Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[O:6][CH:5]1[CH2:4][O:3][CH2:2]2.[NH4+].[Cl-].CCOC(C)=O.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([NH:22][C@@H:5]1[CH2:4][O:3][CH2:2][C@H:1]1[OH:6])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: C1OCC2OC12
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: O[C@@H]1COC[C@H]1NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Ti(O′Pr)4 (1.0 mL, 3.48 mmol) was added to a solution of 3,6-dioxabicyclo[3.1.0]hexane (1.5 g, 17.4 mmol) in benzylamine (2.0 mL). The mixture was irradiated in a microwave reactor at 130° C. for 2 hours. It was cooled to room temperature, and 50 mL of saturated aqueous NH4Cl solution and 20 mL of EtOAc were added to the reaction. The mixture was stirred for 10 minutes. The resulting gummy precipitate was filtered over a celite bed, and the filtrate was extracted using EtOAc (100 mL). The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by reverse phase chromatography on a C-18 column (0-100% CH3CN/water) to afford trans-4-(benzylamino)tetrahydrofuran-3-ol. MS APCI calc'd for C11H15NO2 [M+H]+ 194. found 194.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([CH2:12][O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][N:15]=2)=[CH:10][O:9][N:8]=1.[CH2:23]([NH2:25])[CH3:24]>>[CH2:23]([NH:25][C:18](=[O:20])[C:17]1[CH:21]=[CH:22][C:14]([O:13][CH2:12][C:11]2[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:8][O:9][CH:10]=2)=[N:15][CH:16]=1)[CH3:24]
Reactant: CCN
Reactant: O=C(O)c1ccc(OCc2conc2-c2ccccn2)nc1
Product: CCNC(=O)c1ccc(OCc2conc2-c2ccccn2)nc1
Yield: 81 %

Procedure:
As described for example 358 g, 6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.34 mmol) was converted using ethylamine (2 M solution in THF) instead of 4-aminotetrahydropyran to the title compound (88 mg, 81%) which was obtained as a white solid. MS: m/e=325.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:13][C:12]3[CH:14]=[CH:15][C:16]4[C:21]([C:11]=3[NH:10][C:9]2=[O:22])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH2:26][CH2:27][CH2:28][Cl:29].O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:13][C:12]3[CH:14]=[CH:15][C:16]4[C:21]([C:11]=3[N:10]([CH2:26][CH2:27][CH2:28][Cl:29])[C:9]2=[O:22])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:4][CH:3]=1
Reactant: O=C1Nc2c(ccc3ccccc23)SC1c1ccc(Cl)cc1
Reactant: ClCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C1C(c2ccc(Cl)cc2)Sc2ccc3ccccc3c2N1CCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.1 %

Procedure:
To a solution of 3-(4-chlorophenyl)-1H-naphtho-[2,1-b][1,4]thiazin-2(3H)-one (10.0 g) and 96% sodium hydroxide (1.96 g) in dimethylsulfoxide (150 ml) is added 1-bromo-3-chloropropane (6.78 g) under ice cooling, and the mixture is stirred at room temperature overnight. The reaction mixture is poured into water, and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed and distilled to remove the solvent. The residue is purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate=5:1) and further is recrystallized from methanol to give 3-(4-chlorophenyl)-1-(3-chloropropyl)-lH-naphtho[2,1-b][1,4]thiazin-2(3H)-one (8.04 g). M.p. 110°-112.5° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)[C:6]([CH3:22])=[C:5]2[C:23]([O:25][CH3:26])=[O:24].[CH3:27][S:28]([O-:30])=[O:29].[Na+].IC>[Cu]I.O>[CH3:22][C:6]1[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[N:8][C:9]2[C:4]([C:5]=1[C:23]([O:25][CH3:26])=[O:24])=[CH:3][C:2]([S:28]([CH3:27])(=[O:30])=[O:29])=[CH:11][CH:10]=2
Reactant: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2ccc(Br)cc12
Reactant: CS(=O)[O-]
Agent: [Cu]I
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(C)(=O)=O)cc12
Temperature: 120 °C
Reaction time: 2 h
Yield: 63.8 %

