Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].I[CH2:29][CH:30]([CH3:32])[CH3:31]>C1COCC1.CCCCCC>[CH2:26]([O:25][C:23]([C:20]1([CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:21][CH2:22][N:17]([C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])[CH2:18][CH2:19]1)=[O:24])[CH3:27]
Reactant: CC(C)CI
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C1(CC(C)C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
4.7 g (47 mmol) DIPEA in THF at −5° C. was treated slowly with 29.1 mL (47 mmol) n-Buli (1.6N in hexane) and stirred for 30 min at −5° C. and subsequently cooled to −75° C. and stirred for 2 h. A solution of 10 g (39 mmol) ethyl 1-tert-butoxycarbonylpiperidine-4-carboxylate (commercially available) in THF was added and the mixture was stirred for 2 h at −75° C. 8.51 g (47 mmol) 1-iodo-2-methylpropane was added and the mixture was allowed to stir to room temperature over night. The mixture was quenched at 0° C. with citric acid 10% aq. and extracted with ethyl acetate. The combined organic layers were washed with NaCl aq. sat., dried with Na2SO4, filtered and evaporated. The residue was purified by column chromatography on silica eluting with a gradient formed heptane and t-butyl-methylether. The combined product fractions were evaporated to yield 10.2 g (84%) of the title compound as light yellow oil. MS (m/e): 331.2 (M+NH4+).
Reaction SMILES: C([Mg]Cl)(C)C.O1CCCC1.I[C:12]1[N:13]=[C:14]2[C:20]3[CH:21]=[CH:22][C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:24][C:19]=3[O:18][CH2:17][CH2:16][N:15]2[CH:29]=1.[CH2:30]([Sn:34](Cl)([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH2:37][CH3:38])[CH2:31][CH2:32][CH3:33].[NH4+].[Cl-]>>[CH2:39]([Sn:34]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:35][CH2:36][CH2:37][CH3:38])[C:12]1[N:13]=[C:14]2[C:20]3[CH:21]=[CH:22][C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:24][C:19]=3[O:18][CH2:17][CH2:16][N:15]2[CH:29]=1)[CH2:40][CH2:41][CH3:42]
Reactant: COC(=O)c1ccc2c(c1)OCCn1cc(I)nc1-2
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn2c(n1)-c1ccc(C(=O)OC)cc1OCC2
Reaction time: 2.5 h

Procedure:
Isopropylmagnesium chloride in tetrahydrofuran (2.0 M, 1.5 mL, 3.00 mmol) was added dropwise to a solution of methyl 2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate (740 mg, 2.00 mmol) in Tetrahydrofuran (12 mL, 150 mmol) at room temperature. The mixture was stirred for 2.5 hours. Tributyltin chloride (0.8138 mL, 3.000 mmol) was added and the mixture was stirred for 18 hours. The mixture was mixed with sat aq. NH4Cl and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and purified on 25 g silica column eluting with 15-20% ethyl acetate in heptane. Yield 160 mg (15%). MS(ESI+): 535.2
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH:21]([CH2:23][OH:24])[OH:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:25](Cl)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[H-].[Na+].[CH3:47]I>N1C=CC=CC=1.C1COCC1.O>[CH2:1]([O:19][CH2:20][CH:21]([CH2:23][O:24][C:25]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[O:22][CH3:47])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCCOCC(O)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCCOCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OC
Reaction time: 16 h

