Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:43])=[C:5]([C:21]([O:23][CH2:24][CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][O:36]C3CCCCO3)=[CH:30][CH:29]=2)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(Cl)Cl.O>CO>[CH3:1][C:2]1[NH:3][C:4]([CH3:43])=[C:5]([C:21]([O:23][CH2:24][CH2:25][CH2:26][O:27][C:28]2[CH:29]=[CH:30][C:31]([CH2:34][CH2:35][OH:36])=[CH:32][CH:33]=2)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCOc2ccc(CCOC3CCCCO3)cc2)C1c1cccc([N+](=O)[O-])c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCOc2ccc(CCO)cc2)C1c1cccc([N+](=O)[O-])c1
Reaction time: 24 h
Yield: 70.2 %

Procedure:
To a solution of 2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-(3-[4-(2-tetrahydropyran-2-yloxyethyl)phenoxy]propoxycarbonyl)-1,4-dihydropyridine (4.0 g, 6.7 mmoles) in methanol (50 mL) was added a catalytic amount of 4-toluenesulfonic acid. After 24 hours, 200 mL of CH2Cl2 and 100 mL of H2O were added. The organic extracts were dried over anhydrous Na2SO4 and the solvent evaporated. The residue (3.5 g) was purified by flash chromatography (80:20 CH2Cl2 :acetone). Evaporation of the pure fractions gave 2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-(3-[4-(2-hydroxyethyl)phenoxy]propoxycarbonyl)-1,4-dihydropyridine (2.4 g, mp <50° C.). NMR (CDCl3)δppm: 8.1-6.5(m, 9H); 5.02(s, 1H); 4.13(t, 2H); 4.0-3.4(m, 7H); 2.68(t, 2H); 2.47(s, 1H); 2.27(s, 6 H); 2.3-1.8(m, 2H).
Reaction SMILES: [O:1]=[Si]=O.[OH-].[Na+:5].[O-:6][Si:7]([O-:9])=[O:8].[Na+].[Na+]>O>[Si:7]([O-:1])([O-:9])([O-:6])[O-:8].[Na+:5].[Na+:5].[Na+:5].[Na+:5]
Reactant: O=[Si]=O
Reactant: O=[Si]([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: [O-][Si]([O-])([O-])[O-]

Procedure:
A process for producing amorphous sodium silicates having a water content of 0.3 to 6% by weight and an SiO2 /Na2O molar ratio of (1.9 to 2.8) : 1 from a waterglass solution containing at least 20% by weight of solids, the water-glass solution is obtained by reacting quartz sand with sodium hydroxide solution at an SiO2 /Na2O molar ratio of (2.0 to 2.8) : 1 at temperatures of 180 to 240° C. and pressures of 10 to 30 bar. This waterglass solution is treated in a spray-drying zone with hot air at 200 to 300° C. for a residence time of 10 to 20 seconds and at a temperature of the exit gas leaving the spray-drying zone of 90° to 130° C., to form a pulverulent amorphous sodium silicate having a water content (determined as the loss on ignition at 700° C.) of 15 to 23% by weight and a bulk density of more than 300 g/l. The pulverulent sodium silicate is introduced into an obliquely arranged rotary kiln fitted with devices for moving solids and treated therein with flue gas in countercurrent at temperatures from 250° up to 500° C. for 1 to 60 minutes. The rotary kiln is here insulated in such a way that its outside wall temperature is less than 60° C. Finally, the amorphous sodium silicate emerging from the rotary kiln is comminuted by means of a mechanical crusher to grain sizes of 0.1 to 12 mm.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:12]([O:14]C)=[O:13])[C:5]([C:8]([O:10]C)=[O:9])=[CH:6][CH:7]=1.[Na+].[Br-]>[Zn].Cl[Ni]Cl.CC(N(C)C)=O>[C:2]1([C:4]2[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=2)[CH:7]=[C:6]([C:12]([OH:14])=[O:13])[C:5]([C:8]([OH:10])=[O:9])=[C:4]([C:12]([OH:14])=[O:13])[C:3]=1[C:8]([OH:10])=[O:9]
Reactant: COC(=O)c1ccc(Cl)cc1C(=O)OC
Agent: Cl[Ni]Cl
Agent: [Br-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=C(O)c1cc(-c2ccccc2)c(C(=O)O)c(C(=O)O)c1C(=O)O
Reaction time: 1 h
Yield: 96.9 %

