Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]([F:17])([F:16])[C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.Cl[CH:19]([O:21]C(Cl)Cl)Cl.Cl>C(Cl)Cl.O.[N+](C)([O-])=O>[F:17][C:6]([F:5])([F:16])[C:7]1[NH:8][C:9]2[C:14]([C:15]=1[CH:19]=[O:21])=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: FC(F)(F)c1cc2ccccc2[nH]1
Reactant: ClC(Cl)OC(Cl)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: ClCCl
Solvent: O
Product: O=Cc1c(C(F)(F)F)[nH]c2ccccc12
Temperature: -65 °C
Reaction time: 0.25 h

Procedure:
6.1 g of aluminum chloride and 20 ml of methylene chloride were mixed together at -65° C. under an inert atmosphere and a solution of 4.61 g of 2-trifluoromethyl-(1H)-indole (J. Org. Chem., 1974 Vol. 39, p. 1836), 1.4 ml of nitromethane and 20 ml of methylene chloride were added at -60° C. 3.3 ml of dichloromethyl ether in solution in 10 ml of methylene chloride were added to the suspension of the resulting mixture was stirred for 15 minutes at -65° C. The temperature was allowed to rise and at about -10° C., a strong evolution of hydrochloric acid was observed which ceased at about 0° C. The black solution obtained was stirred for 30 minutes at 25° C. and the reaction mixture was poured into water and extracted with methylene chloride. The organic phases were washed with an aqueous solution of sodium bicarbonate, then with water and concentrated to dryness under reduced pressure to obtain 4.6 g of 2-trifluoromethyl-3-formyl-(1H)-indole.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:21][C:22]1[S:30][C:29]2[C:28]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[N:27][C:26]([Cl:37])=[N:25][C:24]=2[CH:23]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:21][C:22]2[S:30][C:29]3[C:28]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[N:27][C:26]([Cl:37])=[N:25][C:24]=3[CH:23]=2)[S:14]([CH3:17])(=[O:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(NS(C)(=O)=O)C1
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(N(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)S(C)(=O)=O)C1
Reaction time: 0.67 h
Yield: 48.4 %

Procedure:
To a solution of 3-Methanesulfonylamino-pyrrolidine-1-carboxylic acid tert-butyl ester (0.47 g) in DMF (5 mL) was added NaH (63 mg). The mixture was stirred for 40 min. then a solution of 6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (0.52 g) in DMF (5 mL) was added via cannular. The resulting mixture was stirred at R.T. for 5 h. An aqueous work-up followed by purification on silica gave 3-[(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methanesulfonyl-amino]-pyrrolidine-1-carboxylic acid tert-butyl ester (384 mg).
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].O=[C:8]1[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.CCOCC>[CH:1](=[C:8]1[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: CC(C)(C)[O-]
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Product: CC=C1CN(C(=O)OC(C)(C)C)C1
Reaction time: 4.5 h
Yield: 46 %

Procedure:
Potassium tert-butoxide (1.672 g, 14.9 mmol) and ethyltriphenylphosphonium bromide (5.538 g, 14.9 mmol) were stirred in ether (30 mL) at amibient for 1 h. 1,1-Dimethylethyl 3-oxoazetidine-1-carboxylate (954 mg, 6.0 mmol), prepared using procedures similar to those described in Example 3, was added and the mixture was 35° C. for 4.5 h. Mixture was filtered through celite and the solid was washed with ether. The filtrate was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 20% ether in hexanes) gave 1,1-dimethylethyl 3-ethylideneazetidine-1-carboxylate (506 mg, 2.76 mmol, 49% yield): 1H NMR (400 MHz, CDCl3): 5.37-5.28 (m, 1H), 4.47-4.39 (m, 4H), 1.56-1.51 (m, 3H), 1.45 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[N:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=2)[CH:3]=1.[NH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]1.C(N(CC)CC)C>CN1CCCC1=O>[NH:22]1[CH2:23][CH2:24][CH:19]([CH2:18][NH:17][C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[N:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=3)[CH:3]=2)[CH2:20][CH2:21]1
Reactant: N#Cc1cnc(Nc2cc(Cl)ncn2)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: N#Cc1cnc(Nc2cc(NCC3CCNCC3)ncn2)cn1
Temperature: 145 °C
Reaction time: 1 h
Yield: 6.2 %

