Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[C:12]2[C:21]3[C:20](=[O:22])[N:19]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)[C:18](=[O:32])[N:17]([C:33]4[CH:38]=[CH:37][C:36]([I:39])=[CH:35][C:34]=4[F:40])[C:16]=3[N:15]([CH3:41])[C:14](=[O:42])[C:13]=2[CH3:43])(=O)=O)=CC=1.N1C(C)=CC=CC=1C.[NH2:52][C:53]1[CH:54]=[C:55]([CH:59]=[CH:60][CH:61]=1)[C:56]([OH:58])=[O:57].O>CC(N(C)C)=O>[F:40][C:34]1[CH:35]=[C:36]([I:39])[CH:37]=[CH:38][C:33]=1[N:17]1[C:16]2[N:15]([CH3:41])[C:14](=[O:42])[C:13]([CH3:43])=[C:12]([NH:52][C:53]3[CH:54]=[C:55]([CH:59]=[CH:60][CH:61]=3)[C:56]([OH:58])=[O:57])[C:21]=2[C:20](=[O:22])[N:19]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[C:18]1=[O:32]
Reactant: COc1ccc(Cn2c(=O)c3c(OS(=O)(=O)c4ccc(C)cc4)c(C)c(=O)n(C)c3n(-c3ccc(I)cc3F)c2=O)cc1
Reactant: Nc1cccc(C(=O)O)c1
Solvent: CC(=O)N(C)C
Solvent: Cc1cccc(C)n1
Solvent: O
Product: COc1ccc(Cn2c(=O)c3c(Nc4cccc(C(=O)O)c4)c(C)c(=O)n(C)c3n(-c3ccc(I)cc3F)c2=O)cc1
Temperature: 130 °C
Yield: 73.5 %

Procedure:
To a stirred solution of 1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl 4-methylbenzene sulfonate (2a) (2.0 gm, 2.79 mmol) in DMA (5 ml) was added 2,6-lutidine (0.98 ml, 8.36 mmol) and 3-aminobenzoic acid (1.147 gm, 8.36 mmol). The reaction mixture was heated at 130° C. for 16 h. The reaction mixture was cooled to room temperature and water was added followed by extraction with Ethyl acetate. The organic phase was dried over sodium sulphate. The solvent was evaporated in vacuo and the residual solid was purified by silica gel column chromatography, eluting with Hexane:Ethyl acetate (1:1), to yield the titled compound (2b) (1.4 g)
Reaction SMILES: Br[CH2:2][CH2:3][S:4][C:5]1[S:6][C:7]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:9]=1.[OH-:26].[K+]>O>[OH:26][CH2:2][CH2:3][S:4][C:5]1[S:6][C:7]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:9]=1
Reactant: COc1ccc(-c2nc(SCCBr)sc2-c2ccc(OC)cc2)cc1
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: COc1ccc(-c2nc(SCCO)sc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.2 g of 2-(2-bromoethylthio)-4,5-bis-(p-methoxyphenyl)-thiazole are dissolved in 10 ml of polyethylene glycol, 0.5 ml of water and 0.5 g of potassium hydroxide are added, the mixture is heated at 120° for 30 minutes, cooled to room temperature, diluted with 50 ml of water and left to stand at +5° for 2 hours. The precipitated crystals are filtered off and recrystallised from diethyl ether/hexane. 2-(2-Hydroxyethylthio)-4,5-bis-(p-methoxyphenyl)-thiazole having a melting point of 82°-83° is obtained.
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[CH2:6][CH2:5][C:4]2([C:18]3[CH:17]=[N:16][NH:15][C:14]=3[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[O:7]2)[CH2:3][CH2:2]1>CO.[Pd]>[NH:1]1[CH2:6][CH2:5][C:4]2([C:18]3[CH:17]=[N:16][NH:15][C:14]=3[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[O:7]2)[CH2:3][CH2:2]1
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)Oc1ccccc1-c1[nH]ncc12
Agent: [Pd]
Solvent: CO
Product: c1ccc2c(c1)OC1(CCNCC1)c1cn[nH]c1-2
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.8 %

