Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([C:12]([NH:14][CH2:15][CH3:16])=O)[CH2:11][CH2:10]CC=1.[CH3:17][CH2:18]OCC>>[CH:16]1([CH2:15][NH:14][CH2:12][CH:7]2[CH2:11][CH2:10]2)[CH2:18][CH2:17]1
Reactant: CCNC(=O)C1=CCCC1
Reactant: CCOCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: C1CC1CNCC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a suspension of lithium aluminum hydride (1.3 g, 9.35 mmol) in 10 mL dry ether, a solution of N-cyclopentenoyl-ethylamine (1.7 g, 13.3 mmol) in dry ether (10 mL) was added under a nitrogen atmosphere. This reaction was stirred at RT for 8 h and the reaction mixture was then quenched with saturated sodium sulfate solution, filtered, and the precipitate was washed with diethyl ether. The filtrate was concentrated to afford the title amine (0.8 g), yield: 69%.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[N+:6]([C:9]1[N:14]=[CH:13][C:12]([C:15](=O)[CH2:16][NH:17]C(=O)C)=[CH:11][CH:10]=1)([O-:8])=[O:7].[OH-].[K+]>CO>[NH2:4][C:3]1[NH:17][CH:16]=[C:15]([C:12]2[CH:13]=[N:14][C:9]([N+:6]([O-:8])=[O:7])=[CH:10][CH:11]=2)[C:2]=1[C:1]#[N:5]
Reactant: CC(=O)NCC(=O)c1ccc([N+](=O)[O-])nc1
Reactant: N#CCC#N
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1c(-c2ccc([N+](=O)[O-])nc2)c[nH]c1N
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 83.8 %

Procedure:
0.022 g (0.336 mmol) of malononitrile is added at a temperature in the region of 20° C., under an argon atmosphere, to 0.050 g (0.224 mmol) of N-[2-(6-nitropyridin-3-yl)-2-oxoethyl]acetamide in solution in 5 cm3 of methanol. The reaction medium is cooled to a temperature in the region of 0° C. and then 0.1 cm3 of a 50% aqueous potassium hydroxide solution is added. After stirring for 15 minutes at a temperature in the region of 20° C. and then for 1.15 hours at a temperature in the region of 65° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) and then diluted in 50 cm3 of ethyl acetate. The organic phase is washed with 10 cm3 of water and 10 cm3 of a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 0.043 g of 2-amino-4-(6-nitropyridin-3-yl)-1H-pyrrole-3-carbonitrile in the form of a brown solid. ES+: m/z=230 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10](Cl)=[O:11])[CH2:7]1.[CH3:16][NH2:17]>O1CCCC1.O>[CH3:16][NH:17][C:10]([N:8]1[CH2:9][CH:6]([O:5][C:4]2[CH:13]=[CH:14][CH:15]=[C:2]([CH3:1])[CH:3]=2)[CH2:7]1)=[O:11]
Reactant: CN
Reactant: Cc1cccc(OC2CN(C(=O)Cl)C2)c1
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)N1CC(Oc2cccc(C)c2)C1
Temperature: -78 °C
Reaction time: 17 h
Yield: 18.2 %

Procedure:
A stirred solution of 3.92 g (0.01 mole) of 3-(3-methylphenoxy)-1-azetidinecarbonyl chloride in 15 ml of tetrahydrofuran was treated with 2.4 g (0.03 mole) of 40% aqueous monomethylamine and stirring continued for 17 hr. The reaction mixture was diluted with 200 ml of water. The reddish oil residue was cooled to -78° C. whereupon it crystallized (4.28 g). Recrystallization from benzene-ligroin gave 400 mg of fine white crystals, m.p. 143°-144° C. Addition of more ligroin yielded an additional 800 mg of "cream" colored crystalline product, m.p. 138°-142° C. The two fractions were combined and recrystallized from ethanol-isopropyl ether, yielding 600 mg (27.3%) of fine white crystals, m.p. 143°-144° C.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][N:3]1[C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1.[C:21]([NH:24][C@H:25]([C:28]([OH:30])=[O:29])[CH2:26][SH:27])(=[O:23])[CH3:22]>>[C:21]([NH:24][CH:25]([CH2:26][S:27][S:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:2](=[O:1])[NH:3][C:11]1[CH:16]=[CH:15][C:14]([S:17](=[O:19])(=[O:18])[NH2:20])=[CH:13][CH:12]=1)[C:28]([OH:30])=[O:29])(=[O:23])[CH3:22]
Reactant: CC(=O)N[C@@H](CS)C(=O)O
Reactant: NS(=O)(=O)c1ccc(-n2sc3ccccc3c2=O)cc1
Product: CC(=O)NC(CSSc1ccccc1C(=O)Nc1ccc(S(N)(=O)=O)cc1)C(=O)O
Yield: 81.6 %

