Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N:6]([CH2:9][C:10]([C:13]1[C:18]([F:19])=[CH:17][N:16]=[C:15]([Br:20])[CH:14]=1)([OH:12])[CH3:11])=[N+:7]=[N-:8].CCN(CC)CC>C(Cl)Cl>[N:6]([CH2:9][C:10]([O:12][S:2]([CH3:1])(=[O:4])=[O:3])([C:13]1[C:18]([F:19])=[CH:17][N:16]=[C:15]([Br:20])[CH:14]=1)[CH3:11])=[N+:7]=[N-:8]
Reactant: CC(O)(CN=[N+]=[N-])c1cc(Br)ncc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(CN=[N+]=[N-])(OS(C)(=O)=O)c1cc(Br)ncc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At 0° C., methanesulfonyl chloride (2.04 ml, 3.00 g, 26.20 mmol) was dropwise added to a solution of 1-azido-2-(2-bromo-5-fluoro-pyridin-4-yl)-propan-2-ol (6.00 g, 21.81 mmol) and NEt3 (3.65 ml, 2.65 g, 26.2 mmol) in DCM (200 ml). The reaction mixture was stirred at 0° C. for 1 h, then for another 1 h at 0° C. to rt. The reaction mixture was quenched with 1M aq. NaHCO3 soln. and diluted with DCM. The phases were separated and the aq. phase was twice reextracted with DCM. The combined org. phases were dried over Na2SO4, filtered and concentrated. HPLC purification (Alltech Grom Saphir 65 Si 10 μM column, 250×50 mm, gradient n-heptane:EtOAc 0-1.6 min 85:15, 1.6-16 min 0:100, 16-21.2 min 0:100, flow 100 ml/min, detection 254 nm) yielded the title compound as well as recovered starting material that could be reacted again according to the above procedure. HPLC RtH4=0.96 min; ESIMS: 353, 355 [(M+H)+]; 1H NMR (400 MHz, CDCl3): δ 8.28 (d, 1H), 7.56 (d, 1H), 4.08 (d, 1H), 3.82 (d, 1H), 3.22 (s, 3H), 2.13 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:13][O:12][C:5]2([CH2:11][CH2:10][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3]1.[CH2:15]([NH2:18])[CH2:16][CH3:17].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[CH3:1][C:2]1([CH3:14])[CH2:13][O:12][C:5]2([CH2:11][CH2:10][C:8](=[N:18][CH2:15][CH2:16][CH3:17])[CH2:7][CH2:6]2)[O:4][CH2:3]1
Reactant: CC1(C)COC2(CCC(=O)CC2)OC1
Reactant: CCCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCN=C1CCC2(CC1)OCC(C)(C)CO2

Procedure:
A 500 ml round bottom flask was charged with 20.32 g (0.103 mol) of 3,3-dimethyl-1,5-dioxazpiro[5.5]undecan-9-one (also known as 1,4-cyclohexanedione mono-2,2-dimethyltrimethylene ketal, from Aldrich Chemical Company, Milwaukee, Wis.), 21.6 g (0.365 mol) of n-propylamine (Eastman Chemical Company, Rochester, N.Y.), 0.01 g of p-toluenesulfonic acid and 100 ml of toluene. The reaction mixture was refluxed for 24 hours with a water separator charged with 16 g of 3-A molecular sieves. The volatiles were removed in vacuo and the residue was held for further synthetic modifications as described below.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([CH3:19])[CH:13]=[C:12]2Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1([CH:27]2[CH2:31][CH2:30][NH:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCCO)C.O>[CH2:1]([NH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([CH3:19])[CH:13]=[C:12]2[N:29]1[CH2:30][CH2:31][CH:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:28]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(Cl)c2cc(NCc3ccccc3)ccc2n1
Reactant: c1ccc(C2CCNC2)cc1
Solvent: O
Solvent: CCOCCO
Product: Cc1cc(N2CCC(c3ccccc3)C2)c2cc(NCc3ccccc3)ccc2n1

