Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:10][C:5]2[CH2:6][O:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)=O.Cl[Si](C)(C)C.CN([CH:28]=[O:29])C>>[CH3:2][C:3]1[C:4]([CH2:5][C:6]([O:29][CH3:28])=[O:7])=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:3]2[C:4]3[CH2:9][CH2:8][O:7][CH2:6][C:5]=3[S:10][C:2]=2[N:1]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc(C(=O)c2c(N)sc3c2CCOC3)cc1
Agent: C[Si](C)(C)Cl
Product: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCOC3
Yield: 36 %

Procedure:
This compound was prepared according to the procedure B from (2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3-yl)-(p-tolyl)-methanone (0.546 g; 2 mmol), methyl levunilate (0.282 mL; 2.2 mmol), chlorotrimethylsilane (1 mL; 8 mmol) in DMF (8 mL) for 22 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-80%) in heptane furnished 0.270 g (36%) of the title compound as a yellow solid.
Reaction SMILES: C([O:8][C:9](=[O:48])[CH2:10][C@@H:11]([N:29]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][C:37]([C:40]3[CH:45]=[CH:44][C:43]([C:46]#[N:47])=[CH:42][CH:41]=3)=[CH:36][CH:35]=2)=[CH:30]1)[C:12]([NH:14][C@H:15]([C:20](=[O:28])[NH:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])C1C=CC=CC=1.C(O)=O>[Pd].CO>[CH:9]([OH:48])=[O:8].[C:46]([C:43]1[CH:42]=[CH:41][C:40]([C:37]2[CH:38]=[CH:39][C:34]([C:31]3[CH:32]=[CH:33][N:29]([C@@H:11]([C:12]([NH:14][C@H:15]([C:20](=[O:28])[NH:21][C:22]4[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=4)[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])[CH2:10][C:9]([OH:48])=[O:8])[CH:30]=3)=[CH:35][CH:36]=2)=[CH:45][CH:44]=1)#[N:47]
Reactant: CC(C)(C)[C@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccc(C#N)cc3)cc2)c1)C(=O)Nc1ccncc1
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: CC(C)(C)[C@H](NC(=O)[C@@H](CC(=O)O)n1ccc(-c2ccc(-c3ccc(C#N)cc3)cc2)c1)C(=O)Nc1ccncc1
Yield: 89.9 %

Procedure:
A mixture of palladium on carbon and 3(R)-[3-(4′-cyanobiphenyl-4-yl)-1H-pyrrol-1-yl]-N-[2,2-dimethyl-1(S)-(pyridin-4-ylcarbamoyl)propyl]succinamic acid benzyl ester (72 mg, 0.112 mmol) in MeOH with formic acid afforded 30 mg(49%) of 3(R)-[3-(4′-cyanobiphenyl-4-yl)-1H-pyrrol-1yl]-N-[2,2-dimethyl-1(S)-(pyridin-4-ylcarbamoyl)propyl]succinamic acid formate salt as a solid, mp 134-6° C. 1H NMR (DMSO-d6): δ 8.39-8.35 (m, 3H), 7.81 (d, 2H, J=5.9 Hz), 7.63 (s, 2H), 7.34-7.23 (m, 4H), 7.28 (d, 2H, J=10.3 Hz), 7.24 (s, 1H), 6.96-6.92 (m, 1H), 6.52 (dddd, 1H, J=1.8, 2.9, 4.8, 7.4 Hz), 5.35-5.29 (m, 1H), 3.39-3.18 (bm, 1H), 3.09-2.91 (bm, 1H), 1.06 (s, 9H). IR (KBr): 2966, 2225, 1719, 1654, 1594, 1560, 1507, 1396, 1196 cm1. HRFABMS: Calculated for C28H31N4O4 (M+H+): 550.2454. Found: 550.2450. Anal. Calculated for C32H31N5O4.1.0HCO2H.2.5CH3OH: C, 63.10; H, 6.41; N, 10.36. Found: C, 63.03, H, 6.75; N. 10.38.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11]O)[CH:6]=[CH:7][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:37]I>C(#N)C.C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][I:37])[CH:6]=[CH:7][CH:8]=1
Reactant: II
Reactant: COc1cccc(CCCO)c1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CC#N
Product: COc1cccc(CCCI)c1
Reaction time: 0.75 h
Yield: 84.9 %

