Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:4][CH:5]=[CH:6][N:7]=1.C(N(CC)CC)C.[C:15](Cl)(=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].O>ClCCl>[C:15]([NH:1][CH2:2][C:3]1[S:4][CH:5]=[CH:6][N:7]=1)([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:21]
Reactant: NCc1nccs1
Reactant: CCOC(=O)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)NCc1nccs1
Reaction time: 0.5 h

Procedure:
To a solution of 3.43 g (30 mmol) of 2-aminomethylthiazole and 3.34 g (33 mmol) of triethylamine in 60 ml of dichloromethane, a solution of 4.512 g of ethyl chloroxalate in 10 ml of dichloromethane was added dropwise with ice-cooling. The reaction solution was stirred for 30 minutes. 20 ml of water was added to the solution, and the mixture was stirred for 10 minutes. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (30 ml×5). The organic layers were combined, washed with a small amount of a saturated aqueous solution of sodium hydrogencarbonate, and dried over anhydrous sodium sulfate. The resultant was concentrated to dryness under reduced pressure to give solid 2-(ethoxalylamino)methylthiazole. To this was added 50 ml of phosphorus oxychloride with ice-cooling. The mixture was refluxed for 12 hours, cooled to room temperature, and concentrated to dryness under reduced pressure. To the residue were added 50 ml of water and 50 ml of dichloromethane to obtain a solution. 50 g of potassium carbonate was added to the solution little by little with ice-cooling. The reaction solution was stirred for 10 minutes, and then filtered to remove insoluble matters. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (30 ml×2). The combined organic layers were dried over anhydrous potassium carbonate, and purified by flash column chromatography using silica gel, eluting with ethyl acetate to give 4.68 g (yield 80%) of the title compound as light yellow crystals.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH3:11].[OH-].[K+]>O1CCOCC1.O>[CH3:11][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH:3]1[CH2:2][O:12]1
Reactant: COc1ccccc1C(O)CCl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccccc1C1CO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.4 %

Procedure:
1.4 g of α-chloromethyl-2-methoxybenzylalcohol (crude oil) are dissolved in 12 ml of dioxane, and a solution of 840 mg of potassium hydroxide in 5 ml of water is added thereto. The mixture is stirred at room temperature for 3 hours. Then, the reaction mixture is poured into ice-water, and the aqueous mixture is extracted with benzene. The extract is dried and evaporated to remove solvent. 0.5 g of 2-(2-methoxyphenyl)oxirane are obtained as a crude product.
Reaction SMILES: C1COCC1.[C:6]([O:10][C:11](=[O:29])[NH:12][C@@H:13]([CH:17]=[N:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[C:26](=[O:28])[NH2:27])[CH:14]([CH3:16])[CH3:15])([CH3:9])([CH3:8])[CH3:7].O.[OH-].[Li+].Cl>O>[C:6]([O:10][C:11](=[O:29])[NH:12][C@@H:13]([C:17]1[NH:27][C:26](=[O:28])[C:20]2[C:19](=[CH:24][C:23]([Cl:25])=[CH:22][CH:21]=2)[N:18]=1)[CH:14]([CH3:16])[CH3:15])([CH3:8])([CH3:9])[CH3:7]
Reactant: CC(C)[C@H](C=Nc1cc(Cl)ccc1C(N)=O)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)[nH]1
Temperature: 25 °C

Procedure:
A dry 3-necked, round bottomed flask, equipped with a magnetic stirrer, nitrogen inlet, heating mantle, and a water condenser, is charged with 60 mL of THF, 3.70 g (10 mmol) of (R)-{1-[(2-carbamoyl-5-chloro-phenylimino)-methyl]-2-methyl-propyl}-carbamic acid tert-butyl ester (the compound of Formula 201 prepared, e.g., as described in Example 6.1), and 0.46 g (11 mmol) of lithium hydroxide monohydrate. The mixture is heated to reflux and the reaction monitored by TLC (hexanes/ethyl acetate 7:3) by which, after 1 h of refluxing, the reaction is shown to be complete. The mixture is allowed to cool to room temperature and transferred to a round bottom 1-necked flask followed by dilution with 60 mL of water. The stirring mixture is then slowly acidified to pH=5 by adding 1N hydrochloric acid and the THF is removed by rotary evaporation. The white suspension is separated by filtration and dried in high vacuum to afford the title compound of Formula 202, (R)-[1-(7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methylpropyl]-carbamic acid tert-butyl ester.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH2:20].Cl>CN(C)C1C=CN=CC=1.CN(C=O)C>[C:11]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[C:3]([OH:20])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:2]1=[O:10])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: O
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C1C(=C(O)c2ccccc2)c2ccccc2N1C(=O)c1ccccc1
Temperature: 45 °C
Reaction time: 0.75 h

