Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH3:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4][N:3]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[BH4-].[Na+]>>[CH3:16][NH:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:6]2[CH2:7][CH2:2][N:3]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:4][CH2:5]2)=[CH:10][CH:11]=1
Reactant: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Agent: [BH4-]
Agent: [Na+]
Product: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 50 °C

Procedure:
The title compound was prepared from D11 using a method similar to that described for D3 in Description 3A although the reaction was heated at 50° C. overnight prior to addition of sodium borohydride and no column chromatography was required. δH (CDCl3, 400 MHz) 7.11 (2H, d), 6.57 (2H, d), 3.69 (1H, br.s), 3.40 (6H, m), 2.83 (3H, s), 2.36 (4H, m), 1.45 (9H, s) [δ values corrected for incorrectly referenced TMS at 0.58 ppm on spectrum]. MS (ES+): 206.2, no molecular ion (MH+) observed.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:13])[CH2:4][N:5]1[CH:10]([CH3:11])[CH2:9][CH2:8][CH2:7][CH:6]1[CH3:12].[CH3:14][O:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:12][CH:6]1[CH2:7][CH2:8][CH2:9][CH:10]([CH3:11])[N:5]1[CH2:4][CH:3]([OH:13])[CH2:2][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[O:18][CH2:17][CH2:16][O:15][CH3:14]
Reactant: CC1CCCC(C)N1CC(O)CCl
Reactant: COCCOc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCCOc1ccccc1OCC(O)CN1C(C)CCCC1C
Reaction time: 20 h
Yield: 67.4 %

Procedure:
4.5 g of 1-chloro-3-(2,6-dimethylpiperidino)-2-propanol is added to a mixture of 3.4 g of 2-(2-methoxyethoxy)phenol, 2.8 g of anhydrous potassium carbonate and 70 ml of acetone, and the resulting mixture is refluxed with stirring for 20 hours. The insoluble matter is then filtered off, and the filtrate is concentrated under reduced pressure. To the residue is added ether, and the ethereal solution is extracted with two 80 ml portions of 10% hydrochloric acid. The aqueous layer is made alkaline with sodium hyroxide, and the separated oil is extracted twice with ether. The ether layer is dried over anhydrous potassium carbonate, and the ether is removed to give 4.6 g of 1-(2,6-dimethylpiperidino)-3-[2-(2-methoxyethoxy)phenoxy]-2-propanol, melting at 92°-94°C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([CH:16]4[CH2:18][CH2:17]4)[N:13]([CH3:19])[C:12]=3[CH:20]=2)[C:4](=[O:21])[CH:3]=1.[F:22][C:23]([F:32])([F:31])[C:24]1[S:28][CH:27]=[C:26]([CH2:29][OH:30])[CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>O>[CH:16]1([C:14]2[N:13]([CH3:19])[C:12]3[CH:20]=[C:8]([N:5]4[CH:6]=[CH:7][C:2]([O:30][CH2:29][C:26]5[CH:25]=[C:24]([C:23]([F:32])([F:22])[F:31])[S:28][CH:27]=5)=[CH:3][C:4]4=[O:21])[CH:9]=[CH:10][C:11]=3[N:15]=2)[CH2:18][CH2:17]1
Reactant: OCc1csc(C(F)(F)F)c1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(Cl)cc3=O)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4csc(C(F)(F)F)c4)cc3=O)cc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 21.7 %

Procedure:
A mixture of 4-chloro-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (800 mg), (5-(trifluoromethyl)-3-thienyl)methanol (972 mg), cesium carbonate (2.61 g) and DMF (8 ml) was stirred at 80° C. overnight. The mixture was poured into water and extracted with EtOAc-THF. The extract was washed with brine, dried over MgSO4, concentrated and purified by NH silica gel column chromatography (hexane/EtOAc). The resulting solid was recrystallized from EtOH-water to give the title compound (258 mg) as a white solid.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:27]([OH:29])=O)[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].O[N:31]=[C:32]([NH2:34])[CH3:33]>>[CH3:33][C:32]1[N:34]=[C:27]([CH:13]2[CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:16][N:11]([C:9]([N:6]3[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]3)=[O:10])[CH2:12]2)[O:29][N:31]=1
Reactant: CC(N)=NO
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CC1
Product: Cc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCC(C#N)CC3)C2)n1

