Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@H:16]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([C:23]([NH:25][CH2:26][CH3:27])=[O:24])[O:17]2)=[C:9]([NH:28][CH2:29][CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]=1)=[O:6].[N:43]1([CH2:49][CH2:50][NH:51][C:52](N2C=CN=C2)=[O:53])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1.C1(C)C=CC=CC=1.C(O)(C)C>ClCCl>[C:31]1([CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:29][NH:28][C:9]2[N:8]=[C:7]([C:5]([NH:4][CH2:3][CH2:2][NH:1][C:52]([NH:51][CH2:50][CH2:49][N:43]3[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)=[O:53])=[O:6])[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[C@H:16]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([C:23]([NH:25][CH2:26][CH3:27])=[O:24])[O:17]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCN)nc32)[C@H](O)[C@@H]1O
Reactant: O=C(NCCN1CCCCC1)n1ccnc1
Solvent: ClCCl
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNC(=O)NCCN4CCCCC4)nc32)[C@H](O)[C@@H]1O
Reaction time: 4 h
Yield: 54.9 %

Procedure:
N-(2-Aminoethyl)-6-[(2,2-diphenylethyl)amino]-9-{(2R,3R,4S, 5S)-5-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-9H-purine-2-carboxamide (Preparation 10) (90 mg, 0.15 mmol) and N-[2-(1-piperidinyl)ethyl]-1H-imidazole-1-carboxamide (Preparation 18) (36 mg, 0.16 mmol) were dissolved in dichloromethane (3 ml). Toluene (4 ml) and isopropanol (1 ml) were added and the dichloromethane removed by evaporation at atmospheric pressure. The residual solution was heated under reflux for four hours. TLC analysis showed the reaction to be incomplete so further N-[2-(1-piperidinyl)ethyl]-1H-imidazole-1-carboxamide (25 mg, 0.11 mmol) was added and heating continued for four hours. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel eluting with dichloromethane:methanol concentrated aqueous ammonia (90:10:1, by volume). Product containing fractions were evaporated and the resulting solid triturated with diethyl ether, filtered and dried to afford the title compound as a white powder (60 mg).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](Br)=[CH:4][C:3]=1[S:19]([OH:22])(=[O:21])=[O:20].[NH3:23]>O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([NH2:23])=[CH:4][C:3]=1[S:19]([OH:22])(=[O:21])=[O:20]
Reactant: N
Reactant: Nc1c(S(=O)(=O)O)cc(Br)c2c1C(=O)c1ccccc1C2=O
Solvent: O
Product: Nc1cc(S(=O)(=O)O)c(N)c2c1C(=O)c1ccccc1C2=O

Procedure:
It must be described as extremely suprising that the reaction of 1-amino-4-bromo-anthraquinone-2-sulphonic acid with ammonia in water under the reaction conditions employed, under pressure, should take place so uniformly and smoothly to give 1,4-diamino-anthraquinone-2-sulphonic acid, without the formation of significant amounts of 1-amino-4-hydroxy-anthraquinone-2-sulphonic acid, as reported in German Patent Specification No. 1,142,174.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH:16]([CH3:18])[O:15][CH:14]([CH3:19])[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20].[CH3:21][C:22]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH3:27])[CH2:23][C:24](O)=[O:25]>>[CH3:18][CH:16]1[O:15][CH:14]([CH3:19])[CH2:13][N:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:20])[N:2]([NH:1][C:24](=[O:25])[CH2:23][C:22]([CH3:21])([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH3:27])[N:11]=2)[CH2:17]1
Reactant: CC1CN(c2nn(N)c(=O)c3ccccc23)CC(C)O1
Reactant: CC(C)(CC(=O)O)c1ccccc1
Product: CC1CN(c2nn(NC(=O)CC(C)(C)c3ccccc3)c(=O)c3ccccc23)CC(C)O1

Procedure:
The product from Example 60A and 3-methyl-3-phenylbutanoic acid were processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 8.30 (d, J=7.5, 1H), 8.03-7.92 (m, 2H), 7.92-7.84 (m, 1H), 7.44 (dd, J=8.4, 1.1, 2H), 7.32 (dd, J=10.5, 5.0, 2H), 7.19 (dd, J=10.4, 4.2, 1H), 3.91-3.83 (m, 2H), 3.30 (m, 2H, buried), 2.57 (s, 2H), 2.45-2.36 (m, 2H), 1.46 (s, 6H), 1.13 (d, J=6.3, 6H); MS (DCI+) M/Z 452 (M+HN4)+.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][CH:3]=1.[C:13](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)c2ccccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1ccc(F)c2ccccc12
Reaction time: 72 h
Yield: 48.4 %

