Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[O:9][C:4]=2[CH:3]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].N1C=CC=CC=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH3:10][C:8]1([CH3:11])[C:7](=[O:12])[N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]2[CH:19]=[CH:20][C:2]([NH:1][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:3][C:4]=2[O:9]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)Oc2cc(N)ccc2N(c2ccccc2)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC1(C)Oc2cc(NS(C)(=O)=O)ccc2N(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 7-amino-2,2-dimethyl-4-phenyl-2H-1,4-benzoxazin-3(4H)-one (compound obtained in Reference Example 1(3), 50 mg) in chloroform (2 mL) were added dropwise successively methanesulfonyl chloride (22 μL) and pyridine (30 μL) under ice-cooling and the mixture was stirred at room temperature for 18 hours. To the reaction mixture was added a saturated sodium hydrogencarbonate solution, and the mixture was extracted with chloroform. The organic layer was washed successively with water, 10% HCl solution and brine, dried over sodium sulfate and concentrated in vacuo. The resultant residue was purified by column chromatography on NH-silica gel (solvent; n-hexane/ethyl acetate=1/1→ethyl acetate) to give N-(2,2-dimethyl-3-oxo -4-phenyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)methanesulfonamide (55 mg) as a colorless powder. MS (APCI) m/z: 347 [M+H]+
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]3[CH:41]=[C:40](Br)[CH:39]=[CH:38][C:37]=3[F:43])([CH3:35])[N:26]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.[F:44][C:45]([F:54])([F:53])[C:46]1[N:51]=[CH:50][C:49]([NH2:52])=[CH:48][CH:47]=1>>[NH2:24][C:25]1[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:33])([CH3:34])[C@:27]([C:36]2[CH:41]=[C:40]([NH:52][C:49]3[CH:50]=[N:51][C:46]([C:45]([F:54])([F:44])[F:53])=[CH:47][CH:48]=3)[CH:39]=[CH:38][C:37]=2[F:43])([CH3:35])[N:26]=1
Reactant: Nc1ccc(C(F)(F)F)nc1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(C)(C)C(=O)N2C)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Nc3ccc(C(F)(F)F)nc3)ccc2F)N=C1N

Procedure:
The coupling of (S)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-6-(5-bromo-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate K) and 6-trifluoromethyl-pyridin-3-ylamine according to procedure B followed by deprotection yielded the title compound as a pale yellow foam. MS (ESI): m/z=424.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([OH:9])[C:5]2[O:10][CH:11]=[CH:12][C:4]=2[CH2:3]1.F[C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1>>[CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([O:9][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[C:5]2[O:10][CH:11]=[CH:12][C:4]=2[CH2:3]1
Reactant: Fc1ccc(C(F)(F)F)cc1
Reactant: CN1CCC(O)c2occc2C1
Product: CN1CCC(Oc2ccc(C(F)(F)F)cc2)c2occc2C1

Procedure:
The same method as in Example 1 was conducted using 5-methyl-5,6,7,8-tetrahydro-4H-furo[3,2-c]azepin-8-ol (Reference Example 21) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 4-fluorobenzotrifluoride instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>>[CH:33]1([C:36]([N:2]2[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]3[C:14]4[N:15]=[CH:16][N:17]=[C:18]([C:19]5[C:27]6[O:26][CH2:25][O:24][C:23]=6[CH:22]=[CH:21][C:20]=5[O:28][CH2:29][CH:30]5[CH2:32][CH2:31]5)[C:13]=4[NH:12][CH:11]=3)=[O:9])[CH2:3]2)=[O:37])[CH2:35][CH2:34]1
Reactant: O=C(N[C@@H]1CCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: O=C(Cl)C1CC1
Agent: Cl
Product: O=C(N[C@@H]1CCN(C(=O)C2CC2)C1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide hydrochloride (example A142) and cyclopropanecarbonyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17](O)=[O:18])[CH:15]=3)[N:10]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:63][N:64]1[CH2:69][CH2:68][CH2:67][C:66]([CH2:78][OH:79])([CH2:70][C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][C:72]=2[F:77])[CH2:65]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[F:77][C:72]1[CH:73]=[CH:74][CH:75]=[CH:76][C:71]=1[CH2:70][C:66]1([CH2:78][OH:79])[CH2:67][CH2:68][CH2:69][N:64]([NH:63][C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]([C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:9]=[C:8]3[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)=[O:18])[CH2:65]1
Reactant: NN1CCCC(CO)(Cc2ccccc2F)C1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)O)cc23)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)NN4CCCC(CO)(Cc5ccccc5F)C4)cc23)ccn1
Reaction time: 1 h

