Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:5][C:6]([NH:8][C@@H:9]([CH2:25]O)[CH2:10][CH2:11][CH2:12][CH2:13][NH:14]C(=O)OCC1C=CC=CC=1)=[S:7])(C)(C)C.[ClH:27]>C(O)C>[ClH:27].[ClH:27].[NH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:25][S:7][C:6]([NH2:5])=[N:8]1
Reactant: CC(C)(C)NC(=S)N[C@@H](CO)CCCCNC(=O)OCc1ccccc1
Agent: Cl
Solvent: CCO
Product: NCCCC[C@@H]1CSC(N)=N1

Procedure:
The process is performed as in Example 1, starting with 5.9 g of benzyl (5R)-5-{[(tert-butylamino)carbothioyl]amino}-6-hydroxyhexylcarbamate in 40 cm3 of aqueous 6N hydrochloric acid at a temperature in the region of 100° C. for 3 hours. After concentration of the reaction medium under reduced pressure (5 kPa) at a temperature in the region of 50° C., the residue obtained is taken up in ethanol and then concentrated again under the above conditions. The paste obtained is crystallized by trituration from an ethanol/methanol mixture (8/2 by volume). The crystals are filtered off, washed with acetonitrile and air-dried. 1.3 g of (+)-(4R)-4-(4-aminobutyl)-4,5-dihydro-1,3-thiazol-2-ylamine dihydrochloride are obtained in the form of a white solid melting at 188° C. (αD20=+16.2±0.7 at a concentration of 0.5% in methanol).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:5]=1[CH2:6]P(=O)(OCC)OCC.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].COCCOC>O>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][C:31](=[CH:6][C:5]2[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:4]=2[Br:3])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CCOP(=O)(Cc1cc(OC)ccc1Br)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(Br)c(C=C2CCN(C(=O)OC(C)(C)C)CC2)c1
Reaction time: 1.5 h
Yield: 79 %

Procedure:
Sodium hydride (60% in paraffin, 14.4 g, 0.360 mol) was added in small portions to a mixture of the crude product (147 g) of diethyl 2-bromo-5-methoxybenzylphosphonate, N-tert-butoxycarbonyl-4-piperidone (65.1 g, 0.327 mol) and 1,2-dimethoxyethane (200 mL) at room temperature, and the resulting mixture was stirred as it was for 1.5 hours. Water (1200 mL) was added to the reaction mixture, followed by extraction with ether (500 mL×3). The combined organic layer was washed with water (200 mL) and a saturated aqueous sodium chloride solution (200 mL). The combined organic layer washed was dried over anhydrous magnesium sulfate and then concentrated to dryness, and the residue was washed with hexane to obtain 98.2 g (0.257 mol, 79%) of N-tert-butoxycarbonyl-4-(2-bromo-5-methoxybenzal)piperidine.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:21]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:22]1>CCCCO>[Br:1][C:2]1[C:3]([N:21]2[CH2:25][CH2:24][CH:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[CH2:22]2)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1cccnc1
Reactant: c1ccc(C2CCNC2)nc1
Solvent: CCCCO
Product: O=C(Nc1c[nH]c2ncc(Br)c(N3CCC(c4ccccn4)C3)c12)c1cccnc1
Yield: 20.9 %

Procedure:
N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (100 mg, 0.3 mmol, Example 1, Step I) in n-BuOH (3 mL) and 2-(pyrrolidin-3-yl)pyridine (133 mg, 0.9 mmol) were heated to 160° C. in a sealed tube for 48 hours. After cooling down, the reaction was concentrated to dryness, and the residue purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 10-90% CH3CN/water gradient; 30 CV) to yield N-(5-bromo-4-(3-(pyridin-2-yl)pyrrolidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (29 mg) as a solid. This solid was dissolved in MeOH (1 mL), and then the solution was added dropwise to a 4N HCl solution in dioxane. The resulting solid was collected and dried to yield N-(5-bromo-4-(3-(pyridin-2-yl)pyrrolidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide hydrochloride (35 mg, 25% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.07 (d, 1H), 10.52 (s, 1H), 9.30 (d, 1H), 8.94-8.91 (m, 1H), 8.72-8.66 (m, 2H), 8.39-8.33 (m, 2H), 7.92-7.76 (m, 3H), 7.71 (d, 1H), 7.20 (br s, 2H), 4.06-3.95 (m, 2H), 3.80-3.67 (m, 3H), 2.48-2.40 (m, 1H), 2.23-2.11 (m, 1H). LCMS (APCI+) m/z 463, 465 (M+H)+, Retention time=2.78 minutes (Method 1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[C:6]([CH3:18])[C:5]([Br:19])=[CH:4][CH:3]=1.[F:20][C:21]1[CH:22]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1.N1C=CC=CC=1>ClCCl>[Br:19][C:5]1[C:6]([CH3:18])=[C:7]([C:2]([NH:1][S:27]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([F:20])[CH:22]=2)(=[O:29])=[O:28])=[CH:3][CH:4]=1)[C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: Cc1c(Br)ccc(N)c1C(=O)OCc1ccccc1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1c(Br)ccc(NS(=O)(=O)c2cccc(F)c2)c1C(=O)OCc1ccccc1
Reaction time: 18 h

