Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=[O:9])C(CCC)CCC.[O-]CC.[Mg+2:14].[O-]CC.C(#N)C.[C:21]([O-:30])(=[O:29])[CH:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25].[Mg+2].[C:32]([O-:41])(=[O:40])[CH:33]([CH2:37][CH2:38][CH3:39])[CH2:34][CH2:35][CH3:36]>C(O)C>[OH2:9].[C:21]([O-:30])(=[O:29])[CH:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25].[Mg+2:14].[C:32]([O-:41])(=[O:40])[CH:33]([CH2:37][CH2:38][CH3:39])[CH2:34][CH2:35][CH3:36]
Reactant: CCCC(CCC)C(=O)O
Agent: CCCC(CCC)C(=O)[O-]
Agent: CC[O-]
Agent: [Mg+2]
Solvent: CCO
Solvent: CC#N
Product: O
Reaction time: 1 h

Procedure:
A solution of magnesium valproate in absolute ethanol was obtained in the following manner. To a magnetically stirred, clear, colorless solution of valproic acid (3.17 g; 0.022 mol; Sigma Aldrich Chemical Co.) in 25 mL of absolute ethanol was added 1.14 g (0.01 mol) of magnesium ethoxide solid; residual solid was rinsed in with 1 mL of absolute ethanol. Within 60 minutes, a clear, pale yellow solution was obtained; no heating was observed. One milliliter portions of the solution were aliquoted into test tubes, and a second solvent or solution was added in portions. The results of the additions are summarized in Table 2. A 15 mL portion of acetonitrile was added to an equal volume of the ethanol solution of magnesium valproate. A white precipitate formed, which was isolated by filtration, washed with a fresh portion of acetonitrile, and dried to constant mass. The product, magnesium valproate hydrate, was obtained in 89% yield as a white solid, which exhibited an elemental composition identical to that calculated for magnesium valproate hydrate. The product did not melt at temperatures as high as 300° C. The product was not hygroscopic or deliquescent. The theoretical valproate content (weight %) of magnesium valproate hydrate is 88.6%; the valproate content found by HPLC analysis was 88.5%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:48][N:49]([CH3:55])[C@H:50]1[CH2:54][CH2:53][NH:52][CH2:51]1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:48][N:49]([CH3:55])[C@H:50]1[CH2:54][CH2:53][N:52]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH2:51]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: COC(=O)c1cccc(Br)c1
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(N2CC[C@H](N(C)C)C2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of methyl 3-bromobenzoate (1.0 g, 4.7 mmol), 2-(dicyclohexylphosphino)-2′-(N,N-dimethylamino)biphenyl (0.037 g, 0.093 mmol), tris(dibenzylidineacetone)dipalladium (0) (0.021 g, 0.023 mmol), anhydrous K3PO4 (1.4 g, 6.5 mmol) in 9.3 mL toluene under argon was added (S)-N,N-dimethylpyrrolidin-3-amine (0.71 mL, 5.6 mmol). The reaction was sealed and heated to 80 deg. C. for 3 days. The reaction was cooled to ambient temperature, was diluted with ethyl acetate, and filtered through celite. The filtrate was concentrated in vacuo to give a brown oil, which was further purified by silica gel chromatography, using 90/10/1 dichloromethane/methanol/sat'd ammonium hydroxide as eluent to give (S)-methyl 3-(3-(dimethylamino)pyrrolidin-1-yl)benzoate as a light brown oil.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:25])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([O:19][CH3:20])[CH:13]=1)[CH:9]=[C:8]([C:21]([OH:23])=[O:22])[C:7]2=[O:24].[CH3:27][NH2:28]>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([NH:28][CH3:27])=[C:4]([F:25])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([O:19][CH3:20])[CH:13]=1)[CH:9]=[C:8]([C:21]([OH:23])=[O:22])[C:7]2=[O:24]
Reactant: COc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)ccc1F
Reactant: CN
Solvent: c1ccncc1
Product: CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3ccc(F)c(OC)c3)c2c1Cl
Temperature: 25 °C
Reaction time: 27 h
Yield: 88.1 %

