Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:33])/[CH:5]=[C:6](\[CH3:32])/[CH:7]=[CH:8]/[C@@H:9]1[CH2:11][C@@:10]1([C:13]1[CH:14]=[C:15]([C:24]2[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:31])[C:16]2[O:20][CH2:19][C:18]([CH3:22])([CH3:21])[C:17]=2[CH:23]=1)[CH3:12])C.C(O)C.[OH-].[Na+]>CCCCCC>[CH3:30][C:29]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:31])[C:24]=1[C:15]1[C:16]2[O:20][CH2:19][C:18]([CH3:22])([CH3:21])[C:17]=2[CH:23]=[C:13]([C@@:10]2([CH3:12])[CH2:11][C@H:9]2/[CH:8]=[CH:7]/[C:6](/[CH3:32])=[CH:5]/[C:4]([OH:33])=[O:3])[CH:14]=1
Reactant: CCOC(=O)/C=C(C)/C=C/[C@@H]1C[C@]1(C)c1cc(-c2c(C)cccc2C)c2c(c1)C(C)(C)CO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCO
Product: CC(/C=C/[C@@H]1C[C@]1(C)c1cc(-c2c(C)cccc2C)c2c(c1)C(C)(C)CO2)=C\C(=O)O

Procedure:
Following General Procedure H and using 5-{(1S, 2S)-2-[7-(2,6-dimethyl-phenyl)-3,3-dimethyl-2,3-dihydro-benzofuran-5-yl]-2-methyl-cyclopropyl}-3-methyl-penta-2E,4 Edienoic acid ethyl ester (Compound 23, 0.109 g, 0.24 mmol), ethanol (15 mL), and 5M aqueous sodium hydroxide (1 mL) followed by flash column chromatography using 25% in hexane as the eluent, and reverse phase HPLC, the title compound was obtained (0.049 g, 50%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[C:11]([OH:15])=[C:10]([CH3:16])[CH:9]=2)[N:4]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29]O)=[CH:23][N:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C(Cl)Cl>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][O:15][C:11]2[C:12]([CH3:14])=[CH:13][C:8]([C:5]3[N:4]=[C:3]([C:2]([F:17])([F:1])[F:18])[O:7][N:6]=3)=[CH:9][C:10]=2[CH3:16])=[CH:23][N:22]=1
Reactant: COc1ccc(CCCO)cn1
Reactant: Cc1cc(-c2noc(C(F)(F)F)n2)cc(C)c1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(CCCOc2c(C)cc(-c3noc(C(F)(F)F)n3)cc2C)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.8 %

Procedure:
To a suspension of 1.54 g (6 mmol) of 4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenol, 1.2 g (1.2 eq) of 2-methoxy-5-(3-hydroxypropyl)-pyridine, 1.9 g (1.2 eq) of triphenylphosphine in 50 ml of methylene chloride under nitrogen at 5° C. was added in portions 1.22 g (1.2 eq) of DEAD. The mixture was stirred at room temperature for 20 h, concentrated in vacuo, the residue was triturated with ether, and filtered. The crude product was purified by MPLC (50 id, Kreselgel 60 column, hexane/ethyl acetate, 3:1) to afford 2 g (82%) of 2-methoxy-5-[3-[4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]-propyl]-pyridine, as a clear oil, which upon recrystallization from isopropyl acetate/hexane afforded white powder, m.p. 62°-64° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:5]([S:14][CH3:15])=[C:4](Cl)[N:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[CH3:15][S:14][C:5]1[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:7][C:2]([C:29]2[CH:28]=[N:27][CH:26]=[CH:25][CH:30]=2)=[N:3][C:4]=1[C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Reactant: CSc1c(Cl)nc(Cl)nc1N1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CSc1c(-c2cccnc2)nc(-c2cccnc2)nc1N1CCOCC1
Temperature: 90 °C
Reaction time: 16 h
Yield: 22.1 %

