Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15]([OH:17])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=2)[C:21]([CH2:29][CH2:30][C:31]([CH3:34])([OH:33])[CH3:32])=[CH:20]1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CN(C=O)C>[F:28][C:24]1[CH:23]=[C:22]2[C:27](=[CH:26][CH:25]=1)[N:19]([NH:18][C:15]([C:11]1[C:12]([CH3:14])=[N:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=1)=[O:17])[CH:20]=[C:21]2[CH2:29][CH2:30][C:31]([OH:33])([CH3:32])[CH3:34]
Reactant: CC(C)(O)CCc1cn(N)c2ccc(F)cc12
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1cc(CCC(C)(C)O)c2cc(F)ccc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (278 mg, 1.2 mmol) and 4-(1-amino-5-fluoro-1H-indol-3-yl)-2-methyl-butan-2-ol (1.2 mmol) in DMF (10 mL) is stirred at 50° C. for 1 h. The mixture is treated with DMTMM (331 mg, 1.2 mmol) and stirred at 50° C. for 1 h. The mixture is concentrated in vacuo, diluted with saturated aqueous Na2CO3 (50 mL), and extracted with EtOAc (3×50 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 50% EtOAc in heptane to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid [5-fluoro-3-(3-hydroxy-3-methyl-butyl)-indol-1-yl]-amide (330 mg, 61%). MS: 451 (M+H); 1H NMR (300 MHz, CD3OD): δ 9.10 (s, 1H), 8.36 (d, 1H), 8.23 (d, 1H), 7.55 (m, 1H), 7.32 (m, 3H), 7.18 (s, 1H), 7.03 (m, 1H), 3.91 (s, OH, 1H), 2.84 (s, 3H), 2.82 (m, 2H), 1.91 (m, 2H), 1.31 (s, 6H).
Reaction SMILES: C(N(CCCC)CCCC)CCC.[C:14]([O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=1[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][C:36]([O:39]C)=[CH:35][CH:34]=1)=[O:32])(=O)[CH2:15][CH2:16][CH2:17][CH3:18].Cl>C1(C)C(C)=CC=CC=1>[CH2:15]([C:14]1[O:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=2[C:30]=1[C:31](=[O:32])[C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCCC(=O)Oc1ccc([N+](=O)[O-])cc1CC(=O)c1ccc(OC)cc1
Agent: Cl
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccccc1C
Product: CCCCc1oc2ccc([N+](=O)[O-])cc2c1C(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 ml of dry xylene, 2.1 ml (8.9 mmol) of tri-n-butylamine and 10 g of the recovered molecular sieve from example 3 were heated under reflux using a Dean-Stark condenser. Then 2.20 g (5.92 mmol) of 2-(2-pentanoyloxy-5-nitrophenyl)-1-(4-methoxyphenyl)-ethanone (example 2) dissolved in 5 ml of dry xylene were added to the reaction mixture. After 8 h LC-MS analysis indicated the complete consumption of the starting material. The reaction mixture was cooled to room temperature and the molecular sievel was filtered off. After evaporation of the solvent, 2.1 ml (8.9 mmol) of tri-n-butylamine were added followed by the addition of 17.8 mmol of gaseous HCl. The resulting mixture was heated at 200° C. for 4 h until LC-MS analysis indicated the complete consumption of the 2-n-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofuran. The reaction mixture was cooled to room temperature and 20 ml of water and 50 ml MTBE were added. The organic phase was washed once with 25 ml of 1M aqueous HCl and 20 ml of water dried over MgSO4 and concentrated to dryness. Flash chromatography of the residue provided the pure title compound which crystallized directly to yield 1.30 g (65%).
Reaction SMILES: [CH:1]1([NH:4][S:5]([C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([N+:15]([O-:17])=[O:16])[C:9]=2Cl)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[H-].[Na+].[OH2:21]>>[CH:1]1([NH:4][S:5]([C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([N+:15]([O-:17])=[O:16])[C:9]=2[OH:21])(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: O
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NC2CC2)c1Cl
Agent: [H-]
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NC2CC2)c1O
Yield: 68.3 %