Procedure:
A magnetically stirred solution of 3-(3-methoxyphenyl)propan-1-ol (62.48 g, 375.9 mmol), triphenylphosphine (128.6 g, 490.4 mmol), and imidazole (35.53 g, 516.7 mmol) in anhydrous acetonitrile (300 mL)/anhydrous diethyl ether (600 mL) at 5° C. was treated portion wise with iodine (136.20 g, 536.6 mmol). The yellow suspension turned orange with the last addition. The suspension was stirred 45 min, filtered, the cake washed with fresh diethyl ether (300 mL), the combined filtrate was concentrated in vacuo to 300 mL and diluted with diethyl ether (200 mL). The resultant organic solution was washed with saturated sodium thiosulfate (2×500 mL), saturated cupric sulfate (2×500 mL), brine (2×500 mL), filtered and concentrated in vacuo. The residue was digested with hexanes (300 mL), filtered and concentrated in vacuo. Kugelrohr distillation (0.1 torr, 120° C.) provided the desired product as a yellow liquid (88.10 g, 85%): 1H NMR (CDCl3) δ 7.20 (t, J=8 Hz, 1 H), 6.81-6.73 (m, 3 H), 3.81 (s, 3 H), 3.17 (t, J=8 Hz, 2 H), 2.70 (t, J=8 Hz, 2 H), 2.14 (quint, J=8 Hz, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[CH:22][N:21]=[C:20]([C:24]([C:26]2[CH:27]=[C:28]3[C:32](=[C:33]([CH3:35])[CH:34]=2)[N:31]([CH3:36])[CH2:30][C:29]3([CH3:38])[CH3:37])=[O:25])[CH:19]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:36][N:31]1[C:32]2[C:28](=[CH:27][C:26]([C:24]([C:20]3[N:21]=[CH:22][N:23]=[C:18]([N:1]4[CH2:2][CH2:3][CH:4]([N:7]5[C:15]6[C:10](=[N:11][CH:12]=[CH:13][CH:14]=6)[NH:9][C:8]5=[O:16])[CH2:5][CH2:6]4)[CH:19]=3)=[O:25])=[CH:34][C:33]=2[CH3:35])[C:29]([CH3:38])([CH3:37])[CH2:30]1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2c1N(C)CC2(C)C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)c2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)ncn2)cc2c1N(C)CC2(C)C
Temperature: 40 °C
Reaction time: 8 h

Procedure:
38 mg (0.17 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one, 55 mg (0.17 mmol) (6-chloro-pyrimidin-4-yl)-(1,3,3,7-tetramethyl-2,3-dihydro-1H-indol-5-yl)-methanone and 0.050 mL (0.29 mmol) DIPEA were combined in 2 mL DMF and stirred overnight at 40° C. Then the reaction mixture was purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:31][NH2:32]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH:31][NH2:32])=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(C(=O)O)cc1
Reactant: NN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCOc1ccc(C(=O)NN)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
To a stirred solution of 4-(heptyloxy)benzoic acid (679 mg, 2.87 mmol) in THF (5 mL) was added 1,1′-carbonyldiimidazole (559 mg, 3.45 mmol). After stirring at room temperature for 2 h, the solution was added to a stirred mixture of hydrazine hydrate (0.729 mL, 5.75 mmol) in THF (2 mL) and stirred a further 2 h. The reaction mixture was poured onto water (20 mL) and stirred for 30 min. The resulting precipitate was collected by filtration, washed with water (2×10 mL) then acetonitrile (3 mL) to afford 0.54 g (71%) of 4-(heptyloxy)benzohydrazide as a white solid. LCMS-ESI (m/z) calculated for C14H22N2O2: 250.3 found 251.0 [M+H]+, tR=2.05 min. (Method 4).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:7]=3[C:8]=2[CH:9]=1.[O:29]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30]1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(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>[O:29]1[CH:33]=[CH:32][C:31]([C:2]2[S:3][C:4]3[CH2:5][C:6]4[C:12]([C:13]5[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=5)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:26])[CH3:27])[C:7]=4[C:8]=3[CH:9]=2)=[CH:30]1
Reactant: OB(O)c1ccoc1
Reactant: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(Br)cc2-3)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(-c4ccoc4)cc2-3)cc1
Temperature: 100 °C
Yield: 67 %

