Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].N([O-])=O.[Na+].[C:21]([O-:24])(=O)[CH3:22].C([N:31]1[C:40]2[C:35](=[CH:36][C:37]([O:42][CH3:43])=[C:38]([NH2:41])[CH:39]=2)[NH:34][C:33](=[O:44])[C:32]1=[O:45])(=O)CC(C)=O>>[O:24]=[C:21]([CH3:22])[CH:38]([C:37](=[O:42])[NH:41][C:38]1[CH:39]=[C:40]2[C:35]([NH:34][C:33](=[O:44])[C:32](=[O:45])[NH:31]2)=[CH:36][C:37]=1[O:42][CH3:43])[N:41]=[N:2][C:3]1[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: CC(=O)[O-]
Reactant: COc1cc2[nH]c(=O)c(=O)n(C(=O)CC(C)=O)c2cc1N
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Product: COC(=O)c1ccc(C(=O)OC)c(N=NC(C(C)=O)C(=O)Nc2cc3[nH]c(=O)c(=O)[nH]c3cc2OC)c1
Temperature: 96 °C

Procedure:
0.1 mol of dimethyl aminoterephthalate hydrochloride is diazotized with sodium nitrite at from 0 to 10° C. The clarified diazonium salt solution is added dropwise at room temperature over 1 hour to an acetate-buffered suspension of 0.1 mol of N-acetoacetyl-6-methoxy-7-aminoquinoxaline-2,3-dione in the presence of a sufactant, such as ®LUTENSOL AT 25. When coupling is at an end the mixture is heated to 96° C.and the product is filtered and washed free of salt. The moist presscake is suspended in N-methylpyrrolidone, the water is removed by distillation and the product is subsequently heated at from 100 to 170° C. It is then cooled to 70° C., filtered, dried and milled. This gives 51 g of a yellow pigment.
Reaction SMILES: Cl.Cl.[CH2:3]([NH:5][C:6]1[NH:10][C:9]2[CH:11]=[CH:12][C:13]([C:15]3[CH:16]=[CH:17][C:18]4[O:24][CH2:23][CH2:22][NH:21][CH2:20][C:19]=4[CH:25]=3)=[CH:14][C:8]=2[N:7]=1)[CH3:4].Cl[C:27]1[C:36]2[C:31](=[CH:32][C:33]([O:37][CH3:38])=[CH:34][CH:35]=2)[N:30]=[C:29]([CH3:39])[N:28]=1.C(N(C(C)C)CC)(C)C.O>CN1C(=O)CCC1>[CH2:3]([NH:5][C:6]1[NH:7][C:8]2[CH:14]=[C:13]([C:15]3[CH:16]=[CH:17][C:18]4[O:24][CH2:23][CH2:22][N:21]([C:27]5[C:36]6[C:31](=[CH:32][C:33]([O:37][CH3:38])=[CH:34][CH:35]=6)[N:30]=[C:29]([CH3:39])[N:28]=5)[CH2:20][C:19]=4[CH:25]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1)[CH3:4]
Reactant: COc1ccc2c(Cl)nc(C)nc2c1
Reactant: CCNc1nc2cc(-c3ccc4c(c3)CNCCO4)ccc2[nH]1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: CCNc1nc2ccc(-c3ccc4c(c3)CN(c3nc(C)nc5cc(OC)ccc35)CCO4)cc2[nH]1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a mixture of N-ethyl-5-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-benzimidazol-2-amine dihydrochloride (50 mg, 0.13 mmol) and 4-chloro-7-methoxy-2-methylquinazoline (27 mg, 0.13 mmol) in NMP (1 mL) was added diisopropylethylamine (91 uL, 0.52 mmol). The mixture was heated to 90° C. and stirred for 1 h. After cooling to rt, water was added, and the resulting aqueous mixture was extracted twice with 10% methanol in ethyl acetate. The organic extracts were combined, dried over magnesium sulfate, filtered, and then concentrated. The residue was purified by reverse-phase preparative HPLC to provide N-ethyl-6-{4-[2-methyl-7-(methyloxy)quinazolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}-1H-benzimidazol-2-amine as an acetate salt (34.2 mg, 0.063 mmol, 49% yield). 1H NMR (400 MHz, DMSO-d6) δ 11.91 (br s, 1H), 10.83 (br s, 1H), 7.92 (d, 1H), 7.58 (d, 1H), 7.43 (dd, 1H), 7.35 (s, 1H), 7.20-7.10 (m, 3H), 7.05-6.97 (m, 2H), 6.61 (br s, 1H), 4.99 (s, 2H), 4.44-4.38 (m, 2H), 4.18-4.11 (m, 2H), 3.33-3.25 (m, 2H), 2.44 (s, 3H), 1.91 (s, 4H), 1.19 (t, 3H); MS (EI) for C28H28N6O2: 481 (MH+).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]2[C:13]3=[C:14]4[S:20][CH:19]=[CH:18][C:15]4=[N:16][CH:17]=[C:12]3[N:11]=[C:10]2[CH2:21][C:22]#[N:23])[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33]>C(Cl)Cl.C1(C)C=CC=CC=1>[C:22]([CH2:21][C:10]1[N:9]([C@H:6]2[CH2:7][CH2:8][C@H:3]([CH2:2][NH:1][C:32](=[O:33])[O:34][CH:35]([CH3:37])[CH3:36])[CH2:4][CH2:5]2)[C:13]2=[C:14]3[S:20][CH:19]=[CH:18][C:15]3=[N:16][CH:17]=[C:12]2[N:11]=1)#[N:23]
Reactant: N#CCc1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CN)CC1
