Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=[O:4].[OH-].[Na+]>CO>[CH3:10][C:9]1[O:8][N:7]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[CH:12]=2)[C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1c(-c2cccc(C(F)(F)F)c2)noc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1onc(-c2cccc(C(F)(F)F)c2)c1C(=O)O
Yield: 94.2 %

Procedure:
In a similar manner as described in Preparation Example 25, by using methanol (60 mL), methyl-5-methyl-3-(3-(trifluoromethyl)phenyl)isoxazol-4-carboxylate (6.0 g, 21.03 mmol) and 3% sodium hydroxide aqueous solution (60 mL), a white solid required compound (5.37 g, 19.80 mmol, 94%) was obtained.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[O:8])(=O)C.[OH-].[Na+].C(Cl)(Cl)Cl>CO>[SH:4][CH2:5][CH:6]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:8]
Reactant: COC(=O)CCCCCCCNC(=O)C(CSC(C)=O)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(O)CCCCCCCNC(=O)C(CS)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75.8 %

Procedure:
The methyl ester product from part (b) (1.69 g., 4.3 mmole) is dissolved in methanol (13 ml.) and chilled in an ice bath under nitrogen. 1N Sodium hydroxide (13 ml., about 3 eq.) is added dropwise over 10 minutes to this solution. The mixture is stirred at 0° for 10 minutes and then allowed to warm to room temperature and stirred for 4 hours. This solution is then flushed with argon and stored under refrigeration overnight. (A white precipitate forms after stirring for about 3.5 hours.) Methanol is added and the solution is concentrated in vacuo to remove all the methanol. The residue is diluted with water (40 ml.), washed with chloroform (2×20 ml.), and the aqueous portion is acidified to pH of about 1.5 with concentrated hydrochloric acid. The resulting white suspension is extracted with ethyl acetate (3×15 ml.). These extracts are combined, washed with water and brine (20 ml. each), dried (Na2SO4), and concentrated to yield 720 mg. of a white solid. The original chloroform layer is reextracted with 1N sodium hydroxide (2×15 ml.). The aqueous portion is acidified, combined with the previous acidified layer, and extracted with ethyl acetate (2×20 ml.). These extracts are washed with water and brine, dried and concentrated to yield an additional 380 mg. of white solid. The two portions of solid are combined to give 1.10 g of (±)-8-[[2-(mercaptomethyl)-1-oxo-3-phenylpropyl]amino]octanoic acid; m.p. 81°-83° (sinters above 68°). TLC (silica gel, benzene/acetic acid 4:1) Rf =0.42.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3]/[CH:4]=[CH:5]/[Sn](CCCC)(CCCC)CCCC.Br[C:21]1[CH:22]=[CH:23][C:24]([O:44][CH3:45])=[C:25]([C:27]([C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=3[F:43])=[CH:31][CH:30]=2)=[O:28])[CH:26]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>COCCOCCOC.Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:43][C:37]1[CH:38]=[C:39]([F:42])[CH:40]=[CH:41][C:36]=1[NH:35][C:32]1[CH:31]=[CH:30][C:29]([C:27]([C:25]2[CH:26]=[C:21](/[CH:5]=[CH:4]/[CH2:3][N:2]([CH3:1])[CH3:19])[CH:22]=[CH:23][C:24]=2[O:44][CH3:45])=[O:28])=[CH:34][CH:33]=1
Reactant: CCCC[Sn](/C=C/CN(C)C)(CCCC)CCCC
Reactant: COc1ccc(Br)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: COCCOCCOC
Product: COc1ccc(/C=C/CN(C)C)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1
Yield: 27.4 %

