Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[C:20](Cl)(=[O:29])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:20](=[O:29])[CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: O=C(Cl)CCc1ccccc1
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)CCc1ccccc1
Yield: 48.8 %

Procedure:
Using the method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.2 g, 0.78 mmol) was reacted with hydrocinnamoyl chloride (0.11 mL, 0.74 mmol) to provide 0.14 g of N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-3-phenylpropanamide as a white solid, m.p. 148-150° C.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([NH:11][CH2:12][C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][N:28]([C:31](=[O:33])[CH3:32])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:31]([N:28]1[CH2:27][CH2:26][N:25]([C:22]2[CH:23]=[CH:24][C:19]([NH:18][C:2]3[CH:10]=[C:9]([NH:11][CH2:12][C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)[C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=3)=[CH:20][CH:21]=2)[CH2:30][CH2:29]1)(=[O:33])[CH3:32]
Reactant: NC(=O)c1cnc(Cl)cc1NCc1cccs1
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(=O)N1CCN(c2ccc(Nc3cc(NCc4cccs4)c(C(N)=O)cn3)cc2)CC1
Reaction time: 3 h

Procedure:
A mixture of 6-chloro-4-(thiophen-2-ylmethylamino)nicotinamide (84 mg, 0.314 mmol), 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (82 mg, 0.374 mmol), Cs2CO3 (200 mg, 0.613 mmol), BINAP (35 mg, 0.056 mmol) and Pd(OAc)2 (25 mg, 0.111 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 120 C for 3 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to the titled compound (12 mg). MS 451.4 (M+H); UV 200.0, 244.3 nm; t 0.485 min.
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:18])([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:3]1.C(OC([N:27]1[CH2:32][CH2:31][CH:30]([CH2:33]O)[CH2:29][CH2:28]1)=O)(C)(C)C>>[F:19][C:2]1([F:1])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:18])([C:11]2[CH:12]=[CH:13][C:14]([Br:17])=[CH:15][CH:16]=2)[C:8]([O:10][CH2:33][CH:30]2[CH2:31][CH2:32][NH:27][CH2:28][CH2:29]2)=[O:9])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: O=C(O)[C@](O)(c1ccc(Br)cc1)[C@@H]1CCC(F)(F)C1
Product: O=C(OCC1CCNCC1)[C@](O)(c1ccc(Br)cc1)[C@@H]1CCC(F)(F)C1

Procedure:
Using (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-bromophenyl)acetic acid and N-t-butoxycarbonyl-4-piperidine-methanol, the title compound was prepared by a method similar to Steps 2 and 3 of Referential Example 12.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:5]=[C:6]2[S:19][CH:18]=[CH:17][N:7]2[C:8](=[O:16])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:3].[NH2:20][C:21]1[N:29]=[C:28]2[C:24]([NH:25][CH:26]=[N:27]2)=[C:23](Br)[N:22]=1.C(N(CC)C(C)C)(C)C>C(O)C>[NH2:20][C:21]1[N:29]=[C:28]2[C:24]([N:25]=[CH:26][NH:27]2)=[C:23]([NH:1][CH:2]([C:4]2[N:5]=[C:6]3[S:19][CH:18]=[CH:17][N:7]3[C:8](=[O:16])[C:9]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:3])[N:22]=1
Reactant: Nc1nc(Br)c2[nH]cnc2n1
Reactant: CC(N)c1nc2sccn2c(=O)c1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(Nc1nc(N)nc2[nH]cnc12)c1nc2sccn2c(=O)c1-c1ccccc1
Temperature: 110 °C

