Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:21])([CH3:20])[CH2:18][CH3:19])=[CH:13][C:12]=1[C:22]([CH3:26])([CH3:25])[CH2:23][CH3:24])([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:21])[CH2:18][CH3:19])=[CH:13][C:12]=1[C:22]([CH3:25])([CH3:26])[CH2:23][CH3:24]
Reactant: [H][H]
Reactant: CCC(C)(C)c1ccc(Oc2ccncc2[N+](=O)[O-])c(C(C)(C)CC)c1
Agent: [Pd]
Solvent: CCO
Product: CCC(C)(C)c1ccc(Oc2ccncc2N)c(C(C)(C)CC)c1

Procedure:
3-Nitro-4-(2,4-bis(1,1-dimethylpropyl)phenoxy)-pyridine (6.0 g, 0.017 mol) was dissolved in ethanol (50 mL) and catalytically reduced by hydrogen with Pd/C catalyst at room temperature for 2 hours. The mixture was filtered through filter-cel and the ethanol removed in vacuo to yield the pure product 3-amino-4-(2,4-bis(1,1-dimethylpropyl)phenoxy)-pyridine in 98% recovered yield. Mass spectral and NMR data were consistent with the proposed structure.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[CH2:6]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:7][CH2:8][CH2:9][CH3:10]>>[CH2:12]([N:11]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH2:2][C:1]([OH:5])=[O:4])[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCNCCCCC
Reactant: C=CC(=O)O
Product: CCCCCN(CCCCC)CCC(=O)O
Yield: 95 %

Procedure:
After completion of the reaction, acrylic acid and di-n-pentylamine were assayed by gas chromatography. As a result, formation of 69.2 g (yield 95%) of N,N-di-n-pentyl-β-alanine was confirmed, with the rates of conversion of acrylic acid and di-n-pentylamine being 95% and 95%, respectively.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].Cl[C:12]1[CH:13]=[CH:14][C:15]2[N:16]([C:18]([CH2:21][C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[N:28]=[CH:27][CH:26]=[CH:25]4)=[CH:19][N:20]=2)[N:17]=1>CN1C(=O)CCC1.CCOC(C)=O>[Cl:3][C:4]1[CH:5]=[C:6]([NH:7][C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([CH2:21][C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[N:28]=[CH:27][CH:26]=[CH:25]5)=[CH:19][N:20]=3)[N:17]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: Clc1ccc2ncc(Cc3ccc4ncccc4c3)n2n1
Reactant: Nc1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Clc1cccc(Nc2ccc3ncc(Cc4ccc5ncccc5c4)n3n2)c1
Temperature: 85 °C
Reaction time: 0.17 h

Procedure:
NaH (34 mg, 0.85 mmol) was suspended in NMP (1.5 mL) under argon. 3-Chloroaniline (108 μL, 1.017 mmol) was added and the RM was heated to 85° C. After 10 min, 6-(6-chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-quinoline (Example 14, 100 mg, 0.339 mmol) was added and the RM was stirred at 85° C. for 1 h. The mixture was then heated to 160° C. for 10 min. The mixture was diluted with EtOAc and washed with water (3×). The aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (Flashmaster) and crystallized in Et2O to afford the title compound as a yellow solid (tR 4.99 min (conditions 4), MH+=386.1, 1H-NMR in DMSO-d6: 9.57 (s, 1H); 8.82 (m, 1H); 7.93 (m, 3H); 7.86 (m, 1H); 7.71 (m, 1H); 7.56 (s, 1H); 7.47 (dd, 1H); 7.43 (m, 1H); 7.25 (t, 1H); 6.99 (m, 1H); 6.85 (d, 1H); 4.50 (s, 2H)).
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])([O-])=O.C(N(CC)CC)C.[CH3:30][O:31][CH2:32]Cl>CN(C=O)C.C(=O)([O-])O.[Na+]>[NH2:1][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:30][O:31][CH3:32])=[O:21]
Reactant: O=C(O)CCCCCCc1ccc2ccccc2c1[N+](=O)[O-]
Reactant: COCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCOC(=O)CCCCCCc1ccc2ccccc2c1N
Temperature: 25 °C
Reaction time: 20 h
Yield: 100.3 %

