Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][C:22]([OH:24])=[CH:23][C:17]=3[S:16](=[O:26])(=[O:25])[CH2:15][CH2:14]2)[CH:3]=1.I[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][C:22]([O:24][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:23][C:17]=3[S:16](=[O:26])(=[O:25])[CH2:15][CH2:14]2)[CH:3]=1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4cc(O)ccc4C3)cc(Cl)c2c1
Reactant: Ic1ccccc1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4cc(Oc5ccccc5)ccc4C3)cc(Cl)c2c1
Temperature: 120 °C
Reaction time: 6 h
Yield: 720.1 %

Procedure:
A mixture of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-ol 1,1-dioxide (250.0 mg, 0.65 mmol, prepared in analogy to 4-(4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-ol 1,1-dioxide in Example 34), iodo-benzene (0.1 mL, 0.089 mmol), copper(I) iodide (74.0 mg, 0.35 mmol), N,N-dimethylglycine hydrochloride (72.0 mg, 0.52 mmol) and potassium carbonate (267.0 mg, 1.9 mmol) in dimethyl sulfoxide (1.5 mL). The reaction mixture was heated with stirring at 120° C. for 6 hours. After being cooled to room temperature, the reaction mixture was extracted with ethyl acetate (150 mL×2), washed with water (50 mL×2) and a saturated aqueous ammonium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 298.0 mg of the crude product as a yellow oil which was used for next step without further purification. MS obsd. (ESI+) [(M+H)+] 465.
Reaction SMILES: Br[C:2]1[C:3]([Cl:30])=[C:4]([O:20][C:21]2[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[C:23]([Cl:29])[CH:22]=2)[C:5]([F:19])=[C:6]([CH2:8][NH:9][C:10]([C:12]2[NH:16][C:15]([CH3:17])=[N:14][C:13]=2[Cl:18])=[O:11])[CH:7]=1.[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32].[CH3:38][N:39](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[F:34][C:33]([F:36])([F:35])[C:31]([OH:37])=[O:32].[Cl:18][C:13]1[N:14]=[C:15]([CH3:17])[NH:16][C:12]=1[C:10]([NH:9][CH2:8][C:6]1[CH:7]=[C:2]([C:38]#[N:39])[C:3]([Cl:30])=[C:4]([O:20][C:21]2[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[C:23]([Cl:29])[CH:22]=2)[C:5]=1[F:19])=[O:11]
Reactant: CN(C)C=O
Reactant: Cc1nc(Cl)c(C(=O)NCc2cc(Br)c(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(Cl)c(C(=O)NCc2cc(C#N)c(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)[nH]1
Yield: 7 %

Procedure:
A solution of N-({5-bromo-4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-4-chloro-2-methyl-1H-imidazole-5-carboxamide (70 mg, 0.131 mmol), zinc cyanide (7.72 mg, 0.066 mmol) and tetrakis(triphenylphosphine)palladium(0) (30.4 mg, 0.026 mmol) in DMF (1.5 ml) was irradiated for 35 minutes at 130° C. in a microwave reactor. The reaction mixture was purified via reverse phase HPLC to give 4-chloro-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-5-cyano-2-fluorophenyl}methyl)-2-methyl-1H-imidazole-5-carboxamide trifluoroacetate (5.8 mg, 9.79 μmol, 7% yield) as the TFA salt. 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.79 (d, 1H), 7.58 (s, 1H), 7.37 (s, 1H), 7.32 (s, 1H), 4.62 (s, 2H), 2.33 (s, 3H). LC-MS (ES+) m/z 477.95, [M+H].
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(C(C)C)CC)(C)C.[CH2:22]([CH:24]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:25][NH2:26])[CH3:23].CCCCCCC>C1COCC1.CCOCC>[Cl:12][C:11]1[C:2]([NH:26][CH2:25][CH:24]([CH2:22][CH3:23])[CH2:27][CH2:28][CH2:29][CH3:30])=[N:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:10]=1
Reactant: Clc1nc2ccccc2nc1Cl
Reactant: CCCCC(CC)CN
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCC(CC)CNc1nc2ccccc2nc1Cl

