Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:15])=[C:4]([NH:9][CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:16](C1NC=CN=1)(C1NC=CN=1)=[O:17]>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:15])=[C:4]2[N:9]([CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:16]([OH:17])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CCC(CC)Nc1c(N)ncc(Cl)c1C
Solvent: C1CCOC1
Product: CCC(CC)n1c(O)nc2ncc(Cl)c(C)c21
Temperature: 25 °C
Yield: 17.9 %

Procedure:
To a room-temperature solution of 5-chloro-4-methyl-N3-(pentan-3-yl)pyridine-2,3-diamine (49 mg, 0.22 mmol, 1.0 equiv) in THF (10 mL) was added carbonyl diimidazole (211 mg, 1.3 mmol, 6.0 equiv) as a solid in one portion. The resulting mixture was heated to reflux overnight. After the reaction was cooled to room temperature, the excess carbonyl diimidazole was quenched by the careful addition of water. The mixture was then diluted with EtOAc, washed with saturated aq. NaHCO3, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel preparative thin layer chromatography (0.5% Et3N, 5% MeOH, 94.5% CH2Cl2) provided the title compound as a solid (10 mg, 22%). m/z=252.3 [M−H]−
Reaction SMILES: Br[C:2]([F:20])([F:19])[C:3]([CH:6]1[CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH:7]1[C:15]([O:17][CH3:18])=[O:16])([F:5])[F:4].C(=O)(O)[O-].[Na+:25].[S:26](S([O-])=O)([O-:28])=[O:27].[Na+].[Na+].C(#N)C>O>[CH3:18][O:17][C:15]([CH:7]1[CH2:8][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:10][CH:6]1[C:3]([F:5])([F:4])[C:2]([F:20])([F:19])[S:26]([O-:28])=[O:27])=[O:16].[Na+:25]
Reactant: COC(=O)C1CC(C(=O)OC)C(C(F)(F)C(F)(F)Br)C1
Reactant: O=S([O-])S(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COC(=O)C1CC(C(=O)OC)C(C(F)(F)C(F)(F)S(=O)[O-])C1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Into a glass flask equipped with a thermometer and a capacitor were charged 2.00 g (5.49 mmol) of dimethyl 4-(2-bromo-1,1,2,2-tetrafluoroethyl)cyclopentane-1,3-dicarboxylate, 0.920 g (11.0 mmol) of sodium bicarbonate, 1.62 g (9.30 mmol) of sodium dithionite, 15 mL of acetonitrile and 15 mL of water, and the mixture was stirred at 50° C. for 8 hrs. The disappearance of the raw material was confirmed by 19F-NMR to decide completion of the reaction. Thereafter, acetonitrile was distilled off in vacuo to obtain an aqueous solution of crude sodium 2-(2,4-bis(methoxycarbonyl)cyclopentyl)-1,1,2,2-tetrafluoroethanesulfinate (precursor compound (a-4)) represented by the following formula (a-4) without carrying out further purification, which was used for the following reaction.
Reaction SMILES: COC1C=CC(N2C=CN=C2C=N[S@@](C(C)(C)C)=O)=CC=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:33][CH:32]=[N:31][C:30]=2/[CH:34]=[N:35]/[S:36]([C:38]([CH3:41])([CH3:40])[CH3:39])=[O:37])=[CH:25][CH:24]=1.[F:42][C:43]1[CH:44]=[C:45]([CH:49]=[C:50]([F:52])[CH:51]=1)[CH2:46][Mg]Br>>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:33][CH:32]=[N:31][C:30]=2[CH:34]([NH:35][S:36]([C:38]([CH3:41])([CH3:40])[CH3:39])=[O:37])[CH2:46][C:45]2[CH:44]=[C:43]([F:42])[CH:51]=[C:50]([F:52])[CH:49]=2)=[CH:25][CH:24]=1
Reactant: Fc1cc(F)cc(C[Mg]Br)c1
Reactant: CC(C)(C)S(=O)/N=C/c1ncoc1-c1ccc(Cl)cc1
Agent: COc1ccc(-n2ccnc2C=N[S@](=O)C(C)(C)C)cc1
Product: CC(C)(C)S(=O)NC(Cc1cc(F)cc(F)c1)c1ncoc1-c1ccc(Cl)cc1

