Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Cl:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl.[NH2:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][OH:28]>CN(C=O)C.CC(C)=O>[ClH:20].[NH2:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: NCCOCCO
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCC(=O)OCCOCCN
Reaction time: 16 h
Yield: 40 %

Procedure:
Stearoyl chloride (6.4 g; 21 mmol) (commercial product) was added dropwise in 5 min to a solution of 2-(2-aminoethoxy)ethanol hydrochloride (2.9 g; 20 mmol) in DMF (50 mL) at room temperature to afford a suspension. After 16 h, the suspension was diluted with acetone and the precipitated solid filtered and washed with acetone. The crude was crystallized from EtOAc; the solid was filtered, washed with EtOAc and dried under reduced pressure to give the desired compound (3.3 g; 8 mmol). Yield 40%. Acidic titer (0.1 N NaOH): 93%. K.F.: 1.06%. The 1H-NMR, 13C-NMR, MS and IR spectra were consistent with the structure.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.[CH3:21][O:22][C:23]1[CH:28]=[C:27]([N:29]2[CH2:35][CH2:34][CH2:33][N:32]([CH:36]3[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]3)[CH2:31][CH2:30]2)[CH:26]=[CH:25][C:24]=1[NH2:43].COC1C=C(C2CCN(C[C@H](OC3N=CC4=CC=C(C5C=CC=CC=5OC)N4N=3)C(F)(F)F)CC2)C=CC=1N>>[CH3:21][O:22][C:23]1[CH:28]=[C:27]([N:29]2[CH2:35][CH2:34][CH2:33][N:32]([CH:36]3[CH2:37][CH2:38][N:39]([CH3:42])[CH2:40][CH2:41]3)[CH2:31][CH2:30]2)[CH:26]=[CH:25][C:24]=1[NH:43][C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1
Reactant: COc1cc(N2CCCN(C3CCN(C)CC3)CC2)ccc1N
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Agent: COc1cc(C2CCN(C[C@H](Oc3ncc4ccc(-c5ccccc5OC)n4n3)C(F)(F)F)CC2)ccc1N
Product: COc1cc(N2CCCN(C3CCN(C)CC3)CC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1

Procedure:
Following the experimental procedure described in Example 753, 2-methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine and 2-methoxy-4-[4-(1-methyl-piperidin-4-yl)-perhydro-1,4-diazepin-1-yl]-phenylamine were converted to 2-methoxy-4-(1-{(S)-3,3,3-trifluoro-2-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yloxy]-propyl}-piperidin-4-yl)-phenylamine as a yellow solid (61 mg, 46%). MP: 71-80° C.; 1H-NMR (CDCl3) δ 8.64 (s, 1H), 8.13 (d, J=8.7 Hz, 1H), 8.06 (d, J=7.6 Hz, 1H), 7.40 (m, 1H), 7.15 (s, 1H), 7.11 (m, 1H), 7.05 (d, J=8.4 Hz, 1H), 7.00 (d, J=2.5 Hz, 1H), 6.78 (d, J=3.2 Hz, 1H), 6.27 (s, 1H), 6.18 (d, J=8.8 Hz, 1H), 3.86 (s, 3H), 3.84 (s, 3H), 3.50 (br s, 4H), 2.87 (m, 4H), 2.64 (br s, 2H), 2.47 (m, 1H), 2.25 (s, 3H), 1.93 (m, 4H), 1.72 (m, 2H), 1.61 (m, 2H); LC/MS (ESI+): 542.3 (M+H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:22]=[CH:21][C:20]4=[CH:23][CH:24]=[C:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[O:32][CH3:33])[N:19]4[N:18]=3)=[C:12]([O:34][CH3:35])[CH:11]=2)[C@@H:6]([OH:36])[CH2:5]1.C(N(CC)CC)C.C(Cl)Cl.[Br:47][C:48]1[CH:56]=[CH:55][C:51]([C:52](Cl)=[O:53])=[CH:50][CH:49]=1>>[OH:36][C@@H:6]1[C@@H:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:22]=[CH:21][C:20]4=[CH:23][CH:24]=[C:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[O:32][CH3:33])[N:19]4[N:18]=3)=[C:12]([O:34][CH3:35])[CH:11]=2)[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][O:1][C:52](=[O:53])[C:51]2[CH:55]=[CH:56][C:48]([Br:47])=[CH:49][CH:50]=2)[CH2:5]1
Reactant: COc1cc([C@H]2CCN(CCO)C[C@@H]2O)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc([C@H]2CCN(CCOC(=O)c3ccc(Br)cc3)C[C@@H]2O)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.8 %

Procedure:
To a mixture of (3R,4R)-1-(2-hydroxy-ethyl)-4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-3-ol (Example 16b; 40.00 mg, 0.082 mmol) and triethylamine (12 uL, 0.09 mmol) in methylene chloride (0.400 mL, 6.24 mmol) was added 4-bromo-benzoyl chloride, (19 mg, 0.086 mmol) at 0° C. The reaction was stirred overnight allowing the cooling bath/reaction to slowly warm to room temperature. The volatile were evaporated and the crude residue was further dried on high vacuum, The product was isolated by preparative reverse phase hplc (Gilson) and the free base was released by using a strong cation exchange resin column (Strata, from Phenomenex) to give 33 mg (60% yield) of 4-bromo-benzoic acid 2-((3R,4R)-3-hydroxy-4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-ethyl ester. 1H NMR (CDCl3): 8.70 (br s, 1H), 8.35 (d, J=8.1 Hz, 1H), 7.96 (d, J=7.6 Hz, 1H), 7.92 (d, J=8.4 Hz, 2H), 7.60 (d, J=8.4 Hz, 2H), 7.47 (br s, 1H), 7.46-7.40 (m, 1H), 7.12 (app t, J=7.5 Hz, 1H), 7.07 (d, J=8.3 Hz, 1H), 7.02 (d, J=4.7 Hz, 1H), 6.85 (d, J=4.7 Hz, 1H), 6.78 (d, J=8.7 Hz, 1H), 6.76 (br s, 1H), 4.50 (app t, J=5.8 Hz, 2H), 3.89 (s, 3H), 3.84 (s, 3H), 3.80 (m, 1H), 3.31 (m, 1H), 3.04 (br d, J=11.3 Hz, 1H), 2.90 (app t, J=5.8 Hz, 2H), 2.35 (m, 1H), 2.26 (m, 1H), 2.15 (app t, J=10.2 Hz, 1H), 1.86 (m, 2H), 1.67 (br s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=O)[O:13][C:14](=[O:21])[C:15]=2[C:16]2[CH:20]=[CH:19][NH:18][CH:17]=2)=[CH:3]1.C[N:24](C=O)C.N>O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:13])[NH:24][C:14](=[O:21])[C:15]=2[C:16]2[CH:20]=[CH:19][NH:18][CH:17]=2)=[CH:3]1
Reactant: CN(C)C=O
Reactant: Cn1cc(C2=C(c3cc[nH]c3)C(=O)OC2=O)c2ccccc21
Agent: N
Solvent: O
Product: Cn1cc(C2=C(c3cc[nH]c3)C(=O)NC2=O)c2ccccc21
Temperature: 140 °C

Procedure:
135 mg of 3-(1-methyl-3-indolyl)-4-(3-pyrrolyl)furan-2,5-dione were treated with 5 ml of DMF and 5 ml of 33% aqueous ammonia. The solution was heated at 140° C. for 4 hours. The cooled solution was diluted with water and extracted with dichloromethane. The dichloromethane extracts were dried and concentrated. Chromatography of the residue on silica gel with ethyl acetate/hexane (1:1) followed by crystallization from ethyl acetate/hexane gave 50 mg of 3-(1-methyl-3-indolyl)-4-(3-pyrrolyl)-1H-pyrrole-2,5-dione, m.p. 240°-241° C.
Reaction SMILES: C([C@]1(CO)O[C@@](C(=O)C)([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[C@](C(=O)C)(O)[C@]1(C(=O)C)O)(=O)C.[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[ClH:41]>C(#N)C>[ClH:41].[ClH:41].[CH2:33]([N:11]1[C:12]2[C:13](=[O:14])[NH:15][C:16]([NH2:17])=[N:18][C:19]=2[N:9]=[CH:10]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(=O)[C@@]1(O)[C@@](O)(C(C)=O)[C@](CO)(C(C)=O)O[C@@]1(C(C)=O)n1cnc2c(=O)[nH]c(N)nc21
Reactant: BrCc1ccccc1
Agent: Cl
Solvent: CC#N
Product: Nc1nc2ncn(Cc3ccccc3)c2c(=O)[nH]1
Temperature: 50 °C
Reaction time: 17 h
Yield: 57.4 %

Procedure:
Tetraacetylguanosine (0.904 g, 2.00 mmols) was dissolved in 2 ml of acetonitrile, and 0.59 ml (2.48 equivalents) of benzyl bromide were added thereto. The reaction was conducted at 50° C. for 17 hours. After it was identified through HPLC that the starting material disappeared, 5 ml (29.6 equivalents) of conc. hydrochloric acid were added to the reaction solution, and the mixture was stirred at 50° C. for 3 hours. Then, the reaction solution turned black, and the gray solid was precipitated. The temperature was returned to room temperature, and 5 ml of methanol were added to the solid. The slurry was stirred for 20 minutes, and then filtered. The crystals were washed with 10 ml of methanol, and dried at 50° C. under reduced pressure to give 0.690 g of gray crystals in a yield of 57.4%.
Reaction SMILES: [CH2:1]([O:5][C:6]([NH:8]C(CNS(CCCCl)(=O)=O)COC(=O)NCCCCCCCCCCCCCCCCCC)=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:42]([S:58][CH2:59][CH:60](OC)[CH2:61][NH:62][S:63]([CH2:66][CH2:67][CH2:68][I:69])(=[O:65])=[O:64])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57]>>[CH2:1]([O:5][C:6]([NH:8][CH:60]([CH2:61][NH:62][S:63]([CH2:66][CH2:67][CH2:68][I:69])(=[O:64])=[O:65])[CH2:59][S:58][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)NC(=O)OCCCC
Product: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)NC(=O)OCCCC

Procedure:
2-Butoxycarbonylamino-3-(3-chloropropylsulfonylamino)-1-hexadecylthiopropane III e4 is allowed to react and worked up by the same procedure as described in (5). m.p. 82°-83° C. The summary of the experimental condition and the physical data of the product are listed in Table 8.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.C(=O)(O)[O-].[Na+]>CCO>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:1]=2)[CH:4]=1
Reactant: Cc1ccc(N)nc1
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc2nc(-c3ccccc3)cn2c1
Temperature: 25 °C
Yield: 72 %

Procedure:
A stirred mixture of 2-amino-5-picoline (0.56 g, 5.22 mmol) and 2-bromoacetophenone (1.0 g, 5.02 mmol) in EtOH (50 ml) was heated under reflux for 2 h. The reaction mixture was left to cool to room temperature and then sodium bicarbonate (0.76 g, 9.04 mmol) was added and the reaction mixture was heated under reflux for 15 h. The solvent was then removed under reduced pressure and the residue was dissolved in EtOAc (70 ml) and washed with water (40 ml). The organic phase was dried (Na2SO4) and the solvent was removed under reduced pressure to give an orange solid. This solid was purified by flash chromatography (1:1 Hexane/EtOAc) to give the title compound (0.753 g, 70%) as a pale orange solid.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][C:21]2([C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25][CH2:24]2)[CH2:20][CH2:19]1)=[O:17].[NH2:32][C:33]1[C:34]([CH3:39])=[CH:35][CH:36]=[CH:37][CH:38]=1>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[CH3:39])=[C:3]([C:16]([N:18]3[CH2:19][CH2:20][C:21]4([C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH2:25][CH2:24]4)[CH2:22][CH2:23]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: Cc1ccccc1N
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC4(CCc5ccccc54)CC3)cnc12
Product: CCOC(=O)c1cnn2c(Nc3ccccc3C)c(C(=O)N3CCC4(CCc5ccccc54)CC3)cnc12
Yield: 83.3 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(spiro[indane-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine (0.15 g, 0.33 mmol) obtained in step 2 and o-toluidine (0.053 g, 0.5 mmol), the title compound (0.14 g, 85%) was obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:19])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:20][C:21]1[N:22]=[C:23]([CH3:29])[NH:24][C:25]=1[C:26](O)=[O:27]>>[Cl:20][C:21]1[N:22]=[C:23]([CH3:29])[NH:24][C:25]=1[C:26]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[CH:17][CH:16]=[C:13]([C:14]#[N:15])[CH:12]=2)[C:4]=1[F:19])=[O:27]
Reactant: N#Cc1cccc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: Cc1nc(Cl)c(C(=O)O)[nH]1
Product: Cc1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cccc(C#N)c3)c2F)[nH]1
Yield: 40.1 %

