Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[S:5][C:4]=1[C:16]([O:18][CH3:19])=[O:17].[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27](B(O)O)[CH:28]=2)[CH:23]=[CH:22][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1.O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:8]([C:7]1[C:3]([CH2:2][C:27]2[CH:28]=[C:29]3[C:24]([CH:23]=[CH:22][N:21]=[CH:20]3)=[CH:25][CH:26]=2)=[C:4]([C:16]([O:18][CH3:19])=[O:17])[S:5][C:6]=1[N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)#[N:9]
Reactant: OB(O)c1ccc2ccncc2c1
Reactant: COC(=O)c1sc(N2CCOCC2)c(C#N)c1CBr
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1sc(N2CCOCC2)c(C#N)c1Cc1ccc2ccncc2c1
Temperature: 90 °C
Yield: 70.6 %

Procedure:
A mixture of methyl 3-(bromomethyl)-4-cyano-5-(morpholin-4-yl)thiophene-2-carboxylate (0.128 g, 0.371 mmol), isoquinoline-7-boronic acid (101 mg, 0.584 mmol), tetrakis(triphenylphosphine)palladium(0) (21.4 mg, 0.0185 mmol) and cesium carbonate (0.242 g, 0.742 mmol) was suspended in 1,4-dioxane (8.0 mL, 100 mmol) and Water (0.60 mL, 33 mmol) under N2 atmosphere in a 20 mL vial. The vial was capped and heated to 90° C. for 1 hour. The mixture was cooled to room temperature and concentrated in vacuum. The residue was suspended in DCM and filtered over a celite pad. The filtrate was chromatographed in a silica gel column using MeOH/DCM (0/100 to 3/97) to afford a solid product (103 mg, 66.4%). LC/MS: (FA) ES+ 394. 1H NMR (400 MHz, d-chloroform) δ 9.20 (s, 1H), 8.47 (d, J=5.77 Hz, 1H), 7.87 (s, 1H), 7.73 (d, J=5.77 Hz, 1H), 7.60 (d, J=5.77 Hz, 1H), 7.44-7.48 (m, 1H), 4.60 (s, 2H), 3.86 (s, 3H), 3.84 (m, 4H), 3.59 (m, 4H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[CH3:16][CH:17]([CH3:24])[CH2:18][C:19](=[O:23])[C:20](O)=[O:21]>>[CH2:8]([O:7][C:3]([O:4][CH2:5][CH3:6])([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH2:2][NH:1][C:20](=[O:21])[C:19](=[O:23])[CH2:18][CH:17]([CH3:24])[CH3:16])[CH3:9]
Reactant: CCOC(CN)(OCC)c1cccnc1
Reactant: CC(C)CC(=O)C(=O)O
Product: CCOC(CNC(=O)C(=O)CC(C)C)(OCC)c1cccnc1

Procedure:
In a manner analogous to Example 1, by condensing 3-(2-amino-1,1-diethoxyethyl)pyridine with 4-methyl-2-oxo-pentanoic acid there is obtained N-(2,2-diethoxy-2-(3-pyridyl)ethyl]-4-methyl2-oxovaleramide as a colorless, amorphous solid. Acidic hydrolysis yields 4-methyl-N-(nicotinoylmethyl)-2-oxovaleramide and subsequent ring closure yields 3-isobutyl-5-(3-pyridyl)-2(1H)-pyrazinone as a crystalline solid, melting point 195°-196° (from ethyl acetate). The conversion into the corresponding chloride, 2-chloro-3-isobutyl-5-(3-pyridyl)pyrazine, is also effected analogously to Example 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:18][CH2:17][C:16]([C:19]4[NH:28][C:27](=[O:29])[C:26]5[CH2:25][C:24]6([CH2:31][CH2:30]6)[CH2:23][CH2:22][C:21]=5[N:20]=4)=[CH:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CO.[ClH:34]>ClCCl>[ClH:34].[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C@@H:14]3[CH2:18][CH2:17][C:16]([C:19]4[NH:28][C:27](=[O:29])[C:26]5[CH2:25][C:24]6([CH2:30][CH2:31]6)[CH2:23][CH2:22][C:21]=5[N:20]=4)=[CH:15]3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=c1[nH]c(C2=CC(N3CCN(c4ccc(F)cc4)CC3)CC2)nc2c1CC1(CC2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: O=c1[nH]c(C2=C[C@H](N3CCN(c4ccc(F)cc4)CC3)CC2)nc2c1CC1(CC2)CC1
Temperature: 25 °C
Reaction time: 0.71 h
Yield: 98.7 %

