Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26](ON3C(=O)CCC3=O)=[O:27])=[C:24]([CH2:36][OH:37])[N:23]=[C:22]2[CH2:38][CH2:39][CH2:40][CH3:41])=[CH:16][CH:15]=1)=[O:7])(C)(C)C.Cl.[NH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46]>C(N(CC)CC)C>[CH2:48]([O:47][C:45]([CH2:44][NH:43][C:26]([C:25]1[N:21]([CH2:20][C:17]2[CH:16]=[CH:15][C:14]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[C:6]([OH:7])=[O:5])=[CH:19][CH:18]=2)[C:22]([CH2:38][CH2:39][CH2:40][CH3:41])=[N:23][C:24]=1[CH2:36][OH:37])=[O:27])=[O:46])[CH3:49]
Reactant: CCCCc1nc(CO)c(C(=O)ON2C(=O)CCC2=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Product: CCCCc1nc(CO)c(C(=O)NCC(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Following a procedure similar to that described in Example 53, but using 0.307 g of succinimido 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-hydroxymethylimidazole-5-carboxylate [prepared as described in Example 52(a)], 89 mg of ethyl glycinate hydrochloride and 0.089 ml of triethylamine, 0.202 g of the
Reaction SMILES: CO[C:3]([CH:5]1[CH2:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[NH:8][C:7](=[O:16])[C:6]1=[O:17])=[O:4].[Br:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>C1(C)C(C)=CC=CC=1>[Br:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:3]([CH:5]2[CH2:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[NH:8][C:7](=[O:16])[C:6]2=[O:17])=[O:4])=[CH:21][CH:20]=1
Reactant: COC(=O)C1Cc2ccccc2NC(=O)C1=O
Reactant: Nc1ccc(Br)cc1
Solvent: Cc1ccccc1C
Product: O=C1Nc2ccccc2CC(C(=O)Nc2ccc(Br)cc2)C1=O
Temperature: 25 °C

Procedure:
To the boiling suspension of 4.0 g of 2,3,4,5-tetrahydro-1-benzazepine-2,3-dione-4-carboxylic acid methyl ester in 130 ml of xylene, 3.85 g of 4-bromoaniline are added while stirring and the mixture refluxed for 6 hours under nitrogen. It is cooled to room temperature, filtered and the residue recrystallized from acetonitrile-acetic acid, to yield the 4-(4-bromophenylcarbamoyl)-2,3,4,5-tetrahydro-1-benzazepine-2,3,-dione melting at 226°-228°.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1.[SH-:17].[Na+]>O>[CH2:15]([O:14][C:12]([CH2:11][C:4]1[CH:3]=[C:2]([SH:17])[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[N:5]=1)=[O:13])[CH3:16]
Reactant: CCOC(=O)Cc1cc(Cl)n2ncnc2n1
Reactant: [SH-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)Cc1cc(S)n2ncnc2n1
Yield: 92.6 %

Procedure:
The product obtained in Step 2 (24 g) was added all at once, under a nitrogen stream, to a solution of 23 g sodium hydrosulfide in 600 ml of water, the mixture was stirred at room temperature for two hours, and the insoluble matters were filtered off. The filtrate was acidified to pH 2.0 with concentrated hydrochloric acid, and the crystals thus formed were collected by filtration, washed twice with 40 ml of water and dried, affording 22 g of the objective compound as yellow crystals.
