Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:13]3[N:12]=[C:11]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([NH:21][S:22]([C:25]5[C:26]([CH3:32])=[N:27][N:28]([CH3:31])[C:29]=5Cl)(=[O:24])=[O:23])=[CH:17][CH:16]=4)[NH:10][C:9]=3[C:8](=[O:33])[N:7]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[F:41])[C:6]2=[O:42])[CH2:3][CH2:2]1.C([O-])(=O)C.[Na+]>C(Cl)Cl.CO.CO.C(Cl)Cl.[Pd]>[CH:1]1([CH2:4][N:5]2[C:13]3[N:12]=[C:11]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([NH:21][S:22]([C:25]5[C:26]([CH3:32])=[N:27][N:28]([CH3:31])[CH:29]=5)(=[O:23])=[O:24])=[CH:17][CH:16]=4)[NH:10][C:9]=3[C:8](=[O:33])[N:7]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[F:41])[C:6]2=[O:42])[CH2:3][CH2:2]1
Reactant: Cc1nn(C)c(Cl)c1S(=O)(=O)Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1nn(C)cc1S(=O)(=O)Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Reaction time: 24 h
Yield: 65 %

Procedure:
A mixture of 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-amide (300 mg, 0.49 mmol) in methylene chloride (125 mL) and methanol (125 mL) at 25° C. was treated with 10% Pd/C (1.0 g) and sodium acetate (134 mg, 1.22 mmol). The resulting mixture was hydrogenated in a Parr bomb at 50 psi for 24 h. At this time, the reaction was filtered through a pad of celite and was washed with an 8/2 methylene chloride/methanol solution (200 mL). The filtrate was concentrated in vacuo to afford a white solid. This solid was dissolved in a 5/95 methanol/methylene chloride solution. The organics were washed with water (1×25 mL). The aqueous layer was then back-extracted with chloroform (1×50 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 1,3-dimethyl-1H-pyrazole-4-sulfonic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-amide (184 mg 65%) as a white solid; (ES)+-HRMS m/e calculated for C28H28FN7O4S (M+H)+ 578.1980, found 578.1987.
Reaction SMILES: C([O:3][P:4]([CH2:9][O:10][C:11]1[CH:23]=[CH:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH:12]=1)(=[O:8])[O:5]CC)C.C[Si](I)(C)C.CO>ClCCl>[CH:12]1[C:13]2[NH:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]=2[CH:22]=[CH:23][C:11]=1[O:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5]
Reactant: CCOP(=O)(COc1ccc2c(c1)[nH]c1ccccc12)OCC
Agent: C[Si](C)(C)I
Solvent: ClCCl
Solvent: CO
Product: O=P(O)(O)COc1ccc2c(c1)[nH]c1ccccc12
Reaction time: 2 h
Yield: 93.8 %

Procedure:
To a stirred solution of diethyl-2-carbazolyloxymethylphosphonate (0.33 g, 1 mmol) dissolved in dry dichloromethane (8 ml) under an atmosphere of nitrogen was added trimethyl silyl iodide (0.6 ml). The red solution was stirred for 2 h then methanol (15 ml) was added. After 2 h the solvent was removed under reduced pressure and then water (20 ml) was added to the residue. The mixture was concentrated under reduced pressure. Water (20 ml) was added and the mixture was concentrated under reduced pressure. This was repeated four times to afford 2-carbazolyloxymethyl phosphonic acid as a yellow green solid (0.26 g, 95%), m.p. 291° C., High Resolution Mass Spec. Pound: 277.0496, C13H12NO4PM+ requires 277.0504. δH (270 MHz, DMSO-d6) 11.13 (1H, s), 7.983 (1H, d, J 5.7 Hz), 7.98 (1H, d, J 5.7 Hz), 7.42 (1H, d, J 8 Hz), 7.28 (1H, dd, J1 8 Hz, J2 8 Hz), 7.10 (1H, dd, J1 8 Hz, J2 8 Hz), 7.05 (1H, d, J 2 Hz), 6.81 (1H, dd, J1 8 Hz, J2 2 Hz), 4.17 (2H, d, J 10.2 Hz), λex (DMSO, nm) 385, λem 421.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[C:9]([CH:13]1[CH2:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[C:16]2=[C:24]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[C:25]3[CH:26]=[CH:27][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][C:30]=3[N:15]2[CH2:14]1)([O:11][CH3:12])=[O:10].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:51])(=O)=O)=CC=1>C1COCC1>[CH:35]1([C:24]2[C:25]3[CH:26]=[CH:27][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][C:30]=3[N:15]3[CH2:14][C:13]([C:9]([O:11][CH3:12])=[O:10])([F:51])[CH2:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[C:16]=23)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)OC)Cc1ccccc1-3
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(F)(C(=O)OC)Cc1ccccc1-3
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 29 %