Procedure:
8-Chloro-6,7-difluoro-1-(4-fluoro-3-methoxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (160 mg) and an aqueous solution (about 40%; 400 mg) of methylamine were added to pyridine (1,000 mg), and the mixture was stirred at room temperature for 27 hours. The reaction mixture was concentrated under reduced pressure, and ethanol (1 ml) was added to the residue. Deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (145 mg) as a colorless powder
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([F:15])[CH:10]=2)=[C:6]([C:16]#[N:17])[C:5]=1[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])(=O)[CH3:2].COC(OC)[N:29]([CH3:31])C.CC(O)=O.O.[NH2:39]N>>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[C:5]1[C:6]([C:16]#[N:17])=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([F:15])[CH:10]=2)[S:8][C:4]=1[C:1]1[NH:39][N:29]=[CH:31][CH:2]=1
Reactant: COC(OC)N(C)C
Reactant: NN
Reactant: CC(=O)c1sc(-c2ccnc(F)c2)c(C#N)c1-c1ccc(Cl)cc1Cl
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1c(-c2ccnc(F)c2)sc(-c2ccn[nH]2)c1-c1ccc(Cl)cc1Cl
Temperature: 90 °C
Yield: 78.7 %

Procedure:
A solution of [A] 5-acetyl-4-(2,4-dichlorophenyl)-2-(2-fluoropyridin-4-yl)thiophene-3-carbonitrile (0.407 g, 1.04 mmol) in 1,1-Dimethoxy-N,N-dimethylmethanamine (5.53 mL, 41.6 mmol) was irradiated in microwave at 120° C. for 20 min. The solvent was removed and the residue was taken up by AcOH (21 mL, 370 mmol). Hydrazine hydrate (3 mL, 60 mmol) was added the above mixture and then heated at 90° C. for 10 min. The mixture was concentrated and the residue was suspended in water. The precipitated was collected and dried in air to afford the title compound as a yellow powder (0.34 g, 79%). LC/MS (FA) ES+ 415, 417. 1H NMR (400 MHz, d4-methanol) δ: 8.45 (1H, d, J=5.33 Hz), 7.85 (1H, td, J=5.32, 1.57, 1.57 Hz), 7.80 (1H, d, J=1.99 Hz), 7.54 (1H, d, J=8.24 Hz), 7.60 (1H, dd, J=8.27, 2.04 Hz), 7.63 (2H, d, J=2.47 Hz), 5.69 (1H, d, J=2.44 Hz)
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=3)[C:12]([C:20](O)=[O:21])=[CH:11]2)[C:4]=1[CH3:23].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.[CH2:49]([CH2:51][NH2:52])[OH:50]>ClCCl>[OH:50][CH2:49][CH2:51][NH:52][C:20]([C:12]1[C:13]2=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=[C:18]2[N:10]([CH2:9][C:5]2[C:4]([CH3:23])=[C:3]([O:2][CH3:1])[N:8]=[CH:7][N:6]=2)[CH:11]=1)=[O:21]
Reactant: NCCO
Reactant: COc1ncnc(Cn2cc(C(=O)O)c3ncc(C)cc32)c1C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ncnc(Cn2cc(C(=O)NCCO)c3ncc(C)cc32)c1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 52.7 %

Procedure:
See FIG. 20(a). 1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (75 mg, 0.24 mmol) was taken in dichloromethane (10 mL) to get a suspension. Added triethyl amine (0.0669 mL, 0.48 mmol) followed by the addition of 1-Propanephosphonic acid cyclic anhydride (0.286 mL, 0.48 mmol). The reaction mass was stirred at RT for 5 minutes. Ethanol amine (0.029 mL, 0.48 mmol) was added and stirred at RT for overnight. After the completion of the reaction, diluted the reaction mass with DCM, washed with water and brine solution. The DCM layer was dried over sodium sulphate, evaporated to get the crude compound which was purified by column chromatography. Yield-52.7%. ES+MS m/z: 356.4 (M+1). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.23 (s, 3 H ) 2.39 (s, 3 H) 3.39-3.65 (m, 4 H ) 3.93 (s, 3 H ) 4.84 (t, J=5.09 Hz, 1 H ) 5.63 (s, 2 H ) 7.74 (s, 1 H ) 8.12 (s, 1 H) 8.33 (s, 1 H ) 8.41 (s, 1 H ) 8.80 (t, J=5.65 Hz, 1 H ).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][NH:9]2)=[CH:5][CH:4]=1.[S-:14][C:15]#[N:16].[K+].BrBr>CO>[S:14]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:3]=1[C:2]([F:1])([F:12])[F:13])[NH:9][CH2:8][CH2:7]2)[C:15]#[N:16]
Reactant: N#C[S-]
Reactant: FC(F)(F)c1ccc2c(c1)NCC2
Agent: BrBr
Agent: [K+]
Solvent: CO
Product: N#CSc1cc2c(cc1C(F)(F)F)NCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
A mixture of 6-trifluoromethylindoline (D 16) (9.7 g, 52 mmol) and potassium thiocyanate (10.09 g, 104 mmol) in methanol (200 ml) was treated with a solution of bromine (2.82 ml, 55 mmol) in methanol (35 ml) dropwise over 0.5 h at -5-0° C. The reaction mixture was allowed to warm to room temperature and stirred overnight then evaporated to dryness. The residue was partitioned between aqueous K2CO3 (100 ml) and dichloromethane (3×100 ml). The combined extracts were dried (Na2SO4) and evaporated and the residue chromatographed on silica using 2-30% ethyl acetate/petroleum ether as eluant to afford the title compound (9.1 g, 72%) as a yellow solid.
Reaction SMILES: CO[CH:3](OC)[N:4](C)[CH3:5].[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17](=[O:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:12][CH:11]=1.C(O[CH2:29][CH2:30][CH3:31])(=O)C>>[F:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[C:17](=[O:24])[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:3][N:4]([CH:30]([CH3:31])[CH3:29])[CH:5]=2)=[CH:14][CH:15]=1
Reactant: CCOC(=O)CC(=O)Cc1ccc(F)cc1
Reactant: COC(OC)N(C)C
Reactant: CCCOC(C)=O
Product: CCOC(=O)c1cn(C(C)C)cc(-c2ccc(F)cc2)c1=O
Temperature: 90 °C
Reaction time: 4 h

