Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[CH:3]=1>C(OCC)(=O)C.[Pt]>[F:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(/C=C/c2cccc(F)c2)cc1
Agent: [Pt]
Solvent: CCOC(C)=O
Product: Nc1ccc(/C=C/c2cccc(F)c2)cc1
Reaction time: 4 h
Yield: 61.9 %

Procedure:
A solution of 2.41 g (10 mmol) (E)-1-fluoro-3-[2-(4-nitrophenyl)ethenyl]-benzene in 25 ml of ethyl acetate is flushed with argon and, thereafter, hydrogenated at RT and atmospheric pressure during 4 hours using 0.241 g of platinum on carbon (5%) as the catalyst. For the working-up, the catalyst is filtered over Dicalit and the resulting solution is evaporated under reduced pressure. The solid material obtained is crystallised from a mixture of ether and heptane to yield 1.32 g (62.5% of theory) of (E)-4-[2-(3-fluoro-phenyl)-vinyl]-phenylamine as an orange solid; MS: m/e=213 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:29]=[C:12]2[CH:13]=[C:14]([NH:17][C:18]([C:20]3[N:24]([CH3:25])[N:23]=[CH:22][C:21]=3[C:26](O)=[O:27])=[O:19])[CH:15]=[CH:16][N:11]2[N:10]=1.[NH:30]1[CH2:33][CH2:32][CH2:31]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:29]=[C:12]2[CH:13]=[C:14]([NH:17][C:18]([C:20]3[N:24]([CH3:25])[N:23]=[CH:22][C:21]=3[C:26]([N:30]3[CH2:33][CH2:32][CH2:31]3)=[O:27])=[O:19])[CH:15]=[CH:16][N:11]2[N:10]=1
Reactant: C1CNC1
Reactant: COc1ccccc1-c1nc2cc(NC(=O)c3c(C(=O)O)cnn3C)ccn2n1
Product: COc1ccccc1-c1nc2cc(NC(=O)c3c(C(=O)N4CCC4)cnn3C)ccn2n1
Yield: 44.4 %

Procedure:
The product was prepared in the same manner as described in example 3 using 5-(2-(2-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (75 mg, 191 μmol) and azetidine (51.5 μl, 765 μmol) as starting materials. The reaction affords 4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid [2-(2-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-amide (36.6 mg, 44.4%) off-white solid. mp.: 258.1° C., MS: m/z=432.3 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[C:17]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:19][CH3:20])[N:10]=[CH:9][CH:8]=[C:7]2[O:6][C:5]1[CH:21]=[CH:22][C:2]([NH:1][C:30]([NH:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:31])=[CH:3][CH:4]=1)#[N:18]
Reactant: O=C=Nc1ccccc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1C#N
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccccc4)cc3)c2cc1C#N

Procedure:
4-(4-Aminophenoxy)-6-cyano-7-methoxyquinoline (148 mg) was added to 5.5 ml of toluene, and the mixture was heated to reflux. After then adding phenyl isocyanate (0.08 ml), the mixture was further heated to reflux for 1 hour. After cooling, the precipitated solid was filtered out and washed with ethyl acetate/toluene=1/1 to obtain 150 mg of the title compound as light brown crystals.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH:15][C:16](OCC)=[O:17].[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1.ClCCl>[F:1][C:2]([F:28])([F:29])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:25])([F:27])[F:26])[CH:23]=1)[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH:15][CH2:16][OH:17]
Reactant: CCOC(=O)C=CCCCCCCOCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: OCC=CCCCCCCOCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 85.1 %