Procedure:
To a stirred solution of 2′-(3-(4-(4-fluorophenyl)piperazin-1-yl)cyclopent-1-en-1-yl)-7′,8′-dihydro-3′H-spiro[cyclopropane-1,6′-quinazolin]-4′(5′H)-one (550 mg, 1.308 mmol) in dichloromethane (15 ml), and methanol (15 ml) was added hydrochloric acid (2.62 ml, 5.23 mmol, 2M solution in ether) was added at 5-10° C. Reaction mix was stirred at 25° C. for 40-45 mins. Reaction mixture was concentrated under reduced pressure to obtain sticky solid, which was washed with ether (2×10 ml) to afford title compound (0.590 gm).
Reaction SMILES: [ClH:1].[NH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH:12][C:13]([NH2:15])=[O:14])[C:3]([NH2:5])=[NH:4].Cl.Cl.[NH2:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:32])[CH:29](O)[OH:30].C(O)(=O)CCCC(O)=O>O>[ClH:1].[ClH:1].[ClH:1].[NH2:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:32])[CH:29]([NH:15][C:13](=[O:14])[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][NH:2][C:3]([NH2:5])=[NH:4])[OH:30]
Reactant: NCCCNCCCCNC(=O)C(O)O
Reactant: N=C(N)NCCCCCC=CC(N)=O
Agent: Cl
Agent: O=C(O)CCCC(=O)O
Solvent: O
Product: N=C(N)NCCCCCC=CC(=O)NC(O)C(=O)NCCCCNCCCN
Temperature: 60 °C
Yield: 87.9 %

Procedure:
A mixture of 202.4 mg (0.86 mmole) of 8-guanidino-2-octenamide hydrochloride, 302.4 mg (1.04 mmoles) of N-[4-(3-aminopropyl)aminobutyl]-2,2-dihydroxyethanamide dihydrochloride, 113.9 mg (0.86 mmole) of glutaric acid and 0.2 ml of water was heated at 60° C. for 24 hours. After completion of the reaction the reaction mixture was purified in a manner similar to that in Example 1 using CM-Sephadex® C-25 (Na-type) and Sephadex® LH-20 to obtain 128.3 mg (29.2% yield) of N-[4-(3-aminopropyl)aminobutyl]-2-(8-guanidino-2-octenamido)-2-hydroxyethanamide trihydrochloride.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]([NH:8][C:9]1[S:10][C:11]([Br:21])=[C:12]([C:14](=[N:18][O:19][CH3:20])[C:15]([OH:17])=O)[N:13]=1)=[O:7].[NH2:22][CH:23]1[C:41](=[O:42])[N:25]2[C:26]([C:38]([OH:40])=[O:39])=[C:27]([CH2:30][S:31][C:32]3[S:33][C:34]([CH3:37])=[N:35][N:36]=3)[CH2:28][S:29][C@H:24]12.C[Si](CC(N)=O)(C)C>C(OCC)(=O)C.O.CN(C)C=O>[CH:6]([NH:8][C:9]1[S:10][C:11]([Br:21])=[C:12]([C:14](=[N:18][O:19][CH3:20])[C:15]([NH:22][CH:23]2[C:41](=[O:42])[N:25]3[C:26]([C:38]([OH:40])=[O:39])=[C:27]([CH2:30][S:31][C:32]4[S:33][C:34]([CH3:37])=[N:35][N:36]=4)[CH2:28][S:29][C@H:24]23)=[O:17])[N:13]=1)=[O:7]
Reactant: CON=C(C(=O)O)c1nc(NC=O)sc1Br
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Agent: C[Si](C)(C)CC(N)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(C)s3)CS[C@H]12)c1nc(NC=O)sc1Br
Reaction time: 0.5 h
Yield: 59.2 %