Procedure:
Diol Compound 20 (2.0 g, 5.97 mmol) was added dropwise to a solution of trityl chloride (1.66 g, 6.0 mmol) in anhydrous pyridine (10 mL). The reaction was left to stir for 16 hours after which the solvent was removed by co-evaporation with toluene (2×5 mL). Then, part of the residue (1.0 g, 1.7 mol) was added dropwise to a suspension of NaH (0.14 g, 3.4 mmol) in THF (50 mL), followed by the addition of MeI (0.22 mL, 3.4 mmol). After 16 hours, TLC analysis showed that the reaction had gone to completion and H2O (5 mL) was added followed by concentration of the reaction mixture. The residue was partitioned between H2O (20 mL) and diethyl ether (100 mL), the organic extract was washed with sat NaHCO3 (10 mL), dried (MgSO4) and concentrated to give 1-O-oleyl-2-O-methyl-3-O-trityl glycerol (Compound 21) as an oil. Crude Compound 21 (1.16 g) was dissolved in CH2Cl2 (10 mL) after which trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred for 5 min and excess TFA was quenched by adding solid NaHCO3 until effervescence ceased. The mixture was diluted with H2O (10 mL), extracted with CH2Cl2 (2×50 mL) and the combined organic phases were dried (MgSO4), concentrated and subjected to silica-gel column chromatography [eluent: hexane/ethyl acetate, 80/20, v/v] to give glycerol derivative Compound 22 (0.28 g, 42%) as an oil.
Reaction SMILES: O=C1[CH2:5][CH:4]([C:6]([OH:8])=[O:7])[CH2:3]1.[CH:9]([O:14][CH3:15])([O:12][CH3:13])OC.O.[C:17]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:17][O:8][C:6]([CH:4]1[CH2:3][C:9]([O:12][CH3:13])([O:14][CH3:15])[CH2:5]1)=[O:7]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C1CC(C(=O)O)C1
Reactant: COC(OC)OC
Solvent: CO
Solvent: O
Product: COC(=O)C1CC(OC)(OC)C1
Yield: 97 %

Procedure:
To the solution of 3-oxo-cyclobutanecarboxylic acid (1.0 g, 8.77 mmol) in methanol (12 ml) was added trimethyl orthoformate (6 ml, 58.29 mmol) and a catalytic amount of p-toluenesulfonic acid monohydrate. The reaction was stirred at reflux for 2 h. After such a time it was cooled and concentrated in vacuo to remove the methanol. The remaining residue was dissolved in ether and then washed with a saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo to afford 3,3-dimethoxy-cyclobutanecarboxylic acid methyl ester (1.48 g, 97%) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ ppm 2.33-2.51 (m, 4H, 2×CH2), 2.82-2.97 (m, 1H, CH), 3.16 (s, 3H, OCH3), 3.18 (s, 3H, OCH3), 3.71 (s, 3H, CO2CH3).
Reaction SMILES: C[Si]([N+:5]#[C-:6])(C)C.[CH3:7][O:8][C:9]1[N:14]=[CH:13][C:12]([N:15]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[CH:18][C:17]([C:26]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]3)=[O:27])=[N:16]2)=[CH:11][CH:10]=1.C[OH:35]>O1CCOCC1>[CH3:7][O:8][C:9]1[N:14]=[CH:13][C:12]([N:15]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[CH:18][C:17]([C:26]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][N:29]3[C:6]([NH2:5])=[O:35])=[O:27])=[N:16]2)=[CH:11][CH:10]=1
Reactant: CO
Reactant: [C-]#[N+][Si](C)(C)C
Reactant: COc1ccc(-n2nc(C(=O)N3CCCCN3)cc2-c2ccccn2)cn1
Solvent: C1COCCO1
Product: COc1ccc(-n2nc(C(=O)N3CCCCN3C(N)=O)cc2-c2ccccn2)cn1
Temperature: 110 °C
Reaction time: 96 h
Yield: 25 %

Procedure:
Trimethylsilyl isocyanide (0.920 mL) was added to 1-[1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]hexahydropyridazine (0.397 g) obtained in Example 162 in 1,4-dioxane (3 mL) at room temperature, followed by stirring at an external temperature of 110° C. in a sealed tube for 4 days. Subsequently, the mixture was cooled in air. After methanol was added to the reaction mixture, the reaction solvent was removed under reduced pressure. The residue was partitioned between saturated aqueous solution of sodium hydrogencarbonate and a mixture solvent of chloroform-methanol (20:1). The organic layer was washed with saturated brine, and then dried over sodium sulfate anhydrate. The mixture was subjected to filtration, and the solvent was removed under reduced pressure. The residue was purified through silica gel column chromatography (chloroform-methanol), to thereby give the title compound as a solid (0.122 g, 25%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH:10]([NH2:20])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O-])([O-])=O.[K+].[K+].ClC(OCC)=O.B>C1COCC1.O>[CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[C@H:10]([NH:20][CH3:21])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Reactant: O=C([O-])[O-]
Agent: B
Agent: CCOC(=O)Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CN[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)cc1
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 77.1 %

