Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([CH2:19][N:20]3[CH:24]=[C:23]([C@@:25]([OH:32])([CH2:30][CH3:31])[C:26]([F:29])([F:28])[F:27])[N:22]=[N:21]3)=[CH:7][CH:8]=2)[N:3]=1.[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:27][C:26]([F:29])([F:28])[C@:25]([C:23]1[N:22]=[N:21][N:20]([CH2:19][C:6]2[CH:5]=[C:4]3[C:9]([C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[CH:11][C:2]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[N:3]3)=[CH:8][CH:7]=2)[CH:24]=1)([OH:32])[CH2:30][CH3:31]
Reactant: CC[C@](O)(c1cn(Cc2ccc3c(-c4ccc(F)cc4)cc(Cl)nc3c2)nn1)C(F)(F)F
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC[C@](O)(c1cn(Cc2ccc3c(-c4ccc(F)cc4)cc(-c4ccccc4)nc3c2)nn1)C(F)(F)F

Procedure:
To a solution of (S)-2-(1-{[2-chloro-4-(4-fluorophenyl)quinolin-7-yl]methyl}-1H-1,2,3-triazol-4-yl)-1,1,1-trifluorobutan-2-ol (100 mg, 0.22 mmol) in DME (5 mL) was added Pd(PPh3)4 (12 mg, 0.01 mmol), phenylboronic acid (34 mg, 0.29 mmol) and sodium carbonate (2M, 0.2 mL, 0.44 mmol). The mixture was refluxed for 14 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification on silica gel (eluting with acetone/dichloromethane, 1:9) gave the title compound. MS (+ESI): 507. (M+H)+.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7]([OH:9])=O)(=[O:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[CH3:27][O:28][CH:29]([O:32][CH3:33])[CH2:30][NH2:31]>O1CCCC1>[CH3:27][O:28][CH:29]([O:32][CH3:33])[CH2:30][NH:31][C:7](=[O:9])[CH:6]([CH2:5][S:4][C:1](=[O:3])[CH3:2])[CH2:10][CH:11]([CH3:13])[CH3:12]
Reactant: COC(CN)OC
Reactant: CC(=O)SCC(CC(C)C)C(=O)O
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(CNC(=O)C(CSC(C)=O)CC(C)C)OC
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 45.6 %

Procedure:
A solution of 2-[(acetylthio)methyl]-4-methylpentanoic acid (2.0 g) and triethyl amine (1.0 g) in 50 ml of tetrahydrofuran (THF) is cooled to -5° C. Ethyl chloroformate (1.1 g) in 5 ml of THF is added dropwise and the reaction mixture is stirred at -5° C. for 30 minutes. Amino acetaldehyde dimethyl acetal (1.1 g) in 20 ml of THF is added dropwise to the mixed anhydride solution at -5° C. After addition, it is stirred at 10°-20° C. for 2 hours and stored at 0° C. for about 16 hours. Triethylamine hydrochloride is filtered off and the filtrate is concentrated in vacuo. The residue (2.1 g) is dissolved in 3 ml of ether. Silica gel (5 g) is added and ether is evaporated off. This is placed on top of 40 g of dry silica gel and washed through with pentane, 1:1 pentane:ether and finally ether. Product elutes with ether to yield 1.3 g of product which solidifies to give a low melting waxy solid.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([SH:12])=[CH:8][CH:7]=1)([OH:5])[CH3:4].[OH-].[Na+].Cl[C:18]1[N:19]=[C:20]([NH2:23])[S:21][CH:22]=1.O>CCO>[NH2:23][C:20]1[S:21][CH:22]=[C:18]([S:12][C:9]2[CH:10]=[CH:11][C:6]([C:3]([OH:5])([CH3:4])[C:2]([F:1])([F:13])[F:14])=[CH:7][CH:8]=2)[N:19]=1
Reactant: CC(O)(c1ccc(S)cc1)C(F)(F)F
Reactant: Nc1nc(Cl)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(O)(c1ccc(Sc2csc(N)n2)cc1)C(F)(F)F
Reaction time: 2 h
Yield: 63.3 %

