Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.P(Cl)(Cl)(Cl)=O.[NH2:11][C:12]1[NH:13][C:14](=O)[C:15]2[N:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:16]=2[N:17]=1>C(#N)C>[Cl:22][C:20]1[CH:19]=[CH:18][C:16]2[N:17]=[C:12]([NH2:11])[N:13]=[C:14]([N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)[C:15]=2[N:21]=1
Reactant: c1nc[nH]n1
Reactant: Nc1nc2ccc(Cl)nc2c(=O)[nH]1
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1nc(-n2cncn2)c2nc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.9 %

Procedure:
A solution of 1,2,4-triazole (1.4 g, 20 mmol) and phosphorus oxychloride (1.4 mL, 15 mmol) in dry acetonitrile (40 mL) was adder to a stirred suspension of 2-amino-6-chloro-3H-pyrido[3,2-d]pyrimidin-4-one (1 g, 5 mmol) and N-N-di-isopropyl-ethyl-amine (DIEA; 4.4 ml, 25 mmol) in dry acetonitrile (30 ml). The mixture was stirred at room temperature for 24 hours. 2 molar equivalents of 1,2,4-triazole (0.7 g, 10 mmol), 1.5 equivalent of phosphorus oxychloride (0.7 ml, 7.5 mmol) and 2.5 equivalents of DIEA (2.2 ml, 12.5 mmol) were added to the mixture. After stirring at room temperature for 48 hours, the same amount of the above reagents was added again. The reaction mixture was stirred for 7 full days and the yellow precipitate was filtered off, washed successively with acetonitrile, DCM and ether. The solid was dried under vacuum, providing the pure title compound as a yellow solid (667 mg, yield 53%) which was characterised as follows: MS (m/z) 248.8 [M+H]+.
Reaction SMILES: [CH2:1]1[O:14][C:4]2([CH2:11][CH2:10][CH:9]3[CH2:12][CH:5]2[CH2:6][CH2:7][CH:8]3[NH2:13])[O:3][CH2:2]1.C(N(CC)CC)C.[CH2:22]([O:29][C:30](Cl)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl.O>[CH2:2]1[O:3][C:4]2([CH2:11][CH2:10][CH:9]3[CH2:12][CH:5]2[CH2:6][CH2:7][CH:8]3[NH:13][C:30]([O:29][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:31])[O:14][CH2:1]1
Reactant: NC1CCC2CC1CCC21OCCO1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(NC1CCC2CC1CCC21OCCO1)OCc1ccccc1
Reaction time: 8 h

Procedure:
1.97 g of 6-Amino-bicyclo[3.3.1]nonan-2-one ethylene ketal (98) were dissolved in 30 mL of dry dichloromethane and 1.52 mL of dry triethylamine and 1.42 mL of benzylchloroformate were added. The mixture was stirred overnight, taken up in water and extracted three times with ethyl acetate. The combined organic layer was dried over sodium sulfate and evaporated to dryness. The crude product was purified by chromatography to give 0.92 g of the desired product. Rt=3.18 min (Method E). Detected mass: 332.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:8]([CH2:12][O:13][CH2:14][CH:15](OC)OC)[NH:9][C:10]=1[CH3:11])=[O:4].Cl>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[CH:6]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:8]2[N:9]([C:10]=1[CH3:11])[CH:15]=[CH:14][O:13][CH2:12]2)=[O:4]
Reactant: CCOC(=O)C1=C(COCC(OC)OC)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)C1=C2COC=CN2C(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 25 °C
Yield: 65.8 %