Procedure:
7-(3',5'-bistrifluoromethylbenzyloxy)heptan-1-al (See Example 2, 4.97g, 13.96 mmol) was reacted with carboethoxymethylene triphenylphosphorane (4.86g, 13.96 mmol, Lancaster Synthesis Ltd., U.K.) in dry dichloromethane to give ethyl 9-(3',5'-bistrifluoromethylbenzyloxy)nona-2- enoate (5g). The ester (5g, 13.55 mmol) was reacted with diisobutylaluminium hydride (27 mmol) in toluene-dichloromethane at -30°. After conventional work-up, 9-(3',5'-bistrifluoromethylbenzyloxy)nona-2-en-1-ol (4.43g) was obtained. The alcohol was converted into 9-(3',5'-bistrifluoromethylbenzyloxy)nona-2-en-al by Swern oxidation (oxalyl chloride-dimethylsulphoxide, see EP-A-164 187).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])[N:10]([C:20]([C:22]3[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][C:23]=3[F:30])=[O:21])[N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:38][C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][CH:47]=1)[C:42]([NH2:44])=[O:43]>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH2:38][C:39]3[CH:40]=[C:41]([CH:45]=[CH:46][CH:47]=3)[C:42]([NH2:44])=[O:43])[N:10]([C:20](=[O:21])[C:22]3[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][C:23]=3[F:30])[N:9]=2)=[CH:4][CH:3]=1
Reactant: NC(=O)c1cccc(CBr)c1
Reactant: O=C(c1c(F)cc(F)cc1F)N1N=C(c2ccc(F)cc2)SC1c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)c1cccc(COc2ccccc2C2SC(c3ccc(F)cc3)=NN2C(=O)c2c(F)cc(F)cc2F)c1
Temperature: 90 °C
Reaction time: 12 h

Procedure:
To [5-(4-fluoro-phenyl)-2-(2-hydroxy-phenyl)-[1,3,4]thiadiazol-3-yl]-(2,4,6-trifluoro-phenyl)-methanone (41 μmol) dissolved in acetonitrile (1 mL) is added K2CO3 (61.5 μmol) and 3-bromomethyl-benzamide (94.2 μmol) and the mixture is heated at 90° C. After 12 hours, the reaction is complete as determined by LC/MS. Purification is accomplished by preparative LC/MS (20-100% MeCN/H2O) to give 3-{2-[5-(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxymethyl}-benzamide: 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.9 (d, J=7.6 Hz, 1H), 7.7 (s, 1H), 7.6-7.5 (m, 4H) 7.35 (d, J=7.6 Hz, 1H), 7.06 (t, J=8.4 Hz, 1H), 6.99 (t, J=7.6 Hz, 2H), 6.88 (d, J=8 Hz), 6.79 (t, J=8.4 Hz, 2H), 6.26 (bs, 1H), 5.33 (d, J=7.6 Hz); LC/MS (ES+): 566.1 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:25]3[CH2:29][CH2:28][CH2:27][NH:26]3)=[N:9][C:10]=2[C:11]2[CH:24]=[CH:23][C:14]([C:15]([NH:17][C:18]3[S:19][CH:20]=[CH:21][N:22]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[CH3:30][N:31]([CH3:38])[CH2:32]/[CH:33]=[CH:34]/[C:35](O)=[O:36]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:25]3[CH2:29][CH2:28][CH2:27][N:26]3[C:35](=[O:36])/[CH:34]=[CH:33]/[CH2:32][N:31]([CH3:38])[CH3:30])=[N:9][C:10]=2[C:11]2[CH:12]=[CH:13][C:14]([C:15]([NH:17][C:18]3[S:19][CH:20]=[CH:21][N:22]=3)=[O:16])=[CH:23][CH:24]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c([C@@H]3CCCN3)nc(-c3ccc(C(=O)Nc4nccs4)cc3)c12
Reactant: CN(C)C/C=C/C(=O)O
Product: CN(C)C/C=C/C(=O)N1CCC[C@H]1c1nc(-c2ccc(C(=O)Nc3nccs3)cc2)c2c(N)nccn12
Yield: 29.7 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 2, from (S)-4-(8-amino-3-(pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(thiazol-2-yl)benzamide (intermediate 20) and (E)-4-(dimethylamino)but-2-enoic acid, to afford the title compound (18.9 mg, 29.7%). Data: UPLC (C) Rt: 1.38 min; m/z 517.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>>[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:21]
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: O=C(Cl)c1ccccc1F
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3ccccc3F)c2)CC1
Yield: 98.5 %