Procedure:
21.7 g of 4-Fluoro-naphthalen-1-ol were dissolved in 250 mL acetone. 39.0 g of potassium carbonate and 14.6 mL dimethyl sulfate were added at room temperature. The reaction was placed under nitrogen and stirred for 72 h. The mixture was filtrated, the solid washed with acetone, and the filtrate was concentrated to a viscous oil, which was taken up in ethyl acetate. This was washed with water and with brine, dried over sodium sulfate, filtered through celite and concentrated. The resulting oil was distilled using a Kugelrohr-apparatus, yielding 11.4 g of 4-fluoro-1-methoxynaphthalene.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([Cl:23])=[CH:11][C:10]=1[C:24]1[O:28][N:27]=[C:26]([CH3:29])[C:25]=1I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:31]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)=[O:32].C(=O)([O-])O.[Na+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([Cl:23])=[CH:11][C:10]=1[C:24]1[O:28][N:27]=[C:26]([CH3:29])[C:25]=1[C:37]1[CH:38]=[C:33]([CH:34]=[CH:35][CH:36]=1)[CH:31]=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: Cc1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1cccc(C=O)c1

Procedure:
5-(2,4-Bis-benzyloxy-5-chloro-phenyl)-4-iodo-3-methyl-isoxazole (200 mg, 0.38 mmol), and 3-formylbenzene boronic acid (85 mg, 1.5 equiv.) were dissolved in DMF (12 ml) before 1M Sodium hydrogen carbonate solution (1.1 ml, 3.0 equiv) and Pd(Ph3P)2Cl2 (21 mg, 0.08 equiv.) were added with stirring. The reaction mixture was transferred to three microwave tubes which were sealed and the mixtures within degassed before being irradiated by an initial power of 200 W to a temperature of 150° C. for 15 minutes in a CEM microwave apparatus. Upon cooling the reaction mixtures were combined and partitioned between ethyl acetate (10 ml) and water (10 ml). The aqueous layer was separated and extracted again with ethyl acetate (10 ml). The organics were then combined washed with water (2×20 ml), brine (20 ml), dried over Na2SO4 before being condensed in vaccuo and purified by flash chromatography on silica gel, eluting with 25% ethyl acetate in hexane.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18].C(N(CC)CC)C.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH2:17]([N:19]([CH2:20][CH3:21])[C:14]([CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:16])[CH3:18]
Reactant: CCNCC
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)C1CCNCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 86 %

Procedure:
To a stirred solution of 1-tert-butoxycarbonylpiperidine-4-carboxylic acid (5 g, 22.0 mmol) in DMF (100 mL) was added diethyl amine (4.6 mL, 44 mmol), triethylamine (9.1 mL, 66.0 mmol), HOAt (22.0 mL, 0.5 M in DMF, 22.0 mmol) and finally EDCI (8.4 g, 44 mmol). This was allowed to stir for 14 hours at room temperature. The solvent was then removed under reduced pressure. The mixture was taken up in DCM (100 mL). The organic layer was then washed with water (100 mL), 1N HCl (100 mL), NaCl (sat.) (100 mL), dried over MgSO4 and then filtered. To the organic layer was added TFA (33 mL). The reaction was allowed to stir at room temperature for 2 hours. The solvent was then removed under reduced pressure. The mixture was taken up in DCM (100 mL). The organic layer was then washed with 1N NaOH (100 mL), water (100 mL), NaCl (sat.) (100 mL), dried over MgSO4 and then filtered. The solvent was removed under reduced pressure. The crude material was sufficiently pure to use without further purification. The title compound was obtained in 86% yield (3.5 g, 19.0 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[Cl:11][CH2:12][CH2:13][CH2:14][C:15](Cl)=[O:16].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:15](=[O:16])[CH2:14][CH2:13][CH2:12][Cl:11])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1cccc(Cl)c1Cl
Reactant: O=C(Cl)CCCCl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)CCCCl)c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2,3-Dichloroanisole (120 gm, 0.65 mole) and 4-chlorobutyryl chloride (100 gm, 0.709 mole) were dissolved in methylene chloride (425 ml) and aluminum chloride (98.8 g, 0.741) added portionwise with stirring over 30 minutes. The temperature rose to 32° C. and hydrogen chloride was evolved. After stirring for 3 hours, the mixture was poured into ice containing concentrated hydrochloric acid (80 ml). The layers were separated and the aqueous layer extracted with methylene chloride.
Reaction SMILES: C([O:3][C:4](=[O:40])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Li+].C(O)C.Cl>O>[F:39][C:36]([F:37])([F:38])[C:33]1[CH:34]=[CH:35][C:30]([C:27]2[CH:26]=[CH:25][C:24]([C:20]3[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]4[CH:11]=[CH:10][C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:40])=[O:3])=[CH:14][CH:13]=4)[N:19]=3)=[CH:29][CH:28]=2)=[CH:31][CH:32]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccc(C(F)(F)F)cc4)cc3)oc2C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1oc(-c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1

