Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[CH3:30])[CH2:5][N:6]1[C:10](=O)[CH:9]([CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:8]([CH2:23][CH2:24][CH3:25])[C:7]1=[O:26].[CH3:31][Mg]Br.CCOCC>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[CH3:30])[CH2:5][N:6]1[C:10]([CH3:31])=[C:9]([CH2:12][CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[N:8]([CH2:23][CH2:24][CH3:25])[C:7]1=[O:26]
Reactant: CCCN1C(=O)N(Cc2ccc(C)c(C)c2)C(=O)C1CCCc1ccc(OC)cc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCn1c(CCCc2ccc(OC)cc2)c(C)n(Cc2ccc(C)c(C)c2)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A 0° C. solution of 3-(3,4-dimethyl-benzyl)-5-[3-(4-methoxy-phenyl)-propyl]-1-propyl-imidazolidine-2,4-dione (0.155 g, 0.379 mmol) in THF (6 mL) was treated dropwise with a 3 molar solution of methyl magnesium bromide in Et2O (0.76 mL, 2.28 mmol) and then stirred at 0° C. under N2 for 1 h. The reaction was quenched with 1 N HCl (5 mL) and stirred at room temperature for 15 minutes to effect elimination and then was worked up extractively with EtOAc and water. The organic layer dried (MgSO4), and the solvent removed in vacuo to afford 0.155 g (100%) 1-(3,4-dimethyl-benzyl)-4-[3-(4-methoxy-phenyl)-propyl]-5-methyl-3-propyl-1,3-dihydro-imidazol-2-one that was utilized without purification. MS (ES+) Calc'd for C26H35N2O2 (M+1) 407. Found m/z 407 (100%). 1H NMR.
Reaction SMILES: I[CH2:2][C:3]1[CH:4]=[C:5]([CH3:22])[CH:6]=[C:7]2[C:12]=1[O:11][CH:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8]2.[CH3:23][S-:24].[Na+]>CO>[CH3:22][C:5]1[CH:6]=[C:7]2[C:12](=[C:3]([CH2:2][S:24][CH3:23])[CH:4]=1)[O:11][CH:10]([C:13]([F:16])([F:14])[F:15])[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8]2
Reactant: CCOC(=O)C1=Cc2cc(C)cc(CI)c2OC1C(F)(F)F
Reactant: C[S-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C1=Cc2cc(C)cc(CSC)c2OC1C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
The ethyl 8-(iodomethyl)-6-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in Example 605e, Step 2 (0.2 g, 0.47 mmole) was dissolved in methanol (4 mL) and cooled to 0° C. (ice bath). Sodium thiomethoxide (0.04 g, 0.52 mmole) was added dropwise and stirred for 2 hours at 0° C. The solution was warmed to room temperature and stirred for an additional 2 hours. The reaction was condensed in vacuo to give a yellow oil (0.16 g, 98%). No further purification was performed: GCMS m/z 346.00 (M+).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[CH2:10][CH2:11][C@H:12]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:13]([OH:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=C[C:35]=2N=N1.CN1CCOCC1.[OH-].[Na+]>C(#N)C.CO>[CH3:35][O:14][C:13](=[O:15])[C@@H:12]([NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:11][CH2:10][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:24]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CO
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](CCC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 121.5 %

Procedure:
To a mixture of (S)-2-tert-butoxycarbonylamino-pentanedioic acid 5-benzyl ester (300 mg, 0.89 mmol) and methanol (4 mL) were added benzotriazol-1-yloxytris-(dimethylamino)-phosphonium hexafluorophosphate (390 mg, 0.89 mmol), N-methylmorpholine (98 μL, 0.89 mmol), and acetonitrile (1 mL) at 0° C., which was stirred overnight at room temperature. A 1N sodium hydroxide aqueous solution was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed first with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under a reduced pressure, so as to obtain the titled compound (380 mg, purity of 66%) in a crude form.
Reaction SMILES: [SH:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[H-].[Na+].ClN1C(=O)CCC1=O.[CH3:17][C:18]1[N:19]=[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]2[CH:26]=1>CN(C)C=O>[CH3:17][C:18]1[N:19]=[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]2[C:26]=1[S:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1
Reactant: Sc1nc[nH]n1
Reactant: Cc1cn2ccccc2n1
Agent: O=C1CCC(=O)N1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc2ccccn2c1Sc1nc[nH]n1
Reaction time: 0.25 h
Yield: 27.4 %

