Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([OH:15])=O.O=S(Cl)Cl.[CH3:20][O:21][C:22]([C:24]1[NH:25][CH:26]=[CH:27][CH:28]=1)=[O:23]>ClC(Cl)C>[CH3:20][O:21][C:22]([C:24]1[NH:25][CH:26]=[C:27]([C:13]([C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[O:15])[CH:28]=1)=[O:23]
Reactant: Cc1onc(-c2ccccc2)c1C(=O)O
Reactant: COC(=O)c1ccc[nH]1
Solvent: CC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(C(=O)c2c(-c3ccccc3)noc2C)c[nH]1
Temperature: 25 °C

Procedure:
A mixture of 406 mg (2 mmol) 5-methyl-3-phenyl-isoxazole-4-carboxylic acid (commercially available) and 4 mL SOCl2 was heated to reflux for 3 h. After evaporation of all volatiles the residue was added to a mixture of 206 mg (2 mmol) 1H-pyrrole-2-carboxylic acid methyl ester (commercially available) and 440 mg (3 mmol) AMCl3 in 25 mL dichloroethane and heated to reflux for 3 h. After cooling to room temperature the precipitate was collected and washed with dichloromethane. The residue was purified on silica eluting with a gradient of ethyl acetate and heptane affording 210 mg (37%) of the title compound as white foam. (m/e): 311.0 (MH+; 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][CH:4]=1.[Cl:12][CH2:13][C:14]([CH2:16]Cl)=O>>[Cl:12][CH2:13][C:14]1[N:9]=[C:7]([C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[O:8][CH:16]=1
Reactant: O=C(CCl)CCl
Reactant: COc1ccc(C(N)=O)cc1
Product: COc1ccc(-c2nc(CCl)co2)cc1
Yield: 78 %

Procedure:
This compound was synthesized from 4-methoxybenzamide and 1,3-dichloroacetone as described in example 74 step 1 (2.3 g, yield 78%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.98-7.96 (d, J=8.3 Hz, 2H), 7.65 (s, 1H), 6.97-6.95 (d, J=8.3 Hz, 2H), 4.56 (s, 2H), 3.86 (s, 3H). MS (ESI) m/z: Calculated for C11H10ClNO2: 223.04. found: 223.8 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([S:42](Cl)(=[O:44])=[O:43])[CH:37]=[CH:38][C:39]=1[O:40][CH3:41].N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:42]([C:36]1[CH:37]=[CH:38][C:39]([O:40][CH3:41])=[C:34]([O:33][CH3:32])[CH:35]=1)(=[O:44])=[O:43]
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)Nc2ccc(F)c(Nc3ncccc3-c3ncnc4c3ncn4C3CCCCO3)c2F)cc1OC
Temperature: 50 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 3,4-dimethoxybenzenesulfonyl chloride (12 mg, 0.052 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 28 mg of the target compound, N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-3,4-dimethoxybenzenesulfonamide (percentage yield: 96%), was obtained.
Reaction SMILES: O.NN.[CH2:4]([O:6][P:7]([C:12]([F:26])([F:25])[CH2:13][N:14]1C(=O)C2C(=CC=CC=2)C1=O)(=[O:11])[O:8][CH2:9][CH3:10])[CH3:5]>C(Cl)Cl>[CH2:4]([O:6][P:7]([C:12]([F:26])([F:25])[CH2:13][NH2:14])(=[O:11])[O:8][CH2:9][CH3:10])[CH3:5]
Reactant: CCOP(=O)(OCC)C(F)(F)CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: ClCCl
Solvent: O
Product: CCOP(=O)(OCC)C(F)(F)CN
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Hydrazine monohydrate was added to a methylene chloride solution of diethyl[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1,1-difluoroethyl]phosphonate, for stirring at ambient temperature for one hour, to obtain diethyl(2-amino-1,1-difluoroethyl)phosphonate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[CH3:12])[N:8]=[CH:7][N:6]=[C:5]2Cl.[NH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.CC(O)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[CH3:12])[N:8]=[CH:7][N:6]=[C:5]2[NH:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1
Reactant: Cc1c(Br)cc2c(Cl)ncnc2c1[N+](=O)[O-]
Reactant: N#Cc1ccc(N)cc1
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: Cc1c(Br)cc2c(Nc3ccc(C#N)cc3)ncnc2c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 72.5 %