Procedure:
A mixture of 7-(1-aminoethyl)-6-phenyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.025 g, 0.092 mmol), 2-amino-6-bromopurine (0.035 g, 0.16 mmol), and N,N-diisopropylethylamine (0.029 mL, 0.16 mmol) in ethanol (0.5 mL) was heated at 110° C. overnight. The mixture was filtered, and the filtrate was purified on preparative-LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH) to give the desired product. LCMS calculated for C19H17N8OS (M+H)+: m/z=405.1. Found: 405.1. 1H NMR (DMSO-d6, 400 MHz) δ 80.1 (1H, d, J=4.8 Hz), 7.65 (1H, s), 7.55 (1H, d, J=4.8 Hz), 7.47 (2H, m), 7.40 (3H, m), 6.79 (1H, br s), 5.48 (2H, br s), 5.13 (1H, m), 1.29 (3H, d, J=6.8 Hz) ppm.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].O=[C:7]1[NH:12][C:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[N:10][C:9]2[S:23][C:24]([CH3:26])=[CH:25][C:8]1=2.CN(C)C1C=CC=CC=1>>[Cl:3][C:7]1[C:8]2[CH:25]=[C:24]([CH3:26])[S:23][C:9]=2[N:10]=[C:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[N:12]=1
Reactant: COC(=O)c1ccc(-c2nc3sc(C)cc3c(=O)[nH]2)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: COC(=O)c1ccc(-c2nc(Cl)c3cc(C)sc3n2)cc1

Procedure:
A mixture of 18 ml of POCl3 with 6 g of methyl 4-(3,4-dihydro-4-oxo-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoate is boiled for 4 hours with the addition of 1.8 ml of N,N-dimethylaniline. Customary working up gives 5 g of methyl 4-(4-chloro-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoate.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:25]([F:28])([F:27])[F:26])=[N:5][N:6]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=2[Cl:24])[C:7]=1[N:8]=[CH:9]OCC)#[N:2].[BH4-].[Na+]>CO>[C:1]([C:3]1[C:4]([C:25]([F:27])([F:28])[F:26])=[N:5][N:6]([C:13]2[C:14]([Cl:24])=[CH:15][C:16]([C:20]([F:22])([F:21])[F:23])=[CH:17][C:18]=2[Cl:19])[C:7]=1[NH:8][CH3:9])#[N:2]
Reactant: CCOC=Nc1c(C#N)c(C(F)(F)F)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNc1c(C#N)c(C(F)(F)F)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C

Procedure:
To a suspension of 4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-ethoxymethyleneamino-3-trifluoromethylpyrazole (1.0 g) in methanol (10 ml) stirred at room temperature was added sodium borohydride (0.17 g). After 2 hours an additional 0.17 g of sodium borohydride was added, and another 0.34 g added after 1 hours. One hour later the mixture was poured onto water (80 ml). The combined extracts were dried over anhydrous magnesium sulphate, filtered, and evaporated in vacuo. The white solid thus obtained was purified by chromatography on silica (Merck, 230-400 mesh, 0.7 kg cm-2) with dichloromethane as eluent, to furnish 4-cyano-5-methylamino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-trifluoromethylpyrazole as a white solid )0.6 g), m.p. 200°-202° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][NH:9][C:10]2[C:15]([C:16]#[N:17])=[CH:14][N:13]=[C:12]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][C:27]([F:30])([F:29])[F:28])[N:11]=2)[CH2:4][CH2:3]1.Br[CH2:32][CH2:33][CH2:34]Br.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[N:1]1([C@H:2]2[CH2:3][CH2:4][C@H:5]([CH2:8][NH:9][C:10]3[C:15]([C:16]#[N:17])=[CH:14][N:13]=[C:12]([NH:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][C:27]([F:29])([F:30])[F:28])[N:11]=3)[CH2:6][CH2:7]2)[CH2:34][CH2:33][CH2:32]1
Reactant: N#Cc1cnc(NCc2ccccc2OC(F)(F)F)nc1NC[C@H]1CC[C@H](N)CC1
Reactant: BrCCCBr
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cnc(NCc2ccccc2OC(F)(F)F)nc1NC[C@H]1CC[C@H](N2CCC2)CC1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of 4-{[(trans-4-aminocyclohexyl)methyl]amino}-2-{[2-(trifluoromethoxy)benzyl]-amino}pyrimidine-5-carbonitrile (150 mg, 0.36 mmol) in DMF (1 mL) were added 1,3-dibromo-propane (86 mg, 0.43 mmol) and DIPEA (124 μL, 0.71 mmol). The reaction mixture was stirred at 50° C. for 24 h. The reaction mixture was then diluted with EtOAc and washed with NaHCO3 (×1) and water (×4). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting residue was purified by silica gel preparative TLC using 10:1:0.2 CH2Cl2:MeOH:NH4OH as an eluent to afford 54 mg (33%) of the title compound as a white solid, m/z 461.6 (M+1)+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[C:8]([CH3:27])[C:6]=2[N:7]=1.[NH2:34][C:35]1[N:40]=[CH:39][C:38](B(O)O)=[CH:37][N:36]=1>>[CH3:27][C:8]1[C:6]2[N:7]=[C:2]([C:38]3[CH:37]=[N:36][C:35]([NH2:34])=[N:40][CH:39]=3)[N:3]=[C:4]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:5]=2[S:10][C:9]=1[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:14][CH2:13]1
Reactant: Nc1ncc(B(O)O)cn1
Reactant: Cc1c(CN2CCN(S(=O)(=O)c3ccccc3)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Product: Cc1c(CN2CCN(S(=O)(=O)c3ccccc3)CC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12