Procedure:
7-(1-Nitro-2-naphthyl)heptanoic acid (2 g) and triethylamine (2.02 g) were dissolved in DMF (10 ml) followed by addition of chloromethyl methyl ether (0.802 g), and the mixture was stirred at room temperature for 20 hours. This reaction mixture was diluted with cold saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated to dryness. Using the residue, 10% palladium-on-carbon (0.23 g), and ethanol (23 ml), a catalytic hydrogenation reaction was carried out at atmospheric temperature and pressure for 18 hours. The catalyst was then filtered off and the filtrate was concentrated under reduced pressure to provide methoxymethyl 7-(1-amino-2-naphthyl)heptanoate (2.1 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:12][O:13]/[N:14]=[C:15](/[C:19]2[N:20]=[C:21]([NH2:24])[S:22][CH:23]=2)\[C:16]([OH:18])=[O:17])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[OH:8].[NH2:25][C@@H:26]1[C:33](=[O:34])[N:32]2[C@@H:27]1[S:28][CH2:29][C:30]([CH2:38][S:39][C:40]1[N:41]([CH3:48])[N:42]=[C:43]([OH:47])[C:44](=[O:46])[N:45]=1)=[C:31]2[C:35]([OH:37])=[O:36].[OH-].[Na+:50]>>[Na+:50].[Na+:50].[NH2:24][C:21]1[S:22][CH:23]=[C:19](/[C:15](=[N:14]/[O:13][CH2:12][S:9]([C:4]2[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([OH:1])[CH:3]=2)(=[O:10])=[O:11])/[C:16]([NH:25][C@@H:26]2[C:33](=[O:34])[N:32]3[C@@H:27]2[S:28][CH2:29][C:30]([CH2:38][S:39][C:40]2[N:41]([CH3:48])[N:42]=[C:43]([OH:47])[C:44](=[O:46])[N:45]=2)=[C:31]3[C:35]([O-:37])=[O:36])=[O:18])[N:20]=1.[NH2:24][C:21]1[S:22][CH:23]=[C:19](/[C:15](=[N:14]/[O:13][CH2:12][S:9]([C:4]2[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([OH:1])[CH:3]=2)(=[O:10])=[O:11])/[C:16]([NH:25][C@@H:26]2[C:33](=[O:34])[N:32]3[C@@H:27]2[S:28][CH2:29][C:30]([CH2:38][S:39][C:40]2[N:41]([CH3:48])[N:42]=[C:43]([OH:47])[C:44](=[O:46])[N:45]=2)=[C:31]3[C:35]([O-:37])=[O:36])=[O:17])[N:20]=1
Reactant: Nc1nc(/C(=N/OCS(=O)(=O)c2ccc(O)c(O)c2)C(=O)O)cs1
Reactant: Cn1nc(O)c(=O)nc1SCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: [Na+]
Agent: [OH-]
Product: Cn1nc(O)c(=O)nc1SCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)/C(=N\OCS(=O)(=O)c3ccc(O)c(O)c3)c3csc(N)n3)[C@H]2SC1

Procedure:
37 mg of 2-amino-4-thiazoleglyoxylic acid (Z)-O-[[(3,4-dihydroxyphenyl)-sulphonyl]methyl] oxime were reacted with 47 mg of (6R,7R)-7-amino-3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.01oct-2-ene-2-carboxylic acid according to the procedure described in Example 5. The product fractions obtained upon chromatography on MCI gel according to the method described in Example 1 were concentrated and the pH of solution thus obtained was adjusted to 7 with dilute sodium hydroxide solution. By lyophilization, there was obtained (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[[(3,4-dihydroxyphenyl)sulphonyl]methoxy]imino]acetamido]-3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid disodium salt as a pale yellow powder.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18](B3OC(C)(C)C(C)(C)O3)[CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:32]1[C:33]2[C:38]([C:39]([Br:46])=[C:40]3[C:45]=1[CH:44]=[CH:43][CH:42]=[CH:41]3)=[CH:37][CH:36]=[CH:35][CH:34]=2.C([O-])([O-])=O.[Na+].[Na+].O>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.O1CCCC1>[Br:46][C:39]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([C:20]2[CH:21]=[C:16]([C:8]3[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=3)[CH:17]=[CH:18][CH:19]=2)=[C:45]2[C:40]=1[CH:41]=[CH:42][CH:43]=[CH:44]2
Reactant: Brc1c2ccccc2c(Br)c2ccccc12
Reactant: CC1(C)OB(c2cccc(-c3nc4ccccc4n3-c3ccccc3)c2)OC1(C)C
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: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Brc1c2ccccc2c(-c2cccc(-c3nc4ccccc4n3-c3ccccc3)c2)c2ccccc12
Temperature: 85 °C
Yield: 75.1 %