Procedure:
To 1,1,1-trifluoro-2-(4-mercaptophenyl)propan-2-ol (5.7 g, 25 mmol) was added NaOH (1.7 g, 42 mmol), a solution of 4-chlorothiazol-2-amine (2.5 g, 18 mmol) in EtOH (18 mL), and water (36 mL). The mixture was brought to reflux and stirred for 2 h. The solution was poured onto water (100 mL) and extracted with Et2O (3×50 mL). The combined organics were washed with brine (100 mL) and dried over MgSO4 and concentrated in vacuo to provide 3.65 g of 2-(4-(2-aminothiazol-4-ylthio)phenyl)-1,1,1-trifluoropropan-2-ol.
Reaction SMILES: C1(S(Cl)(=O)=O)C=CC=CC=1.[CH2:11]([C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[N:25]=[CH:24][C:23]([C:26]([NH2:28])=O)=[CH:22][N:21]=2)[CH2:16][CH2:15]1)[CH2:12][CH3:13].N1C=CC=CC=1.Cl>CCOCC>[CH2:11]([C@H:14]1[CH2:15][CH2:16][C@H:17]([C:20]2[N:25]=[CH:24][C:23]([C:26]#[N:28])=[CH:22][N:21]=2)[CH2:18][CH2:19]1)[CH2:12][CH3:13]
Reactant: CCC[C@H]1CC[C@H](c2ncc(C(N)=O)cn2)CC1
Agent: Cl
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCC[C@H]1CC[C@H](c2ncc(C#N)cn2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
20.3 g of benzenesulphonyl chloride are added while stirring to a mixture of 9.45 g of trans-2-(4-propylcyclohexyl)-5-pyrimidinecarboxamide and 55 ml of pyridine. After 2 hours, the solution is poured into a mixture of 100 g of ice and 0.9 ml of half-concentrated hydrochloric acid. The precipitated product is taken up in ether and the ether extract is washed neutral with water, dried and evaporated. The crude product is purified by chromatography on 200 g of silica gel with hexane/benzene (1:1) and subsequent bulb-tube distillation at 135° C./0.05 mmHg. There is obtained trans-2-(4-propylcyclohexyl)-5-pyrimidinecarbonitrile; m.p. 74° C., cl.p 89.5° C., smectic-nematic phase transition 71.5° C. (monotropic).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].[NH2:9][C:10]1[N:15]=[C:14]([N:16]([CH2:23][CH2:24][O:25][CH3:26])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:13]=[C:12]([C:27]2[N:31]=[C:30]([C:32]3[CH:33]=[CH:34][C:35]([CH2:38]OS(C)(=O)=O)=[N:36][CH:37]=3)[O:29][N:28]=2)[N:11]=1>C1COCC1>[CH3:26][O:25][CH2:24][CH2:23][N:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14]1[N:15]=[C:10]([NH2:9])[N:11]=[C:12]([C:27]2[N:31]=[C:30]([C:32]3[CH:37]=[N:36][C:35]([CH2:38][O:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[CH:34][CH:33]=3)[O:29][N:28]=2)[N:13]=1
Reactant: OCC(F)(F)F
Reactant: COCCN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(COS(C)(=O)=O)nc3)n2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(COCC(F)(F)F)nc3)n2)n1
Reaction time: 0.5 h
Yield: 9.5 %

