Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.Cl.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31](Cl)=[O:32].C(=O)([O-])O.[Na+]>CN1CCCC1=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:31]([C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=5)=[O:32])[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1ccccn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.2 %

Procedure:
To a solution of N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (155 mg, 0.50 mmol) in N-methylpyrrolidone (3 mL) was added pyridine-2-carbonylchloride hydrochloride (107 mg, 0.60 mmol), and the mixture was stirred at room temperature for 18 hr. A 5% aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→80/20) and crystallized from ethyl acetate to give the title compound (131 mg, yield 63%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].O.[C:15]1(C)C=CC(S(O)(=O)=O)=C[CH:16]=1>C(O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([O:13][CH2:15][CH3:16])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CC(=O)O)cc1O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)Cc1ccc(OC)c(O)c1

Procedure:
The stirred solution of 2-(3-Hydroxy-4-methoxyphenyl)acetic acid (9.82 g, 53.90 mmol) and p-Toluenesulfonic acid monohydrate (1.15 g, 6.0 mmol) in abs ethanol (100 ml) was refluxed for 4 hours or until all the starting material is consumed. The reaction mixture was concentrated, diluted with ethyl acetate and washed with 1M HCl. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex:ethyl acetate 2:1) to give the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH:3]=[N:4][S:5]([C:8]1[S:9][C:10]2[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:11]=2[N:12]=1)(=[O:7])=[O:6].[CH2:19](Br)[CH:20]=[CH2:21].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:1][N:2]([CH3:18])[CH:3]=[N:4][S:5]([C:8]1[S:9][C:10]2[CH:16]=[C:15]([O:17][CH2:21][CH:20]=[CH2:19])[CH:14]=[CH:13][C:11]=2[N:12]=1)(=[O:6])=[O:7]
Reactant: C=CCBr
Reactant: CN(C)C=NS(=O)(=O)c1nc2ccc(O)cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCOc1ccc2nc(S(=O)(=O)N=CN(C)C)sc2c1
Temperature: 60 °C
Yield: 70.7 %

Procedure:
A solution of product from Step A (1.14 gm, 4.0 mmol) and allyl bromide (0.5 mL, 5.5 mmol) in dimethyl sulfoxide (8 mL) containing potassium carbonate (0.75 gm, 5.4 mmol) was warmed at 60° C. for 15-20 hours. The reaction mixture was poured into water and the product was extracted into ethyl acetate, dried (Na2SO4) and evaporated to give a viscous oil (0.92 gm).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[CH:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Li])CCC.[CH3:23][O:24][CH2:25][O:26][C:27]1[CH:36]=[C:35]2[C:30]([C:31](=[O:48])[C:32]([C:38]3[CH:43]=[CH:42][C:41]([O:44][CH2:45][O:46][CH3:47])=[CH:40][CH:39]=3)([CH3:37])[CH2:33][O:34]2)=[CH:29][CH:28]=1>O1CCCC1>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][C:31]1([OH:48])[C:30]2[C:35](=[CH:36][C:27]([O:26][CH2:25][O:24][CH3:23])=[CH:28][CH:29]=2)[O:34][CH2:33][C:32]1([C:38]1[CH:39]=[CH:40][C:41]([O:44][CH2:45][O:46][CH3:47])=[CH:42][CH:43]=1)[CH3:37])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2=O)cc1
Reactant: C#CCCCCCCCO[Si](C)(C)C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2(O)C#CCCCCCCCO[Si](C)(C)C(C)(C)C)cc1
Temperature: -20 °C
Reaction time: 1.33 h
Yield: 98.5 %

Procedure:
9-(t-Butyl dimethylsilyloxy)-1-nonyne (7.1 g, 27.9 mmol) was dissolved in dry tetrahydrofuran (70 mL) under argon atmosphere, which was then cooled down to −78° C. n-Butyllithium (15.1 ml, 25.1 mmol, 1.66 mol/l solution in tetrahydrofuran) was slowly added dropwise thereto, and the mixture was stirred at −20° C. for 80 minutes. To this mixture was added dropwise 7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-3-methylchroman-4-one (2.0 g, 5.58 mmol) dissolved in dry tetrahydrofuran (15 mL) at −20° C., and the resulting reaction mixture was stirred at the same temperature for 3 hours, and then stirred at −10° C. overnight. The reaction was quenched with water, and the reaction solution was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to flash chromatography on silica gel (n-hexane:ethyl acetate=9:1) to give the title compound (3.37 g, yield 99%) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[N:21]1([CH2:26][CH2:27][NH:28][C:29]([C:31]2[C:35]([CH3:36])=[C:34]([CH:37]=O)[NH:33][C:32]=2[CH3:39])=[O:30])[CH2:25][CH2:24][CH2:23][CH2:22]1>C(O)C.N1CCCCC1>[N:21]1([CH2:26][CH2:27][NH:28][C:29]([C:31]2[C:35]([CH3:36])=[C:34]([CH:37]=[C:11]3[C:10]4[C:14](=[CH:15][CH:16]=[CH:17][C:9]=4[C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:4]=4)[NH:13][C:12]3=[O:18])[NH:33][C:32]=2[CH3:39])=[O:30])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Reactant: O=C1Cc2c(cccc2-c2cccc(C(F)(F)F)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(C(F)(F)F)c4)c32)c(C)c1C(=O)NCCN1CCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 53 %

