Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:22])[N:4]([CH2:8][C:9]([NH:11][CH:12]([CH:19]([CH3:21])[CH3:20])[C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:23]1([CH2:29][CH2:30][C:31](Cl)=[O:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>ClCCl>[C:23]1([CH2:29][CH2:30][C:31]([NH:1][C:2]2[C:3](=[O:22])[N:4]([CH2:8][C:9]([NH:11][CH:12]([CH:19]([CH3:20])[CH3:21])[C:13](=[O:18])[C:14]([F:16])([F:17])[F:15])=[O:10])[CH:5]=[CH:6][CH:7]=2)=[O:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)C(NC(=O)Cn1cccc(N)c1=O)C(=O)C(F)(F)F
Reactant: O=C(Cl)CCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(NC(=O)Cn1cccc(NC(=O)CCc2ccccc2)c1=O)C(=O)C(F)(F)F
Reaction time: 2 h

Procedure:
To a stirred suspension of 2-(3-amino-2-oxo-1,2-dihydro-1-pyridyl)-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide (0.399) in dichloromethane at 0° C. was added 3-phenylpropionyl chloride (0.247 g) and triethylamine (0.247 g). The mixture was allowed to stir for 2 h, was diluted with dichloromethane (100 mL), washed (1N hydrochloric acid, saturated aqueous sodium bicarbonate, brine), dried, and evaporated to give a residue which was purified by chromatography, using methanol:dichloromethane as an eluent (gradient, 0.5:99.5, 2:98), to yield the title compound; mp 154°-155° C.; NMR: 0.80-0.98 (m,6), 2.21 (m,1), 4.09(m, NHCH hydrate), 4.52-4.82 (m, NHCH keto, CH2CO), 6.23 (m), 7.15-7.34 (m), 7.91 (d, J=10, NH hydrate), 8.24 (dd,1, J=7.5, 1.5), 8.93 (d, NH keto), 9.26 (s, NH hydrate), 9.29 (s, NH keto).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].C(S[C:15](=[O:29])[CH:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28])[C:17](=[O:19])[CH3:18])(C)(C)C>>[F:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[CH2:20][CH:16]([C:17](=[O:19])[CH3:18])[C:15]([NH:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8])=[O:29]
Reactant: Nc1cc(O)ccc1F
Reactant: CC(=O)C(Cc1ccc(F)cc1F)C(=O)SC(C)(C)C
Product: CC(=O)C(Cc1ccc(F)cc1F)C(=O)Nc1cc(O)ccc1F

Procedure:
The title compound was prepared by the method of Preparation 34b using 3-amino-4-fluorophenol and 2-(2,4-difluorobenzyl)-3-oxothiobutyric acid S-tert-butyl ester.
Reaction SMILES: [C:1]1([C:11]([OH:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]=1.[CH2:14]=[CH:15][CH:16]=[CH2:17].OC1C=CC=CC=1C>C1(C)C=CC=CC=1>[CH2:14]1[C@@H:2]2[C@@:1]([C:11]([OH:13])=[O:12])([C:10]3[C:5]([CH2:4][CH2:3]2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:17][CH:16]=[CH:15]1
Reactant: C=CC=C
Reactant: O=C(O)C1=CCCc2ccccc21
Agent: Cc1ccccc1O
Solvent: Cc1ccccc1
Product: O=C(O)[C@]12CC=CC[C@H]1CCc1ccccc12
Yield: 27 %

Procedure:
To a solution of 3,4-dihydronaphthalene-1-carboxylic acid (29.7 g) in toluene (75 ml) was added butadiene (16 g) and a trace of butyrated hydroxy toluene (BHT). The solution was heated to 180° for 18 hours in a sealed reactor, then chromatographed twice over silica gel. Recrystallization from ethyl acetate/heptane affords the title compound as a colorless crystalline solid (10.5 g). The recovered starting material was rereacted with butadiene to afford, after workup, additional title product (8.0 g). ##STR19##
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:12][C:13](Br)=[CH:14][C:15]=1[CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][NH:29][C:28](=[O:32])[CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:1]([NH:8][C:9]([C:11]1[S:12][C:13]([N:29]2[CH:30]=[CH:31][C:26]([O:25][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:27][C:28]2=[O:32])=[CH:14][C:15]=1[CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: Cc1cc(Br)sc1C(=O)NCc1ccccc1
Product: Cc1cc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)NCc1ccccc1
Yield: 49 %