Procedure:
Following the general hydrolysis procedure outlined in example 15, N-cyclopropyl-2,6-dichloro-3-nitrobenzenesulfonamide (1.15 g, 3.70 mmol), 60% NaH (444 mg, 11.1 mmol) and water (67 μL, 3.70 mmol) were reacted to form the desired product (740 mg, 68%). 1H NMR (MeOD-d4): δ 8.06 (d, 1H), 7.24 (d, 1H), 2.29 (m, 1H), 0.60 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1[C:10]([CH3:12])=[CH2:11].[H][H]>CO.[Pd]>[CH:10]([C:4]1[CH:5]=[CH:6][C:7]([NH2:9])=[N:8][C:3]=1[O:2][CH3:1])([CH3:12])[CH3:11]
Reactant: C=C(C)c1ccc(N)nc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1nc(N)ccc1C(C)C
Reaction time: 8 h
Yield: 52.6 %

Procedure:
To a solution of 5-fluoro-6-isopropenyl-pyridin-2-ylamine (crude from Step 1, 8.47 mmol) in methanol (17.5 mL) was added 10% palladium on carbon (123 mg) at room temperature. A hydrogen balloon (1 atm) was attached and the mixture was stirred overnight. After 18 hours, the mixture was filtered over Celite, concentrated onto silica gel, and chromatographed (10% to 40% ethyl acetate in hexanes) to give 5-isopropyl-6-methoxypyridin-2-amine (740 mg, 53% over two steps). 1H NMR (400 MHz, CHLOROFORM-d6) δ ppm 7.26 (d, J=7.8 Hz, 1H), 6.07 (d, J=8.1 Hz, 1H), 4.19 (br. s, 2H), 3.90 (s, 3H), 3.08 (m, 1H), 1.17 (d, J=6.9 Hz, 6H).
Reaction SMILES: [OH-].[Na+].[N:3]1([CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH2:7][CH2:6][CH2:5][CH2:4]1.Cl>O1CCCC1.CO.C(OCC)(=O)C>[N:3]1([CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC(=O)c1ccc(N2CCC(N3CCCC3)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(N2CCC(N3CCCC3)CC2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
A 5 M sodium hydroxide solution (15 mL, 75.0 mmol) was added to a solution of methyl 4-(4-(pyrrolidin-1-yl)piperidin-1-yl)benzoate described in Production Example 8-1 (2.06 g, 7.14 mmol) in tetrahydrofuran (10 mL) and methanol (10 mL). The reaction liquid was stirred at 50° C. for 4 hours. The reaction liquid was cooled to 0° C. and then 5 M hydrochloric acid was dripped until pH reached 1. The liquid mixture was diluted with ethyl acetate. The organic layer was washed with a saturated saline solution and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and then the filtrate was concentrated under vacuum to obtain the title compound (1.61 g, 82%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[CH3:3].[N-:15]([C:18]#[N:19])[C:16]#[N:17].[Na+].Cl>C(O)CCC>[CH3:3][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:18]([NH:15][C:16]#[N:17])=[NH:19])[N:9]=1)[CH3:1]
Reactant: N#C[N-]C#N
Reactant: CN(C)Cc1nc(CSCCN)cs1
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Product: CN(C)Cc1nc(CSCCNC(=N)NC#N)cs1

Procedure:
A reaction mixture was prepared from 1.16 g of 2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylamine, 0.45 g of sodium dicyanamide, 4.8 ml 1N aqueous hydrochloric acid and 8 ml of n-butanol. The reaction mixture was heated to reflux temperature for about 16 hours and then was filtered. Evaporation of the filtrate to dryness yielded a residue which was purified by chromatography over silica using a 98:2 ethyl acetate:methanol solvent mixture as the eluant. Fractions shown by tlc to contain the desired product were combined and the solvent evaporated therefrom. N-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N'-cyanoguanidine thus obtained was a glass.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[CH:2]=[CH2:3].[CH3:21][C:22]1[C:28]([N+:29]([O-:31])=[O:30])=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24]>>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH:24][C:23]2[CH:25]=[CH:26][CH:27]=[C:28]([N+:29]([O-:31])=[O:30])[C:22]=2[CH3:21])=[CH:11][CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(C)cc(Oc2ccc(C=O)cc2)c1
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Product: C=CCOc1cc(C)cc(Oc2ccc(CNc3cccc([N+](=O)[O-])c3C)cc2)c1

