Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].C(OC(C)C)(C)C.[Cl:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>O>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][C:20](=[O:21])[CH2:19][CH2:18][Cl:17]
Reactant: O=C(Cl)CCCl
Reactant: Cc1cccc(C)c1N
Solvent: O
Solvent: CC(C)OC(C)C
Product: Cc1cccc(C)c1NC(=O)CCCl
Reaction time: 3 h
Yield: 59.7 %

Procedure:
A 2 l three-necked flask, is charged with 121.8 g of 2,6-dimethylaniline, 300 ml of isopropyl ether and 150 ml of water. 126.5 g of 3-chloropropanoyl chloride are added at a rate such that the internal temperature is between 5 and 10° C. At the end of the addition, the reaction medium is stirred for 3 h. The precipitate formed is filtered off with suction, washed with isopropyl ether and then with water and finally dried. 126 g of white crystals are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:15])[CH2:13][CH3:14])[CH2:7][CH2:6][C:5]2=[O:16].CO[CH:19](OC)[N:20](C)[CH3:21].C(N(CC)CC)C>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:15])[CH2:13][CH3:14])[CH2:7][C:6](=[CH:19][NH:20][CH3:21])[C:5]2=[O:16]
Reactant: COC(OC)N(C)C
Reactant: CCC(=O)N1CCC(=O)c2cc(Cl)ccc21
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCC(=O)N1CC(=CNC)C(=O)c2cc(Cl)ccc21
Reaction time: 1 h
Yield: 86.1 %

Procedure:
A solution of 6-chloro-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (2 g), N,N-dimethylformamide dimethyl acetal (7.009 g), and triethylamine (0.87 g) in benzene (50 m) was refluxed with stirring for 1 hour and then about three-fourths of the solvent was distilled slowly at atmospheric pressure over a period ximately 1 hour. To the residue was added benzene (100 ml) and the solvent was distilled again. The resulting solid was collected by filtration, washed with diethyl ether, and dried to give 6-chloro-3-methylaminomethylene-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (2.02 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[CH3:11][C:12]1([CH3:19])[CH2:17][C:16](=[O:18])[O:15][C:13]1=[O:14]>O1CCCC1>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][C:16](=[O:18])[CH2:17][C:12]([CH3:19])([CH3:11])[C:13]([OH:15])=[O:14])[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: CC1(C)CC(=O)OC1=O
Solvent: C1CCOC1
Product: CC(C)(CC(=O)Nc1cccc([N+](=O)[O-])c1)C(=O)O
Yield: 94.4 %

Procedure:
3-Nitroaniline (27.6 grams (g)) was dissolved by stirring in 200 milliliters (ml) tetrahydrofuran. 2,2-Dimethyl succinic anhydride (25.6 g) in some tetrahydrofuran was added dropwise with stirring. The reaction was stirred at room temperature for four hours. The reaction product was recovered by addition of 500 ml ethyl acetate, followed by three washings with 3% hydrochloric acid and one with distilled water. The solution was dried with sodium sulfate and rotary evaporated to yield 50.2 g of N-(3-nitrophenyl)-2,2-dimethylsuccinamic acid.
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>O1CCCC1.CN(C)C=O>[Si:17]([N:13]1[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: c1ccc2c(c1)Nc1ccccc1O2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)N1c2ccccc2Oc2ccccc21

Procedure:
5 Grams of phenoxazine was dissolved in 100 ml of dry tetrahydrofuran, then 1.63 g of 50% sodium hydride in mineral oil was added and the mixture refluxed for 30 minutes. Then 6.19 g of t-butyldimethylsilyl chloride in dimethylformamide (2 ml) and tetrahydrofuran (8 ml) was added and reflux was continued for five more minutes. The reaction was quenched by the addition of water, the organic layer was separated and dried over sodium sulfate. Then the solvent was removed under reduced pressure and the residue purified by column chromatography (silica as solid phase, hexane:ethylacetate (95:5) as mobile phase). N-t-butyldimethylsilylphenoxazine had a melting point of 57° C. after crystallization from pentane.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](F)[N:16]=1>C(OCC)C>[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:16]=1
Reactant: Fc1ccc(Br)cc1
Reactant: Fc1cccc(F)n1
Agent: [Li]CCCC
Solvent: CCOCC
Product: Fc1ccc(-c2cccc(F)n2)cc1
Temperature: -40 °C
Reaction time: 1 h
Yield: 41.4 %