Procedure:
To a solution of 4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (68.5 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2,4-dimethyl-5-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (69.2 mg, 53%).
Reaction SMILES: [CH3:1][C:2](=[CH2:5])[CH2:3][OH:4].O[N:7]1[C:11](=[O:12])[C:10]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]2[C:8]1=[O:17].N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:5][C:2](=[CH2:1])[CH2:3][O:4][N:7]1[C:11](=[O:12])[C:10]2[C:9](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]1=[O:17]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: C=C(C)CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: C1CCOC1
Product: C=C(C)CON1C(=O)c2ccccc2C1=O
Reaction time: 2 h
Yield: 82.6 %

Procedure:
To a solution of 2-methyl-2-propen-1-ol (0.856 g) triphenyl phosphine (4.67 g) and N-hydroxyphthalimide (2.90 g) in THF (90 mL), at 0° C., diisopropyl azodicarboxylate (3.51 mL) was added. After stirring for 2 hours, the solvent was evaporated and the crude product was purified by flash chromatography (SiO2, cyclohexane/EtOAc 85/15) to give 2-(2-methylallyloxy)isoindole-1,3-dione (2.13 g, 83%). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 7.80 (4H, bs), 5.02 (2H, d), 4.54 (2H, s), 1.83 (3H, s).
Reaction SMILES: [CH3:1][CH:2]([OH:7])[CH2:3][CH2:4][CH2:5][Br:6].ClC(Cl)(Cl)C(=N)O[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1CCCCC1.FC(F)(F)S(O)(=O)=O>ClCCl>[Br:6][CH2:5][CH2:4][CH2:3][CH:2]([CH3:1])[O:7][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Reactant: CC(O)CCCBr
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCCCC1
Solvent: ClCCl
Product: CC(CCCBr)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
To a solution of 1-methyl-4-bromo-1-butanol (9.0 g, 0.05384 mol) and benzyl 2,2,2-trichloroacetimidate (16.3 g,) in a mixture of anhydrous cyclohexane (100 ml) and anhydrous dichloromethane (50 ml) cooled to 0° C., trifluoromethanesulfonic acid (1.0 ml) was added, and the mixture was stirred overnight at room temperature under argon. The mixture was filtered, washed with a saturated solution of NaHCO3 (250 ml) and deionized water (250 ml), and dried with anhydrous Na2SO4. The solvents were removed by distillation under reduced pressure. The crude product (9.2 g) was subjected to vacuum distillation, giving 7.2 g of colorless viscous liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22]I)=[CH:14][CH:13]=3)[CH:10]([CH2:24][CH2:25][CH:26]([OH:34])[C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:9]2=[O:35])=[CH:4][CH:3]=1.[CH3:36][NH:37][CH2:38][CH2:39][S:40]([OH:43])(=[O:42])=[O:41].C(=O)([O-])[O-].[K+].[K+]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9](=[O:35])[CH:10]([CH2:24][CH2:25][CH:26]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[OH:34])[CH:11]2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][N:37]([CH3:36])[CH2:38][CH2:39][S:40]([OH:43])(=[O:42])=[O:41])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(OCCCCI)cc2)N1c1ccc(F)cc1
Reactant: CNCCS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CN(CCCCOc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)CCS(=O)(=O)O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
64.5 mg of 1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-hydroxypropyl]-4-[4-(4-iodobutoxy)phenyl]azetidin-2-one are dissolved in 3 ml of methanol. 60.7 mg of 2-methylaminoethanesulfonic acid are then dissolved in 1 ml of water, and 30.4 mg of potassium carbonate are added. The reaction is stirred at 50° C. for 8 h. After concentration using a rotary evaporator at 40° C., the residue is passed over a reverse-phase cartridge (methanol). The resulting crude product is dissolved in hot methanol. The precipitate formed on cooling is filtered off, and the mother liquor is concentrated using a rotary evaporator. The product is obtained as an oil. C31H36F2N2O6S (602) MS (ESI): M+-18
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]([NH2:11])=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[Cl:21][C:22]1[N:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>C1COCC1>[Cl:21][C:22]1[N:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[NH:4][CH:1]1[CH2:3][CH2:2]1)=[O:25]
Reactant: Nc1ccccc1NC1CC1
Reactant: O=C(Cl)c1cccnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1NC1CC1)c1cccnc1Cl
Yield: 65.5 %

