Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=O)[O:28]C4C=CC=CC=4)[N:21]=3)[C:12]2=[O:36])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:37][NH:38][CH3:39]>O1CCCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=[O:28])[N:38]([CH3:39])[CH3:37])[N:21]=3)[C:12]2=[O:36])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(NC(=O)Oc4ccccc4)n3)C(C)(C)C2=O)cc1
Solvent: C1CCOC1
Product: CN(C)C(=O)Nc1nccc(CN2C(=O)N(c3ccc(C(C)(C)C)cc3)C(=O)C2(C)C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 70 mg of phenyl (4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]methyl}pyrimidin-2-yl)carbamate obtained in stage a) below in 3 mL of tetrahydrofuran is introduced, under argon, 0.71 mL of a 2M solution of dimethylamine in tetrahydrofuran. After stirring for one hour at room temperature, the reaction medium is concentrated under reduced pressure and the residue is purified by chromatography on a column of silica, eluting with a dichloromethane/acetonitrile/methanol mixture (98/1/1 by volume) to give 20 mg of 3-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]methyl}pyrimidin-2-yl)-1,1-dimethylurea in the form of a white powder, the characteristics of which are as follows:
Reaction SMILES: CC1(C)COB([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]3[CH2:18][O:17][CH2:16]3)=[CH:10][CH:9]=2)OC1.Br[C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][C:29]=1[Cl:30])[NH:26][CH:25]=[C:24]2[CH:31]=[O:32].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(OCC)(=O)C>[Cl:30][C:29]1[CH:28]=[C:27]2[C:23]([C:24]([CH:31]=[O:32])=[CH:25][NH:26]2)=[CH:22][C:21]=1[C:8]1[CH:9]=[CH:10][C:11]([O:14][CH:15]2[CH2:16][O:17][CH2:18]2)=[CH:12][CH:13]=1
Reactant: O=Cc1c[nH]c2cc(Cl)c(Br)cc12
Reactant: CC1(C)COB(c2ccc(OC3COC3)cc2)OC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=Cc1c[nH]c2cc(Cl)c(-c3ccc(OC4COC4)cc3)cc12
Temperature: 110 °C
Yield: 87.2 %

Procedure:
To a solution of 5,5-dimethyl-2-[4-(oxetan-3-yloxy)phenyl]-1,3,2-dioxaborinane (90 mg, 0.35 mmol) in ethanol (1.4 mL) was added 5-bromo-6-chloro-1H-indole-3-carbaldehyde (110 mg, 0.43 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (26 mg, 0.036 mmol), 2M aqueous potassium carbonate (0.7 mL, 1.4 mmol) and toluene (4 mL). The mixture was degassed with N2 for 3 min and heated to 110° C. by microwave irradiation for 1 h. The mixture was concentrated in vacuo to give a residue, which was dissolved with ethyl acetate (30 mL) and washed with brine (2×10 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo to give a residue, which was purified by flash chromatography on silica gel eluting with EtOAc/petroleum ether (1:10 to 1:1) to give 6-chloro-5-[4-(oxetan-3-yloxy)phenyl]-1H-indole-3-carbaldehyde (100 mg, 87%) as a colorless oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([CH:13]([OH:22])[C:14]#[C:15][CH2:16][N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O>CCOCC>[C:7]1([CH:13]([OH:22])[CH2:14]/[CH:15]=[CH:16]/[N:17]([CH2:18][CH3:19])[CH2:20][CH3:21])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCN(CC)CC#CC(O)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CCN(/C=C/CC(O)c1ccccc1)CC
Reaction time: 5 h

Procedure:
To an ethereal solution (1000 ml) of lithium aluminum hydride (57.0 g) was added a solution of N-(4-phenyl-4-hydroxy-2-butynyl)-N,N-diethylamine (164.05 g) in ether (500 ml) with stirring under ice-cooling for 1.5 hours, and then stirring was continued for 5 hours at room temperature. Water was added to the cooled reaction mixture in order to decompose excess lithium aluminum hydride. The precipitates were filtered, and the filtrate was evaporated and distilled to afford N-(4-phenyl-4-hydroxy-2-trans-butenyl)-N,N-diethylamine, b.p., 116°-120° C./0.12 mmHg.
Reaction SMILES: N[C:2]1[S:3][C:4]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[N:6]=1.NC(N)=S.[ClH:25].N([O-])=O.[Na+]>Cl[Cu].O.CC(O)=O>[Cl:25][C:2]1[S:3][C:4]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[N:6]=1
Reactant: CCOC(=O)c1sc(N)nc1-c1ccc([N+](=O)[O-])cc1
Reactant: Cl
Agent: Cl[Cu]
Agent: NC(N)=S
Agent: O=N[O-]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1sc(Cl)nc1-c1ccc([N+](=O)[O-])cc1
Reaction time: 0.17 h