Procedure:
To a solution of (3RS,4SR)-1-benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-ylamine (1.86 g, 6.51 mmol) in THF (20 ml) was added a solution of K2CO3 (1.80 g, 13.02 mmol) in H2O (15 ml). After 10 minutes, ethyl chloroformate (0.68 ml, 7.16 mmol) was added and stirring was continued at RT for an additional 4 h. The intermediate carbamate was then extracted with Et2O, dried over Na2SO4 and concentrated under vacuo to give viscous oil. The oil was taken up in THF (20 ml) and a solution of borane in THF (1M) was added (26 ml). The reaction mixture was then heated at 65° C. over night, cooled to RT and carefully quenched with conc. HCl (5 ml). The mixture was then heated at 80° C. for 2 h, cooled to RT, concentrated under vacuo, diluted with Et2O (100 ml) and neutralized with an aqueous solution of NaHCO3. The organic phases were dried over Na2SO4 and the product purified by flash chromatography (SiO2, CH2Cl2/MeOH 9:1) to afford 1.51 g (77%) of rac-[(3S,4R)-1-benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-amine as a colorless oil.
Reaction SMILES: [BrH:1].[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[S:12](=[O:15])(=[O:14])[NH2:13])[C:8](=[O:16])[CH2:7][CH2:6]2.BrBr.OS([O-])=O.[Na+]>C(O)(=O)C>[Br:1][CH:7]1[CH2:6][C:5]2[C:9](=[CH:10][C:11]([S:12](=[O:14])(=[O:15])[NH2:13])=[C:3]([Cl:2])[CH:4]=2)[C:8]1=[O:16]
Reactant: Br
Reactant: NS(=O)(=O)c1cc2c(cc1Cl)CCC2=O
Agent: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: NS(=O)(=O)c1cc2c(cc1Cl)CC(Br)C2=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
0.1 Milliliter of 48% aqueus HBr is added to a suspension of 52 g (0.21 mole) of 5-chloro-6-sulfamoyl-1-indanone in 530 ml of glacial acetic acid. Subsequently a solution of 34.0 g (0.21 mole) of bromine in 160 ml of glacial acetic acid is added dropwise. The mixture is stirred for another 1.5 hours, and is then poured into a solution of 4.5 g of NaHSO3 in 2 of ice water. The 2-bromo-5-chloro-6sulfamoyl-1-indanone which crystallizes after stirring for some time is filtered off with suction and is washed with water.
Reaction SMILES: [CH3:1][CH2:2][O-:3].[Na+].Cl[C:6]1[N:7]=[C:8](Cl)[C:9]2[C:10](=[CH:12][S:13][CH:14]=2)[N:11]=1.[CH2:16]([OH:18])[CH3:17]>>[CH2:2]([O:3][C:6]1[N:7]=[C:8]([O:18][CH2:16][CH3:17])[C:9]2[C:10](=[CH:12][S:13][CH:14]=2)[N:11]=1)[CH3:1]
Reactant: CC[O-]
Reactant: Clc1nc(Cl)c2cscc2n1
Reactant: CCO
Agent: [Na+]
Product: CCOc1nc(OCC)c2cscc2n1

Procedure:
A solution of 0.06 mole sodium ethylate in ethyl alcohol is added dropwise while cooling to a suspension of 6.15 g (0.03 mole) of 2,4-dichloro-thieno[3,4-d]pyrimidine in 100 ml absolute ethyl alcohol. The speed of addition is regulated in such a way that the temperature of the reaction medium is maintained at between 0° and 5°C. When addition is completed, the solution is left to rise to room temperature and is then heated under reflux for 4 hours. It is then evaporated to dryness. The remaining solid is drained, washed with water and left to dry. AFter recrystallization from a 50/50 mixture of ethyl alcohol and water, 2.8 g (42% of theory) of 2,4-diethoxy-thieno[3,4-d]pyrimidine are obtained. M.P. 84°-86°C.
Reaction SMILES: [NH:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH:5]=[C:4]([CH3:17])[S:3]1.C(NCC)C.[C:23](=[O:26])([O-])[O-].[K+].[K+].[F:29][C:30]([F:34])=C(F)F>CN(C)C=O>[F:29][CH:30]([F:34])[C:23]([N:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:14])[F:15])[CH:8]=2)[CH:5]=[C:4]([CH3:17])[S:3]1)=[O:26]
Reactant: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=N)s1
Reactant: FC(F)=C(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCNCC
Solvent: CN(C)C=O
Product: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=NC(=O)C(F)F)s1
Temperature: 50 °C
Reaction time: 32 h
Yield: 53 %