Procedure:
Methyl 6-bromo-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (50 g, 118 mmol) was combined with copper(I) iodide (44.9 g, 236 mmol) and sodium methylsulfinate (24.07 g, 236 mmol) in a 2 L round bottom flask and the vessel was purged with N2 (3×). The solids were suspended in dimethyl sulfoxide (400 mL), the atmosphere was exchanged for nitrogen (3×Vac/N2 purges), and the reaction was heated to 120° C. overnight. The reaction was cooled to 50° C., and iodomethane (50.2 g, 354 mmol) was added. The reaction was stirred for 2 hours at 50° C. and cooled to RT. The crude reaction mixture was added slowly 1 L of water with stirring over 30 minutes. The resulting yellow slurry was filtered through a buchner funnel. The filter cake was washed with 3×500 mL water and dried overnight. The solids were suspended in 625 mL CH2Cl2, and the suspension was stirred for ca. 30 min. The solids were purified by flash chromatography eluting with 100% CH2Cl2→40% EtOAc/CH2Cl2. Fractions containing the product were further purified by trituration with MeOH. Mixed fractions were repurified using the same conditions and combined with the previously isolated solid to provide 31.9 g (64%) of the product as a white solid. MS (m/z) 423.7 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[C:4](OCC)=[O:5].C([O-])=O.[NH4+].[CH:18]([NH2:20])=O>CCOC(C)=O>[CH:10]1[C:11]([F:13])=[CH:12][C:2]2[NH:1][CH:18]=[N:20][C:4](=[O:5])[C:3]=2[CH:9]=1
Reactant: CCOC(=O)c1ccc(F)cc1N
Reactant: NC=O
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: O=c1nc[nH]c2cc(F)ccc12

Procedure:
To a suspension of ethyl 2-amino-4-fluorobenzoate (1.73 g, 9.45 mmol) in formamide (8 mL) was added ammonium formate (0.9 g, 14 mmol). The reaction mixture was stirred at 140° C. for 24 hr, with additional ammonium formate (0.92 g, 15 mmol) at 6 hr. The reaction was dilute with EtOAc, washed with water, back-extracted with EtOAc, dried and concentrated in vacuo to give 7-fluoro-3-hydroquinazolin-4-one (2.82 g) which contains some formamide. ES-MS (M+H)+=165.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:35]=[CH:34][C:11]([C:12]([N:14]3[CH2:19][CH2:18][N:17]([S:20]([C:23]4[CH:32]=[CH:31][C:30]5[C:25](=[CH:26][CH:27]=[C:28]([Cl:33])[CH:29]=5)[CH:24]=4)(=[O:22])=[O:21])[CH2:16][CH2:15]3)=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH2:36]([N:38](CC)CC)[CH3:37].Cl.C(=N)(OCC)C>CO>[ClH:33].[C:36]([N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:35]=[CH:34][C:11]([C:12]([N:14]3[CH2:19][CH2:18][N:17]([S:20]([C:23]4[CH:32]=[CH:31][C:30]5[C:25](=[CH:26][CH:27]=[C:28]([Cl:33])[CH:29]=5)[CH:24]=4)(=[O:22])=[O:21])[CH2:16][CH2:15]3)=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1)(=[NH:38])[CH3:37]
Reactant: CCN(CC)CC
Reactant: O=C(c1ccc(C2CCNCC2)cc1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Agent: CCOC(C)=N
Agent: Cl
Solvent: CO
Product: CC(=N)N1CCC(c2ccc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 195 %

Procedure:
To a solution of 1-[4-(piperidin-4-yl)benzoyl]-4-(6-chloronaphthalene-2-sulfonyl)piperazine hydrochloride (40 mg) and triethylamine (156 mg) in methanol (15 ml) was added ethyl acetimidate hydrochloride (46 mg), and the solution was stirred at room temperature for 15 hours. The reaction solution was concentrated. To the residue was added 1 N sodium hydroxide solution, and the solution was extracted with dichloromethane. The extract was dried and concentrated. The residue was dissolved in ethyl acetate, to which was added 4 N hydrochloric acid in ethyl acetate. The precipitate was filtered, washed with ether and dried to give a colorless solid of the title compound (42 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@@H:10]([OH:15])[C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][O:23][C:24]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:25]=1[CH:26]=O.O>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C@@H:9]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C@H:10]([C:11]([O:13][CH3:14])=[O:12])[O:15][CH:26]1[C:25]1[CH:28]=[CH:29][C:30]([O:32][CH3:33])=[CH:31][C:24]=1[O:23][CH3:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: COC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1OC(c2ccc(OC)cc2OC)N(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Temperature: 20 °C
Yield: 93.8 %

