Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[NH:14][C:13]4[CH2:15][CH2:16][NH:17][CH2:18][C:12]=4[C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1.F[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+].CS(C)=O>O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[NH:14][C:13]4[CH2:15][CH2:16][N:17]([C:20]5[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=5)[CH2:18][C:12]=4[C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: Clc1ccc2c(c1)ncc1c3c([nH]c12)CCNC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc(N2CCc3[nH]c4c(cnc5cc(Cl)ccc54)c3C2)cc1
Yield: 4.3 %

Procedure:
A solution of 1.00 g (3.88 mmol) of 3-chloro-8,9,10,11-tetrahydro-7H-pyrido[3',4':4,5]pyrrolo[3,2-c]quinoline, 0.47 g (3.88 mmol) of p-fluorobenzonitrile, 0.54 g (3.88 mmol) of K2CO3 and 8 ml of dimethylsulfoxide are stirred at 80° C. for 3 days. The reaction mixture is allowed to cool and is diluted with water producing a brown precipitate which is collected by filtration and dried. The crude product is purified by flash column chromatography (5% methanol in chloroform) to yield 0.06 g (4%) of the title compound as a pink solid: m.p.>275° C.; m/e 358.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]2[C:16](=O)[C:15]3[C:6](=[CH:7][C:8]4[C:13]([CH:14]=3)=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:5](=O)[C:4]=2[CH:3]=1.C1(O)CCCCC1>[Al](OC(CC)C)(OC(CC)C)OC(CC)C>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]2[C:4](=[CH:5][C:6]3[C:15]([CH:16]=2)=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=3)[CH:3]=1
Reactant: O=C1c2ccc(Cl)cc2C(=O)c2cc3ccccc3cc21
Agent: CCC(C)O[Al](OC(C)CC)OC(C)CC
Solvent: OC1CCCCC1
Product: Clc1ccc2cc3cc4ccccc4cc3cc2c1
Temperature: 159 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
A 2-necked, 500 mL round-bottomed flask was fitted with a distillation head and receiver, and charged with 2-chloro-5,12-tetracenequinone (11.5 g, 39.4 mmol), cyclohexanol (100 mL), and Al(O-sec-Bu)3 (50 mL) under nitrogen. The mixture was heated until distillate began collecting in the receiver at a pot temperature of ca. 115° C. The distillation was continued until the temperature of the dark orange mixture reached 162° C., and the solution was then heated at 159° C. for 36 h. The mixture was cooled to 50° C., an equal volume of dry THF was added, and then it was heated up to 80° C. and stirred. The hot mixture was poured onto a 10–20 μm frit to isolate a bright orange solid that was washed with water (150 mL), 5% HCl (150 mL), and additional water (150 mL). The filtrate was mixed with some additional water and conc. HCL, stirred, and allowed to sit overnight. The solid was air-dried for a couple of hours to afford 5.04 g of material. Purification by high vacuum (pressure ˜10−5 Torr) train sublimation at 130–150° C. afforded 4.0 g of fluorescent orange product. An additional crop of crude material was isolated from the filtrate above and afforded another 1.37 g after sublimation. Net yield 52%. DSC (20° C./min): 361° C. (ΔH=96 Jg−1, decomp). EIMS: 262 ([M]+, 100%), 226 ([M−HCl]+, 23%). Anal. Calcd. for C18H11Cl: C, 82.3; H, 4.22. Found: C, 82.5; H, 4.27.
Reaction SMILES: [C:1]1([C:7]2[C:12]3[N:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=C2C(=O)OC(=O)C=12.C1([Mg]Cl)C=CC=CC=1.Cl>[Pt](=O)=O.CN(C)C=O>[C:1]1([C:7]2[C:12]3[NH:13][CH2:14][CH2:15][CH2:16][C:11]=3[C:10](=[O:17])[NH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1[nH]nc(-c2ccccc2)c2ncccc12
Agent: O=[Pt]=O
Agent: Cl
Agent: Cl[Mg]c1ccccc1
Solvent: CN(C)C=O
Product: O=c1[nH]nc(-c2ccccc2)c2c1CCCN2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Under an atmosphere of hydrogen, a mixture of 8-phenylpyrido[2,3-d]pyridazin-5(6H)-one (100 mg; It was prepared by the same procedure as described in Reference example 1→Example 1 using furo[3,4-b]pyridine-5,7-dione instead of 4,5,6,7-tetrahydro-2-benzofuran-1,3-dione, and phenylmagnesium chloride instead of 3-(bis(trimethylsilyl)amino)phenylmagnesium chloride), platinum(IV)oxide (10 mg), 1N hydrochloric acid (0.5 mL) and dimethylformamide (5 mL) was stirred at room temperature for 6 hours. The reaction mixture was filtrated through Celite. The filtrate was concentrated. The residue was diluted with ethyl acetate. The diluted solution was washed with a saturated aqueous sodium hydrogen carbonate solution and brine sequentially, dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized from ethanol to give the compound of the present invention (42 mg) having the following physical data. Moreover, the compound was converted to a corresponding salt thereof by conventional method.
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11](F)=[CH:10][CH:9]=1.[C:15]([O:19][C:20]([N:22]1[CH2:25][CH:24]([OH:26])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>C1COCC1>[C:15]([O:19][C:20]([N:22]1[CH2:25][CH:24]([O:26][C:11]2[CH:12]=[CH:13][C:8]([Br:7])=[CH:9][CH:10]=2)[CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: Fc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc(Br)cc2)C1
Temperature: 70 °C
Yield: 46.4 %