Procedure:
Compound 5 (see WO 2007046658 A1, US 20070205412 A1 and WO 2007086695 A1, which are incorporated by reference herein for their relevant teachings) was prepared as follows: a mixture of Compound 2 (5.270 g, 13.30 mmol), 9,10-dibromoanthracene (13.41 g, 39.90 mmol), tetrakis(triphenylphosphine)palladium(0) (0.922 g, 0.798 mmol), Na2CO3 (9.539 g, 90.00 mmol), H2O (90 mL) and tetrahydrofuran (THF) (150 mL) was degassed with argon for 1.5 h. while stirring. The reaction mixture was then maintained under argon at 85° C. while stirring for 46 h. Upon completion, the reaction was cooled to RT and poured over dichloromethane (about 500 mL). The soluble organics were then washed with H2O and brine, dried over MgSO4, filter and concentrated in vacuo. The crude product was purified via flash chromatography (SiO2, 100% dichloromethane) to provide Compound 5 (5.25 g, 75%) as a light yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([O:14]CC)=O.[H-].[Na+].O>C(N)CC>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([NH:5][CH2:4][CH2:3][CH3:2])=[O:14]
Reactant: CCOC(=O)c1cnc2ccccc2c1O
Agent: [H-]
Agent: [Na+]
Solvent: CCCN
Solvent: O
Product: CCCNC(=O)c1cnc2ccccc2c1O
Temperature: 50 °C
Reaction time: 16 h
Yield: 95.6 %

Procedure:
A suspension of 2.17 g of ethyl 4-hydroxy-3-quinoline-carboxylate in 20 ml of propylamine in the presence of traces of sodium hydride was refluxed and then was stirred at 50° C. for 16 hours. The mixture was pouredinto water and the suspension was vacuum filtered. The product was washed with water, dried in an oven at 100° C. and was crystallized from methanol to obtain 1.1 g of 4-hydroxy-N-propyl-3-quinoline-carboxamide melting at 210° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH3:10])[CH:9]=1)=[O:4].[Br:11]N1C(=O)CCC1=O>C1C=CC=CC=1.C(OCC)(=O)C>[Br:11][CH2:10][C:8]1[CH:9]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[S:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(C)cs1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: COC(=O)c1cc(CBr)cs1

Procedure:
A stirred mixture of 4-methyl-2-thiophenecarboxylic acid methyl ester (0.252 g) (Coll. Czechoslov. Commun. 1958, 23, 452, Synth. Commun. 1994, 24, 1721) and N-bromosuccinimide (0.287 g) in benzene (20 ml) was irradiated under a 500 W halogen lamp for 2 hours. The mixture was diluted with ethyl acetate, washed with water and dried (MgSO4). The residue was evaporated and purified by chromatography eluting with 50% ethyl acetate in isohexane. Yield 0.29 g.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:8]1[CH2:11][CH:10]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)=[O:13])[CH2:9]1.[NH:34]1CC(C(NC2C=CC(OC3CCN(C(OC(C)(C)C)=O)CC3)=CC=2)=O)C1>>[CH3:3][C:2]1[N:34]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:11][CH:10]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]3)=[CH:17][CH:16]=2)=[O:13])[CH2:9]1
Reactant: Brc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC(=O)C3CNC3)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)C3CNC3)cc2)CC1
Product: Cc1nnccc1N1CC(C(=O)Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)C1

Procedure:
The title compound was prepared as described in Example 1C, substituting 4-chloro-3-methylpyridazine for 3-bromopyridine and tert-butyl 4-(4-(azetidine-3-carboxamido)phenyl)piperidine-1-carboxylate for tert-butyl 4-(4-(azetidine-3-carboxamido)phenoxy)piperidine-1-carboxylate.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([C@H:16]4[C@H:20]([CH3:21])[CH2:19][NH:18][CH2:17]4)[NH:13][C:14](=[O:15])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:22]1[C:31]2[C:26](=[CH:27][C:28]([CH:32]=O)=[CH:29][CH:30]=2)[N:25]=[CH:24][CH:23]=1>>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([C@H:16]4[C@H:20]([CH3:21])[CH2:19][N:18]([CH2:32][C:28]5[CH:27]=[C:26]6[C:31](=[CH:30][CH:29]=5)[N:22]=[CH:23][CH:24]=[N:25]6)[CH2:17]4)[NH:13][C:14](=[O:15])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[C@@H]1CNC[C@H]1c1nc2c(cnn2C2CCCC2)c(=O)[nH]1
Reactant: O=Cc1ccc2nccnc2c1
Product: C[C@@H]1CN(Cc2ccc3nccnc3c2)C[C@H]1c1nc2c(cnn2C2CCCC2)c(=O)[nH]1