Procedure:
The title compound was prepared as a mixture of diastereomers according to the method presented for the synthesis of compound 5C and 5D of Example 5 utilizing 33E and (3,5-difluorobenzyl)magnesium bromide. MS (m/z) 438.9 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][N:4]=1)#[CH:2].[N:12]([C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1)=[N+:13]=[N-:14]>O1CCOCC1.O.C(OCC)(=O)C>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([N:12]2[CH:2]=[C:1]([C:3]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[NH:5][N:4]=3)[N:14]=[N:13]2)=[CH:16][CH:17]=1
Reactant: [N-]=[N+]=Nc1ccc(Br)cc1
Reactant: C#Cc1n[nH]c2ccccc12
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Brc1ccc(-n2cc(-c3n[nH]c4ccccc34)nn2)cc1
Temperature: 80 °C
Yield: 62.7 %

Procedure:
To a solution of 3-Ethynyl-1H-indazole (6.0 g, 42.2 mmol) in Dioxane (60 mL) were added 4-Azidobromobenzene (Ukrorgsynthesis Ltd., 9.19 g, 46.4 mmol), D-(−)-Iso ascorbic acid sodium salt (0.83 g, 4.2 mmol) and a solution of CuSO4.5H2O (0.21 g, 0.8 mmol) in water (10 mL). The reaction mixture was heated at 80° C. for 3 days. After completion of the reaction, the reaction mixture was cooled to RT, diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated. The crude compound was recrystallized from methanol and dried under vacuum to afford the title compound as brown solid (9.0 g, 63%). 1H NMR (400 MHz, DMSO-d6) δ 13.36 (s, 1H), 9.36 (s, 1H), 8.35-8.33 (d, J=8.1 Hz, 1H), 8.06-8.02 (m, 2H), 7.86-7.82 (m, 2H), 7.61-7.59 (d, J=8.4 Hz, 1H), 7.45-7.41 (m, 1H), 7.26-7.22 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([O:16]C)=O)[CH:13]=[C:8]2[C:7]([CH2:18][N:19]2[CH2:24][CH2:23][C@@H:22]3[C:25](=[O:28])[NH:26][CH2:27][C@@H:21]3[CH2:20]2)=[CH:6]1.[OH-:34].[Na+].[NH2:36]O>CO>[F:1][C:2]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([NH:36][OH:34])=[O:16])[CH:13]=[C:8]2[C:7]([CH2:18][N:19]2[CH2:24][CH2:23][C@@H:22]3[C:25](=[O:28])[NH:26][CH2:27][C@@H:21]3[CH2:20]2)=[CH:6]1
Reactant: NO
Reactant: COC(=O)c1cc2c(CN3CC[C@@H]4C(=O)NC[C@@H]4C3)cn(Cc3ccc(F)cc3F)c2cn1
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: O=C(NO)c1cc2c(CN3CC[C@@H]4C(=O)NC[C@@H]4C3)cn(Cc3ccc(F)cc3F)c2cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35 %

