Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]2[O:8][CH2:9][C:10]3([CH2:12][CH2:11]3)[C:6]=2[C:5]([O:13][C:14]2[N:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][N:15]=2)=[CH:4][CH:3]=1.O.[Cl-].[NH4+]>O1CCCC1>[CH3:1][C:2]1[C:7]2[O:8][CH2:9][C:10]3([CH2:12][CH2:11]3)[C:6]=2[C:5]([O:13][C:14]2[N:15]=[CH:16][C:17]([NH2:20])=[CH:18][N:19]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(Oc2ncc([N+](=O)[O-])cn2)c2c1OCC21CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(Oc2ncc(N)cn2)c2c1OCC21CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 22.7 %

Procedure:
To a solution of 2-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxy-5-nitro-pyrimidine (Intermediate 161, 255 mg) in tetrahydrofuran (5 ml)/water (2.5 ml) iron (234 mg, 4.25 mmol) and then ammonium chloride (227 mg, 4.25 mmol) were added and the reaction mixture was stirred for 48 hours at room temperature. The catalyst was filtered off and the residue was diluted with an aqueous saturated solution of NaHCO3 (5 ml) and extracted with ethyl acetate (3×10 ml). The organic layer was dried over sodium sulphate, filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and cyclohexane/ethyl acetate 8:2 to cyclohexane/ethyl acetate 4:6 as eluents affording the title compound (52 mg) as a light orange solid.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:14]=[N:15][CH:16]=[C:17]([O:19][C@H:20]4[CH2:24][CH2:23][NH:22][CH2:21]4)[CH:18]=3)=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:4]1=[O:25].[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1.C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[CH:26]1([C:29]([N:22]2[CH2:23][CH2:24][C@H:20]([O:19][C:17]3[CH:18]=[C:13]([C:9]4[CH:8]=[C:7]5[C:12](=[CH:11][CH:10]=4)[N:3]([CH3:2])[C:4](=[O:25])[CH2:5][CH2:6]5)[CH:14]=[N:15][CH:16]=3)[CH2:21]2)=[O:30])[CH2:28][CH2:27]1
Reactant: CN1C(=O)CCc2cc(-c3cncc(O[C@H]4CCNC4)c3)ccc21
Reactant: O=C(Cl)C1CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN1C(=O)CCc2cc(-c3cncc(O[C@H]4CCN(C(=O)C5CC5)C4)c3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.8 %

Procedure:
To a solution of 1-methyl-6-[5-((S)-pyrrolidin-3-yloxy)-pyridin-3-yl]-3,4-dihydro-1H-quinolin-2-one hydrochloride (example 60, 0.05 g, 0.139 mmol) in dry DCM (1.5 mL) was added cyclopropanecarbonyl chloride (0.015 g, 0.139 mmol) followed by TEA (0.035 g, 0.347 mmol) and the reaction mixture was stirred at room temperature for 1 h. Then, the reaction mixture was diluted with EtOAc, poured into sat. NaHCO3 solution (10 mL) and extracted with EtOAc (2×20 mL). Combined organics were dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 5% MeOH-DCM gradient to give the title compound (0.032 g, 59%) as a colorless foam. MS: 392.2 (M+H+).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[C-:11]#[N:12].[K+].[OH2:14]>Cl>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:5]1([C:11]#[N:12])[CH2:6][CH2:7][O:14][CH2:3][CH2:4]1
Reactant: [C-]#N
Reactant: c1ccc2c(c1)CCNC2
Reactant: O
Agent: Cl
Agent: [K+]
Product: N#CC1(N2CCc3ccccc3C2)CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
3,4,5,6-Tetrahydro-4H-pyran-4-one (0.37 g, 3.75 mmol) was added to a solution of 1,2,3,4-tetrahydroisoquinoline (0.47 mL, 3.75 mmol) in conc. HCl (0.4 mL) diluted with ice water (1.5 mL), followed by a solution of KCN (0.24 g, 3.75 mmol) dissolved in water (2 mL), and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then diluted with water and the organic product was extracted with EtOAc. The organic layer was washed with H2O and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica 60-120 mesh, eluent 6% EtOAc in petroleum ether) to afford 4-(3,4-dihydroisoquinolin-2(1H)-yl)tetrahydro-2H-pyran-4-carbonitrile (300 mg, yield 33%). 1H NMR (300 MHz, CDCl3) δ 7.19-7.11 (m, 3H), 7.07-7.05 (m, 1H), 4.10-4.04 (dt, J=12.3 Hz, 3.5 Hz, 2H), 3.87 (s, 2H), 3.76-3.68 (m, 2H), 2.97-2.91 (m, 4H), 2.28-2.23 (dd, J=13.3 Hz, 1.4 Hz, 2H), 1.93-1.84 (td, J=12.4 Hz, 4.2 Hz, 2H). MS (ESI) m/z: Calculated for C15H18N2O: 242.14. found: 243.2 (M+H)+.
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(Cl)(=O)C([Cl:24])=O>C(Cl)CCl>[C:1]([Cl:24])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Product: CCCCCCCCCCCCCCCCCC(=O)Cl
Temperature: 45 °C