Procedure:
A mixture of 6-bromo-4-chloro-7-methyl-8-nitroquinazoline (211 mg, 0.70 mmol) and 4-aminobenzonitrile (208 mg, 1.76 mmol) in toluene (25 mL) was refluxed overnight. i-PrOH (25 mL) was added and the mixture was refluxed for 5 h. After cooling to rt the precipitate was filtered and washed with i-PrOH to give 4-(6-bromo-7-methyl-8-nitroquinazolin-4-ylamino)benzonitrile (195 mg, 72%). MS (ESI, pos. ion) m/z: 384 [M+H]+
Reaction SMILES: [CH:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][C:9]2([OH:15])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH2:18]([O:25][C:26]1[CH:27]=[CH:28][C:29]2[O:33][CH:32]([CH2:34]Br)[CH2:31][C:30]=2[CH:36]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][C:9]2([OH:15])[CH2:10][CH2:11][N:12]([CH2:34][CH:32]3[CH2:31][C:30]4[CH:36]=[C:26]([O:25][CH2:18][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[CH:27]=[CH:28][C:29]=4[O:33]3)[CH2:13][CH2:14]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: BrCC1Cc2cc(OCc3ccccc3)ccc2O1
Reactant: CC(C)c1ccc(CC2(O)CCNCC2)cc1
Product: CC(C)c1ccc(CC2(O)CCN(CC3Cc4cc(OCc5ccccc5)ccc4O3)CC2)cc1

Procedure:
The title compound MS: m/e=472.6 (M+H+) was prepared from 4-(4-isopropyl-benzyl)-piperidin-4-ol and 5-benzyloxy-2-(RS)-bromomethyl-2,3-dihydro-benzofuran.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][N:9]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[C:8]3[CH:18]=[CH:19][CH:20]=[CH:21][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].I[CH3:25]>CN(C)C=O>[CH3:25][N:6]1[C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[CH2:10][N:9]([C:12](=[O:17])[C:13]([F:16])([F:14])[F:15])[C:8]2[CH:18]=[CH:19][CH:20]=[CH:21][C:7]1=2
Reactant: CI
Reactant: O=C(N1Cc2ccccc2Nc2ccccc21)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1c2ccccc2CN(C(=O)C(F)(F)F)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(10,11-Dihydro-5H-dibenzo[b,e][1,4]diazepin-10-yl)-2,2,2-trifluoroethanone of Step A (3.12 g) was added to dry N,N-dimethylformamide (50 mL) containing sodium hydride (60% dispersion in oil, 0.60 g, washed with hexane). After a short while iodomethane was added (2.0 g) and the mixture stirred overnight at room temperature, quenched with ice and diluted with brine. The precipitate was collected and redissolved in dichloromethane. The solution was dried over anhydrous sodium sulfate and filtered through a short column of Magnesol® which was eluted with several additional volumes of dichloromethane. The total effluent was evaporated to dryness and the residue crystallized from hexane to provide the title compound as colorless crystals (1.23 g), m.p. 104–106° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([NH:27][C:28](=O)[O:29]C2C=CC=CC=2)[CH:4]=[N:3]1.[NH:37]1[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:38]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH3:1][N:2]1[C:6]([NH:7][C:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[C:5]([NH:27][C:28]([N:37]2[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:46])([CH3:48])[CH3:47])[CH2:38]2)=[O:29])[CH:4]=[N:3]1
Reactant: Cn1ncc(NC(=O)Oc2ccccc2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc(NC(=O)N2CC[C@H](NC(=O)OC(C)(C)C)C2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 59.9 %