Procedure:
Following the procedure as described in Example 8, making variations only as required to use N-benzyl-5-bromo-3-methylthiophene-2-carboxamide in place of N-benzyl-5-bromothiophene-3-carboxamide to react with 4-(benzyloxy)pyridin-2(1H)-one, the title compound was obtained as colorless solid in 49% yield: mp 153-154° C.; 1H NMR (300 MHz, CDCl3) δ 7.55 (d, J=7.9 Hz, 1H), 7.43-7.27 (m, 10H), 6.84 (s, 1H), 6.20-6.11 (m, 2H), 6.05 (d, J=2.7 Hz, 1H), 5.03 (s, 2H), 4.59 (d, J=5.7 Hz, 2H), 2.54 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 166.4, 162.5, 161.9, 139.2, 137.6, 134.2, 128.43, 128.40, 128.3, 127.5, 127.4, 127.2, 126.7, 121.8, 102.9, 97.8, 70.3, 43.6, 15.6; MS (ES+) m/z 431.3 (M+1).
Reaction SMILES: [H-].[Na+].[C:3]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[CH2:14]([Li])[CH2:15][CH2:16][CH3:17].ICCCC.[Cl-].[NH4+]>C1COCC1>[C:10]([O:9][C:3](=[O:8])[CH2:4][C:5](=[O:6])[CH2:7][CH2:14][CH2:15][CH2:16][CH3:17])([CH3:13])([CH3:12])[CH3:11]
Reactant: [Li]CCCC
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCCCI
Solvent: C1CCOC1
Product: CCCCCC(=O)CC(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 92.7 %

Procedure:
Anhydrous THF (200 ml) was introduced into a dried two-necked flask to which sodium hydride (60 w/w %, 2.71 g, 67.8 mmol) was added. The temperature thereof was allowed to fall to 0° C., and t-butyl acetoacetate (9.00 g, 56.9 mmol) was added dropwise thereto. The resulting mixture was stirred for 10 minutes while maintaining the temperature thereof at 0° C., and then n-butyllithium (1.6M hexane solution, 39.1 ml, 62.6 mmol) was added dropwise. After the obtained mixture was stirred for 30 minutes at 0° C., 1-iodobutane (13.6 g, 73.9 mmol) was added thereto, and then stirred for 6 hours. A saturated ammonium chloride solution was added to the obtained mixture and extracted 3 times with diethyl ether. The resulting organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated. The obtained residue was purified by column chromatography (silica gel: 200 g, n-hexane/ethyl acetate=10/1) to produce the target compound (11.3 g, 73%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][N:6]([CH3:16])[C:7]2=[O:15]>CO.[Pd]>[NH2:12][C:11]1[C:3]([O:2][CH3:1])=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:15])[N:6]([CH3:16])[CH2:5]2
Reactant: COc1c([N+](=O)[O-])ccc2c1CN(C)C2=O
Agent: [Pd]
Solvent: CO
Product: COc1c(N)ccc2c1CN(C)C2=O
Temperature: 50 °C
Reaction time: 6 h
Yield: 52 %

Procedure:
To a solution of 4-methoxy-2-methyl-5-nitroisoindolin-1-one (155 mg, 0.7 mmol) in MeOH (10 mL) was added Pd/C (60 mg). The mixture was stirred at 50° C. under H2 for 6 h. The resulting suspension was filtered. The filtrate was concentrated under reduced pressure to afford 5-amino-4-methoxy-2-methylisoindolin-1-one (70 mg, yield 52%). m/z (ES+APCI)+: [M+H]+193.1.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:17]=[C:16]([C:18](Cl)=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][NH:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C(Cl)Cl>[CH:23]1([N:22]([CH3:21])[C:18]([C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=[C:8]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:17]=2)=[O:19])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CNC1CCCCC1
Reactant: O=C(Cl)c1cc(-c2ccccc2)nc2ccccc12
Agent: Cl
Solvent: ClCCl
Product: CN(C(=O)c1cc(-c2ccccc2)nc2ccccc12)C1CCCCC1

Procedure:
The procedure of Example 41 is followed using 2-phenylquinoline-4-carboxylic acid chloride hydrochloride (9.1 g) and N-methylcyclohexylamine (13.5 g) in methylene chloride (100 ml) as the starting materials.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][NH:10][C:11]2=[O:16].[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(O)C>[N:17]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][NH:10][C:11]3=[O:16])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C1NCCc2c(OCCCCl)cccc21
Reactant: C1CCNCC1
Solvent: CCO
Product: O=C1NCCc2c(OCCCN3CCCCC3)cccc21
Yield: 61 %

