Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([Si:4](Cl)([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[F:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19]([C@@H:22]3[CH2:26][CH2:25][CH2:24][N:23]3[CH2:27][CH2:28][CH2:29][OH:30])=[N:20][N:21]=2)[CH:18]=1.CCN(CC)CC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19]([C@@H:22]3[CH2:26][CH2:25][CH2:24][N:23]3[CH2:27][CH2:28][CH2:29][O:30][Si:4]([CH:8]([CH3:10])[CH3:9])([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2])=[N:20][N:21]=2)[CH:18]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: OCCCN1CCC[C@H]1c1nnc2ccc(F)cn12
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[Si](OCCCN1CCC[C@H]1c1nnc2ccc(F)cn12)(C(C)C)C(C)C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
Triisopropylsilyl chloride (266 μ□L, 1.24 mmol) was added to a solution of Intermediate 84e (218 mg, 0.82 mmol) and Et3N (26 μ□L, 1.24 mmol) in DCM (8.00 mL). The reaction was stirred overnight then 4-(dimethylamino)pyridine (10.0 mg, 0.082 mmol) added. The reaction was stirred for 3 h then partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-7.5% [2M NH3 in MeOH] in DCM, to give the title compound (317 mg, 92%). 1H NMR (300 MHz, CDCl3): 0.92 (2H, s), 1.56-1.68 (2H, m), 1.89-2.10 (3H, m), 2.21-2.40 (3H, m), 2.56 (1H, dt, J 12.1, 7.9), 3.40 (1H, m), 3.46-3.64 (2H, m), 4.22 (1H, t, J 8.4), 7.16 (1H, ddd, J 9.9, 7.5, 2.3), 7.71 (1H, ddd, J 10.0, 4.9, 0.6), 8.64 (1H, m).
Reaction SMILES: C(O)(=O)C.[C:5]([O:9][C:10]([N:12]1[CH2:17][C@H:16]([CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:15](CC2C=CC=CC=2)[CH2:14][C@H:13]1[CH3:32])=[O:11])([CH3:8])([CH3:7])[CH3:6]>CCO.[Pd]>[C:5]([O:9][C:10]([N:12]1[CH2:17][C@H:16]([CH2:18][N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)[NH:15][CH2:14][C@H:13]1[CH3:32])=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: C[C@@H]1CN(Cc2ccccc2)[C@@H](CN2CCOCC2)CN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: C[C@@H]1CN[C@@H](CN2CCOCC2)CN1C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 95 %

Procedure:
Acetic acid (30.0 mL) and Pd/C (10%, 6.0 g) were added to a solution of (2R,5S)-4-benzyl-2-methyl-5-morpholin-4-ylmethyl-piperazine-1-carboxylic acid tert-butyl ester (9.0 g, 23.1 mmol) in EtOH (240 mL) and the resulting mixture was hydrogenated at 1 bar for 3 h. The catalyst was removed by filtration and the solvent was removed in vacuo. The residue was dissolved in DCM (150 mL), the organic solution was washed with saturated aqueous NaHCO3 (150 mL), water (150 mL), dried (MgSO4) and evaporated to give the title compound as a colourless gum (6.57 g, 95%). 1H NMR (CDCl3): 4.32-3.90 (1H, m), 3.77-3.64 (5H, m), 3.30 (1H, dd), 3.16-2.82 (2H, m), 2.67 (1H, dd), 2.59-2.49 (2H, m), 2.47-2.30 (2H, m), 2.21 (1H, dd), 2.17-2.07 (2H, m), 1.47 (9H, s), 1.27 (3H, d).
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)OCC)C.C(OP([CH:24](O)[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)(=O)OCC)C>O1CCCC1>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH:24]=[CH:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:26][CH:27]=1
Reactant: CCOP(=O)(OCC)C(O)c1ccc(Cl)cc1
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Solvent: C1CCOC1
Product: Clc1ccc(C=Cc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
22.8 g (0.1 mol) of benzylphosphonic acid diethyl ester were added dropwise to a solution, cooled to 0° to 5° C., of 22.4 g (0.2 mol) of potassium tert.-butylate in 100 ml of tetrahydrofuran (dried over sodium) in the course of 15 minutes. The mixture was stirred for one hour; a solution of 28 g (0.1 mol) of α-hydroxy-4-chlorobenzylphosphonic acid diethyl ester in 50 ml of tetrahydrofuran was then added to the mixture, while cooling to 0° to 5° C., and the mixture was stirred at room temperature (about 20° C.) for a further 15 hours. It was then poured into 1 liter of ice-water, filtered off and dried. 18 g (84% of theory) of 1-(4-chlorophenyl)-2-phenyl-ethylene were thus obtained in the form of colorless crystals of melting point 130° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:3]=1.[C:19]([O:23][C:24]([NH:26][C@H:27]1[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]1[NH2:33])=[O:25])([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:19]([O:23][C:24]([NH:26][C@@H:27]1[CH2:32][CH2:31][CH2:30][CH2:29][C@@H:28]1[NH:33][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:3]=1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: CCOC(=O)c1nc(Cl)c2cc(OC)ccc2n1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc(N[C@H]2CCCC[C@H]2NC(=O)OC(C)(C)C)c2cc(OC)ccc2n1
Yield: 82.6 %

