Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)[CH2:6][O:7][CH2:8][C:9]([CH3:18])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:10][OH:11].N1C=CC=CC=1.[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>C(Cl)Cl>[CH3:44][C:34]1[CH:39]=[CH:38][C:37]([S:40]([O:11][CH2:10][C:9]([CH3:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][O:7][CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:26])([F:27])[F:1])[CH:21]=[C:20]([C:22]([F:24])([F:23])[F:25])[CH:19]=2)(=[O:42])=[O:41])=[CH:36][CH:35]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(CO)(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC(C)(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc2)cc1
Temperature: -20 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
3-(3,5-bis(trifluoromethyl)benzyloxy)-2-methyl-2-phenylpropan-1-ol (1.72 g, 4.39 mmol) was mixed with pyridine (1.39 g, 17.6 mmol) in anhydrous methylene chloride (20 ml) and cooled to −20° C. Solid p-toluenesulfonyl chloride (3.35 g, 17.6 mmol) was added in one portion and the mixture was warmed up naturally to room temperature and stirred overnight. The mixture was then loaded directly onto silica column and eluted with 5% ethyl aceta in hexanes. 1.89 g (79%) of the desired product was obtained. 1H NMR (500 MHz, CDCl3) δ: 1.37 (s, 3 H) 2.38 (s, 3 H) 3.66 (d, J=2.75 Hz, 2 H) 4.21 (d, J=9.46 Hz, 1 H) 4.27 (d, J=9.46 Hz, 1 H) 4.52 (s, 2 H) 7.27 (m, 5 H) 7.35 (d, J=8.24 Hz, 2 H) 7.62 (s, 2 H) 7.70 (s, 1 H) 7.80 (d, J=8.24 Hz, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:14])[CH:11]([CH3:13])[CH3:12].N1CCCCC1.CC(O)=O>C1C=CC=CC=1.CCOCC.O>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:15]([C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: O=Cc1ccc(F)cc1
Solvent: c1ccccc1
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C(=Cc1ccc(F)cc1)C(=O)C(C)C
Yield: 83.9 %

Procedure:
A mixture of 4-fluorobenzaldehyde (3.00 gm, 24 mmol), ethyl isobutyrylacetate (3.82 gm, 24 mmol), piperdine (240 ul), and HOAc (42 ul) was refluxed in benzene (15 ml) with removal of water (Dean-Stark trap) for 22 hours. The cooled mixture was diluted with Et2O and washed successively with 2% HCl, saturated NaHCO3, H2O, and brine, then dried (Na2SO4), filtered, and stripped to yield an oil. Distillation of the oil (bp 110°-113° C. at 0.25 mm) afforded the title compound (5.32 gm, 83%) as a pale yellow liquid. This reaction has been successfully scaled up to 300 mmol.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].C(N(C(C)C)CC)(C)C.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>ClCCl>[N:23]1([S:2]([C:5]2[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=2)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1cccc(S(=O)(=O)N2CCOCC2)c1
Reaction time: 2 h
Yield: 81.1 %