Procedure:
A mixture of the corresponding 2-Bromo-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.8 g, 1.7 mmol), Furan-3-boronic acid (0.28 g, 2.5 mmol), Na2CO3 (2 M, 3.9 mL), and Pd(PPh3)2Cl2 (15 mg, 0.13 mmol) in toluene/ethanol (1:1, 12 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (20% EtOAc in hexane) to give 2-Furan-3-yl-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene as orange solid in 67% yield.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[Cl:28][C:29]1[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=1[NH:36]N>>[Cl:28][C:29]1[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=1[N:36]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([C:23]([F:24])([F:25])[F:26])(=[O:22])=[O:21])=[CH:16][CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: NNc1cccc(Cl)c1Cl
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(S(=O)(=O)C(F)(F)F)cc2)ccc1=O
Product: O=c1ccn(-c2ccc(S(=O)(=O)C(F)(F)F)cc2)nc1-c1ccnn1-c1cccc(Cl)c1Cl

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethansulfonyl-phenyl)-1H-pyridazin-4-one (A-27) and 2,3-dichloro-phenylhydrazine according to the method described for example 1. MS: M=515.0 (M+H)+
Reaction SMILES: [NH:1]([C:8]([C@H:10]1[N:14]2[C:15](=[O:41])[C:16]([N:19]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)=[CH:17][N:18]=[C:13]2[C@@:12]([CH2:43][C:44]([OH:46])=[O:45])([CH3:42])[CH2:11]1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH:53]1[CH:58]=[CH:57][C:56]([CH2:59]Br)=[CH:55][CH:54]=1>CN(C=O)C.CCOC(C)=O>[NH:1]([C:8]([C@H:10]1[N:14]2[C:15](=[O:41])[C:16]([N:19]([C:31]([O:33][CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[O:32])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)=[CH:17][N:18]=[C:13]2[C@@:12]([CH2:43][C:44]([O:46][CH2:59][C:56]2[CH:57]=[CH:58][CH:53]=[CH:54][CH:55]=2)=[O:45])([CH3:42])[CH2:11]1)=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@]1(CC(=O)O)C[C@@H](C(=O)Nc2ccccc2)n2c1ncc(N(Cc1cccc(C(F)(F)F)c1)C(=O)OCc1ccccc1)c2=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@]1(CC(=O)OCc2ccccc2)C[C@@H](C(=O)Nc2ccccc2)n2c1ncc(N(Cc1cccc(C(F)(F)F)c1)C(=O)OCc1ccccc1)c2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 117b (1.740 mmol) in 7 mL DMF, were added Cs2CO3 (850 mg, 2.61 mmol) and BnBr (0.31 mL, 2.61 mmol). The mixture was stirred at rt for 1 h, then diluted with EtOAc. The organic phase was washed with 0.5 N HCl and brine, dried (Na2SO4), and concentrated. The crude product was purified by flash chromatography (35% EtOAc/hexanes) to afford 533 mg (42%, 2 steps) of 117c as a colorless glass. MS(ESI) 725.3 (M+H+).
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][CH2:4][CH2:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7].C([Li])CCC.[CH2:21]([O:28][C:29](=[O:42])[NH:30][CH:31]([CH:39]1[CH2:41][O:40]1)[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[CH2:21]([O:28][C:29](=[O:42])[NH:30][CH:31]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:39]([OH:40])[CH2:41][CH:5]([S:6]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:7])=[O:8])[CH2:4][CH2:3][CH:2]([CH3:15])[CH3:1])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(NC(Cc1ccccc1)C1CO1)OCc1ccccc1
Reactant: CC(C)CCCS(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)CCC(CC(O)C(Cc1ccccc1)NC(=O)OCc1ccccc1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3.0 equivalents of (4-methyl-pentane-1-sulfonyl)-benzene (previously prepared by Gaoni, J. Org. Chem. 1982, 47, 2564) in tetrahydrofuran cooled to −78° C. is added 3.0 equivalents of n-butyl lithium and stirred for 30 min. One equivalent of (1-oxiranyl-2-phenyl-ethyl)-carbamic acid benzyl ester (previously prepared by Kaldor, et al. J. Med. Chem., 1997, p. 3979) in THF is then added dropwise and the reaction stirred for 1.5 h. The reaction is then quenched with saturated aqueous sodium bicarbonate and warmed to ambient temperature. After standard aqueous work-up and extraction, followed by concentration and silica gel chromatography the title compound is obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[F:16][C:17]([F:27])([F:26])[C:18]1[N:23]=[CH:22][C:21]([CH:24]=[CH2:25])=[CH:20][N:19]=1.[OH-].[K+]>CN1C(=O)CCC1>[F:27][C:17]([F:16])([F:26])[C:18]1[N:19]=[CH:20][C:21]([CH2:24][CH2:25][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)=[CH:22][N:23]=1
Reactant: C=Cc1cnc(C(F)(F)F)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2cnc(C(F)(F)F)nc2)CCN(C)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, 2-(trifluoromethyl)-5-vinylpyrimidine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [O:1]=[C:2]1[C:10](=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][C:13]1[O:17][C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:15][CH:14]=1.[F:23][C:24]([F:33])([F:32])[C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28]>C(Cl)(Cl)Cl>[O:1]=[C:2]1[N:3]([CH2:12][C:13]2[O:17][C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:15][CH:14]=2)[C:4]2[C:9](/[C:10]/1=[N:28]/[C:27]1[CH:29]=[CH:30][CH:31]=[C:25]([C:24]([F:23])([F:32])[F:33])[CH:26]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CCOC(=O)c1ccc(CN2C(=O)C(=O)c3ccccc32)o1
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(CN2C(=O)/C(=N\c3cccc(C(F)(F)F)c3)c3ccccc32)o1
Temperature: 140 °C
Yield: 22.6 %