Reactant: CC(C)OC(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)OC(=O)NC[C@H]1CC[C@H](n2c(CC#N)nc3cnc4ccsc4c32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of {1-[trans-4-(aminomethyl)cyclohexyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}acetonitrile (9.5 mg, 0.029 mmol) and triethylamine (20. μL, 0.14 mmol) in methylene chloride (1 mL) was added 1.0 M isopropyl chloroformate in toluene (35 μL). The mixture was stirred at room temperature for 1 h, then stripped to dryness and purified on prep-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (1.5 mg, 12%). LCMS calculated for C21H26N5O2S (M+H)+: m/z=412.2. Found: 412.1.
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([S:13][CH3:14])[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]1=[O:21])[CH3:2].ClC1C=CC=C(C(OO)=[O:30])C=1>ClCCl>[CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([S:13]([CH3:14])=[O:30])[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:4]1=[O:21])[CH3:2]
Reactant: CCn1c(=O)c(-c2ccccc2)cc2cnc(SC)nc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCn1c(=O)c(-c2ccccc2)cc2cnc(S(C)=O)nc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a solution of 8-ethyl-2-(methylthio)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one (127 mg, 0.43 mmol) in dichloromethane (2 mL) was added 3-chloroperbenzoic acid (70%, 95 mg, 0.38 mmol) at 0-5° C. and the mixture was stirred at room temperature for 18 h. The reaction was diluted with dichloromethane (5 mL) and washed with saturated sodium bicarbonate solution (1×3 mL) then with water (1×3 mL). The organic layer was dried over sodium sulfate, filtered and evaporated to get 8-ethyl-2-(methylsulfinyl)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one as a pale yellow solid (120 mg, 0.38 mmol, 88%). ESMS m/z 314 (M+H)+.
Reaction SMILES: C(OC(=O)[CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C.[CH2:15]=[C:16]1[O:20][C:18](=[O:19])[CH2:17]1.[CH3:21][O-:22].[Na+]>C1C=CC=CC=1.CO>[C:8]1([N:7]2[CH2:6][CH2:5][C:21](=[O:22])[CH:17]([C:16](=[O:20])[CH3:15])[C:18]2=[O:19])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[O-]
Reactant: CCOC(=O)CCNc1ccccc1
Reactant: C=C1CC(=O)O1
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: CC(=O)C1C(=O)CCN(c2ccccc2)C1=O
Temperature: 50 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
N-Phenyl-β-alanine ethyl ester (24,25 g) is dissolved in benzene (60 ml), and thereto is added dropwise diketene (12 ml) at 70° C. The mixture is refluxed overnight. The mixture is distilled to remove the solvent to give crude N-phenyl-N-methoxycarbonylmethylcarbonyl-β-alanine ethyl ester (37.23 g). Said crude compound is dissolved in methanol (70 ml), and the mixture is added dropwise to a solution of sodium methoxide (prepared from 3.90 g of sodium) in methanol (70 ml) at 50° C. The mixture is stirred at 50° C. for 2 hours, and distilled to remove the solvent. The residue is dissolved in water, and the aqueous solution is extracted with ethyl acetate. The aqueous layer is neutralized with 10% HCl, and extracted with ethyl acetate. The extract is washed with a saturated sodium chloride solution, dried and then distilled to remove the solvent. The residue is purified by silica gel column chromatography (solvent, ethyl acetate:n-hexane=1:2) to give 1-phenyl-3-acetyl-2,4-dioxopiperidine (23.87 g, 81.6%) as oil.
Reaction SMILES: C([N:3]([CH2:14][CH3:15])[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7](C)[C:6]=1[CH3:12])C.[OH:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23]CC#N)[CH2:19][CH2:18]1>>[OH:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:15][C:14]2[NH:3][C:4](=[O:13])[C:5]3[C:6]([CH:12]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:19][CH2:18]1
Reactant: N#CCCN1CCC(O)CC1
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Product: O=c1[nH]c(CCN2CCC(O)CC2)cc2ccccc12
Yield: 8.2 %