Procedure:
To a stirring solution of rac-methyl 1-(2,4-difluorobenzyl)-3-{[(3aR*,7aS*)-1-oxooctahydro-5H-pyrrolo[3,4-c]pyridin-5-yl]methyl}-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (0.09 g, 0.198 mmol) in MeOH (5 ml) was added 10% NaOH(aq) (0.5 ml, excess) and H2NOH (1 ml, excess, 50% wt. sol. in water). The resulting mixture was stirred for 16 hours at ambient temperature. The solvent was evaporated and the crude product was purified by reverse phase Prep-HPLC (20-60% acetonitrile:water) to provide the title compound as a white solid (0.032 g, 35%). 1H NMR (MeOH-d4) δ: 8.77 (s, 1H), 8.38 (s, 1H), 7.68 (s, 1H), 7.29-7.25 (m, 1H), 7.03-7.00 (m, 1H), 6.94-6.92 (m, 1H), 5.57 (s, 2H), 3.95-3.93 (m, 2H), 3.44-3.41 (m, H), 3.27-3.25 (m, 1H), 2.99-2.95 (m, 1H), 2.95-2.89 (m, 1H), 2.56-2.52 (m, 2H), 2.50-2.46 (m, 1H), 2.46-2.35 (m, H), 1.84-1.82 (m, H), 1.63-1.62 (m, H). LCMS (APCI, M+H+): 456.15. HPLC: 99% purity.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([N:44]3[C:48]([CH3:49])=[N:47][N:46]=[N:45]3)=[C:40]([F:50])[CH:39]=2)[C:35](O)=[O:36])[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:51][C:52]1[CH:57]=[CH:56][C:55]([Br:58])=[CH:54][N:53]=1>C(Cl)Cl>[Br:58][C:55]1[CH:56]=[CH:57][C:52]([NH:51][C:35](=[O:36])[CH:34]([C:38]2[CH:43]=[CH:42][C:41]([N:44]3[C:48]([CH3:49])=[N:47][N:46]=[N:45]3)=[C:40]([F:50])[CH:39]=2)[CH2:33][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32]2)=[N:53][CH:54]=1
Reactant: Nc1ccc(Br)cn1
Reactant: Cc1nnnn1-c1ccc(C(CC2CCCC2)C(=O)O)cc1F
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nnnn1-c1ccc(C(CC2CCCC2)C(=O)Nc2ccc(Br)cn2)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
A solution of triphenylphosphine (288 mg, 1.1 mmol) in methylene chloride (6 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (196 mg, 1.1 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with 3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-propionic acid (prepared in Example 1, 175 mg, 0.55 mmol). The clear solution was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-amino-5-bromopyridine (476 mg, 2.75 mmol), and the resulting suspension was stirred for 2 d at 25° C. The reaction mixture was then concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (50 mL) and water (50 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×25 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 2/1 hexanes/ethyl acetate) afforded N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-propionamide (190 mg, 73%) as a white solid: mp 73-78° C.; EI-HRMS m/e calcd for C21H22BrFN6O (M+) 472.1022, found 472.1022.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[C:20]3[O:19][CH2:18][CH2:17][O:16][C:15]=3[CH:14]=[CH:13][CH:12]=1)=[O:10])[NH:2]2.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[C:29]([C:34](O)=[O:35])=[CH:30][CH:31]=[CH:32][CH:33]=1>>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[C:29]([C:34]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[C:20]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:14]=[CH:13][CH:12]=3)=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:35])=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)c1cccc2c1OCCO2
Reactant: O=C(O)c1ccccc1-c1ccccc1F
Product: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1ccccc1-c1ccccc1F)c1cccc2c1OCCO2

Procedure:
prepared by reaction of 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 2′-fluoro-biphenyl-2-carboxylic acid. LC-MS (basic): tR=1.39 min; [M+H]+=473.1.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]([CH2:31][CH3:32])[CH2:13][C:14]([C:16]1([O:29][CH3:30])[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)=[O:15].C(N(CC)CC)C>ClCCl>[CH3:30][O:29][C:16]1([C:14](=[O:15])[CH2:13][C:12](=[O:11])[CH2:31][CH3:32])[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:20][CH2:21]1
Reactant: CCC(O)CC(=O)C1(OC)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)CC(=O)C1(OC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 56.6 %

Procedure:
To a solution of oxalyl chloride (0.168 mL, 1.92 mmol) in dichloromethane (10 mL) at −78° C. was slowly added dimethyl sulfoxide (0.272 mL, 3.84 mmol). After 5 min, a solution of tert-butyl 4-(3-hydroxy-1-oxopent-1-yl)-4-methoxypiperidine-1-carboxylate (0.404 g, 1.28 mmol) from Step B in dichloromethane (5 mL) was added via syringe. The reaction mixture was stirred for 45 min at -78° C. and then triethylamine (1.1 mL, 7.68 mmol) was added. After 5 min, the reaction mixture was removed from the cooling bath, allowed to warm to room temperature for 1.5 h, poured into water, and extracted three times with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography eluting with 10% ethyl acetate/hexanes to afford the title compound (0.227 g).
Reaction SMILES: [NH2:1][C:2]1[C:9]([NH2:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:11])[CH:3]=1.[CH:12](O)=O>>[CH3:11][C:4]1[C:5]([C:6]#[N:7])=[CH:8][C:9]2[NH:10][CH:12]=[N:1][C:2]=2[CH:3]=1
Reactant: Cc1cc(N)c(N)cc1C#N
Reactant: O=CO
Product: Cc1cc2nc[nH]c2cc1C#N