Procedure:
A mixture of dimethylformamide (0.3 ml.), phosphoryl chloride (0.35 ml.) and dry ethyl acetate (1.5 ml.) was stirred for 30 minutes under ice-cooling. Dry ethyl acetate (1.5 ml.) and 2-(2-formamido-5-bromothiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer, 1.0 g.) were added to the solution and stirred for 50 minutes under ice-cooling. The solution was added dropwise to a chilled solution of 7-amino-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (1.1 g.) and trimethylsilylacetamide (2.5 g.) in dry ethyl acetate (30 ml.), and stirred at -20° to -10° C. for an hour. To the reaction mixture were added ethyl acetate (30 ml.) and water 20 ml., and the insoluble substance was filtered off. The ethyl acetate layer was separated from the filtrate, and the aqueous layer was washed with ethyl acetate. The washings and the ethyl acetate layer were combined together, washed with a saturated aqueous sodium chloride, dried over magnesium sulfate and then evaporated in vacuo. The residue was pulverized with diethyl ether, and the precipitates were collected by filtration, washed with diethyl ether and dried to give 7-[2-(2-formamido-5-bromothiazol-4-yl)-2-methoxyiminoacetamido]-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer, 1.2 g.).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[H-].[Na+].[CH2:9]([O:16][CH2:17][C:18]([F:26])([F:25])[CH2:19]OS(C)(=O)=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[NH4+]>CN(C=O)C>[CH2:9]([O:16][CH2:17][C:18]([F:25])([F:26])[CH2:19][N:4]1[CH:3]=[C:2]([I:1])[CH:6]=[N:5]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CS(=O)(=O)OCC(F)(F)COCc1ccccc1
Reactant: Ic1cn[nH]c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: FC(F)(COCc1ccccc1)Cn1cc(I)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
A cold (0° C.) solution of 4-iodo-1H-pyrazole (10.1 g, 51.8 mmol) in DMF (20 mL) was treated with NaH (1.56 g, 38.82 mmol, 60%) and allowed to warm to RT. After 1 h, the reaction mixture was treated with methanesulfonic acid 3-benzyloxy-2,2-difluoropropyl ester (Compound 59G, 2.0 g, 6.47 mmol) and was stirred for 24 h at 70° C. The reaction mixture was poured into chilled sat. aq. ammonium chloride (20 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with water (5×30 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography (SiO2, 30% ethyl acetate/hexanes) to give 1.8 g (72%) of the title compound as a white solid. 1H NMR (500 MHz, CDCl3) δ 7.32-7.38 (m, 7H), 4.63 (s, 2H), 3.89 (s, J=12.5 Hz, 2H), 3.77 (t, J=12.5 Hz, 2H).
Reaction SMILES: C1CO[C:3]([C@@H:5]2[C@:22]3([CH3:23])[C@H:8]([C@H:9]4[C@H:19]([C:20](=[O:24])[CH2:21]3)[C@:17]3([CH3:18])[C@H:12]([CH2:13][C@H:14]([OH:25])[CH2:15][CH2:16]3)[CH2:11][CH2:10]4)[CH2:7][CH2:6]2)([CH3:4])[O:2]1.C(O)(=O)C>C(Cl)(Cl)Cl>[OH:25][C@@H:14]1[CH2:15][CH2:16][C@@:17]2([CH3:18])[C@@H:12]([CH2:11][CH2:10][C@@H:9]3[C@@H:19]2[C@H:20]([OH:24])[CH2:21][C@@:22]2([CH3:23])[C@H:8]3[CH2:7][CH2:6][C@@H:5]2[C:3](=[O:2])[CH3:4])[CH2:13]1
Reactant: CC1([C@H]2CC[C@H]3[C@@H]4CC[C@H]5C[C@H](O)CC[C@]5(C)[C@H]4C(=O)C[C@]23C)OCCO1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3[C@H](O)C[C@]12C
Reaction time: 18 h
Yield: 51.5 %

Procedure:
A solution of 20,20-ethylenedioxy-3α-hydroxy-5α-pregnan-11-one (350 mg.) in mthanol (20 ml.) was treated with 25% aqueous acetic acid (2 ml.) at room temperature. After 18 hr. more 25 % aqueous acetic acid (2 ml.) was added and after a further 27 hr. the mixture was diluted with chloroform, washed with water, dried (Na2SO4) and evaporated to leave a white foam (300 mg.). Crystallisation from acetone and petroleum ether (b.p. 60°-80°) gave the title compound (160 mg.) as off-white rods; m.p. 152°-154°; [α]D + 79°.
Reaction SMILES: [CH2:1]([N:8]1[CH:17]=[C:16](Br)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[NH2:25].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([N:8]1[CH:17]=[C:16]([NH:25][C:24]2[CH:26]=[C:27]([O:31][CH3:32])[C:28]([O:29][CH3:30])=[C:22]([O:21][CH3:20])[CH:23]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c2ccccc2c(Br)cn1Cc1ccccc1
Reactant: COc1cc(N)cc(OC)c1OC
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(Nc2cn(Cc3ccccc3)c(=O)c3ccccc23)cc(OC)c1OC
Temperature: 100 °C
Reaction time: 17 h
Yield: 27.6 %

