Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[N:16]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[N:16]=2)=[CH:22][CH:23]=1
Reactant: [H][H]
Reactant: Nc1nccc(-c2ccccc2Oc2ccc([N+](=O)[O-])cc2)n1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(Oc2ccccc2-c2ccnc(N)n2)cc1
Reaction time: 8 h

Procedure:
4-(2-(4-nitrophenoxy)phenyl)pyrimidin-2-amine (0.280 g, 0.908 mmol) and palladium, 10 wt. % (dry basis) on activated carbon 50% water wet (0.193 g, 0.182 mmol) were combined under nitrogen and diluted with 5 mL MeOH. The atmosphere was replaced with hydrogen, and the mixture was stirred rapidly overnight. The reaction was flushed with nitrogen and was filtered through celite, rinsing with MeOH. Concentration in vacuo afforded 4-(2-(4-aminophenoxy)phenyl)pyrimidin-2-amine MS m/z=279 [M+H]+. Calc'd for C16H14N4O: 278.3.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:12][CH2:13]Cl)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:23]#[N:24].[H-].[Na+]>C1COCC1.CN(C=O)C>[C:23]([C:22]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH3:15])[CH2:13][CH2:12][N:4]([C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:3][CH2:2]1)#[N:24]
Reactant: Cc1ccccc1CC#N
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ccccc1C1(C#N)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
A solution of bis(2-chloroethyl)-N-(1,1-dimethylethoxy)carbonyl amine (1.438 g, 5.94 mmol) and 2-methylphenyl acetonitrile (600 mg, 3.96 mmol) in a 4:1 mixture of THF/DMF (15 mL) was treated with NaH (357.9 mg, 8.7 mmol) at 60° C. (3 d). The solvent was removed in vacuo, the residue dissolved in EtOAc (200 ml) and washed with saturated NaHCO3 (50 ml), H2O (2×50 ml), and saturated aqueous NaCl (50 ml), dried (Na2SO4) and concentrated in vacuo. PCTLC (SiO2, 6 mm, 100% hexane) afforded 4-cyano-N-(1,1-dimethylethoxy)carbonyl-4-(2-methylphenyl) piperidine as a yellow/orange oil.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:8]=[C:9]([N:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([O:17][CH3:18])[CH:11]=2)=O.Cl.[CH3:34][N:35](N)[C:36]([NH2:38])=[NH:37].[O-]CC.[Na+]>C(O)C>[CH3:18][O:17][C:12]1[CH:11]=[C:10]2[C:15]([CH:16]=[C:7]([C:5]3[CH:4]=[CH:3][N:38]=[C:36]([NH:35][CH3:34])[N:37]=3)[CH:8]=[C:9]2[N:19]2[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH2:23][CH2:24]2)=[CH:14][CH:13]=1
Reactant: CN(N)C(=N)N
Reactant: COc1ccc2cc(C(=O)/C=C/N(C)C)cc(N3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CNc1nccc(-c2cc(N3CCN(C(=O)OC(C)(C)C)CC3)c3cc(OC)ccc3c2)n1

Procedure:
To a solution of tert-butyl 4-(3-(3-(dimethylamino)acryloyl)-7-methoxynaphthalen-1-yl)piperazine-1-carboxylate 108 (1.5 g) in ethanol (50 ml) was added methyl amino guanidine hydrochloride (0.75 g) and 21% wt sodium ethoxide in ethanol (1 ml). The reaction was stirred at reflux for 2 days, and more sodium ethoxide (0.5 ml) was added to the reaction. The reaction was allowed to reflux overnight. The solvents were concentrated under reduced pressure and the residue was redissolved in ethyl acetate (100 ml) and water (50 ml). The organics were separated, washed with water (1×50 ml), dried over sodium sulfate and concentrated. Column chromatography (pre-packed SiO2, 40% ethyl acetate in hexanes to 75% ethyl acetate in hexanes) gave tert-butyl 4-(7-methoxy-3-(2-(methylamino)pyrimidin-4-yl)naphthalen-1-yl)piperazine-1-carboxylate 111 as a light yellow solid. LC/MS (m/z): 450 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([OH:19])=O)[C:11](=[O:23])[N:10]([CH2:24][C:25]([NH:27][C:28]([CH3:40])([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)[CH3:29])=[O:26])[N:9]=2)=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C[CH2:52][N:53]=[C:54]=NCCCN(C)C.Cl.Cl.CNC.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([N:53]([CH3:54])[CH3:52])=[O:19])[C:11](=[O:23])[N:10]([CH2:24][C:25]([NH:27][C:28]([CH3:40])([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:39])[F:38])[CH:31]=3)[CH3:29])=[O:26])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(Cc2cccc(C(=O)O)c2)c1=O)c1cccc(C(F)(F)F)c1
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cccc(Cn2c(-c3ccc(Cl)cc3)nn(CC(=O)NC(C)(C)c3cccc(C(F)(F)F)c3)c2=O)c1
Reaction time: 0.17 h

