Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C2C(COC([NH:18][CH2:19][C:20]([NH:22][C@H:23]([C:45]([NH2:47])=[O:46])[CH2:24][S:25][C:26]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:21])=O)C3C(=CC=CC=3)C=2C=CC=1.CCN(C(C)C)C(C)C>CN(C)C=O>[NH2:18][CH2:19][C:20]([NH:22][C@H:23]([C:45]([NH2:47])=[O:46])[CH2:24][S:25][C:26]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:21]
Reactant: NC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NCC(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(N)=O

Procedure:
1.53 g (2.38 mmol) of the compound from example 17A was dissolved in 18 ml dimethyl formamide and 0.47 ml (4.79 mmol) DIEA was added. After one hour reaction time, the raw product was purified by preparative RP-HPLC on a C18 column with a water methanol gradient from 9/1 to 1/9. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 416 mg (0.97 mmol, 40% of theory) of the desired product.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:17])=[C:5]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][C:11]2=[O:16])[CH:6]=[C:7]([F:9])[CH:8]=1.[CH3:18][N:19]1[CH:23]=[C:22]([NH:24][C:25]2[N:30]=[C:29]3[NH:31][N:32]=[CH:33][C:28]3=[CH:27][N:26]=2)[CH:21]=[N:20]1>>[F:17][C:4]1[C:3]([CH2:2][N:31]2[C:29]3=[N:30][C:25]([NH:24][C:22]4[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=4)=[N:26][CH:27]=[C:28]3[CH:33]=[N:32]2)=[CH:8][C:7]([F:9])=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][O:13][CH2:12][C:11]1=[O:16]
Reactant: O=C1COCCN1c1cc(F)cc(CBr)c1F
Reactant: Cn1cc(Nc2ncc3cn[nH]c3n2)cn1
Product: Cn1cc(Nc2ncc3cnn(Cc4cc(F)cc(N5CCOCC5=O)c4F)c3n2)cn1

Procedure:
The title compound was prepared as in Procedure D (Step ii) using 4-(3-(bromomethyl)-2,5-difluorophenyl)morpholin-3-one and N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine. 1H NMR (d6-DMSO) δ 9.90 (s, 1H), 8.93 (s, 1H), 8.13-8.05 (m, 2H), 7.56 (s, 1H), 7.48-7.42 (m, 1H), 7.14 (s, 1H), 5.63 (s, 2H), 4.23 (s, 2H), 3.99-3.93 (m, 2H), 3.83 (s, 3H), 3.70-3.63 (m, 2H); LC-MS method B, (ES+) 441, RT=6.82 min.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[O:19])[CH2:14][CH2:13]1)=O>C(O)(=O)C>[CH3:1][N:2]1[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:9]=[C:10]1[CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[O:19])[CH2:14][CH2:13]1
Reactant: CNc1ccccc1NC(=O)C1CCN(C(=O)Oc2cccnc2)CC1
Solvent: CC(=O)O
Product: Cn1c(C2CCN(C(=O)Oc3cccnc3)CC2)nc2ccccc21
Yield: 78.9 %

Procedure:
Pyridin-3-yl 4-({[2-(methylamino)phenyl]amino}carbonyl)piperidine-1-carboxylate (0.41 g) was dissolved in acetic acid (10 ml), followed by heating under reflux for 2 hours. The solvent was evaporated, and the residue was recrystallized from methanol and diethyl ether to obtain (pyridin-3-yl) 4-(1-methyl-1H-benzimidazol-2-yl)piperidine-1-carboxylate (307 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([N+:14]([O-:16])=[O:15])[C:5]=1[NH:17][NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])([O-:3])=[O:2].[C:25](Cl)(Cl)=[O:26]>C1(C)C=CC=CC=1>[CH3:22][C:20]([C:19]1[O:24][C:25](=[O:26])[N:17]([C:5]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]([C:10]([F:11])([F:12])[F:13])=[CH:7][C:6]=2[N+:14]([O-:16])=[O:15])[N:18]=1)([CH3:21])[CH3:23]
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)C(=O)NNc1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)c1nn(-c2c([N+](=O)[O-])cc(C(F)(F)F)cc2[N+](=O)[O-])c(=O)o1
Temperature: 59 °C
Yield: 45.2 %