Procedure:
A reaction mixture of 4,5-diamino-2-methylbenzonitrile (20 mg) and formic acid (6 ml) was refluxed for 3 hours. The reaction solution was cooled and concentrated. To the residue was added a 1M aqueous NaOH solution, and extracted with EtOAc. The organic layer was dried over anhydrous MgSO4, and then filtered, and the filtrate was concentrated to obtain 5-methyl-1H-benzimidazole-6-carbonitrile as colorless powders.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([O:22]C)[C:3]=1[I:24].B(Br)(Br)Br.O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([OH:22])[C:3]=1[I:24]
Reactant: COc1c(I)c(Cl)cc(F)c1-n1c(=O)cc(C(F)(F)F)n(C)c1=O
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c(I)c2O)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 3.0 grams (0.006 mole) of 3-(4-chloro-6-fluoro-3-iodo-2-methoxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1 H,3H)-pyrimidinedione in 75 mL of methylene chloride was cooled in a dry ice/acetone bath and 22.0 mL (0.022 mole) of 1 M boron tribromide (in methylene chloride) was added dropwise during a 20 minute period. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature were it stirred for about one hour. At the conclusion of this period, the reaction mixture was poured into 200 mL of water and extracted with two 50 mL portions of methylene chloride. The combined extracts were washed with one 100 mL portion of an aqueous saturated sodium chloride solution, dried with sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, yielding 2.6 grams of title compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[C:18]3[CH:19]([CH2:23][OH:24])[CH2:20][CH2:21][CH2:22][C:17]=3[N:16]=[C:15]2[CH:25]([CH3:27])[CH3:26])=[CH:9][CH:8]=1>ClCCl>[CH3:4][S:1]([O:24][CH2:23][CH:19]1[C:18]2[N:14]([CH2:13][C:10]3[CH:9]=[CH:8][C:7]([Cl:6])=[CH:12][CH:11]=3)[C:15]([CH:25]([CH3:26])[CH3:27])=[N:16][C:17]=2[CH2:22][CH2:21][CH2:20]1)(=[O:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(CO)CCC2
Solvent: ClCCl
Product: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(COS(C)(=O)=O)CCC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Mesyl chloride (0.874 mL) was added dropwise to a suspension of Intermediate 40 (2.98 g) in dichloromethane (100 mL) at 0° C. under N2. Once addition was complete, the reaction was allowed to stir at 0° C. for a further 30 minutes before the bath was removed and the solution warmed to RT. The reaction mixture was quenched with water, and the aqueous extracted with DCM. The combined organics were passed through a hydrophobic frit and concentrated under reduced pressure, azeotroped with MeOH and dried on the high-vac to give the title compound 3.44 g. LC/MS MH+ 397, Rt 1.78 min (5 minute run).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[CH2:36]([NH:39][CH2:40][CH2:41][CH3:42])[CH2:37][CH3:38].CO>C(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:28](=[O:34])[N:39]([CH2:40][CH2:41][CH3:42])[CH2:36][CH2:37][CH3:38]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCCNCCC
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCN(CCC)C(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline 100 mg) was dissolved in chloroform (3 ml) and triethylamine (0.3 ml), and a solution of triphosgene (90 mg) in chloroform was then added to the solution. The mixture was stirred at room temperature for 15 min. Next, dipropylamine (62 μl) was added to the reaction solution, and the mixture was stirred at room temperature for additional 30 min. Methanol was added to the reaction solution, and the mixture was purified by HPLC by development with chloroform/methanol. The solvent was removed by distillation, and the resultant crystal was washed with hexane to give 48 mg (yield 35%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.[NH2:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1O.[OH-].[Na+]>O>[Br:11][C:5]1[CH:6]=[C:7]([C:8]2[O:10][C:14]3[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=3[N:12]=2)[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ncc(Br)cc1C(=O)O
Reactant: Nc1cc(F)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ncc(Br)cc1-c1nc2cc(F)ccc2o1
Temperature: 200 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
To a mixture of 2-amino-5-bromo-pyridine-3-carboxylic acid (1 g) and 2-amino-4-fluoro-phenol (0.586 g) placed in a round bottom flask was added polyphosphoric acid (10 g). The mixture was heated at 200° C. for 16 hours. After cooling, water (75 ml) was added and the mixture was stirred for 30 min. The mixture was basified to pH 12 with concentrated sodium hydroxide solution (6N and 2N). The solid was filtered, washed with water (150 ml×2), and ether (50 ml×2) to afford 5-bromo-3-(5-fluoro-1,3-benzoxazol-2-yl)pyridin-2-amine (1.0 g). NMR Spectrum: (DMSOd6) 7.53 (ddd, 1H), 7.93 (dd, 1H), 7.99-8.06 (m, 3H), 8.52 (d, 1H), 8.56 (d, 1H); Mass spectrum: M+H+ 308-310
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:8](=[O:10])=[O:9]>>[C:8](=[O:10])([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C=O
Reactant: CCCCCCO
Product: CCCCCCOC(=O)OCCCCCC
Temperature: 30 °C
Reaction time: 6 h
Yield: 14 %