Procedure:
This compound was prepared according to the method of Example 132 using 0.8 g (2.4 mmol) of 4-(3-oxo-3H-benzo[d]isothiazol-2-yl)benzenesulfonamide and 0.39 g (2.4 mmol) of N-acetyl-L-cysteine. The product was washed with ether and dried in vacuo to give 0.92 g of the title compound, mp 218°-220° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-])=O)=[CH:12][CH:13]=2)[C:8](=[O:18])[CH2:7]1)=[O:5])[CH3:2].[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([CH:6]1[C:14]2[C:9](=[CH:10][C:11]([NH2:15])=[CH:12][CH:13]=2)[C:8](=[O:18])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CC(=O)c2cc([N+](=O)[O-])ccc21
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1CC(=O)c2cc(N)ccc21
Temperature: 25 °C

Procedure:
(R/S)-5-Nitro-3-oxo-indan-1-carboxylic acid ethyl ester (3 g, 12 mmol) (Gadient, Fulvio; Suess, Rudolf. Indane carboxylic acids, DE 2505447) is added portionwise over 5 minutes to a stirred suspension of tin (II) chloride (13.9 g, 60.2 mmol) in ethanol (50 mL) at rt under nitrogen. The reaction is then refluxed for 30 min, cooled to rt, poured into ice water and the pH adjusted to 9 with 1M sodium hydroxide. The mixture is extracted with diethyl ether and then washed with brine, dried and concentrated in vacuo to give (R/S)-5-amino-3-oxo-indan-1-carboxylic acid ethyl ester as a light yellow solid. Title compound: ES-MS: 219.96 [M+H]+; tR=0.8 min (System 2).
Reaction SMILES: [CH2:1]([N:5]([CH2:18][CH2:19][CH2:20][CH3:21])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH:14]=O)=[C:8]([O:16][CH3:17])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:22]([C:24]1[C:25](=[C:40]([C:43]#[N:44])[C:41]#[N:42])[O:26][C:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:30]([F:33])([F:32])[F:31])[C:28]=1[CH3:29])#[N:23]>C(O)C>[CH2:1]([N:5]([CH2:18][CH2:19][CH2:20][CH3:21])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH:14]=[CH:29][C:28]2[C:27]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)([C:30]([F:33])([F:31])[F:32])[O:26][C:25](=[C:40]([C:43]#[N:44])[C:41]#[N:42])[C:24]=2[C:22]#[N:23])=[C:8]([O:16][CH3:17])[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)c1ccc(C=CC=O)c(OC)c1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(c1ccccc1)C(F)(F)F
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=CC=CC2=C(C#N)C(=C(C#N)C#N)OC2(c2ccccc2)C(F)(F)F)c(OC)c1
Temperature: 50 °C
Yield: 86.7 %

Procedure:
In 5 ml of ethanol were dissolved 130 mg (0.45 mmol) of 3-(4-dibutylamino-2-methoxyphenyl)propenal and 156 mg (0.50 mmol) of 2-(3-cyano-4-methyl-5-phenyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile. After the mixture was stirred with heating at 50° C. for 2 hours, the solvent was evaporated off. The residue was purified by silica gel column chromatography to give 229 mg of a dark greenish brown crystal (yield: 86.9%; mp: 190-192° C.)
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Br)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[F:15][C:16]([F:25])([F:24])[CH2:17][CH2:18][CH:19]([C:22]#[N:23])[C:20]#[N:21]>CN(C)C=O>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][C:19]([CH2:18][CH2:17][C:16]([F:15])([F:24])[F:25])([C:20]#[N:21])[C:22]#[N:23])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CC(C#N)(C#N)CCC(F)(F)F)cc1
Yield: 44.8 %