Procedure:
Benzyl-(4-chloro-2-methylquinolin-6-yl)amine (0.041 g; see Preparation 4 above) and 3-phenylpyrrolidine in 2-ethoxyethanol (1 mL) were heated in a microwave to 240° C. for 10 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate, washed with water, dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica, eluting with a mixture of dichloromethane, and methanol. The desired fractions were concentrated and the sample evaporated to dryness. Trituration from ether gave the title compound.
Reaction SMILES: [NH2:1][C:2]1([C:5]2[CH:6]=[C:7]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([Cl:19])[CH:12]=3)[CH:8]=[N:9][CH:10]=2)[CH2:4][CH2:3]1.[CH2:20]([S:22](Cl)(=[O:24])=[O:23])[CH3:21]>C(Cl)Cl>[Cl:19][C:13]1[CH:12]=[C:11]([C:7]2[CH:6]=[C:5]([C:2]3([NH:1][S:22]([CH2:20][CH3:21])(=[O:24])=[O:23])[CH2:3][CH2:4]3)[CH:10]=[N:9][CH:8]=2)[CH:18]=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: N#Cc1ccc(-c2cncc(C3(N)CC3)c2)cc1Cl
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Product: CCS(=O)(=O)NC1(c2cncc(-c3ccc(C#N)c(Cl)c3)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(5-(1-aminocyclopropyl)pyridin-3-yl)-2-chlorobenzonitrile (70 mg, 0.26 mmol) in DCM (3 mL) at room temperature was added TEA (0.109 mL, 0.779 mmol) and EtSO2Cl (74 μL, 0.779 mmol) dropwise, and the mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo, re-dissolved in DMF (3 mL) and filtered. The filtrate was purified by Xbridge Phenyl followed by Xbridge C18 eluting with 20-80% ACN-water gradient to give N-(1-(5-(3-chloro-4-cyanophenyl)pyridin-3-yl)cyclopropyl)ethanesulfonamide. HRMS: (ESI) m/z 362.0712 [(M+H)+ Calcd for C17H16ClN3O2S 362.0725]. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.28 (t, J=7.3 Hz, 3H), 1.32-1.38 (m, 2H), 1.49-1.54 (m, 2H), 2.90 (q, J=7.4 Hz, 2H), 7.60 (dd, J=8.1, 1.8 Hz, 1H), 7.74 (d, J=1.8 Hz, 1H), 7.79 (d, J=8.1 Hz, 1H), 8.01 (t, J=2.3 Hz, 1H), 8.67 (d, J=2.3 Hz, 1H), 8.72 (d, J=2.3 Hz, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH:11]=[C:10]([C:22]([O:24][CH3:25])=[O:23])[C:9]=2[C:26]([O:28][CH3:29])=[O:27])[CH:5]=[CH:4][N:3]=1.P(Br)(Br)[Br:31]>ClC(Cl)C(Cl)Cl>[Br:31][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH:11]=[C:10]([C:22]([O:24][CH3:25])=[O:23])[C:9]=2[C:26]([O:28][CH3:29])=[O:27])[CH:5]=[CH:4][N:3]=1
Reactant: BrP(Br)Br
Reactant: COC(=O)c1cc2cc(OC)c(OC)cc2c(-c2ccnc(Cl)c2)c1C(=O)OC
Solvent: ClC(Cl)C(Cl)Cl
Product: COC(=O)c1cc2cc(OC)c(OC)cc2c(-c2ccnc(Br)c2)c1C(=O)OC
Temperature: 100 °C
Reaction time: 10 h