Procedure:
A solution of 0.497 g of methyl (2R,3S)-3-t-butoxycarbonylamino-2-hydroxy-3-phenylpropionate, 0.012 g of pyridinum b-toluenesulphonate and 0.295 g of 2,4-dimethoxybenzaldehyde in 20 cm3 of anhydrous toluene is heated to reflux for 24 hours. The water formed during the reaction is removed by means of a Dean and Stark apparatus. After cooling to a temperature in the region of 20° C., the solution is washed with 37% (w/w) aqueous sodium hydrogen sulphite solution and then with saturated aqueous sodium bicarbonate solution. After concentration of the organic phase under reduced pressure, 0.700 g of (4S,5R)-3-t-butoxycarbonyl-2-(2,4-dimethoxyphenyl)-4-phenyl-5-methoxycarbonyl-1,3-oxazolidine is obtained in an 80% yield in the form of a virtually equimolecular mixture of the diastereo-isomeric forms A and B, the characteristics of which are as follows:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[NH:21][C:22]2[C:23]3[C:30]([CH3:31])=[C:29]([C:32](O)=[O:33])[S:28][C:24]=3[N:25]=[CH:26][N:27]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:35]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[NH:21][C:22]2[C:23]3[C:30]([CH3:31])=[C:29]([C:32]([NH2:35])=[O:33])[S:28][C:24]=3[N:25]=[CH:26][N:27]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCN(C(=O)OC(C)(C)C)C3)c12
Solvent: CO
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCN(C(=O)OC(C)(C)C)C3)c12

Procedure:
Prepared analogously to example 1.4 from 4-[2-((S)-1-tert-butoxycarbonyl-pyrrolidin-3-yloxy)-4-fluoro-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid and ammonia in methanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([C:7]2[O:8][C:9]3[C:14]([C:15](=[O:18])[C:16]=2[CH3:17])=[CH:13][CH:12]=[CH:11]C=3C=CC)=[CH:5][CH:4]=1.[Mn]([O-])(=O)(=O)=O.[K+].S(=O)(O)[O-].[Na+].[C:35]([OH:38])(=[O:37])[CH3:36]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]2[O:8][C:9]3[C:14]([C:15](=[O:18])[C:16]=2[CH3:17])=[CH:13][CH:12]=[CH:11][C:36]=3[C:35]([OH:38])=[O:37])=[CH:22][CH:23]=1
Reactant: CC=Cc1cccc2c(=O)c(C)c(-c3ccc(OC)cc3)oc12
Reactant: CC(=O)O
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=S([O-])O
Agent: [K+]
Product: COc1ccc(-c2oc3c(C(=O)O)cccc3c(=O)c2C)cc1
Reaction time: 8 h

Procedure:
4'-Methoxy-3-methyl-8-propenylflavone (3 grams) is dissolved in 35 ml of glacial acetic acid, small amount of ice is added thereto, 6.8 grams of potassium permanganate is added thereto during eight hours keeping the solution at 20° to 30° C. and stirring throughout, then aqueous solution of sodium bisulfite is added thereto keeping the solution at 30° to 40° C., and the mixture is stirred for one hour. Crystals separated out therefrom are collected by filtration, washed with water, then dissolved in 10% sodium hydroxide solution, the solution is treated with an activated charcoal, filtered, the filtrate is adjusted to pH 3 with concentrated hydrochloric acid, crystals separated out are collected by filtration, and washed with water to give 1.2 grams of 4'-methoxy-3-methylflavone-8-carboxylic acid, colorless needles, melting point 266° to 267° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:21](O)=[O:22])[C:5]2[CH:6]=[N:7][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:9]=2[CH:10]=1.S(Cl)(Cl)=O.[CH3:28][C@H:29]1[O:34][C@@H:33]([CH3:35])[CH2:32][N:31]([CH2:36][C:37]([NH:39][NH2:40])=[O:38])[CH2:30]1.CCN(C(C)C)C(C)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:21]([NH:40][NH:39][C:37](=[O:38])[CH2:36][N:31]2[CH2:32][C@H:33]([CH3:35])[O:34][C@H:29]([CH3:28])[CH2:30]2)=[O:22])[C:5]2[CH:6]=[N:7][N:8]([S:11]([C:14]3[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=3)(=[O:12])=[O:13])[C:9]=2[CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c(C(=O)O)cc(Br)cc32)cc1
Reactant: C[C@@H]1CN(CC(=O)NN)C[C@H](C)O1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2ncc3c(C(=O)NNC(=O)CN4C[C@@H](C)O[C@@H](C)C4)cc(Br)cc32)cc1
Temperature: 100 °C
Yield: 44.3 %

