Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]([N:18]3[CH2:23][CH2:22][CH:21]([C:24](O)=[O:25])[CH2:20][CH2:19]3)=[N:16][CH:17]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8].[C:27]([S:31]([NH2:34])(=[O:33])=[O:32])([CH3:30])([CH3:29])[CH3:28].IC1C=CC(NC(C2C(N3CCC(C(NS(C(C)(C)C)(=O)=O)=O)CC3)=CC=NC=2)=O)=CC=1C>>[I:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]([NH:34][S:31]([C:27]([CH3:30])([CH3:29])[CH3:28])(=[O:33])=[O:32])=[O:25])[CH2:20][CH2:19]3)=[N:16][CH:17]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CC(C)(C)S(N)(=O)=O
Reactant: Cc1ccc(NC(=O)c2ccc(N3CCC(C(=O)O)CC3)nc2)cc1I
Agent: Cc1cc(NC(=O)c2cnccc2N2CCC(C(=O)NS(=O)(=O)C(C)(C)C)CC2)ccc1I
Product: Cc1ccc(NC(=O)c2ccc(N3CCC(C(=O)NS(=O)(=O)C(C)(C)C)CC3)nc2)cc1I

Procedure:
4-(2-Methyl-propane-2-sulfonylaminocarbonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid (3-iodo-4-methyl-phenyl)-amide was prepared from 5′-(3-Iodo-4-methyl-phenylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid and t-butyl sulfonamide in a manner similar to the one described in the synthesis of 4-(2-Methyl-propane-2-sulfonylaminocarbonyl)-3,4,5,6-tetrahydro-2H-[1,4]bipyridinyl-5′-carboxylic acid (4-iodo-3-methyl-phenyl)-amide. The product was isolated after a silica gel column purification with 2-5% MeOH in CH2Cl2. HRMS m/z calcd for C23H29N4O4SI [M+H]+: 585.1027. Found: 585.1027.
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.[C:13]([C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)#[N:14]>ClCCl>[Br:2][CH2:3][CH2:4][NH:5][S:21]([C:18]1[CH:17]=[CH:16][C:15]([C:13]#[N:14])=[CH:20][CH:19]=1)(=[O:23])=[O:22]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCBr
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(S(=O)(=O)NCCBr)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
To an ice cooled solution of 2-bromoethylamine hydrogenbromide (12.2 g, 0.0595 mol) in dry dichloromethane (100 mL) was added triethylamine and the mixture stirred for 15 min. 4-Cyanobenzenesulfonyl chloride (10 g, 0.0486 mol) in dichloromethane was added, dropwise. Stirring was continued at RT for 1 h. The reaction mixture was diluted with dichloromethane, washed with water, followed by brine, then dried over sodium sulfate. Solvents were evaporated and the residue crystallized from petroleum ether to give 12.5 g of the sub-title compound as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH2:23])=[C:16]2[N:15]=1.[N:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[C:25]=[O:26].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:27]([NH:24][C:25]([NH:23][C:22]1[CH:21]=[N:20][N:17]2[CH:18]=[CH:19][C:14]([N:10]3[CH2:11][CH2:12][CH2:13][C@@H:9]3[C:3]3[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=3[F:1])=[N:15][C:16]=12)=[O:26])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)N=C=O
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NC(=O)Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Reaction time: 4 h
Yield: 82.5 %

Procedure:
To a DCM (0.8 mL) solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Preparation B; 25 mg, 0.079 mmol) was added 2-isocyanato-2-methylpropane (9.4 mg, 0.095 mmol) at ambient temperature drop-wise, followed by addition of DIEA (0.028 mL, 0.16 mmol). The reaction was stirred for 4 hours then concentrated, and the residue was directly purified by reverse-phase column chromatography, eluting with 5 to 65% acetonitrile/water to yield the final product as a pale-yellowish solid (27 mg, 82% yield). MS (apci) m/z=415.1 (M+H).
Reaction SMILES: [Br:1][CH2:2]/[C:3](/[CH3:14])=[CH:4]\[C@@H:5]([CH3:13])[C@H:6]([OH:12])[C@@H:7]([O:10][CH3:11])[CH:8]=[CH2:9].N1C(C)=CC=CC=1C.[Si:23](OS(C(F)(F)F)(=O)=O)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>C(Cl)Cl>[Br:1][CH2:2]/[C:3](/[CH3:14])=[CH:4]\[C@@H:5]([CH3:13])[C@H:6]([O:12][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[C@@H:7]([O:10][CH3:11])[CH:8]=[CH2:9]
Reactant: C=C[C@H](OC)[C@@H](O)[C@H](C)/C=C(/C)CBr
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: C=C[C@H](OC)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](C)/C=C(/C)CBr
Temperature: -15 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a solution of secondary alcohol 12 (5.04 g, 19.23 mmol) in CH2Cl2 (150 mL) at −15° C. was added 2,6-lutidine (3.4 mL, 28.85 mmol) and TBSOTf (6.2 mL, 26.92 mmol). After stirring at −15° C. for 1 h, the reaction mixture was quenched with MeOH (20 mL) at −15° C. The mixture was treated with saturated NH4Cl aqueous solution. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated. Purification of the crude product by flash chromatography (EtOAc-hexanes, 1:9) to afford bromide 13 (6.6 g, 91%) as a yellow oil. [α]20D 2.76 (c 1.5, CHCl3); 1H NMR (CDCl3, 400 MHz): δ 5.61 (m, 1 H), 5.35 (d, 1 H, J=9.8 Hz), 5.23 (m, 2 H), 3.88 (s, 2H), 3.48 (dd, 1 H, J=3.0, 7.1 Hz), 3.30 (t, 1 H, J=7.5 Hz), 3.15 (s, 3H), 2.53 (m, 1H), 1.75 (s, 3H), 0.88 (m+s, 12 H), 0.05 (s, 3H), 0.02 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 136.8, 135.6, 130.1, 119.2, 86.5, 78.0, 56.6, 35.1, 32.8, 26.5, 22.3, 18.9, 13.9, −3.4, −4.4; HRMS (ESI) calcd for [C17H33BrO2Si+Na]+: 399.1331. found: 399.1321.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N:19]=C=O)[CH:17]=[CH:18][C:13]=2[N:12]([CH:22]([CH3:24])[CH3:23])[C:11](=[O:25])[C:10]([CH3:27])([CH3:26])[N:9]=1.ClC1C=CC=CC=1C1C2C=C(NC(NCCO)=O)C=CC=2N(C(C)C)C(=O)C(C)(C)N=1>ClCCCl.C(Cl)Cl>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]2[N:12]([CH:22]([CH3:24])[CH3:23])[C:11](=[O:25])[C:10]([CH3:26])([CH3:27])[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:14]=2[CH:15]=1
Reactant: CC(C)N1C(=O)C(C)(C)N=C(c2ccccc2Cl)c2cc(N=C=O)ccc21
Agent: CC(C)N1C(=O)C(C)(C)N=C(c2ccccc2Cl)c2cc(NC(=O)NCCO)ccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)N1C(=O)C(C)(C)N=C(c2ccccc2Cl)c2cc(N)ccc21

Procedure:
From 4 g (0.011 mol) of 7-amino-5-(o-chlorophenyl)-1,3-dihydro-1-isopropyl-3,3-dimethyl-2H-1,4-benzodiazepin-2-one there is obtained, in analogy to the details in Example 4, via [5-(o-chlorophenyl)-2,3-dihydro-1-isopropyl-3,3-dimethyl-2-oxo-1H-1,4-benzodiazepin-7yl]isocyanate, 1-[5-(o-chlorophenyl)2,3-dihydro-1-isopropyl-3,3-dimethyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-3-(2-hydroxyethyl)urea of melting point 243°-244° (1,2-dichloroethane/methylene chloride).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[F:42][C:43]1[CH:44]=[C:45]([S:49](Cl)(=[O:51])=[O:50])[CH:46]=[CH:47][CH:48]=1>C(#N)C>[F:42][C:43]1[CH:44]=[C:45]([S:49]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:51])=[O:50])[CH:46]=[CH:47][CH:48]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3cccc(F)c3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 59.8 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0300 g, 0.0650 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 3-fluorobenzenesulfonyl chloride (0.0260 mL, 0.195 mmol) to obtain 4-(3-fluorobenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0241 g, yield 60%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[N:10]([CH:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[C:9](=[O:24])[NH:8][C:5]2=[N:6][CH:7]=1.[F:25]C(F)(F)C(O)=O>ClCCl>[F:25][N:6]1[CH:7]=[CH:2][CH:3]=[C:4]2[N:10]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:9](=[O:24])[NH:8][CH:5]12
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3ncc(F)cc32)CC1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NC2C(=CC=CN2F)N1C1CCNCC1
Reaction time: 2 h

Procedure:
tert-Butyl 4-(6-fluoro-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (340 mg, 1.01 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (5 mL) was added. After 2 h, the reation was concentrated, diluted with dichlormethane (5 mL) and a solution of 1N hydrochloric acid in 1,4-dioxane (2 mL) was added at room temperature. Concentration afforded the title compound (302 mg). MS 237.2 (M+1)
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:14][CH2:13][C:12]2[S:11][C:10]3[C:5](=[C:6]([NH:15][CH:16]4[CH2:21][CH2:20][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18][CH2:17]4)[N:7]=[CH:8][N:9]=3)[C:4]1=2.C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>ClCCl>[CH3:37][S:38]([O:1][CH2:2][C@H:3]1[CH2:14][CH2:13][C:12]2[S:11][C:10]3[C:5](=[C:6]([NH:15][CH:16]4[CH2:17][CH2:18][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27])[CH2:20][CH2:21]4)[N:7]=[CH:8][N:9]=3)[C:4]1=2)(=[O:40])=[O:39]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2ncnc3sc4c(c23)[C@@H](CO)CC4)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCC(Nc2ncnc3sc4c(c23)[C@@H](COS(C)(=O)=O)CC4)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
To a solution of tert-butyl N-(4-[[(3S)-3-(hydroxymethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yl]amino]cyclohexyl)carbamate (400 mg, 0.96 mmol, 1.00 equiv) and triethylamine (0.27 mL, 2.00 equiv) in dichloromethane (20 mL) was added dropwise MsCl (164 mg, 1.43 mmol, 1.50 equiv). The resulting solution was stirred for 2 h at room temperature. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 2×40 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). Purification afforded 379 mg (80%) of tert-butyl N-(4-[[(3S)-3-[(methanesulfonyloxy)methyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yl]amino]cyclohexyl)carbamate as a light yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][C:5]([C:9]#[N:10])=[C:4]([C:11]#[N:12])[N:3]=1.[C:13]([NH2:17])([CH3:16])([CH3:15])[CH3:14].O>O1CCCC1>[Cl:8][C:7]1[C:2]([NH:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[N:3][C:4]([C:11]#[N:12])=[C:5]([C:9]#[N:10])[N:6]=1
Reactant: CC(C)(C)N
Reactant: N#Cc1nc(Cl)c(Cl)nc1C#N
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)Nc1nc(C#N)c(C#N)nc1Cl
Reaction time: 2 h
Yield: 76.4 %

Procedure:
5.0 g (0.025 mol) of 2,3-dichloro-5,6-dicyanopyrazine was dissolved in 50 ml of dry tetrahydrofuran, and 25 ml of a dry tetrahydrofuran solution containing 3.7 g (0.050 mol) of tert-butylamine was dropwise added thereto at a temperature of from -15°to 0° C. After completion of the dropwise addition, the mixture was stirred for 2 hours, and the reaction solution was poured into 500 ml of water. The precipitated solid was collected by filtration and recrystallized from toluene to obtain 4.5 g of slightly yellow crystals (yield: 76.4%, melting point: 174°-176° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:25][CH3:26])=[CH:5][C:6]2[O:10][C:9]([C:11]([CH2:13][CH2:14]/[CH:15]=[C:16](\[CH3:23])/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[CH2:12])=[CH:8][C:7]=2[CH:24]=1.[CH3:27]O>[Pd]>[CH3:1][O:2][C:3]1[C:4]([O:25][CH3:26])=[CH:5][C:6]2[O:10][C:9]([CH:11]([CH2:13][CH2:14]/[CH:15]=[C:16](\[CH3:23])/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:21])[CH3:22])[CH2:12][CH3:27])=[CH:8][C:7]=2[CH:24]=1
Reactant: CO
Reactant: C=C(CC/C=C(\C)CCC=C(C)C)c1cc2cc(OC)c(OC)cc2o1
Agent: [Pd]
Product: CCC(CC/C=C(\C)CCC=C(C)C)c1cc2cc(OC)c(OC)cc2o1
Reaction time: 0.5 h