Procedure:
A mixture of 1-(2-chloro-4-pyridyl)-2,3-bis(methoxycarbonyl)-6,7-dimethoxynaphthalene (22.7 g), phosphorus tribromide (52 ml) and 1,1,2,2-tetrachloroethane (100 ml) is stirred at 100° C. for 10 hours. After the reaction is complete, the mixture is concentrated under reduced pressure to remove the solvent, and thereto are added methylene chloride and an aqueous potassium carbonate solution. The methylene chloride layer is separated, and concentrated under reduced pressure to remove the solvent. The residue is crystallized from methanol to give 1-(2-bromo-4-pyridyl)-2,3-bis(methoxycarbonyl)-6,7-dimethoxynaphthalene (17.1 g).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([CH3:35])[CH:29]=1>>[Cl:26][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:34][C:31]2[CH:32]=[CH:33][C:28]([F:27])=[CH:29][C:30]=2[CH3:35])=[N:3][CH:4]=1
Reactant: Cc1cc(F)ccc1O
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Product: Cc1cc(F)ccc1Oc1ncc(Cl)cc1C(=O)N[C@@H](C)c1ccc(C(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from tert-butyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 45) and 4-fluoro-2-methylphenol: 1H-NMR (CDCl3) δ 8.57 (1H, d, J=2.6 Hz), 8.22 (1H, d, J=7.6 Hz), 8.11 (1H, d, J=2.6 Hz), 7.96 (2H, d, J=8.4 Hz), 7.41 (2H, d, J=8.4 Hz), 7.13–6.93 (3H, m), 5.39 (1H, dq, J=7.6, 6.9 Hz), 2.12 (3H, s), 1.60 (3H, d, J=6.9 Hz), 1.58 (9H, s); MS (ESI) m/z 485 (M+H)+, 483 (M−H)−.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][C:30]=2[CH3:32])[N:25]=[CH:24][N:23]=1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][C:30]=4[CH3:32])[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(O)c2)no1
Reactant: Cc1cccc2ncnc(Cl)c12
Product: Cc1cccc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c12

Procedure:
To 1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea from Example 1A (83 mg, 0.3 mmol) was added 4-chloro-5-methylquinazoline from the previous step (53 mg, 0.3 mmol) using the procedure described in Example 1B Step 1, to afford the title compound.
Reaction SMILES: C([O:3][CH:4](OCC)/[CH:5]=[CH:6]/[C:7]1[C:8]2[S:16][CH:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)[C:9]=2[C:10]([NH2:13])=[N:11][CH:12]=1)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.CC(C)=O>O>[NH2:13][C:10]1[C:9]2[C:14]([C:17]3[CH:18]=[CH:19][C:20]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:21][CH:22]=3)=[CH:15][S:16][C:8]=2[C:7](/[CH:6]=[CH:5]/[CH:4]=[O:3])=[CH:12][N:11]=1
Reactant: CCOC(/C=C/c1cnc(N)c2c(-c3ccc(Oc4ccccc4)cc3)csc12)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: Nc1ncc(/C=C/C=O)c2scc(-c3ccc(Oc4ccccc4)cc3)c12
Yield: 106 %

Procedure:
A mixture of Example 360A (170 mg, 0.38 mmol), p-toluenesulfonic acid (10 mg), acetone (9 mL), and water (1 mL) was stirred for 1.25 hours and concentrated. The residue partioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic layer was dried (MgSO4), filtered, and concentrated to provide the desired product (150 mg). 1H NMR (DMSO-d6, 400 MHz) δ 9.66 (d, 1H), 8.32 (s, 1H), 7.89 (d, 1H), 7.68 (s, 1H), 7.47 (m, 4H), 7.20 (t, 1H), 7.14 (m, 4H), 6.65 (dd, 1H); MS m/e 373.3 (M+H)+, 371.1 (M−H)−.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[C:7]1(=[N:11][S:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])[CH2:10][CH2:9][CH2:8]1>C(Cl)Cl.CCOC(C)=O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[C:5]([C:7]1([NH:11][S:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])[CH2:8][CH2:9][CH2:10]1)#[N:6]
Reactant: C[Si](C)(C)C#N
Reactant: CC(C)(C)S(=O)N=C1CCC1
Agent: [Ti+4]
Agent: CC[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)S(=O)NC1(C#N)CCC1
Reaction time: 16 h
Yield: 81.5 %