Procedure:
A solution of 1.96 g of 4-chloro-2-ethoxycarbonyl-6-methoxyquinazoline in 70 mL of toluene was combined with 1.58 g of cis-2-tert-butoxycarbonylaminocyclohexylamine and 0.74 g of triethylamine, and heated under reflux for 15 hours. After concentrating, the mixture was combined with water, extracted with chloroform, and dried. After the solvent was distilled off, the residue was purified by column chromatography on silica gel (chloroform) to obtain 2.70 g of the desirable compound.
Reaction SMILES: C[O:2][C:3](=[O:35])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]2[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:34])=[O:26])=[CH:20][CH:19]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][O:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[OH-].[Na+]>C(O)C.O1CCCC1>[Cl:33][C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:34])[C:27]=1[C:25]([NH:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][C@@H:4]([C:3]([OH:35])=[O:2])[NH:5][C:6]([C:8]2([CH2:13][CH2:14][O:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])=[CH:19][CH:20]=1)=[O:26]
Reactant: COCCC1(C(=O)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)OC)CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COCCC1(C(=O)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)O)CCCC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[1-(2-methoxyethyl)cyclopentyl]carbonyl]-L-phenylalanine methyl ester (20.17 mmol, 10.52 g) in ethanol (80 mL) and tetrahydrofuran (10 mL) was added aqueous 1.0 N sodium hydroxide (80 mL) at room temperature. The mixture was heated to 50° C. and the resulting clear solution was stirred overnight. Then, the ethanol solution was concentrated and diluted with 50 mL of water and was extracted with 200 mL of ether to remove neutral impurities. The aqueous layer was acidified with 1N HCl and the precipitated white solid was collected by filtration and washed with 200 mL of water and 200 mL of hexane. After air-drying, 8.4 g (82%) of as a white solid: mp 136-140° C. was obtained. 1H NMR, DMSO-d6, (400 MHz) δ 10.64 (s, 1H), 7.73 (d, 1H, J=22 Hz), 7.46-7.59 (m, 5H), 7.22 (d, 2H, J=22 Hz), 4.43-4.48 (m, 1H), 2.87-31.1 (m, 7H), 1.76-2.01 (m 4H), 1.23-1.47 (m, 6H). HR MS (C25H28Cl2N2O5): Obs. mass, 507.1464. Calcd. mass, 507.1454 (M+H).
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([Li])CCC.[C:33]1(=O)[CH2:38][CH2:37][C:36](=[O:39])[CH2:35][CH2:34]1>C1COCC1.CCCCC>[CH:2](=[C:33]1[CH2:34][CH2:35][C:36](=[O:39])[CH2:37][CH2:38]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1CCC(=O)CC1
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCC
Solvent: C1CCOC1
Product: O=C1CCC(=Cc2ccccc2)CC1
Reaction time: 5 h
Yield: 120 %