Procedure:
To a suspension of phenyl [1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]carbamate (950 mg) and tert-butyl (3S)-3-pyrrolidinylcarbamate (560 mg) in methylene chloride (20 ml) was added N-ethyldiisopropylamine (390 mg), and the mixture was stirred under reflux for 23 hours. The reaction mixture was washed successively with 10% aqueous citric acid solution, brine and saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 4% methanol/chloroform to give tert-butyl [(3S)-1-({[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}carbonyl)-3-pyrrolidinyl]carbamate (680 mg) as a solid.
Reaction SMILES: [N:1]1([C:8]2[CH:15]=[CH:14][C:11]([CH2:12][NH2:13])=[CH:10][C:9]=2[F:16])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:17]1[C:26]2[C:21](=[C:22]([CH:27]([CH3:31])[C:28](O)=[O:29])[CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][N:18]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[N:1]1([C:8]2[CH:15]=[CH:14][C:11]([CH2:12][NH:13][C:28](=[O:29])[CH:27]([C:22]3[CH:23]=[CH:24][CH:25]=[C:26]4[C:21]=3[CH:20]=[CH:19][N:18]=[CH:17]4)[CH3:31])=[CH:10][C:9]=2[F:16])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCc1ccc(N2CCCCCC2)c(F)c1
Reactant: CC(C(=O)O)c1cccc2cnccc12
Agent: O=C(O)Cc1cccc2cnccc12
Product: CC(C(=O)NCc1ccc(N2CCCCCC2)c(F)c1)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 4-(1-azepanyl)-3-fluorobenzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 406 (M+H)+; MS (ESI−) m/z 404 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.53 (m, 7H), 1.72 (m, 4H), 3.32 (m, 4H), 3.65 (s, 2H), 4.18 (q, J 7.1, 1H), 6.86 (m, 3H), 7.58 (m, 2H), 7.74 (m, 1H), 8.13 (m, 2H), 8.52 (d, J 7.8, 1H), 9.30 (s, 1H); Anal. Calcd for C25H28FN3O+3.25 HCl: C, 57.30; H, 6.01. Found: C, 57.26; H, 5.98.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4]([O:14][CH2:15][C:16]([CH3:21])([CH3:20])[C:17]([OH:19])=[O:18])=[CH:3][CH:2]=1.C1C2NC3C(=CC=CC=3)C=2C(OC(C)(C)C(O)=O)=CC=1.Cl[CH2:43][C:44]1[CH:63]=[CH:62][C:47]([O:48][CH2:49][C:50]2[N:51]=[C:52]([C:56]3[CH:61]=[CH:60][N:59]=[CH:58][CH:57]=3)[O:53][C:54]=2[CH3:55])=[C:46]([O:64][CH3:65])[CH:45]=1.ClCC1C=CC(OCC2N=C(C3C=CC=CC=3)OC=2C)=C(OC)C=1>>[CH3:65][O:64][C:46]1[CH:45]=[C:44]([CH:63]=[CH:62][C:47]=1[O:48][CH2:49][C:50]1[N:51]=[C:52]([C:56]2[CH:57]=[CH:58][N:59]=[CH:60][CH:61]=2)[O:53][C:54]=1[CH3:55])[CH2:43][N:12]1[C:13]2[CH:1]=[CH:2][CH:3]=[C:4]([O:14][CH2:15][C:16]([CH3:21])([CH3:20])[C:17]([OH:19])=[O:18])[C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccncc2)oc1C
Reactant: CC(C)(COc1cccc2[nH]c3ccccc3c12)C(=O)O
Agent: CC(C)(Oc1cccc2[nH]c3ccccc3c12)C(=O)O
Agent: COc1cc(CCl)ccc1OCc1nc(-c2ccccc2)oc1C
Product: COc1cc(Cn2c3ccccc3c3c(OCC(C)(C)C(=O)O)cccc32)ccc1OCc1nc(-c2ccncc2)oc1C