Procedure:
In a flask, 3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxylic acid (605 mg, 1.22 mmol), HATU (572 mg, 1.50 mmol) and (1-amino-3-(2-fluorobenzyl)piperidin-3-yl)methanol (258 mg, 0.94 mmol) was dissolved in dimethylformamide (3 mL). Diisopropylethylamine (0.819 mL, 4.7 mmol) was added to the reaction. The reaction was allowed to stir for an additional 1 h. Upon completion, the reaction was quenched with water (10 mL). The water layer was extracted with ethyl acetate (20 mL) three times. The organic fractions were combined, dried with sodium sulfate, and concentrated to yield the crude product. The crude product was progressed to the next step without further purification.
Reaction SMILES: NC(N)=O.C(=O)([O-])N.C12OC(CC1)CN(C1C=C(CS(C)(=O)=O)N=C(C3C=CC(N)=CC=3)N=1)C2.[CH:35]12[O:42][CH:39]([CH2:40][CH2:41]1)[CH2:38][N:37]([C:43]1[CH:48]=[C:47]([CH2:49][S:50]([CH3:53])(=[O:52])=[O:51])[N:46]=[C:45]([C:54]3[CH:59]=[CH:58][C:57]([NH:60][C:61](=[O:82])[NH:62][C:63]4[CH:68]=[CH:67][C:66]([N:69]5[CH2:74][CH2:73][N:72](C(OC(C)(C)C)=O)[CH2:71][CH2:70]5)=[CH:65][CH:64]=4)=[CH:56][CH:55]=3)[N:44]=1)[CH2:36]2.FC(F)(F)C(O)=O>ClCCl>[CH:39]12[O:42][CH:35]([CH2:41][CH2:40]1)[CH2:36][N:37]([C:43]1[CH:48]=[C:47]([CH2:49][S:50]([CH3:53])(=[O:51])=[O:52])[N:46]=[C:45]([C:54]3[CH:59]=[CH:58][C:57]([NH:60][C:61]([NH:62][C:63]4[CH:68]=[CH:67][C:66]([N:69]5[CH2:70][CH2:71][NH:72][CH2:73][CH2:74]5)=[CH:65][CH:64]=4)=[O:82])=[CH:56][CH:55]=3)[N:44]=1)[CH2:38]2
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(NC(=O)Nc3ccc(-c4nc(CS(C)(=O)=O)cc(N5CC6CCC(C5)O6)n4)cc3)cc2)CC1
Agent: CS(=O)(=O)Cc1cc(N2CC3CCC(C2)O3)nc(-c2ccc(N)cc2)n1
Agent: NC(=O)[O-]
Agent: NC(N)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Cc1cc(N2CC3CCC(C2)O3)nc(-c2ccc(NC(=O)Nc3ccc(N4CCNCC4)cc3)cc2)n1