Procedure:
To a 20 mL round-bottomed flask equipped for magnetic stirring and fitted with a reflux condenser was added 2-(4-{2-[2-(4′-trifluoromethylbiphenyl-4-yl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester (0.268 mmoles), lithium hydroxide (0.535 mmoles, 0.268 mL of a 2N solution), and ethanol (5 mL). This solution was heated to reflux for 2 h. Distilled water was added to the mixture and the pH was adjusted to 3 using a 1 N HCl solution. The organic layer was extracted with ethyl acetate, washed with brine, and concentrated in-vacuo. This crude oil was re-solvated in pure ethyl acetate and filtered over a pad of Celite. The filtrate was concentrated in-vacuo, and the crude oil was crystallized using acetonitrile. The crystals were collected and dried in-vacuo affording 2-(4-{2-[2-(4′-trifluoromethylbiphenyl-4-yl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid. 1H NMR (400 MHz, CDCl3) 8.04 (2H, d), 7.92 (2H, d), 7.58 (2H, dd), 7.26 (2H, m), 6.91 (2H, d), 6.79 (2H, d), 4.17 (2H, t), 3.00 (2H, t) 2.39 (3H, s), 1.53 (6H, s).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C@H:7]([OH:9])[CH3:8])=[CH:3][CH:2]=1.[CH3:10][C:11]([OH:13])=[O:12]>CO.O=[Pt]=O>[C:11]([OH:13])(=[O:12])[CH3:10].[NH:1]1[CH2:6][CH2:5][CH:4]([C@H:7]([OH:9])[CH3:8])[CH2:3][CH2:2]1
Reactant: C[C@@H](O)c1ccncc1
Agent: O=[Pt]=O
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@H](O)C1CCNCC1
Reaction time: 8 h
Yield: 79.5 %

Procedure:
(1R)-1-(4-pyridinyl)ethanol (61 g, 495 mmol, 96% ee) was dissolved in MeOH (1.5 L). The mixture was flushed with nitrogen and AcOH (40 mL, 0.7 mol) and PtO2 (15 g) were added. The mixture was stirred overnight under an atmosphere of hydrogen. The catalyst was removed by filtration and washed with MeOH (2×100 mL) and the filtrate was concentrated. The solid residue was mixed with EtOAc (500 mL) and stirred overnight. The resulting solid was collected by filtration, washed with EtOAc (3×100 mL) and dried under vacuum overnight to yield (1R)-1-(4-piperidinyl)ethanol acetic acid salt (74.5 g, 79% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): 3.30 (m, 1H), 3.03 (m, 2H), 2.55-2.50 (m, 2H), 1.76-1.69 (m, 1H), 1.69 (s, 3H), 1.51-1.44 (m, 1H), 1.27-1.16 (m, 3H), 0.96 (d, 3H, J=6.3 Hz).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[F:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[F:17])[N:13]=[CH:12][N:11]=[C:10]2O.C(N(CC)CC)C>>[Cl:3][C:10]1[C:9]2[C:14](=[CH:15][C:16]([F:17])=[C:7]([F:6])[CH:8]=2)[N:13]=[CH:12][N:11]=1
Reactant: Oc1ncnc2cc(F)c(F)cc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: Fc1cc2ncnc(Cl)c2cc1F
Temperature: 100 °C
Yield: 87 %

