Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28][C:29]1[CH:30]=[N:31][C:32]([F:36])=[C:33]([F:35])[CH:34]=1)[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15][N:11]2[C:12](=[O:14])[N:13]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:35][C:33]1[CH:34]=[C:29]([O:28][C:27]2[CH:26]=[CH:25][C:5]([CH2:6][O:7][C:8]3[CH:9]=[C:10]4[NH:17][CH2:16][CH2:15][N:11]4[C:12](=[O:14])[N:13]=3)=[CH:4][C:3]=2[C:1]#[N:2])[CH:30]=[N:31][C:32]=1[F:36]
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1ccc(Oc3cnc(F)c(F)c3)c(C#N)c1)nc2=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(COc2cc3n(c(=O)n2)CCN3)ccc1Oc1cnc(F)c(F)c1

Procedure:
Prepared in a manner similar to that described for E60 using tert-butyl 7-((3-cyano-4-((5,6-difluoropyridin-3-yl)oxy)benzyl)oxy)-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate (14 mg, 0.028 mmol) in DCM (4 mL) and TFA (0.5 mL, 6.49 mmol).
Reaction SMILES: C(OC([N:8]1[C@H:13]([C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=O)(C)(C)C.[ClH:20].O1CCOCC1>>[ClH:20].[CH2:17]([O:16][C:14]([C@@H:13]1[CH2:12][C@@H:11]2[C@@H:9]([CH2:10]2)[NH:8]1)=[O:15])[CH:18]=[CH2:19]
Reactant: C=CCOC(=O)[C@@H]1C[C@H]2C[C@H]2N1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C=CCOC(=O)[C@@H]1C[C@H]2C[C@H]2N1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To (1R,3S,5R)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylic acid 3-allyl ester 2-tert-butyl ester (1.69 g, 6.32 mmol) was added HCl 4N in dioxane (15.8 mL, 63.2 mmol). The reaction mixture was stirred for 6 h at RT and subsequently lyophilized to afford the desired material. MS: 168.0 [M+H]+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][NH:14][C:15]2[C:16](=[O:31])[N:17]([CH:28]([CH3:30])[CH3:29])[S:18](=[O:27])(=[O:26])[C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=O)=O)=CC=1.[CH3:32][S:33]([O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[OH:43])(=[O:35])=[O:34].C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH3:32][S:33]([O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[O:43][CH2:12][CH2:13][NH:14][C:15]1[C:16](=[O:31])[N:17]([CH:28]([CH3:29])[CH3:30])[S:18](=[O:26])(=[O:27])[C:19]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Oc1ccccc1O
Reactant: Cc1ccc(S(=O)(=O)OCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)C)C2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)N1C(=O)C(NCCOc2ccccc2OS(C)(=O)=O)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C
Yield: 15 %

Procedure:
2-[(2-Isopropyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]ethyl 4-methylbenzenesulfonate (200 mg, 0.431 mmol) was dissolved in dry MeCN (4 mL) under nitrogen atmosphere. 2-Hydroxyphenyl methanesulfonate (89 mg, 0.474 mmol) was added followed by potassium carbonate (297 mg, 2.152 mmol). The reaction mixture was heated in a microwave reactor for 15 mins at 120° C. Potassium carbonate was filtered off and the reaction mixture was concentrated and redissolved in EtOAc. The mixture was washed with NaHCO3, dried over Na2SO4, filtered and evaporated. The residue was purified on a Horizon TM flash system using Heptane and EtOAc as eluant and TEA as additative and then purified by column chromatography (ISOLUTE SI, (5 g)) using DCM as eluant to afford the title compound (31 mg, 15%). 1H NMR (CDCl3, 500 MHz): δ 1.59 (d, 6H), 3.22 (s, 3H), 3.31 (q, 2H), 3.96 (t, 2H), 4.38-4.46 (m, 1H), 5.88 (t, 1H), 6.89 (d, 1H), 7.02 (t, 1H), 7.23-7.30 (m, 2H), 7.46-7.48 (m, 3H), 7.53-7.56 (m, 2H); 13C NMR (CDCl3, 125 MHz): δ 20.38, 38.57, 43.36, 47.85, 67.23, 108.08, 114.71, 122.38, 124.59, 125.14, 128.55, 129.15, 130.09, 131.63, 135.62, 138.64, 150.55, 158.40; Mass Spectrum: M+H+ 481.1.
Reaction SMILES: [O:1]=[C:2]1[CH:8]([NH:9][C:10](=[O:19])[CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:7]=[C:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]2[CH:26]=[CH:27][CH:28]=[CH:29][C:4]=2[N:3]1[CH3:30].[H][H]>CO.[Pd]>[O:1]=[C:2]1[C@@H:8]([NH:9][C:10](=[O:19])[CH2:11][CH2:12][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[CH2:7][C@@H:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]2[CH:26]=[CH:27][CH:28]=[CH:29][C:4]=2[N:3]1[CH3:30]
Reactant: CN1C(=O)C(NC(=O)CCC2CCCCC2)C=C(c2ccccc2)c2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN1C(=O)[C@@H](NC(=O)CCC2CCCCC2)C[C@@H](c2ccccc2)c2ccccc21
Yield: 79.6 %

