Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH2:26][CH2:25]3)=[CH:20][N:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[CH3:35][S:32]([CH2:31][CH2:30][N:27]1[CH2:28][CH2:29][N:24]([C:21]2[CH:22]=[CH:23][C:18]([N:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[NH:8][CH2:9][CH2:10]3)=[N:19][CH:20]=2)[CH2:25][CH2:26]1)(=[O:34])=[O:33]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3CCN(CCS(C)(=O)=O)CC3)cn2)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: CS(=O)(=O)CCN1CCN(c2ccc(N3CCNc4ccccc43)nc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.3 %

Procedure:
4-{5-[4-(2-(Methanesulphonyl)ethyl)piperazin-1-yl]pyridin-2-yl}-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester (0.38 g, 0.76 mmol) is placed in 5 ml of dioxane and then 4N HCl in dioxane (2.84 ml, 11.36 mmol) is added. The reaction medium is stirred at ambient temperature for 18 h. 4N HCl in dioxane (2.84 ml, 11.36 mmol) is again added and the reaction medium is stirred at ambient temperature for an additional 18 h. After concentrating to dryness, the reaction medium is diluted with 50 ml of 1N HCl in water and extracted with 100 ml of diethyl ether. The organic phase is again washed with 50 ml of 1N HCl in water. The aqueous phases are combined, basified with K2CO3 powder up to a pH of 10 and extracted 3 times with 50 ml of dichloromethane. The resulting organic phases are combined, washed with a saturated aqueous sodium chloride solution, dried over MgSO4 and concentrated to dryness. 0.3 g of 1-{5-[4-(2-(methanesulphonyl)ethyl)piperazin-1-yl]pyridin-2-yl}-1,2,3,4-tetrahydroquinoxaline is obtained.
Reaction SMILES: C(O)(=O)C(O)=O.[Cl:7][C:8]1[N:13]=[C:12]([C@H:14]([OH:33])[CH2:15][NH:16][C@H:17]([CH3:32])[CH2:18][C:19]2[CH:31]=[CH:30][C:22]([C:23]([CH3:29])=[CH:24][C:25]([O:27]C)=[O:26])=[CH:21][CH:20]=2)[CH:11]=[CH:10][CH:9]=1.[OH-].[K+].Cl>O>[ClH:7].[Cl:7][C:8]1[N:13]=[C:12]([C@H:14]([OH:33])[CH2:15][NH:16][C@H:17]([CH3:32])[CH2:18][C:19]2[CH:31]=[CH:30][C:22]([C:23]([CH3:29])=[CH:24][C:25]([OH:27])=[O:26])=[CH:21][CH:20]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)C=C(C)c1ccc(C[C@@H](C)NC[C@@H](O)c2cccc(Cl)n2)cc1
Agent: Cl
Agent: O=C(O)C(=O)O
Agent: [K+]
Solvent: O
Product: CC(=CC(=O)O)c1ccc(C[C@@H](C)NC[C@@H](O)c2cccc(Cl)n2)cc1
Reaction time: 3 h
Yield: 133.7 %

Procedure:
A solution of 958 mg of methyl p-[(R)-2-[[(R)-2-(6-chloro-2-pyridyl)-2-hydroxyethyl]amino]propyl]-β-methylcinnamate oxalate (Example 2Ga), 60 ml of 5% methanolic KOH and 10 ml of water were heated to 50° under argon while stirring for 3 hours. For the working-up, the mixture was diluted with water, adjusted to pH 5 with 2N hydrochloric acid and extracted repeatedly with ethyl acetate, The combined extracts were dried and evaporated in a vacuum. There were obtained 550 mg of amorphous p-[(R)-2-[[(R)-2-(6-chloro-2-pyridyl)-2-hydroxyethyl]amino]propyl]-β-methylcinnamic acid hydrochloride [Ε]D20 32 =45° (c=0.5 in MeOH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[F:16][C:17]([F:27])([F:26])[C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21]Cl.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:15])[CH:9]([CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[C:18]([C:17]([F:16])([F:26])[F:27])[CH:19]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1cccc(CCl)c1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(Cc1cccc(C(F)(F)F)c1)C(=O)c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 64.7 %