Procedure:
30 mg (0.052 mmol) of 3-(3-(4-chlorophenyl)-1-[2-(1-methyl-1-[3-(trifluoromethyl)phenyl]ethylamino)-2-oxoethyl]-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-ylmethyl)-benzoic acid (Example 471) are placed in 0.5 ml of DMF and treated with 9.2 mg (0.068 mmol) of HOBt and 13.0 mg (0.068 mmol) of EDC hydrochloride. After 10 mins' stirring, 6.0 mg (0.073 mmol) of dimethylamine hydrochloride and 10.2 mg (0.079 mmol) of N,N-diisopropylethylamine are added and the mixture is stirred overnight at RT. Without further workup, the crude product is purified directly by preparative HPLC [Method 10]. 29.8 mg (95% of theory) of the target compound are thus obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[CH2:8][CH2:7][N:6]1[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C@@H:23]([NH:25][C:26](=[O:28])[CH3:27])[CH3:24])=[CH:19][CH:18]=1)=[O:4].Br[CH2:30][CH:31]1[CH2:33][CH2:32]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3]([CH:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:30][CH:31]3[CH2:33][CH2:32]3)=[CH:12][CH:13]=2)[CH2:8][CH2:7][N:6]1[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C@@H:23]([NH:25][C:26](=[O:28])[CH3:27])[CH3:24])=[CH:21][CH:22]=1)=[O:4]
Reactant: COC(=O)C1c2ccc(O)cc2CCN1Cc1ccc([C@H](C)NC(C)=O)cc1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1c2ccc(OCC3CC3)cc2CCN1Cc1ccc([C@H](C)NC(C)=O)cc1

Procedure:
15 mg (39 μmol) 2-[4-((S)-1-Acetylamino-ethyl)-benzyl]-6-hydroxy-1,2,3,4-tetrahydro-isoquinoline-1-carboxylic acid methyl ester (example XXXVIII), 5.8 mg (43 μmol) (bromomethyl)cyclopropane and 10 mg (78 μmol) K2CO3 in 2 mL DMF are stirred at 80° C. over night. The reaction mixture is diluted with water and extracted with DCM. The organic layer is concentrated by evaporation and the residue is purified by HPLC.
Reaction SMILES: [CH2:1]1[S:6][C:4](=[O:5])[NH:3][C@@H:2]1[C:7]([OH:9])=[O:8].P(OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1O)(OP(OP(O)(O)=O)(O)=O)(=O)[OH:11]>>[C:4]([S:6][CH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[NH2:3])([OH:11])=[O:5]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Reactant: O=C1N[C@H](C(=O)O)CS1
Product: N[C@@H](CSC(=O)O)C(=O)O

Procedure:
L-2-oxothiazolidine-4-carboxylate, in vitro, is subjected to the action of 5-oxo-L-prolinase in the presence of adenosine triphosphate to produce S-carboxyl cysteine. S-carboxyl cysteine is then decarboxylated to produce cysteine. Cysteine is then metabolized to provide glutathione. See, U.S. Pat. Nos.: 4,335,210; 4,434,158; 4,438,124; 4,665,082; and 4,647,571 the disclosures of which are incorporated herein by reference.
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1)(OCC)=O)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:30]([C@@H:32]1[CH2:36][CH2:35][CH2:34][N:33]1[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=O>C1COCC1>[CH3:17][O:16][C:14]([C:13]1[CH:12]=[CH:11][C:10](/[CH:9]=[CH:30]/[C@@H:32]2[CH2:36][CH2:35][CH2:34][N:33]2[C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])=[CH:19][CH:18]=1)=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Reactant: CCOP(=O)(Cc1ccc(C(=O)OC)cc1)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(/C=C/[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Temperature: -78 °C
Yield: 61.6 %