Procedure:
A mixture of 4-(2,6-dichloro-5-methylsulfanyl-pyrimidin-4-yl)-morpholine (200 mg, 0.717 mmol.), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (323 mg, 1.577 mmol, 2.2 eq), (PPh3)4Pd (165 mg, 0.2 mmol.), 2M Na2CO3 (2.1 ml, 4.302 mmol, 6.0 eq.) and dioxane (20 ml) was added to a reaction vessel which was then flushed with argon. The reaction mixture was stirred at 90° C. for 16 hrs, and then dried. The solvent was removed by evaporation. The mixture was partitioned between EA and water. The organic layer was collected, washed with brine, dried over MgSO4, filtered and evaporated in vacuo. The resulting residue was purified using flash chromatography on silica gel (Hexane/EtOAc 2:3, few Et3N), recrystallized by (Hexane/EtOAc) to give a pale yellow solid 57.8 mg (22.1%).
Reaction SMILES: CS(Cl)(=O)=O.[NH2:6][C:7]1[S:11][N:10]=[C:9]([O:12][CH2:13][CH2:14][CH3:15])[C:8]=1[C:16]#[N:17].[CH3:18][N:19]([CH3:22])[CH:20]=O>>[C:16]([C:8]1[C:9]([O:12][CH2:13][CH2:14][CH3:15])=[N:10][S:11][C:7]=1[N:6]=[CH:18][N:19]([CH3:22])[CH3:20])#[N:17]
Reactant: CN(C)C=O
Reactant: CCCOc1nsc(N)c1C#N
Agent: CS(=O)(=O)Cl
Product: CCCOc1nsc(N=CN(C)C)c1C#N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 13.7 g of methanesulfonyl chloride in 25 ml of dimethylformamide was stirred at room temperature for about 16 hours. Into the mixture was stirred 11 g of 5-amino-4-cyano-3-propoxyisothiazole which addition caused an exothermic reaction. The mixture was concentrated under reduced pressure and the residue was recrystallized from ethanol to give 2.7 g of crystalline N'-(4-cyano-3-propoxy-5-isothiazolyl)-N,N-dimethylformamidine, m.p. 117°-118°. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:13][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[N:9]=1.[C:19]([O:23][C:24]([NH:26][CH2:27][C:28](O)=[O:29])=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24]([NH:26][CH2:27][C:28]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:13][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[N:9]=1)=[O:29])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: Nc1ccccc1-c1nc2ccccc2c(=O)o1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Product: CC(C)(C)OC(=O)NCC(=O)Nc1ccccc1-c1nc2ccccc2c(=O)o1

Procedure:
Using identical reaction conditions as described for the synthesis of the compounds of formula VII of Scheme 2 above, 480 mg (2.0 mmole) of 2-(2-aminophenyl)-3,1-benzoxazin-4-one was reacted with 525 mg (3.0 mmole) of tert-butyloxycarbonylglycine to give 170 mg of the chromatographically-homogeneous tilted compound in 60% overall yield after three cycles.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1>CN(C=O)C.ClCCl>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[CH:17]=3)[N:12]([CH2:37][O:38][C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=3)[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(CN3CCOCC3)cc2c1O
Reactant: ClCOc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1cn(COc2ccc(Cl)cc2)c2ccc(CN3CCOCC3)cc2c1=O
Temperature: 100 °C
Yield: 71 %

Procedure:
A suspension of N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (0.21 gm) from Preparation No. 40 and cesium carbonate (0.33 gm) in DMF (2 mL) is treated with α,4-dichloroanisole (0.13 gm). The mixture is tightly capped and heated to 100° C. for 3 hrs. The reaction mixture is allowed to cool to room temperature, diluted with dichloromethane (50 mL) and washed with water. The aqueous phase is extracted with two additional portions of dichloromethane. The combined organic phase is washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The crude product is purified by flash column chromatography eluting with 1% to 4% methanol in dichloromethane and then by recrystallization with acetonitrile to afford 0.20 gm of the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]([F:24])([F:23])[C:13]1[CH:14]=[C:15]([NH2:22])[C:16](=[CH:20][CH:21]=1)[C:17](O)=[O:18]>>[F:11][C:12]([F:23])([F:24])[C:13]1[CH:14]=[C:15]2[C:16]([C:17](=[O:18])[N:6]3[C:5]4[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=4[NH:3][C:2]3=[N:22]2)=[CH:20][CH:21]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: Nc1cc(C(F)(F)F)ccc1C(=O)O
Product: O=c1c2ccc(C(F)(F)F)cc2nc2[nH]c3ccccc3n12