Procedure:
The subject compound was prepared by performing the same operation as that of the example 3 by using 3-(9H-carbazole-4-yloxy)-2,2-dimethylpropionic acid prepared by the reference 30 instead of 2-(9H-carbazole-4-yloxy)-2-methylpropionic acid used in the example 3, and using 4-((4-(chloromethyl)-2-methoxyphenoxy)methyl)-2-(pyridine-4-yl)-5 methyloxazole prepared by the reference 4 instead of 4-((4-(chloromethyl)-2-methoxyphenoxy)methyl)-5-methyl-2-phenyloxazole.
Reaction SMILES: [O:1]1[C@H:3]([CH2:4][O:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:2]1.[CH2:13](OC1C=CC(O)=CC=1)[C:14]1C=CC=C[CH:15]=1.[OH-].[Na+].O>CS(C)=O>[CH2:6]([O:5][C:4]1[CH:15]=[CH:14][CH:13]=[CH:2][C:3]=1[OH:1])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: c1ccc(COC[C@@H]2CO2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Oc1ccccc1OCc1ccccc1

Procedure:
A solution of 8.3 g (36.1 mmol) of (2S):1-chloro-2-hydroxy-3-N-mesylisopropylaminopropane and 8.69 g (43.4 mmol) of p-benzyloxyphenol in 75 ml DMSO was treated with 10.86 ml 4 N NaOH (43.4 mmol) and the mixture was heated at 100° for 5 hours. To the cooled reaction mixture 40 ml 1 N NaOH and 60 ml H2O were added with stirring and the resulting solid was collected by filtration and was washed well with H2O. The dried crude product was recrystallized from EtOAc-hexane to yield the end product as white needles, mp 93°-94°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1.[C:25]([O:29][CH2:30][C@@H:31]([C:33]([OH:35])=[O:34])[NH2:32])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][CH2:30][C@H:31]([NH:32][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4](/[CH:12]=[CH:13]/[C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:22])([F:24])[F:23])=[CH:16][CH:15]=2)[CH:5]=1)[C:33]([OH:35])=[O:34])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC[C@H](N)C(=O)O
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Product: COc1ccc(C(=O)N[C@@H](COC(C)(C)C)C(=O)O)cc1/C=C/c1ccc(OC(F)(F)F)cc1