Reaction SMILES: Cl[CH:2]([O:4][C:5](=[O:32])[N:6]([C:29](=[O:31])[CH3:30])[CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][S:23](=[O:27])(=[O:26])[CH2:22][CH2:21]3)=[C:16]([F:28])[CH:15]=2)[CH2:9]1)[CH3:3].[CH3:33][C:34]([CH3:39])([CH3:38])[C:35]([O-:37])=[O:36].[Cs+].[I-].[Na+].C(#N)C>O>[C:29]([N:6]([CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][S:23](=[O:27])(=[O:26])[CH2:22][CH2:21]3)=[C:16]([F:28])[CH:15]=2)[CH2:9]1)[C:5]([O:4][CH:2]([O:37][C:35](=[O:36])[C:34]([CH3:39])([CH3:38])[CH3:33])[CH3:3])=[O:32])(=[O:31])[CH3:30]
Reactant: CC(C)(C)C(=O)[O-]
Reactant: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OC(C)Cl
Agent: [Cs+]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OC(C)OC(=O)C(C)(C)C
Temperature: 25 °C
Yield: 30 %

Procedure:
Acetyl-{3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5(R)-ylmethyl}-carbamic acid 1-chloro-ethyl ester (11) (0.40 g, 0.81 mmol), cesium 2,2-dimethyl-propionate (0.38 g, 1.63 mmol), sodium iodide (0.121 g, 0.81 mmol) and acetonitrile (25 mL) are heated to reflux overnight. After cooling to RT, water is added and the reaction mixture is extracted with EtOAc and then with dichloromethane. The organic phases are washed separately with brine and then the organic layers are combined, dried over MgSO4, filtered, and conc in vacuo. The isolated residue is subjected to silica gel flash chromatography, eluting with MeOH/CH2Cl2 gradient (0-4% MeOH over 1 hour and 30 minutes) to afford the title compound. Isolated yield: 30%. 1H NMR (400 MHz, DMSO-d6): δ 7.41-7.38 (m, 1H), 7.33 (t, 1H), 7.22 (dd, 1H), 6.71-6.65 (m, 1H), 4.77-4.68 (m, 1H), 4.12-3.94 (m, 2H), 3.88-3.74 (m, 2H), 3.36-3.28 (m, 2H), 3.18-3.12 (m, 1H), 3.07-3.03 (m, 2H), 2.37 (d, 3H), 2.15-2.06 (m, 2H), 2.00-1.97 (m, 2H) 1.44 (dd, 3H); 1.08 (d, 9H),
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14]C)[CH:8]=2)[N:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:14])[CH:8]=2)[N:3]=1
Reactant: COc1ccc2nc(Cl)c(C=O)cc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1cc2cc(O)ccc2nc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
To a stirred solution of 2-chloro-6-methoxyquinoline-3-carbaldehyde (5.27 g, 23.8 mmol) in anhydrous CH2Cl2 (180 mL) in a 500 mL round-bottomed flask equipped with a magnetic stirrer was added dropwise BBr3 (71.3 mL, 71.3 mmol) at 0° C. and the mixture was stirred at RT overnight. The mixture was then added dropwise to a water/ice mixture, and the solid was filtered and dried under vacuum to give 2-chloro-6-hydroxyquinoline-3-carbaldehyde SLA 47016 as a yellow solid (3.14 g, 64% yield).
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=[O:3].[H-].[Na+].I[CH3:15]>CN(C=O)C>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([N:4]([CH3:15])[C:2](=[O:3])[CH3:1])=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1ccc(Br)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N(C)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-bromoacetanilide (1.0 g, 4.67 mmol) in DMF (5 mL) is added dropwise to a suspension of sodium hydride (224 mg, 5.61 mmol, 60% dispersion in mineral oil) in DMF (5 mL) at 0° C. After stirring 1 h at 0° C., iodomethane (349 μl, 5.61 mmol) is added and the reaction mixture warmed to RT and stirred 16 h. The reaction is quenched with water (15 mL) and extracted into EtOAc (3×15 mL); the combined organic phases are then dried over Na2SO4 and reduced in vacuo. Purification by column chromatography (40% EtOAc in heptane) gives the title compound.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=2[F:22])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[CH3:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[CH3:32])[CH2:27][NH2:28]>>[CH3:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[CH3:32])[CH2:27][NH:28][C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:16]([F:22])=[CH:17][CH:18]=[CH:19][C:20]=2[F:21])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5]
