Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:7].Br[C:30]([CH3:37])([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[CH3:36][C:30]([O:23][C:20]1[CH:21]=[CH:22][C:17]([C:14]2[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:16][CH:15]=2)=[CH:18][CH:19]=1)([CH3:37])[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: COc1ccc(C(=O)NCCc2ccc(-c3ccc(O)cc3)cc2)cc1OC
Reactant: CCOC(=O)C(C)(C)Br
Product: CCOC(=O)C(C)(C)Oc1ccc(-c2ccc(CCNC(=O)c3ccc(OC)c(OC)c3)cc2)cc1
Yield: 22 %

Procedure:
Ethyl 2-methyl-2-{4-[2-(3,4-dimethoxy-benzamido)-ethyl]-biphenyl-4'-oxy}-propionate was prepared from 4-[2-(3,4-dimethoxy-benzamido)-ethyl]-4'-hydroxy-biphenyl and ethyl 2-bromo-2-methyl-propionate analogous to Example 31. Yield: 22% of theory; m.p. 118° C.
Reaction SMILES: [CH2:1]([CH:3]([CH2:14][CH3:15])[CH2:4][CH:5]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7](OC)=[N:6]1)[CH3:2].[Cl-:16].[NH4+:17]>CO>[ClH:16].[CH2:1]([CH:3]([CH2:14][CH3:15])[CH2:4][CH:5]1[NH:6][C:7](=[NH:17])[CH2:8][CH2:9][CH2:10][CH2:11]1)[CH3:2]
Reactant: [Cl-]
Reactant: [NH4+]
Reactant: CCC(CC)CC1CCCCC(OC)=N1
Solvent: CO
Product: CCC(CC)CC1CCCCC(=N)N1
Product: Cl
Yield: 57.8 %

Procedure:
The product of EXAMPLE 196 (470 mg, 2.2 mmol) in 18 mL of MeOH was reacted with ammonium chloride (98 mg, 1.8 mmol) by the method of EXAMPLE 27 to yield 242 mg of the title material.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH2:13][OH:14].C([O-])([O-])=O.[K+].[K+].C(O)C>O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8](=[N:13][OH:14])[NH2:9])=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: NC(=NO)c1ccc([N+](=O)[O-])cc1

Procedure:
A solution of 29.6 g. (0.20 mole) of p-nitrobenzonitrile, 13.9 g. (0.20 mole) of hydroxylamine HCl, 13.8 g. (0.10 mole) of K2CO3 in 700 ml. of ethanol and 70 ml. of water is refluxed for 20 hours, cooled and diluted with 200 ml. of water. After removal of the ethanol by distillation in vacuo, the product is collected by filtration, washed with water and dried to yield 21.6 g. (60%).
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([NH:17][C:18]([C:20]3[CH:42]=[CH:41][C:23]([C:24]([N:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]4[O:35][CH2:36][C:37]([CH3:40])([CH3:39])[N:38]=4)[CH3:27])=[O:25])=[CH:22][C:21]=3[O:43][CH3:44])=[O:19])[C:11]=2[N:10]=[CH:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([NH:17][C:18]([C:20]3[CH:42]=[CH:41][C:23]([C:24]([N:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]4[O:35][CH2:36][C:37]([CH3:40])([CH3:39])[N:38]=4)[CH3:27])=[O:25])=[CH:22][C:21]=3[O:43][CH3:44])=[O:19])[C:11]=2[N:10]=[CH:9]1
Reactant: COc1cc(C(=O)N(C)c2ccccc2C2=NC(C)(C)CO2)ccc1C(=O)Nc1cccc2c1ncn2C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)N(C)c2ccccc2C2=NC(C)(C)CO2)ccc1C(=O)Nc1cccc2[nH]cnc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
To a solution of 4-[N-[1-[(tert-butyl)oxycarbonyl]benzimidazol-4-yl]carbamoyl]-N-[2-[4,4-dimethyl(2,5-oxazolinyl)]phenyl]-3-methoxy-N-methylbenzamide (400 mg) in dichloromethane (10 ml) was added trifluoroacetic acid (4 ml). The mixture was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated in vacuo and the residue was diluted with a mixture of chloroform and saturated aqueous sodium bicarbonate solution. The organic layer was separated and washed with water and brine. The solution was dried over magnesium sulfate and the solvent was evaporated in vacuo. The residue was purified by column chromatography (chloroform:methanol=100:3) to give 4-[N-(1H-benzimidazol-4-yl)carbamoyl]-N-[2-[4,4-dimethyl(2,5-oxazolinyl)]phenyl]-3-methoxy-N-methylbenzamide (290 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@:10]([CH:15]3[CH2:17][CH2:16]3)([C:13]#[N:14])[C:9]2=[O:18])[CH:5]=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([C:29]([OH:31])=[O:30])[CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C(O)(=O)C>CC(O)C>[ClH:1].[C:13]([C@@:10]1([CH:15]2[CH2:17][CH2:16]2)[CH2:11][CH2:12][N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([C:26]4([C:29]([OH:31])=[O:30])[CH2:28][CH2:27]4)=[CH:24][CH:25]=3)[N:7]=2)[C:9]1=[O:18])#[N:14]
Reactant: N#C[C@@]1(C2CC2)CCN(c2ccnc(Cl)n2)C1=O
Reactant: Nc1ccc(C2(C(=O)O)CC2)cc1
Solvent: CC(=O)O
Solvent: CC(C)O
Product: Cl
Product: N#C[C@@]1(C2CC2)CCN(c2ccnc(Nc3ccc(C4(C(=O)O)CC4)cc3)n2)C1=O
Yield: 78.2 %

