Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@@H:6]([NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]3[CH2:26][CH2:25][CH2:24][O:23]3)=[CH:16][N:15]=1)=[O:13])[CH2:5]2.[CH2:27](C([Sn])=C(CCCC)CCCC)[CH2:28]CC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C=O)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[CH:27]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@@H:6]([NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]3[CH2:26][CH2:25][CH2:24][O:23]3)=[CH:16][N:15]=1)=[O:13])[CH2:5]2)=[CH2:28]
Reactant: O=C(N[C@@H]1Cc2ccc(Br)cc2C1)c1ccc(OC[C@@H]2CCCO2)cn1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=Cc1ccc2c(c1)C[C@H](NC(=O)c1ccc(OC[C@@H]3CCCO3)cn1)C2

Procedure:
A mixture of N-((R)-5-bromoindan-2-yl)-5-[(S)-1-(tetrahydrofuran-2-yl)methoxy]pyridine-2-carboxamide (1.70 g), tributylvinyltin (1.55 g), triphenylphosphine (85.5 mg), palladium(II) acetate (18.3 mg) and DMF (20 ml) was admixed under argon with triethylamine (7.4 ml) and heated to reflux for 4 hours. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. The residue was filtered through silica gel. This afforded the product with the molecular weight of 364.45 (C22H24N2O3); MS (ESI): 365 (M+H+).
Reaction SMILES: [CH:1]1([CH:7]([NH:24][C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)[C:8]2[C:9]([CH2:22][CH3:23])=[N:10][N:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH3:21])[CH:14]=3)[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.[NH2:57][CH2:58][C:59]([CH2:67][CH3:68])([CH2:65][CH3:66])[C:60]([O:62][CH2:63][CH3:64])=[O:61]>CN(C)C=O.O.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:24][C:25]2[CH:33]=[CH:32][C:28]([C:29]([NH:57][CH2:58][C:59]([CH2:65][CH3:66])([CH2:67][CH3:68])[C:60]([O:62][CH2:63][CH3:64])=[O:61])=[O:30])=[CH:27][CH:26]=2)[C:8]2[C:9]([CH2:22][CH3:23])=[N:10][N:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH3:21])[CH:14]=3)[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(CC)(CC)CN
Reactant: CCOc1cccc(-n2cc(C(Nc3ccc(C(=O)O)cc3)C3CCCCC3)c(CC)n2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CC)(CC)CNC(=O)c1ccc(NC(c2cn(-c3cccc(OCC)c3)nc2CC)C2CCCCC2)cc1
Reaction time: 8 h
Yield: 74.2 %

Procedure:
4-({Cyclohexyl[1-(3-ethoxyphenyl)-3-ethyl-1H-pyrazol-4-yl]methyl}amino)benzoic acid (0.18 g) synthesized in Example 92(2) was dissolved in N,N-dimethylformamide (3 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.11 g), 1-hydroxybenzotriazole.monohydrate (0.09 g), ethyl 2-(aminomethyl)-2-ethylbutanoate hydrochloride (0.12 g) and triethylamine (0.09 mL) were added at room temperature, and the mixture was stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give ethyl 2-[({[4-({cyclohexyl[1-(3-ethoxyphenyl)-3-ethyl-1H-pyrazol-4-yl]methyl}amino)phenyl]carbonyl}amino)methyl]-2-ethylbutanoate (0.18 g) as a yellow oil. This was dissolved in ethanol (2.0 mL), 1N aqueous sodium hydroxide solution (2.0 mL) was added at room temperature, and the mixture was stirred at 60° C. overnight. Ethanol was evaporated under reduced pressure, and 1N hydrochloric acid (2.0 mL) was added to the residue. The precipitate was washed with water to give the title object compound (0.17 g, 74%) as a colorless solid.
Reaction SMILES: [Br-:1].[C:2]1([C:8](=[O:20])[CH2:9][C:10](=[O:19])[CH2:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)(Cl)Cl>[Br:1][C:11]1[C:10](=[O:19])[CH:9]=[C:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[O:20][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: [Br-]
Reactant: CCOC(=O)C(=O)CC(=O)CC(=O)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1oc(-c2ccccc2)cc(=O)c1Br
Reaction time: 3 h