Procedure:
Following the procedure for the preparation of 1-cyclopentyl-6-[(3,4-trans)-4-methyl-1-(pyridin-3-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting 1-cyclopentyl-6-[(3S,4S)-4-methylpyrrolidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one and quinoxaline-6-carbaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 8.82 (s, 2H), 8.14 (d, J=8.3 Hz, 1H), 8.07-7.93 (m, 3H), 5.15-5.08 (m, 1H), 4.00-3.87 (m, 2H), 3.37 (t, J=8.7 Hz, 1H), 3.04 (d, J=9.5 Hz, 1H), 2.85-2.84 (m, 1H), 2.66-2.62 (m, 1H), 2.46-2.42 (m, 1H), 2.11-1.92 (m, 7H), 1.71-1.63 (m, 2H), 1.20 (d, J=7.05 Hz, 3H), MS: (M+H m/z=430.1).
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH2:3][NH:4][CH2:5][C:6]1[CH:16]=[CH:15][C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:8]=2[CH:7]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][O:28][CH:27]([C:31](O)=[O:32])[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>ClCCl>[CH2:3]([N:4]([CH2:5][C:6]1[CH:16]=[CH:15][C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:8]=2[CH:7]=1)[C:31]([CH:27]1[O:28][CH2:29][CH2:30][N:25]([C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])[CH2:26]1)=[O:32])[CH:2]([CH3:17])[CH3:1]
Reactant: CC(C)CNCc1ccc2c(c1)OCCCC2
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)CN(Cc1ccc2c(c1)OCCCC2)C(=O)C1CN(C(=O)OC(C)(C)C)CCO1
Reaction time: 8 h
Yield: 85.5 %

Procedure:
A mixture of 0.51 g (2.2 mmol) of 2-methyl-N-(2,3,4,5-tetrahydro-1-benzoxepin-8-ylmethyl)propan-1-amine, 0.51 g (2.2 mmol) of (±)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (Chem-Impex International), 0.59 g (4.4 mmol) of 1-hydroxybenzotriazole hydrate, 0.84 g (4.4 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 0.71 mL (5.1 mmol) of triethylamine in 15 mL in dichloromethane was stirred overnight. The mixture was concentrated under reduced pressure, partitioned between 90 mL of ethyl acetate and 30 mL of saturated sodium bicarbonate, and the layers were separated. The organic layer was washed with 30 mL each of water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow oil. Purification by flash chromatography (10-70% ethyl acetate in hexanes) gave 0.84 g (86%) of product as a solid white foam. MS (m+1)=447.4; H NMR (400 MHz, CDCl3) 7.09 (m, 1H), 6.8 (m, 2H), 4.7 (m, 1H), 4.44 (d, 1H, J 17 Hz), 4.2-3.8 (m, 6H), 3.50 (m, 1H), 3.21 (m, 2H), 3.02 (m, 2H), 2.79 (m, 2H), 1.96 (m, 3H), 1.72 (m, 2H), 1.45 (d, 9H, J 13 Hz), 0.85 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][NH2:20])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[OH:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]2[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]2)=[CH:24][CH:23]=1.FC(F)(F)C(O)=O.C([BH3-])#N.[Na+]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][NH:20][CH:31]2[CH2:30][CH2:29][CH:28]([C:25]4[CH:26]=[CH:27][C:22]([OH:21])=[CH:23][CH:24]=4)[CH2:33][CH2:32]2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: O=C1CCC(c2ccc(O)cc2)CC1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccccc3c2CCN)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Cc1cc(C)cc(-c2[nH]c3ccccc3c2CCNC2CCC(c3ccc(O)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 2-[2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethylamine (EXAMPLE 2, Step D, 345 mg) and 4-(4-hydroxyphenyl)cyclohexanone (62 mg) were solvated in 8 mL dry methanol to which ca. 2 g powdered 3 Å molecular sieves were added. The pH of this mixture was adjusted to 6 by the addition of 0.65 mL of a 10% solution of trifluoroacetic acid in methanol and then 90 mg sodium cyanoborohydride was added and the mixture stirred at room temperature. After 20 hours, the mixture was filtered through diatomaceous earth, concentrated in vacuo and purified by flash chromatography on silica gel [(methylene chloride:methanol:, 92:8) then again (chloroform:methanol, 90:10) to separate the diastereomers] to give the title compound (isomer A 40 mg, isomer B 36 mg). m/e=439 (M+H)
Reaction SMILES: C([Cl:4])(=O)C.[O:5]=[C:6]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[CH2:7][NH:8]C(=O)OC(C)(C)C>CO>[Cl-:4].[Cl-:4].[NH3+:8][CH2:7][C:6]([C:16]1[CH:21]=[CH:20][NH+:19]=[CH:18][CH:17]=1)=[O:5]
Reactant: CC(C)(C)OC(=O)NCC(=O)c1ccncc1
Reactant: CC(=O)Cl
Solvent: CO
Product: [Cl-]
Product: [NH3+]CC(=O)c1cc[nH+]cc1
Reaction time: 0.25 h
Yield: 95.7 %