Procedure:
A mixture of ethyl 3-(4-fluorophenyl)-3-oxopropionate (10 g, 47.6 mmol), 3-trifluoromethylbenzyl chloride (8.33 g, 42.8 mmol), potassium carbonate (13.2 g, 95.1 mmol) and acetonitrile (200 ml) was stirred at 60° C. for 24 hrs. The reaction solution was concentrated under reduced pressure, water (200 ml) was added, and the mixture was extracted with ethyl acetate (200, 100 ml). The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:toluene=1:1-1:2-toluene) to give ethyl 3-(4-fluorophenyl)-3-oxo-2-(3-trifluoromethylbenzyl)propionate (10.2 g, 65%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][C:10](=[O:22])[CH2:11][CH:12]([CH:19]([CH3:21])[CH3:20])[CH2:13][C:14]([O:16]CC)=O)[CH:4]=1.[O-]CC.[Na+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH:9]2[C:10](=[O:22])[CH2:11][CH:12]([CH:19]([CH3:20])[CH3:21])[CH2:13][C:14]2=[O:16])[CH:4]=1
Reactant: CCOC(=O)CC(CC(=O)Cc1cc(OC)ccn1)C(C)C
Agent: CC[O-]
Agent: [Na+]
Product: COc1ccnc(C2C(=O)CC(C(C)C)CC2=O)c1

Procedure:
The title compound was prepared from ethyl 6-(4-methoxy-2-pyridinyl)-3-(1-methylethyl)-5-oxohexanoate and ethanolic sodium ethoxide, refluxing for 2 hours according to the procedure of Example 2. The product separated from the aqueous phase as a yellow solid upon adjusting the pH to about 6 and was recovered by extraction with dichloromethane. Evaporation of the dried extract and recrystallization from acetonitrile gave the product as a white solid, mp 152°-154.5° C. The confirmatory elemental analysis is shown in Table II.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(OC([NH:32][C:33]1([C:48]([OH:50])=O)[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=O)(C)(C)C.[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([C@@H:58]([NH2:60])[CH3:59])=[CH:54][CH:53]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[NH2:32][C:33]1([C:48]([NH:60][C@H:58]([C:55]2[CH:56]=[CH:57][C:52]([Cl:51])=[CH:53][CH:54]=2)[CH3:59])=[O:50])[CH2:34][CH2:35][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:37][CH2:38]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Reactant: C[C@H](N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: C[C@H](NC(=O)C1(N)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 70.4 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.418 g) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (0.361 g), (S)-1-(4-chlorophenyl)ethanamine (0.140 mL) and DIPEA (0.524 mL) in DMA (10 mL) at 25° C. under nitrogen. The resulting solution was stirred at 60° C. for 4 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and pure fractions were evaporated to dryness. This crude material was then treated with a 20% solution of TFA in DCM (10 mL) and stirred at room temperature. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M ammonia/MeOH and pure fractions were evaporated to dryness. This material was purified by preparative LCMS using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (S)-4-amino-N-(1-(4-chlorophenyl)ethyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide as a white solid (0.281 g, 70.4%). 1H NMR (400.13 MHz, DMSO-d6) δ 1.37 (3H, d), 1.42-1.45 (2H, m), 1.88-2.01 (2H, m), 2.27 (2H, s), 3.49-3.59 (2H, m), 4.34-4.44 (2H, m), 4.83-4.90 (1H, m), 6.57-6.58 (1H, m), 7.14-7.16 (1H, m), 7.32-7.38 (4H, m), 8.12 (1H, s), 8.30 (1H, d), 11.62 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]([CH3:17])([CH3:16])[C:14]#[N:15])[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH:8]=[CH:7]2.[Br:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23](Br)[C:20]=1[CH:21]=[O:22].C(=O)(O)[O-].[Na+]>CS(C)=O.[Cu](I)I>[Br:18][C:19]1[C:20]([CH:21]=[O:22])=[C:23]([N:9]2[CH:8]=[CH:7][C:6]3[C:11](=[C:2]([F:1])[CH:3]=[C:4]([C:13]([CH3:17])([CH3:16])[C:14]#[N:15])[CH:5]=3)[C:10]2=[O:12])[CH:24]=[CH:25][CH:26]=1
Reactant: O=Cc1c(Br)cccc1Br
Reactant: CC(C)(C#N)c1cc(F)c2c(=O)[nH]ccc2c1
Agent: I[Cu]I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C#N)c1cc(F)c2c(=O)n(-c3cccc(Br)c3C=O)ccc2c1
Temperature: 110 °C
Reaction time: 3.5 h
Yield: 63.3 %