Procedure:
The product from Example 89B and 2-methyl-3-nitroaniline were processed as in Example 6A to provide the title compound. MS (ESI−) m/z 403 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]2([CH3:15])[NH:13][C:12](=S)[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.[NH3:16].CO>>[Br:1][C:2]1[N:7]=[C:6]([C:8]2([CH3:15])[CH2:9][O:10][CH2:11][C:12]([NH2:16])=[N:13]2)[CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: CC1(c2cccc(Br)n2)COCC(=S)N1
Solvent: CO
Product: CC1(c2cccc(Br)n2)COCC(N)=N1
Temperature: 50 °C
Reaction time: 72 h

Procedure:
A mixture of 5-(6-bromo-pyridin-2-yl)-5-methyl-morpholine-3-thione (1.4 g, 4.88 mmol) in 7N NH3/MeOH (20.89 ml, 146 mmol) was stirred at 50° C. for 3 d in an autoclave. The reaction mixture was evaporated to dryness and purified by FC (gradient cyclohexane:EtOAc 75:25 to 50:50, then +10% Et3N, finally MeOH+10% Et3N) to obtain the crude title compound that was further purified by washing with DCM. HPLC RtH4=0.54 min; ESIMS: 270, 272 [(M+H)+]; 1H NMR (400 MHz, DMSO-d6): δ 8.51 (br s, 2H), 7.83-7.79 (m, 1H), 7.63-7.61 (m, 2H), 4.45 (s, 2H), 4.11 (d, 1H), 3.84 (d, 1H), 1.51 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([NH:16][CH2:17][CH3:18])=[N:7][C:8]3[C:9](I)=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1.[C:21]([NH2:25])(=[O:24])[C:22]#[CH:23].C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl.[Cu]I.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([NH:16][CH2:17][CH3:18])=[N:7][C:8]3[C:9]([C:23]#[C:22][C:21]([NH2:25])=[O:24])=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1
Reactant: C#CC(N)=O
Reactant: CCNc1nc2c(I)c[nH]c(=O)c2c2cc(Br)ccc12
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCNc1nc2c(C#CC(N)=O)c[nH]c(=O)c2c2cc(Br)ccc12
Reaction time: 8 h

Procedure:
To a solution of 9-bromo-6-(ethylamino)-4-iodobenzo[c]-1,6-naphthyridin-1(2H)-one (2.5 g, 5.63 mmol) in DMF at room temperature (49.3 ml) was added propiolamide (583 mg, 8.44 mmol), Copper (I) Iodide (161 mg, 0.844 mmol), triethylamine (1.569 ml, 11.26 mmol), and tetrakis(triphenylphosphine) palladium (651 mg, 0.563 mmol). The flask was put under a blanket of argon, sealed and allowed to stir overnight. The next day the reaction was diluted with 100 ml of DCM, which caused the product to precipitate out of solution. The precipitate was collected by filtration, washed with 50 ml of DCM and dried in vacuo to give the product, 3-[9-bromo-6-(ethylamino)-1-oxo-1,2-dihydrobenzo[c]-1,6-naphthyridin-4-yl]prop-2-ynamide. 1H NMR (600 MHz, DMSO-D6) δ 11.76 (br s, 1H), 10.00 (s, 1H), 8.40 (t, 1H), 8.27 (d, 1H), 7.79-7.76, (m, 3H), 7.47 (s, 1H), 3.66 (m, 2H), 1.25 (t, 3H). LRMS (ESI) calc'd for (C17H13BrN4O2) [M+H]+, 385.0; found 385.0.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1)#[N:2].C(N(CC)C(C)C)(C)C.[CH:20]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)=[O:21]>CN(C)C1C=CN=CC=1>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([CH:20]=[O:21])=[CH:23][CH:24]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: O=Cc1ccc(C(=O)Cl)cc1
Reactant: N#Cc1ccc(CN)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(CNC(=O)c2ccc(C=O)cc2)cc1
Yield: 55.5 %

