Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH:15]=[N:14][N:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].[Cl-].[NH4+].Cl.C[N:20](C)CCCN=C=NCC.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH:15]=[N:14][N:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([NH2:20])=[O:8]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cc(Cl)ccc1-n1cnnn1
Agent: Cl
Agent: On1nnc2cccnc21
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cc(Cl)ccc1-n1cnnn1
Yield: 115.6 %

Procedure:
A solution of 5-chloro-2-(1H-tetraazol-1-yl)benzoic acid (2.0 g, 8.9 mmol), ammonium chloride (0.95 g, 17.8 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.4 g, 17.8 mmol), HOAt (2.4 g, 17.8 mmol) and DIEA (6.2 mL, 35.6 mmol) in DMF (26 mL) was stirred at room temperature overnight. Water was added and the reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with brine. Drying and solvent evaporation gave 5-chloro-2-(1H-tetrazol-1-yl)benzamide (2.3 g); 1H NMR (400 MHz, CD3OD): δ 9.44 (s, 1H), 7.82 (d, J=2.3 Hz, 1H), 7.75 (dd, J=2.3, 8.5 Hz, 1H), 7.66 (d, J=8.5 Hz, 1H).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:31])[C@@H:6]([O:11][C@H:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:13]1[CH:18]=[CH:17][C:16]([C:19]#[C:20][Si](C)(C)C)=[CH:15][CH:14]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])#[N:2].CO>C1COCC1.CC(O)=O.[Na]>[C:1]([CH2:3][NH:4][C:5](=[O:31])[C@@H:6]([O:11][C@@H:12]([C:13]1[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][CH:14]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])#[N:2]
Reactant: CC(C)C[C@H](O[C@H](c1ccccc1)c1ccc(C#C[Si](C)(C)C)cc1)C(=O)NCC#N
Agent: [Na]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: C#Cc1ccc([C@H](O[C@@H](CC(C)C)C(=O)NCC#N)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of (2S)-N-(cyanomethyl)-4-methyl-2-[((R)-phenyl{4-[(trimethylsilyl)ethynyl]phenyl}methyl)oxy]pentanamide from example 70 (0.12 mmol, 50 mg) in THF:MeOH (1.3 mL: 50 uL) at 0° C., AcOH (3 drops) was added followed by tetrabutylammonium triphenyldifluorosilicate (0.01 mmol, 7 mg). The mixture was stirred 20 minutes at 0° C. The mixture was diluted with 1% sodium hydroxyde (3 mL) and diethlyl ether (5 mL). The phases were separated. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. Purification: 30:70 (AcOEt:Hex.) gave the title amide.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][C:21]2[C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[S:26][C:20]=2[CH2:19]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C1COCC1>[OH:2][CH2:3][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][C:21]2[C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[S:26][C:20]=2[CH2:19]1
Reactant: COC(=O)c1ccc2[nH]cc(CCCCN3CCc4c(sc5ccccc45)C3)c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc2[nH]cc(CCCCN3CCc4c(sc5ccccc45)C3)c2c1
Reaction time: 1 h

Procedure:
A solution of 4.18 g of 2-[4-(5-methoxycarbonyl-3-indolyl)butyl]-1,2,3,4-tetrahydrobenzothieno[2,3-c]pyridine in 40 ml of THF is added dropwise to a stirred suspension of 0.57 g of lithium aluminium hydride in 20 ml of THF at 20° under N2. The mixture is stirred at 20° for 1 hour, and decomposition is carried out with dilute sodium hydroxide solution and then with water, and the mixture is filtered, the usual working up is carried out on the filtrate, and 2-[4-(5-hydroxymethyl-3-indolyl)butyl]-1,2,3,4-tetrahydrobenzothieno[2,3-c]pyridine is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]([N:16]([CH3:18])[CH3:17])[C:13](=[O:15])[CH3:14])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+].S(=O)(=O)(O)O.Cl>C(O)C.CC(O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH:12]([N:16]([CH3:17])[CH3:18])[CH:13]([OH:15])[CH3:14])[CH2:9][CH2:10][CH2:11]2)=[CH:6][CH:7]=1
