Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)[C:4]=1[CH3:16].[CH:19]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C1COCC1.N1CCCCC1>C(N(CC)CC)C>[CH:19]1([NH:25][C:13]([C:11]2[S:12][C:8]([C:5]3[C:4]([CH3:16])=[C:3]([C:2]([F:1])([F:18])[F:17])[O:7][N:6]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NC1CCCCC1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: C1CCNCC1
Product: Cc1c(-c2ccc(C(=O)NC3CCCCC3)s2)noc1C(F)(F)F

Procedure:
Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and cyclohexylamine by the method described in Example 2 Method B reversing the order of addition such that intermediate solid acid chloride was added to a THF solution of triethylamine and piperidine derivative. Colorless solid (80 mg, 89%). 1H NMR (CDCl3) 1.18-1.36 (m, 1H), 1.36-1.50 (m, 1H), 1.60-1.82 (m, 4H), 1.98-2.10 (m, 2H), 2.37 (d, J=0.9, 3H), 3.90-4.04 (m, 1H), 5.88 (br d, J=7.0, 1H), 7.49 (d, J=4.0, 1H), 7.51 (d, J=3.5, 1H). 19F NMR −63.36. LC/MS 7.18 min, [M+1]+ 359.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[C:10]([C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: O=Cc1cccc(Br)c1
Reactant: C#CCCCCCCCCCCC
Product: CCCCCCCCCCCC#Cc1cccc(C=O)c1
Yield: 85 %

Procedure:
Reaction of 3-bromobenzaldehyde with 1-tridecyne as described in example 3 gave 85% of the title compound after chromatography on silica, eluting with dichloromethane:petrol (bp 40:60) (1:3) νmax (neat) 2920, 2215, 1705, 1600, 1575, 1465, 1280, 1155, 795, and 680 cm-1, δ(CDCl3) 0.86 (3H, distorted t), 0.9-1.7 (18H, m), 2.4(2H, t, J=6 Hz), 7.7-7.9 (4H, m, aromatic), and 10.0 (1H, s, aldehyde). Analysed as the 2,4-dinitrophenylhydrazone m.p. 127° C. (recrystallized from acetic acid). Found, C, 67.27, H, 6.86; N, 12.01, C26H32N4O4 requires, C, 67.33, H, 6.79, N, 12.08%.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][Cl:28])=[CH:25][CH:24]=1)([CH3:22])[CH3:21]>CO>[Cl-:28].[CH:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][P+:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:25][CH:24]=1)([CH3:22])[CH3:21]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)c1ccc(CCl)cc1
Solvent: CO
Product: CC(C)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: [Cl-]

Procedure:
A 5 liter reactor was obtained, and to this reactor was charged 655 g of triphenylphosphine, 1050 ml of methyl alcohol, and 422.5 g of para-isopropylbenzyl chloride. The reactants were heated to reflux temperature, approximately 65°-67° C., and refluxed for about 5 hours. There was obtained 1856.9 g of a 50% solution of para-isopropylbenzyl triphenylphosphonium chloride in methyl alcohol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[F:13])[O:5][CH2:6][C:7](Cl)=[O:8].[S:14]1[CH:18]=[CH:17][N:16]=[C:15]1[NH:19][S:20]([C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][NH:27][CH2:26]2)(=[O:22])=[O:21].CCN(CC)CC.C(Cl)Cl>CC#N>[S:14]1[CH:18]=[CH:17][N:16]=[C:15]1[NH:19][S:20]([C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][N:27]([C:7](=[O:8])[CH2:6][O:5][C:4]1[CH:10]=[CH:11][C:12]([F:13])=[C:2]([Cl:1])[CH:3]=1)[CH2:26]2)(=[O:22])=[O:21]
Reactant: O=S(=O)(Nc1nccs1)c1ccc2c(c1)CNC2
Reactant: O=C(Cl)COc1ccc(F)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC#N