Procedure:
Dimethyl-((E)-3-tributylstannanyl-allyl)-amine (213 mg, 0.57 mmol) and (5-bromo-2-methoxy-phenyl)-[4-(2,4-difluoro-phenylamino)-phenyl]-methanone (200 mg, 0.475 mmol) are added to a solution of Pd(OAc)2 (10 mg, 0.047 mmol) and PPh3 (50 mg, 0.19 mmol) in diethylene glycol dimethyl ether (12 ml) and heated to 135 C under argon for 30 minutes. The reaction mixture is evaporated to dryness and purified via chromatography (SiO2, acetone/hexanes 6/4>1/0 followed by TBME/MeOH/NH3conc 100/0/0>90/10/1) to yield the crude product, which is dissolved in 2N HCl, washed with TBME and the aqueous phase made alkaline with saturated Na2CO3. Extraction with EtOAc and evaporation of the organic phase delivers the title compound, which was dissolved in acetone and filtered through a bed of SiO2 to give the desired product as yellow foam (55 mg; 28%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][C:41]=1[Cl:42])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([C@H:13]2[CH2:38][O:37][C:16]3=[CH:17][C:18]4[CH2:19][C@@H:20]([C:34](O)=[O:35])[N:21]([C@H:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:26][CH3:27])[CH2:22][C:23]=4[CH:24]=[C:15]3[O:14]2)[CH:10]=[CH:11][CH:12]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C[O:65][C:66](=[O:85])[C@@H:67]([NH2:84])[CH2:68][C:69]1[CH:74]=[CH:73][C:72]([O:75][C:76]2[CH:81]=[CH:80][N:79]=[C:78]([CH3:82])[C:77]=2[CH3:83])=[CH:71][CH:70]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][C:41]=1[Cl:42])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([C@H:13]2[CH2:38][O:37][C:16]3=[CH:17][C:18]4[CH2:19][C@@H:20]([C:34]([NH:84][C@@H:67]([CH2:68][C:69]5[CH:74]=[CH:73][C:72]([O:75][C:76]6[CH:81]=[CH:80][N:79]=[C:78]([CH3:82])[C:77]=6[CH3:83])=[CH:71][CH:70]=5)[C:66]([OH:65])=[O:85])=[O:35])[N:21]([C@H:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:26][CH3:27])[CH2:22][C:23]=4[CH:24]=[C:15]3[O:14]2)[CH:10]=[CH:11][CH:12]=1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1cccc(OCc2ccc(Cl)c(Cl)c2)c1)O3
Reactant: COC(=O)[C@@H](N)Cc1ccc(Oc2ccnc(C)c2C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(Oc2ccnc(C)c2C)cc1)C(=O)O)OC[C@H](c1cccc(OCc2ccc(Cl)c(Cl)c2)c1)O3
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 49.9 %

Procedure:
(3S,8S)-3-[3-(3,4-Dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid (25 mg), EDCI (10 mg), HOBT (8 mg) and (S)-2-amino-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester (16 mg) were taken up in 1 mL of anhydrous DCM and stirred for 5 minutes. The reaction mixture was cooled to 0° C. and DIEA (21 mg) was added and reaction was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was loaded on a silica gel column (1:3 EtOAc:hexanes to 4% MeOH in 1:1 EtOAc:hexanes) to get purified (S)-2-{[(3S,8S)-3-[3-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester (22 mg). This was hydrolyzed according to General Procedure B to give the title compound (18 mg). LCMS (m/z): 873.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][OH:17])[CH2:10][C@H:9]1[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1)=[O:7].C(N(CC)CC)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>ClCCl>[F:37][C:2]([F:1])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][O:17][S:46]([CH3:45])(=[O:48])=[O:47])[CH2:10][C@H:9]1[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CCCO)C[C@H]1Cc1ccc2ccccc2c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccc3ccccc3c2)C1
Reaction time: 2 h
Yield: 78.2 %

Procedure:
To a stirred mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(3-hydroxypropyl)-2-(2-naphthylmethyl)piperazine (1.1 g) and triethylamine (425 mg) in dichloromethane (10 ml) was added dropwise methanesulfonyl chloride (252 mg) at ice-bath temperature. After 2 hours, the reaction mixture was washed with water and then dried over magnesium sulfate. After evaporation of the solvent, the resulting residue was chromatographed on silica gel using ethyl acetate as an eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)-4-(3-methylsulfonyloxypropyl)piperazine (988 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[CH3:15])=[O:4].[NH2:16][C:17]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:18]=1[O:19][C@@H:20]1[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:22]([CH2:32][OH:33])[CH2:21]1>>[CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:16][C:17]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:18]=3[O:19][C@H:20]3[CH2:21][C@@H:22]([CH2:32][OH:33])[N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24]3)[C:7]=2[C:6]=1[CH3:15])=[O:4]
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Reactant: CC(C)(C)OC(=O)N1C[C@@H](Oc2cc(F)ccc2N)C[C@H]1CO
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O[C@H]3C[C@@H](CO)N(C(=O)OC(C)(C)C)C3)c2c1C

