Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)=[CH:5][CH:4]=1.[CH3:19][C@H:20]1[NH:25][C@@H:24]([CH3:26])[CH2:23][N:22]([C:27]([C:29]2[C:30]([CH3:37])=[C:31]([CH:35]=O)[NH:32][C:33]=2[CH3:34])=[O:28])[CH2:21]1>C(O)C.N1CCCCC1>[CH3:19][C@H:20]1[NH:25][C@@H:24]([CH3:26])[CH2:23][N:22]([C:27]([C:29]2[C:30]([CH3:37])=[C:31]([CH:35]=[C:11]3[C:10]4[C:14](=[CH:15][CH:16]=[CH:17][C:9]=4[C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[NH:13][C:12]3=[O:18])[NH:32][C:33]=2[CH3:34])=[O:28])[CH2:21]1
Reactant: COc1ccc(-c2cccc3c2CC(=O)N3)cc1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1C[C@@H](C)N[C@@H](C)C1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc(-c2cccc3c2C(=Cc2[nH]c(C)c(C(=O)N4C[C@@H](C)N[C@@H](C)C4)c2C)C(=O)N3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.6 %

Procedure:
To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (68.5 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-[4-[(cis)-3,5-Dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (88 mg, 73%).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].C(N(CC)CC)C.[C:16](Cl)(=O)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C(Cl)Cl>[CH2:17]([C:16]1[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=1)[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: Nc1ccccc1N
Reactant: CCCCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCc1nc2ccccc2[nH]1
Yield: 46.6 %

Procedure:
To a solution of 0-phenylenediamine (2.2 g) and triethylamine (2.0 g) in methylene chloride (20 ml) was added dropwise caproyl chloride (2.3 g) with stirring under ice-cooling. The mixture was stirred for 3 hours at room temperature, washed with a saturated aqueous sodium bicarbonate and water, then dried. The solvent was evaporated. To the residue was added 3N-HCl, and the mixture was heated for 1.5 hour under reflux. The reaction mixture was made basic with 6N NaOH. Then precipitating crystals were recrystallized from ethyl acetate-hexane to give colorless needles (1.5 g, 47%), m.p. 161°-162° C.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[C:8]([C:17]([NH:19][C:20]3C=C(C=CC=3)C(O)=O)=[O:18])=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:4]([O:31][CH3:32])[CH:3]=1.FC1C=CC(OC2C(C(O)=O)=NC3C(N=2)=CC=CC=3)=C(OC)C=1.NC1[S:58][CH:59]=[C:60]([C:62]([O:64]CC)=[O:63])[N:61]=1>>[F:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[C:8]([C:17]([NH:19][C:20]3[S:58][CH:59]=[C:60]([C:62]([OH:64])=[O:63])[N:61]=3)=[O:18])=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:4]([O:31][CH3:32])[CH:3]=1
Reactant: COc1cc(F)ccc1Oc1nc2ccccc2nc1C(=O)Nc1cccc(C(=O)O)c1
Reactant: CCOC(=O)c1csc(N)n1
Agent: COc1cc(F)ccc1Oc1nc2ccccc2nc1C(=O)O
Product: COc1cc(F)ccc1Oc1nc2ccccc2nc1C(=O)Nc1nc(C(=O)O)cs1

Procedure:
2-(3-(4-Fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamido)thiazole-4-carboxylic acid (37) was prepared using a similar experimental procedure as described above for cmpd (36) from 3-(4-fluoro-2-methoxy-phenoxy)quinoxaline-2-carboxylic acid and ethyl 2-aminothiazole-4-carboxylate.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][N:6]2[CH:12]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[N:21]1[CH2:22][CH2:23][N:24]([CH2:2][C:3]2[N:4]=[C:5]3[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][N:6]3[CH:12]=2)[CH2:25][CH2:26]1
Reactant: Clc1ccc(N2CCNCC2)c(Cl)c1
Reactant: Cc1cccn2cc(CCl)nc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cccn2cc(CN3CCN(c4ccc(Cl)cc4Cl)CC3)nc12
Temperature: 75 °C

