Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]2[CH:10]=[N:9][NH:8][C:6]=2[N:7]=1.P(Br)(Br)([Br:18])=O>C(#N)C>[Br:18][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]2[CH:10]=[N:9][NH:8][C:6]=2[N:7]=1
Reactant: O=P(Br)(Br)Br
Reactant: CCOC(=O)c1cc(O)nc2[nH]ncc12
Solvent: CC#N
Product: CCOC(=O)c1cc(Br)nc2[nH]ncc12
Yield: 77.1 %

Procedure:
Ethyl 6-hydroxy-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (25 g, 120 mmol) was suspended in acetonitrile (250 mL) and POBr3 (69.56 g, 241.54 mmol) was added to it. The reaction mixture was refluxed for 6 h. On completion of reaction, acetonitrile was removed under reduced pressure and residue neutralized with saturated NaHCO3 solution was added to it. Extraction was carried out using ethyl acetate; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to provide the desired intermediate (25 g, 77%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]3[N:16]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:17]=[CH:18][C:13]3=[C:12]([N:24]3[CH2:31][CH:30]4[O:32][CH:26]([CH2:27][N:28]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29]4)[CH2:25]3)[N:11]=2)=[CH:6][CH:5]=1)([O-])=O>O1CCCC1.C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:15]=[C:14]3[N:16]([CH2:19][C:20]([F:22])([F:23])[F:21])[N:17]=[CH:18][C:13]3=[C:12]([N:24]3[CH2:31][CH:30]4[O:32][CH:26]([CH2:27][N:28]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29]4)[CH2:25]3)[N:11]=2)=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CC2CN(c3nc(-c4ccc([N+](=O)[O-])cc4)nc4c3cnn4CC(F)(F)F)CC(C1)O2
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2CN(c3nc(-c4ccc(N)cc4)nc4c3cnn4CC(F)(F)F)CC(C1)O2
Reaction time: 8 h
Yield: 94.3 %

Procedure:
A suspension of tert-butyl 7-(6-(4-nitrophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (0.54 g, 0.98 mmol) in tetrahydrofuran (10 mL) and ethanol (10 mL) was degassed by the addition of crushed dry ice and then treated with 10% palladium on carbon (30 mg). The resulting suspension was evacuated under weak vacuum and then filled with hydrogen gas (balloon). This evacuation/fill cycle was performed three more times and on the final iteration, the mixture was left to stir overnight under a hydrogen-filled balloon. The mixture was filtered through a pad of diatomaceous earth, eluting with ethanol. The filtrate was concentrated under reduced pressure to afford tert-butyl 7-(6-(4-aminophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate as a white solid (0.48 g, 94%). MS (ES+): 520.2 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13](N)[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.C(Cl)(Cl)[Cl:21].N(OC(C)(C)C)=O.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C>[Cl:21][C:13]1[N:14]=[CH:15][C:16]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[CH3:19])[CH:17]=2
Reactant: ClC(Cl)Cl
Reactant: Cc1ccc(F)cc1-c1ccc2cc(N)ncc2c1
Agent: CC(C)(C)ON=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1ccc(F)cc1-c1ccc2cc(Cl)ncc2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 36.3 %

Procedure:
To a solution of 7-(5-fluoro-2-methylphenyl)isoquinolin-3-amine (0.5177 g, 2.052 mmol) in chloroform (10 mL, 100 mmol) was added cuprous monochloride (0.3159 g, 3.191 mmol) and tert-butyl nitrite (0.50 mL, 3.8 mmol). The reaction mixture was stirred at room temperature in a flask shielded from the light with foil for 20 hours. To the reaction mixture was added 2M aqueous Na2CO3 and ethyl acetate, and the resulting mixture was filtered through celite. The organic layer was then dried over MgSO4, filtered, and evaporated in vacuo. The resulting residue was purified via flash chromatography on silica gel (40 g silica, solvent gradient: 0-50% ethyl acetate in heptanes) to yield 202.6 mg (36%) of 3-chloro-7-(5-fluoro-2-methylphenyl)isoquinoline. LCMS (ESI): M+H=272.2; 1H NMR (400 MHz, DMSO-d6) δ 9.26 (s, 1H), 8.19 (s, 1H), 8.11 (s, 1H), 8.05 (d, J=8.5 Hz, 1H), 7.87 (d, J=8.5 Hz, 1H), 7.45-7.36 (m, 1H), 7.19 (t, J=7.9 Hz, 2H), 2.24 (s, 3H).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[O:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1)[CH2:2][CH2:3][CH3:4].[C:17](Cl)(=[O:21])[CH:18]([CH3:20])[CH3:19]>>[CH2:1]([N:5]([C:6]1[O:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1)[C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)C(=O)Cl
Reactant: CCCCNc1nc(-c2ccccc2)co1
Product: CCCCN(C(=O)C(C)C)c1nc(-c2ccccc2)co1