Procedure:
The (S)-3-t-butoxy-2-{4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoylamino}propionic acid was synthesized from 4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid obtained in step B of Example 2-2-1 and O-t-butyl-L-serine in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][OH:19])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[N:20]1([C:24](=[O:35])[CH2:25][C:26]2[CH:33]=[CH:32][C:31](O)=[CH:30][C:27]=2[C:28]#[N:29])[CH2:23][CH2:22][CH2:21]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>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N:20]1([C:24](=[O:35])[CH2:25][C:26]2[CH:33]=[CH:32][C:31]([O:19][CH2:18][CH2:17][C@@H:15]3[CH2:16][C@@H:14]3[CH:11]3[CH2:12][CH2:13][N:8]([C:5]4[N:6]=[CH:7][C:2]([Cl:1])=[CH:3][N:4]=4)[CH2:9][CH2:10]3)=[CH:30][C:27]=2[C:28]#[N:29])[CH2:21][CH2:22][CH2:23]1
Reactant: N#Cc1cc(O)ccc1CC(=O)N1CCC1
Reactant: OCC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: N#Cc1cc(OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)ccc1CC(=O)N1CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanol (22 mg, 0.076 mmol) was dissolved in toluene (1 ml) and 2-[2-(azetidin-1-yl)-2-oxoethyl]-5-hydroxybenzonitrile (15 mg, 0.069 mmol), triphenylphosphine (36 mg, 0.139 mmol), and DIAD (27 μl, 0.139 mmol) added and the mixture stirred at RT overnight. The mixture was diluted with ethyl acetate (20 mL), washed with brine (10 ml), dried over MgSO4, filtered and the solvent removed in vacuo. The reside was purified by column chromatography using a Biotage SiO2 cartridge (25 g) using a gradient eluant of 10-100% EtOAc:hexanes to afford the title compound. LC/MS (m/z): 480 (M+H)+. GPR119 Human EC50: 0.32 nM.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[Cl:9][C:10]([Cl:18])=[CH:11][CH:12](Cl)[C:13](Cl)([CH3:15])[CH3:14].ClC(Cl)=CC=C(C)C>C(#N)C>[C:1]([C:3]1([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:12]([CH:11]=[C:10]([Cl:18])[Cl:9])[C:13]1([CH3:15])[CH3:14])#[N:2]
Reactant: CC(C)(Cl)C(Cl)C=C(Cl)Cl
Reactant: CCOC(=O)CC#N
Agent: CC(C)=CC=C(Cl)Cl
Solvent: CC#N
Product: CCOC(=O)C1(C#N)C(C=C(Cl)Cl)C1(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of ethyl cyanoacetate (12.44 parts), 1,1,3,4-tetrachloro-4-methylpent-1-ene (11.1 parts), 1,1-dichloro-4-methylpenta-1,3-diene (7.55 parts), cupric acetate H2O (2.0 parts) and in two cases lithium halide, in acetonitrile (100 parts by volume) is heated to reflux and held at 75°-80° C. for 6 hours. After cooling to room temperature the suspension is filtered and the residue is washed twice with acetonitrile (20 parts by volume). The combined filtrate and washes are distilled under reduced pressure to remove acetonitrile and the residue is extracted with a mixture of toluene (100 parts by volume), water (150 parts by volume) and concentrated hydrochloric acid (100 parts by volume). After filtering from extraneous matter the filtrates are separated and the toluene layer is washed twice with hydrochloric acid (50 parts by volume) diluted with water (50 parts) and finally four times with water (50 parts). The toluene is removed by distillation under reduced pressure to yield crude ethyl 1-cyano-3-(2',2'-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylate. Details are given in the following table:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:10][CH2:11][NH2:12])=[CH:5][CH:4]=1.[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:10][CH2:11][NH:12][S:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:29])=[O:28])=[CH:18][CH:17]=1
Reactant: COc1ccc(C(=CCN)c2ccc(OC)cc2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(C(=CCNS(=O)(=O)c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 5 h
Yield: 88 %

Procedure:
2.69 g of 3,3-bis-(4-methoxyphenyl)allylamine was dissolved in 5 ml of pyridine. To the obtained solution, 1.9 g of benzenesulfonyl chloride was added under icecooling and the mixture was stirred for five hours. After the completion of the reaction, the reaction mixture was dissolved in ethyl acetate and washed with 5% hydrochloric acid and a saturated saline solution successively. The crude product thus obtained was purified by silica gel chromatography in a conventional manner. Thus 3.6 g of the title compound was obtained in the form of a colorless oily product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:17](=[O:18])[O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Reactant: O=C(Cl)OCc1ccccc1
Product: O=C(NC1CCCc2c1[nH]c1ccc(Br)cc21)OCc1ccccc1

Procedure:
Benzyl 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-ylcarbamate was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and benzyl chloroformate in a similar manner as described above to give a white solid (16% yield). 1H-NMR (CDCl3): δ 8.69 (s, 1H), 7.60 (s, 1H), 7.43-7.31 (m, 5H), 7.27-7.21 (m, 1H), 7.17 (d, 1H), 5.16 (q, 2H), 5.08 (m, 1H), 4.92 (m, 1H), 2.66 (m, 2H), 2.20 (m, 1H), 1.89 (m, 2H), 1.80 (m, 1H); MS m/z 400 (M+1).
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(=O)(O)O.[NH2:25][NH:26][C:27]([NH2:29])=[NH:28].C1(C)C=CC=CC=1.C(=O)=O>O>[C:1]([NH2:25])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:25][NH:26][C:27]([NH2:29])=[NH:28]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: N=C(N)NN
Agent: O=C(O)O
Agent: O=C=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCC(N)=O
Temperature: 140 °C