Procedure:
A solution of 2-imino-3-(3-trifluoromethylphenyl)-5-methylthiazoline (0.77 g, 3.0 mmol), diethylamine (1.32 g, 18.0 mmol) and potassium carbonate (1.04 g, 7.5 mmol) in N,N-dimethylformamide (15 ml) charged in a reaction flask was reacted with tetrafluoroethylene, which was made to flow intothe flask (ca. 0.3 liter/hr), with vigorous stirring at 50° C. for 32 hours. After cooling to an ambient temperature, the reaction mixture was poured into ice-water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and then brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography, which afforded 2-difluoroacetylimino-3-(3-trifluoromethylphenyl)-5-methylthiazoline (0.53 g, 1.6 mmol, yield 53%).
Reaction SMILES: [OH-].[K+:2].[Cl:3][C:4]1[C:8]([Cl:9])=[C:7]([CH3:10])[NH:6][C:5]=1[C:11]([NH:13][C@@H:14]1[CH2:19][CH2:18][N:17]([C:20]2[S:21][C:22]([C:25]([OH:27])=[O:26])=[CH:23][N:24]=2)[CH2:16][C@@H:15]1[F:28])=[O:12].CC(C)=O>CO.CC(C)=O.O>[Cl:3][C:4]1[C:8]([Cl:9])=[C:7]([CH3:10])[NH:6][C:5]=1[C:11]([NH:13][C@@H:14]1[CH2:19][CH2:18][N:17]([C:20]2[S:21][C:22]([C:25]([O-:27])=[O:26])=[CH:23][N:24]=2)[CH2:16][C@@H:15]1[F:28])=[O:12].[K+:2]
Reactant: Cc1[nH]c(C(=O)N[C@@H]2CCN(c3ncc(C(=O)O)s3)C[C@@H]2F)c(Cl)c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Solvent: CO
Product: Cc1[nH]c(C(=O)N[C@@H]2CCN(c3ncc(C(=O)[O-])s3)C[C@@H]2F)c(Cl)c1Cl
Reaction time: 1 h
Yield: 73.3 %

Procedure:
An aqueous solution of potassium hydroxide (0.1 M, 4.75 ml, 0.475 mmol) was added to a solution of 2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-fluoropiperidin-1-yl)-1,3-thiazole-5-carboxylic acid (Example 42, 200 mg, 0.475 mmol) in methanol (35 ml). The mixture was stirred for 1 h and then concentrated under reduced pressure to provide the crude salt (230 mg). The salt was dissolved in acetone/water (50 ml; 48:2) and acetone was added slowly to the stirred mixture until it became cloudy. Stirring was continued and more acetone was added very slowly over 20 min. The mixture was stored at 4° C. overnight. The solid was collected by filtration and air dried for 24 h to provide the salt (160 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]3[CH2:7][CH2:8][CH2:9][NH:10][C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1.[C:16]1(=[O:32])[N:20]([CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25])[C:19](=[O:27])[C:18]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:17]12>C(Cl)Cl>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]3[CH2:7][CH2:8][CH2:9][N:10]([C:24](=[O:25])[CH2:23][CH2:22][CH2:21][N:20]4[C:16](=[O:32])[C:17]5=[CH:31][CH:30]=[CH:29][CH:28]=[C:18]5[C:19]4=[O:27])[C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1
Reactant: O=C(Cl)CCCN1C(=O)c2ccccc2C1=O
Reactant: Clc1ccc2c(c1)CCC1=C2CCCN1
Solvent: ClCCl
Product: O=C(CCCN1C(=O)c2ccccc2C1=O)N1CCCC2=C1CCc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
31.4 g (0.143 mol) of 8-chloro-1,2,3,4,5,6-hexahydrobenzo[f]quinoline dissolved in 300 ml of methylene chloride are added at 0° to a solution of 36.0 g (0.143 mol) of 4-phthalimidobutyryl chloride in 360 ml of methylene chloride and the mixture is stirred at room temperature for 1 hour. The solution is concentrated, extracted with methylene chloride and aqueous sodium hydrogen carbonate solution dried with magnesium sulfate and the solvent is distilled in a vacuum. Extractive crystallization with acetone gives 8-chloro-1,2,3,4,5,6-hexahydro-4-(4-phthalimidobutyryl)benzo[f]quinoline as white crystals with melting point 182-183°.
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].[C:5]([O:13][CH2:14][CH2:15]I)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(C(C)C)C(C)C)C.O>CN(C)C=O>[C:5]([O:13][CH2:14][CH2:15][S:1][CH2:2][CH2:3][OH:4])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OCCS
Reactant: O=C(OCCI)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCCSCCO)c1ccccc1