Procedure:
100 mg (0.244 mmol) of 1-[(4-cyanopiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 100A) and 19.9 mg (0.269 mmol) of N′-hydroxyethanimidamide were reacted according to the General Method 1. Yield: 55.5 mg (47% of theory).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:14]([O:21][C:22](Cl)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+].O>CC(C)=O>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:22]([O:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:23])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 2 h
Yield: 32.1 %

Procedure:
To 15 g of BOC-piperazine (80.6 mmol) dissolved in acetone (50 ml) was added in alternating portions benzylchloroformate (11.5 ml, 80.6 mmol) and 1N NaOH (15 ml) keeping the pH at 8-8.5 and the temperature 0°-5° C. After 2 hours, starting material was still present (tlc) and an additional quantity of benzylchloroformate (5 ml) and 1N NaOH (5 ml) was added. The reaction mixture was aged at 5° C. overnight and at room temperature an additional 7 hours. Water was added and the mixture extracted with ethyl acetate (3×50 ml), dried with Na2SO4 and concentrated to 21 g of an oil. This oil was dissolved in 10 ml of ethyl acetate, passed through 40 ml of silica gel and eluted with 200 ml of ethylacetate. Crystallization was effected by trituration with petroleum ether and the crystals collected, affording 8.28 g (32%) of N-t-butoxycarbonyl-N'-benzyloxycarbonylpiperazine, m.p. 90.5°-91.5° C.
Reaction SMILES: [CH:1]12[CH2:8][CH2:7]C[CH:5]1[CH2:4]C(=O)[O:2]2.[H-].C([Al+]C[CH:17]([CH3:19])[CH3:18])C(C)C>C1(C)C=CC=CC=1>[CH3:4][CH2:5][CH:1]([OH:2])[CH2:8][CH2:7][CH2:19][CH2:17][CH3:18]
Reactant: CC(C)C[Al+]CC(C)C
Reactant: O=C1CC2CCCC2O1
Agent: [H-]
Solvent: Cc1ccccc1
Product: CCCCCC(O)CC

Procedure:
The compound (52) (12.1 g) was reduced with diisobutylaluminum hydride (1.5M, 65.1 ml) in toluene (500 ml) at -78° C. and the obtained crude product was subjected to silicagel column chromatography to give the titled compound (53). Yield: 11.1 g (91%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C:13]([F:23])([CH:16](OS(C)(=O)=O)[CH3:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C)C=O.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C:13]([CH:16]([N:24]=[N+:25]=[N-:26])[CH3:17])([F:23])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(OS(C)(=O)=O)C1(F)CCN(C(=O)OCc2ccccc2)C1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(N=[N+]=[N-])C1(F)CCN(C(=O)OCc2ccccc2)C1
Temperature: 120 °C
Yield: 76 %

Procedure:
To a solution of 3-fluoro-3-(1-methanesulfonyloxyethyl)pyrrolidine-1-carboxylic acid benzyl ester (Example A15, 0.25 g, 0.72 mmol) in N,N-dimethylformamide (5 mL) is added sodium azide (0.13 g, 2 mmol). The reaction mixture is heated at 120° C. overnight. The mixture is diluted with water and extracted with ethyl acetate. The extracts are washed with brine, dried over Na2SO4 and concentrated to afford the title compound (0.160 g). 1H NMR (200 MHz, CDCl3): δ 7.28 (s, 5H), 5.08 (s, 2H), 3.80-3.25 (m, 5H), 2.13-1.75 (m, 2H), 1.40 (d, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH:12]([CH3:14])[CH3:13])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH:35]=[C:34](OS(C(F)(F)F)(=O)=O)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.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>[C:24]([O:28][C:29]([N:31]1[CH2:32][CH:33]=[C:34]([C:3]2[CH:4]=[C:5]([O:11][CH:12]([CH3:13])[CH3:14])[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[CH3:1])[CH2:35][CH2:36]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: Cc1cc([N+](=O)[O-])c(OC(C)C)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
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: [Cs+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc([N+](=O)[O-])c(OC(C)C)cc1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C

