Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][C:3]#[C:4][CH3:5].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:20][C:21]1[CH2:27][N:26]=[C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])[C:24]2[CH:35]=[C:36]([Cl:39])[CH:37]=[CH:38][C:23]=2[N:22]=1>O1CCCC1.CN(C)C=O>[Cl:39][C:36]1[CH:37]=[CH:38][C:23]2[N:22]3[C:3]([CH2:4][CH3:5])=[CH:2][C:1](=[O:7])[N:20]=[C:21]3[CH2:27][N:26]=[C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:34])[C:24]=2[CH:35]=1
Reactant: CC#CCC(=O)O
Reactant: NC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCc1cc(=O)nc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 16 carbonyldiimidazole β-pentynoic acid and 2-amino-7-chloro-5-(o-chlorophenyl)-3H-1,4-benzodiazepine were stirred in tetrahydrofuran-di-methylformamide to give 9-chloro-1-ethyl-7-(o-chlorophenyl) pyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]=2)=[CH:4][CH:3]=1.[OH:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34](O)=[O:35])=[CH:28][CH:27]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:12]=2)[C:34](=[O:35])[CH2:33][CH2:32][C:29]2[CH:30]=[CH:31][C:26]([OH:25])=[CH:27][CH:28]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(NCCc2cccc(OCc3ccccc3)c2)cc1
Reactant: O=C(O)CCc1ccc(O)cc1
Product: O=C(CCc1ccc(O)cc1)N(CCc1cccc(OCc2ccccc2)c1)c1ccc(F)cc1
Yield: 88.9 %

Procedure:
The title compound was prepared as described in Example 44. D using (4-fluorophenyl){2-[3-(phenylmethoxy)phenyl]ethyl}amine (1.4 g, 4.36 mmol) and 3-(4-hydroxyphenyl)propanoic acid (1.01 g, 6.11 mmol) to provide the title compound (1.82 g, 89% yield): ES-MS (m/z) 470 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10]([CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:8]([NH:9][CH2:10][CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1)[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NCCc1ccccc1)C1CCc2ccccc2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc(CCNCC2CCc3ccccc3C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
The solution of N-(2-phenylethyl) 1,2,3,4-tetrahydro-2-naphthoic amide (693 mg, 2.48 mmol) in 15 ml of THF was treated with LiAlH4 (149 mg, 3.72 mmol). The mixture was refluxed for 4 hrs then carefully quenched by addition of solid Na2SO4 ·10H2O. After stirred at r.t. overnight, the solid was removed by filtration and concentration of filtrate in vacuo gave a colorless oil (604 mg, 91.7%). The product was converted to HCl salt, crystallization with MeOH/Et2O gave a white powder; mp 260°-263° C.; Calcd for C19H23N·HCl: C 75.58, H 8.03, N 4.64: Found: C 75.77, H, 8.24, N 4.45.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]([C:8](=[O:25])[N:9]([CH2:21][CH2:22][CH:23]=[CH2:24])[CH2:10][C:11]1[CH:16]=[CH:15][C:14](OC)=[CH:13][C:12]=1OC)=C>C(Cl)Cl.[Ru]>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[C:8](=[O:25])[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:21][CH2:22][CH2:23][CH:24]=1
Reactant: C=CCCN(Cc1ccc(OC)cc1OC)C(=O)C(=C)CCC(=O)OC
Agent: [Ru]
Solvent: ClCCl
Product: COC(=O)CCC1=CCCCN(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 79 %