Procedure:
A mixture of benzyl spiro[1H-chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxylate (1.11 g, 2.96 mmol) and palladium (10% wt on carbon, 157 mg, 0.15 mmol) in MeOH (15 mL) was set under hydrogen (1 atm) and stirred vigorously at room temperature for 3 hours. The reaction mixture was filtered through Celite and the filtrate was concentrated to afford 1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] (570 mg, 80%). ESI-MS m/z calc. 241.1, found 242.5 (M+1)+; Retention time: 0.42 minutes (3 min run).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[N:8]([C:9](=[O:19])[C:10]=1C1C=CC(C#N)=CC=1)[C:7]1[CH:20]=[CH:21][CH:22]=[CH:23][C:6]=1[S:5]2.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.O>[CH3:1][C:2]1[N:3]=[C:4]2[N:8]([C:9](=[O:19])[C:10]=1[C:29]1[CH:30]=[CH:31][C:26]([C:25]([F:36])([F:35])[F:24])=[CH:27][CH:28]=1)[C:7]1[CH:20]=[CH:21][CH:22]=[CH:23][C:6]=1[S:5]2
Reactant: Cc1nc2sc3ccccc3n2c(=O)c1-c1ccc(C#N)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nc2sc3ccccc3n2c(=O)c1-c1ccc(C(F)(F)F)cc1
Yield: 107.8 %

Procedure:
The title compound was prepared by treatment of Step 2 intermediate, Intermediate 22 (2.0 g, 5.845 mmol) with 4-trifluoromethylphenylboronic acid (1.50 g, 8.18 mmol) in the presence of Pd[(C6H5)3P]4 (270 mg, 0.233 mmol) and sodium carbonate (3.71 g, 35.07 mmol) in a mixture of toluene, ethanol and water to afford 2.27 g of the desired product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 2.30 (s, 3H), 7.42-7.48 (m, 2H), 7.65-7.67 (m, 2H), 8.00-8.03 (m, 2H), 8.86-8.88 (m, 2H); ESI-MS (m/z) 361.32 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:19][CH2:20][O:21][CH3:22])=[C:7]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:12]=3[N:13]=2)[CH:8]=1.[Br:23]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:23][CH2:18][C:14]1[C:12]2[N:13]=[C:9]([C:7]3[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[O:19][CH2:20][O:21][CH3:22])[O:10][C:11]=2[CH:17]=[CH:16][CH:15]=1
Reactant: COCOc1ccc(OC)cc1-c1nc2c(C)cccc2o1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COCOc1ccc(OC)cc1-c1nc2c(CBr)cccc2o1
Temperature: 0 °C
Yield: 76.4 %

Procedure:
A mixture of 2-(5-methoxy-2-methoxymethoxyphenyl)-4-methylbenzoxazole (F8) (1.78 g, 5.95 mmol), N-bromosuccinimide (1.01 g, 5.95 mmol), and AIBN (82 mg, 0.5 mmol) in CCl4 (100 mL) was refluxed for 15 h under dry N2 gas flowing. The reaction mixture was cooled to 0° C., the precipitation was removed by filtration maintaining the temperature. After the solvent was evaporated, the residue was washed with small amount of ethanol several times to afford a pinkish solid (1.72 g, 76%). 1H-NMR (500 MHz, CDCl3) δ3.57 (s, 3H), 3.88 (s, 3H), 4.96 (s, 2H), 5.27 (s, 2H), 7.05 (dd, 1H, J=8.5, 3.0 Hz), 7.22 (d, 1H, J=8.5 Hz), 7.34 (t, 1H, J=8.0 Hz), 7.42 (d, 1H, J=8.0 Hz), 7.54 (d, 1H, J=8.0 Hz), 7.66 (d, 1H, J=3.0 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([CH2:27][N:28]3[C:32](=[O:33])[CH2:31][CH2:30][C:29]3=[O:34])=[CH:24][CH:25]=2)[N:20]=[C:19]([C:35]#[N:36])[CH:18]=1>O1CCOCC1.O.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>[O:33]=[C:32]1[CH2:31][CH2:30][C:29](=[O:34])[N:28]1[CH2:27][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:18][C:19]([C:35]#[N:36])=[N:20]2)=[CH:25][CH:24]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: N#Cc1cc(Cl)c2ccc(CN3C(=O)CCC3=O)cc2n1
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
Solvent: O
Product: N#Cc1cc(-c2ccc(F)cc2)c2ccc(CN3C(=O)CCC3=O)cc2n1
Temperature: 100 °C