Procedure:
To a solution of 2-methyl-4-nitro-5-isopropoxy-phenylboronic acid pinacol ester (2.04 g, 6.4 mmol) and 4-Trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (3.2 g, 9.6 mmol) in 110 mL of DME/H2O (10:1 V/V) is added Pd(PPh3)4 (365 mg, 0.32 mmol) and Cs2CO3 (4.2 g, 12.8 mmol). The reaction mixture is heated under N2 at 80° C. overnight. After cooling to room temperature, the reaction is filtered through Celite and the filtrate is diluted with 100 mL of EtOAc, sequentially washed with H2O, brine, and finally concentrated in vacuo. The crude product is purified by silica gel flash chromatography (5%-15% EtOAc in Hexanes as eluent) to afford 4-(5-Isopropoxy-2-methyl-4-nitro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as a yellow oil. 1H NMR (CD3OD, 400 Mz): 7.59 (s, 1H), 6.96 (s, 1H), 5.67 (broad s, 1H), 4.73 (m, 1H), 4.06 (m, 2H), 3.65 (m, 2H), 2.37 (m, 2H), 2.25 (s, 3H), 1.50 (s, 9H), 1.33 (d, J=6.0 Hz, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][C:8]1[CH:24]=[CH:23][C:11]([O:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[C:10]([C:25]#[N:26])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>N.CO.[Ni]>[NH2:26][CH2:25][C:10]1[CH:9]=[C:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:27])[CH:24]=[CH:23][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=1
Reactant: COC(=O)c1ccc(Oc2ccc(CC(=O)OC(C)(C)C)cc2C#N)cc1
Agent: [Ni]
Agent: N
Solvent: CO
Product: COC(=O)c1ccc(Oc2ccc(CC(=O)OC(C)(C)C)cc2CN)cc1
Reaction time: 8 h
Yield: 62.8 %

Procedure:
To a stirred solution of the methyl 4-(4-(2-tert-butoxy-2-oxoethyl)-2-cyanophenoxy)benzoate (1.086 mg, 2.96 mmol) in 7N ammonia/methanol (30 ml) under nitrogen was added Raney Nickel (25.3 mg, 0.296 mmol). The reaction was purged with a hydrogen balloon and stirred under hydrogen overnight. The reaction was filtered through GF paper and the solid catalyst was rinsed with methanol and ethyl acetate. The filtrate was concentrated, and the crude product was purified by silica gel chromatography to give methyl 4-(2-(aminomethyl)-4-(2-tert-butoxy-2-oxoethyl)phenoxy)benzoate (0.69 g).
Reaction SMILES: C(N1C2C(=O)[N:11]([CH2:15][C:16]3[CH:21]=[CH:20][C:19](C#N)=[CH:18][CH:17]=3)C([Cl:24])=NC=2N=C1N1CCCC(NC(=O)OC(C)(C)C)C1)C#CC.Cl.[NH2:40][CH:41]1[CH2:46][CH2:45][CH2:44][N:43]([C:47]2[N:55]([CH2:56][C:57]#[C:58][CH3:59])[C:54]3[C:53](=[O:60])[N:52]([CH2:61]C4C=CC=CC=4C#N)[C:51]([C:70]#[N:71])=[N:50][C:49]=3[N:48]=2)[CH2:42]1>>[ClH:24].[NH2:40][CH:41]1[CH2:46][CH2:45][CH2:44][N:43]([C:47]2[N:55]([CH2:56][C:57]#[C:58][CH3:59])[C:54]3[C:53](=[O:60])[N:52]([CH2:61][C:19]4[CH:20]=[CH:21][C:16]([C:15]#[N:11])=[CH:17][CH:18]=4)[C:51]([C:70]#[N:71])=[N:50][C:49]=3[N:48]=2)[CH2:42]1
Reactant: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2nc(Cl)n(Cc3ccc(C#N)cc3)c(=O)c21
Reactant: CC#CCn1c(N2CCCC(N)C2)nc2nc(C#N)n(Cc3ccccc3C#N)c(=O)c21
Agent: Cl
Product: CC#CCn1c(N2CCCC(N)C2)nc2nc(C#N)n(Cc3ccc(C#N)cc3)c(=O)c21

Procedure:
The title compound was synthesized by using t-butyl [1-[7-(2-butynyl)-2-chloro-1-(4-cyanobenzyl)-6-oxo-6,7-dihydro-1H-purin-8-yl]piperidin-3-yl]carbamate according to the method described in Examples 242 (f) and (g).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)=[O:4].[OH:15][C:16]1([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[CH2:22]([C:16]1([OH:15])[CH2:21][CH2:20][N:19]([CH2:2][C:3]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9](=[O:14])[CH2:8]3)=[O:4])[CH2:18][CH2:17]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C1Cc2cc(C(=O)CCl)ccc2N1
Reactant: OC1(Cc2ccccc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: O=C1Cc2cc(C(=O)CN3CCC(O)(Cc4ccccc4)CC3)ccc2N1