Procedure:
150 mg of the compound (c) (0.476 mmol) prepared by the above Step 2 was added to the catalyst solution containing 40 mg of ruthenium (0.047 mmol) dissolved in CH2Cl2. Then the mixture was stirred for 24 hrs at room temperature, filtered and concentrated in vacuo. The resultant was purified by Silica gel column chromatography with methanol/chloroform (1:10) solvent mixture as an eluant to give 108 mg of the title compound (d) (yield: 79%).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([F:31])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:61])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([O:51][Si](C(C)(C)C)(C)C)[CH:47]([O:59][CH3:60])[CH2:46]2)[CH:7]([CH3:62])[CH:6]([O:63][Si](C(C)(C)C)(C)C)[CH2:5][C:4]1=[O:71])[CH3:2].C1C=CN=CC=1.F.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([F:31])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:61])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:59][CH3:60])[CH2:46]2)[CH:7]([CH3:62])[CH:6]([OH:63])[CH2:5][C:4]1=[O:71])[CH3:2]
Reactant: CCC1C=C(C)C(F)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C)(C)C(C)(C)C)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: *CC(*)C
Agent: F
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCC1C=C(C)C(F)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 28 h
Yield: 76.9 %

Procedure:
To a solution of 17-ethyl-20-fluoro-1-hydroxy-14-(tert-butlydimethylsiloxy)-12-[2'-(4"-(tert-butyldimethylsiloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (10 mg) in tetrahydrofuran (0.6 ml) contained in a polypropylene vial was added 40 μl of an HF-pyridine solution in tetrahydrofuran, and the mixture was stirred at room temperature. After 28 hours, the mixture was added to a saturated sodium bicarbonate solution, extracted with ethyl acetate and dried by passage through a magnesium sulfate column. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate: hexane (2:1)+1% methanol) gave the title compound (6 mg).
Reaction SMILES: [F:1][CH:2]([F:20])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:14](O)=[O:15])[C:8]([C:17]([OH:19])=[O:18])=[CH:7]2>C(OC(=O)C)(=O)C>[F:1][CH:2]([F:20])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]1[C:14]([O:18][C:17](=[O:19])[C:8]1=[CH:7]2)=[O:15]
Reactant: O=C(O)c1cc2cc(OC(F)F)ccc2nc1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2nc3ccc(OC(F)F)cc3cc21
Temperature: 85 °C
Reaction time: 1 h

Procedure:
A mixture of 6-difluoromethoxyquinoline-2,3-dicarboxylic acid (0.14 mol) in 125 mL acetic anhydride is heated at 85° C. for one-half hour and then at 100° C. for one hour. The mixture is cooled, then filtered and the solids washed with ether to give 6-difluoromethoxyquinoline-2,3-dicarboxylic acid anhydride mp 157.5°-158.5° C.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29])([CH3:22])[CH3:21].CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH2:15][CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:17][CH3:18])[C:4]([OH:3])=[O:19])=[CH:12][CH:11]=1)([CH3:22])[CH3:21]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Reactant: CC(C)c1ccccc1O
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCOc2ccccc2C(C)C)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and 2-isopropyl-phenol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a white solid. MS (ES) for C21H26O5 [M+Na]+: 381.4.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1.[CH2:19](Br)[CH:20]=[CH2:21]>>[CH2:21]([O:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1)[CH:20]=[CH2:19]
Reactant: C=CCBr
Reactant: COC(=O)c1ccc(Oc2cccc(O)c2)cc1
Product: C=CCOc1cccc(Oc2ccc(C(=O)OC)cc2)c1
Yield: 96 %

Procedure:
The title compound was prepared in 96% yield as an oil from methyl 4-(3-hydroxyphenoxy)benzoate and allyl bromide by the procedure of Preparation 36. NMR.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:33])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=1>C(#N)C>[Br:1][C:2]1[C:3]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:33])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: NCCCCNC(=O)c1cccc([N+](=O)[O-])c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(NCCCCNc1nc(Cl)ncc1Br)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 502 mg (2.2 mmol) of 5-bromo-2,4-dichloro-pyrimidine and 0.4 ml of triethylamine (2.3 mmol) in 2.5 ml of acetonitrile is mixed at 0° C. while being stirred with 547 mg (2.3 mmol) of N-(4-amino-butyl)-3-nitro-benzamide. The batch is stirred overnight at room temperature. The precipitate that is formed is suctioned off, washed with water and dried. 574 mg (1.3 mmol, corresponding to 61% of theory) of the product is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[CH3:14][N:15]([CH3:19])[C:16](=[S:18])[S-:17].C[NH2+]C>C(=S)=S>[CH3:14][N:15]([CH3:19])[C:16](=[S:17])[S:18][CH:7]([CH2:8][N+:9]([O-:11])=[O:10])[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:13][CH:12]=1
Reactant: COc1ccc(C=C[N+](=O)[O-])cc1
Reactant: CN(C)C(=S)[S-]
Agent: C[NH2+]C
Solvent: S=C=S
Product: COc1ccc(C(C[N+](=O)[O-])SC(=S)N(C)C)cc1