Procedure:
By the reaction in the same manner as in Example 1a, using N,N-diethyl-2,3-dimethylbenzamide (5.6017 g) and 3-(4-hydroxypiperidin-1-yl)propionitrile (2.26 g), 3-[2-(4-hydroxypiperidin-1-yl)ethyl]-2H-isoquinolin-1-one (327.5 mg) was obtained.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=O)[CH2:2]1.[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH:13]=O.[NH2:19][C:20]1[CH:24]=[CH:23][NH:22][N:21]=1>>[F:9][C:10]1[CH:11]=[C:12]([CH:13]2[C:2]3[C:1](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]=3[NH:19][C:20]3=[CH:24][CH:23]=[N:22][N:21]23)[CH:15]=[CH:16][C:17]=1[F:18]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: O=C1CCCC(=O)C1
Reactant: Nc1cc[nH]n1
Product: O=C1CCCC2=C1C(c1ccc(F)c(F)c1)n1nccc1N2

Procedure:
1,3-Cyclohexanedione, 3,4-difluorobenzaldehyde and 3-aminopyrazole were processed as described in General Procedure A to provide the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:4][N:3]=1.C[C@@H:20]1[NH:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]1.[CH:33](N(C(C)C)CC)(C)C>CS(C)=O>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([N:25]3[CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[C@@H:21]([CH3:33])[CH2:20]3)=[N:3][N:4]=2)=[CH:13][CH:14]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: Fc1ccc(-c2nnc(Cl)c3ccccc23)cc1
Solvent: CS(C)=O
Product: C[C@H]1CN(c2nnc(-c3ccc(F)cc3)c3ccccc23)CCN1C(=O)OC(C)(C)C
Temperature: 120 °C
Yield: 38.6 %