Procedure:
Using 0.23 g of 4-t-butylbenzyl bromide, 3 ml of N,N-dimethylformamide, 0.05 g of sodium hydride (60% in oil), and 0.17 g of (3,3,3-trifluoropropyl)malononitrile, and according to the process described in the Production Example 26, there was obtained 0.14 g of 2-(4-t-butylbenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (33)).
Reaction SMILES: CN(C)C=O.Cl[CH2:7][CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([O:20][C:21]3[C:22]([CH3:31])=[N:23][C:24]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].[NH:40]1[CH:44]=[CH:43][N:42]=[CH:41]1>O>[N:40]1([CH2:7][CH2:8][O:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14]([O:20][C:21]4[C:22]([CH3:31])=[N:23][C:24]5[C:29]([CH:30]=4)=[CH:28][CH:27]=[CH:26][CH:25]=5)=[CH:15][CH:16]=[N:17]3)=[CH:12][C:11]=2[O:32][CH3:33])[CH:44]=[CH:43][N:42]=[CH:41]1
Reactant: c1c[nH]cn1
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCn1ccnc1
Temperature: 80 °C
Reaction time: 72 h
Yield: 57.4 %

Procedure:
N,N-Dimethylformamide (1.5 ml) was added to 7-(2-chloro-ethoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline (compound 353) (50 mg), potassium carbonate (53 mg), and imidazole (26 mg), and the mixture was stirred at 80° C. for 3 days. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (31 mg, yield 57%).
Reaction SMILES: [SH:1][C:2]1[N:6]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1.[CH3:19][O:20][C:21](=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28]Br)[CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:11]([O:10][C:8](=[O:9])[CH2:7][N:6]1[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=[C:2]1[S:1][CH2:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([O:20][CH3:19])=[O:30])[CH:23]=1)([CH3:13])([CH3:14])[CH3:12]
Reactant: CC(C)(C)OC(=O)Cn1c(S)nc2ccccc21
Reactant: COC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(CSc2nc3ccccc3n2CC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 75.2 %

Procedure:
A mixture of tert-butyl (2-mercapto-benzoimidazol-1-yl)-acetate (Intermediate 3-1,264 mg, 1 mmol), 3-bromomethyl-benzoic acid methyl ester (252 mg, 1.1 mmol) and K2CO3 (276 mg, 2 mmol) in acetone (4 ml) is allowed to stir at rt for 2.5 h. The suspension is cooled down to rt and filtered on a funnel filled with cotton wool. Evaporation of the solvent in vacuo affords a residue that is purified by flash-chromatography on silica-gel (AcOEt/heptane, 1:3), yielding the title compound (310 mg) in 75% as a colourless syrup: tR=7.19 min (LC-1), ESI-MS (pos.): m/z 413.3 [M+H]+; 1H-NMR (CDCl3): δ (ppm) 1.42 (s, 9H, tBu), 3.92 (s, 3H, OMe), 4.65 (s, 2H), 4.69 (s, 1H), 7.19-7.26 (m, 3Harom), 7.36 (t, 1Harom), 7.59 (d, 1Harom), 7.73 (m, 1 Harom), 7.92 (d, 1Harom), 8.06 (s, 1Harom).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[NH:12][NH2:13].[C:14](Cl)(=O)[CH2:15][CH2:16][CH3:17].C(N(CC)CC)C>ClCCl>[CH2:15]([C:14]1[N:6]2[CH:5]=[CH:4][C:3]3[C:8]([C:7]2=[N:12][N:13]=1)=[CH:9][CH:10]=[CH:11][C:2]=3[Br:1])[CH2:16][CH3:17]
Reactant: CCCC(=O)Cl
Reactant: NNc1nccc2c(Br)cccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1nnc2c3cccc(Br)c3ccn12