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (50 mg, 0.229 mmol) and 2-fluorobenzoyl chloride (82 μl, 0.687 mmol), 76.8 mg (99%) of the title compound were recovered.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:11])[NH:6]2.[NH:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH:17]=O.O>N1CCCCC1.CC(O)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:17]/[C:13]1[NH:12][CH:16]=[CH:15][CH:14]=1)/[C:5](=[O:11])[NH:6]2
Reactant: O=Cc1ccc[nH]1
Reactant: O=C1Cc2c(Br)cccc2N1
Solvent: O
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: O=C1Nc2cccc(Br)c2/C1=C/c1ccc[nH]1
Temperature: 85 °C

Procedure:
A mixture of 4-bromo-1,3-dihydro-2H-indol-2-one (0.2 g, 0.94 mmol) (see Kosuge et al., supra), and excess pyrrole-2-carboxaldehyde (0.11 g, 1.13 mmol) (Aldrich) in 1% piperidine in 2-propanol (2 mL) was heated at 85° C. for 2 h. Hot water (2 mL) was added. On cooling, the crystallized product was filtered off, washed with aqueous 2-propanol and dried. (Yield 0.26 g, 96%).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5](=[O:8])[NH:6][N:7]=1)[CH3:2].Cl[CH:19]([OH:22])[CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[OH:22][CH2:19][CH2:20][CH2:21][N:6]1[C:5](=[O:8])[N:4]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]([CH2:1][CH3:2])=[N:7]1
Reactant: CCC(O)Cl
Reactant: CCc1n[nH]c(=O)n1CCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCc1nn(CCCO)c(=O)n1CCOc1ccccc1

Procedure:
The product of Example 5 "5-ethyl-4-(2-phenoxyethyl)-2H-1,2,4-triazol-3(4H)-one" (5.0 g., 23.5 mmol), chloropropanol (2.44 g., 25.8 mmol) and potassium carbonate (9.72 g., 70.4 mmol) in 50 ml. of acetonitrile is heated to reflux for a period of 48 hr. with stirring. Water (50 ml.) is added and the mixture extracted with methylene chloride which is dried over magnesium sulfate and concentrated under reduced pressure to afford 2-(3-hydroxypropyl)-5-ethyl-2,4-dihydro-4-(2-phenoxyethyl)-3H-1,2,4-triazol-3-one (XIV, Y=H, X1 =0, n=2, R2 =C2H5). Purification is carried out by flash chromatography with ethyl acetate.
Reaction SMILES: C([N:8]([C@@H:17]([CH2:27][CH2:28][CH2:29][CH3:30])[C@H:18]([OH:26])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@@H](C)C1C=CC=CC=1)C1C=CC=CC=1>C(O)(=O)C.[Pd]>[NH2:8][C@@H:17]([CH2:27][CH2:28][CH2:29][CH3:30])[C@H:18]([OH:26])[C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20]
Reactant: CCCC[C@@H]([C@H](O)C(=O)OC(C)(C)C)N(Cc1ccccc1)[C@@H](C)c1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCC[C@H](N)[C@H](O)C(=O)OC(C)(C)C
Yield: 98.5 %