Procedure:
N,N-Dimethylformamide dimethylacetal (3.6 ml) was added to a solution of ethyl 4-(4-fluorophenyl)-3-oxobutanoate (1200 mg) in n-propyl acetate (13 ml) at room temperature, and the mixture was stirred at 90° C. for four hours. The solvent was distilled off under reduced pressure, and ethanol (18 ml) was added, followed by addition of 2-propylamine (688 μl). After stirring at 60° C. for one hour, 2-propylamine (459 μl) was added and the mixture was further stirred at 60° C. for one hour. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform:methanol=300:1->80:1 (v/v)] to give 620 mg of the title compound as an oily substance.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:35]=[CH:34][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:18](=[O:19])[N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:16]([CH3:30])=[C:15]([C:31](O)=[O:32])[CH:14]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH3:36].Cl[CH2:38][C:39]([CH3:41])=O.C([O-])([O-])=O.[Ca+2]>CN1C(=O)CCC1>[CH3:1][S:2]([C:5]1[CH:35]=[CH:34][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:18](=[O:19])[N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:29])[F:28])[CH:21]=3)[C:16]([CH3:30])=[C:15]([C:31]3[O:32][CH:38]=[C:39]([CH3:41])[N:36]=3)[CH:14]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: N
Reactant: Cc1c(C(=O)O)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CN1CCCC1=O
Product: Cc1coc(-c2cc(C(=O)NCc3ccc(S(C)(=O)=O)cc3)c(=O)n(-c3cccc(C(F)(F)F)c3)c2C)n1
Temperature: 155 °C

