Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8].C(O[CH2:18][C:19]([CH2:21][Si](C)(C)C)=[CH2:20])(=O)C>C1COCC1.CCCCCC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:18]=[C:19]1[CH2:21][C@@H:6]([C:7]([O:9][CH3:10])=[O:8])[C@H:5]([C:4]2[CH:11]=[CH:12][CH:13]=[C:2]([F:1])[CH:3]=2)[CH2:20]1
Reactant: COC(=O)/C=C/c1cccc(F)c1
Reactant: C=C(COC(C)=O)C[Si](C)(C)C
Agent: [Pd]
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C1C[C@@H](C(=O)OC)[C@H](c2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.9 %

Procedure:
A mixture of methyl trans-3-fluorocinnamate (41.25 g, 229 mmol), tetrakis(triphenylphosphine) palladium(0) (18.5 g, 16 mmol), 1,2-bis(diphenylphosphino)ethane (5.5 g, 13.7 mmol) and 2-((trimethylsilyl)methyl)-2-propen-1-yl acetate (42.66 g, 229 mmol) in THF (300 mL) under nitrogen was heated to reflux for 6 h and then stirred at rt for 16 h. The reaction was diluted with hexane and filtered to remove yellow precipitate. The volatiles were then removed in vacuo and the residue was purified by FC (3 to 5% ethyl acetate in hexanes) to afford the title compound (45 g).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.ClC[C:29]1[N:30]=[C:31]([CH3:34])[S:32][CH:33]=1>>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[S:20][CH2:21][C:29]1[N:30]=[C:31]([CH3:34])[S:32][CH:33]=1
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: Cc1nc(CCl)cs1
Agent: Cl
Product: Cc1nc(CSc2c(Cl)ccc3c2CCNCC3)cs1

Procedure:
Use a method similar to the Example 332, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 4-chloromethyl-2-methylthiazole hydrochloride to give, after deprotection by the General Procedure 1-4, the title compound as a white solid. MS (APCI+) m/z: 325 (M+H)+.
Reaction SMILES: [Mg].II.[C:4]1([CH2:10][CH2:11][CH2:12]Br)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br-].C([O:17][P:18](Cl)[O:19]CC)C.C([Mg]Br)CC1C=CC=CC=1.Cl>C(OCC)C.O>[C:4]1([CH2:10][CH2:11][CH2:12][PH:18](=[O:17])[OH:19])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCCCc1ccccc1
Reactant: CCOP(Cl)OCC
Agent: Br[Mg]CCc1ccccc1
Agent: Cl
Agent: II
Solvent: CCOCC
Solvent: O
Product: O=[PH](O)CCCc1ccccc1
Temperature: 35 °C
Reaction time: 0.33 h
Yield: 53.2 %

Procedure:
To magnesium turnings (2.44 g, 0.10 mol) in 20 mL of dry diethyl ether under an atmosphere of nitrogen was added several iodine crystals. Phenylpropyl bromide (20.0 g, 0.10 mol) in 80 mL of diethyl ether was placed in a dropping funnel. Approximately 10 mL of the bromide solution was added to the magnesium turnings and stirring was initiated. After several minutes the iodine was consumed and additional phenylpropyl bromide was added while maintaining a temperature of 35° C. Once addition was complete (1.5 hours) the mixture was sealed and stored at 5° C. Diethylchlorophosphite (15.7 g, 0.1 mol) in 50 mL of dry diethyl ether was cooled to 5° C. under an atmosphere of nitrogen. Phenethylmagnesium bromide (100 mL, 0.1 mol, 1.0 M solution of in Et2O) was added dropwise over 2 hours while maintaining a temperature between 0-10° C. A thick white slurry formed and was stirred for an additional 30 minutes. The mixture was filtered under a nitrogen atmosphere and the filtrate evaporated under reduced pressure to give a clear and colorless liquid. To the liquid was added 20 mL of water followed by 0.5 ml of concentrated hydrochloric acid. An exothermic reaction was observed and stirring continued for 20 minutes followed by extraction with ethyl acetate. The organics were combined, washed with brine, dried (MgSO4) and evaporated. To the clear liquid was added sodium hydroxide (40 mL, 2.0 M NaOH), the resulting solution stirred for 1 hour and then washed with diethyl ether. The aqueous layer was acidified to pH 1.0 with concentrated hydrochloric acid and extracted twice with ethyl acetate. The organics were combined, dried (MgSO4) and evaporated to give 3-phenylpropylphosphinic acid (1, R=CH2CH2CH2Ph, R1=H) (9.8 g, 53%) as a clear and colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([C:11]=1[F:12])=[N+:7]([O-])[O:8][N:9]=2.P(OC)(OC)OC>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2=[N:9][O:8][N:7]=[C:6]2[C:11]=1[F:12]
Reactant: [O-][n+]1onc2ccc(Br)c(F)c21
Agent: COP(OC)OC
Product: Fc1c(Br)ccc2nonc12
Temperature: 95 °C