Procedure:
A solution of bromide (10.25 ml, 0.198 mol) in chloroform (50 ml) was added dropwise over 30 minutes to a stirred solution of ethyl 6-phenyl-2,4,6-trioxohexanoate (52.0 g) in chloroform (400 ml) at -10 to -20° C. The pale solution was stirred for a further 3 hours without cooling, washed with water and evaporated. The residual solid was recrystallised from ethanol-water to give ethyl 3-bromo-4-oxo-6-phenyl-4H-pyran-2-carboxylate (mp 135° C.). This ester was hydrolysed as in Example 33 to give the title product (mp 247° C. with decomposition).
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[NH:2][NH2:3].[CH3:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[CH3:19])[CH:14]=O>C(OCC)(=O)C>[CH3:10][C:11]1[CH:12]=[C:13]([CH:14]=[N:3][NH:2][C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH:16]=[CH:17][C:18]=1[CH3:19]
Reactant: Cc1ccc(C=O)cc1C
Reactant: CC(C)(C)OC(=O)NN
Solvent: CCOC(C)=O
Product: Cc1ccc(C=NNC(=O)OC(C)(C)C)cc1C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 92.1 %

Procedure:
To a solution of t-butyl carbazate (5.06 g, 38.3 mmol) in ethyl acetate (15 mL) was added with stirring 3,4-dimethylbenzaldehyde (5.20 mL, 5.26 g, 39.2 mmol). Crystallization occurred and the resulting slurry was stirred at rt for 45 min. Hexanes (70 mL) was added and the slurry was cooled to 0° C. The slurry was stirred at 0° C. for 60 min, then filtered and rinsed with cold hexanes (20 mL), and dried in vacuo at 40° C. to afford the title compound as a solid (8.76 g, 92.1%): mp 167.7-168.6° C. 1H NMR (DMSO-d6) δ 10.82 (s, 1H), 7.92 (s, 1H), 7.36 (s, 1H), 7.28 (d, 2H, J=3 Hz), 7.14 (d, 2H, J=3 Hz), 2.206 (s, 3H), 2.20 (s, 3H) 1.44 (s, 9H); 13C NMR (DMSO-d6) δ 153.0, 144.1, 138.5, 137.3, 132.9, 130.5, 128.1, 124.8, 79.9, 28.8, 19.99, 19.97; IR (KBr mull) 3361, 3009, 2981, 2981, 1513, 1495 cm−1. A portion was further purified by recrystallization from ethyl acetate for analysis. Anal. Calcd. for C14H20N2O2: C, 67.71; H, 8.12; N, 11.28. Found: C, 67.51; H, 8.07; N, 11.22.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][C:10](=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][C@@H:20]1[NH:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O.C(O)(=O)C.C1COCC1>[C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][CH:10]([N:25]3[CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][C@@H:20]3[CH3:19])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C1CN(C(c2ccccc2)c2ccccc2)C1
Yield: 92.8 %