Procedure:
Prepared analogously to example 1.1 from 4-chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester and (2S,4S)-tert-butyl 4-(2-amino-5-fluorophenoxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate.
Reaction SMILES: [CH3:1][C:2]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:16])=[C:12](F)[CH:13]=2)[C:8](=[O:17])[C:7]([C:18]([OH:20])=[O:19])=[CH:6]1)([CH3:4])[CH3:3].Cl.[F:22][C:23]([F:33])([F:32])[C:24]([NH:26][CH:27]1[CH2:31][CH2:30][NH:29][CH2:28]1)=[O:25].N12CCCN=C1CCCCC2>N1C=CC=CC=1>[F:33][C:23]([F:22])([F:32])[C:24]([NH:26][CH:27]1[CH2:31][CH2:30][N:29]([C:12]2[CH:13]=[C:14]3[C:9]([C:8](=[O:17])[C:7]([C:18]([OH:20])=[O:19])=[CH:6][N:5]3[C:2]([CH3:4])([CH3:1])[CH3:3])=[CH:10][C:11]=2[F:16])[CH2:28]1)=[O:25]
Reactant: O=C(NC1CCNC1)C(F)(F)F
Reactant: CC(C)(C)n1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: CC(C)(C)n1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(NC(=O)C(F)(F)F)C3)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.5 %

Procedure:
A mixture of 600 mg (2.13 mmoles) 1-(1,1-dimethylethyl)-1,4-dihydro-6,7-difluoro-4-oxo-3-quinolinecarboxylic acid, 700 mg (3.2 mmoles) of 3-trifluoroacetylamino pyrrolidine hydrochloride and 1.3 mL (8.5 mmoles) of 1,8-diazabicyclo[5.4.0]undec-7-ene in 3 mL pyridine was stirred 30 minutes at room temperature, evaporated to dryness and poured into water. The pH was adjusted to 7.5 with 1N hydrochloric acid. The precipitate was filtered to give 430 mg of 7-(3-trifluoroacetylamino-1-pyrrolidinyl)-1-(1,1-dimethylethyl)-1,4-dihydro-6-fluoro-4-oxo-3-quinolinecarboxylic acid. mp 200° C. dec. 409 mg (0.92 mmole) of that compound was suspended in 2 mL 1N NaOH and refluxed 2 hours. The solution was cooled and diluted with water, the pH was adjusted to 7.5 with 10% acetic acid. The precipitate was filtered, washed with water, dried and recrystallized as an hydrochloride in ethanol to give 180 mg of titled compound. MP>270° C.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([C:13](=[O:17])[C:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].O1CCOCC1.C(O)C>O>[CH2:1]([C:8]1[S:12][C:11]([C:13](=[O:17])[C:14]([OH:16])=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])C(=O)c1ccc(Cc2ccccc2)s1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCO
Product: O=C(O)C(=O)c1ccc(Cc2ccccc2)s1
Reaction time: 3 h

Procedure:
A mixture of the 5-benzylthien-2-ylglyoxylate (1.37 g, 0.005 mole), potassium hydroxide (0.66 g, 0.01 mole), dioxane (3.3 ml), ethanol (33 ml) and H2O (6.6 ml) was stirred 3 hrs. at 27° C. The reaction mixture was concentrated and chilled to induce crystallization of 0.9 g of the potassium salt of 5-benzylthien-2-ylglyoxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[O:6][C:7]3[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=3[CH:9]([CH2:15][N+:16]([O-])=O)[CH:10]([C:11]([O:13][CH3:14])=[O:12])[C:4]=2[CH:3]=1.[H][H]>O1CCCC1.[Ni]>[NH2:16][CH2:15][CH:9]1[C:8]2[CH:19]=[CH:20][CH:21]=[CH:22][C:7]=2[O:6][C:5]2[CH:23]=[CH:24][C:2]([Cl:1])=[CH:3][C:4]=2[CH:10]1[C:11]([O:13][CH3:14])=[O:12]
Reactant: [H][H]
Reactant: COC(=O)C1c2cc(Cl)ccc2Oc2ccccc2C1C[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Product: COC(=O)C1c2cc(Cl)ccc2Oc2ccccc2C1CN

Procedure:
An aqueous slurry of Ni-Raney (containing 30 g of Ni on a dry basis) was washed with tetrahydrofuran, and added over a solution of 270 g (0.78 mol) of methyl 2-chloro-10-nitromethyl-10,11-dihydrodibenzo[b,f]oxepine-11-carboxylate (compound XIa), as obtained in Example 18, in 2.7 L of tetrahydrofuran. The suspension was stirred under 50-60 psi (3447-4136 hPa) of hydrogen at room temperature for 2 days. The catalyst was removed by filtration, and the resulting solution was concentrated under reduced pressure to obtain methyl 10-aminomethyl-2-chloro-10,11-dihydrodibenzo[b,f]oxepine-11-carboxylate (compound XIIa), which was used in the next step (see Example 20) without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([NH:27][CH2:28][CH2:29][OH:30])[CH2:23][CH2:22]2)[N:3]=1.Br[CH2:32][CH2:33][OH:34].C(=O)(O)[O-].[Na+]>O1CCOCC1>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([N:27]([CH2:32][CH2:33][OH:34])[CH2:28][CH2:29][OH:30])[CH2:23][CH2:22]2)[N:3]=1
Reactant: OCCBr
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(N[C@H]2CC[C@H](NCCO)CC2)nc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(N[C@H]2CC[C@H](N(CCO)CCO)CC2)nc1N
Temperature: 113 °C