Procedure:
To a mixture of 3-mercapto-1H-1,2,4-triazole (1.15 g) and N,N-dimethylformamide (15 ml) was added 60% sodium hydride (450 mg). After foaming was completed, N-chlorosuccinimide in small portions was added to the mixture on an ice bath, and stirred at this temperature for 15 minutes. 2-methylimidazo[1,2-a]pyridine (1.0 g) was then added, and the reaction mixture was heated and stirred at room temperature for 1 hour, and then for 3 hours on an oil bath at 70° C. The reaction solution was concentrated under reduced pressure. The residue was washed twice with diethyl ether, and methanol was added to the residue to remove undissolved materials. The filtrate was concentrated, and then crystals precipitated by the addition of water were collected by filtration, washed with water, followed by diethyl ether, and dried to yield the title compound (480 mg).
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]=1[C:7]#[N:8].[CH:21](O)=O.C(OC(=O)C)(=O)C.[OH2:31]>>[C:9]1([C:5]2[C:6]3[C:2](=[O:3])[NH:1][CH:21]=[N:8][C:7]=3[O:31][C:4]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N#Cc1c(N)oc(-c2ccccc2)c1-c1ccccc1
Reactant: O
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Product: O=c1[nH]cnc2oc(-c3ccccc3)c(-c3ccccc3)c12
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A mixture of 2-amino-4,5-diphenylfuran-3-carbonitrile (2.0 g) and formic acid (24 mL) was cooled to 0° C. and acetic anhydride (24 mL) was added dropwise. The resulting mixture was stirred for another 1 h and was then heated at 100° C. for 16 h. The reaction mixture was cooled and water was added (40 mL). The precipitate was collected by filtration and washed thoroughly with water and hexanes to give the title compound (2.1 g, 95%). 1H NMR (300 MHz, CDCl3): δ 7.94 (s, 1H), 7.56-7.52 (m, 4H), 7.46-7.43 (m, 3H), 7.32-7.28 (m, 3H), 7.22 (s, 1H). LC-MS (ESI) m/z 289.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:34]/[CH:35]=[CH:36]/[CH:37]1[CH2:39][CH2:38]1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:34]/[CH:35]=[CH:36]/[CH:37]2[CH2:39][CH2:38]2)=[CH:24][CH:25]=1
Reactant: BrC/C=C/C1CC1
Reactant: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OC/C=C/C4CC4)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 3 h

Procedure:
To a stirred solution of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (intermediate D1) (37 mg, 0.097 mmol) in 1.5 ml of DMF was added Cs2CO3 (48 mg, 0.146 mmol) and (E)-(3-bromoprop-1-enyl)cyclopropane (intermediate BY) (50 mg) at room temperature. After stirring for 3 h, the reaction was quenched with 2 ml of ice water. The mixture was extracted 3× with ethyl acetate (5 ml), and the combined organic layers were washed 2× with water (5 ml) and brine, dried over Na2SO4, concentrated, and purified by preparative LC-MS to obtain compound BZ (8.6 mg). 1H NMR (CD3OD, 400 MHz): δ 7.37˜7.33 (2H, m), 7.30˜7.27 (1H, dd, J=8.2, 2 Hz), 7.11˜7.09 (2H, d, J=8.8 Hz), 6.82˜6.79 (2H, d, J=8.8 Hz), 5.77˜5.70 (1H, dt, J=15.2, 6 Hz), 5.39˜5.33 (1H, dd, J=15.2, 8.8 Hz), 4.43˜4.41 (2H, dd, J=6.4, 1.0 Hz), 4.10 (1H, d, J=9.6 Hz), 4.08˜3.98 (2H, dd, J=23.6, 15.2 Hz), 3.90˜3.87 (1H, m), 3.72˜3.67 (1H, m), 3.49˜3.39 (3H, m), 3.31˜3.27 (1H, m), 1.47˜1.45 (1H, m), 0.76˜0.71 (2H, m), 0.41˜0.37 (2H, m); MS ESI (m/z) 461 (M+H)+, calc. 460.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[N:6]([CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH2:5]2.[H-].[Na+].Br[CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[OH2:30]>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[CH2:7][N:6]([CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[C:5]2=[O:30]
Reactant: BrCC1CCCCC1
Reactant: O
Reactant: CCN(CC)CCN1Cc2cc(Cl)ccc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCN(CC)CCN1CN(CC2CCCCC2)c2ccc(Cl)cc2C1=O
Yield: 85 %