Procedure:
To a solution of [5-(3-{4-amino-6-[(2-methoxy-ethyl)-phenyl-amino]-[1,3,5]triazin-2-yl}-[1,2,4]oxadiazol-5-yl)-pyridin-2-yl]-methanol (Intermediate 130, 185 mg, 0.44 mmol) in DCM (40 mL) was added methanesulfonyl chloride (48 μL, 0.61 mmol) drop-wise, followed by triethylamine (92 μL, 0.66 mmol). The resulting solution was stirred for 3 h under an inert atmosphere. Incomplete reaction was observed so additional methanesulfonyl chloride (9 μL, 0.10 mmol) and triethylamine (16 μL, 0.11 mmol) were added and stirring was continued for 1 h. The reaction mixture was washed with water (2×50 mL) and the organic phase dried over magnesium sulfate and evaporated to dryness to afford the methanesulfonic acid 5-(3-{4-amino-6-[(2-methoxy-ethyl)-phenyl-amino]-[1,3,5]triazin-2-yl}-[1,2,4]oxadiazol-5-yl)-pyridin-2-ylmethyl ester intermediate. In a separate flask 2,2,2-trifluoro-ethanol (190 μL, 2.64 mmol) was added dropwise to a suspension of sodium hydride (60% dispersion in mineral oil, 97 mg, 2.42 mmol) in anhydrous THF (30 mL) at 0 C under nitrogen. The resulting solution was stirred at 0 C for 30 min and then transferred via cannula to a solution of the methanesulfonic acid 5-(3-{4-amino-6-[(2-methoxy-ethyl)-phenyl-amino]-[1,3,5]triazin-2-yl}-[1,2,4]oxadiazol-5-yl)-pyridin-2-ylmethyl ester intermediate (220 mg, 0.44 mmol) in anhydrous THF (30 mL) at 0 C drop wise. The reaction mixture was stirred at room temperature for 18 h. The reaction was quenched with a saturated ammonium chloride aq. solution (5 mL) and extracted with EtOAc (3×50 mL). Combined organics were washed with brine (25 mL), dried over magnesium sulfate and evaporated to dryness. The crude product was purified by silica chromatography (2% MeOH in DCM) and then further by preparative HPLC-MS (Method C) to afford the title compound as an off-white solid (21 mg, 10%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:36][CH:37]1[CH2:41][CH2:40][O:39][CH2:38]1)(=O)=O>CN(C)C=O.C(OCC)(=O)C>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:36][CH:37]2[CH2:41][CH2:40][O:39][CH2:38]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCNc1nc(N)c2nc(OC)[nH]c2n1
Reactant: CS(=O)(=O)OCC1CCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCNc1nc(N)c2nc(OC)n(CC3CCOC3)c2n1
Temperature: 60 °C

Procedure:
To a solution of N2-butyl-8-methoxy-9H-purine-2,6-diamine trifluoroacetic acid salt (3.89 g) in dry N,N-dimethylformamide (46 ml) at room temperature and under was added potassium carbonate (6.14 g) in one go. The reaction was heated to 60° C., under nitrogen, for 1.5 hours. A solution of tetrahydro-3-furanylmethyl methanesulfonate, Isomer 1 (2.2 g) in dry N,N-dimethylformamide (2 ml) was added via a Pasteur pipette and the reaction heated at 70° C. for 16 hours. The reaction was cooled to room temperature, diluted with ethyl acetate (100 ml) and washed with brine (20 ml). The organic layer was concentrated in vacuo. The product was purified by C18 reverse phase chromatography using water (0.1% formic acid)-acetonitrile (0.05% formic acid) as eluant (10-50%) to afford the title compound as a clear viscous oil (2.79 g).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([CH2:18][O:19][C:20]2[C:28]([CH:29]3[CH2:31][CH2:30]3)=[CH:27][C:23]([C:24]([OH:26])=O)=[C:22]([F:32])[CH:21]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]([S:35]([NH2:38])(=[O:37])=[O:36])[CH3:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCCl>[CH:1]([N:14]1[CH2:17][CH:16]([CH2:18][O:19][C:20]2[C:28]([CH:29]3[CH2:30][CH2:31]3)=[CH:27][C:23]([C:24]([NH:38][S:35]([CH2:33][CH3:34])(=[O:37])=[O:36])=[O:26])=[C:22]([F:32])[CH:21]=2)[CH2:15]1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCS(N)(=O)=O
Reactant: O=C(O)c1cc(C2CC2)c(OCC2CN(C(c3ccccc3)c3ccccc3)C2)cc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC2CN(C(c3ccccc3)c3ccccc3)C2)cc1F
Temperature: 35 °C
Reaction time: 1 h