Procedure:
Into the above-mentioned 200-ml autoclave containing the reaction mixture (containing an organometal compound having a hexyloxy group) was charged 61.5 g (602 mmol) of hexanol (manufactured and sold by Aldrich, U.S.A.; a dehydrated grade), and the autoclave was sealed. Then, from a carbon dioxide gas bomb, carbon dioxide gas, the pressure of which was lowered to 5 MPa by means of a pressure regulator connected to the carbon dioxide gas bomb, was introduced into the autoclave. Stirring of the contents of the autoclave was started. 10 Minutes after the start of the stirring, the valve of the carbon dioxide gas bomb was closed. Then, the internal temperature of the autoclave was elevated to 180° C. while stirring. In this instant, the internal pressure of the autoclave was about 7.5 MPa. Then, a reaction was performed for 6 hours while maintaining the internal pressure of the autoclave at about 7.5 MPa. Thereafter, the inside of the autoclave was cooled to about 30° C. and the internal pressure of the autoclave was returned to atmospheric pressure by gently purging the carbon dioxide gas, and there was obtained a transparent reaction mixture. In the reaction mixture, dihexyl carbonate was obtained in a yield of about 14%.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)=O.[NH2:15][C:16]([NH2:18])=[S:17]>CO>[BrH:1].[F:12][C:11]([F:14])([F:13])[C:7]1[CH:6]=[C:5]([C:3]2[N:15]=[C:16]([NH2:18])[S:17][CH:2]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: NC(N)=S
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Solvent: CO
Product: Br
Product: Nc1nc(-c2cccc(C(F)(F)F)c2)cs1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 8.1 g of 2-bromo-1-(3-trifluoromethyl-phenyl)-ethanone in 70 ml of methanol was treated at room temperature with 3.2 g of thiourea and boiled for 1 hour. 4.1 g of 4-(3-trifluoromethyl-phenyl)-thiazol-2-ylamine hydrobromide separated as colorless crystals upon cooling to 0° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:11][C@@H:12]1[O:17][C:16]2[C:18]([F:22])=[CH:19][CH:20]=[CH:21][C:15]=2[O:14][CH2:13]1)[CH2:9][CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[CH3:28][S:29]C.[NH4+].[Cl-]>C1COCC1>[CH2:1]([N:8]([CH2:11][C@@H:12]1[O:17][C:16]2[C:18]([F:22])=[C:19]([S:29][CH3:28])[CH:20]=[CH:21][C:15]=2[O:14][CH2:13]1)[CH2:9][CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(Cc1ccccc1)C[C@H]1COc2cccc(F)c2O1
Reactant: CSC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCN(Cc1ccccc1)C[C@H]1COc2ccc(SC)c(F)c2O1
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 51.3 %

