Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C@H:17]3[CH2:22][CH2:21][C@H:20]([C:23]#[N:24])[CH2:19][CH2:18]3)=[CH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]>C1(C)C=CC=CC=1.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C@H:17]3[CH2:22][CH2:21][C@H:20]([C:23]#[N:24])[CH2:19][CH2:18]3)=[CH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N#C[C@H]1CC[C@H](C=Cc2ccc(-c3ccc(F)c(F)c3)nc2)CC1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: N#C[C@H]1CC[C@H](CCc2ccc(-c3ccc(F)c(F)c3)nc2)CC1

Procedure:
A solution of 4.9 g of trans-4-[2-[2-(3,4-difluorophenyl)-5-pyridyl]vinyl]cyclohexanecarbonitrile in 120 ml of toluene is hydrogenated with 0.5 g of 10 percent palladium/carbon at room temperature and normal pressure. Filtration and evaporation of the filtrate yields trans-4-[2-[2-(3,4-difluorophenyl)-5-pyridyl]ethyl]cyclohexanecarbonitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([CH3:19])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[C:20]1([C@@H:26]([CH3:30])[C:27](O)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:19][N:12]1[C:13]2[N:14]=[CH:15][N:16]=[CH:17][C:18]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:27](=[O:28])[C@@H:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:30])[CH:7]=[N:6][CH:5]=2)=[O:9])=[CH:11]1
Reactant: C[C@@H](C(=O)O)c1ccccc1
Reactant: Cn1cc(C(=O)c2cncc(N)c2)c2cncnc21
Product: C[C@@H](C(=O)Nc1cncc(C(=O)c2cn(C)c3ncncc23)c1)c1ccccc1

Procedure:
The title compound was prepared according to the method described for Library protocol 1 starting from (5-amino-pyridin-3-yl)-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (Preparation 110) and (2R)-2-phenylpropanoic acid to afford the title compound. LCMS: Rt=2.52 min; m/z 386 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:10][C:9]2[C:11]([Cl:14])=[CH:12][S:13][C:8]=2[CH:7]=1)=[O:5])C.O[Li].O>>[Cl:14][C:11]1[C:9]2[NH:10][C:6]([C:4]([OH:5])=[O:3])=[CH:7][C:8]=2[S:13][CH:12]=1
Reactant: CCOC(=O)c1cc2scc(Cl)c2[nH]1
Agent: [Li]O
Solvent: O
Product: O=C(O)c1cc2scc(Cl)c2[nH]1

Procedure:
3-Chloro-4H-thieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester was hydrolyzed according to Procedure F (7 equiv LiOH—H2O; room temperature overnight, then at 50° C. overnight again; acidified aqueous phase extracted with ethyl acetate; combined organic phases dried over MgSO4, concentrated).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:15]([CH2:16]O)=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:7]1)=[O:5])[CH3:2].C(Br)(Br)(Br)[Br:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:3][C:4]([CH:6]1[C:15]([CH2:16][Br:19])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:7]1)=[O:5])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CCOC(=O)C1Oc2ccccc2C=C1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)C1Oc2ccccc2C=C1CBr
Temperature: 0 °C
Reaction time: 6 h
Yield: 49 %