Procedure:
A solution of 2-(8-fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-methyl-propionitrile (250 mg, 1.09 mmol), 2,6-dibromobenzaldehyde (459 mg, 1.74 mmol) and sodium bicarbonate (182 mg, 2.17 mmol) in dry dimethylsulfoxide (8 ml) was placed under vacuum and back-filled with argon (repeat twice more). To this was added copper iodide (207 mg, 1.09 mmol) and the flask was evacuated and back-filled with argon (repeat twice more). The mixture was heated in an oil bath to 110° C. and stirred for 3.5 hours. The reaction mixture was cooled to ambient and taken up in ethyl acetate (40 ml) and water (40 ml). The biphasic material was filtered through a plug of celite, rinsing well with ethyl acetate. The filtrate and washes were transferred to a separatory funnel and the organic phase was collected. This was washed with an equal volume of 50% diluted brine solution and the ethyl acetate phase collected. The aqueous phases were back extracted with ethyl acetate (2×30 ml). The combined organic phase was dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by HPLC on silica gel, eluting with 1% methanol/dichloromethane to provide the desired product as a light yellow solid (285 mg). (M+H)+=413/415 m/e.
Reaction SMILES: O.OO.N[C:5]([NH2:7])=[O:6].[OH-].[Na+].C([C:12]1[N:13]=[CH:14][C:15]([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[C@H:23]([N:27]2[CH2:30][C:29]4([CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]4)[CH2:28]2)[CH2:22][CH2:21]3)=[N:16][CH:17]=1)#N>CCO>[C:39]([O:38][C:36]([N:33]1[CH2:34][CH2:35][C:29]2([CH2:28][N:27]([C@H:23]3[C:24]4[C:20](=[CH:19][C:18]([C:15]5[CH:14]=[N:13][C:12]([C:5](=[O:6])[NH2:7])=[CH:17][N:16]=5)=[CH:26][CH:25]=4)[CH2:21][CH2:22]3)[CH2:30]2)[CH2:31][CH2:32]1)=[O:37])([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN([C@@H]1CCc3cc(-c4cnc(C#N)cn4)ccc31)C2
Reactant: NC(N)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN([C@@H]1CCc3cc(-c4cnc(C(N)=O)cn4)ccc31)C2
Temperature: 25 °C
Yield: 53.3 %

Procedure:
A round-bottomed flask was charged with water (100 mL) and urea hydrogen peroxide (495 mg, 5.11 mmol). Sodium hydroxide (119 mg, 2.98 mmol) was added and the reaction was stirred at room temperature. Once a clear solution was obtained, the reaction was placed in an ice bath and fitted with an addition funnel. A solution of tert-butyl 2-((R)-5-(5-cyanopyrazin-2-yl)-2,3-dihydro-1H-inden-1-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (10-1a, 379 mg, 0.85 mmol) in 25 mL EtOH was added dropwise over a period of 30 minutes via the funnel. The reaction was warmed to room temperature and stirred overnight. The resulting white suspension was collected by vacuum filtration. The solids were washed with 50 mL water and air-dried to give 210 mg (53%) of the title compound as an off-white powder. MS (ES+) 464.4 (M+H)+. 1H NMR (DMSO-d6) δ 1.38 (s, 9H), 1.54-1.61 (m, 4H), 1.89 (d, 1H), 2.08 (s, 1H), 2.76-2.80 (m, 2H), 2.99 (d, 3H), 3.11 (d, 2H), 3.19-3.22 (m, 3H), 3.90 (d, 1H), 7.45 (d, 1H), 7.83 (br s, 1H), 8.01 (d, 1H), 8.08 (s, 1H), 8.23 (s, 1H), 9.20 (d, 1H), 9.24 (d, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][C:9]=1[NH:22][C:23](=[O:32])[CH2:24][C:25](=O)[C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:14]([C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:25]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)[CH2:24][C:23](=[O:32])[NH:22][C:9]=2[CH:10]=1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)c2ccccc2)cc1NC(=O)CC(=O)c1cccs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccs2)=Nc2ccc(C(=O)c3ccccc3)cc2N1
Yield: 19.2 %