Procedure:
A 5 liter, 3-neck flask was charged with 847.5 grams (3 moles) oleic acid, 3 moles of aminoguanidine bicarbonate, 300 mls of toluene and 15 drops of a silicone anti-foam agent. The reaction mixture was heated to reflux under a nitrogen blanket. Vigorous foaming was noted as carbon dioxide gas evolved. When the foaming subsided, water evolution began. A total of about 57 ml of water was collected from the reaction by means of a Dean-Stark trap. The temperature of the reaction mixture was raised to about 140° C. to facilitate the removal of toluene. The reaction product, believed to be primarily aminoguanidine oleamide, was filtered and placed under nitrogen for storage.
Reaction SMILES: [Br:1][C:2]1[CH:47]=[CH:46][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH:16]([CH2:20][C:21]([C:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([Br:39])=[CH:35][CH:34]=4)[C:24]=3[CH:40]([CH3:42])[CH3:41])=O)C(O)=O)=[C:8]2[CH:43]([CH3:45])[CH3:44])=[CH:4][CH:3]=1.C1(=O)[O:53][C:51](=[O:52])C=C1.BrC1C=CC(CN2C3C(=CC=CC=3)C=C2C(C)C)=CC=1.C(N1C2C(=CC=CC=2)C(C(CC(C2C3C(=CC=CC=3)N(CC)C=2C)=O)C(O)=O)=C1C)C>>[Br:39][C:36]1[CH:37]=[CH:38][C:33]([CH2:32][N:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:23]([CH:21]3[CH:20]=[C:16]([C:9]4[C:10]5[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=5)[N:7]([CH2:6][C:5]5[CH:46]=[CH:47][C:2]([Br:1])=[CH:3][CH:4]=5)[C:8]=4[CH:43]([CH3:45])[CH3:44])[O:53][C:51]3=[O:52])=[C:24]2[CH:40]([CH3:42])[CH3:41])=[CH:34][CH:35]=1
Reactant: CC(C)c1c(C(=O)CC(C(=O)O)c2c(C(C)C)n(Cc3ccc(Br)cc3)c3ccccc23)c2ccccc2n1Cc1ccc(Br)cc1
Reactant: O=C1C=CC(=O)O1
Agent: CC(C)c1cc2ccccc2n1Cc1ccc(Br)cc1
Agent: CCn1c(C)c(C(=O)CC(C(=O)O)c2c(C)n(CC)c3ccccc23)c2ccccc21
Product: CC(C)c1c(C2=CC(c3c(C(C)C)n(Cc4ccc(Br)cc4)c4ccccc34)C(=O)O2)c2ccccc2n1Cc1ccc(Br)cc1

Procedure:
Following a procedure similar to that described above in part A of this example except that 2,4-bis[1-(4-bromobenzyl)-2-isopropyl-3-indolyl]-4-oxobutanoic acid (prepared by the interaction of maleic anhydride and 1-(4-bromobenzyl)-2-isopropylindole in a similar manner to that described in Example 3, part A) is used in place of 2,4-bis(1-ethyl-2-methyl-3-indolyl)-4-oxobutanoic acid, there is obtained 3,5-bis[1-(4-bromobenzyl)-2-isopropyl-3-indolyl]-2(3H)-furanone (Formula II: R=4-BrC6H4CH2 ; R1 =(CH3)2CH; Y=H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:16][CH2:17][N:18]([C:24](=[O:25])[C:23]3[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=3[F:21])[CH2:19][CH2:20]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=C(Cl)c1ccccc1F
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2ccccc2F)CC1
Reaction time: 2 h
Yield: 121.4 %

Procedure:
1-(5-Chloro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.030 g, 0.10 mmol, from Example 47, Step 1) was combined with 2-fluorobenzoyl chloride (0.018 mL, 0.16 mmol) and triethylamine (0.043 mL, 0.31 mmol) in methylene chloride (1.0 mL) at room temperature and stirred for 2 hrs. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give the desired product (50 mg). LCMS calculated for C22H20ClFN3O2 (M+H)+: m/z=412.1; Found: 412.1.