Procedure:
A mixture of 4-((1-benzhydrylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid (35.6 mg), ethanesulfonamide (22.5 mg), HBTU (41.9 mg), and DIPEA (0.073 mL) in DCE (0.83 mL) was heated at 35° C. for 16 hr then at 55° C. for 1 hr. More ethyanesulfonamide (9 mg) was added. Heating continued for 1 hr. Added with 1M NaH2PO4, the contents were extracted with DCM (2×). The combined extracts were dried (Na2SO4). The crude was purified with HPLC (23 mg). LCMS (Method D): RT=5.08 min, m/z: 523.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 11.78 (s, 1H), 7.49-7.36 (m, 4H), 7.28 (dd, J=8.3, 6.8 Hz, 4H), 7.22-7.09 (m, 3H), 6.95 (d, J=12.8 Hz, 1H), 4.49 (s, 1H), 4.21 (d, J=6.2 Hz, 2H), 3.47-3.36 (m, 2H), 3.02 (s, 2H), 2.93-2.81 (m, 1H), 2.10-1.99 (m, 1H), 1.22 (t, J=7.5 Hz, 3H), 0.95-0.82 (m, 2H), 0.71-0.61 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:3]([N:10]2[CH2:14][CH2:13][CH:12]([F:15])[CH2:11]2)=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:16][C:17]([CH3:22])([CH3:21])[CH2:18][CH2:19][NH2:20]>C1(C)C=CC=CC=1>[F:1][C:2]1[C:3]([N:10]2[CH2:14][CH2:13][CH:12]([F:15])[CH2:11]2)=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[N:20][CH2:19][CH2:18][C:17]([CH3:22])([CH3:21])[CH3:16]
Reactant: CC(C)(C)CCN
Reactant: O=Cc1cccc(F)c1N1CCC(F)C1
Solvent: Cc1ccccc1
Product: CC(C)(C)CCN=Cc1cccc(F)c1N1CCC(F)C1

Procedure:
3-Fluoro-2-(3-fluoropyrrolidin-1-yl)benzaldehyde (403.8 mg, 1.912 mmol) was taken in toluene (15 mL) and 3,3-dimethylbutan-1-amine (193.5 mg, 257.3 μL, 1.912 mmol) was added. The reaction mixture was refluxed overnight with a Dean Stark trap to remove the water. The reaction mixture was concentrated to give crude N-(3-fluoro-2-(3-fluoropyrrolidin-1-yl)benzylidene)-3,3-dimethylbutan-1-amine which was used directly in the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:19]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=3[F:18])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([C:33]2[CH:38]=[CH:37][C:36]([NH:39][C:2]3[N:19]=[C:5]4[C:6]([C:10]5[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=5[F:18])=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:35][CH:34]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: COc1ccc(-c2cccn3nc(Cl)nc23)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Product: COc1ccc(-c2cccn3nc(Nc4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)cc4)nc23)c(F)c1

Procedure:
4-{4-[8-(2-Fluoro-4-methoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(2-fluoro-4-methoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridine (0.250 g, 0.900 mmol) and 4-(4-amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.298 g, 1.08 mmol) in a manner analogous to Example 311a and 311b to give product (0.253 g, 41%). MP=93-95° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.62 (s, 1H), 8.79 (d, 1H), 7.80 (m, 1H), 7.58 (m, 3H), 7.15 (m, 3H), 6.98 (m, 2H), 4.05 (m, 2H), 3.85 (s, 3H), 2.75 (br m, 2H), 2.55 (m, 1H) 1.75 (m, 2H), 1.45 (m, 2H), 1.41 (s, 9H). MS=518 (MH)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:11]([OH:12])=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1.[CH:19]1([C:22](Cl)=[O:23])[CH2:21][CH2:20]1.O>N1C=CC=CC=1>[C:16]([NH:15][CH2:14][CH2:13][CH:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([NH:2][C:22]([CH:19]3[CH2:21][CH2:20]3)=[O:23])[C:11]=2[OH:12])[CH2:7][CH2:8]1)(=[O:18])[CH3:17]
Reactant: O=C(Cl)C1CC1
Reactant: CC(=O)NCCC1CCc2ccc(N)c(O)c21
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)NCCC1CCc2ccc(NC(=O)C3CC3)c(O)c21
Reaction time: 3 h
Yield: 106.7 %

Procedure:
N-[2-(6-Amino-7-hydroxy-2,3-dihydro-1H-inden-1-yl)ethyl]acetamide hydrochloride (100 mg, 0.369 mmol) was dissolved in pyridine (4 mL), cyclopropylcarbonyl chloride (36.8 μL, 0.406 mmol) was added under ice-cooling, and the mixture was stirred for 3 hr. Water was added to the reaction solution, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→95/5) to give the title compound (119 mg, yield 100%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:18]2[C:13](=[C:14]([CH3:22])[C:15]([C:19]([OH:21])=O)=[CH:16][CH:17]=2)[S:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.[I-].ClC1C=CC=C[N+]=1C>>[C:1]([O:5][C:6]([NH:8][CH:9]1[C:18]2[C:13](=[C:14]([CH3:22])[C:15]([C:19]([NH:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[O:21])=[CH:16][CH:17]=2)[S:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(C(=O)O)ccc2c1SCCC2NC(=O)OC(C)(C)C
Reactant: Nc1ccncc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Product: Cc1c(C(=O)Nc2ccncc2)ccc2c1SCCC2NC(=O)OC(C)(C)C
Yield: 461.4 %