Procedure:
A solution of (3S)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-2-oxopyrrolidine-3-carbonitrile (100 mg) obtained in Step E of Example 103, 1-(4-aminophenyl)cyclopropanecarboxylic acid (67 mg) obtained in Step C of Example 145 and acetic acid (30 μL) in 2-propanol (1.5 mL) was stirred in a microwave reactor at 150° C. for 1 hr, and the resulting solid was collected by filtration to give the title compound (130 mg).
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH2:12][C:13]3[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:15]([CH3:26])[CH:14]=3)[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28]>>[C:20]([O:19][C:17]([C:16]1[CH:24]=[CH:25][C:13]([CH2:12][N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:27]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:28])[C:7]=3[CH2:8]2)=[CH:14][C:15]=1[CH3:26])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: O=COc1ccccc1
Reactant: Cc1cc(CN2Cc3c(ccnc3Cl)C2=O)ccc1C(=O)OC(C)(C)C
Product: Cc1cc(CN2Cc3c(ccnc3C(=O)Oc3ccccc3)C2=O)ccc1C(=O)OC(C)(C)C
Yield: 90 %

Procedure:
The title compound is prepared in 90% yield (280 mg, brown oil) from tert-butyl 4-((4-chloro-1-oxo-1H-pyrrolo[3,4-c]pyridin-2(3H)-yl)methyl)-2-methylbenzoate (250 mg, 0.67 mmol, Step-1) and phenyl formate (160 mg, 1.3 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:44]=[CH:43][C:24]([C:25]([N:27]2[C:35]3[C:30](=[CH:31][C:32]([O:36][CH3:37])=[CH:33][CH:34]=3)[C:29]([CH2:38][C:39]([OH:41])=O)=[C:28]2[CH3:42])=[O:26])=[CH:23][CH:22]=1.[CH2:45]([CH2:47][NH2:48])O.C(N(CC)CC)C>C(#N)C.C(Cl)(Cl)(Cl)Cl>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([N:27]2[C:35]3[C:30](=[CH:31][C:32]([O:36][CH3:37])=[CH:33][CH:34]=3)[C:29]([CH2:38][C:39]3[O:41][CH2:45][CH2:47][N:48]=3)=[C:28]2[CH3:42])=[O:26])=[CH:43][CH:44]=1
Reactant: NCCO
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc2c(c1)c(CC1=NCCO1)c(C)n2C(=O)c1ccc(Cl)cc1
Reaction time: 18 h

