Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([CH2:8][C:9]([O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][C:19]1[CH:20]=[C:21]([NH:25][C:26](=[O:32])[NH:27][CH2:28][C:29](O)=[O:30])[CH:22]=[CH:23][CH:24]=1.S(Cl)(Cl)=O>>[CH3:18][C:19]1[CH:20]=[C:21]([NH:25][C:26](=[O:32])[NH:27][CH2:28][C:29]([N:1]([CH2:8][C:9]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:10])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:30])[CH:22]=[CH:23][CH:24]=1
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Reactant: O=C(CNc1ccccc1)OC1CCCCC1
Solvent: O=S(Cl)Cl
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OC2CCCCC2)c2ccccc2)c1
Yield: 14.7 %

Procedure:
The procedure is similar to that described in Example 28, but starting with cyclohexyl 2-anilinoacetate (8.6 g), 2-[3-(3-methylphenyl)ureido]acetic acid (7.7 g) and thionyl chloride (2.7 cc). The product obtained is purified by chromatography on silica gel (0.063-0.200 mm; 150 g) contained in a column 3.5 cm in diameter [eluant: methylene chloride/methanol (99:1 by volume)], collecting 20-cc fractions. Fractions 6 to 18 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization in isopropanol, cyclohexyl 2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}acetate (2.3 g), m.p. 176° C., is obtained.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](Cl)=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: O=C(Cl)c1ccc(-c2ccc(OCCCCl)cc2)cc1
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(-c2ccc(OCCCCl)cc2)cc1)N1CCOCC1
Yield: 85 %

Procedure:
The product from Example 10D (185 mg, 0.6 mmol), morpholine (0.058 ml, 0.65 mmol) and diisopropylethylamine (100 μl, 0.6 mmol) in 2 mL of dichloromethane were stirred at 20° C. for 18 hours. The mixture was evaporated under reduced pressure and the residue was purified by chromatography (CHCl3/MeOH/NH4OH 9:1:0.1) to provide the title compound (85% yield).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]([F:12])[C:6]([C:7](O)=[O:8])=[C:5]([F:13])[CH:4]=1)#[N:2].S(Cl)([Cl:16])=O>>[C:1]([C:3]1[CH:11]=[C:10]([F:12])[C:6]([C:7]([Cl:16])=[O:8])=[C:5]([F:13])[CH:4]=1)#[N:2]
Reactant: O=S(Cl)Cl
Reactant: N#Cc1cc(F)c(C(=O)O)c(F)c1
Product: N#Cc1cc(F)c(C(=O)Cl)c(F)c1
Temperature: 25 °C
Yield: 91.18 %

Procedure:
A mixture of 4-cyano-2,6-difluorobenzoic acid (0.3 gm, 0.5 mmol) and thionyl chloride (5 mL) were refluxed for about 3 hours. The reaction mixture was cooled to ambient temperature, and concentrated under vacuum at 50° C. to afford 4-cyano-2,6-difluorobenzoyl chloride (0.3 gm, 91.18%).
Reaction SMILES: C([O:5][C:6]([C@H:8]([C@@H:18]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:19]([NH:21][N:22]1[C:26](=[O:27])[CH2:25][NH:24][C:23]1=[O:28])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:6]([C@H:8]([C@@H:18]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:19]([NH:21][N:22]1[C:26](=[O:27])[CH2:25][NH:24][C:23]1=[O:28])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([OH:7])=[O:5]
Reactant: CC(C)C[C@@H](C(=O)NN1C(=O)CNC1=O)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)NN1C(=O)CNC1=O)[C@H](C/C=C/c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 117.7 %

Procedure:
A solution of 0.783 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methyl-N-(2,5-dioxo-1-imidazolidinyl)valeramide in 20 ml of dichloromethane was treated with 10 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 4 hours and evaporated. Traces of trifluoroacetic acid were removed by the three-fold addition and evaporation of toluene to give 0.805 g of (E)-2(R)-[1(S)-(carboxy)-4-phenyl-3-butenyl]-4-methyl-N-(2,5-dioxo-1-imidazolidinyl)valeramide in the form of a white solid.
Reaction SMILES: [NH2:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][CH:17]([CH2:22][CH2:23][S:24][CH3:25])[CH2:18][C:19]([OH:21])=[O:20])=[O:15])=[CH:6][CH:5]=1.[OH2:26].OO>C(O)(=O)C>[NH2:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][CH:17]([CH2:22][CH2:23][S:24]([CH3:25])=[O:26])[CH2:18][C:19]([OH:21])=[O:20])=[O:15])=[CH:6][CH:5]=1
Reactant: O
Reactant: CSCCC(CC(=O)O)NC(=O)CCCCc1ccc(C=NN)cc1
Agent: OO
Solvent: CC(=O)O
Product: CS(=O)CCC(CC(=O)O)NC(=O)CCCCc1ccc(C=NN)cc1
Reaction time: 14 h

Procedure:
(±)-3-[[5-[4-(Aminoiminomethyl)phenyl]-1-oxopentyl]amino]-5-(methylthio)pentanoic acid (2.5 g) was added to water (15 ml) and acetic acid (5 ml) and 30% H2O2 (10 ml) . The oxidation was allowed to proceed for 14 hours after which the reaction mixture was purified by reverse phase chromatography (water/acetonitrile) and lyophilized to give 1.6 g of the title compound as a white solid: 1H NMR (d6 -DMSO) δ1.51 (m, 4H), 1.56 (m, 2H), 2.0(m, 2H), 2.18 (s, 3H), 2.90 (m, 4H), 2.71 (m, 2H), 4.10 (m, 1H), 7.35 (m, 9H), 7.7 (bd, 1H, J=7.9 Hz), 9.10 (bs, 2H), 9.25 (bs, 2H); MS (FAB) m/e 382 2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[N:13]1[C:17]([N:18](C(=O)CC)[CH2:19][CH2:20][CH3:21])=[C:16]([C:26]#[N:27])[CH:15]=[N:14]1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:10])([F:11])[F:12])[CH:5]=[CH:4][C:3]=1[N:13]1[C:17]([NH:18][CH2:19][CH2:20][CH3:21])=[C:16]([C:26]#[N:27])[CH:15]=[N:14]1
Reactant: CCCN(C(=O)CC)c1c(C#N)cnn1-c1ccc(OC(F)(F)F)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCNc1c(C#N)cnn1-c1ccc(OC(F)(F)F)cc1Cl
Yield: 91.9 %

Procedure:
5.0 g (0.012 mole) of 1-(2-chloro-4-trifluoromethoxyphenyl)-4-cyano-5-(N-propionyl-N-n-propylamino)pyrazole in 200 ml of methanol are stirred with 11.6 ml (0.012 mole) of 1 normal sodium hydroxide solution at room temperature for 48 hours. For working up, the mixture is concentrated in vacuo, the residue is taken up in methylene chloride, the mixture is washed twice with 100 ml of water each time, dried iover sodium sulphate and concentrated and the residue is crystallized from petroleum ether. 3.8 g (92% of theory) of 1-(2-chloro-4-trifluoromethoxyphenyl)-4-cyano-5-n-propylamino-pyrazole of melting point 63° C. are obtained.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:22]4[C:23]5[CH:35]=[CH:34][CH:33]=[N:32][C:24]=5[NH:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[C:21]4=[N:20][C:19]=3[C:36]3[CH:41]=[CH:40][C:39]([C:42]([N:44]4[CH2:48][CH2:47][CH2:46][CH2:45]4)=[O:43])=[CH:38][CH:37]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.[ClH:50].O1CCOCC1>CO>[ClH:50].[ClH:50].[ClH:50].[N:44]1([C:42]([C:39]2[CH:40]=[CH:41][C:36]([C:19]3[N:20]=[C:21]4[C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=5[NH:25][C:24]5[N:32]=[CH:33][CH:34]=[CH:35][C:23]=5[N:22]4[C:18]=3[C:15]3[CH:14]=[CH:13][C:12]([C:8]4([NH2:7])[CH2:9][CH2:10][CH2:11]4)=[CH:17][CH:16]=3)=[CH:37][CH:38]=2)=[O:43])[CH2:45][CH2:46][CH2:47][CH2:48]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(C(=O)N5CCCC5)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NC1(c2ccc(-c3c(-c4ccc(C(=O)N5CCCC5)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Reaction time: 12 h

Procedure:
tert-Butyl[1-(4-{2-[4-(pyrrolidin-1-ylcarbonyl)phenyl]-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl}phenyl)cyclobutyl]carbamate (12 mg, 0.018 mmol) in MeOH (0.5 mL) was added 4N HCl-dioxane (2 mL) and stirred at r.t for 12 hours. The mixture was concentrated to afford the desired product (12 mg, quant) as a yellow solid. 1HNMR (DMSO-d6) 400 MHz δ: 8.62 (s, 1H), 8.60 (br s, 2H), 8.11 (dd, J=4.6 Hz and 1.7 Hz, 1H), 7.97 (dd, J=8.0 Hz and 1.7 Hz, 1H), 7.53 (t, J=8.0 Hz, 4H), 7.45 (d, J=8.6 Hz, 2H), 7.39-7.34 (m, 3H), 7.30 (d, J=7.4 Hz, 1H), 7.13 (td, J=8.6 Hz and 1.1 Hz, 1H), 6.90 (dd, J=8.0 Hz and 1.7 Hz, 1H), 6.74 (dd, J=8.0 Hz and 4.6 Hz, 1H), 3.73-3.65 (m, 1H), 2.61-2.53 (m, 6H), 2.23-2.14 (m, 1H), 1.89-1.78 (m, 6H). LCMS: 553 [M+H].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[CH2:34][C:35]1[CH:39]=[CH:38][S:37][CH:36]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[CH2:34][C:35]2[CH:39]=[CH:38][S:37][CH:36]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccsc1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C#N)cc2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(N(Cc2ccsc2)c2ccc(C#N)cc2)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 60.9 %

Procedure:
To a solution of 4-(4-cyano-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 106) (1.17 g, 3.89 mmol) in THF (20 mL) cooled to −78° C. was added KHMDS (0.5M, 12.0 mL, 6.0 mmol) and the mixture was stirred at −78° C. for 20 minutes. The reaction was quenched with 3-(bromomethyl)thiophene (1.06 g, 5.99 mmol) and warmed to room temperature to afford 4-[(4-cyano-phenyl)-thiophen-3-ylmethyl-amino]-piperidine-1-carboxylic acid tert-butyl ester (941 mg, 61%) following work-up and purification.
Reaction SMILES: [CH3:1][CH2:2][N:3]([C:15]1[CH:20]=[CH:19][C:18](/[C:21](/[C:43]2[CH:48]=[CH:47][C:46]([NH:49][C:50]3[CH:55]=[CH:54][C:53]([O:56][CH2:57][CH3:58])=[CH:52][CH:51]=3)=[CH:45][CH:44]=2)=[C:22]2\[CH:23]=[CH:24][C:25]([CH:40]=[C:41]\2[CH3:42])=[N+:26]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([S:36]([O-:39])(=[O:38])=[O:37])[CH:31]=2)[CH2:27][CH3:28])=[C:17]([CH3:59])[CH:16]=1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11]([O-:14])(=[O:13])=[O:12])[CH:6]=1.[Na+].[P:61](=[O:65])([OH:64])([OH:63])[OH:62].O>C(O)C>[CH3:1][CH2:2][N:3]([C:15]1[CH:20]=[CH:19][C:18](/[C:21](/[C:43]2[CH:44]=[CH:45][C:46]([NH:49][C:50]3[CH:55]=[CH:54][C:53]([O:56][CH2:57][CH3:58])=[CH:52][CH:51]=3)=[CH:47][CH:48]=2)=[C:22]2/[CH:23]=[CH:24][C:25]([CH:40]=[C:41]/2[CH3:42])=[N+:26]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([S:36]([OH:39])(=[O:37])=[O:38])[CH:31]=2)[CH2:27][CH3:28])=[C:17]([CH3:59])[CH:16]=1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11]([OH:14])(=[O:13])=[O:12])[CH:6]=1.[P:61](=[O:62])([OH:65])([OH:64])[OH:63]
Reactant: CCOc1ccc(Nc2ccc(/C(=C3/C=CC(=[N+](CC)Cc4cccc(S(=O)(=O)[O-])c4)C=C3C)c3ccc(N(CC)Cc4cccc(S(=O)(=O)[O-])c4)cc3C)cc2)cc1
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1ccc(Nc2ccc(/C(=C3\C=CC(=[N+](CC)Cc4cccc(S(=O)(=O)O)c4)C=C3C)c3ccc(N(CC)Cc4cccc(S(=O)(=O)O)c4)cc3C)cc2)cc1
Yield: 0.01 %

