Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[O:2]1[C:11]2[CH:10]=[C:9]([CH2:12][NH:13][CH:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][N:22]4[C:31]5[C:26](=[N:27][C:28]([CH3:33])=[C:29](F)[CH:30]=5)[CH:25]=[CH:24][C:23]4=[O:34])[CH2:16][CH2:15]3)[N:8]=[CH:7][C:6]=2[O:5][CH2:4][CH2:3]1.[C:35](=O)([O-])[OH:36].[Na+]>C(Cl)(Cl)Cl>[ClH:1].[O:2]1[C:11]2[CH:10]=[C:9]([CH2:12][NH:13][CH:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][N:22]4[C:31]5[C:26](=[N:27][C:28]([CH3:33])=[C:29]([O:36][CH3:35])[CH:30]=5)[CH:25]=[CH:24][C:23]4=[O:34])[CH2:16][CH2:15]3)[N:8]=[CH:7][C:6]=2[O:5][CH2:4][CH2:3]1
Reactant: O=C([O-])O
Reactant: Cc1nc2ccc(=O)n(CCN3CCC(NCc4cc5c(cn4)OCCO5)CC3)c2cc1F
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1cc2c(ccc(=O)n2CCN2CCC(NCc3cc4c(cn3)OCCO4)CC2)nc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 0.16 g of 1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluoro-6-methyl-1,5-naphthyridin-2(1H)-one hydrochloride, chloroform and a saturated aqueous sodium hydrogen carbonate solution were added, the organic layer was separated and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To the residue, 2.6 mL of methanol and 0.15 mL of a 28% sodium methoxide/methanol solution were added, and the mixture was heated under reflux while stirring for 2 hours. The reaction mixture was cooled to room temperature, thereto were added chloroform and a saturated aqueous sodium hydrogen carbonate solution, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To the resultant residue, 1.4 mL of isopropyl alcohol and 93 μL of concentrated hydrochloric acid were added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was cooled with ice, and the solid was filtered off to obtain 0.15 g of 1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-6-methyl-1,5-naphthyridin-2(1H)-one hydrochloride as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.O>N1C=CC=CC=1>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: C1COCCN1
Solvent: c1ccncc1
Solvent: O
Product: O=S(=O)(c1ccc(Br)cc1)N1CCOCC1
Yield: 88.6 %

Procedure:
To a solution of 1.67 g (19.14 mmol) of morpholine in 50 ml of dry pyridine was added 3.26 g (12.76 mmol) of 4-bromobenzenesulfonyl chloride in an atmosphere of argon, and the mixture was allowed to react at 0° C for 3 hours. To the solution was added water followed by extraction with ethyl acetate. The organic layer was washed with water and then concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography for separation and purification. Elution with dichloromethane yielded 3.45 g (11.3 mmol) of N-(4-bromobenzenesulfonyl)morpholine.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=[O:28])[CH2:10][CH:11]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.[CH2:29]([CH2:31][NH2:32])[OH:30].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>O1CCCC1>[OH:30][CH2:29][CH2:31][NH:32][C:23](=[O:25])[C:22]1[CH:26]=[CH:27][C:19]([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH2:10][C:9]([C:4]2[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=2)=[O:28])=[CH:20][CH:21]=1
Reactant: NCCO
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NCCO)cc1

Procedure:
In analogy to example 207, step 2, 4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzoic acid (example 207, step 1) was coupled with ethanolamine using BOP reagent in tetrahydrofuran to give the title compound as a colorless foam, MS (ESI+): m/z=419.3 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[NH:13][N:12]=[N:11][C:10]=2[N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:27]I>CN(C=O)C>[CH3:27][N:12]1[NH:11][C:10]([N:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]2)=[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:13]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nn[nH]c2-c2ccccc2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1NC(c2ccccc2)=C(N2CCN(C(=O)OC(C)(C)C)CC2)N1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (0.02 g) was taken in dry DMF (5 ml) and a solution of tert-butyl 4-(5-phenyl-1H-1,2,3-triazol-4-yl)piperazine-1-carboxylate (0.015 g in 5 ml of DMF) was added slowly at 0° C. The reaction mixture was stirred for 30 min at 0° C. and methyl iodide (0.13 g) was added very slowly. The reaction mixture was allowed to stir over night at room temperature. The reaction mixture was quenched with cold water (5 ml) and extracted with ethyl acetate (3×40 ml). Evaporation of solvent under reduced pressure gave crude product, which, was purified by column chromatography using 60-120 silica gel methanol\dichloromethane (1:9) as eluent to afford tert-butyl 4-(2-methyl-5-phenyl-1H-1,2,3-triazol-4-yl)piperazine-1-carboxylate.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9](=[O:17])[C:8]2[N:18]([CH3:22])[CH:19]=[C:20]([CH3:21])[C:7]1=2)=[O:5].[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[CH3:22][N:18]1[C:8]2[C:9](=[O:17])[NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:6]([C:4](=[O:5])[CH2:3][CH2:2][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[C:7]=2[C:20]([CH3:21])=[CH:19]1
Reactant: C1CCNC1
Reactant: Cc1cn(C)c2c1N(C(=O)CCBr)c1ccccc1NC2=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cn(C)c2c1N(C(=O)CCN1CCCC1)c1ccccc1NC2=O

