Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9]C)[CH:5]=[CH:4][C:3]=1[CH2:11][C:12]([O:14]C)=[O:13]>Br.O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[CH2:11][C:12]([OH:14])=[O:13]
Reactant: COC(=O)Cc1ccc(OC)c(Cl)c1Cl
Agent: Br
Solvent: O
Product: O=C(O)Cc1ccc(O)c(Cl)c1Cl

Procedure:
2,3-Dichloro-4-methoxybenzeneacetic acid, methyl ester, 46 gm, was refluxed for 18 hours in concentrated HBr, 350 mL. The reaction mixture was poured in water, 1.4 L, and the solution was extracted with EtOAc, 2×500 mL. The organic layers were washed with water, dried (Na2SO4) and concentrated to dryness. The residue was slurried in 20% EtOAc-hexane to yield 2,3-dichloro-4-hydroxybenzeneacetic acid, mp 189°-190° C. The acid was stirred at room temperature in methanolic HCl, 100 mL, for 30 minutes. The volatiles were removed in vacuo and the residue was slurried in hexane, filtered and air-dried to yield 17.6 gm of the title compound, mp 105°-106° C., analysis, calculated: C, 45.98; H, 3.43; Cl, 30.16; obtained: C, 46.10; H, 3.65; Cl, 30.31.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Cl:24])(Cl)(Cl)Cl.[CH2:25]([S:27]([C:30]1[CH:50]=[CH:49][C:33]([CH2:34][C:35]2[C:44]3[C:39](=[CH:40][CH:41]=[C:42]([F:45])[CH:43]=3)[CH:38]=[C:37](CO)[C:36]=2[CH3:48])=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH3:26]>O1CCCC1.C(OCC)(=O)C>[CH2:25]([S:27]([C:30]1[CH:50]=[CH:49][C:33]([CH2:34][C:35]2[C:44]3[C:39](=[CH:40][CH:41]=[C:42]([F:45])[CH:43]=3)[CH:38]=[C:37]([CH2:20][Cl:24])[C:36]=2[CH3:48])=[CH:32][CH:31]=1)(=[O:28])=[O:29])[CH3:26]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CCS(=O)(=O)c1ccc(Cc2c(C)c(CO)cc3ccc(F)cc23)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)c1ccc(Cc2c(C)c(CCl)cc3ccc(F)cc23)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.1 %

Procedure:
A mixture of triphenylphosphine (1.10 g, 4.19 mmol), carbon tetrachloride (1.62 mL, 16.8 mmol) and tetrahydrofuran (5 mL) was stirred at room temperature for 10 minutes. A mixture of [4-(4-ethanesulfonyl-benzyl)-6-fluoro-3-methyl-naphthalen-2-yl]-methanol (780 mg, 2.09 mmol) in tetrahydrofuran (2.5 mL) was added, and the reaction mixture was stirred at 75° C. for 4 hours. The reaction mixture was cooled to room temperature, and then diluted with ethyl acetate. The resulting mixture was washed with water. The organic phase was dried over MgSO4, filtered, and concentrated. A solution of the crude product in dichloromethane was evaporated over silica gel, and the silica gel supported crude product was loaded onto an Analogix SuperFlash™ column. Flash chromatography (10%-30% ethyl acetate in hexanes) afforded 450 mg (55%) of 1-(4-ethanesulfonyl-benzyl)-3-chloromethyl-7-fluoro-2-methyl-naphthalene as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.04 (s, 1 H), 7.96-8.04 (m, 1 H), 7.76 (d, J=8.2 Hz, 2 H), 7.68-7.75 (m, 1 H), 7.41 (td, J=8.6, 2.1 Hz, 1 H), 7.30 (d, J=8.2 Hz, 2 H), 5.01 (s, 2 H), 4.63 (s, 2 H), 3.22 (q, J=7.2 Hz, 2 H), 2.47 (s, 3 H), 1.06 (t, J=7.2 Hz, 3 H). MS (ES+) cald. for C21H20CIFO2S [(M−Cl)+] 355, obsd. 355.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH2:12][O:13][CH3:14])=[C:4]([OH:10])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH:22]([F:24])[F:23]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH:22]([F:24])[F:23])[C:3]=1[O:11][CH2:12][O:13][CH3:14]
Reactant: COCOc1c(Br)ccc(OC)c1O
Reactant: FC(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCOc1c(Br)ccc(OC)c1OC(F)F
Temperature: -45 °C
Yield: 30 %