Product: O=C(COc1ccc(F)c(Cl)c1)N1Cc2ccc(S(=O)(=O)Nc3nccs3)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(3-Chloro-4-fluorophenoxy)acetyl chloride (52 mg, 0.23 mmol) was added to a stirring solution of 2,3-Dihydro-1H-isoindole-5-sulfonic acid thiazol-2-ylamide (65 mg, 0.23 mmol), Et3N (64 μl, 0.46 mmol) and CH2Cl2 (500 μl), under N2. The reaction mixture was stirred at room temperature for 30 minutes. Product formation was observed by LC/MS (10-99% CH3CN). Purification by Gilson preparative HPLC (10-99% CH3CN) gave the desired amide. LC/MS (10-99% CH3CN), M/Z: M+1 obs=468.1; tR=2.95 min.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH:14]([S:18][CH3:19])[C:15]([OH:17])=O)=[C:8]([F:20])[C:7]=2[CH3:21])#[CH:2].CN(C(ON1N=[N:37][C:32]2[CH:33]=CC=C[C:31]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:44]CN(CC)CC.[NH4+].[Cl-]>CC#N.C(N)(C)(C)C>[C:32]([NH:37][C:15](=[O:17])[CH:14]([O:13][C:9]1[CH:10]=[C:11]2[C:6](=[C:7]([CH3:21])[C:8]=1[F:20])[N:5]=[CH:4][C:3]([C:1]#[CH:2])=[CH:12]2)[S:18][CH3:19])([CH3:44])([CH3:33])[CH3:31]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: C#Cc1cnc2c(C)c(F)c(OC(SC)C(=O)O)cc2c1
Reactant: CCN(CC)CC
Agent: F[B-](F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)(C)N
Solvent: CC#N
Product: C#Cc1cnc2c(C)c(F)c(OC(SC)C(=O)NC(C)(C)C)cc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture containing (3-ethynyl-7-fluoro-8-methyl-quinolin-6-yloxy)-methylsulfanyl-acetic acid (250 mg) from Step 8, aza-HOBT (116 mg), TBTU (273 mg) and Et3N (0.32 ml) in CH3CN (12 ml), tert-butyl amine was added at room temperature, under a nitrogen atmosphere. The resulting brown suspension was stirred 1 hour at room temperature then poured into aqueous NH4Cl solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulphate anhydrous, filtered and concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate) to give N-tert-butyl-2-(3-ethynyl-7-fluoro-8-methyl-quinolin-6-yloxy)-2-methylsulfanyl-acetamide (201 mg) as white solid. 1H NMR (CDCl3) δ ppm: 8.88 (1H, d); 8.17 1H, d); 7.17 (1H, d); 6.64 (1H, br s); 5.59 (1H, s); 3.27 (1H, s); 2.69 (3H, d); 2.18 (3H, s); 1.44 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=1)[O:8][CH:7]([C:21]([F:24])([F:23])[F:22])[C:6]([C:25]([O:27]CC)=[O:26])=[CH:5]2.[OH-].[Li+].Cl>C1COCC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH3:20])=[CH:17][CH:18]=1)[O:8][CH:7]([C:21]([F:24])([F:22])[F:23])[C:6]([C:25]([OH:27])=[O:26])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(Oc3ccc(CC)cc3)cc2OC1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCc1ccc(Oc2cc3c(cc2Cl)C=C(C(=O)O)C(C(F)(F)F)O3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
To a solution of 4.43 g (10.4 mmole) of the product of step 1 in 70 mLs of THF and 20 mL of methanol was added a solution of 1.0 g of lithium hydroxide monohydate in 10 mL of water. The mixture was heated to reflux for 30 min and allowed to cool to rt. After stirring overnight, the mixture was treated with 75 mL of 1N HCl and extracted three times with diethyl ether. The combined extracts were washed with brine, dried and concd in vacuo to afford 4.02 g (97%) of a yellow solid: mp 195.5-196.5° C.; 1H NMR (d6-acetone/400 MHz) 1.22 (t, 3H, J=7.5 Hz), 2.66 (q, 2H, J=7.6 Hz), 5.78 (q, 1H, J=7.1 Hz), 6.45 (s, 1H), 7.04 (d, 2H, J=8.4 Hz), 7.31 (d, 2H, J=8.3 Hz), 7.66 (s, 1 H), 7.87 (s, 1H); 19F NMR (d6-acetone/400 MHz) −79.4 (d, 3F, J=7.7 Hz); 13C NMR (d6-acetone/100 MHz) 15.4, 28.1, 70.9 (q, J=32.7 Hz), 105.6, 115.3, 116.0, 117.5, 119.9, 123.9 (q, J=286.8 Hz), 129.8, 131.1, 135.7, 141.5, 153.1, 153.3, 157.3, 164.3; MS (ES−) 397 (M−1, 100); HRMS (ES−) m/z calcd for (C19H13ClF3O4) 397.0449, found 397.0484.