Procedure:
Into a nitrogen-flushed reaction flask, under N2 atmosphere, was added 4.50 g (20 mmol) of dimethyl 4-chloro-benzenedicarboxylate (CBDM) 5.2 g (20 mmol) of anhydrous NaBr, 2.68 g (40 mmol) zinc powder and 0.52 g (0.8 mmol) (Ph3P)2.NiCl2. The mixture was maintained under a nitrogen atmosphere while 30 ml of DMAC, dried over molecular sieves was added. The mixture was heated with stirring to 80.C in one hour. The color of the solution turned from bluish-green to brown in 0 5 hours. After 4 hours, the solution was cooled, filtered and the solvent was removed on a rotary evaporator. Chloroform was added and the solution filtered again. The filtrate was washed three times with saturated aqueous NaCl. CHCl3 was removed. 50 ml of 20% NaOH solution was added to the residue and and the mixtures was heated to reflux for 4 hours. The mixture was filtered and the filtrate was acidified with concentrated hydrochloric acid. A white precipitate formed, was filtered, washed with H2O several times, and dried in an oven at 100° C. to afford 3.2 g of biphenyltetracarboxylic acid (97% yield). The tetra acid was heated slowly to 210°-220° C. to dehydrate and afford biphenyldianhydride, m.p. 299°-302° C.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([O:21]C)=[O:20])=[CH:17][C:18]=4[N:9]3[CH2:8][CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH-].[Na+].Cl>CN(C=O)C.O.C1COCC1.CO.C(N(CC)CC)C>[CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([OH:21])=[O:20])=[CH:17][C:18]=4[N:9]3[CH2:8][CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc2cc3n(c2c1)CC=Cc1ccccc1-3
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)c1ccc2cc3n(c2c1)CC=Cc1ccccc1-3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 7H-indolo[2,1-a][2]benzazepine-10-carboxylate, 13-cyclohexyl, 6-carboxylic acid (366 mg, 0.88 mmol), 2-N,N-dimethyl-2-(methylamino)acetamide (120 mg, 1.03 mmol) and triethylamine (0.37 mL) in DMF (6 mL) was added HATU (400 mg, 1.05 mmol). The reaction mixture was stirred at rt for 2 h, diluted with H2O (˜20 mL) and the resulting solids were collected by filtration, washed with H2O and dried on the filter with aspirator vacuum for 1 h. The solids were dissolved into THF/MeOH (1:1, 6 mL) and 1M NaOH (aq.) (1.5 mL, 1.5 mmol). The reaction mixture was heated in a sealed tube with microwave irradiation at 85° C. for 20 min. The reaction was cooled, neutralized with 1M HCl (aq.) (1.5 mL, 1.5 mmol) and concentrated to remove organic solvents. The residue was slurried with H2O and the solids were collected by filtration, flushed with H2O and dried to yield 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[[[2-(dimethylamino)-2-oxoethyl]methylamino]carbonyl]- (406 mg, 0.81 mmol, 92%) as a yellow solid. Mixture of amide rotamers: 1HNMR (300 MHz, DMSO-d6) δ 12.58 (br s, 1H), 8.17 (br s, 0.5H), 8.13 (br s, 0.5H), 7.89 (d, J=8.8 Hz, 1H), 7.66-7.45 (m, 5H), 7.07 (br s, 0.5H), 6.90 (br s, 0.5H), 5.24-4.96 (m, 1H), 4.39-4.03 (m, 3H), 3.08-2.75 (m, 7H), 2.63 (s, 1.5H), 2.54 (s, 1.5H), 2.14-1.63 (m, 6H), 1.52-1.04 (m, 4H). LCMS: m/e 498 (M−H)−, ret time 1.36 min, column A, 2 minute gradient.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5]([C:15]([NH2:17])=[O:16])=[CH:4][CH:3]=1.[NH2:18][C:19]1[S:20][C:21]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([OH:36])([CH3:35])[CH3:34])=[CH:29][C:28]=2[F:37])=[CH:22][C:23]=1[C:24]([NH2:26])=[O:25]>>[NH2:26][C:24]([C:23]1[CH:22]=[C:21]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([OH:36])([CH3:35])[CH3:34])=[CH:29][C:28]=2[F:37])[S:20][C:19]=1[NH:18][C:2]1[CH:3]=[CH:4][C:5]([C:15]([NH2:17])=[O:16])=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:7]=1)=[O:25]
Reactant: NC(=O)c1ccc(Cl)nc1CN1CCOCC1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3ccc(C(N)=O)c(CN4CCOCC4)n3)s2)c(F)c1