Procedure:
A solution of LDA in THF (0.7 mL of 0.5 N, 0.35 mmol) was added to a solution of methyl (±)-6-carbomethoxy-13-cyclohexyl-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxylate (100 mg, 0.23 mmol) in THF (1 mL) at −78° C. Stirring was continued at −78° C. for 15 min and N-fluorobenzenesulfonimide (110 mg, 0.35 mmol) was added in one portion. The mixture was then slowly warmed to −0° C. and Stirring was continued for 1 hr at 0° C. The solution was quenched with MeOH. The solution was extracted with ethyl acetate and the extract washed with dilute HCl (2×), brine (3×), and then dried (Na2SO4). The extract was concentrated and the crude product purified on the Shimadzu preparative liquid chromatograph. The product containing fraction was concentrated on a Speed Vac® to leave the titled compound as a white solid (30 mg, 29%). ESI-MS m/z 449 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([NH2:12])[N:3]=1.[CH2:13]([NH2:17])[CH2:14][CH2:15][CH3:16]>O>[NH2:12][C:4]1[N:3]=[C:2]([NH:17][CH2:13][CH2:14][CH2:15][CH3:16])[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=1
Reactant: Nc1nc(Cl)c2c(n1)CCCC2
Reactant: CCCCN
Solvent: O
Product: CCCCNc1nc(N)nc2c1CCCC2
Temperature: 90 °C
Reaction time: 4 h
Yield: 78.9 %

Procedure:
A mixture of 4-chloro-5,6,7,8-tetrahydroquinazoline-2-ylamine (100 mg, 0.545 mmol) and butylamine (2 ml) was stirred for 4 hours at 90° C. The reaction mixture was poured into water and extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered and the solvent in the filtrate was removed in vacuo. The residue was purified by column chromatography (10% MeOH/CHCl3) to give the object compound (94.5 mg, 78.9%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[N:12]([CH2:13][C:14]([C:16]3[C:17]([CH3:22])=[N:18][O:19][C:20]=3[CH3:21])=[O:15])[C@H:11]([C:23]([F:26])([F:25])[F:24])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.Cl.[C@H:28]12[CH2:34][C@H:31]([NH:32][CH2:33]1)[CH2:30][O:29]2.C(N(CC)CC)C>O>[CH3:22][C:17]1[C:16]([C:14](=[O:15])[CH2:13][N:12]2[C:4]3=[N:3][C:2]([N:32]4[CH2:33][C@@H:28]5[CH2:34][C@H:31]4[CH2:30][O:29]5)=[CH:7][C:6](=[O:8])[N:5]3[CH2:9][CH2:10][C@H:11]2[C:23]([F:26])([F:25])[F:24])=[C:20]([CH3:21])[O:19][N:18]=1
Reactant: Cc1noc(C)c1C(=O)CN1c2nc(Cl)cc(=O)n2CC[C@H]1C(F)(F)F
Reactant: C1O[C@@H]2CN[C@H]1C2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1noc(C)c1C(=O)CN1c2nc(N3C[C@@H]4C[C@H]3CO4)cc(=O)n2CC[C@H]1C(F)(F)F
Temperature: 130 °C
Yield: 56.2 %