Procedure:
A mixture of Example 126B (760 mg, 2.1 mmol), 3-fluorobenzenesulfonyl chloride (600 mg, 3.1 mmol) in dichloromethane (10 mL) was treated with pyridine (0.690 mL, 8.5 mmol), stirred for 18 hours, diluted with dichloromethane (90 mL), washed with 0.5M HCl (2×100 mL) and brine, dried (Na2SO4), filtered, concentrated and purified on a Biotage silica gel cartridge (40 g) with 50-75% dichloromethane in hexanes to provide the desired product. MS (ESI(+)) m/e 478, 480 (M+H)+, 495, 497 (M+NH4)+, 500, 502 (M+Na)+; (ESI(−)) m/e 476, 478 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 10.23 (s, 1H), 7.64-7.35 (m, 10H), 6.83 (d, 1H), 5.25 (s, 2H), 2.19 (s, 3H).
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([CH2:5][CH2:6]1)[CH2:3][C@H:2]2[NH:8][C:9]1[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]([C:19](O)=[O:20])=[CH:11][N:10]=1.CN1CCOCC1.ClC(OCC(C)C)=O>COCCOC>[C@H:1]12[CH2:7][C@H:4]([CH2:5][CH2:6]1)[CH2:3][C@H:2]2[NH:8][C:9]1[N:14]=[C:13]([C:15]([F:18])([F:16])[F:17])[C:12]([CH2:19][OH:20])=[CH:11][N:10]=1
Reactant: O=C(O)c1cnc(N[C@@H]2C[C@H]3CC[C@@H]2C3)nc1C(F)(F)F
Agent: CC(C)COC(=O)Cl
Solvent: COCCOC
Solvent: CN1CCOCC1
Product: OCc1cnc(N[C@@H]2C[C@H]3CC[C@@H]2C3)nc1C(F)(F)F
Temperature: -10 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
A mixture of rac-2-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-ylamino]-4-(trifluoromethyl)pyrimidine-5-carboxylic acid (2.0 g), 4-methyl morpholine (1.1 mL) and 1,2-dimethoxyethane (40 mL) was cooled to −10° C., isobutyl chloroformate (1.1 mL) was added thereto, and the mixture was stirred at the same temperature for 1 hour. The insoluble materials in the reaction mixture were filtered and washed with 1,2-dimethoxyethane. The filtrate was cooled to −60° C. and a solution of sodium borohydride (377 mg) in water (4.0 mL) was added thereto, followed by stirring as it is for 1 hour. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=10:90 to 20:80) to obtain rac-{2-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-ylamino]-4-(trifluoromethyl)pyrimidin-5-yl}methanol (1.05 g) as a colorless oily substance.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:18]2[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=2)[CH:3]=1.[CH3:26][C:27]1([CH3:41])[CH2:32][C:31](=[O:33])[CH2:30][C:29]([CH3:35])([CH3:34])[N:28]1[CH2:36][C:37]([F:40])([F:39])[F:38]>>[CH3:24][C:21]1([CH3:25])[CH2:22][CH2:23][C:18]([C:4]2[CH:3]=[C:2]([C:31]3([OH:33])[CH2:30][C:29]([CH3:35])([CH3:34])[N:28]([CH2:36][C:37]([F:38])([F:39])[F:40])[C:27]([CH3:41])([CH3:26])[CH2:32]3)[CH:7]=[CH:6][C:5]=2[NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[CH:19][CH2:20]1
Reactant: CC1(C)CC(=O)CC(C)(C)N1CC(F)(F)F
Reactant: CC1(C)CC=C(c2cc(Br)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Product: CC1(C)CC=C(c2cc(C3(O)CC(C)(C)N(CC(F)(F)F)C(C)(C)C3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1