Procedure:
Butyl lithium (105.0 mL, 0.26 mol, 2.5M solution in hexane) is added to a solution of 1-bromo-4-fluoro benzene (34.3 mL, 0.31 mol) in anhydrous diethyl ether (200 mL) at -20° C. The mixture is stirred for 60 min and then chilled to -40° C. 2,6-Difluoropyridine (22.7 mL, 0.25 mol) is added and the reaction mixture is allowed to warm to ambient temperature. Subsequently, the mixture is washed with saturated aqueous ammonium chloride (300 mL). The layers are separated and the aqueous layer is washed with diethyl ether 3 times (100 mL each). After drying of the combined organic layers with anhydrous magnesium sulphate, the solvent is removed in vacuo. The crude product is purified by flash column chromatography (silica gel, hexane/AcOEt 8/2) yielding colorless crystals of 2-fluoro-6-(4'-fluorophenyl)-pyridine (19.8 g, 41.0% of th.) with mp 34° C.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[C:15]1([C:21]2[CH2:22][CH2:23][NH:24][CH2:25][CH:26]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29].CO>C(OCC)(=O)C>[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:24]3[CH2:23][CH:22]=[C:21]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:26][CH2:25]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CC=C(c2ccccc2)CC1

Procedure:
The title compound was prepared according to Example 1 from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-phenyl-1,2,3,6-tetrahydropyridine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 60% overall yield as a white foam. FDMS m/e=348 (M+ of free base). α[D]589 =-17.09 (c=0.49, methanol).
Reaction SMILES: [C:1]([NH:4][S:5]([C:8]1[CH:9]=[C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:18]=2)[C:11]([OH:16])=[C:12]([CH:14]=O)[CH:13]=1)(=[O:7])=[O:6])(=[O:3])[CH3:2].[NH2:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][C:36]=1[NH2:37])[C:31]([NH2:33])=[NH:32].C1(=O)C=CC(=O)C=C1>CO>[C:1]([NH:4][S:5]([C:8]1[CH:13]=[C:12]([C:14]2[NH:37][C:36]3[CH:35]=[CH:34][C:30]([C:31]([NH2:33])=[NH:32])=[CH:29][C:28]=3[N:27]=2)[C:11]([OH:16])=[C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([S:23](=[O:25])(=[O:24])[NH2:26])[CH:18]=2)[CH:9]=1)(=[O:7])=[O:6])(=[O:3])[CH3:2]
Reactant: CC(=O)NS(=O)(=O)c1cc(C=O)c(O)c(-c2cccc(S(N)(=O)=O)c2)c1
Reactant: N=C(N)c1ccc(N)c(N)c1
Agent: O=C1C=CC(=O)C=C1
Solvent: CO
Product: CC(=O)NS(=O)(=O)c1cc(-c2cccc(S(N)(=O)=O)c2)c(O)c(-c2nc3cc(C(=N)N)ccc3[nH]2)c1
Temperature: 25 °C
Yield: 14 %