Procedure:
A mixture of 2-(chloromethyl)-8-methylimidazo[1,2-a]pyridine (Example 54, Step 1; 0.294 g), 1-(2,4-dichlorophenyl)piperazine (Example 31, Step 1; 0.396 g) diisopropylethylamine (0.35 mL), and THF (2 mL) is heated at 75° C. for 5 hours. The mixture is then concentrated under reduced pressure, partitioned between saturated aq. sodium bicarbonate and dichloromethane, and the combined organic layers are dried with MgSO4 and concentrated under reduced pressure. The residue is chromatographed on silica gel using methanol/dichloromethane (4/96) and the appropriate fractions are combined and concentrated to give 2-[[4-(2,4-dichlorophenyl)-1-piperazinyl]methyl]-8-methylimidazo[1,2-a]pyridine. The maleic acid salt is formed by adding maleic acid (0.101 g) to the product dissolved in dichloromethane/methanol. Crystallization from dichloromethane/ether gives 0.2192 g of the title compound; mp 151-152° C.; MS m/z 374, 376; IR (mineral oil) 1482, 1345, 1570, 1357, 867 cm-1 ; 1H NMR (CDCl3) δ2.61, 2.80, 3.09, 3.85, 6.67, 6.95, 7.18, 7.35, 7.56, 7.95.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:11][C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=2[F:20])[CH:4]=1.[C:21]1([CH2:27][C:28]([N:30]=[C:31]=[S:32])=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[CH3:1][S:2][C:3]1[S:11][C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:31]([NH:30][C:28](=[O:29])[CH2:27][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[S:32])=[CH:15][C:14]=2[F:20])[CH:4]=1
Reactant: CSc1cc2nccc(Oc3ccc(N)cc3F)c2s1
Reactant: O=C(Cc1ccccc1)N=C=S
Solvent: C1CCOC1
Product: CSc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2s1
Reaction time: 3 h
Yield: 26 %