Procedure:
26.6 g (0.2 mol) of 2-indolinone and 53.8 g (0.44 mol) of 4-dimethylamino-pyridine are dissolved in 400 ml of DMF and after the addition of 30.9 g (0.22 mol) of benzoylchloride in 100 ml of DMF stirred for 45 minutes at 45° C. The solution is poured onto 3 l of water and 100 ml of conc. hydrochloric acid, the precipitate formed is suction filtered, recrystallised from glacial acetic acid and dried.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC.ClC1C=C(Cl)C=CC=1[C:38]1[N:39]=[C:40]([CH3:56])[C:41]([NH:45][CH:46]2[C:55]3[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=3)[CH2:49][CH2:48][CH2:47]2)=[N:42][C:43]=1[CH3:44].[CH3:57][C:58]1[CH:63]=[C:62]([O:64][CH3:65])[CH:61]=[CH:60][C:59]=1B(O)O>>[CH3:65][O:64][C:62]1[CH:61]=[CH:60][C:59]([C:38]2[N:39]=[C:40]([CH3:56])[C:41]([NH:45][CH:46]3[C:55]4[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=4)[CH2:49][CH2:48][CH2:47]3)=[N:42][C:43]=2[CH3:44])=[C:58]([CH3:57])[CH:63]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2Cl)c(C)nc1NC1CCCc2ccccc21
Reactant: COc1ccc(B(O)O)c(C)c1
Agent: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Product: COc1ccc(-c2nc(C)c(NC3CCCc4ccccc43)nc2C)c(C)c1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 5-(2,4-dichlorophenyl)-3,6-dimethyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine and 2-methyl-4-methoxy phenyl boronic acid, and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 1.81, 2.01, 2.06, 2.13, 2.22, 2.77, 3.71, 4.38, 5.39, 6.70, 7.09, 7.31; 13C NMR (CDCl3) δ 20.07, 20.47, 20.54, 22.09, 29.96, 30.28, 48.94, 55.68, 111.58, 116.05, 126.64, 127.57, 129.43, 129.60, 131.24, 132.37, 135.83, 138.31, 138.56, 138.74, 140.69, 147.04, 150.92, 159.51; HRMS (ESI+) for C24H27N3O1 m/z cald 374.2232 (M+H)+ found 374.2226.
Reaction SMILES: [CH2:1]([C:3]([CH2:12][CH3:13])=[CH:4][CH2:5][CH2:6][C:7]([CH3:11])(O)[CH:8]=[CH2:9])[CH3:2].N1C=CC=CC=1.P(Br)(Br)[Br:21]>CCCCCC>[Br:21][CH2:9][CH:8]=[C:7]([CH3:11])[CH2:6][CH2:5][CH:4]=[C:3]([CH2:12][CH3:13])[CH2:1][CH3:2]
Reactant: C=CC(C)(O)CCC=C(CC)CC
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: CCCCCC
Product: CCC(=CCCC(C)=CCBr)CC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
18.2 g. of 7-ethyl-3-methyl-1,6-nonadien-3-ol, 100 ml. of hexane and 1 ml. of anhydrous pyridine are cooled to -15° C. and treated dropwise in the course of 1.5 hours with a solution of 4 ml. of phosphorus tribromide in 50 ml. of hexane, the temperature being maintained at between -15° C. and -10° C. The mixture is stirred for a further 1.5 hours during which time it is allowed to warm up to room temperature slowly. For working up, the mixture is poured onto 50 ml. of ice-water, the organic phase separated and washed in turn with 20 ml. of 10% by weight aqueous sodium carbonate solution, 50 ml. of semi-saturated aqueous sodium chloride solution and 50 ml. of saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure. There is obtained 1-bromo-7-ethyl-3-methyl-2,6-nonadiene which is used in the process without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]([CH2:14][CH3:15])[C:12](=[O:16])[CH2:11][N:10]=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:8]=2[CH:24]=1)(=[O:3])[CH3:2].[BH4-].[Na+].O>CO>[CH2:14]([N:13]1[C:7]2[CH:6]=[CH:5][C:4]([CH:1]([OH:3])[CH3:2])=[CH:24][C:8]=2[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])=[N:10][CH2:11][C:12]1=[O:16])[CH3:15]
Reactant: CCN1C(=O)CN=C(c2ccccc2F)c2cc(C(C)=O)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCN1C(=O)CN=C(c2ccccc2F)c2cc(C(C)O)ccc21
Temperature: 25 °C
Reaction time: 17 h

