Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CSC.O[CH2:13]/[CH:14]=[C:15](/[CH2:17][CH2:18]/[CH:19]=[C:20](/[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])\[CH3:21])\[CH3:16]>ClCCl>[CH2:13]([Cl:1])/[CH:14]=[C:15](/[CH2:17][CH2:18]/[CH:19]=[C:20](/[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])\[CH3:21])\[CH3:16]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CO
Solvent: ClCCl
Solvent: CSC
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCl
Reaction time: 0.22 h
Yield: 103.8 %

Procedure:
A solution of N-chlorosuccinimide (6.8 g, 50.9 mmol) in dry dichloromethane (338 ml) was cooled to -30° and dimethylsulfide (4.1 ml, 55.3 mmol) was added dropwise over 3 min. After 13 min., the cooling bath was removed and the mixture was stirred for 30 min. The mixture was cooled to -40° and a solution of (E,E)-farnesol (11.3 ml, 44 mmol) in 112 ml dichloromethane was added over 10 min. The cooling bath was removed and the mixture was stirred for 30 min. The temperature of the reaction mixture rose to 0° and a clear solution was obtained. After stirring for two more hours the solvent (about 400 ml) was removed on a rotary evaporator and the material was taken up in hexane (600 ml). The solution was washed with ice cold water (3×90 ml) and cold brine (2×35 ml) and then dried (MgSO4). The solvent was removed under vaccum at ambient temperature and finally dried under pump vaccum to give 11.0 g (100%) of title compound as a pale yellow liquid.
Reaction SMILES: F[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[C:4]([F:11])[N:3]=1.Cl.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][O:22][CH2:23][C:24]([NH2:26])=[NH:25])=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][O:22][CH2:23][C:24]2[NH:26][C:8](=[O:10])[C:7]3[CH:6]=[CH:5][C:4]([F:11])=[N:3][C:2]=3[N:25]=2)=[CH:18][CH:19]=1
Reactant: N=C(N)COCCc1ccc(Cl)cc1
Reactant: O=C(O)c1ccc(F)nc1F
Agent: Cl
Product: O=c1[nH]c(COCCc2ccc(Cl)cc2)nc2nc(F)ccc12

Procedure:
The title compound was prepared in analogy to example 85 from 2,6-difluoropyridine-3-carboxylic acid and 2-[2-(4-chloro-phenyl)-ethoxy]-acetamidine hydrochloride (example 83.2). Off-white solid. MS: m/e=334.2 [M+H+].
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.C([O-])([O-])=O.[K+].[K+].[C:21]1([SH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C=O)C>[N+:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:4]([S:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:5]=1[C:6]#[N:7])([O-:14])=[O:13]
Reactant: Sc1ccccc1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1c(Sc2ccccc2)cccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2,6-dinitrobenzonitrile (2.0 g, 10.36 mmol) and K2CO3 (1.43 g, 10.36 mmol) in 5 mL of anhydrous DMF was added PhSH (1.14 ml in 5 mL of DMF) dropwise under nitrogen at 0° C. After the completion of addition, the reaction mixture was stirred at 0° C. for 0.5 hr. Then the reaction mixture was poured into 50 mL of water, the resultant precipitation was collected by filtration, washed with water and dried in the air to give the title product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8]([CH3:10])=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[N:3]=1.SC[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:5]([C:11]#[N:12])=[C:6]([S:8][CH2:10][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[N:7]=1
Reactant: SCCc1ccccn1
Reactant: COc1ccccc1-c1nc(N)nc(S(C)=O)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccccc1-c1nc(N)nc(SCCc2ccccn2)c1C#N

Procedure:
From 2-amino-4-methanesulfinyl-6-(2-methoxy-phenyl)-pyrimidine-5-carbonitrile, 2-mercaptoethylpyridine and DBU in DME. ES-MS m/e (%): 364 (M+H+, 100).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[N:11]=[C:10]([Cl:12])[NH:9][N:8]=1)=[O:6].[CH3:13][Si:14]([CH2:17][CH2:18][O:19][CH2:20]Cl)([CH3:16])[CH3:15]>CN(C=O)C>[CH3:3][O:4][C:5]([C:7]1[N:11]=[C:10]([Cl:12])[N:9]([CH2:20][O:19][CH2:18][CH2:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[N:8]=1)=[O:6]
Reactant: COC(=O)c1n[nH]c(Cl)n1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1nc(Cl)n(COCC[Si](C)(C)C)n1
Reaction time: 0.5 h
Yield: 57.6 %

