Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:12][C:11]([C:21](=[O:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])([C:13]([O:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[Cl-].[NH4+]>CO>[CH2:1]([O:8][CH:9]1[CH2:12][C:11]([CH:21]([OH:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])([C:13]([O:15][CH2:16][CH2:17][CH:18]([CH3:19])[CH3:20])=[O:14])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)C1(C(=O)OCCC(C)C)CC(OCc2ccccc2)C1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CCOC(=O)CC(O)C1(C(=O)OCCC(C)C)CC(OCc2ccccc2)C1

Procedure:
A 11.37 g (29.12 mmol) portion of ethyl 3-[1-benzyloxy-3-(isoamyloxycarbonyl)cyclobutan-3-yl]-3-oxopropionate was dissolved in 100 ml of methanol to which, while cooling in an ice bath and stirring, was subsequently added 441 mg (11.65 mmol) of sodium tetrahydroborate. After 10 minutes of stirring at the same temperature, to this was gradually added saturated ammonium chloride aqueous solution. After evaporation of methanol under a reduced pressure, ethyl acetate was added to the thus obtained residue to effect separation of layers. The resulting organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under a reduced pressure to give 11.41 g (29.07 mmol) of the title compound. The thus obtained compound was used in the following reaction without purification.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][CH:7]([C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([Cl:18])=[CH:12][C:11]=1[Cl:19])[C:8]#[N:9].[OH2:20].N>O>[NH2:6][CH:7]([C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([Cl:18])=[CH:12][C:11]=1[Cl:19])[C:8]([NH2:9])=[O:20]
Reactant: COc1cc(C(N)C#N)c(Cl)cc1Cl
Reactant: O
Agent: N
Agent: O=S(=O)(O)O
Product: COc1cc(C(N)C(N)=O)c(Cl)cc1Cl
Reaction time: 3 h
Yield: 46 %

Procedure:
Then, 3.6 g of concentrated sulfuric acid was added to 0.33 g of water, to which 15.0 g of 2-amino-2-(2,4-dichloro-5-methoxyphenyl)acetonitrile was added under ice cooling, and the mixture was heated at 50° to 60° C. under stirring for 3 hours. After completion of the reaction, the reaction mixture was poured into 15 ml of concentrated ammonia water cooled with ice in such a manner that the temperature of the solution became not higher than 20° C. The precipitated crystals were collected by filtration, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was combined with the previously collected crystals, followed by recrystallization, which afforded 7.42 g (yield, 46%) of 2-amino-2-(2,4-dichloro-5-methoxyphenyl)acetamide.
Reaction SMILES: [OH:1][CH:2]([CH2:14][CH3:15])[CH2:3][CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=1O>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][C:22]=1[O:1][CH:2]([CH2:14][CH3:15])[CH2:3][CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:10])([CH3:11])[CH3:9]
Reactant: Oc1cc(C(F)(F)F)ccc1Cl
Reactant: CCC(O)CCN(C)C(=O)OC(C)(C)C
Product: CCC(CCN(C)C(=O)OC(C)(C)C)Oc1cc(C(F)(F)F)ccc1Cl

Procedure:
The title compound was prepared according to the method of Example 2 step (b) but using (3-hydroxypentyl)methylcarbamic acid, 1,1-dimethylethyl ester and 2-chloro-5-(trifluoromethyl)phenol.
Reaction SMILES: [N+:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)([O-:3])=[O:2].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[H-].[Na+]>>[CH2:10]([C:4]1([N+:1]([O-:3])=[O:2])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])C1CCCCC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: O=[N+]([O-])C1(Cc2ccccc2)CCCCC1