Procedure:
1.9 g of 4-(3-bromopropionyl)-1,3-dimethyl-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5]benzodiazepin-10-one and 0.75 g of pyrrolidine are warmed at 80° C. for 4 hours in 50 ml of dioxane. After the solvent has been stripped off in vacuo, the residue is taken up in a little saturated sodium carbonate solution. The mixture is extracted three times with 30 ml of ethyl acetate each time, the combined extracts are dried over sodium sulfate, and the solvent is stripped off in vacuo. The remaining crystalline residue is recrystallized from a little acetonitrile. Yield: 1.5 g of the title compound of m.p. 185° C.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[CH:4][C:3]=1[O:14][CH3:15].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:15][O:14][C:3]1[CH:4]=[C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])[CH:12]=[CH:13][C:2]=1[O:1][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23]
Reactant: OCCCCCCBr
Reactant: COC(=O)/C=C/c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)/C=C/c1ccc(OCCCCCCO)c(OC)c1

Procedure:
A mixture of 0.5 g of methyl (E)-4-hydroxy-3-methoxycinnamate, 10 ml of 2-butanone, 0.35 ml of 6-bromohexanol and 1 g of ground potassium carbonate was heated under reflux for 5 hrs. Then, the reaction mixture was cooled and partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulphate, filtered and evaporated. Chromatography on 100 g of silica gel with toluene/ethyl acetate (1:1) gave 750 ml of methyl (E)-3-[3-methoxy-4-(6-hydroxyhexyloxy)phenyl]acrylate as a colorless solid, λmax. (CH2Cl2): 323 nm (ε=20513).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[NH:11]1[CH:15]=[C:14]([S:16](Cl)(=[O:18])=[O:17])[N:13]=[CH:12]1>C1(C)C=CC=CC=1>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[S:16]([C:14]1[N:13]=[CH:12][NH:11][CH:15]=1)(=[O:18])=[O:17]
Reactant: O=S(=O)(Cl)c1c[nH]cn1
Reactant: c1ccc2c(c1)CCNC2
Solvent: Cc1ccccc1
Product: O=S(=O)(c1c[nH]cn1)N1CCc2ccccc2C1
Reaction time: 8 h

Procedure:
A solution of 1,2,3,4-tetrahydroisoquinoline (13.22 g) and imidazole-4-sulphonyl chloride (7.57 g) in toluene (70 ml) was stirred for 1 hour and then allowed to stand overnight. It was evaporated and the residue partitioned between diethyl ether and aqueous sodium hydroxide. The aqueous layer was clarified by ether extraction and then acidified with concentrated hydrochloric acid. The precipitate was collected, washed with water and dried to give crude 4-(1,2,3,4-tetrahydroisoquinolin-2-ylsulphonyl)-1H-imidazole. A solution of this product (9 g) in dimethylformamide was treated with sodium hydride (1.13 g of 80% in oil), followed by dimethylsulphamoyl chloride (5.4 g). The mixture was stirred for 1 hour and poured into water. The precipitate was collected and worked up to give the starting material.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=[O:8])[CH:2]=[CH2:3].[CH3:13][C:14]1[O:18][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:16][C:15]=1[CH2:25][CH2:26]OS(C)(=O)=O>>[CH2:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:26][CH2:25][C:15]1[N:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:18][C:14]=1[CH3:13])[CH:7]=[O:8])[CH:2]=[CH2:3]
Reactant: Cc1oc(-c2ccccc2)nc1CCOS(C)(=O)=O
Reactant: C=CCc1cc(C=O)ccc1O
Product: C=CCc1cc(C=O)ccc1OCCc1nc(-c2ccccc2)oc1C