Procedure:
To a suspension of NaH (60% dispersion, 53.9 mg, 1.34 mmol) in DMF (5 mL) at 0° C., a solution of 5-chloro-1H-[1,2,4]-triazole-3-carboxylic acid methyl ester (Bull. Pharm. Sci., 20(1): 47-61, (1997), 218 mg, 1.35 mmol) in DMF (10 mL) was added dropwise. The resulting suspension was stirred at the same temperature for 30 min and then treated with SEMCl (0.24 mL, 1.4 mmol). The resulting solution was stirred at RT for 30 min and poured onto ice. The mixture was extracted with ether (3×20 mL) and the ether layers were combined, dried (Na2SO4) and concentrated in vacuo. The residue obtained was chromatographed on silica (10% EtOAc/hexane) to obtain the title compound (227 mg, 58%). Mass spectrum (ESI, m/z): Calcd. for C10H18C1N3O3Si, 292.0 and 294.0 (M+H). found 291.5 and 293.6.
Reaction SMILES: C1(C(=O)CC#[N:7])CC1.[NH2:9][C:10]1[CH:24]=[CH:23][CH:22]=[CH:21][C:11]=1[C:12]([C:14]1C=CC(F)=[CH:16][CH:15]=1)=O>>[N:9]1[C:10]2[C:11](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:12]=[CH:14][C:15]=1[C:16]#[N:7]
Reactant: Nc1ccccc1C(=O)c1ccc(F)cc1
Reactant: N#CCC(=O)C1CC1
Product: N#Cc1ccc2ccccc2n1

Procedure:
The cyclization reaction step of the present invention is a step of reacting 3-cyclopropyl-3-oxopropanenitrile of the formula (1) with 2-amino-4′-fluorobenzophenone of the formula (2) preferably in the presence of an acid to obtain a quinolinecarbonitrile derivative [2-cyclopropyl-4-(4′-fluorophenyl)quinoline-3-carbonitrile] of the formula (3).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11]2[C:12]([CH:16]=1)=[N:13][O:14][N:15]=2.[Br-:17].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.O>ClCCl>[Br:17][C:5]1[CH:4]=[C:3]([C:8]2[CH:9]=[CH:10][C:11]3[C:12]([CH:16]=2)=[N:13][O:14][N:15]=3)[C:2]([OH:1])=[CH:7][CH:6]=1
Reactant: [Br-]
Reactant: Oc1ccccc1-c1ccc2nonc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: O
Product: Oc1ccc(Br)cc1-c1ccc2nonc2c1
Temperature: 18 °C
Reaction time: 18 h

Procedure:
A stirred mixture of 5-(2-hydroxyphenyl)benzofurazan (11.2 g, 52.8 mmol), and tetrabutylammonium tribromide (25.5 g, 52.8 mmol) in dichoromethane (530 mL) is stirred at 18° C. for 18 h. The solvent is evaporated off under reduced pressure to yield a residue which is treated with water (300 mL) and extracted with ethyl acetate (3×100 mL). The combined extracts are washed (saturated NaCl), dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by recrystallisation from ethyl acetate-hexane to give 5-(3-bromo-6-hydroxyphenyl)benzofurazan as a pale-yellow crystalline solid, m.p. 179-181° C.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C@@:9]2([OH:23])[CH2:14][CH2:13][N:12]([C:15](=[O:20])[C@H:16]([NH3+:19])[CH2:17][CH3:18])[CH2:11][C:10]2([CH3:22])[CH3:21])=[CH:5][CH:4]=1.[CH:24]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C@@:9]2([OH:23])[CH2:14][CH2:13][N:12]([C:15](=[O:20])[C@H:16]([NH:19][C:29]([CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:30])[CH2:17][CH3:18])[CH2:11][C:10]2([CH3:22])[CH3:21])=[CH:7][CH:8]=1
Reactant: O=C(Cl)C1CCCC1
Reactant: CC[C@@H]([NH3+])C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC[C@@H](NC(=O)C1CCCC1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Yield: 52.3 %