Procedure:
A mixture of 5-bromo-1-hydrazinoisoquinoline (4.76 g., 0.02 mol.) and butyryl chloride (2.1 ml., 0.02 mol.) in dichloromethane (100 ml.) was allowed to reflux overnight. The solvent was removed in vacuo and the residue was heated at reflux for three hours in xylene (100 ml.) and triethylamine (2.8 ml., 0.02 mol.). The mixture was filtered and the xylene removed in vacuo to provide the crude product. Recrystallization from ethanol (≈100 ml.) gave the pure product, 4.4 g. (76%); m.p. 197°-199°C., m.p. (hydrochloride salt) 200°-201°C.
Reaction SMILES: CN(C=O)C.[NH2:6][C:7]1[C:12]2=[CH:13][C:14]([CH2:16][OH:17])=[CH:15][N:11]2[N:10]=[CH:9][N:8]=1.[Cl-].[CH2:19]=[N+:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>CO>[NH2:6][C:7]1[C:12]2=[CH:13][C:14]([CH2:16][OH:17])=[C:15]([CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:11]2[N:10]=[CH:9][N:8]=1
Reactant: Nc1ncnn2cc(CO)cc12
Reactant: C=[N+]1CCOCC1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1ncnn2c(CN3CCOCC3)c(CO)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of DMF (50 mL) was added (4-aminopyrrolo[2,1-f][1,2,4]triazin-6-yl)methanol (550 mg, 3.35 mmol) and 4-methylenemorpholin-4-ium chloride (Eur. J. Med. Chem. 1989, 24, 379-384) (636 mg, 4.69 mmol). The solution was stirred at rt for 1 h and then the solvent was evaporated. The oil was triturated with CH2Cl2 and a white solid was collected. The free based was obtained by stirring over a Dowex 66 solid support resin in MeOH. The material was filtered and evaporated yielding 794 mg (90%) of the desired product as a white solid. MS [M+H]+=264; LCMS RT=1.07.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[S:11][CH:10]=[C:9]([CH:12]=O)[CH:8]=1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[N:3]1[CH:4]=[CH:5][CH:6]=[N:1][C:2]=1[C:7]1[S:11][CH:10]=[C:9](/[CH:12]=[CH:22]/[CH:23]=[O:24])[CH:8]=1
Reactant: O=Cc1csc(-c2ncccn2)c1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=C/C=C/c1csc(-c2ncccn2)c1

Procedure:
The title compound is prepared by a procedure analogous to Reference Example 30 by substituting 5-(2-pyrimidinyl)-3-thiophenecarboxaldehyde (prepared as described in Reference Example 93) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 217 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15](S(C)(=O)=O)[C:14]([F:21])=[CH:13][N:12]=3)=[CH:9][N:8]([S:22]([C:25]3[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:5]2=[N:6][CH:7]=1.[NH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH:35]([OH:39])[CH2:34]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:32][CH:33]4[CH2:38][CH2:37][CH2:36][C@H:35]([OH:39])[CH2:34]4)[C:14]([F:21])=[CH:13][N:12]=3)=[CH:9][N:8]([S:22]([C:25]3[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)(=O)=O)n3)c3cc(Cl)cnc32)cc1
Reactant: NC1CCCC(O)C1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4CCC[C@H](O)C4)n3)c3cc(Cl)cnc32)cc1
Temperature: 130 °C

Procedure:
To a solution of 5-chloro-3-(5-fluoro-4-(methylsulfonyl)pyrimidin-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine, 1a, (1.09 g, 2.34 mmol) and 3-aminocyclohexanol (0.32 g, 2.82 mmol) in THF was added DIEA (0.60 g, 4.69 mmol). The reaction mixture was heated at 130° C. in microwave for 10 min. The solvent was removed under reduced pressure and the resulting residue was purified by silica gel chromatography to afford 550 mg of the desired product, 27a.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=3)[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[H][H]>O=[Pt]=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:14][CH2:15][N:16]([C:19]3[CH:20]=[C:21]([C:29]([F:30])([F:31])[F:32])[CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=3)[CH2:17][CH2:18]2)(=[O:11])=[O:12])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCN(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)cc1
Agent: O=[Pt]=O
Product: Nc1ccc(S(=O)(=O)N2CCN(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)cc1