Procedure:
6-Methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3,5-dicarboxylic acid 5-amide 4-methanesulfonyl-benzylamide [prepared from the acid chloride of 5-(4-methanesulfonyl-benzylcarbamoyl)-2-methyl-6-oxo-1-(3-trifluoromethyl-phenyl)-1,6-dihydro-pyridine-3-carboxylic acid [described in Example 14 (b)] and ammonia] (0.05 g, 0.098 mmol), 1-chloroacetone (0.025 g, 0.27 mmol), CaCO3 (0.015 g, 0.15 mmol), NMP (1.5 ml) and a magnetic stirrer bar were placed in a tube designed for microwave synthesis. The vial was sealed and the mixture was heated in a CEM Discover Microwave apparatus (100 W, 155° C.) for 60 minutes, giving complete conversion of the amide according to LC-MS. The crude mixture was dissolved in acetonitrile (2 ml) and water (2 ml) and was purified directly on preparative HPLC giving the title compound (0.006 g, 11%) as a solid after freeze-drying the pure fractions.
Reaction SMILES: C1C2CCC3C=CC=CC=3N(C(Cl)=O)C=2C=CC=1.[CH:19]1[C:29]2[CH2:28][CH2:27][C:26]3[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=3[N:24]([C:34]([N:36]=[C:37]=[S:38])=[O:35])[C:23]=2[CH:22]=[CH:21][CH:20]=1.[CH3:39][O:40][C:41]1[CH:42]=[C:43]2[C:48](=[CH:49][C:50]=1[O:51][CH3:52])[N:47]=[CH:46][CH:45]=[C:44]2[O:53][C:54]1[CH:60]=[CH:59][C:57]([NH2:58])=[CH:56][C:55]=1F.C1(C)C=CC=CC=1>C(O)C>[CH:19]1[C:29]2[CH2:28][CH2:27][C:26]3[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=3[N:24]([C:34]([N:36]=[C:37]=[S:38])=[O:35])[C:23]=2[CH:22]=[CH:21][CH:20]=1.[CH:19]1[C:29]2[CH2:28][CH2:27][C:26]3[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=3[N:24]([C:34]([NH:36][C:37]([NH:58][C:57]3[CH:59]=[CH:60][C:54]([O:53][C:44]4[C:43]5[C:48](=[CH:49][C:50]([O:51][CH3:52])=[C:41]([O:40][CH3:39])[CH:42]=5)[N:47]=[CH:46][CH:45]=4)=[CH:55][CH:56]=3)=[S:38])=[O:35])[C:23]=2[CH:22]=[CH:21][CH:20]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: O=C(Cl)N1c2ccccc2CCc2ccccc21
Agent: O=C(N=C=S)N1c2ccccc2CCc2ccccc21
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)N4c5ccccc5CCc5ccccc54)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
10,11-Dihydro-5H-dibenzo(b,f)azepine-5-carbonyl isothiocyanate was prepared using commercially available 10,11-dihydro-5H-dibenzo(b,f)azepine-5-carbonyl chloride (80 mg) as a starting compound according to the description of the literature. 10,11-Dihydro-5H-dibenzo(b,f)azepine-5-carbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (61 mg, yield 65%).
Reaction SMILES: [C:1](=[O:6])(OCC)[NH2:2].N[C:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]=1[C:15]#[N:16].[F:17][C:18]1[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=1[C:20]([NH:22][NH2:23])=O>CN1CCCC1=O>[F:17][C:18]1[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=1[C:20]1[N:16]=[C:15]2[N:23]([C:1](=[O:6])[NH:2][C:8]3[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]=32)[N:22]=1
Reactant: N#CC1=C(N)CCCCC1
Reactant: NNC(=O)c1ccccc1F
Reactant: CCOC(N)=O
Solvent: CN1CCCC1=O
Product: O=c1[nH]c2c(c3nc(-c4ccccc4F)nn13)CCCCC2
Yield: 63 %

Procedure:
A mixture of the ethyl carbamate of 1-amino-2-cyanocyclohept-1-ene (11.6 g), o-fluorobenzhydrazide (8.74 g) and 1-methyl-2-pyrrolidone (140 mL) is stirred at reflux under nitrogen for 18 hours, cooled and triturated with water to produce solid material. It is recrystallized from (±)1-methoxy-2-propanol to afford pure 2-(2-fluorophenyl)-8,9,10,11-tetrahydro-7H-cyclohepta[e][1,2,4]triazolo-[1,5-c]pyrimidin-5(6H)one, m.p. 257°-259°, in 63% yield.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:22]([C:25]1[CH:34]=[C:33]2[C:28]([CH2:29][CH2:30][NH:31][CH2:32]2)=[CH:27][CH:26]=1)([O-:24])=[O:23].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21])[CH2:10][C:11]([N:31]1[CH2:30][CH2:29][C:28]2[C:33](=[CH:34][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=2)[CH2:32]1)=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccccc1F
Reactant: O=[N+]([O-])c1ccc2c(c1)CNCC2
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCc2ccc([N+](=O)[O-])cc2C1)Cc1ccccc1F

Procedure:
(3R)-3-[(tert-Butoxycarbonyl)amino]4-(2-fluorophenyl)butanoic acid (0.69 g; 2.34 mmol) and 7-nitro-1,2,3,4 tetrahydroisoquinoline (0.50 g; 2.34 mmol) were treated with EDC (0.54 g, 2.8 mmol), HOBt (0.38 g, 2.8 mmol) and N,N-diisopropylethylamine (0.60 g, 4.67 mmol) essentially following the procedure outlined in Example 1, Step A. Purification by flash chromatography (silica gel; 35% ethyl acetate/hexanes as eluant) afforded the title compound. LC/MS: 358.1 (M+1-BOC)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6](/[CH:7]=[CH:8]/[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.OS(O)(=O)=O.[CH3:19][CH2:20]O>>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6](/[CH:7]=[CH:8]/[C:9]([O:11][CH2:19][CH3:20])=[O:10])=[CH:5][CH:4]=1
Reactant: CCO
Reactant: COc1ccc(/C=C/C(=O)O)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)/C=C/c1ccc(OC)cc1
Temperature: 90 °C
Yield: 96 %