Procedure:
N-acetyl 5-formyl-6-hydroxy-biphenyl-3,3′-disulfonamide (74 mg, 0.19 mmol) was dissolved in methanol (10 mL)and stirred at room temperature. 3,4-Diaminobenzamidine (39 mg, 0.21 mmol) and 1,4-benzoquinone (20 mg, 0.2 mmol) were added to the solution and the mixture was refluxed for 1 hour. The solvent was removed by rotary evaporation under reduced pressure and the residue was dissolved in water and acetonitrile and purified by reverse phase HPLC (0.02N HCl/ACN) to give 2-(5-acetylsulfarnoyl-2-hydroxy-3′-sulfamoyl-biphenyl-3-yl)-1H-benzoimidazole-5-carboxamidine (14.1 mg) as a yellow amorphous powder. MS m/z: 527.4 (M−H+) and 529.3 (M+H+). 1H NMR (400 MHz, DMSO-d6): δ 9.36 (bs, 2H), 8.94 (bs, 2H), 8.08 (d, J=2.2 Hz, 1H), 8.22 (bs, 1H), 8.10 (t, J=1.5 Hz, 1H), 7.96 (d, J=2.2 Hz, 1H) 7.89 (d, J=1.8 Hz, 1H), 7.87-7.85 (m, 2H), 7.76 )dd, J=10, 1.5 Hz, 1H), 7.71 (t, J=7.7 Hz, 1H), 7.46 (s, 2H) and 1.96 (s, 3H).
Reaction SMILES: C([O:3][C:4](=[O:42])[C:5]([O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][C:24]2[N:25]=[C:26]([C:30]3[CH:31]=[C:32]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH:33]=[CH:34][CH:35]=3)[O:27][C:28]=2[CH3:29])=[CH:17][CH:16]=1)([CH3:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.[OH-].[Na+]>CO>[C:32]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:33]=[CH:34][CH:35]=[C:30]([C:26]2[O:27][C:28]([CH3:29])=[C:24]([CH2:23][CH2:22][O:21][C:18]3[CH:19]=[CH:20][C:15]([O:14][C:5]([CH3:13])([CH2:6][C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:4]([OH:42])=[O:3])=[CH:16][CH:17]=3)[N:25]=2)[CH:31]=1
Reactant: CCOC(=O)C(C)(Cc1ccccc1)Oc1ccc(OCCc2nc(-c3cccc(-c4ccccc4)c3)oc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1oc(-c2cccc(-c3ccccc3)c2)nc1CCOc1ccc(OC(C)(Cc2ccccc2)C(=O)O)cc1
Reaction time: 0.5 h

Procedure:
2-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenoxy}-2-methyl-3-phenyl-propionic acid ethyl ester (24.7 mmol) was dissolved in methanol (200 mL) and 2N NaOH (150 mL) was added. The resulting cloudy solution became clear after 30 min and the reaction was stirred vigorously overnight. The solution was concentrated under reduced pressure, diluted with H2O (100 mL) and acidified to pH=1 with 5N HCl. The mixture was extracted with ethyl acetate (2×200 mL), dried (MgSO4), and concentrated under reduced pressure to provide an oil. The oil (8.23 g) was recrystallized from ethyl acetate (24 mL) and hexanes (56 mL) to afford 2-{4-[2-(2-biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenoxy}-2-methyl-3-phenyl-propionic acid as colorless needles after drying at 50° C. under vacuum for 6 h: 1H NMR (400 MHz, CDCl3) δ 8.23-8.21 (m, 1H), 7.94 (d, 1H, J=7.43 Hz), 7.65 (dd, 3H, J=7.04 Hz, J=1.17 Hz), 7.50 (t, 1H, J=7.63 Hz), 7.45 (t, 2H, J=7.04 Hz), 7.38-7.28 (m, 1H), 7.28-7.25 (m, 5H), 6.84 (d, 2H, J=8.99 Hz), 6.75 (d, 2H, J=8.99 Hz), 4.16 (t, 2H, J=6.45 Hz), 3.31 (d, 1H, J=13.69 Hz),3.14(d, 1H, J=13.69 Hz). 3.01 (t, 2H, J=6.45 Hz), 2.40 (s, 3H), 1.34 (s, 3H); HRMS (ES+) m/z exact mass calculated for C34H32NO5 534.2280, found 534.2278.
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[CH3:25])[CH:20]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:19]2=[O:34])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][N:36]([CH:38](N(C)C)OC(C)(C)C)[CH3:37].C(OCC)(=O)C.O>CN(C)C=O>[CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[CH:25]=[CH:35][N:36]([CH3:38])[CH3:37])[CH:20]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:19]2=[O:34])=[O:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)OC(C)(C)C)C2SC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)OC(C)(C)C)C2SC1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 100.1 %