Procedure:
Prepared from [4-benzoyl-2-(3-oxo-3-thiophen-2-yl-propionylamino)-phenyl]-carbamic acid tert.-butyl ester (Example K19) (54 mg, 0.12 mmol) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (8 mg).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5](=[N:7][C:8]2[N:13]=[C:12]([CH2:14]O)[CH:11]=[CH:10][CH:9]=2)[N:4]([CH2:16][O:17][CH3:18])[CH:3]=1.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.[NH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>CS(C)=O.C(Cl)(Cl)Cl>[Br:1][C:2]1[S:6][C:5](=[N:7][C:8]2[N:13]=[C:12]([CH2:14][N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[CH:11]=[CH:10][CH:9]=2)[N:4]([CH2:16][O:17][CH3:18])[CH:3]=1
Reactant: C1CNCCN1
Reactant: COCn1cc(Br)sc1=Nc1cccc(CO)n1
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: COCn1cc(Br)sc1=Nc1cccc(CN2CCNCC2)n1
Reaction time: 1 h
Yield: 70.6 %

Procedure:
To a mixture of 330 mg (1.00 mmol) of (6-(5-bromo-3-methoxymethyl-3H-thiazol-2-ylideneamino)-pyridin-2-yl)-methanol, 0.348 ml (2.00 mmol) of N,N-diisopropylethylamine and 15 ml of chloroform was added 0.116 ml (1.50 mmol) of methanesulfonyl chloride at room temperature followed by stirring for 1 hour. The reaction mixture was washed with brine, the organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated in vacuo. The resulting residue was dissolved in 4 ml of dimethyl sulfoxide and dropped into 2 ml of a solution of 861 mg (10.0 mmol) of piperazine in dimethyl sulfoxide and the mixture was stirred at room temperature for 4 hours and 30 minutes. The reaction solution was filtered and purified by a reversed phase preparative liquid chromatography to give 281 mg (0.706 mmol) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3]/[CH:4]=[CH:5]/[C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][CH2:11][C:12]2=O)=[CH:8][CH:7]=1.[CH:16]1([NH2:19])[CH2:18][CH2:17]1.[BH4-].[Na+].O>CO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH:16]1([NH:19][CH:12]2[C:13]3[C:9](=[CH:8][CH:7]=[C:6](/[CH:5]=[CH:4]/[CH2:3][O:2][CH3:1])[CH:14]=3)[CH2:10][CH2:11]2)[CH2:18][CH2:17]1
Reactant: NC1CC1
Reactant: COC/C=C/c1ccc2c(c1)C(=O)CC2
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: O
Solvent: CO
Product: COC/C=C/c1ccc2c(c1)C(NC1CC1)CC2
Reaction time: 0.5 h

Procedure:
To a solution of 6-[(1E)-3-methoxyprop-1-en-1-yl]indan-1-one (1 eq.) from the previous step in MeOH (2 M) was added cyclopropylamine (2 eq.) and titanium(IV) isopropoxide (1.3 eq.). The solution was stirred at RT for 1 h before sodium borohydride (1 eq.) was added at 0° C. After 30 min, water was added and the mixture was extracted with ethyl acetate. The combined organic extracts were then washed with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product by way of flash chromatography (SiO2, Hex→1:9 (v/v) Hex:EtOAc) afforded the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]#[N:20])=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][C:7]([CH3:15])([CH3:14])[C:8]([NH:10][CH2:11][CH2:12][CH3:13])=[O:9].[S:21](Cl)(=[O:24])(=[O:23])[NH2:22]>CC(N(C)C)=O.CCOC(C)=O>[S:21]([NH:1][C:2]1[C:3]([C:19]#[N:20])=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][C:7]([CH3:15])([CH3:14])[C:8]([NH:10][CH2:11][CH2:12][CH3:13])=[O:9])(=[O:24])(=[O:23])[NH2:22]
Reactant: CCCNC(=O)C(C)(C)COc1cccc(N)c1C#N
Reactant: NS(=O)(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCCNC(=O)C(C)(C)COc1cccc(NS(N)(=O)=O)c1C#N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-(3-amino-2-cyanophenoxy)-2,2-dimethyl-N-propylpropanamide (16.5 g, 59.92 mmol) (Example 215b) in DMA (50 mL) was added sulfamoyl chloride (13.85 g, 119.84 mmol) at 0° C. under nitrogen. The reaction mixture was then stirred at room temperature under nitrogen for 3 hrs then diluted, with EtOAc, washed successively with NaHCO3, brine, dried over Na2SO4, filtered and evaporated to give the title compound as a off white solid (18.52 g, 87%). 1H NMR (400 MHz, DMSO-d6) δ 0.79 (t, J=7.6 Hz, 3H), 1.20 (s, 6H), 1.38 (m, 2H), 3.01 (q, J=6.5 Hz, 2H), 4.05 (s, 2H), 6.92 (d, J=8.4 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 7.24 (s, 2H), 7.53 (t, J=8.4 Hz, 1H), 7.55 (t, J=5.6 Hz, 1H), 9.42 (s, 1H). MS 355 (MH+).
Reaction SMILES: [CH:1]1([S:6]([C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11](OC)=[O:12])(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Li+]>O1CCCC1CCO>[CH:1]1([S:6]([C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[CH2:11][OH:12])(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccccc1S(=O)(=O)C1CCCC1
Agent: OCCC1CCCO1
Agent: [BH4-]
Agent: [Li+]
Product: O=S(=O)(c1ccccc1CO)C1CCCC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 84.4 %

