Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]2[C:7]3[CH2:8][CH2:9][CH2:10][NH:11][C:12]=3[CH2:13][CH2:14][C:5]=2[CH:4]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>N1C=CC=CC=1>[C:17]([N:11]1[C:12]2[CH2:13][CH2:14][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:16]=[CH:15][C:6]=3[C:7]=2[CH2:8][CH2:9][CH2:10]1)(=[O:19])[CH3:18]
Reactant: COc1ccc2c(c1)CCC1=C2CCCN1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1ccc2c(c1)CCC1=C2CCCN1C(C)=O
Reaction time: 20 h

Procedure:
A mixture of 4.70 g of 8-methoxy-1,2,3,4,5,6-hexahydrobenzo[f]-quinoline in 15 ml of pyridine and 11 ml of acetic anhydride is left to stand at room temperature for 20 hours and evaporated. The residue remaining behind is taken up twice in 50 ml of dry toluene each time and the solutions obtained are evaporated to dryness. The residue is chromatographed on 50 g of silica gel with methylene chloride and gives 4-acetyl-8-methoxy-1,2,3,4,5,6-hexahydrobenzo[f]quinoline with a melting point of 119°-120° after recrystallization from ispropyl ether.
Reaction SMILES: [Cl-].[NH4+:2].C[Al](C)C.[CH2:7]([O:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[C:12]#[N:13])[CH3:8].C(Cl)(Cl)[Cl:19]>C1(C)C=CC=CC=1.CCCCCC>[ClH:19].[CH2:7]([O:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[C:12]([NH2:2])=[NH:13])[CH3:8]
Reactant: CCOc1ccccc1C#N
Reactant: [NH4+]
Reactant: ClC(Cl)Cl
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCOc1ccccc1C(=N)N
Product: Cl
Temperature: 0 °C

Procedure:
21.4 g (400 mmol) of ammonium chloride are suspended in 375 ml of toluene, and the suspension is cooled to 0° C. 200 ml of a 2 M solution of trimethylaluminum in hexane are added dropwise, and the mixture is stirred at room temperature until the evolution of gas has ceased. Following addition of 29.44 g (200 mmol) of 2-ethoxybenzonitrile, the reaction mixture is stirred at 80° C. (bath) overnight. The cooled reaction mixture is, with ice-cooling, added to a suspension of 100 g of silica gel and 950 ml of chloroform, and the mixture is stirred at room temperature for 30 minutes. The mixture is filtered off with suction and the filter cake is washed with the same amount of methanol. The mother liquor is concentrated, the resulting residue is triturated with a mixture of dichloromethane and methanol (9:1), the solid is filtered off with suction and the mother liquor is concentrated. This gives 30.4 g (76%) of a colorless solid.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]([C:7]#[N:8])[CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].F[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([CH3:28])[CH:21]=1>C1COCC1>[C:24]([C:23]1[CH:26]=[CH:27][C:20]([C:4]2([C:7]#[N:8])[CH2:5][CH2:6][S:1][CH2:2][CH2:3]2)=[CH:21][C:22]=1[CH3:28])#[N:25]
Reactant: Cc1cc(F)ccc1C#N
Reactant: N#CC1CCSCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(C2(C#N)CCSCC2)ccc1C#N
Temperature: -78 °C
Yield: 67.1 %

