Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]3[C:14]([CH2:17]Cl)=[N:15][N:16]=[C:7]3[C:6]=2[CH:19]=1.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.[OH-].[Na+]>COCCOC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]3[C:14]([CH2:17][N:24]4[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]4)=[N:15][N:16]=[C:7]3[C:6]=2[CH:19]=1
Reactant: CN1C(=O)Cn2c(CCl)nnc2-c2cc(Cl)ccc21
Reactant: CN1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: CN1CCN(Cc2nnc3n2CC(=O)N(C)c2ccc(Cl)cc2-3)CC1

Procedure:
5 g. of 10-chloro-3-(chloromethyl)-7-methyl-5H-s-triazolo[4,3-d] [1,4]benzodiazepin-6(7H)-one from part (a) is suspended in 50 ml. of 1,2-dimethoxyethane. N-methylpiperazine (5.4 g.) is added to the suspension and the mixture is heated under reflux for 5 hours. The solvent is stripped off, 3N aqueous sodium hydroxide is added to the residue and the mixture is extracted with several portions of chloroform. The combined chloroform extracts are dried over sodium sulfate and the solvent is removed under vacuum to leave a residue which is recrystallized from absolute ethanol to yield 4 g. of the title compound, melting point 228.5°-230.5°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[NH2:8].C1C[O:13][CH2:12]C1>>[CH3:9][C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:12](=[O:13])[NH:1][C:2]=2[CH:3]=1
Reactant: Cc1ccc(N)c(N)c1
Reactant: C1CCOC1
Product: Cc1ccc2[nH]c(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
Into a 100 mL round bottomed flask, 3,4-diaminotoluene (1.00 g, 8.2 mmol) was dissolved in THF (8.2 mL). CDT (1.59 g, 9.8 mmol) in THF (25 mL) was added slowly via addition funnel. After addition the mixture was stirred overnight at room temperature. Solvent was removed under vacuum and the residue was purified by column chromatography (5% MeOH/DCM) to give the product 5-methyl-1H-benzo[d]imidazol-2(3H)-one (110A) as a brown-tan solid (990 mg, 82% yield). ESI-MS:m/z 149.4 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)=[N:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][C:35]([S:40]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)(=[O:42])=[O:41])=[CH:34]2>CN(C)C=O>[Cl:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][C:35]([S:40]([N:43]1[CH2:48][CH2:47][N:46]([C:13]([C:12]3[CH:11]=[CH:10][C:9]([C:4]4[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[N:3]=4)=[CH:17][CH:16]=3)=[O:15])[CH2:45][CH2:44]1)(=[O:42])=[O:41])=[CH:34]2
Reactant: Cn1nc(-c2ccc(C(=O)O)cc2)ccc1=O
Reactant: O=S(=O)(c1cc2cc(Cl)ccc2[nH]1)N1CCNCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cn1nc(-c2ccc(C(=O)N3CCN(S(=O)(=O)c4cc5cc(Cl)ccc5[nH]4)CC3)cc2)ccc1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 74.2 %

Procedure:
To a solution of 4-(1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzoic acid, (0.637 g, 2.76 mmol) in N,N-dimethylformamide was added 1,1′-carbonyldiimidazole (0.930 g, 5.74 mmol, 2.07 eq.). The resulting solution was stirred at room temperature for 5 hours, whereupon 5-chloro-2-(piperazin-1-ylsulphonyl)-1H-indole (see WO 99/57113, 0.622 g, 2.08 mmol, 1.11 eq.) was added. The reaction mixture was stirred at 25° C. for 14 h and then evaporated in vacuo. The residue was purified by flash column chromatography: first eluting with ethyl acetate:toluene (2:1), then with ethyl acetate. During concentration of the desired fraction, a white solid precipitated. The solid was triturated with hot ethyl acetate (50 mL) to remove a trace of impurity. After drying, pale yellow solid were isolated. De-colorization on charcoal using hot methanol together with the re-crystallization in methanol, gave 0.79 gram 6-{4-[4-(5-chloro-1H-indole-2-sulphonyl)-piperazine-1-carbonyl]-phenyl}-2-methyl-2H-pyridazin-3-one as fine white crystals (yield 56%).
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].N1C=CC=CC=1.[CH3:16][CH:17]([SiH:19]([CH:21]([CH3:23])[CH3:22])Cl)[CH3:18]>CCCCCC>[CH3:16][CH:17]([SiH:19]([CH:21]([CH3:23])[CH3:22])[O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:18]
Reactant: CC(C)[SiH](Cl)C(C)C
Reactant: CCCCCCCCO
Solvent: CCCCCC
Solvent: c1ccncc1
Product: CCCCCCCCO[SiH](C(C)C)C(C)C
Temperature: -5 °C
Reaction time: 8 h