Procedure:
12.7 g (39.2 mmol) of 7-acetyl-1-ethyl-5-(o-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one in 240 ml of methanol are treated in the cold while stirring with 743 mg (19.6 mmol) of sodium borohydride. The mixture is subsequently stirred at room temperature for 17 hours, treated with water and then with 2 N sulphuric acid and extracted with methylene chloride. The organic phase is washed with water, dried and evaporated. The residue is chromatographed on 500 g of silica gel using ethyl acetate/toluene (1:1) as the elution agent, and gives, from cyclohexane, 1-ethyl-5-(o-fluorophenyl)-1,3-dihydro-7-(1-hydroxyethyl)-2H-1,4-benzodiazepin-2-one of melting point 55°-57°.
Reaction SMILES: CN(CCN(C)C)C.C([Li])CCC.[Cl:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.CN([CH:24]=[O:25])C>CCOCC>[Cl:14][C:15]1[C:16]([CH:24]=[O:25])=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: Clc1cccnc1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=Cc1ncccc1Cl
Reaction time: 0.5 h
Yield: 27 %

Procedure:
To a solution of TMEDA (660 uL, 2.58 mmol) in ether (20 mL) at −78° C. was added a solution of n-butyl lithium in ether (2.5 M, 1.76 mL, 4.40 mmol). After 30 minutes at −78° C., 3-chloropyridine (419 uL, 4.40 mmol) was added. After another 2 hours at −78° C., DMF (375 uL, 4.84 mmol) was added. After a further 2 hours at −78° C., the reaction was quenched with saturated aqueous NaHCO3 (20 mL), extracted with ether (4×15 mL), dried (Na2SO4), filtered and concentrated in vacuo to give the crude oil. Purification by column chromatography on silica gel (Hexanes: EtOAc 4:1) afforded the title compound as a crystalline solid (168 mg, 27%). 1H NMR (CDCl3) 7.45 (dd, 1H, J=8.3, 4.4 Hz), 7.83 (dd, 1H, J=4.8, 1.4 Hz), 8.70 (dd, 1H, J=4.8, 1.5 Hz), 10.28 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=3)[C:9]([S:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[C:8]2[CH2:22][C:23]([CH3:29])([CH3:28])[C:24]([O:26][CH3:27])=[O:25])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:39][C:40]1[CH:49]=[CH:48][C:47]2[C:42](=[CH:43][CH:44]=[C:45]([F:50])[CH:46]=2)[N:41]=1>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:39][C:40]4[CH:49]=[CH:48][C:47]5[C:42](=[CH:43][CH:44]=[C:45]([F:50])[CH:46]=5)[N:41]=4)=[CH:13][CH:14]=3)[C:9]([S:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[C:8]2[CH2:22][C:23]([CH3:29])([CH3:28])[C:24]([O:26][CH3:27])=[O:25])=[CH:30][CH:31]=1
Reactant: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(O)ccc2n1Cc1ccc(Cl)cc1
Reactant: Fc1ccc2nc(CBr)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OCc3ccc4cc(F)ccc4n3)ccc2n1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of Methyl 3-[N-(p-chlorobenzyl)-3-(t-butylthio)-5-hydroxyindol-2-yl]-2,2-dimethylpropanoate (See EP419,049, Example 1, Step C) (322 mg) in acetonitrile (7 mL) were added solid cesium carbonate (456 mg) and 2-bromomethyl-6-fluoroquinoline (190 mg) from Step A. The mixture was stirred at room temperature for 18 hr. The mixture was poured into 25% aqueous NH4OAc (50 mL), extracted with ethyl acetate (2×50 mL), washed with brine (50 mL), dried (MgSO4) and evaporated to dryness. The residue was chromatographed on flash silica gel using ethyl acetate:toluene (5:95) as eluant to give the title compound as a white solid; m.p. 165°-167° C.
Reaction SMILES: [SH:1][C:2]1[N:3]=[N:4][C:5]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:7]=1.[CH3:22]I.[OH-].[Na+]>C(O)C>[CH3:22][S:1][C:2]1[N:3]=[N:4][C:5]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=2)[N:7]=1
Reactant: Fc1ccc(-c2nnc(S)nc2-c2ccc(F)cc2)cc1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSc1nnc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1

