Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=O)[CH2:8][C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.O1CCCC1.[CH3:26][NH2:27]>C1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([NH:27][CH3:26])[CH2:8][C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: O=C1CC(=O)N(c2ccccc2)c2cc(Cl)ccc2N1
Reactant: CN
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CNC1=Nc2ccc(Cl)cc2N(c2ccccc2)C(=O)C1
Reaction time: 0.25 h

Procedure:
A suspension of 14.3g (0.05 mol) of 7-chloro-5-phenyl-1,2,3,5-tetrahydro-4H-1,5-benzodiazepin-2,4-dione in 1l of tetrahydrofuran and 200 ml of benzene was saturated with methylamine. A solution of 11.5 g (0.06 mol) of titanium tetrachloride in 200 ml of benzene was added at 0° through a dropping funnel. After stirring at 0° to 10° for 15 min, the mixture was heated to reflux for 1 1/2 hrs. It was then partitioned between water and benzene. The benzene layer was separated, dried and evaporated. Crystallization of the residue form methylene chloride/hexane yielded the above-named product, mp 215°-217°.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH3:24][C:25]1[N:26]([CH2:34][CH2:35][O:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][O:38]2)[CH:27]=[C:28]([Sn](C)(C)C)[N:29]=1>O1CCOCC1.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>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:22]=[CH:23][C:2]([C:28]5[N:29]=[C:25]([CH3:24])[N:26]([CH2:34][CH2:35][O:36][CH:37]6[CH2:42][CH2:41][CH2:40][CH2:39][O:38]6)[CH:27]=5)=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: Cc1nc([Sn](C)(C)C)cn1CCOC1CCCCO1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cc1nc(-c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)cn1CCOC1CCCCO1
Temperature: 120 °C
Reaction time: 0.58 h
Yield: 32.3 %

Procedure:
A mixture of 9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (300 mg, 0.8 mmol), Pd(PPh3)4 (93 mg, 0.08 mmol), 2-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(trimethylstannyl)-1H-imidazole (600 mg, 1.6 mmol) in dioxane (2 ml) was bubbled with N2 for about 2 min and then stirred at 120° C. for 35 min under the irradiation of microwave. Filtered, concentrated and purified by pre-TLC (EtOAc) to give 130 mg of 256. Yield=32%. 1H NMR (CDCl3, 400 MHz): δ8.44-8.42 (m, 1 H, ArH), 7.81 (s, 1 H), 7.58 (s, 1 H), 7.48-7.46 (m, 1 H), 7.42 (d, J=1.6 Hz, 1 H), 7.19 (s, 1 H), 4.51-4.95 (m, 1 H), 4.45-4.44 (t, 1 H), 4.39-4.38 (m, 2 H), 4.38-4.37 (m, 2 H), 4.07-4.04 (m, 2 H), 4.00-4.97 (m, 1 H), 3.63-3.54 (m, 2 H), 3.40-3.36 (m, 1 H), 2.49 (s, 3 H), 1.76-1.60 (m, 4 H), 1.48-1.47 (m, 2 H) LC-MS: m/z=504 [M+H+]
Reaction SMILES: [NH2:1][C@H:2]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[OH:17][CH:18]1[CH:26]2[CH:21]([CH:22]3[CH2:27][CH:25]2[CH:24]=[CH:23]3)[C:20](=O)[O:19]1>C1C=CC=CC=1>[O:17]=[C:18]1[C@H:26]2[C@H:21]([C@@H:22]3[CH2:27][C@H:25]2[CH:24]=[CH:23]3)[C@@H:20]([NH:1][C@@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[O:19]1
Reactant: O=C1OC(O)C2C3C=CC(C3)C12
Reactant: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Solvent: c1ccccc1
Product: CC(C)C[C@H](N[C@H]1OC(=O)[C@H]2[C@@H]1[C@H]1C=C[C@@H]2C1)C(=O)OCc1ccccc1