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O.O>[O:21]([CH2:20][CH2:19][O:1][C:2]1[C:11]([OH:12])=[CH:10][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Oc1cc2ccccc2cc1O
Reactant: BrCCOc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1cc2ccccc2cc1OCCOc1ccccc1
Temperature: 135 °C
Yield: 40 %

Procedure:
A mixture of 2,3-dihydroxynaphthalene (5.6 g) and sodium bicarbonate powder (2.9 g) in dimethylformamide (50 mL) was stirred and heated at 135° C. for 1 hour. When the gas evolution ceased, the mixture was cooled to about 60° C. and beta-bromophenetole (7 g) was added. The mixture was stirred at 60° C. overnight, cooled, diluted with water and filtered. The solids were crystallized from dichloromethane-diethyl ether to give 3.9 g of 3-(2-phenoxyethoxy)-2-naphthol as a colorless solid, mp 141°-142° C.
Reaction SMILES: [N:1]1([C:6]2[CH:30]=[CH:29][C:9]([O:10][CH2:11][CH2:12][C@@H:13]3[CH2:15][C@@H:14]3[CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][CH:26](C)[CH3:27])=[O:23])[CH2:18][CH2:17]3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.[CH2:31](N(CC)CC)C.C(=O)(OC1(C)CC1)ON1C(=O)CCC1=O>ClCCl>[N:1]1([C:6]2[CH:30]=[CH:29][C:9]([O:10][CH2:11][CH2:12][C@@H:13]3[CH2:15][C@@H:14]3[CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]4([CH3:31])[CH2:26][CH2:27]4)=[O:23])[CH2:18][CH2:17]3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: CC(C)COC(=O)N1CCC([C@H]2C[C@H]2CCOc2ccc(-n3cnnn3)cc2)CC1
Reactant: CCN(CC)CC
Agent: CC1(OC(=O)ON2C(=O)CCC2=O)CC1
Solvent: ClCCl
Product: CC1(OC(=O)N2CCC([C@H]3C[C@H]3CCOc3ccc(-n4cnnn4)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-((1R,2S)-2-(2-(4-(1H-Tetrazol-1-yl)phenoxy)ethyl)cyclopropyl)piperidine (Step B, Example 1; 100 mg, 0.319 mmol) and triethylamine (97 mg, 0.96 mmol) were dissolved in dichloromethane (5 mL). 2,5-Dioxopyrrolidin-1-yl 1-methylcyclopropyl carbonate (81 mg, 0.38 mmol) was added. The mixture was stirred at RT for 30 min and concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography (12 g RediSep, eluted with dichloromethane/methanol, 199:1, 1 L). The product containing fractions were combined and concentrated under reduced pressure. The compound was further purified by prep-HPLC (SunFire C18 OBD, 10 μm, 50×150 mm, 118 mL/min, acetonitrile/water 10:90 to 90:10 at 25 min, total run 30 min) to provide the title compound as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 8.90 (s, 1H), 7.59 (d, J=9.0 Hz, 2H), 7.07 (d, J=9.0 Hz, 2H), 4.30-3.90 (m, 4H), 2.80-2.60 (m, 2H), 2.25-2.10 (m, 1H), 1.85-1.70 (m, 2H), 1.60-1.45 (m, 1H), 1.55 (s, 3H), 1.40-1.20 (m, 2H), 1.10-0.80 (m, 4H), 0.80-0.55 (m, 4H), −0.09 (q, J=5.2 Hz, 1H). MS (ESI) m/z 412 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CC(C)([O-])C.