Procedure:
6-Bromo-1-[(4-methylphenyl)sulfonyl]-1H-indazole-4-carboxylic acid (1.5 g, 3.80 mmol) was suspended in thionyl chloride (8.31 ml, 114 mmol) and heated to 100° C. for 30 mins. The thionyl chloride was removed in vacuo and excess aziotroped with dry diethyl ether to give a yellow solid. This was dissolved in dry tetrahydrofuran (40 ml) and 2-[(2R,6S)-2,6-dimethyl-4-morpholinyl]acetohydrazide (1.066 g, 5.69 mmol) and DIPEA (2.65 ml, 15.18 mmol) added. The reaction mixture was heated to 60° C. for 20 mins. The solvent was removed in vacuo and the residue partitioned between dichloromethane (50 ml) and water (50 ml). The layers were separated and the organic concentrated in vacuo to give a yellow foam. This was purified by column chromatography, loading in dichloromethane onto a silica cartridge (50 g), eluting with 0-100% ethyl acetate-cyclohexane over 30 mins. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a yellow solid (950 mg).
Reaction SMILES: B(Br)(Br)Br.C([O:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=1)C>ClCCl>[F:16][C:15]([F:17])([F:18])[C:10]1[CH:9]=[C:8]([OH:7])[CH:13]=[CH:12][C:11]=1[OH:14]
Reactant: CCOc1ccc(O)c(C(F)(F)F)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(O)c(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 63.2 %

Procedure:
Boron tribromide (11.8 g) was slowly added dropwise to dichloromethane (41 mL) cooled to −78° C., and then Compound (e) (6.47 g) dissolved in dichloromethane (60 mL) was slowly added dropwise at the same temperature and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then poured into ice water and the aqueous layer was extracted with ether. The organic layers were combined, washed with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 3.53 g of Compound (g).
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([O:7][CH2:8][C@@H:9]2[CH2:11][N:10]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:5][CH:4]=1)#[N:2].[CH2:21]([N:28]1[CH2:34][CH:33]2[NH:35][CH:30]([CH2:31][CH2:32]2)[CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)(C)C>[CH2:21]([N:28]1[CH2:34][CH:33]2[N:35]([CH2:11][C@H:9]([NH:10][C:12](=[O:13])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])[CH2:8][O:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:20][CH:19]=3)[CH:30]([CH2:31][CH2:32]2)[CH2:29]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: c1ccc(CN2CC3CCC(C2)N3)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@H]1COc1ccc(C#N)cc1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N[C@H](COc1ccc(C#N)cc1)CN1C2CCC1CN(Cc1ccccc1)C2
Temperature: 60 °C
Reaction time: 48 h
Yield: 77 %

Procedure:
tert-Butyl (2S)-2-[(4-cyanophenoxy)methyl]-1-aziridinecarboxylate (3 g, 11 mmol; see step (d) above) and 3-benzyl-3,8-diazabicyclo[3.2.1]octane (2.2 g, 0.011 mol; from Preparation B, step (e) above) were mixed in isopropanol (50 mL) and stirred at 60° C. for 48 h, and then at 80° C. for 2 h. The solvent was evaporated and the residue purified by chromatography, eluting with DCM/MeOH (9:1), to give the sub-title compound in 77% yield.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][C:15]=1[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CO.[Cl-].[NH4+]>C1COCC1>[CH2:3]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][OH:19])=[CH:16][C:15]=1[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)Oc1cc(C=O)ccc1OCCOCc1ccccc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)Oc1cc(CO)ccc1OCCOCc1ccccc1
Reaction time: 0.17 h