Procedure:
Nitrocyclohexane and benzylbromide are subjected to condensation reaction in the presence of sodium hydride to obtain 1-benzyl-1-nitrocyclohexane. The product is reduced with lithium aluminum hydride to obtain 1-benzyl-1-aminocyclohexane. The product is reacted with methyl chloroformate to obtain 1-benzyl-1-methoxycarbonylaminocyclohexane, and the product is subjected to intramolecular cyclization in the presence of phosphorous oxychloride to obtain spiro[1,2,3,4-tetrahydroisoquinoline-2,1'-cyclohexan]-1-one.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][CH:9]([F:46])[C:10]([N:12]1[C@H:16]([CH2:17][F:18])[C@@H:15]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:26]=[CH:27][C:28]([CH:31]([NH:33][C:34](=[O:43])[O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH3:32])=[N:29][CH:30]=3)=[CH:21][CH:20]=2)[O:14]C1(C)C)=[O:11]>C(Cl)Cl>[F:46][CH:9]([F:8])[C:10]([NH:12][C@H:16]([CH2:17][F:18])[C@@H:15]([C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:26]=[CH:27][C:28]([CH:31]([NH:33][C:34](=[O:43])[O:35][CH2:36][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH3:32])=[N:29][CH:30]=2)=[CH:23][CH:24]=1)[OH:14])=[O:11]
Reactant: CC(NC(=O)OCc1ccccc1)c1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(NC(=O)OCc1ccccc1)c1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
Trifluoroacetic acid (2.2 mL) is added to the product of step 2, Example 95A (1.05 g, 1.94 mmol) in CH2Cl2 (39 mL) at 0° C. After 30 minutes the ice bath is removed and the mixture stirred at room temperature for 8 hours. Saturated NaHCO3 (60 mL) is added and the mixture extracted with CH2Cl2 (40 mL). The combined organics are dried over MgSO4, filtered and evaporated to give the title product (850 mg): m/z: 501.19.
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:8][CH3:9])[CH2:5][CH2:6]Cl)[CH3:3].[NH2:10][CH2:11][CH2:12][OH:13]>[OH-].[Na+]>[CH2:2]([N:4]([CH2:8][CH3:9])[CH2:5][CH2:6][NH:10][CH2:11][CH2:12][OH:13])[CH3:3]
Reactant: CCN(CC)CCCl
Reactant: NCCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCN(CC)CCNCCO
Temperature: 120 °C
Reaction time: 5 h
Yield: 43.1 %

Procedure:
A mixture of 2-(diethylamino)ethylchloride hydrochloride (18 g, 0.11 mol) and 2-aminoethanol (19 mL, 0.32 mol) was stirred at 120° C. for 5 hours. After the reaction mixture was cooled to room temperature, a 1.0 mol/L aqueous solution of sodium hydroxide (40 mL) was added thereto, and the mixture was extracted with chloroform (100 mL×6). The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was distilled to obtain N,N-diethyl-N′-(2-hydroxyethyl)ethylenediamine (7.6 g, 45%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:15][CH3:16])=[C:6]([CH:8]2[C:12](=[O:13])[CH2:11][CH2:10][C:9]2=[O:14])[CH:7]=1.[Cl:17][C:18]1[CH:19]=[C:20]([OH:25])[CH:21]=[CH:22][C:23]=1[Cl:24].C(=O)([O-])[O-].[Cs+].[Cs+]>[O-]S(C(F)(F)F)(=O)=O.[Cu+2].[O-]S(C(F)(F)F)(=O)=O.C1(C)C=CC=CC=1>[Cl:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][C:23]=1[Cl:24])[O:25][C:2]1[CH:3]=[CH:4][C:5]([CH2:15][CH3:16])=[C:6]([CH:8]2[C:12](=[O:13])[CH2:11][CH2:10][C:9]2=[O:14])[CH:7]=1
Reactant: CCc1ccc(Br)cc1C1C(=O)CCC1=O
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: [Cu+2]
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: Cc1ccccc1
Product: CCc1ccc(Oc2ccc(Cl)c(Cl)c2)cc1C1C(=O)CCC1=O
Temperature: 160 °C