[K+].C(OCC)(=O)C>CS(C)=O.O>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: Oc1ccccc1
Reactant: Brc1cccc(Br)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: Brc1cccc(Oc2ccccc2)n1
Temperature: 160 °C
Reaction time: 7 h
Yield: 93 %

Procedure:
To a solution of 2,6dibromopyridine (20 g, 84.4 mmol) and phenol (7.94 g, 84.4 mmol) in dimethylsulfoxide (200 mL) was added potassium tert-butoxide (9.47 g, 84.4 mmol), and the solution was stirred at 160° C. for 7 hours. The reaction solution was allowed to room temperature, ethyl acetate and water were added for partitioning, the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1), and 2-bromo-6-phenoxy-pyridine (19.6, 93%) was obtained as a yellow solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:20])[C@H:3]([NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18])[CH2:4][OH:5].[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[Si:21]([O:5][CH2:4][C@@H:3]([NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18])[CH:2]([CH3:20])[CH3:1])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)[C@@H](CO)Nc1c([N+](=O)[O-])cnc2ccccc12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(C)[C@@H](CO[Si](C)(C)C(C)(C)C)Nc1c([N+](=O)[O-])cnc2ccccc12
Temperature: 56 °C
Reaction time: 48 h
Yield: 97.3 %

Procedure:
(2S)-3-Methyl-2-[(3-nitroquinolin-4-yl)amino]butan-1-ol (3.97 g, 14.4 mmol) was dissolved in 15 mL of dry pyridine and treated with tert-butyldimethylsilyl chloride (2.40 g, 15.9 mmol) and a catalytic amount of 4-(dimethylamino)pyridine (DMAP) (176 mg, 1.44 mmol). The reaction mixture was stirred under N2 and heated to 56° C. After 2 days, the reaction mixture was concentrated under reduced pressure. The resulting solid was partitioned between 100 mL of H2O and 100 mL of ethyl acetate. The layers were separated and the organic portion was washed with H2O and brine. The organic portion was then dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 20% ethyl acetate/hexanes) gave N-[(1S)-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-methylpropyl]-3-nitroquinolin-4-amine (5.46 g) as a yellow syrup.