Reactant: Cc1ccc(CN)cc1C
Reactant: CCOC(=O)c1nc(-c2c(F)cccc2F)n(C)c(=O)c1O
Product: Cc1ccc(CNC(=O)c2nc(-c3c(F)cccc3F)n(C)c(=O)c2O)cc1C

Procedure:
Prepared according to the procedure described for example 2 from 2-(2,6-difluoro-phenyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and 3,4-dimethylbenzylamine (68 mg, 0.5 mmol). The title product was obtained as an off-white solid (32.7 mg, 82% yield). 1HNMR (500 MHz, CDCl3) δ: 12.41 (1H, s), 7.74 (1H, br s), 7.51–7.45 (1H, m), 7.10–7.02 (5H, m), 4.51 (2H, d, J=6.10 Hz), 3.40 (3H, s), 2.24 (3H, s), 2.23(3H, s). HRMS (ESI) calcd for C21H20F2N3O3 (M+H): 400.1473; found: 400.01464.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.Br.N1CCCCC1>>[OH:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: OCCCCCCCCCCCBr
Reactant: C1CCNCC1
Agent: Br
Product: OCCCCCCCCCCCN1CCCCC1
Yield: 96.3 %

Procedure:
11-Bromoundecanol (11.00 g., 43.79 mmole) was dissolved in 100 ml. of piperidine and heated at reflux temperature for 18 hours. The reaction mixture was allowed to cool and most of the precipitated piperidine hydrobromide was removed by filtration. The excess piperidine is removed by simple distillation and the resultant solid residue is recrystallized from ethanol and water. After drying, 10.78 g. (96.3% yield) of 1-hydroxy-11-(N-piperidyl)undecane was obtained. m.p. 62°-65° C., 1H-NMR (200 MHz, CDCl3) δ=1.2-1.7 ppm, m, 24H; 2.10, broad s, 1H; 2.20-2.45, m, 6H; 3.63, t, 2H.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]([C:11]1[CH:15]=[CH:14][NH:13][CH:12]=1)=[O:10].Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][N:18]=1.O>CS(C)=O>[CH3:7][O:8][C:9]([C:11]1[CH:15]=[CH:14][N:13]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][N:18]=2)[CH:12]=1)=[O:10]
Reactant: COC(=O)c1cc[nH]c1
Reactant: Clc1nccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccn(-c2nccc3ccccc23)c1
Temperature: 100 °C
Reaction time: 22 h
Yield: 88.5 %

Procedure:
1.04 g (7.5 mmol) of potassium carbonate are added at 20° C. under an argon atmosphere to 0.376 g (3 mmol) of 3-methoxycarbonyl-1H-pyrrole and 0.49 g (3 mmol) of 1-chloroisoquinoline dissolved in 6 mL of dimethyl sulphoxide. After stirring at 100° C. for 22 hours, the reaction mixture is poured into 15 mL of water and is then allowed to crystallise for 1 hour at 20° C. After filtering the reaction mixture and air-drying the solid residue, 0.67 g of 3-methoxycarbonyl-1-(isoquinol-1-yl)-1H-pyrrole is obtained in the form of a beige-coloured solid melting at 86° C. Mass spectrum (EI): m/e 252 (M+.), m/e 221.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)[N:3]=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>CN1C(=O)CCC1.C(Cl)Cl>[N:20]1([C:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:4]3[N:3]=[C:2]([N:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:10]=[CH:9][C:5]=3[C:6]([NH2:8])=[O:7])=[CH:13][CH:14]=2)=[O:19])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: NC(=O)c1ccc(Cl)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Reactant: C1CNCCN1
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: NC(=O)c1ccc(N2CCNCC2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Yield: 63.3 %

Procedure:
A solution of 6-chloro-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide (100 mg, 0.277 mmol) and piperazine (477 mg, 5.54 mmol) in NMP (2 mL) was heated to 120° C. overnight. The reaction mixture was diluted with CH2Cl2, washed with satd NaHCO3, separated, and concentrated. The residue was purified by MPLC chromatography (ISCO, 8% NH4OH/MeOH/CH2Cl2, 40 g silica gel column) to give 72 mg of 2-(4-(morpholine-4-carbonyl)phenylamino)-6-(piperazin-1-yl)nicotinamide as a white solid. LCMS: (M+H)+=411.35. 1H NMR (400 MHz, CDCl3) δ ppm 11.20 (1H, s), 7.70 (2H, d, J=8.56 Hz), 7.54 (1H, d, J=9.06 Hz), 7.38 (2H, d, J=8.56 Hz), 6.04 (1H, d, J=8.81 Hz), 5.58 (2H, s), 3.58-3.78 (12H, m), 2.92-3.01 (4H, m).