Procedure:
In the same manner as that described in Example 2(1), a reaction was carried out using 4-cyanobenzylamine (329 mg, 2.5 mmol), described in J. Am. Chem. Soc., 81, 4328 (1959), N,N-diisopropylethylamine (0.91 ml, 5.2 mmol), 4-formylbenzoyl chloride (350 mg, 2.1 mmol) and 4-(dimethylamino)pyridine (a catalytic amount) and the reaction mixture was treated according to a similar procedure to that described in Example 2(1) to afford N-(4-cyanobenzyl)-4-formylbenzamide (308 mg, yield 56) as a white solid which was recrystallized from ethyl acetate to give white fluffy crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:20])([CH3:19])[CH2:13][S:14]([O:16]CC)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C([O-])(=O)C.[Na+].[NH2:28]OS(O)(=O)=O>C(O)C.O>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:20])([CH3:19])[CH2:13][S:14]([NH2:28])(=[O:16])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NOS(=O)(=O)O
Reactant: CCOS(=O)CC(C)(C)NC(=O)OCc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(CS(N)(=O)=O)NC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 86 %

Procedure:
In ethanol (10 ml) was dissolved 0.60 g (2 mmol) of ethyl 2-(benzyloxycarbonylamino)-2-methylpropane-1-sulfinate, and 0.9 g (2.2 mmol) of 10% aqueous sodium hydroxide solution was slowly dropped thereinto under ice-cooling. The reaction was carried out at room temperature for 1 hour and then the ethanol was distilled off. Water (10 ml), 0.18 g (2.2 mmol) of sodium acetate and 0.25 g (2.2 mmol) of hydroxylamine-O-sulfonic acid were added to the residue, and the reaction was carried out at room temperature for 1 hour. The reaction mixture was poured into water, followed by three runs of extraction with ethyl acetate. The extract solution was washed with saturated aqueous sodium hydrogencarbonate solution and then saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off and 0.49 g (yield 86%) of the thus obtained crude 2-(benzyloxycarbonylamino)-2-methylpropane-1-sulfonamide was used without further purification in the subsequent reaction.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14]3[C:19]([F:20])=[C:18]([F:21])[C:17]([C:22]4[CH:27]=[CH:26][C:25]([CH2:28][N:29]5[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]5)=[CH:24][CH:23]=4)=[C:16]([F:35])[C:15]=3[F:36])[NH:10][C:9]=2[CH:8]=[C:7]([CH3:37])[CH:6]=1)=[O:4].[OH-].[Na+]>O1CCCC1>[CH3:37][C:7]1[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:13]2[N:12]=[C:11]([C:14]3[C:15]([F:36])=[C:16]([F:35])[C:17]([C:22]4[CH:27]=[CH:26][C:25]([CH2:28][N:29]5[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]5)=[CH:24][CH:23]=4)=[C:18]([F:21])[C:19]=3[F:20])[NH:10][C:9]=2[CH:8]=1
Reactant: COC(=O)c1cc(C)cc2[nH]c(-c3c(F)c(F)c(-c4ccc(CN5CCCCC5)cc4)c(F)c3F)nc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)c2nc(-c3c(F)c(F)c(-c4ccc(CN5CCCCC5)cc4)c(F)c3F)[nH]c2c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To the solution of 6-methyl-2-(2,3,5,6-tetrafluoro-4′-piperidin-1-ylmethyl-biphenyl-4-yl)-1H-benzoimidazole-4-carboxylic acid methyl ester (0.145 g, 0.283 mmol) in tetrahydrofuran (50 mL) was added an aq. solution of 5 N sodium hydroxide (10 mL). The reaction mixture was stirred at 60° C. for 4 hours. TLC shows completion of the reaction. The reaction mixture was cooled to room temperature, then concentrated and the obtained residue was acidified with an aq. solution of 50% HCl. The resulting precipitate was filtered and purified by preparative HPLC.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].CN(C)C=O.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(OCC)(=O)C>[CH2:25]([O:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)c1cccc(C)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed methyl 2-hydroxy-3-methylbenzoate (25 g, 150.44 mmol, 1.00 equiv), N,N-dimethylformamide (250 mL) and Cs2CO3 (103 g, 316.13 mmol, 2.10 equiv). This was followed by the addition of (bromomethyl)benzene (31 g, 181.25 mmol, 1.20 equiv). The resulting solution was stirred for 2 h at room temperature. The resulting solution was diluted with 1.2 L of ethyl acetate. The resulting mixture was washed with 3×800 mL of water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 40 g (crude) of methyl 2-(benzyloxy)-3-methylbenzoate as brown oil. MS (ESI) m/z 257 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[O:15]=[C:16]1[O:20][CH:19]([O:21][CH2:22][CH2:23][C:24]2C=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:18]([NH:30][C:31]([CH:33]2[CH2:37][CH2:36][CH2:35][N:34]2[C:38](=[O:52])[CH:39]([NH:41]C(=O)C2C=CC(N)=C(Cl)C=2)[CH3:40])=[O:32])[CH2:17]1>>[CH2:22]([O:21][CH:19]1[CH:18]([NH:30][C:31]([CH:33]2[CH2:37][CH2:36][CH2:35][N:34]2[C:38](=[O:52])[CH:39]([NH:41][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([NH2:1])=[C:3]([C:11]([F:14])([F:13])[F:12])[CH:4]=2)[CH3:40])=[O:32])[CH2:17][C:16](=[O:15])[O:20]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Nc1ccc(C(=O)O)cc1C(F)(F)F
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Product: CC(NC(=O)c1ccc(N)c(C(F)(F)F)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1
Yield: 48 %