Procedure:
To a solution of compound A4 (0.7 g 1.9 mmol) in MeOH was added 10 Mol % Pd/C and reaction was shacked at 40 psi pressure for 0.5 hrs. After completion of the reaction (monitored by TLC) filtered the reaction mixture and evaporated the methanol completely. Chromatography of the residue on silica gel (3% EtOAc/Hexanes) afforded the compound A5 (0.633 g) in 90% yield colorless liquid: 1H NMR (500 MHz, CDCl3) δ 7.04 (s, 1H), 6.98 (s, 1H), 6.294 (s, 1H), 5.15-5.12 (m, 4H), 3.940 (s, 6H), 2.94-2.91 (m, 1H), 2.10-1.98 (m, 4H), 1.87-1.82 (m, 2H), 1.74 (s, 3H), 1.634 (s, 3H), 1.59 (s, 3H), 1.34-1.32 (d, 3H), ppm. Mass: ESI [M+Na]+: 356.24; Elemental anal. calcd. for C23H32O3; C, 77.49; H, 9.05. found C, 77.49; H, 9.05.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][C:8]2[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]3[N:19]=[CH:20][CH:21]=[C:22]([O:23][C@@H:24]4[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:37][N:38]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[N:39]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH3:37][N:38]1[CH:42]=[C:41]([C:2]2[N:10]=[CH:9][C:8]3[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:17])([CH3:18])[CH3:16])[C:6]4[N:19]=[CH:20][CH:21]=[C:22]([O:23][C@@H:24]5[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:35])([CH3:36])[CH3:34])=[O:31])[CH2:25]5)[C:5]=4[C:4]=3[CH:3]=2)[CH:40]=[N:39]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2ccnc3c2c2cc(Br)ncc2n3COCC[Si](C)(C)C)C1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cn1cc(-c2cc3c4c(O[C@@H]5CCCN(C(=O)OC(C)(C)C)C5)ccnc4n(COCC[Si](C)(C)C)c3cn2)cn1
Temperature: 130 °C

Procedure:
A mixture of (R)-tert-butyl 3-(6-bromo-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-4-yloxy)piperidine-1-carboxylate (50 mg, 0.09 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (90 mg, 0.43 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (6.3 mg, 0.009 mmol), and saturated aqueous sodium carbonate solution (0.1 mL) in acetonitrile (0.9 mL) was heated under microwave irradiation at 130° C. for 30 minutes. The reaction mixture was concentrated in vacuo, and purified flash chromatography (silica, 4 g, ISCO, 0-90% ethyl acetate in heptane) to afford the title compound as a light brown oil, which was used in the next step without any further purification (50 mg).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[CH:23]=[C:24]([CH:33]=[CH:34][C:35]=3[Cl:36])[CH2:25][NH:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[N:17]=2)=[CH:12][CH:11]=1>CN(C=O)C>[Cl:36][C:35]1[CH:34]=[CH:33][C:24]([CH2:25][NH:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:23][C:22]=1[N:18]1[C:19](=[O:21])[NH:20][C:16]([C:13]2[CH:12]=[CH:11][C:10]([CH2:9][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:15][CH:14]=2)=[N:17]1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(CBr)cc3)[nH]c2=O)c1
Reactant: C1CCNC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(CN4CCCC4)cc3)[nH]c2=O)c1
Reaction time: 1 h
Yield: 10.2 %

Procedure:
To a cold solution of pyrrolidine (0.060 g, 0.830 mmol) in DMF was added NaH (0.034 g, 0.830 mmol) at 0° C. and stirred the reaction mass for 1 h. Then solution of N-(3-(3-(4-(bromomethyl)phenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)-4-chlorobenzyl)pivalamide (Intermediate-103, 0.200 g, 0.419) in DMF was added at 0° C. and continued stirring at 5-10° C. for 2-3 h. The reaction mass was quenched in ice and pH adjusted to 6-7 and extracted with DCM. The organic layer was dried over anhydrous sodium sulphate and concentrated. The obtained crude product was purified by column chromatography on basic alumina, eluting with 5% MeOH:DCM to afford 0.020 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.23 (s, 9H), 1.79 (br s, 4H), 2.53 (br s, 4H), 3.66 (s, 2H), 4.48 (d, J=5.7 Hz, 2H), 6.08 (m, 1H), 7.26-7.54 (m, 5H), 7.79 (d, J=7.8 Hz, 2H); MS (m/z): 468.51 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:12]([OH:14])=O)[S:7][C:8]=1[CH:9]([CH3:11])[CH3:10])([CH3:3])[CH3:2].[F:15][C:16]1[CH:25]=[C:24]([NH2:26])[CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19]>>[F:15][C:16]1[CH:25]=[C:24]([NH:26][C:12]([C:6]2[S:7][C:8]([CH:9]([CH3:10])[CH3:11])=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=2)=[O:14])[CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: CC(C)c1cc(C(=O)O)sc1C(C)C
Reactant: COC(=O)c1ccc(N)cc1F
Product: COC(=O)c1ccc(NC(=O)c2cc(C(C)C)c(C(C)C)s2)cc1F
Yield: 32.8 %

Procedure:
In the same manner as that of Example 24, 4,5-diisopropylthiophene-2-carboxylic acid (80 mg, 0.377 mmol) and methyl 2-fluoro-4-aminobenzoate (115 mg, 0.680 mmol) were condensed, the reaction mixture was treated in a conventional manner, and then the residue was purified by silica gel chromatography [n-hexane-ethyl acetate (40:1)] and recrystallized to obtain methyl 2-fluoro-4-[(4,5-diisopropylthiophene-2-carbonyl)amino]benzoate (45 mg, 33%) as colorless prisms.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([S:10][CH3:11])[N:7]=[C:6]([C:12]2[S:16][C:15]([C:17](=[O:19])[CH3:18])=[CH:14][CH:13]=2)[CH:5]=1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:30][C:31]([F:38])([F:37])[C:32](OCC)=[O:33].Cl>C1COCC1.O>[CH2:1]([O:3][C:4]1[N:9]=[C:8]([S:10][CH3:11])[N:7]=[C:6]([C:12]2[S:16][C:15]([C:17](=[O:19])[CH2:18][C:32](=[O:33])[C:31]([F:38])([F:37])[F:30])=[CH:14][CH:13]=2)[CH:5]=1)[CH3:2]
Reactant: CCOc1cc(-c2ccc(C(C)=O)s2)nc(SC)n1
Reactant: CCOC(=O)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(-c2ccc(C(=O)CC(=O)C(F)(F)F)s2)nc(SC)n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
1-[5-(6-Ethoxy-2-methylsulfanyl-pyrimidin-4-yl)-thiophen-2-yl]-ethanone (210 mg, 0.71 mmol) was dissolved in anhydrous THF (7 mL) and cooled to −78° C. under nitrogen atmosphere. A solution of lithium bis(trimethylsilyl)amide (0.71 mL, 1.0 M) in THF was added. The reaction mixture was stirred at −20° C. under nitrogen atmosphere for 1 h. The reaction mixture was then cooled to −78° C. To this reaction mixture was added ethyl trifluoroacetate (170 μL, 1.43 mmol). The vigorously stirred solution was allowed to warm to ambient temperature overnight. The reaction mixture was poured into 20 mL of ice and water and was brought to pH=3˜4 by adding 10% HCl aqueous solution. The mixture was then extracted with diethyl ether (20 mL×3) three times. The ether layer was separated and dried with anhydrous MgSO4 and concentrated in vacuo to give crude product 1-[5-(6-ethoxy-2-methylsulfanyl-pyrimidin-4-yl)-thiophen-2-yl]-4,4,4-trifluoro-butane-1,3-dione (272 mg, 98% yield). 1H-NMR (CDCl3): δ 7.81 (m, 1H), 7.68 (m, 1H), 6.70 (s, 1H), 6.47 (s, 1H), 4.47 (q, J=7.1 Hz, 2H), 2.61 (s, 3H), 1.41 (t, J=7.1 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([OH:25])=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36](Br)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([O:25][C:21]2[CH:20]=[C:19]3[C:24]([C:15]([C:8]4[C:7]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)=[N:11][N:10]5[CH2:12][CH2:13][CH2:14][C:9]=45)=[CH:16][CH:17]=[N:18]3)=[CH:23][CH:22]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC(Br)CC1
Reactant: Oc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(-c4c(-c5ccccn5)nn5c4CCC5)ccnc3c2)CC1
Temperature: 80 °C