Procedure:
(R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-1-oxobutan-2-aminium chloride (52.4 mg, 0.14 mmol), cyclopentane carbonylchloride (20 mg, 0.17 mmol), THF (5 mL), and DIPEA (135 mg, 1.1 mmol) were stirred overnight at rt. The reaction was concentrated, and Example 627 was isolated as a white solid using preparative reverse-phase HPLC (30.75 mg, 52.3% yield), M+H=421.31.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:26]([F:37])[CH:25]=2)=[CH:20][CH:19]=1.O>CN(C)C=O>[C:1]([C:5]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:26]([F:37])[CH:25]=3)=[CH:38][CH:39]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C(C)(C)C)[nH]n1
Reactant: CCOC(=O)CCc1ccc(OCc2ccc(CCl)cc2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(OCc2ccc(Cn3nc(C(C)(C)C)cc3C(C)(C)C)cc2)cc1F
Reaction time: 0.33 h
Yield: 52.7 %

Procedure:
To a solution of 3,5-di-tert-butyl-1H-pyrazole (0.50 g, 2.8 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 0.13 g, 3.3 mmol) under ice-cooling and the mixture was stirred for 20 min. Then ethyl 3-(4-{[4-(chloromethyl)benzyl]oxy}-2-fluorophenyl)propanoate (0.98 g, 2.8 mmol) was added, and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract washed with aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:4) to give the title compound (0.73 g, yield 57%) as colorless crystals. melting point 73-74° C.
Reaction SMILES: Cl[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)[C:6](=[O:17])[N:5]([CH:18]2[CH2:20][CH2:19]2)[C:4](=[O:21])[CH:3]=1.C(O)C.[CH3:25][NH2:26]>CO>[CH:18]1([N:5]2[C:4](=[O:21])[CH:3]=[C:2]([NH:26][CH3:25])[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=3)[C:6]2=[O:17])[CH2:20][CH2:19]1
Reactant: CN
Reactant: O=c1cc(Cl)n(-c2cccc([N+](=O)[O-])c2)c(=O)n1C1CC1
Solvent: CCO
Solvent: CO
Product: CNc1cc(=O)n(C2CC2)c(=O)n1-c1cccc([N+](=O)[O-])c1
Temperature: 80 °C
Yield: 55 %

Procedure:
To the mixture (30 g) of 6-chloro-3-cyclopropyl-1-(3-nitrophenyl)-1H-pyrimidine-2,4-dione 6 and 4-chloro-3-cyclopropyl-1-(3-nitrophenyl)-1H-pyrimidine-2,6-dione 7 obtained in Step 3 were added ethanol (300 ml) and a 40% solution (150 ml) of methylamine in methanol, and the mixture was stirred with heating at 80° C. for 4.5 hrs, ice-cooled and the precipitated solid was filtered by suction. The residue was washed with water (1 liter) and dried to give 3-cyclopropyl-6-methylamino-1-(3-nitrophenyl)-1H-pyrimidine-2,4-dione 8 (16 g, 55%) as a white solid.
Reaction SMILES: NCCNC(=O)OCC1C=CC=CC=1.[N:15]([C:18](=[CH:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[CH:27][NH:28]2)[C:19]([O:21][CH3:22])=[O:20])=[N+]=[N-].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>[CH:23]1[C:24]2=[C:25]3[C:29]([CH:30]=[CH:31][C:32]2=[N:15][C:18]=1[C:19]([O:21][CH3:22])=[O:20])=[N:28][CH:27]=[CH:26]3
Reactant: COC(=O)C(=Cc1cccc2[nH]ccc12)N=[N+]=[N-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NCCNC(=O)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C1=Cc2c3c(ccc2=N1)=NC=C3
Temperature: 25 °C
Reaction time: 4 h
Yield: 260.6 %