Procedure:
2.00 Grammes (7.1 mmoles) of 6-chloro-3-[2-(diethylamino)ethyl]-2,3-dihydro-(1H)-quinazolinone are suspended in 5 ml of anhydrous dimethylacetamide. Milligrammes (17.8 mmoles) of sodium hydride are added to this solution and, after 30 minutesat room temperature, 0.72 ml (7.8 mmoles) of bromomethylcyclohexane are dripped. After 3 hours of reaction at room temperature the reaction solution is poured into water and ice. The product, of an oily consistency, is recovered through extraction with ethyl acetate, with a yield of 85%, and presents the following chemical-physical characteristics.
Reaction SMILES: CS(C)=O.[F:5][C:6]1[C:7]([C:12]2([C:16]#[N:17])[CH2:15][CH2:14][CH2:13]2)=[N:8][CH:9]=[CH:10][CH:11]=1.C(=O)([O-])[O-:19].[K+].[K+].OO>O.C(OCC)(=O)C>[F:5][C:6]1[C:7]([C:12]2([C:16]([NH2:17])=[O:19])[CH2:15][CH2:14][CH2:13]2)=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: N#CC1(c2ncccc2F)CCC1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)C1(c2ncccc2F)CCC1
Temperature: 0 °C
Yield: 58.8 %

Procedure:
To a 250 mL round bottom flask containing DMSO (60 mL) was added 1-(3-fluoropyridin-2-yl)cyclobutanecarbonitrile (2.96 g, 16.8 mmol, 1.0 equiv) and the mixture was stirred until homogenous. Potassium carbonate (7.0 g, 50.4 mmol, 3.0 equiv) was then added and the reaction mixture was cooled to 0° C., followed by the addition of 35% hydrogen peroxide (6.5 mL). The reaction was stirred at 0° C. for 30 min and then warmed to room temperature. At this time, the reaction was diluted with water (50 mL) and ethyl acetate (100 mL). After transferring to a separatory funnel and shaking, the organic layer was separated from the aqueous layer and then washed with brine (3×50 mL). The organic layer was then dried over Na2SO4, filtered, and concentrated to give a crude solid that was purified by silica gel chromatography (10% EtOAC/hexanes) to afford 1.92 g (59%) of 1-(3-fluoropyridin-2-yl)cyclobutanecarboxamide as a white solid.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[BH4-].[Na+].[CH:9](=O)[C:10]1[C:11](=[CH:13][CH:14]=[CH:15][CH:16]=1)[OH:12]>[OH-].[Na+]>[OH:12][C:11]1[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=1[CH2:9][NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3]
Reactant: O=Cc1ccccc1O
Reactant: C[C@H](N)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Product: C[C@H](NCc1ccccc1O)C(=O)O
Reaction time: 1 h

