Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12](Br)[C:13]([O:19][CH3:20])=[C:14]([S:15]([CH3:18])(=[O:17])=[O:16])[C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][C:13]([O:19][CH3:20])=[C:14]([S:15]([CH3:18])(=[O:16])=[O:17])[C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: COc1c(Br)cc2c(c1S(C)(=O)=O)CCN(C(C)=O)CC2
Agent: [Pd]
Solvent: CO
Product: COc1ccc2c(c1S(C)(=O)=O)CCN(C(C)=O)CC2

Procedure:
A mixture of 3-acetyl-8-bromo-7-methoxy-6-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine (3.7 g, 0.01 m) and 10% palladium-on-carbon (0.37 g) in methanol (50 ml) is stirred in an atmosphere of hydrogen (60 psi) until uptake is complete. The mixture is degassed, filtered and concentrated in vacuo to give 3-acetyl-7-methoxy-6-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: BrC1C=CC(S(NC2C=CN=C(Cl)C=2)(=O)=O)=CC=1.[CH3:19][C@H:20]1[NH:25][C@@H:24]([CH3:26])[CH2:23][N:22]([C:27]2[CH:28]=[C:29]([NH2:33])[CH:30]=[N:31][CH:32]=2)[CH2:21]1.[Br:34][C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][C:36]=1[F:45]>>[Br:34][C:35]1[CH:40]=[CH:39][C:38]([S:41]([NH:33][C:29]2[CH:30]=[N:31][CH:32]=[C:27]([N:22]3[CH2:23][C@H:24]([CH3:26])[NH:25][C@H:20]([CH3:19])[CH2:21]3)[CH:28]=2)(=[O:43])=[O:42])=[CH:37][C:36]=1[F:45]
Reactant: C[C@@H]1CN(c2cncc(N)c2)C[C@H](C)N1
Reactant: O=S(=O)(Cl)c1ccc(Br)c(F)c1
Agent: O=S(=O)(Nc1ccnc(Cl)c1)c1ccc(Br)cc1
Product: C[C@@H]1CN(c2cncc(NS(=O)(=O)c3ccc(Br)c(F)c3)c2)C[C@H](C)N1

Procedure:
The title compound was prepared in a manner similar to 4-bromo-N-(2-chloro-4-pyridinyl)benzenesulfonamide (D3) using 5-[cis-3,5-dimethyl-1-piperazinyl]-3-pyridinamine (D36) and 4-bromo-3-fluorobenzenesulfonyl chloride as the starting materials.
Reaction SMILES: [N+:1]([CH2:4][CH:5]1[CH2:13][C:8]2(OCC[O:9]2)[CH:7]([CH2:14][CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:6]1[CH:23]=[CH:24][C:25]([CH3:32])([OH:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([O-:3])=[O:2].O1CCCC1.Cl>O>[OH:31][C:25]([CH3:32])([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:24]=[CH:23][CH:6]1[CH:5]([CH2:4][N+:1]([O-:3])=[O:2])[CH2:13][C:8](=[O:9])[CH:7]1[CH2:14][CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21]
Reactant: CCCCCC(C)(O)C=CC1C(C[N+](=O)[O-])CC2(OCCO2)C1CC=CCCCC(=O)O
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCCCCC(C)(O)C=CC1C(C[N+](=O)[O-])CC(=O)C1CC=CCCCC(=O)O

Procedure:
A solution of 0.20 g. of 7-[8-nitromethyl-7-(3-methyl-3-hydroxy-1-octenyl)-1,4-dioxaspiro[4.4]non-6-yl]-5-heptenoic acid in 4 ml. of tetrahydrofuran was treated at 0° C. with 0.4 ml. of concentrated hydrochloric acid and stirred at 0° C. for 1.5 hours. The reaction mixture was added to water and extracted with ether. After washing with water and drying over magnesium sulfate, the extract was evaporated and the residue chromatographed on silica. Elution with 15% ethyl acetate in hexane gave 0.11 g. of the title product as an oil, λmaxfilm 3.00 (shoulder), 3.50, 5.80, 6.45, 7.25, 10.30 μ. NMR: δ 1.32 (S, 15-methyl), 4.49 (M, 2, --CH2NO2), 5.80 (M, 4, olefinic --H), 5.92 (S, 2, OH) ppm. Mass spectrum: M+ --H2O at m/e 391.2402 (theory 391.2358).
Reaction SMILES: [CH3:1][N:2]1[C:6](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:5][C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:3]1.[C:24]1([C:30]#[CH:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CCCCCCC.C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:31]#[C:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:5][C:4]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:3]1
Reactant: C#Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(-c3ccccc3)nn2C)cc1
Solvent: CCCCCCC
Solvent: ClCCl
Product: Cn1nc(-c2ccccc2)cc1C#Cc1ccccc1

