Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-:4])C.[K+].C(OCC)(=O)C(OCC)=O.[O:17]([CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.OS(O)(=O)=O>O1CCCC1>[C:30]1(=[O:4])[C:31]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[O:17][CH2:24][CH2:25][C:26]=2[C:27](=[O:28])[O:29]1
Reactant: CCOC(=O)CCCOc1ccccc1
Reactant: CC(C)(C)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(=O)C(=O)OCC
Product: O=C1OC(=O)C2=C1CCOc1ccccc12
Reaction time: 8 h

Procedure:
To potassium tert-butoxide (1.35 g, 12 mmol) in tetrahydrofuran (30 mL) was added diethyl oxalate (2.2 g, 15 mmol) and ethyl 4-phenoxybutanoate (2.08 g, 10 mmol) in tetrahydrofuran (30 mL) at 0° C. dropwise. The mixture was allowed to stir overnight, concentrated, quenched with 1 N HCl(aq), extracted with ethyl acetate, and concentrated. A fraction of this material (308 mg, 1 mmol) was added to concentrated H2SO4 at 0° C. The mixture was stirred for 1.5 hours and was poured onto ice chips. The precipitate was collected to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.44 (dd, J=1.5, 8.1 Hz, 1H), 7.48 (t, J=8.1 Hz, 1H), 7.25 (t, J=7.8 Hz, 1H), 7.14 (d, J=8.4 Hz, 1H), 4.28 (t, J=5.1 Hz, 2H), and 3.02 (t, J=5.1 Hz, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10]([C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2snc(-c3ccccc3)c2c1O
Reactant: COc1ccc(B(O)O)cc1
Product: CCOC(=O)c1nc(-c2ccc(OC)cc2)c2snc(-c3ccccc3)c2c1O

Procedure:
The title compound was synthesized in analogy to Example 1 from 7-bromo-4-hydroxy-3-phenyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and 4-methoxyphenylboronic acid: MS (m/z) 407.2 (M+1).
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12](Cl)(=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16].C(N(CC)CC)C>ClCCl>[C:1]1([CH:7]2[CH2:11][CH2:10][N:9]([C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCC(=O)Cl
Reactant: c1ccc(C2CCNC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(=O)N1CCC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 81.7 %

Procedure:
A solution of 3-phenylpyrrolidine (294 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath and pentanoyl chloride (301 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:4). The fractions containing 1-(3-phenylpyrrolidin-1-yl)pentan-1-one are collected and the solvent is removed in vacuo to give 378 mg of colorless oil.
Reaction SMILES: [C:1]1([S:7](OC)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[K+].[CH3:13][C@H:14]1[C@H:19]([CH2:20][CH:21]=[CH2:22])[CH2:18][CH2:17][C:16](=[O:23])[CH2:15]1.Cl>C(COC)OC>[CH3:13][CH:14]1[CH2:15][C:16](=[O:23])[CH:17]([S:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:18][CH:19]1[CH2:20][CH:21]=[CH2:22]
Reactant: COS(=O)c1ccccc1
Reactant: C=CC[C@@H]1CCC(=O)C[C@H]1C
Agent: Cl
Agent: [H-]
Agent: [K+]
Solvent: COCCOC
Product: C=CCC1CC(Sc2ccccc2)C(=O)CC1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 0° C. mixture of 16.9 g. (0.109 mole) of methyl benzenesulfinate and 8.68 g. (0.217 mole) of potassium hydride in 100 ml. of dimethoxyethane was slowly added a solution of 15.0 g. (0.0987 mole) of trans-3-methyl-4-(2-propenyl)cyclohexanone in 50 ml. of dimethoxyethane. The reaction was stirred 30 minutes longer at 0° C. and then cautiously added to 500 ml. of ice-saturated sodium chloride and 45 ml. 6N hydrochloric acid. The quenched reaction mixture was extracted once with 300 ml. ether and once with 200 ml. dichloromethane. The organic extract was dried over magnesium sulfate and evaporated to give a quantitative yield of the title compound as a semisolid mixture of axial and equatorial sulfenates. Crystallization from ether yields 7.8 g. of pure axial sulfenate.
Reaction SMILES: N1C=CC=CC=1.[OH:7][CH:8]([CH:15]1[CH2:20][CH:19]2[CH2:21][CH:16]1[CH:17]=[CH:18]2)[CH:9]1[CH2:14][CH2:13][O:12][C:10]1=[O:11].[C:22](OC(=O)C)(=[O:24])[CH3:23]>CN(C)C1C=CN=CC=1.O>[C:22]([O:7][CH:8]([CH:15]1[CH2:20][CH:19]2[CH2:21][CH:16]1[CH:17]=[CH:18]2)[CH:9]1[CH2:14][CH2:13][O:12][C:10]1=[O:11])(=[O:24])[CH3:23]
Reactant: O=C1OCCC1C(O)C1CC2C=CC1C2
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OC(C1CCOC1=O)C1CC2C=CC1C2
Reaction time: 10 h
Yield: 98 %