Procedure:
To a room temperature solution of 4-fluorophenylboronic acid (5.96 g, 42.6 mmol, 1.2 equiv.) in dioxane:water (10:1, 177 mL, 0.2 M) was added sodium bicarbonate (5.96 g, 71.0 mmol, 2.0 equiv.), 4-chloro-7-[(2,5-dioxopyrrolidin-1-yl)methyl]quinoline-2-carbonitrile (2-5, 10.6 g, 35.5 mmol), and Pd(PPh3)4 (4.1 g, 3.55 mmol, 0.1 equiv.). The resulting mixture was warmed to 100° C. for 4 hr. The reaction was then cooled to 0° C. and a precipitate formed. The solids were then collected by vacuum filtration and washed with water and cold acetonitrile to afford 7-[(2,5-dioxopyrrolidin-1-yl)methyl]-4-(4-fluorophenyl)quinoline-2-carbonitrile (2-6) which was taken to the next step without further purification. 1H NMR (400 MHz, CDCl3): δ 8.115 (d, J=1.10 Hz, 1H); 7.897 (d, J=8.79 Hz, 1H); 7.655 (dd, J1=8.79 Hz, J2=1.83 Hz, 1H); 7.603 (s, 1H); 7.439-7.475 (m, 2H); 7.243-7.286 (m, 2H); 4.909 (s, 2H); 2.796 (s, 4H). LRMS m/z (M+H)+ 360.3 found, 360.1 required.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][C:12]([OH:14])=[O:13])[NH:3]1.[C:15]1(C)C=CC(S(O)(=O)=O)=C[CH:16]=1>C(O)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:3]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)CC1NC(=O)c2ccccc21
Solvent: CCO
Product: CCOC(=O)CC1NC(=O)c2ccccc21
Reaction time: 4 h

Procedure:
A solution of 2,3-dihydro-3-oxo-1H-isoindole-1-acetic acid (described by F. M. Rowe et al., cited above, 2.0 g) in ethanol (40 ml) containing p-toluene-sulfonic acid (0.10 g) is refluxed with stirring for 4.0 hr. Most of the ethanol is evaporated and the residue is dissolved in chloroform. The solution is washed with water, dried and evaporated. The residue (2.2 g) is crystallized from benzenehexane to give ethyl 1,3-dihydro-3-oxo-2H-isoindole-1-acetate, mp 116°-118° C.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:12][C:13]([F:24])([F:23])[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][NH2:22])=[CH:17][CH:16]=1>CCO>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[N:22][NH:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][C:13]([F:12])([F:24])[F:23])=[CH:16][CH:17]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NNc1ccc(OC(F)(F)F)cc1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: CCO
Product: O=[N+]([O-])c1ccc(C=NNc2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a magnetically stirred solution of 4-nitrobenzaldehyde (1.57 g, 10.41 mmoL) dissolved in EtOH (21 mL) was added (4-(trifluoromethoxy)phenyl)-hydrazine (2 g, 10.41 mmoL) and the reaction was stirred at room temperature overnight. The solvent was concentrated under reduced pressure and dried under high vacuum to give the title compound as a mixture of E and Z-isomers (3.35 g, 99%): 1H NMR (400 MHz, CDCl3) δ 10.17 (s, 1H), 8.40 (d, J=8.6 Hz, 2H, isomer A), 8.24 (d, J=8.6 Hz, 2H, isomer B), 8.08 (d, J=8.7 Hz, 2H, isomer A), 7.79-7.74 (m, 4H, mixture of isomers A & B), 7.19-7.13 (m, 6H, mixture of isomers A & B); 19F NMR (376 MHz, CDCl3) δ −58.34; ESIMS m/z 325 ([M+H])+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:15])[N:5]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:7]=1.[C:16]([OH:35])(=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([CH3:15])[N:5]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:7]=1.[C:16]([O-:35])(=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: Cc1cc(C)nc(Nc2ccccc2)n1
Solvent: Cc1ccccc1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)[O-]
Reaction time: 8 h

Procedure:
A solution of pyrimethanil (1.0 g), toluene (50 ml) and oleic acid (1.42 g) was allowed to stand overnight at room temperature. The toluene was evaporated under reduced pressure to give pyrimethanil oleate, as an oil. (compound 1) nmr data:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH:29]=[CH:28][C:27]4[C:26]([CH3:31])([CH3:30])[CH2:25][CH2:24][C:23]([CH3:33])([CH3:32])[C:22]=4[CH:21]=3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH:29]=[CH:28][C:27]4[C:26]([CH3:31])([CH3:30])[CH2:25][CH2:24][C:23]([CH3:33])([CH3:32])[C:22]=4[CH:21]=3)[N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)n2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)n2)CC1