Procedure:
This product was prepared from toluene-4-sulfonic acid 2-methyl-5-phenyl-2H-pyrazol-3-yl ester and phenylacetylene. Chromatography eluent: heptane/DCM 1:1; yield (64 mg, 50%); 1H NMR δ (CDCl3): 7.78 (d, J=8.22 Hz, 2H), 7.65-7.57 (m 5H), 7.43-7.34 (m, 3H), 6.63 (s, 1H), 3.98 (s, 3H); LCMS m/z: 258.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4](=[O:8])[CH2:5][CH2:6][CH3:7].[CH2:9]([Mg]Br)[CH:10]=[CH2:11].C(Br)C=C.[NH4+].[Cl-].Cl>C(OCC)C>[OH:8][C:4]([CH2:9][CH2:10][CH3:11])([CH2:5][CH2:6][CH3:7])[CH2:3][CH:2]=[CH2:1]
Reactant: CCCC(=O)CCC
Reactant: C=CC[Mg]Br
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C=CCBr
Solvent: CCOCC
Product: C=CCC(O)(CCC)CCC
Temperature: 0 °C

Procedure:
113 g of 4-heptanone in 1000 ml of dry diethyl ether was slowly added to a solution of allylmagnesium bromide, prepared from 36.5 g of Mg and 178 g of allyl bromide in 500 ml dry diethyl ether. After the addition the mixture was refluxed for 10 hrs. The reaction mixture was poured on a mixture of 150 g ice, 450 ml of 20% NH4Cl and 350 ml of 5M HCl. The ether phase was separated and the water phase extracted with diethyl ether (3×100 ml). The combined organic phases were then washed with a Na2CO3 -solution and water, dried with Na2SO4 and evaporated. The residue was distilled. Yield: 142 g (b.p. 38°-40° C./0.1 torr) 1H-NMR(CDCl3): δ0.9(6H,CH3), 1.3-1.6(9H,CH2,OH), 2.1-2.3 (CH2C=C), 5.0-5.2(CH2 =C), 5.6-6.1 (CH=C)
Reaction SMILES: [CH:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:14]([C:18]1[CH:23]=[CH:22][C:21]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)[CH2:15][CH2:16][CH3:17]>>[CH2:14]([C:18]1[CH:23]=[CH:22][C:21]([N:24]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)[C:11]([CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[O:13])=[CH:20][CH:19]=1)[CH2:15][CH2:16][CH3:17]
Reactant: O=C(O)C1CCCc2ccccc21
Reactant: CCCCc1ccc(NCc2ccc(N(C)C)cc2)cc1
Product: CCCCc1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3ccccc32)cc1
Yield: 37.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.45 g) and (4-butylphenyl)[(4-dimethylaminophenyl)-methyl]amine (0.6 g) as starting materials, N-(4-butylphenyl)-N-[(4-dimethylaminophenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.35 g) was obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:7][C:8]([C:10]1[CH:15]=[C:14]([O:16][C:17]2[CH:26]=[C:25]3[C:20]([CH:21]=[CH:22][C:23]([C:27]([NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH:31]=4)=[O:28])=[CH:24]3)=[CH:19][CH:18]=2)[CH:13]=[CH:12][N:11]=1)=S>CCOC(C)=O.[Cl-].[Na+].O>[C:36]([C:32]1[CH:31]=[C:30]([NH:29][C:27]([C:23]2[CH:22]=[CH:21][C:20]3[C:25](=[CH:26][C:17]([O:16][C:14]4[CH:13]=[CH:12][N:11]=[C:10]([C:8](=[NH:7])[N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)[CH:15]=4)=[CH:18][CH:19]=3)[CH:24]=2)=[O:28])[CH:35]=[CH:34][CH:33]=1)([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc3ccc(Oc4ccnc(C(N)=S)c4)cc3c2)c1