Procedure:
tert-Butyl 4-(4-(3-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(methylsulfonylmethyl)pyrimidin-2-yl)phenyl)ureido)phenyl)piperazine-1-carboxylate was obtained according to the general procedure for formation of urea or carbamate compounds from 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(methylsulfonylmethyl)pyrimidin-2-yl)aniline (44). Removal of the Boc group in tert-butyl 4-(4-(3-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(methylsulfonylmethyl)pyrimidin-2-yl)phenyl)ureido)phenyl)piperazine-1-carboxylate (85.2 mg, 0.126 mmoles) by treatment with trifluoroacetic acid in dichloromethane gave the title compound. Yield: 70.0 mg (38% over 2 steps). RT 1.64, M+H=578.2.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([CH3:18])[CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(I)cc1
Reactant: CC1CCN(CCCl)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1CCN(CCOc2ccc(I)cc2)CC1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A suspension of 1.55 g (52.50 mmol) of 4-iodophenol, 8.50 g (52.57 mmol) of 1-(2-chloroethyl)-4-methylpiperidine, and 14.51 g (105.00 mmol) of potassium carbonate in 200 mL of DMF was stirred for 6 hours at 80° C., the reaction mixture was cooled to RT, filtered, and the filtrate was evaporated down in vacuo. The residue was taken up in EtOAc, and the organic phase was washed with 2M aqueous NaOH solution, dried over magnesium sulfate, and evaporated down in vacuo. The crude product was purified by column chromatography (silica gel, gradient EtOAc/MeOH/sat. aqueous ammonia 100:0:0→95:5:0.5). Yield: 12.90 g (71% of theoretical); C14H20INO (M=345.219); calc.: molpeak (M+H)+: 346; found: molpeak (M+H)+: 346; Rf value: 0.30 (silica gel, DCM/MeOH/sat. aqueous ammonia 95:5:0.5).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH:5]1[CH:10]=[C:9]2[CH:11]=[CH:12][C:13]3[C:18]([C:19](=[O:20])[C:8]2=[CH:7][CH:6]=1)=[CH:17][CH:16]=[CH:15][CH:14]=3.[Cl-].[NH4+]>CCOCC>[CH2:8]([C:19]1([OH:20])[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:12]=[CH:11][C:9]2[CH:10]=[CH:5][CH:6]=[CH:1][C:2]1=2)[CH3:7]
Reactant: CC[Mg]Br
Reactant: O=c1c2ccccc2ccc2ccccc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCC1(O)c2ccccc2C=Cc2ccccc21
Reaction time: 3 h
Yield: 93.8 %

Procedure:
To 150 mmol of ethyl magnesium bromide in 150 ml of ether are added 10 g (48.5 mmol) of dibenzosuberenone in 250 ml of ether at 0° C. After 3 hours at about 10° C., the mixture is cooled in an ice bath and 40 ml of saturated aqueous ammonium chloride are added slowly. Extractions of the aqueous phase with ether affords 10.75 g of a yellow oily residue. Purification by flash chromatography yields 8.5 g (74%) of the expected product.
Reaction SMILES: [O:1]=[C:2]([CH2:4][N:5]([C:7](=[NH:9])[NH2:8])[CH3:6])[OH:3].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:28][C:29]1[CH:30]=[C:31]([N:35]=[C:36]=[O:37])[CH:32]=[CH:33][CH:34]=1.Cl>CO.CN(C=O)C.O>[NH2:9][C:7](=[N:8][C:36]([NH:35][C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([Cl:28])[CH:30]=1)=[O:37])[N:5]([CH3:6])[CH2:4][C:2]([OH:3])=[O:1]
Reactant: CN(CC(=O)O)C(=N)N
Reactant: O=C=Nc1cccc(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: CN(CC(=O)O)C(N)=NC(=O)Nc1cccc(Cl)c1
Reaction time: 2 h
Yield: 30 %

Procedure:
A solution of 9.58 g (0.073 mole) of anhydrous creatine in 96 ml (0.073 mole) of 0.76M tetrabutylammonium hydroxide in methanol was evaporated to an oil in vacuo. The residue was dissolved in 100 ml of DMF. An 11.2 g (0.073 mole) sample of m-chlorophenylisocyanate was added dropwise and the reaction was stirred for two hours. The mixture was poured into 200 ml of water and 73 ml of 1N HCl. The gummy precipitate was induced to crystallize by scratching. The solid was collected and triturated with tetrahydrofuran to give 6.6 g (30% yield) of light yellow solid N-{amino[(3-chlorophenyl)aminocarbonyl]iminomethyl}-N-methylglycine. A hydrochloride salt was prepared from conc. HCl to yield a pink solid, m.p. 228°-234° C.
Reaction SMILES: Br[C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[C:28]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH:29]=[CH:30][CH:31]=2)O1>CC(P(C(C)(C)C)[C]1[CH][CH][CH][CH]1)(C)C.CC(P(C(C)(C)C)[C]1[CH][CH][CH][CH]1)(C)C.Cl[Pd]Cl.[Fe]>[F:15][C:14]([F:17])([F:16])[O:13][C:10]1[CH:11]=[CH:12][C:7]([N:4]2[CH:5]=[N:6][C:2]([C:30]3[CH:29]=[C:28]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH:27]=[CH:26][CH:31]=3)=[N:3]2)=[CH:8][CH:9]=1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(Br)n2)cc1
Reactant: COC(=O)CCc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: CC(C)(C)P([C]1[CH][CH][CH][CH]1)C(C)(C)C
Product: COC(=O)CCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1

