Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].[BrH:20]>C(O)(=O)C>[Br:20][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=C(O)CCCCCCCCCCCCCCCO
Reactant: Br
Solvent: CC(=O)O
Product: O=C(O)CCCCCCCCCCCCCCCBr
Yield: 99 %

Procedure:
16-Bromohexadecanoic acid was prepared by refluxing for 48 hrs 5.0 gr (18.35 mmole) of 16-hydroxyhexadecanoic acid in 24 ml of 1:1 v/v mixture of HBr (48% aqueous solution) and glacial acetic acid. Upon cooling, crude product was solidified inside the reaction vessel. It was filtered out and washed with 3×100 ml of cold water. 6.1 gr (99% yield) of the desired product were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:15])=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH:11]([CH3:13])[CH3:12])[C:6]=2[CH:14]=1.[C:16](Cl)(Cl)=[O:17].C1(C)C=CC=CC=1>C1(C)C=CC=CC=1>[F:15][C:3]1[C:2]([N:1]=[C:16]=[O:17])=[CH:14][C:6]2[N:7]([CH:11]([CH3:13])[CH3:12])[C:8](=[O:10])[S:9][C:5]=2[CH:4]=1
Reactant: O=C(Cl)Cl
Reactant: CC(C)n1c(=O)sc2cc(F)c(N)cc21
Solvent: Cc1ccccc1
Product: CC(C)n1c(=O)sc2cc(F)c(N=C=O)cc21

Procedure:
A solution of 5-amino-3-isopropyl-6-fluoro-2(3H)-benzothiazolone (5 g) in toluene (70 ml) was added to 1M phosgene/toluene, and the resultant solution was stirred at 90° to 95° C. for 1 hour, followed by concentration under reduced pressure. The residue was crystallized from n-hexane to give 6-fluoro-3-isopropyl-2(3H)-benzothiazolon-5-yl isocyanate (5.2 g). m.p., 149°-150° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[CH3:20][NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:20][N:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19]
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OCC
Reactant: CNc1ccccc1
Product: CCOc1cc2ncc(C#N)c(N(C)c3ccccc3)c2cc1OCC

Procedure:
In the manner of Example 105 reaction of 4-chloro-6,7-diethoxy-3-quinolinecarbonitrile with N-methylaniline gave the title compound as a tan solid, mp 153-155° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5](=O)[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)=O)[CH3:2].Cl.[Cl:22][C:23]1[CH:24]=[C:25]([NH:29][NH2:30])[CH:26]=[CH:27][CH:28]=1>>[Cl:22][C:23]1[CH:24]=[C:25]([N:29]2[C:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=3)=[CH:6][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:20])=[N:30]2)[CH:26]=[CH:27][CH:28]=1
Reactant: NNc1cccc(Cl)c1
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(OC)c(OC)c1
Agent: Cl
Product: CCOC(=O)c1cc(-c2ccc(OC)c(OC)c2)n(-c2cccc(Cl)c2)n1
Yield: 74 %