Procedure:
In the manner given in Example 5B, 1-[(p-nitrophenyl)sulfonyl]-4-[3,5-di(trifluoromethyl)-phenyl]piperazine is reduced with hydrogen over PtO2 to give 1-[(p-aminophenyl)sulfonyl]-4-[3,5-di(trifluoromethyl)phenyl]piperazine.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6](B(O)O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:13][O:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22]Br)[CH:17]=1.C1COCC1.C([O-])([O-])=O.[K+].[K+]>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.O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:22][C:18]3[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=3)[C:15]([O:14][CH3:13])=[O:24])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cccc(Cc2ccc3[nH]ccc3c2)c1
Temperature: 80 °C
Yield: 48 %

Procedure:
Indole-5-boronic acid, 193 mg (1.2 mmol) and methyl-3-(bromomethyl)benzoate, 230 mg (1.0 mmol) were added into a 100 ml round-bottomed flask containing 15 ml THF, then 50 mg Pd(PPh3)4 was added, followed by 2 ml 2M K2CO3. The mixture was stirred and heated to 80° C. under N2 protection for over 4 hours. The reaction was monitored by TLC. After the reaction was completed and the mixture was cooled to room temperature, 10 ml H2O was added and the product extracted with ethyl acetate (15 ml×3). The organic solvent was combined and dried with anhydrous Na2SO4, filtered and evaporated to dryness. The crude product was purified by chromatographic column using hexane:ethyl acetate (7:1) as eluent. 260 mg methyl 3-(1H-indol-5-ylmethyl)benzoate was obtained as a pale yellow solid, yield 48%. Saponification of the ester yielded the target compound, 8.2 mg target compound was obtained as a grey powder. Mass calculated for C16H13NO2: 251; LCMS: 252.6 (M+H)+; 1HNMR (400 MHz, DMSO-d6) δ ppm 7.78 (1H, s), 7.74 (1H, d, J=7.9 Hz), 7.50 (1H, d, J=7.3 Hz), 7.38 (2H, m), 7.29 (2H, m), 6.95 (1H, dd, J=8.5 Hz, J=1.2 Hz), 6.35 (1H, s), 4.05 (2H, s).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:16]([O:17][CH3:18])=[CH:15][C:14]([OH:19])=[CH:13][C:11]=3[CH:12]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl.[OH-].[Na+].Cl.[C:28]([O-])(O)=[O:29].[Na+]>CN(C=O)C>[OH:19][C:14]1[C:13]([CH:28]=[O:29])=[C:11]2[CH:12]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)[O:9][C:10]2=[C:16]([O:17][CH3:18])[CH:15]=1
Reactant: O=C([O-])O
Reactant: COc1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc(O)c(C=O)c2cc(-c3ccc(O)cc3)oc12

Procedure:
A solution of 62 (0.25 g, 1.0 mmol) in DMF (20 mL) was treated with POCl3 (1 mL, 11 mmol) and heated at 80° C.–100° C. for 15 minutes. The reaction mixture was worked up by allowing to cool and then poured into crushed ice. 2N NaOH aq was added and the solution stirred for several minutes and then the mixture was acidified with 2N HCl aq and then neutralized with NaHCO3 aq. The mixture was then extracted with EtOAc and washed with brine, dried over MgSO4, filtered, concentrated and chromatographed on silica gel (2:8 to 4:6 EtoAc/hexanes) to yield a solid which still contained some starting material, but that was purified by trituration with EtOAc to yield 47 mg the desired pdt as a white solid: Mp=254–255° C.; 1H NMR (DMSO-d6) δ 10.29 (s, 1 H), 10.0 (br s, 1 H), 7.73 (d, 2 H, J=8.7 Hz), 7.59 (s, 1 H), 6.88 (d, 2 H, J=8.7 Hz), 6.46 (s, 1 H), 4.00 (s, 3 H); MS 281 (M−H)−.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][C:14]([NH2:19])=[CH:15][C:16]=3[C:17]=2[N:18]=1)=[O:5])C.[BrH:20]>CS(C)=O>[NH2:19][C:14]1[CH:13]=[CH:12][C:11]2[NH:10][C:9]3[CH:8]=[N:7][C:6]([C:4]([OH:3])=[O:5])=[N:18][C:17]=3[C:16]=2[C:15]=1[Br:20]
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(N)cc3c2n1
Reactant: Br
Solvent: CS(C)=O
Product: Nc1ccc2[nH]c3cnc(C(=O)O)nc3c2c1Br
Reaction time: 2 h