Procedure:
L-alanine (2.9 g) was dissolved in 20 ml of a 2-N sodium hydroxide aqueous solution, and 3.5 ml of salicylaldehyde and 0.4 g of sodium borohydride were then added thereto in this order. After the mixture was stirred for 1 hour, 3.5 ml of salicylaldehyde and 0.4 g of sodium borohydride were added thereto again. The mixture was stirred at room temperature for 1 hour, and the insoluble matter was then separated through filtration. The filtrate was extracted with diethyl ether. The pH was adjusted to 6 with hydrochloric acid to obtain 5.8 g of N-(2-hydroxybenzyl)-L-alanine. The resulting N-(2-hydroxybenzyl)-L-alanine (4.6 g) and 8.8 g of 1-dodecanol were added to 150 ml of toluene, and a hydrogen chloride gas was blown thereto up to the saturation. Ten grams of a molecular sieve were added thereto, and the mixture was stirred overnight. After the insoluble matter was separated through filtration, the filtrate was concentrated, and the resulting oil was dissolved in methylene chloride. The mixture was washed with a saturated aqueous solution of sodium chloride. The resulting mixture was dried over magnesium sulfate, and concentrated under reduced pressure to give 8 g of N-(2-hydroxybenzyl)-L-alanine lauryl ester.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:18]([OH:20])=[O:19])[CH2:6][S:7][S:8][CH2:9][C@H:10]([NH:14][C:15](=[O:17])[CH3:16])[C:11]([OH:13])=[O:12])(=[O:3])[CH3:2].[CH2:21]([NH2:24])[CH2:22][NH2:23].C(O)C>O>[CH2:21]([NH3+:24])[CH2:22][NH3+:23].[C:15]([NH:14][C@H:10]([C:11]([O-:13])=[O:12])[CH2:9][S:8][S:7][CH2:6][C@H:5]([NH:4][C:1](=[O:3])[CH3:2])[C:18]([O-:20])=[O:19])(=[O:17])[CH3:16]
Reactant: NCCN
Reactant: CC(=O)N[C@@H](CSSC[C@H](NC(C)=O)C(=O)O)C(=O)O
Solvent: O
Solvent: CCO
Product: CC(=O)N[C@@H](CSSC[C@H](NC(C)=O)C(=O)[O-])C(=O)[O-]
Product: [NH3+]CC[NH3+]
Temperature: 10 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
To N,N'-Diacetyl-L-cystine (30.9 mmol, 10 g) dissolved in 20 mL of water was added ethylenediamine (61.8 mmol, 3.73 g) and ethanol (30 mL). The solution was concentrated to a thick paste which was redissolved in 80 mL of ethanol. Crystallisation occurred after 2 hours stirring at 10° C. Filtration and drying gave 6.2 g (45%) of the title compound.
Reaction SMILES: [Cl:1][C:2]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](Cl)=[O:4].Cl.[NH2:19][CH2:20][C:21]#[C:22][CH2:23][OH:24].C(N(CC)CC)C.Cl>C(Cl)Cl>[OH:24][CH2:23][C:22]#[C:21][CH2:20][NH:19][C:3](=[O:4])[C:2]([Cl:1])([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NCC#CCO
Reactant: O=C(Cl)C(Cl)(c1ccccc1)C1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC#CCO)C(Cl)(c1ccccc1)C1CCCCC1
Reaction time: 0.17 h
Yield: 69 %

Procedure:
A solution of 2-chloro-2-cyclohexyl-2-phenylacetyl chloride (9.0 g) in methylene chloride (50 ml) was added dropwise to a solution of 4-amino-2-butyn-1-ol hydrochloride (5.38 g) and triethylamine (30.8 ml) in methylene chloride (120 ml) at 0° C. The mixture was stirred at the same temperature for 10 minutes and then at room temperature for an additional 3.5 hours and 1N hydrochloric acid was added thereto. The organic layer was separated, washed with saturated sodium bicarbonate, aqueous solution, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of chloroform and ethyl acetate (6:1) as an eluent to give N-(4-hydroxy-2-butynyl)-2-chloro-2-cyclohexyl-2-phenylacetamide (7.32 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)=[CH:4][CH:3]=1.C(O)(=O)C.[Cl:31]Cl>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:17][CH:18]=3)[N:11]=[C:10]([C:23]([F:24])([F:25])[F:26])[C:9]=2[Cl:31])=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(Cl)cc2)cc1
Reactant: ClCl
Solvent: CC(=O)O
Solvent: O
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(Cl)c2-c2ccc(Cl)cc2)cc1
Yield: 75 %

Procedure:
A 100 mL three-necked round-bottomed flask equipped with reflux condenser, gas dispersion tube and provisions for magnetic stirring was charged with 4-[5-(4-chlorophenyl)-3-trifluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide (Example 1) (500 mg, 1.2 mmol) and 50 mL of glacial acetic acid. The solution was stirred at room temperature and treated with a stream of chlorine gas for a period of 15 minutes. The solution was then stirred at room temperature for 1.25 hours and then diluted with 100 mL of water. The solution was then extracted three times with ether and the combined ethereal phase washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give a white solid that was recrystallized from ether/petroleum ether to provide 390 mg (75%) of 4-[5-(4-chlorophenyl)-4-chloro-3-trifluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide: mp 180-182° C.; 1H NMR (CDCl3/300 MHz) 7.97 (d, J=6.6 Hz, 2H), 7.49 (d, J=6.3 Hz, 2H), 7.45 (d, J=6.3 Hz, 2H), 7.25 (d, J=6.6 Hz, 2H), 5.78 (brs, 2H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14].[OH-].[Na+].C(O)(=O)C>C(O)C.O>[CH3:1][S:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14]
Reactant: COC(=O)c1ccc(SC)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CSc1ccc(C(=O)O)cc1[N+](=O)[O-]
Yield: 93.8 %