Procedure:
Starting from 1 g (3.57 mmol) of 4-(3,4-dimethoxyphenyl)-2,4-dioxobutanoic acid ethyl ester from example 12A and 868.8 mg (4.85 mmol) of 3-chlorophenylhydrazine hydrochloride, 1.03 g (2.7 mmol, 74% yield of theory) of product are obtained according to the method described in example 4A and after purification by preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([CH3:9])[S:5][C:6]=1[CH:7]=[O:8].[OH:15]OS([O-])=O.[K+].O>CN(C=O)C>[Cl:1][C:2]1[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([CH3:9])[S:5][C:6]=1[C:7]([OH:15])=[O:8]
Reactant: O=S([O-])OO
Reactant: CCOC(=O)c1c(C)sc(C=O)c1Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)sc(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of ethyl 4-chloro-5-formyl-2-methylthiophene-3-carboxylate (F-4) (9.72 g, 41.77 mmol, 1.0 eq) in DMF (150 mL), Oxone (77.1 g, 125.3 mmol, 3.0 eq) is added in portions and the resulting mixture is stirred at RT overnight. The mixture is poured into H2O (800 mL) and stirred for 30 min. The precipitate is collected by filtration, rinsed with H2O (100 mL) and then slurried in H2O (80 mL) for 30 min. The solid is collected by filtration, rinsed with H2O (3×60 mL) and petroether (3×60 mL), and dried in vacuo to afford the product, 3-chloro-4-(ethoxycarbonyl)-5-methylthiophene-2-carboxylic acid (F-5).
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[CH:28]=[C:29]([S:34]([NH2:37])(=[O:36])=[O:35])[CH:30]=[CH:31][C:32]=1[Cl:33]>>[Cl:33][C:32]1[CH:31]=[CH:30][C:29]([S:34](=[O:35])(=[O:36])[NH2:37])=[CH:28][C:27]=1[NH:26][C:12]([C:11]1[CH:10]=[N:9][N:8]2[C:3]([CH:2]([F:1])[F:25])=[CH:4][C:5]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=3)=[N:6][C:7]=12)=[O:14]
Reactant: Nc1cc(S(N)(=O)=O)ccc1Cl
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NS(=O)(=O)c1ccc(Cl)c(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-amino-4-chloro-benzenesulfonamide [CAS-No. 29092-34-0; commercially available] according to general procedure II. Light yellow solid. MS (ISP) 545.1 [(M−H−]; mp 286° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[NH:15][CH:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)[CH:8]=[N:7][CH:6]=1)(=[O:4])=[O:3].[ClH:29].CO>>[ClH:29].[CH3:1][S:2]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[NH:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:8]=[N:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccc3cncc(S(C)(=O)=O)c23)CC1
Agent: Cl
Solvent: CO
Product: CS(=O)(=O)c1cncc2cccc(NC3CCNCC3)c12
Temperature: 25 °C

Procedure:
According to the method of Example 1, Step C, deprotection was performed (50° C., 2 hours) by using Intermediate 80 (40.9 mg) and 10% hydrogen chloride/methanol solution (1 ml). The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. The residue was added with methanol (1 ml) and diethyl ether (3 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (11.4 mg) as brown powdery solid.
Reaction SMILES: Cl[C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[C:18]1([CH2:24][CH2:25][NH2:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[N+:15]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])[C:2]=1[NH:26][CH2:25][CH2:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:6]([OH:8])=[O:7])([O-:17])=[O:16]
Reactant: NCCc1ccccc1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Solvent: O
Product: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1NCCc1ccccc1

Procedure:
A mixture of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (22.4 g), β-phenylethylamine (29 g), and water (200 ml) was refluxed for 2.5 hours. After cooling, the reaction mixture was adjusted to a pH of 9.5 and extracted with diethyl ether. The aqueous layer was then acidified by addition of 4N hydrochloric acid, and the precipitated 3-nitro-4-(β-phenylethylamino)-5-sulphamyl-benzoic acid was collected by suction. After recrystallization from aqueous ethanol, the melting point was 208°-208.5°C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH3:21])[C:11]=2[C:22]([O:24][CH3:25])=[O:23])[CH:5]=[CH:6][C:7]=1[CH3:8].[H-].[Na+].[CH3:28]I.Cl.O>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:28])[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH3:21])[C:11]=2[C:22]([O:24][CH3:25])=[O:23])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CI
Reactant: COC(=O)c1c(Nc2ccc(C)c(C)c2)c2ccccc2c(=O)n1C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(N(C)c2ccc(C)c(C)c2)c2ccccc2c(=O)n1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.7 %