Procedure:
To a stirring solution of 3-bromo-6-methoxy-2-(methoxymethoxy)phenol (700 mg, 2.64 mmol) in dimethylformamide (15 mL) was added potassium carbonate (729 mg, 5.28 mmol), cooled to −45° C. and chlorodifluoromethane gas was passed for 10 min and the resultant reaction mixture was heated to 80° C. for 2 h. The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate (3×). The combined ethyl acetate layers were dried over sodium sulphate and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 0-5% ethyl acetate in pet ether) afforded 1-Bromo-3-(difluoromethoxy)-4-methoxy-2-(methoxymethoxy)benzene as a liquid (250 mg, 30%).
Reaction SMILES: C([O:5][C:6](=[O:25])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([CH3:24])([C:16](=[O:23])[NH:17][C:18]2[S:19][CH:20]=[CH:21][N:22]=2)[CH3:15])[CH:8]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:24][C:14]([C:16](=[O:23])[NH:17][C:18]1[S:19][CH:20]=[CH:21][N:22]=1)([O:13][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[C:6]([OH:25])=[O:5])[CH3:15]
Reactant: CC(C)(C)OC(=O)c1cccc(OC(C)(C)C(=O)Nc2nccs2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Oc1cccc(C(=O)O)c1)C(=O)Nc1nccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
To a solution of 3-[1-Methyl-1-(thiazol-2-ylcarbamoyl)-ethoxy]-benzoic acid tert-butyl ester (0.1 g, 0.275 mmol) in DCM (2 ml) a solution of TFA (3 ml) in DCM (3 ml) was added at 0° C. for 15 min. Reaction mixture was stirred at RT for 1 h, diluted with DCM (10 ml) washed with brine (2×4 ml) dried over Na2SO4 and concentrated under reduced pressure to obtain crude product. The crude product was triturated with hexane to obtain white solid, filtered and dried to obtain 3-[1-Methyl-1-(thiazol-2-ylcarbamoyl)-ethoxy]-benzoic acid (0.06 g, 85%). 3-[1-Methyl-1-(thiazol-2-ylcarbamoyl)-ethoxy]-benzoic acid.
Reaction SMILES: [C:1]1(=[O:6])[O:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:9]=1[CH2:10]I>>[Cl:7][C:8]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:9]=1[CH2:10][CH:2]1[CH2:3][CH2:4][O:5][C:1]1=[O:6]
Reactant: Clc1ccc(CI)c(Cl)c1
Reactant: O=C1CCCO1
Product: O=C1OCCC1Cc1ccc(Cl)cc1Cl
Yield: 78.5 %

Procedure:
Using the procedure to synthesize Example 1 and using reagents γ-butyrolactone (1.1 g, 13 mmol), and 2,4-dichlorobenzyl iodide (5.6 g, 20 mmol) affords 2.5 g (78%) of the title compound as a tan solid. 1H NMR (CDCl3) δ 7.36 (d, 1H), 7.17 (m, 2H), 4.30 (m, 1H), 4.10 (m, 1H), 3.32 (dd, 1H), 2.87-2.78 (m, 2H), 2.20 (m, 1H), 1.95 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:8][C:9]=1[N:10]([C:18]([CH:20]1[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][CH2:21]1)=[O:19])[NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])=[O:4].[CH3:33]I>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[CH:8][C:9]=1[N:10]([C:18]([CH:20]1[CH2:21][CH2:22][CH:23]([CH3:26])[CH2:24][CH2:25]1)=[O:19])[N:11]([CH3:33])[C:12](=[O:17])[C:13]([F:16])([F:14])[F:15])=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(NC(=O)C(F)(F)F)C(=O)C1CCC(C)CC1
Reactant: CI
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)C1CCC(C)CC1)N(C)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-(3,3-dimethyl-but-1-ynyl)-3-[N-(4-methyl-cyclohexanecarbonyl)-N′-(2,2,2-trifluoro-acetyl)-hydrazino]-thiophene-2-carboxylic acid methyl ester (1.6 g, 3.4 mmol) in THF (17 mL) was added K-OtBu (4.1 mmol, 1.0 M in THF), followed by MeI (1.0 g, 6.8 mmol). After stirring at rt for 16 h the reaction was diluted with EtOAc washed once with 20 mL of brine and purified by silica gel chromatography 0-20% EtOAc/hexanes to give 5-(3,3-dimethyl-but-1-ynyl)-3-[N′-methyl-N-(4-methyl-cyclohexanecarbonyl)-N′-(2,2,2-trifluoro-acetyl)-hydrazino]-thiophene-2-carboxylic acid methyl ester. This was then diluted with EtOAc (20 mL) and treated with NaOH (6.8 mL of 2M aq solution) to give 5-(3,3-Dimethyl-but-1-ynyl)-3-[N′-methyl-N-(4-methyl-cyclohexanecarbonyl)-hydrazino]-thiophene-2-carboxylic acid.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9](=O)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:5]=[CH:4][N:3]=1.S(=O)(=O)(O)[OH:25].C([O-])(O)=O.[Na+]>CC(O)C>[C:10]1([C:9]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]3[N:5]=[CH:4][NH:3][C:2](=[O:25])[C:7]=3[N:8]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Nc1c(Cl)ncnc1Nc1ccccc1)c1ccccc1
Reactant: O=S(=O)(O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: O=c1[nH]cnc2c1nc(-c1ccccc1)n2-c1ccccc1
Temperature: 90 °C
Yield: 71.6 %

Procedure:
To a stirred solution of N-(4-chloro-6-(phenylamino)pyrimidin-5-yl)benzamide obtained in step 2 (35 g, 108 mmol) in 2-propanol (360 mL) was added sulfuric acid (18.2 mL, 323.3 mmol) at 0° C. The reaction mixture was heated to reflux at 90° C. overnight. After cooled to room temperature NaHCO3 (aq) was added to the resulting reaction mixture and stirred. The resulting mixture was filtered with water (600 mL). The collected solid was dried under reduced pressure to obtain the title compound (22.3 g, 72%) as white solid.
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[N:19]([CH3:40])[N:20]=[CH:21][C:22]=2[NH:23][C:24]([C:26]2[N:27]=[C:28](Br)[S:29][C:30]=2[NH:31]C(OC(C)(C)C)=O)=[O:25])[CH2:13][CH2:12]1)C1C=CC=CC=1.[F:42][C:43]1[CH:48]=[C:47]([CH3:49])[CH:46]=[CH:45][C:44]=1B(O)O>>[NH2:31][C:30]1[S:29][C:28]([C:44]2[CH:45]=[CH:46][C:47]([CH3:49])=[CH:48][C:43]=2[F:42])=[N:27][C:26]=1[C:24]([NH:23][C:22]1[CH:21]=[N:20][N:19]([CH3:40])[C:18]=1[N:14]1[CH2:15][CH2:16][CH2:17][C@@H:11]([NH2:10])[CH2:12][CH2:13]1)=[O:25]
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1N1CCC[C@@H](NC(=O)OCc2ccccc2)CC1
Reactant: Cc1ccc(B(O)O)c(F)c1
Product: Cc1ccc(-c2nc(C(=O)Nc3cnn(C)c3N3CCC[C@@H](N)CC3)c(N)s2)c(F)c1
Yield: 20.5 %

Procedure:
Following the procedures from Example 210 and shown in FIG. 3, using ((R)-1-{4-[(2-bromo-5-tert-butoxycarbonylamino-thiazole-4-carbonyl)-amino]-2-methyl-2H-pyrazol-3-yl}-perhydro-azepin-4-yl)-carbamic acid benzyl ester and 2-fluoro-4-methyl-phenylboronic acid as starting materials, 211 was obtained in 20.5% yield over two steps: 1H NMR (400 MHz, DMSO) δ 8.88 (s, 1H), 8.14 (t, J=8.2 Hz, 1H), 7.47 (s, 1H), 7.36 (broad s, 2H), 7.22-7.14 (m, 2H), 3.66 (s, 3H), 3.45-3.05 (m, 7H), 2.36 (s, 3H), 1.98-1.78 (m, 3H), 1.72-1.54 (m, 3H); MS (ESI) m/z: 444.2 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[F:32][C:33]([F:43])([F:42])[C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:39][CH2:38][C:37]4[CH:36]=[CH:35][C:34]([C:33]([F:32])([F:42])[F:43])=[CH:41][CH:40]=4)=[O:24])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: NCc1ccc(C(F)(F)F)cc1
Product: O=C(NCc1ccc(C(F)(F)F)cc1)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-(trifluoromethyl)benzylamine as in General Procedure 10 to give the title compound. LCMS: m/z=604.92 (M+H+); retention time=1.01 minutes.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:7][C:6](=O)[C:5]=2[CH:4]=[CH:3]1.[C:18]([NH:21][NH2:22])([NH2:20])=[NH:19].[ClH:23].Cl.O>C(O)C>[ClH:23].[NH:21]([N:22]=[C:6]1[CH2:7][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][C:10]2[N:2]([CH3:1])[CH:3]=[CH:4][C:5]1=2)[C:18]([NH2:20])=[NH:19]
Reactant: Cn1ccc2c1CC(c1ccccc1)CC2=O
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cn1ccc2c1CC(c1ccccc1)CC2=NNC(=N)N
Yield: 52.5 %

Procedure:
A mixture of 1-methyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.50 g), aminoguanidine hydrochloride (0.26 g), concentrated hydrochloric acid (0.11 ml), water (0.11 ml) and ethanol (50 ml) was refluxed for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with diethylether, and to the mixture was added 1N sodium hydroxide solution. The mixture was extracted with ethyl acetate, and the organic layer was dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethanol. To the solution was added 1N hydrochloric acid, and the solvent was evaporated. The residue was recrystallized from ethanol to give 4-guanidinoimino-1-methyl-6-phenyl-4,5,6,7-tetrahydroindole hydrochloride (Compound 7) (0.37 g) as colorless crystals.
Reaction SMILES: FC(F)(F)C(O)=O.CC(OC([NH:15][CH2:16][CH2:17][C:18]1[C:23]([CH3:24])=[C:22]([O:25][CH3:26])[CH:21]=[CH:20][C:19]=1/[CH:27]=[CH:28]/[C:29]([O:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:30])=O)(C)C>ClCCl>[CH2:32]([O:31][C:29](=[O:30])[CH2:28][CH:27]1[C:19]2[C:18](=[C:23]([CH3:24])[C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:17][CH2:16][NH:15]1)[CH2:33][CH2:34][CH3:35]
Reactant: CCCCOC(=O)/C=C/c1ccc(OC)c(C)c1CCNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCOC(=O)CC1NCCc2c1ccc(OC)c2C
Reaction time: 1 h
Yield: 211.8 %

Procedure:
Trifluoroacetic acid (20.0 ml) was added dropwise to a solution of butyl(2E)-3-[2-[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)ethyl]-3-methyl-4-(methyloxy)phenyl]-2-propenoate (Preparation 13; 950 mg, 2.43 mmol) in dichloromethane (20 ml) at 0° C. After 1 h at 0° C., the solvent was removed; purification using a sulphonic acid ion exchange cartridge (SCX; 20 g), eluting with dichloromethane followed by 2N ammonia in methanol, and evaporation of the methanol/ammonia phase gave a brown solid (1.5 g). The solid was triturated with toluene, the mixture filtered, and the mother liquor concentrated in vacuo and dried under vacuum to give the title compound as a brown oil (960 mg).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]2[CH2:10][O:9][C:8](=[O:12])[C:7]=2[CH:6]=[CH:5][C:4]=1[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[N:21]1([C:26]2[N:31]=[CH:30][C:29]([CH2:32][CH:33]=O)=[CH:28][CH:27]=2)[CH:25]=[N:24][N:23]=[N:22]1>>[CH3:2][C:3]1[C:4]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([CH2:33][CH2:32][C:29]3[CH:30]=[N:31][C:26]([N:21]4[CH:25]=[N:24][N:23]=[N:22]4)=[CH:27][CH:28]=3)[CH2:17][CH2:16]2)=[CH:5][CH:6]=[C:7]2[C:11]=1[CH2:10][O:9][C:8]2=[O:12]
Reactant: O=CCc1ccc(-n2cnnn2)nc1
Reactant: Cc1c(CCN2CCNCC2)ccc2c1COC2=O
Agent: Cl
Product: Cc1c(CCN2CCN(CCc3ccc(-n4cnnn4)nc3)CC2)ccc2c1COC2=O

Procedure:
4-Methyl-5-[2-[4-[2-[6-(tetrazol-1-yl)-3-pyridyl]ethyl]piperazin-1-yl]ethyl]-3H-isobenzofuran-1-one was prepared in a similar fashion to that described for the synthesis of Example 38 starting from 4-methyl-5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride and [6-(1H-tetrazol-1-yl)pyridin-3-yl]acetaldehyde. LC-MS (IE, m/z): 406.1 [(M+1)+−28]. (0.61 μm)
Reaction SMILES: [CH:1]1[C:10]([S:11]([OH:14])(=[O:13])=[O:12])=[CH:9][C:8]2[C:3](=[C:4]([S:16]([OH:19])(=[O:18])=[O:17])[CH:5]=[CH:6][C:7]=2[NH2:15])[CH:2]=1.[OH-].[Na+:21].C(O)C>O>[Na+:21].[Na+:21].[NH2:15][C:7]1[C:8]2[C:3](=[CH:2][CH:1]=[C:10]([S:11]([O-:14])(=[O:13])=[O:12])[CH:9]=2)[C:4]([S:16]([O-:19])(=[O:18])=[O:17])=[CH:5][CH:6]=1
Reactant: Nc1ccc(S(=O)(=O)O)c2ccc(S(=O)(=O)O)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1ccc(S(=O)(=O)[O-])c2ccc(S(=O)(=O)[O-])cc12

Procedure:
A 50.0 g amount of (61.5%) 1-naphthylamine-4,7-disulfonic acid is dissolved in 150 ml of water and 5N sodium hydroxide is added until basic pH (10-11). The solution is warmed and ethyl alcohol is added until a precipitate forms. The solid is collected by filtration, washed with 85% ethyl alcohol, ethyl alcohol and ether and is dried in vacuo at 110° C. to give 31.0 g of 4-amino-1,6-naphthalenedisulfonic acid disodium salt.
Reaction SMILES: [CH:1]([O:14][C:15]1[C:24]2[N:23]=[CH:22][CH:21]=[N:20][C:19]=2[C:18]([O:25]C)=[C:17]2[C:27](=[O:39])[N:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[C:29](=[O:30])[C:16]=12)(C1C=CC=CC=1)C1C=CC=CC=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:38][C:35]1[CH:34]=[CH:33][C:32]([CH2:31][N:28]2[C:27](=[O:39])[C:17]3[C:16](=[C:15]([O:14][CH3:1])[C:24]4[N:23]=[CH:22][CH:21]=[N:20][C:19]=4[C:18]=3[OH:25])[C:29]2=[O:30])=[CH:37][CH:36]=1
Reactant: COc1c2c(c(OC(c3ccccc3)c3ccccc3)c3nccnc13)C(=O)N(Cc1ccc(F)cc1)C2=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1c2c(c(O)c3nccnc13)C(=O)N(Cc1ccc(F)cc1)C2=O
Reaction time: 1.5 h
Yield: 78.9 %

Procedure:
Into a flask containing 5-benzhydryloxy-7-(4-fluoro-benzyl)-9-methoxy-pyrrolo[3,4-g]quinoxaline-6,8-dione 246 (10 mg, 0.019 mmol, 1 equiv.) was added CH2Cl2 (1 mL) and under a nitrogen atmosphere was added triethylsilane (200 μL) followed by trifluoroacetic acid (200 μL). The reaction was allowed to stir for 1.5 hours and concentrated in vacuo until thoroughly dried. To the oil was added Hexanes/Ethyl ether (20 mL, 1/1 ratio) and sonicated. The resulting solid was filtered, washed in hexanes and air dried to give 7-(4-fluoro-benzyl)-5-hydroxy-9-methoxy-pyrrolo[3,4-g]quinoxaline-6,8-dione 249 (67%, 4.6 mg, 0.015 mmol). 1H NMR (300 MHz) CDCl3 δ 9.07 (d, J=1.8 Hz, 1 H), 8.97 (d, J=1.8 Hz, 1 H), 7.23-7.27 (m, 2 H), 6.96-7.05 (s, 2 H), 4.87 (s, 2 H), 4.46 (s, 3 H). 19F NMR (300 MHz) CDCl3 δ 62.77 MS: 354.0 (M+1)
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:22].C(OCC)(=O)C.CCCCCC>C(OCC)(=O)C>[ClH:22].[O:14]([C@H:11]1[CH2:10][CH2:9][C@H:8]([NH2:7])[CH2:13][CH2:12]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Oc2ccccc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: N[C@H]1CC[C@H](Oc2ccccc2)CC1
Reaction time: 1 h

Procedure:
The compound (1.80 g) obtained in Step 1 of this Reference Example was dissolved in ethyl acetate (18.0 mL). To the solution, 4 M hydrochloric acid/ethyl acetate (18.0 mL) was added at room temperature, and the mixture was stirred for 1 hour. To the reaction solution, hexane (18.0 mL) was added, and the precipitated solid was then collected by filtration and washed with a mixed solvent of hexane and ethyl acetate (50:50) to obtain the title compound (1.01 g).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[O:3][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[O:7][C:8]1[C:9]([CH2:23]O)=[N:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:12]=1.[OH-].[Na+].[BrH:32]>C(O)(=O)C.O>[Br:32][CH2:23][C:9]1[C:8]([O:7][C:6]2[CH:25]=[CH:26][CH:27]=[C:4]([O:3][C:2]([F:29])([F:28])[F:1])[CH:5]=2)=[N:12][N:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:10]=1
Reactant: Br
Reactant: OCc1nn(-c2ccc(C(F)(F)F)cc2)nc1Oc1cccc(OC(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: FC(F)(F)Oc1cccc(Oc2nn(-c3ccc(C(F)(F)F)cc3)nc2CBr)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
5-[3-(Trifluoromethoxy)phenoxy]-2-[4-(trifluoromethyl)phenyl]-2H-1,2,3-triazole-4-methanol (i.e. the product of Example 5, Step I, 0.17 g, 0.4 mmol) was suspended in 33% hydrobromic acid in acetic acid (2 mL) and 48% hydrobromic acid in water (2 mL). The mixture was heated to reflux with stirring for 4 h. The reaction mixture was cooled to 0° C. and basified with 50% aqueous sodium hydroxide solution. The reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (3×15 mL), and washed with saturated aqueous sodium bicarbonate solution (10 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure to obtain the title compound (0.19 g) as a pale yellow solid. The title compound was used directly in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH:14]([C:17]1[CH:21]=[C:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[NH:19][N:18]=1)([CH3:16])[CH3:15]>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:19]2[C:20]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])=[CH:21][C:17]([CH:14]([CH3:16])[CH3:15])=[N:18]2)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CC(C)c1cc(C(=O)OC(C)(C)C)[nH]n1
Reactant: O=[N+]([O-])c1cc(B(O)O)ccc1F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CC(C)c1cc(C(=O)OC(C)(C)C)n(-c2ccc(F)c([N+](=O)[O-])c2)n1
Temperature: 25 °C
Reaction time: 168 h
Yield: 43.2 %

