Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[N:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[C:4](=[O:14])[CH:3]=1.Br[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:25])[F:24])=[N:21][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)Cl>[O:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH:8]1[N:5]1[C:4](=[O:14])[CH:3]=[C:2]([O:1][CH2:16][C:17]2[CH:22]=[N:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=2)[CH:7]=[N:6]1
Reactant: FC(F)(F)c1ccc(CBr)cn1
Reactant: O=c1cc(O)cnn1C1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=c1cc(OCc2ccc(C(F)(F)F)nc2)cnn1C1CCCCO1
Yield: 123.1 %

Procedure:
5-Hydroxy-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (2.3 g, 12 mmol), 5-(bromomethyl)-2-(trifluoromethyl)pyridine (7.2 g, 30 mmol) and K2CO3 (8.4 g, 60 mmol) were stirred in DMF (40 ml) and CH2Cl2 (40 ml) for 48 h. The mixture was diluted with CH2Cl2, washed with 5% LiCl solution (4×) and concentrated. The residue was purified by column chromatography (40 g ISCO column column eluting with methylene chloride and a 10:1 methanol/ammonium hydroxide mixture; gradient 100% methylene chloride to 95% methylene chloride) to yield the title compound (5.25 g, >100%) as a waxy white solid containing some DMF: 1H NMR (300 MHz, CDCl3) δ 8.78 (d, J=1.8 Hz, 1H), 7.97-7.88 (m, 1H), 7.76 (d, J=7.9 Hz, 1H), 7.72 (m, 1H), 6.20 (d, J=2.9 Hz, 1H), 6.03-5.98 (d, J=10.9, 2.0 Hz, 1H), 5.11 (s, 2H), 4.16-4.08 (m, 1H), 3.79-3.69 (m, 1H), 2.24-1.96 (m, 2H), 1.83-1.48 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[CH:10]=2)=[CH:6][CH:5]=[C:4]([N+:28]([O-])=O)[N:3]=1>CO.[Pd]>[CH3:1][C:2]1[N:3]=[C:4]([NH2:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH:10]=1
Reactant: Cc1nc([N+](=O)[O-])ccc1Oc1ccnc(-c2ccc(C3CCN(C)CC3)cc2)c1
Agent: [Pd]
Solvent: CO
Product: Cc1nc(N)ccc1Oc1ccnc(-c2ccc(C3CCN(C)CC3)cc2)c1
Yield: 87.1 %

Procedure:
A solution of 2-methyl-3-((2-(4-(1-methylpiperidin-4-yl)phenyl)pyridin-4-yl)oxy)-6-nitropyridine (0.553 g, 1.367 mmol) in MeOH (20 mL) was treated with 10% Pd/C (50% w/w water, 146 mg, 0.137 mmol) and hydrogenated (1 atm) overnight. The solids were removed via filtration, washed with MeOH and the filtrate concentrated to dryness to afford 6-methyl-5-((2-(4-(1-methylpiperidin-4-yl)phenyl)pyridin-4-yl)oxy)pyridin-2-amine (446 mg, 87%). MS (ESI) m/z: 375.2 (M+H+).
Reaction SMILES: [C:1]([NH:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([NH:18][C:19]3[CH:24]=[C:23]([NH:25][C:26]([NH:28][C:29]4[CH:34]=[CH:33][C:32](Cl)=[C:31]([C:36]([F:39])([F:38])[F:37])[CH:30]=4)=[O:27])[CH:22]=[CH:21][C:20]=3[CH3:40])=[O:17])[C:10]=2[CH:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].[F:41]C1C=CC(C(F)(F)F)=CC=1N=C=O>>[C:1]([NH:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([NH:18][C:19]3[CH:24]=[C:23]([NH:25][C:26]([NH:28][C:29]4[CH:30]=[C:31]([C:36]([F:39])([F:38])[F:37])[CH:32]=[CH:33][C:34]=4[F:41])=[O:27])[CH:22]=[CH:21][C:20]=3[CH3:40])=[O:17])[C:10]=2[CH:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1NC(=O)c1cccc2c(NC(C)(C)C)nccc12
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Product: Cc1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1NC(=O)c1cccc2c(NC(C)(C)C)nccc12
Yield: 42 %