Procedure:
To a solution of methyl 4-[(3,4-dimethylphenyl)amino]-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (2.03 g, 6.03 mmol) in DMF (40 mL) at 0° C. was added sodium hydride (0.362 g, 9.05 mmol) followed by methyl iodide (5.66 mL, 91 mmol). The mixture was stirred at room temperature for 18 hours. 1M HCl/water was added and the mixture was extracted with EtOAc. The organic phase was washed with brine, dried over sodium sulfate and evaporated in vacuo. The crude product was purified on silica using EtOAc/hexanes 30-50% to provide the title compound as an off-white solid (2 g, 95%): 1H NMR (400 MHz, CDCl3) δ ppm 8.56-8.37 (m, 1 H), 8.03 (s, 1 H), 7.62-7.47 (m, 2 H), 6.93 (d, J=8.4 Hz, 1 H), 6.48 (d, J=2.3 Hz, 1 H), 6.40 (dd, J=2.5, 8.2 Hz, 1 H), 3.77 (s, 3 H), 3.57 (s, 3 H), 3.24 (s, 3 H), 3.04-2.95 (m, 2 H), 2.89 (s, 2 H), 2.17 (d, J=8.8 Hz, 6 H);); ES-LCMS: 351.3 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([NH:10][C:11]([NH:13][CH2:14][CH2:15][O:16][CH3:17])=[O:12])[NH:7][C:6]=2[CH:18]=1.Cl[S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:25][CH:24]=1)(=[O:22])=[O:21].C(N(CC)CC)C>CC(C)=O>[CH3:17][O:16][CH2:15][CH2:14][NH:13][C:11](=[O:12])[NH:10][C:8]1[NH:9][C:5]2[CH:4]=[CH:3][C:2]([O:1][S:20]([C:23]3[CH:24]=[CH:25][C:26]([O:29][C:30](=[O:37])[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:27][CH:28]=3)(=[O:22])=[O:21])=[CH:18][C:6]=2[N:7]=1
Reactant: COCCNC(=O)Nc1nc2ccc(O)cc2[nH]1
Reactant: O=C(Oc1ccc(S(=O)(=O)Cl)cc1)c1ccccc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COCCNC(=O)Nc1nc2cc(OS(=O)(=O)c3ccc(OC(=O)c4ccccc4)cc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 11.4 %

Procedure:
A stirred solution of 1-(6-hydroxy-1H-benzoimidazol-2-yl)-3-(2-methoxy-ethyl)-urea (31 mg, example 82) and benzoic acid 4-chlorosulfonyl-phenyl ester (37 mg) in acetone (0.6 ml) was treated with triethylamine (33 μl). After stirring at ambient temperature for 4 hours, the reaction mixture was evaporated. The residue was filtered and the filtrate evaporated. The residue was directly purified by LCMS triggered purification to give benzoic acid 4-{2-[3-(2-methoxy-ethyl)-ureido]-1H-benzoimidazol-5-yloxysulfonyl}-phenyl ester (7.2 mg) as a off-white solid Mass spectrum: 511 [M+H]+; retention time=9.90 minutes.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]([F:14])([F:13])[F:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C-:15]#[N:16].[Na+]>C(C(C)=O)C.[Zn].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:12][C:11]([F:14])([F:13])[S:8]([C:5]1[CH:6]=[CH:7][C:2]([C:15]#[N:16])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(F)(F)F
Reactant: [C-]#N
Agent: [Na+]
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCC(C)=O
Product: N#Cc1ccc(S(=O)(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85.9 %