Procedure:
(Step 2) To a solution of methyl 2-(cyclopentylsulfonyl)benzoate obtained in Step 1 (4.1 g) in tetrahydrofuran-ethanol (100 ml+10 ml) was added lithium borohydride (500 mg) at 0° C. The mixture was stirred at 60° C. for 3 hr, quenched with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure to give [2-(cyclopentylsulfonyl)phenyl]methanol (3.1 g).
Reaction SMILES: O.[N:2](=[CH:4][C:5](=[O:17])[CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[OH:3].[CH2:18](O)[CH2:19][OH:20].C1(C)C(S(O)(=O)=O)=CC=CC=1>C1C=CC=CC=1>[CH2:19]1[O:20][C:5]([CH:4]=[N:2][OH:3])([CH2:6][C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[O:17][CH2:18]1
Reactant: OCCO
Reactant: O=C(C=NO)CC(=O)OCc1ccccc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: c1ccccc1
Product: O=C(CC1(C=NO)OCCO1)OCc1ccccc1
Yield: 35 %

Procedure:
In a two liter flask fitted with a Dean Stark water separator and an condenser were placed 186.5 g. (0.85 mole) of benzyl oximino-acetoacetate (17), 62 g. (1 mole) of ethylene glycol, 800 ml. of benzene (reagent grade) and 2 g. of toluenesulfonic acid. The reaction mixture was boiled at reflux until 15 ml. of water was removed (3 hours). The benzene solution was washed once with saturated sodium bicarbonate solution and once with brine. After drying over anhydrous sodium sulfate, the benzene solution was evaporated, leaving 212 g. (94%) of 17 as a light yellow oil. Its NMR spectrum was consistent with the assigned structure. Generally the compound was used as such in subsequent reaction but one of the isomers can be crystallized in 35% yield from toluene-petroleum ether, m.p. 52° C. ##STR177##
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH2:12][CH2:13]Cl)=[C:10](Cl)[C:9]2[C:4](=[C:5]([O:16][CH3:17])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.[CH3:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22]>C(O)CCC>[CH3:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[N:22]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([O:16][CH3:17])[C:4]=3[N:3]=[C:2]([CH3:1])[C:11]=2[CH2:12][CH2:13]1
Reactant: Cc1ccccc1N
Reactant: COc1cccc2c(Cl)c(CCCl)c(C)nc12
Agent: Cl
Solvent: CCCCO
Product: COc1cccc2c3c(c(C)nc12)CCN3c1ccccc1C
Yield: 21.6 %