Procedure:
The title compound was prepared as described in Example 1, step (h) using 4-cyano-1H-imidazole-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (as prepared in Example 1, step (g) and 2,2,6,6-tetramethyl-1-(2,2,2-trifluoro-ethyl)-piperidin-4-one (as prepared above). 1H-NMR (CD3OD; 400 MHz): δ 8.22 (d, 1H, J=8.4 Hz), 7.98 (s, 1H), 7.43 (dd, 1H, J=8.4, 2.0 Hz), 7.33 (d, 1H, J=2.0 Hz), 5.73 (br s, 1H), 4.18 (m, 2H), 2.28-2.36 (m, 4H), 2.08 (m, 4H), 1.73 (s, 6H), 1.58 (m, 2H), 1.42 (m, 6H), 1.08 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C30H38F3N5O2, 558.3 (M+H). found 558.0.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([F:16])([F:15])[F:14])[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-])=O.Cl>CO.O1CCOCC1>[N+:10]([C:8]1[CH:9]=[C:4]([CH:5]=[C:6]([C:13]([F:14])([F:15])[F:16])[CH:7]=1)[NH2:1])([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Nc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
3,5-Dinitrobenzotrifluoride (10 g) was dissolved in a mixture of methanol (200 ml) and 1,4-dioxane (125 ml) and heated under reflux. To this solution was added concentrated hydrochloric acid (30 ml) and then in small portions, reduced iron powder (9 g). CARE: violent effervescence. Refluxing was continued for a further 1 hour and the reaction mixture allowed to cool to room temperature. The mixture was filtered through `Celite` and the pad washed well with dichloromethane. The solvents were removed under reduced pressure to give a residue which was partitioned between dichloromethane and water. The organic layer was washed with brine, dried (MgSO4) and evaporated under reduced pressure to give a brown semi-solid (8 g). This was chromatographed on silica gel using ethyl acetate-hexane (1:9) as eluant to give the title compound as fine golden crystals, yield 4.98 g.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1[NH:11][C:12]1[C:13]2[N:14]([C:21]([CH3:25])=[C:22]([CH3:24])[N:23]=2)[CH:15]=[C:16]([C:18]([OH:20])=O)[CH:17]=1.[CH3:26][NH:27][CH3:28]>ClCCl>[OH:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1[NH:11][C:12]1[C:13]2[N:14]([C:21]([CH3:25])=[C:22]([CH3:24])[N:23]=2)[CH:15]=[C:16]([C:18]([N:27]([CH3:28])[CH3:26])=[O:20])[CH:17]=1
Reactant: Cc1nc2c(N[C@@H]3c4ccccc4C[C@H]3O)cc(C(=O)O)cn2c1C
Reactant: CNC
Solvent: ClCCl
Product: Cc1nc2c(N[C@@H]3c4ccccc4C[C@H]3O)cc(C(=O)N(C)C)cn2c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
3.0 g (8.9 mmol)-8-(trans-2,3-dihydro-2-hydroxy-1-indenylamino)-2,3-dimethyl-imidazo[1,2-a]pyridine-6-carboxylic acid and 3.7 g (11.6 mmol) —O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) are suspended in 150 ml dichloromethane and 3.2 ml (17.8 mmol) dimethylamine (5.6 M in ethanol) are added to the reaction mixture. After stirring for 16 h at room temperature, the reaction mixture is extracted with saturated aqueous sodium hydrogencarbonate. The organic phase is separated, dried over anhydrous magnesium sulphate and evaporated. The residue is dissolved in 10 ml dichloromethane and 50 ml diethyl ether are added. After stirring for 30 min, the precipitate is collected, washed with diethyl ether and dried in vacuo to give 2.35 g (73%) of the title compound as a colourless solid (m.p. 148-149° C.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])[CH:3]=1.[CH:18]1(B2OC(C)(C)C(C)(C)O2)[CH2:20][CH2:19]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.O1CCOCC1>[CH:18]1([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH2:9][C:10]3[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=3[F:17])[CH:3]=2)[CH2:20][CH2:19]1
Reactant: Fc1cccc(F)c1COc1cc(Br)ccn1
Reactant: CC1(C)OB(C2CC2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Fc1cccc(F)c1COc1cc(C2CC2)ccn1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 500 mg (1.66 mmol) of 4-bromo-2-[(2,6-difluorobenzyl)oxy]pyridine (Example 145A), 365 μl (2.0 mmol) of 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 139 mg (0.17 mmol) of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride-dichloromethane complex and 1.63 g (5.0 mmol) of caesium carbonate in 0.5 ml of water and 4 ml of dioxane was degassed with argon for 5 min and stirred in a sealed tube at 100° C. for 2 h. The reaction mixture was cooled to room temperature and the residue was partitioned between ethyl acetate and water. The organic phase was removed and washed with saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated. The residue was purified by chromatography on silica gel (40 g silica gel cartridge, mobile phase: methanol/ethyl acetate, gradient 0% to 25%). This gave 350 mg of the target compound (80% of theory).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([F:28])[CH2:18][CH2:17][C:16]([CH2:26][NH2:27])([C:19]2[CH:20]=[N:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:15][CH2:14]1>>[F:28][C:13]1([F:12])[CH2:14][CH2:15][C:16]([CH2:26][NH:27][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:2]=2[F:1])([C:19]2[CH:20]=[N:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:17][CH2:18]1
Reactant: O=C(O)c1cc(F)ccc1F
Reactant: NCC1(c2ccc(F)nc2)CCC(F)(F)CC1
Product: O=C(NCC1(c2ccc(F)nc2)CCC(F)(F)CC1)c1cc(F)ccc1F