Reactant: CC(=O)C(N(C)C)C1(c2ccc(Cl)cc2)CCC1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [BH4-]
Solvent: CC(C)O
Solvent: CCO
Product: CC(O)C(N(C)C)C1(c2ccc(Cl)cc2)CCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 1-[1-(4-chlorophenyl)cyclobutyl]-1-dimethylaminopropan-2-one (1.9 g prepared as described in Example 47) in ethanol (10 ml) was added dropwise to a suspension of sodium borohydride (0.4 g) in ethanol (20 ml) and the mixture was stirred for 4 hours at ambient temperature. 5N Sulphuric acid (10 ml) was added and then the acidified mixture was basified. The resulting mixture was extracted with ether and the ether extracts were washed with water and dried. Removal of the solvent gave an oil which was converted into a hydrochloride salt by treatment with a mixture of excess concentrated hydrochloric acid and propan-2-ol. The residue after the removal of the solvents were dried by azeotropic distillation with propan-2-ol to give 1-[1-(4-chlorophenyl)cyclobutyl]-1-dimethylaminopropan-2-ol hydrochloride (m.p. 255° C.).
Reaction SMILES: [Na].[F:2][C:3]1[CH:4]=[C:5](/[CH:9]=[C:10](\[C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)/[C:11](OCC)=[O:12])[CH:6]=[CH:7][CH:8]=1.Cl.[NH2:23][C:24]([NH2:26])=[NH:25]>C(O)C>[NH2:25][C:24]1[NH:26][C:11](=[O:12])[C:10]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([F:2])[CH:4]=2)[N:23]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)/C(=C/c1cccc(F)c1)c1ccncc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Nc1nc(-c2cccc(F)c2)c(-c2ccncc2)c(=O)[nH]1
Reaction time: 2 h
Yield: 43.9 %

Procedure:
Sodium (3.4 g, 147 mmol) was dissolved in ethanol (500 ml), and then ethyl (E)-3-(3-fluorophenyl)-2-(4-pyridyl)-2-propenoate (33 g, 121 mmol) and guanidine hydrochloride (13.9 g, 146 mmol) were added thereto, followed by heating under reflux for 13 hours. After cooling as it was, the solvent was removed. Tetrahydrofuran (500 ml) was added to the residue, the insoluble matters were filtered off, and the filtrate was concentrated. To a solution of the residue in tetrahydrofuran (1500 ml)-methanol (100 ml) was added active manganese dioxide (250 g), followed by heating under reflux. After 2 hours, additional active manganese dioxide (100 g) was added thereto, followed by heating under reflux further for 1 hour and 15 minutes. After cooling as it was, the manganese dioxide was filtered off through Celite and washed with tetrahydrofuran and methanol. The collected filtrate was concentrated and acetonitrile was added to the residue. The resulting precipitates were collected by filtration, to give the title compound (15 g, 44%) as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[CH:12]1(O)[CH2:16][CH2:15][CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:4]([Cl:11])[N:3]=1
Reactant: OC1CCCC1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Temperature: 0 °C
Reaction time: 60 h

Procedure:
Dissolve 2,6-dichloropurine (1, 680 mg, 3.60 mmol), cyclopentanol (2a, 260 mg, 3.02 mmol), and triphenyl phosphine (950 mg, 3.60 mmol) in dry THF (20 mL) and cool to 0° C. Add diethyl azodicarboxylate (DEAD, 570 μL, 3.60 mmol) dropwise over a period of 15 minutes under a nitrogen atmosphere. Stir the resulting solution for 60 hours at room temperature. Evaporate the solvent in vacuo, charge directly onto a 500 g silica gel column, and elute with DCM and concentrate the desired fractions to give 2,6-dichloro-9-cyclopentyl-9H-purine (3a).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:12][C:11]=2[F:20])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[CH:29]=[N:30][NH:31][CH:32]=2)[N:23]=1>>[F:20][C:11]1[CH:12]=[C:13]([C:16]([OH:19])([CH3:17])[CH3:18])[CH:14]=[CH:15][C:10]=1[C:4]1[S:3][C:2]([NH:1][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]3[CH:29]=[N:30][NH:31][CH:32]=3)[N:23]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: Brc1cccc(-c2cn[nH]c2)n1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(-c4cn[nH]c4)n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (77 mg, 0.26 mmol) and 2-bromo-6-(1H-pyrazol-4-yl)pyridine (59 mg, 0.262 mmol) as starting materials.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[CH2:15][CH2:14][C:13]1([CH3:19])[C:16]([OH:18])=O)=[O:11].C1COCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:47][C:48]1[CH:55]=[CH:54][C:51]([CH2:52][NH2:53])=[CH:50][CH:49]=1>CN(C=O)C>[CH3:47][C:48]1[CH:55]=[CH:54][C:51]([CH2:52][NH:53][C:16]([C:13]2([CH3:19])[CH2:14][CH2:15][N:12]2[C:10](=[O:11])[CH2:9][C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[O:18])=[CH:50][CH:49]=1
Reactant: Cc1ccc(CN)cc1
Reactant: CC1(C(=O)O)CCN1C(=O)Cc1ccc(Cl)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc(CNC(=O)C2(C)CCN2C(=O)Cc2ccc(Cl)cc2Cl)cc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-[2-(2,4-dichloro-phenyl)-acetyl]-2-methyl-azetidine-2-carboxylic acid, Intermediate 120 (1 eq.) in either THF or DMF was added TEA (4 eq.) and TBTU (2 eq.). The reaction was stirred at 20° C. for 30 min, then 4-methyl-benzylamine (1.5 eq.) was added. The reaction was stirred at 20° C. for 72 h. The crude was concentrated under reduced pressure then partitioned between water and EtOAc. The organic layer was washed twice with water, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by preparative LCMS to afford 1-[2-(2,4-dichloro-phenyl)-acetyl]-2-methyl-azetidine-2-carboxylic acid 4-methyl-benzylamide.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:5])[CH3:4].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14]Cl)=[CH:9][CH:8]=1.O>[Au].C1(C)C=CC=CC=1>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:1][CH2:2][CH:3]([OH:5])[CH3:4])=[CH:9][CH:8]=1
Reactant: CC(O)CN
Reactant: ClCCc1ccc(Cl)cc1
Agent: [Au]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(O)CNCCc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Into a 5-L jacketed reactor equipped with a chiller, overhead stirring, an anchor impeller, a thermocouple, a glycol condenser, and a nitrogen inlet vented to a caustic scrubber, was charged 1-aminopropan-2-ol (1102 mL, 14.3 mol). The reactor contents were heated to 80° C. and 1-chloro-4-(2-chloroethyl)benzene (Method 4, Step A, 500 g, 2856 mmol) was slowly charged over 40 min. The temperature of the gold-colored reaction mixture reached 97° C. during the addition and 101° C. approximately 1 min after addition was complete. The mixture was then allowed to cool to 90 to 95° C. and stirring was continued at that temperature for 2 h. Water (500 mL) and toluene (1000 mL) were added and the mixture was stirred at 75 to 80° C. for 15 min. The layers were allowed to separate at 70 to 75° C. The organic phase was removed and the aqueous phase was extracted with toluene at 70 to 75° C. for 15 min (2×500 mL). The combined organic phases were washed with water at 70 to 75° C. for 15 min (2×500 mL) and stirred overnight under nitrogen at 50° C. The solution was concentrated by distillation at 60° C. (jacket) under reduced pressure, and the residue was diluted with toluene to a total volume of about 800 mL. This solution was distilled a second time at 65° C. (jacket) under reduced pressure and the residue was diluted with toluene to a total volume of about 400 mL. The water content of the solution was 0.03% by Karl Fisher titration.