Procedure:
12 g (60.3 mmol) of 2,3-dichloroquinoxaline are dissolved in 125 ml of THF with 9.5 g (72.1 mmol) of diisopropylethylamine. 8.5 g (66 mmol) of 2-ethylhexylamine are added dropwise to the solution, and the reaction is refluxed for a total of 48 hours until starting material is no longer visible according to TLC (silica gel: n-heptane/MTB ether). The reaction solution is evaporated to dryness in a rotary evaporator, and the crude product is chromatographed over silica gel using n-heptane/MTB ether. The product-containing fractions are collected and evaporated in a rotary evaporator. Yield: 11.8 g (67%)
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:19]=1[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)=[CH:17][C:16]([S:29]([C:32]1[CH:33]=[C:34]([CH:57]=[CH:58][CH:59]=1)[C:35]([NH:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]3[CH:49]=[CH:48][C:47]([CH2:50][CH2:51][CH2:52][C:53](OC)=[O:54])=[CH:46][CH:45]=3)=[CH:40][CH:39]=1)=[O:36])(=[O:31])=[O:30])=[CH:15][C:14]=2[CH3:60])(=[O:9])[NH2:8].O.[OH-].[Na+]>C1COCC1.CCOC(C)=O.C(Cl)Cl.CO>[OH:54][CH2:53][CH2:52][CH2:51][CH2:50][C:47]1[CH:48]=[CH:49][C:44]([C:41]2[CH:42]=[CH:43][C:38]([NH:37][C:35]([C:34]3[CH:33]=[C:32]([S:29]([C:16]4[CH:17]=[C:18]5[C:13](=[C:14]([CH3:60])[CH:15]=4)[N:12]=[CH:11][C:10]([C:7]([NH2:8])=[O:9])=[C:19]5[NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=4)(=[O:30])=[O:31])[CH:59]=[CH:58][CH:57]=3)=[O:36])=[CH:39][CH:40]=2)=[CH:45][CH:46]=1
Reactant: COC(=O)CCCc1ccc(-c2ccc(NC(=O)c3cccc(S(=O)(=O)c4cc(C)c5ncc(C(N)=O)c(Nc6cccc(OC)c6)c5c4)c3)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(-c6ccc(CCCCO)cc6)cc5)c4)cc23)c1
Reaction time: 1 h
Yield: 43.1 %

Procedure:
Solid LiAlH4 (29 mg, 0.713 mmol) was added to a stirring solution of Intermediate 86 (265 mg, 0.357 mmol) in THF (5 mL) at 0° C. After stirring for an hour H2O (0.029 mL), 15% (w/v) NaOH (0.029 mL), and H2O (0.087 mL) were added in order then stirred for additional 1 h. The resulting suspension was diluted with EtOAc (10 mL) and the organic layer was washed with H2O (15 mL), brine (15 mL), dried over Na2SO4, and concentrated to give crude alcohol (224 mg) as yellow solid. Chromatography (9:1, CH2Cl2/MeOH) afforded the title compound (110 mg, 43%) as yellow solid. ES/MS calcd. for C41H39N4O6S+ 715.3. Found m/z=715.4 (M+H)+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=3[OH:22])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[OH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O>>[OH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=3[OH:22])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1O
Reactant: COc1cccc(-c2cccc(-c3cccc(Br)n3)n2)c1O
Product: COc1cccc(-c2cccc(-c3cccc(-c4ccccc4O)n3)n2)c1O
Yield: 39 %