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[N+:6]([C:9]1[C:14]([N+]([O-])=O)=[CH:13][C:12]([OH:18])=[C:11]([O:19][CH3:20])[CH:10]=1)([O-:8])=[O:7]>O>[CH2:1]([NH:5][C:14]1[C:9]([N+:6]([O-:8])=[O:7])=[CH:10][C:11]([O:19][CH3:20])=[C:12]([OH:18])[CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1O
Reactant: CCCCN
Solvent: O
Product: CCCCNc1cc(O)c(OC)cc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
A mixture consisting of 80 ml of n-butylamine, 10 ml of water and 0.1 ml (21.4 g) of 4,5-dinitro-2-methoxyphenol, prepared in Example 2, is heated under reflux. After 4 hours' heating, the reaction mixture is diluted with 800 g of ice-cold water; the expected product precipitates. After being drained and dried, it is taken up in 300 ml of dilute caustic soda and precipitated by adding acetic acid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][NH:9][C@H:10]([CH:13]([CH3:15])[CH3:14])[CH2:11][OH:12])[CH:5]=[CH:4][CH:3]=1.[Si:16]([C:23]1[S:24][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:27]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[Si:16]([C:23]1[S:24][C:25]([C:2]2[N:7]=[C:6]([CH2:8][NH:9][C@H:10]([CH:13]([CH3:15])[CH3:14])[CH2:11][OH:12])[CH:5]=[CH:4][CH:3]=2)=[CH:26][CH:27]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)[C@H](CO)NCc1cccc(Br)n1
Reactant: CC1(C)OB(c2ccc([Si](C)(C)C(C)(C)C)s2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)[C@H](CO)NCc1cccc(-c2ccc([Si](C)(C)C(C)(C)C)s2)n1
Temperature: 80 °C
Yield: 47.6 %

Procedure:
To a solution of Example 227A (0.521 g, 1.91 mmol) in dioxane (10 mL) at ambient temperature was added 2-(t-butyldimethylsilyl)thiophene-5-boronic acid pinacol ester (0.619 g, 1.91 mmol), 2 molar cesium carbonate (0.9 mL, 1.9 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.031 g, 0.038 mmol). The solution was degassed (3× vacuum/purge N2) and heated to 80° C. overnight. The mixture was cooled and partioned between water and CH2Cl2. The organic phase concentrated and the residue triturated with ether to provide 355 mg (41%) of the title compound. MS (DCI30 ) m/z 391 (M+H); 1H NMR (300 MHz, CDCl3) δ 7.69-7.60 (m, 2H), 7.54 (d, J=7.6 Hz, 1H), 7.25 (d, J=3.6 Hz, 1H), 7.12 (d, J=7.4 Hz, 1H), 3.99 (s, 2H), 3.70 (dd, J=10.9, 4.0 Hz, 1H), 3.50 (dd, J=10.9, 6.4 Hz, 1H), 2.51 (td, J=6.5, 4.0 Hz, 1H), 1.92 (td, J=13.6, 6.8 Hz, 1H), 1.06 (d, J=6.8 Hz, 3H), 1.00-0.92 (m, 12H), 0.37-0.28 (m, 6H).
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([C:17]#[N:18])=[CH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH2:19]([Mg]Br)[CH:20]=[CH2:21].[Cl-].[NH4+]>C1COCC1>[CH2:6]([O:5][P:4]([CH:9]([C:17]#[N:18])[CH:10]([CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)[CH2:21][CH:20]=[CH2:19])(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOP(=O)(OCC)C(C#N)=CC1CCCCC1
Reactant: C=CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCC(C1CCCCC1)C(C#N)P(=O)(OCC)OCC
Temperature: 7.5 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of the oil isolated in Step A (17.5 g, 65 mmol), and cuprous iodide (0.75 g) in THF (100 mL) at 0° C., a solution of allylmagnesium bromide in THF (2 M, 42 mL, 84 mmol) was added slowly while the temperature was maintained at about 5-10° C. The reaction mixture then was stirred at room temperature overnight. Aqueous saturated ammonium chloride solution (100 mL) was then added. The reaction mixture was stirred 30 min at room temperature and then extracted with ethyl acetate (200 mL). The organic solution washed with saturated ammonium chloride solution three times and with brine one time, and then was dried over sodium sulfate. The reaction mixture was then filtered and concentrated to yield a residue. The residue was purified by Kugelrohr distillation to yield a colorless oil (GC showed it contained 20% starting material, but the oil was used as is without further purification).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.C([O-])([O-])=O.[K+].[K+].[CH:19]1[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=1>CN(C=O)C>[CH2:25]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2)[C:22]1[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1CCc2cc(O)ccc2N1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCc2cc(OCc3ccccc3)ccc2N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