Procedure:
A solution of 3.93 g of triphenylphosphine in 80 ml of absolute acetonitrile was added dropwise under stirring at 25° C. under argon to a solution of 1.789 g of 1-p-chlorobenzoyl-2-methyl-5-methoxyindol-3-acetic acid, 0.305 g of ethanolamine, 2.02 g of triethylamine, and 3.176 g of carbon tetrachloride in 100 ml of absolute acetonitrile, for a period of three and a half hours. After 18 hours at 24° C., the mixture was evaporated under vacuum and the crystalline residue agitated with 200 ml of ethyl ether and 75 ml of 2 N aqueous sodium hydroxide solution. After separation of the aqueous phase and secondary extraction with three times 40 ml of ethyl ether, the combined ether extracts were dried (Na2SO4) and concentrated, during which step triphenylphosphine oxide was crystallized. The filtrate was evaporated and chromatographed with toluene on 210 g of aluminum oxide, activity stage IV (alkaline; Woelm); after a forerun of 300 ml, the subsequent 800 ml of eluate yielded 1.38g of a light-yellow, oily (4-chlorophenyl)-[5-methoxy-2-methyl-3-(oxazolin-2-ylmethyl)-1-indolyl]ketone.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:33][CH2:34][CH3:35])=[C:16]([C:22]4[CH:23]=[CH:24][C:25]([C:28]([N:30]([CH3:32])[CH3:31])=[O:29])=[N:26][CH:27]=4)[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[N:9]=[C:10](I)[C:3]=12.[Cu](C#N)[C:37]#[N:38]>CN(C)C=O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:33][CH2:34][CH3:35])=[C:16]([C:22]4[CH:23]=[CH:24][C:25]([C:28]([N:30]([CH3:32])[CH3:31])=[O:29])=[N:26][CH:27]=4)[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[N:9]=[C:10]([C:37]#[N:38])[C:3]=12
Reactant: CCOc1c(C(C)n2nc(I)c3c(N)ncnc32)cc(Cl)c(C)c1-c1ccc(C(=O)N(C)C)nc1
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Product: CCOc1c(C(C)n2nc(C#N)c3c(N)ncnc32)cc(Cl)c(C)c1-c1ccc(C(=O)N(C)C)nc1
Temperature: 120 °C

Procedure:
A mixture of 5-{3-[1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide (13 mg, 0.021 mmol, racemic intermediate from Example 15) and copper cyanide (12 mg, 0.13 mmol) in N,N-dimethylformamide (0.2 mL) was heated at 120° C. overnight. The mixture was filtered and purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. The product was isolated as a racemic mixture. LCMS calculated for C25H26ClN8O2 (M+H)+: m/z=505.2; Found: 505.2.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][CH:13]([C:21]4[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=4)[CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:5]([C:6]=23)=[N:4][NH:3]1.[C:29](O)(=O)[CH3:30].[NH:33]1C[CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CO>[C:15]1([CH:14]2[C:5]3=[N:4][NH:3][C:2](=[O:1])[C:11]4[CH:10]=[CH:9][CH:8]=[C:7]([C:6]=43)[NH:12][CH:13]2[C:21]2[CH:28]=[CH:27][C:24]([CH2:25][N:33]3[CH2:30][CH2:29][CH2:35][CH2:34]3)=[CH:23][CH:22]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C1CNC1
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)cc1
Reactant: CC(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccc(CN3CCCC3)cc1)C2c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.5 %