Procedure:
6-(2-Hydroxyphenyl)-6′-(2-hydroxy-3-methoxyphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-3-methoxyphenyl)-2,2′-bipyridine and 2-hydroxyphenyl boronic acid in 39% yield using method F; δH [2H6]-DMSO 13.48,(1H, b), 13.38,(1H, b), 8.33,(2H, m), 8.23, (2H, t), 8.17,(2H, d), 8.13,(1H, d), 7.70,(2H, d), 7.37,(1H, t), 7.09,(1H, d), 7.02,(1H, d), 6.94,(1H, t), 3.84,(3H, s); MS 371 (MH)+; HPLC retention time (system 1) 4.03 minutes.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:42][N:43]([CH:52]=[O:53])[O:44]CC2C=CC=CC=2)[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][C@@H:25]4[CH3:31])[N:19]=3)=[O:16])[CH2:13][CH2:12][N:11]2C(OCC2C=CC=CC=2)=O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1>[OH-].[OH-].[Pd+2].CO>[CH:1]1([CH2:6][C@H:7]([CH2:42][N:43]([CH:52]=[O:53])[OH:44])[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][C@@H:25]4[CH3:31])[N:19]=3)=[O:16])[CH2:13][CH2:12][NH:11]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C[C@H]1CN(C)CCN1c1nccc(NC(=O)[C@@H]2CCN(C(=O)OCc3ccccc3)N2C(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: C[C@H]1CN(C)CCN1c1nccc(NC(=O)[C@@H]2CCNN2C(=O)[C@H](CC2CCCC2)CN(O)C=O)n1
Reaction time: 2 h
Yield: 75.1 %

Procedure:
A mixture of phenylmethyl (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-3-[({2-[(2S)-2,4-dimethyl-1-piperazinyl]-4-pyrimidinyl}amino) carbonyl]-1-pyrazolidinecarboxylate (236 mg, 0.325 mmol) and Pearlman's catalyst (45.6 mg, 0.065 mmol) in methanol (1.81 ml) was degassed and placed under 1 atm of H2 at ambient temperature. After 2 hrs, the reaction mixture was filtered and concentrated to give a residue which was purified by RP-HPLC to give (3S)-2-((2R)-3-cyclopentyl-2-{[formyl(hydroxy)amino]methyl}propanoyl)-N-{2-[(2S)-2,4-dimethyl-1-piperazinyl]-4-pyrimidinyl}-3-pyrazolidine carboxamide (125 mg, 0.244 mmol, 75% yield). MS (ES+) m/z 503.1 (MH+).
Reaction SMILES: [C:1]([CH:9]([CH2:15][CH2:16][CH3:17])[C:10]([O:12]CC)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[NH2:19]>C(O)C>[C:2]1([C:1]2[C:9]([CH2:15][CH2:16][CH3:17])=[C:10]([OH:12])[N:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[N:19]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC(C(=O)OCC)C(=O)c1ccccc1
Reactant: NNc1ccccn1
Solvent: CCO
Product: CCCc1c(-c2ccccc2)nn(-c2ccccn2)c1O
Temperature: 100 °C
Reaction time: 20 h
Yield: 80 %

Procedure:
Ethyl 2-benzoylpentanoate (355 mg, 1.5 mmol) was dissolved in 5 mL of ethanol to which 2-hydrazinopyridine (163 mg, 1.5 mmol) was then added, followed by refluxing at 100° C. After 20 hours, ethanol was concentrated, followed by extraction with ethyl acetate. The extract was washed two or three times with water, and the organic layer was dried over anhydrous MgSO4 and then concentrated. The resulting residue was purified by column chromatography (n-hexane:EA=10:1) to afford the title compound.
Reaction SMILES: CS(OCCCCO[C:11]1[CH:12]=[CH:13][C:14]2[NH:19][C:18](=[O:20])[O:17][C:16]([CH3:22])([CH3:21])[C:15]=2[CH:23]=1)(=O)=O.[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[CH:27][CH:26]=1>>[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([S:31][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:12]2[CH:11]=[CH:23][C:15]3[C:16]([CH3:21])([CH3:22])[O:17][C:18](=[O:20])[NH:19][C:14]=3[CH:13]=2)=[CH:27][CH:26]=1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCOS(C)(=O)=O)cc21
Reactant: Cc1ccc(S)cc1
Product: Cc1ccc(SCCCCOc2ccc3c(c2)NC(=O)OC3(C)C)cc1