Procedure:
Di(2-propyl)octyloxysilane was prepared in the following manner. Dry octanol (52.5 g, 0.40 mole) and dry pyridine (32.9 g, 0.42 mole) were added to a 500 ml round-bottom flask. The solution was cooled to -5° C. with stirring. Di(2-propyl)chlorosilane (67.1 g, 0.44 mole) was added in a dropwise fashion over 60 minutes. After this addition, the temperature of the reaction mixture was maintained at -5° C. for another 30 minutes, then allowed to come to room temperature overnight. Hexane (100 ml) was then added to this reaction mixture. The organic phase was extracted with 500 ml 0.1N aq. HCl and 500 ml water. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled to produce di(2-propyl)octyloxysilane.
Reaction SMILES: [CH:1]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:8][CH:9]=[C:10]([CH:14]=2)[C:11]([OH:13])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:21]1[CH:26]=[C:25]([NH2:27])[CH:24]=[N:23][CH:22]=1>>[CH:1]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:8][CH:9]=[C:10]([CH:14]=2)[C:11]([NH:27][C:25]2[CH:26]=[N:21][CH:22]=[N:23][CH:24]=2)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1cncnc1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1
Product: O=C(Nc1cncnc1)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1

Procedure:
This compound was prepared following the same procedure as described in Example 11 using 5-cyclopentyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (Example 9c) (100 mg, 0.35 mmol) and 5-pyrimidinamine (CAN 591-55-9, 39.5 mg, 0.41 mmol) as starting materials; off white solid (61 mg, 48.2%). MS (ESI): 367.2 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([O:8][CH3:9])=[N:4][CH:5]=[N:6][CH:7]=1.[B:10](OC(C)C)([O:15]C(C)C)[O:11]C(C)C.C([Li])CCC>C1COCC1>[CH3:9][O:8][C:3]1[C:2]([B:10]([OH:15])[OH:11])=[CH:7][N:6]=[CH:5][N:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ncncc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ncncc1B(O)O
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 44.4 %

Procedure:
To a solution of 5-bromo-4-methoxypyrimidine (0.460 g, 2.43 mmol) and triisopropyl borate (0.671 mL, 2.92 mmol) in 12 mL of THF at −70° C. was added butyllithium (1.6 m in hexanes, 1.83 mL, 2.92 mmol) dropwise. The addition took 15 minutes and the reaction turned light yellow. The reaction stirred for 30 minutes at −70° C. and was then allowed to warm up to −20° C. The reaction was quenched with ammonium chloride (sat.) and extracted with ethyl acetate. The aqueous layer was concentrated and NaCl (sat.) was added. The aqueous layer was extracted with 3/2 chloroform/iPrOH (3×). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 166 mg of 4-methoxypyrimidin-5-ylboronic acid as a light yellow solid. ES+=155.2 (M+H)
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][C:4]=1[N+:14]([O-:16])=[O:15])=O.C1(P(=[CH:36][C:37]([O:39][CH3:40])=[O:38])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:40][O:39][C:37](=[O:38])/[CH:36]=[CH:1]/[C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][C:4]=1[N+:14]([O-:16])=[O:15]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1ccc(C=O)c([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(/C=C/C(=O)OC)c([N+](=O)[O-])c1
Yield: 90.7 %