Procedure:
To a mixture of 2-(5-bromo-2-ethylphenyl)cyclopentane-1,3-dione (0.200 g, 0.71 mmol), 3,4-dichlorophenol (0.577 g, 3.56 mmol), cesium carbonate (0.502 g, 1.42 mmol), copper triflate (13 mg, 0.04 mmol) and activated (powdered) 5 Å molecular sieves (0.400 g) is added anhydrous toluene (2.5 ml). The reaction mixture is purged with nitrogen then heated at 160° C. for 1 hour under microwave irradiation. After cooling to room temperature dichloromethane is added and mixture is quenched with 2M aqueous hydrochloric acid then filtered. The organic phase is concentrated under reduced pressure to give a crude oil which is purified by preparative reverse-phase HPLC to afford 2-[5-(3,4-dichlorophenoxy)-2-ethylphenyl]cyclopentane-1,3-dione.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])O.[Na+]>COCCOC.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>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:3]=2)=[CH:24][CH:23]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(Br)c2ccccc21
Reactant: COc1ccc(B(O)O)cc1
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: [Na+]
Solvent: COCCOC
Product: COc1ccc(-c2cn(S(=O)(=O)c3ccccc3)c3ccccc23)cc1
Temperature: 85 °C
Reaction time: 0.08 h

Procedure:
3-bromo-1-(phenylsulfonyl)-1H-indole (500 mg, 1.49 mmol) and 5 mol % tetrakis(triphenylphosphine)palladium were mixed in 9 ml degassed DME. The mixture was stirred for 5 min under nitrogen and was then heated to 85° C. 4-Methoxyphenyl boronic acid (1.2 eq) dissolved in 3 ml DME and 5.95 ml sodium hydrogen carbonate (1 M) were simultaneously added drop wise at 85° C. over 5 min. The reaction was stirred at 85° C. for 10 min and then cooled to room temperature. DME was concentrated, water was added and the remaining aqueous mixture was extracted with DCM. The combined organic layers were concentrated and the crude product was purified on silica using EtOAc/n-heptane (1:9 to 2:8) as eluents. 363 mg 3-(4-methoxyphenyl)-1-(phenylsulfonyl)-1H-indole was obtained as white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[C:6]([OH:13])[CH:5]=1)[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH3:45][N:46]1[C:50]2[C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][C:56]=3[O:57][C:58]3([CH2:63][CH2:62][NH:61][CH2:60][CH2:59]3)[C:49]=2[CH:48]=[N:47]1>CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([N:61]2[CH2:62][CH2:63][C:58]3([C:49]4[CH:48]=[N:47][N:46]([CH3:45])[C:50]=4[C:51]4[CH:52]=[CH:53][CH:54]=[CH:55][C:56]=4[O:57]3)[CH2:59][CH2:60]2)=[O:10])=[C:6]([OH:13])[CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C(=O)O)c(O)c1
Reactant: Cn1ncc2c1-c1ccccc1OC21CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1ccc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2c3cnn2C)c(O)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 31.6 %

Procedure:
In a vial were added 4-ethoxy-2-hydroxybenzoic acid (0.40 mmol) followed by HATU (170 mg, 0.44 mmol), DMF (0.7 mL), and triethylamine (220 μL, 1.6 mmol). The mixture was stirred for 10 minutes before 1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] (100 mg, 0.40 mmol) was added. The reaction mixture was allowed to stir at 25° C. for 12 hours before it was filtered and purified by HPLC (1-99%) MeOH:H2O to yield (4-ethoxy-2-hydroxyphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone (53 mg, 32%). ESI-MS m/z calc. 419.5, found 420.4 (M+1)+. Retention time: 2.96 minutes (4 min run).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][C@H:11]([NH:16]C(OC(C)(C)C)=O)[C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1.C(Cl)(C)=O>CCOC(C)=O.CO>[NH2:16][C@@H:11]([CH2:10][C:9]#[C:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)[C@H](CC#Cc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Solvent: CO
Solvent: CC(=O)Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](N)CC#Cc1ccc(Br)cc1
Yield: 96 %