Procedure:
Dry MeOH (10 mL) was treated with acetyl chloride (1.8 mL, 25 mmol) at 0° C. under nitrogen. The solution was allowed at room temperature and stirred for 15 minutes before being added to a chilled (ice bath) solution of tert-butyl [2-oxo-2-(pyridin-4-yl)ethyl]carbamate (785 mg, 3.0 mmol) in dry MeOH (10 mL). The resulting yellow solution was allowed at room temperature and stirred for 4 hours and then concentrated in vacuo to give the crude 4-(ammonioacetyl)pyridinium dichloride as a yellow solid (600 mg, yield 96%). The material was carried through without purification. 1H-NMR (400 MHz, d6-DMSO): δ 7.35 (t, 1H, 50.8 Hz), 8.01-8.05 (m, 2H), 8.60 (br s, 2H), 8.93-8.97 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][CH2:10][CH2:11]Cl)=[CH:4][CH:3]=1.[NH:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:21]=[C:22]([NH:26][C:27]([CH:29]3[CH2:31][CH2:30]3)=[O:28])[CH:23]=[CH:24][CH:25]=2)[CH2:16][CH2:15]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][CH2:10][CH2:11][N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:21]=[C:22]([NH:26][C:27]([CH:29]4[CH2:30][CH2:31]4)=[O:28])[CH:23]=[CH:24][CH:25]=3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1
Reactant: O=C(CCCCl)c1ccc(Br)cc1
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Product: O=C(CCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1)c1ccc(Br)cc1

Procedure:
Prepared by Procedure K and Scheme B using 1-(4-bromophenyl)-4-chloro-1-butanone and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 469.1 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11](=[O:21])[CH:12]=[CH:13][NH:14]2)C1C=CC=CC=1.[H][H].C(Cl)(Cl)[Cl:25]>CO.[C].[Pd]>[ClH:25].[OH:8][C:9]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11](=[O:21])[CH:12]=[CH:13][NH:14]2
Reactant: COc1ccc2[nH]ccc(=O)c2c1OCc1ccccc1
Reactant: ClC(Cl)Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1ccc2[nH]ccc(=O)c2c1O
Product: Cl

Procedure:
In a mixed solvent of methanol (9 ml) and chloroform (1 ml) was dissolved 5-benzyloxy-6-methoxy-4(1H)-quinolone (120 mg). To this solution was added 10% palladium-carbon (50 mg), and the mixture was stirred under a stream of hydrogen at room temperature for 2 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The crude product thus obtained was recrystallized from chloroform-methanol-n-hexane to obtain 5-hydroxy-6-methoxy-4(1H)-quinolone hydrochloride (a salt of compound 1, 73 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH:11]1[CH2:14][CH2:13][CH2:12]1.[H-].[Na+].Br[CH:18]([CH3:20])[CH3:19]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:18]([CH3:20])[CH3:19])[N:6]=[C:5]2[CH:11]1[CH2:14][CH2:13][CH2:12]1
Reactant: Brc1ccc2[nH]nc(C3CCC3)c2c1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Product: CC(C)n1nc(C2CCC2)c2cc(Br)ccc21
Yield: 69.7 %

