Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OCC1CC1.C(Cl)(Cl)=O.Cl[C:11]([O:13][CH2:14][CH:15]1[CH2:17][CH2:16]1)=[O:12].[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]([CH3:32])[CH2:27][C:28](=[O:31])[NH:29][N:30]=2)=[CH:21][CH:20]=1>CCOCC.C1(C)C=CC=CC=1>[CH:15]1([CH2:14][O:13][C:11]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:26]([CH3:32])[CH2:27][C:28](=[O:31])[NH:29][N:30]=3)=[CH:21][CH:20]=2)=[O:12])[CH2:17][CH2:16]1
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: O=C(Cl)OCC1CC1
Agent: O=C(Cl)Cl
Agent: OCC1CC1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)OCC2CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34 %

Procedure:
3.2 g (44.4 millimoles) of (hydroxymethyl)cyclopropane, dissolved in 50 ml of absolute ether, are added dropwise to a stirred solution of 8.8 g (89.0 millimoles) of phosgene in 50 ml of absolute ether at 10°-15° C. The reaction solution is then stirred for 3 hours at room temperature. The excess phosgene is removed by means of a dry stream of nitrogen, and the ether is then removed under reduced pressure at room temperature. The cyclopropylmethyl chloroformate which remains is mixed with 6.0 g (29.5 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone and 100 ml of absolute toluene and the mixture is kept for 7 hours at 80° C. The product is filtered off at 10° C., washed first with toluene and then with water, and recrystallized twice from dimethylformamide/water. 3.0 g (34% of theory) of 6-(p-cyclopropylmethoxycarbonylaminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone are obtained as colorless crystals of melting point 240°-241° C.
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]([CH2:7][NH:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:5][CH:4]=1)#[N:2].[N+:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)([O-:21])=[O:20]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[C:26](=[O:27])[C:25]2[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:30][CH:29]=2)=[CH:17][CH:18]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)CNCc1ccc(C#N)cc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN(Cc1ccc(C#N)cc1)C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 61 %

Procedure:
Prepared using General Procedure 7: To a stirred solution of tert-butyl 2-((4-cyanobenzyl)amino)acetate (14.7 g, 47.7 mmol) INT-31 in DCM (150 mL) stirring in a 0° C. in an ice bath was added TEA (9.98 mL, 71.6 mmol) followed by 4-nitrobenzoyl chloride. The reaction mixture was allowed to warm to room temperature over 1.5 h. The reaction mixture was diluted with DCM (300 mL) and washed with NaHCO3 (2×200 mL). The organics were dried over dried over MgSO4 and concentrated in vacuo. The crude product was purified by chromatography (MeOH/DCM) followed by evaporation from hexanes to provide 11.5 g (61%) tert-butyl 2-(N-(4-cyanobenzyl)-4-nitrobenzamido)acetate INT-56 as a white powder. LCMS-ESI (m/z) calculated for C21H21N3O5: 395; found 394 [M−H]−, tR=2.33 min broad (Method 10).
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:2]1.[CH3:27][O-:28].[Na+]>CO>[CH3:27][O:28][CH2:2][C:3]1([OH:1])[CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]3=[O:25])=[CH:11][C:10]=2[F:26])[CH2:7][CH2:8]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CO4)c(F)c2)C(=O)O1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCC1(O)CCN(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)CC1
Yield: 82 %

Procedure:
The title compound was prepared by reacting (S)—N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.3 mmol) with sodium methoxide (1.6 mmol) in methanol (10 ml) at a temperature 65° C. for 6 hours and by purifying the compound by silica gel column chromatography in 82% yield.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][C:14](O)=[O:15]>O1CCOCC1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>[C:20]([O:19][C:17](=[O:18])[NH:12][CH2:13][C:14](=[O:15])[NH:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: NCCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)NCCCCc1ccccc1
Reaction time: 16 h