Procedure:
6-Bromo-7-fluorobenzo[c][1,2,5]oxadiazole 1-oxide (1.2 g, 5.0 mmol) was added to neat trimethyl phosphite (6.2 g, 50 mmol) and heated to 95° C. for 2 h. After cooling the solution was deposited on silica gel and chromatographed with a 0-10% ethyl acetate-hexane gradient to give the partially purified product which was further purified by Kugelrohr distillation to give the title compound as low melting, white crystals (460 mg, 43%): 1H NMR (400 MHz, CDCl3) δ 7.61 (m, 1H), 7.51 (dd, J=9.4, 5.6 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −111.68; EIMS m/z 216.
Reaction SMILES: [CH3:1][C:2]([N:6]1[Si:10]([CH3:12])([CH3:11])[CH2:9][CH2:8][Si:7]1([CH3:14])[CH3:13])([CH3:5])[C:3]#[CH:4].[CH2:15]([Li])CCC.CI>O1CCCC1>[CH3:5][C:2]([N:6]1[Si:7]([CH3:14])([CH3:13])[CH2:8][CH2:9][Si:10]1([CH3:11])[CH3:12])([CH3:1])[C:3]#[C:4][CH3:15]
Reactant: [Li]CCCC
Reactant: C#CC(C)(C)N1[Si](C)(C)CC[Si]1(C)C
Solvent: CI
Solvent: C1CCOC1
Product: CC#CC(C)(C)N1[Si](C)(C)CC[Si]1(C)C
Temperature: -5 °C

Procedure:
The product from Step 1 (13.0 g) in dry tetrahydrofuran (140 ml) was cooled to −70° C. under an atmosphere of nitrogen with stirring and a solution of n-butyl lithium (23.1 ml of 2.5M solution in hexanes) was added at −65 to −70° C. during 5 minutes. The mixture was allowed to warm to −5° C. and methyl iodide (3.93 ml) was added dropwise over 10 minutes. The reaction mixture was allowed to warm to 10° C. when an exothermic reaction occurred. The mixture was maintained at 20° C. by cooling for 2 hours then evaporated under reduced pressure to a small volume. The residue was dissolved in hexane, filtered to remove the insoluble material and evaporated under reduced pressure to give 1-(1,1-dimethyl-2-butynyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane as a yellow oil, 13.0 g.
Reaction SMILES: [CH3:1][C:2]([O:13][Si:14]([CH3:17])([CH3:16])[CH3:15])([CH3:12])[CH2:3][N:4]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[N:5]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:28]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:28][C:8]1[N:4]([CH2:3][C:2]([CH3:1])([O:13][Si:14]([CH3:15])([CH3:17])[CH3:16])[CH3:12])[N:5]=[CH:6][C:7]=1[N+:9]([O-:11])=[O:10]
Reactant: CC(C)(Cn1cc([N+](=O)[O-])cn1)O[Si](C)(C)C
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(Cn1ncc([N+](=O)[O-])c1Cl)O[Si](C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
A solution of 1-(2-methyl-2-((trimethylsilyl)oxy)propyl)-4-nitro-1H-pyrazole (1 equiv) in THF (0.41 M) was cooled into −78° C., followed by addition of lithium bis(trimethylsilyl)amide (2.6 equiv). After 1 h, hexachloroethane (1.5 equiv) was added. The reaction mixture was stirred at −78° C. for 2 h then the mixture was quenched with saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate and the organic layer was dried over sodium sulfate, filtered and concentrated. The product was purified by silica gel flash chromatography (15% ethyl acetate in petroleum ether) to afford the title compound as a colorless oil (80.1% yield). 1H NMR (400 MHz, CHLOROFORM-d1) δ ppm 8.12 (s, 1H), 4.06 (s, 2H), 1.51 (s, 6H), 0.01 (s, 9H). MS (ESI) m/z 292.1 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.[CH:9]1(C(O)=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(C1C=CC(C=O)=CN=1)(C)(C)C>>[CH:9]1([C:6]2[CH:5]=[CH:4][C:3]([CH:7]=[O:8])=[CH:2][N:1]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: OCc1cccnc1
Reactant: O=C(O)C1CCCCC1
Agent: CC(C)(C)c1ccc(C=O)cn1
Product: O=Cc1ccc(C2CCCCC2)nc1
Yield: 6 %