Procedure:
From 2,5-difluorobenzoic acid and C-[4,4-difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS (MH+): m/z=385.2, tR (minutes, Method D)=0.71
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)[CH2:4][P:5](C(OCC)OCC)(=[O:9])[O:6]CC>Cl>[NH2:1][CH2:2][CH:3]([C:17]1[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=1)[CH2:4][P:5]([OH:9])[OH:6]
Reactant: CCOC(OCC)P(=O)(CC(CN)c1ccc(C)cc1)OCC
Agent: Cl
Product: Cc1ccc(C(CN)CP(O)O)cc1
Temperature: 25 °C

Procedure:
A solution of 3.7 g of ethyl 3-amino-2-(4methylphenyl)propyl-(diethoxymethyl)phosphinate in 40 ml of 36% aqueous hydrochloric acid is heated to reflux for a period of 1 h. The reaction mixture is then allowed to cool to room temperature, concentrated under reduced pressure and co-evaporated twice with 20 ml of water under reduced pressure. The crude product is dissolved in 20 ml of water, washed twice with 20 ml of diethyl ether and the aqueous layer is then separated and evaporated under reduced pressure. The crude product is dissolved in 50 ml ethanol and 5 ml of propylene oxide is added dropwise. The precipitated solid is collected by filtration and dried to give 3-amino-2-(4-methylphenyl)propylphosphonous acid, m.p. 250°-255° C., 31P=+24.5 ppm (D2O).
Reaction SMILES: [Na].[NH2:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][CH:4]=1.[CH2:14](O)C=C>CCCCCC>[NH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH2:10][CH:11]=[CH2:14])=[O:8])=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: C=CCO
Agent: [Na]
Solvent: CCCCCC
Product: C=CCOC(=O)c1ccc(N)cc1

Procedure:
50 ml of allyl alcohol are introduced into a round-bottomed flask, 750 mg (22 mmol) of sodium are added in small portions and the mixture is stirred until the metal has reacted completely. 30.2 g (0.2 mol) of ethyl 4-aminobenzoate, dissolved in 200 ml of allyl alcohol, are then introduced and the mixture is heated to reflux and distilled until 180 ml of distillate have been obtained. The reaction medium is evaporated, the residue is taken up with water and ethyl ether and the organic phase is separated after settling has taken place, dried over magnesium sulphate and evaporated. The residue obtained is ground in 200 ml of hexane and filtered off. 29 g (82%) of allyl ester, melting point 48°-50° C., are collected.
Reaction SMILES: [C:1]([OH:12])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[K+]>O>[C:8]([OH:10])(=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12]
Reactant: Nc1ccccc1
Reactant: O=C(O)CCCCCCC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCCCCCC(=O)Nc1ccccc1
Temperature: 175 °C
Reaction time: 0.33 h

