Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FCC[CH2:4][CH2:5][O:6][C:7]1[CH:12]=CC(S(N(CC(O)=O)CC2C=CC(OC)=CC=2)(=O)=O)=C[CH:8]=1.C1C=[CH:32][C:33]2[N:38]([OH:39])N=NC=2C=1.C[O:41]C(ON)(C)C>CN(C=O)C.O>[CH2:5]([O:6][C:7]([CH3:8])([O:39][NH:38][C:33](=[O:41])[CH3:32])[CH3:12])[CH3:4]
Reactant: COc1ccc(CN(CC(=O)O)S(=O)(=O)c2ccc(OCCCCF)cc2)cc1
Reactant: On1nnc2ccccc21
Reactant: COC(C)(C)ON
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(C)(C)ONC(C)=O
Reaction time: 1 h

Procedure:
To a solution of 0.425 g (1 mmol) of desired {[4-(4-fluorobutoxy)-benzenesulfonyl](4-methoxy-benzyl)-amino}-acetic acid and 0.27 g (2 mmol) of HOBT in 4 ml of DMF, a solution of 0.116 g of O-(1-methoxy-1-methyl-ethyl)-hydroxylamine in 1 ml of DMF and 0.23 g of WSCD were successively added at 0–5° C. and the mixture was stirred for 1 h. After stirring for additional 2 h at r.t., the mixture is diluted with H2O and extracted with AcOEt. The combined extracts are dried over MgSO4 and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent; AcOEt:n-hexane=1:1) to give 2-{[4-(4-fluorobutoxy)-benzenesulfonyl]-4-methoxy-benzyl)-amino}-N-(1-ethoxy-1-methyl ethoxy) acetamide; NMR (CDCl3): 1.35 (s, 6H), 1.83–2.0 (m, 4H), 3.29 (s, 3H), 3.70 (s, 2H), 3.78 (s, 3H), 4.08–4.11 (m, 2H), 4.32 (s, 2H), 4.47–4.49 (m, 1H), 4.60 (br s, 1H), 6.80–6.90 (m, 2H), 6.95–7.05 (m, 2H), 7.10–7.25 (m, 2H), 7.79 (d, 2H, J=9.06 Hz), 8.46 (br s, 1H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C@@H:15]2[CH2:20][CH2:19][CH2:18][CH2:17][N:16]2[CH3:21])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C1COCC1.[Pd]>[CH3:21][N:16]1[CH2:17][CH2:18][CH2:19][CH2:20][C@H:15]1[CH2:14][N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CN1CCCC[C@H]1CN1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CN1CCCC[C@H]1CN1CCNCC1
Yield: 50 %