Procedure:
200 mg (0.51 mmol) of (8S)-2-chloro-9-[2-(3,5-dimethylisoxazol-4-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 83.28 mg (0.61 mmol) of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride are mixed together. The powder obtained is placed in a tube and 178 μl (1.28 mmol) of triethylamine are added. The tube is sealed and heated at 130° C. in an oil bath for 6 hours. The crude product obtained is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and then evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 95/5 EtOAc/MeOH) to give 130 mg of (8S)-9-[2-(3,5-dimethylisoxazol-4-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, the characteristics of which are as follows:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Cl.Cl.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[N:23]([C:24]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][N:36]4[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)=[CH:28][C:27]=3[F:42])=[O:25])[CH2:22][C:21]3[CH:20]=[N:19][N:18]([CH3:43])[C:17]=3[NH:16][C:15]=2[CH:44]=1>CN(C=O)C.C(N(CC)CC)C>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[N:23]([C:24]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][N:36]4[CH2:41][CH2:40][N:39]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:38][CH2:37]4)=[CH:28][C:27]=3[F:42])=[O:25])[CH2:22][C:21]3[CH:20]=[N:19][N:18]([CH3:43])[C:17]=3[NH:16][C:15]=2[CH:44]=1
Reactant: CCCCCCBr
Reactant: Cn1ncc2c1Nc1cc(Cl)ccc1N(C(=O)c1ccc(OCCCN3CCNCC3)cc1F)C2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCCN1CCN(CCCOc2ccc(C(=O)N3Cc4cnn(C)c4Nc4cc(Cl)ccc43)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 1-bromohexane (0.83 mg, 0.005 mmol) in DMF (0.05 ml) was added to a solution of (6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-[2-fluoro-4-(3-piperazin-1-yl-propoxy)-phenyl]-methanone dihydrochloride from Example E5a (2.85 mg, 0.005 mmol) in DMF (0.05 ml) and triethylamine (0.0021 ml). The mixture was stirred for 20 h at room temperature then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=583.6
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:26]([NH:27][C:28](=[O:37])[CH2:29][O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25](=[O:38])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[CH:39]1[C:44](O)=[CH:43][CH:42]=[C:41]([Br:46])[CH:40]=1>>[Br:46][C:41]1[CH:42]=[CH:43][C:44]([O:1][CH2:2][C:3]2[CH2:4][S:5][C@@H:6]3[CH:26]([NH:27][C:28](=[O:37])[CH2:29][O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25](=[O:38])[N:7]3[C:8]=2[C:9]([O:11][CH:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:10])=[CH:39][CH:40]=1
Reactant: Oc1ccc(Br)cc1
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS[C@H]12
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COc3ccc(Br)cc3)CS[C@H]12

Procedure:
The procedure described in Example 1(a) was repeated, but using 2.00 g of diphenylmethyl 3-hydroxymethyl-7-phenoxyacetamido-3-cephem-4-carboxylate and p-bromophenol, to afford 420 mg of the title compound as a powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.O.[CH2:17](OCC)C>C(O)=O.C=O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][N:11]([CH3:17])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COC1(c2cc(F)cc(F)c2)CCNC1
Reactant: CCOCC
Agent: C=O
Solvent: O
Solvent: O=CO
Product: COC1(c2cc(F)cc(F)c2)CCN(C)C1
Temperature: 85 °C