Procedure:
A mixture of 0.35 g (1 mmol) of N'-(2,6-dinitro-4-trifluoromethylphenyl)-2,2-dimethylpropionhydrazide, 0.3 g (3.1 mmols) of phosgene and 2.1 ml of toluene was heated to reflux for 2.5 hours (inner temperature of 59° C.). A solution (0.7 ml) of 0.1 g (1 mmol) of phosgene in toluene was further added to the reaction mixture followed by heating to reflux for further 2.5 hours. An excess of phosgene and toluene were distilled off and the residue was taken up in 20 ml of ether. After washing with saturated sodium chloride aqueous solution, the solution was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The thus obtained crude product was subjected to silica gel column chromatography to give 0.17 g of 5-(1,1-dimethylethyl)-3-(2,6-dinitro-4-trifluoromethylphenyl)-1,3,4-oxadiazolin-2-one.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[C:4]([N:6]1[CH2:11][CH:10]2[C:8]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)([CH2:9]2)[CH2:7]1)=O.[H-].COCCO[Al+]OCCOC.[Na+].[H-].Cl>CCOCC>[ClH:18].[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:8]23[CH2:9][CH:10]2[CH2:11][N:6]([CH2:4][C:3]2[CH:19]=[CH:20][CH:21]=[CH:22][C:2]=2[F:1])[CH2:7]3)=[CH:13][CH:14]=1
Reactant: O=C(c1ccccc1F)N1CC2CC2(c2ccc(Cl)cc2)C1
Agent: COCCO[Al+]OCCOC
Agent: Cl
Agent: [H-]
Solvent: CCOCC
Product: Fc1ccccc1CN1CC2CC2(c2ccc(Cl)cc2)C1

Procedure:
A 13.9 g portion of 3-(o-fluorobenzoyl)-1-(p-chlorophenyl)-3-azabicyclo[3.1.0]hexane is reacted as described in Example 19 with 50 ml of sodium bis(2-methoxyethoxy)aluminum hydride (70% benzene solution) yielding a light yellow oil. This base is treated with ethanolic hydrochloric acid and ether to give the hydrochloride as a white solid, mp 204°-206° C.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2)=O.[C:16]([NH:19][C:20]([NH2:22])=[S:21])(=[NH:18])[NH2:17]>C(O)C>[NH:19]([C:20]1[S:21][CH:2]=[C:3]([C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]3)[N:22]=1)[C:16]([NH2:18])=[NH:17]
Reactant: O=C1CCc2cc(C(=O)CCl)ccc2N1
Reactant: N=C(N)NC(N)=S
Solvent: CCO
Product: N=C(N)Nc1nc(-c2ccc3c(c2)CCC(=O)N3)cs1

Procedure:
A mixture of 6-(chloroacetyl)-3,4-dihydrocarbostyril (7 g), amidinothiourea (3.8 g) and absolute ethanol (250 ml) is stirred under reflux for about 24 hours. The reaction mixture is cooled to ice bath temperature and the precipitate filtered, washed with ethanol, and dried. The solid is suspended in aqueous sodium hydroxide, filtered, the filtered solid washed with water, and dried in vacuo. The dried solid is recrystallized from 50% aqueous DMF, and dried in vacuo yielding the desired product, M.P. >250° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:35])[C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=3)[CH2:16][CH:15]2[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.N[CH2:43][CH2:44][OH:45]>C(Cl)(Cl)Cl>[F:30][C:27]([F:28])([F:29])[C:25]1[CH:26]=[C:21]([C:20]([N:17]2[CH2:18][CH2:19][CH:14]([N:11]3[CH2:12][CH2:13][N:8]([CH2:43][CH2:44][OH:45])[CH2:9][CH2:10]3)[CH:15]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:16]2)=[O:35])[CH:22]=[C:23]([C:31]([F:33])([F:34])[F:32])[CH:24]=1
Reactant: NCCO
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2c2ccccc2)CC1
Solvent: ClC(Cl)Cl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC(N2CCN(CCO)CC2)C(c2ccccc2)C1