Procedure:
1420g (5 moles) of stearic acid and 6 liters of ethylene dichloride are placed in a 12-liter flask and warmed to 45° C. 1270 g (10 moles) of oxalyl chloride is added dropwise over a 2.5 hour time period. After 1 hour of refluxing, the flask is blanketed with argon and cooled overnight. The solvent is removed and the stearoyl chloride is used without further purification.
Reaction SMILES: FC(F)(F)C([NH:5][C@H:6]([C:26]([C:28]([C:44](=[O:72])[C@H:45]([CH2:53][C:54]1[CH:61]=[C:59]([I:60])[C:58]([O:62][C:63]2[CH:70]=[C:68]([I:69])[C:67]([OH:71])=[C:65]([I:66])[CH:64]=2)=[C:56]([I:57])[CH:55]=1)[NH:46]C(=O)C(F)(F)F)([CH2:32][O:33][CH2:34][CH2:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][C:41]([NH2:43])=[O:42])[C:29]([NH2:31])=[O:30])=[O:27])[CH2:7][C:8]1[CH:15]=[C:13]([I:14])[C:12]([O:16][C:17]2[CH:24]=[C:22]([I:23])[C:21]([OH:25])=[C:19]([I:20])[CH:18]=2)=[C:10]([I:11])[CH:9]=1)=O.[OH-].[Na+].[ClH:77]>CO.C(O)C>[ClH:77].[ClH:77].[NH2:5][C@H:6]([C:26]([C:28]([C:44](=[O:72])[C@H:45]([CH2:53][C:54]1[CH:55]=[C:56]([I:57])[C:58]([O:62][C:63]2[CH:64]=[C:65]([I:66])[C:67]([OH:71])=[C:68]([I:69])[CH:70]=2)=[C:59]([I:60])[CH:61]=1)[NH2:46])([CH2:32][O:33][CH2:34][CH2:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][C:41]([NH2:43])=[O:42])[C:29]([NH2:31])=[O:30])=[O:27])[CH2:7][C:8]1[CH:9]=[C:10]([I:11])[C:12]([O:16][C:17]2[CH:18]=[C:19]([I:20])[C:21]([OH:25])=[C:22]([I:23])[CH:24]=2)=[C:13]([I:14])[CH:15]=1
Reactant: NC(=O)CCOCCCCOCC(C(N)=O)(C(=O)[C@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)NC(=O)C(F)(F)F)C(=O)[C@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)NC(=O)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: NC(=O)CCOCCCCOCC(C(N)=O)(C(=O)[C@@H](N)Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)[C@@H](N)Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1
Reaction time: 40 h