Procedure:
Under an atmosphere of nitrogen, a mixture of 4 g of bis-triphenylphosphine-nickel dichloride, 3 g of triphenylphosphine and 100 ml of MEK was stirred at room temperature for 10 minutes. 1.2 g of activated zinc powder were then added, and the reaction mixture was stirred at 70° C. for 30 minutes. Following this, the mixture was allowed to cool to 25° C., and a solution of 92 g of 4-chloro-trifluoromethanesulphonylbenzene in 50 ml of MEK was added dropwise. The mixture was stirred for 10 minutes, 18.5 g of sodium cyanide were then added and the reaction mixture was stirred at from 65 to 70° C. for 20 h. The conversion after this period of time was greater than 98% (GC). After cooling to RT, the mixture was filtered, the solid filter residue was washed 2× with 30 ml of MEK each time and the combined organic phases were concentrated under reduced pressure. Fractionation under reduced pressure via a 30 cm Vigreux column and heated distillation bridge gave 76 g (85% of theory) of 4-trifluoromethanesulphonylbenzonitrile as a white solid (boiling point at 0.2 mbar: 115° C.). A formation of coupling products was not observed.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:18][C@@H:17]([CH3:19])[CH2:16][C@H:9]2[C:10]([NH:12][CH2:13][C:14]#[N:15])=[O:11])[CH:5]=[CH:6][CH:7]=1.[Cl:20]N1C(=O)CCC1=O>C(O)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:20])=[C:4]([N:8]2[CH2:18][C@@H:17]([CH3:19])[CH2:16][C@H:9]2[C:10]([NH:12][CH2:13][C:14]#[N:15])=[O:11])[CH:3]=1
Reactant: C[C@H]1C[C@@H](C(=O)NCC#N)N(c2cccc(Br)c2)C1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(C)O
Product: C[C@H]1C[C@@H](C(=O)NCC#N)N(c2cc(Br)ccc2Cl)C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a hot (60° C.) solution of (4S)-1-(3-bromophenyl)-N-(cyanomethyl)-4-methyl-L-prolinamide (630 mg, 1.96 mmol) in isopropyl alcohol (20 mL) was added N-chlorosuccinimide and the reaction mixture was stirred at 60° C. for 2 hours. The reaction was concentrated in vacuo and the product purified by flash chromatography over silica gel (MTBE/Hex, 1/1, then 6/4, then 8/2) to afford (4S)-1-(5-bromo-2-chlorophenyl)-N-(cyanomethyl)-4-methyl-L-prolinamide.
Reaction SMILES: [C:1]1([C:11]2[CH:35]=[CH:34][C:14]([C:15]([N:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[CH2:21][N:20]4[C:28]([C:31](O)=[O:32])=[CH:29][CH:30]=[C:19]4[CH2:18]3)=[O:16])=[CH:13][CH:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH:36]([CH2:40][CH2:41][OH:42])[CH2:37][CH2:38][OH:39]>>[OH:39][CH2:38][CH2:37][N:36]([CH2:40][CH2:41][OH:42])[C:31]([C:28]1[N:20]2[C:19]([CH2:18][N:17]([C:15](=[O:16])[C:14]3[CH:34]=[CH:35][C:11]([C:1]4[C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[CH:4]=[CH:3][CH:2]=4)=[CH:12][CH:13]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21]2)=[CH:30][CH:29]=1)=[O:32]
Reactant: O=C(O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(-c3cccc4ccccc34)cc1)C2
Reactant: OCCNCCO
Product: O=C(c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(-c3cccc4ccccc34)cc1)C2)N(CCO)CCO

Procedure:
The title compound was prepared by coupling the 10-[4-(naphthalen-1-yl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Step D, with diethanolamine (1.25 equiv) in the manner of Example 1, Step G.
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]([C:7]1[CH2:8][N:9]([CH2:14][C:15]2[C:18]3[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:17]=3[CH:16]=2)[CH2:10][CH2:11][C:12]=1[OH:13])=[O:6])[CH3:3]>C(O)C.[Pt]=O>[ClH:1].[CH2:2]([O:4][C:5]([C@H:7]1[C@@H:12]([OH:13])[CH2:11][CH2:10][N:9]([CH2:14][C:15]2[C:18]3[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:17]=3[CH:16]=2)[CH2:8]1)=[O:6])[CH3:3]
Reactant: CCOC(=O)C1=C(O)CCN(CC2=Cc3ccc(OC)cc32)C1
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)[C@@H]1CN(CC2=Cc3ccc(OC)cc32)CC[C@@H]1O