Procedure:
Prepared analogously to Example 210 from 6-(4-methanesulfonyloxy-butoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-methyl-thiophenol.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:3]=1[NH:4][C:5](=[O:16])[C:6]([F:15])([C:11]([F:14])([F:13])[F:12])[C:7]([F:10])([F:9])[F:8].CI.[C:26](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:26][N:4]([C:5](=[O:16])[C:6]([F:15])([C:11]([F:12])([F:13])[F:14])[C:7]([F:8])([F:9])[F:10])[C:3]1[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:2]=1[Br:1]
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1Br)C(F)(C(F)(F)F)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CN(C(=O)C(F)(C(F)(F)F)C(F)(F)F)c1ccc([N+](=O)[O-])cc1Br
Yield: 70 %

Procedure:
2'-Bromo-4'-nitro-2,3,3,3-tetrafluoro-2-(trifluoromethyl)propionanilide was reacted with methyl iodide, in acetone and in the presence of potassium carbonate, yielding N-methyl-2'-bromo-4'-nitro-2,3,3,3-tetrafluoro-2-(trifluoromethyl)propionanilide, an oil, yield 70% (>99% branched isomer).
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4].[CH2:8]([O:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[O:20][CH2:21][CH3:22])[C:14](Cl)=[O:15])[CH3:9]>>[CH2:8]([O:10][C:11]1[CH:12]=[C:13]([C:14](=[O:15])[C:2]([CH3:7])([CH3:1])[C:3]([O:5][CH3:6])=[O:4])[CH:17]=[CH:18][C:19]=1[O:20][CH2:21][CH3:22])[CH3:9]
Reactant: CCOc1ccc(C(=O)Cl)cc1OCC
Reactant: COC(=O)C(C)C
Product: CCOc1ccc(C(=O)C(C)(C)C(=O)OC)cc1OCC

Procedure:
Prepared analogously as described for example D1 using methyl 2-methylproponate and 3,4-diethoxybenzoyl chloride as starting compounds.
Reaction SMILES: OCCN1CCN(CC(NC2C(SC)=NC(C)=CC=2SC)=O)CC1.O[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([NH:37][C:38]2[C:39]([N:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)=[N:40][C:41]([CH3:50])=[CH:42][C:43]=2[N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)=[O:36])[CH2:30][CH2:29]1.SC1NC2C=CC=CC=2N=1.[SH:67][C:68]1[S:69][C:70]2[CH:76]=[CH:75][CH:74]=[CH:73][C:71]=2[N:72]=1>>[S:69]1[C:70]2[CH:76]=[CH:75][CH:74]=[CH:73][C:71]=2[N:72]=[C:68]1[S:67][CH2:26][CH2:27][N:28]1[CH2:29][CH2:30][N:31]([CH2:34][C:35]([NH:37][C:38]2[C:39]([N:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)=[N:40][C:41]([CH3:50])=[CH:42][C:43]=2[N:44]2[CH2:45][CH2:46][O:47][CH2:48][CH2:49]2)=[O:36])[CH2:32][CH2:33]1
Reactant: Cc1cc(N2CCOCC2)c(NC(=O)CN2CCN(CCO)CC2)c(N2CCOCC2)n1
Reactant: Sc1nc2ccccc2s1
Agent: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCO)CC1
Agent: Sc1nc2ccccc2[nH]1
Product: Cc1cc(N2CCOCC2)c(NC(=O)CN2CCN(CCSc3nc4ccccc4s3)CC2)c(N2CCOCC2)n1