Reaction SMILES: [CH3:1][C:2]1[C:7]([SH:8])=[N:6][C:5]([CH3:9])=[CH:4][N:3]=1.CC1C2[O:18][CH:17]=[CH:16]C=2C=CC=1.C(OC(=O)C)(=O)C>>[CH3:1][C:2]1[C:7]([S:8][C:17](=[O:18])[CH3:16])=[N:6][C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: Cc1cnc(C)c(S)n1
Reactant: Cc1cccc2ccoc12
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Sc1nc(C)cnc1C

Procedure:
2,5-Dimethyl-3-acetylthio-pyrazine was prepared by acetylating 2,5-dimethyl-3-mercapto-pyrazine [compound (2) a.] with acetic anhydride in an alkaline medium according to the method described in Houben- Weyl, 4th ed., vol. 9, 753 (1955). The product has a m.p. of 36°-42° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1/[CH:7]=[N:8]/[OH:9].[Cl:10]N1C(=O)CCC1=O.O>CN(C)C=O>[OH:9][N:8]=[C:7]([Cl:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: O/N=C/c1ccccn1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: ON=C(Cl)c1ccccn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
To a colorless, homogeneous solution of (E)-picolinaldehyde oxime (6.75 g, 55.3 mmol) in N,N-dimethylformamide (55 mL) at room temperature was added N-chlorosuccinimide (7.38 g, 55.3 mmol) portion-wise. After the addition of ˜⅕ of the NCS, the reaction mixture was immersed in an oil bath at 60° C., and the remaining NCS was added portion-wise over 1.5 h. After the addition was complete, the homogeneous reaction mixture was stirred for 60 min. at 60° C. and was then cooled to room temperature. Water (400 mL) was added, and the aqueous mixture was extracted with ether (3×200 mL). The organic layer was collected, washed with water (2×200 mL), washed with a saturated aqueous solution of brine (100 mL), and dried over anhydrous magnesium sulfate. Concentration under reduced pressure afforded N-hydroxypicolinimidoyl chloride (6.45 g, 41.2 mmol, 75% yield) as a tan solid. The compound had an HPLC retention time=0.515 min.—Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=156.8. 1H NMR (400 MHz, CDCl3) δ ppm 7.37-7.43 (m, 1H), 7.80 (td, J=7.78, 1.76 Hz, 1H), 7.91-7.97 (m, 1H), 8.72 (d, J=4.02 Hz, 1H), and 9.85 (br. s., 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[S:5][C:6]=1[CH:7]=O.[CH:15]([NH:18][C:19]([C@@H:21]1[C@H:26]([NH:27][C:28]2[C:33]([Cl:34])=[CH:32][N:31]=[C:30]([NH2:35])[C:29]=2[NH2:36])[C@@H:25]2[CH2:37][C@H:22]1[CH:23]=[CH:24]2)=[O:20])([CH3:17])[CH3:16].C([O-])(=O)C.[NH4+]>>[CH:15]([NH:18][C:19]([C@@H:21]1[C@H:26]([NH:27][C:28]2[C:33]([Cl:34])=[CH:32][N:31]=[C:30]3[NH:35][C:7]([C:6]4[S:5][C:4]([N:9]5[CH2:14][CH2:13][O:12][CH2:11][CH2:10]5)=[N:3][C:2]=4[Cl:1])=[N:36][C:29]=23)[C@@H:25]2[CH2:37][C@H:22]1[CH:23]=[CH:24]2)=[O:20])([CH3:17])[CH3:16]
Reactant: CC(C)NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: O=Cc1sc(N2CCOCC2)nc1Cl
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CC(C)NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4sc(N5CCOCC5)nc4Cl)nc23)[C@H]2C=C[C@@H]1C2
Yield: 9 %

Procedure:
In a similar fashion to Compound LXXXVII 4-Chloro-2-morpholin-4-yl-thiazole-5-carbaldehyde (75.00 mg, 0.3223 mmol), (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid isopropylamide (97.42 mg, 0.2901 mmol), and Ammonium acetate (44.72 mg, 0.5802 mmol were reacted to produce 14.26 mg (9%) of the title compound. (300 MHz, DMSO-d6) 12.78 (s, 1H), 8.11 (d, J=7.5 Hz, 1H), 7.94 (s, 1H), 6.95 (s, 1H), 6.39-6.29 (m, 2H), 4.98 (t, J=17 Hz, 8.5 Hz, 1H), 3.88 (m, 1H), 3.73 (m, 4H), 3.49 (m, 4H), 2.83 (s, 1H), 2.83 (s, 1H), 2.76 (s, 1H), 2.54 (d, J=8 Hz, 1H), 2.54 (d, J=8 Hz, 1H), 2.25 (d, J=8 Hz, 1H), 1.07 (d, J=6.5 Hz, 3H, 1.00 (d, J=6.5 Hz, 3H). MS=547 (M+H), HPLC: 2.92 min. (G Method)
