with anhydrous Na2SO4. The reaction mixture is filtered, and the filtrate evaporated. The residue is chromatographed on 9 grams of silica gel using 50/1 chloroform/methanol as the eluant. Appropriate fractions are combined and evaporated to yield 65 mg of 5-benzyl-3,4,5,6-tetrahydro-3,5,10-triaza-benzo[e]azulene-1-carboxylic acid pyridin-2-ylamide. 1H NMR (CDCl3) δ 14.1 (s, 1H), 11.0 (s, 1H), 8.8 (m, 1H), 8.4 (m, 2H), 7.7 (s, 1H), 7.6 (m, 2H), 7.4 (m, 6H), 6.95 (m, 1H), 3.7 (s, 2H), 3.55 (s, 2H), 3.50 (s, 2H). Mass spectrum: m/e=396.3 (p+1). TLC (10/1 chloroform/methanol) Rf=0.6
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)\[CH2:5][O:6][C:7]1[CH:26]=[CH:25][C:10]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:21][CH:20]3[C:22]([OH:24])=[O:23])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[OH-].[Na+:36]>>[CH3:1][O:2]/[N:3]=[C:4](/[C:27]1[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)\[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:21][CH:20]3[C:22]([O-:24])=[O:23])=[CH:15][CH:14]=2)=[CH:25][CH:26]=1.[Na+:36]
Reactant: CO/N=C(\COc1ccc(COc2ccc(C3CC3C(=O)O)cc2)cc1)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Product: CO/N=C(\COc1ccc(COc2ccc(C3CC3C(=O)[O-])cc2)cc1)c1ccc(OC)cc1
Yield: 27.84 %

Procedure:
Compound 57 was synthesized from 2-{4-[(4-{[(2Z)-2-(methoxyimino)-2-(4-methoxyphenyl)ethyl]oxy}benzyl)oxy]phenyl}cyclopropanecarboxylic acid (0.08 g, 0.2 mmol) and sodium hydroxide (0.013 g, 0.3 mmol) by following the procedure described in scheme 12 (0.022 g, yield: 27.84%); Purity: 98.61%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[C:10](=S)(OCC)[S-:11].[K+]>C(O)C>[SH:11][C:10]1[O:9][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=2[N:1]=1
Reactant: CCOC(=S)[S-]
Reactant: Cc1cccc(O)c1N
Agent: [K+]
Solvent: CCO
Product: Cc1cccc2oc(S)nc12

Procedure:
5 g (41 mmol) of 2-amino-3-methylphenol and 6.51 g (41 mmol) of potassium O-ethyl dithiocarbonate, in suspension in 70 ml of ethanol, are successively introduced into a 500 ml round-bottomed flask and the mixture is heated at reflux for 24 h. The solvent is removed by evaporation under reduced pressure, the residue is taken up-in 50 ml of water and 4 ml of acetic acid are added. The precipitate obtained is filtered off, rinsed with water and dried under vacuum.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=O.[CH3:12][C:13]([C:16]([NH2:18])=[NH:17])([CH3:15])[CH3:14].Cl.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:17]=[C:16]([C:13]([CH3:15])([CH3:14])[CH3:12])[NH:18][CH:2]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=N)N
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc(-c2ccc(Br)cc2)c[nH]1
Temperature: 50 °C
Yield: 80.7 %

Procedure:
A solution of 2,4′-dibromoacetophenone (4.17 g, 15.0 mmol) in N,N-dimethylformamide (60.0 mL) was treated with t-butylcarbamidine hydrochloride (2.05 g, 15.0 mmol) and K2CO3 (4.15 g, 30.0 mmol) and heated to 50° C. for 4 h. Following cooling, the reaction was quenched with water, diluted with brine, and extracted thrice with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. Purification via flash column chromatography (10-40% EtOAc/hexanes) gave the title compound as a light yellow solid (3.38 g; 81%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.58 (d, J=8.1 Hz, 2H) 7.46 (d, J=8.6 Hz, 2H) 7.18 (s, 1H) 1.42 (s, 9H). MS (ES+) m/e 279/281 [M+H]+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][C:13]3([C:19]([NH:21][CH3:22])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[O:23]=[C:24]1[CH:33]=[N:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]1[CH2:34][CH:35]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][C:13]3([C:19]([NH:21][CH3:22])=[O:20])[CH2:14][CH2:15][N:16]([CH2:35][CH2:34][N:25]4[C:26]5[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=5)[N:32]=[CH:33][C:24]4=[O:23])[CH2:17][CH2:18]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CNC(=O)C1(NCc2ccc3c(c2)OCCO3)CCNCC1
Reactant: O=CCn1c(=O)cnc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CNC(=O)C1(NCc2ccc3c(c2)OCCO3)CCN(CCn2c(=O)cnc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.7 %