Procedure:
To a solution of title compound 381 (0.83 g, 5.84 mmol) and diisopropylethylamine (1.02 mL, 0.74 mmol) in THF (50 mL) was added a solution of 2-chloronicotinoyl chloride (1.03 g, 5.84 mmol) in THF at 0° C. The reaction mixture was stirred over night and concentrated. To the residue was added a saturated solution of bicarbonate (3 mL) and this aqueous layer was extracted with DCM (2×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated. The solid was triturated in DCM (3 mL) and filtered. The filtrate was evaporated and purified by flash chromatography (0% to 80% ethyl acetate in hexanes). The 2 solids were mixed to afford title compound 382 (1.1 g, 65%) as a white solid. MS (m/z): 288.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([CH3:13])[CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[N+:14]([O-])([OH:16])=[O:15]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([CH3:13])[CH2:8][CH2:7][C:6]=2[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1
Reactant: CN1CCc2cccc(Cl)c2CC1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CN1CCc2c(Cl)ccc([N+](=O)[O-])c2CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cold solution of 67.2 g (0.34 mol, U.S. Pat. No. 4,265,890) of 6-chloro-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in 100 ml of sulfuric acid was added, dropwise over 2 hours, 40 ml of concentrated nitric acid. The mixture was stirred at room temperature overnight and quenched in ice. It was made basic with 10% sodium hydroxide solution and extracted with methylene chloride. The organic phase was washed, dried and evaporated to leave a residue, which was chromatographed over a "Waters prep 500" high pressure liquid chromatographic silica gel column, using isopropanol-hexanediethylamine, to give pure 6-chloro-3-methyl-9-nitro-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH:6]=[CH:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]2[O:16][CH2:15]2)=[CH:10][CH:9]=1)=[O:4].[CH:19]([NH2:22])([CH3:21])[CH3:20]>C(O)(C)C>[CH3:1][O:2][C:3]([NH:5][CH:6]=[CH:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:22][CH:19]([CH3:21])[CH3:20])=[CH:10][CH:9]=1)=[O:4]
Reactant: COC(=O)NC=Cc1ccc(OCC2CO2)cc1
Reactant: CC(C)N
Solvent: CC(C)O
Product: COC(=O)NC=Cc1ccc(OCC(O)CNC(C)C)cc1

Procedure:
9.4 g (0.038 mol) of 1-[p-(2-methoxycarbonylaminovinyl)-phenoxy]-2,3-epoxy-propane are dissolved in 200 ml of isopropanol, 3.25 ml (0.038 mol) of isopropylamine are added and thereafter the mixture is heated to the boil for 3 hours, under a reflux condenser. It is then evaporated in vacuo and the resulting crude base is crystallised from acetone-ether. 1-[p-(2-Methoxycarbonylaminovinyl)-phenoxy]-2-hydroxy-3-isopropylamino-propane of melting point 128°-129° C. is obtained.
Reaction SMILES: [C:1]([Si:5]([CH3:31])([CH3:30])[O:6][CH2:7][C@H:8]([N:10]1[C:15]2=[N:16][C:17](Cl)=[N:18][CH:19]=[C:14]2[CH2:13][N:12]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=2)[C:11]1=[O:29])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1>CC(O)C.ClCCl>[C:1]([Si:5]([CH3:31])([CH3:30])[O:6][CH2:7][C@H:8]([N:10]1[C:15]2=[N:16][C:17]([NH:37][C:36]3[CH:38]=[CH:39][C:33]([F:32])=[CH:34][CH:35]=3)=[N:18][CH:19]=[C:14]2[CH2:13][N:12]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=2)[C:11]1=[O:29])[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(F)cc1
Reactant: CCc1ccc(N2Cc3cnc(Cl)nc3N([C@H](C)CO[Si](C)(C)C(C)(C)C)C2=O)cc1
Solvent: CC(C)O
Solvent: ClCCl
Product: CCc1ccc(N2Cc3cnc(Nc4ccc(F)cc4)nc3N([C@H](C)CO[Si](C)(C)C(C)(C)C)C2=O)cc1
Temperature: 160 °C