Procedure:
To a mechanically stirred suspension of 15.24 g (0.035 mole) of benzyltriphenylphosphonium bromide in 150 ml of THF there was added first 22 ml of 1.61 N n-butyllithium in pentane and then 5.0 g (0.032 mole) of cyclohexane-1,4-dione, ethylene monoketal in 50 ml of THF. Following 5 hours' heating at reflux the mixture was allowed to cool and was then washed in turn with water and brine. The organic layer was concentrated, and the residue was chromatographed on 1 liter of silica gel, eluting with 20% ethyl acetate in Skellysolve® B, to afford 7.15 g (97%) of 4-benzylidenecyclohexanone, ethylene ketal as an oil, the nmr spectrum of which is in consonance with the structure.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[F:25][C:26]([F:41])([F:40])[C:27]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=1B(O)O>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:9]=[C:4]([C:3]([OH:2])=[O:24])[C:5]([C:28]4[CH:29]=[CH:30][C:31]([C:33]([F:36])([F:34])[F:35])=[CH:32][C:27]=4[C:26]([F:25])([F:40])[F:41])=[CH:6][CH:7]=3)[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1C(F)(F)F
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(F)(F)F)cc1C(F)(F)F
Yield: 5 %

Procedure:
Using the conditions of General Procedure A for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 111 mg, 0.25 mmol) was reacted with 2,4-bis(trifluoromethyl)phenylboronic acid (available from Combi-Blocks Inc.; 129 mg, 0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-2′,4′-bis-trifluoromethyl-biphenyl-2-carboxylic acid (7 mg, 5%). 1H NMR (300 MHz, DMSO-d6) δ 13.17 (br s, 1H), 8.62 (s, 1H), 8.50 (s, 1H), 8.27-8.37 (m, 2H), 8.05-8.15 (m, 3H), 7.77 (d, J=8.3 Hz, 1H), 7.64 (d, J=7.9 Hz, 1H), 7.48 (d, J=8.1 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][C:7]([CH:23]1C(C(C)C)CCC(C)C1)([CH:13]1C(C(C)C)CCC(C)C1)[CH2:6][C:5]2=[O:33].C(=O)([O-])[O-].[K+].[K+].[CH2:40](I)[CH3:41]>CC(CC)=O>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:40][CH3:41])[O:8][C:7]([CH3:13])([CH3:23])[CH2:6][C:5]2=[O:33]
Reactant: CCI
Reactant: CC1CCC(C(C)C)C(C2(C3CC(C)CCC3C(C)C)CC(=O)c3cc(O)c(O)cc3O2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOc1cc2c(cc1O)C(=O)CC(C)(C)O2
Reaction time: 3 h
Yield: 85 %

Procedure:
In 100 ml of methyl-ethyl-ketone 4.2 g (2 (20 millimoles) of 6,7-dihydroxy-2,2-dimenthyl-4chromanone are dissolved. To the solution 4.1 (30 millimoles) of potassium carbonate and 4.7 g (2.4 ml, 30 millimoles) of ethyl iodide are added and the reaction mixture is heated to boiling for 3 hours. The reaction mixture is worked up according to Example 17. Thus 4.0 g of the title compound are obtained, yield 85%. Mp.: 129°-130° C.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:3]([NH2:5])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH2:5][CH2:3][CH:2]([NH2:1])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCCCCCCCCC(N)C(N)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCC(N)CN
Yield: 69 %

Procedure:
To a slurry of 2-aminoeicosanamide prepared as in Example 28C (57.5 g, 0.176 mol) in anhydrous THF (1.0 l) under a dry argon atmosphere was added a solution of lithium aluminum hydride (880 ml-1.0 M in THF, 0.880 mol) over a 30 min period. The mixture was refluxed for 17.5 h and then quenched by the dropwise addition of H2O (100 ml) while cooling in an ice bath. The solid was filtered, washed with hot THF (2×1 l) and then hot methanol (1 l). The solids were then refluxed with THF (1 l) for 15 min and filtered again. The filtrates and washings were combined and the solvent was removed in vacuo. The crude product was dissolved in THF and solid impurities were removed by filtration. The solvent was again removed in vacuo and the procedure was continued using CH2Cl2. The crude product was recrystallized from CH2Cl2 -hexane to give 37.9 g (69% yield) of the product as : mp 98-101° C.; 1H NMR (CDCl3) δ 0.91 (t, J=6.5 Hz, 3 H), 1.33 (m, 34 H), 1.96 (br s, 4 H), 2.52 (m, 1 H), 2.78 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:3]=1[CH:4]=O.[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:15]1>C1(C)C=CC=CC=1>[CH2:20]([N:17]1[CH2:18][CH2:19][CH:14]([NH:13][CH2:4][C:3]2[C:6]([N+:10]([O-:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=2[Cl:1])[CH2:15][CH2:16]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=Cc1c(Cl)cccc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cccc(Cl)c1CNC1CCN(Cc2ccccc2)CC1