Procedure:
To POCl3 (15 mL) was added 6,7-difluoro-4-hydroxyquinazoline (910 mg, 5 mmol) followed by triethylamine (700 uL, 5 mmol). The solution was then heated at 100° C. for 4 hours and concentrated in vacuo. The resulting sludge was triturated with EtOAc (2×100 mL), and the combined decanted org layers were flushed through a plug of silica gel to give 4-chloro-6,7-difluoroquinazoline (870 mg, 4.35 mmol, 87%). LC-MS (ESI) m/z 201 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4](OS(C2C=CC(C)=CC=2)(=O)=O)=[N:3]1.[CH2:22]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:23][CH2:24][C:25]#[CH:26]>CCCCCCC.C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]([F:8])([F:9])[F:10])=[CH:5][C:4]([C:26]#[C:25][CH2:24][CH2:23][CH2:22][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:3]1
Reactant: C#CCCCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(C(F)(F)F)n(C)n2)cc1
Solvent: ClCCl
Solvent: CCCCCCC
Product: Cn1nc(C#CCCCc2ccccc2)cc1C(F)(F)F

Procedure:
This product was prepared from toluene-4-sulfonic acid 1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl ester and pent-4-ynyl-benzene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/DCM 7:3; yield (86 mg, 60%); 1H NMR δ (CDCl3): 7.31-7.25 (m, 2H), 7.22-7.16 (m, 3H), 6.64 (s, 1H), 3.98 (s, 3H), 2.78 (t, J=7.44 Hz, 2H), 2.42 (t, J=7.04 Hz, 2H), 1.95 (p, J=7.33 Hz, 2H); LCMS m/z: 292.
Reaction SMILES: [ClH:1].[CH2:2]([C:7]1[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=1)[CH2:3][CH2:4][C:5]#[CH:6].[N:13]([CH2:16][C:17]([CH3:25])=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[N+:14]=[N-:15]>>[ClH:1].[CH3:25][C:17](=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][N:13]1[CH:6]=[C:5]([CH2:4][CH2:3][CH2:2][C:7]2[NH:8][C:9]([NH2:12])=[N:10][CH:11]=2)[N:15]=[N:14]1
Reactant: C#CCCCc1c[nH]c(N)n1
Reactant: CC(=Cc1ccccc1)CN=[N+]=[N-]
Agent: Cl
Product: CC(=Cc1ccccc1)Cn1cc(CCCc2cnc(N)[nH]2)nn1
Yield: 41 %

Procedure:
4-Pent-4-ynyl-1H-imidazol-2-ylamine hydrochloride (0.096 g, 0.517 mmol) was reacted with (3-Azido-2-methyl-propenyl)-benzene (0.110 g, 0.635 mmol) following the general procedure for click reactions outlined above to produce 5-{3-[1-(2-Methyl-3-phenyl-allyl)-1H-[1,2,3]triazol-4-yl]-propyl}-1H-imidazol-2-ylamine hydrochloride (0.076, 41%) as a pale yellow solid. 1H NMR (300 MHz, CD3OD) δ 7.65 (s, 1H), δ 7.14-7.04 (m, 5H), δ 6.35 (s, 1H), δ 6.28 (s, 1H), δ 4.94 (s, 2H), δ 2.57 (t, 2H), δ 2.34 (t, 2H), δ 1.75 (m, 2H), δ 1.57 (s, 3H) ppm; 13C NMR (75 MHz, CD3OD) δ 147.5, 136.9, 132.5, 129.7, 128.8, 128.6, 128.4, 128.3, 128.2, 126.9, 122.5, 109.2, 58.1, 61.9, 28.0, 24.3, 24.3, 24.1, 14.6 ppm; HRMS (ESI) calcd for C18H22N6 (M+) 323.1978. Found 323.1984.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:30][C:31]1[CH:32]=[CH:33][C:34]2[NH:35][C:36]3[C:41]([C:42]=2[CH:43]=1)=[CH:40][CH:39]=[CH:38][CH:37]=3>CC(N(C)C)=O>[CH:33]1[C:34]2[NH:35][C:36]3[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:42]=2[CH:43]=[C:31]([O:30][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:32]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCCC1
Reactant: Oc1ccc2[nH]c3ccccc3c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc4[nH]c5ccccc5c4c3)ncnc2cc1OCCCN1CCCCC1
Temperature: 85 °C
Reaction time: 3 h
Yield: 73.8 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (200 mg, 0.595 mmol), (prepared as described for the starting material in Example 67), potassium carbonate (411 mg, 2.98 mmol) and 3-hydroxycarbazole (142 mg, 0.774 mmol) in DMA (2.0 ml) was stirred at 85° C. for 3 hours then allowed to cool to ambient temperature. The reaction mixture was filtered and the filtrate evaporated to give a solid residue. The residue was purified by silica column chromatography with gradient elution using dichloromethane with 0%, 2%, 4%, 10% methanolic ammonia to give 4-(9H-carbazol-3-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline (212 mg, 74%).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[O:11][C:12]([NH:14][C:15]([CH3:29])([C:26]([OH:28])=O)[CH2:16][C:17]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=1)=[O:13])[CH2:8]2.Cl.Cl.[NH:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1[CH2:41][CH2:42][NH2:43]>C(N(CC)CC)C>[NH:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1[CH2:41][CH2:42][NH:43][C:26](=[O:28])[C:15]([NH:14][C:12](=[O:13])[O:11][CH:2]1[CH:3]2[CH2:9][CH:7]3[CH2:6][CH:5]([CH2:10][CH:1]1[CH2:8]3)[CH2:4]2)([CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[CH3:29]
Reactant: NCCc1nc2ccccc2[nH]1
Reactant: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)NCCc1nc2ccccc2[nH]1