Procedure:
2-(N-butylamino)-4-phenyloxazole was acylated with isobutyryl chloride as described in Example 9. An almost colourless oil was obtained on distillation. Wt. = 4.9 g., b.p. 140° C (air-bath temperature)/1 mm., 80%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1.Br[C:16]1[CH:24]=[C:23]2[C:19]([C:20]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][C:21]=3[N:22]2[CH3:25])=[CH:18][CH:17]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]([C:16]3[CH:24]=[C:23]4[C:19]([C:20]5[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][C:21]=5[N:22]4[CH3:25])=[CH:18][CH:17]=3)[C:10](=[O:14])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=c1cc(-c2ccc(Cl)cc2)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)cc31)CCN(C(=O)OC(C)(C)C)C2
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(Cl)cc5)cc4=O)cc31)CCN(C(=O)OC(C)(C)C)C2
Yield: 54.2 %

Procedure:
4-(4-Chlorophenyl)pyridin-2(1H)-one (74 mg, 0.32 mmol) and tert-butyl 7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (74 mg, 0.36 mmol) were coupled following the procedure of Example 30 (step g) to provide the title compound (85 mg, 54%) as a yellow solid: 1H NMR (300 MHz, CD3OD) δ 7.58-7.55 (m, 3H), 7.51-7.44 (m, 3H), 7.35 (s, 1H), 7.07 (dd, J=8.2, 1.6 Hz, 1H), 6.87 (d, J=1.8 Hz, 1H), 6.47 (dd, J=7.1, 1.8 Hz, 1H), 4.65 (br m, 2H), 3.75 (br m, 2H), 3.64 (s, 3H), 2.81 (br m, 2H), 1.52 (s, 9H).
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][NH:4][C:5](=[O:15])[CH:6]([C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=1)[CH3:7].[S:17]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[CH3:1][CH:2]([CH3:16])[CH2:3][NH:4][C:5](=[O:15])[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([C:19]2[CH:20]=[CH:21][S:17][CH:18]=2)=[CH:10][CH:9]=1)[CH3:7]
Reactant: CC(C)CNC(=O)C(C)c1ccc(Br)cc1
Reactant: OB(O)c1ccsc1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)CNC(=O)C(C)c1ccc(-c2ccsc2)cc1
Yield: 26.8 %

Procedure:
To a solution of N-2-methylpropyl-2-(4-bromophenyl)2-methylacetamide 1.1 g (3.9 mmol, part B above), 0.7 g (5.8 mmol) of thiophene-3-boronic acid and 0.8 g (5.8 mmol) of potassium carbonate in 12 mL of 3:1 dioxane/water was added 0.2 g (0.2 mmol) of tetrakis(triphenylphosphine)palladium. The mixture was heated to reflux for 16 hours, cooled and diluted with 10 mL of water. The mixture was extracted three times with 10 mL each of dichloromethane. The combined organics were dried (Na2SO4), filtered and concentrated in vacuo. Chromatography (65 g of silica gel, 35% ethyl acetate/hexanes) of the residue afforded 0.3 g (31%) of the final title compound.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:11]([CH3:13])[CH3:12]>ClCCl>[CH2:10]([C:14]1[CH:19]=[CH:18][C:17]([C:1](=[O:4])[CH2:2][CH3:3])=[CH:16][CH:15]=1)[CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)Cc1ccccc1
Reactant: CCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(=O)c1ccc(CC(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Propionyl chloride (13.0 ml) was added to a suspension of aluminum chloride (20.0 g) in dichloromethane (200 ml) at 0° C. After the mixture was stirred at 0° C. for 1 hour, isobutylbenzene (23.6 ml) was added to the mixture. The mixture was stirred at 0° C. for 2 hours and poured into ice water. The organic layer was washed with water, dried over magnesium sulfate and evaporated. The residual oil was distilled under reduced pressure to give 4'-isobutylpropiophenone as a colourless oil (24.4 g).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[OH:29])([CH3:22])[CH3:21])[C:14]3=[O:30])[CH:7]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:39][CH2:40][N:41]([CH3:52])[C:42](=[O:51])[O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C(#N)C>[CH:1]1([NH:4][C:5]([C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH2:39][CH2:40][N:41]([CH3:52])[C:42](=[O:51])[O:43][CH2:44][C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([CH3:22])[CH3:21])[C:14]3=[O:30])[CH:7]=2)=[O:31])[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2O)c1=O
Reactant: CN(CCCl)C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2OCCN(C)C(=O)OCc2ccccc2)c1=O
Temperature: 85 °C
Yield: 55.9 %