Procedure:
Add 1-chloro-4-(4-fluorophenyl)phthalazine (200 g, 773 mmol) to a solution of (S)-tert-butyl 3-methylpiperazine-1-carboxylate (232 g, 1.16 mol), diisopropylethylamine (674 mL, 28.1 mol), and DMSO (2.0 L). Heat the mixture to 120° C. for 60 h. Cool the mixture to 25° C., pour into ice water (3.0 L) and filter. Collect the solids, dissolve in CH2Cl2 (2.0 L), and extract with water (2.0 L). Concentrate the organic phase and add to a silica plug (3.0 kg silica) eluting with 3% THF in CH2Cl2 to yield the title compound as a yellow foam (126 g, 38%). ES/MS m/z 423.0 (M+1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]=[CH:3][C:2]1=[O:7].CO[CH2:10][N:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:12][Si](C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:17]([N:11]1[CH2:12][CH:4]2[CH2:5][CH2:6][O:1][C:2](=[O:7])[CH:3]2[CH2:10]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1C=CCCO1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1OCCC2CN(Cc3ccccc3)CC12
Temperature: 0 °C
Reaction time: 6 h
Yield: 82.87 %

Procedure:
To a solution of 5,6-dihydro-2H-pyran-2-one (1.00 g, 1 eq) in CH2Cl2 (150 mL) was added N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (1.2 eq). After the mixture was cooled to 0° C., a solution of TFA in CH2Cl2 (0.1 eq, 1M) was added slowly. The reaction mixture was slowly heated to room temperature and stirred for 6 h. The reaction mixture was washed with water and brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was chromatographed with a silica gel column (eluting agent: 2:1 (v/v) PE/EA) to give the title compound as colorless oil (1.95 g, 82.87%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 232.3 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8]([CH2:11]O)=[N:9][S:10][C:6]=2[CH:5]=[C:4]([CH3:13])[CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:34]>C(Cl)Cl>[Br:34][CH2:11][C:8]1[C:7]2[C:2]([CH3:1])=[CH:3][C:4]([CH3:13])=[CH:5][C:6]=2[S:10][N:9]=1
Reactant: Cc1cc(C)c2c(CO)nsc2c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(C)c2c(CBr)nsc2c1
Reaction time: 1 h
Yield: 70.3 %

Procedure:
To a solution of (4,6-dimethyl-1,2-benzisothiazol-3-yl)-methanol (100 mg, 0.5 mmol) in CH2Cl2 (15 mL) are added PPh3 (200 mg, 0.78 mmol) and CBr4 (340 mg, 1 mmol) at room temperature. The solution is stirred at the same temperature for 1 hour. The solution is concentrated and the residue is purified by flash chromatography with 10% EtOAc in Hexane as the eluent to afford 3-bromomethyl-4,6-dimethyl-1,2-benzisothiazole (90 mg, 68%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH3:15][C:16]1[O:20][C:19]([CH2:21][NH2:22])=[CH:18][CH:17]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=2[CH:32]=O)[CH2:26][CH2:25]1>>[CH3:15][C:16]1[O:20][C:19]([CH2:21][NH:22][C:8]2[CH:7]=[CH:6][C:5]3[C:4]([NH:1][CH2:32][C:31]4[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=4[N:27]4[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]4)=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=2)=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: CN1CCN(c2ccccc2C=O)CC1
Reactant: Cc1ccc(CN)o1
Product: Cc1ccc(CNc2ccc3c(NCc4ccccc4N4CCN(C)CC4)cccc3n2)o1

Procedure:
The title compound, MS: m/e=442.5 (M+H+), was prepared from 5-nitro-2-chloroquinoline, 5-methyl-2-furanmethanamine and 2-(4-methylpiperazino)benzaldehyde as described in example 26.
Reaction SMILES: [C:1]1([C:7]([O:9][Si](C)(C)C)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22][CH:23]([C:27](O)=[O:28])[C:24](O)=[O:25])[CH3:15]>>[CH2:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22][C:23]1[C:24](=[O:25])[O:9][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8][C:27]=1[OH:28])[CH3:15]
Reactant: CCc1ccccc1SC(C(=O)O)C(=O)O
Reactant: C=C(O[Si](C)(C)C)c1ccccc1
Product: CCc1ccccc1Sc1c(O)cc(-c2ccccc2)oc1=O