Procedure:
To a solution of (S)-1-benzyl-4-[(1-methylpiperidin-2-yl)methyl]piperazine 0.87 g (3.03 mmol) in THF (40 ml) was added 10% Pd/C 0.4 g and exposed to 1 atm hydrogen overnight. The reaction mixture was filtered. The filtrate was concentrated 0.3 g of desired product in 50% yield.
Reaction SMILES: [CH2:1]([CH2:13][NH2:14])[CH2:2][C:3]([P:9]([O-:12])([OH:11])=[O:10])([P:5]([OH:8])([OH:7])=[O:6])[OH:4].[Na+:15].[Na].[NH2:17]CCCC(P(=O)(O)O)(P(=O)(O)O)O.[OH-].[Na+].[N+]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[S:42](Cl)(=[O:44])=[O:43])([O-])=O>O1CCCC1.O>[NH2:17][C:40]1[CH:39]=[CH:38][C:37]([S:42]([NH:14][CH2:13][CH2:1][CH2:2][C:3]([P:5](=[O:8])([O-:7])[O-:6])([P:9](=[O:11])([O-:12])[O-:10])[OH:4])(=[O:44])=[O:43])=[CH:36][CH:41]=1.[Na+:15].[Na+:15].[Na+:15].[Na+:15]
Reactant: NCCCC(O)(P(=O)([O-])O)P(=O)(O)O
Reactant: NCCCC(O)(P(=O)(O)O)P(=O)(O)O
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(S(=O)(=O)NCCCC(O)(P(=O)([O-])[O-])P(=O)([O-])[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium (4-(4-aminobenzenesulfonylamino)-1-hydroxybutane-1,1-diyl)bisphosphonate was synthesized using sodium alendronate. On this occasion, as the sodium alendronate, monosodium salt of (4-amino-1-hydroxybutane-1,1-diyl)bisphosphonic acid (manufactured by Zentiva) was used. An alendronate (34 g: 104 mmol) was added to 150 mL of pure water in a 500-mL beaker and was dissolved by adjusting the pH to 11 with an aqueous concentrated sodium hydroxide solution. To this solution was dropwise added nitrophenyl sulfonyl chloride (25 g: 110 mmol) dissolved in 100 mL of tetrahydrofuran. On this occasion, an aqueous sodium hydroxide solution was further added thereto to maintain the pH of the solution to 10 to 11. After completion of adding, this solution was stirred at room temperature for 2 hours. Subsequently, tetrahydrofuran was evaporated in vacuum, and the solution was adjusted to a pH of 4 to precipitate a solid, followed by cooling at 4 degrees Celsius overnight. Subsequently, the solid was collected by filtration and was washed with pure water and then dried to yield sodium (4-(4-aminobenzenesulfonylamino)-1-hydroxybutane-1,1-diyl)bisphosphonate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[NH:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:15](=[O:34])[CH2:16][C:17]([CH3:33])([CH3:32])[CH2:18][C@H:19]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@@H:20]([OH:23])[CH2:21][NH2:22])[CH2:6]1.C(=O)([O-])[O-].[Na+].[Na+].[C:42](Cl)(=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44]>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:35])[NH:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:15](=[O:34])[CH2:16][C:17]([CH3:33])([CH3:32])[CH2:18][C@H:19]([NH:24][C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[C@@H:20]([OH:23])[CH2:21][NH:22][C:42](=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:6]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: COC(=O)NC1Cc2ccccc2N(C(=O)CC(C)(C)C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CN)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)NC1Cc2ccccc2N(C(=O)CC(C)(C)C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CNC(=O)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 0.030 g of [1-(7-amino-5(S)-tert-butoxycarbonylamino-6(S)-hydroxy-3,3-dimethyl-heptanoyl)-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl]-carbamic acid methyl ester in 0.6 ml of ethyl acetate at room temperature under argon is added 0.6 ml of saturated aqueous sodium carbonate solution. The mixture is stirred for 15 minutes at room temperature and and 0.011 ml of pivaloyl chloride are added. The mixture is stirred at room temperature for 1.5 hours. The layers are separated and the aqueous layer is extracted with ethyl acetate (2×). The combined organic layers are dried over sodium sulphate, filtered and concentrated. The title compound is obtained as a beige oil from the residue by means of flash chromatography (SiO2 60 F). Rt=4.46 (gradient I).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][C:4]=1[NH2:15].[C:16]([N:24]=[C:25]=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O>[C:16]([NH:24][C:25]([NH:15][C:4]1[CH:5]=[C:6]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COc1ccc(C2CCOCC2)cc1N
Solvent: CC(C)=O
Product: COc1ccc(C2CCOCC2)cc1NC(=S)NC(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a stirred solution of 2.75 g (13.3 mmol) 2-methoxy-5-(tetrahydro-pyran-4-yl)-phenylamine in 60 ml acetone was added dropwise a solution of 2.04 ml (15.2 mmol) benzoyl isothiocyanate in 30 ml acetone and stirring continued for 30 minutes at room temperature. The mixture was then concentrated in vacuo. Flash chromatography (1/1 ethyl acetate/hexane) followed by trituration in ether afforded 3.25 g (66%) 1-benzoyl-3-[2-methoxy-5-(tetrahydro-pyran-4-yl)-phenyl]-thiourea as a white solid. ES-MS m/e (%): 371 (M+H+, 100).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:3][O:4][C:5]1[C:6]([C:22]#N)=[CH:7][C:8]2[C:17]3[C:12](=[C:13]([CH3:18])[N:14]=[CH:15][CH:16]=3)[C:11](=[O:19])[N:10]([CH3:20])[C:9]=2[CH:21]=1.[OH2:28].[OH-:29].[Na+]>C(O)C>[NH2:1][C@@H:2]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:3][O:4][C:5]1[C:6]([C:22]([OH:29])=[O:28])=[CH:7][C:8]2[C:17]3[C:12](=[C:13]([CH3:18])[N:14]=[CH:15][CH:16]=3)[C:11](=[O:19])[N:10]([CH3:20])[C:9]=2[CH:21]=1
Reactant: O
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@@H](N)CC(C)C)c(C#N)cc21
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@@H](N)CC(C)C)c(C(=O)O)cc21
Temperature: 80 °C