Procedure:
The title compound was prepared as described in Example 10 using 3-bromo-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (C1), methyl 3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (C13a), and [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) at 80° C. and isolated as a dark orange solid (9.86 g, 91%): 1H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 8.12-8.03 (m, 2H), 8.01-7.91 (m, 2H), 7.66-7.58 (m, 2H), 7.49-7.40 (m, 1H), 7.34 (dt, J=7.8, 1.6 Hz, 1H), 3.59 (s, 3H), 2.95 (t, J=7.5 Hz, 2H), 2.70 (t, J=7.6 Hz, 2H); 19F NMR (376 MHz, DMSO-d6) δ −57.01; ESIMS m/z 392 ([M+H]+).
Reaction SMILES: [N+:1]([C:4]1[CH:48]=[CH:47][C:7]([CH2:8][O:9][C:10](=[O:46])/[C:11](/[N:19]2[CH:22]([S:23]S(C3C=CC(C)=CC=3)(=O)=O)[CH:21]([NH:34][C:35](=[O:44])[CH2:36][O:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:20]2=[O:45])=[C:12](\N2CCCC2)/[CH3:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(C)C=CC=CC=1.C(OCC)(=[O:58])C.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C(#N)C.C1C=CC=CC=1>[N+:1]([C:4]1[CH:48]=[CH:47][C:7]([CH2:8][O:9][C:10]([C:11]2[N:19]3[C:20](=[O:45])[C@@H:21]([NH:34][C:35](=[O:44])[CH2:36][O:37][C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[C@H:22]3[S:23][CH2:13][C:12]=2[OH:58])=[O:46])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(C)=O
Reactant: C/C(=C(/C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1)N1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: c1ccccc1
Product: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 160 mg (0.23 mmol) of a mixture consisting of 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-(1-pyrrolidyl)-crotonic acid p-nitrobenzyl ester and the corresponding isocrotonic acid ester in 3 ml of dry acetonitrile is heated under nitrogen for about 4 hours at 80° C. until no further starting material can be detected by thin layer chromatography (silica gel; toluene/ethyl acetate , 1:1). The heating bath is removed, p-toluenesulphonic acid (about 0.23 mmol) and 0.2 ml of water are added to the reaction mixture containing the 7β-phenoxyacetamido-3-pyrrolidino-cephem-4-carboxylic acid p-nitrobenzyl ester and the mixture is stirred for a further 2 hours at room temperature. The reaction mixture is diluted with benzene, washed with water, dried over sodium sulphate and evaporated in vacuo. The residue is triturated at 0° C. with diethyl ether and gives the pale yellow 7β-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester. IR spectrum (methylene chloride): characteristic bands at 2.95; 3.3; 5.6; 5.75 (sh); 5.9; 5.95 (sh); 6.55; 7.45; 8.15 and 8.3μ; NMR spectrum (deuterochloroform): δ in ppm: 3.4 (2H, 2, J= 17 Hz); 4.57 (2H, s); 5.06 (1H, d; J=5 Hz); 5.35 (2H, q, J=14 Hz); 5.7 (1H, dd, J=5.10 Hz); 6.8-8.4 (10H, c) and 11.4 (1H, br.s.).
Reaction SMILES: [C:1]([C:4]12[CH2:11][C:8]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([CH2:9][CH2:10]1)[CH2:7][CH2:6][CH2:5]2)(=[O:3])[NH2:2].C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Cl[C:76]1[CH:81]=[CH:80][N:79]=[C:78]([CH3:82])[N:77]=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:82][C:78]1[N:79]=[C:80]([NH:2][C:1]([C:4]23[CH2:11][C:8]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)([CH2:9][CH2:10]2)[CH2:7][CH2:6][CH2:5]3)=[O:3])[CH:81]=[CH:76][N:77]=1
Reactant: Cc1nccc(Cl)n1
Reactant: NC(=O)C12CCCC(NC(=O)OCc3ccccc3)(CC1)C2
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1nccc(NC(=O)C23CCCC(NC(=O)OCc4ccccc4)(CC2)C3)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 76.8 %