Procedure:
3-Trifluoromethylbenzimidazo[2,1-b]quinazolin-12(6H)one is prepared with 2-chlorobenzimidazole and 4-trifluoromethyl-anthranilic acid.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4](=[O:11])[C:5]2[C:6](=[CH:8][S:9][CH:10]=2)[N:7]=1.[Cl:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15]>C(O)(=O)C>[Cl:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH:15][C:4]([C:5]1[C:6]([NH:7][C:2](=[O:3])[CH3:1])=[CH:8][S:9][CH:10]=1)=[O:11]
Reactant: Cc1nc2cscc2c(=O)o1
Reactant: Nc1ccccc1Cl
Solvent: CC(=O)O
Product: CC(=O)Nc1cscc1C(=O)Nc1ccccc1Cl

Procedure:
To a slurry of 2-methyl-thieno[3,4-d][1,3]oxazin-4-one (1.3 g, 7.78 mmol) and acetic acid (15 mL) was added 2-chloroaniline (1.64 mL, 15.57 mmol). The mixture was refluxed 4 hours, cooled, and concentrated. The residue was partitioned between ethyl acetate and water and the aqueous phase was made basic by careful addition of saturated aqueous sodium bicarbonate. The phases were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over sodium sulfate and concentrated to a black oil. The oil was flash chromatographed on silica gel (30×100 mm) eluting with 10% ethyl acetate/hexane. The first component eluting from the column, 0.363 g of white solid was identified as 3-acetamidothiophene-4-carboxylic acid 2-chlorophenylamide.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][N:3]=1.[CH2:11](O)[CH3:12]>>[CH2:11]([O:9][C:8]([C:5]1[CH:6]=[CH:7][N:2]=[N:3][CH:4]=1)=[O:10])[CH3:12]
Reactant: CCO
Reactant: O=C(O)c1ccnnc1
Agent: Cl
Product: CCOC(=O)c1ccnnc1
Yield: 49 %

Procedure:
In a 250 mL round bottom flask, 1 mL concentrated HCl and 70 mL ethanol was added to pyridazine-4-carboxylic acid (3.78 g, 30.4 mmol). The mixture was refluxed overnight. The reaction was 80% complete based on HPLC. The reaction mixture was concentrated down. The residue was purified (silica gel, 2-10% MeOH/DCM) to give light yellow oil (1.8 g, 49%). 1H NMR (300 MHz, CD3OD): δ 9.62 (s, 1H), 9.43 (d, 1H), 8.08 (d, 1H), 4.52 (dd, 2H), 1.43 (t, 3H).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[Br:7].[F:8][C:9]1[C:14]([Sn](CCCC)(CCCC)CCCC)=[CH:13][CH:12]=[CH:11][N:10]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN1CCCC1=O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:7][C:6]1[CH:5]=[CH:4][S:3][C:2]=1[C:14]1[C:9]([F:8])=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: Brc1ccsc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Fc1ncccc1-c1sccc1Br
Temperature: 75 °C
Reaction time: 3 h
Yield: 40.7 %

Procedure:
A mixture of 2,3-dibromothiophene (2.86 g), 2-fluoro-3-tributylstannylpyridine (3.93 g), Pd(Ph3P)2Cl2 (0.153 g) in N-methylpyrrolidinone (25 mL) was heated at 75° C. under argon for 3.5 hours. Tetrabutylammonium fluoride (1M in tetrahydrofuran, 10 mL) was added and the mixture was stirred for 3 hours. The mixture was diluted with ethyl acetate, washed with water, dried, filtered and evaporated. Chromatography of the residue over silica gel gave 3-bromo-2-(2-fluoropyridin-3-yl)thiophene (1.07 g) as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:9][C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)[CH:7]=[N:8][C:4]=2[C:3]=1[N+:18]([O-:20])=[O:19].Cl.Cl[CH2:23][C:24]1C2C(=CC=CC=2)N=[CH:26][CH:25]=1>>[CH3:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:9][C:10]3[C:11]4[C:12](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:13]=[CH:14][CH:15]=3)[CH:7]=[N:8][C:4]=2[C:3]=1[N+:18]([O-:20])=[O:19]
Reactant: ClCc1ccnc2ccccc12
Reactant: Cc1ccc2c(ncn2Cc2ccncc2)c1[N+](=O)[O-]
Agent: Cl
Product: Cc1ccc2c(ncn2Cc2ccnc3ccccc23)c1[N+](=O)[O-]