Procedure:
The title compound was prepared according to the general procedure in Example 1 using 6-chloro-2-(morpholin-4-ylmethyl)pyridine-3-carboxamide (87 mg, 0.34 mmol) and 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (100 mg, 0.34 mmol) as the starting materials.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[C:7]([CH:11]=1)[C:8]([OH:10])=O.Cl.[NH:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-].CN1CCOCC1>CN(C=O)C.O>[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[C:7]([CH:11]=1)[C:8]([N:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)=[O:10]
Reactant: O=C1CCNCC1
Reactant: Cc1ccc(-c2ccncc2)c(C(=O)O)c1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccncc2)c(C(=O)N2CCC(=O)CC2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 31 %

Procedure:
A suspension of 5-methyl-2-(pyridin-4-yl)benzoic acid hydrochloride (2.0 g), piperidin-4-one hydrochloride (1.2 g), DMTMM (3.3 g) and N-methylmorpholine (2.6 mL) in DMF (30 mL) was stirred at room temperature for 5 hr, and then overnight at 100° C. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.73 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])[C:5]([Cl:18])=[CH:4][N:3]=1.[CH3:19][Si](C=[N+]=[N-])(C)C>C(Cl)Cl.CO.C(OCC)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([O:13][CH3:19])=[O:12])[C:5]([Cl:18])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reaction time: 0.5 h

Procedure:
To a solution of 2-(2,5-dichloropyrimidin-4-ylamino)benzoic acid (300 mg, 1.1 mmol) in DCM/MeOH (10/5 mL) is added trimethylsilyl diazomethane in ethyl ether solution (2.0 M, 2 mL). The mixture is stirred for 30 min and concentrated to afford methyl 2-(2,5-dichloropyrimidin-4-ylamino)benzoate as yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH:7]([CH:15](C(C)=O)[C:16]([O:18]CC)=[O:17])[CH:8](C(C)=O)[C:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.C(O)C.[OH-].[Na+].COC1C=CC(C(C(C(C)=O)C([O-])=O)C(C(C)=O)C([O-])=O)=CC=1>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:7]([CH2:15][C:16]([OH:18])=[O:17])[CH2:8][C:9]([OH:11])=[O:10])=[CH:24][CH:25]=1
Reactant: CCOC(=O)C(C(C)=O)C(c1ccc(OC)cc1)C(C(C)=O)C(=O)[O-]
Agent: COc1ccc(C(C(C(C)=O)C(=O)[O-])C(C(C)=O)C(=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(C(CC(=O)O)CC(=O)O)cc1
Yield: 16.1 %