Procedure:
To a stirred solution of 4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (150 mg, 0.41 mmol) in dry dichloromethane (20 mL) and MeOH (2 mL) was added acetic acid (120 mg) followed by azetidine (70 mg, 1.23 mmol). After the addition, the mixture was stirred at room temperature overnight. Then sodium triacetoxyborohydride (131 mg, 0.62 mmol) was added at 0° C. After the addition, the mixture was stirred at this temperature for 5 hr. DCM was removed under reduced pressure. The residue was washed with ethyl acetate/methanol (10/1) and filtered. The filtrate was concentrated to give the crude product, which was purified by column chromatography (silica gel, dichloromethane/methanol=100:1 to 15:1) to give the title compound (84 mg, yield 51%) as yellow solid. LC-MS (ESI) m/z: 409 (M+1)+. 1H-NMR (400 MHz, CD3OD) δ (ppm): 2.38-2.43 (m, 2H), 3.98 (t, J=8 Hz, 4H), 4.20 (s, 2H), 4.27 (d, J=8 Hz, 1H), 4.77 (d, J=8 Hz, 1H), 7.03-7.05 (m, 2H), 7.10-7.17 (m, 4H), 7.27-7.35 (m, 4H), 7.50-7.52 (m, 1H), 7.57-7.62 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([S:13]([NH2:16])(=[O:15])=[O:14])[S:10][N:9]=1.[C:17](OC)(OC)([O:21][CH3:22])[CH:18]([CH3:20])[CH3:19]>CCCCCC>[CH3:22][O:21][C:17](=[N:16][S:13]([C:11]1[S:10][N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[N:12]=1)(=[O:15])=[O:14])[CH:18]([CH3:20])[CH3:19]
Reactant: Cc1ccccc1-c1nsc(S(N)(=O)=O)n1
Reactant: COC(OC)(OC)C(C)C
Solvent: CCCCCC
Product: COC(=NS(=O)(=O)c1nc(-c2ccccc2C)ns1)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3 g of 3-(2-methylphenyl)-1,2,4-thiadiazole-5-sulfonamide and 11 ml of trimethyl orthoisobutyrate was heated to reflux and stirred for 2 hours. The mixture was allowed to cool to room temperature, whereupon a precipitate formed. Hexane was added and the mixture was stirred for 15 minutes. The solid was filtered and washed with hexane and dried in vacuum (P2O5) to give 3.49 g of solid, m.p. 116°-118°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2/[CH:14]=[CH:15]/[C:16]2[S:17][C:18]([C:22](O)=[O:23])=[C:19]([CH3:21])[N:20]=2)=[CH:4][CH:3]=1.CN(C(O[N:33]1N=N[C:35]2C=CC=[CH:39][C:34]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C(N)(C)C>CN(C=O)C>[CH:34]([NH:33][C:22]([C:18]1[S:17][C:16](/[CH:15]=[CH:14]/[C:9]2[N:10]([CH3:13])[N:11]=[N:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[N:20][C:19]=1[CH3:21])=[O:23])([CH3:39])[CH3:35]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1nc(/C=C/c2c(-c3ccc(F)cc3)nnn2C)sc1C(=O)O
Agent: F[B-](F)(F)F
Solvent: CC(C)N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(/C=C/c2c(-c3ccc(F)cc3)nnn2C)sc1C(=O)NC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
To a solution of 2-{(E)-2-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-yl]-vinyl}-4-methyl-thiazole-5-carboxylic acid (75 mg, 0.22 mmol) and TBTU (77 mg, 0.24 mmol) in DMF (0.4 mL) was added DIPEA (186 μL, 1.09 mmol). Then isopropylamine (21 μL, 0.24 mmol) was added and the mixture was stirred at room temperature under Ar for 1 h. The mixture was then evaporated and purification by chromatography (silica, 1 to 5% methanol in dichloromethane) afforded the title compound (28 mg, 33%) as an off white solid after recrystallisation from ethylacetate and heptane. MS: m/e=386.4 [M+H]+.
Reaction SMILES: Br[C:2]1[C:11]([NH:12][C:13](=[O:26])[C:14](=[O:25])[CH2:15][C:16]([CH3:24])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][O:5][C:6]2=[O:7].N[C:28]1C=C2C(=CC=1)C(=O)OC2.C1(C2(CC(=O)C(O)=O)CCC2)C=CC=CC=1>>[C:18]1([C:16]2([CH2:15][C:14](=[O:25])[C:13]([NH:12][C:11]3[CH:2]=[C:3]4[C:8](=[CH:9][CH:10]=3)[C:6](=[O:7])[O:5][CH2:4]4)=[O:26])[CH2:24][CH2:28][CH2:17]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccc2c(c1)COC2=O
Reactant: CC(C)(CC(=O)C(=O)Nc1ccc2c(c1Br)COC2=O)c1ccccc1
Agent: O=C(O)C(=O)CC1(c2ccccc2)CCC1
Product: O=C(CC1(c2ccccc2)CCC1)C(=O)Nc1ccc2c(c1)COC2=O

Procedure:
was obtained analogously to the process that is described for 4-bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide from 5-aminophthalide and 3-(1-phenyl-cyclobutyl)-2-oxo-propionic acid, melting point 142-146° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10](=[O:12])[CH3:11])=[CH:4][C:3]=1[O:13][CH3:14].C([O-])([O-])=O.[K+].[K+].[F:21][C:22]([F:33])([F:32])[O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>CCO.O>[OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10](=[O:12])/[CH:11]=[CH:28]/[C:27]2[CH:30]=[CH:31][C:24]([O:23][C:22]([F:21])([F:32])[F:33])=[CH:25][CH:26]=2)=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: COc1cc(/C=C/C(C)=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1cc(/C=C/C(=O)/C=C/c2ccc(OC(F)(F)F)cc2)ccc1O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 16.9 %