Procedure:
A mixture of 5-(6-chloropyrimidin-4-ylamino)pyrazine-2-carbonitrile (124 mg, 0.533 mmol), tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (228 mg, 1.066 mmol) and triethylamine (150 μL, 1.07 mmol) in 1-methyl-2-pyrrolidinone (1 mL) was heated at 145° C. for 15 minutes using microwave irradiation. The mixture was concentrated in vacuo and the residue purified by preparative HPLC. The purified solid was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (3 mL) and was stirred for 1 hour at room temperature before being applied to a MP-TsOH cartridge. After washing with methanol, the pure product was eluted using 7M ammonia to give 5-(6-(piperidin-4-ylmethylamino)pyrimidin-4-ylamino)pyrazine-2-carbonitrile (10.3 mg, 6%).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2[S:19][C:18]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)=O.Cl.[CH2:26](NCCC1C=CC(S(C2SC(S(N)(=O)=O)=CC=2)(=O)=O)=CC=1)[CH3:27].CN(C)CCCC1C=CC(S(C2SC(S(N)(=O)=O)=CC=2)(=O)=O)=CC=1.CN(C)CCCCC1C=CC(S(C2SC(S(N)(=O)=O)=CC=2)(=O)=O)=CC=1>O1CCCC1>[CH3:1][N:2]([CH3:24])[CH:3]([CH2:26][CH3:27])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2[S:19][C:18]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1
Reactant: CN(C)C(=O)Cc1ccc(S(=O)(=O)c2ccc(S(N)(=O)=O)s2)cc1
Reactant: CCNCCc1ccc(S(=O)(=O)c2ccc(S(N)(=O)=O)s2)cc1
Agent: CN(C)CCCCc1ccc(S(=O)(=O)c2ccc(S(N)(=O)=O)s2)cc1
Agent: CN(C)CCCc1ccc(S(=O)(=O)c2ccc(S(N)(=O)=O)s2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CCC(Cc1ccc(S(=O)(=O)c2ccc(S(N)(=O)=O)s2)cc1)N(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-(4-dimethylcarbamoylmethylphenylsulfonyl)thiophene-2-sulfonamide (1.35 g) was dissolved in 30 ml of tetrahydrofuran under a nitrogen atmosphere. Borane tetrahydrofuran complex (8 ml of 1 molar solution) was added and the mixture was stirred at room temperature for 3 hours. Hydrochloric acid (20 ml of 6N) was then added cautiously and the mixture was heated on a steam bath, boiling off tetrahydrofuran. The acidic solution was cooled to room temperature and extracted with chloroform. The aqueous phase was separated and its pH adjusted to pH 8.5 before extracting it with ethyl acetate. The ethyl acetate phase was dried over sodium sulfate and concentrated under vacuum to give a residue of an oily solid. This was chromatographed on silica gel to give a pure product, m.p. 169°-172° C. N.M.R. (DMSO, d6) δ: 2.17 (6H, s), 2.50 (2H, T, J=6 Hz), 2.82 (2H, T, J=6 Hz), 7.55 (2H, d, J=9 Hz), 7.60 (1H, d, J=4 Hz), 7.87 (1H, d, J=4 Hz), 7.94 (2H, d, J=9 Hz), 8.04 (2H, broad s). Anal Calc'd for C14H18N2O4S3 : C, 44.90; H, 4.84; N, 7.48. Found: C, 44.54; H, 4.89; N, 7.60. The following compounds where also made by similar procedures: 5-[4-(2-ethylaminoethyl)phenylsulfonyl]thiophene-2-sulfonamide (m.p. 174-177). 5-[4-(3-methylaminopropyl)phenylsulfonyl]thiophene-2-sulfonmide (m.p. 178°-179.5° C.), 5-[4-(3-dimethylaminopropyl)phenylsulfonyl]thiophene-2-sulfonamide (m.p. 163°-164.5° C.), and 5-[4-(4-dimethylaminobutyl)phenylsulfonyl]thiophene-2-sulfonamide (m.p. 186°-189° C.).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([OH:24])=O)=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=2)[CH2:6][C@@H:5]1[CH3:34])(=[O:3])[CH3:2].[CH2:35]([CH2:37][NH2:38])[OH:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][C:22]([NH:38][CH2:37][CH2:35][OH:36])=[O:24])=[CH:18][CH:19]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=2)[CH2:6][C@@H:5]1[CH3:34])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(CCC(=O)O)cc3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Reactant: NCCO
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: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3ccc(CCC(=O)NCCO)cc3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Reaction time: 0.67 h
Yield: 47 %