Procedure:
The reaction and treatments of Example 12 were repeated, except that 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide was replaced by 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(morpholino)-6-methylpyridin-3-yl]acetamide, and 2-mercaptobenzimidazole was replaced by 2-mercaptobenzothiazole, to thereby yield the title compound as a colorless foamed substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]2[NH:20][CH2:19][CH2:18][C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]2=3)=[CH:5][CH:4]=1.Br[CH:22]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:23]([NH:25][CH3:26])=[O:24].C(N(C(C)C)C(C)C)C.[I-].[Na+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]2[N:20]([CH:22]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:23]([NH:25][CH3:26])=[O:24])[CH2:19][CH2:18][C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]2=3)=[CH:5][CH:4]=1
Reactant: CNC(=O)C(Br)c1ccccc1
Reactant: COc1ccc(CCC2NCCc3ncccc32)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CNC(=O)C(c1ccccc1)N1CCc2ncccc2C1CCc1ccc(OC)cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 34.7 %

Procedure:
To a solution of 615 mg (2.29 mmol) 5-[2-(4-methoxy-phenyl)-ethyl]-5,6,7,8-tetrahydro-[1,6]naphthyridine in 25 mL acetonitrile, were added 682 mg (2.98 mmol) 2-bromo-N-methyl -2-phenyl-acetamide, 1.2 mL (6.87 mmol) N-ethyldiisopropylamine and 343 mg (2.29 mmol) sodium iodide. The solution was stirred at 60° C. for 6 h. The solvent was removed in vacuo and the residue was taken in ethyl acetate. The mixture was washed once with water and once with a 2M Na2CO3 solution, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified on silica eluting with a gradient formed from heptane and ethyl acetate. The product containing fractions were evaporated to yield 330 mg (35%) of 2-{5-[2-(4-methoxy-phenyl)-ethyl]-7,8-dihydro-5H-[1,6]naphthyridin-6-yl}-N-methyl-2-phenyl-acetamide (diastereoisomer 1, first eluting diastereoisomer) as yellow foam
Reaction SMILES: [OH:1][CH2:2][C:3](=[O:5])[CH3:4].C(N(CC)CC)C.[C:13](Cl)(=[O:17])[C:14]([CH3:16])=[CH2:15]>O1CCCC1.C1(C=CC(O)=CC=1)O>[C:13]([O:1][CH2:2][C:3](=[O:5])[CH3:4])(=[O:17])[C:14]([CH3:16])=[CH2:15]
Reactant: C=C(C)C(=O)Cl
Reactant: CC(=O)CO
Agent: Oc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCC(C)=O
Temperature: 5 °C
Reaction time: 3 h
Yield: 89.1 %