Procedure:
To a mixed solution of a commercially available product of 1-(diphenylmethyl)azetidin-3-one (300 mg, 1.26 mmol), THF (6.0 mL) and acetic acid (500 μL) was added a commercially available product of tert-butyl(3S)-3-methylpiperazine-1-carboxylate (304 mg, 1.51 mmol) at room temperature. The resultant mixture was stirred at room temperature for 1 hour and 40 minutes. Sodium triacetoxyborohydride (536 mg, 2.52 mmol) was added to the reaction mixture at room temperature, and the resultant mixture was stirred at room temperature for 13 hours and 45 minutes. Sodium hydrogen carbonate and water were added to the reaction mixture, and the resultant solution was extracted with ethyl acetate. An organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate and then filtrated. A filtrate was concentrated under a reduced pressure and the resultant residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=5:1) to give the title compound (493 mg, yield: 93%).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1([CH2:15][N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[Cl:27][C:28]1[C:29]([OH:37])=[C:30]([CH:33]=[C:34]([Cl:36])[CH:35]=1)[CH:31]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl.C(N(CC)CC)C>[Cl:27][C:28]1[C:29]([OH:37])=[C:30]([CH:33]=[C:34]([Cl:36])[CH:35]=1)[CH2:31][N:12]1[CH2:13][CH2:14][C:9]([CH2:15][N:16]2[C:17](=[O:26])[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24]2=[O:25])([F:8])[CH2:10][CH2:11]1
Reactant: O=Cc1cc(Cl)cc(Cl)c1O
Reactant: O=C1c2ccccc2C(=O)N1CC1(F)CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1CC1(F)CCN(Cc2cc(Cl)cc(Cl)c2O)CC1
Reaction time: 0.08 h

Procedure:
Triethylamine (9 ml) was added to a solution of a trifluoroacetic acid salt of 2-(4-fluoro-piperidin-4-ylmethyl)-isoindole-1,3-dione (22.6 g) in dichloromethane (300 ml). The obtained solution was stirred for 5 minutes, and then 3,5-dichloro-2-hydroxy-benzaldehyde (12.4 g) and NaBH(OAc)3 (19 g) were added and the mixture was stirred at room temperature for 3 hours. The obtained solution was washed with a saturated aqueous solution of sodium hydrogen carbonate, the dichloromethane was concentrated out, and the residue was recrystallized from ether to obtain 2-[1-(3,5-dichloro-2-hydroxy-benzyl)-4-fluoro-piperidin-4-ylmethyl]-isoindole-1,3-dione.
Reaction SMILES: [F:1][C:2](=[C:7]([F:9])[F:8])[CH2:3][C:4]([Cl:6])=[O:5].Cl.[NH2:11][CH2:12][CH2:13][SH:14]>CCOCC>[ClH:6].[F:1][C:2](=[C:7]([F:9])[F:8])[CH2:3][C:4](=[O:5])[S:14][CH2:13][CH2:12][NH2:11]
Reactant: NCCS
Reactant: O=C(Cl)CC(F)=C(F)F
Agent: Cl
Solvent: CCOCC
Product: NCCSC(=O)CC(F)=C(F)F
Temperature: 25 °C
Yield: 33.9 %