Procedure:
A mixture of 2-benzyl-4-bromoisoquinolin-1(2H)-one (0.500 g, 1.59 mmol) and 3,4,5-trimethoxyaniline (0.349 g, 1.91 mmol) in dry toluene (30 mL) was degassed under nitrogen. Pd2(dba)3 (0.218 g, 0.24 mmol) and BINAP (0.297 g, 0.48 mmol) were added and the mixture was degassed again. Sodium tert-butoxide (0.306 g, 3.18 mmol) was then added and the reaction was stirred at 100° C. for 17 h under nitrogen. After that time, the reaction mixture was cooled to rt, diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL). The organic phase was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 25:75 hexanes/ethyl acetate to 50:50 hexanes/ethyl acetate) followed by trituration with methanol to give 2-benzyl-4-((3,4,5-trimethoxyphenyl)amino)isoquinolin-1(2H)-one (0.183 g, 28%) as a light brown solid: mp 162-164° C.; 1H NMR (400 MHz, CDCl3) δ 8.53 (d, J=8.2 Hz, 1H), 7.61-7.68 (m, 2H), 7.54 (ddd, J=8.2, 5.6, 2.7 Hz, 1H), 7.27-7.35 (m, 5H), 7.17 (s, 1H), 5.85 (s, 2H), 5.23 (s, 2H), 5.10 (s, 1H), 3.75 (s, 3H), 3.65 (s, 6H); ESI MS m/z 417 [M+H]+.
Reaction SMILES: C(O)(=O)C.[NH2:5][CH:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:10]=1)[C:7]#[N:8].[C:23]([NH:26][C:27]1[CH:37]=[CH:36][CH:35]=[C:29]2[C:30]([O:32][C:33](=O)[C:28]=12)=[O:31])(=[O:25])[CH3:24]>C(O)(=O)C.CCOC(C)=O>[C:7]([CH:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:10]=1)[N:5]1[C:33](=[O:32])[C:28]2[C:29](=[CH:35][CH:36]=[CH:37][C:27]=2[NH:26][C:23](=[O:25])[CH3:24])[C:30]1=[O:31])#[N:8]
Reactant: COc1ccc(C(N)C#N)cc1OC1CCCC1
Reactant: CC(=O)Nc1cccc2c1C(=O)OC2=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc(C(C#N)N2C(=O)c3cccc(NC(C)=O)c3C2=O)cc1OC1CCCC1
Yield: 65 %

Procedure:
A mixture of 2-amino-2-(3-cyclopentyloxy-4-methoxyphenyl)ethanenitrile acetate (3.5 g, 11.0 mmol) and 3-acetamidophthalic anhydride (2.3 g, 11.0 mmol) in glacial acetic acid (40 mL) was heated to reflux for 17 hours. The mixture was concentrated in vacuo to give an oil. The oil was dissolved in EtOAc and washed with water, brine and dried (MgSO4). Solvent was removed and the residue was purified by chromatography (SiO2, CH2Cl2: EtOAc 98:2) to give 3.1 g (62%) of N-{2-[cyano(3-cyclopentyloxy-4-methoxyphenyl)methyl]-1,3-dioxoisoindolin-4-yl}acetamide as white solid; mp 124-126° C.; 1H NMR (CDCl3) δ 9.44 (s, 1H), 8.76 (d, J=8.4 Hz, 1H), 7.67 (t, J=7.6 Hz, 1H), 7.52 (d, J=7.2 Hz, 1H), 7.03-6.99 (m, 2H), 6.84 (d, J=8.0 Hz, 1H), 5.60-5.53 (dd, J=6.2 and 10.4 Hz, 1H), 4.79-4.74 (m, 1H), 3.86-3.75 (m, 1H), 3.82 (s, 3H), 3.29-3.20 (dd, J=6.4 and 17 Hz, 1H), 2.72 (s, 3H0, 1.97-1.56 (m, 8H); 3C NMR (CDCl3) δ 169.58, 169.11, 167.18, 150.61, 147.98, 137.72, 136.28, 130.89, 128.66, 125.09, 119.80, 118.29, 116.78, 114.19, 111.90, 80.68, 56.02, 51.10, 32.73, 24.92, 24.03, 21.07. Analy. Calculated for C25H25N3O5: C, 67.10; H, 5.63; N, 9.39. Found: C, 66.89; H, 5.42; N, 9.26.
Reaction SMILES: [CH:1]1([C:6]([C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1.C(=O)([O-])O.[Na+].C([BH3-])#N.[Na+]>O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C.ClCCl.C(N(CC)CC)C>[CH:1]1([CH:6]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:28][CH:29]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(C(=O)C2CCCC2)oc2ccc(F)cc12
Reactant: COC(=O)c1ccc(N)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(c2oc3ccc(F)cc3c2C)C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.1 %