Procedure:
Compound 5a was synthesized in the same manner as compound 2c using 4-chloromethylquinoline hydrochloride instead of 4-chloromethylpyridine hydrochloride.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:21])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[CH:11]=[C:10]([CH3:21])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:26]4[CH:27]=[CH:28][C:23]([NH2:22])=[N:24][CH:25]=4)[CH:7]=[CH:6][CH:5]=3)[N:13]=2)=[CH:15][CH:16]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(-c2cccc(Br)c2)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-c2cccc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-(4-chloro-phenyl)-6-methyl-pyrimidine (example E.44) (0.18 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as a white solid (0.090 g, 48%). MS (ISP) 373.0 [(M+H)+]; mp 168.5° C.
Reaction SMILES: [CH3:1][NH2:2].[C:3]([O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]2[C@H:13]3[C@H:22]([CH2:23][CH2:24][C@:8]12[CH3:9])[C:21]1[CH:20]=[CH:19][C:18]([O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:17][C:16]=1[CH2:15][C@H:14]3[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]OS(C1C=CC(C)=CC=1)(=O)=O)(=[O:5])[CH3:4]>O1CCCC1>[C:3]([O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]2[C@H:13]3[C@H:22]([CH2:23][CH2:24][C@:8]12[CH3:9])[C:21]1[CH:20]=[CH:19][C:18]([O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:17][C:16]=1[CH2:15][C@H:14]3[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:2][CH3:1])(=[O:5])[CH3:4]
Reactant: CN
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3[C@H](CCCCCOS(=O)(=O)c4ccc(C)cc4)Cc4cc(OC5CCCCO5)ccc4[C@H]3CC[C@]12C
Solvent: C1CCOC1
Product: CNCCCCC[C@@H]1Cc2cc(OC3CCCCO3)ccc2[C@H]2CC[C@]3(C)[C@@H](OC(C)=O)CC[C@H]3[C@H]12
Yield: 79.8 %

Procedure:
6.3 g of methylamine is condensed in a pressure pipe while being cooled with ice in a solution of 8.2 g of 17β-acetoxy-3-(tetrahydropyran-2-yloxy)-7α-(5-p-toluenesulfonyloxypentyl)-estra-1,3,5(10)-triene in 80 ml of tetrahydrofuran. The closed pressure pipe is then heated for 6 hours to 60° C. After cooling, it is evaporated to dryness in a vacuum, and the residue is chromatographed on silica gel. 5.1 g of 17β-acetoxy-7α-(5-methylaminopentyl)-3-(tetrahydropyran-2-yloxy)-estra-1,3,5(10)-triene is obtained as an oil. [α]D=+29.7° (c=0.535% in chloroform)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]([O:16][CH3:17])([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:41][C:42]1[N:46]2[C:47](=[O:56])[N:48]([CH:50]3[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]3)[CH2:49][C:45]2=[CH:44][N:43]=1>C(#N)C.C(N(CC)CC)C>[CH3:17][O:16][C:13]([CH3:15])([CH3:14])[CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]([N:53]1[CH2:52][CH2:51][CH:50]([N:48]2[CH2:49][C:45]3=[CH:44][N:43]=[C:42]([CH3:41])[N:46]3[C:47]2=[O:56])[CH2:55][CH2:54]1)=[O:12]
Reactant: COC(C)(C)C(NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1ncc2n1C(=O)N(C1CCNCC1)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(C)(C)C(NC(=O)OC(C)(C)C)C(=O)N1CCC(N2Cc3cnc(C)n3C2=O)CC1
Yield: 99 %