Procedure:
To 127 g of pyridine were added 208 g of α-[hydroxy(5-norbornen-2-yl)methyl]-γ-butyrolactone (Monomer 1), 123 g of acetic anhydride and 6 g of 4-dimethylaminopyridine. Reaction was effected at 25° C. for 10 hours. Water, 30 g, was added to the reaction mixture to stop reaction, followed by hexane extraction. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum. Purification by silica gel column chromatography yielded 245 g (yield 98%) of α-[acetoxy(5-norbornen-2-yl)methyl]-γ-butyrolactone.
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=5)=[CH:18]4)=[CH:13][C:12]=3[O:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CN(C=O)C.[H-].[Na+].I[CH2:45][CH2:46][CH3:47]>O>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:29]=[CH:28][C:24]([C:25]([O:27][CH2:45][CH2:46][CH3:47])=[O:26])=[CH:23][CH:22]=5)=[CH:18]4)=[CH:13][C:12]=3[O:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: CCCI
Reactant: COCCOCOc1cc2ccc(-c3ccc(C(=O)O)cc3)cc2cc1C12CC3CC(CC(C3)C1)C2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOC(=O)c1ccc(-c2ccc3cc(OCOCCOC)c(C45CC6CC(CC(C6)C4)C5)cc3c2)cc1

Procedure:
3 g (6.1 mmol) of 4-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]benzoic acid and 100 ml of DMF were introduced into a three-necked flask under a stream of nitrogen. 200 mg (6.7 mmol) of sodium hydride (80% in oil) were added portionwise and stirring was carried out until gas evolution had ceased. 500 μl (6.1 mmol) of iodopropane were then added and the reaction mixture was stirred for one hour. The reaction mixture was poured into water and extracted with ethyl acetate and the organic phase was separated by settling, dried over magnesium sulfate and evaporated.
Reaction SMILES: [OH:1][CH2:2][C:3](=O)[CH2:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:6]=1[Cl:13].N1C=CC=CC=1.Cl.[CH3:22][O:23][NH2:24]>CO>[CH3:22][O:23][N:24]=[C:3]([CH2:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:6]=1[Cl:13])[CH2:2][OH:1]
Reactant: CON
Reactant: O=C(CO)Cc1c(Cl)cc(Cl)cc1Cl
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CON=C(CO)Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 24 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
To a stirred solution of 1-hydroxy-3-(2,4,6-trichloro-phenyl)-propan-2-one (30 g; 118 mmol) in methanol (240 ml) was added pyridine (15 ml; 189 mmol) followed by a portionwise addition of methoxyamine hydrochloride (15 g; 178 mmol). The reaction mixture was stirred at 24° C. for 18 h under nitrogen. Methanol was removed under reduced pressure, the residue poured in water (300 ml) and 1N hydrochloric acid was added (100 ml). The solution was extracted with dichloromethane (3×150 ml). Combined organic layers were washed with water (300 ml) and dried over sodium sulfate. The solvent was removed in vacuo to afford 33 g (99% of theory) of 1-hydroxy-3-(2,4,6-trichloro-phenyl)-propan-2-one O-methyl-oxime (isomers E/Z 1:1) as a brown oil.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]([O:17]CC)=[O:16])=[CH:13][N:14]=2)[CH:11]=1)#[N:2].[Li+].[OH-].Cl>C1COCC1.CO>[C:1]([CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]([OH:17])=[O:16])=[CH:13][N:14]=2)[CH:11]=1)#[N:2]
Reactant: CCOC(=O)c1cnc2ccc(CCCC#N)cn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: N#CCCCc1ccc2ncc(C(=O)O)n2c1
Temperature: 50 °C