Procedure:
Commercially available 3-(chlorosulfonyl)benzoic acid (3 g, 13.5 mmol) was suspended in dichloromethane (50 mL). Diisopropylethylamine (5.19 mL, 30 mmol) and morpholine (1.67 mL, 21 mmol) were added slowly. After 2 h, the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with 3N HCl three times. The ethyl acetate phase was dried over magnesium sulfate and the solvent was removed under reduced pressure, to provide the title product (2.97 g, 81%) as a white solid. 1HNMR (DMSO-d6) δ8.28 (d, J=8 Hz, 1H), 8.20 (s, 1H), 8.01 (d, 8 Hz, 1H), 7.83 (t, J=8 Hz, 1H), 3.91(m, 4H), 3.12 (M, 4H). MS (EI-NEG):[M+] 270.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:6][C:5]([C:15]#[N:16])=[CH:4][C:3]=1[NH:17]C(=O)OC(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:17][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([CH2:8][N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[C:2]=1[Cl:1])[C:15]#[N:16]
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(CN2CCOCC2)c1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(N)c(Cl)c(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
A solution of tert-butyl (2-chloro-5-cyano-3-(morpholinomethyl)phenyl)carbamate (45 mg, 0.128 mmol) in a mixture of DCM (2 mL) and TFA (2 mL) was left stirring at room temperature for 1 hr. The solvent was removed and the residue was dissolved in MeOH and applied onto an SCX column. This was washed with MeOH and the product was eluted with 2N NH3 in MeOH. The solvent was removed to leave 3-amino-4-chloro-5-(morpholinomethyl)benzonitrile (32 mg).
Reaction SMILES: C(Cl)CCl.[NH2:5][C:6]1[N:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([OH:16])=O)=[CH:8][CH:7]=1.[CH3:17][NH:18][CH2:19][C:20]1[S:27][C:23]2[S:24][CH:25]=[CH:26][C:22]=2[CH:21]=1.C1C=CC2N(O)N=NC=2C=1.O.CCN(CC)CC>CN(C=O)C>[NH2:5][C:6]1[N:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([N:18]([CH3:17])[CH2:19][C:20]2[S:27][C:23]3[S:24][CH:25]=[CH:26][C:22]=3[CH:21]=2)=[O:16])=[CH:8][CH:7]=1
Reactant: CNCc1cc2ccsc2s1
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CN(Cc1cc2ccsc2s1)C(=O)/C=C/c1ccc(N)nc1
Yield: 41.9 %

Procedure:
EDC (230 mg, 1.2 mmole) was added to a solution (E)3-(6-aminopyridin-3-yl)acrylic acid (164 mg, 1.0 mmole), 2-(methylaminomethyl)thieno[2,3-b]thiophene (220 mg, 1.2 mmole), HOBt H2O (162 mg, 1.2 mmole), and Et3N (0.35 mL, 2.5 mmole) in dry DMF (5 mL) at RT. After 18 hr the mixture was concentrated. Flash chromatography on silica gel (5% EtOH/EtOAc) gave the title compound (138 mg, 42%) as a tan solid: IH NMR (400 MHz, d6-DMSO) δ 8.15 (d, J=2.0 Hz, 1H), 7.84 (bs,1H), 7.57 (d, J=5.2 Hz, 1H), 7.43 (d,J=15.2 Hz,1H), 7.27 (m, 2H), 6.44 (m, 2H), 4.75 (s, 2H), 3.13(s, 3H); for minor rotomer 8 5.00 (s, 2H), 2.95 (s, 3H); MS (ES) nme 330 (M+H)+.
Reaction SMILES: [OH-:1].[Na+].[C:3]1([CH3:9])[CH:8]=CC=C[CH:4]=1>>[C:3]([O:1][C:3]([CH3:4])([CH3:8])[CH3:9])([CH3:9])([CH3:8])[CH3:4]
Reactant: Cc1ccccc1
Reactant: [OH-]
Agent: [Na+]
Product: CC(C)(C)OC(C)(C)C

Procedure:
The exemplary synthesis depicted in Scheme 1 involves condensation of 2-chloromalonic acid dimethyl ester 11 with an appropriately deuterated guaiacol 10 to afford the 2-(2-methoxyphenoxy)malonic acid dimethyl ester 12, followed by cyclization of 12 with 13 to afford the corresponding bipyrimidinedione 14. This compound 14 is treated with refluxing POCl3 to afford the dichlorobipyrimidine 15, which is subsequently treated with an appropriately deuterated 4-tert-butylphenylsulfonamide 16, K2CO3 and tetrabutylammonium bromide (TBAB) in toluene to provide the monosubstituted sulfonamide 17. Compound 17 is thereafter treated with an appropriately deuterated or fluorinated ethyleneglycol mono-tert-butyl ether 18b and NaOH in hot toluene to afford the tert-butyl ether protected intermediate, which is thereafter deprotected by reaction with formic acid to afford the formate ester. This ester is then hydrolyzed with NaOH in a mixture of water and ethanol, to afford the target compounds of Formula I. Such compounds of Formula I are readily purified by crystallization, comprising heating the crude product into a mixture of ethanol and water to afford a solution and thereafter allowing the solution to cool. Other approaches to synthesizing compounds of the formulae herein (e.g., Formula I) can readily be adapted from references cited herein. Variations of these procedures and their optimization are within the skill of the ordinary practitioner.
Reaction SMILES: C[CH2:2][N:3]=[C:4]=NCCCN(C)C.Cl.[CH2:13]([O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][C:22]=1[C:30]([NH:32][C:33]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[C:35]([C:43]([F:46])([F:45])[F:44])[CH:34]=1)=[O:31])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.CNC.C(N(CC)CC)C>O1CCCC1.O>[CH2:13]([O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([N:3]([CH3:4])[CH3:2])=[O:26])=[CH:23][C:22]=1[C:30]([NH:32][C:33]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[C:35]([C:43]([F:46])([F:45])[F:44])[CH:34]=1)=[O:31])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1ccc(OCc2ccccc2)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Agent: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)c1ccc(OCc2ccccc2)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.7 %