Procedure:
To a solution of 4-(2-chlorophenyl)-2-(2,2-dimethoxy-ethoxymethyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylic acid 3-ethyl 5-methyl ester (XX, 9.2 g) in tetrahydrofuran (200 mL) was added 3N hydrochloric acid (40 mL). The mixture was then refluxed for 4 h. On cooling to room temperature, tetrahydrofuran was removed under reduced pressure and the residue taken up in ethyl acetate (200 mL). The organic phase was washed with brine, dried (sodium sulfate), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (grade 9385, Merck, 230-400 mesh, 60 Å) using a solvent mixture of hexane and ethyl acetate as eluent (90:10; 1L) as eluent to afford the title compound (XXI 5.2 g). 1H-NMR (CDCl3) δ (ppm): 1.22 (t, 3H, J=7.1 Hz), 2.43 (s, 3H), 3.68 (s, 3H), 4.12 (q, 2H, J=7. 1 Hz),4,60(d,1H, J=13.5 Hz), 5.48 (s, 1H), 5.70 (d, 1H, J=13.8 Hz), 6.21 (d, 1H, J=4.7 Hz), 6.30(d, 1H, J=4.6 Hz), 7.07-7.28 (m, 4H); 13C-NMR (CDCl3) δ (ppm): 14.1, 15.7, 36.6, 51.2, 60.6, 63.5, 105.8, 106.7, 107.8, 127.3, 127.8, 129.5, 130.4, 131.8, 132.5 139.2, 142.0, 143.4, 166.4, 168.1; HRMS: calc. for C20H20CIN2O5 389.1030 found 389.1020; Elemental Analysis (%): calc. (found) C 61.62 (61.78), H 5.17 (5.27), N 3.59 (3.51); M.p. 126.0°-126.8° C.; IR (KBr, cm-1): 1693, 1662, 1645, 1581.
Reaction SMILES: Br[CH2:2][Mg].Cl[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=2)[CH:8]=[CH:7][N:6]=1.Cl>[Ni](Cl)Cl.C1COCC1>[CH3:2][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=2)[CH:8]=[CH:7][N:6]=1
Reactant: [Mg]CBr
Reactant: COc1cc(-c2ccnc(Cl)c2)cc(OC)c1OC
Agent: Cl[Ni]Cl
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc(-c2ccnc(C)c2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Nickel chloride (3.0 mg) was added to THF (1 mL) under an argon atmosphere, and the mixture was kept at 0° C. To the mixture, a THF solution (0.38 mL) of 0.93 M bromomethylmagnesium was slowly added, and a THF solution (2 mL) of 2-chloro-4-(3,4,5-Trimethoxyphenyl)pyridine (50 mg) was then slowly added. The mixture was stirred at 0° C. for 10 minutes and then at 70° C. for 1.5 hours. A small amount was diluted hydrochloric acid was added to the reaction mixture at 0° C. to conduct extraction with ethyl acetate. The resultant organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=15:1) to obtain the title compound.
Reaction SMILES: [C:1]([C:3]([CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])C(OCC)=O)#[N:2].O.[Br-].[Li+].Cl>CN(C)C=O>[CH3:19][Si:16]([CH3:17])([CH3:18])[CH2:15][CH:3]([C:1]#[N:2])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CC(C#N)(C[Si](C)(C)C)C(=O)OCC
Agent: Cl
Agent: [Br-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC(C#N)C[Si](C)(C)C
Temperature: 150 °C
Reaction time: 15 h
Yield: 91 %

Procedure:
A solution of diethyl 2-cyano-2-(trimethylsilylmethyl)succinate (592 mg, 2.08 mmol) in dimethylformamide (DMF, 5 ml) was added with water (45 μl, 2.50 mmol) and lithium bromide (217 mg, 2.49 mmol), and the mixture was stirred at 150° C. for 15 hours. The reaction mixture was cooled on ice, and added with aqueous hydrochloric acid (1 N), and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and then dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel chromatography [hexane/ethyl acetate (14:1)] to obtain ethyl 4-trimethylsilyl-3-cyanobutanoate (404 mg, 91%) mentioned in the title as colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[Cl:30][C:31]1[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=1O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:29][C:32]2[CH:33]=[CH:34][C:35]([CH3:37])=[CH:36][C:31]=2[Cl:30])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(Br)cc3)CC2)c1
Reactant: Cc1ccc(O)c(Cl)c1
Product: Cc1ccc(OC(CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccc(Br)cc2)c(Cl)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-bromophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 2-chloro-4-methylphenol: ESMS m/e: 583.0 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[S:6][CH:7]=1.[NH:21]1[CH2:26][CH2:25][CH:24]([C:27]([O:29][CH3:30])=[O:28])[CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:30][O:29][C:27]([CH:24]1[CH2:25][CH2:26][N:21]([CH2:2][C:3]2[N:4]=[C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)[S:6][CH:7]=2)[CH2:22][CH2:23]1)=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(CCl)cs2)CC1
Reactant: COC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1CCN(Cc2csc(N3CCN(C(=O)OC(C)(C)C)CC3)n2)CC1
Temperature: 70 °C
Reaction time: 18 h
Yield: 50.2 %