Procedure:
A mixture of 3,4,4-trifluoro-3-butenoyl chloride (2.5 g, 0.0158 mole) and 2-aminoethanethiol hydrochloride (1.14 g, 0.010 mole) is slowly heated to reflux for 15 min. The mixture is cooled to room temperature and treated with dry ether and filtered. The product is recrystallized from absolute ethanol to give 0.8 g of the title compound as a off-white solid, a 34% yield. m.p. 95°-115° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[C:16]([C:17]2[NH:25][C:20]3[CH2:21][NH:22][CH2:23][CH2:24][C:19]=3[N:18]=2)=[CH:15][CH:14]=[CH:13][C:12]=1[C:26]1[NH:30][C:29]2[CH:31]=[CH:32][C:33]([C:35]([NH2:37])=[NH:36])=[CH:34][C:28]=2[N:27]=1.Cl.[N:39]1([C:44](N)=[NH:45])C=CC=N1.O>CN(C=O)C.C(OCC)C>[C:35]([C:33]1[CH:32]=[CH:31][C:29]2[NH:30][C:26]([C:12]3[C:11]([OH:10])=[C:16]([C:17]4[NH:25][C:20]5[CH2:21][N:22]([C:44]([NH2:45])=[NH:39])[CH2:23][CH2:24][C:19]=5[N:18]=4)[CH:15]=[CH:14][CH:13]=3)=[N:27][C:28]=2[CH:34]=1)(=[NH:37])[NH2:36]
Reactant: N=C(N)c1ccc2[nH]c(-c3cccc(-c4nc5c([nH]4)CNCC5)c3O)nc2c1
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: N=C(N)c1ccc2[nH]c(-c3cccc(-c4nc5c([nH]4)CN(C(=N)N)CC5)c3O)nc2c1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
Hunig's base (0.042 mL, 0.24 mmol) was added to a suspension of 2-[2-Hydroxy-3-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-phenyl]-1H-benzoimidazole-5-carboxamidine 75 (19 mg, 0.04 mmol) and 1H-pyrazole-1-carboxamidine hydrochloride (12 mg, 0.082 mmol) in anhydrous DMF and the mixture was stirred for 12-18 h at 80° C. The mixture was poured into water (15 mL)/diethyl ether (15 mL). The aqueous layer was washed with diethyl ether (3×10 mL) and concentrated to dryness. HPLC purification (2-50% acetonitrile/60 minutes) afforded 2-[3-(5-Carbamimidoyl-1H-benzoimidazol-2-yl)-2-hydroxy-phenyl]-3,4,6,7-tetrahydro-imidazo[4,5-c]pyridine-5-carboxamidine 76 as a lyophilized yellow light powder (15.5 mg, 75% yield) (Example 298, Table 2a).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])=[O:2].C1(C)C=CC(S([CH2:21][N+:22]#[C-:23])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[O:2]1[C:1]([C:3]2[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=2)[C:6]([OH:8])=[O:7])=[CH:23][N:22]=[CH:21]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1cccc(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(O)c1cccc(-c2cnco2)c1
Yield: 76.8 %

Procedure:
To a mixture of 3-formylbenzoic acid (500 mg) and p-toluenesulfonylmethyl isocyanide (715 mg) in methanol (20 mL) was added potassium carbonate (1.38 g) and the mixture was heated under reflux for 2 hours. After evaporation of solvent, the residue was partitioned between ethyl acetate and water. The aqueous layer was separated and acidified with 1N hydrochloric acid. The resulting precipitates were collected and washed with water, methanol and ether to give 3-(1,3-oxazol-5-yl)benzoic acid as a colorless amorphous powder (484 mg).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:22](/[CH:23]=[CH:24]/[C@@H:25]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C@H:12]2[CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([OH:21])[C:19]=3[CH2:20][C@H:11]2[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:39](OC(=O)C)(=[O:41])[CH3:40]>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C.C(=O)(O)[O-].[Na+]>[C:39]([O:21][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[CH2:20][C@H:11]1[CH2:10][C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C@H:22](/[CH:23]=[CH:24]/[C@@H:25]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:34])[CH3:33])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C@H:12]1[CH2:13]2)(=[O:41])[CH3:40]
Reactant: CCCCC[C@@H](/C=C/[C@@H]1[C@H]2Cc3cccc(O)c3C[C@H]2C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCC[C@@H](/C=C/[C@@H]1[C@H]2Cc3cccc(OC(C)=O)c3C[C@H]2C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Yield: 84.1 %

