Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C:4](=[O:7])[N:3]1[CH2:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[CH:14][C:15]([C:19]#[N:20])=[N:16]2)=[CH:11][CH:10]=1.C([O-])([O-])=[O:29].C([O-])([O-])=O.OO.OO.OO.[Na+].[Na+].[Na+].[Na+].[NH4+].[Cl-]>CC(C)=O.O>[O:7]=[C:4]1[CH2:5][CH2:6][C:2](=[O:1])[N:3]1[CH2:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)=[CH:14][C:15]([C:19]([NH2:20])=[O:29])=[N:16]2)=[CH:11][CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cc(-c2ccc(F)cc2)c2ccc(CN3C(=O)CCC3=O)cc2n1
Agent: OO
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CC(C)=O
Product: NC(=O)c1cc(-c2ccc(F)cc2)c2ccc(CN3C(=O)CCC3=O)cc2n1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 41.1 %

Procedure:
7-[(2,5-Dioxopyrrolidin-1-yl)methyl]-4-(4-fluorophenyl)quinoline-2-carbonitrile (2-6, 12.8 g, 35.5 mmol, 1.0 equiv.) was dissolved in acetone (473 mL)/water (237 mL) and sodium percarbonate (55.7 g, 178 mmol, 5.0 equiv) was added. The resulting mixture was stirred at 50° C. for 1.5 hours. The mixture was cooled and poured over aqueous NH4Cl (saturated, 250 mL), extracted with ethyl acetate (3×200 mL), dried over Na2SO4, filtered and concentrated to afford 7-[(2,5-dioxopyrrolidin-1-yl)methyl]-4-(4-fluorophenyl)quinoline-2-carboxamide (2-7, 5.5 g, 41% over 3 steps) as a colorless solid. 1H NMR (400 MHz, CDCl3): δ 8.216 (s, 1H); 8.156 (s, 1H); 8.091 (br s, 1H); 7.908 (d, J=8.69 Hz, 1H); 7.614 (dd, J1=8.79 Hz, J2=1.71 Hz, 1H); 7.470-7.498 (m, 2H); 7.211-7.262 (m, 2H); 5.668 (br s, 1H); 4.902 (s, 2H); 2.776 (s, 4H). LRMS m/z (M+H)+ 378.3 found, 378.1 required.
Reaction SMILES: NC1C=C(F)C(OC)=CC=1C(C1C=CC=CC=1Cl)=O.NC1C(C)=NN(CC=C)C=1Cl.[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]1[C:44]2[CH:45]=[C:46]([O:50][CH3:51])[C:47]([F:49])=[CH:48][C:43]=2[N:42]=[C:41]2[N:52](CC=C)[NH:53][C:54]([CH3:55])=[C:40]2[N:39]=1.[H-].C([Al+]CC(C)C)C(C)C>>[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]1[C:44]2[CH:45]=[C:46]([O:50][CH3:51])[C:47]([F:49])=[CH:48][C:43]=2[N:42]=[C:41]2[NH:52][NH:53][C:54]([CH3:55])=[C:40]2[N:39]=1
Reactant: C=CCN1NC(C)=C2N=C(c3ccccc3Cl)c3cc(OC)c(F)cc3N=C21
Agent: C=CCn1nc(C)c(N)c1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: COc1cc(C(=O)c2ccccc2Cl)c(N)cc1F
Product: COc1cc2c(cc1F)N=C1NNC(C)=C1N=C2c1ccccc1Cl

Procedure:
5-(2-chlorophenyl)-1,2-dihydro-8-fluoro-7-methoxy-3-methyl-pyrazolo[3,4-b][1,4]benzodiazepine (IVdd) was prepared by reacting 0.0023 moles of (2-amino-4-fluoro-5-methoxyphenyl)-(2-chlorophenyl)-methanone (Xdd) with 4-amino-5-chloro-3-methyl-1-(2-propenyl)-1 H-pyrazole (XIII), and subsequent dealkylation of the intermediate, 5-(2-chlorophenyl)-1,2-dihydro-8-fluoro-7-methoxy-3-methyl-1-(2-propenyl)-pyrazolo[3,4-b][1,4]benzodiazepine (XIVdd) with diisobutylaluminum hydride in a manner analogous to Example 72. MH+/Z=357.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH2:9][C:10]#[N:11])=[CH:4][CH:3]=1.[S:13]1CC(O)S[CH2:15][CH:14]1O.C(NCC)C>C(O)C>[NH2:11][C:10]1[S:13][CH:14]=[CH:15][C:9]=1[C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:12]
Reactant: OC1CSC(O)CS1
Reactant: N#CCC(=O)c1ccc(F)cc1
Solvent: CCNCC
Solvent: CCO
Product: Nc1sccc1C(=O)c1ccc(F)cc1
Temperature: 50 °C
Yield: 86.2 %