Procedure:
2-Benzhydryloxycarbonyl-7-tert.-butoxycarbonylamino-3-methyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (90.5 g) is dissolved in anhydrous N,N-dimethylformamide (400 cc). The solution obtained is heated at 80° C. under an atmosphere of nitrogen. A solution, preheated to 80° C., of bis-dimethylamino-tert.-butoxymethane (36.1 g) in anhydrous N,N-dimethylformamide (60 cc) is then added rapidly. The reaction mixture is kept at 80° C. for 5 minutes and then poured into ethyl acetate (3 liters). After addition of distilled water (1 liter), the organic phase is decanted, washed with distilled water (4×1 liter), dried over sodium sulphate and filtered in the presence of decolorising charcoal. The filtrate is concentrated to dryness under reduced pressure (20 mm Hg) at 30° C., and 2-benzhydryloxycarbonyl-7-tert.-butoxycarbonylamino-3-(2-dimethylaminovinyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (E-form) (101 g) is obtained in the form of an orange-coloured froth.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][C:14]([CH3:17])([NH2:16])[CH3:15].[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]=O>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][C:14]([CH3:17])([NH:16][CH2:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=1)[CH3:15]
Reactant: O=Cc1ccccn1
Reactant: CC(C)(N)COc1ccc2ccccc2c1Cl
Product: CC(C)(COc1ccc2ccccc2c1Cl)NCc1ccccn1
Yield: 34 %

Procedure:
Prepared from 1-[(1-chloronaphthalen-2-yl)oxy]-2-methylpropan-2-amine and pyridine-2 carbaldehyde in 34% yield as a colourless oil.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[CH2:29][CH2:30][NH2:31].[BH4-].[Na+]>CO>[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[CH2:29][CH2:30][NH:31][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1
Reactant: NCCc1ccc(F)cc1F
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(CNCCc2ccc(F)cc2F)ccc1Oc1ccc(C(N)=O)cn1
Reaction time: 8 h

Procedure:
Place 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.300 g, 1.10 mmol), 2-(2,4-difluorophenyl)ethylamine (0.343 g, 2.184 mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol (4.4 mL), cap and stir overnight. Add NaBH4 (ca. 3-5 eq in two portions) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 2% to 20% (2.0 M NH3 in methanol) in ethyl acetate to give 6-(4-{[2-(2,4-difluorophenyl)ethylamino]methyl}-2-methoxyphenoxy)nicotinamide. Dissolve the compound in methanol (5.0 mL) and add 1 equivalent of 0.50 M methanesulfonic acid in dichloromethane. Stir the solution for a short time before concentrating to give the title compound: TOF MS ES+ 414.2 (M+H)+, HRMS calcd for C22H22N3O3F2 414.1629 (M+H)+, found 414.1613, time 0.52 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=11.6 min, 100% purity.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH:7]1[NH:19][S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]=[C:33]([CH3:41])[CH:32]=2)=[CH:25][CH:24]=1)(=[O:22])=[O:21])=[O:5])C.[OH-].[Li+]>C1COCC1.CO.O>[C:15]([O:14][C:12]([N:9]1[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH:7]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=[C:33]([CH3:41])[CH:32]=3)=[CH:25][CH:24]=2)(=[O:21])=[O:22])[CH2:8]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1NS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(COc2ccc(S(=O)(=O)NC3CN(C(=O)OC(C)(C)C)CCC3C(=O)O)cc2)c2ccccc2n1