Procedure:
Phenylbutylamine (8.2 g, 52 mmol) is added to a mixture of BOC-Gly-PNB (14.82 g, 50 mmol) in dioxane (60 mL) and 1 M K2CO3 (60 mL). The mixture is stirred 16 h and then diluted with CH2Cl2 and washed with a saturated NaHCO3 solution until the organic phase is colorless. The organics are dried (MgSO4) and concentrated to provide [(4-phenyl-butylcarbamoyl)-methyl]-carbamic acid tert-butyl ester which is used as is without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH:15]([CH3:17])[CH3:16])[N:13]=[C:12]([CH2:18]O)[C:11]=2[CH2:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.S(Cl)([Cl:29])=O>ClCCl>[ClH:1].[Cl:29][CH2:18][C:12]1[C:11]([CH2:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[C:10]([S:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)[N:14]([CH:15]([CH3:17])[CH3:16])[N:13]=1
Reactant: CC(C)n1nc(CO)c(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)n1nc(CCl)c(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution containing 108 mg of 5-(3,5-dichlorophenylthio)-1-isopropyl-4-[(4-pyridyl)methyl]-1H-pyrazole-3-methanol in 5 ml of anhydrous dichloromethane at −78° C. under nitrogen was treated with 45 μl of thionyl chloride. The mixture was stirred for 1 h and left to warm to room temperature. The solvent was removed under reduced pressure and the residue was azeotroped with toluene to give 120 mg of 4-[3-chloromethyl-5-(3,5-dichloro-phenylthio)-1-isopropyl-1H-pyrazol-4-ylmethyl]pyridine hydrochloride as a white solid which was used without further purification. Mass spectrum (ESI) 426 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:13]3[C:8](=[N:9][C:10]([C:14]4[C:22]5[C:17](=[N:18][CH:19]=[CH:20][CH:21]=5)[N:16]([CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[F:30])[N:15]=4)=[N:11][CH:12]=3)[N:7](CC3C=CC(OC)=CC=3OC)[C:6]2=[O:42])[CH2:3][CH2:2]1.C([SiH](CC)CC)C.O.C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O.C(OCC)(=O)C>[CH:1]1([CH2:4][N:5]2[C:13]3[C:8](=[N:9][C:10]([C:14]4[C:22]5[C:17](=[N:18][CH:19]=[CH:20][CH:21]=5)[N:16]([CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[F:30])[N:15]=4)=[N:11][CH:12]=3)[NH:7][C:6]2=[O:42])[CH2:3][CH2:2]1
Reactant: COc1ccc(Cn2c(=O)n(CC3CC3)c3cnc(-c4nn(Cc5ccccc5F)c5ncccc45)nc32)c(OC)c1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Product: O=c1[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)ncc2n1CC1CC1
Yield: 53.6 %

Procedure:
482 mg (0.70 mmol) of the compound from example 84A were dissolved in 21 ml of trifluoroacetic acid, 817 mg (7.02 mmol) of triethylsilane were added and the mixture was heated to reflux for 18 h. The reaction mixture was admixed with water and ethyl acetate, and neutralized with saturated aqueous sodium hydrogencarbonate solution. The organic phase was dried over sodium sulfate and concentrated on a rotary evaporator. The residue was dried under high vacuum, and purified by means of preparative HPLC (eluent: methanol/water with 0.1% trifluoroacetic acid, gradient 30:70→90:10). 156 mg of the title compound were obtained (53% of theory).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=[O:2].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S([CH2:28][N+:29]#[C-:30])(=O)=O)=CC=1>CO>[O:2]1[C:1]([C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=2)=[CH:30][N:29]=[CH:28]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1ccc(-c2cnco2)cc1
Yield: 79.9 %