Procedure:
As in Example 17, reaction of p-methoxy-β-nitrostyrene with dimethylammonium dimethyldithiocarbamate in the presence of carbon disulfide gave p-methoxy-α-(nitromethyl)benzyl dimethyldithiocarbamate melting at 86° - 89° C. when recrystallized without heating from acetone-ethanol solution.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=O)=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]21[O:16][CH2:15][CH2:14][O:13]2.[NH3:17].[O-]S([O-])(=O)=O.[Mg+2]>C1COCC1.C(Cl)Cl.O=[Mn]=O>[CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:17])=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]21[O:16][CH2:15][CH2:14][O:13]2
Reactant: O=Cc1ccc2c(c1)CCC1(C2)OCCO1
Reactant: N
Agent: O=[Mn]=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: C1CCOC1
Product: N#Cc1ccc2c(c1)CCC1(C2)OCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
Following the literature procedure of Lai, G. et al. (Synleft, 2001, 230-231), a stirred solution of 3′,4′-dihydro-1′H-spiro[[1,3]dioxolane-2,2′-naphthalene]-6′-carbaldehyde (440 mg, 2.0 mmol) in THF (2 mL) was charged with NH3 (2M solution in isopropanol, 15 mL, 30 mmol, 15 eq) and anhydrous MgSO4 (3.64 g, 30 mmol, 15 eq). After 1 hour, MnO2 (Aldrich, 85%, 3.1 g, 30 mmol, 15 eq) was added in small portions and the resulting mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with CH2Cl2 (40 mL) and filtered through Celite. The filtrate was concentrated in vacuo to give 0.42 g (100%) of 3′,4′-dihydro-1′H-spiro[[1,3]dioxolane-2,2′-naphthalene]-6′-carbonitrile as a brown oil. 1H NMR (300 MHz, CDCl3): δ 7.42 (s, 1H), 7.40 (d, 1H, J=8.0 Hz), 7.12 (d, 1H, J=8.0 Hz), 4.03 (s, 4H), 3.02 (s, 2H), 3.00 (t, 2H, J=6.9 Hz), 1.96 (t, 2H, J=6.9 Hz). The material was sufficiently pure and it was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][C:8]#[N:9])=[C:4]([F:12])[CH:3]=1.[CH:13]1([CH:18]([OH:21])[CH:19]=[CH2:20])[CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[CH:13]1([C:18](=[O:21])[CH2:19][CH2:20][C:2]2[CH:11]=[CH:10][C:5]([O:6][CH2:7][C:8]#[N:9])=[C:4]([F:12])[CH:3]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C=CC(O)C1CCCC1
Reactant: N#CCOc1ccc(Br)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: N#CCOc1ccc(CCC(=O)C2CCCC2)cc1F
Temperature: 140 °C
Yield: 90.8 %

Procedure:
A mixture of (4-bromo-2-fluorophenoxy)acetonitrile (2.5 g, 10.8 mmol), 1-Cyclopentyl-2-propen-1-ol (2.0 g, 16.2 mmol), dichlorobis (triphenylphosphine) palladium (II) (151 mg, 0.22 mmol), and sodium bicarbonate (1.08 g, 12.9 mmol) in N-methylpyrrolidinone (20 mL) was heated to 140° C. under N2 for 5 hours. The reaction mixture was partitioned between 1N HCl and EtOAc. The organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated to a black oil. The oil was purified by flash column chromatography (Hexanes to 10% EtOAc in hexanes) to give the desired product (2.7 g, 93%). 1H NMR (CDCl3): δ 1.52–1.83 (m, 8H), 2.75 (m, 2H), 2.85 (m, 3H), 4.80 (s, 2H), 6.92–7.06 (m, 3H).
Reaction SMILES: [C:1]([C:3]1([C:8]2[CH:9]=[C:10]([C:19]([O:21]CC)=[O:20])[CH:11]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2].[OH-].[Na+]>C1COCC1.CCO>[CH2:17]([O:16][C:14]([C:12]1[CH:11]=[C:10]([CH:9]=[C:8]([C:3]2([C:1]#[N:2])[CH2:7][CH2:6][CH2:5][CH2:4]2)[CH:13]=1)[C:19]([OH:21])=[O:20])=[O:15])[CH3:18]
Reactant: CCOC(=O)c1cc(C(=O)OCC)cc(C2(C#N)CCCC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C(=O)O)cc(C2(C#N)CCCC2)c1