Procedure:
Add dropwise potassium tert-butoxide in THF (34.6 mL, 34.6 mmol) to a solution of p-bromofluorobenzene (6.1 g, 34.6 mmol) in THF (144 mL) and 3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester (5.0 g, 28.9 mmol) at RT. Heat the mixture at 70° C. overnight. Cool the mixture to RT, quench with water, dilute with Et2O, and wash once with saturated NH4Cl. Back extract the aqueous with Et2O, dry the combined organics over Na2SO4, filter, and concentrate. Purify the crude material by flash chromatography, eluting with 25% EtOAc/hexane to give 4.4 g (46%) of the title compound. LC-MS/ES m/z (81Br) 274 [M−tertBu+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1C=CC=CC=1.Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[CH:11][C:12]([OH:14])=[O:13]
Reactant: O=Cc1cccc(Cl)c1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)C=Cc1cccc(Cl)c1

Procedure:
The starting material is prepared as follows: The mixture of 50 g of 3-chlorobenzaldehyde, 41 g of malonic acid and 36 ml of pyridine is heated on the steam bath for 3 hours. The residue is dissolved in 200 ml of water, the solution acidified with hydrochloric acid, filtered, and the residue recrystallized from aqueous ethanol, to yield the 3-chlorocinnamic acid melting at 150°-152°.
Reaction SMILES: [C:1](OCC)(=O)CC([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-].S(Cl)(Cl)=O.[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([OH:30])=O)=[CH:23][CH:22]=1)([O-:20])=[O:19]>O.COC(C)(C)C.ClCCl>[N+:18]([C:21]1[CH:22]=[CH:23][C:24]([CH2:27][C:28](=[O:30])[CH3:1])=[CH:25][CH:26]=1)([O-:20])=[O:19]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: COC(C)(C)C
Product: CC(=O)Cc1ccc([N+](=O)[O-])cc1
Temperature: 72.5 °C
Reaction time: 0.75 h
Yield: 35.2 %