Procedure:
To a solution of 3-(4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)propanoic acid (for a preparation see Intermediate 10)(44 mg, 0.097 mmol) and ethanolamine (0.012 mL, 0.194 mmol) in DMF (3 mL) were added HATU (55.2 mg, 0.145 mmol) and DIPEA (0.051 mL, 0.290 mmol). The resulting mixture was stirred for 40 min, then partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc (×3), the combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was dissolved in 1:1 MeOH/DMSO and was purified by MDAP (formate). The appropriate fractions were combined and concentrated in vacuo to give 3-(4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)-N-(2-hydroxyethyl)propanamide (22.8 mg, 47%) as a, viscous yellow oil. LCMS (Formate, 2 min), Rt=0.80 min, MH+=498.
Reaction SMILES: [CH:1]1([NH:7][C@@H:8]2[CH2:25][C@@:23]3([CH3:24])[C@@H:19]([CH2:20][CH2:21][C@@H:22]3[C:26]([O:28][CH3:29])=[O:27])[C@H:18]3[C@H:9]2[C@:10]2([CH3:31])[C@@H:15]([CH2:16][CH2:17]3)[CH2:14][C@H:13]([OH:30])[CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC1C=CC(S(O)(=O)=O)=CC=1.[C:43](OC(=O)C)(=[O:45])[CH3:44]>C(Cl)(Cl)Cl.C(O)C.C([O-])(O)=O.[Na+].O>[C:43]([O:30][C@@H:13]1[CH2:12][CH2:11][C@@:10]2([CH3:31])[C@@H:15]([CH2:16][CH2:17][C@@H:18]3[C@@H:9]2[C@H:8]([NH:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:25][C@@:23]2([CH3:24])[C@H:19]3[CH2:20][CH2:21][C@@H:22]2[C:26]([O:28][CH3:29])=[O:27])[CH2:14]1)(=[O:45])[CH3:44]
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3[C@H](NC3CCCCC3)C[C@]12C
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OC(C)=O)CC[C@]4(C)[C@H]3[C@H](NC3CCCCC3)C[C@]12C
Reaction time: 0.33 h

Procedure:
Methyl 11α-cyclohexylamino-3α-hydroxy-5α-androstane-17β-carboxylate (550 mg) in chloroform (5.5 ml) containing dry PTSA (440 mg) was stirred for 20 min then treated with acetic anhydride (1.0 ml) and left for 18 h. The reaction mixture was diluted with ethanol and evaporated to give an oil. The residue is ethanol (10 ml) was diluted with 5% NaHCO3 solution (50 ml) and water (100 ml) and extracted with ether (3×). The extracts were washed with water (1×), dried and evaporated to give an oil. This was crystallised from methanol to give the title compound (249 mg), m.p. 126°-128°, [α]D +12°.
Reaction SMILES: O[C:2]1([OH:11])[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[CH:3]1[OH:10].[CH3:12][CH2:13][O:14]CC.C(#N)C.Cl>[Cl-].[Zn+2].[Cl-].O>[OH:11][C:2]1[C:3]([OH:10])=[C:4]([OH:9])[CH:5]=[C:6]([OH:8])[C:7]=1[C:13]([CH3:12])=[O:14]
Reactant: CCOCC
Reactant: OC1=CC(O)(O)C(O)C(O)=C1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC#N
Solvent: O
Product: CC(=O)c1c(O)cc(O)c(O)c1O
Temperature: 0 °C
Reaction time: 13 h
Yield: 31.8 %