Procedure:
To a stirring solution of ethyl 6-(3-cyanopropyl)imidazo[1,2-a]pyridine-3-carboxylate (24w) (375 mg, 1.46 mmol) in THF:MeOH (4:1, 5 mL) was added 2N LiOH (500 μL). The reaction was heated at 50° C. for 45 minutes then cooled to room temperature and the pH was adjusted between 3-4 with 1N HCl. The solvent was partially concentrated and the remaining aqueous was lyophilized to yield 6-(3-cyanopropyl)imidazo[1,2-a]pyridine-3-carboxylic acid (25). 1H NMR (400 MHz, d6-DMSO) δ 9.21-9.19 (m, 1H), 8.45 (s, 1H), 7.85 (dd, J=0.8, 9.2 Hz, 1H), 7.70 (dd, J=1.6, 9.2 Hz, 1H), 2.82 (t, J=7.2 Hz, 2H), 2.55 (t, J=7.2 Hz, 2H), 1.97-1.90 (m, 2H). MS m/z 230.3 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>CO.C(Cl)(Cl)Cl>[CH3:12][O:11][C:3]1[C:2]([NH:1][S:14]([CH3:13])(=[O:16])=[O:15])=[CH:7][CH:6]=[CH:5][C:4]=1[C:8](=[O:10])[CH3:9]
Reactant: CS(=O)(=O)Cl
Reactant: COc1c(N)cccc1C(C)=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1c(NS(C)(=O)=O)cccc1C(C)=O
Reaction time: 12 h

Procedure:
According to the method reported by A. A. Larsen in J. Med. Chem., 10, 462-472 (1967), the above compound was produced from Intermediate 66 (1.59 g) and methanesulfonyl chloride (750 μl). Here, however, the following alteration was incorporated in the purification step from the reaction mixture. Thus, the reaction was terminated with water (50 ml) and the mixture was agitated for 12 hours before extraction with ethyl acetate (once with 50 ml and twice with each 30 ml) with subsequent washing with 1 N hydrochloric acid (twice with each 25 ml) and with saturated aqueous sodium chloride solution, successively, followed by distilling off of the solvent under a reduced pressure, whereby the above-identified compound was obtained (1.93 g). Rf=0.55 (methanol/chloroform of 1/19).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:13](Cl)(=[O:17])/[CH:14]=[CH:15]/[CH3:16].Cl>O.C(=S)=S>[CH:14]([C:13]([C:4]1[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=1)=[O:17])=[CH:15][CH3:16]
Reactant: COc1ccccc1
Reactant: C/C=C/C(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: O
Product: CC=CC(=O)c1ccc(OC)cc1

Procedure:
Into a round bottom three-necked flask equipped with a stirrer, a reflux condenser, and a dropping funnel were placed 583 g. of anisole, 720 g. of aluminum chloride, and 2.37 liters of carbon disulfide. The reaction solution was stirred and 565 g. of crotonyl chloride were added by dropwise addition at such a rate as to maintain a continuous reflux. As the reaction mixture thickened, an additional 2.37 liters of carbon disulfide were added. The resulting reaction mixture which had the consistency of a slurry was refluxed for 4 hours and thereafter was poured into a mixture of 9 kg. of ice, 2 liters of water and 900 ml. of concentrated hydrochloric acid. The carbon disulfide was removed from the dilute acidified reaction mixture under vacuum. The aqueous residue was then extensively extracted with dichloromethane. The extract was washed with water and dried and was then evaporated in vacuo to yield the condensation product, p-methoxyphenyl propenyl ketone as an oil having a boiling point of about 135° C. (0.5 mm).
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=O.[CH2:11]([O:13][CH:14]([O:19][CH2:20][CH3:21])[CH2:15][CH2:16][CH2:17][NH2:18])[CH3:12].C(OC)(OC)OC.[BH4-].[Na+]>CO>[CH2:20]([O:19][CH:14]([O:13][CH2:11][CH3:12])[CH2:15][CH2:16][CH2:17][NH:18][CH2:1][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)[CH3:21]
Reactant: CCOC(CCCN)OCC
Reactant: N#Cc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: CCOC(CCCNCc1ccc(C#N)cc1)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.9 %