Procedure:
Titanium (IV) ethoxide (3.03 g, 13.3 mmol) was added to a stirring solution of trimethylsilyl cyanide (7.12 mL, 53.1 mmol) and N-cyclobutylidene-2-methylpropane-2-sulfinamide (4.6 g, 27 mmol) in DCM (100 mL) at rt. The reaction was allowed to stir for 16 h. An additional 1.7 mL of TMS-CN was added followed by 1.5 g of TiOEt4. The reaction was allowed to stir at rt for an additional 16 h. The mixture was diluted with EtOAc and washed with sat NaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give N-(1-cyanocyclobutyl)-2-methylpropane-2-sulfinamide (4.5 g, 22 mmol, 85% yield) consistent by NMR. 1H NMR (400 MHz, CHLOROFORM-d) δ 2.82-2.67 (m, 2H), 2.62-2.34 (m, 2H), 2.26-2.02 (m, 2H), 1.26 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[CH3:13][NH:14][CH2:15][CH2:16][OH:17]>C(Cl)Cl.[OH-].[Na+]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([N:14]([CH2:15][CH2:16][OH:17])[CH3:13])(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Reactant: CNCCO
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CN(CCO)S(=O)(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.4 %

Procedure:
2,4-Difluorobenzenesulfonyl chloride (4 g, 18.81 mmol) in DCM (10 mL) was added slowly to a solution of 2-(methylamino)ethanol (1.66 mL, 20.70 mmol) in DCM (200 mL) and 10% sodium hydroxide solution (200 mL) at 0° C. The reaction was allowed to warm to RT and stirred for 20 hours. The DCM layer was separated and the aqueous re-extracted into DCM (2×50 mL). The combined organics were washed with brine, dried (MgSO4), filtered and reduced in vacuo to give the desired compound as a colourless oil (4.7 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][N:11]3[CH2:14][C:13](=[CH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][C:17]=4[Cl:25])[CH2:12]3)[CH:8]=2)[CH:3]=[CH:2]1.CCN(C(C)C)C(C)C.[C:35]([O:39][C:40](=[O:49])[NH:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[NH2:48])([CH3:38])([CH3:37])[CH3:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][N:11]3[CH2:14][C:13](=[CH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20]([NH:48][C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=5[NH:41][C:40](=[O:49])[O:39][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:21])=[CH:18][C:17]=4[Cl:25])[CH2:12]3)[CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)c1ccc(C=C2CN(Cc3ccc4cc[nH]c4c3)C2)c(Cl)c1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C=C2CN(Cc3ccc4cc[nH]c4c3)C2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.8 %

Procedure:
To a solution of 4-((1-((1H-indol-6-yl)methyl)azetidin-3-ylidene)methyl)-3-chlorobenzoic acid (0.26 g, 0.74 mmol) in DCM (25 mL) was added DIPEA (0.29 g, 2.22 mmol), tert-butyl-2-aminophenylcarbamate (0.27 g, 1.18 mmol) and HATU (0.37 g, 0.96 mmol). The reaction mixture was stirred overnight at room temperature under a nitrogen atmosphere. After completion of the reaction as indicated by HPLC, the mixture was washed with saturated sodium bicarbonate (2×20 mL) and brine (1×15 mL). It was dried (Na2SO4), filtered and evaporated to give the crude product which was purified by column chromatography (10% MeOH: 90% DCM). After evaporation of pooled fractions of pure product, tert-butyl (2-(4-((1-((1H-indol-6-yl)methyl)azetidin-3-ylidene)methyl)-3-chlorobenzamido)phenyl)carbamate (0.2 g) was isolated as an off-white solid. ES+(M+H)+ 543.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:23])([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[CH2:9][NH:10][C:11](=[O:14])[CH2:12]Cl)=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].O>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=3)[CH2:9][NH:10][C:11](=[O:14])[CH2:12][O:23]2)=[CH:4][CH:3]=1
Reactant: COc1cccc(C(O)(CNC(=O)CCl)c2ccc(Br)cc2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Product: COc1cccc(C2(c3ccc(Br)cc3)CNC(=O)CO2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.2 %