Procedure:
This compound was synthesized in 6% yield from 3-pyridine methanol and cyclohexane carboxylic acid using the same procedure as for 6-tert-butylnicotinaldehyde.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.CN(C)P(N(C)C)(N(C)C)=O.Cl[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1>O>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)=[CH:27][CH:28]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: COc1ccc(CCl)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCOC(=O)c1ccc(NCc2ccc(OC)cc2)cc1

Procedure:
A mixture of 33 g. of ethyl p-aminobenzoate, 100 ml. of hexamethylphosphoramide and 15.7 g. of p-(chloromethyl)anisole are heated at 100°-110° C. for 22 hours. The solution is chilled, diluted with 60 ml. of water, chilled, filtered and the solid washed with ethanol and with water to give yellow crystals. Recrystallization from ethanol gives pale yellow crystals, m.p. 128°-130° C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:16][CH2:15][C@@H:14]([OH:17])[CH2:13]3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.ClC1[CH:22]=[CH:23][C:24]2[N:25]([C:27]([C:30](F)(F)F)=NN=2)N=1.N1CC[C@@H](O)C1>>[N:25]1[CH:24]=[CH:23][CH:22]=[C:30]([O:17][C@H:14]2[CH2:15][CH2:16][N:12]([C:9]3[CH:10]=[CH:11][C:6]4[N:7]([C:3]([C:2]([F:1])([F:18])[F:19])=[N:4][N:5]=4)[N:8]=3)[CH2:13]2)[CH:27]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: O[C@@H]1CCN(c2ccc3nnc(C(F)(F)F)n3n2)C1
Agent: O[C@@H]1CCNC1
Product: FC(F)(F)c1nnc2ccc(N3CC[C@H](Oc4cccnc4)C3)nn12

Procedure:
The (3R)-1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]pyrrolidin-3-ol used as starting material was prepared in 81% yield by an analogous method to Example 216, preparation of starting materials, starting from 6-chloro-3-(trifluoromethyl)-[1,2,4]-triazolo[4,3-b]pyridazine and (R)-pyrrolidin-3-ol.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.CO>CO>[CH2:18]([NH:25][CH:14]1[CH2:15][CH2:16][CH:11]([NH:10][C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][N:2]=[CH:3]3)[CH2:12][CH2:13]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1CCC(Nc2ccc3[nH]ncc3c2)CC1
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: c1ccc(CNC2CCC(Nc3ccc4[nH]ncc4c3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.6 %

Procedure:
4-(1H-5-Indazolylamino)-1-cyclohexanone (intermediate 3) (57 mg) and benzylamine (53 mg) were dissolved in methanol (1 ml), and sodium triacetoxyborohydride (105 mg) was added by portions at room temperature. The reaction mixture was stirred at room temperature for 18 hr. Hydrochloric acid-methanol was then added thereto, and the mixture was stirred and was then concentrated. The residue was purified by HPLC [0.5% aqueous trifluoroacetic acid solution/acetonitrile]. A saturated aqueous sodium hydrogencarbonate solution (2 ml) was added to fractions containing respective compounds, follwed by extraction with chloroform-propanol (3/1). The organic layers were dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure to give an anti-form compound (14 mg) and a syn-form compound (24 mg).
Reaction SMILES: [N:1]1([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br.ClCCC1C=C[C:23]([C:26]2[NH:27][C:28](=[O:31])[S:29][CH:30]=2)=[CH:22]C=1.C(=O)([O-])[O-].[Na+].[Na+].C(N(C(C)C)CC)(C)C.[I-].[Na+]>CC(CC(C)C)=O>[S:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:7]([N:1]2[CH2:6][CH2:5][N:4]([CH2:22][CH2:23][C:26]3[NH:27][C:28](=[O:31])[S:29][CH:30]=3)[CH2:3][CH2:2]2)=[N:8]1
Reactant: O=c1[nH]c(-c2ccc(CCCl)cc2)cs1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)CC(C)C
Product: O=c1[nH]c(CCN2CCN(c3nsc4ccccc34)CC2)cs1