Procedure:
To a mixture of cyclopentyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methanone (1.3 g) synthesized in Example A67(3), methyl 4-aminobenzoate (798 mg), triethylamine (5.88 mL) and dichloromethane (13 mL) was added titanium (IV) chloride (1.0M dichloromethane solution, 6.3 mL) at 0° C., and the mixture was stirred at room temperature for 2 hr under nitrogen atmosphere. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction. The solvent was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a dark brown solid. To a solution of the obtained solid in tetrahydrofuran (20 mL) were added sodium cyanoborohydride (657 mg) and acetic acid (1.50 mL), and the mixture was stirred at room temperature for 16 hr. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 90:10) to give the title compound (1.27 g, 63%) as a yellow amorphous compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[NH:15][C:14](=O)[C:9]21[CH2:13][CH2:12][CH2:11][CH2:10]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl[Si](C)(C)C.O>C1COCC1>[CH2:1]([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[NH:15][CH2:14][C:9]21[CH2:10][CH2:11][CH2:12][CH2:13]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CN(Cc2ccccc2)C2(CCCC2)C(=O)N1
Agent: C[Si](C)(C)Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CN(Cc2ccccc2)C2(CCCC2)CN1
Temperature: 55 °C
Reaction time: 2.5 h
Yield: 92.6 %

Procedure:
Under Argon atmosphere to a solution of 10.78 g of 6-benzyl-8,8-dimethyl-6,9-diaza-spiro[4.5]decan-10-one in 160 ml of THF 33 ml of a 2.4 M solution of lithium aluminium hydride in THF were slowly added. The reaction was heated to 55° C., and 5 ml of chlorotrimethylsilane were added dropwise. The reaction was kept at 55-60° C. for 2.5 h and then cooled to 0° C. 16 ml of water were added dropwise, and THF was added. The mixture was filtered by suction over celite and the filtrate was concentrated in vacuo. The product was precipitated by treatment with methyl tert-butyl ether. 9.47 g (93%) of the title compound were obtained.
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH3:13])[CH:3]=1.C(Cl)(=O)C(Cl)=O.C(N(C(C)C)CC)(C)C.Cl.[Br:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[C:33]([F:39])[CH:32]=1>ClCCl.CN(C=O)C>[Br:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH:36][C:6](=[O:8])[C:5]2[CH:9]=[C:10]([CH3:11])[C:2]([F:1])=[CH:3][C:4]=2[O:12][CH3:13])=[C:33]([F:39])[CH:32]=1
Reactant: NCc1ccc(Br)cc1F
Reactant: COc1cc(F)c(C)cc1C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(F)c(C)cc1C(=O)NCc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 21 h
Yield: 97.3 %

Procedure:
Under a dry atmosphere of nitrogen, a solution of 4-fluoro-2-methoxy-5-methyl-benzoic acid (1.19 g, 6.47 mmol) in dichloromethane (16 mL, 0.5 M) was treated with oxalyl chloride (1.7 mL, 19.4 mmol) and a drop of DMF at 0° C. The mixture was allowed to gradually warm to room temperature and was then concentrated to afford a yellow powder. The powder was dissolved in dichloromethane (16 mL, 0.5 M). To the stirring solution at 0° C. was added diisopropylethylamine (2.8 mL, 16.2 mmol) followed by 4-bromo-2-fluorobenzylamine hydrochloride salt (2.34 g, 9.71 mmol). Stirring under nitrogen, the mixture was gradually allowed to warm to room temperature. After 21 hours, the reaction was washed successively with 1N HCl (3×50 mL) and saturated aq NaCl (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to afford N-(4-bromo-2-fluoro-benzyl)-4-fluoro-2-methoxy-5-methyl-benzamide (2.33 g, 97%) as a brown oil which was used without further purification: Rf 0.40 (30% ethyl acetate in heptane); 1H NMR (CDCl3, 300 MHz) δ 8.17 (bd s, 1 H), 8.06 (d, J=9.3 Hz, 1 H), 7.33–7.22 (m, 3 H), 6.65 (d, J=11.1 Hz, 1 H), 4.63 (d, J=6.3 Hz, 2 H), 3.92 (s, 3 H), 2.23 (bd d, J=1.8 Hz, 3 H).
Reaction SMILES: [H-].[Na+].[C:3]([O:8][CH3:9])(=[O:7])[CH2:4][CH2:5][CH3:6].[CH:10](OC)=[O:11]>COCCOC>[OH:11]/[CH:10]=[C:4](/[CH2:5][CH3:6])\[C:3]([O:8][CH3:9])=[O:7]
Reactant: CCCC(=O)OC
Reactant: COC=O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC/C(=C/O)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.2 %