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:15])[O:4][CH2:5][C@H:6]([NH2:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CS(O)(=O)=O.[O-:21][C:22]#[N:23].[Na+].[OH-].[Na+].Cl>ClCCl.C(OCC)C.O>[NH2:23][C:22]([CH2:1][NH:2][C:3](=[O:15])[O:4][CH2:5][C@H:6]([NH2:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:21]
Reactant: N#C[O-]
Reactant: CNC(=O)OC[C@H](N)Cc1ccccc1
Agent: CS(=O)(=O)O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: ClCCl
Product: NC(=O)CNC(=O)OC[C@H](N)Cc1ccccc1
Reaction time: 24 h

Procedure:
(2R)-2-amino-3-phenylpropyl methylcarbamate (11.932 mmol) was dissolved in dichloromethane and methansulfonic acid (3.1 ml, 4 eq) and sodium cyanate (5.39 g, 3 eq) was added in an ice bath. The resulting reaction mixture was stirred for 1 day. Water was added to terminate the reaction and the reaction mixture was basicified to pH8-9 with 1N NaOH solution. The organic layer was extracted 3 times with dichloromethane, dried over magnesium sulfate and concentrated in vacuo, to give oil. This was dissolved in dichloromethane and the solution was treated with a solution of HCl in ethyl ether. The resulting precipitate was filtered to give (2R)-2-amino-3-phenylpropyl (aminocarbonyl)methylcarbamate; hydrochloride
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[C:7]([NH:9][C:10]1([C:13]([O:15]CC)=[O:14])[CH2:12][CH2:11]1)=[O:8])([O-:3])=[O:2].[OH-].[Na+].Cl>C(O)C.O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[C:7]([NH:9][C:10]1([C:13]([OH:15])=[O:14])[CH2:12][CH2:11]1)=[O:8])([O-:3])=[O:2]
Reactant: CCOC(=O)C1(NC(=O)c2cccc([N+](=O)[O-])c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(NC1(C(=O)O)CC1)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To the solution of ethyl 1-(3-nitrobenzamido)cyclopropanecarboxylate (0.5 g, 1.797 mmol) in ethanol 10 ml, sodium hydroxide (aq) (5 ml, 25.00 mmol) was added and stirred at room temperature for 10 hr. Reaction mixture was diluted with water (20 ml), and acidified by adding 5N HCl. Obtained white precipitates were filtered. The residue was dried by azetrope with toluene (0.38 g, 85%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C@@H:9]([OH:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:20]I>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C@@H:9]([O:17][CH3:20])[CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:3]=1
Reactant: O[C@@H](Cc1ccccc1)Cc1cccc(Br)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@@H](Cc1ccccc1)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
To a solution of 1-(3-bromophenyl)-3-phenyl-2(S)-propanol (365 mg, 1.25 mmol) in 15 mL of anhydrous THF was added NaH (70% dispersion in mineral oil, 100 mg, 2.9 mmol, 2.3 equiv.) at 0° C. under N2. The mixture was warmed to room temperature and stirred for 30 min, then CH3I (1.75 g, 12.3 mmol, 9.8 equiv.) was added at room temperature. The mixture was stirred overnight at room temperature. The reaction was quenched with saturated aqueous NH4Cl solution, and the mixture was extracted with EtOAc (3×50 mL). The combined organic phases were washed with brine and dried over Na2SO4. After filtration and concentration, the residue was purified by CC on silica gel with EtOAc/petroleum ether 1:20 to provide the methyl ether (300 mg, 78%) as a yellow oil. LC-MS (ESI) m/z 306 (M+H+).