Procedure:
The procedures of Steps (1), (2) and (3) of Example 12 were repeated step by step, except for using 1-fluoro-2-isocyanato-4-trifluoromethyl benzene instead of benzene in Step (1) of Example 12 to obtain the title compound (60 mg, 42%).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]([NH:17][CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[C@H:27]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:26][CH2:25]4)[C:14]([C:37]([F:40])([F:39])[F:38])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH3:4].[CH3:41]N(C=O)C>>[CH2:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:16]=[C:15]([N:17]([CH3:41])[CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[C@H:27]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:26][CH2:25]4)[C:14]([C:37]([F:40])([F:38])[F:39])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)[CH3:4]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCNc3nc(-c4ccc(CC)cc4)ccc3C(F)(F)F)ccc21
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCN(C)c3nc(-c4ccc(CC)cc4)ccc3C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8 %

Procedure:
Sodium hydride (0.02 g, 0.86 mmol) was added to a solution of ethyl [(1 S)-5-(3-{[6-(4-ethylphenyl)-3-(trifluoromethyl)-2-pyridinyl]amino}propoxy)-2,3-dihydro-1H-inden-1-yl]acetate (Example 318) (0.21 g, 0.39 mmol) in DMF (2 mL). After stirring at rt for 30 min, Mel (0.05 mL, 6.32 mmol) was added. The mixture was stirred at rt for 18 h, quenched with water (5 mL), and extracted with ether (3×). The combined ether extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The product (0.017 g, 8%) was isolated after silica gel flash chromatography (2:1 hexanes/EtOAc). 1H NMR (400 MHz, CD2Cl2) δ 7.99 (d, 2H), 7.85 (d, 1H), 7.35-7.25 (m, 3H), 7.01 (d, 1H), 6.72 (d, 1H), 6.65 (dd, 1H), 4.15 (q, 2H), 4.00 (t, 2H), 3.73 (t, 2H), 3.47 (qt, 1H), 3.08 (s, 3H), 2.90-2.68 (m, 5H), 2.42-2.30 (m, 2H), 2.15 (qt, 2H), 1.78-1.68 (m, 1H), 1.32-1.26 (m, 6H).
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[CH2:15][OH:16])=O)(C)(C)C>O1CCOCC1>[ClH:1].[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[CH2:15][OH:16]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1CO
Agent: Cl
Solvent: C1COCCO1
Product: OC[C@@H]1CCCCN1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 4M HCl solution in dioxane (30 mL) was added to (S)-2-Hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (5.12 g, 23.78 mmol). The mixture was stirred at rt for 3 h. The solvent was removed in vacuo to yield the title product as a hydrochloride salt (3.43 g, 95%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:40]=[CH:41][C:42]=1[F:43])[C:5]([NH:7][CH2:8][CH2:9][CH:10]([C:22]1([CH2:36][CH2:37][CH2:38][OH:39])[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]1=[O:35])[C:11]([NH:13][O:14]CC1C=CC=CC=1)=[O:12])=[O:6]>CCO>[F:1][C:2]1[CH:3]=[C:4]([CH:40]=[CH:41][C:42]=1[F:43])[C:5]([NH:7][CH2:8][CH2:9][CH:10]([C:22]1([CH2:36][CH2:37][CH2:38][OH:39])[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:23]1=[O:35])[C:11]([NH:13][OH:14])=[O:12])=[O:6]
Reactant: O=C(NCCC(C(=O)NOCc1ccccc1)C1(CCCO)CCN(CCc2ccccc2)C1=O)c1ccc(F)c(F)c1
Solvent: CCO
Product: O=C(NCCC(C(=O)NO)C1(CCCO)CCN(CCc2ccccc2)C1=O)c1ccc(F)c(F)c1
Reaction time: 7 h
Yield: 63.1 %