Procedure:
To 3 mL of dichloromethane solution containing 0.11 g of 4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)-N-methylpiperidine-4-carboxamide, 65 mg of (2-oxoquinoxalin-1(2H)-yl)acetaldehyde and 20 μl of acetic acid were added and stirred at room temperature for 3 hours. To the reaction mixture, 0.11 g of sodium triacetoxyborohydride was added and stirred at the same temperature for 30 min. Chloroform and aqueous saturated sodium hydrogen carbonate solution were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=10:1] to give 0.12 g of 4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)-N-methyl-1-(2-(2-oxoquinoxalin-1(2H)-yl)ethyl)piperidine-4-carboxamide as a yellow oil.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[F:7][CH:8]([C:12](=O)[CH3:13])[C:9](=O)[CH3:10].N1CCCCC1>CCO>[F:7][C:8]1[C:12]([CH3:13])=[C:3]([C:1]#[N:2])[C:4](=[O:5])[NH:6][C:9]=1[CH3:10]
Reactant: N#CCC(N)=O
Reactant: CC(=O)C(F)C(C)=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(=O)c(C#N)c(C)c1F
Reaction time: 3 h
Yield: 58.8 %

Procedure:
To a stirred solution of 2-cyanoacetamide (689 mg, 8.2 mmol) in anhydrous EtOH (7.0 ml) at 75° C., was added 3-fluoropentane-2,4-dione (880 mg, 7.5 mmol), followed by piperidine (96 μl, 0.97 mmol). The reaction mixture was stirred at this temperature for 3 hours and the reaction mixture left to reach room temperature before being stored in the refrigerator for 4 days. The beige solid was collected by filtration and rinsed with cold EtOH (4×0.4 ml) until the filtrate ran clear. The resulting beige solid was dried in-vacuo at 40° C. for 5 hours to give the title compound (733 mg, 58%) as a beige solid. LC-MS 97%, m/z=166.9, 1H NMR (500 MHz, Chloroform-d) δ ppm 13.67 (br. s., 1H) 2.46 (d, J=2.05 Hz, 3H) 2.45 (d, J=2.84 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15](Cl)(=[O:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O:23][C:24](=[O:35])[CH2:25][C@H:26]([NH2:34])[CH:27]([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])([CH3:22])([CH3:21])[CH3:20].N1C=CC=CC=1>C(Cl)(Cl)Cl.C(OCC)(=O)C>[C:19]([O:23][C:24](=[O:35])[CH2:25][C@H:26]([NH:34][S:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:17])=[O:16])[CH:27]([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])([CH3:21])([CH3:20])[CH3:22]
Reactant: CCOC(OCC)[C@@H](N)CC(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccccc1OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 91.2 %

Procedure:
2-Benzyloxy-benzenesulfonyl chloride (see Example 23, step 1) (1.7 g, 6 mmol) and (S)-3-amino-4,4-diethoxy-butyric acid tert-butyl ester (see Example 93) (1.5 g, 6 mmol) and pyridine (1.9 g, 30 mmol) were dissolved in chloroform (150 mL) and stirred at room temperature for 3 days. The reaction was diluted with ethyl acetate (500 mL) and washed with 5% citric acid, sat. sodium bicarbonate, and sat. sodium chloride. The organic layer was then dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash chromatography (SiO2, hexane:ethyl acetate, 8:1, then 4:1) gave the desired product (2.7 g, 91%) as a colorless oil. 1H NMR (400 MHz) CDCl3 δ 7.92 (m, 1H), 7.52 (d, 2H), 7.47 (t, 1H), 7.40 (t, 2H), 7.34 (d, 1H), 7.04 (t, 2H), 5.61 (d, 1H), 5.23 (q, 2H), 4.30 (d, 1H), 3.77 (m, 1H), 3.47 (m, 2H), 3.36 (m, 1H), 3.15 (m, 1H), 2.45 (t, 2H), 1.37 (s, 9H), 1.02 (t, 3H), 0.92 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[S:23](=[O:25])(=[O:24])[N:22](CC[Si](C)(C)C)[C:21](=[O:32])[CH2:20]3)=[C:15]([O:33]CC3C=CC=CC=3)[CH:14]=2)=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>>[OH:33][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[N:19]1[CH2:20][C:21](=[O:32])[NH:22][S:23]1(=[O:25])=[O:24])[CH2:12][C:3]1[C:2]([NH:1][S:42]([CH3:41])(=[O:44])=[O:43])=[CH:11][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: CS(=O)(=O)Cl
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(Cc3cc4ccccc4cc3N)cc2OCc2ccccc2)S1(=O)=O
Product: CS(=O)(=O)Nc1cc2ccccc2cc1Cc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1