Procedure:
Under a stream of argon, 2.00 g (14.08 mmol) of 1,2,3,5-tetrahydroxyphenol (3) and 20 ml of ether were placed to form a suspension and 1.00 g (24.3 mmol, 1.73 equivalents) of acetonitrile was added to the suspension. While the resultant mixture was cooled with ice water, 0.70 g (5.14 mmol, 0.36 equivalent) of zinc chloride was added to the mixture and hydrogen chloride gas was bubbled at room temperature for four hours with stirring. The aeration of the mixture with the gas was stopped and the aerated mixture was left standing still at 4° C. for 13 hours. The ether layer was removed by decantation from the tarry precipitates consequently formed. The precipitates were stirred in an ice bath and 60 ml of water was added-to the stirred precipitates and they were heated under reflux for 4 hours. The product of the reflux, after adding a small amount of active carbon, was filtered while kept in hot. From the filtrate, yellow crystals were obtained as precipitates. By dissolving the crystals again in ether, removing the insoluble by filteration, and then concentrating the filtrate, 0.82 g (yield 31.8%) of the product (11) was obtained in the form of yellow platelike crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([NH:11]C(=O)/C=C\C(O)=O)=[O:10])[CH:6]=[CH:5][N:4]=1.O=P(Cl)(Cl)Cl.[NH2:24][NH:25][C:26]([C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][N:36]=1)=[N:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:34].C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:41][C:38]1[CH:39]=[CH:40][C:35]([C:26]2[N:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:34])[C:6](/[CH:7]=[CH:8]/[C:3]3[O:10][C:9]([C:7]4[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=4)=[N:11][N:4]=3)=[N:24][N:25]=2)=[N:36][CH:37]=1
Reactant: NNC(=Nc1ccccc1Cl)c1ccc(Cl)cn1
Reactant: COc1cc(C(=O)NC(=O)/C=C\C(=O)O)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: COc1cc(-c2nnc(/C=C/c3nnc(-c4ccc(Cl)cn4)n3-c3ccccc3Cl)o2)ccn1
Temperature: 25 °C

Procedure:
To a suspension of (Z)-4-(2-methoxypyridine-4-carboamido)-4-oxobut-2-enoic acid 4 (0.2 g, 0.75 mmol) in CH3CN was added POCl3 (0.37 g, 2.4 mmol). The mixture was stirred under reflux for 16 hours, cooled to ambient temperature and concentrated under reduced pressure. The residue was dissolved in CH3CN, treated with a solution of N-amino-5-chloro-N′-(2-chlorophenyl)pyridine-2-carboxamidine 8 (0.38 g, 1.2 mmol) in CH3CN and K2CO3 (0.38 g, 1.2 mmol). The mixture was stirred at ambient temperature for 1 hour, refluxed for 2 hours, and filtered. The filtrate was concentrated. The residue was subjected to FCC (50-60% EtOAc/hexanes) to afford the title compound 5-chloro-2-(4-(2-chlorophenyl)-5-((E)-2-(5-(2-methoxypyridin-4-yl)-1,3,4-oxadiazol-2-yl)vinyl)-4H-1,2,4-triazol-3-yl)pyridine as a white solid. Yield: 0.11 g, 28%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)[CH2:9][C:8]2([CH3:23])[CH3:22])=[O:4].[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:16]=1)[CH2:9][C:8]2([CH3:23])[CH3:22])=[O:4]
Reactant: C1CCNC1
Reactant: COC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(Br)c1)N2
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: COC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(N3CCCC3)c1)N2
Temperature: 25 °C
Yield: 93.3 %