Procedure:
3-Mercapto-5,6-bis(4-fluorophenyl)-1,2,4-triazine, 16.6 g. (0.05 mole), was reacted with 7 g. (0.05 mole) of methyl iodide in 75 ml. of ethanol containing 2 g. (0.05 mole) of sodium hydroxide by the method of Example 4(B). The yield was 13.2 g. of 3-methylthio-5,6-bis(4-fluorophenyl)-1,2,4-triazine, mp about 132°-135°C., after crystallization from ethanol.
Reaction SMILES: [C:1]1([CH:7]=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H].[CH:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(OC)(C)(C)C.ClCCl.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[CH:4]1[CH:3]=[CH:2][C:1]([C@H:7]2[O:19][C@@H:12]2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: [N-]=[N+]=Cc1ccccc1
Reactant: O=Cc1ccccc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Yield: 5 %

Procedure:
A solution of phenyldiazomethane (0.45 mmol in 6 ml of t-butylmethyl ether was added to a solution of a compound of formula (C') wherein R' and R" are both hydrogen (90 mg; 0.45 mmol), rhodium (II) acetate (2 mg; 0.0045 mmol) and benzaldehyde (46 μl; 0.45 mmol) in dichloromethane (2 ml). Upon completion of the addition, the solvent was removed in vacuo and the residue chromatographed using silica gel and elating with dichloromethane:petrol 40:60 to give the title compound (4 mg, 5%, 71%ee).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=1.CC[N:22]([CH:26]([CH3:28])[CH3:27])C(C)C>O1CCOCC1>[C:13]1([CH3:12])[CH:18]=[CH:17][C:16]([NH:19][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([NH:22][C:26]3[CH:27]=[CH:18][C:13]([CH3:14])=[CH:12][CH:28]=3)[N:3]=2)=[CH:15][CH:14]=1
Reactant: Cc1ccc(N)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1ccc(Nc2ccc([N+](=O)[O-])c(Nc3ccc(C)cc3)n2)cc1
Temperature: 200 °C
Reaction time: 0.33 h
Yield: 87 %

Procedure:
A mixture of 2,6-dichloro-3-nitropyridine (193 mg, 1 mmol), p-tolylamine (236 mg, 2.2 mmol) and DIEA (524 μL, 3 mmol) in 3 mL dioxane was stirred in microwave at 200° C. for 20 min. After removal of the solvent, the residue was dissolved in chloroform and subjected to silica gel column purification to give 291 mg (yield: 87%) title compound. Calculated mass=334. Observed mass=335.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][NH:25][S:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:28])=[O:27]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:32]4[CH:31]=[CH:30][C:29]([S:26](=[O:27])(=[O:28])[NH:25][CH3:24])=[CH:34][CH:33]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Reactant: CNS(=O)(=O)c1ccc(B(O)O)cc1
Product: CNS(=O)(=O)c1ccc(-c2cc3c(cn2)OC(C2CCN(C(=O)OC(C)(C)C)CC2)C3)cc1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 4-(methylaminosulfonyl)phenylboronic acid acid following a procedure analogous to that described in Example 28. LC (method 7): tR=1.33 min; Mass spectrum (ESI+): m/z=474 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=2)[C:3]=1[C:17]([NH2:19])=[O:18].[OH:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1.N1CCCCC1>C(O)C>[CH3:16][N:14]([CH3:15])[C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:4]2[C:3]([C:17]([NH2:19])=[O:18])=[C:2]([N:1]=[CH:25][C:24]3[CH:27]=[CH:28][C:21]([OH:20])=[CH:22][CH:23]=3)[NH:6][N:5]=2)=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CN(C)c1ccc(Nc2n[nH]c(N)c2C(N)=O)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: CN(C)c1ccc(Nc2n[nH]c(N=Cc3ccc(O)cc3)c2C(N)=O)cc1
Yield: 90 %