Procedure:
In analogy to the procedures described in examples 114 b], c] and d], 3-allyl-4-hydroxy-benzaldehyde was reacted with methanesulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester [PCT Int. Appl. (2000) WO0008002] to give 3-allyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde. Treatment of 3-allyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde with (benzyloxycarbonyl-ethoxy-methyl)-triphenyl-phosphonium chloride (prepared in analogy to the procedure described for the synthesis of (benzyloxycarbonyl-methoxy-methyl)-triphenyl-phosphonium chloride in example 114 a]) then gave 3-{3-allyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2(Z,E)-ethoxy-acrylic acid benzyl ester, which was hydrogenated to yield [rac]-2-ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-3-propyl-phenyl}-propionic acid as colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C:5]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([CH2:19][CH:20]=O)[CH2:6][CH2:7][CH2:8][CH2:9][B:10]1[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]1)[CH3:2].[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([O:3][C:4](=[O:30])[C:5]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])([CH2:19][CH2:20][N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1)[CH2:6][CH2:7][CH2:8][CH2:9][B:10]1[O:14][C:13]([CH3:15])([CH3:16])[C:12]([CH3:18])([CH3:17])[O:11]1)[CH3:2]
Reactant: CCOC(=O)C(CC=O)(CCCCB1OC(C)(C)C(C)(C)O1)NC(=O)OC(C)(C)C
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCOC(=O)C(CCCCB1OC(C)(C)C(C)(C)O1)(CCN1CCCC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
A solution of 2-tert-Butoxycarbonylamino-2-(2-oxo-ethyl)-6-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-hexanoic acid ethyl ester (100 mg, 0.23 mmol, 1.0 equiv.) and pyrrolidine (21 mg, 0.29 mmol, 1.2 equiv.) in 1,2-dichloroethane (0.5 mL) was treated with sodium triacetoxyborohydride (125 mg, 0.59 mmol) in one portion. After stirring at room temperature overnight, the reaction mixture was quenched with saturated aqueous NaHCO3 (1 mL) and stirred for an additional 5 min. The resulting mixture was added to a separatory funnel, diluted with saturated aqueous NaCl (5 mL) and extracted with dichloromethane (2×10 mL). The organic layer was dried over MgSO4, filtered and concentration under reduced pressure. Purification by flash column chromatography eluting with 5% methanol in chloroform to give 2-tert-butoxycarbonylamino-2-(2-pyrrolidin-yl-ethyl)-6-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-hexanoic acid ethyl ester as a pale yellow oil (92 mg, 83%). Rf 0.32 (10% methanol in dichloromethane); 1H NMR (CDCl3, 300 MHz) δ 5.67 (br, s, NH, 1H), 4.19 (m, 2H), 2.46-2.82 (m, 6H), 2.18 (m, 2H), 1.88 (m, 3H), 1.76 (m, 2H), 1.42 (s, 9H), 1.26-1.41 (m, 3H), 1.28 (t, J=7.0 Hz, 3H), 1.22 (s, 12H), 1.06 (m, 1H) and 0.73 (t, J=7.5 Hz, 2H).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[F:13][C:14]1[C:22]([O:23][C:24]2[C:33]3[C:28](=[CH:29][C:30]([OH:36])=[C:31]([O:34][CH3:35])[CH:32]=3)[N:27]=[N:26][CH:25]=2)=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[C:17]([CH3:37])[NH:18]2.O[CH2:39][CH2:40][O:41][C:42]1[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C>[F:13][C:14]1[C:22]([O:23][C:24]2[C:33]3[C:28](=[CH:29][C:30]([O:36][CH2:39][CH2:40][O:41][C:42]4[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=4)=[C:31]([O:34][CH3:35])[CH:32]=3)[N:27]=[N:26][CH:25]=2)=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[C:17]([CH3:37])[NH:18]2
Reactant: OCCOc1ccncc1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1OCCOc1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.6 %

Procedure:
DEAD (0.19 ml, 1.2 mmol) was added dropwise to a solution of 4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxycinnoline (0.2 g, 0.6 mmol), (prepared as described in Example 4), 4-(2-hydroxyethoxy)pyridine (0.125 g, 0.9 mmol), (J. Chem. Soc. Perkin II, 1987, 1867), and triphenylphosphine (0.31 g, 1.2 mmol) in DMF (4 ml). After stirring for 2 hours at ambient temperature, the volatiles were removed under vacuum to give an oil that crystallised on standing. The solid was triturated with methylene chloride, filtered, washed with methylene chloride and dried under vacuum to give 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(2-(4-pyridyloxy)ethoxy)cinnoline (90 mg, 33%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([CH2:10][CH3:11])[CH:3]=1.[H-].[Na+].[CH3:14]N(C=O)C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH3:14])=[C:4]([CH2:10][CH3:11])[CH:3]=1
Reactant: CCc1cc(Br)ccc1CO
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CCc1cc(Br)ccc1COC
Reaction time: 16 h
Yield: 69 %