Procedure:
(R)-1-[2-(tert-Butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-7-chloro-3-(4-ethyl-phenyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (100 mg, 0.21 mmol) (from Example 38e supra) was suspended in 2-propanol (2 mL) (Fisher). 4-Fluoroaniline (0.03 mL, 0.32 mmol) (Aldrich) was added and the mixture was heated to 160° C. in a microwave synthesizer (SmithSynthesizer™) for 30 minutes. After cooling to room temperature, the heterogeneous reaction mixture was diluted with dichloromethane. The resulting solution was washed with 1 N aqueous hydrochloric acid. The layers were separated and the organic phase was dried over anhydrous sodium sulfate, filtered and then concentrated under reduce pressure to give (R)-1-[2-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-3-(4-ethyl-phenyl)-7-(4-fluoro-phenylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as a pale yellow solid. (Yield 107 mg, 91%).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C@@H:2]([CH3:4])[OH:3].C(N(CC)CC)C.Cl.CN(C)C.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(#N)C>[CH3:30][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:3][C@H:2]([CH3:4])[C:1]([O:6][CH3:7])=[O:5])(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: COC(=O)[C@@H](C)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](C)OS(=O)(=O)c1ccc(C)cc1
Yield: 87.2 %

Procedure:
A solution of methyl(R)-(+)-lactate (6.66 g) in acetonitrile (33 ml) was cooled to 5° C. and triethylamine (9.8 ml) added followed by trimethylamine hydrochloride (0.62 g). A separate solution of p-toluenesulfonyl chloride (11.6 g) in acetonitrile (33 ml) was added dropwise over 20 min maintaining the temperature below 5° C. The reaction mixture was filtered and concentrated, Diethylether and water were added and the organic fraction dried (MgSO4) and concentrated in vacuo to give the sub-title compound as a yellow oil (13.71 g).
Reaction SMILES: FC1C=C(F)C=CC=1[OH:9].[F:10][C:11]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:12]=1[O:13][C:14]1[C:15](=[O:31])[O:16][C:17]([CH3:30])([CH3:29])[C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1>ClCCl>[CH3:29][C:17]([O:16][C:15](=[O:31])[CH2:14][O:13][C:12]1[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:11]=1[F:10])([CH3:30])[C:18]([C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1)=[O:9]
Reactant: Oc1ccc(F)cc1F
Reactant: CC1(C)OC(=O)C(Oc2ccc(F)cc2F)=C1c1ccc(S(C)(=O)=O)cc1
Solvent: ClCCl
Product: CC(C)(OC(=O)COc1ccc(F)cc1F)C(=O)c1ccc(S(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride, 60% dispersion (66 mg, 1.66 mmol), was rinsed with hexane, suspended in 7 mL of DMF and cooled to 0° C. To this suspension was added 2,4-difluorophenol (170μL, 1.79 mmol). After 5 minutes at 0° C., 2-bromoacetic acid 2-methyl-1-(4-(methylsulfonyl)phenyl)propan-1-one ester (Step 1) (233 mg, 1.79 mmol) was added and the reaction mixture was stirred for 30 minutes. Dichloromethane was added and the mixture was washed with 1N HCl and the organic solvent was evaporated under vacuum. The residue was dissolved in 25%EtOAc/Et2O and washed with 1N NaOH, water (2×) brine and dried over MgSO4. After filtration and evaporation of the solvent under vacuum 470 mg of the title compound was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH:24](Br)CC>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:24][CH2:23]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1O
Reactant: CCC(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCOc2ccccc21
Yield: 80.6 %