Procedure:
A solution of N-(2,3-Dihydro-2-oxo-1-methyl-5-phenyl-1H-1-benzazepin-3-yl)-3-cyclohexyl-propanamide (250 mg) in methanol (20 ml) was added to a suspension of 10% palladium on carbon (100 mg) in methanol (20 ml). This mixture was subjected to 50 psi of hydrogen on a Parr shaker for two hours. The mixture was then filtered over celite and concentrated at reduced pressure. The resulting foam was crystallized from a mixture of ethyl acetate and hexane, yielding a white solid (200 mg, 80%), which is a cis, racemic mixture. m.p. 156°-158° C.
Reaction SMILES: Br[C:2]1[N:6]2[C:7](=[O:18])[N:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[CH2:9][CH2:10][C:5]2=[N:4][C:3]=1[CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH3:27]B(O)O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CN(C=O)C.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>[F:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][C:5]3=[N:4][C:3]([CH2:19][O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[C:2]([CH3:27])[N:6]3[C:7]2=[O:18])=[CH:12][CH:13]=1
Reactant: CB(O)O
Reactant: O=C1N(c2ccc(F)cc2)CCc2nc(COc3ccccc3)c(Br)n21
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: [K+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Cc1c(COc2ccccc2)nc2n1C(=O)N(c1ccc(F)cc1)CC2
Temperature: 150 °C
Reaction time: 0.75 h
Yield: 57.7 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (6.4 mg, 0.0055 mmol) was added to a stirred suspension of 3-bromo-6-(4-fluoro-phenyl)-2-phenoxymethyl-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one (116 mg, 0.18 mmol), methylboronic acid (55.05 mg, 0.92 mmol) and K2CO3 (76.3 mg, 0.23 mmol) in a mixture of 1,4-dioxane (7.07 mL) and DMF (1.77 mL) under nitrogen and in a sealed tube. The mixture was stirred at 150° C. for 45 minutes under microwave irradiation. The solvents were evaporated in vacuo and the crude product was purified by flash column chromatography (silica; 7 M solution of ammonia in MeOH in DCM with a gradient of 0/100 to 1.5/98.5 and then AcOEt in DCM with a gradient of 0/100 to 10/90). The desired fractions were collected and the solvents evaporated in vacuo. The product was purified by RP HPLC (C18 XBridge 19×100 5 um, gradient from 80% of 0.1% solution of ammonium formate/ammonium hydroxide buffer pH 9 solution in water and 20% CH3CN to 0% of 0.1% solution of ammonium formate/ammonium hydroxide buffer pH 9 solution in water and 100% MeOH) to yield 6-(4-fluoro-phenyl)-3-methyl-2-phenoxymethyl-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one (36.5 mg, 56% yield). 1H NMR (400 MHz, CDCl3) 8 ppm 2.52 (s, 3H), 3.26 (t, J=6.5 Hz, 2H), 3.98 (t, J=6.6 Hz, 2H), 4.96 (s, 2H), 6.97 (br. t, J=7.4, 7.4 Hz, 1H), 7.00-7.06 (m, 2H), 7.09-7.18 (m, 2H), 7.27-7.37 (m, 4H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH:13]([S:17][CH3:18])[C:14]([OH:16])=O)=[CH:7][C:6]=2[CH3:19].[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([NH:24][C:14](=[O:16])[CH:13]([O:12][C:8]1[CH:9]=[C:10]2[C:5](=[C:6]([CH3:19])[CH:7]=1)[N:4]=[CH:3][C:2]([I:1])=[CH:11]2)[S:17][CH3:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)N
Reactant: CSC(Oc1cc(C)c2ncc(I)cc2c1)C(=O)O
Product: CSC(Oc1cc(C)c2ncc(I)cc2c1)C(=O)NC(C)(C)C