Procedure:
To a solution of (S)-8-((2-amino-4-methylpentyl)oxy)-4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridine-9-carbonitrile (450 mg, 1.235 mmol), prepared as described in Example 64, in ethanol (5 mL) and water (5 mL) was added NaOH (494 mg, 12.35 mmol). The mixture was heated to 80° C. for 12 h. The volatiles were evaporated and the residue was diluted with water The pH was adjusted to 3 using 1.5N HCl. The solution was extracted with ethyl acetate (2×5 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford (S)-8-((2-amino-4-methylpentyl)oxy)-4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridine-9-carboxylic acid (90 mg, 0.235 mmol, 19% crude yield) as a yellow solid. The material was carried forward without further purification. LC/MS (ESI) m/e 384.1 [(M+H)+, calcd for C21H26N3O4 384.2]; LC/MS retention time (method D): tR=0.72 min.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[N:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH:22]4[CH2:27][CH2:26][CH:25]([C:28]([CH3:32])([CH3:31])[CH2:29][CH3:30])[CH2:24][CH2:23]4)[CH:17]=3)[N:12]=2)[CH2:6]1)=[O:4].CO.O1CCCC1.[OH-].[Li+].O>>[CH3:32][C:28]([CH:25]1[CH2:24][CH2:23][CH:22]([O:21][C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([CH2:10][N:7]2[CH2:8][CH2:9][CH:5]([C:3]([OH:4])=[O:2])[CH2:6]2)[N:20]=[CH:19]3)[CH2:27][CH2:26]1)([CH3:31])[CH2:29][CH3:30]
Reactant: CCC(C)(C)C1CCC(Oc2ccc3nc(CN4CCC(C(=O)OC)C4)ncc3c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCC(C)(C)C1CCC(Oc2ccc3nc(CN4CCC(C(=O)O)C4)ncc3c2)CC1
Yield: 90 %

Procedure:
1-{6-[4-(1,1-Dimethyl-propyl)-cyclohexyloxy]-quinazolin-2-ylmethyl}-pyrrolidine-3-carboxylic acid methyl ester (229.50 mg, 5.2208E-4 mol) was dissolved in Methanol (5 mL, 0.1 mol) and Tetrahydrofuran (5 mL, 0.06 mol), followed by 2 M of Lithium hydroxide in Water (2 mL, 0.004 mol) at 23° C. for 10 minutes. Excess of solvents were removed under vacuum, and the solid residue was treated with HCl (2N, 3 mL), and extracted with DCM (20×3 mL). The organic layers were dried over Na2SO4. Removal of solvent gave a pure product (200 mg, 90%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.69-0.94 (m, 12H) 1.13-1.37 (m, 10H) 1.39-1.59 (m, 2H) 1.76-1.96 (m, 3H) 2.18-2.37 (m, 2H) 4.84 (br. s., 1H) 7.16-7.38 (m, 2H) 7.55-7.71 (m, 1H) 7.99 (br. s., 1H) MS (ESI, M+1): 426.30.
Reaction SMILES: [O:1]1[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:13].[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[Cl-].[Cl-].[Al+3]>C(=S)=S>[OH:20][C:14]1[CH:19]=[CH:18][C:17]([C:2](=[O:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:1])=[O:12])=[CH:16][CH:15]=1
Reactant: Oc1ccccc1
Reactant: O=C1CCCCCCCCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: O=C(O)CCCCCCCCC(=O)c1ccc(O)cc1
Reaction time: 72 h