Procedure:
A mixture of 0.6 g (2.5 mmol) of 5-(3-chloropropoxy)-3,4-dihydro-1(2H)-isoquinolinone and 0.6 ml (10 mmol) of piperidine in 30 ml of ethanol was refluxed for 40 hours. The mixture was concentrated, dissolved in chloroform and washed with saturated sodium bicarbonate. The organic layer was dried and concentrated. The solid was recrystallized from water to provide 0.44 g (61%) of the desired product; mp 112°-114°.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[C:9]([C:11]1[C:16]2[N:17]=[C:18]([C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[O:19][C:15]=2[C:14](F)=[C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:12]=1[CH3:32])#[N:10].C(N(CC)CC)C>CS(C)=O>[C:9]([C:11]1[C:16]2[N:17]=[C:18]([C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[O:19][C:15]=2[C:14]([N:5]2[CH2:6][CH2:7][C@H:3]([N:2]([CH3:8])[CH3:1])[CH2:4]2)=[C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:12]=1[CH3:32])#[N:10]
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C(=O)N(C)C)nc2c1C#N
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(C(=O)N(C)C)nc2c1C#N
Reaction time: 0.83 h

Procedure:
Under nitrogen atmosphere, a dimethyl sulfoxide (2 ml) solution (3S)-3-(dimethylamino)pyrrolidine (75 μl, 594 μmol) was added at 150° C. to a dimethyl sulfoxide (8 ml) solution of 4-cyano-7-fluoro-N,N,5-trimethyl-6-phenyl-1,3-benzoxazole-2-carboxamide (I-114) (160 mg, 495 μmol) and triethylamine (90 μl, 644 μmol), followed by stirring at the same temperature for 50 minutes.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11])[CH2:2][CH2:3][CH2:4][CH3:5].[C:15](#[N:17])[CH3:16]>>[OH:11][CH:10]([C:9]1[CH:12]=[CH:13][CH:14]=[C:7]([O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH:8]=1)[CH2:16][C:15]#[N:17]
Reactant: CCCCCOc1cccc(C=O)c1
Reactant: CC#N
Product: CCCCCOc1cccc(C(O)CC#N)c1

Procedure:
Addition of acetonitrile to 3-pentyloxybenzaldehyde gave 3-hydroxy-3-(3-pentyloxyphenyl)propionitrile as a yellow oil. Yield (1.11 g, 67%): 1H NMR (400 MHz, CDCl3) δ 7.30 (d, J=7.6 Hz, 1H), 6.92-6.98 (m, 2H), 6.87 (d, J=7.6 Hz, 1H), 5.02 (m, 1H), 3.98 (t, J=6.4 Hz, 2H), 2.76 (d, J=6.0 Hz, 2H), 1.75-1.83 (m, 2H), 1.32-1.49 (m, 4H), 0.92 (t, J=6.8 Hz, 3H).
Reaction SMILES: Cl.C[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:14](=[O:16])[CH3:15])[CH:8]=[CH:7]2>ClCCl>[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:14](=[O:16])[CH3:15])[CH:8]=[CH:7]2
Reactant: COc1ccc2cc(C(C)=O)ccc2c1
Agent: Cl
Solvent: ClCCl
Product: CC(=O)c1ccc2cc(O)ccc2c1
Yield: 88.6 %