Procedure:
A solution of 0.5 g of tert-butyl 3(S)-[N-benzyl-N-(α(S)-methylbenzyl)amino]-2(S)-hydroxyheptanoate in acetic acid containing 0.2 g of palladium-on-charcoal was hydrogenolyzed overnight at 0.5 MPa. The catalyst was removed by filtration and the acetic acid was evaporated. The crude product was dissolved in dichloromethane and washed with saturated sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane and the combined organic layers were washed with saturated sodium bicarbonate solution, dried over magnesium sulphate and evaporated to give 0.26 g of tert-butyl 3(S)-amino-2(S)-hydroxyheptanoate, MS: m/e 218.3 [M+H]+.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6](/[CH:12]=[CH:13]/[C:14]([OH:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[C:17](OC(=O)C)(=[O:19])[CH3:18]>C1COCC1>[C:17]([O:3][C:4]1[CH:5]=[C:6](/[CH:12]=[CH:13]/[C:14]([OH:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])(=[O:19])[CH3:18]
Reactant: COc1ccc(/C=C/C(=O)O)cc1O
Reactant: CC(=O)OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(/C=C/C(=O)O)cc1OC(C)=O
Yield: 75.1 %

Procedure:
Sodium hydride (1.40 g, 58 mmol) was added portionwise to a solution of (E)-3-(3-hydroxy-4-methoxy-phenyl)-acrylic acid (5.15 g, 26.5 mmol) in THF (100 mL) at 0° C. The resulting mixture was allowed to reach the RT, and acetic anhydride (4 mL, 42.4 mmol) was added. After stirring at reflux temperature for 6 hrs, the reaction mixture was concentrated under reduced pressure. The residue was taken up with AcOEt, and washed with water, aqueous sodium hydrogencarbonate, and brine. The organic layer was then dried over sodium sulphate and evaporated. The resulting raw material was triturated with AcOEt. After filtration and drying, 4.7 g of the title (E)-3-(3-acetoxy-4-methoxy-phenyl)-acrylic acid were obtained, as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[C:22]2[C:21]3[CH:20]=[C:19]([OH:23])[C:18]([O:24][CH3:25])=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:12]([CH3:26])[C:11]1=[O:27])[C:5]#[N:6].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:35][C:36]1[CH:40]=[CH:39][S:38][CH:37]=1.O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[C:22]2[C:21]3[CH:20]=[C:19]([O:23][CH2:35][C:36]4[CH:40]=[CH:39][S:38][CH:37]=4)[C:18]([O:24][CH3:25])=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:12]([CH3:26])[C:11]1=[O:27])[C:5]#[N:6]
Reactant: COc1cc2ncc3c(c2cc1O)n(-c1ccc(C#N)cc1F)c(=O)n3C
Reactant: ClCc1ccsc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncc3c(c2cc1OCc1ccsc1)n(-c1ccc(C#N)cc1F)c(=O)n3C
Temperature: 50 °C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
3-Fluoro-4-(8-hydroxy-7-methoxy-3-methyl-2-oxo-2,3-dihydroimidazo[4,5-c]quinolin-1-yl)benzonitrile (80 mg, 220 μmol) was dissolved in N,N-dimethylformamide (4.0 ml) under a dry argon atmosphere. Potassium carbonate (85 mg, 618 μmol) and 3-chloromethylthiophene (112 mg, 845 μmol; prepared from 3-thiophenemethanol using SOCl2 in CH2Cl2) were subsequently added. The reaction mixture was stirred at 50° C. for 18 h overnight. When the reaction was complete, the mixture was poured into water (60 ml), stirred for 30 min and extracted twice with ethyl acetate (75 ml each time). The combined organic phases were washed with water (25 ml), subsequently dried over Na2SO4, filtered with suction and evaporated in vacuo. The residue chromatographed over flash silica gel (solvent gradient ethyl acetate/0-17% by vol. of ethanol), giving 3-fluoro-4-(7-methoxy-3-methyl-2-oxo-8-(thiophen-3-ylmethoxy)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl)benzonitrile (64 mg, 139 μmol), as solid. MS: 461.1 (M+H+), TLC (HPTLC): Rf=0.33 (ethyl acetate/ethanol 5:1, parts by volume).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:6]=1[C:7]([OH:9])=O)(=[O:4])=[O:3].NS(C1C=CC(C(O)=O)=CC=1F)(=O)=O.Cl.Cl.[CH3:31][C:32]1[N:36]([CH:37]2[CH2:43][CH:42]3[N:44]([CH2:45][CH2:46][C:47]4([C:53]5[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=5)[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]4)[CH:39]([CH2:40][CH2:41]3)[CH2:38]2)[C:35]2[CH:59]=[CH:60][CH:61]=[CH:62][C:34]=2[N:33]=1.CC1N(C2CC3N(CCC4(C5C=CC=CC=5)CCN(C(C5C=CC=CC=5S(NC(=O)OC(C)(C)C)(=O)=O)=O)CC4)C(CC3)C2)C2C=CC=CC=2N=1>>[F:14][C:11]1[CH:12]=[CH:13][C:5]([S:2]([NH2:1])(=[O:3])=[O:4])=[C:6]([C:7]([N:50]2[CH2:49][CH2:48][C:47]([CH2:46][CH2:45][N:44]3[CH:39]4[CH2:40][CH2:41][CH:42]3[CH2:43][CH:37]([N:36]3[C:35]5[CH:59]=[CH:60][CH:61]=[CH:62][C:34]=5[N:33]=[C:32]3[CH3:31])[CH2:38]4)([C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)[CH2:52][CH2:51]2)=[O:9])[CH:10]=1
Reactant: NS(=O)(=O)c1ccc(F)cc1C(=O)O
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCNCC1
Agent: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=O)c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: NS(=O)(=O)c1ccc(C(=O)O)cc1F
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=O)c2cc(F)ccc2S(N)(=O)=O)CC1
Yield: 20 %