Procedure:
In 70 ml of toluene was dissolved 3.2 g of ethyl 4-formyl-3-nitrobenzoate and then 5.75 g of methyl triphenylphosphoranylideneacetate, followed by 6 hours of stirring under reflux. After cooling, the reaction solution was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to obtain 3.63 g of ethyl 4-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]-3-nitrobenzoate as a white solid.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[N:13]2[C:14]3[N:5]([C:6](=[O:16])[CH2:7][CH2:8][C:9]=3[CH:10]=[CH:11][C:12]2=[O:15])[CH2:4]1.CCN(CC)CC.[CH3:24][S:25](Cl)(=[O:27])=[O:26].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:24][S:25]([O:1][CH2:2][C@H:3]1[N:13]2[C:14]3[N:5]([C:6](=[O:16])[CH2:7][CH2:8][C:9]=3[CH:10]=[CH:11][C:12]2=[O:15])[CH2:4]1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1CCc2ccc(=O)n3c2N1C[C@H]3CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@@H]1CN2C(=O)CCc3ccc(=O)n1c32
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (1S)-1-(hydroxymethyl)-1,2,5,6-tetrahydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione (1.909 g, 8.67 mmol) in DCM (100 ml) at 0° C. under argon was treated with Et3N (1.450 ml, 10.40 mmol) and then methanesulfonyl chloride (0.743 ml, 9.54 mmol) and then allowed to warm to rt and stirred at rt for 1 h. The reaction mixture was then treated with saturated aqueous NaHCO3 (100 ml) and the mixture was extracted with DCM (2×100 ml). The combined organic solvents were then dried (MgSO4), filtered, evaporated to give the crude intermediate [(2S)-4,9-dioxo-1,2,8,9-tetrahydro-4H,7H-imidazo[1,2,3-ij]-1,8-naphthyridin-2-yl]methyl methanesulfonate. This was dissolved in dry CH3CN (100 ml) and then treated with pyridine (1.402 ml, 17.34 mmol) and 1,1-dimethylethyl 4-piperidinylcarbamate (3.47 g, 17.34 mmol) and heated at 70° C. for 20 h. After 20 h more 1,1-dimethylethyl 4-piperidinylcarbamate (3.47 g, 17.34 mmol) and pyridine (1.402 ml, 17.34 mmol) were added and the temperature was increased to reflux (heating block 95° C.) and reaction was stirred at this temperature for a further 4 h. The reaction mixture was then evaporated, treated with saturated aqueous NaHCO3 (200 ml) was then added and the mixture was extracted with DCM (3×200 ml). The combined organic solvents were then dried (MgSO4), filtered, evaporated to give the crude product as a brown solid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][C:9]2[NH:10][CH:11]=[N:12][C:8]=2[CH:7]=1)=[O:4].[F:15][C:16]1[CH:28]=[CH:27][C:19]([CH2:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:18][CH:17]=1>C(OCC)C>[F:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][CH:21]2[CH2:22][CH2:23][N:24]([CH2:2][C:3]([NH:5][C:6]3[CH:14]=[CH:13][C:9]4[NH:10][CH:11]=[N:12][C:8]=4[CH:7]=3)=[O:4])[CH2:25][CH2:26]2)=[CH:27][CH:28]=1
Reactant: O=C(CCl)Nc1ccc2[nH]cnc2c1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Solvent: CCOCC
Product: O=C(CN1CCC(Cc2ccc(F)cc2)CC1)Nc1ccc2[nH]cnc2c1

Procedure:
The title compound is prepared from 2-chloro-N-(1H-benzimidazol-5-yl)-acetamide (Example 151 a) and 4-(4-fluoro-benzyl)-piperidine according to the method described in Example 142b. Melting Point: 203.5-204.5° C. (diethylether)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=O)[CH2:9][NH:10][C:11](=O)[C@@H:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]([CH3:15])[CH3:14])=[N:6][CH:7]=1.C([O-])(=O)C.[NH4+:30]>C1(C)C(C)=CC=CC=1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:30]=[C:11]([C@@H:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]([CH3:15])[CH3:14])[NH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: [NH4+]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)c1ccc(Br)cn1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)c1nc(-c2ccc(Br)cn2)c[nH]1
Temperature: 130 °C
Yield: 62.9 %