Procedure:
A solution of α-[2-[(3,4-difluorobenzoyl)amino]ethyl]-N-benzyloxy-3-(3-hydroxypropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide (215 mg, 0.368 mmol) is dissolved in EtOH (5 mL) and purged with N2. Pearlman's catalyst (22 mg) is added and the atmosphere was replaced with H2 . After 7 hours, the mixture is filtered through celite, washing the residual solids with MeOH, EtOH, and CH2Cl2. The filtrate is concentrated to give 171 mg of a slightly brown foam. The material is crystallized from hot EtOAc (diluting with hexane). The product is isolated and dried in the vacuum oven (45° C.) overnight to provide 117 mg (63%) of the title compound as a cream-colored, powdery solid (mp 118° C., dec.):
Reaction SMILES: C([O:3][C:4](=[O:22])[C@@H:5]([O:20][CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([C:17]([OH:19])=O)([CH3:16])[CH3:15])=[CH:9][CH:8]=1)C.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][CH2:31][NH2:32].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][CH2:31][NH:32][C:17]([C:14]([CH3:15])([O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:20][CH3:21])[C:4]([OH:3])=[O:22])=[CH:12][CH:11]=1)[CH3:16])=[O:19]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C(=O)O)cc1)OC
Reactant: NCCc1ccccc1Cl
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OC(C)(C)C(=O)NCCc2ccccc2Cl)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (PREPARATION 5, step 2) and 2-(2-chloro-phenyl)-ethylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C22H26ClNO5 [M−H]−: 420.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[C:15]3/[C:16](=[O:22])[N:17]=[C:18](SC)[S:19]/3)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:23]#[N:24])[CH3:2].[F:25][C:26]([F:35])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[CH2:27][NH2:28].CCN(C(C)C)C(C)C>>[F:35][C:26]([F:25])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[CH2:27][NH:28][C:18]1[S:19]/[C:15](=[CH:14]\[C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]=[CH:6][C:5]([C:23]#[N:24])=[C:4]3[O:3][CH2:1][CH3:2])/[C:16](=[O:22])[N:17]=1
Reactant: NCC(F)(F)c1ccccn1
Reactant: CCOc1c(C#N)cnc2ccc(/C=C3\SC(SC)=NC3=O)cc12
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1c(C#N)cnc2ccc(/C=C3\SC(NCC(F)(F)c4ccccn4)=NC3=O)cc12

Procedure:
Similar procedure as described in example 14h was used, starting from 4-ethoxy-6-[2-methylsulfanyl-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carbonitrile (example 14g), 2,2-difluoro-2-pyridin-2-yl-ethylamine and DIEA to give 6-[2-(2,2-Difluoro-2-pyridin-2-yl-ethylamino)-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-ethoxy-quinoline-3-carbonitrile. LC-MS m/e 466 (MH+).
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[N:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][C:14]=1[CH3:22].O>COCCOC.C([O-])([O-])=O.[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[S:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[N:3]=2)=[CH:15][C:14]=1[CH3:22]
Reactant: FC(F)(F)c1nsc(Cl)n1
Reactant: COc1ccc(B(O)O)cc1C
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: O
Solvent: COCCOC
Product: COc1ccc(-c2nc(C(F)(F)F)ns2)cc1C
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
5-Chloro-3-(trifluoromethyl)-1,2,4-thiadiazole (2.26 g, 12.0 mmol) (synthesis described in DE 3228147) was dissolved in 1,2-dimethoxyethane (50 mL) and 4-methoxy-3-methylphenylboronic acid (2.4 g, 14.4 mmol) and tetrakis(triphenylphosphine)palladium (0.1 g, 0.09 mmol) were added. After 1.5 h at rt, Na2CO3 (19.2 mL, 2M aqueous solution) was added and the mixture was stirred for 4 h at 80° C. and for 14 h at rt. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. Due to low conversion the crude product was again reacted with 5-chloro-3-(trifluoromethyl)-1,2,4-thiadiazole (2.4 g, 14.4 mmol), tetrakis(triphenylphosphine)palladium (0.1 g, 0.09 mmol) in DME (50 mL) and Na2CO3 (19.2 mL, 2M aqueous solution). After stirring at 80° C. for 16 h, the reaction mixture was cooled and water was added. The mixture was extracted with ethyl acetate, the organic phase dried over MgSO4, filtered and concentrated under reduced pressure. The crude product (3.2 g) had a purity of ˜90% and was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[CH:13][N:14]3[CH3:17])=[C:10]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=3)[N:9]=2)[N:3]=1>CO.ClCCl.[Pd]>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[CH:13][N:14]3[CH3:17])=[C:10]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=3)[N:9]=2)[N:3]=1
Reactant: Cc1cc(C)n(-c2nc(Nc3ccc([N+](=O)[O-])cc3)c3ncn(C)c3n2)n1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(C)n(-c2nc(Nc3ccc(N)cc3)c3ncn(C)c3n2)n1
Reaction time: 24 h
Yield: 98.1 %