Procedure:
Methyl 4-formylbenzoate (Aldrich Chemical Co., St. Louis, Mo.) (5.0 g, 30.5 mmol), anhydrous potassium carbonate (4.55 g, 33 mmol) and p-toluenesulfonylmethyl isocyanide (TOSMIC, Aldrich Chemical Co.) (6.83 g, 30.5 mmol) were refluxed in methanol (100 ml) for 3.5 hours The mixture was then concentrated to dryness in vacuo. The residue was dissolved in ethyl acetate, washed twice with water, dried and concentrated in vacuo to give methyl 4-(1,3-oxazol-5-yl)benzoate as a beige solid (4.95 g).
Reaction SMILES: C([NH:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][C@H:16]([C:33]([NH:35][C@@H:36]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)[CH3:37])=[O:34])[NH:17][C:18](=[O:32])[CH:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[S:11])(=O)C1C=CC=CC=1.CO.C([O-])([O-])=O.[K+].[K+]>O>[NH2:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][C@H:16]([C:33]([NH:35][C@@H:36]([C:38]1[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=1)[CH3:37])=[O:34])[NH:17][C:18](=[O:32])[CH:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[S:11]
Reactant: COc1ccc([C@@H](C)NC(=O)[C@@H](CCCNC(=S)NC(=O)c2ccccc2)NC(=O)C(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccc([C@@H](C)NC(=O)[C@@H](CCCNC(N)=S)NC(=O)C(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.6 %

Procedure:
(R)-N5 -(Benzoylaminothiocarbonyl)-N2 -(diphenylacetyl)-(R)-N-[1-(4-methoxyphenyl)ethyl]ornithine amide (2.25 g; 3.6 mmol; from step (a) above), methanol (250 mL), water (250 mL) and K2CO3 (1.49 g; 10.8 mmol) were combined and stirred for 24 h at room temperature. The reaction mixture was then partitioned between EtOAc (250 mL) and brine (250 mL). The EtOAc layer was separated and washed with brine, dried over Na2SO4 and concentrated in vacuo to afford 1.86 g (99%) of the sub-title compound as a white foam.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[N:10]([C:24]([CH2:27][CH3:28])=[CH:25][CH:26]=3)[N:11]=[C:12]([CH3:23])[C:13]=2[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:5]=[N:6][CH:7]=1.[CH2:29]=O.[C:31]([BH3-])#[N:32].[Na+]>C(#N)C.CO.C(O)(=O)C.C(=O)(O)[O-].[Na+]>[CH3:29][N:32]([CH3:31])[C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[N:10]([C:24]([CH2:27][CH3:28])=[CH:25][CH:26]=3)[N:11]=[C:12]([CH3:23])[C:13]=2[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:5]=[N:6][CH:7]=1
Reactant: [BH3-]C#N
Reactant: C=O
Reactant: CCOC(=O)CCCCc1c(C)nn2c(CC)ccc2c1-c1cncc(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: CO
Product: CCOC(=O)CCCCc1c(C)nn2c(CC)ccc2c1-c1cncc(N(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.8 %