Procedure:
The title compound, MS: m/e=530.3 (M+H+), [α]58920=−8.02, [α]54620=−5.61, [α]43620=−20.05, [α]36520=−59.35 (c 0.1247, chloroform), was prepared in accordance with the general method of example 114 from (−)-4-[1-(3,5-bis-trifluoromethyl-benzoyl)-3-phenyl-piperidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester and 2-amino ethanol.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][C:13]1[N:17]2[C:18](=[O:30])[C:19]3[NH:20][CH:21]=[N:22][C:23]=3[N:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:16]2=[N:15][N:14]=1)C1C=CC=CC=1>CO.[Pd]>[NH2:10][CH2:11][CH2:12][C:13]1[N:17]2[C:18](=[O:30])[C:19]3[NH:20][CH:21]=[N:22][C:23]=3[N:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:16]2=[N:15][N:14]=1
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(CCNC(=O)OCc3ccccc3)nnc12
Agent: [Pd]
Solvent: CO
Product: CCCCCn1c2nc[nH]c2c(=O)n2c(CCN)nnc12
Yield: 92.2 %

Procedure:
To a solution of benzyl[2-(5-oxo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-3-yl)ethyl]carbamate (0.52 g, 1.2 mmol) in methanol (50 mL) was added 10% Pd/C (100 mg). The reaction mixture was shaken in a hydrogenation reactor under 50 Psi H2 for 3 hours. The reaction mixture was filtered through a pad of celite. The filtrate was concentrated to give the desired product (320 mg, 90% yield). LCMS calculated for C13H20N7O (M+H): 290.2. Found: 290.1.
Reaction SMILES: CN1CCN(C2C=CC(N[C:15]([C:17]3[C:18]4[N:19]=[CH:20][CH:21]=[N:22][C:23]=4[C:24]([C:27]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[CH:30]=[CH:29][CH:28]=4)=[CH:25][CH:26]=3)=[O:16])=CC=2)CC1.CO.C1COCC1.CO.[CH3:46][N:47]1[CH2:52][CH2:51][N:50]([CH2:53][C:54]2[N:55]=[C:56]([N+:59]([O-])=O)[NH:57][CH:58]=2)[CH2:49][CH2:48]1>[Ni].C(Cl)Cl.CO>[CH3:46][N:47]1[CH2:52][CH2:51][N:50]([CH2:53][C:54]2[N:55]=[C:56]([NH:59][C:15]([C:17]3[C:18]4[N:19]=[CH:20][CH:21]=[N:22][C:23]=4[C:24]([C:27]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[CH:30]=[CH:29][CH:28]=4)=[CH:25][CH:26]=3)=[O:16])[NH:57][CH:58]=2)[CH2:49][CH2:48]1
Reactant: CN1CCN(Cc2c[nH]c([N+](=O)[O-])n2)CC1
Reactant: CN1CCN(c2ccc(NC(=O)c3ccc(-c4cccc5ccccc45)c4nccnc34)cc2)CC1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(Cc2c[nH]c(NC(=O)c3ccc(-c4cccc5ccccc45)c4nccnc34)n2)CC1

Procedure:
The title compound was prepared in analogy to the procedures described in Example 14 but using 8-naphthalen-1-yl-quinoxaline-5-carboxylic acid (Example 46) in Step 14.1, Raney nickel and MeOH/THF (1:1) instead of palladium on carbon and MeOH in Step 14.2 and 1-methyl-4-(2-nitro-1H-imidazol-4-ylmethyl)-piperazine (Step 20.1) instead of 2-nitroimidazole in Step 14.3. Title compound: ESI-MS: 478.1 [M+H]+; tR=3.36 min (System 1); TLC: Rf=0.15 (DCM/MeOH, 9:1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1[NH:8][C:9](=O)[CH2:10][CH:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]=12.[Cl-].[NH4+].[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>C1COCC1>[F:23][C:24]([F:34])([F:35])[C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:32]([N:8]2[CH2:9][CH2:10][CH:11]3[CH2:19][C:18]4[C:13]([C:12]3=[N:7]2)=[CH:14][CH:15]=[CH:16][CH:17]=4)=[O:33])=[CH:29][CH:30]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: O=C1CC2Cc3ccccc3C2=NN1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)N1CCC2Cc3ccccc3C2=N1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 13.1 %