Procedure:
In a 2 L four-necked flask subjected to replacement with nitrogen, 50 g of 1-hydroxy-2-propanone was put, and dissolved in 700 g of tetrahydrofuran, and a stirrer, a thermometer and a Dimroth cooling tube were connected thereto. After the resulting solution was stirred and cooled to about 5° C., 76.8 g of triethylamine and 25 mg of hydroquinone were added thereto. While the resulting mixture was cooled to about 5° C. under stirring, 71.9 g of methacryloyl chloride (made by Wako Pure Chemical Industries Ltd., purity: 97.0% or more) was slowly added dropwise thereto, and stirring was further continued for 3 hours to carry out an esterification reaction. While the reaction mixture was held at about 5° C., the mixture was acid-washed with 2N-hydrochloric acid, and an extraction operation was performed twice using 300 mL of ethyl acetate to obtain an organic layer. The organic layer was washed with a 10% sodium hydrogen carbonate aqueous solution and saturated brine, dried over anhydrous magnesium sulfate, and separated by filtration to obtain a reaction crude liquid. The solvent was distilled off from the reaction crude liquid using an evaporator to obtain 85.5 g of crude 2-oxopropyl methacrylate. A yield of 2-oxopropyl methacrylate determined from a proton ratio by NMR was 67.1 g (yield: 69.9% based on 1-hydroxy-2-propanone).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][CH2:12][C:13]([OH:15])=O)=[C:5]2[CH3:16].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:40][C:41]1([C:47]2[CH:48]=[C:49]([NH:53][S:54]([CH3:57])(=[O:56])=[O:55])[CH:50]=[CH:51][CH:52]=2)[CH:46]2[CH:42]1[CH2:43][NH:44][CH2:45]2.C(=O)([O-])O.[Na+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][CH2:12][C:13]([N:44]1[CH2:45][CH:46]3[CH:42]([C:41]3([C:47]3[CH:48]=[C:49]([NH:53][S:54]([CH3:57])(=[O:56])=[O:55])[CH:50]=[CH:51][CH:52]=3)[CH3:40])[CH2:43]1)=[O:15])=[C:5]2[CH3:16]
Reactant: Cc1c(CCC(=O)O)[nH]c2ccc(F)cc12
Reactant: CC1(c2cccc(NS(C)(=O)=O)c2)C2CNCC21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(CCC(=O)N2CC3C(C2)C3(C)c2cccc(NS(C)(=O)=O)c2)[nH]c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-(5-fluoro-3-methyl-1H-indol-2-yl)propanoic acid (prepared according to the method described in EP 510398 A2, 200 mg, 0.90 mmol) in N,N-dimethylformamide (20 ml) was added 1-hydroxybenzotriazole monohydrate (154 mg, 1.00 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (262 mg, 1.36 mmol). After stirring at room temperature for 10 min, the mixture was treated with the hydrochloride salt of N-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide (Preparation 53, 308 mg, 0.90 mmol) and sodium hydrogen carbonate (150 mg, 1.80 mmol). The reaction mixture was stirred at room temperature overnight before concentrating in vacuo. Water (15 ml) was added and the reaction mixture was extracted with ethyl acetate (2×20 ml). The combined organic extracts were washed with water (15 ml), dried (MgSO4), and concentrated in vacuo to afford 350 mg of a brown viscous oil which was not purified further.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[C:6]([Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[C:5]([F:16])=[C:4]([F:17])[N:3]=1.C([Li])CCC.[Cl:23][C:24]1[C:29]([CH:30]=[O:31])=[C:28]([Cl:32])[N:27]=[CH:26][N:25]=1>C1COCC1>[Si:9]([C:6]1[C:5]([F:16])=[C:4]([F:17])[N:3]=[C:2]([CH:30]([C:29]2[C:24]([Cl:23])=[N:25][CH:26]=[N:27][C:28]=2[Cl:32])[OH:31])[C:7]=1[F:8])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: O=Cc1c(Cl)ncnc1Cl
Reactant: CC(C)(C)[Si](C)(C)c1c(F)c(F)nc(Br)c1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)c1c(F)c(F)nc(C(O)c2c(Cl)ncnc2Cl)c1F
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 37.2 %

Procedure:
To a solution of (2-bromo-3,5,6-trifluoro-4-pyridyl)-tert-butyl-dimethyl-silane (2.5 g, 7.66 mmol) in THF (15 mL) cooled at −78° C. was added butyllithium (2.5M in hexanes) (3.22 mL of 2.5 M, 8.05 mmol) at a rate which maintained the temperature below −70° C. On complete addition, the reaction mixture was stirred at −78° C. for 40 minutes and then a solution of 4,6-dichloropyrimidine-5-carbaldehyde (1.43 g, 8.05 mmol) in THF (25 mL) was added at a rate which maintained the temperature below −70° C. The reaction mixture was stirred at −78° C. for 1.5 hours. After this time, the reaction mixture was quenched with water and extracted with EtOAc (3×). The organics were combined, washed with water, brine, dried (MgSO4), filtered and concentrated in vacuo. The crude mixture was purified by column chromatography (ISCO Companion™, 80 g column, eluting with 0-5% EtOAc/petroleum ether) to give the sub title compound as a cream solid (1.21 g, 37.2% Yield). H1 NMR (400 MHz, DMSO) δ 8.91 (1H, s), 6.69 (1H, s), 6.48 (1H, s), 0.88 (9H, s) and 0.39 (6H, s).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[CH:23]([CH3:25])[CH3:24].[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>>[CH2:26]([N:28]([CH2:29][CH3:30])[C:6]1[C:5]2[C:10](=[CH:11][C:2]([F:1])=[C:3]([CH:23]([CH3:24])[CH3:25])[CH:4]=2)[N:9]=[C:8]([N:12]2[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]2)[N:7]=1)[CH3:27]
Reactant: CCNCC
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(C(C)C)cc3c(=O)[nH]2)c1
Product: CCN(CC)c1nc(-n2cc(C(=O)O)cn2)nc2cc(F)c(C(C)C)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-fluoro-6-isopropyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and diethylamine in step E. MS (ESI): predicted mass calcd. for C19H22FN5O2, 371.2
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Cl:18][C@@H:19]([CH3:31])[CH2:20][C@H:21]([CH3:30])[O:22][C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1.C1(N=C=NC2CCCCC2)CCCCC1.N1(C2C=CN=CC=2)CCCC1>C(Cl)Cl>[Cl:18][C@@H:19]([CH3:31])[CH2:20][C@H:21]([CH3:30])[O:22][C:23]1[CH:28]=[CH:27][C:26]([O:14][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[CH:10][CH:11]=2)=[CH:25][CH:24]=1
Reactant: COc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: C[C@H](Cl)C[C@H](C)Oc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: COc1ccc(-c2ccc(C(=O)Oc3ccc(O[C@@H](C)C[C@H](C)Cl)cc3)cc2)cc1