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].O[CH2:13][CH2:14][C@@H:15]1[CH2:17][C@@H:16]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1.C(OCC)(=O)C.O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:13][CH2:14][C@@H:15]2[CH2:17][C@@H:16]2[CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:20][CH2:19]2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC([C@H]2C[C@H]2CCO)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC([C@H]2C[C@H]2CCOc2ccc(S(C)(=O)=O)cc2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
4-(methylsulfonyl)phenol (17 mg, 0.1 mmol), tert-butyl 4-[(1R,2S)-2-(2-hydroxyethyl)cyclopropyl)piperidine-1-carboxylate (27 mg, 0.1 mmol), and triphenylphosphine (70 mg, 0.21 mmol) were dissolved in tetrahydrofuran (1 mL) under an atmosphere of nitrogen and cooled at 0° C. DIAD (32 mg, 0.14 mmol) was added and the resulting mixture was warmed to RT and stirred overnight. The mixture was diluted with ethyl acetate (10 mL) and water (5 mL), and the layers were separated. The organic layer was washed with brine (2×10 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by MS directed HPLC (30 minute, standard gradient 0-90% acetonitrile/water 0.1% formic acid buffer) and the fractions containing product combined. The solution was concentrated to dryness via GenoVac to afford the title compound. LC/MS (m/z): 424 (M+H)+. GPR119 Human EC50: 0.9 nM
Reaction SMILES: [H-].[Na+].[NH:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]1=[O:12].[C:13]([CH:17]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[CH:34]=1)[O:18][C:19]1[C:26]([CH2:27][CH2:28][CH3:29])=[CH:25][C:22]([CH2:23]Br)=[CH:21][C:20]=1[CH2:30][CH2:31][CH3:32])([O:15][CH3:16])=[O:14].[C:40](OCC)(=O)C>CN(C=O)C>[C:13]([CH:17]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[CH:34]=1)[O:18][C:19]1[C:26]([CH2:27][CH2:28][CH3:29])=[CH:25][C:22]([CH2:23][N:3]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[NH:5][C:4]2=[O:12])=[CH:21][C:20]=1[CH2:30][CH2:31][CH3:32])([O:15][CH2:16][CH3:40])=[O:14]
Reactant: CCCc1cc(CBr)cc(CCC)c1OC(C(=O)OC)c1cccc(C)c1
Reactant: CCOC(C)=O
Reactant: O=c1[nH]c2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1cc(Cn2c(=O)[nH]c3ccccc32)cc(CCC)c1OC(C(=O)OCC)c1cccc(C)c1
Reaction time: 0.33 h

Procedure:
To a suspention of 4 mg (0.17 mmol) of sodium hydride in 1.0 mL of DMF was added 75 mg (0.17 mmol) of (3H)-benzimidazolone and the reaction mixture was stirred for 20 minutes. 75 mg (0.17 mmol) of 4-(1-carbomethoxy-1-(3-methylphenyl)methoxy)-3,5-dipropylbenzylbromide in 1.0 mL of DMF was added and the reaction mixture was stirred at room is temperature overnight. The reaction mixture was poured into ethyl acetate and washed with water and then brine. The organic layer was dried over sodium sulfate, decanted and concentrated. Purification by flash chromatography (silica gel, hexane/ethyl acetate 2:1) provided 41 mg of a dialkylated compound and 16 mg (0.03 mmol) of the title compound.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][N:3]=1.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.ClCl.[C:36]([C:40]1[CH:45]=[CH:44][C:43]([CH2:46][CH2:47]O)=[CH:42][CH:41]=1)([CH3:39])([CH3:38])[CH3:37]>C(Cl)Cl.C1(C)C=CC=CC=1.N1C=CC=CC=1>[C:36]([C:40]1[CH:41]=[CH:42][C:43]([CH2:46][CH2:47][O:1][C:2]2[C:11]3[C:6](=[N:7][CH:8]=[CH:9][N:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:44][CH:45]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)c1ccc(CCO)cc1