A solution of 6-hydroxy-3,4-dihydro-1H-quinolin-2-one (2.93 g, 17.9 mmol) in DMF (20 mL) is treated with K2CO3 (4.97 g) and BnBr (4.61 g, 26.9 mmol). The suspension is stirred at room temperature for 4 hours and quenched with water (100 mL). The mixture is extracted with EtOAc (50 mL×2) and the combined organics are dried (Na2SO4), concentrated, and purified on silica gel chromatography column with 30-60% EtOAc/Hexanes to yield the title compound (4.40 g, 97%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH2:13][C:14]([OH:17])([CH3:16])[CH3:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[C:19](Cl)(=[O:21])[CH3:20]>C(Cl)Cl>[C:19]([O:17][C:14]([CH3:15])([CH2:13][CH2:12][O:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH3:16])(=[O:21])[CH3:20]
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)(C)O)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CC(=O)OC(C)(C)CCOS(=O)(=O)c1ccc(C)cc1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
To a mixture of the alcohol 2 (0.500 g, 1.937 mmol), ZrOCl28.H2O (0.0031 g, 0.5 mol %) in methylene chloride (5 mL), acetyl chloride (0.304 g, 3.87 mmol) is added and the reaction is stirred for overnight at 20° C. The reaction on completion, is diluted with methylene chloride (5 mL) and washed with saturated sodium bicarbonate (2×10 mL), brine (1×10 mL) and dried. The solvent is evaporated to get the crude product. 1H NMR (400 MHz, CDCl3): δ 1.54 (s, 6H), 1.59 (s, 3H), 2.14-2.07 (m, 2H), 2.43 (s, 3H), 4.26 (dt, J=6.9, 13.5, 3H), 7.33 (d, J=7.9, 2H), 7.77 (d, J=8.2, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH2:23][CH2:24][CH:25]=[CH2:26])([C:18]([O:20]CC)=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].CC(O)=O>C(O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])([CH2:23][CH2:24][CH:25]=[CH2:26])[C:18]([OH:20])=[O:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCCC(NC(=O)OCc1ccccc1)(C(=O)OCC)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: C=CCCC(NC(=O)OCc1ccccc1)(C(=O)O)C(=O)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
A solution of diethyl 2-(benzyloxycarbonylamino)-2-(but-3-enyl)malonate (4.8 g, 13.23 mmol) in ethanol (45 mL) was cooled to −30° C. and treated with an aqueous solution of potassium hydroxide (1.55 g, 27.76 mmol in 15 mL water). After the addition was complete, the solution was warmed to 0° C. for 30 minutes followed by room temperature for 1 h. With the reaction complete, the mixture was acidified with AcOH (1.8 g) and extracted with ethyl acetate (1×50 mL). The aqueous layer was acidified to pH 3 with 3 N hydrochloric acid and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with saturated aqueous sodium chloride (1×50 mL), dried over MgSO4 and concentrated to give 2-(benzyloxycarbonylamino)-2-(ethoxycarbonyl)hex-5-enoic acid (3.0 g, 68%). 1H NMR (CDCl3) δ 10.00 (bs, 1H), 7.37 (m, 5H), 7.26-6.93 (m, 1H), 6.21 (bs, 1H), 5.76 (m, 1H), 5.94-5.22 (m, 4H), 4.27 (m, 2H) 2.43 (m, 2H), 1.96-1.93 (m, 2H), 1.27-1.21 (m, 3H). MS found for C17H21NO6 m/z [336 (M+1)].
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=O)=[O:5])[CH3:2].Cl.CN.[C:15]([BH3-])#[N:16].[Na+]>C(O)C.C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH2:10][CH2:9][CH2:8][C:7]=1[NH:16][CH3:15])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCCC1=O
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C1=C(NC)CCC1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A solution of 2-oxo-cyclopentanecarboxylic acid ethyl ester (3.00 g, 19.2 mmol) in ethanol (20 mL) was treated with methylamine hydrochloride (1.296 g, 19.2 mmol), sodium cyanoborohydride (2.42 g, 38.4 mmol), and glacial acetic acid (10 drops) and stirred for 16 h at 50° C. After cooling to 25° C. the solvent was removed in vacuo, the crude material was redissolved in ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate solution (100 mL). The aqueous layer was discarded and the organic layer was washed with 1.0 M aqueous hydrochloric acid solution (50 mL). The organic layer was discarded, 1.0 M aqueous sodium hydroxide solution (75 mL) was added and the aqueous layer was extracted with ethyl acetate (100 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was removed in vacuo to afford the crude product, 2-methylamino-cyclopent-1-enecarboxylic acid ethyl ester, as a light yellow oil. LC-MS (ESI) calcd for C9H15NO2 169.11, found 170.2 [M+H+].