Procedure:
A mixture solution of 2-(3-bromo-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (1.94 g, 5 mmol), pyrrolidine (2.1 mL, 25 mmol), copper(I) iodide (0.38 g, 2 mmol), N,N-dimethylglycine hydrochloride (0.42 g, 3 mmol), and potassium carbonate (2.07 g, 15 mmol) in dimethyl sulfoxide (10 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature. The reaction mixture was extracted with ethyl acetate (50 mL×2), washed with saturated aqueous ammonium chloride solution (20 mL×3) and brine (20 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 30-50% ethyl acetate in petroleum ether) to afford 4,4-dimethyl-2-(3-pyrrolidin-1-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (1.7 g, 90%) as a yellow solid: MS (ESI) M+1=379.1.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][C:27]([OH:29])=O)=[CH:20][CH:19]=3)[C:10]2=[S:30])=[CH:5][C:4]=1[C:31]([F:34])([F:33])[F:32])#[N:2].ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[CH3:47][S:48]([NH2:51])(=[O:50])=[O:49]>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][CH2:26][C:27]([NH:51][S:48]([CH3:47])(=[O:50])=[O:49])=[O:29])=[CH:22][CH:23]=3)[C:10]2=[S:30])=[CH:5][C:4]=1[C:31]([F:34])([F:32])[F:33])#[N:2]
Reactant: N#Cc1ccc(N2C(=O)C3(CCC3)N(c3ccc(CCCC(=O)O)cc3)C2=S)cc1C(F)(F)F
Reactant: CS(N)(=O)=O
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)CCCc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 94 %

Procedure:
A mixture of 4-{4-[7-(4-cyano-3-trifluoromethylphenyl)-8-oxo-6-thioxo-5,7-diaza-spiro[3.4]oct-5-yl]phenyl)butanoic acid (42c) (0.049 g, 0.1 mmol), 2,4,6-trichlorobenzoyl chloride (0.244 g, 1 mmol), 4-dimethylaminopyridine (0.122 g, 1 mmol) and methanesulfonamide (0.019 g, 0.2 mmol) in dichloromethane was stirred at room temperature for 20 hours. The mixture was concentrated and chromatographed (dichloromethane:acetone, 80:20) to yield N{4-{4-[7-(4-cyano-3-trifluoromethylphenyl)-8-oxo-6-thioxo-5,7-diaza-spiro[3.4]oct-5-yl]phenyl}-butanoyl)-methanesulfonamide (42f) [RD157] (0.053 g, 0.094 mmol, 94%), the structure of which is illustrated in Formula 8, as a white powder.
Reaction SMILES: [H-].[Li+].[Al+3].[H-].[H-].[H-].[N:7]1([CH2:13][CH2:14][NH:15][C:16](=O)OC(C)(C)C)[CH2:12][CH:11]=[CH:10][CH2:9][CH2:8]1.[OH-].[Na+]>O1CCCC1>[N:7]1([CH2:13][CH2:14][NH:15][CH3:16])[CH2:8][CH:9]=[CH:10][CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)NCCN1CC=CCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCCN1CC=CCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 42.8 %

Procedure:
80% Aluminum lithium hydride (0.36 g, 7.5 mmol) was suspended in tetrahydrofuran (10 mL). A solution of 1,1-dimethylethyl N-[2-(3,6-dihydropyridin-1(2H)-yl)ethyl]carbamate (0.68 g, 3.0 mmol) in tetrahydrofuran (10 mL) was added dropwise thereto at room temperature over 10 minutes, and the mixture was refluxed for 3 hours. The reaction solution was cooled to room temperature, and then a 1 N aqueous sodium hydroxide solution (20 mL) was added portionwise thereto. Insolubles were filtered off through a Celite, and the Celite was washed with tetrahydrofuran. The filtrate was concentrated under reduced pressure, and the residue was purified with amino silica gel column chromatography (hexane:ethyl acetate=19:1 to ethyl acetate) to obtain the title compound (0.18 g, yield 42%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[CH:7]=[C:8]1O[C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[CH2:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2)([O-])=O.[OH2:26].O.[Sn](Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1>C(O)C.C(OCC)(=O)C>[C:8]1(=[CH:7][C:6]2[CH:5]=[C:4]([NH2:1])[CH:25]=[CH:24][CH:23]=2)[C:9]2[C:22]([O:26][CH2:13][C:15]3[CH:16]=[CH:17][CH:18]=[CH:12][C:11]=3[CH:10]=2)=[CH:21][CH:20]=[CH:19]1
Reactant: O=[N+]([O-])c1cccc(C=C2Oc3ccccc3Cc3ccccc32)c1
Reactant: O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Nc1cccc(C=c2cccc3c2=Cc2ccccc2CO3)c1
Yield: 33 %