Procedure:
In a sealed tube, a mixture of (S)-tert-butyl 1-(2-(5-bromopyridin-2-yl)-2-oxoethylamino)-3-methyl-1-oxobutan-2-ylcarbamate (0.1 g) and ammonium acetate (0.186 g) in xylene was heated at 130° C. for 3 hrs. The reaction was diluted with EtOAc, washed with sat. NaHCO3, water and sat. NaCl, dried over anhydrous Na2SO4, filtered and concentrated to yield a yellow oil. The residue was purified by silica chromatography (0-100% EtOAc in hexane) to yield (S)-tert-butyl 1-(4-(5-bromopyridin-2-yl)-1H-imidazol-2-yl)-2-methylpropylcarbamate (0.06 g) as a pale yellow solid. LC/MS (Cond. N-1): [M+H]+ 395.17, RT=3.06 min.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[C:11]=1[O:25][CH3:26])=[O:8])=[N+:2]=[N-:3].[C:31]([C:33]1[CH:34]=[CH:35][C:36]([N:39]([CH3:41])[CH3:40])=[N:37][CH:38]=1)#[CH:32]>>[C:16]([C:14]1[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[C:11]([O:25][CH3:26])=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:27]=[CH:28][C:29]([CH3:30])=[C:4]([N:1]3[CH:32]=[C:31]([C:33]4[CH:38]=[N:37][C:36]([N:39]([CH3:41])[CH3:40])=[CH:35][CH:34]=4)[N:3]=[N:2]3)[CH:5]=2)[CH:15]=1)([CH3:18])([CH3:19])[CH3:17]
Reactant: COc1c(NC(=O)c2ccc(C)c(N=[N+]=[N-])c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: C#Cc1ccc(N(C)C)nc1
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4ccc(N(C)C)nc4)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
Example 24 was prepared from 3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide and (5-ethynyl-pyridin-2-yl)-dimethyl-amine in the same manner as Example 15. ESI MS m/z 578 [C29H35N7O4S+H]+.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]1=[O:11].[H-].[Na+].CS(O[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][CH2:22]1)(=O)=O.C(OC(=O)NC1CCN(CCN2C3C(=CC=C(F)C=3)N=CC2=O)CC1)(C)(C)C>ClCCl.CO>[C:31]([O:30][C:28](=[O:29])[NH:27][CH:24]1[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][C:2]2=[O:11])[CH2:22][CH2:23]1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Reactant: O=c1ccc2ccccc2[nH]1
Agent: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ccccc32)CC1
Yield: 34.8 %

Procedure:
Quinolin-2(1H)-one (250 mg, 1.7 mmol) was deprotonated with sodium hydride (60% in oil, 70 mg, 1.7 mmol) and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6) (1.7 mmol) as described for Intermediate 141. Chromatography on silica gel with 0-5% methanol in dichloromethane gave 220 mg (35%) of product as a colorless solid.
Reaction SMILES: C([C@H]1COC(C)(C)N1C(=O)C(C1C=CN(C2C=CC(C3C=CC=CC=3)=CC=2)C=1)=O)C1C=CC=CC=1.[C:36]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:41]=[CH:40][C:39]([C:42]2[O:43][CH:44]=[CH:45][CH:46]=2)=[CH:38][CH:37]=1.[C:53](OCC)(=[O:59])[C:54]([O:56][CH2:57][CH3:58])=[O:55]>>[CH2:57]([O:56][C:54](=[O:55])[C:53]([C:44]1[O:43][C:42]([C:39]2[CH:40]=[CH:41][C:36]([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)=[CH:37][CH:38]=2)=[CH:46][CH:45]=1)=[O:59])[CH3:58]
Reactant: c1ccc(-c2ccc(-c3ccco3)cc2)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC1(C)OC[C@H](Cc2ccccc2)N1C(=O)C(=O)c1ccn(-c2ccc(-c3ccccc3)cc2)c1
Product: CCOC(=O)C(=O)c1ccc(-c2ccc(-c3ccccc3)cc2)o1
Yield: 74 %

Procedure:
According to the procedure described in Example 13 for the preparation of 1-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-(biphenyl-4-yl-1H-pyrrol-3-yl)ethane-1,2-dione, 2-biphenyl-4-yl-furan was deprotonated and alkylated with diethyl oxalate to give in 74% yield 2-(2-biphenyl-4-yl-furan-5-yl)-2-oxoacetic acid ethyl ester as a yellow solid, mp 91-94° C. 1H NMR: δ 7.94 (d, 2H, J=8.5 Hz), 7.83 (d, 1H, J=4.1 Hz), 7.69 (d, 2H, J=8.1 Hz), 7.64 (d, 2H, J=7.7 Hz), 7.47 (t, 2H, J=7.4 Hz), 7.39 (t, 1H, J=7.2 Hz), 6.90 (d, 1H, J=4.2 Hz), 4.44 (q, 2H, J=7.0 Hz), 1.45 (t, 3H, J=7.2 Hz). Anal. Calculated for C20H16O4: C, 74.99; H, 5.03. Found: C, 75.11; H, 5.07.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]([O:14][CH3:15])=[O:13])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl.Cl.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][N:28]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([C:9]4([C:12]([O:14][CH3:15])=[O:13])[CH2:11][CH2:10]4)=[CH:5][CH:4]=3)[CH2:27][CH2:26]2)=[CH:23][CH:24]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: COC(=O)C1(c2ccc(CCl)cc2)CC1
Agent: Cl
Product: COC(=O)C1(c2ccc(CN3CCN(c4ccc(F)cc4)CC3)cc2)CC1