Reactant: C1COCCN1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cccc(NC(=O)c2ccc3ccc(Oc4ccnc(C(=N)N5CCOCC5)c4)cc3c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Morpholine (2.00 mL, 22.9 mmol) and 7-{[2-(aminocarbonothioyl)pyridin-4-yl]-oxy}-N-(3-tert-butylphenyl)-2-naphthamide (0.155 g, 0. 34 mmol) were combined. The reaction mixture was allowed to stir at rt overnight in a sealed vial. And then heated at 60° C. for 6 h. The reaction mixture was diluted with EtOAc and poured into brine. The aqueous and organic solutions were separated and the aqueous solution was further extracted with EtOAc. The organic solutions were combined, dried over Na2SO4, and loaded onto a silica gel column. The product was collected from the column, concentrated, and redissolved in MeOH. To this solution was added 1M HCl in Et2O. The solution was concentrated to give N-(3-tert-butylphenyl)-7-({2-[imino(morpholin-4-yl)methyl]pyridin-4-yl}oxy)-2-naphthamide I-99 (21 mg). 1H NMR (400 MHz, CD3OD; 2*HCl salt) δ: 8.48 (d, 1H), 8.47 (s, 1H), 7.99-8.12 (m, 3H), 7.81 (dd, 2H), 7.58 (dd, 1H), 7.46 (dd, 1H), 7.31 (dd, 1H), 7.22 (ddd, 1H), 7.14 (d, 1H), 7.08 (d, 1H), 3.69 (dd, 4H), 3.31-3.33 (m, 4H), and 1.35 (s, 9H). LCMS: (FA) ES30 509.3, ES− 507.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:25])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:13][CH2:12][C@@H:11]([O:14][Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])[CH2:10]1.C[Al](C)C.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[S:38][C:39]3[C:45](=[O:46])[O:44][CH2:43][CH2:42][C:40]=3[N:41]=2)=[CH:33][CH:32]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:25][C:45]([C:39]2[S:38][C:37]([C:34]3[CH:35]=[CH:36][C:31]([Cl:30])=[CH:32][CH:33]=3)=[N:41][C:40]=2[CH2:42][CH2:43][OH:44])=[O:46])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:13][CH2:12][C@@H:11]([O:14][Si:15]([CH:19]([CH3:21])[CH3:20])([CH:22]([CH3:24])[CH3:23])[CH:16]([CH3:18])[CH3:17])[CH2:10]1
Reactant: COc1cc(N)ccc1N1CC[C@@H](O[Si](C(C)C)(C(C)C)C(C)C)C1
Reactant: O=C1OCCc2nc(-c3ccc(Cl)cc3)sc21
Agent: C[Al](C)C
Product: COc1cc(NC(=O)c2sc(-c3ccc(Cl)cc3)nc2CCO)ccc1N1CC[C@@H](O[Si](C(C)C)(C(C)C)C(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.1 %