Procedure:
To a suspension of 231 (61 mg) in THF (2 mL) was added 2-phenylacetyl isothiocyanate (42 mg, 0,199 mmol). The reaction mixture was stirred for 3 hours, concentrated under reduced pressure and the residue was purified by column chromatography, eluent EtOAc/hexane (35:65), to produce yellow oil. Purification of this material by preparative HPLC (column C-18 Aquasil, gradient: 60% MeOH to 95% MeOH) afforded title compound 232a (25 mg, 26% yield) as a cream solid. Characterization of 232a is provided in the table 22.
Reaction SMILES: [H-].C[O:3]CCO[Al+]OCCOC.[Na+].[H-].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][CH:23]2[CH2:25][CH2:24]2)=[C:18]([Cl:26])[CH:17]=1.CO.[OH2:29]>O1CCCC1>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH:23]2[CH2:24][CH2:25]2)(=[O:3])=[O:29])=[C:18]([Cl:26])[CH:17]=1
Reactant: O
Reactant: COCCO[Al+]OCCOC
Reactant: Clc1cc(Br)ccc1SC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=S(=O)(c1ccc(Br)cc1Cl)C1CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Oxone(R) (20.3 g) was added to a solution of 4-bromo-2-chloro-1-(cyclopropylsulfanyl)benzene obtained in Reference Example 5-22 (964 mg) in tetrahydrofuran (20 mL)-methanol (20 mL)-water (10 mL), and the mixture was stirred at room temperature for one day. Oxone(R) (6.8 g) was further added and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform only) to give the title compound as a pale yellow amorphous (597 mg, 55%).
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1.CCN(CC)CC.Br[CH2:21][C:22]([O:24][CH3:25])=[O:23]>CC#N>[OH:12][C:8]1[CH:7]=[C:6]([C:5]2[N:4]=[N:3][N:2]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[N:1]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)CBr
Reactant: Oc1cccc(-c2nn[nH]n2)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)Cn1nnc(-c2cccc(O)c2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(2H-tetrazol-5-yl)phenol (250.8 mg, 1.547 mmol) in MeCN (10 mL) at rt was added Et3N (0.237 mL, 1.701 mmol) followed by methyl bromoacetate (260 mg, 1.701 mmol). The reaction was stirred at rt for 16 h. Volatiles were removed. Chromatography over silica eluting with 30-60% EtOAc/hexanes afforded the title compound as a white solid. 1H NMR (500 MHz, CDC13): δ 7.75 (d, 1H, J=7.5 Hz), 7.69 (s, 1H), 7.39 (t, 1H, J=8.0 Hz), 7.01 (dd, 1H, J=8.0, 2.3 Hz), 5.53 (bs, 1H), 5.50 (s, 2H), 3.86 (s, 3H).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH:11]2[CH2:13][CH2:12]2)[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.[C:22](O)(=[O:26])[C@H:23]([CH3:25])[OH:24].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.Cl.CN(C)CCCN=C=NCC>O1CCCC1>[CH:11]1([CH2:10][N:7]2[C:8](=[O:9])[C@@H:2]([NH:1][C:22](=[O:26])[C@@H:23]([OH:24])[CH3:25])[C:3]3[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=3[C:5]3[CH:17]=[CH:16][CH:15]=[CH:14][C:6]2=3)[CH2:13][CH2:12]1
Reactant: N[C@@H]1C(=O)N(CC2CC2)c2ccccc2-c2ccccc21
Reactant: C[C@H](O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[C@H](O)C(=O)N[C@@H]1C(=O)N(CC2CC2)c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
A solution of 0.47 g (1.69 mmol) (S)-7-amino-5-cyclopropylmethyl-5H,7H-dibenzo[b,d]azepin-6-one in 15 ml tetrahydrofurane was treated at 0° C. with 0.17 g (1.86 mmol) L-lactic acid, 0.26 g (1.69 mmol) 1-hydroxybenzotriazole hydrate, 590 μl (3.38 mmol) N-ethyldiisopropylamine and 0.33 g (1.69 mmol) N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimid-hydrochlorid. After stirring at room temperature overnight the mixture was extracted with 1N aqueous hydrochloric acid/ethylacetate. Purification by chromatography on silicagel with ethylacetate/cyclohexane (0-100/100-0) yielded 0.50 g (84%) (S)—N—((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-hydroxy-propionamide as white solid; MS: m/e: 351.4 (M+H+), [α] 589=−131° (1% in MeOH).
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([OH:3])=O.[NH2:13][C@@H:14]([C:18]([N:20]1[CH2:25][CH2:24][CH:23]([CH:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)[CH2:22][CH2:21]1)=[O:19])[CH:15]([CH3:17])[CH3:16].C(P(=O)(OCC)OCC)#N>C(Cl)Cl>[NH3:10].[NH:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([C:1]([NH:13][C@@H:14]([C:18]([N:20]3[CH2:25][CH2:24][CH:23]([CH:26]4[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]4)[CH2:22][CH2:21]3)=[O:19])[CH:15]([CH3:16])[CH3:17])=[O:3])[CH:12]=2)[CH:8]=[CH:9]1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: CC(C)[C@@H](N)C(=O)N1CCC(C2CCN(C)CC2)CC1
Agent: CCOP(=O)(C#N)OCC
Solvent: ClCCl
Product: CC(C)[C@@H](NC(=O)c1ccc2cc[nH]c2c1)C(=O)N1CCC(C2CCN(C)CC2)CC1
Product: N
Temperature: -15 °C
Reaction time: 2 h
Yield: 184.2 %