Procedure:
By similar reaction and treatment to that in Example 1(5) using methyl 1-(4-chloromethylphenyl)cyclopropanecarboxylate obtained in Example 75(2) instead of N-(4-chloromethylphenylmethyl)acetamide and 1-(4-fluorophenyl)piperazine dihydrochloride instead of phenylpiperazine, the title compound was obtained as a pale-yellow oil.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH2:27][O:28][CH3:29])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39].CN(C)C(=O)C>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH2:27][O:28][CH3:29])[N:8]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)CI
Reactant: CCCCc1nc(COC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCCCc1nc(COC)n(CC(C)(C)C)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
A mixture of 4′-{[4-butyl-2-(methoxymethyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (5 g), cesium carbonate (8.4 g), 1-iodo-2,2-dimethylpropane (3.4 mL) and N,N-dimethylacetamide (50 mL) was stirred at 130° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.76 g, 30%).
Reaction SMILES: C1(S([CH2:10][C:11]2[C:12]([N+:24]([O-:26])=[O:25])=[N:13][C:14]([CH:19]3[O:23][CH2:22][CH2:21][O:20]3)=[C:15]([O:17][CH3:18])[CH:16]=2)(=O)=O)C=CC=CC=1.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].CC(C)([O-])C.[K+]>C(O)C>[CH2:32]([O:31][C:29](=[O:30])[CH:28]=[CH:10][C:11]1[C:12]([N+:24]([O-:26])=[O:25])=[N:13][C:14]([CH:19]2[O:20][CH2:21][CH2:22][O:23]2)=[C:15]([O:17][CH3:18])[CH:16]=1)[CH3:33]
Reactant: CCOC(=O)CBr
Reactant: COc1cc(CS(=O)(=O)c2ccccc2)c([N+](=O)[O-])nc1C1OCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C=Cc1cc(OC)c(C2OCCO2)nc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 126.7 %

Procedure:
A mixture of 0.28 g (0.73 mmol) 3-benzenesulfonylmethyl-6-[1,3]dioxolan-2-yl-5-methoxy-2-nitro-pyridine and 0.8 ml (0.73 mmol) of ethyl bromoacetate was dissolved in 10 ml of ethanol. To this solution was added 0.5 ml of potassium t-butoxide (1M in t-butyl alcohol) and the reaction mixture was stirred at room temperature for 1 hour. The solvent was evaporated and the residue was added to 5 ml of water. The suspension was extracted with ethyl acetate. The ethyl acetate extract was dried (Na2SO4) and evaporated to yield approximately 0.3 g of an oil. Mass spectrum: m/e=325.1 (p+1). This material was used directly in step 6.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][C:12]1[S:13][CH:14]=[C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH3:26])[C:21]2[N:27]([CH3:40])[C:28](=[O:39])[C:29]([C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=4[Cl:38])=[CH:30][C:20]3=2)[N:16]=1)C1C=CC=CC=1.C1(SC)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>FC(F)(F)C(O)=O>[NH2:10][CH2:11][C:12]1[S:13][CH:14]=[C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH3:26])[C:21]2[N:27]([CH3:40])[C:28](=[O:39])[C:29]([C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=4[Cl:38])=[CH:30][C:20]3=2)[N:16]=1
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4csc(CNC(=O)OCc5ccccc5)n4)ccc3n(C)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4csc(CN)n4)ccc3n(C)c21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
780 mg (1.3 mmol) of compound A {4-[3-(2,4-dichlorophenyl)-1,9-dimethyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indol-6-yl]thiazol-2-ylmethyl}carbamic acid benzyl ester are dissolved in 12 ml of trifluoroacetic acid. 8 ml (10.3 mmol) of thioanisole are added and the mixture is stirred at ambient temperature for 16 hours. It is poured into a saturated K2CO3 solution and the mixture is extracted with EtOAc. The organic phase is adsorbed onto silica and purification is carried out on a silica column, elution being carried out with EtOAc and then with 90/10/1 EtOAc/MeOH/NH3.
Reaction SMILES: Cl.[CH3:2][NH2:3].[CH3:4][O:5][C:6]1[C:11]([NH:12][C:13]2[C:18]([F:19])=[CH:17][N:16]=[C:15]([NH:20][C:21]3[CH:22]=[CH:23][C:24]4[O:28][CH:27]([C:29]([O:31]C)=O)[CH2:26][C:25]=4[CH:33]=3)[N:14]=2)=[CH:10][CH:9]=[C:8]([O:34][CH3:35])[N:7]=1>>[CH3:4][O:5][C:6]1[C:11]([NH:12][C:13]2[C:18]([F:19])=[CH:17][N:16]=[C:15]([NH:20][C:21]3[CH:22]=[CH:23][C:24]4[O:28][CH:27]([C:29]([NH:3][CH3:2])=[O:31])[CH2:26][C:25]=4[CH:33]=3)[N:14]=2)=[CH:10][CH:9]=[C:8]([O:34][CH3:35])[N:7]=1
Reactant: CN
Reactant: COC(=O)C1Cc2cc(Nc3ncc(F)c(Nc4ccc(OC)nc4OC)n3)ccc2O1
Agent: Cl
Product: CNC(=O)C1Cc2cc(Nc3ncc(F)c(Nc4ccc(OC)nc4OC)n3)ccc2O1