Procedure:
A solution of tetrahydro-2H-thiopyran-4-carbonitrile (197 mg, 1.55 mmol) and THF (2.0 mL) is slowly added via syringe to a mixture of KHMDS (324 mg, 1.63 mmol) in THF (3.0 mL), stirring at −78° C. under nitrogen. The temperature is maintained at −78° C. for 30 min. before a mixture of 4-fluoro-2-methylbenzonitrile (222 mg, 1.64 mmol) in THF (1.0 mL) is slowly added to the vessel. The mixture is allowed to warm to room temperature and is stirred for 3 hours before being quenched with saturated aqueous NH4Cl. The solvent is removed by rotary evaporator and EtOAc (10.0 mL) and water (10.0 mL) are added. The phases are partitioned and the organic is washed with brine, dried with Na2SO4 and concentrated to yield the product (252 mg, 1.04 mmol, 67%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.84-1.95 (m, 2H), 2.03-2.14 (m, 2H), 2.51 (s, 3H), 2.57-2.72 (m, 4H), 7.23-7.31 (m, 1H), 7.41 (dd, J=9.96, 1.76 Hz, 1H), 7.89 (dd, J=8.59, 5.86 Hz, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14](=[O:32])[CH:15]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O)(C)(C)C.F[C:34](F)(F)C(O)=O.C(N(CC)CC)C.Cl[C:48](=[O:52])[C:49]([O-:51])=[O:50]>C(Cl)Cl>[CH3:34][O:51][C:49](=[O:50])[C:48](=[O:52])[N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14](=[O:32])[CH:15]([CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C([O-])C(=O)Cl
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)C(CCc1ccccc1)CCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(=O)N1CCCCC1C(=O)C(CCc1ccccc1)CCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of 0.24 g (0.55 mmol) of 3 in CH2Cl2 (2 mL) was added dropwise 0.13 mL (1.65 mmol) of trifluoroacetic acid, and the mixture was allowed to stir for 2 hours. The solution was diluted with CH2Cl2 (10 mL) and cooled to 0° C. followed by dropwise addition of 0.3 g (3.00 mmol) of triethylamine. After 5 minutes, to the solution was added dropwise 0.08 g (0.61 mmol) of chlorooxoacetate, and the mixture was stirred for 2 hours. The solution was quenched with H2O and extracted with CH2Cl2 (2×200 mL). The organic phase was dried (MgSO4) and evaporated to a clear oil which was subject to column chromatography (EtOAc/Hexanes, 1:3) to yield 0.19 g (81.9%) of 5 as a clear oil. TLC Rf=0.5 (EtOAc/Hexanes, 1:3)
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:12]2[N:13]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)[N:14]=[C:15]3[C:11]=2[CH2:10][CH2:9][NH:8][CH2:17][CH2:16]3)=[CH:35][CH:34]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCCCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Product: Clc1ccc(-c2c3c(nn2C2CCCCC2)CCNCC3)cc1
Yield: 52.7 %