Procedure:
To compound 1 (50 mg, 0.079 mmol) in DMF (2 mL) was added 2 (49 mg, 0.085 mmol) and HATU (33 mg, 0.086 mmol) followed by adding DIPEA (45 uL) and the reaction mixture was stirred for 4 hrs at room temperature. The solvent was removed under vacuo and the product was purified by Prep HPLC (SymmetrPrep C18, 7 μm, 19×150 mm column), eluted at 10 ml/min (0.01% TFA in water/acetonitrile) with a gradient: 10% acetonitrile in 5 min, 10% to 50% acetonitrile in 15 min, maintaining 50% acetonitrile in 5 min, 50% to 100% acetonitrile in 5 min, to give 3 (47 mg, 60%). MS: (M+H)+ 1003.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:6][N:7]([C@H:14]1[CH2:20][CH2:19][CH2:18][N:17]([CH2:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[C:16]2[CH:28]=[C:29]([C:33]([F:36])([F:35])[F:34])[C:30]([CH3:32])=[CH:31][C:15]1=2)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[CH2:46]([O:48][C:49](=[O:52])[CH2:50]Br)[CH3:47].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH2:46]([O:48][C:49](=[O:52])[CH2:50][N:25]1[CH2:24][CH2:23][CH:22]([CH2:21][N:17]2[CH2:18][CH2:19][CH2:20][C@H:14]([N:7]([CH2:6][C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:44])[F:45])[CH:39]=[C:38]([C:40]([F:41])([F:42])[F:43])[CH:37]=3)[C:8]3[N:9]=[N:10][N:11]([CH3:13])[N:12]=3)[C:15]3[CH:31]=[C:30]([CH3:32])[C:29]([C:33]([F:34])([F:35])[F:36])=[CH:28][C:16]2=3)[CH2:27][CH2:26]1)[CH3:47]
Reactant: Cc1cc2c(cc1C(F)(F)F)N(CC1CCNCC1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCC(CN2CCC[C@H](N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)c3cc(C)c(C(F)(F)F)cc32)CC1
Temperature: 50 °C

Procedure:
To a solution of (S)-(3,5-Bis-trifluoromethyl-benzyl)-(7-methyl-1-piperidin-4-ylmethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amine (Example 120) (0.18 mmol) in DMF (3 mL), add bromo-acetic acid ethyl ester (0.54 mmol) and cesium carbonate (0.90 mmol). After heating the mixture at 50° C. for 30 minutes, cool to room temperature and dilute the reaction with water (15 mL) and extract with ethyl acetate (3×10 mL). Dry the combined organic phases over sodium sulfate, filter, and remove solvent under vacuum. Chromatograph the product over silica gel, eluting with ethyl acetate/hexane (5-50%), to give the title compound as a colorless foam. MS (ES+): 736 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Br:24]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:24])[N:6]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1nc(OCCCCO)nc2c1ncn2Cc1ccccc1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Nc1nc(OCCCCO)nc2c1nc(Br)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
6-Amino-9-benzyl-2-(4-hydroxybutoxy)purine (200 mg, 0.638 mmol) and bromine (1.0 ml) were dissolved in methylene chloride (50 ml). The solution was stirred at room temperature for 2 hours. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on sodium sulfate and the solvent was removed. The residue was purified with silica gel chromatography (2% methanol/chloroform) to give the subject compound (213 mg, yield 85%).
Reaction SMILES: C([S:7][CH2:8][C@@H:9]([CH3:13])[C:10]([OH:12])=[O:11])CCCC=C.Br[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([I:22])[CH:17]=1>>[I:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][S:7][CH2:8][C@@H:9]([CH3:13])[C:10]([OH:12])=[O:11]
Reactant: C=CCCCCSC[C@@H](C)C(=O)O
Reactant: BrCc1cccc(I)c1
Product: C[C@H](CSCc1cccc(I)c1)C(=O)O