Procedure:
4-Formylbenzonitrile (612.0 mg) was dissolved in methanol (18.4 ml), and 4,4-diethoxybutylamine (752.5 mg) and trimethyl orthoformate (1.53 ml) were added thereto. The whole was stirred at room temperature for 18 hours. Subsequently, the solution was added with sodium borohydride (529.7 mg) under ice-cooling and stirred at room temperature for additional 30 minutes. The reaction solution was concentrated under reduced pressure. The residue was added with water and the whole was subjected to extraction with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (1.16 g) as a yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16](=O)[C:17]([NH:19][C:20]3[S:24][N:23]=[C:22]([CH3:25])[CH:21]=3)=[O:18])=[CH:8]2)=[CH:4][CH:3]=1.Cl.[NH2:30][OH:31].C([O-])(=O)C.[Na+]>CCO.C1COCC1>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16](=[N:30][OH:31])[C:17]([NH:19][C:20]3[S:24][N:23]=[C:22]([CH3:25])[CH:21]=3)=[O:18])=[CH:8]2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1cc(NC(=O)C(=O)c2cn(Cc3ccc(Cl)cc3)c3ccccc23)sn1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)C(=NO)c2cn(Cc3ccc(Cl)cc3)c3ccccc23)sn1
Temperature: 25 °C

Procedure:
A stirred mixture of 2-[1-(4-chlorobenzyl)-1H-indol-3-yl]-N-(3-methyl-isothiazol-5-yl)-2-oxo-acetamide (0.102 g, 0.25 mmol), hydroxylamine hydrochloride (17 mg, 0.25 mmol), and sodium acetate (0.1 g, 1.2 mmol) in EtOH (3 mL) and THF (3 mL) was heated to reflux for 3 days. After being cooled to rt, the reaction mixture was poured into ice-H2O (20 mL). The precipitated product 2-[1-(4-Chloro-benzyl)-1H-indol-3-yl]-2-hydroxyimino-N-(3-methyl-isothiazol-5-yl)-acetamide was collected by filtration, washed with H2O, and dried in vacuo (95 mg, 90%). 1H NMR (DMSO-d6) δ 2.3 (s, 3H), 5.6 (s, 2H), 6.9 (s, 1H), 7.0-7.5 (m, 7H), 8.1 (d, 1H, J=7), 8.65 (s, 1H). ESMS calcd for (C21H17ClN4O2S): 424.1; found 425.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].[Cl-].[C:14]([O:19][CH3:20])(=[O:18])[C:15]([O-])=[O:16]>C(=S)=S>[F:1][C:2]1[CH:3]=[C:4]([F:8])[CH:5]=[CH:6][C:7]=1[C:15](=[O:16])[C:14]([O:19][CH3:20])=[O:18]
Reactant: Fc1cccc(F)c1
Reactant: COC(=O)C(=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COC(=O)C(=O)c1ccc(F)cc1F
Temperature: 20 °C
Reaction time: 2.5 h

Procedure:
50 g (0.44 mol) of 1,3-difluorobenzene is dissolved at 20° C. in 135 ml of carbon disulfide with 73.5 g (0.55 mol) AlCl3 and then 55.15 g (0.45 mol) of methyl oxalate chloride is added and the mixture is stirred for 2.5 hours at 20° C. Ice-cold 2 N aqueous hydrochloric acid is added dropwise while cooling, extracted with ethyl acetate; the organic phase is washed with water and 10% aqueous Na2CO3 solution, dried over MgSO4, and evaporated to dryness. Yield: 38.0 g (43% of theory).
Reaction SMILES: Cl.[I:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH:14]1[CH2:18][CH2:17][NH:16][CH2:15]1)[CH:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]2=[O:24].[CH2:25](Cl)[CH:26]1[O:30][CH2:29][CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[I:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH:14]1[CH2:18][CH2:17][N:16]([CH2:25][CH:26]3[CH2:27][CH2:28][CH2:29][O:30]3)[CH2:15]1)[CH:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]2=[O:24]
Reactant: ClCC1CCCO1
Reactant: CCOC(=O)c1cn(CC2CCNC2)c2ccc(I)cc2c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(CC2CCN(CC3CCCO3)C2)c2ccc(I)cc2c1=O
Temperature: 70 °C
Reaction time: 36 h
Yield: 32 %