Procedure:
Ethyl 2-chloro-p-nitrobenzoylacetate, obtained from ethyl p-nitrobenzoylacetate and sulfuryl chloride in accordance with the procedure of Balog et al, Studio. Univ. Bebes. Boylai., Vol. 1, No. 2, Page 155 (1960), was converted to ethyl 2-amino-4-p-nitrophenyl-5-thiazolecarboxylate with thiourea in accordance with a procedure in the above-mentioned publication. To a cooled (15° C.) solution of 10.0 g (0.0334 mole) of ethyl 2-amino-4-(p-nitrophenyl)-5-thiazolecarboxylate in 100 ml. of concentrated HCl and 100 ml. of glacial HOAc was added 7.0 g (0.101 mole) of NaNO2 in 15 minutes. The reaction mixture was stirred for 10 minutes and poured into a solution of 3.78 g (0.038 mole) of CuCl in 60 ml. of concentrated HCl. A slow gas evolution occurred which was accelerated when 50 ml. of water was added to the reaction mixture. The reaction mixture gradually turned yellow with precipitation of white solid. The precipitate was extracted with CHCl3. The CHCl3 solution was dried (MgSO4) and concentrated under reduced pressure. The residue was boiled with hot MeOH and filtered. The solid was recrystallized from acetone-chloroform to give 2.4 g of the desired product, m.p. 146°-148° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][C:11](Cl)=[N:12][OH:13])=[N:2]1.[NH3:15]>C(Cl)(Cl)Cl.C(O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][C:11](=[N:12][OH:13])[NH2:15])=[N:2]1
Reactant: N
Reactant: ON=C(Cl)Cc1noc2ccccc12
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: NC(Cc1noc2ccccc12)=NO
Reaction time: 0.5 h

Procedure:
In a mixture of chloroform (250 ml) and ethanol (250 ml) was dissolved 1,2-benzisoxazole-3-acetohydroximic chloride (0.5 g) and the mixture was saturated with ammonia by passing through thereto ammonia gas under ice-cooling. The mixture was allowed to stand for 0.5 hour and then the solvent was distilled off under a reduced pressure. To the residue was added chloroform and the insoluble substance was filtered off. The filtrate was distilled to remove the solvent and the residue was recrystallized from ethanol to give the desired compound (0.38 g). m.p. 161° to 163°C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11](Cl)(=[O:13])=[O:12].[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(C(C)C)CC)(C)C>ClCCl>[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[N:23]1[CH2:24][CH2:25][N:26]([S:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)(=[O:13])=[O:12])[CH2:27][CH2:28]1
Reactant: Fc1ccc(N2CCNCC2)c(F)c1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(c1ccc2ccccc2c1)N1CCN(c2ccc(F)cc2F)CC1
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a stirred solution of naphthalene-2-sulfonyl chloride (350 mg, 1.54 mmol) and 1-(2,4-difluorophenyl)piperazine (305.0 mg, 1.54 mmol) in anhydrous dichloromethane (5 mL) was added diisopropylethylamine (0.670 mL, 3.85 mmol). The mixture was stirred for 30 minutes. Reaction was complete as determined by TLC. The reaction mixture was purified via flash column chromatography to afford 1-(2,4-difluorophenyl)-4-(2-naphthylsulfonyl)piperazine in 55% yield (327 mg) as white solid.
Reaction SMILES: [NH2:1][C:2]1[C:9]([C:10]#[C:11][Si](C)(C)C)=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[Br:16].O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>O>[NH2:1][C:2]1[C:9]([C:10]#[CH:11])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[Br:16]
Reactant: C[Si](C)(C)C#Cc1cc(C#N)cc(Br)c1N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1cc(C#N)cc(Br)c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
To a mixture of 4-amino-3-bromo-5-[(trimethylsilyl)ethynyl]benzonitrile (0.80 g) and tetrahydrofuran (3.0 mL) was added a 1 M tetrabutyl ammonium fluoride-THF solution (3.0 mL) under ice-cooling, followed by stirring at room temperature for 0.5 hour. To the reaction mixture was added water under ice-cooling, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/hexane=30-50%) to obtain 4-amino-3-bromo-5-ethynylbenzonitrile (0.57 g).
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:11][C:10](=[O:12])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>C(Cl)Cl>[CH2:1]([C@@H:8]1[N:11]([Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C:10](=[O:12])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C[C@H](Cc2ccccc2)N1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)N1C(=O)C[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.7 %