Procedure:
5-amino-3-((4-(dimethylamino)phenyl)amino)-1H-pyrazole-4-carboxamide (900 mg) was suspended in 10 mL of ethanol and 4-hydroxybenzaldehyde (634 mg, 1.5 eq.) and piperidine (0.25 eq., 89 mL) was added. The reaction was stirred at reflux until the starting material was absent and confirmed by HPLC. After the reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 3-((4-(dimethylamino)phenyl)amino)-5-((4-hydroxybenzylidene)amino)-1H-pyrazole-4-carboxamide t as a yellow to orange powder. The product was washed with ethanol to remove any excess 4-hydroxybenzaldehyde. Product was allowed to dry under vacuum for 1 hr (1.130 g, 90% yield).
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][C:21]3[CH:24]=[CH:25][S:26][C:20]=3[CH:19]=2)=[CH:8]1)(C)(C)C.Cl[CH2:28][CH2:29][C:30]1(Cl)[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH2:31]1>>[F:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][O:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][C:21]4[CH:24]=[CH:25][S:26][C:20]=4[CH:19]=2)=[CH:8][C:7]3=[N:6][OH:5])=[CH:31][CH:32]=1
Reactant: CC(C)(C)ON=c1cc(-c2cc3sccc3cn2)oc2ccc(O)cc12
Reactant: FC1=CCC(Cl)(CCCl)C=C1
Product: ON=c1cc(-c2cc3sccc3cn2)oc2ccc(OCCc3ccc(F)cc3)cc12

Procedure:
6-[2-(4-Fluoro-phenyl)-ethoxy]-2-thieno[3,2-c]pyridin-6-yl-chromen-4-one oxime was prepared in 18% overall yield using the method described in example 127, starting from 6-Hydroxy-2-thieno[3,2-c]pyridin-6-yl-chromen-4-one O-tert-butyl-oxime (example 127B) and 1-(2-Chloro-ethyl)-4-fluorophenyl hydrochloride.
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][C:6]2=[N:7][S:8][N:9]=[C:5]2[CH:4]=1.C(=O)([O-])[O-:13].[Ca+2]>O1CCOCC1.O>[OH:13][CH2:2][C:3]1[CH:11]=[CH:10][C:6]2=[N:7][S:8][N:9]=[C:5]2[CH:4]=1
Reactant: BrCc1ccc2nsnc2c1
Reactant: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1COCCO1
Solvent: O
Product: OCc1ccc2nsnc2c1
Yield: 76.4 %

Procedure:
5-Bromomethylbenzo-2,1,3-thiadiazole (4.8 g) and calcium carbonate (10 g) were heated at reflux in 1:1 dioxane/water (120 mL) for 3 hours. The solvents were evaporated and the residue was partitioned between 2N hydrochloric acid and methylene 6 3 chloride. The organic layers were dried (magnesium sulfate), evaporated and chromatographed on silica gel eluting with 1:1 ethyl acetate/hexane to provide 2.66 g of the title compound.
Reaction SMILES: C(OCC)(=O)C.Br.[NH2:8][CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19]3[CH:20]=[CH:21][C:22](=[O:25])[NH:23][N:24]=3)[CH:16]=2)[CH2:11]1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:32]([S:34](Cl)(=[O:36])=[O:35])[CH3:33]>O1CCCC1>[CH2:32]([S:34]([NH:8][CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19]3[CH:20]=[CH:21][C:22](=[O:25])[NH:23][N:24]=3)[CH:16]=2)[CH2:11]1)(=[O:36])=[O:35])[CH3:33]
Reactant: CCS(=O)(=O)Cl
Reactant: NCC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCS(=O)(=O)NCC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Reaction time: 3 h
Yield: 82.5 %