Procedure:
WSC.HCl (95 mg, 0.50 mmol) was added to a solution of 4-benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]isophthalamic acid (242 mg, 0.50 mmol), dimethylamine hydrochloride (41 mg, 0.50 mmol) and triethylamine (51 mg, 0.50 mmol) in tetrahydrofuran (5 mL) under ice cooling, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with diluted hydrochloric acid, water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by chromatography on silica gel (hexane:ethyl acetate=1:4) to give the title compound (165 mg, 64.9%) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH2:8][CH2:7][CH:6]([C:9]([OH:12])([CH3:11])[CH3:10])[CH2:5][CH:4]=1.Cl.C(N(CC)CCCl)C.[F:22][C:23]1[CH:38]=[CH:37][C:26]([O:27][C:28]2[N:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30](O)=[O:31])=[CH:25][CH:24]=1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[F:22][C:23]1[CH:24]=[CH:25][C:26]([O:27][C:28]2[N:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30]([NH:1][CH2:2][C:3]2[CH2:8][CH2:7][CH:6]([C:9]([OH:12])([CH3:10])[CH3:11])[CH2:5][CH:4]=2)=[O:31])=[CH:37][CH:38]=1
Reactant: O=C(O)c1cccnc1Oc1ccc(F)cc1
Reactant: CC(C)(O)C1CC=C(CN)CC1
Agent: CCN(CC)CCCl
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(O)C1CC=C(CNC(=O)c2cccnc2Oc2ccc(F)cc2)CC1
Yield: 9.8 %

Procedure:
A solution of 2-(4-Aminomethyl-cyclohex-3-enyl)-propan-2-ol (0.360 grams, 2.127 mmole), 2-diethylaminoethyl chloride hydrochloride (0.530 grams, 2.765 mmole), 2-(4-Fluoro-phenoxy)-nicotinic acid (0.645 grams, 2.765 mmole), 1-hydroxybenzotriazole hydrate (0.374 grams, 2.765 mmole) and triethyl amine (0.430 grams, 4.254 mmole) in methylene chloride (40 ml) was added and stirred over night. The mixture was concentrated and partitioned between ethyl acetate and 1 N HCl. The organic extracts were washed with saturated sodium hydrogencarbonate and brine, dried over MgSO4, filtered and concentrated to give an oil which was purified by chromatography on silica eluting with 50% ethyl acetate/hexane to 100% ethyl acetate to give a yellow oil (0.080 g); M.W. 384.455; MS 385 (M++1).
Reaction SMILES: C([S:8][C:9]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=O)C1C=CC=CC=1.Cl.[NH2:20]O.C([O-])(=O)C.O>C(O)C>[CH3:18][O:17][C:16]1[C:9]2[S:8][N:20]=[CH:11][C:10]=2[CH:13]=[CH:14][CH:15]=1
Reactant: NO
Reactant: COc1cccc(C=O)c1SCc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cccc2cnsc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5 g of 2-benzylthio-3-methoxybenzaldehyde are dissolved in 40 ml of ethanol, and 3.9 g of hydroxylamine hydrochloride are added. 40 ml of acetate buffer (pH=5) are added to this solution, and the mixture is stirred for 30 minutes at room temperature. The mixture is poured into water and extracted using ethyl acetate. The organic phase is washed using saline, dried over sodium sulfate, filtered and concentrated. The resulting oil is added to a suspension of 1.6 g of phosphorus pentoxide in20 ml of methanesulfonic acid, and the mixture is stirred overnight at room temperature. The reaction mixture is poured onto ice and extracted using ethyl acetate. The organic phase is washed with saturated sodium hydrogen carbonate solution and with saline and dried over sodium sulfate, filtered and concentrated. After purification by chromatography, 7-methoxybenzisothiazole is obtained in the form of an oil.
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:16][C@H:15]2[N:17]([CH3:18])[C@H:12]([CH2:13][CH2:14]2)[C@H:11]1[CH:19]=[CH2:20])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si](O[C@H]1C[C@H]2N(C)[C@H](CC2)[C@H]1/C=C/[Cl:40])(C(C)(C)C)(C)C>>[C:1]([O:9][C@H:10]1[CH2:16][C@H:15]2[N:17]([CH3:18])[C@H:12]([CH2:13][CH2:14]2)[C@H:11]1/[CH:19]=[CH:20]/[Cl:40])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C[C@H]1[C@@H](OC(=O)c2ccccc2)C[C@@H]2CC[C@H]1N2C
Reactant: CN1[C@H]2CC[C@@H]1[C@@H](/C=C/Cl)[C@@H](O[Si](C)(C)C(C)(C)C)C2
Product: CN1[C@H]2CC[C@@H]1[C@@H](/C=C/Cl)[C@@H](OC(=O)c1ccccc1)C2
Yield: 22 %