Procedure:
A solution of diethyl 5-(1-cyanocyclopentyl)benzene-1,3-dioate (0.33 g, 1.05 mmol) and NaOH (1N in H2O, 0.945 mL, 0.945 mmol) in 5 mL THF and 5 mL EtOH was stirred at rt overnight. The reaction mixture was concentrated, diluted with H2O and extracted with ether. The aqueous phase was made acidic with 1N HCl, extracted with EtOAc and the combined organic layers were washed with brine. Drying and solvent evaporation gave 3-(ethoxycarbonyl)-5-(1-cyanocyclopentyl)benzoic acid. 1H NMR (400 MHz, CD3OD) δ 8.58 (m, 1H), 8.35 (m, 2H), 4.43 (q, J=7.1 Hz, 2H), 2.51 (m, 2H), 2.18 (m, 2H), 2.05 (m, 4H), 1.42 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([CH3:44])=[C:14]([C:18]2[C:30]3[C:29]4[C:24](=[CH:25][C:26]([NH:31][C:32]([O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])=[O:33])=[CH:27][CH:28]=4)[NH:23][C:22]=3[C:21]([C:41]([OH:43])=O)=[N:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].F[P-](F)(F)(F)(F)F.[N:54]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.CN1CCOCC1>CN(C=O)C.O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([CH3:44])=[C:14]([C:18]2[C:30]3[C:29]4[C:24](=[CH:25][C:26]([NH:31][C:32]([O:34][CH2:35][CH2:36][Si:37]([CH3:39])([CH3:38])[CH3:40])=[O:33])=[CH:27][CH:28]=4)[NH:23][C:22]=3[C:21]([C:41]([NH2:54])=[O:43])=[N:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: Cc1c(NC(=O)OCc2ccccc2)cccc1-c1cnc(C(=O)O)c2[nH]c3cc(NC(=O)OCC[Si](C)(C)C)ccc3c12
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1c(NC(=O)OCc2ccccc2)cccc1-c1cnc(C(N)=O)c2[nH]c3cc(NC(=O)OCC[Si](C)(C)C)ccc3c12
Reaction time: 2.5 h
Yield: 87.4 %

Procedure:
To a dark, homogeneous solution of 4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-((2-(trimethylsilyl)ethoxy)carbonylamino)-9H-pyrido[3,4-b]indole-1-carboxylic acid (0.4181 g, 0.685 mmol) in DMF (2.74 mL) were added ammonium chloride (0.146 g, 2.74 mmol), BOP (0.394 g, 0.890 mmol), DIPEA (0.574 mL, 3.29 mmol) and N-methylmorpholine (0.294 mL, 2.67 mmol). After 2.5 hr, water was added, and the precipitate was collected and dried over Drierite to give the desired product (0.365 g, 0.599 mmol, 87% yield) as a light brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:12])[CH:3]=1.[CH3:13][Si](C=[N+]=[N-])(C)C.CC(O)=O>CO>[Br:1][C:2]1[CH:3]=[C:4]([F:12])[C:5]([C:6]([O:8][CH3:13])=[O:7])=[C:9]([F:11])[CH:10]=1
Reactant: O=C(O)c1c(F)cc(Br)cc1F
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1c(F)cc(Br)cc1F
Yield: 47 %