Procedure:
Dichloromethane (3 ml) and ethyl malonate (1.31 g, 8.15 mmol) were added to aluminium chloride (1.10 g, 8.28 mmol) (hereinafter, abbreviated as Solution B). Thionyl chloride (1.58 g, 13.25 mmol) was added to 4-nitrophenylacetic acid (1.00 g, 5.52 mol), followed by stirring at 70-75° C. for 45 minutes. Thionyl chloride was distilled off under reduced pressure, followed by azeotropy with toluene (3 ml) twice. Dichloromethane (3 ml) was added to the azeotropic residue to dissolve the residue, which was added to Solution B dropwise. After stirred for 7 hours under reflux, the reaction solution was cooled to room temperature and poured into water (10 ml). The layers were separated, and the aqueous layer was extracted with dichloromethane (3 ml). The organic layers were combined, and the solvent was distilled off under reduced pressure. After the solvent was distilled off, acetic acid (1.7 ml), water (1.1 ml) and concentrated sulfuric acid (0.21 ml) were added thereto, which was refluxed at an external temperature of 125° C. for 4 hours while stirring vigorously. After completion of the reaction, the mixture was ice-cooled, returned to room temperature, and t-butyl methyl ether (6 ml) and water (6 ml) were added thereto, followed by extraction. After the organic layer was washed with an aqueous saturated sodium hydrogen carbonate solution (6 ml) twice and brine (6 ml) twice, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give 4-nitrophenylacetone (0.51 g, 2.87 mmol, 52%).
Reaction SMILES: Cl.C(OCC)(=O)C.[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[C:16]1[C:17]2[N:18]([C:22]([NH:27]C(=O)OC(C)(C)C)=[C:23]([CH2:25][CH3:26])[N:24]=2)[N:19]=[CH:20][CH:21]=1.[OH-].[Na+]>C(OCC)(=O)C>[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[C:16]1[C:17]2[N:18]([C:22]([NH2:27])=[C:23]([CH2:25][CH3:26])[N:24]=2)[N:19]=[CH:20][CH:21]=1
Reactant: CCc1nc2c(-c3ccc(C)cc3C)ccnn2c1NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCc1nc2c(-c3ccc(C)cc3C)ccnn2c1N
Temperature: 25 °C
Reaction time: 15 h

Procedure:
4N hydrochloric acid/ethyl acetate (15 mL) was added to a solution of the crude tert-butyl N-[8-(2,4-dimethylphenyl)-2-ethylimidazo[1,2-b]pyridazin-3-yl]carbamate in ethyl acetate (5 mL), and the mixture was stirred at room temperature for 15 hours. The mixture was neutralized by adding a 5N aqueous sodium hydroxide solution under ice-cooling, and extracted with ethyl acetate. It was washed with brine, dried over anhydrous magnesium sulfate and evaporated, to give crude 8-(2,4-dimethylphenyl)-2-ethylimidazo[1,2-b]pyridazin-3-amine.
Reaction SMILES: [C:1]([O:9][CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]CO.C(OC(C)C)(C)C>>[C:1]([O:9][CH2:10][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][NH2:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCCCCCO
Reactant: COC(=O)c1ccccc1
Solvent: CC(C)OC(C)C
Product: NCCCCCCOC(=O)c1ccccc1
Yield: 82 %

Procedure:
In an argon atmosphere, a mixture of methyl benzoate (3.0 mmol), 6-aminohexan-1-ol (3.6 mmol), Zn4(OCOCF3)6O (1.25 mol % in terms of the mole number of zinc atoms; in the following Examples, the amount will be similarly expressed in terms of the mole number of zinc atoms) and diisopropyl ether (5.0 ml) was heated to reflux for 18 hours, and as a result, 6-aminohexyl benzoate having an acylated hydroxyl group was obtained at a yield of 82% (the yield is based on the carboxylic acid ester. The same applies in the following). The yield of 6-benzoylaminohexyl benzoate in which an amino group and a hydroxyl group were both acylated, was 18%.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]#[N:15])[C:10]=2[O:12][CH3:13])[N:5]([C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:4]=1)=[CH2:2].Br[C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1.C1(C)C=CC(P(C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)=CC=1>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:13][O:12][C:10]1[C:9]([C:14]#[N:15])=[CH:8][CH:7]=[C:6]2[C:11]=1[C:3](/[CH:1]=[CH:2]/[C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1)=[N:4][N:5]2[C:16]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C=Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(C#N)c(OC)c12
Reactant: Brc1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccc(P(c2ccc(C)cc2)c2ccc(C)cc2)cc1
Solvent: CCN(CC)CC
Product: COc1c(C#N)ccc2c1c(/C=C/c1cccnc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 110 °C