Procedure:
2-Chloro-6-(4-benzenesulfonyl-piperazin-1-ylmethyl)-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Purification on silica and ether trituration gave 272. NMR (CDCl3): 2.45 (3H, s), 2.67-2.70 (4H, m), 3.10-3.15 (4H, br), 3.86 (2H, s), 3.39-3.41 (4H, m), 4.03-4.05 (4H, m), 5.23 (2H, br), 7.55-7.60 (2H, m), 7.62-7.65 (1H, m), 7.79 (2H, d, J=8.6), 9.35 (2H, s). MS (ESI+): MH+ 567.27 (35%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:21])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1.C1CCCCC1.C(OCC)(=O)C.C1(N)CCCCC1>CC(C)=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:21])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(F)cc2F)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: C1CCCCC1
Product: O=C(O)CCC(O)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
Prepared analogous to Example 25 from 4-(2',4'-difluoro-4-biphenylyl)-4-oxo-butyric acid. Melting point 111°-112.5° C. (from cyclohexane/ethyl acetate 4:1); melting point of the cyclohexylamine salt: 160°-161° C. (from acetone/ethyl acetate 1:2).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=[O:6])[CH3:2].[NH2:8][C:9]1[C:10]([Cl:30])=[N:11][C:12]2[C:17]([C:18]=1[NH:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:16][CH:15]=[CH:14][CH:13]=2>C(#N)C>[Cl:30][C:10]1[C:9]([NH:8][C:5](=[O:6])[CH2:4][O:3][CH2:1][CH3:2])=[C:18]([NH:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: CCOCC(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCNc1c(N)c(Cl)nc2ccccc12
Solvent: CC#N
Product: CCOCC(=O)Nc1c(Cl)nc2ccccc2c1NCCNC(=O)OC(C)(C)C
Reaction time: 0.08 h
Yield: 93.1 %

Procedure:
A solution of ethoxyacetyl chloride (857 mg, 6.99 mmol) in acetonitrile (5 mL) was added to solution of tert-butyl 2-[(3-amino-2-chloroquinolin-4-yl)amino]ethylcarbamate (2.14 g, 6.35 mmol) in acetonitrile (20 mL). After five minutes, the solution was cooled in an ice bath and a white precipitate began to form. After one hour, the precipitate was isolated by filtration and dried under vacuum to afford the hydrochloride salt of tert-butyl 2-({2-chloro-3-[(ethoxyacetyl)amino]quinolin-4-yl}amino)ethylcarbamate (2.50 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][C:5]=1[Cl:11].Cl.[CH3:14][NH:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([N:15]([CH3:16])[CH3:14])=[CH:6][C:5]=1[Cl:11]
Reactant: CNC
Reactant: COC(=O)c1ccc(F)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N(C)C)cc1Cl
Yield: 99 %