Procedure:
To a solution of 4-bromo-2,6-difluorobenzoic acid (800 mg, 3.38 mmol) in MeOH (11 mL) at room temperature, trimethylsilyldiazomethane (5.63 mL, 3.38 mmol) was slowly added until yellow solution was turned on. The small amount of AcOH was added until yellow color disappered. All volatile materials were removed in vacuo yielding methyl 4-bromo-2,6-difluorobenzoate (47%). LCMS (m/z): 251.1 (MH+), 0.86 min.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][C@@H:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[N:19][CH:20]=[C:21]([O:23][CH2:24][C@@H:25]3[CH2:29][CH2:28][CH2:27][N:26]3C(OC(C)(C)C)=O)[CH:22]=2)[CH2:13]1)C1C=CC=CC=1>[Pd].CO.C(Cl)(Cl)Cl>[NH:26]1[CH2:27][CH2:28][CH2:29][C@H:25]1[CH2:24][O:23][C:21]1[CH:22]=[C:17]([N:14]2[CH2:15][CH2:16][C@H:12]([CH2:11][CH2:10][CH2:9][OH:8])[CH2:13]2)[CH:18]=[N:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(N2CC[C@@H](CCCOCc3ccccc3)C2)c1
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: OCCC[C@H]1CCN(c2cncc(OC[C@@H]3CCCN3)c2)C1
Temperature: 70 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
In a 100 mL round-bottom flask with reflux condenser, 10% palladium on carbon (100 mg) was added to a solution of 3-[3(R)-[3-(benzyloxy)propyl]-1-pyrrolidinyl]-5-[[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]pyridine (500 mg, 1.01 mmol) in a mixed solvent of methanol/CHCl3 (40/5 mL). The reaction mixture was deoxygenated under vacuum, then H2 was admitted from a balloon placed above the condenser. The process was repeated three times, and the reaction mixture was stirred for 16 h at 70° C. in an oil bath. After cooling, the mixture was filtered through celite, and the filtrate was evaporated under reduced pressure. The crude product (340 mg) was purified by preparative HPLC (column: SunFire Prep C18, 100×19 mm, 5 μm particle size; UV detection at 220 nm; flow 20 mL/min; mobile phase: A, water with 0.05% CF3COOH; B, CH3OH; 15 to 100% B in A within 7 min). The eluate was partially evaporated under reduced pressure (bath 30° C.) to remove CH3OH. The residue was basified with saturated aqueous NaHCO3 solution and extracted with EtOAc. The combined organic layers were washed with brine and dried. After concentration in vacuo, the free base (250 mg, 81%) was obtained as a light-yellow oil. 1H NMR (CD3OD, 300 MHz) δ 7.54 (s, 1H), 7.50 (s, 1H), 6.53 (s, 1H), 4.10-4.04 (m, 1H), 3.99-3.97 (m, 1H), 3.61 (t, 2H, J=6.0 Hz), 3.53-3.50 (m, 2H), 3.35-3.30 (m, 1H), 3.00-2.94 (m, 3H), 2.38-2.18 (m, 2H), 2.09-1.95 (m, 2H), 1.91-1.81 (m, 2H), 1.71-1.51 (m, 6H). LC-MS (ESI) m/z 306 (M+H+).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@@H:2]([C:15]([O:17][CH3:18])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=1.[ClH:29]>[Pd].CO>[NH2:1][C@@H:2]([C:15]([O:17][CH3:18])=[O:16])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[CH:8][CH:9]=1.[ClH:29]
Reactant: COC(=O)[C@@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)[C@H](N)Cc1ccc(OC(C)(C)C)cc1
Reaction time: 2 h