Procedure:
Dissolve 11-(3-Nitro-benzylidene-6,11-dihydro-dibenzo[b,e]oxepine (200 mg) in ethanol (10 mL) add tin chloride dihydrate (680 mg) and reflux for 5 h. Concentrate the reaction in vacuo, re-dissolve in ethyl acetate and wash with 1N sodium hydroxide solution. Separate the layers wash with brine and dry over sodium sulfate. Purity using filter chromatography eluting with 10% ethyl acetate:toluene to give 60 mg of product (56% yield).
Reaction SMILES: [OH-].[Na+].Cl[C:4]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].[NH2:14][CH2:15][C:16]([OH:18])=[O:17].C(=O)([O-])[O-].[K+].[K+]>O.C(=O)([O-])[O-].[Cu+2]>[C:16]([CH:15]=[N:14][C:4]1[C:5](=[CH:9][CH:10]=[C:11]([Cl:13])[CH:12]=1)[C:6]([OH:8])=[O:7])([OH:18])=[O:17]
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Reactant: NCC(=O)O
Agent: [Cu+2]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)C=Nc1cc(Cl)ccc1C(=O)O
Temperature: 80 °C
Yield: 90 %

Procedure:
20 g (0.5 mol) of NaOH are dissolved in 100 ml of water, and 38.2 g (0.2 mol) of 2,4-dichlorobenzoic acid, 22.5 g (0.3 mol) of glycine and 1.4 g (6 mmol) of basic copper carbonate are added. The mixture is heated to 80° C., and 28 g (0.2 mol) of potassium carbonate are added. It is heated at 100° C. for 3 h. The filtrate after filtration with suction while hot is added to 100 ml of water and adjusted to pH 1-2 with hydrochloric acid. The product then precipitates and is filtered with suction and dried. 41 g (0.18 mol; 89%) of N-carboxymethylene-4-chloroanthranilic acid are obtained.
Reaction SMILES: O[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[N:3]=1.P(Cl)(Cl)([Cl:22])=O.C(=O)([O-])[O-].[K+].[K+]>>[Cl:22][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[N:3]=1
Reactant: CCOC(=O)c1cnc(-c2ccccc2C)nc1O
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1cnc(-c2ccccc2C)nc1Cl
Temperature: -5 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
A solution of 4.00 g of ethyl 4-hydroxy-2-o-tolylpyrimidine-5-carboxylate (15.5 mmol) in 11.6 mL of phosphorous oxychloride (124 mmol) was heated to reflux (calcium chloride filled tube as protection from the outside atmosphere). After 3 h, the excess POCl3 was removed by distillation (˜20 Torr, 90-100° C. oil bath). The residual red oil on cooling solidified. The solids were pulverized and covered with 100 mL of EtOAc. The slurry was cooled to −5° C. and agitated vigorously for 10 min with 25 mL of a potassium carbonate solution (2 M, 50 mmol). The resulting organic phase was separated, dried (MgSO4), filtered and evaporated to give, after triturating in hexanes, the title compound as a light orange solid, 3.58 g, 84% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[OH-].[Na+].[CH:16]1([C:19](Cl)=[O:20])[CH2:18][CH2:17]1>C1COCC1.O>[CH:16]1([C:19]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=2)=[O:20])[CH2:18][CH2:17]1
Reactant: Nc1ccc(C(=O)O)c([N+](=O)[O-])c1
Reactant: O=C(Cl)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(NC(=O)C2CC2)cc1[N+](=O)[O-]

Procedure:
6 g (0.033 mol) of 4-amino-2-nitrobenzoic acid were dissolved in a mixture (100 ml) of THF and water (1:1). The solution was adjusted to pH 8.5 with 2 N NaOH and reacted at room temperature with 3.78 g (0.0363 mol) of cyclopropanecarboxylic acid chloride in 25 ml of THF. The pH value of the reaction solution was kept at 8.0 - 8.5 to the end by further addition of 2 N sodium hydroxide solution. After a reaction time of 3.5 hours, the solvent was next distilled off. The residue was diluted with water and the aqueous solution was extracted by shaking once with ethyl acetate and was finally acidified with 2 N HCl to pH 2.0. The oil which precipitated was isolated by extraction with ethyl acetate. After washing and drying the ethyl acetate phase, the solution was concentrated to dryness. The product was crystallized from ethyl acetate/petroleum ether.