Procedure:
[2-(3,5-Dimethyl-pyrazol-1-yl)-9-methyl-9H-purin-6-yl]-(4-nitro-phenyl)-amine (2.89 g, 7.93 mmol) was dissolved in methanol (50 mL) and dichloromethane (50 mL). Palladium on carbon (5%, 600 mg) was added and the reaction mixture was stirred under a hydrogen atmosphere for 24 hours. Filtration through celite followed by concentration in vacuo gave N-[2-(3,5-dimethyl-pyrazol-1-yl)-9-methyl-9H-purin-6-yl]-benzene-1,4-diamine (2.6 g, 98%) as a yellow foam.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:22][CH3:23])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH2:20][CH3:21])[CH:11]=3)=[CH:4][CH:3]=1.[P:24](Cl)([O:29][CH2:30][CH3:31])([O:26][CH2:27][CH3:28])=[O:25].C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>O1CCOCC1>[C:17]([C:16]1[C:15]2[C:10](=[CH:11][C:12]([O:19][CH2:20][CH3:21])=[CH:13][CH:14]=2)[N:9]([CH2:22][CH3:23])[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([NH:1][P:24](=[O:25])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[CH:7][CH:6]=1)#[N:18]
Reactant: CCOP(=O)(Cl)OCC
Reactant: CCOc1ccc2c(C#N)c(-c3ccc(N)cc3)n(CC)c2c1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc2c(C#N)c(-c3ccc(NP(=O)(OCC)OCC)cc3)n(CC)c2c1
Temperature: 80 °C
Yield: 50.6 %

Procedure:
A solution of 2-(4-aminophenyl)-6-ethoxy-1-ethyl-1H-indole-3-carbonitrile (148 mg, 0.484 mmol), diethyl chlorophosphate (0.086 mL, 0.58 mmol) and diisopropylethylamine (0.10 mL, 0.57 mmol) in 1,4-dioxane (5 mL) is stirred at ambient temperature for 12 hours, then heated to 80° C. for an additional 24 hours. The solution is cooled and poured into 50 mL of ethyl acetate. This is washed with water and saturated brine (50 mL each), then dried over anhydrous magnesium sulfate, filtered and evaporated. The residual material is separated by flash chromatography (eluting 2/1 ethyl acetate/hexane on silica gel 60) to afford diethyl [4-(3-cyano-6-ethoxy-1-ethyl-1H-indol-2-yl)-phenyl]-phosphoramidate (108 mg, 0.245 mmol, 51%) as a white powder after evaporation.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)([CH3:5])[CH3:4])#[N:2].C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:26][C:27]1[CH:28]=[C:29]([CH:46]=[CH:47][C:48]=1[F:49])[O:30][C:31]1[CH:43]=[CH:42][C:34]2[N:35]=[C:36]([NH:38][C:39](=[O:41])[CH3:40])[S:37][C:33]=2[C:32]=1[C:44]#[N:45]>O1CCCC1.C(OCC)(=O)C>[C:39]([NH:38][C:36]1[S:37][C:33]2[C:32]([C:44]#[N:45])=[C:31]([O:30][C:29]3[CH:46]=[CH:47][C:48]([F:49])=[C:27]([NH:26][C:9](=[O:11])[C:8]4[CH:12]=[CH:13][CH:14]=[C:6]([C:3]([C:1]#[N:2])([CH3:4])[CH3:5])[CH:7]=4)[CH:28]=3)[CH:43]=[CH:42][C:34]=2[N:35]=1)(=[O:41])[CH3:40]
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Reactant: CC(=O)Nc1nc2ccc(Oc3ccc(F)c(N)c3)c(C#N)c2s1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc2ccc(Oc3ccc(F)c(NC(=O)c4cccc(C(C)(C)C#N)c4)c3)c(C#N)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.7 %

Procedure:
To a solution of 3-(1-cyano-1-methylethyl)benzoic acid (66 mg, 0.350 mmol) in tetrahydrofuran (1 mL) were added oxalyl chloride (37 μL, 0.438 mmol) and N,N-dimethylformamide (10 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (1 mL). N-[6-(3-Amino-4-fluorophenoxy)-7-cyano-1,3-benzothiazol-2-yl]acetamide (100 mg, 0.292 mmol) produced in Example 34(ii) was added to the solution, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate (25 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was successively purified by basic silica gel column chromatography (ethyl acetate/n-hexane=60/40→100/0) and silica gel column chromatography (ethyl acetate/n-hexane=60/40→100/0), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate/n-hexane to give the title compound (43 mg, 28%) as a white powder.
Reaction SMILES: [C:1]1([C:7]([CH:9]=[CH2:10])=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:12]([C@@H:19]1NC(C)(C)N(C)[C:20]1=[O:27])C1C=CC=CC=1.C(C=C)=O>C[N+]([O-])=O.O>[C:1]1([C:7]2[CH2:8][CH2:12][C@@H:19]([CH:20]=[O:27])[CH2:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CC(=C)c1ccccc1
Reactant: CN1C(=O)[C@H](Cc2ccccc2)NC1(C)C
Agent: C=CC=O
Agent: Cl
Solvent: O
Solvent: C[N+](=O)[O-]
Product: O=C[C@H]1CC=C(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 7 h
Yield: 90 %