Procedure:
A mixture of 5-(chloroacetyl)-2(1H,3H)-indolone (2.05 g, 9.78 mmol), 4-hydroxy-4-benzylpiperidine (1.87 g, 9.78 mmol), potassium carbonate (2.97 g, 21.49 mmol), and potassium iodide (0.08 g, 0.48 mmol) in acetonitrile (200 ml) was refluxed overnight. The reaction was cooled and filtered through a celite pad. The filtrate was concentrated to give an orange foam which was flash chromatographed on silica gel with ethyl acetate elution. This afforded 0.79 g of oily yellow solid product. NMR 9.41 (br s, 1H), 7.91 (d, J=8 Hz, 1H), 7.86 (s, 1H), 7.28-7.14 (m, 5H), 6.90 d, J=8 Hz, 1H), 3.76 (s, 2H), 3.52 (s, 2H), 2.78-2.73 (m, 4H), 2.43 {t, J=10.5 Hz, 2H}, 1.86-1.76 (m, 2H), 1.50 (br d, J=12 Hz, 2H), 1.36 (br s, 1H). IR(KBr) 2920, 2815, 1710, 1685, 1615, 1240, 1115. FAB HRMS calcd for C22H25N2O3 (MH+): 365.1867. Observed m/e: 365.1883.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:21][C:20]1=[O:35].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(N(CC)CC)C>[CH2:28]([O:27][C:25]([N:22]1[CH2:23][CH2:24][N:19]([NH:18][C:15](=[O:17])[CH2:14][CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)[C:20](=[O:35])[CH2:21]1)=[O:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Reactant: NN1CCN(C(=O)OCc2ccccc2)CC1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)NN2CCN(C(=O)OCc3ccccc3)CC2=O)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.9 %

Procedure:
A solution of 1-(tert-butoxycarbonyl)-4-piperidinylacetic acid (440 mg), 1-amino-4-benzyloxycarbonyl-2-piperazinone (541 mg), triethylamine (273 mg) and HOBt (333 mg) in DMF (30 ml) was combined with WSC (518 mg) and stirred at room temperature for 15 hours. The reaction mixture was concentrated to obtain a residue, which was partitioned between ethyl acetate and water, and the organic phase was washed with water, aqueous sodium bicarbonate, an aqueous solution of citric acid and brine, dried and concentrated to obtain N-(4-benzyloxycarbonyl-2-oxo-1-piperazinyl)-2-[1-(tert-butoxycarbonyl)-4-piperidinyl]acetamide (840 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][C:9]([C:13]([OH:15])=O)=[C:8]2[NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][CH:26]2[CH2:31][CH2:30][N:29]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:28][CH2:27]2)=[O:24])=[CH:19][CH:18]=1.[CH3:39][N:40]([CH3:46])[CH2:41][CH2:42][NH:43][CH2:44][CH3:45]>>[CH3:39][N:40]([CH3:46])[CH2:41][CH2:42][N:43]([CH2:44][CH3:45])[C:13]([C:9]1[CH:10]=[N:11][C:12]2[C:7]([C:8]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][CH:26]3[CH2:31][CH2:30][N:29]([CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:28][CH2:27]3)=[O:24])=[CH:19][CH:18]=1)=[CH:6][CH:5]=[CH:4][C:3]=2[O:2][CH3:1])=[O:15]
Reactant: CCNCCN(C)C
Reactant: COc1cccc2c(Nc3ccc(C(=O)NC4CCN(Cc5ccccc5)CC4)cc3)c(C(=O)O)cnc12
Product: CCN(CCN(C)C)C(=O)c1cnc2c(OC)cccc2c1Nc1ccc(C(=O)NC2CCN(Cc3ccccc3)CC2)cc1