Procedure:
The title compound was prepared by Method A using 1-phenyl-1-(trimethylsilyloxy)ethylene (4.17 g, 21.72 mmol) and diethyl ester of [(2-ethylphenyl)thio]propanedioic acid (1.5 g, 10.86 mmol). m.p. 190°-192° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.25 (t, 3H), 2.78 (q, 2H), 6.89 (s, 1H), 6.92 (m, 1H), 7.08 (m, 2H), 7.2 (m, 1H), 7.58 (m, 3H), 7.86 (m, 2H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:10]N)[CH:5]=[C:6]([I:9])[C:7]=1[I:8].[CH3:12][CH:13]([C:22](=O)[CH3:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20]>C(O)(=O)C>[I:1][C:2]1[C:7]([I:8])=[C:6]([I:9])[CH:5]=[C:4]2[C:3]=1[C:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])([CH3:12])[C:22]([CH3:23])=[N:10]2
Reactant: NNc1cc(I)c(I)c(I)c1
Reactant: CC(=O)C(C)CCCCCC(=O)O
Solvent: CC(=O)O
Product: CC1=Nc2cc(I)c(I)c(I)c2C1(C)CCCCCC(=O)O
Yield: 23.5 %

Procedure:
A mixture of 3,4,5-triiodophenylhydrazine 2 g (4 mmol) and 1 g (5 mmol) of 7-methyl-8-oxononanoic acid was refluxed in 15 mL of acetic acid for 16 hours. The acetic acid was evaporated, and the residue was dissolved in CHCl3, and washed by aqueous NaHCO3 and water. The organic layer was dried with CaCl2 and solvent was removed under reduced pressure by a rotary evaporator. The residue was column purified (Silica gel 60, 0-4% methanol-chloroform) to give 0.6 g of 6-(4,5,6-triiodo-2,3-dimethyl-3H-3-indolyl)hexanoic acid. 1H-NMR (200 MHz, DMSO-d6), δ, ppm: 8.02 (1H, s, arom.), 2.16 (3H, s, 2-CH3), 2.07 (2H, t, CH2COOH), 1.65-1.05 (6H, m, CH2), 1.26 (3H, s, CH3), 0.58-0.20 (2H, m, CH2).
Reaction SMILES: [Br:1][C:2]1[S:10][C:9]2[C:8](Cl)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[CH:16]2>ClC(Cl)C.C(O)(C)(C)C>[Br:1][C:2]1[S:10][C:9]2[C:8]([NH:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][CH:17]=[CH:16]4)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: Clc1ncnc2cc(Br)sc12
Reactant: Nc1ccc2[nH]ccc2c1
Solvent: CC(Cl)Cl
Solvent: CC(C)(C)O
Product: Brc1cc2ncnc(Nc3ccc4[nH]ccc4c3)c2s1
Temperature: 25 °C
Yield: 121.7 %

Procedure:
6-Bromo-4-chloro-thieno[3,2-d]pyrimidine (7.73 g, 31 mmol) was dissolved in 50 mL of dichloroethane and 50 mL of t-butyl alcohol, and 5-aminoindole (4.09 g, 31 mmol) were added. The reaction mixture was refluxed for 14 hours, cooled to room temperature, and concentrated in vacuo to afford 13.02 g of (6-bromo-thieno[3,2-d]pyrimidin-4-yl)-(1H-indol-5-yl)-amine. The crude material was used without further purification (83% purity). 1H NMR (400 MHz, DMSO) d 11.1 (s, 1H), 9.62 (s, 1H), 8.38 (s, 1H), 7.63 (s, 1H), 7.49 (s, 1H), 7.35 (m, 2H), 7.10 (d, 1H), 6.40 (s, 1H); LC-MS: 345, 347 (MH+); HPLC RT: 3.77 minutes.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[N:24]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=1)=[C:25]=[O:26]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:24]([C:27]3[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=3)[C:25]2=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Reactant: Cc1cccc(N=C=O)c1
Product: COc1cccc2c1ncc1c(=O)n(-c3cccc(C)c3)c(=O)n(C3CCCC3)c12
Yield: 72.2 %