Procedure:
A solution of tert-butyl 4-(4-chloromethylthiazol-2-yl)piperazine-1-carboxyate (860 mg, 2.7 mmol) and methyl piperidine-4-carboxylate (539 mg, 3 mmol) in DMF was treated with potassium carbonate (414 mg, 3 mmol). The mixture was stirred at 70° C. for 18 hours and then concentrated under vacuum. Product was purified from the residue by flash chromatography on silica gel to provide tert-butyl 4-[4-(4-methoxycarbonylpiperidin-1-ylmethyl)thiazol-2-yl]piperazine-1-carboxylate (575 mg, 50% yield). HNMR (dmso-d6): 6.58 (1H, s), 3.59 (2H, s), 3.42 (4H, m), 3.34 (4H, m), 3.32 (3H, s), 2.78 (2H, m), 2.28 (1H, m), 2.02 (2H, m), 1.77 (2H, m), 1.57 (2H, m), 1.41 (3H, s).
Reaction SMILES: C1(C2C=NN(C3C=CC=CC=3OC(F)(F)F)C=2COC2C=CC(N(CC3C=CC(C(O)=O)=C(OC)C=3)C)=C(C)C=2)CC1.C[O:44][C:45](=[O:87])[C:46]1[CH:51]=[CH:50][C:49]([CH2:52][N:53]([C:55]2[CH:60]=[CH:59][C:58]([O:61][CH2:62][C:63]3[N:64]([C:71]4[CH:76]=[CH:75][CH:74]=[CH:73][C:72]=4[O:77][C:78]([F:81])([F:80])[F:79])[N:65]=[CH:66][C:67]=3[CH:68]3[CH2:70][CH2:69]3)=[CH:57][C:56]=2[CH3:82])[CH3:54])=[CH:48][C:47]=1[O:83][CH:84]([CH3:86])[CH3:85]>>[CH:68]1([C:67]2[CH:66]=[N:65][N:64]([C:71]3[CH:76]=[CH:75][CH:74]=[CH:73][C:72]=3[O:77][C:78]([F:81])([F:79])[F:80])[C:63]=2[CH2:62][O:61][C:58]2[CH:59]=[CH:60][C:55]([N:53]([CH2:52][C:49]3[CH:50]=[CH:51][C:46]([C:45]([OH:87])=[O:44])=[C:47]([O:83][CH:84]([CH3:85])[CH3:86])[CH:48]=3)[CH3:54])=[C:56]([CH3:82])[CH:57]=2)[CH2:70][CH2:69]1
Reactant: COC(=O)c1ccc(CN(C)c2ccc(OCc3c(C4CC4)cnn3-c3ccccc3OC(F)(F)F)cc2C)cc1OC(C)C
Agent: COc1cc(CN(C)c2ccc(OCc3c(C4CC4)cnn3-c3ccccc3OC(F)(F)F)cc2C)ccc1C(=O)O
Product: Cc1cc(OCc2c(C3CC3)cnn2-c2ccccc2OC(F)(F)F)ccc1N(C)Cc1ccc(C(=O)O)c(OC(C)C)c1

Procedure:
In a manner similar to the preparation of 4-[({4-[4-cyclopropyl-2-(2-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-methyl-amino)-methyl]-2-methoxy-benzoic acid, utilizing 4-[({4-[4-cyclopropyl-2-(2-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-methyl-amino)-methyl]-2-isopropoxy-benzoic acid methyl ester, the title compound is prepared. LC-ES/MS m/e 610.2 (M+1).
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[NH2:19][C:20]1[C:24]([C:25]#[N:26])=[C:23]([S:27][CH3:28])[NH:22][N:21]=1>O1CCCC1>[CH3:28][S:27][C:23]1[NH:22][N:21]=[C:20]([NH:19][CH:8]=[C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[C:24]=1[C:25]#[N:26]
Reactant: O=C1Nc2ccccc2/C1=C/O
Reactant: CSc1[nH]nc(N)c1C#N
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: CSc1[nH]nc(NC=C2C(=O)Nc3ccccc32)c1C#N

Procedure:
The named compound is prepared by substituting 3-amino-5-methylsulfanyl-1H-pyrazole-4-carbonitrile for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.100 gms.) is reacted with 0.2003 gms. of 3-amino-5-methylsulfanyl-1H-pyrazole-4-carbonitrile by refluxing in tetrahydrofuran (2.5 mL).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)[CH3:2].[CH:12]([NH:15][OH:16])([CH3:14])[CH3:13]>>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[N+:15]([CH:12]([CH3:14])[CH3:13])[O-:16])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C=O)cc1
Reactant: CC(C)NO
Product: CCOc1ccc(C=[N+]([O-])C(C)C)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 11 using 4-ethoxybenzaldehyde and N-isopropylhydroxylamine. The title compound was isolated in 41.2% yield as a solid, m.p. 115.1 ° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[O:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[CH2:20][OH:21]>>[O:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[CH2:20][O:21][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12]
Reactant: O=C(O)c1ccc(C(F)(F)F)c(Cl)n1
Reactant: OCC1CCCO1
Product: O=C(O)c1ccc(C(F)(F)F)c(OCC2CCCO2)n1