Procedure:
To a 0° C. solution of 2-phenyl-1,3-butadiene (89 mg, 0.68 mmol) in CH3NO2/H2O (95/5 v/v, 1.0 M) was added 5 (29.8 mg, 0.14 mmol) and acrolein (135 μL, 2.1 mmol). The solution was stirred at 0° C. for 7 hr, then directly placed onto a silica gel column and eluted with 5% EtOAc/hex affording the title compound as a cololess oil in 90% yield (114 mg, 0.61 mmol, 83% ee). Product ratios were determined, after reduction to the corresponding alcohol (4 eq NaBH4, MeOH (0.1 M)), by HPLC (Chiralcel OD-H column, 6% isopropanol in hexanes, 1 mL/min) tr=16.2 and 20.4, min. (1R)-4-phenyl-3-cyclohexene-1-carboxaldehyde: IR (CH2Cl2) 2926, 2837, 2714, 1722, 1494, 1444 cm−1; 1H NMR (400 MHZ, CDCl3) δ9.78 (s, 1H, CHO), 7.40-7.23 (m, 5H, ArH), 6.16-6.12 (m, 1H, PhC=CH), 2.64-2.50 (m, 5H), 2.23-2.15 (m, 1H), 1.90-1.79 (m, 1H). 13C NMR (100 MHZ, CDCl3) δ204.2, 141.6, 136.8, 128.2, 126.9, 125.0, 122.0, 45.7, 26.0, 25.0, 22.6; HRMS (CI) exact mass calcd for (C13H19N2OCl) requires m/z 186.1045, found m/z 186.1041. (1R)-4-phenyl-3-cyclohexene-1-ol: IR (CH2Cl2) 3374, 3289, 2918, 2860, 1444, 1034 cm−1; 1H NMR (500 MHZ, CDCl3) δ7.41-7.39 (d, J=7.6 Hz, 2H, o-PhH), 7.34-7.31 (t, J=7.7 Hz, 2H, m-PhH), 7.26-7.22 (m, 1H,p-PhH), 6.13 (br, 1H, PhC═CH), 3.66-3.58 (m, 2H, CH2OH), 2.58-2.41 (m, 2H), 2.40-2.31 (m, 1H), 2.05-1.83 (m, 3H), 1.72-1.68 (s, 1H), 1.50-1.41 (m, 1H); 13C NMR (125 MHZ, CDCl3) δ142.1, 136.5, 128,2, 126.6, 124.9, 123.3, 67.6, 35.9, 28.8, 26.8, 25.7; HRMS (CI) exact mass calcd for (C13H19N2OCl) requires m/z 188.1201, found m/z 188.1203.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:22][C:21](C(O)=O)=[N:20][N:19]=2)[CH2:14][CH2:13]1)=[O:10].C(#N)C>C([O-])(=O)C.[NH4+]>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[S:22][CH:21]=[N:20][N:19]=2)[CH2:16][CH2:17]1)=[O:10]
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3nnc(C(=O)O)s3)CC2)c(Cl)c1Cl
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC#N
Product: Cc1[nH]c(C(=O)NC2CCN(c3nncs3)CC2)c(Cl)c1Cl
Yield: 42.6 %

Procedure:
5-(4-{[(3,4-Dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-1,3,4-thiadiazole-2-carboxylic acid (Example 223; 0.250 g, 0.60 mmol) was stirred in 10 mM ammonium acetate (pH 8) (15 ml) and acetonitrile (15 ml) overnight. The mixture was concentrated then the residue was stirred in acetonitrile and filtered. The solid was dissolved in DMSO and purified using semi-preparative HPLC (10% ammonium acetate:water/acetonitrile (20:80-95:5)) to give the title compound as a white solid (0.092 g).
Reaction SMILES: [CH3:1][NH2:2].[NH2:3][C:4]1[C:5]([F:29])=[CH:6][C:7]([F:28])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:23])=[C:17](F)[C:18]=3[CH2:20][OH:21])[C:13](=[O:24])[C:12]([C:25]([OH:27])=[O:26])=[CH:11]2)[CH:9]=1>N1C=CC=CC=1>[NH2:3][C:4]1[C:5]([F:29])=[CH:6][C:7]([F:28])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:23])=[C:17]([NH:2][CH3:1])[C:18]=3[CH2:20][OH:21])[C:13](=[O:24])[C:12]([C:25]([OH:27])=[O:26])=[CH:11]2)[CH:9]=1
Reactant: CN
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(CO)c32)c(F)cc1F
Solvent: c1ccncc1
Product: CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1CO
Temperature: 40 °C
Reaction time: 8 h