Procedure:
In a 3 L two-neck round bottom flask, equipped with a reflux condenser and a dropping funnel, 2 L of hydrochloric acid (d=1.16) were stirred and heated to boiling. A solution of 6.06 g (30.3 mmol) of 1-(6-methoxy-2-naphthyl)-1-ethanone (prepared as described in Arsenijevic et al., Org. Synth. Coll. 6:34 (1988), the disclosure of which is incorporated herein by reference) in a minimum amount of dichloromethane was added, and the mixture was stirred and heated at reflux for 2 hours. The hot solution was filtered through a mineral wool plug to remove oily residue. The solid that separated after cooling was filtered on a glass frit and dissolved in 130 mL of ethyl acetate. The solution was washed with brine, dried with anhydrous magnesium sulfate and evaporated to give 5 g (89%) of 1-(6-hydroxy-2-naphthyl)-1-ethanone.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH3:13][C@H:14]1[S:20][C@H:19]([C:21]([OH:23])=O)[CH2:18][C:17]2[CH:24]=[C:25]3[O:30][CH2:29][O:28][C:26]3=[CH:27][C:16]=2[C:15]1=[O:31].[NH2:32][C:33]1[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][CH:34]=1.ON1C2C=CC=CC=2N=N1>ClCCl.CN(C)C=O.O>[CH2:43]([O:42][P:38]([CH2:37][C:36]1[CH:35]=[CH:34][C:33]([NH:32][C:21]([C@@H:19]2[CH2:18][C:17]3[CH:24]=[C:25]4[O:30][CH2:29][O:28][C:26]4=[CH:27][C:16]=3[C:15](=[O:31])[C@@H:14]([CH3:13])[S:20]2)=[O:23])=[CH:47][CH:46]=1)([O:39][CH2:40][CH3:41])=[O:45])[CH3:44]
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Reactant: C[C@H]1S[C@H](C(=O)O)Cc2cc3c(cc2C1=O)OCO3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOP(=O)(Cc1ccc(NC(=O)[C@@H]2Cc3cc4c(cc3C(=O)[C@@H](C)S2)OCO4)cc1)OCC
Temperature: 0 °C
Reaction time: 15 h
Yield: 40.9 %

Procedure:
A solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.69 g) in dichloromethane (12 ml) was added to a solution of (2S,4R)-(+)-1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxylic acid (0.84 g) and diethyl 4-aminobenzylphosphonate (0.73 g) in N,N-dimethylformamide (DMF) (12 ml) at 0° C., followed by the addition of 1-hydroxybenzotriazole (HOBt) (0.51 g). This mixture was stirred at 0° C. for 1 hour and at room temperature for 15 hours, after which it was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), after which the solvent was distilled off; the residual crystals were collected by filtration, followed by recrystallization from ethyl acetate-hexane and successively from methanol-hexane to yield (2S, 4R)-(+)-N-[4-(diethoxyphosphorylmethyl)phenyl]-1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxamide (0.62 g, 41%). Colorless prisms. Melting point 183-184° C. Optical rotation [α]D (23° C.) +190.5° (c=0.50, CHCl3).
Reaction SMILES: [O:1]=[CH:2][CH2:3][C@H:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([NH:16][CH:17]4[CH2:22][CH2:21][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]4)[C:6]=3[C:5]1=2.[CH3:31][Mg+].[Br-]>O1CCCC1>[OH:1][CH:2]([CH3:31])[CH2:3][C@H:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([NH:16][CH:17]4[CH2:18][CH2:19][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])[CH2:21][CH2:22]4)[C:6]=3[C:5]1=2
Reactant: C[Mg+]
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2ncnc3sc4c(c23)[C@@H](CC=O)CC4)CC1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(O)C[C@H]1CCc2sc3ncnc(NC4CCC(NC(=O)OC(C)(C)C)CC4)c3c21
Temperature: 0 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
For the preparation of the starting material compound 26.3, see Example 26. Into a 50-mL 3-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl N-(4-[[(3R)-3-(2-oxoethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]amino]cyclohexyl)carbamate (250 mg, 0.58 mmol, 1.00 equiv) in freshly distilled tetrahydrofuran (10 mL) at 0° C. under nitrogen. The CH3MgBr (1.0 M in THF, 2.9 mL, 5.0 equiv) was added at 0° C. via syringe. The resulting solution was stirred for 2 h at 0° C. and quenched with saturated aqueous NH4Cl and extracted with 3×30 mL of ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate and concentrated under reduced pressure. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5) to give the desired racemic tert-butyl N-(4-[[(3R)-3-(2-hydroxypropyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]amino]cyclohexyl)carbamate (109 mg, 42%) as a colorless oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.Cl.[NH2:13][OH:14].C([O-])([O-])=O.[Na+].[Na+]>CCO>[OH:14][NH:13][C:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH:2]=[CH:3][C:4]=2[CH:9]=1)=[NH:11]
Reactant: N#Cc1ccc2occc2c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: N=C(NO)c1ccc2occc2c1
Temperature: 75 °C
Reaction time: 8 h
Yield: 172.6 %