Procedure:
To N-cyclopropyl-3-(3-(2-(2-hydroxyphenyl)propan-2-ylamino)-2-oxopyrazin-1(2H)-yl)-4-methylbenzamide (Example 134, 4.3 g) in acetonitrile (5 mL) was added potassium carbonate (2.84 g) followed by benzyl 2-chloroethyl(methyl)carbamate (2.69 g) and the reaction heated at 85° C. for 16 h under nitrogen. After cooling to room temperature, the mixture was evaporated to dryness and the residue partitioned between water (20 mL) and DCM (20 mL). The aqueous layer was separated and further extracted into DCM (2×20 mL). The combined organics were evaporated to leave crude benzyl 2-(2-(2-(4-(5-(cyclopropylcarbamoyl)-2-methylphenyl)-3-oxo-3,4-dihydropyrazin-2-ylamino)propan-2-yl)phenoxy)ethyl(methyl)carbamate (3.50 g) as a gum. Ethanol (150 mL) and P/C (0.611 g of 5%) were added and the reaction stirred under H2 atmosphere (2 bar) for 4 h. The mixture was filtered through Celite (washing pad with aliquots of ethanol) and the combined filtrates evaporated to leave the crude product (2.1 g). Recrystallisation from ethyl acetate gave the title product (1.15 g) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][CH2:20][C:17]([CH:22]=[CH:23][C:24]#[N:25])([CH2:18][CH2:19]3)[CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:26])[N:3]1[CH2:27][CH2:28][CH3:29].[H][H]>CO.C(Cl)Cl.[Pd]>[O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:19][CH2:18][C:17]([CH2:22][CH2:23][C:24]#[N:25])([CH2:20][CH2:21]3)[CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:26])[N:3]1[CH2:27][CH2:28][CH3:29]
Reactant: [H][H]
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(C=CC#N)(CC3)CC4)nc2n(CCC)c1=O
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CCCn1c(=O)c2[nH]c(C34CCC(CCC#N)(CC3)CC4)nc2n(CCC)c1=O
Reaction time: 8 h
Yield: 90.5 %

Procedure:
A solution of 3-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-acrylonitrile (110 mg, 0.278 mmol) in MeOH (20 ml) and CH2Cl2 (5 ml) was hydrogenated using Pd on carbon (10 mol %) and a ballon of hydrogen affixed to a 3-way stopcock/ground glass adapter. After stirring overnight, the mixture was degassed, filtered through Celite and concentrated in vacuo to give a brittle foam (100 mg, 90%). 1H NMR (400 MHz, CDCl3); δ 0.93 (coincident triplets, 6H), 1.53 (m, 6H),1.57 (t, 2H), 1.67 (m, 2H), 1.77 (m, 2H), 2.00 (m, 6H), 2.24 (t, 2H), 3.99 (t, 2H), 4.05 (t, 2H), 12.17 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[NH:12]([CH2:14][C:15]([OH:17])=[O:16])[CH3:13].C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N:12]([CH2:14][C:15]([OH:17])=[O:16])[CH3:13])[CH:3]=1
Reactant: CNCC(=O)O
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CN(CC(=O)O)c1cc(Br)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 86.5 %