Procedure:
By the same procedure used for the preparation of 2a, 180 mg (0.57 mmol) of the product of Example 5 gave 39 mg (22% yield) of compound 2b (column chromatography, hexane: ethyl acetate=2:1): [α]22D =-47.2° (c=1.925, CH2Cl2); IR (thin film) 3063, 2942, 2880, 2801, 1717, 1451, 1277, 1115, 939, 822, 712 cm-1 ; 1H NMR (CDCl3, 300 MHz) δ 7.97 (d, 2H, J=7.4 Hz), 7.55 (t, 1H, J=7.4 Hz), 7.43 (t, 1H, J=7.3 Hz), 6.42 (dd, 1H, J=13.4, 10.0 Hz), 5.93 (d, 1H, J=13.4 Hz), 5.19 (dt, 1H, J=11.4, 6.5 Hz), 3.30-3.20 (m, 1H), 3.15-3.05 (m, 1H), 2.85-2.75 (m, 1 H), 2.22 (s, 3H), 2.20-1.60 (m, 6H); 13C NMR (CDCl3, 75.46 MHz) δ166.0, 132.9, 130.4, 129.6, 128.4, 118.2, 68.6, 66.7, 61.4, 47.1, 41.3, 35.6, 26.1, 25.1; mass spectrum, m/z 307 (M+, 37Cl), 305 (M+, 35Cl), 270, 224, 184, 148, 105, 82, 77; HRMS calcd for C17H20NO235Cl (M+) 305.1178, found 305.1170.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:16]([C:18]2[N:19]=[N:20][N:21]([C:23]3[CH:28]=[C:27]([C:29](=[O:48])[NH:30][C:31]4[CH:36]=[C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:34]=[C:33]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])[C:32]=4[O:46][CH3:47])[CH:26]=[CH:25][C:24]=3[CH3:49])[CH:22]=2)=[O:17])[CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1.CO>[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:16]([C:18]2[N:19]=[N:20][N:21]([C:23]3[CH:28]=[C:27]([C:29](=[O:48])[NH:30][C:31]4[CH:36]=[C:35]([C:37]([CH3:38])([CH3:39])[CH3:40])[CH:34]=[C:33]([NH:41][S:42]([CH3:45])(=[O:43])=[O:44])[C:32]=4[O:46][CH3:47])[CH:26]=[CH:25][C:24]=3[CH3:49])[CH:22]=2)=[O:17])[CH2:9]1
Reactant: COc1c(NC(=O)c2ccc(C)c(-n3cc(C(=O)NCC4CCCN(C(=O)OC(C)(C)C)C4)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(C(=O)NCC4CCCNC4)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reaction time: 8 h
Yield: 66.1 %