Procedure:
To a solution of N-[2-(4-bromo-phenyl)-2-hydroxy-2-(3-methoxy-phenyl)-ethyl]-2-chloro-acetamide (3.67 g, 9.2 mmol), in benzene (205 mL) at room temperature was added t-BuOK (4.54 g, 40.5 mmol). The reaction mixture was stirred at room temperature for 2 h. To the mixture was added water (40 mL) and the aqueous layer was washed with CH2Cl2 (2×50 mL). The combined organic extracts were dried over MgSO4 and concentrated. Purification by flash chromatography with hexanes/EtOAc (3:1) afforded 3.34 g of 6-(4-bromo-phenyl)-6-(3-methoxy-phenyl)-morpholin-3-one. 1HNMR (400 MHz, CDCl3) δ 7.46-7.41 (comp, 2H), 7.27-7.17 (comp, 2H), 6.89-6.70 (comp, 3H), 6.69 (br, 1H), 4.10 (s, 2H), 3.93-3.80 (comp, 2H), 3.76 (s, 3H); MS (M+1) 362.1, 364.1.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6]([CH3:8])=[C:5]([C:9]([O:11][CH3:12])=[O:10])[CH:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[Cl:20])[C:3]=1[C:21]#[N:22].[C:23](OC(=O)C)(=[O:25])[CH3:24].C(OC)(=O)C>CO>[C:23]([NH:1][C:2]1[NH:7][C:6]([CH3:8])=[C:5]([C:9]([O:11][CH3:12])=[O:10])[CH:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[Cl:20])[C:3]=1[C:21]#[N:22])(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)C1=C(C)NC(N)=C(C#N)C1c1cccc(Cl)c1Cl
Solvent: COC(C)=O
Solvent: CO
Product: COC(=O)C1=C(C)NC(NC(C)=O)=C(C#N)C1c1cccc(Cl)c1Cl

Procedure:
6.7 g (20 mmol) of methyl 6-amino-5-cyano-4-(2,3-dichlorophenyl)-2-methyl-1,4-dihydropyridine-3-carboxylate and 33.5 ml (350 mmol) of acetic anhydride are heated under reflux for 30 minutes. Excess acetic anhydride is then converted into methyl acetate by addition of methanol at 25° C., while stirring. The reaction solution is evaporated in vacuo and toluene is then shipped off from the residue twice in vacuo. The residue is then boiled up with 50 ml of toluene. The crystals which have separated out are filtered off and washed with toluene.
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([Cl:11])[C:5]=2[NH:4][CH:3]=1.[CH3:12]N(C)C=O.[H-].[Na+].CI>C(OCC)(=O)C>[Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([Cl:11])[C:5]=2[N:4]([CH3:12])[CH:3]=1
Reactant: Clc1ncnc2c(Br)c[nH]c12
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Product: Cn1cc(Br)c2ncnc(Cl)c21
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To 7-bromo-4-chloro-5H-pyrrolo[3,2-d]pyrimidine (147 mg), N,N-dimethylformamide (10 mL) was added, and NaH (36 mg) was further added thereto, followed by stirring for 30 min. Subsequently, methyl iodide was added thereto, and the reaction mixture was heated to 50° C. and stirred for 2 hours. After completion of the reaction, the reaction mixture was mixed with ethyl acetate and washed with water. The washed mixture was dried over anhydrous sodium sulfate, and filtered and distilled under reduced pressure to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:9]([CH2:11][OH:12])=[CH:10][C:5]=2[NH:4][N:3]=1.[C:21]1(=O)[O:26][C:24](=[O:25])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12>O1CCOCC1>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:8]1[C:9]([CH2:11][OH:12])=[CH:10][C:5]2[NH:4][N:3]=[C:2]([N:1]3[C:24](=[O:25])[C:23]4[C:22](=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:21]3=[O:26])[C:6]=2[C:7]1=[O:20]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1n[nH]c2cc(CO)n(-c3ccccc3Cl)c(=O)c12
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)N1c1n[nH]c2cc(CO)n(-c3ccccc3Cl)c(=O)c12
Temperature: 25 °C
Yield: 49.1 %