Procedure:
Ethyl 6-iodo-4-oxo-1-(pyrrolidin-3-ylmethyl)-1,4-dihydroquinoline-3-carboxylate hydrochloride (Intermediate 126, 500 mg, 1.08 mmol) was suspended in dimethyl formamide (3 mL) then tetrahydrofurfuryl chloride (1 mL) and potassium carbonate powder (400 mg, 22.2 mmol) were added. The reaction was stirred at 70° C. for 36 h. Water (15 mL) was added and the suspension was extracted with ethyl acetate (3×10 mL). The organic phases were combined, dried over sodium sulfate, and the solvent was removed in vacuo. The residue was chromatographed on a 4 g Analogix column using 0-10% methanol in dichloromethane. The solid was then dried in a vacuum oven at 50° C. for 18 h to give 181 mg (32% yield) of ethyl 6-iodo-4-oxo-1-((1-((tetrahydrofuran-2-yl)methyl)pyrrolidin-3-yl)methyl)-1,4-dihydroquinoline-3-carboxylate as an off white solid.
Reaction SMILES: [Br:1][CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl.[CH3:11][O:12][NH2:13]>C(O)C>[CH3:11][O:12][N:13]=[C:3]([CH2:2][Br:1])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CON
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(CBr)=NOC
Yield: 80 %

Procedure:
Ethyl bromopyruvate (80% purity), 38.9 g (200 mmol as calculated on an assumption of 100% purity) was dissolved in 100 ml of ethanol. At room temperature, 16.6 g (200 mmol) of methoxyamine hydrochloride was added to the solution, followed by heating under reflux for 2 hours. After reaction had been completed, ethanol was distilled away, and 200 ml of ethyl acetate was added to the residue. The reaction product was washed sequentially with a saturated aqueous solution of sodium hydrogencarbonate and an aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. Filtration and subsequent distillation to remove the solvent gave 36.9 g (165 mmol) of ethyl 2-methoxyimino-3-bromopropionate as a light yellow oily matter. The yield was 80%. The product synthesized was subjected to the next reaction without purification.
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][N:7]2[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.[N-:18]=[N+:19]=[N-:20].[Na+].O>CN(C)C=O>[N:18]([CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][N:7]2[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)=[N+:19]=[N-:20]
Reactant: BrCc1cccc2c1cnn2C1CCCCO1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1cccc2c1cnn2C1CCCCO1
Temperature: 90 °C
Yield: 94.9 %

Procedure:
A mixture of 4-bromomethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (150 mg, 0.508 mmol) and sodium azide (132 mg, 2.0 mmol) in N,N-dimethylformamide (1.5 mL) was heated in a 90° C.-oil-bath for 30 min, then allowed to cool, and poured into water (5 mL). The mixture was extracted with ether (2×10 mL), dried (MgSO4), filtered, evaporated, and dried under high vacuum overnight to give 4-azidomethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (124 mg, 95%) as a yellow oil.
Reaction SMILES: C[O-].[Na+].[SH:4][C:5]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]([CH3:13])[N:6]=1.Cl[CH2:15][C:16](=[O:28])[CH2:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>CO.O>[NH2:12][C:11]1[C:10]2[C:5](=[N:6][C:7]([CH3:13])=[CH:8][CH:9]=2)[S:4][C:15]=1[C:16](=[O:28])[CH2:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19]
Reactant: O=C(CCl)CS(=O)(=O)c1ccc(Cl)cc1
Reactant: Cc1ccc(C#N)c(S)n1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ccc2c(N)c(C(=O)CS(=O)(=O)c3ccc(Cl)cc3)sc2n1
Yield: 67.2 %

Procedure:
To a mixture of 5.4 g (0.1 mol) of sodium methoxide and 7.5 g (0.05 mol) of 2-mercapto-3-cyano-6-methyl pyridine in 100 ml methanol was slowly added 13.3 g (0.05 mol) of 3-chloro-1-(4-chloro-phenylsulfonyl)-2-propanone. The reaction mixture was refluxed for 7 hours. It was then cooled, diluted with water and filtered to give 15.5 g of crude product which was crystallized from acetonitrile to give 12.8 g of pure product, m.p. 265°-7° C.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:14](O)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:14]([N:11]1[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccccc2)CC1
Yield: 95.7 %

