Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:14]([NH2:16])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[NH:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@@H:18]([C:29]([OH:31])=O)[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.C(OCC)(=O)C>[NH:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@@H:18]([C:29]([NH:2][C@@H:3]([C:14]([NH2:16])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:31])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1
Reactant: NC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(N)=O
Reaction time: 1 h
Yield: 99.8 %

Procedure:
In 10 ml of DMF, HCl, H-D-Trp-NH2 (8.9 mmol; 1 eq.), Boc-D-Trp-OH (2.98 g; 9.8 mmol; 1.1 eq.), NMM (2.26 ml; 2.1 eq.) and BOP (4.33 g; 1.1 eq.) were added successively. After 1 hr, the mixture was diluted with ethyl acetate (100 ml) and washed with saturated aqueous sodium hydrogen carbonate (200 ml), aqueous potassium hydrogen sulfate (200 ml, 1M), and saturated aqueous sodium chloride (100 ml). The organic layer was dried over sodium sulfate, filtered and the solvent removed in vacuo to afford 4.35 g of Boc-D-Trp-D-Trp-NH2 as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[C:21]([CH3:24])[S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([CH:48]=O)=[CH:44][CH:43]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl.N.CN(C=O)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[C:21]([CH3:24])[S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:48]([C:45]3[CH:44]=[CH:43][C:42]([CH2:41][N:38]4[CH2:37][CH2:36][N:35]([C:33]([O:32][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:34])[CH2:40][CH2:39]4)=[CH:47][CH:46]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C=O)cc2)CC1
Reactant: Cc1nc(CN2CCN(c3c(Br)cnc(N)c3[N+](=O)[O-])CC2)cs1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCO
Product: Cc1nc(CN2CCN(c3c(Br)cnc4[nH]c(-c5ccc(CN6CCN(C(=O)OC(C)(C)C)CC6)cc5)nc34)CC2)cs1
Temperature: 85 °C
Yield: 33 %

Procedure:
To a mixture of 5-bromo-4-(4-((2-methylthiazol-4-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.062 g, 0.15 mmol), EtOH (2.6 mL) and DMF (0.35 mL), tert-butyl-4-(4-formylbenzyl)piperazine-1-carboxylate (0.050 g, 0.165 mmol) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.45 mL, 0.45 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 96:4) to give the title compound as a solid (0.033 g, 33%); 1H-NMR (500 Mz, DMSO-d6): δ 1.39 (s, 9H, C(CH3)3), 2.34 (t, J=5.0 Hz, 4H), 2.62-2.72 (m, 7H), 3.28-3.36 (m, 4H), 3.55 (s, 2H, NCH2), 3.64 (s, 2H, NCH2), 3.67 (t, J=4.0 Hz, 4H), 7.32 (s, 1H, thiazole 5-H), 7.47 (d, J=8.0 Hz, 2H, ArH, C6H4), 8.14 (d, J=8.5 Hz, 2H, ArH, C6H4), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.47 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z) 2.76 min—667/669 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 667.2190, calculated for C31H40BrN8O2S (M+H)+: 667.2178.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH2:3][C:4]#[C:5][CH2:6][CH2:7][CH2:8][NH2:9].CO[C:13]1[C:17](OC)=[N:16][S:15](=[O:21])(=[O:20])[N:14]=1.[CH2:22]([NH2:25])[CH:23]=[CH2:24]>>[CH2:22]([NH:25][C:13]1[C:17]([NH:9][CH2:8][CH2:7][CH2:6][C:5]#[C:4][CH2:3][N:2]([CH3:10])[CH3:1])=[N:16][S:15](=[O:21])(=[O:20])[N:14]=1)[CH:23]=[CH2:24]
Reactant: C=CCN
Reactant: COC1=NS(=O)(=O)N=C1OC
Reactant: CN(C)CC#CCCCN
Product: C=CCNC1=NS(=O)(=O)N=C1NCCCC#CCN(C)C