Procedure:
To an ice-cooled mixture of 3-Hydroxymethyl-2H-chromene-2-carboxylic acid ethyl ester (1.73 g, 7.39 mmol) in methylene chloride (25 mL) was added commercially available carbon tetrabromide (2.70 g, 8.13 mmol) and commercially available triphenylphosphine (1.94 g, 7.39 mmol). After addition was complete the mixture was stirred at 0° C. for 6 hours. Upon completion of the reaction, the methylene chloride was removed under reduced pressure. The crude product obtained was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 40 g; (0% to 90% ethyl acetate/hexane) to afford 3-bromomethyl-2H-chromene-2-carboxylic acid ethyl ester as a yellow oil, 1.08 g (49% yield).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[C:21]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[C:21]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:16][CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=2)[CH:22]=1
Reactant: Oc1cccc(-c2ccccc2)c1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCCOc2cccc(-c3ccccc3)c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 284, Step 2) and biphenyl-3-ol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a colorless oil. MS (ES) for C25H25O5 [M+Na]+429.4.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]1[C:19]2[CH:18]([CH2:20][O:21][C:22]([N:24]3[CH2:28][CH2:27][CH2:26][C@H:25]3[C:29]([OH:31])=[O:30])=[O:23])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1.C(N(C(C)C)C(C)C)C.O[C@H:42]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:43]([OH:45])=[O:44]>C(Cl)Cl.CN(C)C=O>[CH:16]1[C:17]2[CH:18]([CH2:20][O:21][C:22]([N:24]3[CH2:28][CH2:27][CH2:26][C@H:25]3[C:29]([O:31][C@H:42]([CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:43]([OH:45])=[O:44])=[O:30])=[O:23])[C:19]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: O=C(O)[C@H](O)Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(O)[C@@H](Cc1ccccc1)OC(=O)[C@@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Yield: 74.1 %

Procedure:
Oxalyl chloride (1.17 mL, 13.3 mmol) was added dropwise to a solution of (S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)pyrrolidine-2-carboxylic acid (Fmoc-Pro-OH) (3.00 g, 8.89 mmol) and N,N-dimethylformamide (34 μL, 0.445 mmol) in methylene chloride (36 mL) with stirring at 0° C. under a nitrogen atmosphere, and the reaction mixture was then stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, the resulting residue was mixed with methylene chloride (36 mL), N-ethyldiisopropylamine (DIPEA) (2.33 mL, 13.3 mmol) and (R)-2-hydroxy-3-phenylpropanoic acid (2.22 g, 13.3 mmol) at 0° C., and the reaction mixture was stirred at room temperature for 2 hours. The reaction solution was washed with 1 N hydrochloric acid twice and a saturated aqueous sodium chloride solution twice, dried over sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by reverse-phase silica gel column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to afford (R)-2-(((S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)pyrrolidine-2-carbonyl)oxy)-3-phenylpropanoic acid (Fmoc-Pro-D-PhLac-OH) (Compound SP635) (3.20 g, 6.59 mmol, 74%).
Reaction SMILES: [F:1][C:2]1[C:3]([CH:14]([CH2:30]O)[CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18][CH2:17]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([O:12]C)=[N:5]2.CS(OS(C)(=O)=O)(=O)=O.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6](=[O:12])[N:5]3[CH2:30][CH:14]([CH2:15][N:16]4[CH2:21][CH2:20][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:18][CH2:17]4)[C:3]=1[C:4]=23
Reactant: COc1cnc2ccc(F)c(C(CO)CN3CCC(NC(=O)OC(C)(C)C)CC3)c2n1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCN(CC2Cn3c(=O)cnc4ccc(F)c2c43)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
A mixture of 1,1-dimethylethyl (1-{2-[6-fluoro-3-(methyloxy)-5-quinoxalinyl]-3-hydroxypropyl}-4-piperidinyl)carbamate (10.8 g, 25 mmol), methanesulfonic anhydride (5.12 g, 28.7 mmol) and N,N-diisopropylethylamine (9.8 ml, 56 mmol) in dry chloroform (140 ml) was stirred at room temperature for 0.5 h, then heated under reflux for 3 days. The mixture was washed with aqueous sodium bicarbonate and the aqueous phase was extracted with dichloromethane. The combined organic fractions were dried and evaporated. The residue was chromatographed on silica (500 g), eluting with 0-5% methanol/dichloromethane to give the product (8.13 g, 81%).
Reaction SMILES: [BrH:1].[CH3:2][O:3][C:4]1[C:5]([O:19][CH3:20])=[CH:6][C:7]2[O:11][N:10]=[C:9]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:8]=2[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:30][CH2:31][CH2:32][CH:33]([C:41]1[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=1)[C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1>O.CN(C)C=O>[BrH:1].[CH3:2][O:3][C:4]1[C:5]([O:19][CH3:20])=[CH:6][C:7]2[O:11][N:10]=[C:9]([CH:12]3[CH2:13][CH2:14][N:15]([CH2:30][CH2:31][CH2:32][CH:33]([C:34]4[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=4)[C:41]4[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=4)[CH2:16][CH2:17]3)[C:8]=2[CH:18]=1
Reactant: COc1cc2onc(C3CCNCC3)c2cc1OC
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2onc(C3CCN(CCCC(c4ccc(F)cc4)c4ccc(F)cc4)CC3)c2cc1OC
Temperature: 25 °C
Yield: 49.4 %