Procedure:
Following a procedure described in J. Med. Chem. 2002, 45, 382-389; 0.44 g (2.7 mmol) 3-(4-fluoro-phenyl)-3-oxo-propionitrile (the preparation of which is described in example 17), 0.33 g (2.15 mmol) [1,4]dithiane-2,5-diol, 0.16 ml (2.15 mmol) diethyl-amine and 5 ml ethanol were charged in a sealed tube. The reaction mixture was heated at 50° C. for 6 h. The tube was then placed in a fridge (about 4° C.) for the night, and the product was collected by filtration and dried under vacuum to afford 0.41 g (69%) (2-amino-thiophen-3-yl)-(4-fluoro-phenyl)-methanone as a light brown crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](OCC)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reaction time: 1.5 h
Yield: 35.8 %

Procedure:
To a solution of 39.2 gm (152 mMol) ethyl 1-tert-butoxycarbonylpiperidine-4-carboxylate in 600 mL diethyl ether were cautiously added 6.1 gm (152 mMol) lithium aluminum hydride in portions. The reaction mixture was stirred for about 1.5 hours after the addition was complete and was then carefully quenched with water. The reaction mixture was partitioned between diethyl ether and 5 N sodium hydroxide. The organic phase was washed with saturated aqueous sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure to provide about 24 gm of a waxy solid. This solid was crystallized from a mixture of diethyl ether and hexane to provide 11.7 gm (36%) of 1-tert-butoxycarbonyl-4-hydroxymethylpiperidine as a white solid.
Reaction SMILES: N([O-])=[O:2].[Na+].N[C@H:6]([C:14]([OH:16])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O.S(=O)(=O)(O)O>[C:8]1([CH2:7][CH:6]([OH:2])[C:14]([OH:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=N[O-]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)C(O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 74.6 %

Procedure:
A solution of 0.829 g of sodium nitrite in 4.2 ml of water is added dropwise at 0° C. to a suspension of 1.6 g of phenylalanine in 5.3 ml of sulphuric acid (2.5N). The reaction mixture is stirred for 2 hours at 0° C. and then for 17 hours at room temperature. The reaction mixture is extracted with twice 100 ml of ethyl acetate. The pooled organic phases are washed with 100 ml of a saturated sodium chloride solution in water. 1.2 g of yellow crystals are obtained after drying.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([N:11]([C:19](=[O:27])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[S:9][CH:10]=1)=[O:5])C.C(O)(=O)C.Cl>O1CCOCC1>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:19]([N:11]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:8]1[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=1)=[O:27]
Reactant: CCOC(=O)c1csc(N(C(=O)c2ccccc2Cl)c2ccc(Cl)cc2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: O=C(O)c1csc(N(C(=O)c2ccccc2Cl)c2ccc(Cl)cc2)n1
Temperature: 60 °C

Procedure:
A mixture of 1.97 g (4.68 mmol) 2-[(2-Chloro-benzoyl)-(4-chloro-phenyl)-amino]-thiazole-4-carboxylic acid ethyl ester, 2.5 ml acetic acid and 7.5 ml HCl conc. in 10 ml dioxane was heated to 60° C. for 2 h. The mixture was subjected to reversed phase HPLC purification eluting with an acetonitrile/water gradient to yield after evaporation of the product fractions 1.02 g (56%) of the title compound. MS (m/e): 393.1 (MH+, 100%)
Reaction SMILES: [C:1]([C:3]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:4]=1/[CH:5]=[CH:6]/[C:7](OC)=[O:8])#[N:2]>CO.[Ni]>[CH3:15][C:13]1[CH:12]=[CH:11][C:4]2[CH2:5][CH2:6][C:7](=[O:8])[NH:2][CH2:1][C:3]=2[CH:14]=1
Reactant: COC(=O)/C=C/c1ccc(C)cc1C#N
Agent: [Ni]
Solvent: CO
Product: Cc1ccc2c(c1)CNC(=O)CC2
Reaction time: 17 h
Yield: 53 %