Procedure:
The title compound was prepared from a mixture of 2-(aminosulfonyl)-5-fluorobenzoic acid and 4-(aminosulfonyl)-3-fluorobenzoic acid 6b and endo 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-aza bicyclo[3.2.1]oct-3-yl}-1H-benzimidazole dihydro-chloride II following the general procedure for tert-butyl {2-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]phenyl}sulfonylcarbamate 1c. The desired regioisomer was purified by column chromatography on silica gel eluting with 20% methanol in ethyl acetate to afford 4-fluoro-2-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzenesulfonamide 6 as a white solid (9.8 mg, 20% yield). 1H NMR (400 MHz, CDCl3) δ 7.90 (t, 1H. J=7.7 Hz), 7.64 (m, 1H), 7.39 (m, 2H), 7.30-7.12 (m, 8H), 5.69 (broad s, 2H), 4.59 (m, 1H), 4.20 (m, 1H), 3.48-3.19 (m, 5H), 2.52 (s, 3H), 2.40-2.32 (m, 3H), 2.18 (m, 1H), 2.04-1.70 (m, 10H), 1.62 (m, 2H). ES-LCMS m/z 630.19 (M+H). Analytical HPLC (Method Y) Rt 4.16 (90.0%).
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:25]2[CH:29]=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:27]=[N:26]2)[CH2:7][N:6]([C:8]2[C:22]([F:23])=[CH:21][C:11]([C:12]([NH:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[O:13])=[C:10]([F:24])[CH:9]=2)[CH2:5]1)#[N:2].Br[C:40]1[C:41]([CH3:46])=[N:42][NH:43][C:44]=1[CH3:45].C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.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>[C:1]([CH2:3][C:4]1([N:25]2[CH:29]=[C:28]([C:40]3[C:41]([CH3:46])=[N:42][NH:43][C:44]=3[CH3:45])[CH:27]=[N:26]2)[CH2:5][N:6]([C:8]2[C:22]([F:23])=[CH:21][C:11]([C:12]([NH:14][C@@H:15]([CH3:20])[C:16]([F:17])([F:18])[F:19])=[O:13])=[C:10]([F:24])[CH:9]=2)[CH2:7]1)#[N:2]
Reactant: C[C@H](NC(=O)c1cc(F)c(N2CC(CC#N)(n3cc(B4OC(C)(C)C(C)(C)O4)cn3)C2)cc1F)C(F)(F)F
Reactant: Cc1n[nH]c(C)c1Br
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: Cc1n[nH]c(C)c1-c1cnn(C2(CC#N)CN(c3cc(F)c(C(=O)N[C@@H](C)C(F)(F)F)cc3F)C2)c1
Temperature: 110 °C
Reaction time: 1 h
Yield: 9.7 %