Procedure:
A mixture of 5.2 g of benzyl L-leucinate, 4 g of (3RS, 3aRS,4RS,7RS,7aRS) 3-hydroxy-3a,4,7,7a-tetrahydro-1H,3H-4,7-methano-isobenzofuran1-one and 40 ml of anhydrous benzene was refluxed for 90 minutes while azeotropically distilling off the water of reaction formed and was then evaporated to dryness under reduced pressure. The residue was added to isopropyl ether and the mixture was vacuum filtered to obtain 2.3 g of benzyl (αS,3S,3aS,4R,7S,7aR) α-[(1-oxo-3a,4,7,7a-tetrahydro-1H,3H-4,7-methano-isobenzofuran-3-yl)-amino]-isohexanoate melting at 95° C.
Reaction SMILES: CO[CH:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[NH:6][C:5]1=[O:15].[N:16]1([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1>CN(C)C=O>[N:16]1([CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([NH:29]/[CH:3]=[C:4]3\[C:5](=[O:15])[NH:6][C:7](=[O:14])[C:8]4[C:13]\3=[CH:12][CH:11]=[CH:10][CH:9]=4)=[CH:27][CH:28]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Nc1ccc(CCN2CCCC2)cc1
Reactant: COC=C1C(=O)NC(=O)c2ccccc21
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccccc2/C1=C/Nc1ccc(CCN2CCCC2)cc1
Temperature: 110 °C
Yield: 71.4 %

Procedure:
A mixture of 4-methoxymethylene-4H-isoquinoline-1,3-dione (101.5 mg, 0.5 mmol), 4-(2-pyrrolidin-1-yl-ethyl)-phenylamine (95.2 mg, 0.5 mmol) in 1 mL of N,N-dimethylformamide is heated at 110° C. for 1.5 h. After cooling in the refrigerator, the precipitate is collected, and washed with ether to give 129 mg (71%) of yellow solid mp 224-225° C.; MS (ESI) m/z 362.20 (M+1); Analysis for C22H23N3O2: Calcd: C, 73.11; H, 6.41; N, 11.63. Found: C, 72.33; H, 6.45; N, 11.59.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH:21]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C(Cl)Cl>[Cl:1][C:2]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:3]=1[C:4]([C:6](=[CH:12][NH:27][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1ccc(I)cc1Cl
Reactant: NC1CCCCC1
Solvent: ClCCl
Product: CCOC(=O)C(=CNC1CCCCC1)C(=O)c1ccc(I)cc1Cl
Reaction time: 6 h
Yield: 54.5 %

Procedure:
mf) A solution of 31.18 g of ethyl 2-(2-chloro-4-iodo-benzoyl)-3-ethoxy-acrylate in 500 ml of methylene chloride is treated dropwise with 7.95 g of cyclohexylamine while cooling with ice and stirring. After 6 hrs. at room temperature the reaction mixture is concentrated and, for crystallization, the residue is stirred with 200 ml of hexane. The precipitate is filtered off under suction, washed with 100 ml of hexane and dried. 19.2 g (55%) of ethyl 2-(2-chloro-4-iodo-benzoyl)-3-cyclohexylamino-acrylate are obtained as a colourless solid. M.p. 154°-156° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[C:23](#[N:26])[CH:24]=[CH2:25]>C(O)(=O)C>[C:23]([CH2:24][CH2:25][NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][N:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:15][CH2:16]2)=[CH:6][CH:7]=1)#[N:26]
Reactant: C=CC#N
Reactant: Nc1ccc(CCCN2CCN(c3ccccc3)CC2)cc1
Solvent: CC(=O)O
Product: N#CCCNc1ccc(CCCN2CCN(c3ccccc3)CC2)cc1
Yield: 81.2 %

Procedure:
A mixture consisting of 29.5 gm (0.1 mol) of N-[γ-(p-amino-phenyl)-n-propyl]-N'-phenyl-piperazine (m.p. 102° C), 5.8 gm (0.11 mol) of acrylnitrile and 20 ml of glacial acetic acid was refluxed for 20 hours. Thereafter, the solvent was distilled off in vacuo, and the residue was recrystallized from dilute methanol, yielding 28.3 gm (81.3% of theory) of N-[γ-(p-[β-cyanoethyl-amino]phenyl)-n-propyl]-N'-phenyl-piperazine, M.P. 141°-143° C.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].CC(C)=O.[OH-].[K+].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=[O:19]>O>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]([CH:17]2[CH:1]([OH:9])[C:2]3[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=3)[O:4]2)=[O:19])=[CH:21][CH:22]=1
Reactant: O=Cc1ccccc1O
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(c1ccc(Cl)cc1)C1Oc2ccccc2C1O