Procedure:
1-Cyclopentyl-7-methoxy-3-m-tolyl-1H-pyrimido[5,4-c]quinoline-2,4-dione (29 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.1 mmol) and 1-isocyanato-3-methyl-benzene (0.5 mmol) following general procedure C. LCMS: m/z 402 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 9.46 (s, 1H), 7.77 (d, 1H), 7.53 (t, 1H), 7.46 (d, 1H), 7.32 (s, 1H), 7.16 (d, 1H), 7.14 (d, 1H), 6.83 (d, 1H), 5.06 (p, 1H), 4.12 (s, 3H), 2.41 (m, 2H), 2.32 (s, 3H), 1.98 (m, 4H), 1.32 (m, 2H) ppm.
Reaction SMILES: C(C1C=C2C(C3C=C(C=CC=3)CNC(C3C(=O)N(CC4C=CC(F)=C(F)C=4)C=CC=3)=O)=CNC2=NC=1)#N.CC1(C)C(C)(C)OB([C:46]2[S:50][C:49]([CH2:51][NH:52][C:53]([C:55]3[C:56](=[O:70])[N:57]([CH2:61][C:62]4[CH:67]=[CH:66][C:65]([F:68])=[C:64]([F:69])[CH:63]=4)[CH:58]=[CH:59][CH:60]=3)=[O:54])=[CH:48][CH:47]=2)O1.[B].C[O:74][C:75]([C:77]1[CH:78]=[C:79]2[CH:85]=[CH:84][NH:83][C:80]2=[N:81][CH:82]=1)=[O:76]>>[F:69][C:64]1[CH:63]=[C:62]([CH:67]=[CH:66][C:65]=1[F:68])[CH2:61][N:57]1[CH:58]=[CH:59][CH:60]=[C:55]([C:53]([NH:52][CH2:51][C:49]2[S:50][C:46]([C:85]3[C:79]4[C:80](=[N:81][CH:82]=[C:77]([C:75]([OH:76])=[O:74])[CH:78]=4)[NH:83][CH:84]=3)=[CH:47][CH:48]=2)=[O:54])[C:56]1=[O:70]
Reactant: CC1(C)OB(c2ccc(CNC(=O)c3cccn(Cc4ccc(F)c(F)c4)c3=O)s2)OC1(C)C
Reactant: COC(=O)c1cnc2[nH]ccc2c1
Agent: N#Cc1cnc2[nH]cc(-c3cccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)c3)c2c1
Agent: [B]
Product: O=C(O)c1cnc2[nH]cc(-c3ccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)s3)c2c1

Procedure:
Except where indicated, 3-[5-({[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-methyl)-thiophen-2-yl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid was synthesized as per Example 68, 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-(5-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-benzylamide using 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid [5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophen-2-ylmethyl]-amide as activated boron species and 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid methyl ester as substituted bicyclic heterocycle, to yield the product. 1H NMR (400 MHz, DMSO-d6) d ppm 12.338 (m, 1H) 10.072 (t, J=5.8 Hz, 1H) 8.829 (d, J=1.7 Hz, 1H) 8.688 (d, J=1.9 Hz, 1H) 8.403 (dd, J=7.3, 2.2 Hz, 1H) 8.234 (dd, J=6.6, 2.2 Hz, 1H) 7.944 (d, J=2.5 Hz, 1H) 7.480-7.347 (m, 2H) 7.224 (d, J=3.6 Hz, 1H) 7.188-7.134 (m, 1H) 7.040 (d, J=3.5 Hz, 1H) 6.591 (t, J=7.1 Hz, 1H) 5.194 (s, 2H), 4.685 (d, J=5.9 Hz, 2H); MS m/z=521.05 M+H.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][S:12]([OH:15])(=O)=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)(Cl)=O.S(Cl)(Cl)(=O)=O.[CH3:25][NH:26][CH3:27]>C(Cl)Cl>[CH3:25][N:26]([CH3:27])[S:12]([CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:15])=[O:13]
Reactant: O=[N+]([O-])c1ccc(CCS(=O)(=O)O)cc1
Reactant: CNC
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CN(C)S(=O)(=O)CCc1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 41 %