Procedure:
The title compound was prepared in analogy to the procedure described in Example 230 b), using 6-chloro-5-(trifluoromethyl)picolinic acid and (tetrahydrofuran-2-yl)methanol (CAN 97-99-4) as starting materials. MS: 290.0 [M−H]−.
Reaction SMILES: COC(C1CC2C(=CC=C(S)C=2)C1)=O.[CH3:15][O:16][C:17](=[O:48])[CH2:18][N:19]1[C:28]2[C:23](=[CH:24][C:25]([S:29]CC3SC(C4C=CC(C(F)(F)F)=CC=4)=NC=3C)=[CH:26][CH:27]=2)[CH2:22][CH2:21][C:20]1=[O:47]>>[CH3:15][O:16][C:17](=[O:48])[CH2:18][N:19]1[C:28]2[C:23](=[CH:24][C:25]([SH:29])=[CH:26][CH:27]=2)[CH2:22][CH2:21][C:20]1=[O:47]
Reactant: COC(=O)CN1C(=O)CCc2cc(SCc3sc(-c4ccc(C(F)(F)F)cc4)nc3C)ccc21
Agent: COC(=O)C1Cc2ccc(S)cc2C1
Product: COC(=O)CN1C(=O)CCc2cc(S)ccc21
Yield: 92 %

Procedure:
12C was prepared analogously to compound 1C. 92% yield. MS: 252 (M+1)+. Preparation of {6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-2-oxo-3,4-dihydro-2H-quinolin-1-yl}-acetic acid methyl ester (Compound 12D)
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH2:11][NH2:12].[CH:13](=O)[CH2:14][CH2:15][CH3:16]>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH2:11][NH:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCC=O
Reactant: Cn1c(CN)cc2ccccc21
Product: CCCCNCc1cc2ccccc2n1C
Yield: 10.4 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 137, (1-methyl-1H-indol-2-yl)methanamine (500 mg, 3.12 mmol) and butyraldehyde (310 μL, 3.43 mmol) were converted to the title compound (70 mg, 6%). 1H NMR (CDCl3) δ 7.62-7.54 (m, 1H), 7.36-7.27 (m, 1H), 7.27-7.16 (m, 1H), 7.17-7.03 (m, 1H), 6.50 (s, 1H), 4.05 (s, 2H), 3.77 (s, 3H), 2.82-2.70 (m, 2H), 1.60 (ddd, J=15.1, 7.5, 7.4 Hz, 2H), 1.45-1.16 (m, 2H), 0.96-0.87 (m, 3H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([C@@H:8]([NH2:15])[C:9]1C=CC=CC=1)=[O:7])([CH3:4])[CH3:3].[ClH:16].Cl.C(OC(=O)[C@H:24]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[NH2:25])(C)(C)C>>[NH2:15][C@H:8]([C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])[CH2:9][C:26]1[C:27]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:25][CH:24]=1.[ClH:16]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H](N)c1ccccc1
Agent: Cl
Product: CC(C)(C)OC(=O)[C@@H](N)Cc1c[nH]c2ccccc12

Procedure:
H-PhG-OtBu HCl for phenylalanine tert butyl ester hydrochloride, the following compounds were prepared:
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1.[H-].[Na+]>>[C:1]([O:5][C:6](=[O:13])[N:7]([CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1)[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)Nn1cccc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N(Cc1ccc2ccccc2c1)n1cccc1

Procedure:
Prepared according to the benzylation condition used in Example 1 step b) from pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.), 2-bromomethyl-naphthalene (1.03 eq.) and sodium hydride (1.3 eq.). ESI (m/z): 323 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=CC(C(O)=O)=C[C:6]=1[NH:14][C:15](=[O:33])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:4])([CH3:3])[CH3:2].[CH3:34][CH:35]([CH3:39])[C:36]([NH2:38])=[O:37]>C(#N)C>[C:1]([C:5]1[CH:10]=[CH:39][C:35]([C:36]([NH:38][C:24](=[O:31])[CH:23]([CH3:28])[CH3:17])=[O:37])=[CH:34][C:6]=1[NH:14][C:15](=[O:33])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)C(N)=O
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)O)ccc1C(C)(C)C)c1ccc(OC)cc1OC
Solvent: CC#N
Product: CCCCCC(CC(=O)Nc1cc(C(=O)NC(=O)C(C)C)ccc1C(C)(C)C)c1ccc(OC)cc1OC