Procedure:
6-Carboxyindole (4.0 g, 24.8 mmol) and 1-(D-valinyl)-4-(1-methylpiperidin-4-yl)piperidine (10.1 g, 27.8 mmol) are slurried in anhydrous CH2Cl2 (250 mL) and cooled to −15° C. To this slurry is added diethyl cyanophosphonate (4.5 mL, 29.8 mmol), followed by TEA (11.1 mL, 79.4 mmol) maintaining the temperature below −10° C. The reaction is allowed to warm to room temperature overnight. The following morning, if TLC indicates starting material still present, additional 6-carboxyindole (0.5 g, 3.1 mmol) and diethyl cyanophosphonate (0.5 mL, 3.3 mmol) are added, followed by TEA (1.0 mL, 7.2 mmol). After stirring for an additional 2 h, the reaction is quenched with the addition of brine (100 mL), forming an insoluble brown oil on the sides of the flask. The layers are separated and the aqueous layer is extracted with CH2Cl2 (3×100 mL). The organic layers are combined, dried over Na2SO4, filtered and concentrated. The crude material is then purified using chromatography over silica gel, with 5% (2 M NH3 in MeOH)/CHCl3 as the eluent, to give 9.7 g (92%) of the title compound as a light yellow foam.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[C:12]([CH3:22])[C:11]2=[O:23])[CH2:4][CH2:3]1.[O:24]=[C:25]1[CH2:30][O:29][C:28]2[CH:31]=[CH:32][C:33]([CH:35]=O)=[N:34][C:27]=2[NH:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:21][O:20][C:17]1[CH:18]=[C:19]2[C:14]([N:13]=[C:12]([CH3:22])[C:11](=[O:23])[N:10]2[CH2:9][CH2:8][N:5]2[CH2:4][CH2:3][CH:2]([NH:1][CH2:35][C:33]3[CH:32]=[CH:31][C:28]4[O:29][CH2:30][C:25](=[O:24])[NH:26][C:27]=4[N:34]=3)[CH2:7][CH2:6]2)=[CH:15][CH:16]=1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: COc1ccc2nc(C)c(=O)n(CCN3CCC(N)CC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: COc1ccc2nc(C)c(=O)n(CCN3CCC(NCc4ccc5c(n4)NC(=O)CO5)CC3)c2c1
Yield: 69.7 %

Procedure:
1-[2-(4-Aminopiperidin-1-yl)ethyl]-7-methoxy-3-methylquinoxalin-2(1H)-one (Intermediate 159, 75 mg, 0.24 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (42 mg, 0.24 mmol), and sodium triacetoxy borohydride (150 mg, 0.72 mmol) were reacted as described according to Example 69 to give 80 mg (73% yield) of the free base of the product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[C:12](Cl)(=O)[C:13](Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-].C=C>C(Cl)Cl.CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[CH2:8][C:9](=[O:11])[CH2:13][CH2:12]2
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: O=C(Cl)C(=O)Cl
Agent: C=C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1CCc2cc(Br)ccc2C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 88.5 %

Procedure:
A single neck 3 liter round bottom flask under an Ar atmosphere was charged with 4-bromobenzeneacetic acid (250.0 g, 1.15 mol), methylene chloride (1.5 L) and dimethylformamide (0.5 mL). This magnetically stirred solution was cooled to 0° C. and treated dropwise with oxalyl chloride (156 mL, 1.74 mol). The reaction was allowed to reach room temperature and stirred 16 h. The reaction was concentrated on a rotary evaporator to approximately 1 L of volume. A separate dry 5 liter 3 neck round bottom flask under Ar, fitted with gas inlet tube, overhead stirrer, and digital thermometer was charged with methylene chloride (1.5 L) and AlCl3 (312.0 g, 2.34 mol). This suspension was cooled to 0° C. and stirred while the above solution of acid chloride was added to it slowly via cannula. When the addition was complete, ethylene gas was introduced for 1-2 h. to the vigorously stirred suspension while maintaining the internal temperature at 15° C. Upon completion by HPLC, the reaction was warmed to room temperature and stirred for 0.5 h. The mixture was recooled to 0° C. and cautiously quenched slowly with water (1.5 L). The layers were separated, and the aqueous one washed with methylene chloride (500 mL). The organic portion was washed with 2N aqueous HCl (2×800 mL), brine (400 mL), and saturated aqueous NaHCO3 (2×800 mL). Each aqueous extract was washed with the same 500 mL methylene chloride extract from above. The methylene chloride extracts were combined, dried (Na2SO4), filtered, and concentrated to approximately 500 mL of volume. This was then added to 5.0 L of hexane warmed to 50° C. The methylene chloride was distilled off and the hot solution decanted from an insoluble brown tar. The solution was allowed to cool to 25° C. and placed in the freezer overnight. The precipitate was collected and washed with hexane (200 mL), and dried in vacuo to give 229.0 g of 6-bromo-3,4-dihydro-2(1H)-napthalenone as a pale yellow solid (88%).
Reaction SMILES: N.[K].[C:3]1([CH3:11])[C:4]([C:9]#[N:10])=[CH:5][CH:6]=[CH:7][CH:8]=1.[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)#[N:13]>O.O1CCCC1>[NH2:10][C:9]1[C:4]2[C:3](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:13]=1
Reactant: N#Cc1ccccn1
Reactant: Cc1ccccc1C#N
Agent: N
Agent: [K]
Solvent: C1CCOC1
Solvent: O
Product: Nc1nc(-c2ccccn2)cc2ccccc12
Reaction time: 8 h
Yield: 24.8 %