Procedure:
N-[2-(Dimethylamino)ethyl]-N-ethyl-8-methoxy-4-[[4-[[[1-(phenylmethyl)-4-piperidinyl]amino]carbonyl]phenyl]amino]-3-quinolinecarboxamide was prepared by coupling 8-methoxy-4-[[4-[[[1-(phenylmethyl)-4-piperidinyl]amino]carbonyl]phenyl]amino]-3-quinolinecarboxylic acid and commercially available N,N-dimethyl-N'-ethylethylenediamine as described for Example 17, Step 5. The compound is purified by reverse phase HPLC on C18 silica gel (gradient elution from 0.1% trifluoroacetic acid in 5% MeCN/H2O to 100% MeCN). Neutralization of the trifluroacetate salt after concentrating the fractions from the HPLC run afforded the title compound as an amorphous solid that was triturated in ether: mp 120°-123 ° C.; 1H NMR (Me2SO-d6, 400 MHz), 1:1 mixture of amide rotamers, a: b) δ 9.00 (s, 1Ha), 8.94 (s, 1Hb), 8.54 (s, 1Ha), 8.51 (s, 1Hb), 7.99 (d, J=7.9 Hz, 1Hb), 7.96 (d, J=8.1 Hz, 1Ha), 7.73 (d, J=8.5 Hz, 2Hb), 7.69 (m, 2Ha, 1 H), 7.49 (t, J=8.1 Hz, 1 H), 7.30 (m, 5 H), 7.26 (d, J=8.3 Hz, 1 H), 6.89 (d, J=8.7 Hz, 2Hb), 6.85 (d, J=8.5 Hz, 2Ha), 3.96 (s, 3 H), 3.74(m, 1 H), 3.46(s, 2H),3.11 (m, 4H),2.80(d,J=10.4Hz, 2H),2.18(t,J=5.6 Hz, 2Hb), 2.02 (m, 2 H), 1.99 (s, 6Hb), 1.83 (s, 6Ha), 1.70 (m, 2 H, 2Ha), 1.56 (qd, J=10.8, 3.6Hz, 2 H), 0.91 (t, J=6.9 Hz, 3Hb), 0.61 (t, J=6.9 Hz, 3Ha).
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:4]=2[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.FC(F)(F)C(O)=[O:24].OO.S(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[Br:1][C:2]1[C:3]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:4]=2[S:5](=[O:24])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2Br)cc1
Reactant: O=C(O)C(F)(F)F
Agent: O=S([O-])O
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C2=C(Br)c3ccc(OC)cc3S2=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88 %

Procedure:
To a solution of 3-bromo-6-methoxy-2-(4-methoxyphenyl)-benzo[b]thiophene (4 g, 11.45 mmol) in DCM (20.02 mL) at room temperature was added trifluoroacetic acid (20.02 mL) dropwise, the reaction went from orange to dark brown in color. Upon addition the resulting mixture was stirred at room temp for 10 min and then hydrogen peroxide (30% wt. aq) (1.583 mL, 16.47 mmol) was added dropwise. After 90 min at room temperature the reaction mixture was quenched with sodium bisulfite (1.714 g, 16.47 mmol) (vigorous bubbling was observed) followed by 3.0 mL of water. The resulting suspension was stirred vigorously for 15 min and then concentrated in vacuo to remove DCM and most of the TFA. The residue was partitioned between DCM (40 mL) and sat. aq. NaHCO3 solution (40 mL) and separated. The organic layer was collected (phase separator) and concentrated in vacuo to afford the crude product, which was purified by column chromatography (SiO2, 1-40% EtOAc/Heptane) to afford 3-bromo-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene 1-oxide (4.6 g, 10.08 mmol, 88% yield) as an orange solid. 1H NMR (400 MHz, CD3OD) δ ppm=7.51-7.65 (m, 2 H), 7.37-7.51 (m, 2 H), 7.08 (dd, J=2.27, 8.34 Hz, 1H), 6.79-6.96 (m, 2 H), 3.74 (s, 3 H), 3.68 (s, 3 H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=3)=[CH:9][N:8]([C@@H:25]3[CH2:28][C@H:27]([CH2:29][N:30]4C(=O)C5C(=CC=CC=5)C4=O)[CH2:26]3)[C:4]=2[N:5]=[CH:6][N:7]=1.O.NN>C(O)C>[NH2:30][CH2:29][C@@H:27]1[CH2:26][C@H:25]([N:8]2[C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=3[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=3)=[CH:9]2)[CH2:28]1
Reactant: Nc1ncnc2c1c(-c1cccc(OCc3ccccc3)c1)cn2[C@H]1C[C@@H](CN2C(=O)c3ccccc3C2=O)C1
Agent: NN
Solvent: O
Solvent: CCO
Product: NC[C@H]1C[C@@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Reaction time: 20 h