Procedure:
Following a similar procedure to that described in Example 139, but using N-(2-t-butyl-5-carboxyphenyl)-3-(2,4-dimethoxyphenyl)octanamide (prepared as described in Preparation 7) and 2-methylpropanamide, the title compound was obtained as crystals, melting at 157°-159° C. (from acetonitrile).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:10]([C:13]1[CH:18]=[C:17]([F:19])[C:16]([CH:20]=[CH2:21])=[C:15]([F:22])[CH:14]=1)(=[O:12])=[O:11].ClC1C=C(C=CC=1)C(OO)=[O:32]>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:10]([C:13]1[CH:18]=[C:17]([F:19])[C:16]([CH:20]2[CH2:21][O:32]2)=[C:15]([F:22])[CH:14]=1)(=[O:12])=[O:11]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1c(F)cc(S(=O)(=O)N(CC(C)C)c2ccc(C)cc2C)cc1F
Solvent: ClCCl
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2cc(F)c(C3CO3)c(F)c2)c(C)c1
Reaction time: 24 h

Procedure:
To a solution of N-(2,4-dimethylphenyl)-3,5-difluoro-N-isobutyl-4-vinylbenzenesulfonamide (1.5 g, 3.95 mmol) in dichloromethane (DCM) at 0° C. was added meta-chloroperoxybenzoic acid (mCPBA) (2.73 g, 15.81 mmol) and the reaction mixture stirred for 24 hours from 0° C. to 25° C. Additional mCPBA (1.364 g, 7.91 mmol) was then added and the reaction stirred for a further 6 hours. The reaction was then washed with water (2 mL), sodium hydroxide solution (2M, 2 mL) and brine (2 mL), then evaporated in vacuo. The crude was purified by flash silica (Si) chromatography (0-100% dichloromethane-cyclohexane gradient). The appropriate fractions were combined and evaporated in vacuo to give the required product, 926 mg, as a yellow oil. LCMS [LCMS2] Rt. 1.45, m/z (ES+) 396 (M+H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2.C(N(CC)CC)C.[CH3:31][C:32]1[CH:33]=[C:34]([N:39]=[C:40]=[O:41])[CH:35]=[CH:36][C:37]=1[CH3:38]>C1COCC1>[CH3:31][C:32]1[CH:33]=[C:34]([NH:39][C:40]([NH:2][CH2:3][C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[C:6](=[O:23])[N:7]([CH:15]2[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]2=[O:22])[C:8]([CH3:14])=[N:9]3)=[O:41])[CH:35]=[CH:36][C:37]=1[CH3:38]
Reactant: Cc1ccc(N=C=O)cc1C
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)NCc2cccc3nc(C)n(C4CCC(=O)NC4=O)c(=O)c23)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
To a stirred suspension of 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.53 g, 1.6 mmol) and triethylamine (0.31 mL, 2.2 mmol) in THF (15 mL) at 5˜10° C., was added 3,4-dimethyl phenyl isocyanate (0.29 mL, 2.1 mmol). Then the mixture was stirred at room temperature overnight. The mixture was quenched with methanol (˜1 mL), and the solvent was evaporated. The residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 1-(3,4-dimethyl-phenyl)-3-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-urea as an off-white solid (520 mg, 73% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 6.14 min (96.6%); mp, 241-243° C.; 1HNMR (DMSO-d6)2.11-2.21 (m, 7H, CHH, 2ArCH3), 2.59-2.94 (m, 6H, CHCH2, CH3), 4.71 (d, J=5 Hz, 2H, CH2NH), 5.27 (dd, J=6, 11 Hz, 1H, CH), 6.56 (t, J=5 Hz, 1H, CH2NH), 6.92-7.78 (m, 6H, Ar), 8.58 (s, 1H, NH), 11.05 (s, 1H, NH); 13C NMR (DMSO-d6) δ 18.58, 19.59, 20.70, 23.24, 30.62, 42.26, 56.52, 115.18, 117.76, 118.99, 125.54, 126.28, 128.50, 129.46, 134.01, 136.03, 138.15, 141.69, 148.27, 154.87, 155.11, 160.94, 169.47, 172.65. LCMS MH=448; Anal Calcd For C24H25N5O4+2.0H2O: C, 59.62; H, 6.05; N, 14.48. Found: C, 59.36; H, 5.95; N, 14.24.
Reaction SMILES: [CH2:1]([N:4]([CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([CH3:20])=[C:14]2[CH3:21])[CH3:5])[CH:2]=[CH2:3].F[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1>>[CH2:1]([N:4]([CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)[C:15]([CH3:20])=[C:14]2[CH3:21])[CH3:5])[CH:2]=[CH2:3]
Reactant: C=CCN(C)CCCCOc1ccc2[nH]c(C)c(C)c2c1
Reactant: Fc1ccc(C(F)(F)F)cc1
Product: C=CCN(C)CCCCOc1ccc2c(c1)c(C)c(C)n2-c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to example 9.1, Allyl-[4-(2,3-dimethyl-1H-indol-5-yloxy)-butyl]-methyl-amine and 1-Fluoro-4-trifluoromethyl-benzene were converted to yield Allyl-{4-[2,3-dimethyl -1-(4-trifluoromethyl-phenyl)-1H-indol-5-yloxy]-butyl}-methyl-amine as yellow oil, MS: 431 (MH+).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:7]([OH:9])=[O:8])=[CH:5][N:6]=1.[Li+].CC([N-]C(C)C)C.Cl[CH2:19][C:20]1[C:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:22][O:23][C:24]=1[CH3:25]>C1COCC1>[CH3:25][C:24]1[O:23][N:22]=[C:21]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]=1[CH2:19][CH2:1][C:2]1[S:3][C:4]([C:7]([OH:9])=[O:8])=[CH:5][N:6]=1
Reactant: Cc1ncc(C(=O)O)s1
Reactant: Cc1onc(-c2ccccc2)c1CCl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1onc(-c2ccccc2)c1CCc1ncc(C(=O)O)s1
Temperature: 25 °C
Yield: 61.3 %