Procedure:
Following the procedure of Example 70, the title compound was prepared from 0.50 g (1.26 mmol) of 2-adamantyloxycarbonyl-α-methyl-DL-tryptophan and 0.33 g (1.41 mmol) of 1H-benzimidazole-2-ethanamine dihydrochloride with 0.5 mL of added triethylamine. The purified product after chromatography was obtained as a white foam, 0.38 g (56%); 1H NMR (CDCl3) δ1.46-1.91 (17H, m), 3.01-3.16 (2H, m), 3.27 (1H, d, J 15 Hz), 3.43 (1H, d, J 15 Hz), 3.58 (2H, m), 4.80 (1H, br s), 5.23 (1H, s), 6.67 (1H, m), 6.89-7.72 (10H, m), 8.28 (1H, br s).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[C:26]([C:27]3[CH:32]=[CH:31][C:30]([CH2:33][NH:34][C:35](=[O:37])[CH3:36])=[CH:29][CH:28]=3)=[N:25][CH:24]=[CH:23][N:22]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[N:18]1([C:21]2[C:26]([C:27]3[CH:28]=[CH:29][C:30]([CH2:33][NH:34][C:35](=[O:37])[CH3:36])=[CH:31][CH:32]=3)=[N:25][CH:24]=[CH:23][N:22]=2)[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1
Reactant: CC(=O)NCc1ccc(-c2nccnc2N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)NCc1ccc(-c2nccnc2N2CCNCC2)cc1
Reaction time: 3 h
Yield: 92.3 %