Procedure:
Charge an oven-dried round bottom flask with (R)-3-methoxy-4-(3-triisopropylsilanyloxy-pyrrolidin-1-yl)-phenylamine (750 mg, 2.05 mmol), purge with nitrogen, and dilute with CH2Cl2 (11 mL). Add trimethylaluminum (2M in hexanes, 1.03 mL, 2.05 mmol) dropwise by syringe and stir 20 min at room temperature. Add solid 2-(4-chloro-phenyl)-6,7-dihydro-pyrano[4,3-d]thiazol-4-one (364 mg, 1.37 mmol) to the reaction mixture and stir overnight at ambient temperature. Absorb the reaction mixture on silica gel and purify by silica gel flash chromatography, using a gradient of EtOAc/hexane (0-100%) to give the title compound (1.02 g, 73%). MS (ES+) 630.1 (M+1)+. 1H NMR (CDCl3): δ 9.88 (bs, 1H), 7.82 (d, J=8.8 Hz, 2H), 7.48 (bs, 1H), 7.37 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.4 Hz, 1H), 6.69 (bs, 1H), 4.60-4.52 (m, 1H), 4.19-4.11 (m, 2H), 3.81 (s, 3H), 3.69-3.58 (m, 1H), 3.39-3.29 (m, 1H), 3.26 (t, J=5.3 Hz, 2H), 3.20-3.02 (m, 2H), 2.21-2.08 (m, 1H), 1.93-1.83 (m, 1H), 1.59 (bs, 1H), 1.12-0.95 (m, 21H).
Reaction SMILES: [Na].[C:2]1([C:8]2[N:9]=[C:10]([CH2:19]P(=O)(OC)OC)[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:26]([C:28]1[CH:39]=[CH:38][C:31]([O:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:30][CH:29]=1)=O>CO.O>[C:2]1([C:8]2[N:9]=[C:10]([CH:19]=[CH:26][C:28]3[CH:39]=[CH:38][C:31]([O:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:30][CH:29]=3)[O:11][C:12]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COP(=O)(Cc1nc(-c2ccccc2)c(-c2ccccc2)o1)OC
Reactant: COC(=O)COc1ccc(C=O)cc1
Agent: [Na]
Solvent: O
Solvent: CO
Product: COC(=O)COc1ccc(C=Cc2nc(-c3ccccc3)c(-c3ccccc3)o2)cc1
Reaction time: 0.17 h

Procedure:
Sodium metal (570 mg, 25 mg atom) was dissolved in methanol (50 mL) and dimethyl [(4,5-diphenyl-2-oxazolyl)methyl]phosphonate (7.80 g, 22 mmol) added. The mixture was stirred for 10 minutes before adding methyl (4-formylphenoxy)acetate (4.00 g, 20 mmol). After stirring at room temperature for 1 hour, the mixture was diluted with water and a yellow solid filtered off and air dried to give crude product (3.80 g, 44%). This was combined with 3.50 g from a previous experiment and recrystallized twice from methanol to afford analytically pure methyl [4-[2-(4,5-diphenyl-2-oxazolyl)ethenyl]phenoxy]acetate, m.p. 122°-123° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N-:10]=[N+:11]=[N-:12].[Na+].[Cl-].[NH4+]>CN(C)C=O>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]1[NH:12][N:11]=[N:10][N:5]=1
Reactant: N#Cc1ccccc1N
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ccccc1-c1nnn[nH]1
Temperature: 120 °C
Yield: 65.2 %

Procedure:
2-Aminobenzonitrile (9.44 g, 80 mmol), sodium azide, (6.24 g, 0.1 mol), ammonium chloride (5.12 g, 0.1 mol) and dimethylformamide (50 mL) were mixed and heated at 120° C. overnight. The solvent was evaporated and the residue taken up in water. The crude product was isolated by filtration and re-crystallised from water. A yield of 8.4 g of pure product was obtained
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.[N-:8]=[C:9]=[O:10].[K+].[Na+].[Cl-]>O>[O:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:9]([NH2:8])=[O:10])[CH2:3][CH2:2]1
Reactant: NC1CCOCC1
Reactant: [N-]=C=O
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: NC(=O)NC1CCOCC1
Temperature: 25 °C
Yield: 18 %