Procedure:
The title compound (48 mg) was prepared as in Example 177, Steps C and D, using 129 mg of 2-cyclohexyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 177, Step B) and 173 mg of 4-chlorophenylboronic acid. MS (ESI): exact mass calculated for C19H24ClN3, 329.17; found, m/z 330.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.60-7.53 (m, 2H), 7.36-7.27 (m, 2H), 3.94-3.83 (m, 1H), 3.43-3.36 (m, 2H), 3.34-3.26 (m, 2H), 3.2-3.12 (m, 2H), 2.80-2.72 (m, 2H), 1.98-1.76 (m, 6H), 1.67 (br s, 1H), 1.32-1.17 (m, 3H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([N+:20]([O-])=O)[C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12]2)=[CH:7][C:6]=1[O:23][CH3:24].[Cl:25][CH2:26][CH2:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[CH:35]=[C:34]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[C:33]([N+:46]([O-])=O)=[CH:32]2>C(O)C.[Pd]>[NH2:20][C:10]1[C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][C:13]2[C:8]([CH:9]=1)=[CH:7][C:6]([O:23][CH3:24])=[C:5]([O:4][CH2:3][CH2:2][Cl:1])[CH:14]=2.[NH2:46][C:33]1[C:34]([C:41]([O:43][CH2:44][CH3:45])=[O:42])=[CH:35][C:36]2[C:31]([CH:32]=1)=[CH:30][C:29]([O:28][CH2:27][CH2:26][Cl:25])=[C:38]([O:39][CH3:40])[CH:37]=2
Reactant: CCOC(=O)c1cc2cc(OC)c(OCCCl)cc2cc1[N+](=O)[O-]
Reactant: CCOC(=O)c1cc2cc(OCCCl)c(OC)cc2cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc2cc(OC)c(OCCCl)cc2cc1N
Product: CCOC(=O)c1cc2cc(OCCCl)c(OC)cc2cc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 1.60 g portion of ethyl 7-(2-chloroethoxy)-6-methoxy-3-nitro-2-naphthoate and ethyl 6-(2-chloroethoxy)-7-methoxy-3-nitro-2-naphthoate (1:1 mixture) is heated in 100 mL absolute ethanol until dissolved. The solution is allowed to cool to room temperature and 0.2 g of 10% palladium on carbon is added. Hydrogenation is carried out in a Parr apparatus at 50 psi for 2 hours. The reaction mixture is filtered through celite and the filter cake is rinsed with ethanol. The filtrate and washes are combined and evaporated to give ethyl 3-amino-7-(2-chloroethoxy)-6-methoxy-2-naphthoate and ethyl 3-amino-6-(2-chloroethoxy)-7-methoxy-2-naphthoate (1:1 mixture) as a greenish yellow solid, 1.28 g (87%), m.p. 104-8° C.
Reaction SMILES: [N:1]([CH2:4][C:5]([F:43])([F:42])[CH2:6][CH2:7][C@H:8]([N:18]([CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[NH2:1][CH2:4][C:5]([F:43])([F:42])[CH2:6][CH2:7][C@H:8]([N:18]([CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[S:19]([C:22]1[CH:23]=[CH:24][C:25]([CH2:28][O:29][Si:30]([C:33]([CH3:34])([CH3:35])[CH3:36])([CH3:31])[CH3:32])=[CH:26][CH:27]=1)(=[O:21])=[O:20])[CH2:9][O:10][Si:11]([C:14]([CH3:16])([CH3:15])[CH3:17])([CH3:12])[CH3:13]
Reactant: CCCCCN([C@@H](CCC(F)(F)CN=[N+]=[N-])CO[Si](C)(C)C(C)(C)C)S(=O)(=O)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCCCCN([C@@H](CCC(F)(F)CN)CO[Si](C)(C)C(C)(C)C)S(=O)(=O)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
To a stirred solution of the material from Step 9 (60 mg, 0.09 mmol) in THF (1.7 mL) and water (86 μL) was added triphenylphosphine (50 mg, 0.19 mmol). The reaction mixture was stirred at room temperature for 2 hours. Then additional water (86 μL) was added, the reaction mixture was heated at reflux for 5 hours. Upon cooling to room temperature, the reaction mixture was concentrated to dryness in vacuo and the residue was purified by flash chromatography on silica gel using EtOAc-hexanes to afford 42 mg of the title compound. LCMS (M+Na)=637.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH3:34])[N:14]([CH2:15][C:16]([O:18]CC)=[O:17])[C:13](=[O:21])[C:12]3([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[N:11]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[Li+:35].[OH-].Cl>C1COCC1.O>[C:30]([O:29][C:27]([N:11]1[C:12]2([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)[C:13](=[O:21])[N:14]([CH2:15][C:16]([O-:18])=[O:17])[C@@:9]([C:4]2[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=2)([CH3:34])[CH2:10]1)=[O:28])([CH3:31])([CH3:32])[CH3:33].[Li+:35]
Reactant: CCOC(=O)CN1C(=O)C2(CCCCC2)N(C(=O)OC(C)(C)C)C[C@@]1(C)c1cc(F)cc(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@](C)(c2cc(F)cc(F)c2)N(CC(=O)[O-])C(=O)C12CCCCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (3R)-3-(3,5-difluorophenyl)-4-(2-ethoxy-2-oxoethyl)-3-methyl-5-oxo-1,4-diazaspiro[5.5]undecane-1-carboxylate from Step I (65 mg, 0.135 mmol) in THF (1.5 μL) and H2O (0.5 mL) was added 1 N aqueous LiOH (0.14 mL, 0.14 mmol) and the resulting mixture was stirred at ambient temperature for 1 h. The mixture was adjusted to pH 7 by addition of 1 N HCl and concentrated to dryness in vacuo to give the title compound. MS: m/z=397 (M−C4H7).
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:14]3[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=3[O:12][N:11]=2)[CH2:6][CH2:5]1.FC1C=CC2C(C3CCNCC3)=NOC=2C=1.[ClH:37]>C(O)(C)C.C(O)C>[ClH:37].[ClH:37].[F:19][C:17]1[CH:16]=[CH:15][C:14]2[C:10]([CH:7]3[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH3:20])[CH2:5][CH2:6]3)=[N:11][O:12][C:13]=2[CH:18]=1
Reactant: Fc1ccc2c(C3CCN(CC4CO4)CC3)noc2c1
Agent: Cl
Agent: Fc1ccc2c(C3CCNCC3)noc2c1
Solvent: CC(C)O
Solvent: CCO
Product: CC(O)CN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 65 °C
Reaction time: 16 h