Procedure:
To a stirred mixture of 1.00 g (26.5 mmol) sodium borohydride in 80 ml THF was added 2, 0.9 g (8.83 mmol) 4-[2-(benzyloxy)ethoxy]-3-tert-butoxybenzaldehyde diluted in 40 ml THF drop by drop. The reaction mixture was stirred for 10 min. Methanol (5.8 ml) was added to this mixture drop by drop. The reaction mixture was stirred for 2 hours and poured onto ˜200 ml stirred ice-cooled saturated aqueous ammonium chloride solution. The solution was extracted trice with dichloromethane. The combined organic phases were dried with sodium sulfate and concentrated in vacuo. The crude product was used in the following reaction without further purification.
Reaction SMILES: [CH2:1]([C:4]1[C:13]2[O:14][C:15]([C:19]([OH:21])=[O:20])=[CH:16][C:17](=S)[C:12]=2[CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:2][CH3:3].CC(C)=[O:24]>CI.O>[O:24]=[C:17]1[CH:16]=[C:15]([C:19]([OH:21])=[O:20])[O:14][C:13]2[C:4]([CH2:1][CH2:2][CH3:3])=[C:5]3[C:10](=[CH:11][C:12]1=2)[CH2:9][CH2:8][CH2:7][CH2:6]3
Reactant: CCCc1c2c(cc3c(=S)cc(C(=O)O)oc13)CCCC2
Reactant: CC(C)=O
Solvent: O
Solvent: CI
Product: CCCc1c2c(cc3c(=O)cc(C(=O)O)oc13)CCCC2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 10-propyl-6,7,8,9-tetrahydro-4-thioxo-4H-naphtho[2,3-b]pyran-2-carboxylic acid (0.025 g), methyl iodide (3 drops), acetone (10 ml) and water (4 drops) was stirred in the dark at ambient temperature for 2 days. Concentration of the reaction mixture in vacuo gave a brown solid which on crystallisation from acetone gave the title compound as a light-yellow solid, mp 245°-8°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1[S:9][C:10]([CH:14]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[C:22]([Cl:25])[CH:23]=3)[N:18]([S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH:17]=2)O)=[C:11]([Cl:13])[N:12]=1)([CH3:4])([CH3:3])[CH3:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1[S:9][C:10]([CH2:14][C:16]2[C:24]3[C:19](=[N:20][CH:21]=[C:22]([Cl:25])[CH:23]=3)[N:18]([S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:27])=[O:28])[CH:17]=2)=[C:11]([Cl:13])[N:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1nc(Cl)c(C(O)c2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)s1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)Nc1nc(Cl)c(Cc2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.8 %

Procedure:
To 5-[(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-4-chloro-thiazol-2-yl-carbamic acid tert-butyl ester (590, 0.200 g, 0.32 mmol) in dichloromethane (15.0 mL) were added triethylsilane (0.600 mL, 376 mmol) and trifluoroacetic acid (0.300 mL, 3.89 mmol). The reaction was stirred at room temperature for 3 hours, then concentrated, poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 25% to 100% ethyl acetate in hexane to give the desired compound (591, 0.155 g, 88.7%). MS (ESI) [M+H+]+=538.9.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:5]([C:12]2[CH:13]=[CH:14][C:15](=[O:21])[N:16]([CH:18]([CH3:20])[CH3:19])[N:17]=2)=[N:6][C:7]=1S(C)(=O)=O.[CH3:28][O-:29].[Na+].O>CO.CC(C)=O>[NH2:1][C:2]1[N:3]=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:5]([C:12]2[CH:13]=[CH:14][C:15](=[O:21])[N:16]([CH:18]([CH3:20])[CH3:19])[N:17]=2)=[N:6][C:7]=1[O:29][CH3:28]
Reactant: CC(C)n1nc(-c2nc(S(C)(=O)=O)c(N)nc2-c2ccccc2)ccc1=O
Reactant: C[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CO
Product: COc1nc(-c2ccc(=O)n(C(C)C)n2)c(-c2ccccc2)nc1N
Yield: 85.8 %