Procedure:
300 mg of 3-vinyl-4-methoxy-1-trityl-1H-indazole-5-carbonitrile and 180 μl of 3-bromopyridine were dissolved in a mixed solvent of 1 mL triethylamine/5 mL acetonitrile, added with 40 mg of tri-p-tolylphosphine and 27 mg of palladium acetate (II), and heated at 110° C. for 24 hours. The reaction solution was added with silica gel, the solvent was evaporated, and the resultant residue was purified by column chromatography (hexane:ethyl acetate=7:3), to afford 120 mg of the title compound as a pale yellow oil.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([CH:7]([S+:14]([O-])[CH2:15][C:16](N)=[O:17])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:5][CH:6]=1.C1(C(C2C=CC=CC=2)[OH:27])C=CC=CC=1.NC(N)=S.Br.ClCC(O)=O>>[C:4]1([CH:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[S:14][CH2:15][C:16]([OH:17])=[O:27])[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: NC(=O)C[S+]([O-])C(c1ccccc1)c1ccccc1
Agent: Br
Agent: NC(N)=S
Agent: O=C(O)CCl
Product: O=C(O)CSC(c1ccccc1)c1ccccc1

Procedure:
Scheme 2 describes an industrial method for the preparation of Modafinil (II) wherein the all the reaction steps may be carried out in situ. In this scheme, the starting material is diphenylmethanol which is reacted with thiourea in the presence of HBr followed by basic hydrolysis and reaction with chloroacetic acid to form compound III. Hydrogen peroxide is then passed through the reaction mixture followed by acidification with hydrochloric acid to form (benzhydrylsulfinyl)acetic acid. The acid is reacted with dimethyl sulphate in presence of soda lye and sodium bicarbonate to obtain methyl(benzhydrylsulfinyl)acetate. After filtration methyl(benzhydrylsulfinyl)acetate is dissolved in methanol and ammonia is bubbled through the reaction mixture. After recrystallization and drying of the reaction mass Modafinil (II) is obtained with 41% total yield calculated from benzhydrol. The in-situ reaction scheme 2 is set out below.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:33]=[CH:32][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([OH:31])=O)[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH2:67]([O:69][CH:70]([O:73][CH2:74][CH3:75])[CH2:71][NH2:72])[CH3:68]>CN(C=O)C.O>[CH2:67]([O:69][CH:70]([O:73][CH2:74][CH3:75])[CH2:71][NH:72][C:29]([C:26]1[CH:25]=[C:24]([C:20]2[CH:19]=[C:18]([O:17][C:16]3[CH:15]=[CH:14][C:13]([NH:12][C:10]([NH:9][C:3]4[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=4[F:1])=[O:11])=[CH:33][CH:32]=3)[CH:23]=[CH:22][N:21]=2)[NH:28][CH:27]=1)=[O:31])[CH3:68]
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2)c1
Reactant: CCOC(CN)OCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(CNC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)ccn2)c1)OCC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (500 mg, 1.12 mmol), HATU (467 mg, 1.23 mmol) and N,N-diisopropylethylamine (322 mg, 2.5 mmol) in anhydrous DMF (10 ml) was stirred at room temperature for 10 minutes, followed by addition of aminoacetaldehyde diethyl acetal (194 mg, 1.46 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water. The precipitates were filtered, washed with water and dried in vacuo to give N-(2,2-diethoxyethyl)-5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide as white solid. Yield: 580 mg, 92%.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([C:19]2[CH:24]=[CH:23][C:22]([CH:25](C(OC(C)(C)C)=O)[C:26]([O:28]C(C)(C)C)=[O:27])=[C:21]([N+:40]([O-:42])=[O:41])[CH:20]=2)=[N:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1>ClCCl>[Cl:8][C:9]1[C:10]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]([OH:28])=[O:27])=[C:21]([N+:40]([O-:42])=[O:41])[CH:20]=2)=[N:11][CH:12]=[C:13]([C:15]([F:17])([F:16])[F:18])[CH:14]=1
Reactant: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc(-c2ncc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cc1ccc(-c2ncc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Temperature: 23 °C
Reaction time: 65 h