Reaction SMILES: [C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:20]3=[CH:19][CH:18]=[CH:17][C:16]=5[OH:23])=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH2:32][Cl:33]>CN(C=O)C>[Cl:33][CH2:32][CH2:31][O:23][C:16]1[C:15]2[C:14]3[C:22]4=[C:10]([O:9][CH2:8][CH:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[N:21]4[C:20]=2[CH:19]=[CH:18][CH:17]=1)[CH:11]=[CH:12][CH:13]=3
Reactant: Oc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClCCOc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Temperature: 85 °C
Yield: 93.8 %

Procedure:
To a mixture of 1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-ol (3.0 g 9.96 mmol) and potassium carbonate (6.9 g, 50 mmol) in dry DMF (70 mL) is added 1-bromo-2-chloroethane (4.0 mL, 50 mmol). The mixture is heated to 85° C. for 8.25 h. The mixture is then partitioned between water and Et2O. The organic layer is separated and washed three times with water (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (200 mL silica) using CH2Cl2/hexanes (1/1) as eluent gave 3.4 g (94%) of 7-(2-chloroethoxy)-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazole.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7][CH:8]=[C:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1>[Pd].C(OCC)(=O)C>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7][CH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]2[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=2)[CH2:13][CH2:14]1
Reactant: CCOC(=O)c1ccc(N2CCC(=CCC3OCCCO3)CC2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(N2CCC(CCC3OCCCO3)CC2)cc1

Procedure:
A mixture of Example 199A (1.2 g, 3.6 mmol), Pd/C (0.42 g), and ethyl acetate (25 mL) was hydrogenated at 4 atmospheres in a Parr shaker at room temperature for 3 days. The catalyst was removed by filtration, solvent was evaporated, and the crude product was purified by flash column chromatography on silica gel with 30% ethyl acetate/hexanes to provide the desired product. MS(DCI) m/e 348 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([NH2:12])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]1(=O)[O:18][C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12>C(O)(=O)C.O>[C:1]1([C:7]2[CH:11]=[C:10]([N:12]3[C:16](=[O:17])[C:15]4[C:14](=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:13]3=[O:18])[NH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1cc(-c2ccccc2)n[nH]1
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1c1cc(-c2ccccc2)n[nH]1
Temperature: 120 °C
Yield: 91 %

Procedure:
A mixture of 3-phenyl-1H-pyrazol-5-amine (6 g, 0.038 mol), phthalic anhydride (5.6 g, 0.038 mol) in acetic acid (60 mL) was heated at 100° C. for 2 h and at 120° C. for 2 h and cooled to room temperature. The reaction mixture was diluted with water and the suspension was filtered. The collected solid was washed with water, dried, yielding the title compound as a solid (10 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]2[CH2:13][N:14]([C:16]3[CH:17]=[N:18][CH:19]=[C:20]([CH:24]=3)[C:21]([OH:23])=O)[CH2:15][C@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:31]=[C:32]([O:34][CH3:35])[CH:33]=1)[NH2:30]>>[CH3:35][O:34][C:32]1[CH:31]=[C:29]([NH:30][C:21]([C:20]2[CH:24]=[C:16]([N:14]3[CH2:13][C@@H:11]4[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C@@H:10]4[CH2:15]3)[CH:17]=[N:18][CH:19]=2)=[O:23])[CH:28]=[C:27]([O:26][CH3:25])[CH:33]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)O)c3)C[C@@H]2C1
Reactant: COc1cc(N)cc(OC)c1
Product: COc1cc(NC(=O)c2cncc(N3C[C@H]4CN(C(=O)OC(C)(C)C)C[C@H]4C3)c2)cc(OC)c1

Procedure:
The product from Example 33B and 3,5-dimethoxyaniline were processed as described in Example 33C to provide the title compound. MS (APCI) m/z 469 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[C:7]2[S:9][C:10]3[CH2:11][N:12]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:13][CH2:14][C:15]=3[C:6]2=[C:5]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=2)[C:4]=1[Cl:33].[C:34](OC(=O)C)(=[O:36])[CH3:35]>N1C=CC=CC=1>[C:34]([NH:1][CH2:2][C:3]1[N:8]=[C:7]2[S:9][C:10]3[CH2:11][N:12]([CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:13][CH2:14][C:15]=3[C:6]2=[C:5]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=2)[C:4]=1[Cl:33])(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(-c2c(Cl)c(CN)nc3sc4c(c23)CCN(Cc2ccccc2)C4)cc1OC
Solvent: c1ccncc1
Product: COc1ccc(-c2c(Cl)c(CNC(C)=O)nc3sc4c(c23)CCN(Cc2ccccc2)C4)cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of the compound (0.3 g) obtained in Example 18B, acetic anhydride (0.142 g) and pyridine (2.5 ml) was stirred at room temperature for 1 hour and concentrated under reduced pressure. Ethyl acetate was added to the residue, which was washed with water, dried (MgSO4) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate to yield 2-acetylaminomethyl-7-benzyl-3-chloro-4-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydrothieno[2,3-b:5,4-c']dipyridine as an oil, which was then treated with ethanolic hydrochloride to yield the hydrochloride which was recrystallized from dichloromethane-ethyl ether to yield light-yellow powder having a melting point of 172 to 174° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][C:13]3[C:19]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=[CH:28][C:27]=1[CH:36]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[S:12][C:13]3[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH2:36][C:27]5[CH:28]=[N:29][C:30]6[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=6)[N:26]=5)[CH2:22][CH2:21]4)=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1cnc2ccccc2n1
Reactant: CC(C)(C)c1ccc(-c2nc3cccc(N4CCNCC4)c3s2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)c1ccc(-c2nc3cccc(N4CCN(Cc5cnc6ccccc6n5)CC4)c3s2)cc1
Temperature: 25 °C
Yield: 55 %

Procedure:
The piperazine template (0.075 g, 0.213 mmol) of Example 24 was dissolved in 1,2-dichloroethane (3 mL) and treated with quinoxaline-2-carbaldehyde (0.044 g, 0.277 mmol) and glacial acetic acid (2 drops). Sodium triacetoxyborohydride (0.090 g, 0.426 mmol) was added, and the mixture was stirred at room temperature until the reaction was complete by LCMS analysis. The solvent was removed under reduced pressure, and the resulting residue was purified by RP-HPLC to yield the free base (0.0578 g, 55% yield). MS (ESI) m/z 494.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH2:8][CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([CH:17]=[O:18])[CH2:13][CH2:12]2)[CH:5]=[CH:6][N:7]=1.[Mn]([O-])(=O)(=O)=[O:20].[K+]>CC(C)=O>[C:2]([C:3]1[N:4]([CH2:8][CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([CH:17]=[O:18])[CH2:13][CH2:12]2)[CH:5]=[CH:6][N:7]=1)([OH:20])=[O:1]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O=CN1CCC(CCCn2ccnc2CO)CC1
Agent: [K+]
Solvent: CC(C)=O
Product: O=CN1CCC(CCCn2ccnc2C(=O)O)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
The solution of 4-[3-(2-hydroxymethyl-1H-imidazol-1-yl)propyl]-1-piperidine carboxaldehyde in acetone (63 ml) was cooled to 0° C. and potassium permanganate (5.5 g, 0.035M) was added portionwise. After complete addition, the reaction was stirred at 0° C. for 2 hrs. The acetone solution was separated by filtration, and the residue was stirred twice with water (50 ml). The aqueous solution was freeze dried to yield 4-[3-(2-carboxy-1H-imidazol-1-yl)propyl]-1-piperidine carboxaldehyde (5.5 g, 83% yield). This product (7.1 g, 0.027M) in water (26 ml) and 1N NaOH (26 ml) was heated at 100° C. for 5 hrs. The reaction was adjusted pH 6 and purified on ion-exchange column (Bio-Rex 70) eluted with 0.01N, 0.02N, 0.04N, 0.08N and 0.1N HCl solution successively to give 1-[3-(4 -piperidinyl)propyl]-1H-imidazole-2-carboxylic acid 1.75 molar hydrochloride 0.65 molar hydrate (4.6 g, 73% yield).