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 53 using 4-(tert-butoxycarbonylamino)-8-methylthiochromane-7-carboxylic acid (400 mg), 4-aminopyridine (91.9 mg) and 2-chloro-1-methylpyridinium iodide (474 mg), the objective 4-(tert-butoxycarbonylamino)-8-methyl-N-(4-pyridyl)thiochromane-7-carboxamide (1.80 g) was obtained as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@@H:9]([CH2:13][CH3:14])[C:10](O)=[O:11])=[C:4]([N+:15]([O-])=O)[CH:3]=1>CO.C(O)(=O)C.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([NH:8][C@@H:9]([CH2:13][CH3:14])[C:10](=[O:11])[NH:15]2)=[CH:6][CH:7]=1
Reactant: CC[C@H](Nc1ccc(Br)cc1[N+](=O)[O-])C(=O)O
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Product: CC[C@@H]1Nc2ccc(Br)cc2NC1=O
Yield: 54.4 %

Procedure:
A solution of (2S)-2-[(4-Bromo-2-nitrophenyl)amino]butanoic acid (8.3 g, 27.4 mmol) in methanol (20 mL) and acetic acid (20 mL) was treated with iron filings (5.0 g, 89.5 mmol). The reaction was heated at reflux for 3 h, after which time the reaction was cooled, and filtered. The filtrate was concentrated in vacuo, and the resulting residue was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate, dried over magnesium sulfate, and concentrated in vacuo to yield 3.8 g (54%) of (3S)-7-bromo-3-ethyl-3,4-dihydroquinoxalin-2(1H)-one as a yellow solid. [α]D25=+33.23° (c=0.008 G/ML, DMSO); MS (ESI) m/z 255/257 ([M+H]+); Anal. Calcd for C10H11BrN2O: C, 47.08; H, 4.35; N, 10.98. Found: C, 46.98; H, 4.08; N, 10.90.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].C1(C)C=CC=CC=1.COC1C=CC(C(C2C=CC(OC)=CC=2)(N)[C@@H](N)C(C)C)=CC=1>CC(O)(C)C.CC(O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C@H:8]([OH:13])[C:9]([F:10])([F:11])[F:12])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)nc1)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: COc1ccc(C(N)(c2ccc(OC)cc2)[C@@H](N)C(C)C)cc1
Agent: [K+]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: O[C@@H](c1ccc(Cl)nc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 96 h
Yield: 99 %

Procedure:
To a solution of 1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethanone (46.8 g, 223.3 mmol) and 1.0 M KOtBu (4.47 mL, 4.47 mmol) in t-BuOH in IPA (136 mL) and toluene (34 mL) in a autoclave was added dichloro{(S)-(−)-2,2′-bis[di(3,5-xylyl)-phosphino-1,1′-binaphthyl}[(2S)-(+)-1,1-bis(4-methoxyphenyl)-3-methyl-1,2-butanediamine (0.273 g, 0.22 mmol) (Strem Chemicals). The reaction mixture was degassed by three vacuum-filling with nitrogen cycles. Hydrogen was introduced into the autoclave at a pressure of 300 psi and then reduced to 20 psi by slowly releasing the stop valve. After this procedure was repeated three times, the autoclave was pressurized to 300 psi with hydrogen. The reaction mixture was vigorously stirred at ambient temperature for 4 days (pressure was recharged to 300 psi when the internal pressure dropped below 200 psi). The pressure was released and the solvent was removed under reduced pressure. Ethyl acetate (300 mL) and 10% citric acid solution (50 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (3:1 DCM/ethyl acetate) to give (S)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethanol (46.76 g, 99.0%) as white solid. Enantiomeric excess was determined by chiral HPLC (Chiralcel OD-H, 90% hexanes: 10% (1:1 MeOH/EtOH) at 1.0 mL/min, 86.4% e.e. (S)-enantiomer). (S)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoro ethanol (97.8 g, 462 mmol, 76% e.e.) was dissolved in 4.5% ethyl acetate/hexane (v/v) (2170 mL) with heating to reflux. After complete dissolution, it was slowly cooled to ambient temperature overnight. The resulting solid was collected by filtration, washed with hexane and dried to give (S)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethanol (62.5 g, 63.9%) as white solid. Enantiomeric excess was determined by chiral HPLC (Chiralcel OD-H, 90% hexanes: 10% (1:1 MeOH/EtOH) at 1.0 mL/min, 98.8% e.e. (S)-enantiomer).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:5])#[N:2].[CH:12]([CH:14]=[CH2:15])=O>O1CCOCC1.[Cl-].[Zn+2].[Cl-]>[C:1]([C:3](=[CH:15][CH:14]=[CH2:12])[C:4]([O:6][CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:5])#[N:2]
Reactant: CC(C)(C)COC(=O)CC#N
Reactant: C=CC=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1COCCO1
Product: C=CC=C(C#N)C(=O)OCC(C)(C)C
Yield: 37.9 %