Procedure:
To 100 mg Coomassie Brilliant Blue (G-250) was added 47 g ethanol, 85 g phosphoric acid and 850 g water. This solution was mixed for 20 minutes, to ensure all components were dissolved, resulting in a reagent comprising 0.01% (w/v) Coomassie Brilliant Blue G-250, 4.7% ethanol (w/v) and 8.5% (w/v) phosphoric acid. To this solution different dextrins were added as indicated in the specific examples.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15](Cl)[N:14]=[CH:13][N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][CH:25]=[N:26]2)=[CH:21][CH:20]=1.[H-].[Na+]>CN(C=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[CH:13][N:14]=[C:15]([O:18][C:19]3[CH:28]=[C:27]4[C:22]([CH:23]=[CH:24][CH:25]=[N:26]4)=[CH:21][CH:20]=3)[CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(-c2cc(Cl)ncn2)cc1
Reactant: Oc1ccc2cccnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(-c2cc(Oc3ccc4cccnc4c3)ncn2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 100-mL, round-bottomed flask containing 4-(4-tert-butyl-phenyl)-6-chloro-pyrimidine, (Example 1(a)), (0.15 g, 0.61 mmol) and 7-hydroxyquinoline (0.12 g, 0.85 mmol, Acros) in DMF (4 mL), was added NaH (34 mg, 0.85 mmol, 60% in mineral oil, Aldrich) at room temperature. The solution was then stirred at room temperature for 4 h. After the solvent was removed in vacuum, the residue was taken up in EtOAc (10 mL), and the organic layers were washed with water (8 mL), dried over Na2SO4, filtered, and concentrated in vacuum. Silica gel chromatography (3:1 hexanes/EtOAc) gave the title compound as a white solid. Mp: 133–135° C. MS (ESI, pos. ion) m/z: 356 (M+1). Anal. Calcd for C23H21N3O: C, 77.72; H, 5.96; N, 11.82. Found: C, 77.43; H, 5.99; N, 11.74.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[N:23]=[C:22](Cl)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[NH2:34][C:35]1[CH:36]=[CH:37][C:38]([O:46][CH3:47])=[C:39]([NH:41][C:42](=[O:45])[CH:43]=[CH2:44])[CH:40]=1>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[N:19]=[CH:20][N:21]=[C:22]([NH:34][C:35]4[CH:36]=[CH:37][C:38]([O:46][CH3:47])=[C:39]([NH:41][C:42](=[O:45])[CH:43]=[CH2:44])[CH:40]=4)[N:23]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncnc(Nc2ccc3c(cnn3Cc3ccccc3)c2)n1
Reactant: C=CC(=O)Nc1cc(N)ccc1OC
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cc(Nc2ncnc(Nc3ccc4c(cnn4Cc4ccccc4)c3)n2)ccc1OC
Temperature: 100 °C

Procedure:
To a slurry of (1-benzyl-1H-indazol-5-yl)-(4-chloro-[1,3,5]triazin-2-yl)-amine (Example 3, Step 3) (90 mg, 0.267 mmol) in IpOH (3 ml) was added DIEA (0.070 mL, 0.401 mmol) and N-(5-amino-2-methoxyphenyl)acrylamide (Step 2) (56.5 mg, 0.294 mmol). The mix was heated at 100° C. for 18 h. The solution was then cooled to RT. A precipitate fell out of solution, was filtered off and dried under reduced pressure to give N-{5-[4-(1-benzyl-1H-indazol-5-ylamino)-[1,3,5]triazin-2-ylamino]-2-methoxyphenyl}-acrylamide: MS m/z=493[M+H]+. Calc'd for C27H24N8O2: 492.20.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@@:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl[C:28]1[N:33]=[CH:32][C:31]([Cl:34])=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:34][C:31]1[CH:30]=[N:29][C:28]([N:23]2[CH2:24][CH2:25][CH:20]([C@@:18]3([CH3:26])[O:17][C:14]4=[CH:15][N:16]=[C:11]([C:8]5[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=5)[CH:12]=[C:13]4[CH2:19]3)[CH2:21][CH2:22]2)=[N:33][CH:32]=1
Reactant: C[C@@]1(C2CCNCC2)Cc2cc(-c3ccc(S(C)(=O)=O)cc3)ncc2O1
Reactant: Clc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@@]1(C2CCN(c3ncc(Cl)cn3)CC2)Cc2cc(-c3ccc(S(C)(=O)=O)cc3)ncc2O1

Procedure:
The title compound is prepared from (S)-5-(4-methanesulfonyl-phenyl)-2-methyl-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 32; the configuration of the stereocenter is arbitrarily assigned) and 2,5-dichloro-pyrimidine in dimethylsulfoxide at 105° C. in the presence of potassium carbonate. LC (method 6): tR=1.78 min; Mass spectrum (ESI+): m/z=485 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1)([CH3:6])[CH2:3][CH:4]=O.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>C1COCC1.[Zn]>[CH3:1][C:2]([C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)([CH3:6])[CH2:3][CH2:4][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: CC(C)(CC=O)c1ccc([N+](=O)[O-])cc1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(CCN1CCOCC1)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of aldehyde (509 mg, 2.4 mmol, Step B) and morpholine (0.21 mL, 2.4 mmol) in THF (30 mL) was added NaBH(OAc)3 (0.73 g, 3.4 mmol). The mixture was stirred at RT overnight and washed with HCl (1 M). CH2Cl2 was added and the layers were separated. The aqueous layer was basified to pH 9 using NaOH 1M and extracted with CH2Cl2. The organic layer was dried and evaporated the nitro compound. To a solution of the nitro compound (0.50 g, 1.8 mmol) in THF (40 mL) was added AcOH (1.97 mmol, 34.5 mmol) followed by zinc (9.1 g, 137 mmol). The mixture was stirred for 1 h, filtered on Celite®, diluted with water and aqueous NaHCO3, and the THF layer was evaporated. The residue was extracted with EtOAc, dried and evaporated to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][C:8]([CH2:11][O:12]C)=[CH:7][C:6]=2[C:5]([C:14]2[C:15](=[O:25])[N:16]([CH3:24])[C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)=[C:4]([F:26])[CH:3]=1.ClCCl.B(Br)(Br)Br.O>ClCCl>[Cl:1][C:2]1[C:10]2[O:9][C:8]([CH2:11][OH:12])=[CH:7][C:6]=2[C:5]([C:14]2[C:15](=[O:25])[N:16]([CH3:24])[C:17]([C:20]([F:22])([F:21])[F:23])=[CH:18][CH:19]=2)=[C:4]([F:26])[CH:3]=1
Reactant: COCc1cc2c(-c3ccc(C(F)(F)F)n(C)c3=O)c(F)cc(Cl)c2o1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cn1c(C(F)(F)F)ccc(-c2c(F)cc(Cl)c3oc(CO)cc23)c1=O
Temperature: -65 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
0.20 g (0.51 mmol) of 3-(7-chloro-5-fluoro-2-methoxymethylbenzofuran-4-yl)-1-methyl-6-trifluoromethyl-2-(1H)-pyridone was dissolved in 10 ml of dichloromethane, and 1.54 ml (1.54 mmol) of a 1.0M boron tribromide dichloromethane solution was added thereto at ±65° C. The mixture was stirred at −65° C. for 1 hour and then poured into water, followed by stirring at room temperature for 30 minutes. Then, it was extracted with dichloromethane. After washing with water, the organic layer was dried over anhydrous magnesium sulfate. Dichloromethane was distilled off under reduced pressure. Then, the obtained crude crystals were washed with n-hexane to obtain 0.19 g (yield: 99%) of the desired product. Melting point: 145-147° C. 1H-NMR (300 MHz, CDCl3) δ value: 3.73(3H,s), 4.55(2H,s), 6.66(1H,s), 6.80(1H,d), 7.20(1H,d), 7.55(1H,d)ppm.
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.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][C:29]([N:31]([CH3:33])[CH3:32])=[O:30]>CN(C)C=O.ClCCl>[C:12]([C:10]1[C:9]([N:15]2[CH2:16][CH2:17][N:18]([CH2:28][C:29]([N:31]([CH3:33])[CH3:32])=[O:30])[CH2:19][CH2:20]2)=[C:8]2[C:3]([CH:4]=[CH:5][CH:6]=[N:7]2)=[C:2]([Cl:1])[CH:11]=1)(=[O:14])[CH3:13]
Reactant: CN(C)C(=O)CCl
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(CC(=O)N(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.7 %

Procedure:
To a mix of 1-(5-chloro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.030 g, 0.10 mmol, from Example 47, Step 1) and potassium carbonate (0.043 g, 0.31 mmol) in N,N-dimethylformamide (1 mL) was added 2-chloro-N,N-dimethylacetamide (0.012 mL, 0.11 mmol). The reaction mixture was stirred at room temperature for 4 hrs, and then 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 (19 mg, 49%). LCMS calculated for C19H24ClN4O2 (M+H)+: m/z=375.2; Found: 375.1.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[CH2:20][CH:19]([C:24]([O:26]C)=[O:25])[CH2:18]2)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O.CO>[C:7]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[CH2:20][CH:19]([C:24]([OH:26])=[O:25])[CH2:18]2)(=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)C1Cc2ccc(C(=O)c3ccccc3)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(c1ccccc1)c1ccc2c(c1)CC(C(=O)O)C2