Procedure:
To a solution of ethyl 5-[4-(5-amino-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate (55 mg), 37% formaldehyde solution (277 mg) and sodium cyanoborohydride (27.3 mg) in acetnitrile (1 mL) and methanol (1 mL) was added acetic acid (2 drops) and the mixture was stirred at ambient temperature for 2 hours. The solution was diluted with saturated sodium bicarbonate solution and extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by preparative silica gel column chromatography eluting with a mixture of chloroform and methanol (20:1) to give ethyl 5-{4-[5-(dimethylamino)-3-pyridinyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}pentanoate as yellow oil (36.5 mg)
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[CH2:17]([N:21]([CH2:24][CH2:25][CH2:26][CH3:27])[S:22]Cl)[CH2:18][CH2:19][CH3:20].N1C=CC=CC=1.O>CCCCCC>[CH2:17]([N:21]([CH2:24][CH2:25][CH2:26][CH3:27])[S:22][CH2:1][NH:2][C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CNC(=O)Oc1cccc2c1OC(C)(C)C2
Reactant: CCCCN(CCCC)SCl
Solvent: CCCCCC
Solvent: c1ccncc1
Solvent: O
Product: CCCCN(CCCC)SCNC(=O)Oc1cccc2c1OC(C)(C)C2
Temperature: 35 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
A flask was charged with 15.8 g of 98% 2,3-dihydro-2,2-dimethyl-7-benzofuranyl methylcarbamate (0.07 mole) and 30.2 g of a 50% solution of dibutylaminosulfenyl chloride (0.077 mole) in hexane under nitrogen atmosphere. To this was added with stirring 7.5 g (0.0455 mole) of triethylamine/sulfur dioxide complex prepared as described in Example 3. Pyridine (6.1 g, 0.077 mole) was then added dropwise with stirring over a period of 16 minutes. The temperature increased from 20.5° C. to 23.5° C. Stirring was continued for three hours after the beginning of pyridine addition during which external heating was supplied to maintain a temperature of 35° C. The mixture was cooled to 10.5° C. and 31 ml of water was added. The mixture was filtered, separated, and the organic layer was concentrated to yield 18.99 g of 75% (by hplc) 2,3-dihydro-2,2-dimethyl-7-benzofuranyl (dibutylaminothio)methylcarbamate (53% chemical yield based on the starting carbamate).
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH2:13]([C@@H:20]1[CH2:24][O:23][C:22](=[O:25])[N:21]1[C:26](=[O:42])/[CH:27]=[CH:28]/[C:29]1[CH:30]=[C:31]([CH:39]=[CH:40][CH:41]=1)[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1.CSC>[CH2:13]([C@@H:20]1[CH2:24][O:23][C:22](=[O:25])[N:21]1[C:26](=[O:42])[CH2:27][C@H:28]([C:29]1[CH:30]=[C:31]([CH:39]=[CH:40][CH:41]=1)[C:32]([O:34][C:35]([CH3:37])([CH3:38])[CH3:36])=[O:33])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Brc1ccccn1
Reactant: CC(C)(C)OC(=O)c1cccc(/C=C/C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: CSC
Product: CC(C)(C)OC(=O)c1cccc([C@@H](CC(=O)N2C(=O)OC[C@H]2Cc2ccccc2)c2ccccn2)c1
Reaction time: 1.5 h
Yield: 37 %