Procedure:
A suspension of 6-[5-amino-6-(methylsulfonyl)-3-phenyl-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone (205 mg) and sodium methoxide (57.7 mg) in MeOH (0.6 m) was refluxed for 24 hours. Water (3 ml) was added to the reaction mixture to give a precipitate. The precipitate was collected by filtration and purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (60:40 v/v) to give a solid. The solid was suspended in acetone and collected by filtration to give 6-(5-amino-6-methoxy-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (154 mg).
Reaction SMILES: OC1C=CC(C(O)=O)=CC=1.S(Cl)(Cl)=O.[OH:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1.[NH2:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=1)[C:29]([O:31][CH2:32][CH3:33])=[O:30]>N1C=CC=CC=1>[CH2:32]([O:31][C:29]([C:28]1[CH:27]=[C:26]([NH:25][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][C:16]([OH:15])=[CH:17][CH:18]=2)[CH:36]=[CH:35][CH:34]=1)=[O:30])[CH3:33]
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: O=C(Cl)c1ccc(O)cc1
Agent: O=C(O)c1ccc(O)cc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1cccc(NC(=O)c2ccc(O)cc2)c1

Procedure:
4-Hydroxybenzoic acid can be converted into the corresponding acid chloride upon treatment with thionyl chloride in pyridine. The reaction of equimolar amounts of 4-hydroxybenzoyl chloride and ethyl 3-aminobenzoate in pyridine yields N-(3-ethoxycarbonylphenyl)4-hydroxybenzamide which can be transferred into ethyl 5-{[3-(ethoxycarbonylphenyl)amino]carbonyl}-2-hydroxybenzenepropanoate according to the procedure of Example 92A. Alkylation of this phenol according to the procedure of Example 60 followed by hydrolysis of the resulting diester by the method of Example 56 will provide the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH:6]([CH3:9])[CH2:7][CH3:8])[C:3]([OH:5])=[O:4].C(Cl)Cl.C(Cl)(=O)C(Cl)=O.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]2[S:28][C:27]3=[CH:29][N:30]([CH2:41]O)[C:31](=[O:40])[C:32]([C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=4)=[C:26]3[NH:25][C:24]=2[CH:43]=1>N1C=CC=CC=1>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]2[S:28][C:27]3=[CH:29][N:30]([CH2:41][O:4][C:3](=[O:5])[CH:2]([CH3:1])[CH:6]([CH3:9])[CH2:7][CH3:8])[C:31](=[O:40])[C:32]([C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=4)=[C:26]3[NH:25][C:24]=2[CH:43]=1
Reactant: CCC(C)C(C)C(=O)O
Reactant: O=c1c(-c2ccc(Cl)cc2)c2c(cn1CO)Sc1ccc(Cl)cc1N2
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(C)C(C)C(=O)OCn1cc2c(c(-c3ccc(Cl)cc3)c1=O)Nc1cc(Cl)ccc1S2
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
A mixture of 2.06 g. of 2,3-dimethylvaleric acid (15.8 mmol). in 30 ml. of methylene chloride was cooled in a cold water bath and treated with 2.0 g. of oxalyl chloride (15.8 mmol.). The resulting solution was stirred at room temperature for 2 hours, then the methylene chloride was removed under reduced pressure. The resulting residue was added dropwise to a cold, stirred suspension of 1.2 g. of 7-chloro-4-(4-chlorophenyl)-2-(hydroxymethyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one (3.1 mmol.) in 25 ml. of pyridine. After stirring for 35 minutes, the mixture was poured onto ice-water and allowed to stand for 16 hours at room temperature, resulting in the formation of a yellow precipitate, which was collected, washed with water, air-dried, then purified using flash chromatography on silica gel, employing a mixture of 5% ethyl acetate: 95% methylene chloride as the eluent. Fractions containing the product were combined and triturated with ether to yield 7-chloro-4-(4-chlorophenyl)-2-[(2,3-dimethyl-1-oxopentoxy)methyl]-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one as a pale yellow crystalline solid (1.18 g; 76% yield) having the structural formula, ##STR22## a melting point in the range of 165°-173° C. and the following elemental analysis: