Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:14]1[N:15]=[C:16]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]3[C:34](=[O:35])[NH:33][CH2:32][CH2:31][N:30]3[CH2:36][CH3:37])=[CH:25][CH:24]=2)[C:17](=[O:21])[N:18]([CH3:20])[CH:19]=1.[F:38][C:39]1[C:44]([NH:45][C:46]([C:48]2[S:52][C:51]3[CH2:53][CH2:54][CH2:55][CH2:56][C:50]=3[CH:49]=2)=[O:47])=[C:43]([CH3:57])[C:42](B2OC(C)(C)C(C)(C)O2)=[CH:41][CH:40]=1>O>[CH2:36]([N:30]1[CH2:31][CH2:32][NH:33][C:34](=[O:35])[CH:29]1[C:26]1[CH:27]=[CH:28][C:23]([NH:22][C:16]2[C:17](=[O:21])[N:18]([CH3:20])[CH:19]=[C:14]([C:42]3[C:43]([CH3:57])=[C:44]([NH:45][C:46]([C:48]4[S:52][C:51]5[CH2:53][CH2:54][CH2:55][CH2:56][C:50]=5[CH:49]=4)=[O:47])[C:39]([F:38])=[CH:40][CH:41]=3)[N:15]=2)=[CH:24][CH:25]=1)[CH3:37]
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)ccc(F)c1NC(=O)c1cc2c(s1)CCCC2
Reactant: CCN1CCNC(=O)C1c1ccc(Nc2nc(Br)cn(C)c2=O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCN1CCNC(=O)C1c1ccc(Nc2nc(-c3ccc(F)c(NC(=O)c4cc5c(s4)CCCC5)c3C)cn(C)c2=O)cc1
Temperature: 25 °C
Yield: 41 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer, reflux condenser and nitrogen inlet was charged with 1,4-dioxane (13 mL), water (3 mL) and sodium carbonate (417 mg, 3.93 mmol). After bubbling nitrogen through the resulting mixture for 15 min, 34 (150 mg, 0.370 mmol), N-(6-Fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4,5,6,7-tetrahydro benzo[b]thiophene-2-carboxamide. (192 mg, 0.460 mmol and tetrakis(triphenyl phosphine)palladium(0) (75 mg, 0.065 mmol) were added, and the reaction mixture then heated at reflux for 5 h. After this time, the reaction mixture was cooled to room temperature, filtered and the filter cake washed with diethyl ether (10 mL). The resulting solid was dissolved in methylene chloride/methanol (10:1), absorbed onto silica gel and purified by flash chromatography to afford 35 in 41% yield (93 mg) as a yellow solid: mp 179-180° C.; 1H NMR (500 MHz, CDCl3) δ 8.31 (bs, 1H), 7.79 (d, 2H, J=8.5 Hz), 7.39 (m, 3H), 7.33 (m, 1H), 7.22 (s, 1H), 7.04 (t, 1H, J=8.0 Hz), 6.68 (s, 1H), 5.80 (d, 1H, J=3.5 Hz), 3.99 (s, 1H), 3.65 (s, 3H), 3.64 (m, 1H), 3.36 (m, 1H), 3.11 (m, 1H), 2.82 (t, 2H, J=6.0 Hz), 2.66 (t, 2H, J=6.0 Hz), 2.59 (m, 2H), 2.36 (s, 3H), 2.27 (m, 1H), 1.85 (m, 4H), 0.99 (t, 3H, J=7.0 Hz); MS (ESI+) m/z 615.3 (M+H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.[C:28](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:29].[Na+].OCC(=O)C.C(O)(=O)C.C(=O)(O)[O-].[Na+]>CN1CCCC1=O.C(Cl)Cl>[CH2:28]([N:25]1[CH2:24][CH2:23][N:22]([C:19]2[CH:18]=[CH:17][C:16]([NH:15]/[CH:14]=[C:5]3\[C:6](=[O:13])[NH:7][C:8](=[O:12])[C:9]4[C:4]\3=[CH:3][C:2]([I:1])=[CH:11][CH:10]=4)=[CH:21][CH:20]=2)[CH2:27][CH2:26]1)[CH3:29]
Reactant: O=C1NC(=O)c2ccc(I)cc2/C1=C/Nc1ccc(N2CCNCC2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CCN1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(I)cc43)cc2)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 75.6 %

Procedure:
(4Z)-6-Iodo-4-{[(4-piperazin-1-ylphenyl)amino]methylene}isoquinoline-1,3(2H,4H)-dione (47.4 mg, 0.1 mmol) is dissolved in N-methylpyrrolidinone (1 mL) and methylene chloride (0.3 mL), followed by addition of sodium triacetoxyborohydride (244 mg, 1.15 mmol), 1-hydroxy-propan-2-one (0.177 mL, 2.58 mmol) and acetic acid (0.15 mL, 2.6 mmol). After stirring at room temperature for 40 min, methylene chloride and saturated sodium bicarbonate solution were added. The organic layer is separated and dried to give 38 mg (71%) of the title compound as a yellow solid. MS (ESI) m/z 533.4 (M+H)+1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:28])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([C:26]#[N:27])([CH3:25])[CH3:24])[CH:18]=3)[CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1.[C:29]([N:34]=[C:35]=[S:36])(=[O:33])[O:30][CH2:31][CH3:32].O>CS(C)=O>[C:26]([C:23]([C:19]1[CH:18]=[C:17]([C:16]([NH:15][C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=2)[O:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:35]([NH:34][C:29](=[O:33])[O:30][CH2:31][CH3:32])=[S:36])=[N:7][CH:6]=2)=[O:28])[CH:22]=[CH:21][CH:20]=1)([CH3:24])[CH3:25])#[N:27]
Reactant: CCOC(=O)N=C=S
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc(N)nc3)c2)c1
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)NC(=S)Nc1ccc(Oc2cccc(NC(=O)c3cccc(C(C)(C)C#N)c3)c2)cn1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a solution of N-{3-[(6-aminopyridin-3-yl)oxy]phenyl}-3-(1-cyano-1-methylethyl)benzamide (4.32 g, 11.6 mmol) in DMSO (100 mL) was added ethyl isothiocyanatocarbonate (1.64 mL, 13.9 mmol), and the mixture was stirred at room temperature for 21 hr. Water (300 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (250 mL, 50 mL). The combined organic layer was washed with saturated brine (30 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give ethyl ({5-[3-({[3-(1-cyano-1-methylethyl)phenyl]carbonyl}amino)phenoxy]pyridin-2-yl}carbamothioyl)carbamate as a yellow amorphous solid. The obtained compound was used in the next reaction without further purification.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH:15]([C:26]([O-:28])=[O:27])[C:16]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)([OH:20])[C:17]([O-:19])=[O:18])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd].[C]>[Si:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH:15]([C:26]([OH:28])=[O:27])[C:16]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)([OH:20])[C:17]([OH:19])=[O:18])[CH2:11][CH2:10]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(C(C(=O)[O-])C(O)(C(=O)[O-])C2CCCC2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OC1CCC(C(C(=O)O)C(O)(C(=O)O)C2CCCC2)CC1
Reaction time: 24 h
Yield: 83 %

Procedure:
To a solution of a diastereomeric mixture (330 mg, 0.55 mmol) of dibenzyl 3-(4-((tert-butyldimethylsilyl)oxy)cyclohexyl-2-cyclopentyl-2-hydroxysuccinate in ethanol (10 ml) was added 10% Pd carbon (150 mg) under a nitrogen gas stream. The atmosphere in a reaction vessel for the mixture was replaced five times with nitrogen gas, the reaction vessel was filled with hydrogen gas, and the contents of the reaction vessel were stirred for 24 hr under a hydrogen gas stream. The catalyst was collected by filtration through Celite pad and was washed with ethanol, and the filtrate was concentrated under reduced pressure to give the title compound as a colorless solid (190 mg, yield 83%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C:11](Cl)(Cl)Cl)[N:8]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])[C:7]=2[CH:21]=1.[CH3:22][CH:23]([CH3:47])[CH2:24][NH:25][C@H:26]1[CH2:31][C@@H:30]([C:32]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[O:33])[CH2:29][N:28]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:27]1.C(=O)([O-])[O-:49].[K+].[K+]>C(#N)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C:11]([N:25]([CH2:24][CH:23]([CH3:47])[CH3:22])[C@H:26]3[CH2:31][C@@H:30]([C:32]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[O:33])[CH2:29][N:28]([C:40]([O:42][C:43]([CH3:45])([CH3:44])[CH3:46])=[O:41])[CH2:27]3)=[O:49])[N:8]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])[C:7]=2[CH:21]=1
Reactant: CC(C)CN[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Reactant: COCCCCn1c(C(Cl)(Cl)Cl)nc2ccc(OC)cc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nc2ccc(OC)cc21
Temperature: 80 °C
Reaction time: 5 h
Yield: 13.9 %

Procedure:
6-Methoxy-1-(4-methoxybutyl)-2-(trichloromethyl)-1H-benzimidazole (330 mg) was dissolved in acetonitrile-water (2:1, 50 ml), and tert-butyl (3S,5R)-3-{(2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (350 mg) was added. Potassium carbonate (1.3 g) was added, and the mixture was stirred at 80° C. for 5 hr. The reaction mixture was concentrated under reduced pressure, acidified (pH 3) with 6M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, and a fraction eluted with ethyl acetate-hexane (3:7)-ethyl acetate was concentrated under reduced pressure. The residue was further subjected to reversed-phase preparative HPLC, and a fraction eluted with water-acetonitrile (9:1-6:4) was collected, basified (pH 10) with saturated aqueous potassium carbonate solution, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the object product (82 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[NH2:18][C:19]1[CH:26]=[C:25](F)[C:22]([C:23]#[N:24])=[CH:21][N:20]=1>CC(N(C)C)=O.CCOC(C)=O.O>[NH2:18][C:19]1[CH:26]=[C:25]([O:7][CH:4]2[CH2:5][CH2:6][N:2]([CH3:1])[CH2:3]2)[C:22]([C:23]#[N:24])=[CH:21][N:20]=1
Reactant: CN1CCC(O)C1
Reactant: N#Cc1cnc(N)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN1CCC(Oc2cc(N)ncc2C#N)C1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
1-methylpyrrolidin-3-ol (89 mg, 0.875 mmol) was treated at room temperature with KHMDS (1 M in THF, 0.788 ml, 0.788 mmol). The reaction mixture was stirred for 10 min, then added to a solution of 6-amino-4-fluoronicotinonitrile (intermediate 21, 60 mg, 0.438 mmol) in DMA (1 ml). The mixture was then heated at 100° C. for 40 min, cooled to room temperature, diluted with EtOAc and water. The layers were separated and aq. layer was extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude material was purified twice by normal phase chromatography (4 g silica gel cartridge, DCM/(DCM/(1 M NH3 in MeOH) 9/1) 100:0 to 0:100) to give the title compound as a light brown wax. (UPLC-MS 3) tR 0.27 min; ESI-MS 219.1 [M+H]+.
Reaction SMILES: [BH4-].[Li+].C([C@@H]1COC(=O)N1[C:16](=[O:41])[C@H:17]([CH3:40])[C@@H:18]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)C1C=CC=CC=1.CO>C1COCC1>[Si:33]([O:32][C@@H:18]([CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)[C@@H:17]([CH3:40])[CH2:16][OH:41])([C:36]([CH3:38])([CH3:39])[CH3:37])([CH3:34])[CH3:35]
Reactant: COc1ccc(COCCC[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(COCCC[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)CO)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 77.4 %