Procedure:
A mixture of 3-amino-5-(2-chlorophenyl)-6-(hydroxymethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one obtained in Step H (450 mg), phthalic anhydride (321 mg) and 1,4-dioxane (5.20 mL) was refluxed overnight, and cooled to room temperature. The resulting solid was collected by filtration, and washed with ethyl acetate to give the title compound (320 mg).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].[SH2:12].C(NCC)C>CN(C=O)C>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[S:12])[NH2:7])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: S
Reactant: COc1cc(C#N)ccc1O
Solvent: CCNCC
Solvent: CN(C)C=O
Product: COc1cc(C(N)=S)ccc1O
Temperature: 70 °C

Procedure:
A solution of 4-hydroxy-3-methoxybenzonitrile (15.0 g, 0.1 mol) in DMF (150 mL) was treated with a slow flow of gaseous hydrogen sulfide for 30 minutes at rt. Diethyl amine (15.6 mL, 11.0 g, 0.15 mol) was added and the solution was heated at 70° C. for 4 h. The solution was cooled to rt and the residual H2S was removed by passing argon through the solution for 30 minutes. The solvent was evaporated under reduced pressure and the residue was filtered through a plug of silica, followed by washing with EtOAc. Removal of the solvent resulted in a crude brown oil, which was used in the next step without further purification.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:15][CH2:14][N:13]([CH2:16][C:17]([F:20])([F:19])[F:18])[CH2:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:21][C:22]([OH:24])=O.[NH2:25][C:26]1[N:31]=[CH:30][C:29]2[CH2:32][C:33]3([CH2:43][C:28]=2[CH:27]=1)[C:41]1[C:36](=[N:37][CH:38]=[CH:39][CH:40]=1)[NH:35][C:34]3=[O:42].C1CN(C(Cl)=[N+]2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1>[O:42]=[C:34]1[NH:35][C:36]2=[N:37][CH:38]=[CH:39][CH:40]=[C:41]2[C:33]21[CH2:32][C:29]1[CH:30]=[N:31][C:26]([NH:25][C:22](=[O:24])[CH2:21][N:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[C:10]4([CH2:15][CH2:14][N:13]([CH2:16][C:17]([F:18])([F:19])[F:20])[CH2:12][CH2:11]4)[C:2]3=[O:1])=[CH:27][C:28]=1[CH2:43]2
Reactant: O=C(O)CN1C(=O)C2(CCN(CC(F)(F)F)CC2)c2ccccc21
Reactant: Nc1cc2c(cn1)CC1(C2)C(=O)Nc2ncccc21
Agent: ClC(N1CCCC1)=[N+]1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(CN1C(=O)C2(CCN(CC(F)(F)F)CC2)c2ccccc21)Nc1cc2c(cn1)CC1(C2)C(=O)Nc2ncccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-oxo-1′-(2,2,2-trifluoroethyl)-spiro[indoline-3,4′-piperidine]-1-acetic acid (79 mg, 0.23 mmol, described in Intermediate 11), (±)-3-amino-5,7-dihydrospiro[cyclopenta[c]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (71 mg, 0.28 mmol, described in Intermediate 3), N,N,N′,N′-bis(tetramethylene)chloroformamidinium hexafluorophosphate (153 mg, 0.46 mmol), and N,N-diisopropylethylamine (0.20 mL, 1.15 mmol) in THF (2 mL) is stirred at ambient temperature for 18 h. The reaction mixture is purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and made basic with saturated aqueous NaHCO3. The resulting mixture is extracted with EtOAc (3×20 mL), and the combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound.
Reaction SMILES: [N+:1]([C:4]1[C:5]([O:19][CH2:20][CH2:21][O:22][C:23](=[O:25])[CH3:24])([CH:7]=[CH:8][C:9]([O:12][CH2:13][CH2:14][O:15][C:16](=[O:18])[CH3:17])(O)[CH:10]=1)O)([O-])=O.[H][H]>C(O)C.[Pd]>[C:23]([O:22][CH2:21][CH2:20][O:19][C:5]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][CH2:14][O:15][C:16](=[O:18])[CH3:17])=[CH:10][C:4]=1[NH2:1])(=[O:25])[CH3:24]
Reactant: CC(=O)OCCOC1(O)C=CC(O)(OCCOC(C)=O)C([N+](=O)[O-])=C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(=O)OCCOc1ccc(OCCOC(C)=O)c(N)c1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
2-Nitro-1,4-bis-(2-acetoxyethoxy)hydroquinone (115 g) was dissolved in ethanol at 50° C. and reduced with hydrogen in the presence of palladium catalyst (2 g, 5% Pd/C). When uptake of hydrogen ceased the solution was screened to remove the catalyst and the filtrates allowed to cool to room temperature. The crystalline solid was isolated by filtration and dried under vacuum to give 90 g of product.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.F[C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[C:18](=[O:26])[NH:19][CH:20]=[N:21]2>>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([O:1][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[C:18](=[O:26])[NH:19][CH:20]=[N:21]3)[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=c1[nH]cnc2cccc(F)c12
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc3nc[nH]c(=O)c23)CC1
Yield: 103 %