Procedure:
A mixture of ethyl 5-[(2,3-dioxo-2,3-dihydro-1H-indol-1-yl)methyl]-2-furoate (60 mg, 0.200 mmol) and 3-trifluoromethylaniline (32 mg, 0.200 mmol) was heated at 140° C. for 2 h. The residue was dissolved in CHCl3 (1 mL) and purified by preparative TLC using EtOAc/hexane (6:4), giving the desired product (20 mg, 23%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:9](Cl)=[CH:10][C:11]([C:13]1[C:14]([Cl:24])=[N:15][C:16]([Cl:23])=[CH:17][C:18]=1[C:19]([F:22])([F:21])[F:20])=[O:12]>O1CCOCC1>[NH:1]([C:9]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH:10][C:11]([C:13]1[C:14]([Cl:24])=[N:15][C:16]([Cl:23])=[CH:17][C:18]=1[C:19]([F:22])([F:21])[F:20])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(C=C(Cl)Cl)c1c(C(F)(F)F)cc(Cl)nc1Cl
Reactant: Nc1ccccc1
Solvent: C1COCCO1
Product: O=C(C=C(Nc1ccccc1)Nc1ccccc1)c1c(C(F)(F)F)cc(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
A solution of aniline (18.4 mL, 202 mmol) in TEA (28.2 mL, 202 mmol) was added slowly to a cooled (0° C.) and stirred solution of 3,3-dichloro-1-[2,6-dichloro-4-(trifluoromethyl)-3-pyridinyl]-2-propen-1-one (22.9 g, 67.4 mmol) in dioxane (220 mL). The reaction was allowed to warm to room temperature and was stirred overnight. The mixture was treated with 10% HCI and extracted with Et2O (3×). The combined organic extracts were washed with brine, dried over Na2SO4 and concentrate in vacuo. Silica gel flash chromatography of the residue using 6:1 Hex:EtOAc gave 3,3-dianilino-1-[2,6 dichloro-4-(trifluoromethyl)-3-pyridinyl]-2-propen-1-one as an off-white solid (13.10 g, 43%): 1H-NMR (d6-DMSO, 300 MHz) δ12.24 (br s, 1H), 9.20 (br s, 1H), 7.95 (s, 1H), 7.12-7.42 (m, 1H), 4.82 (s, 1H); Rf=0.60 (6:1 Hex:EtOAc).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:9][CH2:10][C:11]([N:13]2[CH2:26][CH2:25][C:16]3([C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=[CH:17]3)[CH2:15][CH2:14]2)=[O:12])=[CH:4][CH:3]=1.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)[CH2:9][CH2:10][C:11]([N:13]2[CH2:26][CH2:25][C:16]3([C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17]3)[CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:7]=1
Reactant: O=C(CC=C(c1ccc(F)cc1)c1ccc(F)cc1)N1CCC2(C=Cc3ccccc32)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(CCC(c1ccc(F)cc1)c1ccc(F)cc1)N1CCC2(CCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 99.3 %