Procedure:
(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-hexahydro-2-(tert-butyldimethylsilyoxy)-1-((S,E)-3-(tert-butyldimethylsilyoxy)oct-1-enyl)-1H-cyclopenta[b]naphthalen-5-ol (0.5 g, 0.89 mmol) in toluene (5 ml) was treated with acetic anhydride (0.1 ml, 1.07 mmol) and DMAP (1.1 mg, 0.09 mmol) at room temperature for 30 minutes. The reaction was diluted with saturated sodium bicarbonate aqueous (10 ml) and extracted with ethyl acetate (10 ml). The reaction mixture was phase separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate. The solid was filtered off. The solvent was evaporated off under vacuum. The crude product was purified by chromatography on silica gel using a mixture of hexane and ethyl acetate as a gradient eluent. 0.45 g (1R,2R,3aS,9aS)-2,3,3a,4,9,9a-hexahydro-2-(tert-butyldimethylsilyoxy)-1-((S,E)-3-(tert-butyldimethylsilyoxy)oct-1-enyl)-1H-cyclopenta[b]naphthalen-5-yl acetate was obtained. The product was then dissolved in tetrahydrofuran (0.9 ml), and treated with acetic acid (2.7 ml) and distilled water (0.9 ml) overnight at room temperature. The reaction was then diluted with saturated sodium bicarbonate aqueous (12 ml) and extracted with ethyl acetate (15 ml). The reaction mixture was phase separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate. The solid was filtered off. The solvent was evaporated off under vacuum. The crude product was purified by chromatography on silica gel using a mixture of hexane and ethyl acetate as a gradient eluent. The titled compound was obtained in a crystalline form. Melting range was 54˜65° C. Yield: 65%.
Reaction SMILES: ClC1C(C#N)=C2C(=CC=1)N(CC(O)=O)C(C)=C2S(C1C=CC(Cl)=CC=1)(=O)=O.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([C:38]2[C:46]3[C:41](=[C:42]([O:52][CH3:53])[CH:43]=[CH:44][C:45]=3[S:47]([CH2:50][CH3:51])(=[O:49])=[O:48])[N:40]([CH2:54][C:55]([O:57]C)=[O:56])[C:39]=2[CH3:59])(=[O:37])=[O:36])=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([C:38]2[C:46]3[C:41](=[C:42]([O:52][CH3:53])[CH:43]=[CH:44][C:45]=3[S:47]([CH2:50][CH3:51])(=[O:49])=[O:48])[N:40]([CH2:54][C:55]([OH:57])=[O:56])[C:39]=2[CH3:59])(=[O:36])=[O:37])=[CH:31][CH:30]=1
Reactant: CCS(=O)(=O)c1ccc(OC)c2c1c(S(=O)(=O)c1ccc(Cl)cc1)c(C)n2CC(=O)OC
Agent: Cc1c(S(=O)(=O)c2ccc(Cl)cc2)c2c(C#N)c(Cl)ccc2n1CC(=O)O
Product: CCS(=O)(=O)c1ccc(OC)c2c1c(S(=O)(=O)c1ccc(Cl)cc1)c(C)n2CC(=O)O

Procedure:
Prepared by the method of example 5 part (d) using the product of step (c).
Reaction SMILES: CC(CC)C(=O)C(OCCC(C)CCC=C(C)C)=O.C([C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:43])[C:30]([O:32][CH2:33][CH2:34][CH:35]([CH3:42])[CH2:36][CH2:37][CH:38]=[C:39]([CH3:41])[CH3:40])=[O:31])=[CH:25][CH:24]=1)(=O)C.CC(CCC=C(C)C)CCC(C)C(=O)C([O-])=O.CC(CCC=C(C)C)CCCC(=O)C([O-])=O.O=C(C1C=CC=CC=1)C(OCCC(C)CCC=C(C)C)=O>>[CH:26]1([C:29](=[O:43])[C:30]([O:32][CH2:33]/[CH:34]=[C:35](\[CH3:42])/[CH2:36][CH2:37][CH:38]=[C:39]([CH3:40])[CH3:41])=[O:31])[CH2:27][CH2:28][CH2:23][CH2:24][CH2:25]1
Reactant: CC(=O)c1ccc(C(=O)C(=O)OCCC(C)CCC=C(C)C)cc1
Agent: CC(C)=CCCC(C)CCC(C)C(=O)C(=O)[O-]
Agent: CC(C)=CCCC(C)CCCC(=O)C(=O)[O-]
Agent: CC(C)=CCCC(C)CCOC(=O)C(=O)c1ccccc1
Product: CC(C)=CCC/C(C)=C/COC(=O)C(=O)C1CCCCC1