Procedure:
To a solution of 15.3 g. (0.125 mol.) of salicylaldehyde in 100 ml. of acetone was added 7.0 g. (0.125 mol.) of potassium hydroxide dissolved in a minimum amount of water. α-Bromo-p-chloroacetophenone (29.16 g., 0.125 mol.) was added dropwise with stirring and cooling (ice bath). After addition, the reaction mixture was stirred at 25° for 12 hours. The precipitate was collected by filtration, washed with water and combined with the residue remaining after concentration of the filtrate to give 2-(4-chlorobenzoyl)-3-hydroxycoumaran which was immediately dehydrated in the presence of p-toluenesulfonic acid to yield 2-(4-chlorobenzoyl)benzofuran.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]2[CH2:11][NH:10][CH2:9][CH:8]2[OH:12])=[C:4]([O:15][CH3:16])[CH:3]=1.C=O.[C:19](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C@@H:7]2[CH2:11][N:10]([CH3:19])[CH2:9][C@H:8]2[OH:12])=[C:4]([O:15][CH3:16])[CH:3]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COc1cc(Br)ccc1OC1CNCC1O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COc1cc(Br)ccc1O[C@@H]1CN(C)C[C@H]1O
Reaction time: 8 h
Yield: 95.6 %

Procedure:
Dissolve 4-(4-bromo-2-methoxy-phenoxy)-pyrrolidin-3-ol (409 mg, 1.42 mmol) in dichloroethane (15 mL) and add formaldehyde (0.117 mL, 1.56 mmol, 37% aqueous solution), sodium triacetoxyborohydride (451 mg, 2.13 mmol), and acetic acid (0.325 mL, 5.68 mmol). Stir the mixture overnight. Dilute with saturated sodium bicarbonate and extract three times with dichloromethane. Combine all the organics and dry over sodium sulfate, filter, and evaporate the filtrate. Purify by silica gel chromatography, eluting with 0-6% MeOH in dichloromethane with 2 N ammonia to give 410 mg (95%) of the title compound as a clear oil. LC-MS/ES m/z (81Br) 304.0 [M+H]−.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:3][CH:2]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O>C(OC(=O)C)(=O)C.C(N(CC)CC)C>[F:13][C:14]1[CH:15]=[C:16](/[CH:17]=[C:7](\[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)Cc1ccncc1
Reactant: O=Cc1cccc(F)c1
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C(=C/c1cccc(F)c1)c1ccncc1
Yield: 62.2 %

Procedure:
A solution of ethyl 4-pyridylacetate (25.0 g, 0.151 mol) and 3-fluorobenzaldehyde (20.7 g, 0.167 mol) in a mixture of acetic anhydride (100 mL) and triethylamine (20 mL) was heated under reflux for 5.5 hours. After standing to cool, the reaction mixture was concentrated. The residue was diluted with ethyl acetate and a saturated aqueous sodium hydrogencarbonate solution, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium hydrogencarbonate solution twice and brine, dried over anhydrous sodium sulfate and then concentrated. The residue was subjected to silica gel column chromatography (eluent; hexane, hexane:ethyl acetate=9:1), to give the title compound (25.5 g, 62%) as a red-orange oil.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([CH3:12])[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13]1([CH2:23][CH2:24]Br)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.[Mg].C1COCC1>CCOCC.[Br-].[Zn+2].[Br-]>[CH2:1]([O:8][C@H:9]([C@@H:10]([OH:11])[CH2:24][CH2:23][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCc1cccc2ccccc12
Reactant: C[C@@H](C=O)OCc1ccccc1
Agent: [Br-]
Agent: [Mg]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@H](OCc1ccccc1)[C@@H](O)CCc1cccc2ccccc12
Temperature: 4 °C
Reaction time: 1 h
Yield: 30.8 %