Procedure:
52 mg (0.11 mmol) of 6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-3′,6′-dihydro-2′H-2,4′-bipyridinyl-1′-carboxylic acid tert-butyl ester are dissolved in 20 ml of ethanol and hydrogenated using a Pd/C cartridge (10%, 30×4 mm) in an H Cube (Thales Nanotechnology). The solvent is subsequently distilled off.
Reaction SMILES: Cl[C:2]1[C:3]([F:24])=[CH:4][C:5]2[C:6]([CH:23]=1)=[N:7][C:8]1[N:9]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>N1C=CC=CC=1>[F:24][C:3]1[C:2]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:23][C:6]2=[N:7][C:8]3[N:9]([C:19]([CH3:20])([CH3:21])[CH3:22])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=3[CH:14]=[C:5]2[CH:4]=1
Reactant: C1CNCCN1
Reactant: CC(C)(C)n1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Solvent: c1ccncc1
Product: CC(C)(C)n1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCNCC4)cc3nc21
Yield: 64.4 %

Procedure:
7-Fluoro-4-oxo-8-(1-piperazinyl)-1-tert.-butyl-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is prepared under the conditions of Reference Example 5 but starting from 1.7 g of 8-chloro-7-fluoro-4-oxo-1-tert.-butyl-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid and 4.3 g of piperazine in 20 cm3 of pyridine. The pure product is obtained after a single recrystallization from 20 cm3 of dimethylformamide. 1.25 g of 7-fluoro-4-oxo-8-(1-piperazinyl)-1-tert.-butyl-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid are isolated in the form of a yellow solid melting at 90° C., solvated by 4.5% of water.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20](O)=[O:21])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[NH2:30][N:31]1[CH2:36][CH2:35][N:34]([CH3:37])[C:33](=[O:38])[CH2:32]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([C:20]([NH:30][N:31]3[CH2:36][CH2:35][N:34]([CH3:37])[C:33](=[O:38])[CH2:32]3)=[O:21])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:6][CH:7]=1
Reactant: CN1CCN(N)CC1=O
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(NC(=O)c2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)CC1=O

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAN 1018782-82-5) and 4-amino-1-methyl-piperazin-2-one trifluoroacetate (1:1) as starting materials; LC-MS (UV peak area/ESI) 94.7%, 443.1084 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([O:7][C:8]([NH:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:9])([CH3:6])[CH3:5].[CH3:16]I>CCCCCC.C1COCC1>[C:4]([O:7][C:8]([N:10]([CH3:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:9])([CH3:3])([CH3:5])[CH3:6]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN(CCC(=O)O)C(=O)OC(C)(C)C
Yield: 101.8 %

Procedure:
60% NaH in mineral oil (0.528 g, 13.21 mmol) was washed with hexane (2×10 mL). It was suspended in dry THF (6 mL) and cooled to 0° C. before BOC-BETA-ALA-OH (1 g, 5.29 mmol) in dry THF (6 mL) was added. MeI (0.823 mL, 13.21 mmol) in dry THF (6 mL) was dropwise added after 5 min. and the resulting suspension was stirred at 0° C. to room temperature over the weekend. The reaction mixture was quenched with ice cold H2O (50 mL) and washed with Et2O (25 mL). The aqueous layer was acidified with concentrated aqueous HCl (3 mL) and extracted with EtOAc (3×20 mL). The combined EtOAc extracts were dried (Na2SO4) and concentrated to afford the desired product (1.095 g, quantitative) as a yellow oil.
Reaction SMILES: C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=1.[NH:31]1[CH2:36][CH2:35][C:34](=[O:37])[CH2:33][C:32]1=[O:38]>CN(C)C=O.ClCCl>[F:29][C:19]([F:18])([F:30])[C:20]1[CH:21]=[CH:22][C:23]([C:24]([CH:33]2[C:34](=[O:37])[CH2:35][CH2:36][NH:31][C:32]2=[O:38])=[O:26])=[CH:27][CH:28]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C1CCNC(=O)C1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCNC(=O)C1C(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 15.4 %