Procedure:
A solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-bromobenzonitrile (0.20 g, 0.56 mmol), sodium formate (0.057 g, 0.84 mmol) and Pd(Ph3P)4 (0.032 g, 0.028 mmol) in DMF (1.13 ml) was heated at 100° C. for 6 h. Water was added and the mixture was extracted with EtOAc. The organic phase was dried (Na2SO4), filtered, and dried to afford 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}benzonitrile, which was used without further purification. The above amine (0.28 mmol) and 4-chloro-2-methyl-1H-imidazole-5-carboxylic acid (0.040 g, 0.25 mmol) were employed in a similar process described herein to prepare the title compound (0.042 g, 40%) as a white solid after purification by Reverse-Phase HPLC (water:acetonitrile with 0.1% TFA) followed by neutralization. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 11.89 (br. s., 1H), 7.32-7.45 (m, 2H), 7.12-7.31 (m, 4 H), 7.08 (s, 1H), 4.70 (d, J=5.91 Hz, 2H), 2.37 (s, 3H). ES-LCMS: m/z 419.0, 421.0 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[NH:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=2)[C:11](=[O:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([NH:32][C:21]([C:17]1[NH:16][C:15]([N:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][C:11]2=[O:24])=[N:19][C:18]=1[CH3:20])=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NCc1ccccc1
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)[nH]c1C(=O)O
Product: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)[nH]c1C(=O)NCc1ccccc1
Yield: 59 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methyl-1H-imidazole-5-carboxylic acid in place of 4-methyl-2-(2-oxo-4-phenylpyridin-1(2H)-yl)thiazole-5-carboxylic acid to react with benzylamine, the title compound was obtained as a colorless solid in 59% yield: mp 183-184° C.; 1H NMR (300 MHz, CDCl3) δ 11.86 (br s, 1H), 8.42 (d, J=8.0 Hz, 1H), 7.43-7.26 (m, 10H), 6.18 (dd, J=8.0, 2.6 Hz, 1H), 6.04 (d, J=2.6 Hz, 1H), 5.05 (s, 2H), 4.61 (d, J=6.0 Hz, 2H), 2.65 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 167.4, 163.6, 163.4, 138.8, 134.6, 132.2, 129.5, 128.8, 128.7, 128.6, 127.8, 127.8, 127.3, 126.9, 103.5, 98.4, 70.7, 42.7, 11.0; MS (ES+) m/z 415.2 (M+1).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].N1C=CC=CC=1.[NH2:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[S:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1)[C:18](=[O:28])[CH2:17][CH2:16]2.CCN(CC)CC>C(Cl)Cl.O>[CH3:1][S:2]([N:12]([S:2]([CH3:1])(=[O:4])=[O:3])[C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[S:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1)[C:18](=[O:28])[CH2:17][CH2:16]2)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc2c(cc1Sc1nccs1)C(=O)CC2
Solvent: O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N(c1cc2c(cc1Sc1nccs1)C(=O)CC2)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanesulfonyl chloride (710 μL, 9.15 mmol) and pyridine (740 μL, 9.15 mmol) were added to a solution of the aminoindanone from Step 8 in CH2Cl2 (5 mL). After stirring overnight at room temperature, Et3N (400 μL, 2.8 mmol) and methanesulfonyl chloride (220 μL, 2.8 mmol) were added. The mixture was stirred 4 h at room temperature. Water and CH2Cl2 were added, the aqueous phase was extracted with CH2Cl2 and the combined organic phase was washed with 0.1M aqueous citric acid, dried over MgSO4 and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (20% EtOAc in CHCl2) to give 175 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH3:24])[CH2:10][C:11]1[C:19]2[O:18][CH:17]=[CH:16][C:15]=2[CH:14]=[C:13]([C:20]([O:22]C)=[O:21])[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C.O>[C:1]([O:5][C:6]([NH:8][CH:9]([CH3:24])[CH2:10][C:11]1[C:19]2[O:18][CH:17]=[CH:16][C:15]=2[CH:14]=[C:13]([C:20]([OH:22])=[O:21])[CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(CC(C)NC(=O)OC(C)(C)C)c2occc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(Cc1cc(C(=O)O)cc2ccoc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.1 %

Procedure:
A mixture of 0.341 gm (1.02 mMol) N-tert-butoxycarbonyl 1-(5-methoxycarbonylbenzofur-7-yl)-2-aminopropane (EXAMPLE 41) and 0.204 gm (5.1 mMol) sodium hydroxide in 2 mL ethanol and 0.5 mL water was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and the residue dissolved in water. This aqueous solution was washed with ethyl acetate and the organic phase discarded. The remaining aqueous phase was made acidic by the addition of aqueous potassium hydrogen sulfate. The aqueous phase was again extracted with ethyl acetate. This organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from a mixture of chloroform and hexane to provide 0.300 gm (92%) of the title compound as a white crystalline solid in two crops.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[CH2:9]([NH2:11])[CH3:10]>C(Cl)Cl.O>[CH2:9]([NH:11][C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:7])[CH3:10]
Reactant: O=C(Cl)c1cccs1
Reactant: CCN
Solvent: ClCCl
Solvent: O
Product: CCNC(=O)c1cccs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.1 %

Procedure:
A solution of 2-thiophenecarboxylic acid chloride (7.3 g, 50 mmol) in 30 mL CH2Cl2 was added to 70% ethylamine in water (11 g) at -5° C. and the resulting solution was stirred at RT for 18 h. After that, water was added. The organic layer was separated, washed with water, brine, dried and concentrated. Purification of the residue by flash chromatography with 25% ethyl acetate-hexane gave 6.4 g (83.1% yield) of N-ethyl-2-thiophenecarboxamide as a white solid, m.p. 75°-78° C.
Reaction SMILES: CS[C:3]1[N:4]=[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[NH:6][C:7](=[O:11])[C:8]=1[C:9]#[N:10].[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[O:11]=[C:7]1[NH:6][C:5]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[N:4][C:3]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:8]1[C:9]#[N:10]
Reactant: C1CCNCC1
Reactant: CSc1nc(Cc2cccc(C(F)(F)F)c2)[nH]c(=O)c1C#N
Product: N#Cc1c(N2CCCCC2)nc(Cc2cccc(C(F)(F)F)c2)[nH]c1=O

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.31 mmol) of 4-(methylsulphanyl)-6-oxo-2-[3-(trifluoromethyl)benzyl]-1,6-dihydropyrimidine-5-carbonitrile are reacted with 262 mg (3.07 mmol) of piperidine to give 26 mg (22% of theory) of the title compound.
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=O)([C:3](OCC)=[O:4])=[O:2].CN(C=O)C.[Cl-].[NH4+].CO.C(Cl)(Cl)Cl>O.[Zn]>[F:15][C:13]1[CH:14]=[C:9]2[C:10](=[CH:11][CH:12]=1)[N:16]([OH:18])[C:3](=[O:4])[C:1](=[O:2])[NH:8]2
Reactant: CCOC(=O)C(=O)Nc1cc(F)ccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=c1[nH]c2cc(F)ccc2n(O)c1=O
Temperature: 100 °C
Yield: 57.5 %