Procedure:
Prepared using General Procedure 1. To a flask containing benzofuran-5-carbonitrile (200 mg, 0.73 mmol) was added EtOH (6 mL), hydroxylamine hydrochloride (176.7 mg, 2.54 mmol) and Na2CO3 (154 mg, 1.42 mmol). The mixture was stirred at 75° C. overnight then concentrated, re-dissolved in DCM and washed with NaHCO3. The combined organic layers were dried over Na2SO4, and concentrated to provide 222 mg of crude N-hydroxybenzofuran-5-carboximidamide INT-68 as a white solid which was used directly in the next step without purification. LCMS-ESI (m/z) calculated for C9H8N2O2: 176.2; found 177.1 [M+H]+, tR=0.83
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]([OH:7])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][OH:25]>CN(C)C=O>[OH:25][CH2:24][C:23]1[CH:22]=[C:21]([NH:20][C:5](=[O:7])[CH2:4][CH2:3][O:2][CH3:1])[CH:28]=[CH:27][CH:26]=1
Reactant: Nc1cccc(CO)c1
Reactant: COCCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: COCCC(=O)Nc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
0.76 g (7.31 mmol) 3-methoxypropionic acid in 10 ml dry N,N-dimethylformamide (DMF) were treated with 1.25 g (7.71 mmol) 1,1′-carbonyl-diimidazole and stirred for 1 hr at room temperature. 1.00 g 3-aminobenzylalcohol were added and stirring was continued over night. The solvent was removed and the residue chromatographed on silica in ethyl acetate, yielding 1.26 g N-(3-Hydroxymethyl-phenyl)-3-methoxy-propionamide.
Reaction SMILES: [N:1]1[N:2]=[N:3][N:4]2[CH:8]([C:9]([O:11]C)=[O:10])[CH2:7][CH2:6][C:5]=12.[Li+].[OH-]>C1COCC1.O.CO>[N:1]1[N:2]=[N:3][N:4]2[CH:8]([C:9]([OH:11])=[O:10])[CH2:7][CH2:6][C:5]=12
Reactant: COC(=O)C1CCc2nnnn21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1CCc2nnnn21
Temperature: 60 °C

Procedure:
To a solution of methyl 6,7-dihydro-5H-pyrrolo[1,2-d]tetrazole-5-carboxylate (300 mg, 1.78 mmol) in THF/water/MeOH was added LiOH (214 mg, 8.92 mmol) and the resulting solution was heated via oil bath to 60° C. for 16 h. (Round bottom was equipped with a condenser.) The solution was cooled to room temperature and concentrated to remove organic solvents. The aqueous layer was then acidified to pH of ˜5 using 2N HCl. The mixture was concentrated to dryness under vacuum, azeotroping with toluene (2×20 mL) to make sure all water was removed. The material was used without further purification with Lithium chloride as a by-product. LC-MS: m/z (ES)=155 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:5](=[O:14])[CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]([OH:13])=O.[NH2:15][CH2:16][CH:17]([OH:24])[CH2:18][N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>>[OH:24][CH:17]([CH2:18][N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:16][NH:15][C:11]([C:10]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:14])[C:4]=2[NH:3][C:2]=1[CH3:1])=[O:13]
Reactant: Cc1[nH]c2c(c1C(=O)O)CCCC2=O
Reactant: NCC(O)CN1CCCC1
Product: Cc1[nH]c2c(c1C(=O)NCC(O)CN1CCCC1)CCCC2=O
Yield: 81.4 %

Procedure:
Similar procedure as Example 13, 2-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (S4) 0.2 g (1.0 mmol) and 1-amino-3-(pyrrolidin-1-yl)propan-2-ol 0.30 g (2.1 mmol) was reacted to give 0.26 g (82%) of the titled compound as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCCCCC.C([Li])CCC.[CH:33]1([C:39]2[C:43](=C)[CH:42]=[CH:41][CH:40]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>O.C1COCC1>[CH:39]1([C:33]2([C:10]3[C:9]4[CH2:8][C:7]5[C:15](=[CH:16][CH:17]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=5)[C:14]=4[CH:13]=[CH:12][C:11]=3[C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[CH:40]=[CH:41][CH:42]=[CH:43]1
Reactant: C=C1C=CC=C1C1CCCCC1
Reactant: CC(C)(C)c1ccc2c(c1)Cc1cc(C(C)(C)C)ccc1-2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccc2c(c1)Cc1c-2ccc(C(C)(C)C)c1C1(C2C=CC=C2)CCCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 67.9 %