Procedure:
General procedure A was followed using 1-Boc-piperazine (50 mg, 0.27 mmol), benzoic acid (43 mg, 0.35 mmol), HATU (0.14 g, 0.35 mmol), DIPEA (0.23 ml 1.4 mmol) and DMF (2 mL) to furnish the title compound as a beige solid (75 mg, 98%), m.p. 105-107° C.; umax (CHCl3)/cm−1 3011, 2930, 2866, 1691, 1626, 1421, 1249, 1158; m/z (ESI) C16H22N2NaO3 requires 313.1523, found [M+Na]+ 313.1528.
Reaction SMILES: [CH:1]1([C@H:4]([NH:12][C:13]([CH2:15][C:16]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:17]=2[C:18](O)=[O:19])=[O:14])[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=2)[CH2:3][CH2:2]1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>>[C:26]([C:15]1[C:16]2[C:17](=[C:21]([F:25])[CH:22]=[CH:23][CH:24]=2)[C:18](=[O:19])[O:14][C:13]=1[NH:12][C@@H:4]([CH:1]1[CH2:2][CH2:3]1)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)(=[O:28])[CH3:27]
Reactant: O=C(Cc1cccc(F)c1C(=O)O)N[C@H](c1cccc(F)c1)C1CC1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)c1c(N[C@H](c2cccc(F)c2)C2CC2)oc(=O)c2c(F)cccc12
Reaction time: 20 h
Yield: 103.5 %

Procedure:
A mixture of 2-({[(S)-cyclopropyl-(3-fluoro-phenyl)-methyl]-carbamoyl}-methyl)-6-fluoro-benzoic acid (12.92 g, 37.41 mmol) and acetic anhydride (100 mL, 1 mol) was stirred at +65° C. for 20 hours and evaporated in vacuo (65° C., 10 mbar, 2 hours) to give the title compound as a thick brown oil, which was used in the next step without purification (14.30 g, yield 103.5%, purity 95% according to 1H NMR). LC-MS (m/z) 370.1 (MH+); tR=1.65. 1H NMR (500 MHz, DMSO-d6): 0.45-0.59 (m, 3H), 0.64 (m, 1H), 1.41 (m, 1H), 2.53 (s, 3H), 4.36 (t (unres. dd), 1H), 7.03 (dd, J=8.3, 10.7 Hz, 1H), 7.12 (dt, J=1.9, 8.5 Hz, 1H), 7.27 (d, J=10.2 Hz, 1H), 7.3 (d, J=7.8 Hz, 1H), 7.42 (q, J=7.8 Hz, 1H), 7.53 (d, 8.5 Hz, 1H), 7.7 (m, 1H), 11.3 (d, J=7.3 Hz, 1H, NH).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:15]#[N:16])[C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=1.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].Cl>O1CCCC1.O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([C:15]#[N:16])([C:21](=[O:22])[C:20]2[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=2[C:18]([F:17])([F:28])[F:29])[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=1
Reactant: COC(=O)C(C#N)c1ccc(Cl)cc1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(C#N)(C(=O)c1ccccc1C(F)(F)F)c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 58.9 %

Procedure:
0.10 g (2.6 mmols) of sodium hydride was suspended in 20 ml of tetrahydrofuran. To the suspension was added dropwise, while stirring and cooling, 5 ml of a tetrahydrofuran solution in which 0.42 g (2.0 mmols) of methyl 2-(4-chlorophenyl)cyanoacetate and 0.41 g (2.6 mmols) of 2-trifluoromethylbenzoyl chloride had been dissolved. The mixture was stirred at room temperature over night. The reaction mixture was poured into ice water. The water phase thereof was acidified by diluted hydrochloric acid and twice extracted with 30 ml of ethyl acetate. The ethyl acetate extraction solutions were mixed, washed with a saturated brine solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue thus-obtained was purified by silica gel column chromatography (n-hexane:benzene=1:1), giving 0.45 g of the desired product (yield 59%).