Procedure:
In a manner similar to Example 1, reaction of 6-dimethylaminohex-4-ynylamine and 3,4-dimethoxy-1,2,5-thiadiazole-1,1-dioxide followed by treatment with allylamine gives the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9](OCC)OCC)=[CH:4][C:3]=1[F:17].[NH2:18][NH:19][C:20]([NH2:22])=[S:21].[CH3:23]I>C(O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:18]=[N:19][C:20]([S:21][CH3:23])=[N:22][CH:9]=2)=[CH:4][C:3]=1[F:17]
Reactant: NNC(N)=S
Reactant: CI
Reactant: CCOC(OCC)C(=O)c1ccc(Br)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CSc1ncc(-c2ccc(Br)c(F)c2)nn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
A solution of 1-(4-bromo-3-fluorophenyl)-2,2-diethoxyethanone (2.24 g, 0.00734 mol), thiosemicarbazide (0.702 g, 0.00771 mol), and p-toluenesulfonic acid monohydrate (70 mg) in ethanol (50 mL) was heated at 90° C. for 2 h. LCMS showed that the starting material was consumed. After cooled to RT, to the mixture was added methyl iodide (2.3 mL, 0.037 mol). The mixture was stirred at RT for 2 h, and concentrated. To the residue was added acetic acid (15 mL). The mixture was heated at 60° C. for 4 h. The volatiles were evaporated under reduced pressure. The residue was treated with methanol. The formed precipitate was collected by filtration, and dried in-vacuo to afford the desired product (1.15 g, 51%) which was directly used in next step without further purification.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[CH2:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:76][CH:77]1[CH2:82][CH2:81][N:80]([CH2:83][CH3:84])[CH2:79][CH2:78]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:76][CH:77]5[CH2:82][CH2:81][N:80]([CH2:83][CH3:84])[CH2:79][CH2:78]5)=[O:28])=[CH:24][C:23]=4[CH2:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN1CCC(N)CC1
Reactant: CCc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)NC2CCN(CC)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.17 h
Yield: 73.7 %

Procedure:
To a mixture of 0.040 g (0.0899 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethyl-benzoic acid (I-194) and 6 mL of dimethylformamide was added 0.0182 g (0.135 mmole) of 1-hydroxybenzotriazole, 0.0520 g (0.135 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.047 g (0.359 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0173 g (0.135 mmole) of 4-amino-1-ethylpiperidine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0368 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethyl-N-(1-ethyl-piperidin-4-yl)-benzamide (I-196) as a white solid.
Reaction SMILES: [Cl:1]C1C2C(=O)N[C@H]3CN(C(OC(C)(C)C)=O)C[C@@H]3C=2C=CC=1C.[Cl:24][C:25]1[C:34]2[C:33](=[O:35])[NH:32][C@@H:31]3[CH2:36][N:37](C(OC(C)(C)C)=O)[CH2:38][C@H:30]3[C:29]=2[CH:28]=[CH:27][C:26]=1[CH3:46]>>[ClH:1].[Cl:24][C:25]1[C:34]2[C:33](=[O:35])[NH:32][C@H:31]3[CH2:36][NH:37][CH2:38][C@@H:30]3[C:29]=2[CH:28]=[CH:27][C:26]=1[CH3:46]
Reactant: Cc1ccc2c(c1Cl)C(=O)N[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H]21
Reactant: Cc1ccc2c(c1Cl)C(=O)N[C@H]1CN(C(=O)OC(C)(C)C)C[C@H]21
Product: Cc1ccc2c(c1Cl)C(=O)N[C@H]1CNC[C@H]21
Product: Cl

Procedure:
Following the procedure described in Example 45, Part I, (3aR,9bS)-tert-butyl 6-chloro-7-methyl-5-oxo-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate, the first eluting compound from Part B above, was converted into the title compound of Example 68 as a white solid. LRMS (ESI): 237.0/239.0 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1.[CH3:29][N:30]([CH2:32][CH2:33]Cl)[CH3:31]>>[F:28][C:2]([F:1])([F:27])[C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([O:15][CH2:33][CH2:32][N:30]([CH3:31])[CH3:29])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1
Reactant: CN(C)CCCl
Reactant: Cc1cccc(-c2nc3ccc(O)cc3n2Cc2ccccc2C(F)(F)F)c1
Product: Cc1cccc(-c2nc3ccc(OCCN(C)C)cc3n2Cc2ccccc2C(F)(F)F)c1

Procedure:
The title compound was prepared essentially as described in Example 107 except that the compound of Example 120 was reacted with 2-(N,N-dimethylamino)ethyl chloride. mp 93° C., NMR, IR, MS 453.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[CH2:11](Br)[CH3:12].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH2:11]([O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2)[CH3:12]
Reactant: Oc1cccc2[nH]ccc12
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOc1cccc2[nH]ccc12
Reaction time: 18 h