Procedure:
A solution of 27 g. (0.13 moles) of methyl trans-2-cyano-4-methylcinnamate in 1 liter dry methanol is introduced into a 2-liter autoclave. About 5 g. of W-5 Raney nickel are added and the mixture is stirred for 17 hours under a hydrogen pressure (initial pressure 3.5 bars). The reaction mixture is filtered, the catalyst is washed with chloroform and the solvent is removed in vacuo. The red residue obtained is washed with about 20 ml. of 2-propanol and then taken up in hot 2-propanol, whereafter the solution is decolorized over active carbon. After recrystallization, 12.4 g. (53% of theory) of 8-methyl-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one are obtained. M.P. 174°-175° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][C:11]=2[N:17]2[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]2)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:34]=[CH:33][C:32]([CH2:35][NH:36][C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])=[O:38])=[CH:31][C:27]=1[C:28](O)=[O:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C1COCC1>[CH3:23][CH:20]1[CH2:19][CH2:18][N:17]([C:11]2[CH:12]=[CH:13][C:14]([NH:16][C:28](=[O:29])[C:27]3[CH:31]=[C:32]([CH2:35][NH:36][C:37]([C:39]([CH3:40])([CH3:42])[CH3:41])=[O:38])[CH:33]=[CH:34][C:26]=3[Cl:25])=[CH:15][C:10]=2[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[O:24])[CH2:22][CH2:21]1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1
Reactant: CC1CCN(c2ccc(N)cc2C(=O)Nc2ccc(Br)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Product: CC1CCN(c2ccc(NC(=O)c3cc(CNC(=O)C(C)(C)C)ccc3Cl)cc2C(=O)Nc2ccc(Br)cc2)CC1

Procedure:
Prepared analogously to Example 4c from N-(4-bromophenyl)-2-(4-methyl-piperidin-1-yl)-5-amino-benzoic acid amide and 2-chloro-5-(tert-butylcarbonylamino)methyl-benzoic acid with to TBTU and TEA in THF. Purification via chromatography (silica gel, eluent PE:EtOAc 6:4)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:17][C:16]=1[OH:28].[CH2:29](Br)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].C(=O)([O-])[O-].[K+].[K+]>[Cu].CN(C=O)C>[CH2:29]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:17][C:16]=1[OH:28])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCBr
Reactant: CCOC(=O)CCc1ccc(O)c(-c2cc(CCC(=O)OCC)ccc2O)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(CCC(=O)OCC)cc1-c1cc(CCC(=O)OCC)ccc1O
Yield: 121 %

Procedure:
To 5 ml of a DMF solution containing 200 mg (0.5181 mmol) of 2,2'-dihydroxy-5,5'-bis (2-ethoxycarbonylethyl) biphenyl and 913.3 μl (5.181 mmol) of octyl bromide, there were added 85.5 mg (0.6217 mmol) of anhydrous potassium carbonate and a small amount of copper powder and the resulting mixture was agitated overnight at room temperature. The reaction mixture was filtered by suction through Celite to remove the solid matter and the filtrate was washed with ethyl acetate. After the solvent in the filtrate was evaporated off under reduced pressure, the evaporated residue was dissolved in chloroform. This solution was washed with dilute hydrochloric acid, dilute aqueous sodium bicarbonate, water and aqueous sodium chloride solution in this sequence and was dried by adding anhydrous sodium sulfate. The residue obtained after the solvent had been evaporated off was purified by silica gel column chromatography (with 20 g of WAKO-gel C-200, eluent: toluene and toluene/ethyl acetate of 100/1 and 50/1) to obtain 230.4 mg (0.627 mmol, 89%) of 2-octyloxy-2'-hydroxy-5,5'-bis (2-ethoxycarbonylethyl) biphenyl as an oily product.
Reaction SMILES: [O:1]1[CH:3]([CH3:4])[CH:2]1[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:21]([CH3:22])[C:20](=[O:23])[C:19]3[C:14](=[CH:15][C:16]([O:26][CH3:27])=[C:17]([O:24][CH3:25])[CH:18]=3)[N:13]=2)=[CH:8][CH:7]=1.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][CH2:37][NH2:38]>>[OH:1][CH:3]([CH2:4][NH:38][CH2:37][CH2:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[O:29][CH3:28])[CH2:2][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:21]([CH3:22])[C:20](=[O:23])[C:19]3[C:14](=[CH:15][C:16]([O:26][CH3:27])=[C:17]([O:24][CH3:25])[CH:18]=3)[N:13]=2)=[CH:10][CH:11]=1
Reactant: COc1cc2nc(-c3ccc(OC4OC4C)cc3)n(C)c(=O)c2cc1OC
Reactant: COc1ccccc1CCN
Product: COc1ccccc1CCNCC(O)COc1ccc(-c2nc3cc(OC)c(OC)cc3c(=O)n2C)cc1