Procedure:
To a 100 ml round-bottomed flask equipped with condenser and N2 inlet were added 1.0 g (4.57 mmol) 3-piperazinyl-benzisothiazole, 1.46 g (4.57 mmol) 4-(4-(2-chloroethyl)phenyl)thiazol-2-one hydrobromide, 970 mg (9.13 mmol) sodium carbonate, 600 mg (4.57 mmol) diisopropylethylamine, 2 mg sodium iodide, and 35 ml methylisobutylketone. The reaction was refluxed 24 hours, cooled, and evaporated. The residue was taken up in ethyl acetate, washed with water and brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using methylene chloride/ethyl acetate as eluent. The product fractions were dissolved in methylene chloride/ethyl acetate and precipitated with HCl gas. The precipitate was filtered to give a solid, m.p. 190° C., 455 mg (21.9%).
Reaction SMILES: C([C:5]1[CH:10]=[CH:9][CH:8]=C[C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22]3[CH:23]=[C:24]([C:28]4[N:29]=[CH:30][N:31]([CH2:33][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH:32]=4)[CH:25]=[C:26]([CH3:27])[C:21]=3[N:20]=[C:19]2[CH2:40][CH2:41][CH3:42])=[CH:13][CH:12]=1)(C)(C)C.F[C:44](F)(F)[C:45]([OH:47])=[O:46]>C(Cl)Cl>[CH2:40]([C:19]1[N:18]([CH2:17][C:14]2[CH:15]=[CH:16][C:11]([C:6]3[C:44]([C:45]([OH:47])=[O:46])=[CH:8][CH:9]=[CH:10][CH:5]=3)=[CH:12][CH:13]=2)[C:22]2[CH:23]=[C:24]([C:28]3[N:29]=[CH:30][N:31]([CH2:33][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH:32]=3)[CH:25]=[C:26]([CH3:27])[C:21]=2[N:20]=1)[CH2:41][CH3:42]
Reactant: O=C(O)C(F)(F)F
Reactant: CCCc1nc2c(C)cc(-c3cn(Cc4ccccc4)cn3)cc2n1Cc1ccc(-c2ccccc2C(C)(C)C)cc1
Solvent: ClCCl
Product: CCCc1nc2c(C)cc(-c3cn(Cc4ccccc4)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(1-benzyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](Cl)=[N:17][OH:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([C:22]1[C:23]([NH2:29])=[N:24][C:25]([NH2:28])=[CH:26][CH:27]=1)#[CH:21].C(N(CC)CC)C>O1CCCC1>[O:1]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[CH:21]=[C:20]([C:22]3[C:23]([NH2:29])=[N:24][C:25]([NH2:28])=[CH:26][CH:27]=3)[O:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(N)nc1N
Reactant: ON=C(Cl)Cc1ccc(COc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3ccc(COc4ccccc4)cc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.7 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (4-phenoxymethyl-phenyl)-acetohydroximoyl chloride (150 mg, 0.545 mmol) described in Manufacturing Example 86-1-5 and 3-ethynyl-pyridin-2,6-diamine (46.3 mg, 0.348 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (104 μL, 0.747 mmol), which was stirred for 1 hour at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (45 mg, 22%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:7]2.[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[O:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:12](=[O:17])[C:13]([F:16])([F:14])[F:15])[CH2:7]2
Reactant: C1=COCCC1
Reactant: O=C(N1CCc2c(O)cccc2C1)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: O=C(N1CCc2c(cccc2OC2CCCCO2)C1)C(F)(F)F

Procedure:
3.7 g (15.9 mmol) of 5-hydroxy-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline (Example 1) and 4.4 mL (47.7 mmol) 2,3-dihydropyrane were dissolved in dichloromethane and catalytic amount of p-toluenesulfonic acid monohydrate was added. After completion of the reaction (System A), the reaction mixture was diluted with dichloromethane, washed with water and aqueous sodium chloride. The solution was dried over Na2SO4, evaporated to dryness, and the product was purified by silicagel chromatography (System A). Yield 4.13 g, 79%. 1H NMR (CDCl3, 400 MHz): 7.16 (1H, m), 7.00 (1H, m), 6.77 (1H, m), 5.45 (1H, m), 4.79 (2H, ss), 3.8 (3H, m), 3.6 (1H, m), 2.9 (4H, m).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:16])[CH:12]=2)[CH:7]=1)[CH3:5].N1C=CC=CC=1.[Br:24][CH2:25][C:26](Cl)=[O:27]>ClCCl>[CH3:1][O:2][C:3](=[O:17])[CH:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][C:26](=[O:27])[CH2:25][Br:24])[CH:12]=2)[CH:7]=1)[CH3:5]
Reactant: O=C(Cl)CBr
Reactant: COC(=O)C(C)c1ccc2cc(O)ccc2c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C(C)c1ccc2cc(OC(=O)CBr)ccc2c1
Reaction time: 1 h
Yield: 45.9 %