Procedure:
Bis-(trifluoroacetyl-L-thyroxyl)-4,9-dioxadodecane-1,12-diamide (example 8A), 0.34 g, was dissolved in 3 ml methanol. 1M sodium hydroxide was added with stirring and the reaction was allowed to go at room temperature for 40 hours. The reaction mixture was diluted into 20 ml of cold 1M hydrochloric acid to give a fine suspension of product. The suspension was centrifuged and the pellet was dissolved in ethanol. The ethanol solution was evaporated to a solid residue of crude product. The product was recrystallized from methanol/ether to obtain 0.18 g of bis-(L-thyroxyl)-4,9-dioxa-1,12-dodecanediamide, dihydrochloride salt.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][N:5]=1.[CH3:11][O:12][CH2:13]Cl.O>O1CCCC1>[Cl:3][C:4]1[C:9]([O:10][CH2:11][O:12][CH3:13])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: COCCl
Reactant: Oc1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCOc1cccnc1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
Sodium hydride (66%, 633 mg, 17.4 mmol) was added to an ice-cooled solution of 2-chloro-3-hydroxypyridine (2.05 g, 15.8 mmol) in tetrahydrofuran (30 ml) under nitrogen atmosphere, and this reaction mixture was stirred at that temperature for 15 minutes. Chloromethyl methyl ether (1.32 ml, 17.4 mmol) was added, and the resulting reaction mixture was stirred at that temperature for 30 minutes, then at room temperature for another 2 hours. After water was added, the reaction mixture was extracted with ethyl acetate, washed with saturated brine, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (2.44 g).
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[CH3:9][O:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1>ClCCl>[N:6]1[CH:7]=[CH:8][C:3]([NH:15][C:14]2[CH:16]=[CH:17][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)=[CH:4][CH:5]=1
Reactant: Clc1ccncc1
Reactant: COc1ccc(N)cc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(Nc2ccncc2)cc1
Temperature: 140 °C

Procedure:
A stirred mixture of 4-chloropyridine hydrochloride (2 g) and 4-methoxyaniline (4.9 g) was heated at 140° C. for 5 hours. After cooling the residue was dissolved in dichloromethane (250 ml), the solution extracted with water (2×100 ml). The aqueous extracts were treated with sodium hydroxide solution and then extracted with ethyl acetate (4×100 ml). The combined organic extracts were washed with water, and saturated sodium chloride solution, then dried and the solvent evaporated. Purification by flash chromatography on silica, eluting with 10% v/v methanol/dichloromethane gave 4-(4-pyridylamino)-methoxybenzene, 2 g, as a fawn solid: m.p. 159°-160° C.; NMR (d6DMSO) δ 8.47 (1H, s), 8.09 (2H, d), 7.10 (2H, d), 6.92 (2H, d), 6.70 (2H, dd), 3.73 (3H, s); m/e 201 (M+H)+ ; calculated for C12H12N2O3 : C, 72.0; H, 6.0; N, 14.0. found: C, 71.4; H, 6.1; N, 13.8%.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7](C#N)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl-].[NH4+].[N-:14]=[N+:15]=[N-:16].[Na+].[CH3:18][N:19](C=O)C>>[N+:1]([C:4]1[CH:5]=[C:6]([C:18]2[NH:19][N:16]=[N:15][N:14]=2)[CH:7]=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1
Reactant: [N-]=[N+]=[N-]
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: O=[N+]([O-])c1cccc(-c2nnn[nH]2)c1
Temperature: 120 °C

Procedure:
A mixture of 14.8 g of 4-nitrobenzonitril, 32 g of ammoniumchloride and 39 g of sodium azide in 150 ml of DMF was heated for 2 h at 120° C. After evaporating the solvent, the residue was partitioned between 2N hydrochloric acid and ethyl acetate. The organic layer was dried and evaporated. The residue was washed with ether and dried. M.p. 101-102° C.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([Cl:27])=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=O)(C)(C)C.C(OC(NC1CCNC1)=O)(C)(C)C.C(OC(N[C@H]1CCNC1)=O)(C)(C)C>>[NH2:8][CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([Cl:27])=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1.[ClH:27]
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2cccc3cncc(Cl)c23)C1
Agent: CC(C)(C)OC(=O)NC1CCNC1
Agent: CC(C)(C)OC(=O)N[C@H]1CCNC1
Product: Cl
Product: NC1CCN(S(=O)(=O)c2cccc3cncc(Cl)c23)C1