Procedure:
This compound was prepared analogous to Example 2 from 2-[4-(1,2-epoxy-propoxy)-phenyl]-3-methyl-6,7-dimethoxy-3,4-dihydro-quinazolin-4-one and 2-(2-methoxy-phenyl)-ethylamine.
Reaction SMILES: [CH2:1]([C:3]1(O)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[CH2:14]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[NH:23][CH:22]=[CH:21]2)[CH3:15]>>[CH2:14]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[NH:23][CH:22]=[C:21]2[C:3]1([CH2:1][CH3:2])[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:15]
Reactant: CCC1(O)CCc2cc(F)ccc21
Reactant: CCc1cccc2cc[nH]c12
Product: CCc1cccc2c(C3(CC)CCc4cc(F)ccc43)c[nH]c12

Procedure:
Utilizing 1-ethyl-5-fluoro-indan-1-ol and 7-ethylindole, the title compound is prepared as in example 1. 104 mg (58%). LC-MS m/z 308.1 (M++1).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[Cl:22])[CH2:9][C:8]2([CH3:24])[CH3:23])=[O:4].[OH-].[Na+]>O1CCCC1.CO.O>[Cl:22][C:16]1[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=1[CH:10]1[CH2:9][C:8]([CH3:23])([CH3:24])[C:7]2[C:12](=[CH:13][CH:14]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=2)[NH:11]1
Reactant: COC(=O)c1ccc2c(c1)C(C)(C)CC(c1cc(Cl)ccc1Cl)N2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)CC(c2cc(Cl)ccc2Cl)Nc2ccc(C(=O)O)cc21
Temperature: 80 °C
Reaction time: 4 h
Yield: 61.2 %

Procedure:
To a solution of 2-(2,5-dichloro-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (1.0 g, 2.8 mmol) in tetrahydrofuran (8 mL) and methanol (8 mL) was added 3N sodium hydroxide (5 mL). The reaction mixture was stirred at 80° C. for 4 hours, and then diluted with water (10 mL), extracted with diethyl ether (20 mL). The organic layer was discarded. The aqueous layer was acidified with concentrated hydrochloric acid to pH 4 and extracted with ethyl acetate (40 mL×3), and the combined organics were dried over anhydrous Na2SO4. The solvent was removed in vacuo and purified by preparative HPLC to afford 2-(2,5-dichloro-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (600 mg, 61.4%) as a yellow foam. MS (ESI+) [(M+H)+] 350.1.
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([CH2:12][CH3:13])[C:4]=1[CH:5]=[O:6])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].IC.[CH3:22][CH2:23]OCC>CN(C)C=O>[CH2:22]([O:11][C:9]1[CH:8]=[C:7]([CH2:12][CH3:13])[C:4]([CH:5]=[O:6])=[C:3]([CH2:1][CH3:2])[CH:10]=1)[CH3:23]
Reactant: CCOCC
Reactant: CCc1cc(O)cc(CC)c1C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOc1cc(CC)c(C=O)c(CC)c1
Temperature: 60 °C
Yield: 82 %

Procedure:
To a solution of 1.10 g (5.92 mmol)) 2,6-diethyl-4-hydroxy-benzaldehyde in 15 ml N,N-dimethylformamide in a pressure tube were added 4.83 g (14.8 mmol) cesium carbonate and 1.05 ml (13.0 mmol) iodomethane. The tube was sealed and the reaction mixture was heated at 60° C. for 16 h. The reaction mixture was cooled to room temperature, diluted with ether, and washed with saturated brine. The phases were separated and the organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, ethyl acetate/heptane gradient) to afford 1.00 g (82%) of the title compound as a yellow oil. 1H-NMR (CDCl3): 1.25 (6H, t, 2×CH3), 1.44 (3H, t, CH3), 2.98 (4H, q, 2×CH2), 4.10 (2H, q, OCH2), 6.62 (2H, s, 2×ArH), 10.45 (1H, s, CH═O).
Reaction SMILES: ClC1C(C)=C(C2C=CC(C)=CC=2)N=CN=1.[CH3:16][C:17]1[CH:29]=[C:28]([CH2:30][N:31]([C:35]2[C:40]([CH3:41])=[C:39]([C:42]3[CH:47]=[CH:46][C:45]([C:48](F)(F)F)=[CH:44][CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH2:32][CH2:33][CH3:34])[CH:27]=[CH:26][C:18]=1[O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[CH3:16][C:17]1[CH:29]=[C:28]([CH2:30][N:31]([C:35]2[C:40]([CH3:41])=[C:39]([C:42]3[CH:43]=[CH:44][C:45]([CH3:48])=[CH:46][CH:47]=3)[N:38]=[CH:37][N:36]=2)[CH2:32][CH2:33][CH3:34])[CH:27]=[CH:26][C:18]=1[O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1ncnc(-c2ccc(C(F)(F)F)cc2)c1C
Agent: Cc1ccc(-c2ncnc(Cl)c2C)cc1
Product: CCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1ncnc(-c2ccc(C)cc2)c1C