Procedure:
Dry triethylamine (3.24 g) was added at 0°-5° C. to a stirred solution of diethyl cyanophosphate (1.96 g), 4-trifluoromethylbenzoic acid (2.28 g) and piperidine-2,4-dione (1.13 g) in dry dimethylformamide (50 ml) and the mixture stirred at ambient temperature for 5 hours. The mixture was diluted with dichloromethane (70 ml) and the solution washed successively with 2N hydrochloric acid (70 ml) and water (5×30 ml). The dichloromethane solution was dried over magnesium sulphate and evaporated under reduced pressure to give a brown solid which was recrystallised from toluene (11 ml) to give 3-(4-trifluoromethylbenzoyl)piperidine-2,4-dione (0.44 g), mp 197°-200° C., as a pale green crystalline solid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][O:12][C:13]([CH:15]1[C:23]2[C:18](=[CH:19][C:20]([Br:24])=[CH:21][CH:22]=2)[CH2:17][CH2:16]1)=[O:14].I[CH3:26]>C1COCC1>[CH3:11][O:12][C:13]([C:15]1([CH3:26])[C:23]2[C:18](=[CH:19][C:20]([Br:24])=[CH:21][CH:22]=2)[CH2:17][CH2:16]1)=[O:14]
Reactant: COC(=O)C1CCc2cc(Br)ccc21
Reactant: CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(C)CCc2cc(Br)ccc21
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 95.3 %

Procedure:
Lithium bis(trimethylsilyl)amide (6.16 ml, 6.16 mmol, 1M solution in THF) was added dropwise to a solution of (rac)-5-bromo-indan-1-carboxylic acid methyl ester (1.31 g, 5.14 mmol) in dry THF (25 ml) at −78° C. After the addition was completed, the solution was stirred at −78° C. for 45 minutes. Then, iodomethane (2.19 g, 959 μl, 15.4 mmol) was added, the solution was allowed to warm to room temperature and stirred for 48 h. The reaction was quenched by addition of sat. NH4Cl solution and extracted two times with EtOAc. The combined organic layers were washed with brine, dried with Na2SO4 and evaporated. The remaining yellow oil was purified by chromatography (silica gel; heptane/EtOAc 95:5) to obtain the title compound as yellow oil (1.319 g, 95%). MS: 269.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[NH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24](I)=[C:23]([F:28])[CH:22]=2)=[N:16]1.[C:29]([CH:31]1[CH2:33][CH2:32]1)#[CH:30].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.CS(C)=O>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[NH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24]([C:30]#[C:29][CH:31]3[CH2:33][CH2:32]3)=[C:23]([F:28])[CH:22]=2)=[N:16]1
Reactant: CC(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(I)c(F)c3)[nH]c2=O)c1
Reactant: C#CC1CC1
Agent: Cl[Pd]Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: CC(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(C#CC4CC4)c(F)c3)[nH]c2=O)c1
Yield: 12.8 %

Procedure:
The title compound was prepared according to the procedure described in Example-111 by using N-(4-chloro-3-(3-(3-fluoro-4-iodophenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)benzyl)isobutyramide (step 1 of Example-149, 0.080 g, 0.155 mmol), ethynylcyclopropane (0.019 g, 0.233 mmol), TBAF (0.121 g, 0.466 mmol), bis(triphenylphosphine)palladium(II)chloride (0.004 g, 0.006 mmol) and DMSO (3.0 mL) to afford 0.009 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 0.79-0.92 (m, 2H), 1.011 (m, 2H), 1.30 (s, 6H), 1.63 (m, 1H), 2.39 (m, 1H), 4.28 (d, J=5.7 Hz, 2H), 7.35 (m, 1H), 7.43 (s, 1H), 7.57-7.67 (m, 4H), 8.37 (m, 1H); MS (m/z): 453.24 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([C:21](O)=[O:22])[C:15]=3[N:14]=[C:13]2[C:24](=[O:35])[NH:25][CH:26]2[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]2)=[O:10])=[N:6][CH:7]=1.Cl.[F:37][C:38]1([F:44])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[CH:32]([N:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:24]([C:13]2[N:12]([CH2:11][C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)[C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([C:21]([N:41]4[CH2:42][CH2:43][C:38]([F:44])([F:37])[CH2:39][CH2:40]4)=[O:22])[C:15]=3[N:14]=2)=[O:35])[CH2:27][CH2:28]1)([CH3:34])[CH3:33]
Reactant: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)O)cccc3n2CC(=O)Nc2ccc(Cl)cn2)CC1
Reactant: FC1(F)CCNCC1
Agent: Cl
Product: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)N4CCC(F)(F)CC4)cccc3n2CC(=O)Nc2ccc(Cl)cn2)CC1