Procedure:
In a similar procedure to Stage 2 of Example 1, (3-iodo-8-methyl-quinolin-6-yloxy)-methylsulfanyl-acetic acid was condensed with t-butylamine to give N-tert-Butyl-2-(3-iodo-8-methyl-quinolin-6-yloxy)-2-methylsulfanyl-acetamide as a white solid ([M+1]+ 445).
Reaction SMILES: [CH:1]1([N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:8](Cl)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17]([NH:21][C:22]([NH2:24])=[O:23])[CH2:18][CH2:19][CH3:20]>>[CH:1]1([N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:8]([NH:24][C:22]([NH:21][CH2:17][CH2:18][CH2:19][CH3:20])=[O:23])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)N(C1CCCCC1)C1CCCCC1
Reactant: CCCCNC(N)=O
Product: CCCCNC(=O)NC(=O)N(C1CCCCC1)C1CCCCC1

Procedure:
Prepared as described in General Procedure 1 using dicyclohexyl carbamoyl chloride and butyl urea.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:3]=1/[CH:4]=[N:5]/[S@:6]([C:8]([CH3:11])([CH3:10])[CH3:9])=[O:7].[CH3:20][Mg]Br.C1COCC1>ClCCl>[F:1][C:2]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:12][C:3]=1[CH:4]([NH:5][S@:6]([C:8]([CH3:11])([CH3:9])[CH3:10])=[O:7])[CH3:20]
Reactant: CC(C)(C)[S@](=O)/N=C/c1cc(C(F)(F)F)ccc1F
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(N[S@@](=O)C(C)(C)C)c1cc(C(F)(F)F)ccc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
To a solution of (S,E)-N-(2-fluoro-5-(trifluoromethyl)benzylidene)-2-methylpropane-2-sulfinamide (single enantiomer) (150 mg, 0.51 mmol, Step-1) in dichloromethane (5 mL) is added dropwise a solution of methylmagnesium bromide in THF (0.99 M, 2.57 mL, 2.54 mmol) at −78° C. The resulting mixture is stirred at −78° C. for 2 hours and at room temperature for 1 hour. The reaction is quenched by saturated aqueous ammonium chloride solution (50 mL), and the aqueous phase is extracted with EtOAc (50 mL×2). The combined organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (3:1-1:1) to give 63 mg (40% yield) of the title compound as a white solid.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:25])(=O)C.[C:26]([O:30][C:31]([NH:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1)=[O:32])([CH3:29])([CH3:28])[CH3:27].[OH-].[Na+]>CN(C=O)C.CO>[C:26]([O:30][C:31]([NH:33][C:34]1[CH:35]=[CH:36][C:37]([NH:38]/[C:16](=[C:6]2\[C:5](=[O:25])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:39][CH:40]=1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Reactant: COC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-methoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-tert.butoxycarbonylamino-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[CH2:3][CH2:4][CH2:5][CH:6]([C@H:8]1[CH2:13][CH2:12][C@H:11]2[C@H:14]3[C@H:24]([CH2:25][CH2:26][C@:9]12[CH3:10])[C@:22]1([CH3:23])[C:17]([CH:18]=[C:19]([CH2:27][OH:28])[CH2:20][CH2:21]1)=[CH:16][CH2:15]3)[OH:7].C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[F:1][C:2]([F:29])([F:30])[CH2:3][CH2:4][CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][C@H:11]2[C@H:14]3[C@H:24]([CH2:25][CH2:26][C@:9]12[CH3:10])[C@:22]1([CH3:23])[C:17]([CH:18]=[C:19]([CH:27]=[O:28])[CH2:20][CH2:21]1)=[CH:16][CH2:15]3)=[O:7]
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(CO)CC[C@@]43C)[C@@H]1CC[C@@H]2C(O)CCCC(F)(F)F
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)CCCC(F)(F)F
Reaction time: 1 h