Procedure:
Thus, tert-butyl 4-hydroxypiperidine-1-carboxylate (0.33 g) was reacted with 5-fluoro-3,4-dihydroquinazolin-4-one (0.18 g) to give 5-(1-tert-butoxycarbonylpiperidin-4-yloxy)-3,4-dihydroquinazolin-4-one (0.39 g); NMR Spectrum: (CDCl3) 1.5 (s, 9H), 1.9–2.0 (m, 4H), 3.52 (m, 2H), 3.7 (m, 2H), 4.72 (m, 1H), 6.95 (d, 1H), 7.32 (d, 1H), 7.65 (m, 1H), 7.95 (s, 1H), 10.22 (br s, 1H); Mass Spectrum: M+H+ 346;
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:8])([CH3:7])[C:4](=[NH:6])[NH2:5].Br[C:10]1[C:11](=O)[CH2:12][CH2:13][C:14]=1[O:15]C.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>CN(C)C=O>[CH3:2][C:3]([C:4]1[NH:5][C:11]2[CH2:12][CH2:13][C:14](=[O:15])[C:10]=2[N:6]=1)([CH3:8])[CH3:7]
Reactant: COC1=C(Br)C(=O)CC1
Reactant: CC(C)(C)C(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc2c([nH]1)CCC2=O
Temperature: 80 °C
Yield: 73.4 %

Procedure:
A mixture of 2,2-dimethylpropanimidamide hydrochloride (0.858 g), 2-bromo-3-(methyloxy)-2-cyclopenten-1-one (1 g) and potassium carbonate (2.53 g) in N,N-dimethylformamide (15 mL) were heated at 80° C. for 20 h. The reaction mixture was cooled down to room temperature and DCM (20 mL) was added. The mixture was filtered and the filtrate concentrated under vacuum. The residue was purified by reverse phase chromatography using Acetonitrile Water with an ammonium carbonate modifier gradient (5-40%). The desired fractions were combined and concentrated under vacuum to yield 685 mg of the title compound. LC/MS MH+ 179, Rt 1.48 min (5 minute run).