Procedure:
Prepared from {2-[2-(2-benzyloxy-5-oxo-tetrahydro-furan-3-ylcarbmoyl)-pyrrolidin-1-yl]-1-methyl-2-oxo-ethyl}-carbamic acid tert-butyl ester and 4-amino-3-trifluoromethyl-benzoic acid according to the procedure used to prepare 98a to afford 56 mg of title compound (48% yield). 1H-NMR (500 MHz, 1:1 CDCl3:CD3OD) δ 1.20-1.55 (m, 3H), 1.75-2.50 (m, 4H), 2.50-3.10 (m, 2H), 3.50-4.00 (m, 2H), 4.30-5.00 (m, 5H), 5.42 (s, 0.4H), 5.51 (s, 0.2H), 5.62 (d, 0.3H), 5.78 (d, 0.1H), 6.84 (d, 1H), 7.20-8.15 (m, 7H). Analytical HPLC: 14.90, 15.20 min. LC-MS (ES+): m/e=563.2 (M+H+).
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1>C(O)(=O)C.C1COCC1.O>[OH:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: c1cncc(OCCOC2CCCCO2)c1
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: OCCOc1cccnc1
Yield: 84.2 %

Procedure:
A solution of 3-(2-(tetrahydropyran-2-yloxy)ethoxy)pyridine (1.54 g, 7 mmol) in acetic acid (8 ml), THF (4 ml) and water (2 ml) was heated at 50° C. for 4 hours. The volatiles were removed by evaporation and the residue azeotroped with toluene to give 3-(2-hydroxyethoxy)pyridine (820 mg, 86%) as an off-white solid. 1H NMR Spectrum: (DMSOd6) 3.70(t, 2H); 4.05(t, 2H); 4.85(s, 1H); 7.25(dd, 1H); 7.37(dd, 1H); 8.10(d, 1H); 8.24(d, 1H) MS-ESI: 140 [MH]+
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]([OH:14])=O)=[CH:11][C:6]=2[S:5][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[N:3]1.[CH:21]1([NH2:24])[CH2:23][CH2:22]1>O1CCCC1>[CH:21]1([NH:24][C:12]([C:10]2[CH:9]=[CH:8][C:7]3[C:2](=[O:1])[N:3]=[C:4]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=4)[S:5][C:6]=3[CH:11]=2)=[O:14])[CH2:23][CH2:22]1
Reactant: O=C(O)c1ccc2c(=O)nc(-c3ccccn3)sc2c1
Reactant: NC1CC1
Solvent: C1CCOC1
Product: O=C(NC1CC1)c1ccc2c(=O)nc(-c3ccccn3)sc2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 5.8 %