Procedure:
2-((tert-butoxycarbonyl)amino)-3-methoxy-3-methylbutanoic acid (0.20 g) obtained in Example 73c) was dissolved in acetonitrile (10 ml). HOBt (0.19 g), WSC (0.24 g), triethylamine (0.16 ml) and 5-methyl-2-(4-piperidinyl)-1,2-dihydro-3H-imidazo[1,5-c]imidazol-3-one dihydrochloride (0.24 g) were added thereto, and mixed at room temperature for 15 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with a saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a colorless oil (0.36 g, 96%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.O1CCCC1.[CH:23]1([Mg]Cl)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>CCOCC>[CH:23]1([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]4[CH2:17][CH2:16]4)=[O:14])[N:8]=[CH:9]3)=[CH:4][CH:3]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: Cl[Mg]C1CCCCC1
Reactant: O=C(Nc1cc2ccc(Br)cc2cn1)C1CC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(Nc1cc2ccc(C3CCCCC3)cc2cn1)C1CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 19 %

Procedure:
To a solution of N-(7-bromoisoquinolin-3-yl)cyclopropanecarboxamide (131.8 mg, 0.4527 mmol) in tetrahydrofuran (6.0 mL, 74 mmol) in an oven-dried flask at 0° C. was added DPPPNiCl2 (18.2 mg, 0.0336 mmol) followed by 2.0 M of cyclohexylmagnesium chloride in ether (0.60 mL). The reaction was stirred at 0° C. for 1.5 hours and then heated at 40° C. overnight. DPPPNiCl2 (21 mg) and 2.0 M of cyclohexylmagnesium chloride in ether (0.60 mL) were added. The reaction was heated at 50° C. for an additional 3.5 hours. The mixture was then partitioned between ethyl acetate and water, and the organic layer was washed with water and brine, dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via reverse phase HPLC and lyophilized to yield 24.8 mg (19%) of N-(7-cyclohexylisoquinolin-3-yl)cyclopropanecarboxamide. LCMS (ESI): RT (min)=5.228, M+H=295.1, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 9.06 (s, 1H), 8.40 (s, 1H), 7.82 (s, 1H), 7.77 (d, J=8.6 Hz, 1H), 7.61 (dd, J=8.6, 1.7 Hz, 1H), 2.67 (t, J=11.7 Hz, 1H), 2.10-1.99 (m, 1H), 1.93-1.79 (m, 4H), 1.74 (d, J=12.3 Hz, 1H), 1.58-1.20 (m, 5H), 0.82 (dq, J=4.9, 2.9 Hz, 4H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:6][C:5]=1[O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[O:3].[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1.CO.[OH-].[Na+]>C(OCC)(=O)C>[F:21][C:18]([F:19])([F:20])[CH2:17][O:16][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])=[CH:9][C:4]=1[C:2](=[O:3])[CH:1]=[CH:27][C:26]1[CH:29]=[CH:30][C:23]([Cl:22])=[CH:24][CH:25]=1
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(C=Cc1ccc(Cl)cc1)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
The title compound was prepared by stirring a mixture of 2,5-bis(2,2,2-trifluoroethoxy)acetophenone (200 mg, 0.633 mmol), 4-chlorobenzaldehyde (89 mg, 0.633 mmol), methanol (5 ml) and saturated NaOH (200 ul) at room temperature for 4 h. The mixture was diluted with ethyl acetate (100 ml), wash with water (50 ml) and saturated aqueous NaCl (50 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography using hexane:ethyl acetate (5:1, 4:1) to give a yellow solid (143 mg, 51%). 1H NMR (CDCl3): 7.65 (d, J=15.9 Hz, 1H), 7.54 (d, J=8.4 Hz, 2H), 7.44 (d, J=15.9 Hz, 1H), 7.38 (d, J=8.4 Hz, 2H), 7.31 (d, J=3.3 Hz, 1H), 7.14 (dd, J=3.3, 9.3 Hz, 1H), 6.95 (d, J=9.0 Hz, 1H), 4.45-4.32 (m, 4H).
Reaction SMILES: Br[CH:2]([CH3:15])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][N:6]=1)=[O:4].[NH:16]1[CH:20]=[N:19][CH:18]=[N:17]1.[Na]>C(#N)C.C(OCC)(=O)C>[N:16]1([CH:2]([CH3:15])[C:3]([C:5]2[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][N:6]=2)=[O:4])[CH:20]=[N:19][CH:18]=[N:17]1
Reactant: c1nc[nH]n1
Reactant: CC(Br)C(=O)c1ccc(C(F)(F)F)cn1
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C(=O)c1ccc(C(F)(F)F)cn1)n1cncn1
Reaction time: 1.5 h