Procedure:
A suspension of (E)-4-(4-hydroxy-3-methoxyphenyl)but-3-en-2-one (600 mg, 3.1 mmol) in EtOH (10 mL) was stirred for 5 min at 0° C. A solution of K2CO3 (863 mg, 6.2 mmol) in H2O (5 mL) was added and the reaction mixture was stirred for further 10 min at 0° C. After the dropwise addition of 4-(trifluoromethoxy)-benzaldehyde (473 μl, 3.3 mmol), the orange suspension was heated to reflux for 4 d at 40° C. The solvent was evaporated in vacuo and the resulting residue was purified by flash-chromatography on silica gel (Hexane/EtOAc 2:1) and dried in vacuo to obtain NW351 as a yellow solid (191 mg, 17%). mp: 93-95° C. 1H NMR (300 MHz, CD3OD) δ (ppm): 7.72 (d, 3J=8.4 Hz, 2H, HAr), 7.71 (d, 3J=15.9 Hz, 1H, Hvin), 7.68 (d, 3J=15.6 Hz, 1H, Hvin), 7.27 (d, 3J=8.3 Hz, 2H, HAr), 7.24 (d, 4J=1.9 Hz, 1H, HAr), 7.19 (d, 3J=16.0 Hz, 1H, Hvin), 7.15 (dd, 3J=8.4 Hz, 4J=2.0 Hz, 1H, HAr), 7.02 (dd, 3J=15.9 Hz, 5J=0.99, Hz, 1H, Hvin), 6.83 (dd, 3J=8.2 Hz, 5J=0.9 Hz, 1H, HAr), 3.89 (d, 5J=0.9, 3H, OCH3). 13C NMR (75 MHz, CD3OD) δ (ppm): 191.1 (C), 151.7 (q, 4J (C, F)=1.7 Hz), 151.2 (C), 149.4 (C), 146.4 (CH), 142.4 (CH), 135.4 (C), 131.3 (CH), 128.1 (C), 127.6 (CH), 125.0 (CH), 123.6 (CH), 122.3 (CH), 120.2 (C), 116.7 (CH), 112.2 (CH), 56.5 (OCH3). MS (FAB) m/z: 365.2 (M+). Anal. calcd for C19H15F3O4: C, 62.64; H, 4.15. Found: C, 62.45; H, 4.39%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.Br[C@H:31]([CH3:36])[C:32]([NH:34][CH3:35])=[O:33].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([F:22])=[CH:11][C:12]([CH:16]3[CH2:17][CH2:18][N:19]([C@@H:31]([CH3:36])[C:32]([NH:34][CH3:35])=[O:33])[CH2:20][CH2:21]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: CNC(=O)[C@@H](C)Br
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)[C@H](C)N1CCC(c2cc(F)c(Nc3ncc(Cl)c(Nc4cc(C)[nH]n4)n3)cc2C)CC1
Temperature: 150 °C

Procedure:
A mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (50.0 mg, 0.12 mmol), (R)-2-bromo-N-methylpropanamide (100.0 mg, 0.60 mmol), and triethylamine (102.0 μL, 0.60 mmol) in 2 mL of DMF was heated at 150° C. in a microwave reactor for 30 min. The reaction mixture was directly purified by preparative RP-HPLC to afford (S)-2-(4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-methylphenyl)piperidin-1-yl)-N-methylpropanamide; ESMS m/z 501.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([N:40]2[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]2)=[O:16])=[CH:17][CH:18]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)c2ccc(CNC(=O)OC(C)(C)C)cc2)CC1