Procedure:
To a mixture of 6.2 g of 2-ethoxalylamino-4-fluoronitrobenzene and 124 ml of DMF was added a solution of 5.64 g of ammonium chloride in 40 ml of water. Then, 5.7 g of zinc dust was added in small portions to the above mixture. The reaction mixture was stirred under TLC (5% methanol-chloroform) monitoring and, when the starting material had disappeared, the mixture was filtered using Celite and washed with hot DMF. The mixture was heated at 100° C. for 3 hours, after which it was ice-cooled and the resulting inorganic salt crystals were filtered off. To the organic layer was added methanol and the resulting crystals were recovered by filtration to provide 2.73 g of 6-fluoro-1-hydroxyquinoxaline-2,3-(1H,4H)-dione.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]#[CH:10])(=O)=O.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(N(C(C)C)CC)(C)C>C1COCC1>[CH2:6]([N:20]1[CH2:21][CH2:22][N:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=2)[CH2:18][CH2:19]1)[CH2:7][CH2:8][C:9]#[CH:10]
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: C#CCCCOS(C)(=O)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C#CCCCN1CCN(c2ccccn2)CC1
Yield: 71.2 %

Procedure:
A solution of pent-4-ynyl methanesulfonate (1.05 g), 1-(pyridin-2-yl)piperazine (1.02 g) and diisoproylethylamine (1.2 mL) in THF (5 mL) was heated to reflux overnight. The mixture was concentrated, diluted with aq. NaOH 2M (10 mL) and extracted with DCM (2×50 mL). Drying (Na2SO4) and silica gel flash chromatography (EtOAc/hexane 2:1→2:0) afforded 1-(pent-4-ynyl)-4-(pyridin-2-yl)piperazine (1.02 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[N:22]2[C:26]([CH3:27])=[C:25](I)[N:24]=[N:23]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CC(C)=O>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[N:22]2[C:26]([CH3:27])=[CH:25][N:24]=[N:23]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(I)nnn1-c1cc(Cl)ccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Solvent: CC(C)=O
Product: Cc1cnnn1-c1cc(Cl)ccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-tert-butyl-N-(4-chloro-2-(4-iodo-5-methyl 1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide (synthesized according to general procedure P, 75 mg, 0.14 mmol) was placed in a 10 mL 2-neck flask and the flask was evacuated and purged with N2 three times. To the solid was added THF (0.71 mL) and the solution was lowered to −78° C. PhMgBr (0.079 mL, 1.8 M) was added to the solution and it was stirred for 15 minutes. n-BuLi (0.069 mL, 2.0 M) was subsequently added and the reaction was stirred an additional 60 minutes. Acetone (0.042 mL, 0.57 mmol) was added to the reaction and it was warmed to ambient temperature. The solution was subsequently partitioned with EtOAc/10% HCl and the aqueous layer was extracted three times with EtOac. The combined organics were dried over sodium sulfate, concentrated in vacuo, and purified by HPLC to afford the desired triazole: MS (ES) M+H expected 405.1, found 405.4.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:27]1[CH:28]=[N:29][CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1.[CH:37]([Si:40]([CH:45]([CH3:47])[CH3:46])([CH:42]([CH3:44])[CH3:43])[SH:41])([CH3:39])[CH3:38]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[F:34][C:33]([F:36])([F:35])[C:31]1[CH:30]=[N:29][CH:28]=[C:27]([S:41][Si:40]([CH:42]([CH3:44])[CH3:43])([CH:45]([CH3:47])[CH3:46])[CH:37]([CH3:38])[CH3:39])[CH:32]=1
Reactant: FC(F)(F)c1cncc(Br)c1
Reactant: CC(C)[Si](S)(C(C)C)C(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)[Si](Sc1cncc(C(F)(F)F)c1)(C(C)C)C(C)C
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Anhydrous toluene was sparged with argon gas for 1 h before being used. Palladium acetate (0.050 g, 0.22 mmol), triphenylphosphine (0.255 g, 0.973 mmol), cesium carbonate (1.87 g, 5.75 mmol) and 3-bromo-5-trifluoromethyl-pyridine (1.00 g, 4.42 mmol) were introduced into a 50 mL round bottom flask under argon. Toluene (10 mL) and triisopropylsilanethiol (1.23 mL, 5.75 mmol) were added. The reaction was stirred at 100° C. overnight, then cooled to room temperature and diluted with hexanes. The suspension was filtered through a plug of Celite. The filtrate was concentrated to afford 3-trifluoromethyl-5-triisopropylsilanylsulfanyl-pyridine which was used in the next reaction step without further purification.