Procedure:
To a 500 mL flask, equipped with mechanical stirrer and under inert atmosphere, was added the previously made Oxacycloundecane-2,11-dione (20 g, 108.5 mmol), phenol (10.22 g, 108.5 mmol), and 200 mL carbon disulfide. Aluminum (III) trichloride (72.34 g, 542 mmol) was added and the reaction stirred for 72 hours. Carbon disulfide was decanted away, and ice was carefully added until most of mixture was dissolved. The insoluble material was collect by suction filtration and washed with 2×100 mL of water. The solid was then dissolved in 100 mL of 1 M aqueous sodium hydroxide and then carefully acidified with 1 M aqueous hydrochloric acid until pH=7.5 The solids that formed were removed by filtration and the parent solution was continued to be acidified until pH 2.5. The crude product precipitate was collected by filtration and was washed with 1×100 mL water. The crude product was dissolved in 100 mL of 1 M aqueous sodium hydroxide and then carefully acidified with 1 M aqueous hydrochloric acid until pH=7.5 and the impurities that precipitated were filtered off. The parent solution was further acidified until pH 2. The crude product was collected by filtration and washed with 2×50 mL water. The product was recrystallized form acetone. The isolated product (1.2 g, 4%) was collected by filtration. Found: C, 69.00; H, 7.81%; C16H22O4 requires C, 69.04; H, 7.97% 1H NMR (d6-DMSO): δ 12.0, bs, 1H(COOH); δ 10.3, bs, 1H (aryl-hydroxyl); δ 7.8 d, 2H (aryl H's); δ 6.8, d, 2H, (aryl H's); δ 2.9, t, 2H(CH2 α to carbonyl); δ 2.2, t, 2H (CH2 α to COOH); δ 1.5, multiplet, 4H(CH2's β to carbonyl & β to COOH), δ 1.3, multiplet, 8H (rest of CH2's).
Reaction SMILES: [C:1](=[O:5])([O:3][CH3:4])[NH2:2].O=[C:7]([CH2:11][CH2:12][PH:13]([CH2:15][OH:16])=[O:14])[C:8]([OH:10])=[O:9].C(O)(=O)C>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH3:4][O:3][C:1]([NH:2]/[C:7](=[CH:11]\[CH2:12][PH:13]([CH2:15][OH:16])=[O:14])/[C:8]([OH:10])=[O:9])=[O:5]
Reactant: COC(N)=O
Reactant: O=C(O)C(=O)CC[PH](=O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)N/C(=C\C[PH](=O)CO)C(=O)O
Yield: 71.9 %

Procedure:
67.56 g of methyl carbamate, 2.97 g of p-toluenesulfonic acid monohydrate and 108.06 g of 2-oxo-4-(hydroxymethylphosphinyl)-butanoic acid were added to 160 mL of acetic acid to be suspended. After being dissolved by heating, 800 mL of toluene was added thereto and then the solution was refluxed with vigorous stirring. According to the same procedure as Example 1, 102.28 g of the objective compound was obtained (71.9% yield, Z:E=99.8:0.2).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.C(N(CC)CC)C.[C:21]1([C:26](Cl)=[O:27])[S:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[C:21]1([C:26]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[O:27])[S:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1cccs1
Reactant: NCCCSc1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCSc1ccccn1)c1cccs1
Yield: 85.5 %

Procedure:
To a solution of 1.50 g (6.22 mmol) of 2-(3-aminopropylthio)pyridine dihydrochloride and 3.19 ml (22.9 mmol) of triethylamine in 60 ml of methylene chloride, 1.09 ml (7.46 mmol) of 2-thenoyl-chloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain powder. The powder was washed with ether and dried to obtain 1.48 g of the desired compound (yield: 85.5%, colorless powder).
Reaction SMILES: Cl.[CH3:2][C:3]1[N:4]([NH2:16])[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=1.[C:17]1(C)[CH:22]=CC(S(O)(=O)=O)=C[CH:18]=1.O.CO>COC(OC)(C)C>[C:17](=[N:16][N:4]1[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=[C:3]1[CH3:2])([CH3:22])[CH3:18]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1nc2cnc3ccccc3c2n1N
Agent: Cl
Solvent: COC(C)(C)OC
Solvent: O
Solvent: CO
Product: CC(C)=Nn1c(C)nc2cnc3ccccc3c21
Temperature: 100 °C
Reaction time: 24 h
Yield: 1461.4 %