Procedure:
To a suspension of NaH (7.99 g, 200 mmol) in DME (100 mL) was added a mixture of methyl butyrate (5.1 g, 49.9 mmol) and methyl formate (17.99 g, 300 mmol) in DME (100 mL) dropwise at 0° C. under nitrogen. The mixture was stirred at room temperature overnight, and then filtered through a pad of celite. To the filtrate was added ether (200 mL), and let the suspension stand for 4 h. The solid was collected by filtration, washed with diethyl ether and dried in vacuo to afford the title compound (3 g, 23.05 mmol). LCMS: rt=1.108 min, [M+H+]=130
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1.Cl[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[C:28]([CH:31]=1)[C:29]#[N:30].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[C:29]([C:28]1[CH:31]=[C:24]([CH:25]=[CH:26][C:27]=1[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[CH2:23][O:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1)#[N:30]
Reactant: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(O)ccc12
Reactant: N#Cc1cc(CCl)ccc1C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(OCc3ccc(C4CCCCC4)c(C#N)c3)ccc12
Temperature: 50 °C
Reaction time: 16 h
Yield: 85.2 %

Procedure:
To a solution of tert-butyl 2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (40 mg, 0.139 mmol) and 5-(chloromethyl)-2-cyclohexylbenzonitrile (35.8 mg, 0.153 mmol) in N,N-dimethylformamide (3 mL) was added cesium carbonate (54.4 mg, 0.167 mmol). The mixture was stirred at 50° C. for 16 h. The mixture was cooled to room temperature, diluted with ethyl acetate and filtered through Celite®. The filtrate was concentrated under vacuum and purified by silica gel column chromatography to provide the title compound as an off-white foam (57.4 mg). LCMS m/z=485.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.24-1.34 (m, 1H), 1.43-1.53 (m, 4H), 1.50 (s, 9H), 1.80 (dd, J=12.88, 1.26 Hz, 1H), 1.89 (t, J=10.86 Hz, 4H), 2.22-2.34 (m, 1H), 2.50 (dd, J=15.73, 8.40 Hz, 1H), 2.73 (dd, J=15.79, 6.44 Hz, 1H), 2.82-2.92 (m, 1H), 2.99 (t, J=3.09 Hz, 1H), 3.65-3.75 (m, 1H), 3.95-4.04 (m, 1H), 4.07-4.16 (m, 1H), 5.06 (s, 2H), 6.09 (s, 1H), 6.85 (dd, J=8.72, 2.40 Hz, 1H), 7.08 (d, J=2.27 Hz, 1H), 7.14 (d, J=8.72 Hz, 1H), 7.37 (d, J=8.08 Hz, 1H), 7.62 (dd, J=8.15, 1.71 Hz, 1H), 7.71 (d, J=1.52 Hz, 1H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19](C3ON=CC=3)=[CH:18][CH:17]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1.[N:30]1(C2C=C(C=CC=2)N)[CH:34]=[N:33][CH:32]=[N:31]1>>[N:30]1([C:18]2[CH:17]=[C:16]([NH:15][C:13]3[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=[C:9]([NH:8][C@@H:3]4[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]4[NH2:1])[N:14]=3)[CH:21]=[CH:20][CH:19]=2)[CH:34]=[N:33][CH:32]=[N:31]1
Reactant: Nc1cccc(-n2cncn2)c1
Reactant: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Product: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1cccc(-n2cncn2)c1

Procedure:
This compound was synthesised using the synthetic scheme described for the synthesis of compound 122, and using 3-(1H-1,2,4-triazol-1-yl)aniline in step 1.MS: 394.2 (M+H).