Procedure:
The title compound is prepared similarly to (S)-3-hex-5-enylsulfanyl-2-methyl-propionic acid (IIa), using 1-bromomethyl-3-iodo-benzene instead of 6-bromo-hex-1-ene.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].OC(C(F)(F)F)=O.[CH:34]1([N:39]2[CH2:44][CH2:43][NH:42][CH2:41][C:40]2=[O:45])[CH2:38][CH2:37][CH2:36][CH2:35]1>CN1C(=O)CCC1>[F:24][C:14]1[C:13]([CH:11]([C:8]2[N:6]3[N:7]=[C:2]([N:42]4[CH2:43][CH2:44][N:39]([CH:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[C:40](=[O:45])[CH2:41]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:22]([F:23])[CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2
Reactant: O=C1CNCCN1C1CCCC1
Reactant: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Agent: [F-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCCC1=O
Product: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(N3CCN(C4CCCC4)C(=O)C3)nn12
Temperature: 180 °C
Reaction time: 5 h

Procedure:
(rac)-6-[1-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-5,7-difluoro-quinoline (Intermediate C, 50 mg, 0.145 mmol), KF (84 mg, 1.450 mmol), 1-cyclopentylpiperazin-2-one TFA salt (129 mg, 0.435 mmol) were suspended in NMP (483 μL). The RM was stirred at 180° C. for 5 h. The mixture was purified by preparative UPLC with acetonitrile and water (+0.1% TFA) The fractions were collected and acetonitrile was removed. It was taken up with MeOH and passed through an SPE cartridge of PL-HCO3 MP from polymer lab. The solvent was removed and a brown solid was obtained (tR 1.1 min (conditions 4), MH+=477)
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:18])=[O:7].ClS([N:23]=[C:24]=[O:25])(=O)=O.C(#N)C>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[N:10]([C:24]([NH2:23])=[O:25])[C:9]1=[O:18])=[O:7]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: O=C1Nc2cc(F)ccc2C1C(=O)c1ccco1
Solvent: CC#N
Solvent: O
Product: NC(=O)N1C(=O)C(C(=O)c2ccco2)c2ccc(F)cc21
Yield: 17 %

Procedure:
Following substantially the procedure of Example 19, the title was prepared in 17% yield from: 3-(2-furoyl)-6-fluoro-2-oxindole (0.30 g, 1.2 mmole), chlorosulfonyl isocyanate (0.20 g, 1.4 mmole), acetonitrile (15 ml), and water (10 ml), Yield=0,060 g; m.p.=231°-235° C.
Reaction SMILES: [NH2:1][OH:2].[CH3:3][C:4]1[C:8]([C:9]2[N:10]([C:25]#[N:26])[C:11]3[C:16]([C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:7]([CH3:27])[S:6][N:5]=1>CO>[CH3:3][C:4]1[C:8]([C:9]2[N:10]([C:25](=[N:1][OH:2])[NH2:26])[C:11]3[C:16]([C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:7]([CH3:27])[S:6][N:5]=1
Reactant: Cc1nsc(C)c1-c1c(-c2ccc(O)cc2)c2ccccc2n1C#N
Reactant: NO
Solvent: CO
Product: Cc1nsc(C)c1-c1c(-c2ccc(O)cc2)c2ccccc2n1C(N)=NO
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 37 %