Procedure:
1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-4-(4,4-difluoro-piperidine-1-carbonyl)-1H-benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide was prepared by a procedure according to example 22 starting from 870 mg (1.70 mmol) 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid and 302.3 mg (1.87 mmol) 4,4-difluoro-piperidine-hydrochloride. The title compound was obtained as its formiate. Subsequent transformation to the corresponding acetate gave a white amorphous solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[F:27][C:28]([F:39])([F:38])[C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=[C:2]([C:32]2[CH:33]=[N:34][C:29]([C:28]([F:39])([F:38])[F:27])=[CH:30][CH:31]=2)[CH:3]=1)=[O:15]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: OB(O)c1ccc(C(F)(F)F)nc1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C(F)(F)F)nc3)cc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in a similar manner as described for example 8 from 6-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-indazole-4-carboxamide (110 mg, 0.264 mmol) and [6-(trifluoromethyl)-3-pyridinyl]boronic acid (75 mg, 0.395 mmol). The product was collected as a solid (75 mg, 57%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (s, 1H) 9.30 (d, J=2.02 Hz, 1H) 8.66 (t, J=4.93 Hz, 1H) 8.58 (dd, J=8.08, 2.02 Hz, 1H) 8.45 (s, 1H) 8.38 (s, 1H) 8.07 (d, J=8.34 Hz, 1H) 7.98-8.01 (m, 1H) 5.90 (s, 1H) 5.20 (dt, J=13.14, 6.57 Hz, 1H) 4.41 (br. s., 1H) 4.40 (br. s., 1H) 2.22 (s, 3H) 2.13 (s, 3H) 1.53 (s, 3H) 1.51 (s, 3H). LC-MS (ES) m/z=484.1 [M+H]+
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]2[C@H:13]([NH:16][C:17](=[O:29])[C@@H:18]([N:23]3[CH2:28][CH2:27]O[CH2:25][CH2:24]3)[CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)C1C=CC=CC=1.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35](Cl)=[O:36].FC(F)(F)C1C=C(S(Cl)(=O)=O)C=CC=1>>[CH3:21][CH:20]([CH3:22])[CH2:19][C@H:18]([N:23]1[CH2:28][CH2:27][CH2:25][CH2:24]1)[C:17]([NH:16][C@H:13]1[C@H:11]2[C@H:10]([CH2:9][N:8]([C:35](=[O:36])[C:34]3[CH:38]=[CH:39][CH:40]=[C:32]([C:31]([F:42])([F:41])[F:30])[CH:33]=3)[CH2:12]2)[CH2:15][CH2:14]1)=[O:29]
Reactant: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21)N1CCOCC1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Product: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CN(C(=O)c3cccc(C(F)(F)F)c3)C[C@H]21)N1CCCC1

Procedure:
The title compound was prepared by substituting (2S)—N-[(3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-yl]-4-methyl-2-pyrrolidin-1-ylpentanamide from Example 250 for (S)—N-((3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-yl)-4-methyl-2-morpholinopentanamide and 3-(trifluoromethyl)benzoyl chloride for 3-(trifluoromethyl)benzene-1-sulfonyl chloride in the procedures described in Example 319: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.41-8.17 (m, 1H), 8.14-8.05 (m, 1H), 8.01-7.78 (m, 1H), 7.76-7.66 (m, 1H), 7.53 (t, J=7.6, 1H), 4.51-4.29 (m, 1H), 4.20-4.00 (m, 1H), 3.89 (ddd, J=12.0, 6.6, 1.5, 1H), 3.74 (tdd, J=8.3, 5.2, 2.8, 1H), 3.67-3.45 (m, 1H), 3.32-3.13 (m, 2H), 2.87-2.57 (m, 6H), 2.23-2.02 (m, 1H), 1.96-1.78 (m, 2H), 1.73-1.55 (m, 6H), 1.47-1.24 (m, 1H), 1.04-0.79 (m, 6H); MS (ESI+) m/z 466 (M+H)+.