Procedure:
To 250 ml. of liquid ammonia under a nitrogen atmosphere are added 7.5 g. (0.19 gram atom) of potassium in small portions and a few crystals of ferric nitrate. When all the potassium has been converted into the amide (i.e. when the blue color disappears), 11.1 g. (0.095 mole) of o-toluonitrile in 30 ml. of anhydrous tetrahydrofuran are added, upon which the solution immediately takes on a red color. 19.8 g. (0.19 mole) of 2-cyanopyridine in 100 ml. of anhydrous tetrahydrofuran are then added. The mixture is left standing overnight and then decomposed with water. The tetrahydrofuran is evaporated and the residue is extracted with chloroform. The extract is washed with water, dried with magnesium sulphate and the solvent is removed by evaporation. The residue is purified by sublimation. 5.2 g. of 1-amino-3-(2-pyridyl)isoquinoline are obtained. Yield 24.8%, m.p. 152°-153° C. The base is dissolved in diethyl ether and an etheral hydrogen chloride solution is added. The precipitate formed is filtered off and crystallised from ethanol (96%) to yield the monohydrochloride, m.p. 266° C., (with decomposition). 0.95 g. (4.30 mmol) of the base and 2.44 g. (17.2 mmol) of methyl iodide, dissolved in 20 ml of acetone are heated at 43° C under a nitrogen atmosphere for 4 days. The solvent is distilled off and the residue is crystallised from methanol. 1-Amino-3-(2-pyridyl)isoquinoline methyliodide is obtained. Melting point 206° C with decomposition.
Reaction SMILES: [OH:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:15])[CH:3]=1.[C:16](=O)([O-])[O-].[K+].[K+].O.C(O[CH2:27][CH3:28])(=O)C>CN(C)C=O.C1OCCOCCOCCOCCOCCOC1>[CH3:15][C:4]1[CH:3]=[C:2]([O:1][CH2:16][CH:27]=[CH2:28])[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(O)cc1C
Reactant: CCOC(C)=O
Reactant: O=C([O-])[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1cc(C)c(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 4-hydroxy-2-methyl-5-nitrobenzoate (6.3 g) in N,N-dimethyl-formamide (150 ml) were added at room temperature 18-crown-6 (79 mg) and potassium carbonate (8.3 g), and the mixture was stirred at 80° C. for one hour. The mixture was cooled to room temperature, and to the reaction solution were added water and ethyl acetate, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (7.5 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[F:15].Br[CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][N:8]2[CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:4][C:3]=1[F:15]
Reactant: COC(=O)c1c[nH]c2cc(Br)c(F)cc12
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cn(C2CCCC2)c2cc(Br)c(F)cc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
A mixture of methyl 6-bromo-5-fluoro-1H-indole-3-carboxylate (9.0 g, 33 mmol), bromocyclopentane (5.3 mL, 49.6 mmol) and Cs2CO3 (21.5 g, 66 mmol) in DMF (40 mL) was stirred at 80° C. overnight. The mixture was then poured into ice water, filtered and washed with water. The solid was collected and dried to give methyl 6-bromo-1-cyclopentyl-5-fluoro-1H-indole-3-carboxylate (10.3 g, yield 91%), which was used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8](OC)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].O.[NH2:15][NH2:16]>CCO>[N+:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([NH:15][NH2:16])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NN
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 4-nitrobenzoate (5.42 g; 29.92 mmol; 1 eq.) is dissolved in EtOH (120 ml). Hydrazine hydrate (7.27 ml; 149.60 mmol; 5 eq.) is added and the mixture is stirred 1 hour at rt. It is stirred at 60° C. for 6 hours and rt overnight. The precipitate formed is filtrated and dried under vacuo, affording 4-nitrobenzohydrazide as white-off solid (4.31 g; 79%). 1H NMR (DMSO-d6) δ: 4.63 (s, 2H), 8.03 (d, J=9 Hz, 2H), 8.23 (d, J=9 Hz, 2H), 10.12 (s, 1H). HPLC (method A), Rt: 0.78 min (purity: 100.0%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.C([O-])([O-])=O.[K+].[K+].[CH2:18]([NH:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH3:21]>CS(C)=O.O>[CH2:18]([N:22]([CH2:23][CH2:24][CH2:25][CH3:26])[C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[F:1])[CH2:19][CH2:20][CH3:21]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: CCCCNCCCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCN(CCCC)c1ccc([N+](=O)[O-])cc1F
Temperature: 90 °C
Yield: 75.1 %