Procedure:
To a mixture of benzyl 5-carbamoylbicyclo[3.2.1]octan-1-ylcarbamate (1 g, 3.3 mmol) and Cs2CO3 (1.6 g, 4.9 mmol) and BINAP (200 mg, 0.3 mmol) in toluene (60 mL), was added 4-chloro-2-methylpyrimidine (430 mg, 3.3 mmol), followed by Pd2(dba)3 (300 mg, 0.32 mmol). The mixture was stirred at 100° C. under N2 overnight. After cooled to room temperature, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate: 4/1) to give 1 g (77%) of benzyl 5-(2-methylpyrimidin-4-ylcarbamoyl)bicyclo[3.2.1]octan-1-ylcarbamate as a light yellow oil. ESI-MS m/z: 395 (M+H)+.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18]Cl)[C:13]=2[S:20][CH3:21])[CH:4]=1.[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26]>CO>[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26].[Cl:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH2:1])[C:13]=2[S:20][CH3:21])[CH:4]=1
Reactant: CSc1c(CCl)cccc1Oc1cc(Cl)ccc1C#N
Reactant: N
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Product: CSc1c(CN)cccc1Oc1cc(Cl)ccc1C#N
Reaction time: 17 h

Procedure:
7N Ammonia in methanol (30 mL, 210 mmol) was added to 4-chloro-2-(3-chloromethyl-2-methysulfanyl-phenoxy)-benzonitrile (240 mg, 0.8 mmol). After stirring for 17 h, TLC still showed some 4-chloro-2-(3-chloromethyl-2-methysulfanyl-phenoxy)-benzonitrile. The reaction mixture was concentrated to about 10 mL by evaporation in vacuo, concentrated ammonia (7 mL) was added and the mixture was heated with stirring at 60° C. for 17 h. Sodium carbonate solution (4 mL) and ethyl acetate (6 mL) were added and the organic layer was separated and dried with MgSO4. To this, was added fumaric acid (84 mg, 0.64 mmol) in methanol (3 mL). Immediately, the solvent was removed in vacuo and diethyl ether (40 mL) was added to the residue. After stirring for 17 h, 4-chloro-2-(3-aminomethyl-2-methysulfanyl-phenoxy)-benzonitrile fumarate (134.7 mg, 53%) was filtered off as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[CH2:10][S:11][CH3:12].C(C1C=NC=C(CCC(C)C)C=1)#N>>[CH3:1][C:2]1[N:7]=[C:6]([CH2:8][NH2:9])[CH:5]=[CH:4][C:3]=1[CH2:10][S:11][CH3:12]
Reactant: CSCc1ccc(C#N)nc1C
Agent: CC(C)CCc1cncc(C#N)c1
Product: CSCc1ccc(CN)nc1C

Procedure:
(6-methyl-5-(methylthiomethyl)pyridin-2-yl)methanamine was synthesized from 6-methyl-5-(methylthiomethyl)picolinonitrile following the general procedure as described for the 3-cyano-5-isopentylpyridine.
Reaction SMILES: [S:1](S([O-])=O)([O-:4])(=[O:3])=[O:2].[Na+:8].[Na+].[CH2:10]([CH:12]1[O:14][CH2:13]1)[Cl:11].[OH-].[Na+].[Cl-]>O>[Cl:11][CH2:10][CH:12]([OH:14])[CH2:13][S:1]([O-:4])(=[O:3])=[O:2].[Na+:8]
Reactant: O=S([O-])S(=O)(=O)[O-]
Reactant: ClCC1CO1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=S(=O)([O-])CC(O)CCl
Temperature: 87.5 °C
Yield: 50 %

Procedure:
The title alkylating agent was made by reacting sodium metabisulfite (104.5g) with epichlorohydrin (101.8g) in water (481g). To this solution of alkylating agent at 50-60° C. was added the product from Part A (157g). This mixture was stirred and heated to 85-90° C. Reaction was continued with the pH maintained in the range 8 to 9 by the incremental addition of 50% aqueous NaOH. Reaction was continued until the pH had stabilized and the ratio of ionic chloride to total chloride exceeded 0.99. Vacuum was applied to remove water until sufficient water had been removed to give a 50% solids product which was a clear, yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].Cl.Cl[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: ClCc1ccccn1
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(OCc2ccccn2)c(Cl)c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 52.5 %