Procedure:
MS (EI): 184 (M+, 2); 112 (3); 111 (33); 110 (3); 84 (6); 83 (100); 81 (3); 79 (2); 77 (1); 68 (1); 67 (5); 65 (1); 56 (3); 55 (54); 54 (5); 53 (5); 51 (1); 43 (2); 42 (3); 41 (23); 40 (2); 39 (12); 30 (1); 29 (20); 28 (3); 27 (13); 26 (1).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:25]=[CH:24][C:9]2[N:10]=[C:11]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][NH:14][C:11]1[O:12][CH2:13][C:8]2[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)[CH:25]=[CH:24][C:9]=2[N:10]=1
Reactant: CN1CCNCC1
Reactant: COc1ccccc1CNC1=Nc2ccc(NC(=O)CCl)cc2CO1
Product: COc1ccccc1CNC1=Nc2ccc(NC(=O)CN3CCN(C)CC3)cc2CO1
Yield: 225.1 %

Procedure:
Prepared from the above described 2-chloro-N-[2-(2-methoxy-benzylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (50 mg, 0.129 mmol, HPLC 0.889 min 81%) and N-methylpiperazine (900 ul, 8 mmol) according to the procedure described for Example 3 step B. Obtained the title compound as a white foam (123 mg, 73%, HPLC 0.531 min 100%), MS (ISP) m/e=424.4 [(M+H)+].
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([N:7]1[C:20]2[CH:19]=[CH:18][C:17]([CH2:21]O)=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:6].CN(C=O)C>C(Cl)Cl>[Cl:3][CH2:21][C:17]1[CH:18]=[CH:19][C:20]2[N:7]([CH2:5][CH3:6])[C:8]3[C:13]([S:14][C:15]=2[CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: CCN1c2ccccc2Sc2cc(CO)ccc21
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCN1c2ccccc2Sc2cc(CCl)ccc21
Reaction time: 1 h
Yield: 95.7 %

Procedure:
In an atmosphere of argon, thionyl chloride (0.65 ml, 8.86 mmol) was added at 0° C. to a mixture of 10-ethyl-3-hydroxymethylphenothiazine (1.14 g, 4.43 mmol), DMF (0.1 ml) and methylene chloride (12 ml), and the mixture was stirred for 1 hour and then at room temperature for 1 hour. The reaction mixture was concentrated under a reduced pressure, and chloroform and a saturated sodium bicarbonate aqueous solution (each 20 ml) were added to the residue in that order. The reaction product was extracted with ethyl acetate, and the extract was washed with saturated sodium chloride aqueous solution. The extract was dried over anhydrous magnesium sulfate, and then concentrated under a reduced pressure to give 3-chloromethyl-10-ethylphenothiazine (1.17 g, 4.24 mmol, 96%) as brown oil.
Reaction SMILES: [F:1][CH:2]([F:20])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:14]=[C:13]([C:15]([O:17]CC)=[O:16])[CH:12]=[N:11]2)[CH:7]=[CH:8][CH:9]=1.CO.O>C1COCC1.CCCCCCC.C(OCC)(=O)C>[F:20][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[CH:12]=[N:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1cnn(-c2cccc(OC(F)F)c2)c1
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: O=C(O)c1cnn(-c2cccc(OC(F)F)c2)c1
Temperature: 80 °C
Yield: 77.8 %