Procedure:
To a solution of methyl (2S)-5-(4-bromophenyl)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-4-pentynoate (D74, 1.199 g, 3.136 mmol) in dry EtOAc (18 ml) and dry methanol (2 ml) was added AcCl (1.14 ml, 1.25 g, 15.98 mmol). After solvent removal the residue was purified using a SCX cartridge affording the title compound (849 mg, 95%). UPLC: Rt 0.51 min, MS: (ES/+) m/z: 282, 284 [MH+], C12H12BrNO2 requires 282.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:9][C:4]=2[CH:3]=[CH:2]1.S(Cl)(Cl)=O.S1C2C=CC(CCOCCC[N:37]3[CH2:40][CH:39]([OH:41])[CH2:38]3)=CC=2C=C1.[OH-].[Na+]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C.CN(C)C=O>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15]([N:37]3[CH2:40][CH:39]([OH:41])[CH2:38]3)=[O:17])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=C(O)CCOCCc1ccc2sccc2c1
Reactant: OC1CN(CCCOCCc2ccc3sccc3c2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(CCOCCc1ccc2sccc2c1)N1CC(O)C1
Temperature: 15 °C
Reaction time: 1 h
Yield: 117.8 %

Procedure:
In 12.5 mL of toluene was suspended 5.00 g of 3-[2-(1-benzothiophen-5-yl)ethoxy]propionic acid, and 0.1 mL of N,N-dimethylformamide was added thereto, after which 1.68 mL of thionyl chloride was added dropwise thereto at 15° C. and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was added dropwise to a solution of 4.44 g of 3-hydroxyazetidine 1/2 tartrate and 3.76 g of sodium hydroxide in 25 mL of water at 10° C., and stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture and the organic layer was separated. The organic layer was washed with diluted hydrochloric acid and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; chloroform:acetone=3:1 to 1:1) and crystallized from diisopropyl ether to obtain 5.48 g of 3-[2-(1-benzothiophen-5-yl)ethoxy]-1-(3-hydroxy-1-azetidinyl)-1-propanone as colorless crystals.
Reaction SMILES: O1CCCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:16]([O:22][CH2:23][CH3:24])(=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19].FC(F)(F)S(O[Si:31]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:34])[CH3:33])(=O)=O>CN1CCCN(C)C1=O>[CH2:23]([O:22][C:16]([O:21][Si:31]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:34])[CH3:33])=[CH:17][CH:18]([CH3:20])[CH3:19])[CH3:24]
Reactant: CCOC(=O)CC(C)C
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CCOC(=CC(C)C)O[Si](C(C)C)(C(C)C)C(C)C
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
Tetrahydrofuran (100 ml) and 1,3-dimethyl-3,4,5,6-tetrahydro 2 (1H)-pyrimidinone (140 ml) were mixed at −20° C. and lithium bis (trimethylsilyl) amide (1M in tetrahydrofuran, 100 ml) was added. The mixture was cooled to −70° C., ethyl isovalerate (18.75 ml) added and stirred for ½ hour at −70° C. Triisopropylsilyl trifluoromethane sulfonate was added and the mixture left to stir at −75° C. for ½ hour before warming to room temperature and stirring for 3 hours. The reaction mixture was quenched with aqueous sodium bicarbonate (8%, 150 ml) and extracted with hexane (1000 ml). The hexane extract was washed with water (4×500 ml), dried (MgSO4), filtered and concentrated in vacuo to afford a crude yellow oil containing the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([Cl:9])[CH:3]=1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>>[Cl:9][C:4]1[CH:3]=[C:2]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]=1[Cl:8]
Reactant: C1CNCCN1
Reactant: Clc1ccc(Br)cc1Cl
Product: Clc1ccc(N2CCNCC2)cc1Cl
Yield: 48.2 %

Procedure:
Beginning with 4-bromo-1,2-dichlorobenzene (200 mg, 0.88 mmol) and piperazine (91 mg, 1.06 mmol), 98 mg of the title compound was recovered by the procedure described in Example 1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.F[C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][CH:9]=1>O>[N:1]1([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: NC(=O)c1ccc(F)cc1
Solvent: O
Product: NC(=O)c1ccc(N2CCOCC2)cc1
Temperature: 120 °C
Yield: 3373 %