Procedure:
To a stirred solution of 4.00 g (20.6 mmol) 2-chloro-4-fluoro-benzoic acid methyl ester (Apollo) and 60 ml dimethylsulphoxid were added 2.03 g (24.7 mmol) dimethylamine hydrochloride and 5.97 g (43.2 mmol) potassium carbonate. The reaction mixture was stirred over night and is reduced with high vacuum rotation evaporator at 65° C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude product 1a was obtained in 99% yield (4.36 g, 20.4 mmol) and was used for the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[C:11]#[N:12].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:23]2[CH2:22][CH2:21][N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH2:25][CH2:24]2)=[O:8])=[CH:4][C:3]=1[C:11]#[N:12]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#Cc1cc(C(=O)O)ccc1Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(Cl)c(C#N)c2)CC1
Reaction time: 20 h
Yield: 96.2 %

Procedure:
In a 100 mL round-bottom flask under a positive nitrogen pressure of 4-chloro-3-cyanobenzoic acid (4.28 mmol), 1-(tert-butoxycarbonyl)piperazine (1.59 g, 8.56.mmol), EDC (903 mg, 4.71 mmol) and HOBT (694 mg, 5.14 mmol) were dissolved in 17 mL of CH2Cl2. Triethylamine (1.5 mL, 10.7 mmol) was added and the reaction mixture was stirred for 20 h. After this time additional quantities of EDC (411 mg, 2.14 mmol), HOBT (290 mg, 2.14 mmol) and triethylamine (300 □L, 2.14 mmol) were added. After stirring for an additional 20 h the reaction mixture was washed with 6 mL portions of: 10% KHSO4, water, saturated NaHCO3, and saturated NaCl. The organic extracts were dried over Na2SO4, filtered and concentrated to afford 1.44 g of tert-butyl 4-(4-chloro-3-cyanobenzoyl)piperazine-1-carboxylate as a beige solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])[N:9]=[N:10][C:5]2=[N:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:30]([O:32][CH2:33][CH3:34])=[CH2:31])CCC>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:33]([O:32][C:30]([C:2]1[N:7]=[C:6]2[N:8]([CH:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])[N:9]=[N:10][C:5]2=[N:4][CH:3]=1)=[CH2:31])[CH3:34]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC(c1c(F)cc2ncccc2c1F)n1nnc2ncc(Br)nc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=C(OCC)c1cnc2nnn(C(C)c3c(F)cc4ncccc4c3F)c2n1
Temperature: 100 °C
Yield: 80.6 %

Procedure:
A mixture of 6-(1-(6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)ethyl)-5,7-difluoroquinoline (423.0 mg, 1.2 mmol), Pd(Ph3P)4 (125.0 mg, 0.12 mmol) and tributyl(1-ethoxyvinyl)stannane (781.0 mg, 2.2 mmol) in DMF (5 mL) was purged with nitrogen and then heated at 100° C. for 12 hours. After removal of the solvent under reduced pressure, the residue was diluted with DCM, washed sequentially with aqueous KF and water, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel with gradient (DCM/MeOH=50:1) to give the title compound as a yellow solid (370 mg, 91%). LCMS (method E): [MH]+=383, tR=4.24 min.
Reaction SMILES: [CH:1]1[C:15](=[NH:16])[N:14]=[C:13]2[N:3]([C@@H:4]3[O:8][C@H:7]([CH2:9][OH:10])[C@@H:6]([OH:11])[C@@H:5]3[O:12]2)[CH:2]=1.[OH-:17].[NH4+]>>[CH:1]1[C:15]([NH2:16])=[N:14][C:13](=[O:12])[N:3]([C@@H:4]2[O:8][C@H:7]([CH2:9][OH:10])[C@@H:6]([OH:11])[C@@H:5]2[OH:17])[CH:2]=1
Reactant: N=c1ccn2c(n1)O[C@H]1[C@H](O)[C@@H](CO)O[C@H]12
Reactant: [OH-]
Agent: [NH4+]
Product: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)n1
Reaction time: 1.17 h