Procedure:
A mixture of ethyl 2,2'-(4-methoxybenzal)-bis-acetoacetate (30 g), ethanol (450 ml) and 50% sodium hydroxide (450 g) is refluxed vigorously for 1.0 hour. Water (150 ml) is added and most of the ethanol is removed by distillation in vacuo. The concentrate is acidified with concentrated hydrochloric acid and is extracted with ethyl acetate. The ethyl acetate solution is washed with brine, dried, evaporated and the residue is crystallized from benzene-methanol to afford 3.3 g of 3-(4-methoxyphenyl)glutaric acid, melting point 147°-150° C.
Reaction SMILES: [Cl-].[CH3:2][C:3]1[O:7][C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)=[N:5][C:4]=1[CH2:18][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[H-].[Na+].[CH:40]([C:42]1[CH:51]=[CH:50][C:45]([C:46]([O:48][CH3:49])=[O:47])=[CH:44][CH:43]=1)=O>CN(C=O)C>[CH3:2][C:3]1[O:7][C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)=[N:5][C:4]=1/[CH:18]=[CH:40]/[C:42]1[CH:51]=[CH:50][C:45]([C:46]([O:48][CH3:49])=[O:47])=[CH:44][CH:43]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: Cc1oc(-c2ccc3ccccc3c2)nc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(/C=C/c2nc(-c3ccc4ccccc4c3)oc2C)cc1
Temperature: 25 °C
Yield: 78.9 %

Procedure:
[5-Methyl-2-(2-naphthyl)-4-oxazolylmethyl]triphenylphosphonium chloride (18.4 g) was suspended in DMF (200 ml), and sodium hydride (60% in oil, 1.42 g) was added little by little at 0° C. After mixture stirring at room temperature for1 hour, methyl 4-formylbenzoate (5.80 g) was added, followed by stirring for 3 hours. The reaction mixture was poured over ice-water; the resulting crystal was collected by filtration. The crystal was then purified by silica gel column chromatography to yield methyl (E)-4-[2-[5-methyl-2-(2-naphthyl)-4-oxazolyl]vinyl]benzoate (10.3 g, 79%) from the fraction eluted with ethyl acetate-chloroform (5:95, v/v), which was then recrystallized from dichloromethane-methanol to yield light yellow prisms having a melting point of 216°-217° C.
Reaction SMILES: ClC1C=C(C(OO)=[O:9])C=CC=1.[CH3:12][S:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([C:20]#[C:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=1>ClCCl>[CH3:12][S:13]([C:14]1[CH:15]=[N:16][CH:17]=[C:18]([C:20]#[C:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=1)=[O:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cncc(C#Cc2ccccc2)c1
Solvent: ClCCl
Product: CS(=O)c1cncc(C#Cc2ccccc2)c1
Reaction time: 2 h
Yield: 26.7 %

Procedure:
Add 3-chlorobenzenecarboperoxoic acid (27.61 mg, 0.16 mmol) to a cooled solution of 3-methylsulfanyl-5-phenylethynyl-pyridine, (prepared as described in EXAMPLE 128), (35.3 mg, 0.16 mmol) in dichloromethane (1 mL) at room temperature. Stir for 2 h and then quench with a 5% aqueous solution of sodium thiosulfite. Dilute with dichloromethane and separate the layers. Sequentially extract the organic layer with a 5% aqueous solution of sodium thiosulfite and an aqueous saturated solution of sodium chloride, dry (magnesium sulfate), filter and concentrate. Purify the residue by silica gel chromatography, eluting from 100:0 to 100:50 with hexanes:ethyl acetate, to give the title compound (10.3 mg, 27%).
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:8])([CH3:3])[CH3:2].[CH2:21]=O>C(O)=O>[CH3:21][N:4]([CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:8])[CH:1]([CH3:2])[CH3:3]
Reactant: C=O
Reactant: CC(C)NCCC(C)c1ccccc1-c1ccccc1
Solvent: O=CO
Product: CC(CCN(C)C(C)C)c1ccccc1-c1ccccc1
Reaction time: 12 h

Procedure:
A mixture of 2.67 g of 1-isopropylamino-3-p-biphenylylbutane, 12 ml of formic acid and 2 g of 40% formaldehyde solution is heated at 60° for 3 hours and then at 100° for 12 hours and is then evaporated. 1-(N-Methyl-N-isopropylamino)3-p-biphenylyl-butane is obtained after working up in the customary manner.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].N1C=CC=CC=1.[C:16](Cl)(=[O:18])[CH3:17]>C(Cl)Cl>[C:16]([O:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5])(=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: COC(=O)C(C)(C)CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C(C)(C)COC(C)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.4 %