Procedure:
N-{3-[3-Hydroxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-benzyl]-naphthalen-2-yl}-methanesulfonamide is prepared analogously to Example 4, Steps B and C, starting with 5-[4-(3-aminonaphthalen-2-ylmethyl)-2-benzyloxyphenyl]-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one and methanesulfonyl chloride: MS (M−H)−=460.
Reaction SMILES: [CH3:1][C:2]1([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:11][CH:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[NH:3]1.[CH2:24]1[O:26][CH2:25]1>C(O)CCCCCCC>[OH:26][CH2:25][CH2:24][N:3]1[CH:4]2[CH:9]([CH2:8][CH2:7][CH2:6][CH2:5]2)[CH:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:11][C:2]1([CH3:1])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCC1CC(C)(CCCCCC)NC2CCCCC12
Reactant: C1CO1
Solvent: CCCCCCCCO
Product: CCCCCCC1CC(C)(CCCCCC)N(CCO)C2CCCCC12

Procedure:
Following the above procedures, 25 grams of 2-methyl-2,4-dihexyl decahydroquinoline in 50 milliliters of 1-octanol was reacted with ethylene oxide at 200° C. for 8 hours to yield 1-(2'-hydroxyethyl)-2-methyl-2,4-dihexyl decahydroquinoline which had a boiling point at 192° C. at 0.7 mm Hg. The products NMR and infrared spectra were consistent with the desired product.
Reaction SMILES: Br[C:2]1[C:3]([O:17][CH:18]2[CH2:21][CH2:20][CH2:19]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][CH3:15])=[O:13])[C@@H:7]([CH3:16])[CH2:6][CH2:5]2.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[N:32][N:33]([CH:35]3[CH2:38][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:36]3)[CH:34]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[C:42]([O:41][C:39]([N:37]1[CH2:38][CH:35]([N:33]2[CH:34]=[C:30]([C:2]3[C:3]([O:17][CH:18]4[CH2:21][CH2:20][CH2:19]4)=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]([C:12]([O:14][CH3:15])=[O:13])[C@@H:7]([CH3:16])[CH2:6][CH2:5]4)[CH:31]=[N:32]2)[CH2:36]1)=[O:40])([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(C)(C)OC(=O)N1CC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
Reactant: COC(=O)N1c2ccc(Br)c(OC3CCC3)c2CC[C@@H]1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)N1c2ccc(-c3cnn(C4CN(C(=O)OC(C)(C)C)C4)c3)c(OC3CCC3)c2CC[C@@H]1C
Temperature: 100 °C
Yield: 104.6 %

Procedure:
A mixture of methyl (S)-6-bromo-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.096 g, 0.254 mmol), tert-butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (0.113 g, 0.325 mmol), and cesium carbonate (0.264 g, 0.811 mmol) in dioxane (2.0 mL) and water (0.40 mL) was purged with nitrogen to remove any oxygen. XPhos Precatalyst 2nd Generation (0.020 g, 0.027 mmol) was added and the reaction was purged with nitrogen and then heated at 100° C. for 16 h. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous phase was separated and extracted with ethyl acetate, and the combined organic phases were concentrated to afford an oil. This material was purified via column chromatography on silica gel (Biotage 10 g column, gradient elution with 25-50% ethyl acetate-hexane) to afford methyl (S)-6-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.132 g, 98%) as a colorless oil. MS (ESI, pos. ion) m/z 497 [M+H]+.