Procedure:
To a solution of the product of Example 149A (4.02 g, 14.05 mmol) dissolved in THF (50 mL) and cooled to −78° C. was added lithium bis(trimethylsilyl)amide (1.0M in THF, 12.05 mL, 12.05 mmol) dropwise and the resultant solution stirred at −78° C. for 1 additional hour. Afterwards a solution of (S)-tert-butyl 2-formylpyrrolidine-1-carboxylate (2.0 g, 10.04 mmol) in THF (20 mL) was added dropwise, the cooling bath was then removed and after the reaction reached room temperature it was maintained at this temperature for an additional 3 hours. The solution had EtOAc added to it and the mixture extracted with water. The organic extract was then dried, filtered, concentrated and purified by chromatography (silica gel, 10-50% EtOAc in hexanes) to afford 2.05 g (62%) of the title compound. MS (ESI) m/z 332 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[C:3]1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1.O>CN(C)C=O>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2](=[O:1])[C:3]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4]2)=[CH:21][CH:20]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CCOC(=O)c1c[nH]c2ccccc2c1=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(Cc2ccc(OC)cc2)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate (3.17 g, 14.6 mmol) and 4-methoxybenzylchloride (2.18 mL, 16.0 mmol, 1.1 equiv) were combined in N,N-dimethylformamide (50 mL) and stirred at ambient temperature for 72 hours. The mixture was poured into water (500 mL) and extracted with dichloromethane (2×250 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was treated with water (500 mL), hexanes (500 mL) and ethyl acetate (500 mL) and aged for 30 minutes. The mixture was filtered and the solid was dissolved in dichloromethane (500 mL) and combined with the filtrate. The filtrate was partitioned and the aqueous layer was discarded. The organic layer was dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[O:10])=[C:4]([F:22])[CH:3]=1.[F:23][C:24]([F:36])([F:35])[O:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>>[F:22][C:4]1[CH:3]=[C:2]([C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([O:25][C:24]([F:23])([F:35])[F:36])[CH:27]=2)[CH:7]=[C:6]([F:8])[C:5]=1[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:13][CH2:12]1)=[O:10]
Reactant: O=C(c1c(F)cc(Br)cc1F)N1CCC(N2CCCC2)CC1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Product: O=C(c1c(F)cc(-c2cccc(OC(F)(F)F)c2)cc1F)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 1, (4-bromo-2,6-difluoro-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 39) was reacted with 3-trifluoromethoxy-phenyl boronic acid to give the title compound as colorless oil. MS: 455.5 (MH+).
Reaction SMILES: [NH3:1].[O:2]=[C:3]1[N:7]([CH2:8][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=O)[N:6]=C(C(F)(F)F)O1>C(#N)C>[NH2:6][N:7]1[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[NH:1][C:3]1=[O:2]
Reactant: CC(C)(C)C(=O)Cn1nc(C(F)(F)F)oc1=O
Reactant: N
Solvent: CC#N
Product: CC(C)(C)c1cn(N)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
75 ml of aqueous ammonia solution (25%) are added to a solution of 25.6 g of 2,3-dihydro-2-oxo-3-tert-butylcarbonylmethyl-5-trifluoromethyl-1,3,4-oxadiazole in 100 ml of acetonitrile. After the slightly exothermal reaction has subsided, the reaction mixture is stirred for 2 hours at room temperature and then for 14 hours at 80° and then evaporated, the residue is treated with trichloromethane, and the trichloromethane mixture is freed from the undissolved components, dried and evaporated. The residue is triturated with diethyl ether and subjected to filtration with suction. This gives the tide compound in the form of pale yellow crystals which melt at 197-200°.
Reaction SMILES: C[O:2][C:3]([CH2:5][C:6]1[CH:26]=[CH:25][C:9]([O:10][CH2:11][CH:12]([NH:14][CH2:15][CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[OH:17])[CH3:13])=[C:8]([Cl:27])[CH:7]=1)=O.[NH3:28]>CO>[C:3]([CH2:5][C:6]1[CH:26]=[CH:25][C:9]([O:10][CH2:11][CH:12]([NH:14][CH2:15][CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[OH:17])[CH3:13])=[C:8]([Cl:27])[CH:7]=1)(=[O:2])[NH2:28]
Reactant: COC(=O)Cc1ccc(OCC(C)NCC(O)c2cccc(Cl)c2)c(Cl)c1
Reactant: N
Solvent: CO
Product: CC(COc1ccc(CC(N)=O)cc1Cl)NCC(O)c1cccc(Cl)c1