Procedure:
4-Hydroxyindole (1.0 equivalents) is dissolved in dry, degassed acetone. EtBr (5.0 equivalents) and Cs2CO3 (2.5 equivalents) are added, and the resulting solution is stirred for 18 hours. The reaction mixture is filtered through a Celite plug. The solvent is evaporated, and the product is purified by flash chromatography (MeOH:CH2Cl2, 5:95) to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.Cl.[O:12]([NH2:14])[CH3:13].C([BH3-])#N.[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][NH:14][O:12][CH3:13]
Reactant: O=Cc1ccc(F)c(Cl)c1
Reactant: CON
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: CONCc1ccc(F)c(Cl)c1

Procedure:
Reaction of 3-chloro-4-fluorobenzaldehyde with methoxylamine hydrochloride followed by reduction with sodium cyanoborohydride as described in the preparation of compounds 3-A and 3-B gave the title hydroxylamine as a clear oil. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.48 (3H, s), 3.98 (2H, s), 5.72 (1H, broad s), 7.10 (1H, t), 7.22 (1H, mn), 7.42 (1H, m).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([Cl:21])=[C:19]([Cl:22])[N:18]=[C:17]([Cl:23])[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[ClH:21].[ClH:21].[NH:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[C:20]([Cl:21])=[C:19]([Cl:22])[N:18]=[C:17]([Cl:23])[N:16]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc(Cl)nc(Cl)c2Cl)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Clc1nc(Cl)c(Cl)c(NC2CCNCC2)n1

Procedure:
A solution of 4-(2,5,6-trichloro-pyrimidin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.85 g, 2.23 mmol) in 4 M HCl in dioxane (100 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 283.4 [M+H]−.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[CH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][CH2:22][CH:21]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:20][CH2:19]3)[CH:15]=[CH:14][C:13]=2[NH2:28])=[N:2]1.C(N(CC)CC)C.[CH3:36][C:37]1[CH:41]=[CH:40][S:39][C:38]=1[C:42](Cl)=[O:43].C(=O)([O-])O.[Na+]>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[C:16]([N:18]3[CH2:19][CH2:20][CH:21]([S:24]([CH3:27])(=[O:25])=[O:26])[CH2:22][CH2:23]3)[CH:15]=[CH:14][C:13]=2[NH:28][C:42]([C:38]2[S:39][CH:40]=[CH:41][C:37]=2[CH3:36])=[O:43])=[N:2]1
Reactant: CS(=O)(=O)C1CCN(c2ccc(N)c(C=Cc3n[nH]c4ccccc34)c2)CC1
Reactant: Cc1ccsc1C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccsc1C(=O)Nc1ccc(N2CCC(S(C)(=O)=O)CC2)cc1/C=C/c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a similar manner to Example 2, said crude 3-{2-[5-(4-methanesulfonylpiperidin-1-yl)-2-nitrophenyl]vinyl}-1H-indazole (0.23 g, 0.54 mmol) obtained in Step 1 was dissolved in ethanol (7.0 mL) and 2-[2-(1H-indazol-3-yl)vinyl]-4-(4-methanesulfonylpiperidin-1-yl)phenylamine was obtained from tin (0.19 g, 1.6 mmol) and concentrated hydrochloric acid (1.0 mL) at room temperature. In a similar manner to Example 29, a solution of 2-[2-(1H-indazol-3-yl)vinyl]-4-(4-methanesulfonylpiperidin-1-yl)phenylamine (0.22 g, 0.54 mmol) in THF (10 mL) was added with triethylamine (0.23 ml, 1.6 mmol) and 3-methylthiophenecarbonyl chloride (0.09 g, 0.54 mmol), followed by stirring at room temperature for 1 hour. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate solution, extracted with ethyl acetate and the organic layer was concentrated under reduced pressure to obtain crude (E)-N-{2-[2-(1H-indazol-3-yl)vinyl]-4-(4-methanesulfonylpiperidin-1-yl)phenyl}-3-methylthiophene-2-carboxamide. Further, Compound 227 (68 mg, 22%) was obtained using 4 mol/L hydrogen chloride-methanol solution (1.0 mL).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][C:12]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1>[F:10][C:11]1[C:12]([C:2]2[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=2[CH3:9])=[CH:13][C:14]([CH:17]=[O:18])=[CH:15][CH:16]=1
Reactant: Cc1cccc(C)c1Br
Reactant: O=Cc1ccc(F)c(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1cccc(C)c1-c1cc(C=O)ccc1F
Temperature: 80 °C
Reaction time: 8 h