Procedure:
To a solution of ethyl 1-(3-(difluoromethoxy)phenyl)-1H-pyrazole-4-carboxylate (5 g, 17.7 mmol) in a mixture of THF (100 ml), methanol (50 ml) and water (50 ml) lithium hydroxide hydrate (2.23 g, 53.1 mmol) was added. The solution was heated to 80° C. for 2 h. Most of the organic solvent was removed under reduced pressure. Sodium bicarbonate solution was added and the organic layer was separated. The aqueous layer was made acidic by addition of 25% aq. hydrochloric acid (until acidic pH) and the mixture was extracted two times with ethyl acetate. The organic layers were combined, dried (MgSO4) and evaporated to yield a solid. The solid was stirred in a mixture of heptane and ethyl acetate for 2 h, filtered off and dried to yield 1-(3-(difluoromethoxy)phenyl)-1H-pyrazole-4-carboxylic acid as an off-white solid (3.5 g, 78%) which was used for the next step.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH:4]=[CH:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[O:13][CH2:14][C:15]([N:17]1[CH2:22][C@H:21]([CH3:23])[N:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:19][C@H:18]1[CH3:32])=[O:16].O.[OH-].[Li+]>O1CCCC1.CO.O>[Cl:12][C:10]1[CH:9]=[CH:8][C:7]([O:13][CH2:14][C:15]([N:17]2[CH2:22][C@H:21]([CH3:23])[N:20]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH2:19][C@H:18]2[CH3:32])=[O:16])=[C:6]([CH:5]=[CH:4][C:3]([OH:33])=[O:2])[CH:11]=1
Reactant: COC(=O)C=Cc1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1C=CC(=O)O

Procedure:
To a solution of 3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-acrylic acid methyl ester (0.060 g, 0.13 mmol) in tetrahydrofuran, methanol and water (1 ml each) was added lithium hydroxide hydrate (0.020 g, 0.51 mmol). After 1 hour at 50° C. the reaction was concentrated and the title compound was isolated by chromatography on silica gel (0.032 g, LRMS: 461.1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1.[CH3:17][O:18][C:19](=[O:25])[CH:20]([CH3:24])[C:21](O)=[O:22]>ClCCl.CO>[CH3:17][O:18][C:19](=[O:25])[CH:20]([CH3:24])[C:21]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]2[CH:14]=[CH:15][CH:16]=[C:2]([F:1])[CH:3]=2)=[CH:8][CH:9]=1)=[O:22]
Reactant: Nc1ccc(OCc2cccc(F)c2)cc1
Reactant: COC(=O)C(C)C(=O)O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C(C)C(=O)Nc1ccc(OCc2cccc(F)c2)cc1

Procedure:
The title compound is prepared in analogy to example 2, starting from 4-(3-fluoro-benzyloxy)-phenylamine (as prepared in example 1b) and 2-methyl-malonic acid monomethyl ester (Nader et al., Chem. Ber. 1986, 119, 1196). Yield after flash-chromatography with dichloromethane/methanol 98:2: 40%. Colorless solid. Mp=119° C.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.[F:20][C:21]1[CH:26]=[C:25]([F:27])[N:24]=[C:23]([NH2:28])[N:22]=1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:5]2[N:6]=[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]3[C:4]=2[CH2:3][NH:28][C:23]2[N:24]=[C:25]([F:27])[CH:26]=[C:21]([F:20])[N:22]=2)=[CH:14][CH:15]=1
Reactant: Nc1nc(F)cc(F)n1
Reactant: ClCc1c(-c2ccc(Cl)cc2)nc2ccccn12
Agent: Cl
Product: Fc1cc(F)nc(NCc2c(-c3ccc(Cl)cc3)nc3ccccn23)n1
Yield: 34 %

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 139 from 3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloride and 4,6-difluoropyrimidin-2-amine. (0.100 g, 34% yield); 1H-NMR (300 MHz, CDCl3, δ) 8.08 (d, J=6.9 Hz, 1H), 7.64-7.85 (m, 3H) 7.37-7.33 (m, 2H), 7.25-7.20 (m, 1H), 6.85-6.80 (m, 1H), 6.07 (t, J=9.3 Hz, 1H), 5.86-5.85 (m, 1H), 5.99 (d, J=5.4 Hz, 2H).