Procedure:
A mixture of morpholine (2.0 g, 0.23 mmol) and 4-fluorobenzamide (1.2 g, 8.6 mmol) is heated at 120° C. The conversion of the 4-fluorobenzoamide is complete after 10 hours. Water (10 ml) is than added into the reaction mixture. The precipitate is filtered off, washed with water and dried under vacuum (30° C.) to give 1.6 g of the title-compound. Yield: 94%; m.p. 220-221° C.; MS 206 (100, M+); H1 NMR (DMSO): δ 7.76 (d, 2H), 7.75 (b, 1H), 7.05 (b, 1H), 6.94 (d, 21H), 3.73 (t, 4H), 3.20 (t, 4H); C13 NMR (CDCl3): δ 167.61, 152.90, 128.79, 123.93, 113.31, 65.92, 47.36.
Reaction SMILES: Br[C:2]1[C:3]([F:23])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C@:30]([OH:34])([C:32]#[CH:33])[CH3:31]>>[F:23][C:3]1[C:2]([C:33]#[C:32][C@@:30]([OH:34])([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=2)[CH3:31])=[CH:22][C:6]2[C:7]3[N:8]([C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: C#C[C@@](C)(O)c1ccccn1
Reactant: CNC(=O)c1c(C(N)=O)nc2n1CCOc1cc(F)c(Br)cc1-2
Product: CNC(=O)c1c(C(N)=O)nc2n1CCOc1cc(F)c(C#C[C@@](C)(O)c3ccccn3)cc1-2
Yield: 10 %

Procedure:
10-bromo-9-fluoro-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide was reacted (2R)-2-(2-pyridyl)but-3-yn-2-ol via General Procedure E to afford 8.9 mg (10%) of 9-fluoro-10-[(3R)-3-hydroxy-3-(2-pyridyl)but-1-ynyl]-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide. M+1=450.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[C:18]1([CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:32])[CH2:29][C:30]#[N:31])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:14]([C:11]1[CH:10]=[C:7]([CH:8]=[C:29]([C:28]([NH:27][CH2:26][CH2:25][CH2:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:32])[C:30]#[N:31])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:12]=1[OH:13])([CH3:17])([CH3:16])[CH3:15]
Reactant: N#CCC(=O)NCCCc1ccccc1
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Product: CC(C)(C)c1cc(C=C(C#N)C(=O)NCCCc2ccccc2)cc(C(C)(C)C)c1O

Procedure:
M20 was prepared using 3,5-di-t-butyl-4-hydroxybenzaldehyde and N-3-phenyl-n-propyl cyanoacetamide under the similar conditions as descibed for M21 infra.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][N:10]([CH2:18][CH2:19][CH2:20][CH2:21][N:22]3C(=O)C4C(=CC=CC=4)C3=O)[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>C(O)C>[C:1]1([C:7]2[N:8]=[CH:9][N:10]([CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])[C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCn1cnc(-c2ccccc2)c1-c1ccccc1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCCn1cnc(-c2ccccc2)c1-c1ccccc1

Procedure:
Batch size: 14.0 g (33.2 mmol) 2-[4-(4,5-diphenyl-imidazol-1-yl)-butyl]-isoindol-1,3-dione and 3.3 ml (66.4 mmol) hydrazine hydrate in 130 ml ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:40]=[CH:39][CH:38]=[CH:37][C:3]=1[O:4][C:5]1[CH:14]=[C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[CH2:23][O:24][C:25]([CH3:36])([CH3:35])[CH2:26][C:27]=3[C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[CH2:17][CH2:16]2)[CH:12]=[CH:11][C:6]=1[C:7]([O:9]C)=[O:8].O[Li].O.Cl>O1CCCC1.CO.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:40]=[CH:39][CH:38]=[CH:37][C:3]=1[O:4][C:5]1[CH:14]=[C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[CH2:23][O:24][C:25]([CH3:36])([CH3:35])[CH2:26][C:27]=3[C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)[CH2:17][CH2:16]2)[CH:12]=[CH:11][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CC(C)(C)OC3)CC2)cc1Oc1ccccc1Cl
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)CC(c2ccc(Cl)cc2)=C(CN2CCN(c3ccc(C(=O)O)c(Oc4ccccc4Cl)c3)CC2)CO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 38G (254 mg) in tetrahydrofuran (4 mL), methanol (2 mL) and water (2 mL) was added LiOH H2O (126 mg). The mixture was stirred at room temperature overnight. The mixture was then neutralized with 5% aqueous HCl and diluted with ethyl acetate (200 mL). After washing with brine, it was dried over Na2SO4. Filtration and evaporation of solvent gave the product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[F:15][C:16]([F:21])([F:20])[C:17](O)=[O:18].O>ClCCl>[F:15][C:16]([F:21])([F:20])[C:17]([N:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][NH:3]1)=[O:18]
Reactant: O=C(O)C(F)(F)F
Reactant: Nc1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(N=c1cccc[nH]1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 70.1 %