Procedure:
In a 22 L flask was placed 3,500 g (20.09 moles) of suberic acid, and the acid melted with heat. The temperature was raised to 175° C., and then 2,040 g (21.92 moles) of aniline was added. The temperature was raised to 190° C. and held at that temperature for 20 minutes. The melt was poured into a Nalgene tank that contained 4,017 g of potassium hydroxide dissolved in 50 L of water. The mixture was stirred for 20 minutes following the addition of the melt. The reaction was repeated at the same scale, and the second melt was poured into the same solution of potassium hydroxide. After the mixture was thoroughly stirred, the stirrer was turned off, and the mixture was allowed to settle. The mixture was then filtered through a pad of Celite (4,200 g) (the product was filtered to remove the neutral by-product (from attack by aniline on both ends of suberic acid). The filtrate contained the salt of the product, and also the salt of unreacted suberic acid. The mixture was allowed to settle because the filtration was very slow, taking several days). The filtrate was acidified using 5 L of concentrated hydrochloric acid; the mixture was stirred for one hour, and then allowed to settle overnight. The product was collected by filtration, and washed on the funnel with deionized water (4×5 L). The wet filter cake was placed in a 72 L flask with 44 L of deionized water, the mixture heated to 50° C., and the solid isolated by a hot filtration (the desired product was contaminated with suberic acid which is has a much greater solubility in hot water. Several hot triturations were done to remove suberic acid. The product was checked by NMR [D6DMSO] to monitor the removal of suberic acid). The hot trituration was repeated with 44 L of water at 50° C. The product was again isolated by filtration, and rinsed with 4 L of hot water. It was dried over the weekend in a vacuum oven at 65° C. using a Nash pump as the vacuum source (the Nash pump is a liquid ring pump (water) and pulls a vacuum of about 29 inch of mercury. An intermittent argon purge was used to help carry off water); 4,182.8 g of suberanilic acid was obtained.
Reaction SMILES: [CH:1]1([CH:8]=[O:9])[CH2:5][CH2:4][CH:3]([CH:6]=[O:7])[CH2:2]1.[BH4-].[Na+]>O>[CH:1]1([CH2:8][OH:9])[CH2:5][CH2:4][CH:3]([CH2:6][OH:7])[CH2:2]1
Reactant: O=CC1CCC(C=O)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: OCC1CCC(CO)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To 1,3-cyclopentanedicarbaldehyde I-19 (1 equivalent) taken in a flask was added deoxygenated methanol. The reaction mixture was cooled to 0° C. and NaBH4 (2 equivalents) was added in small aliquots in order to avoid a raise in the reaction temperature above 10° C. The reaction mixture was left to warm to room temperature and stirred for an additional 3 h under nitrogen atmosphere. Distilled water was added to the reaction mixture to quench any remaining NaBH4 and then rotary evaporated to remove methanol from the solution. The remaining mixture was extracted with dichloromethane (5 times) and the combined organic fractions were dried over anhydrous sodium sulfate and evaporated to dryness to afford the title compound I-20.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[CH2:28][N:27]([C:29](=[O:31])[CH3:30])[CH2:26][CH2:25][C:9]=2[N:10]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][CH:23]=[N:22][CH:21]=3)=[CH:16][CH:15]=2)[N:12]=1)(=O)=O.[NH2:34][C:35]1([CH2:40][OH:41])[CH2:39][CH2:38][CH2:37][CH2:36]1>CS(C)=O>[OH:41][CH2:40][C:35]1([NH:34][C:7]2[C:8]3[CH2:28][N:27]([C:29](=[O:31])[CH3:30])[CH2:26][CH2:25][C:9]=3[N:10]=[C:11]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]4[O:24][CH:23]=[N:22][CH:21]=4)=[CH:18][CH:19]=3)[N:12]=2)[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: NC1(CO)CCCC1
Reactant: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(OS(=O)(=O)C(F)(F)F)c2C1
Solvent: CS(C)=O
Product: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(NC3(CO)CCCC3)c2C1
Reaction time: 8 h
Yield: 27.1 %