Procedure:
To a solution of 2-(6-hydroxy-naphthalen-2-yl)-propionic acid methyl ester (20 grams) and pyridine (10.3 grams) in dichloromethane (200 ml) maintained at 0-5° C. under N2 atmosphere was added dropwise bromoacetyl chloride (19.6 grams). The reaction was stirred at the same temperature for one hour. The reaction mixture was washed with water (500 ml) and 5% solution of sodium carbonate followed by drying over sodium sulphate and distillation to get crude compound, which was purified by column chromatography using hexane as eluant to get pure 2-[6-(2-bromo-acetoxy)-naphthalen-2-yl]-propionic acid methyl ester (14 grams) as a dark brown syrup. The pure product was characterized using 1H NMR spectroscopy in CDCl3 δ 1.55 (d, 3H, CH3), 3.65 (s, 3H, Ester), 3.82 (q, 1H, CH), 4.08 (s, 2H, OCH2) 7.20 (dd, 1H, Ar), 7.4 (dd, 1H, Ar), 7.57 (d, 1H, Ar), 7.72 (d, 1H, Ar), 7.78 (d, 1H, Ar), 7.84 (d, 1H, Ar).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH:12](O)([CH3:14])[CH3:13]>OS(O)(=O)=O>[CH:12]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Cl:1])[C:3]([Cl:11])=[N:4][CH:5]=1)([CH3:14])[CH3:13]
Reactant: CC(C)O
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Agent: O=S(=O)(O)O
Product: CC(C)OC(=O)c1cnc(Cl)c(Cl)c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of 5,6-dichloro nicotinic acid (12.2 g, 63.5 mmol) in isopropanol (70 mL), H2SO4 (4 mL) is added dropwise. The mixture is stirred at 80° C. for 16 h before it is cooled to rt and concentrated in vacuo. The residue is dissolved in dioxane (100 mL) and concentrated again. The crude product is purified by CC (heptane:EA 1:3) to give 5,6-dichloro nicotinic acid isopropyl ester (9.29 g) as a pale beige oil; LC-MS: tR=1.33 min, [M+1]+=233.94.
Reaction SMILES: Cl[C:2]([C:7]1[CH:8]=[CH:9][C:10]2[O:19][C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH2:12][C:11]=2[CH:20]=1)([CH3:6])[C:3]([OH:5])=[O:4].[OH-].[Na+]>[Ni].[H][H]>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]2[CH2:12][C:11]3[CH:20]=[C:7]([CH:2]([CH3:6])[C:3]([OH:5])=[O:4])[CH:8]=[CH:9][C:10]=3[O:19][C:14]=12
Reactant: [H][H]
Reactant: CC(Cl)(C(=O)O)c1ccc2c(c1)Cc1cccnc1O2
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Product: CC(C(=O)O)c1ccc2c(c1)Cc1cccnc1O2
Yield: 58.7 %

Procedure:
A mixture of 2.9 g of 2-chloro-2-(5H-[1]benzopyrano[2,3-b]pyridin-7-yl)propionic acid, 40 ml of 0.5 N aqueous sodium hydroxide solution and 1 g of Raney nickel is stirred in a hydrogen stream at ordinary pressure and temperature, until absorption of 230 ml of hydrogen is attained. The RAney nickel is then filtered off, and the filtrate is neutralized with hydrochloric acid. The crystalline precipitate is filtered off, washed with water, and recrystallized from aqueous dioxane to give 1.5 g of 2-(5H-[1]benzopyrano-[2,3-b]pyridin-7-yl)propionic acid melting at 183°-184°C.
Reaction SMILES: [C:1]([O:9]CC)(=[O:8])[CH2:2][C:3](OCC)=O.[H-].[Na+].ClC[C:16]1[CH:17]=[N:18][O:19][C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH3:28])[CH:22]=1.Cl>O1CCCC1.O>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]2[O:19][N:18]=[CH:17][C:16]=2[CH2:3][CH2:2][C:1]([OH:9])=[O:8])=[CH:22][C:23]=1[CH3:28]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1cc(-c2oncc2CCl)ccc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(-c2oncc2CCC(=O)O)ccc1Cl
Reaction time: 0.17 h
Yield: 58.3 %