Procedure:
0.50 g (1.13 mmol) of 1-[4,4-bis(4-fluorophenyl)but-3-enoyl]-spiro[piperidine-4,1′-indene] (33) was dissolved in 20 mL of methanol under nitrogen atmosphere and then 200 mg of palladium/Charcoal (5%, Aldrich) was added. The nitrogen atmosphere was replaced with hydrogen gas. The resulting mixture was stirred at room temperature for 6 hours and filtered through a pad of celite. The methanol solution (200 mL) was concentrated and the resulting residue purified by column chromatography using a gradient of ethyl acetate/hexane as eluent to give 0.5 g of the title compound 35. MS: m/z 445. 1H NMR (CDCl3): δ 7.24-7.17 (m, 7H), 7.10-7.07 (m, 1H), 7.02-6.95 (m, 4H), 4.67-4.57 (m, 1H), 4.04-3.93 (m, 1H), 3.68-3.58 (m, 1H), 3.18-3.06 (m, 1H), 2.98-2.85 (m, 2H), 2.82-2.71 (m, 1H), 2.44-2.33 (m, 2H), 2.33-2.24 (m, 2H), 2.14-1.99 (m, 2H), 1.82-1.61 (m, 2H), 1.61-1.48 (m, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])O[C:4](=[O:9])[CH:3]=1.[F:10][C:11]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:12]=1[NH2:13]>O>[F:10][C:11]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:12]=1[N:13]1[C:6]([CH3:8])=[CH:7][C:2]([OH:1])=[CH:3][C:4]1=[O:9]
Reactant: Nc1c(F)cccc1F
Reactant: Cc1cc(O)cc(=O)o1
Solvent: O
Product: Cc1cc(O)cc(=O)n1-c1c(F)cccc1F
Temperature: 170 °C
Yield: 37.5 %

Procedure:
A mixture of 4-hydroxy-6-methyl-2-pyrone (10.0 g, 0.079 mol) and 2,6 difluoroaniline (9.5 g, 0.073 mol) was heated at 170° C. under argon atmosphere for 20 min. The water formed was removed using a Dean-stark apparatus. The melt was cooled, the dark solid was tritutrated with EtOAc., and filtered. This material was washed thoroughly with EtOAc to afford the desired product 1-(2,6-difluorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one 6.5 g (35%) as a light brown solid: 1H NMR (CD3OD/400 MHz) δ7.56 (m, 1H), 7.19 (m, 2H), 6.09 (m, 1H), 5.77 (d, 1H, J=2.4 Hz), and 1.99 (s, 3H); ES-HRMS m/z 238.0679 (M+H C12H10NO2F2 requires 238.0674).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=3[N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[C:21]([OH:23])=O)=[O:17])[CH2:12][CH2:11]2)=[C:6]([F:33])[CH:5]=1)(=[O:3])[CH3:2].[CH3:34][NH:35][CH3:36]>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][N:13]([C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=3[N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[C:21]([N:35]([CH3:36])[CH3:34])=[O:23])=[O:17])[CH2:14][CH2:15]2)=[C:6]([F:33])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(N2CCN(C(=O)c3cc(C(=O)O)ccc3N3CCOCC3)CC2)c(F)c1
Reactant: CNC
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc(C(=O)N(C)C)ccc3N3CCOCC3)CC2)c(F)c1