Procedure:
4-(Tert-butoxycarbonylamino-methyl)-benzoic acid was reacted with WSCI, HOBt, triethylamine and N-methylpiperazine in dichloromethane, to obtain a crude product of [4-(4-methyl-piperazine-1-carbonyl)-benzyl]-carbamic acid tert-butyl ester, and then treated with TFA, to obtain (4-aminomethyl-phenyl)-(4-methyl-piperazin-1-yl)-methanone. Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and (4-aminomethyl-phenyl)-(4-methyl-piperazin-1-yl)-methanone (159 mg) instead of 4-(4-ethyl-piperazin-1-yl)-2,6-difluoro-phenylamine used in Step D in Example 1-D-18, in the same manner as Step D in Example 1-D-18, a crude product of 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid 4-(4-methyl-piperazine-1-carbonyl)-benzylamide was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-293) as a colorless powder (64 mg, 62%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([O:12][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(tert-butoxycarbonylamino)-2-methyl-propionic acid (4.06 g) in N,N-dimethylformamide (40 mL) were added potassium carbonate (4.15 g) and benzyl bromide (2.85 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethylacetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue (solid) was treated with n-hexane and collected by filtration. The crystals were dried under reduced pressure to give benzyl 2-(tert-butoxycarbonylamino)-2-methylpropionate (4.44 g). Hydrochloric acid (4 mol/L 1,4-dioxane solution, 15 mL) was added to the obtained benzyl 2-(tert-butoxycarbonylamino)-2-methyl-propionate (4.44 g), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with diethyl ether, and the resulting mixture was stirred for 1 hour. The insoluble material was collected by filtration, and washed with diethyl ether and dried under reduced pressure to give the title compound (3.4 g).
Reaction SMILES: [CH2:1]([N:3](CC)C(C)C)C.Cl.N1C=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:21]=[CH:20][C:19]([C:22]([OH:24])=O)=[CH:18][N:17]=1.[CH3:25][S:26]([C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[N:34]([NH2:38])[CH:33]=[CH:32]2)(=[O:28])=[O:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:25][S:26]([C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[N:34]([NH:38][C:22]([C:19]1[CH:20]=[N:21][C:16]([C:11]3[CH:1]=[N:3][CH:14]=[CH:13][CH:12]=3)=[N:17][CH:18]=1)=[O:24])[CH:33]=[CH:32]2)(=[O:28])=[O:27]
Reactant: O=C(O)c1cnc(-c2ccccn2)nc1
Reactant: CS(=O)(=O)c1ccc2c(ccn2N)c1
Reactant: CCN(CC)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc2c(ccn2NC(=O)c2cnc(-c3cccnc3)nc2)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 24.8 %

Procedure:
Diethyl-iso-propylamine (3.84 mmol) is added a solution of 2-pyridin-2-yl-pyrimidine-5-carboxylic acid hydrochloride (1.28 mmol), 5-methanesulfonyl-indol-1-ylamine (1.28 mmol) and TBTU (1.92 mmol) in anhydrous DMF (16 mL) at rt. The reaction mixture is stirred at 90° C. overnight and then concentrated in vacuo. The residue is dissolved in EtOAc (60 mL), and washed with water (2×30 mL) and brine (20 mL), The organic layer is separated, washed with water (2×20 mL) and brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 0-5% MeOH in DCM to afford 2-pyridin-3-yl-pyrimidine-5-carboxylic acid (5-methanesulfonyl-indol-1-yl)-amide (125 mg, 25%) as a solid. MS: 394 (M+H); 1H NMR (300 MHz, CDCl3): δ 3.10 (s, 3H), 6.61 (m, H) 6.98 (m, H), 7.34 (s, H), 7.51 (m, H), 7.91 (s, H), 8.83 (m, 2H), 9.49 (s, H), 9.77 (s, H), 10.10 (s, N—H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18](Cl)(=[O:20])=[O:19]>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH3:11])(=[O:20])=[O:19]
Reactant: Brc1cccc2[nH]ccc12
Reactant: Cc1ccccc1S(=O)(=O)Cl
Product: Cc1ccccc1S(=O)(=O)n1ccc2c(Br)cccc21
Yield: 87 %

Procedure:
The compound was prepared from 4-bromoindole (1.02 g, 5.25 mmol) and o-methylbenzenesulfonyl chloride (a 9:1 mixture of ortho and para methyl isomers) (1.29 g, 6.78 mmol) according to method 4. Purification by column chromatography (SiO2, CH2Cl2:heptane) gave 1.6 g (87%) of the title compound which contains ca 10% of the p-methyl isomer) as a light purple viscous oil: 1H NMR (CD3OD) δ 7.94–6.68 (m, 9H), 2.52 (s, 3H); MS (ESI) 352.3 (M+H)+; Purity (HPLC) >95%.