Procedure:
Add TFA (0.6 mL, 7.94 mmol) to a solution of 3′-[4-(Acetylamino-methyl)-phenyl]-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (650 mg, 1.58 mmol) in DCM (6.5 mL) and maintain stirring for 3 hr. Concentrate material to dryness. Redissolve in DCM (10 mL) and add TFA (1.2 mL). Heat reaction mixture at 40° C. for 3 hr. Purify the mixture by SCX-2® ion exchange chromatography, eluting with 2 M NH3 in MeOH to give the title compound as a yellow oil (454 mg, 92%). 1H-NMR (400 MHz, CDCl3) δ 8.14 (d, 1H), 8.08 (d, 1H), 7.90 (d, 2H), 7.36 (d, 2H), 5.81 (bs, 1H), 4.49 (d, 2H), 3.17 (m, 4H), 2.88 (m, 4H), 2.06 (s, 3H).
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=O)(C)(C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:6][NH:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[NH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)NCCc1c[nH]c2cc(Cl)ccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCCc1c[nH]c2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Combine N-t-butoxycarbonyl-2-(6-chloro-1H-indol-3-yl)ethylamine (1.3 g, 4.41 mmol) and dry THF (20 ml) and add dropwise to an ice bath cooled suspension of LiAlH4 (1.0 g, 26.5 mmol) in dry THF (30 ml). Heat to reflux. After 2 hours, cool to ambient temperature and stir. After 15 hours, quench with saturated NaSO4 (100 ml/mol), stir for 1 hour at ambient temperature, then filter under vacuum. Wash precipitate with THF and evaporated filtrate and washes to residue. Chromatograph the residue on silica gel eluting with dichloromethane/2N NH3(methanol) (84/16) to give the title compound: MS (ACPI): m/e 209.0 (M+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([NH:16][C@H:17]3[CH2:22][CH2:21][C@H:20]([C:23]([OH:25])=[O:24])[CH2:19][CH2:18]3)(=[O:15])=[O:14])=[CH:10][CH:11]=2)[C:6]([NH:26][C:27]([NH2:29])=[NH:28])=[N:5][CH:4]=1.[H-].[Na+].Cl[C:33]1[C:42]2C(=CC=C(S(N[C@H]3CC[C@H](C(OCC)=O)CC3)(=O)=O)C=2)C(Cl)=CN=1>COCCOC.CC(N(C)C)=O>[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([NH:16][C@H:17]3[CH2:22][CH2:21][C@H:20]([C:23]([O:25][CH2:33][CH3:42])=[O:24])[CH2:19][CH2:18]3)(=[O:14])=[O:15])=[CH:10][CH:11]=2)[C:6]([NH:26][C:27]([NH2:29])=[NH:28])=[N:5][CH:4]=1
Reactant: CCOC(=O)[C@H]1CC[C@H](NS(=O)(=O)c2ccc3c(Cl)cnc(Cl)c3c2)CC1
Reactant: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)N[C@H]3CC[C@H](C(=O)O)CC3)cc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CC(=O)N(C)C
Product: CCOC(=O)[C@H]1CC[C@H](NS(=O)(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)CC1
Temperature: 60 °C

Procedure:
trans-4-{[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino}cyclohexanecarboxylic acid hydrochloride ##STR59## Guanidine hydrochloride (273 mg, 2.86 mmol) was added in one portion to a stirred suspension of NaH (55 mg, 80% dispersion by wt in mineral oil, 1.82 mmol) in DME (10 mL) and the mixture was heated at 60° C. under N2 for 30 min. A solution of ethyl trans-4-{[(1,4-dichloro-7-isoquinolinyl)sulphonyl]amino}cyclohexanecarboxylate (370 mg, 0.78 mmol) in DMA (10 mL) was added and the mixture heated at 90° C. for 3 h. The solvents were evaporated in vacuo, the residue was partitioned between Et2O (100 mL), aqueous NH4Cl (10 mL), and water (150 mL). The separated aqueous phase was extracted with Et2O (3×100 mL) and the combined organic extracts were dried (MgSO4) and evaporated in vacuo. The residue was purified by column chromatography upon silica gel using toluene-i-PrOH-0.880NH3 (100:0:0 to 90:10:0.05) as eluant to give ethyl trans-4-{[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino}cyclohexanecarboxylate (70 mg, 0.15 mmol).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[NH:15][N:14]=[N:13][C:12]=1[C:16](=[O:18])[NH2:17].O>N1C=CC=CC=1>[C:1]([NH:10][C:11]1[NH:15][N:14]=[N:13][C:12]=1[C:16](=[O:18])[NH2:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1nn[nH]c1N
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: NC(=O)c1nn[nH]c1NC(=O)c1ccccc1
Temperature: 0 °C

Procedure:
Benzoyl chloride (28 ml.) was added dropwise, under anhydrous conditions, to an ice-cooled, stirred suspension of 5-amino-4-carbamoyl-1H-1,2,3-triazole (15.24 g.) in anhydrous pyridine (240 ml.), and the reaction mixture was then stirred at room temperature for 40 hours. The mixture was poured into cold water (1,200 ml.), and the solid filtered off and washed well with water. The crude solid was heated in a large volume of boiling ethanol, and the insoluble material filtered off while still hot, to give 5-benzamido-4-carbamoyl-1H-1,2,3-triazole (20.4 g.), m.p. 301° C. (with decomposition).