Procedure:
The title compound was prepared according to the procedure described for example K/step 2 from 3-[4-(4-Acetyl-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-morpholin-4-yl-benzoic acid and dimethylamine (44%, yellow solid, MS (m/e): 483.2 (M+H, 100%)
Reaction SMILES: [C@H:1]1([NH:11][C:12]2[O:13][CH2:14][C:15]3[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:16]=3[N:17]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.O=C1CCC(=O)N1[O:30][C:31](=O)[CH2:32][Cl:33]>C(#N)C>[Cl:33][CH2:32][C:31]([NH:22][C:20]1[CH:19]=[CH:18][C:16]2[N:17]=[C:12]([NH:11][C@H:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH2:4][CH2:3][CH2:2]3)[O:13][CH2:14][C:15]=2[CH:21]=1)=[O:30]
Reactant: O=C(CCl)ON1C(=O)CCC1=O
Reactant: Nc1ccc2c(c1)COC(N[C@@H]1CCCc3ccccc31)=N2
Solvent: CC#N
Product: O=C(CCl)Nc1ccc2c(c1)COC(N[C@@H]1CCCc3ccccc31)=N2
Temperature: 23 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixture of (R)-N2-(1,2,3,4-tetrahydro-naphthalen-1-yl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 33) (293 mg, 1 mmol) and chloro-acetic acid 2,5-dioxo-pyrrolidin-1-yl ester (CAS 27243-15-8) (192 mg, 1 mmol) in acetonitrile (2 ml) was stirred at 23° C. for 1 h. Poured onto water and extracted with ethyl acetate, dried the combined organic layers over sodium sulfate, filtered off and evaporated totally to give the title compound as a light red oil (370 mg, 100%, HPLC 1.185 min), MS (ISP) m/e=370.1 [(M+H)+] and 372 [(M+2+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][NH:8][CH2:7][CH2:6]2.C1C2C(=CC=CC=2)CCN1[C:25]([Cl:27])=[O:26]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][N:8]([C:25]([Cl:27])=[O:26])[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: O=C(Cl)N1CCc2ccccc2C1
Product: COc1cc2c(cc1OC)CN(C(=O)Cl)CC2
Yield: 94 %

Procedure:
6,7-Dimethoxy-3,4-dihydro-1H-isoquinoline-2-carbonyl chloride (25A) is prepared from 6,7-Dimethoxy-1,2,3,4-tetrahydro-isoquinoline as described for 24A.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]1[C:21]2[CH:29]=[CH:28][N:27]=[C:26]([C:30]3[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=3[F:37])[C:22]=2[N:23]=[CH:24][N:25]=1>ClCCl>[Cl:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]1[C:21]2[CH:29]=[CH:28][N+:27]([O-:9])=[C:26]([C:30]3[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=3[F:37])[C:22]=2[N:23]=[CH:24][N:25]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1ccc(-c2ncnc3c(-c4c(F)cccc4F)nccc23)c(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1ccc2c(-c3ccc(F)cc3Cl)ncnc2c1-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.6 %

Procedure:
Meta-chloroperbenzoic acid (77%) (30 mg, 0.13 mmol) was added portionwise to a solution of the title compound from Example 25 (50 mg, 0.13 mmol) in dichloromethane (2.5 mL) at 0° C. and the reaction mixture was stirred overnight at room temperature. Then, more dichloromethane was added (50 mL) and the solution was washed with 1N NaOH (2×30 ml) and brine. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to yield an oil which was purified by column chromatography on silica gel, using hexane/ethyl acetate (5:1) as eluent, to yield the title compound (24 mg, 46%) as an off-white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[N:19]=[C:18]([C:20]3[O:28][C:27]4[CH:26]=[CH:25][N:24]=[C:23]([C:29]#[N:30])[C:22]=4[CH:21]=3)[O:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Si](I)(C)(C)C.CO.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[NH:8]1[CH2:9][CH2:10][CH:11]([CH2:14][C:15]2[N:19]=[C:18]([C:20]3[O:28][C:27]4[CH:26]=[CH:25][N:24]=[C:23]([C:29]#[N:30])[C:22]=4[CH:21]=3)[O:17][N:16]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2noc(-c3cc4c(C#N)nccc4o3)n2)CC1
Agent: C[Si](C)(C)I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: N#Cc1nccc2oc(-c3nc(CC4CCNCC4)no3)cc12
Reaction time: 1 h

Procedure:
A stirred solution 4-[5-(4-cyanofuro[3,2-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethyl]-piperidine-1-carboxylic acid tert-butyl ester (Example 82, 134 mg, 328 μmol) in anhydrous CHCl3 (7 mL) was treated with TMS-I (140 μL, 983 μmol). After 1 h, the reaction was treated with MeOH (3.4 mL), then solid Na2S2O3 was added slowly to remove the yellow colour. The reaction mixture was filtered and the excess Na2S2O3 collected was washed with MeOH (3×1 mL). The combined filtrates were allowed to stand for 1 h, before being purified by column chromatography (MeOH—CH2Cl2, 1:9) to yield the title compound: RT=2.44 min; m/z (ES+)=310.1 [M+H]+.