Procedure:
Under an argon atmosphere a stirred solution of 10.0 grams (0.076 mole) of methyl 3-hydroxy-2,2-dimethylpropionate and 6.6 grams (0.083 mole) of pyridine in 40 ml of dry methylene chloride was cooled to 0°. To this 6.0 grams (0.076 mole) of acetyl chloride was added dropwise. Upon completion of addition the reaction mixture was allowed to warm to ambient temperature where it was stirred for 18 hours. The reaction mixture was washed with 50 ml of water, two portions of 50 ml each of an aqueous solution of 5% hydrochloric acid, and finally, 50 ml of water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give an oil residue. The oil was distilled under reduced pressure to give 8.0 grams of methyl 3-acetoxy-2,2-dimethylpropionate; bp 85°-90°/33 Pa.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7](OC)=[O:8].[BH4-].[Na+]>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH2:7][OH:8])[CH:11]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cc(Cl)cc(C(=O)OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)cc(CO)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of dimethyl 5-chloroisophthalate (10.0 g, 43.7 mmol, Astatech) in methanol (50 mL) and methylene chloride (50 mL) at 0° C. was added sodium borohydride (5.5 g, 140 mmol, Aldrich). The reaction was allowed to gradually reach room temperature and stir for 1 hour. Additional portions of sodium borohydride (0.50 g, 13 mmol) were added at 2 hours and 3 hours. The reaction mixture was cooled to 0° C. and the reaction was quenched with water. The layers were separated and the aqueous layer was extracted with three portions of DCM. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The product was purified by flash chromatography, eluting with a gradient from 0-25% EtOAc in hexanes. Yield: (4.51 g, 51%).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[C:16]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH:33]([F:35])[F:34])=[C:28]([O:36][CH2:37][CH:38]4[CH2:40][CH2:39]4)[CH:27]=3)[N:17](COCC[Si](C)(C)C)[C:11]=2[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(OC2C=C(C3N(COCC[Si](C)(C)C)C4C=NN(COCC[Si](C)(C)C)C(=O)C=4C=3C)C=CC=2OC(F)F)CC1>>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[C:16]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH:33]([F:34])[F:35])=[C:28]([O:36][CH2:37][CH:38]4[CH2:39][CH2:40]4)[CH:27]=3)[NH:17][C:11]=2[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OCC3CC3)c2)c(-c2ccccc2)c2c(=O)n(Cc3ccccc3)ncc21
Agent: Cc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Product: O=c1c2c(-c3ccccc3)c(-c3ccc(OC(F)F)c(OCC4CC4)c3)[nH]c2cnn1Cc1ccccc1
Yield: 80.5 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 4-(b) except for using 328 mg (0.501 mmol) of 5-benzyl-2-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-3-phenyl-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 38-(d) in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-methyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one, whereby 207 mg of the title compound was obtained as a white solid. (81%)
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]=[C:9]2[CH3:12])=[CH:4][CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH:9]2[CH3:12])=[CH:4][CH:3]=1
Reactant: CC1=NCCc2ccc(F)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC1NCCc2ccc(F)cc21

Procedure:
In close analogy to the procedure described above, 7-fluoro-1-methyl-3,4-dihydro-isoquinoline is reacted with sodium triacetoxyborohydride to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].[Cl:13][C:14]1[C:15]([CH3:34])=[N:16][O:17][C:18]=1[N:19](COC)[S:20]([C:23]1[CH:27]=[CH:26][S:25][C:24]=1[C:28](Cl)=[O:29])(=[O:22])=[O:21]>ClCCl>[C:10]([C:3]1[CH:4]=[C:5]([CH3:9])[CH:6]=[C:7]([CH3:8])[C:2]=1[NH:1][C:28]([C:24]1[S:25][CH:26]=[CH:27][C:23]=1[S:20]([NH:19][C:18]1[O:17][N:16]=[C:15]([CH3:34])[C:14]=1[Cl:13])(=[O:21])=[O:22])=[O:29])(=[O:12])[CH3:11]
Reactant: COCN(c1onc(C)c1Cl)S(=O)(=O)c1ccsc1C(=O)Cl
Reactant: CC(=O)c1cc(C)cc(C)c1N
Solvent: ClCCl
Product: CC(=O)c1cc(C)cc(C)c1NC(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1Cl
Temperature: 25 °C
Reaction time: 10 h
Yield: 43.3 %