Procedure:
Pyridine (300 mg) and a 40% aqueous solution (150 mg) of methylamine were added to 1(5-amino-2,4-difluorophenyl)-6,7-difluoro-8-hydroxymethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (100 mg), and the mixture was stirred overnight at 40° C. The solvent and the like were distilled off, and diethyl ether was added to the residue. A supernatant liquid was removed, and ethanol was added to the resultant residue. Solids deposited were collected by filtration to obtain the title compound (34 mg) as a yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](Br)=[CH:8][CH:9]=1)=[O:4].C([Li])CCC.FC(F)(F)S(O[C:22]1[CH:27]=[C:26]([Cl:28])[C:25]([CH2:29][CH:30]2[CH2:34][CH2:33][N:32]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[C:31]2=[O:41])=[C:24]([Cl:42])[CH:23]=1)(=O)=O.ClCCl>C1COCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:22]2[CH:23]=[C:24]([Cl:42])[C:25]([CH2:29][CH:30]3[CH2:34][CH2:33][N:32]([CH:35]4[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]4)[C:31]3=[O:41])=[C:26]([Cl:28])[CH:27]=2)=[CH:8][CH:9]=1)=[O:4]
Reactant: O=C1C(Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1C1CCCCC1
Reactant: COC(=O)c1ccc(Br)s1
Agent: [Fe+2]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.1 %

Procedure:
To a solution of 5-bromo-thiophene-2-carboxylic acid methyl ester (Preparation 86) (552.5 mg, 2.5 mmol) in 5 mL of THF, add n-butyl lithium (1.6 M, 1,56 mL, 2.5 mmol) at −78° C. and stir at that temperature for 30 min. Add anhydrous zinc chloride (455 mg, 4.0 mmol) and keep in −78° C. for 30 min, and then warm up to room temp. After stirring at room temp for 30 min, add 3,5-dichloro-4-((1-cyclohexyl-2-oxopyrrolidin-3-yl)methyl)phenyl trifluoromethanesulfonate (593 mg, 1.25 mmol). Add 1,1′-bis(diphenylphosphino) ferrocene)dichloroplladium and complex with dichloromethane (102 mg, 0.125 mmol) with 1.0 mL of THF. After heating to reflux for 5 hours. cool the reaction to room temp. Dilute with ethyl acetate, wash with water, separate the organic layer, and dry over anhydrous sodium sulfate. Purify the crude material by flash chromatography on silica gel using hexane:ethyl acetate (10:1.5) as eluent to give 94 mg of the title compound LC/MS (API) m/z: 466.0 (M+1).
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.[CH2:16]([O:23][C:24]1[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=1[O:26]CCBr)[C:17]1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>>[ClH:1].[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]2[CH2:9][CH2:10][N:11]([CH2:17][CH2:16][O:23][C:24]3[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=3[OH:26])[CH2:12][CH2:13]2)=[CH:14][CH:15]=1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Reactant: BrCCOc1ccccc1OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Oc1ccccc1OCCN1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound was prepared from 4-(4-fluorobenzyl)piperidine hydrochloride (298 mg, 1.30 mmol), 2-(2-benzyloxyphenoxy)ethyl bromide (399 mg, 1.3 mmol) and potassium carbonate (449 mg, 3.2 mmol) in two steps as white-off solid (240 mg): mp 233-235° C. (dec.). 1H NMR (CD3OD) 1.532 (m, 2 H), 1.848 (d, J=13.2 Hz, 3 H), 2.571 (d, J=6.3 Hz, 2 H), 3.0 (m, 2 H), 3.483 (m, 2 H), 3.603 (d, J=10.5 Hz, 2 H), 4.262 (t, J=5.1 Hz, 2 H), 6.752-6.825 (m, 3 H), 6.909-6.986 (m, 3 H), 7.126-7.173 (m, 2 H).