Procedure:
To a solution of 4(S)-benzylazetidin-2-one (400 mg, 2.48 mmol) in CH2Cl2 (8 mL) was added DIEA (648 μL, 3.72 mmol), followed by tert-butyldimethylsilyl chloride (411 mg, 2.73 mmol). The reaction mixture was stirred for 16 h at room temperature. The CH2Cl2 was evaporated and the residue was purified by flash chromatography (SiO2, 12% EtOAc in hexane) to give 4(S)-benzyl-1-(tert-butyldimethylsilyl)azetidin-2-one (647 mg, 95% yield) as a white solid. 1H-NMR (400 MHz, CDCl3) δ7.34-7.15 (m, 5H), 3.77-3.70 (m, 1H), 3.25 (dd, J=13.5, 3.5 Hz, 1H), 2.99 (dd, J=15.5 Hz, 5 Hz, 1H), 2.70 (dd, J=15.5, 2.5 Hz, 1H), 2.59 (dd, J=13.5, 11 Hz, 1H), 1.01 (s, 9H), 0.31 (s, 3H), 0.29 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:18][C:17]([CH3:20])([CH3:19])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:21](NS(C)(=O)=O)=[O:22])[CH:15]=3)[NH:10]2)[CH:6]=[CH:7][CH:8]=1.[OH-:28].[Na+].O.Cl>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:18][C:17]([CH3:20])([CH3:19])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:21]([OH:22])=[O:28])[CH:15]=3)[NH:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: [OH-]
Reactant: COc1cccc(C2CC(C)(C)c3cc(C(=O)NS(C)(=O)=O)ccc3N2)c1
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1cccc(C2CC(C)(C)c3cc(C(=O)O)ccc3N2)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 90.4 %

Procedure:
A mixture of N-[2-(3-methoxy-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (1.0 g, 2.95 mmol), sodium hydroxide (0.59 g, 14.75 mmol), water (15 mL) in acetonitrile (30 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(3-methoxy-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (0.83 g, 90%) as a white solid which was used for next step without further purification: MS (ESI) M+1=312.2.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH:6]2[NH:11][C:12]([NH:14][C:15]2[C:19]([CH3:20])=[CH:18][S:17][CH:16]=2)=[NH:13])[O:4][CH2:3][CH2:2]1.[Cl:21]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:21][C:16]1[S:17][CH:18]=[C:19]([CH3:20])[C:15]=1[NH:14][C:12]([NH:11][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][C:5]21[O:1][CH2:2][CH2:3][O:4]2)=[NH:13]
Reactant: Cc1cscc1NC(=N)NC1CCCCC12OCCO2
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: Cc1csc(Cl)c1NC(=N)NC1CCCCC12OCCO2
Yield: 47.9 %