Procedure:
10% palladium on charcoal (1.2 g) was added to a solution of Cbz-D-Tyr(tBu)-OMe (10.2 g) in methanol (100 ml) and 4N hydrogen chloride (5 ml). The mixture was hydrogenated at atmospheric pressure at room temperature for 2 hours. The palladium catalyst was removed by filtration. The filtrate was concentrated to a small volume followed by cystallisation from diethyl ether. Yield: 5.87 g. TLC: Rf=0.10, heptane/ethyl acetate 1/1.
Reaction SMILES: C(#N)C.[CH3:4][C:5]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)=[O:6].OI(C1C=CC=CC=1)[O:19][S:20]([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>C(OCC)(=O)C>[S:20]([O:22][CH2:4][C:5]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)=[O:6])([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:21])=[O:19]
Reactant: Cc1ccc(S(=O)(=O)OI(O)c2ccccc2)cc1
Reactant: CC(=O)c1ccc2ccccc2c1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)OCC(=O)c2ccc3ccccc3c2)cc1
Yield: 68.5 %

Procedure:
Acetonitrile solution (40 mL) containing 2-acetonaphthone (1.70 g, 9.99 mmol) and [hydroxyl(tosyloxy)iodo]benzene (4.00 mg, 10.2 mmol) was heated under ref lux for 3 hours. The reaction mixture was cooled, and ethyl acetate was added thereto. The reaction solution was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo to remove the solvent to obtain the title compound (2.33 g, 68.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][O:8][C:9]([CH3:14])([CH3:13])[C:10](Cl)=[O:11])=[CH:5][CH:4]=1.[NH2:17][C:18]1[C:19](=[O:41])[NH:20][C:21](=[S:40])[N:22]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[CH:27]=2)[C:23]=1[NH2:24].[Cl-]>C1COCC1>[NH2:24][C:23]1[N:22]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[CH:27]=2)[C:21](=[S:40])[NH:20][C:19](=[O:41])[C:18]=1[NH:17][C:10](=[O:11])[C:9]([O:8][CH2:7][C:6]1[CH:15]=[CH:16][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)([CH3:14])[CH3:13]
Reactant: COc1ccc(Cn2c(N)c(N)c(=O)[nH]c2=S)cc1OC1CCCC1
Reactant: COc1ccc(COC(C)(C)C(=O)Cl)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: COc1ccc(COC(C)(C)C(=O)Nc2c(N)n(Cc3ccc(OC)c(OC4CCCC4)c3)c(=S)[nH]c2=O)cc1

Procedure:
A solution with 2.91 g (12 mM) of crude 2-(4-methoxybenzyloxy)-2-methyl-propionyl chloride in 9 ml of THF was added within 90 min to a stirred suspension with 3.62 g (10 mM) of 5,6-diamino-1-(3-cyclopentyloxy-4-methoxy-benzyl)-2-thiouracil. After 20 hr another 485 mg of chloride in 5 ml of THF was added within 30 min. After a further 3 hr the solid was filtered off and the solution evaporated in vacuo to dryness. The residue was dissolved in ethyl acetate, extracted with sodium bicarbonate solution and the organic phase evaporated in vacuo to dryness. The residue was crystallized from methanol: 1.71 g (30.1%) of amide with mp 172-184° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=O)[CH2:11][CH3:12])=O.[NH3:14]>>[CH2:11]([C:10]1[N:14]=[CH:1][C:3]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:9]=1)[CH3:12]
Reactant: N
Reactant: CCC(=O)Nc1ccccc1C=O
Product: CCc1ncc2ccccc2n1
Temperature: 100 °C
Yield: 100 %

Procedure:
N-(2-Formyl-phenyl)-propionamide (1.65 g, 9.3 mmol) was combined with ammonia (24 mL, 2M solution in methanol) in a flask fitted with a condenser and stopper with a needle to vent. The reaction was heated to 100° C. for 1 day. The reaction mixture was concentrated in vacuo to yield the crude product as an orange oil (1.47 g, 100%). This product was used without further purification. 1H NMR (400 MHz, CDCl3) δ 9.36 (s, 1H), 7.99 (d, J=10.0 Hz, 1H), 7.89 (m, 2H), 7.60 (t, J=8.1 Hz, 1H), 3.16 (q, J=7.6 Hz, 2H), 1.47 (t, J=7.6 Hz, 3H); HPLC ret. time 0.61 min, 10-99% CH3CN, 5 min run; ESI-MS m/z 159.0 (MH+).