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([CH2:19][N:20]2[CH2:38][CH2:37][C:23]3([C:27](=[O:28])[N:26]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][CH:31]=4)[CH2:25][CH2:24]3)[CH2:22][CH2:21]2)[CH2:9]1)=O)(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>>[Br:36][C:33]1[CH:32]=[CH:31][C:30]([CH2:29][N:26]2[CH2:25][CH2:24][C:23]3([CH2:22][CH2:21][N:20]([CH2:19][CH:10]4[CH:11]([C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=5)[CH2:12][NH:8][CH2:9]4)[CH2:38][CH2:37]3)[C:27]2=[O:28])=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CC(CN2CCC3(CC2)CCN(Cc2ccc(Br)cc2)C3=O)C(c2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1N(Cc2ccc(Br)cc2)CCC12CCN(CC1CNCC1c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
To 510 mg (0.87 mmol) of 3-(RS)-[2-(4-bromobenzyl)-1-oxo-2,8-diaza-spiro[4.5]dec-8-ylmethyl]-4-(SR)-phenylpyrroli-dine-1-carboxylic acid tert-butyl ester was added a solution of DCM/TFA 20% (12 mL). The reaction mixture was agitated for one hour at room temperature before quenching with 30 mL of aqueous solution of sodium hydroxide (1N). The solution was then extracted with DCM (2×20 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated in vacuo yielding Compound 3 as a pale yellow solid (420 mg, 99.4%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]([C:19]#[N:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:7][C:8](OCC)=[O:9])[CH3:2]>[Ni]>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][C:8](=[O:9])[NH:20][CH2:19]1)[CH3:2]
Reactant: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccccc1
Agent: [Ni]
Product: CCOC(=O)CC1(c2ccccc2)CNC(=O)C1

Procedure:
Prepared by the method of example 1.2.2 using 3-cyano-3-phenyl-pentanedioic acid diethyl ester (37 mmol) and Raney nickel (70 g) to give the title compound:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][C:35]=1[O:36][CH3:37])[N:32]=[CH:31][CH:30]=[C:29]2OS(C(F)(F)F)(=O)=O>N1C(C)=CC=CC=1C>[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][C:35]=1[O:36][CH3:37])[N:32]=[CH:31][CH:30]=[C:29]2[O:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(O)cc1)C1(C(=O)Nc2ccc(F)cc2)CC1
Reactant: COc1cc2nccc(OS(=O)(=O)C(F)(F)F)c2cc1OC
Solvent: Cc1cccc(C)n1
Product: COc1cc2nccc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3)c2cc1OC
Temperature: 165 °C
Reaction time: 18 h
Yield: 43.1 %

Procedure:
To a solution of cyclopropane-1,1-dicarboxylic acid (4-fluoro-phenyl)-amide (4-hydroxy-phenyl)-amide (6.98 g, 22.2 mmol) in anhydrous 2,6-lutidine (50 mL) was added trifluoromethanesulfonic acid 6,7-dimethoxy-quinolin-4-yl ester (5 g, 14.8 mmol). The reaction mixture was heated at 165° C. in a sealed pressure tube with stirring for 18 h. The reaction mixture was concentrated on high vacuum to completely remove lutidine. The resulting solid material was dissolved in DCM (250 mL), and washed several times with 1 N sodium hydroxide to remove the excess phenol. The crude mixture was loaded on a silica gel flash column and eluted with 75% EtOAc-hexanes, affording N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (3.2 g, 44%). 1H NMR (400 MHz, d6-DMSO): δ 10.2 (s, 1H), 10.05 (s, 1H), 8.4 (s, 1H), 7.8 (m, 2H), 7.65 (m, 2H), 7.5 (s, 1H), 7.35 (s, 1H), 7.25 (m, 2H), 7.15 (m, 2H), 6.4 (s, 1H), 4.0 (d, 6H), 1.5 (s, 4H). LC/MS: M+H=502.