Procedure:
To a solution of diethyl malonate (5.82 g) in tetrahydrofuran (40 ml) was gradually added sodium hydride (60%, oil, 1.32 g) at 0° C. The mixture was stirred for 10 min and a solution of 4-chloromethyl-5-(4-chloro-3-methylphenyl)isoxazole (4.00 g) in tetrahydrofuran (40 ml) was added dropwise at 0° C. and the mixture was stirred at room temperature for 15 hr. The reaction mixture was poured into water, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was dissolved in a mixture of 6N hydrochloric acid (40 ml) and acetic acid (60 ml) and heated under reflux for 8 hr. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were filtrated, dried and recrystallized from ethyl acetate to give a colorless prism (2.56 g, yield 58%) of 3-[5-(4-chloro-3-methylphenyl)-4-isoxazolyl]propionic acid. melting point: 158–159° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:14](=O)([O-])[O-].[K+].[K+].CI.Cl>CN(C)C=O.O>[CH3:14][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: Cc1ccc([N+](=O)[O-])c(C(=O)O)c1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
There was dissolved, in 200 mL of N,N-dimethylformamide, 20.0 g of 5-methyl-2-nitrobenzoic acid, 22.9 g of potassium carbonate and then 8.2 mL of methyl iodide were added to the resulting solution and the mixture was stirred at room temperature for 4 hours. To the reaction liquid, there were added 400 mL of water and 200 mL of a 1M hydrochloric acid solution, then extracted with 900 mL of ethyl acetate, the extract was washed with 200 mL of a saturated sodium hydrogen carbonate solution and 200 mL of a saturated common salt solution and the solvent was then distilled off under reduced pressure to thus give 20.6 g of the title compound as a crude product.
Reaction SMILES: [Li+].[OH-].C1COCC1.O.C([O:11][C:12]([C:14]1[S:18][C:17]([NH:19][C:20](=[O:46])[C@@H:21]([NH:29][C:30](=[O:45])/[CH:31]=[CH:32]/[C:33]2[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=2[N:40]2[CH:44]=[N:43][N:42]=[N:41]2)[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:16][CH:15]=1)=[O:13])C.ClCl>>[Cl:39][C:37]1[CH:36]=[CH:35][C:34]([N:40]2[CH:44]=[N:43][N:42]=[N:41]2)=[C:33](/[CH:32]=[CH:31]/[C:30]([NH:29][C@@H:21]([CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:20]([NH:19][C:17]2[S:18][C:14]([C:12]([OH:13])=[O:11])=[CH:15][N:16]=2)=[O:46])=[O:45])[CH:38]=1
Reactant: CCOC(=O)c1cnc(NC(=O)[C@H](Cc2ccccc2)NC(=O)/C=C/c2cc(Cl)ccc2-n2cnnn2)s1
Agent: ClCl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(/C=C/c1cc(Cl)ccc1-n1cnnn1)N[C@@H](Cc1ccccc1)C(=O)Nc1ncc(C(=O)O)s1

Procedure:
LiOH/THF/water hydrolysis of 2-{(S)-2-[(E)-3-(5-chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-3-phenyl-propionylamino}-thiazole-5-carboxylic acid ethyl ester (Example 19) afforded Example 21. HPLC purity: >98%. LCMS m/z 524.2 (M+H, chlorine isotope). 1H NMR (400 MHz, CD3OD) δ: 9.48 (s, 1H), 8.02 (s, 1H), 7.96 (d, J=2.3 Hz, 1H), 7.68 (dd, J=2.3 & 9.2 Hz, 1H), 7.56 (d, J=8.5 Hz, 1H), 7.31-7.19 (m, 5H), 7.10 (d, J=15.7 Hz, 1H), 6.75 (d, J=15.6 Hz, 1H), 4.9 (t, 1H), 3.30 (m, 1H), 3.11 (m, 1H) ppm. Analytical HPLC RT: 5.48 min (Method C, 8 min gradient).