Procedure:
The title compound was prepared by the method outlined for Preparative Example 59 using 5-bromo-3-cyclobutyl-1H-indazole intermediate (1.05 g, 4.16 mmol), NaH (211 mg, 5.26 mmol), and 2-bromopropane (667 mg, 5.42 mmol) to afford titled compound as a light yellow oil (850 mg, 70%). 1H NMR (CDCl3) 7.86 (s, 1H), 7.37 (d, J=8.8, 1H), 7.27 (d, J=8.8, 1H), 4.75 (m, 1H), 3.88 (pent, J=8.4, 1H), 2.55-2.43 (m, 4H), 2.15-2.05 (m, 1H), 2.01 (m, 1H), 1.57 (d, J=6.8, 6H). LC/MS (Method B) 4.72 min, [M+1]+ 293/295.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[NH2:30][CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][N:33]1[CH2:37][CH2:38][CH3:39]>C(Cl)(Cl)Cl.O>[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20]([NH:30][CH2:31][CH:32]4[CH2:36][CH2:35][CH2:34][N:33]4[CH2:37][CH2:38][CH3:39])(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1
Reactant: CCCN1CCCC1CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCN1CCCC1CNS(=O)(=O)c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1
Temperature: 25 °C
Yield: 28 %

Procedure:
4-(7-Chloro-4-quinolinylamino)benzenesulphonyl chloride hydrochloride (5.4 g, 0.014 mol) was added portionwise to a well-stirred two phase mixture of chloroform/water (140 ml/140 ml) containing sodium carbonate (14.8 g) and 2-aminomethyl-1-propylpyrrolidine (2.0 g, 0.014 mol) at about 10° C. The mixture was allowed to warm to room temperature, then stirred for 11/2 hours. The chloroform layer was separated, dried (MgSO4) and evaporated under reduced pressure to give a gum. The gum was crystallised from ethanol/water to give a pale yellow solid (1.8 g). A further recrystallisation from ethanol gave the title compound (0.5 g), melting point 192.5°-194° C.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C@H:10]2[CH2:15][CH2:14][C@@H:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[C:4]=1I)[CH3:2].[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25]>>[CH2:1]([C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C@H:10]2[CH2:15][CH2:14][C@@H:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[C:4]=1[C:28]#[C:27][Si:24]([CH3:26])([CH3:25])[CH3:23])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CCc1ncnc(N[C@H]2CC[C@@H](c3ccccc3)CC2)c1I
Product: CCc1ncnc(N[C@H]2CC[C@@H](c3ccccc3)CC2)c1C#C[Si](C)(C)C

Procedure:
Prepared as in Example 7 from 6-ethyl-5-iodo-4-(cis-4-phenylcyclohexylamino)pyrimidine (Example 8) and trimethylsilylacetylene (colorless solid).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][C:7](C)(C)[CH2:8][CH2:9][C:10]=2[CH:11]=1.[Li]CCCC.[CH3:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(#N)C1C=CC=CC=1.[ClH:33].C1C[O:37][CH2:36]C1>>[ClH:33].[C:36]([CH:6]1[C:5]2[N:4]=[CH:3][C:2]([CH3:1])=[CH:11][C:10]=2[CH2:9][CH2:8][CH2:7]1)(=[O:37])[C:21]1[CH:20]=[CH:19][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cnc2c(c1)CCC(C)(C)C2
Reactant: C1CCOC1
Reactant: CCCCCC
Agent: Cl
Agent: [Li]CCCC
Solvent: N#Cc1ccccc1
Product: Cc1cnc2c(c1)CCCC2C(=O)c1ccccc1
Reaction time: 0.25 h

Procedure:
To a solution of 5,6,7,8-tetrahydro-3-methylquinoline (3g) in THF (20ml) at 0° C under nitrogen was added 1.7 molar n-BuLi/hexane solution (12ml) followed by benzonitrile (2ml). The mixture was stirred at ambient temperature 1/2h then 2N HCl was added and the mixture was stirred a further 15 min. The aqueous layer was separated and washed with ether then basified and extracted with chloroform. The extracts were dried (MgSO4) and evaporated. The product was purified by chromatography, first on fluorisil with chloroform and them on silica with 2% MeOH/CHCl3 as eluant. The product was converted into the hydrochloride in propan-2-ol with a Et2O/HCl solution and allowed to crystallise to give 8-benzoyl-5,6,7,8-tetrahydro-3-methylquinoline hydrochloride (1.5g) m.p. 137°-40° C. (Found: C, 70.7; H, 6.5; N, 4.8. C17H17NO.HCl requires C, 70.95; H, 6.3; N, 4.9%.