Procedure:
In an atmosphere of nitrogen, tetrakistriphenylphosphine palladium was added to a mixture of 2-bromo-1,3-dimethylbenzene, 2-fluoro-5-formylphenyl boronic acid, a 1 M sodium carbonate aqueous solution, ethanol and toluene, followed by stirring at 80° C. for 8 hours to obtain 6-fluoro-2′,6′-dimethylbiphenyl-3-carbaldehyde. Under cooling on an ice-methanol bath, sodium borohydride was added in small portions to an ethanol solution of the resulting 6-fluoro-2′,6′-dimethylbiphenyl-3-carbaldehyde, and the reaction mixture was stirred at the same temperature for 1 hour to obtain (6-fluoro-2′,6′-dimethylbiphenyl-3-yl)methanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:5][CH:6]=[CH:7][CH:8]=1.Cl[CH2:24][C:25]1[CH:26]=[C:27]([C:31]2[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=2)[CH:28]=[N:29][CH:30]=1>>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:24][C:25]2[CH:26]=[C:27]([C:31]3[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=3)[CH:28]=[N:29][CH:30]=2)[CH2:11][CH2:12]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1ccccc1NC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COc1cc(-c2cncc(CCl)c2)cc(OC)c1OC
Product: COc1ccccc1N(Cc1cncc(-c2cc(OC)c(OC)c(OC)c2)c1)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
4-(o-Anisidino)-1-(tert-butoxycarbonyl)piperidine (613 mg) and 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1N.C([N:12](CC)CC)C.CC(C)=O.[SH2]=N.[C:23]1([NH:29][C:30](C2C=CC=CC=2C(O)=O)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[C:23]1([NH:29][C:30]([NH:12][C:7]2[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:6]=2)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccccc1C(=O)Nc1ccccc1
Reactant: COc1ccccc1N
Agent: N=[SH2]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(NC(=O)Nc2ccccc2)cc1

Procedure:
A solution of 0.6 g o-methoxyaniline and 0.7 ml triethylamine with 5 ml aceton was added dropwise to a suspension of 1.5 g phenylcarbamoyl-benzoic acid sulfimide, under stirring. The reaction mixture was stirred at room temperature for 2 hours, then diluted with 100 ml water. The precipitated solid product was cooled, filtered, washed with water and dried. 0.80 g 1-phenyl-3-(4-methoxyphenyl)-urea was obtained, which melted at 196°-198° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[N:12]=[C:11]([OH:22])[N:10]=2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:30][C:31]([F:34])([F:33])[F:32].C(OCC)(=O)C>CS(C)=O>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([N:13]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[N:10][C:11]([O:22][CH2:30][C:31]([F:34])([F:33])[F:32])=[N:12]2)=[CH:15][N:16]=1
Reactant: FC(F)(F)CI
Reactant: COc1ccc(-c2nc(O)nn2-c2ccc(OC)nc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nc(OCC(F)(F)F)nn2-c2ccc(OC)nc2)cc1
Temperature: 100 °C
Yield: 45.6 %

Procedure:
A mixture of 5-(4-methoxyphenyl)-1-(6-methoxypyridin-3-yl)-1H-1,2,4-triazol-3-ol (300 mg, 1.01 mmol), potassium carbonate (417 mg, 3.02 mmol), and 2-iodo-1,1,1-trifluoroethane (0.496 mL, 5.03 mmol) in dimethyl sulfoxide (1.5 mL) were heated at 100° C. for 1 hour. After cooling, ice water and ethyl acetate were poured into the mixture and the organic layer was separated, washed with brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography (toluene-ethyl acetate 8:1) The desired product was washed with hexane to give 2-methoxy-5-(5-(4-methoxyphenyl)-3-(2,2,2-trifluoroethoxy)-1H-1,2,4-triazol-1-yl)pyridine (175 mg, 45.8% yield).
Reaction SMILES: [NH:1]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[N:4]=[C:2]1[NH2:3].[C:12]([OH:15])(=O)[CH3:13].[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:16]([N:3]([C:12](=[O:15])[CH3:13])[C:2]1[NH:1][C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[N:4]=1)(=[O:18])[CH3:17]
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)O
Product: CC(=O)N(C(C)=O)c1nc2nc[nH]c2c(=O)[nH]1
Yield: 95 %