Procedure:
A mixture of trans-4-methoxycinnamic acid (18 g, 101 mmol) and concentrated H2SO4 (0.5 ml) in absolute EtOH (100 ml) was refluxed at 90° C. (bath temperature) for 16 h. After the excess EtOH was removed by a rotary evaporator, the residue was treated with H2O (100 ml), and the resulting mixture was extracted with ether (3×120 ml). The combined extracts were washed with 1N aq. NaOH (2×50 ml), H2O (80 ml) and brine (80 ml), and dried (anhydrous Na2SO4). The solvent was evaporated to dryness to give ethyl trans-4-methoxycinnamate (20 g, 96% yield) as light yellow oil, which was pure enough for the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH3:10].C1C(=O)N([Br:18])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: COc1ccc(F)c(C)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(F)c(CBr)c1
Temperature: 25 °C
Yield: 95.8 %

Procedure:
To a solution of 1-fluoro-4-methoxy-2-methylbenzene (2.0 g, 14.29 mmol) in CCl4, NBS (2.55 g, 14.29 mmol) and PhCO3H (80 mg) were added. The reaction mixture was heated at reflux for 2 h, cooled to room temperature, and the solid was filtered off. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluting with PE/EA=20/1) to give the target compound (3.0 g) as an oil. 1H NMR (CDCl3): δ 6.97-6.83 (m, 3H), 4.48 (s, 2H), 3.78 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:39])[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].F[C:42]1[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[CH:44][C:43]=1[C:50]([F:53])([F:52])[F:51]>>[C:1]([O:5][C:6](=[O:40])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:39])[C:16]2[CH:21]=[C:20]([O:22][C:42]3[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[CH:44][C:43]=3[C:50]([F:51])([F:52])[F:53])[CH:19]=[C:18]([O:23][C:24]3[CH:25]=[CH:26][C:27]([CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:28][CH:29]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Oc2cc(O)cc(C(=O)NC3CCC(NC(=O)OC(C)(C)C)CC3)c2)cc1
Product: CC(C)(C)OC(=O)NCc1ccc(Oc2cc(Oc3ccc(C#N)cc3C(F)(F)F)cc(C(=O)NC3CCC(NC(=O)OC(C)(C)C)CC3)c2)cc1
Yield: 50.5 %

Procedure:
Using 0.46 g (0.82 mmol) of {4-[3-[4-tert-butoxycarbonylaminomethylphenoxy]-5-hydroxybenzoylamino]-cyclohexyl}carbamic acid tert-butyl ester and 4-fluoro-3-tri-fluoromethylbenzonitrile (0.313 g, 1.65 mmol) and following the procedure of Example 42(b) afforded 0.3 g of the required product. NMR (DMSO-d6): δ 1.25 (4H, m), 1.38 (18H, d), 1.8 (4H, m), 3.18 (1H, m), 3.64 (1H, m), 4.12 (2H, d), 6.75 (1H, d), 7.02 (1H, s), 7.08 (2H, d), 7.20 (1H, d), 7.28 (2H, d), 7.41 (3H, m), 8.1 (1H, m), 8.38 (2H, m).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][S:7][C:6]=2[CH:17]=1.[C:18]([O:22][C:23]([N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([CH2:35][CH2:36]O)[N:33]=2)[CH2:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:18]([O:22][C:23]([N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([CH2:35][CH2:36][O:1][C:2]3[CH:3]=[CH:4][C:5]4[C:9]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][S:7][C:6]=4[CH:17]=3)[N:33]=2)[CH2:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CCOC(=O)CCc1csc2cc(O)ccc12
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(CCO)nc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CCc1csc2cc(OCCc3ccc4c(n3)N(C(=O)OC(C)(C)C)CCC4)ccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 0.8 %