Procedure:
Using 4-chloro-5-methyl-6-(4-methylphenyl)pyrimidine (153 mg, 0.7 mmol) and the synthetic procedure described for Intermediate 80. Purification by Biotage™ chromatography (Si, 40 g) eluting 9:1 cyclohexane:EtOAc afforded the title compound as a pale yellow oil (80 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]2.BrC1C=C2C(=CC=1[Cl:24])C(Cl)=NC=C2>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:24])[C:8](=[O:12])[NH:7][CH:6]=[CH:5]2
Reactant: Clc1cc2c(Cl)nccc2cc1Br
Reactant: O=c1[nH]ccc2cc(Br)ccc12
Product: O=c1[nH]ccc2cc(Br)c(Cl)cc12

Procedure:
The title compound was prepared by the method, described for 6-Bromo-2H-isoquinolin-1-one (6), starting from 6-Bromo-1,7-dichloro-isoquinoline (11). Rt=1.26 min (Method C). Detected mass: 258.2/260.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:30])[NH:4][C:5]2[C:10]([N:11]=1)=[C:9]([O:12][C:13]1[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[N:16]=[C:15](Cl)[N:14]=1)[CH:8]=[CH:7][CH:6]=2.[NH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[NH2:1][C:2]1[C:3](=[O:30])[NH:4][C:5]2[C:10]([N:11]=1)=[C:9]([O:12][C:13]1[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[N:16]=[C:15]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[N:14]=1)[CH:8]=[CH:7][CH:6]=2
Reactant: C1CNCCN1
Reactant: Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)nc(Cl)n3)cccc2[nH]c1=O
Product: Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)nc(N4CCNCC4)n3)cccc2[nH]c1=O

Procedure:
The reaction of 3-amino-5-(2-chloro-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)quinoxalin-2(1H)-one (180 mg, 1.0 mmol, Example 106(a)) with piperazine (71 mg, 2.0 mmol, Aldrich) under the conditions of Example 34 afforded the title compound as an amorphous solid. MS (ESI, pos. ion) m/z: 484 (M+1).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]1[CH2:11][CH:10]([OH:12])[CH2:9][CH2:8][N:7]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])(=[O:3])[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[C:1]([O:4][CH2:5][CH:6]1[CH2:11][C:10](=[O:12])[CH2:9][CH2:8][N:7]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1CC(O)CCN1C(=O)OC(C)(C)C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(=O)OCC1CC(=O)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.7 %

Procedure:
To a solution of the product of step H (506 mg, 1.9 mmol) in dichloromethane (15 mL) at 0° C. was added pyridinium chlorochromate (4.0 g, 19 mmol). The reaction was allowed to warm to ambient temperature and stirred for a further 2 h. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to afford the crude product which was purified by flash column chromatography (SiO2, 19:1 to 4:1, hexanes/ethyl acetate) to afford tert-butyl 2-(acetoxymethyl)-4-oxopiperidine-1-carboxylate (220 mg, 43%) as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 4.57 (br s, 1H), 4.03-3.99 (m, 2H), 3.91-3.87 (m, 1H), 3.28-3.21 (s, 1H), 2.52-2.46 (m, 1H), 2.35-2.31 (m, 1H), 2.26-2.18 (m, 2H), 1.83 (s, 3H), 1.50 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]=1.[CH:9]([CH:11]([CH3:17])[C:12](OCC)=O)=[O:10]>C(O)C>[CH3:17][C:11]1[C:9](=[O:10])[N:1]=[C:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]2[CH:12]=1
Reactant: CCOC(=O)C(C)C=O
Reactant: NC1=NCCCCC1
Solvent: CCO
Product: Cc1cn2c(nc1=O)CCCCC2
Reaction time: 24 h
Yield: 37 %