Procedure:
11.7 g (33 mmol) of 4-hydroxy-1-[(5-methoxybenzocyclobuten-1-yl)methyl]-1,2,5,6-tetrahydro-pyridine-3carboxylic acid ethyl ester hydrochloride are hydrogenated at 4·105Pa and room temperature with the addition of 1.2 g of platinum oxide in 300 ml of ethanol. The catalyst is filtered off and the reaction solution is concentrated. Crystallisation from ethanol/diethyl ether yields cis-4-hydroxy-1-[(5-methoxybenzocyclobuten-1-yl)methyl]-piperidine-3-carboxylic acid ethyl ester hydrochloride of m.p. 156°-160°.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][CH:7]([C:25](=O)[CH3:26])[C:8]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:31]O>C(O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C:7]2[C:25]([CH3:26])=[N:31][O:9][C:8]=2[C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])=[CH:4][CH:3]=1
Reactant: CC(=O)C(Cc1ccc(Cl)cc1)C(=O)[C@H]1CCCN1C(=O)OCc1ccccc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1noc([C@H]2CCCN2C(=O)OCc2ccccc2)c1Cc1ccc(Cl)cc1
Temperature: 70 °C
Yield: 75.4 %

Procedure:
To a solution of (2R)-benzyl 2-(2-(4-chlorobenzyl)-3-oxobutanoyl)pyrrolidine-1-carboxylate (300 mg, 0.71 mmol) in ethanol (10 mL) was added hydroxylamine hydrochloride (490 mg, 7.1 mmol). The resulting solution was heated at 70° C. for 3 h and then diluted with EtOAc (30 mL). The organic layer was washed with saturated NaHCO3 solution (1×40 mL) and then brine (1×40 mL). The separated organic layer was then dried over Na2SO4 and concentrated in vacuo. Purification of the resulting residue by silica gel column chromatography (hexanes/ethyl acetate gradient, 10-100% EtOAc) afforded (R)-benzyl 2-(4-(4-chlorobenzyl)-3-methylisoxazol-5-yl)pyrrolidine-1-carboxylate (220 mg, 76%). LCMS: calculated: 410, found (MH+): 411.
Reaction SMILES: C(NC(=O)[NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]3[CH3:35])[C:15]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][C:16]=3[N:17]=2)=[CH:8][CH:7]=1)C.[F:37]C1C=C(B2OC(C)(C)C(C)(C)O2)C=CC=1N>>[F:37][C:11]1[CH:10]=[C:9]([C:12]2[N:13]=[C:14]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]3[CH3:35])[C:15]3[CH2:21][N:19]([CH3:20])[CH2:18][C:16]=3[N:17]=2)[CH:8]=[CH:7][C:6]=1[NH2:5]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)OC(C)(C)C)C3)cc1
Reactant: CC1(C)OB(c2ccc(N)c(F)c2)OC1(C)C
Product: C[C@H]1COCCN1c1nc(-c2ccc(N)c(F)c2)nc2c1CN(C)C2
Yield: 98 %

Procedure:
Method as described for intermediate 5 using 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline as starting material. The crude reaction mixture was filtered through a celite 545 pre-packed cartridge (2.5 g), washed with MeOH and solvent removed in vacuo. The residue was purified by flash SCX2 chromatography affording the title compound (139 mg, 0.40 mmol, 98%).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:33][C:34]1[CH:39]=[C:38]([N:19]2[C:20]3[C:16](=[CH:15][C:14]([C:12]([N:9]4[CH2:8][CH2:7][N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[CH2:11][CH2:10]4)=[O:13])=[CH:22][CH:21]=3)[CH:17]=[C:18]2[C:23]([N:25]2[CH2:26][CH2:27][C:28]([F:31])([F:32])[CH2:29][CH2:30]2)=[O:24])[CH:37]=[CH:36][CH:35]=1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Reactant: OB(O)c1cccc(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1cccc(Cl)c1)N1CCN(C2CCCC2)CC1
Yield: 76 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 8), 3-chlorphenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a white solid (76%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([OH:23])=O)=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)=[O:23])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCOCC4)cc3c2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), morpholine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)=O.[C:24]([O:30][CH2:31][CH2:32][CH2:33][CH3:34])(=[O:29])[CH2:25][C:26]([CH3:28])=O.S(=O)(=O)(O)O>C(O)(=O)C>[CH2:31]([O:30][C:24]([C:25]1[C:26]([CH3:28])=[N:1][C:2]2[C:3]([C:4]=1[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)=[CH:16][C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=2)=[O:29])[CH2:32][CH2:33][CH3:34]
Reactant: CCCCOC(=O)CC(C)=O
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCCCOC(=O)c1c(C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Yield: 53 %