Procedure:
N-(1,4-Dioxaspiro[4.5]dec-6-yl)-N′-(4-methylthiophen-3-yl)guanidine (49 mg) was dissolved in glacial acetic acid (3 ml), and a solution of N-chlorosuccinimide (20.3 mg) in glacial acetic acid (5 ml) was added slowly. The mixture was stirred for a number of hours and then allowed to stand at room temperature over the weekend, after which the glacial acetic acid was removed under reduced pressure, the residue was taken up in water and the mixture was adjusted to pH 10 using 2N sodium hydroxide solution. The basic phase was extracted three times with ethyl acetate and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative chromatography and the product-containing fractions were combined, freed from acetonitrile, made basic and extracted three times with ethyl acetate. The organic phases were combined, dried (MgSO4) and filtered. Removal of the solvent under reduced pressure gave 24 mg of the desired product which was used directly for the next step.
Reaction SMILES: Cl.[CH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][N:7]([C:13]([O:15][C@@H:16]1[CH2:20][C@@H:19]([C:21]([O:23][CH3:24])=[O:22])[NH:18][CH2:17]1)=[O:14])[CH2:8]2)=[CH2:3].[CH3:25][C:26]([CH3:44])([CH2:40][CH2:41][CH:42]=[CH2:43])[CH2:27][O:28][C:29]([NH:31][C@H:32]([C:37](O)=[O:38])[C:33]([CH3:36])([CH3:35])[CH3:34])=[O:30].CCN(C(C)C)C(C)C.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C.CCOCC>[CH3:25][C:26]([CH3:44])([CH2:40][CH2:41][CH:42]=[CH2:43])[CH2:27][O:28][C:29]([NH:31][C@H:32]([C:37]([N:18]1[CH2:17][C@H:16]([O:15][C:13]([N:7]2[CH2:6][C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH:2]=[CH2:3])[CH2:8]2)=[O:14])[CH2:20][C@H:19]1[C:21]([O:23][CH3:24])=[O:22])=[O:38])[C:33]([CH3:34])([CH3:35])[CH3:36])=[O:30]
Reactant: C=CCCC(C)(C)COC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: C=Cc1cccc2c1CN(C(=O)O[C@H]1CN[C@H](C(=O)OC)C1)C2
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOCC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: C=CCCC(C)(C)COC(=O)N[C@H](C(=O)N1C[C@H](OC(=O)N2Cc3cccc(C=C)c3C2)C[C@H]1C(=O)OC)C(C)(C)C
Yield: 50.7 %

Procedure:
To a solution of (3R,5S)-5-(methoxycarbonyl)pyrrolidin-3-yl 4-vinyl-1,3-dihydro-2H-isoindole-2-carboxylate hydrochloride (5.0 g, 14.2 mmol) and N-{[(2,2-dimethylhex-5-enyl)oxy]carbonyl}-3-methyl-L-valine (4.0 g, 14.2 mmol) in DMF (20 ml) at RT was added DIPEA (2.5 mL, 14.2 mmol), EDC (5.5 g, 28.4 mmol), and HOAt (1.9 g, 14.2 mmol). After 18 h the reaction mixture was poured into Et2O, and extracted with 1 N HCl. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with 1 N HCl, water, NaHCO3, and brine. The organic layer was dried over MgSO4 and the solvent was removed in vacuo. The crude product was purified on silica (30% EtOAc in hexanes) to yield 4.2 g of the title compound as a thick oil. LRMS (ESI) m/z 584.4 [(M+H)+; calcd for C32H46N3O7: 584.3].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[CH:14][CH:13]=[N:12][C:11]=2[NH:16][C@@H:17]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(N[C:32](=[O:50])[C:33]2C=CC=NC=2NC2CC(C)(C)NC(C)(C)C2)C=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[CH:14][CH:13]=[N:12][C:11]=2[NH:16][C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([CH2:33][CH2:32][OH:50])[CH2:18]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(Nc2ncccc2C(=O)Nc2cccc(Cl)c2)CC(C)(C)N1
Reactant: O=C(Nc1cccc(Cl)c1)c1cccnc1N[C@@H]1CCCNC1
Product: O=C(Nc1cccc(Cl)c1)c1cccnc1N[C@@H]1CCCN(CCO)C1
Yield: 64.7 %

Procedure:
The title compound was prepared in the same manner as in Example 21, with the exception that (R)—N-(3-chlorophenyl)-2-(3-piperidylamino)nicotinamide of Example 20-A, instead of N-(3-chlorophenyl)-2-(2,2,6,6-tetramethylpiperidin-4-ylamino)nicotinamide, was used in the same molar amount (Yield: 64.7%). 1H NMR (CDCl3) δ 8.48 (br, 1H), 8.40 (s, 1H), 8.17 (d, 1H), 7.76 (d, 1H), 7.59 (s, 1H), 7.42 (d, 1H), 7.19 (t, 1H), 7.03 (d, 1H), 6.48-6.40 (m, 1H), 4.35-4.23 (m, 1H), 3.61 (t, 2H), 3.13 (br, 2H), 2.69 (d, 1H), 2.60-2.36 (m, 4H), 1.85-1.58 (m, 3H) ppm.
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=O)[CH2:5][CH2:4]1)#[N:2].S(Cl)([Cl:14])=O>ClCCl>[C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([Cl:14])=[O:11])[CH2:5][CH2:4]1)#[N:2]
Reactant: O=S(Cl)Cl
Reactant: N#C[C@H]1CC[C@H](C(=O)O)CC1
Solvent: ClCCl
Product: N#C[C@H]1CC[C@H](C(=O)Cl)CC1
Temperature: 38 °C