Procedure:
A stirred mixture of 1-(2,3-epoxypropyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (1.19 g, 4.3 mmol) and 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (0.95 g, 4.3 mmol) in isopropyl alcohol (50 ml) was heated at reflux for 1 hour, then stirred at 65° C. for 16 hours. The solvent was removed on a rotary evaporator. The solid residues were purified by flash chromatography over a silica gel column (SiO2, 35 g; eluted with methylene chloride, DCM, and CH3OH in DCM). The product thus obtained, weighed 2.55 g. This material was dissolved in ethanol and was treated with a solution of HCl (1M in ether). The salt collected weighed 2.35 g, m.p.>270° C. dec.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][C:8]2[N:9]=[C:10]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[S:11][C:12]=2[C:13](=[NH:15])[NH2:14])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:31][C:32](=O)[CH2:33][N:34]1C(=O)C2C(=CC=CC=2)C1=O>CN(C=O)C.C(OCC)(=O)C.O>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[N:9]=[C:10]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[S:11][C:12]=2[C:13]2[NH:14][CH:31]=[C:32]([CH2:33][NH2:34])[N:15]=2)=[CH:22][CH:23]=1
Reactant: N=C(N)c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Reactant: O=C(CBr)CN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NCc1c[nH]c(-c2sc(-c3ccncc3)nc2Cc2ccc(Cl)cc2)n1
Yield: 40.2 %

Procedure:
To a mixture of 4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazole-5-carboximidamide hydrochloride (112 mg, 0.306 mmol) in DMF (2.96 mL) was added sodium carbonate (162 mg, 1.53 mmol) and 2-(3-bromo-2-oxopropyl)isoindoline-1,3-dione (95.0 mg, 0.337 mmol) and the resulting mixture was heated at 100 degrees for 4 hours. The reaction was cooled and taken up in ethyl acetate (30 mL) and water (5 mL). The layers were separated and the organic layer was washed with water (3×5 mL). The organic layer was dried, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH/DCM=0/100→10/90) to give 47 mg (30% yield) of the title compound. LC/MS (FA) ES+ 512. 514. 1H NMR (300 MHz, DMSO-d6) δ: 12.67 (bs, 1H), 8.69-8.67 (m, 2H), 7.91-7.79 (m, 6H), 7.27-7.24 (m, 3H), 7.11-7.08 (m, 2H), 4.77 (s, 2H), 4.45 (s, 2H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][N:11]([CH:15]1[CH2:19][CH2:18][NH:17][CH2:16]1)[C:12](=[O:14])[CH3:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([N:17]2[CH2:18][CH2:19][CH:15]([N:11]([CH3:10])[C:12](=[O:14])[CH3:13])[CH2:16]2)=[CH:3][CH:4]=1)=[O:7]
Reactant: CC(=O)N(C)C1CCNC1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N(C)C1CCN(c2ccc(C=O)cc2)C1
Temperature: 120 °C

Procedure:
A solution of 4-fluorobenzaldehyde (2.01 g, 16.2 mmol) and N-methyl-N-(pyrrolidin-3-yl)acetamide (1.92 g, 13.5 mmol) in DMF (20 mL) was treated with K2CO3 (2.24 g, 16.2 mmol). The mixture was heated at 120° C. under nitrogen for 18 hours, cooled to room temperature, diluted with ethyl acetate (150 mL), washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 100% ethyl acetate to 10% methanol/ethyl acetate, to afford N-(1-(4-formylphenyl)pyrrolidin-3-yl)-N-methylacetamide.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]([N:14]2[CH2:19][CH2:18][C:17]3[CH:20]=[CH:21][O:22][C:16]=3[CH2:15]2)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24].[CH2:28]=O>C(O)(=O)C>[CH2:23]([N:25]([CH2:28][C:21]1[O:22][C:16]2[CH2:15][N:14]([C:12]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:13])[CH2:19][CH2:18][C:17]=2[CH:20]=1)[CH2:26][CH3:27])[CH3:24]
Reactant: C=O
Reactant: CCNCC
Reactant: O=C(OCCCCc1ccccc1)N1CCc2ccoc2C1
Solvent: CC(=O)O
Product: CCN(CC)Cc1cc2c(o1)CN(C(=O)OCCCCc1ccccc1)CC2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 0.267 g of the above 6-(4-phenylbutoxycarbonyl)-4,5,6,7-tetrahydrofuro[2,3-c]pyridine in 20 ml of acetic acid, 0.22 ml (2.1 mmol) of diethylamine and 0.17 g (2.1 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 1 hour. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=9/1) to yield the desired product.
Reaction SMILES: Cl[CH:2]([CH3:21])[C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].[C:22](=O)([O-])[O-].[Na+].[Na+].[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>C(O)C>[CH3:22][N:8]1[C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:5]([C:3](=[O:4])[CH:2]([N:32]2[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]2)[CH3:21])[C:6]2[N:20]=[CH:19][CH:18]=[CH:17][C:7]1=2
Reactant: O=C([O-])[O-]
Reactant: CC(Cl)C(=O)N1c2ccccc2C(=O)Nc2cccnc21
Reactant: CN1CCNCC1
Agent: [Na+]
Solvent: CCO
Product: CC(C(=O)N1c2ccccc2C(=O)N(C)c2cccnc21)N1CCN(C)CC1
Yield: 36 %