Procedure:
A solution of 2 g of 2-[2-(4-methoxycarbonylmethyl-2-chlorophenoxy) -1-methylethyl]amino-1-(3-chlorophenyl)ethanol (prepared as described in Example 22) dissolved in 50 ml of methanol was saturated with gaseous ammonia in a reaction vessel, whilst ice-cooling, after which the reaction vessel was tightly stoppered and allowed to stand at room temperature for one week. At the end of this time, the solvent (methanol) was removed by distillation under reduced pressure, and the residue was recrystallized from ethyl acetate, to give 0.55 g of the title compound as crystals, melting at 99°-101° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[Cl:12][CH2:13][CH2:14][C:15](Cl)=[O:16]>C1C=CC=CC=1>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:15](=[O:16])[CH2:14][CH2:13][Cl:12])=[CH:5][CH:4]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: O=C(Cl)CCCl
Solvent: c1ccccc1
Product: O=C(CCCl)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Trifluoromethylaniline (0.3 mole), β-chloropropionyl chloride (0.35 mole) and benzene (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux with stirring for a period of about 3 hours. After this time the reaction mixture is cooled to room temperature and is washed with dilute aqueous sodium bicarbonate, with dilute hydrochloric acid and with water. The washed mixture is then dried over anhydrous magnesium sulfate, filtered and stripped of benzene under reduced pressure to yield the desired product N-(4-trifluoromethylphenyl)-β-chloropropionamide as the residue.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:20]4[CH:24]=[CH:23][O:22][CH:21]=4)=[O:19])[CH:16]=3)[NH:11][C:10](=[O:25])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].I[CH3:29].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:20]4[CH:24]=[CH:23][O:22][CH:21]=4)=[O:19])[CH:16]=3)[N:11]([CH3:29])[C:10](=[O:25])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccoc1)c1ccc2[nH]c(=O)cc(-c3cccc(Cl)c3)c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)cc(-c2cccc(Cl)c2)c2cc(C(=O)c3ccoc3)ccc21
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 9.6 %

Procedure:
A mixture of (intermediate 26) (0.04 mol) in DMF (200 ml) was cooled to 5° C. under N2 flow. NaH 80% in oil (0.048 mol) was added portionwise. The mixture was stirred at 5° C. for 30 min. Then iodomethane (0.048 mol) was added dropwise. The mixture was stirred at 5° C. for 30 min, hydrolized and poured out into water. The precipitate was filtered off, washed with water and taken up in CH2Cl2. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue (15.5 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/EtOAc 85/15; 15–40 μm). The pure fractions were collected and the solvent was evaporated. The residue (13.3 g, 91.7%) was crystallized from CH3CN and DIPE. The precipitate was filtered off and dried, yielding 1.5 g (9.6%) of 4-(3-chlorophenyl)-6-(3-furanylcarbonyl)-1-methyl-2(1H)-quinolinone (intermediate 27), melting point 192° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[CH2:4][CH:5]=[CH2:6].Br[CH2:9][C:10]([OH:12])=[O:11]>C1COCC1>[CH2:3]([O:7][CH2:9][C:10]([OH:12])=[O:11])[CH2:4][CH:5]=[CH2:6]
Reactant: O=C(O)CBr
Reactant: C=CCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCCOCC(=O)O
Reaction time: 2 h
Yield: 126.8 %

Procedure:
To 480 mg of NaH (50% in mineral oil, ˜20 mmol) in 10 ml of abs. THF was added at 0° 721 mg of 3-buten-1-ol (10 mmol) and the mixture stirred for 5 Min. (H2-evolution). 1.39 g of bromo-acetic acid (10 mmol), dissolved in 10 ml of THF, was then added and the mixture kept for additional 5 Min. at 0° and for 2 h at ambient temperature. Pouring onto crashed ice/HCl dil., twofold extraction with AcOEt, washing with brine, drying over sodium sulfate and evaporation of the solvents afforded 1.65 g of the title compound, contaminated with mineral oil, but sufficiently pure for the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][N:8]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:30]([C:32]1[CH:33]=[C:34]([S:39](Cl)(=[O:41])=[O:40])[CH:35]=[CH:36][C:37]=1[F:38])#[N:31]>C1COCC1>[C:30]([C:32]1[CH:33]=[C:34]([S:39]([N:6]([CH2:5][C:4]2[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:3]=2[O:2][CH3:1])[C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][N:8]=2)(=[O:41])=[O:40])[CH:35]=[CH:36][C:37]=1[F:38])#[N:31]
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Reactant: COc1ccc(CNc2ccc(F)cn2)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ccc(F)cn2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Temperature: 0 °C
Yield: 63 %