Procedure:
A mixture of 4-{3-(cyanomethyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide (329 mg, 0.610 mmol, from Example 4, step 5), 4-bromo-3,5-dimethyl-1H-pyrazole (206 mg, 1.18 mmol), tetrakis(triphenylphosphine)palladium(0) (110 mg, 0.098 mmol) and sodium carbonate (320 mg, 3.0 mmol) in 1,4-dioxane (10 mL)/water (5 mL) was purged with nitrogen and stirred at 110° C. for 1 h. The reaction mixture was diluted with EtOAc, washed with water and brine, concentrated. The residue was purified first with silica gel (eluting with 0-100% EtOAc/hexanes followed by 10% methanol/dichloromethane), and then by prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (30 mg, 9.7%). 1H NMR (500 MHz, DMSO-d6) δ 12.17 (1H, s), 8.45 (1H, d, J=8.0 Hz), 8.10 (1H, s), 7.70 (1H, s), 7.34 (1H, m), 6.61 (1H, s), 4.77 (1H, m), 4.62 (2H, d, J=9.0 Hz), 4.39 (1H, d, J=9.0 Hz), 3.64 (2H, s), 2.22 (6H, s), 1.31 (6H, d, J=7.0 Hz) ppm. LCMS calculated for C23H23F5N7O (M+H)+: m/z=508.2. Found: 508.0.
Reaction SMILES: O=O.[CH2:3]([OH:7])[CH2:4][CH2:5][CH3:6]>>[C:3]([O:7][CH2:3][CH2:4][CH2:5][CH3:6])(=[O:7])[CH2:4][CH2:5][CH3:6]
Reactant: CCCCO
Agent: O=O
Product: CCCCOC(=O)CCC
Temperature: 90 °C

Procedure:
15 mL of n-butanol and 0.5 g of the above-mentioned catalyst were sealed in a 100 mL autoclave equipped with a rotary agitator. The interior of the system was then pressurized to 0.3 MPa with oxygen, after which the temperature was raised to 90° C. under stirring, and this temperature was maintained for 5 hours. During this time the supply of oxygen was continued so as to maintain the above-mentioned internal pressure. The system was then cooled and the seal broken, and the reaction solution was analyzed, which revealed the n-butanol conversion to be 28%, and the butyl n-butyrate (the product) selectivity and yield to be 79% and 22%, respectively.
Reaction SMILES: [CH2:1]1[O:24][C:4]2=[CH:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=4)=[N:11][NH:10][C:9](=[O:22])[CH2:8][C:7]=3[CH:23]=[C:3]2[O:2]1.O.NN.Cl>C(O)C.[Ni]>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[C:6]3[CH:5]=[C:4]4[O:24][CH2:1][O:2][C:3]4=[CH:23][C:7]=3[CH2:8][C:9](=[O:22])[NH:10][N:11]=2)=[CH:14][CH:15]=1
Reactant: O=C1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1)OCO3
Agent: [Ni]
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1ccc(C2=NNC(=O)Cc3cc4c(cc32)OCO4)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 72.5 %