Procedure:
To a solution of 336 mg (0.481 mmol) of 3-[({1-[5-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)-2-methyl-phenyl]-1H-[1,2,3]triazole-4-carbonyl}-amino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (Example 72) in 5 mL CH2Cl2 was added dropwise 1.2 mL of 4N HCl in dioxane. As a gummy yellow precipitate began to form in the flask, 10 drops of MeOH were added and the solution was stirred overnight. The mixture was partitioned between CH2Cl2 (75 mL) and 50% saturated aqueous NaHCO3 (50 mL). The layers were separated and the aqueous portion was extracted with CH2Cl2 (2×30 mL). The combined extracts were washed with water (30 mL), brine (30 mL), dried (Na2SO4), filtered and concentrated to afford 190 mg of 1-[5-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)-2-methyl-phenyl]-1H-[1,2,3]triazole-4-carboxylic acid (piperidin-3-ylmethyl)-amide as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[S:11][C:12]([CH2:15]Cl)=[CH:13][N:14]=1.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[Cl:9][C:10]1[S:11][C:12]([CH2:15][NH:1][C:2]2[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:13][N:14]=1
Reactant: ClCc1cnc(Cl)s1
Reactant: Cc1cccnc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1cccnc1NCc1cnc(Cl)s1
Temperature: 180 °C
Yield: 83.4 %

Procedure:
A mixture of 2-amino-3-methylpyridine (2.16 g, 20 mmol) and 2-chloro-5-(chloromethyl)thiazole (1.68 g, 10 mmol) in N-methylpyrrolidinone (10 mL) was heated at 180° C. in a microwave reactor for 10 min. The cooled reaction mixture was poured into a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium bicarbonate solution, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluted with 10% ethyl acetate in hexanes to provide the title compound as an oil (2.0 g).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=[CH:18][CH:19]=[CH:20][C:21](OCC)=[O:22])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=[O:22])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C=CC=Cc1cn(Cc2ccccc2)c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=CC=CC=Cc1cn(Cc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 26 h
Yield: 77.3 %

Procedure:
To a solution of ethyl 5-(1-benzylindol-3yl)-2,4-pentadienoate (1.5 g, 4.5 mmol) in 100 ml of diethyl of diethyl ether and 20 ml of tetrahydrofuran, stirred at 0° C. (ice bath), was added in portions 0.34 g (9 mmol) of LAH; the resulting mixture was stirred at room temperature for 26 hours, and worked up in manner similar to Example 13 to afford, after purifications by dry column chromatography (2:1, hexane:ethyl acetate), 1.2 g of the intermediate 2,4-pentadienol. This substance was dissolved in 250 ml of dichoromethane and 6 g of activated manganese dioxide was added. The suspension was stirred at room temperature for 6 hours. Manganese dioxide was removed by filtering through Celite® and washed thoroughly with a mixture of ethyl acetate and methylene chloride. The combined filtrate and washing were concentrated on a rotary evaporator to give 1 g of the product as an orange colored oil. This substance was used without purification in Example 15. NMR spectrum shows a singlet a 5.18 ppm and a doublet (J=7.5 Hz) at 9.48 ppm.
Reaction SMILES: [CH2:1]([C:3](=[CH:6][CH2:7][C:8]1[C:9]([O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[C:10]2[C:14](=[C:15]([CH3:19])[C:16]=1[CH2:17][CH3:18])[CH2:13][O:12][C:11]2=[O:20])[CH:4]=[O:5])[CH3:2].[BH4-].[Li+]>CO.CO.O.C1COCC1>[CH2:17]([C:16]1[C:15]([CH3:19])=[C:14]2[C:10](=[C:9]([O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:26])[CH3:27])[C:8]=1[CH2:7][CH:6]=[C:3]([CH2:4][OH:5])[CH2:1][CH3:2])[C:11](=[O:20])[O:12][CH2:13]2)[CH3:18]
Reactant: CCC(C=O)=CCc1c(CC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCC(=CCc1c(CC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)CO
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 70.3 %