Procedure:
A solution of (S)-2-(benzyloxy)propanal (Bull. Chem. Soc. Jpn. (1989) 62, 3038, 16.25 g) in ether (200 ml) was added to a suspension of zinc bromide (26.75 g) in ether (50 ml) below 6° C. and then an ethereal solution of 2-(1-naphthyl)ethylmagnasium bromide, prepared from 2-(1-naphthyl)ethyl bromide (46.55 g) and magnesium turnings (9.63 g) in ether (300 ml), was added below 8° C. The mixture was stirred at 4° C. for 1 h and then THF (200 ml) was added. The final mixture was stirred overnight at room temperature. After cooling, the mixture was quenched with saturated aqueous ammonium chloride solution (200 ml) and insoluble material was filtered. The filtrate was extracted with ethyl acetate and the extract was washed with brine, dried and concentrated in vacuo. Flash chromatography (hexane:ethyl acetate =9:1) gave (2S,3S)-2-benzyloxy-5-(1-naphthyl)pentan-3-ol (9.78 g, 30.8%) as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.[F-].[K+]>C1(C)C=CC=CC=1>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH3:10]
Reactant: COc1ccccc1Br
Reactant: Cc1ccccc1B(O)O
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccccc1-c1ccccc1C
Yield: 97.3 %

Procedure:
2-Bromoanisole (187 mg, 1.00 mmol) reacted with 2-methylphenylboronic acid (150 mg, 1.10 mmol) using 1 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and KF (116 mg, 2.0 mmol) in toluene at 100° C. to give the title compound (193 mg, 98%) as a colorless oil: 1H-NMR (400 MHz, CDCl3): δ 7.43 (t, 1H, J=8.2 Hz, aryl coupling J=1.75 Hz), 7.36-7.24 (m 5H), 7.10 (t, 1H, J=7.4 Hz, aryl coupling 0.91 Hz), 7.05 (d, 1H, J=8.2 Hz), 3.84 (s, 3H), 2.24 (s, 3H). 13C{1H}-NMR (100 MHz, CDCl3): δ 156.53, 138.58, 136.77, 130.95, 130.77, 129.95, 129.52, 128.51, 127.25, 125.40, 120.38, 110.56, 55.31, 19.89. GC/MS(EI): m/z 198 (M+). Anal. Calcd for C14H14O: C, 84.81; H, 7.12. Found: C, 84.97; H, 7.11.
Reaction SMILES: [N:1]([CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH3:17])[C:14]=2[CH3:16])[CH2:9][C:8]2([CH2:22][CH2:21][CH2:20]2)[CH2:7]1)=[N+]=[N-].C(OC(=O)C)C>CO.[Pd]>[CH3:19][O:18][C:12]1[CH:11]=[C:10]2[C:15](=[C:14]([CH3:16])[C:13]=1[CH3:17])[N:6]([CH2:5][CH2:4][NH2:1])[CH2:7][C:8]1([CH2:20][CH2:21][CH2:22]1)[CH2:9]2
Reactant: COc1cc2c(c(C)c1C)N(CCN=[N+]=[N-])CC1(CCC1)C2
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc2c(c(C)c1C)N(CCN)CC1(CCC1)C2
Reaction time: 1 h
Yield: 89.5 %