Procedure:
To a suspension of 4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-ol (0.27 g, 0.84 mmol) in N,N-dimethylformamide (15 mL) is added 4-bromo-piperidine-1-carboxylic acid tert-butyl ester (0.29 mL, 2.28 mmol) and cesium carbonate (1.5 g, 4.57 mmol. The mixture is heated at 80° C. for 48 h and concentrated in vacuo. The residue is taken up in dichloromethane, washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. Purification by flash chromatography (SiO2, 7% methanol in dichloromethane) yields the title compound, 262 mg (61%,) as a yellow oil.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6])=O.C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14].N1CCCCC1.Cl>N1C=CC=CC=1>[C:5]([C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1/[CH:1]=[CH:12]/[C:13]([OH:15])=[O:14])#[N:6]
Reactant: N#Cc1ccccc1C=O
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: N#Cc1ccccc1/C=C/C(=O)O
Temperature: 0 °C
Yield: 69.9 %

Procedure:
A solution of 2-formylbenzonitrile (4.17 g, 31.8 mmol), malonic acid (7.61 g, 73.1 mmol), and piperidine (0.314 mL, 3.18 mmol) in pyridine (40 mL) was heated to reflux for 2 hr. The solution was cooled and poured into crushed ice (150 mL) and 12N HCl (30 mL). The white precipitate was filtered, washed with water, and air dried to give a tan powder (3.85 g, 70%). 1H NMR (500 MHz, DMSO-d6) δ 12.81 (br. s., 1H), 8.09 (d, J=7.9 Hz, 1H), 7.93 (dd, J=7.8, 0.9 Hz, 1H), 7.80-7.74 (m, 2H), 7.62 (td, J=7.6, 0.9 Hz, 1H), 6.80 (d, J=15.9 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([CH3:14])([CH3:13])[CH:7]1[O:15][CH:6]21)#[N:2].[OH:16][C:17]1[N:18]=[N:19][CH:20]=[CH:21][CH:22]=1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>O1CCOCC1>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([CH3:14])([CH3:13])[C@@H:7]([OH:15])[C@@H:6]2[N:18]1[C:17](=[O:16])[CH:22]=[CH:21][CH:20]=[N:19]1)#[N:2]
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: Oc1cccnn1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1COCCO1
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](n2ncccc2=O)[C@@H]1O
Yield: 60.9 %

Procedure:
1 g of 6-cyano-2,2-dimethyl-3,4-epoxychromane and 1 g of 3-hydroxypyridazine are refluxed for 20 hours in 5 ml of dioxane, in the presence of 0.20 ml of a methanolic solution containing 35% of benzyltrimethylammonium hydroxide. The mixture is concentrated under vacuum and the residue is then triturated in 20 ml of water; the precipitate obtained is filtered off, washed with water and isopropyl ether and then recrystallized from 10 ml of isopropyl alcohol to give 0.9 g of the expected product.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.[Cl:13]N1C(=O)CCC1=O>CN(C=O)C>[CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]=1[Cl:13]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN(C)c1cccc([N+](=O)[O-])c1
Solvent: CN(C)C=O
Product: CN(C)c1cccc([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 101.2 %

Procedure:
25 g of N,N-dimethyl-3-nitroaniline is dissolved in 225 ml of DMF. 20 g of N-chlorosuccinimide dissolved in 190 ml of DMF is slowly added dropwise and the solution is stirred at RT. After 24 hours, the solvent is evaporated. About 500 ml of ice is added to the red residue. The suspension is extracted three times with about 200 ml of diethylether. The ether phases are dried over Na2SO4, filtered, and evaporated down. 30.4 g of N,N-dimethyl-2-chloro-3-nitroaniline is obtained as a red oil. The crude product is used further without any additional purification.