Procedure:
To a 1.0 M solution of isopropylmagnesium chloride (1.0 mL, 2.08 mmol) in THF was added 2-bromopyridine (0.198 mL, 2.08 mmol) and the mixture was stirred for 1.5 hours. This dark solution, at 0° C., was quickly added to a cooled (−40° C.) solution of CuBr.DMS complex (0.206 g, 1.01 mmol) in THF (2 mL) and dimethylsulfide (1 mL), and the resulting mixture was stirred at −40° C. for 10 min, then placed in an ice bath. Tert-butyl 3-{(1E)-3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-oxoprop-1-enyl}benzoate from the previous step, dissolved in THF (2 mL), was added dropwise and the mixture was stirred for 1.5 hours. The reaction was quenched with 20% aqueous NH4Cl solution, the dimethylsulfide was removed under reduced pressure and the mixture was partitioned between EtOAc and H2O. The layers were separated, the water layer was extracted with EtOAc, and the combined organics were washed with H2O and brine, dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was chromatographed on a 10 g ISCO column using 0-40% EtOAc/hexanes over 40 min. The lower diastereomer was combined to give tert-butyl 3-{(1R)-3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-oxo-1-pyridin-2-ylpropyl}benzoate as an oil (0.12 g, 37%). Absolute chirality was assigned based on literature precedent. TLC Rf=0.3 (1:1 EtOAc:hexanes, UV visualization); HPLC RT=2.1 min, method B; M+H=488.
Reaction SMILES: Br[CH2:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.BrCC1CCCCO1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]2([C:40]3[C:31](=[CH:32][C:33]4[O:38][CH2:37][CH2:36][O:35][C:34]=4[CH:39]=3)[O:30][CH2:29]2)[C:21]1=[O:41].N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O>>[S:4]1[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=[C:3]1[CH2:2][N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]2([C:40]3[C:31](=[CH:32][C:33]4[O:38][CH2:37][CH2:36][O:35][C:34]=4[CH:39]=3)[O:30][CH2:29]2)[C:21]1=[O:41]
Reactant: BrCc1nc2ccccc2s1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: BrCC1CCCCO1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: O=C1N(Cc2nc3ccccc3s2)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(bromomethyl)-1,3-benzothiazole to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, 1′-(1,3-benzothiazol-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (77%) as a colorless solid: mp 164-166° C.; 1H NMR (300 MHz, CDCl3) δ8.04 (d, J=8.1 Hz, 1H), 7.85 (d, J=8.1 Hz, 1H), 7.54-7.46 (m, 1H), 7.43-7.35 (m, 1H), 7.24-7.17 (m, 2H), 7.05 (dd, J=7.5, 7.5 Hz, 1H), 6.97 (d, J=7.8 Hz, 1H), 6.53 (s, 1H), 6.41 (s, 1H), 5.53 (d, J=16.2 Hz, 1H), 5.24 (d, J=16.2 Hz, 1H), 4.97 (d, J=9.0 Hz, 1H), 4.69 (d, J=9.0 Hz, 1H), 4.24-4.11 (m, 4H); 13C NMR (75 MHz, CDCl3) δ177.2, 165.9, 155.3, 152.9, 144.7, 141.2, 138.3, 135.3, 132.1, 128.9, 126.3, 125.5, 124.0, 123.9, 123.2, 121.9, 120.8, 111.8, 109.2, 99.4, 64.5, 63.9, 58.0, 42.6; MS (ES+) m/z 442.8 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH:7]2[CH2:20][CH2:21][N:22](C(OC(C)(C)C)=O)[CH:6]12)=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])[CH:7]2[CH2:20][CH2:21][NH:22][CH:6]12)=[O:4]
Reactant: COC(=O)C1CN(C(=O)OCc2ccccc2)C2CCN(C(=O)OC(C)(C)C)C12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1CN(C(=O)OCc2ccccc2)C2CCNC12
Reaction time: 1.25 h
Yield: 84.6 %

Procedure:
A solution of 14 (480 mg, 1.2 mmol) in DCM (10 mL) was treated with TFA (3 mL) at ambient temperature. After 75 min, the solution was concentrated, diluted with EtOAc, washed with saturated NaHCO3, brine. The aqueous washes were back extracted with DCM and the combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated to afford crude 15 (309 mg) as an orange-colored oil that was used without further purification. Mass spectrum, m/z [305.2] (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:31]=[CH:30][C:18]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25](SC)=[CH:24][CH:23]=3)=[O:20])=[C:17]([O:32][CH3:33])[CH:16]=2)[N:10]=1.[C:34](#N)C.O[O:38][S:39]([O-:41])=O.[K+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:31]=[CH:30][C:18]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([S:39]([CH3:34])(=[O:41])=[O:38])=[CH:24][CH:23]=3)=[O:20])=[C:17]([O:32][CH3:33])[CH:16]=2)[N:10]=1
Reactant: O=S([O-])OO
Reactant: COc1cc(-n2nc(-c3c(Cl)cccc3Cl)[nH]c2=O)ccc1C(=O)Nc1ccc(SC)cc1
Reactant: CC#N
Agent: [K+]
Solvent: O
Product: COc1cc(-n2nc(-c3c(Cl)cccc3Cl)[nH]c2=O)ccc1C(=O)Nc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-(3-(2,6-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxy-N-(4-(methylthio)phenyl)benzamide (Intermediate-38, 0.070 g, 0.13 mmol) in mixture of acetonitrile:water (3 mL:3 mL) was added oxone (0.053 g, 0.34 mmol). The reaction mass was stirred at RT for 24 h. The reaction mass was diluted with water and extracted with DCM. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 0.020 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.18 (s, 3H), 3.94 (s, 3H), 7.68-7.76 (m, 7H), 7.80 (d, J=8.7 Hz, 1H), 7.90 (d, J=8.7 Hz, 1H), 7.99 (d, J=8.4 Hz, 1H), 10.48 (s, 1H), 12.76 (br s, 1H); MS (m/z): 531.14 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH:7]1[CH:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][CH2:9][CH2:8]1)[CH2:3][C:4]([OH:6])=[O:5].[CH3:17]C1C=CC=CC=1.[OH2:24]>C(O)=O>[CH3:17][CH:3]([C:4]([OH:6])=[O:5])[N:2]([CH:7]1[CH:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][CH2:9][CH2:8]1)[CH:1]=[O:24]
Reactant: Cc1ccccc1
Reactant: CN(CC(=O)O)C1CCCC2CCCCC21
Reactant: O
Solvent: O=CO
Product: CC(C(=O)O)N(C=O)C1CCCC2CCCCC21
Reaction time: 4 h
Yield: 71.3 %