Procedure:
A mixture of N-benzyl-N-{[(2S)-8-fluoro-2,3-dihydro-1,4-benzodioxin-2-yl]methyl}ethanamine (2.2 g, 7.3 mmol) and 2,2-tetramethylpiperidine (2.5 ml, 14.6 mmol) was added dropwise to n-BuLi (10 ml, 25 mmol) in THF (dry, 10 ml) under N2 at −75° C., followed by the addition of dimethylsulfide (1.32 ml, 14.6 mmol) in THF (dry, 10 ml). The mixture was stirred for 30 min at −75° C., and was then warmed to room temperature. NH4Cl (sat.) was added and the solution was extracted with EtOAc. The combined organic phases were washed with Na2SO3 (15%), brine, dried (Na2SO4) and evaporated to dryness. Flash column chromatography (isooctane/EtOAc) yielded the title compound (1.3 g). MS m/z (rel. intensity, 70 eV) 347 (2), 149 (12), 148 (100), 92 (7), 91 (92).
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[S:14]([N:17]1[CH2:23][CH2:22][CH2:21][CH:20]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:19][CH2:18]1)(=[O:16])=[O:15])[CH:2]=C.[O-:32]S([O-])(=S)=O.[Na+].[Na+].[BH3-]C#N.[Na+]>C1COCC1.O.O=[Os](=O)(=O)=O>[CH2:25]([O:24][CH:20]1[CH2:21][CH2:22][CH2:23][N:17]([S:14]([C:5]2[CH:6]=[C:7]([CH:12]=[CH:13][C:4]=2[CH2:1][CH2:2][OH:32])[C:8]([O:10][CH3:11])=[O:9])(=[O:15])=[O:16])[CH2:18][CH2:19]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=S([O-])([O-])=S
Reactant: C=CCc1ccc(C(=O)OC)cc1S(=O)(=O)N1CCCC(OCc2ccccc2)CC1
Agent: O=[Os](=O)(=O)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(CCO)c(S(=O)(=O)N2CCCC(OCc3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.88 %

Procedure:
To a solution of methyl 4-allyl-3-(4-benzyloxyazepan-1-yl)sulfonyl-benzoate (630.00 mg, 1.42 mmol, 1.00 Eq) in THF (10 mL) and H2O (2 mL) were added OsO4 (36.10 mg, 142.00 umol, 0.10 Eq) and NaIO4 (607.45 mg, 2.84 mmol, 2.00 Eq) at 0° C. The mixture was stirred at 25° C. for 3 hr. TLC detected the reaction was complete, the mixture was poured into saturated Na2S2O3 solution, extracted with DCM, the combined organic layer was dried over anhydrous Na2SO4, concentrated, the residue was diluted in MeOH (10 mL), to the formed mixture was added NaBH3CN (88.86 mg, 1.41 mmol, 1.00 Eq). The mixture was stirred at 25° C. for 3 hr. TLC detected the reaction was complete, the reaction was quenched with water, extracted with EA, the combined organic layer was dried over anhydrous Na2SO4, concentrated, the residue was purified by chromatography (silica gel, eluting with PE:EA=3:1 to 1:1) to afford product methyl 3-(4-benzyloxyazepan-1-yl)sulfonyl-4-(2-hydroxyethyl)benzoate (340.00 mg, 759.71 umol, 53.88% yield). LCMS: 448 [M+1].
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N([CH2:18][CH3:19])CC)C.[C:20]([O:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27])(=[O:22])[CH3:21]>O1CCCC1>[C:20]([O:23][C:19]1[CH:18]=[CH:31][CH:32]=[CH:24][C:25]=1[C:26]([NH:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=2[O:23][C:20](=[O:22])[CH3:21])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[O:27])(=[O:22])[CH3:21]
Reactant: CCN(CC)CC
Reactant: COC(=O)c1cc(N)ccc1N
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Solvent: C1CCOC1
Product: COC(=O)c1cc(NC(=O)c2ccccc2OC(C)=O)ccc1NC(=O)c1ccccc1OC(C)=O
Temperature: 0 °C

Procedure:
A mixture of 3.32 g of methyl 2,5-diaminobenzoate, 5.8 ml of triethylamine and 20 ml of tetrahydrofuran was added dropwise to a solution of 8.7 g of 2-acetoxybenzoylchloride in 150 ml of tetrahydrofuran over 30 minutes, while stirring at 5° - 10°C. After completion of the addition, the reaction mixture was stirred at room temperature for 1 hour and then poured into 500 ml of ice-water to precipitate crystals. The crystals were recovered by filtration, washed with water and dried in air. Recrystallization from ethyl acetate gave 8.1 g of methyl 2,5-bis(2'-acetoxybenzamido)-benzoate having a melting point between 170° - 171°C.