Procedure:
A stirred mixture of 2.60 g of 5,6-dimethoxy-3-(4-piperidyl)-1,2-benzisoxazole hydrobromide, 3.30 g of potassium carbonate, 0.25 g of potassium iodide, 2.20 g of 4-chloro-1,1-bis(4-fluorophenyl)butane and 75 ml of dimethylformamide was heated to 90° for 8 hrs and overnight at ambient temperature. The reaction mixture was poured into 500 ml of water and was extracted with ether, dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to yield an oil. The oil was purified by filtering through a silica gel column (25:1), using dichloromethane as eluent. The eluent was evaporated and the residue was dissolved in ether, and a saturated hydrogen bromide-ether solution was added dropwise to precipitate the salt. The salt was collected and washed with 3.0 g of ether. Recrystallization from toluene-water yielded 2.2 g (48.3%) of the product, mp 195°-197°.
Reaction SMILES: [S:1]([CH2:5][CH2:6][OH:7])([O-:4])(=[O:3])=[O:2].[Na+].[C:9](O)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Cl-].[C:32]1([S+:38]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O.C(Cl)Cl>[C:9]([O:7][CH2:6][CH2:5][S:1]([O-:4])(=[O:3])=[O:2])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:45]1([S+:38]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: O=C(O)c1ccccc1
Reactant: O=S(=O)([O-])CCO
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCCS(=O)(=O)[O-])c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 25 g of trifluoroacetic acid were dissolved 3.0 g (20 mmol) of sodium isethionate and 2.4 g (20 mmol) of benzoic acid. To this solution, 6.3 g (30 mmol) of trifluoroacetic anhydride was added dropwise, followed by stirring for 2 hours at room temperature. Then 90 g (30 mmol) of an aqueous solution of triphenylsulfonium chloride prepared in Synthesis Example 1-1 and 120 g of methylene chloride were added, followed by stirring for 30 minutes at room temperature. At the end of stirring, the organic layer was taken out, aqueous sodium bicarbonate was added dropwise until the pH of the aqueous layer ceased to be acidic, and the organic layer was then taken out. The organic layer was washed with water and concentrated in vacuum. Methyl isobutyl ketone was added to the concentrate, which was concentrated in vacuum again while distilling off the residual water. Diisopropyl ether was added to the residue. Subsequent decantation and drying gave the target compound, triphenylsulfonium 2-benzoyloxyethanesulfonate. Colorless oily matter, 3.0 g, yield 30%. The compound, designated PAG-3, has the following structure.
Reaction SMILES: [C:1]1([S:11]([CH2:14][C:15]2[CH:16]=[C:17]([CH:23]=[CH:24][C:25]=2[N+:26]([O-:28])=[O:27])[O:18][CH2:19][CH2:20][CH2:21][OH:22])(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]1([S:11]([CH2:14][C:15]2[CH:16]=[C:17]([CH:23]=[CH:24][C:25]=2[N+:26]([O-:28])=[O:27])[O:18][CH2:19][CH2:20][CH2:21][O:22][S:35]([C:32]2[CH:33]=[CH:34][C:29]([CH3:39])=[CH:30][CH:31]=2)(=[O:37])=[O:36])(=[O:12])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1ccc(OCCCO)cc1CS(=O)(=O)c1cccc2ccccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCOc2ccc([N+](=O)[O-])c(CS(=O)(=O)c3cccc4ccccc34)c2)cc1
Reaction time: 2 h
Yield: 72.9 %