Procedure:
One gram of 8-amino-5H-pyrimido[5,4-b]indole-2-carboxylic acid ethyl ester (Example 11) is combined with such an amount of dimethyl sulfoxide that a clear solution is produced. Then, at 0°-5° C., the same amount of 48% aqueous hydrobromic acid is added dropwise and the mixture stirred thereafter for another 2 hours at this temperature, thus obtaining the ethyl ester of 8-amino-9-bromo-5H-pyrimido[5,4-b]indole-2-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][NH2:10])[C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[N:3]=1.[NH2:15][C:16](=[O:29])[CH2:17][C:18]1[CH:28]=[CH:27][C:21]([O:22][CH2:23][CH:24]2[O:26][CH2:25]2)=[CH:20][CH:19]=1>CO>[NH2:15][C:16](=[O:29])[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:22][CH2:23][CH:24]([OH:26])[CH2:25][NH:10][CH2:9][CH2:8][CH2:7][N:6]2[C:5]3[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=3[N:3]=[C:2]2[CH3:1])=[CH:27][CH:28]=1
Reactant: NC(=O)Cc1ccc(OCC2CO2)cc1
Reactant: Cc1nc2ccccc2n1CCCN
Solvent: CO
Product: Cc1nc2ccccc2n1CCCNCC(O)COc1ccc(CC(N)=O)cc1

Procedure:
A mixture of 4.16 grams of 2-methyl-1H-benzimidazole-1-propanamine and 4.56 grams of 1-[4-(2-amino-2-oxoethyl)phenoxy]-2,3-epoxypropane in 50 ml of 90% methanol was refluxed for 22 hours. The solvent was then evaporated to leave a thick oil which was chromatographed on a silica gel column using methanol. The fractions containing the desired product were determined by thin-layer chromatography and combined. The solvent was evaporated to leave a thick oily residue which solidified partially on standing. This was recrystallized from ethanol to give N-{3-[4-(2-amino-2-oxoethyl)phenoxy]-2-hydroxypropyl}-2-methyl-1H-benzimidazole-1-propanamine melting at about 146°-149° C. This compound has the following structural formula: ##STR14##
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1Br.C(O[C:16]([S-:18])=[S:17])C.[K+].O>CN1CCCC1=O>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:16]([SH:18])[S:17][C:3]=2[CH:4]=1
Reactant: CCOC(=S)[S-]
Reactant: Nc1ccc(C(F)(F)F)cc1Br
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: FC(F)(F)c1ccc2nc(S)sc2c1
Temperature: 160 °C
Reaction time: 3 h
Yield: 25.8 %

Procedure:
4-Amino-3-bromobenzotrifluoride (2.40 g) was dissolved in N-methyl-2-pyrrolidone (10 mL), and potassium ethylxanthate (3.52 g) was added thereto. The mixture was stirred at 160° C. for 3 hr with heating. Water (300 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and brine, and concentrated under reduced pressure to give 6-trifluoromethyl-2-mercaptobenzothiazole (607 mg) as an orange powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.Cl[C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+]>>[O:12]=[C:8]1[CH2:7][CH2:6][CH2:5][C:4]2[CH:3]=[C:2]([O:1][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=3)[CH:11]=[CH:10][C:9]1=2
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: O=C1CCCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCCC3=O)nc1
Yield: 72.1 %

Procedure:
Using a method similar to Intermediate 1, using 6-hydroxy-1-tetralone (5.00 g, 30.8 mmol), 6-chloronicotinamide (4.38 g, 28.0 mmol) and K2CO3 (5.81 g, 42.0 mmol) gives the title compound (5.7 g) as a yellow solid. Mass spectrum (ion spray): m/z=283 (M+1); 1HNMR (DMSO-d6): 8.63 (s, 1H), 8.29 (d, 1H), 8.06 (s, 1H), 7.90 (d, 1H), 7.51 (s, 1H), 7.16 (d, 1H), 7.12 (s, 1H), 7.09 (d, 1H), 2.92 (t, 2H), 2.58 (t, 2H), 2.03 (m, 2H).