Procedure:
In like manner to the preparation of (±)-N4-(3,4-difluorophenyl)-5-fluoro-N2-[2-(N-methylamino)carbonyl-2,3-dihydrobenzofuran-5-yl]-2,4-pyrimidinediamine, the reaction of methyl amine Hydrogen Chloride with (±)-N4-(2,6-dimethoxypyridin-3-yl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine gave (±)-N4-(2,6-dimethoxypyridin-3-yl)-N2-[2,3-dihydro-2-(N-methylamino)carbonylbenzofuran-5-yl]-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.98 (d, 1H, J=8.1 Hz), 7.81 (d, 1H, J=3.6 Hz), 7.39 (bd, 1H, J=2.4 Hz), 7.06 (dd, 1H, J=2.4 and 8.7 Hz), 6.72 (d, 1H, J=8.1 Hz), 6.31 (d, 1H, J=8.7 Hz), 5.07 (dd, 1H, J=6.3 Hz), 3.96 (s, 3H), 3.93 (s, 3H), 3.46 (dd, 1H, J=7.8 and 10.5 Hz), 3.19 (dd, 1H, J=5.7 and 6.3 Hz), 2.77 (d, 3H, J=4.8 Hz); LCMS: purity: 98%; MS (m/e): 441 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:25])=[C:4]([C:22](=[O:24])[CH3:23])[C:5]([OH:21])=[C:6]([O:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH3:9].[Br:26][CH2:27][CH2:28]Br>>[Br:26][CH2:27][CH2:28][O:21][C:5]1[C:6]([O:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[C:7]([O:8][CH3:9])[C:2]([Cl:1])=[C:3]([CH3:25])[C:4]=1[C:22](=[O:24])[CH3:23]
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(O)c1OCCCc1ccc(F)cc1
Reactant: BrCCBr
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCBr)c1OCCCc1ccc(F)cc1
Yield: 64 %

Procedure:
Example 1d (110 mg, 0.30 mmol) was reacted with 1,2-dibromoethane (3.0 eq.) as described under General Procedure F to afford the title compound (86 mg, 64%) as light cream oil. 1H NMR (300 MHz, CDCl3) δ 7.19-7.14 (m, 2H), 6.99-6.93 (m, 2H), 4.28 (t, J=6.2 Hz, 2H), 4.06 (t, J=6.4 Hz, 2H), 3.64 (s, 3H), 3.50 (t, J=6.2 Hz, 2H), 2.78 (t, J=7.4 Hz, 2H), 2.49 (s, 3H), 2.19 (s, 3H), 2.05-2.02 (m, 2H).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[O:6]1[CH:10]=[CH:9][C:8]([NH2:11])=[N:7]1>C(Cl)Cl>[Cl:1][CH2:2][C:3]([NH:11][C:8]1[CH:9]=[CH:10][O:6][N:7]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccon1
Solvent: ClCCl
Product: O=C(CCl)Nc1ccon1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
2-Chloroacetyl chloride (0.21 ml, 2.66 mmol) was dissolved in DCM (10 ml) and the solution was cooled to 0° C. with an ice-bath. Isoxazol-3-amine (0.41 ml, 5.58 mmol) was added dropwise and a white suspension was obtained. The mixture was stirred at room temperature for 2 hours, then the suspension was evaporated and the residue was purified by flash chromatography (ether/EtOAc=8/2 to 7/3) to obtain 2-chloro-N-(isoxazol-3-yl)acetamide (367 mg, 86% yield) as an off-white solid.