Procedure:
Lithium borohydride (2.0 M in THF, 5 mL, 10 mmol) was added dropwise to a stirred solution of 11 (2.77 g, 5 mmol) and methanol (0.4 mL, 10 mmol) in anhydrous THF (20 mL) under an atmosphere of N2 at 0° C. The mixture was stirred for 20 min at 0° C. and then warmed to ambient temperature. After 3 h at room temperature, the reaction was quenched with aqueous NH4Cl (100 mL) and extracted with CH2Cl2 (3×20 mL). The combined organic layers were dried over anhydrous MgSO4, evaporated and chromatographed (hexane/EtOAc 7:3) to yield the alcohol (1.48 g, 78%) as a colorless oil: IR (CHCl3) 2948, 2856, 2302, 1612, 1265 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.27 (d, 2H, J=8.5 Hz), 7.00 (d, 2H, J=8.5 Hz), 4.43 (s, 2H), 3.78 (s, 3H), 3.67 (dd, 1H, J=8.6, 10.5 Hz), 3.51–3.41 (m, 3H), 2.78 (br s, 1H), 1.94 (m, 1H), 1.72–1.49 (m, 4H), 0.90 (s, 9H), 0.81 (d, 3H, J=7.0 Hz), 0.09 (s, 3H), 0.08 (s, 3H); 13C NMR (75 MHz, CDCl3) 159.2, 130.6, 129.3, 113.8, 75.4, 72.6, 70.1, 65.8, 55.9, 55.3, 39.7, 29.1, 26.6, 25.9, 18.0, 12.1, −4.28, −4.38; LRMS (ESI) 405.2 (M+Na).
Reaction SMILES: [OH:1][C@@H:2]([CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[NH:10][C:11]([CH:14]=O)=[C:12]([CH3:13])[C:6]=2[C:5]1=[O:16].[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30](=[O:35])[CH2:29]2>>[OH:1][C@@H:2]([CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[NH:10][C:11](/[CH:14]=[C:29]3\[C:30](=[O:35])[NH:31][C:32]4[C:28]\3=[CH:27][C:26]([O:25][CH3:24])=[CH:34][CH:33]=4)=[C:12]([CH3:13])[C:6]=2[C:5]1=[O:16]
Reactant: COc1ccc2c(c1)CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Product: COc1ccc2c(c1)/C(=C/c1[nH]c3c(c1C)C(=O)N(C[C@@H](O)CN1CCOCC1)CC3)C(=O)N2
Yield: 76.6 %

Procedure:
The title compound was prepared under the same conditions as described in step 6 of Example 5 with (S)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde 5f obtained from step 5 of Example 5 and 5-methoxy-1,3-dihydro-indol-2-one as starting materials to give (S,Z)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-2-(5-methoxy-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one 19 (40 mg, yield 76.6%) as a red solid.
Reaction SMILES: [CH3:1][NH:2][CH3:3].ClC1C=CC=CC=1C([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH2:21]Cl)=[N:19][C:18]([C:23]([OH:25])=[O:24])=[N:17]1)=O.[I-].[Na+].[CH3:32][OH:33]>>[Cl:15][C:13]1[CH:14]=[CH:9][CH:10]=[CH:11][C:12]=1[C:32]([C:11]1[CH:12]=[C:13]([Cl:15])[CH:14]=[CH:9][C:10]=1[N:16]1[C:20]([CH2:21][N:2]([CH3:3])[CH3:1])=[N:19][C:18]([C:23]([OH:25])=[O:24])=[N:17]1)=[O:33]
Reactant: CNC
Reactant: O=C(O)c1nc(CCl)n(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)n1
Reactant: CO
Agent: [I-]
Agent: [Na+]
Product: CN(C)Cc1nc(C(=O)O)nn1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
310 ml (0.226 mole) of a 33% ethanolic dimethylamine solution is added to a suspension of 45.0 g (0.11 mole) of 1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxylic acid (see DT-OS 2,159,527, page 32) and 0.5 g (0.0033 mole) of sodium iodide in 250 ml of methanol, and the mixture is stirred for 6 hours at room temperature. The clear reaction solution is concentrated in vacuo; the residue is dissolved in 200 ml of water, and 2 N hydrochloric acid solution is slowly added until the pH value of 5 is reached. After 16 hours' standing at 0°-5°, the precipitated aminic acid is filtered off and well washed with water and then with ether. Upon drying, there is obtained 1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-[(dimethylamino)-methyl]-1H-1,2,4-triazole-3-carboxylic acid, m.p. 222°-225° with decomposition.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=O)=[CH:4][CH:3]=1.[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1.C1(S(O)(=O)=O)C=CC=CC=1>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[N:31][CH2:30][C:29]2[CH:32]=[CH:33][C:26]([F:25])=[CH:27][CH:28]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(F)cc1)C1CCN(S(=O)(=O)c2ccccc2)CC1
Reactant: NCc1ccc(F)cc1
Agent: O=S(=O)(O)c1ccccc1
Solvent: Cc1ccccc1C
Product: O=S(=O)(c1ccccc1)N1CCC(C(=NCc2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 63.6 %