Procedure:
A mixture of tetrahydro-2H-pyran-4-amine (5.0 g, 49.4 mmol, 1.0 equiv.) and potassium isocyanate (4.0 g, 49.5 mmol, 1.0 equiv.) was refluxed in H2O (50 mL) overnight. The reaction was cooled to room temperature and excess NaCl was added to help saturate the aqueous layer. The precipitate was isolated by filtration to provide the desired product (1.28 g, 8.88 mmol). The aqueous layer was washed with EtOAc (3×15 mL) and then was concentrated and azeotroped with toluene (3×100 mL). The resulting solid was suspended in 1:4 CH3OH:EtOAc (100 mL) and filtered a total of four times. The combined organics were concentrated under reduced pressure and combined with the isolated precipitate to provide 5.01 g (70%) of the title compound. LC/MS: m/z (ES+) 145 (M+H)+. 1H-NMR (400 MHz, DMSO-d6): δ 6.14 (d, J=7.5 Hz, 1H), 5.47 (s, 2H), 3.85 (dt, J=11.6, 3.6 Hz, 2H), 3.65-3.52 (m, 1H), 3.38 (td, J=11.4, 2.2 Hz, 2H), 1.80-1.72 (m, 2H), 1.42-1.27 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:3]=1[O:4][C:5]1[N:13]=[CH:12][C:11]([F:14])=[CH:10][C:6]=1[C:7]([OH:9])=O.S(Cl)(Cl)=O.C(N(C(C)C)C(C)C)C.[CH3:33][CH:34]1[CH2:43][CH2:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35]1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:3]=1[O:4][C:5]1[C:6]([C:7]([N:35]2[C:36]3[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:42][CH2:43][CH:34]2[CH3:33])=[O:9])=[CH:10][C:11]([F:14])=[CH:12][N:13]=1
Reactant: O=C(O)c1cc(F)cnc1Oc1cc(Cl)ccc1Cl
Reactant: CC1CCc2ccccc2N1
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCc2ccccc2N1C(=O)c1cc(F)cnc1Oc1cc(Cl)ccc1Cl
Temperature: 120 °C
Yield: 22.2 %

Procedure:
A solution of 2-(2,5-dichloro-phenoxy)-5-fluoro-nicotinic acid (36.3 mg, 0.12 mmol, 1.0 equiv) in thionyl chloride (492 mg, 300 μL, 4.14 mmol, 34.5 equiv; [CAS RN 7719-09-7]) was heated to 100° C. over night. The reaction mixture was concentrated under reduced pressure, remaining thionyl chloride removed by azotropic distillation with toluene and the residue dissolved in anhydrous DMF (1 mL). To this solution was added N-ethyldiisopropylamine (155 mg, 204 μL, 1.20 mmol, 10.0 equiv; [CAS RN 7087-68-5]) and 2-methyl-1,2,3,4-tetrahydro-quinoline (22.1 mg, 0.15 mmol, 1.25 equiv; [CAS RN 1780-19-4]) and the reaction mixture heated by microwave irradiation to 120° C. for 15 min. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 11.5 mg (22%) of the title compound. MS (ISP): 430.8 [M+H]+.
Reaction SMILES: [OH-].[Na+].C1COCC1.[Cl:8][C:9]1[CH:14]=[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=2[C:27]2[CH:32]=[CH:31][C:30]([C:33]([O:35]C)=[O:34])=[CH:29][CH:28]=2)[CH:12]=[CH:11][C:10]=1[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:38]=1[CH3:44]>CO>[Cl:8][C:9]1[CH:14]=[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=2[C:27]2[CH:28]=[CH:29][C:30]([C:33]([OH:35])=[O:34])=[CH:31][CH:32]=2)[CH:12]=[CH:11][C:10]=1[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:38]=1[CH3:44]
Reactant: COC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2CNc2ccc(-c3ccc(Cl)cc3C)c(Cl)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1-c1ccc(NCc2ccc(C(F)(F)F)cc2-c2ccc(C(=O)O)cc2)cc1Cl
Temperature: 25 °C

Procedure:
A 3M aqueous solution of NaOH (0.6 mL, 1.8 mmol) was added to a THF (3 mL) and MeOH (1.5 mL) solution of methyl 2′-(((2,4′-dichloro-2′-methyl-[1,1′-biphenyl]-4-yl)amino)methyl)-5′-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylate (326 mg, 0.6 mmol) and the resulting homogeneous mixture was stirred at room temperature. After 16 h the resulting mixture was concentrated in vacuo, suspended in water, and acidified with 2 M HCl. The resulting precipitate was filtered off, dried in vacuo, and purified via HPLC to yield the title compound.
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([S:10][C:11]2[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:8][N:9]=1)(=O)C.O1CCCC1.Cl>C(O)C>[NH2:4][C:5]1[S:6][C:7]([S:10][C:11]2[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:8][N:9]=1
Reactant: CC(=O)Nc1ncc(Sc2ncccc2O)s1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ncc(Sc2ncccc2O)s1
Yield: 68.2 %