Procedure:
To a solution of 0.204 g (0.0053 mol) of lithium aluminum hydride suspended in 20 mL THF was added dropwise 1.0 g (0.0053 mol) of the product from step C dissolved in 10 mL THF. The dark reaction mixture was refluxed for 1 hour, cooled to 0° C. and 50 mL of a saturated solution of ammonium chloride was added. The reaction was extracted with ethyl acetate (3×50 mL), washed with brine (1×100 mL), dried over anhydrous magnesium sulfate, filtered into a flask and added 1.0 g (0.0053 mol) α,α,α-trifluoro-p-tolylisocyanate all at once. The reaction was stirred for 0.5 hours, concentrated under vacuum and chromatographed using 30% ethyl acetate/70% hexanes as eluent to afford 0.250 g of a purple solid, mp 136°-138° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:19][C:20](=[O:26])[O:21]C(C)(C)C)[CH:15]=[CH:16][C:17]=1[CH3:18])[N:5]=2.[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1.C(=O)([O-])[O-].[Na+].[Na+]>N1C=CC=CC=1.CO>[CH:27]1([C:30]([NH:1][C:2]2[S:3][C:4]3[C:9]([N:10]=2)=[CH:8][CH:7]=[C:6]([O:11][C:12]2[CH:13]=[C:14]([NH:19][C:20](=[O:26])[O:21][CH2:6][CH2:7][CH2:8][CH3:9])[CH:15]=[CH:16][C:17]=2[CH3:18])[N:5]=3)=[O:31])[CH2:29][CH2:28]1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1Oc1ccc2nc(N)sc2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Product: CCCCOC(=O)Nc1ccc(C)c(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 186.7 %

Procedure:
To a solution of tert-butyl {3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-methylphenyl}carbamate (800 mg, 2.14 mmol) in pyridine (10 mL) was added cyclopropanecarbonyl chloride (390 μL, 4.29 mmol), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with methanol (20 mL), anhydrous sodium carbonate (1.0 g, 9.43 mmol) was added, and the mixture was stirred at room temperature for 6 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (100 mL)/tetrahydrofuran (10 mL), washed with 5% aqueous sodium hydrogen carbonate solution (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was triturated with ethyl acetate and diisopropyl ether to give the title compound (880 mg, 93%) as a pale-yellow powder.
Reaction SMILES: [O:1]=[C:2]1[NH:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:3]21[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][CH2:4]2.[H-].[Na+].I[CH3:27]>CN(C=O)C.O>[CH3:27][N:17]1[CH2:16][CH:15]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:3]2([CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][CH2:4]2)[C:2]1=[O:1]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC2(C1)C(=O)NCC2c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CC(c2ccccc2)C2(CCN(C(=O)OC(C)(C)C)C2)C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl 6-oxo-9-phenyl-2,7-diazaspiro[4.4]nonane-2-carboxylate (commercially available) (1 g, 3.16 mmol)) in DMF (50 mL) was cooled to 0° C. and treated with sodium hydride (126 mg, 3.16 mmol)). The reaction was left to stir at 0° C. for 30 minutes and iodomethane (198 uL, 3.16 mmol) was added. The reaction mixture was left to warm to room temperature. After 3 h 30 mins, the mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL). The organic phase was dried (MgSO4), filtered and concentrated in vacuo to afford a yellow oil. Purification by chromatography on silica eluting with 0-10% MeOH in TBME afforded the following diastereomers:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([Cl:22])=[C:13]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH:14]=2)=[N:6][CH:7]=1.[S-:23][C:24]#[N:25].[K+].BrBr>C(O)(=O)C>[NH2:25][C:24]1[S:23][C:7]2[C:2]([N:1]=1)=[CH:3][CH:4]=[C:5]([O:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:22])=[C:13]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:18])[F:19])[CH:14]=1)[N:6]=2
Reactant: N#C[S-]
Reactant: Nc1ccc(Oc2ccc(Cl)c(NC(=O)C(F)(F)F)c2)nc1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: Nc1nc2ccc(Oc3ccc(Cl)c(NC(=O)C(F)(F)F)c3)nc2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.8 %