Procedure:
A solution of 22.26 g (0.064 mol) of (4-fluorophenyl)[1-(phenylsulfonyl)-4-piperidinyl]methanone, 12.51 g (0.10 mol) of 4-fluorobenzylamine, and 0.76 g (0.0048 mol) of benzenesulfonic acid in 400 mL of xylene was heated at reflux for 25.5 h. Water was removed with a Dean-Stark trap. The solvent was removed in vacuo, and the residue was partitioned between CH2Cl2 and dilute NaOH. The CH2Cl2 solution was dried (Na2SO4), and the solvent was removed in vacuo. The residue was recrystallized from CH2Cl2 -hexane to give 18.49 g (63.68%) of white crystalline solid, mp 114°-116° C. A second crop of 3.27 g (11.28%) of product was isolated from the filtrate as a white solid, mp 110°-112° C.
Reaction SMILES: B1([O-])OO1.[OH2:5].[OH2:6].O.O.[Na+].[Br:10][C:11]1[CH:17]=[C:16]([F:18])[C:14]([NH2:15])=[C:13]([F:19])[CH:12]=1>C(O)(=O)C>[Br:10][C:11]1[CH:17]=[C:16]([F:18])[C:14]([N+:15]([O-:6])=[O:5])=[C:13]([F:19])[CH:12]=1
Reactant: Nc1c(F)cc(Br)cc1F
Reactant: O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1c(F)cc(Br)cc1F
Temperature: 55 °C

Procedure:
To a suspension of sodium perborate tetrahydrate (1.04 g, 5 mmol) in acetic acid (20 mL), stirred at 55° C., was added a solution of 4-bromo-2,6-difluoroaniline in acetic acid (10 mL) over 1 hour in a dropwise fashion. After stirring at 55° C. for an additional 3 hours, the solution was allowed to cool to room temperature and filtered. The filtrate was poured into ice, and extracted twice with ethyl acetate. The combined organic extracts were washed successively with 5×100-mL portions of water, brine, dried (MgSO4), and concentrated in vacuo. The resulting residue was purified by column chromatography over silica gel eluted with ethyl acetate:hexanes (1:20) to afford 780 mg of the title compound as a tan solid. 1H NMR (CDCl3) δ 7.32 (dt, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:27]2[O:32][CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28]2)[CH:12]=[CH:13][C:14]=1[NH:15][C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[N:26])[CH:20]=1)=[O:17].[OH-].[Na+]>O.C(#N)C>[Cl:8][C:9]1[CH:10]=[C:11]([CH:27]2[O:32][CH2:31][CH2:30][NH:29][CH2:28]2)[CH:12]=[CH:13][C:14]=1[NH:15][C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[N:26])[CH:20]=1)=[O:17]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(NC(=O)Nc3cccc(C#N)c3)c(Cl)c2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: N#Cc1cccc(NC(=O)Nc2ccc(C3CNCCO3)cc2Cl)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 65.2 %

Procedure:
To a stirred solution of trifluoroacetic acid (225 μl) in water (4.5 ml) was added a solution of tert-butyl (RS)-2-(3-chloro-4-(3-(3-cyanophenyl)ureido)phenyl)morpholine-4-carboxylate (114 mg) in acetonitrile (2 ml). The reaction mixture was then capped and the mixture was shaken at 80° C. for 3 h. The reaction mixture was then cooled to room temperature and poured into 1 M aq. NaOH and the resulting mixture was extracted twice with EtOAc. The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (Isolute® Flash-NH2 from Separtis); gradient: heptane/EtOAc/MeOH) to afford (RS)-1-(2-chloro-4-(morpholin-2-yl)phenyl)-3-(3-cyanophenyl)urea (58 mg, 72%) as a white solid. MS (ISP): 359.1 ([{37Cl}M+H]+), 357.1 ([{35Cl}M+H]+).
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:9](#N)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl.C(OCC)(=[O:20])C>C1COCC1>[O:20]=[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C[Zn]Br
Reactant: N#Cc1ccccc1
Reactant: CCOC(C)=O
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1ccccc1
Yield: 85 %