Procedure:
To a solution of 3.84 g (7.25 mmol) of cis-2-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-isoindole-1,3-dione in 100 ml of dry ethanol are added dropwise at RT and under argon 3.75 g (3.64 ml; 74.96 mmol) of hydrazine monohydrate. After 2 h most of the starting material is not yet dissolved, and additional 1.6 ml of hydrazine monohydrate are added thereto (total amount: 14.8 equivalents). The reaction is complete after 20 h. The colorless precipitate is filtered off, and washed with ethanol. The filtrate is evaporated to dryness and the crude compound is purified by chromatography on silicagel (dichloromethane:methanol:aqueous concentrated ammonia=90:10:1) to provide cis-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine. Analytical HPLC: tR=7.47 min (Grad 1); ES-MS: m/eo=400; 1H-NMR (CDCl3): 8.31/s (1H); 7.3-7.5/m (6H); 7.12/s (1H); 7.05-7.08/2 peaks (2H); 6.99/m (1H); 5.17/m (1H); 5.14/s (2H); 5.04/broad s (2H); 2.87/d (2H); 2.75-2.65/m (2H); 2.2-2.1/m (2H); 1.55/broad s (2H).
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23](N1CCCC1)[CH2:22][CH2:21]2>C(Cl)(Cl)Cl>[Br:17][C:18]1[CH:27]=[CH:26][C:25]2[C:24]3[CH2:3][CH2:2][C:1](=[O:4])[NH:5][C:23]=3[CH2:22][CH2:21][C:20]=2[CH:19]=1
Reactant: Brc1ccc2c(c1)CCC(N1CCCC1)=C2
Reactant: C=CC(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: O=C1CCC2=C(CCc3cc(Br)ccc32)N1

Procedure:
17.5 g of acrylamide and 0.65 g of p-toluenesulphonic acid were added to 35.5 g of 1-(6-bromo-3,4-dihydro-2-naphthyl)pyrrolidine. The mixture was heated under nitrogen to 100° for 2 hours and to 150° for 2 hours. The reaction mixture was treated with 250 ml of chloroform, whereupon the insoluble constituents were filtered off. There was obtained 8-bromo-1,4,5,6-tetrahydrobenzo[f]quinolin-3(2H)-one of melting point 227°-228°. After recrystallization from ethanol the product exhibits a melting point of 230°-231°.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].[C:13](Cl)([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>O>[C:13]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(OCc1ccccc1)Oc1ccc(C(=O)O)cc1
Reaction time: 24 h
Yield: 100.2 %

Procedure:
To an aqueous solution of 55 mmol (7.6 g) of p-hydroxybenzoic acid and 65 mmol (2.6 g) of sodium hydroxide in 200 ml of water was added 65 mmol (10.6 g) of carbobenzoxy chloride dropwise during cooling with ice. After 24 hours, the generated precipitate was washed with water, filtered, dried, and purified by column chromatography, to obtain 15.0 g of 4-carbobenzoxyoxybenzoic acid (m.p.: 181.9°-183.1° C.). (Yield: 99%).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:17])[C@H:13]([O:15][CH3:16])[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:19]1[CH2:23][CH2:22][C@@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20]1.CC(N(C)C)=O>CCCCO>[Br:1][C:2]1[C:3]([N:19]2[CH2:23][CH2:22][C@@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:20]2)=[C:4]2[C:10]([NH:11][C:12](=[O:17])[C@H:13]([O:15][CH3:16])[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CO[C@H](C)C(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Solvent: CCCCO
Solvent: CC(=O)N(C)C
Product: CO[C@H](C)C(=O)Nc1c[nH]c2ncc(Br)c(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: 135 °C
Yield: 61.1 %

Procedure:
(R)—N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamide (0.6 g, 1.9 mmol), (R)-tert-butyl pyrrolidin-3-ylcarbamate (1.1 g, 5.7 mmol), and DMA (0.99 mL, 5.7 mmol, d 0.742) were place in n-BuOH (4 mL) and heated at 135° C. for 12 hours. The reaction was cooled to room temperature, concentrated, and purified by silica gel chromatography (500:15 DCM:MeOH) to give tert-butyl (R)-1-(5-bromo-3-((R)-2-methoxypropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-ylcarbamate (0.56 g, 61% yield).