Procedure:
A mixture of 9.5 g of the product of Step A, 3.2 g of sodium carbonate and 4 ml of 1-methyl-piperazine in 120 ml of ethanol was refluxed for 7 hours and the hot solution was then vacuum filtered. The filtrate was evaporated to a volume of about 50 ml and the crystalline precipitate was separated. Then the filtrate was evaporated to dryness in vacuo and the residue was crystallized from isopropanol to obtain a 36% yield of 5,11-dihydro-5-methyl-11-[2-(4-methyl-1-piperazinyl)-propionyl]-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one melting at 206°-208° C.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9](SC)[N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[N:20]=4)=[CH:15][CH:14]=3)[N:11]=[C:5]2[N:4]2[C@H:28]3[CH2:33][CH2:32][CH2:31][C@H:29]3[N:30]=[C:3]12.O[O:35][S:36]([O-:38])=O.[K+].[CH3:40]C#N>CO>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([S:36]([CH3:40])(=[O:38])=[O:35])[N:10]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[N:20]=4)=[CH:17][CH:18]=3)[N:11]=[C:5]2[N:4]2[C@H:28]3[CH2:33][CH2:32][CH2:31][C@H:29]3[N:30]=[C:3]12
Reactant: CSc1c2c(nn1Cc1ccc(-c3cccc(F)n3)cc1)N1C(=N[C@@H]3CCC[C@@H]31)N(C)C2=O
Reactant: CC#N
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Product: CN1C(=O)c2c(nn(Cc3ccc(-c4cccc(F)n4)cc3)c2S(C)(=O)=O)N2C1=N[C@@H]1CCC[C@@H]12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(methylthio)-2-(4-(6-fluoropyridin-2-yl)benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one (35.2 mg, 0.076 mmol) is dissolved in CH3CN (0.5 mL) and CH3OH (2 mL), and then an aqueous solution of oxone (139 mg, 0.226 mmol) is added. The reaction mixture is stirred at room temperature for 2 days, and then purified by a semi-preparative HPLC to give pure product as white solids. MS (ESI) m/z 495.2 [M+H]+.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:9]([F:15])=[CH:10][CH:11]=2)[O:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[ClH:22].[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:8]1[C:9]([F:15])=[CH:10][CH:11]=[C:12]2[C:7]=1[O:6][C@@H:5]([CH2:4][NH2:1])[CH2:14][CH2:13]2
Reactant: [N-]=[N+]=NC[C@H]1CCc2ccc(F)c(-c3ccccc3Cl)c2O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cl
Product: NC[C@H]1CCc2ccc(F)c(-c3ccccc3Cl)c2O1
Yield: 134.8 %

Procedure:
Treatment of (2R)-2-(azidomethyl)-8-(2-chlorophenyl)-7-fluorochroman (0.33 g, 1.04 mmol) with polymer-bound triphenylphosphine (3 mmol/g, 0.5 g, 1.50 mmol) in THF (10 mL) and water (0.5 mL) according to the procedure described for Example 69, Step 10 provided 0.23 g (70%) of ((2R)-8-(2-chlorophenyl)-7-fluorochroman-2-yl)methanamine hydrochloride as a white salt, mp 223–225° C.; MS (APPI) m/z 292 ([M+H]+); [α]D25=−40.00° (c=1% SOLN, MeOH).
Reaction SMILES: [C:1]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([NH:16][C:17]3[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][N:18]=3)[N:14]=2)[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:8]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:33]([CH2:35][C:36]([N:38]([CH3:40])[CH3:39])=[O:37])#[N:34].C(O)(=O)C.N1CCCCC1>C(O)C>[C:33]([C:35](=[CH:21][C:20]1[CH:19]=[N:18][C:17]([NH:16][C:13]2[N:14]=[C:15]3[C:7]([C:1](=[O:6])[C:2]([CH3:5])([CH3:3])[CH3:4])=[CH:8][N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:10]3=[N:11][CH:12]=2)=[CH:24][CH:23]=1)[C:36]([N:38]([CH3:40])[CH3:39])=[O:37])#[N:34]
Reactant: CN(C)C(=O)CC#N
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=O)cn3)nc12
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: CCO
Product: CN(C)C(=O)C(C#N)=Cc1ccc(Nc2cnc3c(n2)c(C(=O)C(C)(C)C)cn3COCC[Si](C)(C)C)nc1
Yield: 88.8 %