Procedure:
Tetrapropyl ammonium perruthenate (10 mg, 0.028 mmol) was added to a solution of (17β)-17-(5,5,5-trifluoro-1-hydroxypentyl)-androsta-3,5-diene-3-methanol (65 mg, 0.15 mmol) and 4-methylmorpholine N-oxide (80 mg, 0.68 mmol) in CH2Cl2 (2.0 ml) at RT. After 1 h the reaction was flash chromatographed (silica gel, 20% EtOAc/80% hexanes) to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6](Cl)[CH:5]=1>O1CCOCC1.C1COCC1>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6]([CH:4]([CH2:9][CH3:8])[CH2:5][CH3:6])[CH:5]=1
Reactant: COC(=O)c1cc(Cl)nc(OC)c1
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C(=O)OC)cc(OC)n1
Temperature: 85 °C
Reaction time: 16 h
Yield: 99.4 %

Procedure:
Under argon, Pd(dppf) (83 mg, 101 μmol) is added to a solution of 2-chloro-6-methoxy-isonicotinic acid methyl ester (2.00 g, 9.92 mmol, see preparation of 2-isobutyl-6-methoxy-isonicotinic acid) in dioxane (30 mL). To this mixture, a solution of 1-ethyl-propyl zinkbromide (1.17 g, 9.92 mmol, 20 mL of a 0.5 M solution in THF) is added. The mixture is stirred at 85° C. for 16 h before the reaction is carefully quenched with water and extracted twice with EA. The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 9:1 to give 2-(1-ethyl-propyl)-6-methoxy-isonicotinic acid methyl ester (1.17 g) as a pale yellow oil; LC-MS: tR=1.08 min; [M+1]+=238.03.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][C:12]=1[NH:20][C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=O)(C)(C)C.[ClH:28].C(O)C>C(O)C>[ClH:28].[NH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][C:12]=1[NH:20][C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C(=O)Nc1cc(C(C)C)ccc1CCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(=O)Nc1cc(C(C)C)ccc1CCN
Reaction time: 2 h

Procedure:
To a stirred solution of 0.266 g of ethyl [2-(2-tert-butoxycarbonylaminoethyl)-5-isopropylphenyl]oxalamate in 2 mL of ethanol was added 2 mL of 21% hydrogen chloride-ethanol solution at room temperature. After being stirred at the same temperature for 2 hours, the reaction mixture was concentrated under reduced pressure to give 0.179 g of ethyl N-[2-(2-aminoethyl)-5-isopropylphenyl]oxalamate hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([N:27]([CH2:32][C:33]([OH:35])=[O:34])[CH2:28][C:29]([OH:31])=[O:30])[CH2:10][N:11]([CH2:16][CH2:17][N:18]([CH2:23][C:24]([OH:26])=[O:25])[CH2:19][C:20]([OH:22])=[O:21])[CH2:12][C:13]([OH:15])=[O:14])=[CH:4][CH:3]=1.[C:36](Cl)(Cl)=[S:37].C(Cl)(Cl)Cl>O>[C:33]([CH2:32][N:27]([CH2:28][C:29]([OH:31])=[O:30])[CH:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]=[C:36]=[S:37])=[CH:3][CH:4]=1)[CH2:10][N:11]([CH2:16][CH2:17][N:18]([CH2:19][C:20]([OH:22])=[O:21])[CH2:23][C:24]([OH:26])=[O:25])[CH2:12][C:13]([OH:15])=[O:14])([OH:35])=[O:34]
Reactant: Nc1ccc(CC(CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O)N(CC(=O)O)CC(=O)O)cc1
Reactant: S=C(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(O)CN(CCN(CC(=O)O)CC(Cc1ccc(N=C=S)cc1)N(CC(=O)O)CC(=O)O)CC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a solution of 6a (10 mg, 0.0155 mmol) in water (100 μL) was added dropwise 1M thiophosgene in CHCl3 (18.6 μL, 0.0186 mmol). The resulting mixture was stirred at room temperature for 3 h. The aqueous layer was concentrated in vacuo to provide pure 7a (10 mg, 99%) as a light yellowish solid. 1H NMR (MeOD, 300 MHz) δ 2.50-4.55 (m, 24H), 7.10-70 (m, 4H).
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=2)=[O:12])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([C:13]2[CH:20]=[CH:19][C:16]([CH2:17][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=2)=[O:12])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCN(C(=O)c2ccc(C=O)cc2)CC1
Reactant: C1COCCN1
Product: CCCCN1CCN(C(=O)c2ccc(CN3CCOCC3)cc2)CC1