Procedure:
2-Ethyl-4-[6-ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-but-2-enal (50.3 mg, 0.129 mmol) was dissolved in MeOH (3 mL). A solution of CeCl3 (31.9 mg, 0.129 mmol) in MeOH/water (9/1, 0.66 mL) was added and the solution was cooled to 0° C. A solution of lithium borohydride in THF (2M, 0.065 mL) was added dropwise. After 10 minutes, the reaction was quenched with 1N HCl (0.5 mL). The methanol was removed in vacuo and the crude material was partitioned between DCM and water. The aqueous layer was extracted with DCM and the combined organic layers were washed with sodium bicarbonate solution and were dried over sodium sulfate. Filtration and evaporation of solvents in vacuo yielded a crude oil, which was purified by silica gel chromatography to provide 35.4 mg (70%) of the desired product. 1H NMR (300 MHz, CDCl3): δ=0.04 (s, 9H), 1.10-1.19 (m, 6H), 1.26 (m, 2H), 2.19 (s, 3H), 2.32 (q, J=7.5 Hz, 2H), 2.72 (q, J=7.5 Hz, 2H), 3.54 (d, J=6.6 Hz, 2H), 4.05 (s, 2H), 4.26 (m, 2H), 5.14 (s, 2H), 5.27 (m, 1H) ppm.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].I.[O:14]=O>>[O:1]=[C:2]([OH:14])[C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=O
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: I
Product: O=C(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 50 °C

Procedure:
1200 g of an aqueous solution of 360 g (2 mol) of glucose (HI MESH; a product of Aito Co., Ltd.) and 5.4 g (1.5 wt. % based on glucose) of the catalyst prepared as above were placed in a 2.5 l reaction vessel provided with a stirrer, thermometer, alkali dropping funnel, pH electrodes and oxygen inlet. Oxygen gas was introduced into the aqueous solution under vigorous stirring while the temperature was maintained at 50±1° C. As the reaction proceeded, gluconic acid was formed. Gluconic acid was neutralized with a 40 wt. % aqueous sodium hydroxide solution added dropwise thereto so as to maintain the pH of the aqueous solution at 9.5±0.2. 1.0 h after the initiation of the reaction, a theoretical amount (2 mol) of the alkali was consumed. Thereafter, no more alkali was consumed and the reaction no more proceeded. Thus, the completion of the reaction was evident.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.[CH3:30][N:31]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([Sn](CCCC)(CCCC)CCCC)[CH:38]=2)[C:33](=[O:53])[N:32]1[CH3:54].[Li+].[Cl-]>O1CCOCC1.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.[Cu]I>[C:25]([O:24][C@@H:18]([C:9]1[C:8]([CH3:29])=[CH:7][C:5]2[N:6]=[C:2]([C:37]3[CH:38]=[C:39]4[C:34]([C:33](=[O:53])[N:32]([CH3:54])[N:31]4[CH3:30])=[CH:35][CH:36]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:28])([CH3:27])[CH3:26]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc2c(=O)n(C)n(C)c2c1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(=O)n(C)n(C)c4c3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
To a solution of (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (30.0 mg, 0.060 mmol) and 1,2-dimethyl-6-(tributylstannyl)-1H-indazol-3(2H)-one (32.5 mg, 0.072 mmol) in dioxane (0.7 mL) was added Pd(PPh3)4 (7.0 mg, 0.006 mmol), CuI (4.0 mg, 0.018 mmol) and LiCl (8.0 mg, 0.182 mmol). The reaction was degassed for 5 minutes with N2 and then heated at 100° C. for 7 h. After cooling, the reaction mixture was diluted with EtOAc, extracted with H2O, brine, dried over Na2SO4, filtered and concentrated and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C31H33ClN3O4S: 578.2; found: 578.3.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(=O)[CH2:13]CCC[CH2:9]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.B(F)(F)F.CCOCC.FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.[La+3]>CCC(=O)CC.CC(C)=O>[NH:1]1[C:2]2[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:9]=[CH:8][CH2:13]1
Reactant: O=C1CCCCC1
Reactant: Nc1ccccc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: FB(F)F
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CC(C)=O
Solvent: CCC(=O)CC
Solvent: CCOCC
Product: C1=Cc2ccccc2NC1

Procedure:
In the final step of this novel process, an aniline 10 is treated with a ketone 11, especially acetone, cyclohexanone or 3-pentanone, in the presence of a catalyst, especially camphor sulfonic acid, boron trifluoride etherate or lanthanum tris(trifluoromethanesulfonate), to afford the 1,2-dihydroquinoline 12: