Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][CH3:13])[N:8]=[C:7]2[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([F:21])[CH:15]=1.C(N(C(C)C)CC)(C)C.[CH3:31][C:32]([CH3:38])([CH3:37])[CH2:33][C:34](Cl)=[O:35]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:31][C:32]([CH3:38])([CH3:37])[CH2:33][C:34]([O:20][C:17]1[CH:18]=[CH:19][C:14]([C:7]2[C:6]3[C:10](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=3)[N:9]([CH2:11][CH2:12][CH3:13])[N:8]=2)=[CH:15][C:16]=1[F:21])=[O:35]
Reactant: CCCn1nc(-c2ccc(O)c(F)c2)c2cccc(Cl)c21
Reactant: CC(C)(C)CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCn1nc(-c2ccc(OC(=O)CC(C)(C)C)c(F)c2)c2cccc(Cl)c21
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
To a solution of 4-(7-chloro-1-propyl-1H-indazole-3-yl)-2-fluorophenol (0.10 g, 0.33 mmol) in dichloromethane (20 mL) at −78° C. was added diisopropylethylamine (0.70 mL, 0.41 mmol), 3,3-dimethylbutanoyl chloride (0.05 mL, 0.35 mmol) and catalytic amount of 4-(dimethylamino)pyridine. The reaction was stirred at this temperature for 30 minutes. The mixture was diluted with dichloromethane and the organic layer washed with 1n hydrochloric acid solution, water and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the organic phase was filtered and the filtrate evaporated in vacuo to yield crude title compound. The oil was purified by silica gel column chromatography eluting with hexane/ethyl acetate (5/1) to provide the title compound as a white solid (0.11 g, 0.27 mmol, 83%).
Reaction SMILES: [CH3:1][C:2]([NH:6][C:7](=[O:16])[C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([Cl:15])[CH:9]=1)([CH3:5])[C:3]#[CH:4].[Br:17]Br>C(Cl)Cl.CCCCCC>[BrH:17].[Cl:14][C:12]1[CH:13]=[C:8]([C:7]2[O:16][C:3](=[CH:4][Br:17])[C:2]([CH3:1])([CH3:5])[N:6]=2)[CH:9]=[C:10]([Cl:15])[CH:11]=1
Reactant: C#CC(C)(C)NC(=O)c1cc(Cl)cc(Cl)c1
Reactant: BrBr
Solvent: CCCCCC
Solvent: ClCCl
Product: Br
Product: CC1(C)N=C(c2cc(Cl)cc(Cl)c2)OC1=CBr
Temperature: 25 °C
Yield: 178.3 %

Procedure:
N- (1',1'-dimethylpropynyl)-3,5-dichlorobenzamide (40 gm, 0.156 m) was dissolved in methylene chloride (600 ml) and bromine (25 gm, 0.156 m) in methylene chloride (100 ml) was added gradually with stirring at room temperature. After the complete addition of the bromine, the mixture was stirred for another 15 minutes and diluted with hexane (500 ml). The yellowish-white precipitate which formed was filtered and dried to yield 58 gm of 2-(3',5'-dichlorophenyl)-4,4-dimethyl-5-bromomethylenoxazoline hydrobromide. The oxazoline hydrobromide (55 gm, 0.13 m) was added to concentrated sulfuric acid (200 ml) and stirred to obtain a clear solution. Water (20 ml) was added and the mixture heated at about 50° C. for about 24 hours. The mixture was then poured into ice water (about 2000 ml) and the white precipitate which formed was filtered and dried. Recrystallization from isopropanol, ether and hexane (1:1:2) yielded 21 gm of pure product.
Reaction SMILES: Cl[C:2]1[C:3]([F:21])=[CH:4][C:5]2[C:6]([CH:20]=1)=[N:7][C:8]1[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:34][NH:33][CH2:32][CH2:31][NH:30]2)=[CH:25][CH:24]=1.C(N(CC)CC)C>N1C=CC=CC=1>[F:21][C:3]1[C:2]([N:33]2[CH2:32][CH2:31][NH:30][CH:29]([C:26]3[CH:27]=[CH:28][C:23]([CH3:22])=[CH:24][CH:25]=3)[CH2:34]2)=[CH:20][C:6]2=[N:7][C:8]3[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=3[CH:14]=[C:5]2[CH:4]=1
Reactant: Cc1ccc(C2CNCCN2)cc1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Cc1ccc(C2CN(c3cc4nc5c(cc4cc3F)c(=O)c(C(=O)O)cn5C)CCN2)cc1
Temperature: 115 °C
Yield: 29.9 %

Procedure:
A suspension of 8-chloro-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (1.84 g) in pyridine (20 cc), (RS)-2-(4-methylphenyl)piperazine (5.83 g) and triethylamine (1.24 g) is heated to a temperature in the region of 115° C. for 37 hours. After cooling to approximately 20° C., the insoluble matter is drained and washed with ethanol (2×5 cc) and ethyl ether (2×5 cc). After recrystallization in dimethylformamide (25 cc), (RS)-7-fluoro-1-methyl-8-[3-(4-methylphenyl)-1-piperazinyl]-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (0.8 g) is obtained in the form of a yellow solid, decomposing at 282° C.
Reaction SMILES: [BH4-].[Na+].CC([N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]2[C:27]3[C:22](=[C:23]([C:28](=[O:30])[CH3:29])[CH:24]=[CH:25][CH:26]=3)[C:21]([NH:31][S:32]([C:35]3[S:36][C:37]([Cl:40])=[CH:38][CH:39]=3)(=[O:34])=[O:33])=[N:20]2)[CH:13]=1)C(=O)[O-])(C)C.Cl.O1CCOCC1>CO>[NH2:7][CH2:11][C:12]1[CH:13]=[C:14]([CH2:18][N:19]2[C:27]3[C:22](=[C:23]([CH:28]([OH:30])[CH3:29])[CH:24]=[CH:25][CH:26]=3)[C:21]([NH:31][S:32]([C:35]3[S:36][C:37]([Cl:40])=[CH:38][CH:39]=3)(=[O:34])=[O:33])=[N:20]2)[CH:15]=[CH:16][CH:17]=1
Reactant: CC(=O)c1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN(C(=O)[O-])C(C)(C)C)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: CC(O)c1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium borohydride (20.52 mg, 0.543 mmol) was added to a stirring solution of 1,1-dimethylethyl({3-[(4-acetyl-3-{[(5-chloro-2-thienyl)sulfonyl]amino}-1H-indazol-1-yl)methyl]phenyl}methyl)carbamate (for a preparation see Intermediate 75) (260 mg, 0.452 mmol) in MeOH (5 mL) at 25° C. under N2. The reaction mixture was stirred at room temp for 2 h. About ˜⅔ of the methanol was evaporated in vacuo and the residue was treated slowly with 1M HCl (5 mL). The product was extracted with EtOAc (2×40 mL) and the combined organic layers were dried by passing through a hydrophobic frit and concentrated to afford a yellow oil. 4N HCl in Dioxane (2 mL, 8.00 mmol) was added to the residue at 25° C. and the reaction mixture was stirred for 30 min. The crude sample was loaded straight on to a pre-washed (MeOH) SPE sulphonic acid (SCX-2) cartridge (20 g). The SCX cartridge was washed with 2 column volumes of MeOH and the product was collected by washing with 3 column volumes of 2N Ammonia in MeOH. The appropriate fractions were combined and evaporated in vacuo to give the title compound (235 mg, 91) %. LCMS (System A) RT=0.77 min, ES+ve m/z 477/479 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:13](=O)[C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[O:10][CH:9]([C:19]([O:21][CH3:22])=[O:20])[O:8][C:7]=2[CH:23]=1.C(O)C.C(OCC)(=O)C.[H][H]>[Pd].C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[O:10][CH:9]([C:19]([O:21][CH3:22])=[O:20])[O:8][C:7]=2[CH:23]=1
Reactant: [H][H]
Reactant: COC(=O)C1Oc2ccccc2C(=O)c2ccc(OC)cc2O1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)C1Oc2ccccc2Cc2ccc(OC)cc2O1

Procedure:
Methyl 3-methoxy-12H-dibenzo[d,g][1,3]-dioxocin-12-one-6-carboxylate (1.35 g, 4.3 mmol) was combined with 35 ml of ethanol, 15 ml of ethyl acetate, 6 ml of acetic acid, and 0.70 g of 5 percent palladium on carbon catalyst and the suspension was placed on a Parr hydrogenator under 50 psi of hydrogen for 18 hours. The catalyst was removed by filtration and the filtrate was diluted with 300 ml of ether and 100 ml of water and the layers separated. The organic layer was extracted with 3-100 ml portions of water and 2-100 ml portions of saturated aqueous sodium bicarbonate and was then dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure. The residue was purified by preparative liquid chromatography on silica gel eluting with a 15:85 mixture of ether and hexane to obtain 0.76 g (59 percent of theory) of the title compound as a white powder melting at 93°-95° C. The proton nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [C:1]([O:8]CC)(=[O:7])[C:2](OCC)=O.[O-]CC.[K+].[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1C)([O-:17])=[O:16]>CCOCC>[CH3:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([N+:15]([O-:17])=[O:16])[C:19]=1[CH2:2][C:1]([OH:8])=[O:7]
Reactant: Cc1cccc([N+](=O)[O-])c1C
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [K+]
Solvent: CCOCC
Product: Cc1cccc([N+](=O)[O-])c1CC(=O)O
Yield: 45 %

Procedure:
Diethyl oxalate (30 mL) in 20 mL of dry ether was added with stirring to 19 g of potassium ethoxide suspended in 50 mL of dry ether. The mixture was cooled in an ice bath and 20 mL of 3-nitro-o-xylene in 20 mL of dry ether was slowly added. The thick dark red mixture was heated to reflux for 0.5 hr, concentrated to a dark red solid, and treated with 10% sodium hydroxide until almost all of the solid dissolved. The dark red mixture was treated with 30% hydrogen peroxide until the red color changed to yellow. The mixture was treated alternately with 10% sodium hydroxide and 30% hydrogen peroxide until the dark red color was no longer present. The solid was filtered off and the filtrate acidified with 6N hydrochloric acid. The resulting precipitate was collected by vacuum filtration, washed with water, and dried under vacuum to give 9.8 g (45% yield) of 2-methyl-6-nitrophenylacetic acid as an off-white solid. The solid was hydrogenated in methanol over 10% palladium on carbon to give 9.04 g of the title compound as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[N:13]([CH3:18])[N:14]=[C:15]([CH3:17])[CH:16]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[CH:2].Br[C:20]1[CH:21]=[N:22][CH:23]=[C:24]([CH:37]=1)[C:25]([N:27]=[S@@:28]([CH3:36])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>>[CH3:18][N:13]1[C:12]([C:10]([NH:9][C:5]2[CH:4]=[C:3]([C:1]#[C:2][C:20]3[CH:21]=[N:22][CH:23]=[C:24]([CH:37]=3)[C:25]([N:27]=[S@@:28]([CH3:36])(=[O:35])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[CH:8]=[CH:7][CH:6]=2)=[O:11])=[CH:16][C:15]([CH3:17])=[N:14]1
Reactant: C[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Reactant: C#Cc1cccc(NC(=O)c2cc(C)nn2C)c1
Product: Cc1cc(C(=O)Nc2cccc(C#Cc3cncc(C(=O)N=[S@@](C)(=O)c4ccccc4)c3)c2)n(C)n1
Yield: 63.8 %

Procedure:
In a manner similar to that described in Example 449, 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid (3-ethynyl-phenyl)-amide (0.0354 g, 0.222 mmol) and (S)-5-bromo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (0.050 g, 0.148 mmol) were reacted to give the title compound as a white solid (47 mg, 64%).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12]([C:14]1[CH:15]=[CH:16][N:17]2[C:22]=1[C:21](=[O:23])[NH:20][C:19]([CH3:24])=[N:18]2)=[O:13])[CH3:10].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[CH2:9]([O:11][C:12]([C:14]1[CH:15]=[CH:16][N:17]2[C:22]=1[C:21](=[O:23])[N:20]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:19]([CH3:24])=[N:18]2)=[O:13])[CH3:10]
Reactant: CCOC(=O)c1ccn2nc(C)[nH]c(=O)c12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCOC(=O)c1ccn2nc(C)n(Cc3ccccc3)c(=O)c12
Temperature: 95 °C
Yield: 71 %

Procedure:
Benzyl bromide (0.112 ml, 0.945 mmol) was added to a solution of 2-methyl-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-5-carboxylic acid ethyl ester (0.19 g, 0.86 mmol) and Cs2CO3 (0.34 g, 1.06 mmol) in dioxane (5 mL) and the reaction mixture was heated to 95° C. for 3 h. The reaction mixture was quenched with saturated NaCl (100 mL), extracted with CHCl3 (3×50 mL), the combined organic extracts dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 1/1 hexane/EtOAc to afford the title compound as a solid (0.19 g, 70%): 1H NMR (CDCl3) δ 7.22–7.35 (m, 6H), 7.00–7.01 (m, 1H), 5.28 (s, 2H), 4.38 (q, 2H, J=7.19 Hz), 2.38 (s, 3H), 1.38 (t, 3H, J=7.09 Hz); MS (ESI+) 312 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[O:15][CH2:14][O:13][C:5]=2[CH:6]=[C:7]2[C:12]=1[CH:11]=[N:10][CH:9]=[CH:8]2.[S:16]([O:21]C)([O:19][CH3:20])(=[O:18])=[O:17]>C1(C)C=CC=CC=1>[CH3:20][O:19][S:16]([O-:21])(=[O:18])=[O:17].[CH3:1][O:2][C:3]1[C:4]2[O:15][CH2:14][O:13][C:5]=2[CH:6]=[C:7]2[C:12]=1[CH:11]=[N+:10]([CH3:20])[CH:9]=[CH:8]2
Reactant: COS(=O)(=O)OC
Reactant: COc1c2c(cc3ccncc13)OCO2
Solvent: Cc1ccccc1
Product: COS(=O)(=O)[O-]
Product: COc1c2c(cc3cc[n+](C)cc13)OCO2
Temperature: 60 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
8-Methoxy-6,7-methylenedioxyisoquinoline (5) in an amount of 2.03 g (10 mmol) was dissolved into 40 ml of toluene while heating them at 60° C. Then, 1.13 ml (12 mmol) of dimethyl sulfate was added and stirred at 60° C. for 4 hours. After cooling, deposited crystals were collected by filtration, washed with toluene and then dried to obtain 3.30 g of 8-methoxy-2-methyl-6,7-methylenedioxyisoquinolinium methyl sulfate (6) with a yield of 100%. The resultant product was then recrystallized from ethanol: m.p. 172°-4° C. IR and NMR of the resultant product are listed below.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-:3])=[O:2].C(O)(=O)C.[N+:13]([O-])([OH:15])=[O:14].C(OC(=O)C)(=O)C>O>[N+:13]([N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[CH:6]1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1c[nH]cn1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cn([N+](=O)[O-])cn1

Procedure:
After 20 g of 4-nitroimidazole was put in a flask, 36.4 mL of acetic acid was added thereto and while the temperature of the reaction solution was kept below 20° C., 14.6 mL of 97 mass % nitric acid was added dropwise thereto. After the dropwise addition of nitric acid was completed, 36.4 mL of acetic anhydride was added dropwise thereto and after the temperature of the reaction solution elevated to 25° C., the resultant mixture was allowed to react for 3 hours. After the reaction ended, the reaction solution was added into 100 g of iced water. Extraction with 100 mL of p-xylene was performed four times and this organic layer was washed twice with 100 mL of a saturated sodium hydrogen carbonate aqueous solution. The organic layer was separated and 30 g of magnesium sulfate was added thereto for dehydration to obtain 1,4-dinitroimidazole as a p-xylene solution. Subsequently, the solvent was evaporated with an evaporator to about two third amount, and the solution was heated to 125° C. and allowed to react for 24 hours so as to perform conversion to 2,4-dinitroimidazole. After the reaction ended, the deposited solid was filtered to obtain 24.1 g of 2,4-dinitroimidazole as a solid wetted with p-xylene (wetted with 15 mass % of p-xylene, yield 74.9%). This was identified to be 2,4-dinitroimidazole by
Reaction SMILES: [C:1]([C:4]1[C:22](O)=[CH:21][CH:20]=[CH:19][C:5]=1[O:6][CH2:7][CH:8]([OH:18])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)(=[O:3])C.[O-][CH2:25][CH3:26].[Na+].[Na].C(OCC)(=O)C(OCC)=[O:31]>CCOCC.C(O)C.Cl>[C:1]([C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[O:6][CH2:7][CH:8]([OH:18])[CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)([O:3][CH2:25][CH3:26])=[O:31]
Reactant: CC[O-]
Reactant: CC(=O)c1c(O)cccc1OCC(O)COc1ccc(F)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)c1ccccc1OCC(O)COc1ccc(F)cc1

Procedure:
A suspension of 1-(2-acetyl-3-hydroxyphenoxy)-2-hydroxy-3 -(p-fluorophenoxy) propane (25.6 g) in diethyl oxalate (30 ml) was added to a suspension of sodium ethoxide, prepared from sodium (6.0 g) and ethanol (60 ml) in dry ether (400 ml). The mixture was then heated under reflux for 2 hours, cooled, and poured onto ice (200 g). After acidification with a solution of acetic acid (24 ml) in water (160 ml), the ethereal layer was separated, and the aqueous layer was extracted with ether (3 × 50 ml). The organic extracts were combined and concentrated under reduced pressure to give yellow oil. This was dissolved in ethanol (100 ml) containing hydrochloric acid (10 drops) and the solution heated under reflux for 1 hour. After removal of the solvent under reduced pressure the yellow residue was crystallized from ethanol to give 1-(2-carbethoxy-phenoxy)-2-hydroxy-3-(p-fluorophenoxy) propane (22.0 g) as cream crystals, m.p. 112°-114° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:30][C:31]1[CH:32]=[C:33]([CH2:37][CH2:38]O)[CH:34]=[CH:35][CH:36]=1>>[ClH:1].[C:31]1([CH3:30])[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][CH2:38][O:24][C:23]([C:18]2([C:20]([O:22][CH2:38][CH2:37][C:33]3[CH:32]=[C:31]([CH3:30])[CH:36]=[CH:35][CH:34]=3)=[O:21])[O:17][C:16]3[CH:26]=[CH:27][C:13]([CH2:12][C@H:11]([NH:10][CH2:9][C@@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[OH:29])[CH3:28])=[CH:14][C:15]=3[O:19]2)=[O:25])[CH:32]=1
Reactant: Cc1cccc(CCO)c1
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Product: Cc1cccc(CCOC(=O)C2(C(=O)OCCc3cccc(C)c3)Oc3ccc(C[C@@H](C)NC[C@H](O)c4cccc(Cl)c4)cc3O2)c1
Product: Cl
Yield: 81 %

Procedure:
The title compound was prepared as a brown oil from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and 2-(3-methylphenyl)ethanol according to the procedure of Example 1; yield: 81%; 1H NMR (300 MHz, CDCl3): δ 1.12 (m, J=6.3 Hz, 3H),2.27 (s, 6H), 2.79 (m, 7H), 3.19 (m, 1H), 3.48 (m, 2H), 4.29 (m, J=6.6 Hz, 4H), 5.49 (m, 1H,) 6.75 (m, J=8.1 Hz, 1H), 6.83 (m, 1H), 7.05 (m, 8H), 7.20 (m, 1H), 7.27 (m, 1H), 7.43 (s, 1H), 7.5 (m, 2H); MS (ES) m/z (relative intensity): 658 (M+ +H, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[NH2:17][C:18](N)=S.CS(C)=O>CCCCCC.CCOC(C)=O>[C:6]1([C:4]2[C:3]3[C:2](=[CH:15][C:14]([CH3:16])=[CH:13][CH:12]=3)[N:1]=[CH:18][N:17]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NC(N)=S
Reactant: Cc1ccc(C(=O)c2ccccc2)c(N)c1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCCCCC
Product: Cc1ccc2c(-c3ccccc3)ncnc2c1
Temperature: 140 °C
Yield: 98.9 %

Procedure:
To a 20 mL microwave reaction vial with a micro magnetic stir bar, were added 0.284 g of 2-amino-4-methylbenzophenone, 0.208 g of thiourea and 3 mL of DMSO. Then the vial was sealed and heated with microwave at 140° C. for 20 hours to form an orange liquid. The reaction mixture was treated in a similar method via column chromatography with hexane/EtOAc (6:1) as eluent to afford 0.293 g of 4-phenyl-7-methyl-quinazoline, in a yield of 99.0%.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][C:13]1[CH:17]=[CH:16][O:15][CH:14]=1)[CH2:9][CH2:10]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C1(C)C=CC(S([Cl:34])(=O)=O)=CC=1.O>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([N:8]([CH2:9][CH2:10][Cl:34])[CH2:12][C:13]1[CH:17]=[CH:16][O:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCN(Cc1ccccc1)Cc1ccoc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: ClCCN(Cc1ccccc1)Cc1ccoc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 0.397 g (1.716 mmol) of 2-[benzyl-(3-furylmethyl)amino]ethanol, 0.36 ml (2.6 mmol) of triethylamine and 10 mg of 4-dimethylaminopyridine in 30 ml of dichloromethane, 0.39 g (2.1 mmol) of p-toluenesulfonyl chloride was added at room temperature, followed by stirring at room temperature for 6 hours. The reaction mixture was poured into water and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=15/1 to 9/1) to yield N-benzyl-N-(3-furylmethy)-2-chloroethylamine.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2.[O:14]=[C:15]1[C:20]2=[CH:21][NH:22][C:23]([CH:24]=O)=[C:19]2[CH2:18][CH2:17][NH:16]1.N1CCCCC1>C(O)C>[OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[CH:24][C:23]1[NH:22][CH:21]=[C:20]3[C:19]=1[CH2:18][CH2:17][NH:16][C:15]3=[O:14])[C:7](=[O:13])[NH:8]2
Reactant: O=Cc1[nH]cc2c1CCNC2=O
Reactant: O=C1Cc2c(CCO)cccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2cccc(CCO)c2C1=Cc1[nH]cc2c1CCNC2=O
Temperature: 80 °C

Procedure:
A mixture of 4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one (35.4 mg, 0.2 mmol), 4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (32.8 mg, 0.2 mmol) and 0.1 mL of piperidine in ethanol (1 mL) was heated in a sealed tube at 80° C. for 4 hours. The precipitate was collected by vacuum filtration, washed with cold ethanol and dried to give the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[C@@H:22]1([C:31]([OH:33])=[O:32])[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]1[C:28]([OH:30])=[O:29]>C(#N)C>[C:31]([C@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]1[C:28]([O-:30])=[O:29])([OH:33])=[O:32].[NH2+:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: O=C(O)[C@H]1CCCC[C@H]1C(=O)O
Solvent: CC#N
Product: O=C(O)[C@H]1CCCC[C@H]1C(=O)[O-]
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CC[NH2+]CC1)O2
Temperature: 80 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a mixture of spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione (0.5 g, 1.66 mmol) and acetonitrile (20 ml) which had been preheated to 80° C. was added a preheated (80° C.). solution of cis-cyclohexane-1,2-dicarboxylic acid (0.286 ml, 1.66 mmol) in acetonitrile (20 ml). The reaction mixture was stirred overnight at 80° C. The resulting purple precipitate was filtered, washed with acetonitrile, and dried under reduced pressure to afford the product as a purple solid (0.472 g, 60%). M.p.=204-207° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.90-7.87 (m, 1H), 7.83-7.81 (m, 1H), 7.78-7.73 (m, 1H), 7.58-7.54 (m, 1H), 3.16-3.11 (m, 4H), 3.07-3.00 (m, 2H), 2.53-2.48 (m, 2H), 2.11-2.05 (m, 2H), 1.88-1.75 (m, 4H), 1.52-1.40 (m, 4H), 1.33-1.29 (m, 2H); LCMS: 302 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]12[CH2:16][N:15]([C:17]3[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=3)[CH2:14][CH:13]1[CH2:12][S:11][C:10]([NH2:24])=[N:9]2>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:16][N:15]([C:17]3[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=3)[CH2:14][C@H:13]1[CH2:12][S:11][C:10]([NH2:24])=[N:9]2
Reactant: NC1=NC2(c3ccccc3F)CN(c3ncc(F)cn3)CC2CS1
Solvent: CO
Product: NC1=N[C@@]2(c3ccccc3F)CN(c3ncc(F)cn3)C[C@H]2CS1
Yield: 31.6 %

Procedure:
Racemic 7a-(2-fluorophenyl)-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-amine (361 mg, 1.04 mmol) is purified by chiral HPLC (Column: Chiralpak AD-H (5 u), 3×25 cm; eluent: 100% methanol (0.2% isopropylamine); flow 30 mL/min at UV 225 nm. The second eluting isomer is the title compound (114 mg, 32%, 99% ee). Rt=4.887 minutes; column: Chiralpak AD-H 0.46×15 cm; eluent: 100% methanol (0.2% isopropylamine) in CO2; flow: 1 mL/min at UV 225 nm.