Procedure:
A solution of 3-[3-(naphthalene-1-sulfonylmethyl)-4-nitro-phenoxy]-propan-1-ol (12.9 g, 32.1 mmol), p-toluenesulfonyl chloride (24.6 g, 129 mmol) and triethylamine (37 mL, 270 mmol) in methylene chloride (300 mL) was stirred at ambient temperature under nitrogen. After 2 hours, a second portion of p-toluenesulfonyl chloride (12.1 g, 63.5 mmol) was added. The reaction was stirred for 2 more hours and then concentrated. The residue was partitioned in methylene chloride and aqueous sodium bicarbonate. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography with 20-50% ethyl acetate in hexane, 100% ethyl acetate and then 100% methylene chloride (due to limited solubility). A yellow solid (13.0 g, 73.0%) was obtained as toluene-4-sulfonic acid 2-[3-(naphthalene-1-sulfonylmethyl)-4-nitro-phenoxy]-propyl ester: MP: 162-4° C.; Mass Spectrum (−EI, [M−H]−) m/z 554. 1HNMR (500 MHz, DMSO-d6): δ8.52-8.54 (m, 1H), 8.31 (d, 1H, J=8.18 Hz), 8.09-8.11 (m, 1H), 7.97-8.00 (m, 2H), 7.62-7.73 (m, 5H), 7.35 (d, 2H, J=7.93 Hz), 6.92 (dd, 1H, J=9.15 Hz and 2.81 Hz), 6.73 (d, 1H, J=2.80 Hz), 5.22 (s, 2H), 4.09 (t, 2H, J=5.98 Hz), 3.79-3.82 (m, 2H), 2.29 (s, 3H), 1.91-1.97 ppm (m, 2H). Elemental Analysis for C27H25NO8S2: Calcd: C, 58.37; H, 4.54; N, 2.52; Found: C, 58.13; H, 4.43; N, 2.41.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N+:20]([O-])=O)=[C:11]([C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)[C:12]([NH2:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O>CCO.[Fe]>[NH2:20][C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:17][CH:16]=[C:15]([O:18][CH3:19])[C:11]=1[C:12]([NH2:14])=[O:13]
Reactant: COc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1C(N)=O
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1ccc(OCc2ccccc2)c(N)c1C(N)=O
Temperature: 90 °C

Procedure:
A mixture of 3-(benzyloxy)-6-methoxy-2-nitrobenzamide (10, 0.34 g. 1.1 mmol), iron powder (0.44 g, 7.7 mmol) and concentrated hydrochloric acid (80 mL) in EtOH (4 mL)/water (0.4 mL) was heated at 90° C. for 75 min. The reaction mixture was cooled to room temperature, filtered through Celite and concentrated. The residue was dissolved in EtOAc washed with saturated NaHCO3 solution, dried over Na2SO4, filtered, and concentrated. Purification by silica gel chromatography eluting with 0-10% MeOH in CH2Cl2 afforded the title compound along with its regioisomer (0.267 g, 87%) as a tan solid: 1H NMR (500 MHz, CDCl3) δ 7.83 (br s, 1H), 7.47-7.32 (m, 5H), 6.77 (d, J=8.8 Hz, 1H), 6.60 (br s, 2H), 6.06 (d, J=8.8 Hz, 1H), 5.51 (br s, 1H), 5.04 (s, 2H), 3.85 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[S:10][CH:9]=[C:8]([CH:11]=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1.[O-:13]Cl=O.[Na+]>O.CS(C)=O>[Cl:1][C:2]1[C:3]2[S:10][CH:9]=[C:8]([C:11]([OH:13])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=Cc1csc2c(Cl)ncnc12
Reactant: [O-][Cl+][O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1csc2c(Cl)ncnc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
NaH2PO4.2H2O (170 mg, 1.07 mmol) was dissolved in water (0.6 mL) and 4-chlorothieno[3,2-d]pyrimidine-7-carbaldehyde (100 mg, 0.47 mmol) dissolved in DMSO (4.8 mL) was added thereto at 10° C. The reaction mixture was cooled to 0° C. and NaClO2 (170 mg, 1.88 mmol) dissolved in water (0.6 mL) was added thereto at 0° C. The reaction mixture was heated to room temperature, stirred for 2 hours, and water (10 mL) was added thereto. The reaction mixture was stirred for 2 hours and then filtered. The filtrate was concentrated to obtain the title compound as a white solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]([Cl:17])=[C:15]2[C:10]([CH2:11][CH2:12][NH:13][C:14]2=[O:18])=[CH:9][CH:8]=1)(=O)=O.[CH3:21][N:22]1[C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][CH:24]=[N:23]1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Cl:17][C:16]1[C:7]([C:26]2[N:22]([CH3:21])[N:23]=[CH:24][CH:25]=2)=[CH:8][CH:9]=[C:10]2[C:15]=1[C:14](=[O:18])[NH:13][CH2:12][CH2:11]2
Reactant: O=C1NCCc2ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c21
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1nccc1-c1ccc2c(c1Cl)C(=O)NCC2
Temperature: 80 °C
Reaction time: 48 h
Yield: 20.2 %