Procedure:
Guanine has also been acetylated in acetic anhydride and acetic acid to give different products depending on the workup conditions. H. Matsumoto. et al. Chem.Pharm.Bull. 1988, 36 (3), 1153. For example, after the reaction mixture becomes an almost clear solution, if solvents are removed by distillation, only diacetyl guanine is obtained in 95% yield. However, the addition of water at 60° C. followed by stirring at room temperature overnight produces N2 -acetylguanine in 94.4% yield. If the reaction mixture is merely cooled down, a mixture of mono- and di-acetylguanine is produced.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH:25]=[CH:24][C:19]([C:20](NC)=[O:21])=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:28])[CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[C:41](=[O:42])[C:40]([C:43](F)=[O:44])=[CH:39][CH:38]=[N:37]2)=[CH:32][CH:31]=1.FC1C=CC(NC(C2(C(F)=O)CC2)=[O:55])=CC=1>O>[F:28][C:4]1[CH:3]=[C:2]([NH:1][C:43]([C:40]2[C:41](=[O:42])[N:36]([C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)[N:37]=[CH:38][CH:39]=2)=[O:44])[CH:27]=[CH:26][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[CH:25]=[CH:24][C:19]([C:20]([OH:55])=[O:21])=[CH:18][CH:17]=3)[S:15][C:8]=12
Reactant: O=C(F)c1ccnn(-c2ccc(F)cc2)c1=O
Reactant: CNC(=O)c1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)cc1
Reactant: O=C(F)C1(C(=O)Nc2ccc(F)cc2)CC1
Solvent: O
Product: O=C(O)c1ccc(-c2cc3nccc(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)c3s2)cc1

Procedure:
Prepared according to the procedure for Example 112, Step B substituting 4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)benzoic acid (1.25 g, 3.29 mmol) for 4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)-N-methylbenzamide and 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carbonyl fluoride (1.70 g, 5.75 mmol) for 1-((4-fluorophenyl)carbamoyl)cyclopropanecarbonyl fluoride. When the reaction was complete, water (20 mL) was added and the product (1.59 g, 80%) was collected by filtration to get a brown solid. LRMS (esi+) 597 m/z (M+1) detected.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[C:22](OC(=O)C)(=[O:24])[CH3:23].S(=O)(=O)(O)O.II.[C:36](O)(=[O:38])[CH3:37]>>[CH3:1][O:2][C:3](=[O:21])[C:4]([C:36](=[O:38])[CH3:37])([C:22](=[O:24])[CH3:23])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Reactant: CC(=O)O
Reactant: CC(=O)OC(C)=O
Agent: II
Agent: O=S(=O)(O)O
Product: CCCCCCCCCCCCCCCCC(C(C)=O)(C(C)=O)C(=O)OC

Procedure:
6 Mol of an epoxidized oleic acid methyl ester (epoxide oxygen content: 4.61%) were stirred for 4 hours under vigorous reflux with 12 mol acetic anhydride, 10 mol % acetic acid and 1 mol % concentrated sulfuric acid. After neutralization with sodium methylate, the excess acetic anhydride was distilled off; the residue was distilled in a water jet vacuum (approx. 15 torr) up to 120° C. to remove volatile fractions of acetic anhydride. Precipitated salts were removed from the distillation residue by filtration. A brown clear liquid having the following analytical data was obtained: epoxide oxygen content 0.32%, OH value 2.6, saponification value 294.4, acid value 1.1, iodine value 14.7.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]3[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH2:28].CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>>[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]3[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1ccccn1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(Nc5ccccn5)nc34)cc21
Temperature: 150 °C
Yield: 29 %

Procedure:
Prepared similarly to that described in Example 82 using 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 154 mg, 0.517 mmol), pyridin-2-amine (58.4 mg, 0.621 mmol, Aldrich), BrettPhos precat (Strem, Newburyport, Mass.; 21.90 mg, 0.026 mmol), Brettphos (Strem, Newburyport, Mass.; 15.12 mg, 0.026 mmol), and LHMDS (1.0M in THF; 1138 μl, 1.138 mmol), heating at 150° C. for 30 min in a microwave reactor (Biotage Initiator). Purification by silica gel (100% DCM to 5% MeOH/DCM) provided 2-(2-(pyridin-2-ylamino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (29% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.92 (t, J=6.75 Hz, 2H) 3.45 (td, J=6.80, 2.25 Hz, 2H) 6.96 (br. s., 1H) 6.99 (d, J=2.15 Hz, 1H) 7.02 (dd, J=6.85, 5.48 Hz, 1H) 7.36 (t, J=7.73 Hz, 1H) 7.54 (d, J=8.80 Hz, 1H) 7.58 (d, J=8.22 Hz, 1H) 7.63 (d, J=7.24 Hz, 1H) 7.76 (td, J=6.85, 1.96 Hz, 1H) 8.02 (dd, J=6.46, 0.98 Hz, 1H) 8.20 (d, J=9.00 Hz, 1H) 8.41 (dd, J=4.89, 1.37 Hz, 1H) 10.16 (s, 1H) 12.72 (br. s., 1H). MS (ESI, pos. ion) m/z: 356.1 (M+1).