Procedure:
To a suspension of 7,8-methylenedioxy-1-(4-nitrophenyl)-3,5-dihydro-2,3-benzodiazepin-4(4H)-one (167 mg, 0.51 mmol) in ethanol (8 mL) was added Raney Ni (430 mg), hydrazine hydrate (200 μL, 3.5 mmol) and 2N HCl (150 μL, 0.3 mmol). The mixture was stirred at room temperature for 17 h. The solid Ni was filtered out. The filtrate was concentrated in vacuo and the resulting residue was separated by chromatography (1:4 hexane/EtOAc) to afford the title compound as a yellow solid (110 mg, 0.37 mmol, 73%), mp: 242°-244° C. 1H NMR (CDCl3) 8.32 (s, 1H), 7.41 (d, 2H, J=8.5), 6.81 (s, 1H), 6.70 (s, 1H), 6.68 (d, 2H, J=8.5), 6.02 (s, 2H), 3.94 (brs, 2H), 3.42 (s, 2H). Anal. Calcd. for C16H13N3O3.0.25H2O: C, 64.10; H, 4.54; N, 14.02. Found C, 64.32; H, 4.37; N, 13.48.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23](=S)[CH2:24][C:25](=O)[CH3:26])=[O:4].Cl.[N:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]([NH:40][NH2:41])=[CH:32][CH:31]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:20])([F:21])[F:22])(=[O:11])=[O:12])[CH2:7][N:6]1[C:23]1[N:40]([C:33]2[C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:30]=[CH:31][CH:32]=2)[N:41]=[C:25]([CH3:26])[CH:24]=1)=[O:4]
Reactant: NNc1ccnc2ccccc12
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=S)CC(C)=O
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1-c1ccnc2ccccc12

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-1-(3-oxo-thiobutyryl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (example 192 g) was reacted with quinolin-4-yl-hydrazine hydrochloride (CAS Reg. No. 68500-41-4) to give the title compound as orange oil. MS (ESI): m/z=545.2 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[S:9][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:12]=2)[CH2:4][C@H:3]1[O:18][CH3:19].[Cl:20][C:21]1[N:22]=[C:23]([C:27](O)=[O:28])[NH:24][C:25]=1[Cl:26].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C>[Cl:20][C:21]1[N:22]=[C:23]([C:27]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[S:9][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:12]=3)[CH2:4][C@H:3]2[O:18][CH3:19])=[O:28])[NH:24][C:25]=1[Cl:26]
Reactant: CCOC(=O)c1cnc(N2CC[C@H](N)[C@H](OC)C2)s1
Reactant: O=C(O)c1nc(Cl)c(Cl)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CCOC(=O)c1cnc(N2CC[C@H](NC(=O)c3nc(Cl)c(Cl)[nH]3)[C@H](OC)C2)s1
Yield: 24 %

Procedure:
The same operation as in Example (1g) was performed using ethyl cis(±)-2-(4-amino-3-methoxypiperidin-1-yl)-1,3-thiazole-5-carboxylate obtained by the method described in Example (5d) (0.23 g, 0.81 mmol), 4,5-dichloroimidazole-2-carboxylic acid obtained in Example (7d) (84 mg, 0.46 mmol), WSC hydrochloride (0.24 g, 1.25 mmol) and DMAP (10 mg, 0.083 mmol), to obtain 49 mg of the title compound as a pale yellow solid (24%).
Reaction SMILES: O[C:2]1[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][C:3]=1[C:10]([O:12][CH3:13])=[O:11].C([O-])(=O)C.[NH4+:18]>C(O)C>[NH2:18][C:2]1[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][C:3]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C1=C(O)CCC(C)(C)C1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: COC(=O)C1=C(N)CCC(C)(C)C1
Yield: 75 %

Procedure:
A solution of methyl 2-hydroxy-5,5-dimethylcyclohex-1-enecarboxylate (10.0 g, 54 mmol) and ammonium acetate (10 g, 130 mmol) in ethanol (50 mL) was heated to reflux for 2 hours. The reaction was concentrated to one third original volume, and then diluted with ethyl acetate (100 mL). The organic solution was washed with water (100 mL) and brine (50 mL) and then dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified by silica gel column chromatography (ethyl acetate/hexanes, 1:8) to afford methyl 2-amino-5,5-dimethylcyclohex-1-enecarboxylate (7.42 g, 75% yield) as a yellow solid. MS (EI) for C10H17NO2: 184 (MH+).