Procedure:
To a solution of (4-bromo-2-ethyl-phenyl)-methanol (0.700 g, 3.25 mmol) in DMF (30 mL) was added NaH (0.156 g, 60% dispersion in mineral oil, 3.90 mmol) followed by Mel (0.22 mL, 3.58 mmol). The mixture was stirred for 16 hours and then partitioned between H2O and EtOAc. The aqueous layer was extracted with EtOAc, and the organic layer was washed with brine, dried over Na2SO4, and concentrated to a yellow oil. Purification by flash column chromatography (0% to 4% EtOAc in hexanes) gave the product as a clear oil (0.51 g, 69%). 1H NMR (300 MHz, CDCl3): δ 1.15 (t, J=7.6 Hz, 3 H), 2.58 (q, J=7.5 Hz, 2 H), 3.32 (s, 3 H), 4.35 (s, 2 H), 7.12 (m, 1 H), 7.24 (m, 1 H), 7.27 (d, J=2.1 Hz, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:15][CH:14]([C:16]([O:18]C)=[O:17])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[OH-].[Na+].Cl>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:15][CH:14]([C:16]([OH:18])=[O:17])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: COC(=O)C1Cc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1Cc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Temperature: 25 °C
Reaction time: 12 h
Yield: 108.3 %

Procedure:
To a solution of 8-bromo-5-methoxycarbonyl-5,6-dihydro-1H-pyrrolo[1,2,3-de]quinoxaline-2,3-dione (256 mg, 0.76 mmol) in a mixture of THF (5 mL) and methanol (5 mL) was added aqueous 1N NaOH (2.5 mL) and the mixture was stirred for 12 h at room temperature. Aqueous 1N HCl was added and the resulting mixture was concentrated to ca. 5 mL. The precipitates formed were collected by filtration, washed with distilled water, and dried in vacuo to give 256 mg of the title compound (quant): mp 285° C. (dec); 1H NMR (270 MHz, DMSO-d6) δ13.45 (bs, 1H), 12.09 (s, 1H), 7.22 (d, 1H, J=1Hz), 7.08 (d, 1H, J=1 Hz), 5.18 (dd, 1H, J=11, 4 Hz), 3.79 (dd, 1H, J=17, 11 Hz), 3.33 (dd, 1H, J=17, 4 Hz).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16].C(=O)([O-])[O-].[K+].[K+]>[I-].[K+].C(O)CCC>[OH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CNc1ccccc1
Reactant: OCCCCCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Product: CN(CCCCCCO)c1ccccc1
Reaction time: 96 h
Yield: 71 %

Procedure:
A mixture of 153 g (1.43 mol) freshly distilled N-methylaniline, 200 g (1.46 mol) 6-chlorohexanol, 200 g (1.45 mol) potassium carbonate, 6 g potassium iodide, and 750 mL n-butanol was heated at reflux under nitrogen with vigorous mechanical stirring for 4 days. The solution was cooled, filtered, and the solvent was removed at reduced pressure. The residue was distilled in vacuo to produce 210 g (71%) of a colorless oil, bp 153°-166° C. (0.10 mm).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@@H:9]2[CH2:13][C@H:12]([CH2:14][OH:15])[C@@H:11]([OH:16])[C@H:10]2[OH:17])[C:3]=1[CH2:18][CH:19](OCC)OCC.Cl>O1CCOCC1>[Cl:1][C:2]1[C:3]2[CH:18]=[CH:19][N:8]([C@@H:9]3[CH2:13][C@H:12]([CH2:14][OH:15])[C@@H:11]([OH:16])[C@H:10]3[OH:17])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCOC(Cc1c(Cl)ncnc1N[C@@H]1C[C@H](CO)[C@@H](O)[C@H]1O)OCC
Agent: Cl
Solvent: C1COCCO1
Product: OC[C@H]1C[C@@H](n2ccc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 69.5 h