Procedure:
15 g 2-chloro-6-nitro-benzaldehyde and 4-amino-1-benzylpiperidine in 150 mL toluol were refluxed for 3 h. The toluol was removed and the residue was dissolved in 300 mL methanol. 6.6 g sodium borohydride was added and the reaction was refluxed over night. The solvent was removed, water and dichlormethane were added and the layers were separated. The organic layer was washed with water, dried and filtered to yield 29 g of the desired product.
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[N:29]=[CH:28][C:27]([CH2:30][OH:31])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:34][N:35]([CH3:39])[C:36](Cl)=[O:37]>C1COCC1>[CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[N:29]=[CH:28][C:27]([CH2:30][O:31][C:36](=[O:37])[N:35]([CH3:39])[CH3:34])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)nc1
Reactant: CN(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)C(=O)OCc1ccc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.3 %

Procedure:
{6-[4-(4-Benzyl-phthalazin-1-yl)-piperazin-1-yl]-pyridin-3-yl}-methanol (75 mg, 0.182 mmol) is dissolved in THF (1 mL) and added to a flask containing NaH (7.5 mg, 0.188 mmol). Stir 1 h at room temperature. Add dimethyl carbamoyl chloride (22 mg, 2.096 mmol) and stir for 16 h at room temperature. Incomplete conversion observed. Reaction is heated to 60° C. and stirred 16 h. Add additional NaH (7.5 mg, 0.188 mmol) is added and reaction quickly reaches 95% conversion. Concentrate reaction mixture in vacuo. The residue is purified by flash chromatography on silica gel (MeOH/CH2Cl2) to afford the title compound (24 mg, 27%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[S:3]([O:6][C:7]1[CH:8]=[C:9]2[CH:15]=[CH:14][S:13][C:10]2=[CH:11][N:12]=1)(=[O:5])=[O:4].C([O-])(=O)C.[Na+].[Br:23]Br.CC(O)=O.C([O-])([O-])=O.[Na+].[Na+]>>[F:17][C:2]([F:1])([F:16])[S:3]([O:6][C:7]1[CH:8]=[C:9]2[C:15]([Br:23])=[CH:14][S:13][C:10]2=[CH:11][N:12]=1)(=[O:5])=[O:4]
Reactant: BrBr
Reactant: O=S(=O)(Oc1cc2ccsc2cn1)C(F)(F)F
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=S(=O)(Oc1cc2c(Br)csc2cn1)C(F)(F)F
Temperature: 90 °C
Yield: 55 %