Procedure:
Hydroxylamine (16.3 M solution in water, 0.33 mL, 5.21 mmol) was added to 2-(3,5-dimethylisothiazol-4-yl)-3-(4-hydroxyphenyl)-1H-indole-1-carbonitrile (18 mg, 0.05 mmol) in MeOH (2 mL) and the reaction was stirred at 130° C. for 20 min in the microwave. The mixture was purified by preparative HPLC to give E24 2-(3,5-dimethylisothiazol-4-yl)-N′-hydroxy-3-(4-hydroxyphenyl)-1H-indole-1-carboximidamide (7.0 mg, 35%); ES/MS m/z 379.11 (M+H), 377.14 (M−H); 1H NMR (acetone-d6, 500 MHz): 7.70 (dd, 1H, J=7.9, 1.0 Hz), 7.59 (dd, 1H, J=9.0, 0.9 Hz), 7.29 (m, 1H), 7.20 (m, 1H), 7.09 (m, 2H), 6.81 (m, 2H), 2.30 (s, 3H) and 2.16 (s, 3H) and E25 2-(3,5-dimethylisothiazol-4-yl)-3-(4-hydroxyphenyl)-1H-indole-1-carboxamide (5 mg, 26%), ES/MS m/z 364.11 (M+H), 362.14 (M−H); 1H NMR (acetone-d6, 500 MHz): 8.12 (d, 1H, J=8.4 Hz), 7.67 (d, 1H, J=7.9 Hz), 7.36 (m, 1H), 7.26 (m, 1H), 7.05 (m, 2H), 6.83 (m, 2H) and 2.21 (s, 6H). For each of the title compounds, identification by 1H-NMR showed that the amide oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained.
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([O:10][CH3:11])=[O:9].C(=O)([O-])[O-].[K+].[K+].[OH:18][C:19]1[CH:24]=[CH:23][C:22]([S:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21][CH:20]=1>CN(C=O)C>[CH2:30]([O:29][C:27]([CH2:26][S:25][C:22]1[CH:21]=[CH:20][C:19]([O:18][CH2:2][C:3]2[CH:7]=[CH:6][S:5][C:4]=2[C:8]([O:10][CH3:11])=[O:9])=[CH:24][CH:23]=1)=[O:28])[CH3:31]
Reactant: COC(=O)c1sccc1CBr
Reactant: CCOC(=O)CSc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CSc1ccc(OCc2ccsc2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
Methyl 3-bromomethylthiophene-2-carboxylate (28.2 ml, 120 mmol) and potassium carbonate (36.6 g, 264 mmol) were added to a DMF (300 mL) solution of the compound obtained in Example 18 (28.1 g, 132 mmol), and the mixture was stirred overnight at room temperature. The solvents were distilled off under a reduced pressure, water was added to the residue, and the product was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, and then dried over anhydrous sodium sulfate, and the solvents were distilled off under a reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1), to give 35.1 g (80%) of the captioned compound.
Reaction SMILES: CN(C)CCN(C)C.[CH2:9]([Li:13])[CH2:10][CH2:11][CH3:12].[F:14][C:15]1([F:24])[O:19][C:18]2C=CC=C[C:17]=2[O:16]1>C1(C)C=CC=CC=1.CCCC>[F:14][C:15]1([F:24])[O:19][C:18]2[CH:12]=[CH:11][CH:10]=[C:9]([Li:13])[C:17]=2[O:16]1
Reactant: FC1(F)Oc2ccccc2O1
Reactant: [Li]CCCC
Agent: CN(C)CCN(C)C
Solvent: CCCC
Solvent: Cc1ccccc1
Product: [Li]c1cccc2c1OC(F)(F)O2

Procedure:
39.3 g (339 mmol) of N,N,N',N'-tetramethylethylenediamine are added dropwise under a nitrogen atmosphere at from -15° to -10° C. to 137.8 g (409 mmol) of n-butyllithium solution (19.0% in toluene). The resulting reaction mixture is added dropwise at from -15° to -10° C. under a nitrogen atmosphere to a solution of 53.3 g (337 mmol) of 2,2-difluoro-1,3-benzodioxole in 46 ml of toluene, n-butane being formed in addition to the title compound.
Reaction SMILES: [C:1]([N:4]1[CH2:7][CH:6]([OH:8])[CH2:5]1)(=[O:3])[NH2:2].[Si:9](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1C=CN=C1.C(O)C>CN(C)C=O>[Si:9]([O:8][CH:6]1[CH2:7][N:4]([C:1](=[O:3])[NH2:2])[CH2:5]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NC(=O)N1CC(O)C1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC1CN(C(N)=O)C1)(c1ccccc1)c1ccccc1
Reaction time: 0.17 h
Yield: 18 %

Procedure:
To a solution of 1-carbamoyl-3-hydroxyazetidine (obtained as described in Reference Example 21(1)) in dimethylformamide (100 ml) were added t-butyldiphenylsilyl chloride (18.0 ml, 66.9 mmol) and imidazole (4.55 g, 66.9 mmol) in an ice bath. After stirring the mixture in an ice bath for 10 minutes, the resulting mixture was stirred at room temperature overnight. After checking the completion of the reaction, ethanol (1 ml) was added to the reaction mixture in an ice bath and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was partitioned between ethyl acetate and aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:methanol (10:1) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-carbamoylazetidine (1.45 g, total yield 18%) as a white solid.