Procedure:
In a mixed solution of 30 ml of ethyl acetate and 30 ml of tetrahydrofuran was suspended 3.22 g of 2-aminomethyl-5-[pyridazin-3(2H)-on-6-yl]indane hydrobromide. A sodium carbonate aqueous solution (5.30 g/30 ml of water) was added to the suspension. Under ice cooling, 3.32 g of ethanesulfonyl chloride dissolved in 10 ml of tetrahydrofuran was added to the mixture, and the resulting mixture was stirred for 3 hours. 300 ml of ethyl acetate was added to the mixture. After the organic layer was collected by separation, washed with water and dried, and the solvent was removed. The residue was purified by silica gel column chromatography (chloroform-methanol (100:3)) to obtain 2.75 g of 2-(ethylsulfonylaminomethyl)-5-[pyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][CH2:16][C:17]#[N:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Ni]>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][CH2:15][CH2:16][CH2:17][NH2:18])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCCOC1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: NCCCOC1CCN(Cc2ccccc2)CC1

Procedure:
10.0 g (40.9 mmol) 3-(1-benzylpiperidin-4-yloxy)-propionitrile are dissolved in 100 ml ethanol and added to a spatula tip of Raney-Nickel. The mixture is stirred at RT under hydrogen atmosphere until the uptake of the theoretical amount of hydrogen (ca. 2 days). The mixture is filtered from the catalyst and the solvent is removed under vacuum. The residue is distilled in a ball-pipe apparatus. Yield of colorless oil: 7.5 g (73%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:14]([CH:43]=[CH:44][N:45]=3)[CH:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:40]=[CH:41][CH:42]=3)[C:21]([NH:23][C:24]3[CH:39]=[CH:38][C:27]([C:28]([O:30]CC4C=CC=CC=4)=[O:29])=[CH:26][CH:25]=3)=[O:22])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>C(OCC)(=O)C.C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:14]([CH:43]=[CH:44][N:45]=3)[CH:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:40]=[CH:41][CH:42]=3)[C:21]([NH:23][C:24]3[CH:39]=[CH:38][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[O:22])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2nc(-c3cccc(C(=O)Nc4ccc(C(=O)OCc5ccccc5)cc4)c3)cn3ccnc23)cc1OC
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(Nc2nc(-c3cccc(C(=O)Nc4ccc(C(=O)O)cc4)c3)cn3ccnc23)cc1OC
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 30.8 %

Procedure:
A solution of benzyl 4-(3-(8-(3,4-dimethoxyphenylamino)imidazo[1,2-a]pyrazin-6-yl)benzamido)benzoate (1.75 g, 2.92 mmol) in ethyl acetate (500 mL) and ethanol (500 mL) at 60° C. was treated with 10% palladium on carbon (5.11 g, 50% water by weight) and sparged with hydrogen for 30 min at 60° C. then stirred under balloon pressure hydrogen at 60° C. for 30 min. After this time, the reaction was sparged with nitrogen for 10 min and filtered hot through diatomaceous earth. The filtrate was concentrated under reduced pressure and the residue obtained was exhaustively triturated: boiling acetonitrile (50 mL×2); then boiling methanol (50 mL); then boiling 1:1 methanol/acetonitrile (50 mL); then boiling acetonitrile (50 mL); then boiling 1:1 methanol/acetonitrile (50 mL) to afford 4-(3-(8-(3,4-dimethoxyphenylamino)imidazo[1,2-a]pyrazin-6-yl)benzamido)benzoic acid (458 mg, 31%) as an off-white solid: mp>250° C.; 1H NMR (300 MHz, DMSO-d6) δ 12.74 (br s, 1H), 10.67 (s, 1H), 9.57 (s, 1H), 8.74 (s, 1H), 8.56 (s, 1H), 8.25 (d, J=7.8 Hz, 1H), 8.80-7.89 (m, 7H), 7.69-7.53 (m, 3H), 6.93 (d, J=8.7 Hz, 1H), 3.78 (s, 3H), 3.71 (s, 3H); ESI MS m/z 510 [M+H]+; HPLC, 6.50 min, 95.6% (AUC).