Procedure:
To a solution of 11.2 g. of 7-amino-3,4,5,6-tetrahydro-2H-azepine in 100 ml. ethanol 13.1 g. of ethyl 2-formyl-propionate are added at room temperature and the reaction mixture is stirred for 24 hours and boiled for 3 hours. Ethanol is then evaporated at reduced pressure and the residue is treated with a mixture of acetone and petroleum ether. The precipitated crystals are filtered. 6.6 g. (37%) of 3-methyl-2-oxo-2,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepine are obtained, melting at 202° C. after boiling in acetone.
Reaction SMILES: C1C=CC([As](C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Br[C:21]1[C:25]2[N:26]=[C:27]([N:35]([CH3:37])[CH3:36])[N:28]=[C:29]([C:30]3[O:31][CH:32]=[CH:33][CH:34]=3)[C:24]=2[S:23][CH:22]=1.C([Sn](CCCC)(CCCC)[C:43]1[O:44][CH:45]=[CH:46][CH:47]=1)CCC.O>CN(C=O)C>[O:31]1[CH:32]=[CH:33][CH:34]=[C:30]1[C:29]1[C:24]2[S:23][CH:22]=[C:21]([C:43]3[O:44][CH:45]=[CH:46][CH:47]=3)[C:25]=2[N:26]=[C:27]([N:35]([CH3:37])[CH3:36])[N:28]=1
Reactant: CN(C)c1nc(-c2ccco2)c2scc(Br)c2n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)c1nc(-c2ccco2)c2scc(-c3ccco3)c2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 14.5 %

Procedure:
A mixture of AsPh3 (73 mg, 0.24 mmol) in DMF (2 mL) was treated with Pd(OAc)4 (13 mg, 0.06 mmol), stirred at room temperature for 10 min, treated with 7-bromo-N,N-dimethyl-4-(2-furyl)thieno[3,2-d]pyrimidine-2-amine (194 mg, 0.6 mmol) and 2-(tributylstannyl)-furan (340 μL, 1.1 mmol), heated to 100° C. for 16 h, cooled, poured into water, extracted with EtOAc, dried (MgSO4), concentrated in vacuo and purified by chromatography (SiO2:EtOAc:Heptane, 1:9) to give the title compound (27 mg, 15%) as a orange solid.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:9][N:10]([C:16]2[C:21]([N+:22]([O-])=O)=[CH:20][N:19]=[C:18]([Cl:25])[N:17]=2)[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:8][CH2:7][CH2:6]1)=O.[NH4+].[Cl-]>C(O)C.[Fe]>[Cl:25][C:18]1[N:19]=[CH:20][C:21]2[NH:22][C:3](=[O:2])[C:5]3([CH2:8][CH2:7][CH2:6]3)[CH2:9][N:10]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:16]=2[N:17]=1
Reactant: COC(=O)C1(CN(c2nc(Cl)ncc2[N+](=O)[O-])C2CCCC2)CCC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC12CCC2

Procedure:
Reaction of 1-{[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-methyl}-cyclobutanecarboxylic acid methyl ester with NH4Cl and iron powder in ethanol gave 2′-chloro-9′-cyclopentyl-8′,9′-dihydrospiro[cyclobutane-1,7′-pyrimido[4,5-b][1,4]diazepin]-6′(5′H)-one, isolated directly.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[O:13][C:14](Br)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2.[NH2:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>O1CCCC1.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.O>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[O:13][C:14]([C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([NH2:18])[CH:24]=3)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2
Reactant: Nc1cccc(B(O)O)c1
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1ccc(Br)o1
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: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Nc1cccc(-c2ccc(C(=O)N[C@H]3CN4CCC3CC4)o2)c1

Procedure:
Prepared by a method analogous to that described in Example 1 from (R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromofuran-2-carboxamide) and 3-aminophenylboronic acid, using tetrakis(triphenylphosphine)palladium(0) and sodium carbonate in a mixture of tetrahydrofuran, ethanol and water. The compound was purified by flash chromatography using 5-20% 3.5M methanolic ammonia/chloroform mixtures as the eluent and then by reverse phase HPLC on a Waters Bondapak® C18 column using a gradient of acetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent. The free base was prepared by basification of the product-containing fractions and extraction into chloroform followed by evaporation to gave the title compound; MS (ES+) 312 (MH+).