Procedure:
A solution of 6′-methoxy-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinoline] (1.12 g), 1,2-dibromoethane (2 mL) and Cs2CO3 (3.16 9) in DMF (7 mL) was heated in a bath of 110° C. for 6 hours. The mixture was cooled, water was added, and extracted with dichloromethane. The organic phase was then washed with brine, dried and evaporated. The residue was passed through a column (Hexane/EtOAc, 10:0.6) to give 1′-(2-bromoethyl)-6′-methoxy-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinoline] which was then added NaN3 (1.1 g) and dissolved in dichloromethane (7 mL). After heating the solution in a bath of 90° C. for 1 hour, the mixture was cooled, mixed with water and extracted with dichloromethane. The organic phase was washed with brine, dried and evaporated. The residue was passed through a column (Hexane/EtOAc, 10:0.5-10:0.6) to give 1′-(2-azidoethyl)-6′-methoxy-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinoline] (340 mg) as an oil. 1′-(2-azidoethyl)-6′-methoxy-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinoline] (340 mg) was dissolved in methanol (7 mL) and ethylacetate to which 50 mg Pd/C (10%) was added. The flask was then flushed evacuated and flushed with hydrogen. Under a balloon of hydrogen for 1 hour, the mixture was filtered and evaporated to give 2-(6′-methoxy-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinoline]-1′-yl)ethanamine (278 mg) as an oil. 1H-NMR (300 MHz, C2D6O) δ=6.414 (s, 1H); 3.77 (s, 3H); 3.52 (s, 2H); 3.16-2.92 (m, 4H); 2.81 (s, 2H); 2.18 (s, 3H); 2.12 (s, 3H); 2.03-1.86 (m, 4H); 1.84-1.64 (m, 2H) ppm.
Reaction SMILES: [CH:1]1([N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][CH:17]=3)=[CH:10][C:9]=2[CH:27]([CH3:29])[CH3:28])[CH2:5][CH3:6])[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH:1]1([N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)=[CH:10][C:9]=2[CH:27]([CH3:28])[CH3:29])[CH2:5][CH3:6])[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(CN(CC)C3CC3)c(C(C)C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCN(Cc1ccc(C#Cc2ccc(C(=O)O)cc2)cc1C(C)C)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
Using General Procedure I; a solution of ethyl 4-{4-[(cyclopropyl-ethyl-amino)-methyl]-3-isopropyl-phenylethynyl}-benzoate (Compound 133, 68.0 mg, 0.17 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (600.0 mg, 15.0 mmols, 3.0 mL of a 5N aqueous solution) and stirred overnight at room temperature and then at 55° C. for 9 hours. Work-up followed by crystallization of the solid residue from hot CH3CN afforded 45.0 mg (72%) of the title compound as a pale-yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[C:10](=[O:23])[N:11]([CH3:22])[C:12]3[C:17]([CH:18]=2)=[CH:16][N:15]=[C:14]([NH:19][CH2:20][CH3:21])[CH:13]=3)[C:5]([F:24])=[CH:4][N:3]=1.C(N(CC)CC)C.[CH2:32]([S:35](Cl)(=[O:37])=[O:36])[CH2:33][CH3:34].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:20]([NH:19][C:14]1[CH:13]=[C:12]2[C:17]([CH:18]=[C:9]([C:6]3[C:5]([F:24])=[CH:4][N:3]=[C:2]([NH:1][S:35]([CH2:32][CH2:33][CH3:34])(=[O:37])=[O:36])[C:7]=3[F:8])[C:10](=[O:23])[N:11]2[CH3:22])=[CH:16][N:15]=1)[CH3:21]
Reactant: CCCS(=O)(=O)Cl
Reactant: CCNc1cc2c(cn1)cc(-c1c(F)cnc(N)c1F)c(=O)n2C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCS(=O)(=O)Nc1ncc(F)c(-c2cc3cnc(NCC)cc3n(C)c2=O)c1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution 3-(2-Amino-3,5-difluoropyridin-4-yl)-7-(ethylamino)-1-methyl-1,6-naphthyridin-2(1H)-one (15 mg, 0.05 mmol), triethylamine (3 ml), and DCM (10 mL) was treated with n-propanesulfonyl chloride (0.05 ml, 0.4 mmol) at 0° C. The mixture was allowed to warm to rt and was stirred for 16 h. Aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in methanol (10 mL) and potassium carbonate (2 g) was added. The mixture was stirred at room temperature for 2 h. Water was added and the mixture was extracted with ethyl acetate, then the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was chromatographed on silica gel (2% to 3% methanol in DCM eluant) to provide the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1.[CH2:24]([O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[C:29]([C:36]([F:39])([F:38])[F:37])[CH:28]=1)[CH3:25]>COCCOC.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>[CH2:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([C:2]2[CH:3]=[C:4]3[C:8]4=[C:9]([CH2:11][CH2:12][N:7]4[C@H:6]4[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:16][C@@H:5]34)[CH:10]=2)=[C:29]([C:36]([F:37])([F:38])[F:39])[CH:28]=1)[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CC3
Reactant: CCOc1ccc(B(O)O)c(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: O
Product: CCOc1ccc(-c2cc3c4c(c2)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2N4CC3)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 57.3 %