Procedure:
A mixture of 2-acetylamino-5-(3-hydroxypyridin-2-ylthio)thiazole (2 g) in a mixture of ethanol (40 ml), tetrahydrofuran (20 ml) and aqueous 6N-hydrochloric acid (13 ml) was refluxed for 5 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water. The solution was adjusted to pH 8.5 using aqueous sodium bicarbonate and extracted with a mixture of tetrahydrofuran and ethyl acetate (1:1). The organic layer was washed with aqueous saturated sodium chloride and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to give 2-amino-5-(3-hydroxypyridin-2-ylthio)thiazole (1.15 g, yield: 68.9%).
Reaction SMILES: [CH2:1]([OH:14])[CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]#[C:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].C[O:16][CH2:17][CH2:18]OC.C(N(CC)CC)C.[CH2:28]([N:46]=[C:47]=[O:48])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>CCCCCCC>[CH2:28]([NH:46][C:47]([O:13][CH2:12][CH3:11])=[O:48])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45].[CH2:28]([NH:46][C:47]([O:16][CH2:17][CH3:18])=[O:48])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45].[CH2:12]([OH:13])[CH2:11][CH2:10][CH2:9][C:8]#[C:7][C:6]#[C:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:14]
Reactant: COCCOC
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Agent: OCCCCC#CC#CCCCCO
Solvent: CCCCCCC
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC
Reaction time: 0.83 h
Yield: 99 %

Procedure:
A mixture of 40 parts 5,7-dodecadiyne-1,12-diol, 215 parts 1,2-dimethoxyethane, 1 part dibutyltin-di-2-ethylhexanoate and 15 parts triethylamine was prepared and the resulting mixture was stirred vigorously. A solution of 133 parts n-octadecylisocyanate in 44 parts of 1,2-dimethoxyethane was added dropwise over a period of 60 min. The reaction temperature rose to 42° C. from 18° C. within 50 min. and then subsided. After the addition, 80 parts of 1,2-dimethoxyethane was then added to the reaction mixture and the mixture was stirred for an additional 2 hrs. To this mixture was added 1390 parts of heptane. The precipitate was collected by filtration, washed with petroleum ether (bp 30°-60° C.) and dried, giving 154.6 parts (99% yield) of desired product, mp 118°-119° C.
Reaction SMILES: [CH2:1]([O:4][CH:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[N:8]([O:13][CH2:14][C:15]([OH:18])([CH3:17])[CH3:16])[C:7]([CH3:20])([CH3:19])[CH2:6]1)[CH:2]=[CH2:3].[CH2:21]([SiH:23]([CH2:25][CH3:26])[CH3:24])[CH3:22]>C(O)(C)C.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[OH:18][C:15]([CH3:17])([CH3:16])[CH2:14][O:13][N:8]1[C:7]([CH3:20])([CH3:19])[CH2:6][CH:5]([O:4][CH2:1][CH2:2][CH2:3][Si:23]([CH2:25][CH3:26])([CH2:21][CH3:22])[CH3:24])[CH2:10][C:9]1([CH3:12])[CH3:11]
Reactant: CC[SiH](C)CC
Reactant: C=CCOC1CC(C)(C)N(OCC(C)(C)O)C(C)(C)C1
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: CC[Si](C)(CC)CCCOC1CC(C)(C)N(OCC(C)(C)O)C(C)(C)C1