Procedure:
To a solution of 8-chloro-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl trifluoromethanesulfonate (66a, 300 mg, 0.910 mmol) in DMF (5 mL) was added 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (205 mg, 0.956 mmol), PdCl2(dppf)-DCM (74.3 mg, 0.0910 mmol), and Na2CO3 (289 mg, 2.73 mmol). The reaction mixture was degassed with N2 and stirred in a sealed tube at 80° C. for 2 days. The reaction mixture was adjusted to pH 7 and purified by preparative chromatography to give 8-chloro-7-(1-methyl-1H-pyrazol-5-yl)-3,4-dihydroisoquinolin-1(2H)-one (66b, 48 mg, 20%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1>C(O)C1C=CC=CC=1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][C:13]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(N)nc1
Agent: [Ti+4]
Agent: CC[O-]
Solvent: OCc1ccccc1
Product: Nc1ccc(CC(=O)OCc2ccccc2)cn1
Temperature: 110 °C

Procedure:
Ethyl 2-(6-aminopyridin-3-yl)acetate (described in WO 2009/091014) (1.5 g) was dissolved in benzyl alcohol (10 mL). Titanium(IV) ethoxide (1.74 mL) was added and the reaction was heated to 110° C. for 16 hours. The reaction was cooled to room temperature and quenched with 1N HCl. This mixture was basified with saturated sodium bicarbonate and extracted three times with ethyl acetate. The combined organics were dried over MgSO4, filtered, and concentrated. Purification by column chromatography, eluting with a gradient of 30-100% ethyl acetate in heptane, afforded the title compound Intermediate (5b) (1.04 g, 51% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 3.51 (2 H), 4.37 (2 H), 5.11 (2 H), 6.46 (1 H), 7.27-7.41 (6 H), 7.95 (1H). m/z 243.4 (M+H)+.
Reaction SMILES: [BH4-].[Na+].C[O:4][C:5](=O)[C@H:6]([CH2:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH3:26])[CH:18]=1)[NH:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1>[C:8]([NH:7][CH:6]([CH2:16][C:17]1[CH:18]=[C:19]([O:25][CH3:26])[CH:20]=[C:21]([O:23][CH3:24])[CH:22]=1)[CH2:5][OH:4])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)[C@H](Cc1cc(OC)cc(OC)c1)NC(=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(CC(CO)NC(=O)c2ccccc2)cc(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4.2 gm of sodium borohydride were added to a stirred mixture of 34.3 gm of N-benzoyl-3-(3',5'-dimethoxy-phenyl)alanine methyl ester and 350 ml of tetrahydrofuran at room temperature, the resulting mixture was stirred for 30 minutes more at room temperature, and then it was refluxed for five hours. After cooling of the reaction mixture, the solvent was distilled off in vacuo, the residue was suspended in water, and the suspension was acidified with acetic acid. The crystalline precipitate formed thereby was collected by suction filtration, washed with water, dried and recrystallized from toluene, yielding 2-benzamido-3-(3',5'-dimethoxy-phenyl)-1-propanol having a melting point of 117°-118° C.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:14]2[CH2:15][CH2:16][CH2:17][N:18]=2)[C:7]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[CH:13]=1>CO.O>[F:3][C:4]1[CH:5]=[C:6]([CH:14]2[CH2:15][CH2:16][CH2:17][NH:18]2)[C:7]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[CH:13]=1
Reactant: Fc1cc2c(c(C3=NCCC3)c1)OCCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Fc1cc2c(c(C3CCCN3)c1)OCCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
NaBH4 (0.25 g, 6.69 mmol) was added to a solution of 5-(7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-3,4-dihydro-2H-pyrrole (Int-55) (0.8 g, 3.34 mmol) in a mixture of MeOH and H2O (3:1, 20 mL) and was stirred at 25° C. for 2 h. Reaction mixture was quenched with 1N aqueous HCl solution (50 mL) and basified with 2N aqueous NaOH solution to pH 8 and extracted with DCM (3×20 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 2-(7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)pyrrolidine (Int-56). MS (ESI) m/z 224.5 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[CH2:13]([O:15][C:16](=[O:30])[C:17]([C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:18]OCC)[CH3:14]>C1(C)C=CC=CC=1>[CH2:13]([O:15][C:16](=[O:30])[C:17]([C:22](=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[CH:18][NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][C:4]=1[C:9]([F:10])([F:11])[F:12])[CH3:14]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1ccccc1
Reactant: Nc1ccc(F)cc1C(F)(F)F
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNc1ccc(F)cc1C(F)(F)F)C(=O)c1ccccc1
Reaction time: 18 h
Yield: 62.1 %