Procedure:
To a solution of 3,4-difluoronitrobenzene (3.18 g, 20 mmol) in DMSO (25 mL) were added K2CO3 (6.08 g, 44 mmol) and di-n-butylamine (2.84 g, 22 mmol) with stirring. The mixture was heated at 90° C. overnight, then cooled to rt, diluted with water (100 mL) and extracted with CH2Cl2 (80 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/CH2Cl2 (V/V)=10:1) to give the title compound as yellow oil (4.03 g, 75%).
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([S:14](Cl)(=[O:16])=[O:15])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2].[CH3:18][NH2:19]>>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([S:14](=[O:16])(=[O:15])[NH:19][CH3:18])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2ccc(S(=O)(=O)Cl)cc2C1
Reactant: CN
Product: CNS(=O)(=O)c1ccc2c(c1)CN(C(C)=O)CC2

Procedure:
2-Acetyl-7-chlorosulfonyl-1,2,3,4-tetrahydroisoquinoline was reacted with a concentrated aqueous solution of methylamine with cooling. The resulting solid was filtered and washed with water to give 2-acetyl-7-methylsulfamoyl-1,2,3,4-tetrahydroisoquinoline. Hydrolyzing in refluxing 10% hydrochloric acid by the procedure of Example 15 and then recrystallizing from methanol/ether gave 7-methylsulfamoyl-1,2,3,4-tetrahydroisoquinoline hydrochloride, m.p. 238°-240° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[CH:17]=1.ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[CH2:36]([NH2:40])[CH2:37][CH2:38][CH3:39].CO>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:36]([NH:40][C:28]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][N:7]=2)=[CH:17][C:18]=1[CH3:23])=[O:34])[CH2:37][CH2:38][CH3:39]
Reactant: CCCCN
Reactant: COc1cc2ncnc(Oc3ccc(N)c(C)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-methylaniline (50 mg) was dissolved in chloroform (3 ml) and triethylamine (0.2 ml), and a solution of triphosgene (48 mg) in chloroform was then added to the solution. The mixture was stirred at room temperature for 30 min. Next, butylamine (24 μl) was added to the reaction solution, and the mixture was further stirred at room temperature overnight. Methanol was added to the reaction solution, and the mixture was purified by HPLC by development with chloroform/methanol to give 37 mg (yield 56%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:9][CH:10]([C:16](=O)[CH3:17])[C:11](OCC)=[O:12]>>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:3]=1[N:4]=[C:16]([CH3:17])[C:10]([CH3:9])=[C:11]2[OH:12]
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: Nc1ccccc1Cl
Product: Cc1nc2c(Cl)cccc2c(O)c1C

Procedure:
Prepared according to R using 2-chloroaniline (1.28 mL, 10 mmol) and ethyl 2-methyl-3-oxobutanoate (2.89 g, 20 mmol) in PPA (4 g, 40 mmol). The resulting precipitate was collected by filtration, washed with water, and dried to give 8-chloro-2,3-dimethylquinolin-4-ol as an off white solid. Mass Spectrum (ESI) m/e=208 (M+1).