Procedure:
25 g (270 mmol) of 2-aminopyridine was dissolved in 200 ml of anhydrous dichloromethane, 41 ml (30 g, 300 mmol) of triethylamine was added thereto, and the mixture was cooled to 0° C. 38 ml (57 g, 270 mmol) of anhydrous trifluoroacetic acid was added dropwise thereto over 15 minutes, and the resulting mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was injected into about 100 ml of iced water, and the mixture was stirred for 10 minutes. The mixture was transferred to a separatory funnel to perform liquid separation, and the organic layer was washed twice with 150 ml of water and twice with 150 ml of a 1% HCl aqueous solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 36 g (yield 71%) of 2,2,2-trifluoro-N-(pyridin-2(1H)-ylidene)acetamide.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][CH:7]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:8](O)=[O:9].S(Cl)([Cl:25])=O>>[F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][CH:7]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:8]([Cl:25])=[O:9]
Reactant: O=C(O)C(Oc1cccc(C(F)(F)F)c1)c1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)C(Oc1cccc(C(F)(F)F)c1)c1ccc(Cl)cc1

Procedure:
(3-Trifluoromethylphenoxy) (4-chlorophenyl)acetic acid (6.6 g., 0.02 mole) is placed in a 25 ml. 3-necked flask fitted with a condenser, stirrer and an addition of thionyl chloride (2.2 ml, 0.03 mole) over a 2-minute period at room temperature. The reaction mixture is refluxed for 5 hours and the solvent removed under vacuum to afford (3-trifluoromethylphenoxy) (4-chlorophenyl)acetyl chloride which is employed without purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:11]2[C:12]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19][C:13]=3[NH:14][C:15]=2[CH:16]=[CH:17][CH:18]=1.C([BH3-])#N.[Na+]>FC(F)(F)C(O)=O.CO.O>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:11]2[C@@H:12]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19][C@@H:13]3[NH:14][C:15]=2[CH:16]=[CH:17][CH:18]=1
Reactant: COc1ccccc1-c1cccc2[nH]c3c(c12)CCNCC3
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1-c1cccc2c1[C@@H]1CCNCC[C@@H]1N2
Temperature: 25 °C
Yield: 36 %

Procedure:
A 0° C. solution of 10-(2-methoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole hydrochloride from above (286 mg, 0.87 mmol) in trifluoroacetic acid (4 mL) was treated with a solution of sodium cyanoborohydride (278 mg 4.42 mmol) in methanol (1 mL). The reaction was allowed to slowly warm to room temperature over 3.8 hours then diluted with water and concentrated in vacuo to remove the majority of acid. The residue was made basic with 15% NaOH, extracted with CH2Cl2 dried over MgSO4 and concentrated in vacuo and passed through a column of silica gel with 1:19 methanol/chloroform with 1% NH4OH to give 91 mg (36%) of a white foam as the title compound: 1H NMR (400 MHz, Acetone-d6) δ 7.34-7.30 (m, 1H), 7.17 (dd, J=7.4 Hz, 1.7 Hz, 1H), 7.06 (d, J=8.3 Hz, 1H), 7.00-6.92 (m, 2H), 6.47 (d, J=7.7 Hz, 1H), 6.42 (d, J=7.6 Hz, 1H), 4.90 (br s, 1H), 4.19-4.14 (m, 1H), 3.78 (s, 3 H), 3.65-3.60 (m, 1H), 2.97-2.93 (m, 1H), 2.64-2.56 (m, 2H) 2.35-2.29 (m, 1H), 1.98-1.94 (m, 1H), 1.48-1.44 (m, 1H), 1.28-1.23 (m, 1H); HRMS (FAB) calcd for C19H22N2O1+H1 295.1810, found 295.1798.