Procedure:
Tert-butyl(6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)carboxylate (189 mg, 0.5 mmol) was dissolved in DME (7.8 mL). Ba(OH)2 8H2O (236.6 mg, 0.75 mmol) in H2O (2.6 mL) was added. 4-ethoxy-2-trifluoromethylphenyl boronic acid (140 mg, 0.6 mmol) was added followed by Pd(PPh3)4 (12 mg, 0.01 mmol). The reaction flask was degassed and refluxed under a nitrogen atmosphere for 18 hrs. After cooling to RT, the reaction was concentrated in vacuo. Water (10 mL) and EtOAc (10 mL) were added. The layers were separated and the aqueous phase was extracted with EtOAc (2×10 mL). The combined organic layer was washed with brine (2×10 mL), dried over MgSO4 and concentrated in vacuo and after chromatographic purification (30% EtOAc/Hexane) to afford the title compound (140 mg, 57%). 1H NMR (CDCl3, 300 MHz) δ 7.20 (d, 2H, J=5.9 Hz), 7.19 (s, 1H), 7.01 (dd, 1H, J=6.2, 2.2 Hz), 6.85 (s, 1H), 6.81 (s, 1H), 4.05–4.10 (m, 3H), 3.82–3.94 (m, 1H), 3.64–3.68 (m, 1H), 3.22–3.44 (m, 4H), 2.84–3.10 (m, 3H), 1.80–1.90 (m, 2H), 1.42–1.47 (m, 12H) ppm. MS-ApCI: 489 [M+H+].
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:38][CH2:39][CH3:40])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH:20]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[O:31])[N:28]([CH3:30])[CH3:29])=[CH:23][CH:22]=3)[C:19](=O)[C:18]3[C:17]([C:33]([O:35]CC)=O)=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12]2)=[CH:7][CH:6]=1)[CH3:2].O.[NH2:42][NH2:43]>CO>[CH2:1]([O:3][CH:4]([O:38][CH2:39][CH3:40])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[NH:12][C:13]3[C:18]4[C:19](=[N:42][NH:43][C:33](=[O:35])[C:17]=4[CH:16]=[CH:15][CH:14]=3)[CH:20]2[C:21]2[CH:26]=[CH:25][C:24]([C:27]([N:28]([CH3:30])[CH3:29])=[O:31])=[CH:23][CH:22]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(C(=O)N(C)C)cc1)C(c1ccc(C(OCC)OCC)cc1)N2
Solvent: CO
Solvent: O
Product: CCOC(OCC)c1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(C(=O)N(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 76 %

Procedure:
Ethyl 2-(4-(diethoxymethyl)phenyl)-3-(4-(dimethylcarbamoyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (250 mg, 0.46 mmol) and hydrazine monohydrate (85%, 5 mL) were added in MeOH (15 mL) and the mixture was stirred room temperature for 5 h. The resulting mixture was concentrated under reduced pressure to a volume of 15 mL and then filtered; the filtrate was evaporated to give the title compound as a white solid (180 mg, yield 76%). LC-MS (ESI) m/z: 513(M+1)+.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.O1CC[N:21]([CH:24]=[CH:25][CH2:26][CH3:27])CC1>C(Cl)Cl>[CH2:26]([C:25]1[CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:21][CH:24]=1)[CH3:27]
Reactant: CCOC=C(C(=O)OCC)C(=O)C(=O)OCC
Reactant: CCC=CN1CCOCC1
Solvent: ClCCl
Product: CCOC(=O)c1cc(CC)cnc1C(=O)OCC
Reaction time: 72 h
Yield: 56.9 %

Procedure:
Diethyl ethoxymethyleneoxalacetate (3.17 g, 0.013 mol) is added to a solution of 1-morpholinobutene (1.84 g, 0.013 mol) dissolved in CH2Cl2 (40 mL) at 0°. The solution is concentrated in vacuo, and ammonium acetate (50 g), ammonium hydroxide (10 mL), tetrahydrofuran (20 mL) and 95% ethanol (20 mL) are added. The solution is heated to reflux for 30 minutes, then held at 3° for 72 hours. The reaction solution is then partitioned between water and ethyl acetate. The organic layer is dried over sodium sulfate and concentrated in vacuo to give the product (1.85 g, 0.0074 mol, 57%).