Procedure:
To a mixture of 2-amino-4,5,3',4'-tetramethoxybenzophenone, butyl acetoacetate and acetic acid, concentrated sulfuric acid was added, followed by the same treatment as in Reference Example 1, to yield 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-methylquinoline-3-carboxylic acid butyl ester (53%), which was then recrystallized from ethyl acetate-hexane to yield a colorless prismatic crystal having a melting point of 119° to 120° C.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][OH:24])=[C:17]3[C:13]=2[C:14]2[CH:28]=[C:27]([CH3:29])[CH:26]=[N:25][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].C(S(C1C=C(C2[C:46]3C4C=C(C)C=NC=4[NH:49][C:45]=3[C:44]([O:55]C[C@H](OC(=O)[C@H](C)N)C)=NC=2)C=CC=1)(=O)=O)C>>[NH2:49][C@@H:45]([CH3:46])[C:44]([O:24][CH2:23][CH2:22][O:21][C:18]1[CH:19]=[CH:20][C:12]([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:7]=2)=[C:13]2[C:17]=1[NH:16][C:15]1[N:25]=[CH:26][C:27]([CH3:29])=[CH:28][C:14]2=1)=[O:55]
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(OCCO)c3[nH]c4ncc(C)cc4c23)c1
Reactant: CCS(=O)(=O)c1cccc(-c2cnc(OC[C@@H](C)OC(=O)[C@H](C)N)c3[nH]c4ncc(C)cc4c23)c1
Product: CCS(=O)(=O)c1cccc(-c2ccc(OCCOC(=O)[C@H](C)N)c3[nH]c4ncc(C)cc4c23)c1

Procedure:
The title compound was prepared from Compound 215 by using an analogous procedure to that outlined in the preparation of Compound 64. 1H NMR (400 MHz, DMSO) δ ppm 1.18 (t, J=7.33 Hz, 3H) 1.40 (d, J=7.33 Hz, 3H) 2.27 (s, 3H) 3.42 (q, J=7.33 Hz, 2H) 4.20 (d, J=5.05 Hz, 1H) 4.53 (t, J=4.42 Hz, 2H) 4.58-4.69 (m, 2H) 7.12 (d, J=8.08 Hz, 1H) 7.23 (d, J=8.08 Hz, 1H) 7.55 (s, 1H) 7.87 (t, J=7.83 Hz, 1H) 8.00 (dd, J=12.63, 7.58 Hz, 2H) 8.08 (s, 1H) 8.29 (s, 1H) 8.33 (br. s., 2H) 11.95 (s, 1H) [M+H] calc'd for C25H27N3O5S, 482; found, 482.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH2:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.Cl[CH2:18][CH2:19][N:20]=[C:21]=[O:22]>C1COCC1>[O:22]1[CH2:18][CH2:19][N:20]=[C:21]1[NH:16][CH:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1
Reactant: O=C=NCCCl
Reactant: NC(Cc1ccc(F)cc1)c1ccccc1
Solvent: C1CCOC1
Product: Fc1ccc(CC(NC2=NCCO2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.6 %

Procedure:
A solution of 2-(4-fluoro-phenyl)-1-phenyl-ethylamine (1.50 g) in THF was treated dropwise with 2-chloroethyl isocyanate (0.89 g) at 0° C. After stirring overnight at room temperature the solvent was evaporated and the residue dissolved in dimethoxy ethane (25 ml). DBU (1,8-diazabicyclo[5.4.0]undec-7-en) was added (1.78 g) and the reaction mixture heated under reflux for 1 hour. Column chromatography on silica yielded 1.3 g of the title compound.