Procedure:
A mixture of 4-bromo-2-fluoro-1-nitro-benzene (9 g, 40 mmol), sarcosine (3.6g, 40 mmol), and potassium carbonate (5.5 g, 40 mmol) in ethanol (100 ml) and water (40 ml) was heated to reflux for 5 hours. After cooling to room temperature, the mixture was diluted with water and was adjusted to pH 6 with 1N aqueous HCl solution. The yellow precipitate was collected, washed with water and dried in vacuo to obtain crude [(5-bromo-2-nitro-phenyl)-methyl-amino]-acetic acid (10 g, 87%). A portion of the crude sample was recrystallized from EtOAc/hexane to afford the pure [(5-bromo-2-nitro-phenyl)-methyl-amino]-acetic acid: mp 152-155° C.; 1H-NMR (DMSO-d6) δ 2.81 (s, 3H), 4.00 (s, 2H), 7.06 (dd, 1H, J=8.79, 1.98 Hz), 7.22 (d, 1H, J=1.98 Hz), 7.69 (d, 1H, J=8.79 Hz), 12.8 (s, 1H); MS (+APCI) m/z 289/291 (M+H)+.
Reaction SMILES: C1COCC1.[NH2:6][C@H:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C@H:8]1[O:20][CH3:21].C(=O)(O)[O-].[Na+].Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>O>[CH2:31]([O:30][C:28]([NH:6][C@H:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9][C@H:8]1[O:20][CH3:21])=[O:29])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 94.5 %

Procedure:
THF (20 mL) and water (15 mL) were added to tert-butyl cis(±)-4-amino-3-methoxypiperidine-1-carboxylate (described in Example (1e), 4.6 g, 20 mmol). The mixture was stirred, during which sodium bicarbonate (3.44 g, 40 mmol) and benzyl chloroformate (3.95 g, 22 mmol) were added at room temperature, followed by stirring for one hour. The reaction solution was diluted with water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 1/2, 1/1) to obtain 6.89 g of the title compound as a colorless solid (95%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:20]([NH:22][CH2:23][C:24]1([OH:30])[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]1)[CH3:21]>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:26]4[CH2:27][CH2:28][CH2:29][C:24]([CH2:23][NH:22][CH2:20][CH3:21])([OH:30])[CH2:25]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCNCC1(O)CCCNC1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Product: CCNCC1(O)CCCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1

Procedure:
1-Cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is reacted analogously to Example 1 with 3-ethylaminomethyl-3-hydroxypiperidine to give 1-cyclopropyl-7-(3-ethylaminomethyl-3-hydroxy-1-piperidinyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 199°-203° C. (with decomposition).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16]C(C)([O-])C.[K+].CI>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[C:10]([CH3:16])([CH3:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1(C)CN(Cc2ccccc2)CCC1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 1-Benzyl-3-methyl-piperidin-4-one (2.03 g, 10 mmol) in THF (10 ml) was added potassium t-Butoxide (1.1 g, 10 mmol) and methyl iodide (0.62 ml, 10 mmol). The solution was then stirred at room temperature for about 72 hours. The reaction was quenched with brine and extracted with ethyl acetate. The combined organic layers were concentrated in vacuo, then purified by flash chromatography on silica gel (35 g SiO2, gradient elution from 100% hexane to 100% ethyl acetate) to yield the title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9](Cl)[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:19]1([SH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:19]1([S:25][C:2]2[C:15]3[C:14](=[O:16])[C:13]4[C:8](=[C:9]([S:25][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[CH:10]=[CH:11][CH:12]=4)[C:7](=[O:18])[C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Sc1ccccc1
Reactant: O=C1c2cccc(Cl)c2C(=O)c2cccc(Cl)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2cccc(Sc3ccccc3)c2C(=O)c2cccc(Sc3ccccc3)c21
Temperature: 125 °C
Reaction time: 1 h