Procedure:
To a solution of trans-4-cyanocyclohexanecarboxylic acid (1.29 g, 8.42 mmol) in dichloromethane (7.7 mL) was added thionyl chloride (2.0 M in dichloromethane, 10.11 mL, 20.21 mmol) and the reaction was heated at 38° C. overnight. Then, the reaction was concentrated to afford trans-4-cyanocyclohexanecarbonyl chloride that was used in the next step without further purification.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>C(O)C>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:10][OH:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(CO)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 10.42 g (47.3 mmol) of 3-cyclopentoxy-4-methoxybenzaldehyde in 100 mL of absolute ethanol was added 0.9 g (23.8 mmol) of sodium borohydride in one portion. The mixture was stirred for 1 hour at room temperature after which time the reaction was quenched with excess acetic acid, concentrated and azeotroped to dryness three times with 25 mL portions of toluene. The residue was dissolved in 100 mL of chloroform, washed with two, 25 mL portions of saturated sodium chloride, dried over magnesium sulfate, and concentrated to dryness. Liquid chromatography of the crude oil over 200 g of silica gel with 10% ethyl acetate in hexane provided an analytically pure oil after drying in vacuo.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[C:13]([N+:16]([O-])=O)[CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=[O:5].[H][H]>CO.[Pd]>[CH3:21][N:2]([CH2:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[C:13]([NH2:16])[CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:1]
Reactant: [H][H]
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CN(C)C)CCC2
Agent: [Pd]
Solvent: CO
Product: COc1cc2c(cc1N)N(C(=O)CN(C)C)CCC2
Yield: 74.7 %

Procedure:
N,N-dimethyl-2-[6-(methyloxy)-7-nitro-3,4-dihydro-1(2H)-quinolinyl]-2-oxoethanamine (crude from previous reaction, assumed 0.91 mmol) was dissolved in methanol (5 mL), treated with 10% palladium on carbon (40 mg, Aldrich), and stirred under 60 psi of hydrogen pressure for 16 h in a Fischer-Porter apparatus. The pressure was released, the reaction vessel evacuated, and back-filled with nitrogen twice. The mixture was filtered through celite, the filtrate was concentrated and purified by chromatography on SiO2 (0 to 20% methanol/dichloromethane) to provide 1-[(dimethylamino)acetyl]-6-(methyloxy)-1,2,3,4-tetrahydro-7-quinolinamine (0.18 g, 0.68 mmol, 75% over three steps). 1H NMR (400 MHz, CDCl3) δ ppm 1.88-1.97 (m, J=6.5, 6.5, 6.5, 6.5 Hz, 2 H), 2.35 (s, 6 H), 2.65 (m, 2 H), 3.24 (s, 2 H), 3.74-3.80 (m, 2 H), 3.84 (s, 3 H), 6.55 (s, 1 H), 6.76 (very broad singlet due to amide rotomers, 1 H), aniline NH2 not visible probably due to fast exchange.
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)([CH3:5])[CH2:3][OH:4].CCN(CC)CC.[CH:19]([N:22]1[C:26]([C:27]2[N:36]=[C:35]3[N:29]([CH2:30][CH2:31][O:32][C:33]4[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][C:34]=43)[CH:28]=2)=[N:25][CH:24]=[N:23]1)([CH3:21])[CH3:20]>C(Cl)Cl>[CH:19]([N:22]1[C:26]([C:27]2[N:36]=[C:35]3[C:34]4[CH:37]=[C:38]([S:41]([N:9]5[CH2:8][CH2:7][N:6]([C:2]([CH3:1])([CH3:5])[CH2:3][OH:4])[CH2:11][CH2:10]5)(=[O:43])=[O:42])[CH:39]=[CH:40][C:33]=4[O:32][CH2:31][CH2:30][N:29]3[CH:28]=2)=[N:25][CH:24]=[N:23]1)([CH3:21])[CH3:20]
Reactant: CC(C)(CO)N1CCNCC1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)Cl)ccc1OCC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)N3CCN(C(C)(C)CO)CC3)ccc1OCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.9 %