Procedure:
2-Chloro-4-nitro phenol 10 g (57.6 mmol, 1 eq), 2-(chloromethyl)pyridine hydrogen chloride 9.45 g (57.6 mmol, 1 equiv), cesium carbonate (41.3 g, 126.8 mmol, 2.2 equiv) and sodium iodide 8.64 g (57.6 mmol, 1 equiv) were suspended in 200 mL acetonitrile. The reaction mixture was stirred at 60° C. for 5 h. The resulted suspension was filtered and washed with 400 mL water, yielding 2-(2-chloro-4-nitro-phenoxymethyl)-pyridine (8 g, 52%) as a red solid.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:14][Li]>O1CCCC1>[OH:1][C:2]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](=[O:6])[CH3:14]
Reactant: [Li]C
Reactant: CC(C)c1cccc(C(=O)O)c1O
Solvent: C1CCOC1
Product: CC(=O)c1cccc(C(C)C)c1O
Temperature: -75 °C
Reaction time: 8 h

Procedure:
2-Hydroxy-3-isopropylbenzoic acid (Aldrich, 4.0 g, 22.2 mmol) was dissolved in tetrahydrofuran (20 mL), chilled to −75° C., and methyllithium (1.6M in diethyl ether, 42 mL, 66.6 mmol) was added. The mixture stirred overnight at ambient temperature. The mixture was quenched with methanol (50 mL), concentrate under reduced pressure, and ethyl acetate (200 mL) was added. The mixture was washed with 1N hydrochloric acid (200 mL), water (200 mL), and brine and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrate under reduced pressure. The residue was chromatographed on silica gel eluting with 0-to-30% ethyl acetate in hexane to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.23 (d, 6H), 2.64 (s, 3H), 3.39 (m, 1H), 6.87 (t, 1H), 7.41 (dd, 1H), 7.59 (dd, 1H), 12.69 (s, 1H). MS (DCI) m/z 179.07 (M+H)+.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][C@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][O:4][C:3]1=[O:14].C([O-])([O-])=O.[Na+].[Na+].[C:21](Cl)(=[O:23])[CH3:22]>ClCCl>[C:21]([N:7]1[C@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][O:4][C:3](=[O:14])[C@@H:2]1[CH3:1])(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: C[C@@H]1N[C@H](c2ccccc2)COC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)N1[C@@H](C)C(=O)OC[C@H]1c1ccccc1
Reaction time: 0.25 h
Yield: 74.2 %

Procedure:
To a vigorously stirred mixture of (3S,5R)-3-methyl-5-phenyl-3,4,5,6-tetrahydro-2H-1,4-oxazin-2-one (300 mg, 1.56 mmol), Na2CO3 (500 mg, 4.68 mmol, 3.0 equiv.) in anhydrous dichloromethane (30 mL) was added acetyl chloride (0.17 mL, 2.34 mmol, 1.5 equiv.) dropwise over 1 min. The resulting solution was stirred for 15 minutes under an atmosphere of nitrogen. The reaction was quenched by the addition of saturated Na2CO3 (20 mL), the aqueous phase was extracted with diethyl diethyl ether (3×10 mL) and the combined extracts were dried over MgSO4. The solvents were removed in vacuo and the crude material was purified by flash column chromatography on silica, eluting with diethyl ether and dichloromethane (9:1) to furnish the title compound as fine colourless needles (270 mg, 74%); m.p. 82-85° C.; V(max) (KBr) 2943 (C—H), 1733 (C═O, lactone), 1647 (C═O, amide) cm″1; δH (250 Mhz, DMSO-d) 7.42-7.36 (5H, m, Ph), 5.49 (0.4H, PhCH×0.4) 5.33 (0.6H, PhCH×0.6), 5.08-5.05 (1H, m, CH3CH), 4.65 (2H, d, J 6.10 Hz CH2); 2.13 (1H, s, CH3CON×1), 1.86 (2H, s, CH3CON×2), 1.39 (3H, d, J 12.40 Hz CH3CH): δc (62.5 MHz, DMSO—O 170.5, 169.8, 137.8, 129.4, 128.4, 127.1, 68.6, 55.5, 50.7, 49.7, 22.7, 19.0; m1τ (CL, NH3), 234 (MH+, 8%), 233 (M, 13%), 220 (4%), and 219 (100%); HRMS for C13H16NO3 requires 234.1126. found 234.1130; [α]D20 −29.8 (c 1.16 CHCl3).