Procedure:
To a THF (30 ml) solution including 5.0 g (18.6 mmol) of 2,7-di-tert-butylfluorene, a hexane solution (13.5 ml, 21.6 mmol) of n-butyllithium was added dropwise at −78° C. under nitrogen, followed by stirring at room temperature for 6 hours. Next, a THF (20 ml) solution including 3.42 g (23.4 mmol) of cyclohexylfulvene was added dropwise at 0° C. under a nitrogen atmosphere, followed by stirring at room temperature for 16 hours. The resultant reaction solution was decomposed with cold water, and then extracted with ether. The extract was dried over magnesium sulfate and then filtered, and the used solvent was removed from the filtrate under reduced pressure, thereby obtaining a solid. This solid was recrystallized from methanol to obtain 5.36 g of a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH:4]=[CH2:5].[NH2:7][CH2:8][CH2:9][CH:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:20])[CH:17]=2)[O:12][C:11]1([CH3:22])[CH3:21]>CO>[CH3:21][C:11]1([CH3:22])[CH:10]([CH2:9][CH2:8][NH:7][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:6])[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:20])[CH:17]=2)[O:12]1
Reactant: CC1(C)Oc2ccc(F)cc2CC1CCN
Reactant: C=CC(=O)OC
Solvent: CO
Product: COC(=O)CCNCCC1Cc2cc(F)ccc2OC1(C)C

Procedure:
While stirring at a temperature of from 0° to 5°, a solution of 0.86 g (9.9 mmol) of acrylic acid methyl ester in 10 ml of methanol is added dropwise within a period of 15 minutes to a solution of 2.23 g (10 mmol) of 3-(2-aminoethyl)-2,2-dimethyl-6-fluoro-chroman in 50 ml of methanol. The reaction mixture is then stirred for 16 hours at from 0° to 5° and then concentrated by evaporation in vacuo. The oily residue is chromatographed on 200 g of silica gel (0.040-0.063 mm) with ethyl acetate as eluant, yielding 1.9 g (61.4% of the theoretical yield) of N-[2-(2,2-dimethyl-6-fluoro-chroman-3-yl)-ethyl]-N-(2-methoxycarbonylethyl)-amine in the form of a light-yellow oil. The N-[2-(2,2-dimethyl-6-fluoro-chroman-3-yl)-ethyl]-N-(2-methoxycarbonylethyl)-amine hydrochloride, prepared therefrom with hydrochloric acid in diethyl ether, crystallises from acetone/diethyl ether and melts at 129°-131°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11].N1C=CC=CC=1>>[C:10]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:9])(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccc(Br)cc1F
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(Br)cc1F
Temperature: 100 °C
Yield: 83 %

Procedure:
A mixture of 4-bromo-2-fluorophenol (5 g, 30 mmol) and acetic anhydride (13.4 g, 130 mmol) in pyridine (10.6 ml, 130 mmol) was heated at 100° C. for 3 h and then brought to ambient temperature and poured into water. HCl (1 N and 6 N) was added and the solution was extracted with EtOAc. The combined organic phases were washed with sodium bicarbonate (saturated, 3×50 ml), dried (Na2SO4) and evaporated to dryness to give the title compound (5.8 g). MS m/z (rel. intensity, 70 eV) 233 (M+, 11), 232 (M+, 12), 191 (95), 190 (bp), 161 (8).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]#[N:24])[CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:25](O)=[O:26])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[F:28][C:29]1[CH:30]=[C:31]([C:35](=[N:37]O)[NH2:36])[CH:32]=[CH:33][CH:34]=1>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][CH:11]([C:25]3[O:26][N:37]=[C:35]([C:31]4[CH:32]=[CH:33][CH:34]=[C:29]([F:28])[CH:30]=4)[N:36]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]#[N:24])[CH2:19][CH2:18]3)=[O:16])[CH2:14]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: NC(=NO)c1cccc(F)c1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(C#N)CC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(-c4cccc(F)c4)no3)CN(C(=O)N3CCC(C#N)CC3)C2)cc1

Procedure:
80 mg (0.22 mmol) of 5-(4-ethylphenyl)-1-[(4-cyanopiperidin-1-yl)carbonyl]piperidine-3-carboxylic acid (Example 60A) and 50 mg (0.33 mmol, 1.5 eq.) of 3-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 2. Yield: 81 mg (77% of theory)