Procedure:
To a solution of 2-methyl-2-piperazin-1-ylpropan-1-ol (71 mg, 0.45 mmol) and NEt3 (105 μL, 0.75 mmol) in DCM (10 mL) at 0° C. was added 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene-9-sulfonyl chloride from Example 121 (97 mg, 0.15 mmol) and the resulting mixture warmed to RT after 10 min then stirred for 16 h. The reaction mixture was washed with a saturated aqueous NaHCO3 solution then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-10% MeOH in DCM then C18, gradient 10-40% MeOH in H2O). The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH then freeze-dried from MeCN/H2O to afford 138 (20 mg, 26%) as a white solid. LCMS: RT 2.86 min [M+H]+ 516.4. 1H NMR (CDCl3, 400 MHz): δ 8.95 (1H, d, J=2.37 Hz), 7.88 (1H, s), 7.69 (1H, s), 7.64 (1H, dd, J=8.60, 2.40 Hz), 7.19 (1H, d, J=8.61 Hz), 5.86-5.84 (1H, m), 4.62-4.57 (2H, m), 4.54-4.50 (2H, m), 3.28-3.11 (6H, m), 2.69 (4H, brd s), 1.60 (6H, d, J=6.63 Hz), 1.03 (6H, brd s)
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[CH2:26][O:27][C:28]([CH3:53])([CH3:52])[C:29]([F:51])([F:50])[C@:30]([C:33]3[CH:38]=[C:37]([C:39]4[O:40][C:41]5[CH:47]=[C:46]([Cl:48])[CH:45]=[CH:44][C:42]=5[N:43]=4)[CH:36]=[CH:35][C:34]=3[F:49])([CH3:32])[N:31]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.FC(F)(F)C(O)=O.Cl>C(OCC)C>[ClH:48].[Cl:48][C:46]1[CH:45]=[CH:44][C:42]2[N:43]=[C:39]([C:37]3[CH:36]=[CH:35][C:34]([F:49])=[C:33]([C@:30]4([CH3:32])[C:29]([F:50])([F:51])[C:28]([CH3:53])([CH3:52])[O:27][CH2:26][C:25]([NH2:24])=[N:31]4)[CH:38]=3)[O:40][C:41]=2[CH:47]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(-c4nc5ccc(Cl)cc5o4)ccc3F)C(F)(F)C(C)(C)OC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)OCC(N)=N[C@](C)(c2cc(-c3nc4ccc(Cl)cc4o3)ccc2F)C1(F)F
Yield: 131.5 %

Procedure:
In a manner analogous to that described in Example 18b), the treatment of [bis-(4-methoxy-phenyl)-phenyl-methyl]-{(R)-5-[5-(6-chloro-benzo oxazol-2-yl)-2-fluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl}-amine (38 mg, 51.3 μmol) with trifluoro acetic acid (40 μl, 513 μmol), treatment with hydrochloric acid and followed by trituration with diethyl ether yielded the (R)-5-[5-(6-chloro-benzooxazol-2-yl)-2-fluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-ylamine hydrochloride (16 mg, 66% yield) as an off-white solid. MS (ISP): m/z=438.2 [M+H]+ and 440.3 [M+2+H]+.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:27]=[CH:28][C:29](=[O:32])[CH:30]=[CH:31][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C(O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:27]=[CH:28][C:29](=[O:32])[CH:30]=[CH:31][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(=O)ccc2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1nc2ccc(=O)ccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
An aliquot of the methyl ester from Step (n) (200 mg) was hydrolyzed by stirring it in a mixture of 5 ml of 10° sodium hydroxide and 5 ml ethanol for 4 hr at 25° C. and 1 hr at 100° C. The azeotrope was distilled off, water (10 ml) was added and the resulting solution slowly acidified to pH 2.5 with 2N HCl. The resulting precipitated acid was isolated (60 mg).