Procedure:
A flask was charged with 4.60 g (19.9 mmol) of solid 2-(4-nitro-phenyl)-ethanesulfonic acid (as prepared in Example 26, step (b)), which was treated with 29.0 mL (398 mmol) of thionyl chloride and heated to 80° C. for 6 h. Solvents were evaporated in vacuo, and the resulting solid was dried overnight under high vacuum. A solution of 2.12 g (8.49 mmol) of this solid sulfonyl chloride in 40 mL CH2Cl2 was treated with 15.0 mL (127 mmol) of 40% w/v aqueous dimethylamine and stirred at RT for 16 h then warmed to 40° C. for 3 h. The mixture was diluted with CH2Cl2 (100 mL) and washed with water (2×50 mL). The aqueous layer was extracted with CH2Cl2 (50 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 50% EtOAc-hexane afforded 912 mg (41%) of the title compound as an off-white solid: 1H-NMR (CD3OD; 400 MHz): δ 8.20 (d, 2H, J=8.8 Hz), 7.41 (d, 2H, J=8.8 Hz), 3.29-3.14 (m, 4H), 2.89 (s, 6H).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[Br:15][C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[C:18](F)[N:17]=1>O1CCCC1.C(OCC)(=O)C.O>[CH2:1]([O:8][C:18]1[N:17]=[C:16]([Br:15])[C:21]([Cl:22])=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: Fc1ccc(Cl)c(Br)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Clc1ccc(OCc2ccccc2)nc1Br
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of benzyl alcohol (55.5 mg, 0.513 mmol) in tetrahydrofuran (5 mL) at 0° C. was added potassium tert-butoxide (57.6 mg, 0.513 mmol) and the mixture was stirred at 0° C. for 2 hours. The mixture was cooled to −78° C. and a solution of 2-bromo-3-chloro-6-fluoropyridine (120 mg, 0.570 mmol) in 2 mL tetrahydrofuran was added. After stirring at −78° C. for 1 hour the mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over sodium sulfate and concentrated. Purification by column chromatography (silica gel, 20% ethyl acetate in hexane) afforded the title compound. LCMS: 299.9 (M+3)+.
Reaction SMILES: CN(C=O)C.C([N:9]1[CH2:14][C:13](=[O:15])[N:12]([C:16](=[O:18])[CH3:17])[CH2:11][C:10]1=[O:19])(=O)C.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]=O)[CH:21]=1.CC(C)([O-])C.[K+]>C(O)(C)(C)C.O>[C:16]([N:12]1[CH2:11][C:10](=[O:19])[NH:9][C:14](=[CH:26][C:22]2[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=2)[C:13]1=[O:15])(=[O:18])[CH3:17]
Reactant: O=Cc1cccnc1
Reactant: CC(=O)N1CC(=O)N(C(C)=O)CC1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: CN(C)C=O
Product: CC(=O)N1CC(=O)NC(=Cc2cccnc2)C1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 54.4 %

Procedure:
Add DMF (60 mL) to a mixture of 1,4-diacetyl-piperazine-2,5-dione (5.94 g, 30 mmol) and 3-pyridinecarboxaldehyde (12.84 g, 120 mmol). Cool to 0° C. Add portionwise over 20 min a solution of potassium tert-butoxide (3.36 g, 30 mmol) in tert-butanol (60 mL) to this solution. Warm to room temperature and stir for 2 h. Pour the mixture into water (400 mL) and filter. Wash with water three times, then with hexanes to obtain the title compound as a yellow powder (4.0 g, 54%): 1H NMR (DMSO-d6) δ 2.51 (s, 3H), 4.37 (s, 2H), 6.95 (s, 1H), 7.43 (dd, 1H), 7.96 (d, 1H1), 8.50 (d, 1H), 8.73 (s, 1H), 10.64 (bs, 1H).