Procedure:
A mixture of 4-fluoro-2-trifluoromethyl-aniline (5.0 g, 27.89 mmol) and 2-benzoyl-3-ethoxy-acrylic acid ethyl ester (6.9 g, 27.89 mmol) in toluene (125 mL) was heated at reflux. After 18 hr, the reaction was cooled, concentrated and purified by column chromatography (eluent 10% to 40% Et2O/hexanes) to give 2-benzoyl-3-(2-trifluoromethyl-4-fluoro-phenylamino)-acrylic acid ethyl ester (6.6 g, 62%); MS (ESI) m/z 382 (M+H)+; 1H NMR E:Z (mixture 1:1) (CDCl3): δ 0.88 (t, J=5.38 Hz, 3H), 0.95 (t, J=5.38 Hz, 3H), 4.02 (q, J=5.38 Hz, 2H), 4.07 (t, J=5.38 Hz, 2H), 7.29-7.51 (m, 10H), 7.53-7.56 (dt, J=9.67, 1.54 Hz, 2H), 7.66-7.68 (dt, J=8.33, 1.41 Hz, 2H), 8.10-8.13 (d, J=12.68 Hz, 2H), 8.36-8.39 (d, J=12.43 Hz, 2H), 11.17-11.20 (d, J=12.68 Hz, 1H), 12.39-12.42 (d, J=12.43 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.[CH2:14](O)[CH2:15][OH:16]>C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:9][CH2:10][CH2:11][CH3:12])[O:16][CH2:15][CH2:14][O:13]2)=[CH:6][CH:7]=1
Reactant: CCCCC(=O)c1ccc(Br)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCCC1(c2ccc(Br)cc2)OCCO1
Yield: 91.5 %

Procedure:
To a solution of 4′-bromovalerophenone (2.41 g, 10 mmol) in benzene (60 ml) was added ethylene glycol (2.0 ml, 36 mmol), p-toluenesulfonic acid monohydrate (100 mg, 0.53 mmol) and the mixture refluxed under nitrogen in a Dean-Stark apparatus for 16 h. The reaction mixture was washed with sodium bicarbonate solution (5%, 50 ml), brine (1×50 ml), dried (Na2SO4) and evaporated to give 2-(4-bromophenyl)-2-butyl-1,3-dioxolane (11) as a clear oil (2.61 g, 92%). 1H nmr (CDCl3, 300 MHz) 0.88, t (6.9 Hz), H4″; 1.2-1.4, m, H2″,3″; 1.88, m, H1″; 3.7-3.8, m, CH2O; 4.0-4.1, m, CH2O; 7.34, d (8.4 Hz), H2′,6′; 7.49, d (8.4 Hz), H3′,5′. ESI (+ve) MS m/z 285/287 (M+H, 8%).