Procedure:
N-{5-[(5-Aminopyridin-2-yl)oxy]-2-chlorophenyl}-2,2,2-trifluoroacetamide (12 g, 36.2 mmol) and potassium thiocyanate (14.1 g, 145 mmol) were suspended in acetic acid (145 mL), bromine (8.67 g, 54.3 mmol) was added dropwise under ice-cooling, and the reaction mixture was stirred at room temperature for 16 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residual oil was dissolved in ethyl acetate (100 mL), aqueous sodium hydrogen carbonate solution (150 mL) was slowly added, and the mixture was partitioned. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residual solid was collected by filtration using diisopropyl ether (100 mL), and dried to give the title compound (10.1 g, 72%) as a pale-yellow solid.
Reaction SMILES: [CH2:1]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][NH:2]1.N1C2C(CCCC2)CC1.N1CCC2CCCC12.C1C2(CCCCC2)CCN1.C1C2(CCCC2)CCN1.C12C3CC1(CC3)CCCN2.N1CCC2CCCCCC12.N1CCC2CC12.C1C2C(CCCC2)CN1.C1C2CCCC2CN1.N1C2C(CCC=C2)CC1.N1CCCC1.N1C2C(=CC=CC=2)CC1.S1CCNC1>>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1
Reactant: C1CCC2CNCCC2C1
Agent: C1=CC2NCCC2CC1
Agent: C1CC2CC2N1
Agent: C1CC2CCNC2C1
Solvent: C1CCNC1
Product: c1ccc2c(c1)CCNC2

Procedure:
decahydroisoquinoline (B); octahydroindole (C); octahydrocyclopenta[b]pyrrole (D); 2-azaspiro[4.5]decane (E); 2-azaspiro[4.4]-nonane (F); spiro[(bicyclo[2.2.1]heptane)-2,3'-pyrrolidine] (G); spiro[(bicyclo[2.2.2]octane)-2,3'-pyrrolidine] (H); 2-azatricyclo[4.3.0.16,9 ]decane (I); decahydrocyclohepta[b]pyrrole (J); hexahydrocyclopropa[b]pyrrole (K); octahydroisoindole (L); octahydrocyclopenta[c]pyrrole (M); 2,3,3a,4,5,7a-hexahydroindole (N); 1,2,3,3a,4,6ahexahydrocyclopenta[b]pyrrole (O); pyrrolidine (P); indoline (Q) and thiazolidine (R), all of which can be optionally substituted.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].[CH2:8]([Mg]Br)[CH3:9].C(Br)C.[Mg].[Cl-].[NH4+]>C(OCC)C>[NH:2]=[C:1]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)CC#N
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCBr
Product: CCC(=N)CC(=O)OC

Procedure:
Methyl cyanoacetate (99 g.) was added to a stirred solution of ethyl magnesium bromide [prepared by the method well known in the art, from ethyl bromide (328 g.) and magnesium (71 g.)] in diethyl ether, at such a rate that vigorous reflux was maintained. The mixture was then heated at reflux for 40 hours and then treated with a saturated aqueous solution of ammonium chloride (3000 ml.). The ethereal layer was separated off and the aqueous layer was extracted with diethyl ether. The combined ethereal layers were dried over sodium sulphate, the solvent was removed in vacuo, and the residue distilled under reduced pressure to give methyl 3-iminovalerate (33 g.), b.p. 100°-120° C./20 mm Hg.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[N:13]=[CH:12][N:11]=[C:10]2[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[F:27])(=O)=O.[CH:30]([O:32]CCCC)=[CH2:31].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.C(=O)([O-])O.[Na+]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:26][C:22]1[C:21]([F:27])=[C:20]([NH:19][C:10]2[C:9]3[C:14](=[CH:15][C:16]([O:17][CH3:18])=[C:7]([C:30](=[O:32])[CH3:31])[CH:8]=3)[N:13]=[CH:12][N:11]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: C=COCCCC
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OS(=O)(=O)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1C(C)=O
Temperature: 80 °C
Yield: 74 %