Reactant: Oc1ncnc2nccnc12
Agent: ClCl
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(CCOc2ncnc3nccnc23)cc1
Temperature: -17.5 °C

Procedure:
To a suspension of 2 g of 4-hydroxypteridine in 20 mL of CH2Cl2 under nitrogen was added 1.2 g of 25 pyridine. The mixture was cooled to -30° C and over a 15 minute period a solution of 4.82 g of triphenyl phosphite in CH2Cl2 was added simultaneously with addition of chlorine gas. The mixture was stirred for one and one half hours while maintaining the temperature at -15 to -20° C. The mixture was then allowed to warm to 10° C., and a solution of 2.67 g of 2-[4-(t-butyl)phenyl]ethanol in CH2Cl2 was added. The resulting mixture was refluxed for 45 minutes, then cooled and diluted into toluene. The toluene solution was washed with dilute base, then filtered through phase separating paper and concentrated in vacuo. The resulting bluish oil was adsorbed onto silica gel and chromatographed (silica gel, CH2Cl2 →80% CH2Cl2, 20% EtOAc). Fractions containing the major product were combined. The product was then recrystallized from petroleum ether/CH2Cl2. Yield 60 mg. M.P. 149° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:10]([O-:12])=[O:11])=[C:7]([CH:9]=1)[NH2:8].[Br:13][C:14]1[CH:21]=[C:20]([F:22])[C:17]([CH2:18]N)=[C:16]([F:23])[CH:15]=1.CCN(C(C)C)C(C)C>C(#N)C>[Br:13][C:14]1[CH:21]=[C:20]([F:22])[C:17]([CH2:18][NH:8][C:7]2[CH:9]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[N+:10]([O-:12])=[O:11])=[C:16]([F:23])[CH:15]=1
Reactant: COc1ccc([N+](=O)[O-])c(N)c1
Reactant: NCc1c(F)cc(Br)cc1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc([N+](=O)[O-])c(NCc2c(F)cc(Br)cc2F)c1
Temperature: 140 °C
Yield: 80.4 %

Procedure:
A mixture of 5-methoxy-2-nitroaniline (513 mg, 3 mmol), 4-bromo-2,6-difluorobenzyl amine (616 g, 3 mmol), DIPEA (1.55 mL, 9 mmol) and acetonitrile (10 mL) was heated to 130-150° Celsius for 16 h. The mixture was then cooled to RT and concentrated to dryness. To the residue was added H2O (100 mL) and the resulting solid was collected by filtration and dried to afford the title compound (900 mg, 80.1%).
Reaction SMILES: [OH:1][NH:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=1.[OH-].[Na+].Br[CH2:20][CH2:21][OH:22]>C(O)C.O>[OH:22][CH2:21][CH2:20][O:1][NH:2][C:3](=[O:16])[C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:15])[C:11]([CH3:13])([CH3:12])[CH3:14])=[CH:8][CH:9]=1
Reactant: CC(C)(C)C(=O)c1ccc(C(=O)NO)cc1
Reactant: OCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)C(=O)c1ccc(C(=O)NOCCO)cc1
Temperature: 55 °C

Procedure:
To a solution of 4.0 grams (18.1 mmol) of N-hydroxy-4-pivaloylbenzamide in 10 milliliters of ethanol is added an aqueous solution of 725 milligrams (18.1 mmol) of sodium hydroxide in 1 milliliter of water. To this is added 1.67 milliliters (23.6 mmol) of 2-bromoethanol; and the resulting mixture is heated at 55° C. for 24 hours. The mixture is cooled to 20° C., concentrated, and extracted 3 times with 10 milliliters of chloroform. The combined extracts are washed with 15 milliliters of water and then 15 milliliters of brine, dried over magnesium sulfate and concentrated. The residue is recrystallized from methylene chloride/hexane (1:4) to yield N-(2-hydroxyethoxy)-4-pivaloylbenzamide.