Procedure:
16 ml of trifluoroacetic acid were added dropwise to a solution of 10.2 g of 3-chloro-2-[4-(bis-[1,1-dimethylethoxycarbonyl]-methyl)-3-nitrophenyl]-5-trifluoromethylpyridine in 100 ml of anhydrous dichloromethane. After stirring at 23° C. for 65 hours, the methylene chloride was removed by distillation. The residue was dissolved in 100 ml of ether, after which the ether phase was extracted three times with 50 ml of water each time, dried over sodium sulfate and concentrated. The crude product was stirred with n-hexane/ether (9:1). Yield: 5.1 g (72%) of colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH3:10])[C:6]=2[CH:11]=1.C1C(=O)N([Br:19])C(=O)C1>C(#N)C>[Br:19][C:8]1[S:9][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:11][C:6]=2[C:7]=1[CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1csc2ccc(F)cc12
Solvent: CC#N
Product: Cc1c(Br)sc2ccc(F)cc12
Yield: 95 %

Procedure:
A 3 neck 2 L round bottom flask is fitted with a septum, a mechanical stirrer, and stopper. The flask is charged with 5-fluoro-3-methylbenzothiophene (55.4 g, 0.311 moles) and acetonitrile (350 mL). The mixture is stirred with a mechanical stirrer and the reaction temperature is monitored. NBS is added portion wise. The reaction temperature rises slightly, and the reaction is cooled with ice water bath. A solid crashes out of solution. The solid is filtered and rinsed 2 times with a 1:1 mixture of acetonitrile and water (100 mL). The solid is dried in a vacuum oven overnight at room temperature to obtain the title product (69 g, 95%). 1H-NMR (DMSO-d6), δ 2.41 (s, 3H), 7.34 (td, J=10, 2 Hz, 1H), 7.69 (dd, J=10, 2 Hz, 1H), 8.04 (dd, J=9, 5 Hz, 1H) ppm.
Reaction SMILES: Cl.[C:2]([NH:5][CH2:6][C@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C@@:27]([CH3:42])([S:38]([CH3:41])(=[O:40])=[O:39])[C:28]([NH:30][O:31]C4CCCCO4)=[O:29])=[CH:21][CH:20]=3)=[C:15]([F:43])[CH:14]=2)[CH2:8]1)(=[O:4])[CH3:3]>O1CCOCC1.ClCCl.O>[C:2]([NH:5][CH2:6][C@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][C@@:27]([CH3:42])([S:38]([CH3:41])(=[O:40])=[O:39])[C:28]([NH:30][OH:31])=[O:29])=[CH:23][CH:24]=3)=[C:15]([F:43])[CH:14]=2)[CH2:8]1)(=[O:4])[CH3:3]
Reactant: CC(=O)NC[C@@H]1CN(c2ccc(-c3ccc(CC[C@](C)(C(=O)NOC4CCCCO4)S(C)(=O)=O)cc3)c(F)c2)C(=O)O1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)NC[C@@H]1CN(c2ccc(-c3ccc(CC[C@](C)(C(=O)NO)S(C)(=O)=O)cc3)c(F)c2)C(=O)O1

Procedure:
HCl (4.0 M in 1,4-dioxane, 1.0 mL) was added to a solution of (2R)-4-{4′-[(5R)-5-(acetamidomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2′-fluorobiphenyl-4-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (50 mg, 0.083 mmol) in 1,4 dioxane/dichloromethane/water (1:1:1, 3 mL). After 15 minutes reaction was concentrated to give a white solid. The solid was triturated with a mixture of diethyl ether/2-propanol (10:1, 10 mL) for 2 hours. The title compound was collected as a white solid (16 mg, 37%) by filtration. LCMS m/z 522.6 (M+1) 1H NMR (400 MHz, DMSO-d6) δ ppm 1.55 (s, 3H) 1.84 (s, 3H) 1.88-1.98 (m, 1H) 2.37-2.48 (m, 1H) 2.63-2.76 (m, 2H) 3.05 (s, 3H) 3.43 (t, J=5.47 Hz, 2H) 3.78 (dd, J=9.28, 6.35 Hz, 1H) 4.17 (t, J=8.98 Hz, 1H) 4.70-4.82 (m, 1H) 7.34 (d, J=8.20 Hz, 2H) 7.40 (dd, J=8.49, 2.25 Hz, 1H) 7.45-7.51 (m, 2H) 7.51-7.62 (m, 2H) 8.26 (t, J=5.86 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:9](/[CH3:16])=[CH:10]\[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1.CC([C:20]1[CH:25]=[CH:24][CH:23]=[C:22](OC)[CH:21]=1)=O.C(C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(OCC)=O>>[CH2:1]([O:2][C:3]1[CH:4]=[C:5](/[C:9](/[CH3:16])=[CH:10]\[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1cccc(C(C)=O)c1
Reactant: CCOC(=O)/C=C(/C)c1cccc(OC)c1
Agent: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)/C=C(/C)c1cccc(OCc2ccccc2)c1