Procedure:
Cyclocytidine salt (8.0023 g., 18.25 mmole) and 80 ml. of 2N ammonium hydroxide are stirred at 58°. Hydrolysis is complete at 70 minutes.
Reaction SMILES: Br.Br[CH2:3][CH2:4][NH:5][CH3:6].[F:7][C:8]1[CH:13]=[CH:12][C:11]([SH:14])=[CH:10][CH:9]=1.CC(C)([O-])C.[K+]>C(#N)C>[F:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][CH2:3][CH2:4][NH:5][CH3:6])=[CH:10][CH:9]=1
Reactant: CNCCBr
Reactant: Fc1ccc(S)cc1
Agent: Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC#N
Product: CNCCSc1ccc(F)cc1
Yield: 61.6 %

Procedure:
Reflux a mixture of (2-bromoethyl)methylamine hydrobromic acid salt (500 mg, 2.28 mmol), 4-fluorobenzenethiol (0.243 mL, 2.28 mmol), and potassium t-butoxide (512 mg, 4.56 mmol) in acetonitrile (10 mL) for 17 hours. Remove the solvent under vacuum and dissolve the residue in ether and 5 N sodium hydroxide solution. Extract the organic layer with 1 N hydrochloric acid solution. Neutralize the acidic aqueous layer with 5 N sodium hydroxide solution and extract twice with ether. Dry the combined ether extracts over magnesium sulfate and reduce under vacuum to give 260 mg of the titled compound as an oil.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4]([C:14]2[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=2)=[CH:3][CH:2]=1.[F:21][C:22]([F:32])([F:31])[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1>>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4]([C:14]2[CH:20]=[CH:19][C:17]([NH:18][CH2:27][C:26]3[CH:25]=[CH:24][C:23]([C:22]([F:21])([F:31])[F:32])=[CH:30][CH:29]=3)=[CH:16][CH:15]=2)=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc(-c2cccc3c2oc2ccccc23)cc1
Product: FC(F)(F)c1ccc(CNc2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1
Yield: 78 %

Procedure:
The same procedure as employed in the preparation of Example 226 (step a) but using 4-dibenzo[b,d]furan-4-ylaniline and 4-(trifluoromethyl)benzaldehyde gave the title compound as a colorless oil (78%). 1H NMR (DMSO-d6, 300 MHz) δ 8.15 (d, 1H, J=7.1 Hz), 8.01 (m, 1H), 7.7548 (m, 9H), 7.44-7.37 (m, 2H), 6.74 (m, 3H), 4.47 (m, 2H). M−(LC/MS(ESI)): 416.2; M+(LC/MS(ESI)): 418.2. HPLC (Condition A), Rt: 5.72 min (HPLC purity: 99.3%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:82]1[CH2:87][CH2:86][S:85][CH2:84][CH2:83]1>CN(C=O)C.[Pd]>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([N:82]3[CH2:87][CH2:86][S:85][CH2:84][CH2:83]3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[C:13]([C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[O:20])[CH:14]=1
Reactant: O=C(c1ccncc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(Br)cc1
Reactant: C1CSCCN1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccncc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(N2CCSCC2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of heterocyclyl and heteroaryl substituted phenylsulfonyl derivatives previously described, using 4-Bromo-N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfonamide 0.3 g (0.66 mmol), potassium phosphate tribasic monohydrate 0.91 g (3.96 mmol), rac-2,2′-bis (diphenylphosphino)-1,1′-binaphthyl 0.12 g (0.198 mmol), thiomorpholine 0.34 g (3.3 mmol) and Pd (dba)3 60 mg (0.066 mmol) in 3 ml DMF followed by work up and HPLC purification: LC-MSD, m/z for C22H20ClN3O3S2 [M+H]+: 474.0
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:22]2[CH2:26][CH:25]([CH2:27][CH2:28][CH2:29][OH:30])[O:24][N:23]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21].C(OCC)C>C(Cl)Cl>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:22]2[CH2:26][CH:25]([CH2:27][CH2:28][CH:29]=[O:30])[O:24][N:23]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: COc1ccc(C2=NOC(CCCO)C2)cc1OC
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc(C2=NOC(CCC=O)C2)cc1OC
Reaction time: 6 h
Yield: 52.4 %