Procedure:
To a 100 cm3 reaction vessel equipped with a stirrer and a cooler are successively added: 2.2 g (0.026 mole+50%) of potash dissolved in 40 cm3 of water and 7.3 g (0.026 mole) of methyl 5-benzoyl-indane-2-carboxylate dissolved in 40 cm3 of methanol. The mixture is heated at reflux temperature for 1 hour, the methanol evaporated and the mixture diluted with water; the alkaline mixture is then washed with ether and then acidified by the addition of hydrochloric acid. A precipitate forms which is filtered, washed with water and dried. After recrystallization from ethyl acetate the melting point is steady at 140°-142° C. (in a capillary tube).
Reaction SMILES: [CH3:1][C:2]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:3]=1[C:4]([C:6]1[N:10]([CH3:11])[C:9]([CH:12]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=2F)C(OCC=C)=O)=[CH:8][CH:7]=1)=[O:5].N1CCOCC1>C1COCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:3]=1[C:4]([C:6]1[N:10]([CH3:11])[C:9]([CH2:12][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:8][CH:7]=1)=[O:5]
Reactant: C=CCOC(=O)C(c1ccc([N+](=O)[O-])cc1F)c1ccc(C(=O)c2ccc(C)cc2C)n1C
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)c2ccc(Cc3ccc([N+](=O)[O-])cc3)n2C)c(C)c1
Reaction time: 1.5 h
Yield: 98.1 %

Procedure:
To a solution of allyl 2-[5- (2,4-dimethylbenzoyl)-1-methylpyrrol-2-yl)-2-(2-fluoro-4-nitrophenyl)acetate (3.6 g, 7.99 mmol) [prepared as described in Example 6, Step (d)] in anhydrous THF (40 ml) was added morpholine (6.99 ml, 79.90 mmol) and tetrakis-(triphenylphosphine) palladium (9 mg, 0.008 mmol)). After 1.5 h, the solvent was evaporated and the residue was partitioned between ether and IN NaHSO4. The organic layer was separated, dried over magnesium sulfate, and concentrated to dryness. Purification by column chromatography (ethyl acetate/hexane) gave 4-[5-(2,4-dimethylbenzoyl)-1-methyl-pyrrol-2-yl-methyl)nitrobenzene (2.73 g, 93%) as a pale yellow oil. ##STR37##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=3)=[CH:16][CH:17]=2)=[CH:11][C:10]([C:28](O)=[O:29])=[N:9]1.C(N1C=CN=C1)([N:33]1[CH:37]=[CH:36]N=C1)=O.C(N)C.C1COCC1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=3)=[CH:16][CH:17]=2)=[CH:11][C:10]([C:28]([NH:33][CH2:37][CH3:36])=[O:29])=[N:9]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(C(=O)O)nn3-c3ccccc3Cl)s2)c1
Agent: CCN
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCNC(=O)c1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n(-c2ccccc2Cl)n1
Reaction time: 2 h
Yield: 86.4 %

Procedure:
To a suspension of 1-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazole-3-carboxylic acid (92 mg, 0.2 mmol) in DCM (2 mL) was added carbonyldiimidazole (39 mg, 1.2 equiv) and stirring was continued for 2 h at 20° C. A solution of ethylamine in THF (1.8 M, 0.17 mL, 1.5 equiv) was added and the mixture was stirred overnight at 20° C. Evaporation of solvent gave a crude, which was purified by column chromatography on silica gel eluting with MeOH-DCM (1:19) to afford 1-(2-chlorophenyl)-N-ethyl-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazole-3-carboxamide (84 mg). 1H-NMR (CDCl3): δ 8.03 (m, 1H), 7.83 (m, 1H), 7.74 (m, 1H), 7.62-7.45 (m, 5H), 7.22 (m, 1H), 7.19 (s, 1H), 6.91 (m, 1H), 6.82 (d, 1H), 3.55-3.43 (m, 2H), 3.07 (3 s, H), 1.25 (s, 3H). MS(ES): 486 [M+H]+.