Procedure:
A solution of methyl 4-methylthio-3-nitrobenzoate (11.7 g) and sodium hydroxide (4.1 g) in ethanol (234 ml) and water (117 ml) was heated at reflux for 2 hours and was then concentrated in vacuo to about 70 ml. Water (250 ml) was added and the mixture was warmed to give a solution which was acidified with acetic acid (30 ml). The mixture was stirred while cooling and the resulting solid collected and washed with water to yield 4-methylthio-3-nitrobenzoic acid (10.3 g), m.p. 245°-247° C. [Elemental analysis: C,45.2; H,3.22; N,6.48; S,14.1%; calculated: C,45.07; H,3.29; N,6.57; S,15.02%].
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[N+:8]([C:7]1[C:2]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cccnc1Nc1ccccc1
Yield: 33.9 %

Procedure:
A procedure similar to that described in Preparation 66 was repeated, except that 15 g of 2-chloro-3-nitropyridine, 13.22 g of aniline and 25.07 g of sodium carbonate were reacted in 180 ml of toluene. After working up the product as described in Preparation 66, the resulting crude product was purified by column chromatography through silica gel, using a 1:5 by volume mixture of ethyl acetate and hexane, to give 6.9 g of the title compound, melting at 66°-68° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C[CH2:7][O:8][CH2:9][CH3:10]>>[CH2:10]([N:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1)[CH:9]1[O:8][CH2:7]1
Reactant: CCOCC
Reactant: c1cc[nH]c1
Product: c1ccn(CC2CO2)c1
Temperature: 25 °C
Yield: 80 %

Procedure:
A reaction mixture formed from 200 g of sodium hydroxide NaOH, 8.4 g of tetrabutylammonium hydrogensulfate, 200 ml of water and 125 ml of epichlorohydrin is stirred very vigorously at room temperature in a one liter reactor. 40 g of freshly distilled pyrrole are added dropwise while cooling the solution with a bath of ice-cold water in order to keep the temperature of the mixture between 15° and 20° C. The mixture is left stirring with a stream of nitrogen for 3 hours, 100 ml of ether are added in order to cause an aqueous phase and an organic phase to settle which are separated from each other. The aqueous phase is extracted twice with 100 ml of ether. The whole of the organic phase is washed with aqueous salt solution until neutrality, dried over a molecular sieve, filtered and distilled under vacuum. 58 g of N-glycidylpyrrole ##STR4## or a yield of 80%, are obtained. The product is characterized by 1H NMR and 13C NMR. Its purity is 93%; it is determined by liquid phase chromatography.
Reaction SMILES: Cl[CH:2]1[CH2:7][CH:6]([CH2:8][CH:9]([CH3:11])[CH3:10])[O:5][C:3]1=[O:4].C(=O)([O-])[O-:13].[K+].[K+]>Cl>[OH:13][CH:2]1[CH2:7][CH:6]([CH2:8][CH:9]([CH3:11])[CH3:10])[O:5][C:3]1=[O:4]
Reactant: O=C([O-])[O-]
Reactant: CC(C)CC1CC(Cl)C(=O)O1
Agent: Cl
Agent: [K+]
Product: CC(C)CC1CC(O)C(=O)O1
Temperature: 25 °C
Reaction time: 40 h
Yield: 99 %