Procedure:
To a 1 liter, 3-necked glass reaction flask equipped with a mechanical stirrer, pressure compensating addition funnel and thermometer was added 1,4-dioxane (300 mls), zinc chloride (62.7 g; 0.46 moles), neopentyl cyanoacetate (116.25 g; 0.75 moles) and 1 ml of a solution of 1,4-hydroquinone, prepared by dissolving 1.22 g 1,4-hydroquinone in 100 mls 1,4-dioxane. The mixture was stirred and cooled by means of an ice bath, while a solution of acrolein (52.54 g; 0.94 moles) in 1,4-dioxane (200 mls) was added slowly from the addition funnel. The rate of addition was adjusted such that the reaction temperature did not exceed 40° C. After the reaction exotherm had subsided, the cooling bath was removed and the mixture stirred for a further 5 days. The solvent was removed by distillation under reduced pressure at 28° C. and 45 mbar and the reaction product was transferred to a 2-liter flask. Hexane (900 mls) was added and a yellow polymeric precipitate was formed. The hexane solution was decanted from the polymer and washed 3 times with 1200 ml portions of cold 0.1M hydrochloric acid solution, dried over anhydrous sodium sulfate and the solvent removed by distillation under reduced pressure to yield crude neopentyl 2-cyanopenta-2,4-dienoate (54.95 g; 38%) as a low viscosity orange colored liquid. The structure of the monomer was confirmed by proton NMR and IR analysis. The monomer was stabilized by the addition of 0.6 mg (approximately 10 ppm) of methane sulfonic acid. This monomer was used without further purification in the preparation of the BCPP-TMDS compositions.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[CH2:13]=[CH:14][CH3:15]>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:14]([CH3:15])[CH3:13])[CH:9]=2)[CH:4]=1
Reactant: C=CC
Reactant: COc1ccc2ccccc2c1
Product: COc1ccc2cc(C(C)C)ccc2c1
Temperature: 225 °C
Reaction time: 8 h

Procedure:
A 450 ml autoclave was charged with 158 g 2-methoxynapthalene and 3.2 g dealuminized mordenite catalyst. The autoclave was pressurized to 670 kPa with propylene then heated to 225° C. with agitation. Propylene was added as it was consumed to maintain pressure. In 8 hours, the conversion was 12% with 34% selectivity to 2-methoxy-6-isopropylnaphthalene (as confirmed by gas chromatography). Repetition of the reaction at 275° C. gave 19% conversion in 3 hours with 31% selectivity.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:14]([O:16]C)=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.CCO.[OH-].[K+]>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: COC(=O)C1(c2ccccc2F)CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1(c2ccccc2F)CCOCC1
Temperature: 130 °C
Yield: 84.7 %

Procedure:
A solution of methyl 4-(2-fluorophenyl)-tetrahydro-2H-pyran-4-carboxylate (2.45 g, 10 mmol), water (10 mL, 555 mmol), EtOH (50 mL, 10 mmol) and KOH (2.3 g, 41 mmol) was placed in a sealed flask and then heated at 130° C. for 10 hours. After cooling to room temperature, the reaction was concentrated to afford a yellow oil. The residue was diluted with water (100 mL) and extracted with DCM (120 mL). The separated aqueous phase was then acidified to pH=1 and then extracted with EtOAc (3×10 mL). The organic later was dried (Na2SO4), filtered, and concentrated to afford a tan solid (1.9 g). MS m/e=223.1 (M−1)−.