Procedure:
To a stirred solution of 2-methyl-thiazole-5-carboxylic acid (100 mg, 0.7 mmol) in THF (5 mL) at −72° C. and under argon was added LDA (0.7 mL of a 2M solution in THF, 1.40 mmol) dropwise. After 1.5 h a solution of 4-chloromethyl-5-methyl-3-phenyl-isoxazole (145 mg, 0.7 mmol) in THF (5 mL) was added dropwise. After 1 h the reaction mixture was quenched with HCl (1N, 10 mL) then warmed to room temperature and extracted with ethyl acetate. The combined extracts were dried, filtered and concentrated then triturated with diisopropyl ether to give the title compound (135 mg, 61%) as a light brown solid which was used directly in the next reaction.
Reaction SMILES: Br[C:2]1[CH:13]=[N:12][C:5]2[NH:6][C:7](=[O:11])[NH:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[C:14]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:17])[CH:15]=[CH2:16].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:19]([O:18][C:14](=[O:17])/[CH:15]=[CH:16]/[C:2]1[CH:13]=[N:12][C:5]2[NH:6][C:7](=[O:11])[NH:8][C:9](=[O:10])[C:4]=2[CH:3]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: O=c1[nH]c(=O)c2cc(Br)cnc2[nH]1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)/C=C/c1cnc2[nH]c(=O)[nH]c(=O)c2c1
Yield: 83.5 %

Procedure:
A suspension of 6-bromo-1H-pyrido[2,3-d]pyrimidine-2,4-dione (430 mg, 1.59 mmol) in propionitrile (8 mL) and DMF (2 mL) was treated with tert-butyl acrylate (0.93 mL, 6.4 mmol), (i-Pr)2EtN (0.6 mL, 3.3 mmol) and P(o-tol)3 (100 mg, 0.32 mmol). The solution was deoxygenated with Ar for 20 min. Pd(OAc)2 (36 mg, 0.16 mmol) was added and the mixture was deoxygenated with a stream of Ar for 10 min. The mixture was heated to reflux for 17 h, then allowed to cool. The resulting precipitate was isolated by filtration to give the title compound (384 mg, 83%) as a gray solid: 1H NMR (300 MHz, DMSO-d6) δ 11.88 (s, 1H), 11.54 (s, 1H), 8.96 (d, J=2.2 Hz, 1H), 8.53 (d, J=2.2 Hz, 1H), 7.65 (d, J=16.1 Hz, 1H), 6.72 (d, J=16.1 Hz, 1H), 1.49 (s, 9H); ESI MS m/e 290 (M+H)+.