Procedure:
After dissolving pyridinium chlorochromate (PCC; 2.249 g, 10.435 mmol) and 70-230 mesh SiO2 (2.748 g) in 25 mL of methylene chloride, 3-[3-(3,4-dimethoxyphenyl)-4,5-dihydroisoxazol-5-yl]propan-1-ol (1.374 g, 5.217 mmol) dissolved in 2 mL of methylene chloride was added. After the reaction was continued for about 6 hr, 10 mL of diethyl ether was added and the reaction mixture was filtered through a cellite bed. After removing all the solvent and purifying by column chromatography on silica gel (hexane/ethyl acetate=1.5/1, v/v), 0.72 g (51.6%) of the target compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[CH2:14]([N:18]1[C:26]2[N:25]=[C:24]([Cl:27])[NH:23][C:22]=2[C:21](=[O:28])[N:20]([CH2:29][CH2:30][CH2:31]/[C:32](=[N:35]/[H])/[NH:33]O)[C:19]1=[O:37])[CH2:15][CH2:16][CH3:17]>CN(C=O)C>[CH2:14]([N:18]1[C:26]2[N:25]=[C:24]([Cl:27])[NH:23][C:22]=2[C:21](=[O:28])[N:20]([CH2:29][CH2:30][CH2:31][C:32]2[N:33]=[C:9]([CH2:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[O:12][CH3:13])[O:11][N:35]=2)[C:19]1=[O:37])[CH2:15][CH2:16][CH3:17]
Reactant: [H]/N=C(/CCCn1c(=O)c2[nH]c(Cl)nc2n(CCCC)c1=O)NO
Reactant: COc1c(Cl)cccc1CC(=O)O
Solvent: CN(C)C=O
Product: CCCCn1c(=O)n(CCCc2noc(Cc3cccc(Cl)c3OC)n2)c(=O)c2[nH]c(Cl)nc21
Temperature: 140 °C

Procedure:
A mixture of [3-chloro-2-(methyloxy)phenyl]acetic acid (32 mg, 0.16 mmol) in DMF (1.5 ml) was treated with CDl (26 mg, 0.16 mmol) and left to react for 45 min. (1Z)-4-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxybutanimidamide (60 mg, 0.18 mmol) was added and the mixture heated in the microwave at 140° C. for 15 min. After cooling, the reaction was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated then concentrated and purified by the MDAP. The title compound was obtained as a white solid (25 mg, 28%).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.S(=O)(=O)(O)O.[CH3:18]O>>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]([O:12][CH3:18])=[O:11])=[CH:2]1
Reactant: O=C(O)c1c[nH]c2ncccc12
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1c[nH]c2ncccc12

Procedure:
4.22 g (26 mmol) of 1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid were added to 100 cm3 of methanol at a temperature in the region of 20° C. and then 2.5 cm3 of concentrated sulfuric acid were run in dropwise. After stirring at reflux of the solvent for 16 h, the reaction medium was concentrated to dryness under reduced pressure (2.7 kPa). The residue was rapidly added to 50 cm3 of water and the pH was adjusted to 8 by addition of 1N sodium hydroxide. After extracting with 300 cm3 of ethyl acetate, the organic phase was washed with 2 times 100 cm3 of water and then 100 cm3 of saturated aqueous sodium chloride solution. After drying over magnesium sulfate and then concentrating to dryness under reduced pressure (2.7 kPa), 3.7 g of methyl 1H-pyrrolo[2,3-b]pyridine-3-carboxylate were obtained in the form of a yellow powder. Mass spectrum: EI: m/z=176 M+; base pic: m/z=145 (M−CH3O)+.