Procedure:
A suspension of 2-methyl-1H-imidazo[4,5-c]quinolin-1-amine hydrochloride (1.79 g, 7.62 mmol) in 30 mL of 2,2-dimethoxypropane was treated with 90 mg of p-toluenesulfonic acid. The reaction mixture was heated to 100° C. overnight. The reaction mixture was then treated with 10 mL of H2O and 10 mL of MeOH, and heating was continued for 24 h. The reaction mixture was cooled and concentrated under reduced pressure. The resulting oil was dissolved in 50 mL of CHCl3 and washed with 2% Na2CO3 solution, H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated to give N-isopropylidene(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)amine (1.82 g) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][N:14]([C:18](OC(C)(C)C)=[O:19])[CH2:13][C:12]=3[CH:25]=2)=[CH:4][C:3]=1[N+:26]([O-:28])=[O:27].CCN(C(C)C)C(C)C.[OH:38][C:39]1([C:50]([F:53])([F:52])[F:51])[CH2:45][CH:44]2[N:46](C(Cl)=O)[CH:41]([CH2:42][CH2:43]2)[CH2:40]1>C1COCC1.CN1C(=O)CCC1>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][N:14]([C:18]([N:46]4[CH:44]5[CH2:43][CH2:42][CH:41]4[CH2:40][C:39]([C:50]([F:51])([F:52])[F:53])([OH:38])[CH2:45]5)=[O:19])[CH2:13][C:12]=3[CH:25]=2)=[CH:4][C:3]=1[N+:26]([O-:28])=[O:27]
Reactant: O=C(Cl)N1C2CCC1CC(O)(C(F)(F)F)C2
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(-c3cnc(N)c([N+](=O)[O-])c3)cc2C1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Nc1ncc(-c2ccc3c(c2)CN(C(=O)N2C4CCC2CC(O)(C(F)(F)F)C4)CCO3)cc1[N+](=O)[O-]
Temperature: 50 °C
Yield: 69.9 %

Procedure:
To a solution of 1,1-dimethylethyl 7-(6-amino-5-nitropyridin-3-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (1.1 g, 3.1 mmol) and DIPEA (2.7 mL, 16 mmol) in THF (10 mL) and NMP (5 mL) was added 3-hydroxy-3-(trifluoromethyl)-8-azabicyclo[3.2.1]octane-8-carbonyl chloride (reagent preparation 37, 0.81 g, 3.1 mmol). The reaction mixture was heated (50° C.) for four hours and partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography provided 8-{[7-(6-amino-5-nitropyridin-3-yl)-2,3-dihydro-1,4-benzoxazepin-4 (5H)-yl]carbonyl}-3-(trifluoromethyl)-8-azabicyclo[3.2.1]octan-3-ol (1.1 g, 69% yield) as red oil. MS (ES) for C23H24F3N5O5: 507.2 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:12](S(C3C=CC(C)=CC=3)(=O)=O)[CH:11]=[CH:10][C:5]2=[N:6][C:7]=1[C:8]#[N:9].[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[C:4]2[NH:12][CH:11]=[CH:10][C:5]2=[N:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(C#N)c(F)cc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#Cc1nc2cc[nH]c2cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
To a solution of 6-fluoro-1-tosyl-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile (2742 mg, 7.85 mmol) in MeOH (20 mL) and water (20 mL) was added NaOH (628 mg 15.7 mmol). The mixture was stirred at RT for 1 h. The reaction mixture was quenched by adding a sat'd aq. NH4Cl and extracted with EtOAc. The extract was dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by SiO2 chromatography eluting with a petroleum ether:EtOAc gradient (10:1-0:1) to afford 758 mg (60%) of 6-fluoro-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile. MS (ESI): m/z=162.3 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH2:16][CH2:15][CH2:14]2.C(N(C(C)C)CC)(C)C>C(O)CCC>[Cl:1][C:2]1[N:7]=[C:6]([N:17]2[C:18]3[C:13](=[CH:12][C:11]([O:10][CH3:9])=[CH:20][CH:19]=3)[CH2:14][CH2:15][CH2:16]2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: COc1ccc2c(c1)CCCN2
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COc1ccc2c(c1)CCCN2c1ccnc(Cl)n1
Temperature: 40 °C
Yield: 79.9 %