Procedure:
To a −40° C. solution of N-(2,4-dimethoxybenzyl)-5-fluoropyridin-2-amine (Preparation 20, 2.32 g, 8.84 mmol) in THF (60 ml) was added LiHMDS (9.72 ml, 9.72 mmol, 1M in THF) keeping the temperature below −35° C. The reaction mixture was warmed to 0° C. for 40 minutes before re-cooling to −40° C. 3-Cyano-4-fluorobenzene-1-sulfonyl chloride (1.94 g, 8.84 mmol) was added to the reaction mixture as a solution in THF (10 mL) and the reaction mixture allowed to warm to room temperature for 18 hours. The reaction mixture was quenched with saturated ammonium chloride solution (100 mL) and extracted with EtOAc (2×100 mL). The organic layer was washed with saturated brine (100 mL), dried over MgSO4, filtered and the solvent removed under vacuum. The crude material was purified by silica gel column chromatography eluting with 20-40 EtOAc in heptane followed by reverse phase chromatography eluting with 0-100% MeCN in H2O to afford the title compound as a brown gum (2.48 g, 63%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[C:9]([C:12]2[N:16]([CH3:17])[N:15]=[N:14][N:13]=2)[CH2:10]Br)=[CH:4][CH:3]=1.[P:25]([O:30]C)([O:28][CH3:29])[O:26][CH3:27]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[C:9]([C:12]2[N:16]([CH3:17])[N:15]=[N:14][N:13]=2)[CH2:10][P:25](=[O:30])([O:28][CH3:29])[O:26][CH3:27])=[CH:4][CH:3]=1
Reactant: COP(OC)OC
Reactant: Cn1nnnc1C(CBr)=C(c1ccc(F)cc1)c1ccc(F)cc1
Product: COP(=O)(CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnnn1C)OC
Temperature: 25 °C

Procedure:
A slurry of 3,3-bis-(4-fluorophenyl)-1-bromo-2-(1-methyl-1H-tetrazol-5-yl)-2-propene (1.17 g, 3.0 mmol) and trimethyl phosphite (0.41 g, 3.3 mmol) was heated at 100° C. for 5 minutes. After cooling to ambient temperature, excess trimethylphosphite was removed in vacuo to give a light yellow solid. This solid was recrystallized from ethylacetate/hexane mixture to give the title compound as a pure white solid; m.p.=140°-141° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=O.[CH2:11]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)[CH2:12][CH3:13]>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][C:16]2[S:15][C:14]([CH2:11][CH2:12][CH3:13])=[CH:18][CH:17]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)c1cccc(Br)c1
Reactant: CCCc1cccs1
Product: CCCc1ccc(Cc2cccc(Br)c2)s1

Procedure:
3-Bromobenzoic acid and 2-n-propylthiophene were used and treated in a manner similar to Reference Example 5 to give the target compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:13])[C:11]#[N:12])=[CH:6][CH:5]=1)([O-])=O>[C].[Pd].C1COCC1.CCO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH3:13])[C:11]#[N:12])=[CH:8][CH:9]=1
Reactant: CC(C#N)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C#N)c1ccc(N)cc1
Reaction time: 0.5 h

Procedure:
To the flask was added THF/EtOH (1:1, 70 mL) followed by 2-(4-nitrophenyl)-propionitrile (13.2 g, 74.9 mmol) and 10% palladium carbon (1.07 g) at room temperature. The reaction mixture was hydrogenated and stirred for 30 minutes at 47 psi to 28 psi then filtered through celite bed, and washed with EtOAc. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (1:3) as eluant.
Reaction SMILES: [CH3:1][S:2]([CH:5]1[CH2:9][CH2:8][N:7]([S:10]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:6]1)(=[O:4])=[O:3].[NH:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[CH2:27][N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH3:1][S:2]([CH:5]1[CH2:9][CH2:8][N:7]([S:10]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([N:22]3[CH2:26][CH2:25][CH2:24][C@H:23]3[CH2:27][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:19])=[CH:20][CH:21]=2)(=[O:12])=[O:11])[CH2:6]1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)C1CCN(S(=O)(=O)c2ccc(C(=O)O)cc2)C1
Reactant: C1CN[C@H](CN2CCCC2)C1
Product: CS(=O)(=O)C1CCN(S(=O)(=O)c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)C1
Yield: 49.7 %

Procedure:
The title compound is prepared from 4-(3-methanesulfonyl-pyrrolidine-1-sulfonyl)-benzoic acid (230 mg, 0.69 mmol) and (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (CAS 51207-66-0)(88 mg, 0.57 mmol) in a manner substantially similar to Procedure G to provide 133 mg (50%) of the title compound. MS (ES+) 470.2 (M+H)+.