Procedure:
6-Acetyl-2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate (35 mg, 0.07 mmol, Example 26a) in DMSO (1 mL) dispensed in a library plate. (1-aminocyclopentyl)methanol (8.06 mg, 0.07 mmol) was added and it was left to shake overnight at 80° C. before filtered and purified by preparative HPLC to yield 1-(4-(1-(hydroxymethyl)cyclopentylamino)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (8.5 mg, 26%).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>C(Cl)Cl>[O:8]=[C:6]1[NH:7][CH:3]([CH2:2][O:1][S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=2)(=[O:24])=[O:23])[CH2:4][CH2:5]1
Reactant: O=C1CC[C@@H](CO)N1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2CCC(=O)N2)cc1
Yield: 70.5 %

Procedure:
To of (S)-(+)-5-(Hydroxymethyl)-2-pyrrolidinone (1.0 g 8.69 mmol) and triethylamine (1.21 ml, 8.69 mmol) in 50 mL of methylene chloride was added 1.66 g (8.69 mmol) of p-toluenesulfonyl chloride. The resultant solution was stirred at room temperature for 3 days. The organic solution was washed 1× with water, dried over MgSO4, filtered, and concentrated. Silica gel chromatography (95:5 ethyl acetate/methanol) gave 1.65 g (71%) of toluene-4-sulfonic acid 5-oxo-pyrrolidin-2-ylmethyl ester as a white powder that was used in the next step. Rf=0.29 (95:5 ethyl acetate/methanol). 1H NMR (400 MHz, CDCl3): δ 1.65–1.80 (m, 1H), 2.15–2.35 (m, 3H), 2.42 (s, 3H), 3.80–3.90 (m, 2H), 3.95–4.05 (m, 1H), 6.53 (bs, 1H), 7.30–7.35 (d, J=8.4 Hz, 2H), 7.74–7.76 (d, J=8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 21.7, 22.8, 29.3, 52.6, 72.0, 127.9, 130.1, 132.4, 145.4, 178.0. To 150 mg (0.40 mmol) of 6-Methoxy-1-methyl-7-[(2S,3S)-(2-phenyl-piperidin-3-ylamino)-methyl]-3,4-dihydro-1H-quinolin-2-one, potassium carbonate (55 mg, 0.40 mmol), and catalytic KI in 4 mL of DMF was added toluene-4-sulfonic acid 5-oxo-pyrrolidin-2-ylmethyl ester (107 mg, 0.40 mmol) The suspension was heated to 60° C. for 16 hours. The reaction was diluted with methylene chloride and washed 3× with water, 2× with brine, dried over MgSO4, filtered, and concentrated. Silica gel chromatography using (85:15 ethyl acetate/methanol) gave 19 mg (10%) of the title compound, a white foam. Rf=0.10 (85:15 ethyl acetate/methanol). MS (M+H)+=477.2; 1H NMR (400 MHz, CDCl3): δ 1.30–1.60 (m, 3H), 1.78–1.82 (dd, J=12.6, 3.0 Hz, 1H), 1.98–2.16 (m, 6H), 2.20–2.30 (m, 1H), 2.50–2.52 (dd, J=12.6, 11.0 Hz, 1H), 2.54–2.58 (t, J=7.4 Hz, 2H), 2.68 (bs, 1H), 2.76–2.80 (t, J=7.4 Hz, 2H), 3.14 (s, 3H), 3.25–3.29 (m, 1H), 3.30 (bs, 1H), 3.37–3.40 (d, J=13.9 Hz, 1H), 3.49 (s, 3H), 3.62–3.66 (d, J=13.9 Hz, 1H), 3.86–3.91 (m, 1H), 6.49 (s, 1H), 6.50–6.55 (bs, 1H), 6.60 (s, 1H), 7.20–7.30 (m, 5H); 13C NMR (100 MHz, CDCl3): δ 20.1, 25.0, 25.5, 27.3, 29.6, 29.9, 31.8, 45.6, 50.8, 53.7, 55.5, 56.3, 61.1, 72.4, 109.9, 116.28, 127.1, 128.3, 128.9, 133.6, 140.6, 152.9, 170.0, 177.5. The dihydrochloride salt was prepared by the addition of 2 M HCl in ether to a solution of the product in ethyl acetate. Concentration gave a white solid (Mp=203–207° C.).