Procedure:
A solution of 2-mercaptoethanol (1.52 mL), 2-iodoethyl benzoate (6.00 g) and ethyldiisopropylamine (4.53 mL) in N,N-dimethylformamide (60 mL) was stirred at 40° C. for 3 days. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=4:1→3:7) to give the title compound (3.77 g) as an orange oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:11][C:12]([C:14]2[N:15]=[C:16]([CH2:19][NH2:20])[S:17][CH:18]=2)=[O:13])[CH:6]=[CH:7][CH:8]=1.[F:21][C:22]([F:33])([F:32])[O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]N)=[CH:26][CH:25]=1.C([BH3-])#N.[Na+]>C(O)(=O)C.C(O)C>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:11][C:12]([C:14]2[N:15]=[C:16]([CH2:19][NH:20][CH2:28][C:27]3[CH:30]=[CH:31][C:24]([O:23][C:22]([F:21])([F:32])[F:33])=[CH:25][CH:26]=3)[S:17][CH:18]=2)=[O:13])[CH:6]=[CH:7][CH:8]=1
Reactant: NCc1nc(C(=O)NCCc2cccc(Cl)c2)cs1
Reactant: NCc1ccc(OC(F)(F)F)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(NCCc1cccc(Cl)c1)c1csc(CNCc2ccc(OC(F)(F)F)cc2)n1

Procedure:
2-Aminomethyl-thiazole-4-carboxylic acid [2-(3-chlorophenyl)ethyl]amide hydrochloride (0.10 g, 0.3 mmol) and 4-(trifluoromethoxy)benzyl amine (0.06 g, 0.3 mmol) were mixed with sodium cyanoborohydride (1 M in THF, 0.6 mL), ethanol (5 mL), and a catalytic amount of acetic acid (2 drops). The mixture was heated at reflux for 24 hours. The mixture was concentrated in vacuo, diluted with water and extracted with methylene chloride. The combined organic layers were washed with sodium carbonate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude amine was purified by flash chromatography (EtOAc/hexane), treated with HCl in dioxane, and concentrated in vacuo to afford the title compound: 1H NMR (400 MHz, d6-DMSO): 9.83 (br s, 2H), 8.43 (t, 1H), 8.32 (s, 1H), 7.66 (d, 2H), 7.44 (d, 2H), 7.25 (m, 4H), 4.58 (s, 2H), 4.37 (s, 2H), 3.53 (m, 2H), 2.86 (t, 2H); MS (ESI-LCMS) for C21H20ClF3N3O2S: 470 (MH+).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]([CH:13]=O)=[C:8]2[C:3]=1[C:4](=[O:16])[CH:5]=[C:6]([CH3:15])[O:7]2.[C:17]([CH:19]=[C:20]([O-])[CH3:21])#[N:18].[Na+].[NH2:24]/[C:25](/[CH3:33])=[CH:26]\[C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28].C(O)(=O)C>CC(O)C>[C:17]([C:19]1[CH:13]([C:9]2[CH:10]=[C:11]([F:12])[C:2]([F:1])=[C:3]3[C:8]=2[O:7][C:6]([CH3:15])=[CH:5][C:4]3=[O:16])[C:26]([C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])=[C:25]([CH3:33])[NH:24][C:20]=1[CH3:21])#[N:18]
Reactant: Cc1cc(=O)c2c(F)c(F)cc(C=O)c2o1
Reactant: CC([O-])=CC#N
Reactant: C/C(N)=C/C(=O)OC(C)C
Agent: [Na+]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC1=C(C#N)C(c2cc(F)c(F)c3c(=O)cc(C)oc23)C(C(=O)OC(C)C)=C(C)N1