Procedure:
To a solution of 2-(2-bromopropionyl)-5-trifluoromethyl-pyridine (5.8 g.) in acetonitrile (65 ml.) was added sodium 1,2,4-triazole (2.0 g.) and the solution was stirred for 90 minutes. The acetonitrile was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, dried over magnesium sulphate and concentrated to dryness under reduced pressure to give a yellow gum. Chromatography on silica, using petroleum ether (bp (60°-80°): ethyl acetate 60/40 v/v as eluent, gave 2-[2-(1,2,4-triazol-1-yl)propionyl]-5-trifluoromethylpyridine as a pale yellow oil. Nmr in deuteriochloroform: δ1.88 (3H, d); 6.62 (1H, q); 7.9 (1H, s); 8.14 (2H, m); 8.36 (1H, s); 8.94 (1H, d).
Reaction SMILES: [F:1][C:2]1([F:11])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[O:3]1.CN(CCN(C)C)C.C([Li])CCC.[CH2:25]([O:27][C:28](=[O:36])[C:29](=[CH:32]OCC)[C:30]#[N:31])[CH3:26]>C1(C)C=CC=CC=1.O>[CH2:25]([O:27][C:28](=[O:36])/[C:29](/[C:30]#[N:31])=[CH:32]/[C:10]1[C:4]2[O:3][C:2]([F:1])([F:11])[O:6][C:5]=2[CH:7]=[CH:8][CH:9]=1)[CH3:26]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: FC1(F)Oc2ccccc2O1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)/C(C#N)=C/c1cccc2c1OC(F)(F)O2

Procedure:
40.0 g (253 mmol) of 2,2-difluoro-1,3-benzodioxole in 29.5 g (254 mmol) of TMEDA and 35 ml of toluene are metallated analogously to Example 2c) at from -15° to -10° C. with 106.2 g (307 mmol) of n-butyllithium solution (18.5% in toluene). 52.1 g (308 mmol) of ethoxymethylenecyanoacetic acid ethyl ester in 115 ml of toluene are added to the reaction mixture at from -15° to -10° C. over a period of 2 hours. The resulting suspension is poured, after 20 minutes at +10° C., into 350 ml of water, the aqueous phase is separated off and the organic phase is concentrated by evaporation in a vacuum rotary evaporator to yield the desired product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8].[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1.ClCCl>[C:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:15][C:10]([S:7]([NH:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:22](=[O:24])[CH3:23])(=[O:9])=[O:8])=[CH:11][CH:12]=1
Reactant: NCCCCNS(=O)(=O)c1ccc(-c2ccccc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NCCCCNS(=O)(=O)c1ccc(-c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
Biphenyl-4-sulfonic acid (4-amino-butyl)amide (1 g) was suspended in a mixture of acetic anhydride (45 mL) and pyridine (15 mL) and stirred at 80° C. for 4 hours. The solution was left to stir overnight and then poured into ice water. The aqueous mixture was extracted with dichloromethane, dried (Na2SO4) and evaporated to give a brown oil. The oil was redissolved in dichloromethane and the title compound precipitated as a white solid by addition of a small amount of petrol. δC (CDCl3, 62.9 MHz): 23.2, 26.6, 26.8, 39.1, 42.9, 127.3, 127.6, 127.8, 128.5, 129.1, 138.4, 139.3, 145.6 and 170.9.