Procedure:
2-Methyl-3-(2-chloroethyl)-4-chloro-8-methoxyquinoline (8.37 g, 31 mmol) and 2-methylaniline hydrochloride (4.45 g, 31 mmol) in 1-butanol (100 ml) were heated at reflux for 5 days, then the solvent evaporated, the crude product taken up in dichloromethane, washed with aqueous sodium bicarbonate, dried and evaporated. Chromatography (silica gel, 2% methanolic ammonia in dichloromethane) and recrystallisation from aqueous ethanol gave 1-(2-methylphenyl)-4-methyl-6-methoxy-2,3-dihydropyrrolo[3,2-c]quinoline (2.04 g, 22 %), m.p. 182°-183°.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([C:9]([CH2:12][CH:13]3[CH2:15][CH2:14]3)=[N:10][N:11]=2)[CH:5]=[CH:6][C:7]=1Cl.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].O1CCOCC1>C([O-])(O)=O.[Na+].CCOC(C)=O.O.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>[C:16]([O:20][C:21]([N:23]1[CH2:24][CH:25]=[C:26]([C:7]2[CH:6]=[CH:5][N:4]3[C:9]([CH2:12][CH:13]4[CH2:15][CH2:14]4)=[N:10][N:11]=[C:3]3[C:2]=2[CH3:1])[CH2:27][CH2:28]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Cc1c(Cl)ccn2c(CC3CC3)nnc12
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: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(C2=CCN(C(=O)OC(C)(C)C)CC2)ccn2c(CC3CC3)nnc12
Temperature: 150 °C

Procedure:
A mixture of D98 (0.358 mg, 1.614 mmol), N-(tert-butoxycarbonyl)-3,6-dihydro-2H-pyridine-4-boronic acid pinacol ester (0.6 g, 1.937 mmol) and Pd(PPh3)4 (0.0933 g, 0.0801 mmol) in NaHCO3, (3.5 ml, aqueous sat. solution) and 1,4-dioxane (9 ml) was heated at 150° C. under microwave irradiation for 5 min. After cooling, the mixture was refilled with additional N-(tert-butoxycarbonyl)-3,6-dihydro-2H-pyridine-4-boronic acid pinacol ester (0.5 g) and Pd(PPh3)4 (0.072 g) and NaHCO3, (1 ml, aqueous sat. solution). The mixture was heated at 150° C. under microwave irradiation for 20 min. After cooling to r.t. the mixture was diluted with EtOAc/H2O, filtered through a pad of diatomaceous earth and washed with EtOAc. The organic phase was collected, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; EtOAc/7M solution of NH3 in MeOH up to 6% as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate D99 (0.458 g, 77%).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:5]1[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[C:9](=[O:15])[N:8]([CH3:16])[C:7]2[CH:17]=[C:18]([CH:21]=O)[CH:19]=[CH:20][C:6]1=2)[CH3:4].[NH2:23][CH2:24][CH2:25][N:26]1[CH:31]=[CH:30][C:29]2[O:32][C:33]([CH3:35])=[CH:34][C:28]=2[C:27]1=[O:36]>CO>[CH2:3]([N:5]1[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[C:9](=[O:15])[N:8]([CH3:16])[C:7]2[CH:17]=[C:18]([CH2:21][NH:23][CH2:24][CH2:25][N:26]3[CH:31]=[CH:30][C:29]4[O:32][C:33]([CH3:35])=[CH:34][C:28]=4[C:27]3=[O:36])[CH:19]=[CH:20][C:6]1=2)[CH3:4]
Reactant: Cc1cc2c(=O)n(CCN)ccc2o1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(C=O)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CNCCn3ccc4oc(C)cc4c3=O)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium borohydride(0.15 g) was added to a methanol solution (150 ml) of 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde(1.1 g) and 5-(2-aminoethyl)-2-methyl-5H-furo[3,2-c]pyridin-4-one(1.0 g), and the mixture was stirred at room temperature overnight. The reaction liquid was filtered to remove insoluble matter, and the filtrate was condensed under reduced pressure.
Reaction SMILES: [O-][CH2:2]C.[Na+].C(O)C.CI.[C:10]([NH:15][C:16]([NH2:18])=[S:17])([O:12][CH2:13][CH3:14])=[O:11]>CCOCC>[CH3:2][S:17][C:16](=[NH:18])[NH:15][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CC[O-]
Reactant: CCOC(=O)NC(N)=S
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Solvent: CI
Product: CCOC(=O)NC(=N)SC
Temperature: 21 °C
Reaction time: 1 h

Procedure:
To a solution of sodium ethoxide in ethanol (made by addition of sodium (0.155 g, 6.7 mmol) to dry ethanol(15 ml)) was added methyl iodide (1.47 ml, 23.6 mmol) followed by N-carbethoxythiourea (1.0 g, 6.7 mmol). The resulting solution was stirred at 21° C. under nitrogen for 1 hr. This was then treated with ether (32 ml) and the resultant precipitate filtered off. The filtrate was evaporated to a clear syrup, which crystallised at 0-4° C. to give the title compound as a white solid (0.815 g).