Procedure:
To a stirred solution of trans-[4-amino-2-[4-(2-hydroxy-ethylamino)-cyclohexylamino]-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (106 mg, 0.25 mmol, Example 120) in 1,4-dioxane (3 mL), 2-bromoethanol (80 uL, 1.12 mmol, Aldrich) and sodium bicarbonate (50 mg, 0.60 mmol) were added and the mixture was heated at 113° C. for 24 hours. The reaction was quenched with water and the mixture was extracted with ethyl acetate (3×10 mL) and the extracts were dried with sodium sulfate. The solvent was removed and the residue was chromatographed (8% 9N ammonia in methanol/dichloromethane) to give a pale yellow solid. 97 mg, 84%. MS (ES) MH+=466.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](C(C3C(C)=NC(C)=CC=3)O)[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.N1(C2C=CC(CC3C(Cl)=NC4C(C=3Cl)=CC(Br)=CC=4C)=CC=2)C=CC=N1.[CH3:61][N:62]1[C:66]([C:67]([CH:69]2[CH2:74][CH2:73][O:72][CH2:71][CH2:70]2)=[O:68])=[CH:65][N:64]=[N:63]1.S1C(CC2C(OC)=NC3C(C=2Cl)=CC(C(C2N(C)C=NC=2)(C2C=NC(C(F)(F)F)=CC=2)O)=CC=3)=CC2C=CC=CC1=2>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:67]([C:66]3[N:62]([CH3:61])[N:63]=[N:64][CH:65]=3)([CH:69]3[CH2:74][CH2:73][O:72][CH2:71][CH2:70]3)[OH:68])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][CH:26]=1
Reactant: Cn1nncc1C(=O)C1CCOCC1
Reactant: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: COc1nc2ccc(C(O)(c3ccc(C(F)(F)F)nc3)c3cncn3C)cc2c(Cl)c1Cc1cc2ccccc2s1
Agent: Cc1cc(Br)cc2c(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)nc12
Product: COc1nc2ccc(C(O)(c3cnnn3C)C3CCOCC3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared analogously to the method described in Example 78 using 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (Intermediate 12: step d) in place of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-2,4-dichloro-8-methylquinoline (Intermediate 57) and (1-methyl-1H-1,2,3-triazol-5-yl)(tetrahydro-2H-pyran-4-yl)methanone (Intermediate 30) in place of 1-(4-(6-(trifluoromethyl)nicotinoyl)piperidin-1-yl)ethanone (Intermediate 56: step d). MS m/e 547.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH2:5][CH:6]2[CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][CH2:20][CH2:21][OH:22])=[CH:14][CH:13]=1.CC1(C)C2CC1CCC2NS(C1C=CC(C#CCCO)=CC=1)(=O)=O>>[CH3:1][C:2]1([CH3:23])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH2:5][CH:6]2[CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:14][CH:13]=1
Reactant: CC1(C)C2CCC(CCOc3ccc(C#CCCO)cc3)C1C2
Agent: CC1(C)C2CCC(NS(=O)(=O)c3ccc(C#CCCO)cc3)C1C2
Product: CC1(C)C2CCC(CCOc3ccc(CCCCO)cc3)C1C2
Yield: 99 %

Procedure:
When the product of Step B was substituted for N-(6,6-dimethylbicyclo[3.1.1]heptan-2-yl)-4-(4-hydroxybut-1-ynyl)benzene sulphonamide in Example 18, Step C, the similar process afforded the title compound in 99% yield, as a colourless paste. 1H-NMR (CDCl3) 7.05 (d, 2H, J=8.54 Hz); 6.78 (d, 2H, J=8.58 Hz); 3.91 (t, 2H, J=6.81 Hz); 3.64 (t, 2H, J=6.02 Hz); 2.57-2.53 (m, 2H); 1.90-1.57 (m, 14H); 1.18 (s, 3H); 1.01 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[CH2:19][CH2:20][NH:21][CH2:22]4)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C([O-])([O-])=O.[K+].[K+].Br[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[CH2:19][CH2:20][N:21]([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:22]4)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)Oc1ccc(-c2noc(-c3cccc4c3CCNC4)n2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2noc(-c3cccc4c3CCN(CC(=O)OC(C)(C)C)C4)n2)cc1Cl