Procedure:
Prepared from the product of Example 13 and morpholine.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:3].[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[N:16]1.CCN(CC)CC>C(Cl)Cl>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:5][O:4][C:2]([C:23]2[C:18]3[N:17]=[N:16][NH:15][C:19]=3[CH:20]=[CH:21][CH:22]=2)=[O:3])=[CH:7][CH:8]=1)([O-:14])=[O:13]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: c1ccc2[nH]nnc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)c1cccc2[nH]nnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
p-Nitrobenzyl chloroformate (0.5 mmol) was dissolved in 5 mL of CH2Cl2 and treated with benzotriazole (0.5 mmol) using Et3N (2 mmol) as base. The mixture was stirred overnight at room temperature, diluted with CH2Cl2 (20 mL) and washed with 3×5 mL of 1N HCl, 2×5 mL of 1N NaOH and 1×5 mL of brine. The organic phase was dried and filtered. The volatiles were removed and the product was triturated with diethyl ether to provide a pale yellow solid (59% yield). mp 160-162° C. 1H NMR (CDCl3) δ 8.27 (d, 1H, J=8.9 Hz), 8.17 (m, 3H), 7.72 (d, 1H, J=8.9 Hz), 7.65 (td, 1H, J=8.3 Hz, 1.1 Hz), 7.53 (m, 2H), 5.26 (s, 2H). 13C NMR (CDCl3) δ 154.84, 146.17, 142.27, 141.30, 132.01, 130.82, 128.78, 126.37, 124.16, 120.86, 113.58, 68.66. HRMS (FAB) calcd for C14H11N4O4 ([M+H]+): 299.0775. found 297.0775.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][NH:8][NH:7]1)=[O:5].[C:12]1(=O)[O:17][C:15](=[O:16])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[CH3:2][O:3][C:4]([C@H:6]1[N:7]2[C:12](=[O:17])[C:13]3[C:14]([C:15](=[O:16])[N:8]2[CH2:9][CH2:10][CH2:11]1)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:5]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: COC(=O)[C@@H]1CCCNN1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1CCCn2c(=O)c3ccccc3c(=O)n21
Yield: 100 %

Procedure:
A solution of (S)-hexahydro-pyridazine-3-carboxylic acid methyl ester hydrochloride (Y. Nakamura, C. J Shin, Chem. Lett, 1991, 11, 1953-1956) (370 mg, 2.05 mmol), phthalic anhydride (318 mg, 2.15 mmol) and diisopropylethylamine (291 mg, 2.25 mmol) was heated in toluene (5 mL) for 2 h. The reaction mixture was then cooled and partitioned between ethyl acetate and dilute HCl. The organic phase was washed with saturated aq. NaHCO3, dried (MgSO4), filtered and evaporated. The residue was crystallised from hexane and filtered to afford the title compound as a white solid (562 mg, 82%): 1H NMR (400 MHz, CD3OD) δ 1.59 (1H, m), 1.96 (1H, m), 2.17 (1H, m), 2.55 (1H, m), 3.38 (1H, m), 3.70 (3H, s), 4.89 (1H, m), 5.74 (1H, m), 7.89 (2H, m), 8.16 (2H, m). 13C NMR (100 MHz, CD3OD) δ 21.2 (CH2), 25.7 (CH2), 46.0 (CH2), 53.8 (CH), 58.1 (CH3), 129.0 (CH), 129.1 (CH), 130.1 (C), 130.6 (C), 135.3 (CH), 135.7 (CH), 160.4 (C), 162.4 (C), 171.7 (C). Method N:
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)CC[C:6]1=[O:15].[O:17]1C2C=CC=CC=2NC1=O>>[O:17]=[C:6]1[N:5]([CH2:4][C:3]([OH:2])=[O:16])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:15]1
Reactant: O=c1[nH]c2ccccc2o1
Reactant: COC(=O)CN1C(=O)CCc2ccccc21
Product: O=C(O)Cn1c(=O)oc2ccccc21
Yield: 89 %

Procedure:
Compound 76A was prepared analogously to compound 49A using 3H-benzooxazol-2-one. Yield was 89%. 400 MHz 1H NMR (CDCl3) δ 7.1-7.22 (m, 3H), 6.85 (d, 1H), 4.54 (s, 2H), 3.76 (s, 3H). Step 2. Preparation of (6-Chlorosulfonyl-2-oxo-benzooxazo-3-yl}-acetic acid methyl ester (Compound 76B)
Reaction SMILES: [Si:1]([O:18][C:19]1[CH:26]=[CH:25][C:22](C=O)=[C:21]([Cl:27])[CH:20]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C([C:35]([O:37]O)=[O:36])C=1>C(Cl)(Cl)Cl.C(Cl)Cl>[CH:35]([O:37][C:22]1[CH:25]=[CH:26][C:19]([O:18][Si:1]([C:14]([CH3:17])([CH3:15])[CH3:16])([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:20][C:21]=1[Cl:27])=[O:36]
Reactant: CC(C)(C)[Si](Oc1ccc(C=O)c(Cl)c1)(c1ccccc1)c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)[Si](Oc1ccc(OC=O)c(Cl)c1)(c1ccccc1)c1ccccc1
Yield: 81.9 %