Procedure:
4-Fluoro-3-nitrophenylboronic acid (0.9 g, 4.9 mmol) was dissolved in CH2Cl2 (10 mL) and pyridine (1 mL) with MS (activated 4A) and dried for 6 hours. A mixture of 4-fluoro-3-nitrophenylboronic acid, tert-butyl 3-isopropyl-1H-pyrazole-5-carboxylate (1.0 g, 4.9 mmol), copper(II) acetate (0.88 g, 4.9 mmol) and molecular sieves (4A activated, powder) was stirred at RT for 7 days open to the air. The reaction mixture was filtered through a pad of Celite. The filtrate was concentrated in vacuo and purified by silica gel column chromatography (EtOAc/hexane) to obtain tert-butyl 1-(4-fluoro-3-nitrophenyl)-3-isopropyl-1H-pyrazole-5-carboxylate (0.74 g, 44% yield). MS (ESI) m/z: 350.3 (M+H+).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][O:26][C@:27]1([C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[CH:48]=[CH2:49])=[CH:38][CH:37]=2)[CH2:31][NH:30][C@H:29]([C:32]([O:34][CH3:35])=[O:33])[CH2:28]1.[CH2:50]([O:57][C:58]([NH:60][C@@H:61]([C:65]([CH3:68])([CH3:67])[CH3:66])[C:62](O)=[O:63])=[O:59])[CH2:51][CH2:52][CH2:53][CH2:54][CH:55]=[CH2:56].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:50]([O:57][C:58]([NH:60][C@@H:61]([C:65]([CH3:68])([CH3:67])[CH3:66])[C:62]([N:30]1[CH2:31][C@:27]([O:26][CH3:25])([C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[CH:48]=[CH2:49])=[CH:38][CH:37]=2)[CH2:28][C@H:29]1[C:32]([O:34][CH3:35])=[O:33])=[O:63])=[O:59])[CH2:51][CH2:52][CH2:53][CH2:54][CH:55]=[CH2:56]
Reactant: C=Cc1ccccc1-c1ccc([C@@]2(OC)CN[C@H](C(=O)OC)C2)cc1
Reactant: C=CCCCCCOC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCCCCCOC(=O)N[C@H](C(=O)N1C[C@](OC)(c2ccc(-c3ccccc3C=C)cc2)C[C@H]1C(=O)OC)C(C)(C)C
Temperature: 25 °C
Yield: 74.2 %

Procedure:
HATU (248 mg, 0.652 mmol) was added to a solution of (2S,4R)-methyl 4-methoxy-4-(2′-vinylbiphenyl-4-yl)pyrrolidine-2-carboxylate (200 mg, 0.593 mmol), (S)-2-((hept-6-enyloxy)carbonylamino)-3,3-dimethylbutanoic acid (201 mg, 0.741 mmol) and DIEA (0.311 mL, 1.778 mmol) in DCM (8 mL) and stirred at r.t. 60 hours. The reaction was evaporated and purified on the Biotage (10-40% EtOAc:Hex) to give (2S,4R)-methyl 1-((S)-2-((hept-6-enyloxy)carbonylamino)-3,3-dimethylbutanoyl)-4-methoxy-4-(2′-vinylbiphenyl-4-yl)pyrrolidine-2-carboxylate (260 mg, 0.440 mmol, 74% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.96-1.00 (m, 1H) 1.06-1.10 (m, 1H) 1.11-1.19 (m, 7H) 1.30-1.47 (m, 4H) 1.55-1.64 (m, 2H) 1.99-2.10 (m, 2H) 2.49-2.55 (m, 1H) 2.89 (d, J=13.05 Hz, 1H) 2.93-3.04 (m, 3H) 3.73-3.80 (m, 3H) 3.92-4.10 (m, 3H) 4.11-4.20 (m, 1H) 4.31-4.41 (m, 1H) 4.87-5.05 (m, 3H) 5.23 (dd, J=10.92, 1.13 Hz, 1H) 5.38-5.42 (m, 1H) 5.68-5.75 (m, 1H) 5.75-5.86 (m, 1H) 6.62-6.76 (m, 1H) 7.28-7.43 (m, 7H) 7.63-7.69 (m, 1H). LCMS: r.t.=2.25 min., [M+H]+=591 Phenomenex Luna S10 (3×50 mm); Solvent A=95% water—5% methanol—10 mM ammonium acetate, Solvent B=5% water—95% methanol—10 mM ammonium acetate; gradient=0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 ml/min; inj. vol.=10 ul; wavelength=220 nm.