Procedure:
4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl trifluoromethanesulfonate, (described in Example 1 preparation of starting materials), (3 g, 6.64 mmol) was dissolved in dimethylformamide (21 ml) and n-butyl vinyl ether (4.3 ml, 33.2 mmol), triethylamine (2.3 ml, 16.6 mmol), 1,3-bis(diphenylphosphino)propane (438 mg, 1.06 mmol) and palladium acetate (223 mg, 1 mmol) added. The mixture was heated at 80° C. for 2 hours, allowed to cool and stirred at room temperature over night. 2M aqueous hydrochloric acid (24 ml) was added and the mixture stirred for 0.5 hours. The mixture was basified with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic extracts were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting solid was suspended in methanol and filtered to give 1-{4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}ethanone (1.7 g, 74%) as a pale yellow solid; 1H NMR (spectrum): (DMSO d6) 2.62 (s, 3H); 4.02 (s, 3H); 7.27 (m, 2H); 7.49 (t, 2H); 8.48 (s, 1H); 8.72 (s, 1H); 10.19 (s, 1H). Mass Spectrum: (M+H)+ 346.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[C:6]([CH:8]1[CH2:12][CH2:11]OC1=O)=[O:7])([O-:3])=[O:2].[ClH:18]>>[Cl:18][CH2:11][CH2:12][CH2:8][C:6]([C:5]1[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=1[N+:1]([O-:3])=[O:2])=[O:7]
Reactant: Cl
Reactant: O=C1OCCC1C(=O)c1ccccc1[N+](=O)[O-]
Product: O=C(CCCCl)c1ccccc1[N+](=O)[O-]

Procedure:
The 18% solution of dihydro-3-(o-nitrobenzoyl)-2(3H)furanone in toluene obtained in Example 5 (450 g, 0.34 mole furanone) is treated, with stirring, with 37% HCl (48 g, 0.60 mole HCl), heated at reflux temperature for 6-11 hours, until reaction is complete by LC analysis, cooled to 35°-45° C. and allowed to settle. The phases are separated to give the title product as a toluene solution, 425 g. The product solution is used as is in Example 7.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[N:18]1C=CC=C[CH:19]=1.N.O>CN(C=O)C>[C:19]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1)#[N:18]
Reactant: c1ccncc1
Reactant: O=C(O)Cc1ccc(-c2ccc(Br)cc2)cc1
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2ccc(CC(=O)O)cc2)cc1
Reaction time: 8 h

Procedure:
The compound (840 mg) obtained in the above (2) is dissolved in DMF (7 ml), and thereto are added pyridine (10 μl) and cuprous cyanide (I) (410 mg), and the mixture is refluxed with stirring for 8 hours. To the mixture is further added cuprous cyanide (I) (410 mg), and the mixture is refluxed with stirring for 7.5 hours. After cooling, to the mixture is added a mixture of conc. aqueous ammonia (5 ml) and water (60 ml), and the precipitates are removed by filtration. The filtrate is concentrated under reduced pressure, and the pH value of the residue is adjusted to pH 11 with 1N aqueous sodium hydroxide solution, and washed twice with ether. The pH value of the residue is adjusted to pH 1 with conc. hydrochloric acid, and extracted three times with ethyl acetate. The organic layer is washed with a saturated brine, and dried over anhydrous magnesium sulfate. The desiccant is removed by filtration, and the filtrate is concentrated under reduced pressure to give the title compound (654 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH:9][CH:10]1[CH2:15][CH2:14][C:13]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)([C:16](OC)=[O:17])[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C(OCC)C.Cl>CO>[C:1]([O:5][C:6](=[O:7])[NH:8][N:9]1[C:16](=[O:17])[C:13]2([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[CH2:14][CH2:15][CH:10]1[CH2:11][CH2:12]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C1(c2ccc(C(F)(F)F)cc2)CCC(NNC(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: CC(C)(C)OC(=O)NN1C(=O)C2(c3ccc(C(F)(F)F)cc3)CCC1CC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 51.9 %

Procedure:
Methyl 4-(N′-tert-butoxycarbonylhydrazino)-1-(4-trifluoromethylphenyl)cyclohexanecarboxylate (74.5 mg) was dissolved in methanol (1.5 mL), followed by addition of a 1 N sodium hydroxide solution (1 mL) The mixture was stirred at room temperature for 15 hours and then stirred with heating under reflux for 11 hours and 30 minutes. After leaving to cool, diethyl ether was added to the reaction solution, followed by neutralization with 1 N hydrochloric acid. The organic layer was separated and then washed with brine. The resulting organic layer was dried over anhydrous sodium sulfate. The drying agent was separated by filtration and then the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (35.7 mg). The property values of the compound are as follows.