Procedure:
A sealable vial was charged with thieno[2,3-c]pyridin-5-yl trifluoromethanesulfonate (109 mg, 0.300 mmol), sodium acetate (75.3 mg, 0.900 mmol) and 1.0 M bromine in AcOH (0.900 mL, 0.900 mmol). The reaction was heated in a microwave reactor at 90° C. for 2 h. The reaction mixture was treated with aqueous Na2CO3 until the pH was >9, then extracted with EtOAc (3×20 mL). The combined extracts were washed with water (10 mL) and brine (10 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by ISCO chromatography (0 to 25% EtOAc:heptane) to afford 60 mg (55%) of the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.26 (d, J=0.4 Hz, 1 H), 8.61 (s, 1 H), 7.92 (d, J=1.2 Hz, 1H); MS (ESI): 362.08, 384.04 [M+H]+; HPLC tR=4.39 min (ZQ3: polar—5 min).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH2:10])=[CH:7][CH:8]=2)[CH2:3][C:2]21[O:14][CH2:13][CH2:12][O:11]2.Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17].C(N(CC)CC)C>C(Cl)Cl>[C:19]1([O:18][C:16](=[O:17])[NH:10][C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[CH2:1][C:2]2([O:11][CH2:12][CH2:13][O:14]2)[CH2:3]3)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc2c(c1)CC1(C2)OCCO1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2c(c1)CC1(C2)OCCO1)Oc1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of 1′,3′-Dihydro-spiro[[1,3]dioxolane-2,2′-inden]-5′-ylamine (1.0 g, 5.23 mmol) in CH2Cl2 (15 mL) was added phenyl chloroformate (0.66 mL, 5.23 mmol) drop wise at room temperature followed by triethylamine (1.15 mL, 8.3 mmol). The reaction mixture was stirred at r.t for 30 min and then solvent was removed under vacuum. Water was added to the resulting crude product and the precipitate was filtered and dried to give the crude (1′,3′-Dihydro-spiro[[1,3]dioxolane-2,2′-inden]-5′-yl)-carbamic acid phenyl ester as a pale yellow solid (1.62 g, quantitative).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:12]=[CH:11][C:10]2[C:9](=[O:13])[CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1.[CH3:14][N:15]([CH:17](OC)OC)[CH3:16]>C1(C)C=CC=CC=1>[CH3:14][N:15](/[CH:17]=[C:8]1/[C:9](=[O:13])[C:10]2[CH:11]=[N:12][C:3]([S:2][CH3:1])=[N:4][C:5]=2[CH2:6][CH2:7]/1)[CH3:16]
Reactant: CSc1ncc2c(n1)CCCC2=O
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CSc1ncc2c(n1)CC/C(=C\N(C)C)C2=O
Temperature: 25 °C
Yield: 60.2 %

Procedure:
To a solution of 2-(methylthio)-7,8-dihydroquinazolin-5(6H)-one (0.2 g, 1.0 mmol) in toluene (3 mL) was added DMFDMA (0.2 mL, 1.5 mmol). The reaction mixture was then refluxed for 16 hours. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (SiO2, gradient from 100% dichloromethane to 2% methanol in dichloromethane) to give the pure desired product (0.15 g, 60%) as a solid. 1H NMR (CDCl3, 400 MHz): δ 9.0 (s, 1H), 7.72 (s, 1H), 3.18 (s, 6H), 2.98 (t, J=6.0 Hz, 2H), 2.92 (t, J=6.0 Hz, 2H), 2.60 (s, 3H); LCMS [M+H]: 250.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:6][C:7]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:8][CH:9]=1)[CH3:3].[N+](N[C:19]1[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]2[CH:32]=[CH:31][N:30]([CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])[C:29](=[O:38])[CH:28]=2)=[CH:21][N:20]=1)([O-])=O>N1C=CC=CC=1>[CH3:3][N:2]([CH2:4][C:5]1[O:6][C:7]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:19]2[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]3[CH:32]=[CH:31][N:30]([CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])[C:29](=[O:38])[CH:28]=3)=[CH:21][N:20]=2)=[CH:8][CH:9]=1)[CH3:1]
Reactant: CN(C)CCn1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cc1=O
Reactant: CN(C)Cc1ccc(CSCCN)o1
Solvent: c1ccncc1
Product: CN(C)CCn1ccc(Cc2cnc(NCCSCc3ccc(CN(C)C)o3)[nH]c2=O)cc1=O