Procedure:
1,5-Dichloroanthraquinone (100 parts) is added at room temperature with stirring to a mixture of dimethylformamide (474 parts), thiophenol (135 parts) and potassium carbonate (63 parts). The suspension is heated at 125° C. for 3 hours, cooled to room temperature and then cooled to 5° C. for 1 hour. The precipitate is filtered off and washed with a 50/50 mixture of 95% ethanol and 8% sodium hydroxide solution (2×250 parts). The filter cake is then slurried with a further 500 parts of the ethanol/sodium hydroxide solution mixture. After stirring at room temperature for 1 hour, the precipitate is filtered off and washed again with ethanol/sodium hydroxide solution mixture (5×100 parts), followed by water (250 parts) containing glacial acetic acetic acid (25 parts) and finally water (3×250 parts). The filter-cake is dried at 70° C. giving 140.4 parts of 1,5-bis(phenylthio) anthraquinone, mp (melting point) 256° C.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11])=[C:2]=[O:3].[NH2:13][C@H:14]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1>>[CH3:32][CH:31]([CH3:33])[C:30]([NH:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([CH:20]2[CH2:19][CH2:18][N:17]([CH2:16][CH2:15][C@H:14]([NH:13][C:2]([NH:1][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N+:10]([O-:12])=[O:11])=[O:3])[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:22][CH2:21]2)[CH:24]=1)=[O:34]
Reactant: O=C=Nc1ccccc1[N+](=O)[O-]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=O)Nc3ccccc3[N+](=O)[O-])c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure P and Scheme AB using 1-isocyanato-2-nitrobenzene and N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 543.6 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]2[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=2)[N:3]=1.[I:19][C:20]1[N:21]=[CH:22][NH:23][CH:24]=1>>[I:19][C:20]1[N:21]=[CH:22][N:23]([C:2]2[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]3[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=3)[N:3]=2)[CH:24]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)nc2)nc(Cl)n1
Reactant: Ic1c[nH]cn1
Product: Cc1cc(-c2ccc(C(F)(F)F)nc2)nc(-n2cnc(I)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-methyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example A.4) (0.27 g, 1.0 mmol) and commercially available 4-iodo-imidazole (0.21 g, 1.1 mmol) according to the general procedure IIa. Obtained as a light brown solid (0.35 g, 81%). MS (ISP) 432.1 [(M+H)+]; mp 193.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].CC#N.Cl[C:16]1[N:21]=[CH:20][C:19]([C:22](=[O:24])[CH3:23])=[CH:18][CH:17]=1>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:16]2[CH:17]=[CH:18][C:19]([C:22](=[O:24])[CH3:23])=[CH:20][N:21]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(=O)c1ccc(Cl)nc1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CC#N
Product: CCOC(=O)C1CCN(c2ccc(C(C)=O)cn2)CC1
Yield: 89.9 %

Procedure:
To a stirred solution of piperidine-4-carboxylic acid ethyl ester (12.6 g, 0.080 mol) in CH3CN (250 mol), iPr2Net (33.7 mL, 0.193 mol) and 1-(6-chloro-pyridin-3-yl)-ethanone (10 g, 0.064 mol) were added. The reaction mixture was heated at reflux over night, and then volatiles evaporated under high vacuum. Column chromatography (SiO2, EtOAc/heptane, 1:9 to 1:1) yielded 15.9 g (89%) of 5′-acetyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester as a yellow oil. ES-MS m/e: 277.2 (M+H+).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][C:13]2[C:21]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[NH:15][C:14]=2[CH:22]=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:24]([S:26]([C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33](=[O:38])[CH2:32]2)(=[O:28])=[O:27])[CH3:25]>>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][C:13]2[C:21]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[NH:15][C:14]=2/[CH:22]=[C:32]2\[C:33](=[O:38])[NH:34][C:35]3[C:31]\2=[CH:30][C:29]([S:26]([CH2:24][CH3:25])(=[O:28])=[O:27])=[CH:37][CH:36]=3)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: CC(=O)N1CCN(CCCc2c(C=O)[nH]c3c2CCCC3)CC1
Product: CCS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c3c(c1CCCN1CCN(C(C)=O)CC1)CCCC3)C(=O)N2
Yield: 65 %

Procedure:
3-[3-(4-Acetyl-piperazin-1-yl)-propyl]-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (70 mg, 0.22 mmol), prepared as described in Example 10 above, was condensed with 5-ethylsulfonyloxindole (69.5 mg, 1.01 eq, 72% pure) following the procedure used in Example 1 above. The formed solid was purified by flash chromatography using (dichloromethane: methanol 50/1, 30/1) to give 75 mg of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.C(O[CH:12]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>>[CH2:17]([O:16][C:14](=[O:15])[C:13](=[CH:12][NH:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:18]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: NC1=CC(=O)CCC1
Product: CCOC(=O)C(=CNC1=CC(=O)CCC1)C(=O)OCC
Temperature: 130 °C
Reaction time: 4 h
Yield: 89.8 %

Procedure:
A mixture of 3-amino-cyclohex-2-enone (3.3 g, 29.7 mmol) and diethyl 2-(ethoxymethylene)malonate (6.7 g, 31.2 mmol) was stirred at 130° C. for 4 h. The reaction mixture was concentrated under reduced pressure and the resulting oil was purified by column chromatography (silica gel, ethyl acetate) to give 2-[(3-oxo-cyclohex-1 -enylamino)-methylene]-malonic acid diethyl ester (7.5 g, 90%).