Procedure:
A suspension of crude (1R,2S,3R,5R)-3-((6-chloro-5-(2,2-diethoxyethyl)pyrimidin-4-yl)amino)-5-(hydroxymethyl)cyclopentane-1,2-diol in 1,4-dioxane (160 mL) was treated with a 1 M aqueous solution of HCl (30 in L, 30 mmol) and stirred at RT for 69.5 h; HPLC indicated clean conversion to one product, LC MS showed mass for desired product. The reaction mixture was neutralized with concentrated aqueous NH4OH (to pH 7) and the volatiles were removed in vacuo to afford a brown slurry, which was carried on without further purification: MS (ESI+) for C12H14ClN3O3 m/z 284.1 (M+H)+; MS (ESI−) for C12H14ClN3O3 m/z 282.2 (M−H)−, 328.2 (M+HCO2)−; HPLC purity >95% (ret. time, 1.947 min). Variation on route from J. Med. Chem. 10, 665 (1967).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:26])[C:5]([C:23]([OH:25])=[O:24])=[CH:6][N:7]2[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22].[OH:27][CH:28]1[CH2:32][CH:31]([CH3:33])[NH:30][CH2:29]1>>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:30]2[CH:31]([CH3:33])[CH2:32][CH:28]([OH:27])[CH2:29]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:26])[C:5]([C:23]([OH:25])=[O:24])=[CH:6][N:7]2[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22]
Reactant: CC1CC(O)CN1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2-c1ccc(F)cc1F
Product: CC1CC(O)CN1c1c(F)c(N)c2c(=O)c(C(=O)O)cn(-c3ccc(F)cc3F)c2c1F
Yield: 64 %

Procedure:
The condensation of 5-Amino-1-(2′,4′-difluorophenyl)-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid with 3-hydroxy-5-methylpyrrolidine in a similar manner as described in example 1 gave the titled product. Yield 64%, m.p ° C., C21H17F4N3O4, m/z 453. (M+1)
Reaction SMILES: [C:1]([N:8]([CH2:10][CH2:11][CH2:12][S:13]([C:16]1[CH:17]=[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]3[N:32]([C:33]4[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=4[F:40])[N:31]=[C:30]([C:41]([F:47])([F:46])[C:42]([F:45])([F:44])[F:43])[CH2:29]3)[CH:23]=2)[CH:19]=[CH:20][CH:21]=1)(=[O:15])=[O:14])C)(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[F:40][C:34]1[CH:35]=[C:36]([F:39])[CH:37]=[CH:38][C:33]=1[N:32]1[CH:28]([C:24]2[CH:23]=[C:22]([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([S:13]([CH2:12][CH2:11][CH2:10][NH:8][CH3:1])(=[O:14])=[O:15])[CH:17]=3)[CH:27]=[CH:26][CH:25]=2)[CH2:29][C:30]([C:41]([F:46])([F:47])[C:42]([F:45])([F:43])[F:44])=[N:31]1
Reactant: CN(CCCS(=O)(=O)c1cccc(-c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)c1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCCS(=O)(=O)c1cccc(-c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-{3′[3-(N-BOC-N-methyl-amino)-propane-1-sulfonyl]-biphenyl-3-yl}-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (20.0 mg, 0.03 mmol) prepared in Example 85 and trifluoroacetic acid (22.3 uL, 0.29 mmol) were added at 0° C. to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 1 hour, quenched with a saturated solution of sodium hydrogen carbonate, and then extracted with dichloromethane three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a residue as a white liquid. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2) to give 5.0 mg of the titled compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[CH2:7][CH2:8][CH2:9][CH:10]([NH2:12])[CH2:11][C:5]=2[CH:4]=1.[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C@@H:29]([O:32][Si](CC)(CC)CC)[CH2:30]I)=[CH:25][C:24]=1[NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)C(C)C)(C)C.S([O-])(O)=O.[Na+]>CN(C)C(=O)C>[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C@@H:29]([OH:32])[CH2:30][NH:12][CH:10]2[CH2:9][CH2:8][CH2:7][C:6]3[CH:13]=[CH:14][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[CH2:11]2)=[CH:25][C:24]=1[NH:40][S:41]([CH3:44])(=[O:42])=[O:43])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1ccc2c(c1)CC(N)CCC2
Reactant: CC[Si](CC)(CC)O[C@@H](CI)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COc1ccc2c(c1)CC(NC[C@H](O)c1ccc(OCc3ccccc3)c(NS(C)(=O)=O)c1)CCC2
Yield: 20 %

Procedure:
Under nitrogen, a solution of 3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ylamine (720 mg), N-[2-benzyloxy-5-[(1R)-2-iodo-1-(triethylsilyloxy)ethyl]phenyl]-methanesulfonamide (2.1 g) and N,N-diisopropylethylamine (2.6 ml) in N,N-dimethylacetamide (10 ml) was stirred at 110° C. for 96 hours. The resulting mixture was poured into aqueous 10% sodium hydrogensulfite and extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (chloroform:methanol=40:1 to 20:1) to give N-[2-benzyloxy-5-[(1R)-1-hydroxy-2-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ylamino)ethyl]phenyl]methanesulfonamide (381 mg).