Procedure:
0.50 g of 4-(4'-methoxyphenyl)benzoic acid, 0.44 g of (S,S)-4-(3'-chloro-1'-methylbutoxy)phenol, 0.45 g of dicyclohexylcarbodiimide, 0.05 g of 4-pyrrolidino-pyridine and 20 ml of methylene chloride were stirred together at room temperature for five hours. The crude product obtained in the same manner as the one described in Example 8 was purified by silica gel column chromatography with the use of a mixture of n-hexane and ethyl acetate (85:15) as a developing solvent and recrystallized from ethyl slcohol to thereby give the title compound.
Reaction SMILES: C([CH:6]1[C:10](=O)[CH2:9][N:8]([CH2:12][CH2:13][CH3:14])[C:7]1=[O:15])(OCC)=O.C(N1CC(=O)CC1=O)CC.[NH2:26][C:27]1[C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][S:29][C:28]=1[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40].O.C1(C)C=CC=CC=1>C(#N)C.C1(C)C=CC=CC=1>[CH2:12]([N:8]1[CH2:9][C:10]([NH:26][C:27]2[C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][S:29][C:28]=2[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:6][C:7]1=[O:15])[CH2:13][CH3:14]
Reactant: CCCCCc1scc(C(=O)OC)c1N
Reactant: CCCN1CC(=O)C(C(=O)OCC)C1=O
Agent: CCCN1CC(=O)CC1=O
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CCCCCc1scc(C(=O)OC)c1NC1=CC(=O)N(CCC)C1
Yield: 94.2 %

Procedure:
Freshly prepared 1-propyl-Z,4-dioxopyrrolidine was prepared as described in Example le from 3-carboethoxy-1-propyl-2,4-dioxopyrrolidine (3.55 g) in acetonitrile (100 ml). The 1-propyl-2,4-dioxopyrrolidine was mixed with methyl 3-amino-2-pentylthiophene- 4-carboxylate (2.70 g) in toluene (65 ml). The mixture was refluxed for 2 hours with removal of the water/toluene azeotrope using a Dean-Stark trap. After distilling off the excess toluene, the residue was taken up in ethyl acetate, washed sequentially with saturated aqueous Na2CO3 and brine, then dried (Na2SO4) and concentrated. Chromatographic purification over silica gel afforded the title product (3.92 g, 94%) as a yellow oil; tlc, Rf =0.12, silica gel, ethyl acetate:hexane (1:1). c. 5,6-Dihydro-8-hydroxy-3-pentyl-6-propyl-pyrrolo[3,4-b]thieno[3,4-e]pyridin-7(1H)-one (Formula VII, n=1, X=N, Ra=pentyl, Rb=propyl, W=OH)