Procedure:
Under nitrogen atmosphere, 30 mL of THF was added to 12.2 g (20 mmol, 4.0 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 1.03 g (5 mmol) of benzonitrile in 2.5 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 20˜25° C. for 27 hours. 15 mL of 10% hydrochloric acid was added dropwise at 20° C. or lower, and the mixture was stirred at 20˜25° C., followed by dilution with 50 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 15 mL of 1N hydrochloric acid, 20 mL of an aqueous saturated sodium chloride solution, 20 mL (×3) of an aqueous saturated sodium bicarbonate solution, and 20 mL of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 1.64 g of the desired product (yield 85%).
Reaction SMILES: [C:1]([C:6]1(C(OCC)=O)[CH2:15][CH2:14][C:13]2[NH:12][C:11](=[O:16])[NH:10][C:9](=[O:17])[C:8]=2[CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2].Cl>[OH-].[Na+]>[C:1]([CH:6]1[CH2:15][CH2:14][C:13]2[NH:12][C:11](=[O:16])[NH:10][C:9](=[O:17])[C:8]=2[CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)C1(C(=O)OCC)CCc2[nH]c(=O)[nH]c(=O)c2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)C1CCc2[nH]c(=O)[nH]c(=O)c2C1

Procedure:
A solution of of 6,6-Dicarboethoxy-5,6,7,8-tetrahydro-2,4(1H,3H)-quinazolinedione (25 g) in 1N NaOH (350 mL) was stirred at 40° C. for 35 min. The solution was cooled in an ice bath and acidified with 35 mL of concentrated HCl. The precipitate that formed was collected and refluxed in 20 ml of dimethylformamide (DMF) for 2 h. The reaction was cooled and the DMF removed in vacuo. To the resulting mixture 40 mL of water was added and the solid collected and dried to yield 6-Carboethoxy-5,6,7,8-tetrahydro-2,4(1H ,3H)-quinazolinedione.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:24]2[CH2:28][CH2:27][CH2:26][S:25]2(=[O:30])=[O:29])[CH:3]=1.[CH2:31]([C@@H:34]1[CH2:38][O:37][C:36](=[O:39])[NH:35]1)[CH2:32][CH3:33]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:35]4[C@H:34]([CH2:31][CH2:32][CH3:33])[CH2:38][O:37][C:36]4=[O:39])=[CH:3][C:4]=3[N:24]3[CH2:28][CH2:27][CH2:26][S:25]3(=[O:30])=[O:29])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CCC[C@@H]1COC(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Product: CCC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)c(N2CCCS2(=O)=O)c1
Yield: 69.7 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using [4-bromo-2-(1,1-dioxoisothiazolidin-2-yl)phenyl][4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (247 mg) described in Preparation Example 118 and (R)-4-propyloxazolidin-2-one (64.58 mg) described in Preparation Example 29, the title compound (188.8 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[H-].[Na+].[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:14]=1[CH2:15]Cl.[C:22]1(C)C=CC=C[CH:23]=1>>[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:14]=1[CH2:15][O:8][CH2:7][C:5]1([CH2:22][CH3:23])[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]1
Reactant: Cc1ccccc1
Reactant: ClCc1c(Cl)cccc1Cl
Reactant: CC1(C)OCC(CO)O1
Agent: [H-]
Agent: [Na+]
Product: CCC1(COCc2c(Cl)cccc2Cl)COC(C)(C)O1

Procedure:
A solution of 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane (32.0g) in toluene (25 ml) was added slowly to a stirred suspension of sodium hydride (9.6g of 50% dispersion in oil) in toluene (25 ml). After the addition the mixture was heated under reflux for 2 hours. 2,6-Dichlorobenzyl chloride (39.1g) in toluene (100 ml) was then added dropwise and the mixture heated under reflux for a further 4 hours. The cooled mixture was washed with water (×3) and dried and the solvent was removed under reduced pressure. The residual oil was distilled in vacuo to give the desired product b.p. 156°-162° C. at 1.5 mm Hg.