Procedure:
4-{[t-butyl(diphenyl)silyl]oxy}-2-chlorobenzaldehyde (11.00 g, 28 mmol) was dissolved in CHCl3 (150 ml). In one portion m-chloroperbenzoic acid (MCPBA) (7.21 g, 41.8 mmol) was added and the solution heated to reflux for 72 h. The solution was diluted with CH2Cl2, washed with sat. NaHSO3, sat. NaHCO3, brine and dried (MgSO4). The solvent was removed to provide 9.42 g of the title compound.
Reaction SMILES: [CH2:1]([NH:22][C:23](=[O:35])[C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=1)[CH2:2]/[CH:3]=[CH:4]/[CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1.ClC1C=CC=C(C(OO)=[O:44])C=1>C(Cl)(Cl)Cl>[O:44]1[CH:4]([CH2:3][CH2:2][CH2:1][NH:22][C:23](=[O:35])[C:24]2[CH:25]=[CH:26][C:27]([O:30][C:31]([F:32])([F:33])[F:34])=[CH:28][CH:29]=2)[CH:5]1/[CH:6]=[CH:7]/[NH:8][C:9](=[O:21])[C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17]([F:19])([F:20])[F:18])=[CH:14][CH:15]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(NCC/C=C/CCCNC(=O)c1ccc(OC(F)(F)F)cc1)c1ccc(OC(F)(F)F)cc1
Solvent: ClC(Cl)Cl
Product: O=C(N/C=C/C1OC1CCCNC(=O)c1ccc(OC(F)(F)F)cc1)c1ccc(OC(F)(F)F)cc1
Temperature: 3 °C
Reaction time: 42 h

Procedure:
To a stirred and chilled (3° C., kept in an ice bath) solution containing N,N'-(trans-3-heptene-1,7-diyl)bis(4-trifluoromethoxybenzamide) dissolved in 300 ml. of chloroform was added in one portion 7.2 g. of 3-chloroperbenzoic acid. The reaction mixture was stirred for an additional 30 minutes at 3°-5° C. and then was allowed to stand at 5° C. for an additional 42 hours. The reaction mixture was then washed successively with three 50 ml. portions of cold 5% aqueous potassium carbonate solution and next with saturated brine, and then it was dried over anhydrous potassium carbonate. The solvent was distilled off in vacuo and the remaining white solid was recrystallized from benzene-ethanol to yield 7.75 g. of N,N'-(trans-3,4-epoxyheptane-1,7-diyl)bis( 4-trifluoromethoxybenzamide), m.p. 121°-123° C.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]([F:34])([F:33])[F:32]>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:10][CH2:11][C:4]([C:1]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]([F:32])([F:33])[F:34])=[O:3])([CH2:5][CH2:6]2)[CH2:9][CH2:8]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: Nc1ccccc1C(F)(F)F
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3ccccc3C(F)(F)F)(CC1)CC2
Yield: 39.4 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 2-aminobenzotrifluoride (55.0 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(2-trifluoromethylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (28.4 mg).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.C(N(CC)C(C)C)(C)C.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20].C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:7][C:3]1[CH:2]=[C:1]([NH:8][C:19](=[O:20])[O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: Nc1cccc(N)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cccc(NC(=O)OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.8 %

Procedure:
To a stirred solution of m-phenylenediamine (5.0 g, 0.046 mol) and N,N-diisopropylethylamine (8.0 mL, 0.046 mol) in CH2Cl2 (150 mL) at 0° C. was added slowly benzyl chloroformate (6.6 mL, 0.046 mol). The mixture was stirred at 0° C. for 2 h and then warmed to rt for 2 h. Aq. NaHCO3 solution was added and the organic phase was separated, washed with brine, dried (Na2SO4) and concentrated. The residue was purified by column chromatography on silica gel to give the desired product (8.0 g, 71%) as a syrup. LC-MS: 2.11 min, 243.0 (M+1).