Procedure:
The reaction flask containing 2,4-dichloropyrimidine (372 mg, 2.5 mmol), 6-methoxy-1,2,3,4-tetrahydroquinoline (489 mg, 3 mmol) and diisopropylethylamine (0.52 mL, 3 mmol) in n-butanol (10 mL) was heated at 40° C. overnight. The solvent was evaporated, and the residue was purified by flash column chromatography to give 2-Chloro-4-(6-methoxy-3,4-dihydroquinolin-1(2H)-yl)pyrimidine (551 mg, 80%). This intermediate (250 mg, 0.91 mmol) was then dissolved in dichloromethane and treated with BBr3 (1 M in dichloromethane) (1 mL, 1 mmol) at −78° C. The reaction mixture was slowly warmed up to room temperature and stirred for 1 hr, poured into water, extracted with dichloromethane. The combined organics were dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column chromatography to give 2-Chloro-4-(6-hydroxy-3,4-dihydroquinolin-1(2H)-yl)pyrimidine (154 mg, 65%). To a stirred solution of 2-chloro-4-(6-hydroxy-3,4-dihydroquinolin-1(2H)-yl)pyrimidine (29 mg, 0.11 mmol) and 4-amino-N-(cyclopropylmethyl)benzenesulfonamide (27 mg, 0.12 mmol) in DMF (0.5 mL) was added p-toluenesulfonic acid (2 M in dioxane) (55 μL, 0.11 mmol). The reaction mixture was stirred at 90° C. overnight, then purified by HPLC to give the title compound (27 mg, 56%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([N:20]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH:32]([F:34])[F:33])[CH:26]=3)(=[O:24])=[O:23])[CH3:21])[CH:17]=[CH:16][C:15]=2[O:35][CH3:36])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:37]>C(O)C.C(O)(C)C>[ClH:37].[F:34][CH:32]([F:33])[O:31][C:27]1[CH:26]=[C:25]([S:22]([N:20]([C:18]2[CH:17]=[CH:16][C:15]([O:35][CH3:36])=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:19]=2)[CH3:21])(=[O:24])=[O:23])[CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccc(N(C)S(=O)(=O)c2cccc(OC(F)F)c2)cc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CC(C)O
Solvent: CCO
Product: COc1ccc(N(C)S(=O)(=O)c2cccc(OC(F)F)c2)cc1N1CCNCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.3 g (0.584 mmol) 4-{5-[(3-difluoromethoxy-benzenesulfonyl)-methyl-amino]-2-methoxy-phenyl}-piperazine-1-carboxylic acid tert-butyl ester from preparation example 2 were dissolved in 8 mL of ethanol and 0.8 mL of 5 N HCl in isopropanol were added. After stirring for 16 h at room temperature, the solvent was evaporated to yield 0.255 g of title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:35][CH2:36][CH:37]([CH3:40])[CH2:38][OH:39]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:35][CH2:36][CH:37]([CH3:40])[CH2:38][OH:39])=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O
Reactant: CC(CN)CO
Product: CC(CO)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-(2-oxo-1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 3-amino-2-methyl-1-propanol using methods similar to Example 563 to provide an orange solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 0.89 (d, J=6.95 Hz, 3 H), 1.52-1.65 (m, 4 H), 1.79-1.88 (m, 1 H), 2.03 (t, J=6.00 Hz, 2 H), 3.20-3.47 (m, 6 H), 3.51 (t, J=6.00 Hz, 2 H), 4.16 (s, 2 H), 4.40 (t, J=6.11 Hz, 2 H), 4.64 (s, 1 H), 7.11-7.17 (m, 2 H), 7.38-7.43 (m, 2 H), 8.20 (d, J=1.47 Hz, 1 H), 8.56 (d, J=1.47 Hz, 1 H), 10.38 (t, J=5.90 Hz, 1 H), 17.24 (s, 1 H); ES+ MS: 511 (M+H+).
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:22]([CH3:25])([CH3:24])[CH3:23])[S:8]/[C:9]/1=[N:10]\[C:11](=O)[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])[CH2:2][CH2:3][CH3:4].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:27]>C1(C)C=CC=CC=1>[CH2:1]([C:5]1=[CH:6][N:7]([C:22]([CH3:25])([CH3:24])[CH3:23])[S:8]/[C:9]/1=[N:10]\[C:11]([C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])=[S:27])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)c1cc(Cl)ccc1OC
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: Cc1ccccc1
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=S)c1cc(Cl)ccc1OC
Temperature: 82 °C
Yield: 35.3 %

Procedure:
To a solution of Example 1D (380 mg, 1 mmol) in toluene (25 mL) was added P2S5 (220 mg, 1 mmol) and the reaction mixture was heated at 82° C. for 75 minutes, concentrated under reduced pressure and purified via column chromatography (SiO2, 0-25% EtOAc in hexanes) to provide the title compound (0.14 g, 34% yield). 1H NMR (300 MHz, CDCl3) δ ppm 0.95 (t, J=7.3 Hz, 3H), 1.40 (dd, J=15.1, 7.5 Hz, 2H), 1.61-1.78 (m, 11H), 2.84-3.00 (m, 2H), 3.84 (s, 3H), 6.90 (d, J=8.7 Hz, 1H), 7.27-7.35 (m, 1H), 7.66 (d, J=2.8 Hz, 1H), 8.13 (s, 1H). MS (DCI/NH3) m/z 398 (M+H)+.