Procedure:
A solution of 100 mg (0.45 mmol) of 5,6-difluoro-2-methyl-4-oxo-4H-chromene-8-carbaldehyde in 5 ml of 2-propanol is mixed with 46.9 mg (0.45 mmol) of sodium 1-cyanoprop-1-en-2-olate, 63.88 mg (0.45 mmol) of isopropyl 3-aminocrotonate and 0.04 ml (0.67 mmol) of acetic acid and stirred under reflux for 3 h. After cooling, the mixture is concentrated. The residue is taken up in dichloromethane and washed with water. The organic phase is dried over sodium sulfate and concentrated. The resulting residue is crystallized from diethyl ether. The beige-colored crystals are filtered off with suction and dried at 40° C. in a vacuum drying oven. 105.9 mg (57.3% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([CH2:19]O)=[CH:15][CH:14]=2)=[N:3]1.S(Cl)([Cl:24])=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:1][C:2]1([CH3:21])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][Cl:24])=[CH:15][CH:14]=2)=[N:3]1
Reactant: O=S(Cl)Cl
Reactant: CC1(C)COC(c2ccccc2-c2ccc(CO)cc2)=N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)COC(c2ccccc2-c2ccc(CCl)cc2)=N1
Reaction time: 1 h
Yield: 98.7 %

Procedure:
1.0 g (3.55 mmol) of 4,4-dimethyl-2-(4'-hydroxymethylbiphenyl-2-yl)oxazoline was dissolved in methylene chloride (15 ml). Under cooling with ice, 0.51 g (4.29 mmol) of thionyl chloride was dropwise added thereto, followed by stirring for one hour. The reaction liquid was poured into an aqueous solution of sodium hydrogencarbonate, followed by the extraction with methylene chloride. After washing with water and drying, vacuum concentration was conducted. 1.05 g of the title compound was obtained as a crystal (yield 99%). m.p.; 72°-75° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])=[O:9])[CH:7]=1.[C:27]1([CH2:33][CH2:34][N:35]=[C:36]=[O:37])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCOCC1>[Cl:25][C:11]1[CH:12]=[C:13]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[CH:14]=[CH:15][C:10]=1[C:8]([C:6]1[CH:7]=[C:2]([NH:1][C:36]([NH:35][CH2:34][CH2:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:37])[CH:3]=[CH:4][C:5]=1[CH3:26])=[O:9]
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: O=C=NCCc1ccccc1
Solvent: C1COCCO1
Product: Cc1ccc(NC(=O)NCCc2ccccc2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Temperature: 50 °C
Reaction time: 18 h

Procedure:
Compound 494 (0.03 g, 0.08 mmol) was dissolved in 1,4-dioxan (0.5 mL) and 2-phenylethyl isocyanate (0.016 mL, 0.12 mmol) was added. The solution was stirred at 50° C. for 18 h. Work up as described in the preparation of compound 259. The crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 15:85→60:40 as the eluent. This afforded the title compound as a slightly coloured solid. 13C NMR (CDCl3) δ 196.5, 159.2 (dd), 156.0, 155.6 (dd), 148.1, 139.6, 138.9, 136.5, 135.1, 133.9, 132.2, 131.9, 128.7, 128.5, 126.4, 124.6 (dd), 124.2 (dd), 123.1, 121.1, 116.2, 112.7, 111.6 (dd), 104.9 (dd), 41.5, 36.3, 19.6
Reaction SMILES: [OH-:1].[Ca+2:2].[OH-].[C:4](=[O:7])([O-:6])[O-:5].[Ca+2]>>[C:4](=[O:5])([O-:7])[O-:6].[Ca+2:2].[O-2:1].[Ca+2:2].[C:4](=[O:6])=[O:5]
Reactant: [OH-]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Product: O=C=O
Product: [O-2]

Procedure:
FIG. 2 depicts a process in which calcium hydroxide is used to adjust the pH of the pretreated feedstock. Like reference numbers indicate identical or similar processing steps as in FIG. 1A. FIG. 2 is similar to FIG. 1A, except that, according to this embodiment, the calcium carbonate-containing stream 24 is subjected to calcination in a lime kiln 25. Calcination of calcium carbonate in lime kiln 25 produces calcium oxide and carbon dioxide. The calcium oxide becomes hydrated by the addition of water to form an aqueous solution of calcium hydroxide 29. The resulting calcium hydroxide-containing stream 29 is then the stream used for the neutralization 6. If the calcium carbonate-containing stream 24 additionally contains magnesium carbonate, stream 29 will contain magnesium hydroxide.