Procedure:
To a 50 ml three necked round bottom flask 6-(7-pivaloyl-5-((2-(trimethylsilyl)-ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)-nicotinaldehyde (0.33 g, 0.00072 mole) and 2-cyano-N,N-dimethylacetamide (0.245 g, 0.00218 mole) was taken in ethanol (10 ml). To this reaction mixture, piperidine acetate (3.3 M solution in water) (0.1 ml) was added drop wise at RT. After completion of the addition, reaction mixture was refluxed for 4 hrs. After completion of the reaction, the ethanol was distilled out and water was added to residue. The aqueous layer was extracted with ethyl acetate and organic layers were combined, dried over Na2SO4, filtered and concentrated to afford crude product. The crude compound was purified by triturated with n-pentane (10.0 ml), pentane layer was decanted and solid was dried under vacuum to yield 0.35 g of 2-cyano-N,N-dimethyl-3-(6-(7-pivaloyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)pyridin-3-yl)acrylamide.
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7]([CH2:9][CH2:10]O)[N:8]=1)([CH3:3])[CH3:2].CS(Cl)(=O)=O.[CH2:17]([N:19](CC)CC)C.C(N)C>O1CCCC1.C(OCC)(=O)C>[CH:1]([C:4]1[S:5][CH:6]=[C:7]([CH2:9][CH2:10][NH:19][CH3:17])[N:8]=1)([CH3:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CC(C)c1nc(CCO)cs1
Agent: CCN
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNCCc1csc(C(C)C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2.0 g (12 mmol) of 2-isopropyl-4-(hydroxyethyl)thiazole in 50 ml of tetrahydrofuran was treated with 1.34 g (12 mmol) of methanesulfonyl chloride. The resulting solution was treated dropwise with 3.4 ml (24 mmol) of triethylamine and stirred at ambient temperature for 1 h. A portion (25 ml) of the resulting solution was added to 50 ml of aqueous ethylamine (70% in H2O) with rapid stirring. After addition, the mixture was heated to reflux for 2 h, allowed to cool, diluted with ethyl acetate, washed with aqueous NaHCO3 and saturated brine, dried over Na2SO4, and concentrated in vacuo to provide the crude desired compound. Purification of the residue by silica gel chromatography using 5% methanol in chloroform, 0.52 g (48%) of the desired compound. 1H NMR (CDCl3) δ 1.38 (d, J=7 Hz, 3 H), 2.46 (s, 3 H), 2.93 (s, 4 H), 3.30 (heptet, J=7 Hz, 1 H), 6.79 (s, 1 H). Mass spectrum: (M+H)+ =185.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[CH:16]=[CH:15][C:3]=1[C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9])=[O:5].[CH2:24]([N:26]([CH2:38][CH3:39])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])[CH:28]=1)[CH3:25].C(OC(=O)C)(=O)C>CO>[CH2:34]([N:33]([CH2:36][CH3:37])[C:29]1[CH:28]=[C:27]([N:26]([CH2:24][CH3:25])[CH2:38][CH3:39])[CH:32]=[CH:31][C:30]=1[C:4]1([C:3]2[CH:15]=[CH:16][C:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:18][C:2]=2[Cl:1])[C:6]2[C:7](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:8](=[O:9])[O:5]1)[CH3:35]
Reactant: CCN(CC)c1ccc(C(=O)c2ccccc2C(=O)O)c(Cl)c1
Reactant: CCN(CC)c1cccc(N(CC)CC)c1
Solvent: CO
Solvent: CC(=O)OC(C)=O
Product: CCN(CC)c1ccc(C2(c3ccc(N(CC)CC)cc3N(CC)CC)OC(=O)c3ccccc32)c(Cl)c1
Reaction time: 8 h
Yield: 37.8 %

Procedure:
A mixture of 2-(2-chloro-4-(diethylamino)benzoyl)benzoic acid (6.61 g.), N,N,N',N'-tetraethyl-m-phenylenediamine (4.30 g.) and acetic anhydride (5 ml.) was allowed to stand overnight at room temperature, then diluted with methanol (10 ml.), affording 3-(2,4-bis(diethylamino)phenyl)-3-(2-chloro-4-(diethylamino)phenyl)phthalide (I: X=Y4 =(CH3CH2)2N, Y2 =Cl, Z4 =Z5 =Z6 =Z7 =H) (3.94 g., m.p. 141°-143° C.).