Procedure:
A mixture of 82.2 parts of methyl N-(decahydro-1-naphthalenyl)glycine, 36 parts of formic acid and 360 parts of methylbenzene was stirred for 4 hours at reflux temperature, using a water separator (another portion of 36 parts of formic acid was added each hour). After cooling, the separated organic layer was washed with a formic acid solution 20% and a sodium hydrogen carbonate solution, dried, filtered and evaporated, yielding 66 parts (71.3%) of methyl N-(decahydro-1-naphthalenyl)-N-formylglycine as a residue (intermediate 2).
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]3[C:11]([CH:12]=2)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=3)[CH2:3][CH2:2]1.Br[CH2:20][C:21]1[N:22]=[C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[O:24][CH:25]=1>>[CH:1]1([C:4]2[N:5]([CH2:20][C:21]3[N:22]=[C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)[O:24][CH:25]=3)[C:6]3[C:11]([CH:12]=2)=[C:10]([C:13]([F:14])([F:15])[F:16])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=3)[CH2:2][CH2:3]1
Reactant: FC(F)(F)c1cccc(-c2nc(CBr)co2)c1
Reactant: N#Cc1ccc2[nH]c(C3CC3)cc2c1C(F)(F)F
Product: N#Cc1ccc2c(cc(C3CC3)n2Cc2coc(-c3cccc(C(F)(F)F)c3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 4 using 2-cyclopropyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 165A) and 4-(bromomethyl)-2-[3-(trifluoromethyl)phenyl]-1,3-oxazole (synthesized similarly to Example 353): 1H NMR (400 MHz, CDCl3) δ 8.24 (s, 1H), 8.16 (d, J=7.8 Hz, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.58 (m, 3H), 7.34 (s, 1H), 6.45 (s, 1H), 5.49 (s, 2H), 2.02 (m, 1H), 1.11 (m, 2H), 0.88 (m, 2H); MS (ES) m/z 476 (M+1).
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[C:4]([C:6]1[CH:19]=[CH:18][C:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[H-].[Na+].[Br:24][CH2:25][CH2:26][CH2:27]Br.O>O1CCCC1>[Br:24][CH2:25][CH2:26][CH2:27][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][C:9]1[CH:18]=[CH:19][C:6]([C:4](=[O:5])[N:3]([CH2:1][CH3:2])[CH2:20][CH3:21])=[CH:7][CH:8]=1
Reactant: BrCCCBr
Reactant: CCN(CC)C(=O)c1ccc(Cc2ccccc2O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)C(=O)c1ccc(Cc2ccccc2OCCCBr)cc1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 69 %

Procedure:
2-(4-Diethylcarbamoylbenzyl)phenol (100 mg) was dissolved in tetrahydrofuran (2 ml), added with sodium hydride (60%, in oil, 21 mg) and stirred at 60° C. for 1.5 hours. The reaction mixture was added with 1,3-dibromopropane (0.18 ml) and stirred at the same temperature for 3 hours. After the reaction mixture was added with water (10 ml) and the layers were separated, the aqueous layer was extracted with dichloromethane (10 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate=3:1) to obtain 99 mg of the title compound. Yield: 69%.