Procedure:
To a solution of 3-(3-chloro-4-isopropoxyphenyl)-5-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1,2,4-oxadiazole (0.0726 g, 0.196 mmol) in DMF (1.963 ml) was added K2CO3 (0.054 g, 0.393 mmol) followed by tert-butyl bromoacetate (0.030 ml, 0.206 mmol). After about 48 h the reaction mixture was filtered, concentrated in vacuo and purified by chromatography to provide tert-butyl 2-(5-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-3,4-dihydroisoquinolin-2(1H)-yl)acetate as a colorless oil that solidified on standing. LCMS (Table 1, Method c) Rt=3.41 min, m/z 486 (M+H)+.
Reaction SMILES: [Na:1].S(CCC[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20]CS(O)(=O)=O)=[CH:13][CH:12]=1)(O)(=O)=O.COC1C=CC(O)=CC=1.C1[S:40](=[O:42])(=[O:41])[O:39]CCC1.[Na].COC1C=CC=CC=1OCCCCS(O)(=O)=O>>[Na:1].[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][CH2:20][S:40]([OH:42])(=[O:41])=[O:39])=[CH:15][CH:16]=1
Reactant: O=S1(=O)CCCCO1
Reactant: O=S(=O)(O)CCCCOc1ccc(OCCCCS(=O)(=O)O)cc1
Agent: COc1ccc(O)cc1
Agent: COc1ccccc1OCCCCS(=O)(=O)O
Agent: [Na]
Product: COc1ccc(OCCCS(=O)(=O)O)cc1

Procedure:
In the same manner as in above (1), the objective compound was synthesized from 4-methoxyphenol and butanesultone. The crude product was recrystallized from water to obtain a milky white needle crystal product. The resulting product was determined for its 1H-NMR and IR spectrum to confirm that it was 1-methoxy-4-sulfobutoxybenzene sodium.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N+:16]([O-:18])=[O:17])[CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][C:9]([C:13]#[N:14])=[C:8]2O.P(Cl)(Cl)(Cl)(Cl)[Cl:20].P(Cl)(Cl)(Cl)=O>CCCCCC>[Cl:20][C:8]1[C:7]2[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[C:5]([N+:16]([O-:18])=[O:17])[CH:6]=2)[N:11]=[CH:10][C:9]=1[C:13]#[N:14]
Reactant: COc1cc([N+](=O)[O-])cc2c(O)c(C#N)cnc12
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCCCCC
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc([N+](=O)[O-])cc2c(Cl)c(C#N)cnc12
Yield: 48.6 %

Procedure:
A mixture of 4 g (16 mmol) of 8-Methoxy-4-hydroxy-6-nitro-quinoline-3-carbonitrile, 6.66 g (32 mmol) of phosphorous pentachloride, and 15 ml of phosphorous oxychloride was refluxed for 2.5 hours. The mixture was diluted with hexane and the solid was collected. The solid was dissolved in 500 ml of ethyl acetate and washed with cold diluted sodium hydroxide solution. The solution was dried over magnesium sulfate and filtered through a pad of silica gel. The solvent was removed giving 2.05 g of tan solid: mass spectrum (electrospray, m/e) M+H 263.7.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH:5]=[CH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C=Cc1ccc(OC)cc1OC
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1ccc(OC)cc1OC

Procedure:
100.2 g of ethyl 2,4-dimethoxycinnamate are dissolved in 400 ml of methanol and hydrogenated with palladium/charcoal under atmospheric pressure. The catalyst is filtered off with suction, and the filtrate is concentrated in vacuo.
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:28][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][CH3:42])[CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>FC(F)(F)C(O)=O>[C:1]([O:18][CH:19]([CH2:28][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][CH3:42])[CH2:20][C:21]([OH:23])=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 108 %

Procedure:
To tert-butyl 3-hexadecanoyloxyoctadecanoate (16.56 g) was added trifluoroacetic acid (20 ml) and the mixture was stirred at room temperature for 1 hour. Trifluoroacetic acid was removed off under reduced pressure, and to the residue was added dry benzene, followed by evaporation of the solvent. This operation was repeated three times. To a solution of the dried residue in ethyl acetate (250 ml) were added N-hydroxysuccinimide (3.21 g) and N,N'-dicyclohexylcarbodiimide (5.75 g). The mixture was stirred at ambient temperature overnight and then filtered to remove N,N'-dicyclohexylurea. The filtrate was condensed and dried up by high vacuum pump to give N-hydroxysuccinimide ester of 3-hexadecanoyloxyoctadecanoic acid (16.2 g).