Procedure:
To a solution of 2′-amino-3′,5′-dimethylacetophenone (1.9 g, 11.66 mmol) in dichloromethane (20 mL) at room temperature was added N-(4-chloro-3-methyl-5-isoxazolyl)-N-methoxymethyl-3-sulfamoyl-2-thiophenecarbonyl chloride (Example 51) (1 g, 2.86 mmol). The mixture was stirred for 10 h during which much yellow precipitate formed. The reaction was then concentrated and the residue was diluted with ethyl acetate (50 mL) and washed with 1 N HCl (50 mL). The organic layer was concentrated and the residue was dissolved in methanol (30 mL) followed by the addition of concentrated HCl (15 mL). The mixture was then heated under reflux for 2 h before it was cooled to room temperature, diluted with ethyl acetate (200 mL) and washed with water (2×200 mL). The organic layer was separated, dried (MgSO4), the solids filtered and the filtrate concentrated. The residue was then purified by reverse phase HPLC to give N-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamide (580 mg, 43%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[C:10]([CH3:23])([CH3:22])[CH:9]2O)=[O:5])[CH3:2].FC(F)(F)C(O)=O>C([SiH](CC)CC)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[C:10]([CH3:22])([CH3:23])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cccnc1)N2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccnc1)N2
Temperature: 25 °C
Reaction time: 4 h
Yield: 24.2 %

Procedure:
To a mixture of 4-hydroxy-3,3-dimethyl-2-pyridin-3-yl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (62.5 g, 200 mmol) and triethylsilane (50 mL) at 25° C. was added trifluoroacetic acid (25 mL) dropwise. The resulting mixture was stirred at 25° C. for 4 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with saturated aqueous sodium bicarbonate solution (2×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was triturated with methanol. The resulting precipitate was collected, dried in vacuo to afford 3,3-dimethyl-2-pyridin-3-yl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (15 g, 24%) as a white solid: LC/MS m/e calcd for C19H22N2O2 (M+H)+: 311.40, observed: 311.1.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:10][C@@H:11]1[O:15][C:14](=[O:16])[NH:13][C@H:12]1[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O)(C)(C)C.C1COCC1>Cl.C(Cl)Cl>[NH2:8][C@@H:9]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:10][C@@H:11]1[O:15][C:14](=[O:16])[NH:13][C@H:12]1[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@@H]1OC(=O)N[C@H]1Cc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: N[C@@H](Cc1ccccc1)C[C@@H]1OC(=O)N[C@H]1Cc1ccccc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
The crude, wet product of Example 3a was slurried in 1N HCl (192 mL) and the slurry was heated to 70° C. with stirring. After 1 hour, THF (100 mL) was added and stirring at 65° C. was continued for 4 hours. The mixture was then allowed to cool to 20–25° C. and was stirred overnight at 20–25° C. The THF was removed by evaporation under vacuum and the resulting aqueous solution was cooled to about 5° C., causing some precipitation to occur. The aqueous mixture was adjusted to pH 7 by addition of 50% aqueous sodium hydroxide (about 18.3 g). The resulting mixture was extracted with ethyl acetate (2×100 mL) at about 15° C. The combined organic extracts were washed with 100 mL of brine and the organic layer was separated and stirred with sodium sulfate (5 g) and Darco G-60 (3 g). This mixture was warmed on a hot plate for 1 hour at 45° C. The hot mixture was then filtered through a bed of diatomaceous earth and the filter pad was washed with ethyl acetate (100 mL). The filtrate was evaporated under vacuum to provide an oil. The oil was redissolved in methylene chloride (300 mL) and the solvent was evaporated under vacuum. The resulting oil was dried at room temperature under vacuum to provide the desired product (18.4 g) as a glassy syrup.