Procedure:
In a 50 ml flask with a cooling column, 1.77 g (10 mmole) of α-chloro-γ-isobutyl-γ-butyrolactone and 12 ml of 2N aqueous potassium carbonate were kept at 80 C. for 40 hours under stirring. The reaction mixture was cooled to room temperature and poured into 10 ml of 12N hydrochloric acid. The reaction product was extracted with ether and the ether extract was dried with anhydrous sodium sulfate. After removal of ether, distillation of the residue under reduced pressure gave α-hydroxy-γ-isobutyl-γ-butyrolactone. (yield 99%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:20]=[CH:19][C:11]3[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:21][CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(N(C(C)C)C(C)C)C>CS(C)=O>[O:25]1[CH2:26][CH2:27][CH:22]([NH:21][C:2]2[N:7]=[C:6]([C:8]3[CH:20]=[CH:19][C:11]4[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=4[CH:9]=3)[CH:5]=[CH:4][N:3]=2)[CH2:23][CH2:24]1
Reactant: NC1CCOCC1
Reactant: CC(=O)Nc1nc2ccc(-c3ccnc(Cl)n3)cc2s1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1nc2ccc(-c3ccnc(NC4CCOCC4)n3)cc2s1
Temperature: 150 °C
Reaction time: 0.67 h
Yield: 23.2 %

Procedure:
A mixture of N-(6-(2-chloropyrimidin-4-yl)benzo[d]thiazol-2-yl)acetamide (0.200 g, 0.7 mmol), 4-aminotetrahydropyran (0.07 ml, 0.7 mmol), N-ethyl-N-isopropylpropan-2-amine (0.2 g, 1 mmol) in DMSO (1 g, 13 mmol) was heated under microwave (CEM) at 150° C. and 130 W (Powermax®& off) for 40 min. Then, the mixture was diluted with 1 ml of DMSO and purified by HPLC (5-50% CH3CN in water) to give a light yellow solid (60 mg) as a TFA salt. MS (ESI pos. ion) Found m/z: 370, (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[N:9]([CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]3)[C:8]=2[CH:23]=1)(=[O:3])[CH3:2].[O:24]=[C:25]1[CH2:30][O:29][C:28]2[CH:31]=[CH:32][C:33]([CH:35]=O)=[N:34][C:27]=2[NH:26]1.C([BH3-])#N.[Na+]>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[N:9]([CH2:14][CH2:15][N:16]3[CH2:17][CH2:18][CH:19]([NH:22][CH2:35][C:33]4[CH:32]=[CH:31][C:28]5[O:29][CH2:30][C:25](=[O:24])[NH:26][C:27]=5[N:34]=4)[CH2:20][CH2:21]3)[C:8]=2[CH:23]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)CO2
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(=O)c1ccc2c(c1)N(CCN1CCC(NCc3ccc4c(n3)NC(=O)CO4)CC1)C(=O)CO2
Yield: 7 %

Procedure:
6-Acetyl-4-[2-(4-aminopiperidin-1-yl)ethyl]-2H-1,4-benzoxazin-3(4H)-one (Intermediate 87), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) and sodium cyanoborohydride were reacted as described under Example 21 to give the product as an off-white solid in 7% yield.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH2:4][C@@:5]2([N:22]=1)[C:18]1[CH:17]=[C:16](O)[CH:15]=[C:14]([F:20])[C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8](Br)=[CH:9][CH:10]=1.[F:23][C:24]1[C:29](B(O)O)=[CH:28][CH:27]=[CH:26][N:25]=1.Cl.[F:34][C:35]1([F:40])[CH2:39][CH2:38][NH:37][CH2:36]1>>[F:34][C:35]1([F:40])[CH2:39][CH2:38][N:37]([C:16]2[CH:15]=[C:14]([F:20])[C:13]3[O:12][C:11]4[C:6](=[CH:7][C:8]([C:29]5[C:24]([F:23])=[N:25][CH:26]=[CH:27][CH:28]=5)=[CH:9][CH:10]=4)[C@@:5]4([CH2:4][S:3][C:2]([NH2:1])=[N:22]4)[C:18]=3[CH:17]=2)[CH2:36]1
Reactant: OB(O)c1cccnc1F
Reactant: FC1(F)CCNC1
Reactant: NC1=N[C@@]2(CS1)c1cc(Br)ccc1Oc1c(F)cc(O)cc12
Agent: Cl
Product: NC1=N[C@@]2(CS1)c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(N3CCC(F)(F)C3)cc12

Procedure:
The titled compound was synthesized by stpes analogous to those described in method AA20 above, but using (S)-2-amino-7′-bromo-4′-fluoro-5H-spiro[thiazole-4,9′-xanthen]-2′-ol (prepared as described in Method BB26 and Example 2 but using 7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-one), 2-fluoropyridin-3-ylboronic acid and 3,3-difluoropyrrolidine hydrochloride. MS m/z=487.0 [M+H]+.