Procedure:
N,N′-carbonyldiimidazole (520 mg, 3.2 mmol) was added to a mixture of 4-oxo-2-(2-pyridyl)-4H-1,3-benzothiazine-7-carboxylic acid (700 mg, 2.4 mmol) and tetrahydrofuran (20 ml), and the mixture was stirred at 60° C. for 2 hrs. Successively, cyclopropylamine (700 mg, 12.2 mmol) was added to the reaction mixture, and the mixture was stirred at 60° C. for 1 hr. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate were collected, concentrated and recrystallized from diisopropyl ether-methanol to give the titled compound (45 mg, 5%) as pale yellow crystals.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:30](=[O:32])[CH3:31])[CH:24]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C(NC1C=C(NCC2C=CC=CC=2)C=CC=1)(=O)C.C(OC(=O)CSC1SC(N)=NC=1)C>>[C:30]([NH:29][C:25]1[CH:24]=[C:23]([N:15]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:33])=[O:3])=[CH:8][N:9]=2)[CH:28]=[CH:27][CH:26]=1)(=[O:32])[CH3:31]
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(Cc2ccccc2)c2cccc(NC(C)=O)c2)s1
Agent: CC(=O)Nc1cccc(NCc2ccccc2)c1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Product: CC(=O)Nc1cccc(N(Cc2ccccc2)C(=O)Nc2ncc(SCC(=O)O)s2)c1

Procedure:
The title compound was prepared via {2-[3-(3-acetylamino-phenyl)-3-benzyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using (3-acetylamino-phenyl)-benzylamine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[BH4-].[Na+]>C(O)C.C(OCC)C.Cl>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=Cc1ccc(F)c(Oc2ccccc2)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: OCc1ccc(F)c(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Under argon 2.16 g (0.010 mole) of 4-fluoro-3-phenoxybenzaldehyde was dissolved in 50 ml of absolute ethanol. To this solution was added with stirring 0.28 g (0.0074 mole) of sodium borohydride. After stirring at room temperature for 24 hours, 3 ml of 10% hydrochloric acid was added to the reaction mixture. The solvent was then evaporated under reduced pressure, leaving a milky-white residue. This residue was dissolved in 100 ml of diethyl ether and 5% hydrochloric acid. The organic phase was separated, washed in succession twice with 25 ml of 5% hydrochloric acid and twice with 10 ml of a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, leaving 1.98 g of (4-fluoro-3-phenoxyphenyl)methyl alcohol as a clear, colorless liquid. The nmr and ir spectra were consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[CH:10](=O)/[CH:11]=[CH:12]/[CH3:13].[OH-].[NH4+]>Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:6]([CH:10]=[CH:11][C:12]([CH3:13])=[N:5]2)=[CH:7][C:8]=1[F:9]
Reactant: C/C=C/C=O
Reactant: Nc1ccc(F)c(Br)c1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: Cc1ccc2cc(F)c(Br)cc2n1
Temperature: 106 °C
Reaction time: 2 h
Yield: 25.8 %

Procedure:
To a solution of 3-bromo-4-fluoroaniline (10.00 g, 52.63 mmol) in 6N HCl (150 mL) was added (E)-but-2-enal (7.524 mL, 92.10 mmol) dropwise over 10 minutes at 106° C. The reaction was stirred at 106° C. for 2 hours. After cooling to ambient temperature, the reaction mixture was basified with ammonium hydroxide to about pH 12, extracted with DCM (2×100 mL), dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (hexane/ethyl acetate 5:1) to give 7-bromo-6-fluoro-2-methylquinoline (3.26 g, 25.8%) as a solid.