Procedure:
In like manner, ethyl 3-(3-methoxyphenyl)crotonate is prepared from 3-methoxyacetophenone (43.1 g.) and carbethoxymethylene triphenylphosphorane (200 g.).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][S:6][C:5]2[CH:8]=[CH:9][C:10]([C:12](O)=[O:13])=[N:11][C:4]=2[NH:3]1.C(N(CC)CC)C.ClC(OCC(C)C)=O>C1COCC1>[OH:13][CH2:12][C:10]1[CH:9]=[CH:8][C:5]2[S:6][CH2:7][C:2](=[O:1])[NH:3][C:4]=2[N:11]=1
Reactant: O=C1CSc2ccc(C(=O)O)nc2N1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1CSc2ccc(CO)nc2N1
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
A solution of 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid (500 mg) in THF (24 mL) with triethylamine (0.396 mL) was cooled to −10° C. and isobutyl chloroformate (0.339 ml) was added. After 20 minutes the suspension was filtered through kieselguhr into an ice-cooled solution of sodium borohydride (272 mg) in water (8 mL), the mixture stirred 30 minutes and the pH reduced to 7 with dilute HCl. The solvent was evaporated and the residue triturated under water. The product was filtered and dried under vacuum to give a white solid (346 mg); LC/MS (APCI−) m/z 195 ([M−H]−, 50%), 165(100%).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[C:18]1[CH:26]=O>>[CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:26][C:18]1[NH:17][C:25]2[C:20]([CH:19]=1)=[CH:21][CH:22]=[CH:23][CH:24]=2)(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1cc2ccccc2[nH]1
Product: CN(C)S(=O)(=O)c1ccc2c(c1)C(=Cc1cc3ccccc3[nH]1)C(=O)N2

Procedure:
5-Dimethylaminosulfonyl-2-oxindole was condensed with indol-2-carbaldehyde to give the title compound.
Reaction SMILES: N#N.[C:3]1([CH:9]([OH:15])[C@@H:10]([C:12]([OH:14])=[O:13])[NH2:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[CH3:20]O>>[CH3:20][O:13][C:12](=[O:14])[CH:10]([NH2:11])[CH:9]([OH:15])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CO
Reactant: N[C@H](C(=O)O)C(O)c1ccccc1
Agent: N#N
Solvent: O=S(Cl)Cl
Product: COC(=O)C(N)C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 3-phenylserine (15.00 g, 82.79 mmol) in MeOH (78.0 mL) was treated at 0° C. with thionylchloride (6.23 mL, 91.06 mmol). The resulting mixture was then stirred at rt overnight. The volatiles were removed under reduced pressure and the residue was triturated in EA and filtered to give the title compound as a white solid. LC-MS-conditions 02: tR=0.40 min, [M+AcCN+H]+=237.46.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](O)=[O:17])=[CH:11][CH:10]=1>>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[O:17])=[CH:11][CH:10]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: NC1CCOCC1
Product: O=C(Cc1ccc(Br)cc1)NC1CCOCC1
Yield: 100 %

Procedure:
The title compound was prepared in substantially the same way as intermediate (iv) by coupling of tetrahydropyran-4-yl amine with (4-bromo-phenyl)-acetic acid to give 0.65 g (100% yield) as a thick oil which solidified on standing.