Procedure:
Ethyl 3-(6-hydroxybenzo[b]thiophen-3-yl)propanoate (207 mg, 82.6 mmol), 7-(2-hydroxy-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (276 mg, 99.2 mmol) and triphenylphosphine (435 mg, 165 mmol) were dissolved in THF (15 ml) and stirred for 15 minutes under argon atmosphere at 0° C. Then, diisopropyl azodicarboxylate (0.325 ml, 165 mmol) was added to the mixture. After stirring overnight under argon, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried with sodium sulfate, filtered and evaporated under vacuum. The crude product was chromatographied over silica gel to yield 338 mg (80%) of 7-{2-[3-(2-Ethoxycarbonyl-ethyl)-benzo[b]thiophen-6-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester. NMR 1H Cl3CD δ: 7.59 (d, 1H, J=8.8 Hz), 7.33 (m, 2H), 7.00 (dd, 1H, J=2.3, 8.8 Hz), 6.93 (m, 2H), 4.42 (t, 2H, J=6.7 Hz), 4.14 (m, 2H), 3.76 (m, 2H), 3.22 (m, 2H), 3.12 (m, 2H), 2.73 (m, 4H), 1.92 (m, 2H) 1.51 (s, 9H), 1.26 (m, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.CC(O)(C)C.ClCCCl.[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[CH2:27][CH2:26]2.C(N(CC)CC)C>[Cl-].[Cl-].[Zn+2].ClCCCl>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:22][C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[NH:29][C:28](=[O:33])[CH2:27][CH2:26]3)[N:7]=1
Reactant: Nc1ccc2c(c1)CCC(=O)N2
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C1CCc2cc(Nc3ncc(C(F)(F)F)c(Cl)n3)ccc2N1
Yield: 71.5 %

Procedure:
To a solution of 2,4-Dichloro-5-trifluoromethyl-pyrimidine (963 mg, 4.43 mmol) in 30 mL of 50/50 mixture of t-BuOH/DCE was added a solution of ZnCl2 (1M in THF;4.43 mL). After one hour 6-Amino-3,4-dihydro-1H-quinolin-2-one (480 mg;2.95 mmol) was added followed by the dropwise addition of triethylamine (0.617 ml, 4.43 mmol) in 2 mL t-BUOH/DCE. Following removal of the solvent under reduced pressure, the crude reaction was triturated from methanol and the product filtered off as a yellow solid 723 mg (72% yield). 1H NMR (DMSO-d6, 400 MHz) δ 2.39 (t, J=12 Hz; 2H), 2.80 (t, J=8 Hz; 2H), 6.78 (d, J=8 Hz; 1H), 7.35 (d, J=8 Hz; 1H), 7.40 (br s, 1H), 8.70 (s, 1H), 10.02 (s, 1H), 10.48 (s, 1H). HPLC ret. time: 6.074 (96% purity), LRMS (M+) 343.2/345.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][S:8][C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[CH:5][CH:4]=1.[N+](=[CH2:18])=[N-]>CO.CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C:9]2[N:10]=[N:11][N:12]([CH3:18])[N:13]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(CSc2nnn[nH]2)cc1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Product: COc1ccc(CSc2nnn(C)n2)cc1
Reaction time: 1 h

Procedure:
To a solution of 5-p-methoxybenzylthiotetrazole (7.00 g : 31.5 mMol.) in methanol (150 ml) is added under ice cooling a solution of diazomethane in ether (produced from 14 g of N-nitrosomethylurea), and the mixture is stirred for 1 hour and then concentrated. The residue is purified by Lobar column chromatography (toluene : ethyl acetate=5: 1) to give 5-p-methoxybenzylthio-2-methyltetrazole 4.86 g :
Reaction SMILES: Br[C:2]1(Br)[C:6]2[CH:7]=[N:8][C:9]([Cl:11])=[CH:10][C:5]=2[NH:4][C:3]1=[O:12]>C(O)(=O)C.CO.[Zn]>[Cl:11][C:9]1[N:8]=[CH:7][C:6]2[CH2:2][C:3](=[O:12])[NH:4][C:5]=2[CH:10]=1
Reactant: O=C1Nc2cc(Cl)ncc2C1(Br)Br
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: O=C1Cc2cnc(Cl)cc2N1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 95.2 %

Procedure:
To a solution of 3,3-dibromo-6-chloro-1,3-dihydro-2H-pyrrolo[3,2-c]pyridin-2-one (preparation 36d, 1.14 g, 3.49 mmol) in acetic acid (35 mL) was added zinc dust (2.23 g, 34.10 mmol) in one portion and the mixture was stirred at room temperature for 50 minutes. The mixture was diluted with methanol and filtered through a fine frit. The filtrate was evaporated under reduced pressure and the residue was purified by flash chromatography (95:5 dichloromethane/methanol) to give the title compound (0.56 g, 91%) as a white solid.