Procedure:
A solution of 3-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (0.6 g, 1.03 mmol) and lithium hydroxide (0.148 g, 6.18 mmol) in THF:methanol:water (3:2:2 mL) was stirred at 25° C. for 19 h. The solution was then concentrated in vacuo to provide 3-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester as a crude solid (0.55 g, 96%). MS: 556 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.Cl[CH2:10][CH:11]=O>C(=O)([O-])O.[Na+]>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([CH:10]=[CH:11][N:8]=2)[CH:7]=1
Reactant: O=CCCl
Reactant: Nc1ncc(Br)cn1
Agent: O=C([O-])O
Agent: [Na+]
Product: Brc1cnc2nccn2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
50 mmol of 5-bromo-pyrimidin-2-ylamine are dissolved in 200 ml of saturated aqueous sodium hydrogencarbonate solution. 55 mmol of chloroacetaldehyde are added to the reaction mixture and the mixture is stirred for 24 hours at 25° C. The mixture is extracted with ethyl acetate (3×300 ml) and the combined extracts are dried over sodium sulphate and evaporated under reduced pressure. Flash chromatography (SiO2 60 F) of the residue provides the title compound which is identified on the basis of its Rf-value.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[C:7]2[C:3]=1[CH2:4][CH:5]([CH3:15])[C:6]2([CH3:14])[CH3:13].[CH3:16][N:17]=[C:18]=[O:19]>C(N(CC)CC)C.O>[CH3:13][C:6]1([CH3:14])[C:7]2[C:3](=[C:2]([O:1][C:18](=[O:19])[NH:17][CH3:16])[C:10]([CH3:11])=[CH:9][C:8]=2[CH3:12])[CH2:4][CH:5]1[CH3:15]
Reactant: CN=C=O
Reactant: Cc1cc(C)c2c(c1O)CC(C)C2(C)C
Solvent: CCN(CC)CC
Solvent: O
Product: CNC(=O)Oc1c(C)cc(C)c2c1CC(C)C2(C)C
Temperature: 70 °C
Yield: 63.7 %

Procedure:
34 g of 4-hydroxy-1,1,2,5,7-pentamethyl-indane, 14.3 g of methyl isocyanate and a few drops of triethylamine were dissolved in 102 ml of ligroin and the solution was stirred under slight reflux (about 70° C.) overnight. After cooling to 30° C., the mixture was stirred with 40 ml of water and the colorless crystals were filtered off and dried. Recrystallization from ligroin and toluene gave 27.7 g of N-methyl-carbamic acid 1,1,2,5,7-pentamethylindan-4-yl ester of melting point 130.5°-131° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[S:12][C:11]([CH2:13][NH:14][OH:15])=[CH:10][CH:9]=1.C[Si]([N:22]=[C:23]=[O:24])(C)C.Cl>O1CCOCC1>[OH:15][N:14]([CH2:13][C:11]1[S:12][C:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([F:1])([F:16])[F:17])=[CH:9][CH:10]=1)[C:23]([NH2:22])=[O:24]
Reactant: C[Si](C)(C)N=C=O
Reactant: ONCc1ccc(CCCCCC(F)(F)F)s1
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)N(O)Cc1ccc(CCCCCC(F)(F)F)s1
Reaction time: 1 h