Procedure:
A mixture of 28.5 g (0.10 mol) of the compound obtained in Example 17, 14.5 ml (0.10 mol) of diethylmethylsilane, and 1 ml of a solution of 2% hydrogen hexachloroplatinate(IV) in isopropyl alcohol is heated at reflux for 4 hours. The reaction mixture is distilled under vacuum to obtain a viscous, pale yellow oil. Mass spectroscopy reveals that the reaction product has a molecular ion of 387, which is consistent with formation of the title compound.
Reaction SMILES: C([N:3]([CH2:15][CH3:16])[C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[CH3:13])C.C([Li])(C)(C)C.CCCCC.[F:27][C:28]1[CH:29]=C([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])C#N>C1COCC1>[F:27][C:28]1[CH:29]=[C:16]([C:15]2[N:3]=[C:4]([OH:14])[C:5]3[C:6]([CH:13]=2)=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=3)[CH:33]=[CH:34][C:35]=1[O:36][CH3:37]
Reactant: CCN(CC)C(=O)c1ccc(OC)cc1C
Reactant: COc1ccc(C#N)cc1F
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: COc1ccc2c(O)nc(-c3ccc(OC)c(F)c3)cc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.4 %

Procedure:
To a solution of N,N-diethyl-4-methoxy-2-methylbenzamide (1.00 g, 4.52 mmol) in THF (9 ml) at −78° C. was added dropwise tert-butyllithium 1.7 M in pentane (3.19 ml, 5.42 mmol) and the solution was stirred for 0.5 h before addition of 3-fluoro-4-methoxybenzonitrile (0.683 g, 4.52 mmol) in THF (9 ml). The resulting solution was warmed to rt and stirred for 16 h. The reaction mixture was quenched with water, neutralized with 1 N HCl. The precipitated solid was collected and washed with water to give 3-(3-fluoro-4-methoxyphenyl)-6-methoxyisoquinolin-1-ol (926 mg, 69% yield) as a solid after drying. MS: MS m/z 300.1 (M++1).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:10](=[O:15])([O:13]C)[O:11][CH3:12].C(=O)=O>>[C:10](=[O:13])([O:15][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[O:11][CH3:12]
Reactant: CCCCCCCCCl
Reactant: COC(=O)OC
Agent: O=C=O
Product: CCCCCCCCOC(=O)OC
Temperature: 150 °C
Reaction time: 2 h
Yield: 14.9 %

Procedure:
1-Chlorooctane (297.36 g, 1.0 mole), dimethyl carbonate (450 g, 5.0 moles) and 30.0 g of DOWEX® MWA-1 beads (Trademark of The Dow Chemical Company) are combined in a 2-liter stainless steel Paar bomb. The reactor is pressurized to 100 psi of carbon dioxide and heated with stirring to 150° C. After 2 hours, the bomb is cooled to room temperature and vented. After separating the catalyst by filtration, distillation gives 28.1 g (15 percent yield based on starting 1-chlorooctane) of methyl 1-octyl carbonate.
Reaction SMILES: [Na].C(O)C.[C:5]([O:13]CC)(=[O:12])[CH2:6][C:7]([O:9]CC)=[O:8].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=1[CH2:28]Br>CCOCC>[F:25][C:24]([F:26])([F:27])[C:21]1[CH:20]=[C:19]2[C:18](=[CH:23][CH:22]=1)[CH2:17][C:6]([C:7]([OH:9])=[O:8])([C:5]([OH:13])=[O:12])[CH2:28]2
Reactant: FC(F)(F)c1ccc(CBr)c(CBr)c1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: O=C(O)C1(C(=O)O)Cc2ccc(C(F)(F)F)cc2C1

Procedure:
Sodium (1.12 g, 48.6 mmol) was added to ethanol (16 mL). The solution was heated to reflux until all sodium was dissolved. To this solution was added diethyl malonate (3.71 g, 23.19 mmol) in ether (45 mL) and the above 1,2-bis-bromomethyl-4-trifluoromethylbenzene (7.7 g, 23.19 mmol) in ether (45 mL). The mixture was refluxed for 16 hrs and the precipitate was filtered out. The filtrate was evaporated and the residue was treated with water (35 mL) and potassium hydroxide (5.30 g). The mixture was stirred and refluxed for 5 hrs and treated with water (20 mL). The resulting mixture was extracted with ether (50 mL). The aqueous phase was acidified with concentrated hydrochloric acid and cooled in an ice bath. Solids were filtered and washed with water. After air drying, 5-trifluoromethyl-indan-2,2-dicarboxylic acid was obtained (3.08 g). LC-MS showed a single peak, C12H19F3O4 (m/e) calcd 274.0453, obsd 273.0 (M−H).