Procedure:
2-(2-Dimethylaminomethyl-5-furylmethylthio)ethylamine (4.00 g) and 2-nitroamino-5-[1-(2-dimethylaminoethyl)-2-oxopyridin-4-yl-methyl]pyrimidin-4-one (7.14 g) were refluxed in pyridine (50 ml) for 24 hours. The reaction mixture was evaporated under reduced pressure and the residue subjected to medium pressure column chromatography (Kieselgel 60 silica mesh - main column) using ethyl acetate:methanol (80:20→70:30) gradient elution. The fractions containing the desired title product were evaporated in vacuo and treated with maleic acid (1.79 g) in isopropanol. The solvent was evaporated under reduced pressure and the residue washed with acetone and cold isopropanol. On standing at 5° C. the residue crystallised from ethanol-methanol to yield 2-[2-(2-dimethylaminomethyl-5-furylmethylthio)ethylamino]-5-[1-(2-dimethylaminoethyl)-2-oxopyridin-4-ylmethyl]pyrimidin-4-one as a maleate salt (0.79 g), m.p. 123°-126° C.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@H:6]([CH:22]([CH3:24])[CH3:23])[C:7]([N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)=[O:8])=[O:4].[NH:25]1[CH:29]=[CH:28][CH:27]=[N:26]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH:12]2[CH2:13][CH2:14][N:9]([C:7](=[O:8])[C@H:6]([NH:5][C:3](=[O:4])[CH2:2][N:25]3[CH:29]=[CH:28][CH:27]=[N:26]3)[CH:22]([CH3:24])[CH3:23])[CH2:10][CH2:11]2)=[CH:16][CH:17]=1
Reactant: c1cn[nH]c1
Reactant: CC(C)[C@@H](NC(=O)CCl)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)[C@@H](NC(=O)Cn1cccn1)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Temperature: 75 °C
Yield: 93.4 %

Procedure:
In a sealed vial were added consecutively (R)-2-chloro-N-(1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methyl-1-oxobutan-2-yl)acetamide (31.4 mg, 0.085 mmol), pyrazole (11.5 mg, 0.17 mmol), K2CO3 (35.2 mg, 0.26 mmol) and acetonitrile (0.4 mL). The reaction mixture was then heated at 75° C. for 36 h, cooled to rt., and the solids were filtered. The filtrate was concentrated and purified by preparative HPLC to provide Example 290, (R)—N-(1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methyl-1-oxobutan-2-yl)-2-(1H-pyrazol-1-yl)acetamide (32 mg, 94% yield) as a white solid. MS found: 403.3 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([N:41]5[CH2:46][CH2:45][CH2:44][CH:43](O[Si](C(C)C)(C(C)C)C(C)C)[C@H:42]5C)=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH3:77][OH:78]>C1COCC1.C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([N:41]5[CH2:46][CH2:45][CH2:44][C@@H:43]([CH2:77][OH:78])[CH2:42]5)=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:8]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[N:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCC(O[Si](C(C)C)(C(C)C)C(C)C)[C@H]5C)n4c3)c3ccccc32)cc1
Reactant: CO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCC[C@@H](CO)C5)n4c3)c3ccccc32)cc1

Procedure:
A brown solution of Intermediate 77d (135 mg, 0.168 mmol) and TBAF (1M in THF, 0.184 mL, 0.184 mmol) in THF (3 mL) was stirred at RT for 1 h. The solution was concentrated in vacuo, suspended in water (10 mL) and extracted with EtOAc-MeOH (19:1, 2×10 mL). The combined organics were washed with brine (10 mL), dried (Na2SO4), filtered and concentrated in vacuo to leave a brown solid. FCC, using 5-9% MeOH in DCM, gave a pale brown solid. Further purification by HPLC (XBridge C18 column, 25-75% MeCN in H2O, 0.1% NH4OH) gave the title compound as a white powder after freeze-drying (63.9 mg, 59%). LCMS (Method 5): Rt 4.33 min, m/z 649 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.27 (9H, s), 1.29-1.35 (1H, m), 1.71-1.77 (3H, m), 1.82-1.96 (3H, m), 2.01-2.17 (2H, m), 2.36 (3H, s), 3.02-3.07 (2H, m), 3.20 (1H, dd, J 11.9, 3.3), 3.25-3.28 (1H, m), 3.42 (1H, dt, J 10.5, 5.0), 3.52-3.58 (1H, m), 4.69 (1H, t, J 5.1), 4.81 (1H, td, J 8.6, 5.4), 5.48 (1H, t, J 4.3), 6.32 (1H, s), 7.09 (1H, d, J 8.3), 7.12 (1H, dd, J 9.9, 2.1), 7.27-7.39 (8H, m), 7.60 (1H, d, J 9.9), 7.80 (1H, d, J 2.1), 8.04 (1H, s).