Procedure:
To a solution of N-[5-(6,6,6-trifluorohexyl)thien-2-ylmethyl]hydroxylamine (1.4 g) in dioxan (50 ml) under nitrogen with stirring, was added trimethylsilyl isocyanate (1.42 ml) and the reaction mixture stirred for 1 hour, poured onto 2N hydrochloric acid (100 ml), extracted with ether (2×100 ml), dried over magnesium sulphate and evaporated under reduced pressure to give a pale yellow oil. The oil was flash chromatographed on a Sorbsil C60-40/60H column using 4:1 hexane/ethyl acetate to give a white solid. Recrystallised from ether/petroleum ether (40°-60° C.) to give a white crystlline solid m.p. 94° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[C:8]([CH2:16]Br)[N:9]=[CH:10]2.[CH3:19][NH:20][CH3:21]>C1COCC1>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[C:8]([CH2:16][N:20]([CH3:21])[CH3:19])[N:9]=[CH:10]2
Reactant: CNC
Reactant: COC(=O)Cc1c(Cl)ccc2cnc(CBr)cc12
Solvent: C1CCOC1
Product: COC(=O)Cc1c(Cl)ccc2cnc(CN(C)C)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of (3-bromomethyl-6-chloro-isoquinolin-5-yl)-acetic acid methyl ester (500 mg, 1.52 mmol) in THF (50 mL) was added a 50% solution of dimethylamine in THF (20 mL). The reaction mixture was stirred for 30 min. at room temperature, followed by removal of the solvents in vacuo. The residue was purified by flash column chromatography (silica gel, gradient of CH2Cl2/MeOH 100:0 to 95:5) to afford the title compound as a yellow oil (445 mg, 1.52 mmol, 100%). MS (ES+): 293 (M(C15H1735ClN2O2)+H)+.
Reaction SMILES: FC1C=C(C=CC=1)C=NO.[F:11][C:12]1[CH:13]=[C:14]([C:18]2[C:22]3[C:23](=[O:27])[CH2:24][CH2:25][CH2:26][C:21]=3[O:20][N:19]=2)[CH:15]=[CH:16][CH:17]=1.C([N-]C(C)C)(C)C.[Li+].[Cl:36][CH2:37][CH2:38][CH2:39]I>C1COCC1.CCOCC.O>[Cl:36][CH2:37][CH2:38][CH2:39][CH:24]1[C:23](=[O:27])[C:22]2[C:18]([C:14]3[CH:15]=[CH:16][CH:17]=[C:12]([F:11])[CH:13]=3)=[N:19][O:20][C:21]=2[CH2:26][CH2:25]1
Reactant: ClCCCI
Reactant: O=C1CCCc2onc(-c3cccc(F)c3)c21
Agent: CC(C)[N-]C(C)C
Agent: ON=Cc1cccc(F)c1
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C1c2c(-c3cccc(F)c3)noc2CCC1CCCCl
Temperature: -78 °C

Procedure:
In a similar manner to that of Examples 7a-d starting with 3-fluorobenzaldehyde oxime, the starting ketone is prepared. In 200 ml anhydrous THF was dissolved 11.4 g 6,7-dihydro-3-(3-fluorophenyl)-1,2-benzisoxazol-4(5H)-one under nitrogen atmosphere with stirring. The solution was cooled to -78° C. and 49.4 ml lithium diisopropylamide (1.5 molar in cyclohexane) was added dropwise. The resulting solution was stirred for ten minutes at -78° C. and 6.4 ml 1-chloro-3-iodopropane was added. Upon warming to room temperature, the reaction mixture was poured into water and ether. The layers were separated and the aqueous phase was extracted twice with dichloromethane and once with ether. The combined organic layers were washed with brine and dried (MgSO4). Filtration and concentration gave the crude product. Column chromatography on silica gel (start with 10% dichloromethane in hexane and gradually increase polarity to 100% dichloromethane) gave 4.5 g of 5-(3-chloropropyl)-6,7-dihydro-3-(3-fluorophenyl)-1,2-benzisoxazol- 4(5H)-one.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2O)[NH:4][N:3]=1.CCN(C1C=CC=CC=1)CC.O(Cl)[Cl:24]>>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[Cl:24])[NH:4][N:3]=1
Reactant: Oc1ncnc2[nH]nc(Br)c12
Reactant: ClOCl
Solvent: CCN(CC)c1ccccc1
Product: Clc1ncnc2[nH]nc(Br)c12
Temperature: 106 °C

Procedure:
3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-ol (Intermediate A) (15.08 g, 70.5 mmol) was suspended in 189 ml of phosphous oxychloride. Diethylaniline (19 ml, 119.4 mmol) was added and the resulting reaction mixture was heated to 106° C. for 2 hours. After cooling to room temperature, the solvent was removed and the resulting amber syrup was poured to 300 ml of ice-water. 20 minutes later, the aqueous layer was extracted with diethyl ether (500 ml×4). The combined organic layer was washed, dried and evaporated to give 6.87 g of 3-bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidine as light yellow solid. 1H NMR (DMSO) 8.857 (s, 1H), 14.84 (bs, 1H); LC/MS (MH+=233).