Procedure:
3-(tert-Butoxycarbonylamino)-1-(4-chloro-5-isoquinolinesulfonyl)pyrrolidine (Intermediate 16) can be prepared by using 3-(tert-butoxycarbonylamino)pyrrolidine in the method of Example 19-1, Step A instead of (S)-3-(tert-butoxycarbonylamino)pyrrolidine, and then used in the method of Step B in a similar manner to obtain the title compound as hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17](I)[CH:18]=3)[N:13]=[C:12]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(OCC)(=O)C>O1CCOCC1.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>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:32]4[CH:31]=[CH:30][CH:29]=[C:28]([Cl:27])[CH:33]=4)[CH:18]=3)[N:13]=[C:12]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Fc1ccc(Nc2nc(-c3cccnc3)nc3ccc(I)cc23)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Fc1ccc(Nc2nc(-c3cccnc3)nc3ccc(-c4cccc(Cl)c4)cc23)cc1Cl
Yield: 51.6 %

Procedure:
A mixture of N-(3-chloro-4-fluorophenyl)-6-iodo-2-(pyridin-3-yl)quinazolin-4-amine (1.0 g, 2.10 mmol), 3-chlorophenylboronic acid (0.49 g, 3.13 mmol), Pd(PPh3)4 (0.24 g, 0.210 mmol), K3PO4 (1.34 g, 6.31 mmol) in dioxane (20 mL) and water (2.0 mL) was stirred under reflux for 2 h. Ethyl acetate (20 mL) was added to the cooled mixture and filtered. The filtered solid was recrystallized from DMF and water to give the title compound (0.50 g, 51.6%). 1H NMR (400 MHz, DMSO) δ 10.20 (s, 1H), 9.54 (s, 1H), 8.87 (s, 1H), 8.74-8.65 (m, 2H), 8.31-8.23 (m, 2H), 8.04-7.85 (m, 4H), 7.64-7.49 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:5]=[C:6](Br)[C:7]=1[NH:8][C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:24](B(O)O)[CH:25]([CH3:27])[CH3:26].O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>C(OCC)(=O)C.ClCCl>[CH2:24]([C:2]1[CH:3]=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:5]=[C:6]([CH2:3][CH:4]([CH3:18])[CH3:5])[C:7]=1[NH:8][C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:25]([CH3:27])[CH3:26]
Reactant: O=C(Nc1c(Br)cc(-c2ccccc2)cc1Br)c1ccccc1
Reactant: CC(C)CB(O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CC(C)Cc1cc(-c2ccccc2)cc(CC(C)C)c1NC(=O)c1ccccc1
Temperature: 25 °C
Yield: 171.1 %

Procedure:
A mixture of N-(3,5-dibromobiphenyl-4-yl)benzamide (8.52 g, 19.8 mmol), isobutyl boronic acid (8.06 g, 79.2 mmol), potassium phosphate monohydrate (13.7 g, 59.4 mmol), water. (50 mL) and toluene (150 mL) was purged with nitrogen for 20 min before addition of tris(dibenzylideneacetone) dipalladium(0) (0.27 g 3% Pd) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.49 g, 6 mol %). The reaction was stirred at reflux for 18 h. After cooling to ambient temperature the mixture was diluted with ethyl acetate and water. The layers were separated and the organic layer was concentrated and chromatographed on a silica gel column. Elution first with dichloromethane then dichloromethane and ethyl acetate (49:1) gave 6.53 g (86% yield) of the desired product as a solid. 1H NMR confirmed the structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6]N.[C:13]([BH3-])#[N:14].[Na+]>CO.C1COCC1.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH:14][CH2:13][C:8]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:10]([O:11][CH3:12])[CH:9]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CNCc2ccc(OC)c(OC)c2)cc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3,4-dimethoxybenzaldelyde (1 g, 6 mmol) in anhydrous methanol (10 ml) was added 3,4-dimethoxybenzylamine (1 g, 5.9 mmol) and the solution stirred under nitrogen at room temperature for 3 hours. The methanol was removed under reduced pressure to afford the crude imine, 1.9 g. The imine was dissolved in THF (10 ml) and acetic acid (4 ml), and sodium cyanoborohydride (0.38 g, 6 mmol) was added portionwise over 30 minutes. The solution was stirred for an additional 30 minutes at room temperature, and the solvents were removed under reduced pressure. The residue was neutralized with saturated aqueous sodium hydrogen carbonate, and the solid crude product was isolated by filtration, and dried under vacuum at 50° C. overnight, yield 0.6 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C[O:20][C:21]1[CH:26]=[C:25]([O:27]C)C=C[C:22]=1CCC(C1CCCC1)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[O:13][C:25](=[O:27])[CH2:26][C:21](=[O:20])[CH2:22]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CCC(=O)C2CCCC2)cc1Cl
Reactant: COc1ccc(CCC(=O)C2CCCC2)c(OC)c1
Product: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl

Procedure:
The title compound was prepared analogously to Example B(86), Step 2 substituting 3-(3-chloro-4-methoxy-phenyl)-1-cyclopentyl-propan-1-one from Step 1 above in place of 3-(2,4-dimethoxyphenyl)-1-cyclopentylpropan-1-one.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]1[C:13]([CH3:23])=[C:14]([CH:19]=[C:20]([Cl:22])[CH:21]=1)[C:15]([O:17][CH3:18])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]([CH3:24])[C:12]1[C:13]([CH3:23])=[C:14]([CH:19]=[C:20]([Cl:22])[CH:21]=1)[C:15]([O:17][CH3:18])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(Cl)cc(NCCNC(=O)OC(C)(C)C)c1C
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: COC(=O)c1cc(Cl)cc(N(C)CCNC(=O)OC(C)(C)C)c1C
Temperature: 80 °C
Yield: 62.4 %

Procedure:
To a stirred solution of methyl 3-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-5-chloro-2-methylbenzoate (0.5 g, 1.46 mmol) in acetonitrile (10 mL), cesium carbonate (0.95 g, 2.92 mmol) and methyl iodide (1 g, 7.3 mmol) were added and the resulting reaction mixture heated at 80° C. for 12 h. On completion, the reaction mixture was cooled to room temperature and filtered, the residue washed with ethyl acetate and the filtrate concentrated before purification by column chromatography to afford desired product (0.325 g, 62%).
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]=[CH:9][NH:8][C:7]=2[N:6]([CH2:14][CH2:15][CH3:16])[C:5]1=[O:17])[CH2:2][CH3:3].[CH2:18]=O.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>CCO>[CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]([CH2:18][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:9]=[N:8][C:7]=2[N:6]([CH2:14][CH2:15][CH3:16])[C:5]1=[O:17])[CH2:2][CH3:3]
Reactant: C1CCNC1
Reactant: CCCn1c(=O)c2nc[nH]c2n(CCC)c1=O
Reactant: C=O
Solvent: CCO
Product: CCCn1c(=O)c2c(ncn2CN2CCCC2)n(CCC)c1=O

Procedure:
A solution of 1,3-dipropyl-3,9-dihydro-purine-2,6-dione (446 mg, 1.89 mmol), 37% aqueous formaldehyde (1.2 eq, 2.26 mmol, 0.190 ml) and pyrrolidine (1.2 eq, 2.26 mmol, 161 mg) in EtOH (25 ml) was heated at relux for 36 h. The cool reaction mixture was concentrated in vacuo to give a solid that was dried in vacuo for 24 h (598 mg, 99%). 1H NMR (300 MHz, CDCl3); d 0.94 (coincident t, 6H), 1.64 (m, 2H), 1.75 (m, 4H), 1.78 (m, 2H, partially-obscured), 2.69 (m, 2H), 4.00 (m, 4H), 5.30 (s, 2H), 7.59 (s, 1H); MS: 320 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:13][O:14][C:15]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18].O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9]([NH:18][CH2:17][C:16]2[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:15]=2[O:14][CH3:13])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)Cc1cccc(Cl)c1
Reactant: COc1ccc(CN)c(OC)c1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CNS(=O)(=O)Cc2cccc(Cl)c2)c(OC)c1
Reaction time: 0.5 h