Procedure:
A solution of dry acetone (100 mL) containing N-(tertbutoxycarbonyl)-2-aminophenol (0.722 g, 3.69 mmol), potassium carbonate (10.2 g, 73.8 mmol) and 1,2-dibromobutane (2.54 mL, 29.6 mmol) was refluxed for 18 h. The reaction was monitored by TLC (petrol/ether 8/2). After cooling, the mixture was filtered through celite. After concentration and hydrolysis, the aqueous layer was extracted with EtOAc (3×40 mL), dried over MgSO4 and the solvent was removed under reduce pressure. The crude product was purified by flash chromatography on silica gel (petrol/EtOAc 95/5) to yield the title compound as a white solid (0.70 g, 82%). m.p=78-79° C.; Rf=0.44 (petrol/ether 8/2); LCMS m/z 236 ([M+1]+); 1H NMR (300 MHz, CDCl3): δ 1.59 (9H, s); 3.87 (4H, m); 4.26 (4H, m); 6.86-7.02 (4H, m); 13C NMR (75 MHz, CDCl3): δ 27.4 (3C); 41.1; 64.6 (2C); 80.6 (2C); 116.0; 119.2; 122.6; 123.4; 125.2; 144.9; 151.6. IR (film): 2975; 1696; 1494; 1143 cm−1.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].[CH3:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1F.Cl>CS(C)=O>[CH3:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[CH:5]([C:3]#[N:4])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)CC#N
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)C(C#N)c1ccc([N+](=O)[O-])cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of sodium hydride (60% oil dispersion, 6.13 g) in dimethyl sulfoxide (100 mL) was added ethyl cyanoacetate (18.0 g) at 0° C., and the mixture was stirred at room temperature for 2 hours. 2-Methyl-4-nitrofluorobenzene (9.15 g) was added to the mixture, and the resulting solution was stirred at room temperature for 12 hours. After quenching the reaction by the addition of 6 N hydrochloric acid at 0° C., and the mixture was extracted with ether. The ethereal solution was washed with brine, dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo to give ethyl (2-methyl-4-nitrophenyl)cyanoacetate. A solution of crude ethyl (2-methyl-4-nitrophenyl)cyanoacetate thus obtained in dioxane (200 mL) and 6 N hydrochloric acid (200 mL) was heated at 100° C. for 12 hours. After dilution of the mixture with water and sodium chloride, the mixture was extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. Flash chromatography (silica, hexane:ethyl acetate=2:1) of the residue gave (2-methyl-4-nitrophenyl)acetonitrile (5.32 g).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[S:6][C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:10][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:32][CH2:33][N:34]1[CH2:38][CH2:37][O:36][C:35]1=[O:39]>O.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[S:6][C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:12][CH2:13][N:14]([CH2:32][CH2:33][N:34]4[CH2:38][CH2:37][O:36][C:35]4=[O:39])[CH2:15][CH2:16]3)[CH2:10][C:4]=2[CH:3]=1
Reactant: O=C1OCCN1CCCl
Reactant: Clc1ccc2c(c1)CC(N1CCNCC1)c1ccccc1S2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1OCCN1CCN1CCN(C2Cc3cc(Cl)ccc3Sc3ccccc32)CC1

Procedure:
7.8 g of 1-(2-chloro-10,11-dihydro-dibenzo[b,f]thiepin-10-yl)-piperazine are treated, together with 11.6 g of powdered potassium carbonate, 0.2 g of potassium iodide and 100 ml of toluene, with 8.22 g of N-(β-chloroethyl)-oxazolidinone and the mixture is heated under reflux for 22 hours. Then the mixture is poured on to water and the organic phase washed with saturated soda solution and water, dried over sodium sulphate and concentrated under reduced pressure. There is obtained crude liquid 3-[2-[4-(2-chloro-10,11-dihydro-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl]-2-oxazolidinone. The maleate is prepared by treatment with maleic acid in ethanol/ether; melting point 173°-175° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.Cl.Cl.[NH2:24][C:25]1[N:26]=[N:27][N:28]([CH:30]2[CH2:34][CH2:33][NH:32][CH2:31]2)[CH:29]=1.N1(C2CCCCCCCCCC2)CCCCCCCCCN1>N1C=CC=CC=1>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:32]2[CH2:33][CH2:34][CH:30]([N:28]3[CH:29]=[C:25]([NH2:24])[N:26]=[N:27]3)[CH2:31]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1
Reactant: Nc1cn(C2CCNC2)nn1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: C1CCCCCC(N2CCCCCCCCCN2)CCCC1
Agent: Cl
Solvent: c1ccncc1
Product: Nc1cn(C2CCN(c3c(F)c(N)c4c(=O)c(C(=O)O)cn(C5CC5)c4c3F)C2)nn1
Temperature: 110 °C

Procedure:
A mixture of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (100 mg, 0.67 mmol), 3-(4-amino-1,2,3-triazol-1-yl)pyrrolidine dihydrochloride (185 mg, 0.83 mmol) and diazabicycloundecane (127 mg, 0.83 mmol) in pyridine (3 ml) was heated at 110° C. for 24 hrs. Reaction mixture was concentrated to dryness under vacuum and residue was dissolved in water, extracted with methylene chloride, dried over sodium sulfate and concentrated to dryness. The solid residue thus obtained was crystallized from chloroform to brown solid. Yield 15 mg (10.4%), m.p. 210°-213° C. 1H NMR (TFA) δ: 1.22-1.58 (m, 4H), 2.70-2.90 (m, 2H), 4.06-4.54 (m, 5H), 5.48-5.60 (m, 1H), 7.79 (s, 1H), 9.14 (s, 1H).