Procedure:
At room temperature, 1.06 g of 3-chlorophenylmethanesulfonyl chloride were initially charged in 30 ml of dichloromethane, and 1.42 ml of 2,4-dimethoxybenzylamine were added dropwise. The reaction mixture was stirred for 30 minutes. Then the mixture was admixed with 50 ml of water and 50 ml of water, and then the aqueous phase was washed once more with 30 ml of ethyl acetate. The combined organic phases were washed with 1 N aqueous hydrochloric acid, dried over MgSO4 and concentrated by rotary evaporation. The residue (1.65 g) was used in the next reaction without further purification.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(O[Si](C)(C)C)C.FC(S(O[Si](C)(C)C)(=O)=O)(F)F.C[Si](C)(C)[CH2:36][C:37](=[CH2:45])[CH2:38][CH2:39][O:40][Si](C)(C)C>C(Cl)(Cl)(Cl)Cl>[CH2:36]=[C:37]1[CH2:45][C:11]2([CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)[O:40][CH2:39][CH2:38]1
Reactant: C=C(CCO[Si](C)(C)C)C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Agent: CCO[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClC(Cl)(Cl)Cl
Product: C=C1CCOC2(CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: 2.5 °C
Reaction time: 8 h
Yield: 1000 %

Procedure:
To a solution of 1-Boc-piperidone (2.39 g, 12 mmol) and ethoxytrimethylsilane (3.75 mL, 24 mmol) in 80 mL of CCl4 under stirring at 0° C. was added trimethylsilyl trifluoromethylsulfonate (217 μL, 1.2 mmol) and trimethyl-(2-methylene-4-trimethylsilyloxybutyl)silane (E. I. Marko et al., Journal of Organic Chemistry 1992, 57, 2211-2213) dissolved in in 23 mL of CCl4. After stirring at 0-5° C. for 6 h and overnight resting at 0° C., the reaction mixture was washed with water, dried on Na2SO4, filtered and the solvent was evaporated to dryness in vacuo. The residual 6.5 g of colourless oil was purified by means of automated flash chromatography (SP1®TM-Biotage; Petroleum Ether-EtOAc gradient from 99:1 to 85:15) to give 3.2 g of the title compound as colourless oil. Yield: 1000%
Reaction SMILES: [C:1]([C:3]1[C:8]([Cl:9])=[C:7]([F:10])[N:6]=[C:5]([F:11])[C:4]=1[Cl:12])#N.[H-].C([Al+]CC(C)C)C(C)C.CO.S(=O)(=O)(O)[OH:26]>C1(C)C=CC=CC=1>[Cl:12][C:4]1[C:5]([F:11])=[N:6][C:7]([F:10])=[C:8]([Cl:9])[C:3]=1[CH:1]=[O:26]
Reactant: N#Cc1c(Cl)c(F)nc(F)c1Cl
Reactant: O=S(=O)(O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=Cc1c(Cl)c(F)nc(F)c1Cl
Temperature: 25 °C

Procedure:
To a mixture, of 10.1 g (0.048 mole) of 4-cyano-3,5-dichloro-2,6-difluoropyridine (from Step A) in 50 ml of toluene that had been cooled to 0° C. was added 6.9 g (0.049 mole) of diisobutylaluminum hydride. After complete addition the reaction mixture was allowed to warm to room temperature and was stirred for approximately seventeen hours. A mixture of methanol and petroleum ether (2:1) was added to the reaction mixture which was then acidified with dilute sulfuric acid. The organic layer was separated from the aqueous layer and was dried over anhydrous sodium sulfate. After being filtered, the solvent was evaporated under reduced pressure, leaving 6.0 g of 3,5-dichloro-2,6-difluoropyridine-4-carboxaldehyde as a residue.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2].[Br:23]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClCCl.[W]>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([Br:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1
Agent: [W]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCl
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1Br
Yield: 73.5 %

Procedure:
6-Methoxy-3-phenyl-1H-indene-2-carboxylic acid ethyl ester (1.5 g, 5.10 mmol) prepared in Preparation Example 1 was dissolved in dichloromethane (80 mL), and N-bromosuccinimide (1.09 g, 6.12 mmol) and 2,2′-azobisisobutyronitrile (0.08 mg, 0.51 mmol) were added thereto. The mixture was stirred for 2 hrs at RT under the irradiation of a 375 W tungsten lamp. Upon the completion of the reaction, the mixture washed with saturated saline and extracted with dichloromethane. The organic layer was separated, dried over anhydrous MgSO4 and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography (ethyl acetate/n-hexane=1/20→1/9) to obtain 1.4 g of the titled compound (yield: 74%) as a yellow solid.