Procedure:
A mixture of (+)-3-(3,5-difluorophenyl)-3-methoxypyrrolidine (0.02 g, 0.094 mmol) in formic acid (1 ml) and formaldehyde (37% solution in water, 1 ml) was heated at 85° C. for 5 h. The mixture was allowed to reach ambient temperature, water (5 ml) and diethyl ether was added, the phases were separated and the aqueous phase was basified by the addition of aqueous sodium hydroxide (5 M). The aqueous phase was extracted twice with ethyl acetate, the combined organic phases was dried (Na2SO4) and evaporated to give the crude product which was diluted in methanol and analyzed by GCMS. MS m/z (relative intensity, 70 eV) 227 (M+, 5), 212 (29), 197 (25), 141 (42), 57 (bp).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5](=[O:18])[CH:6]=[C:7]([C:13]([O:15]CC)=[O:14])[NH:8]2)=[CH2:2].[OH-].[Na+]>O>[CH:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5](=[O:18])[CH:6]=[C:7]([C:13]([OH:15])=[O:14])[NH:8]2)=[CH2:2]
Reactant: C=Cc1cccc2[nH]c(C(=O)OCC)cc(=O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=Cc1cccc2[nH]c(C(=O)O)cc(=O)c12
Yield: 70.8 %

Procedure:
Treatment of ethyl 5-ethenyl-4-oxo-1,4-dihydroquinoline-2-carboxylate (0.15 g) with sodium hydroxide (0.1 g), as described in Example 1c, gave 5-ethenyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (0.094 g), mp 265°-266° C., δ (360 MHz, DMSO-d6) 5.24 and 5.54 (2H, 2dd, =CH2), 6.56 (1H, s, 3-H), 7.37 (1H, d, 6-H), 7.62 (1H, t, 7-H), 7.91 (1H, d, 8-H), 8.17 (1H, 2d, CH=) and 11.80 (1H, bs, NH), (Found: C, 66.43; H, 4.37; N, 6.37%, C12H9NO3. 0.1 H2O requires C, 66.35; H, 4.36; N, 6.44%).
Reaction SMILES: [N:1]1([C:11]([C:13]2[CH:17]=[C:16]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[S:15][CH:14]=2)=[O:12])[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.[CH2:24]=O>C(O)=O>[CH3:24][N:21]1[CH2:20][CH2:19][CH:18]([C:16]2[S:15][CH:14]=[C:13]([C:11]([N:1]3[C@@H:10]4[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]4)[CH2:4][CH2:3][CH2:2]3)=[O:12])[CH:17]=2)[CH2:23][CH2:22]1
Reactant: O=C(c1csc(C2CCNCC2)c1)N1CCC[C@@H]2CCCC[C@@H]21
Reactant: C=O
Solvent: O=CO
Product: CN1CCC(c2cc(C(=O)N3CCC[C@@H]4CCCC[C@@H]43)cs2)CC1
Temperature: 150 °C

Procedure:
cis-(Octahydro-quinolin-1-yl)-(5-piperidin-4-yl-thiophen-3-yl)-methanone (CC-033) (0.070 g, 0.21 mmol) was dissolved in aqueous formaldehyde (37% w/w; 0.1 mL) and formic acid (1 mL). The reaction was heated to 150° C. using microwave irradiation for 5 minutes. The product was purified by flash chromatography on a SCX-2 cartridge, eluting with acetonitrile and then 2 M ammonia in methanol. The residue was further purified by flash chromatography on a NH2-SPE cartridge, eluting with 0%-100% ethyl acetate in cyclohexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.035 g). LCMS m/z 347.21 min [M+H]+ RT=6.68 min (Analytical Method 1). 1H NMR (400 MHz, CHCl3-d): δ 7.2 (s, 1H), 6.85 (s, 1H), 4.7 (m, 1H), 3.8 (m, 1H), 3.1 (m, 1H), 2.9 (m, 1H), 2.8-2.7 (m, 1H), 2.30 (s, 3H), 2.1-1.1 (m, 20H).
Reaction SMILES: [C:1]([C:4]1[CH:33]=[CH:32][C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH3:23])[C:13]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=2)=[C:6]([Cl:34])[CH:5]=1)(=O)[CH3:2].[S:35]1[CH2:39][C:38](=[O:40])[NH:37][C:36]1=[O:41].C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[Cl:34][C:6]1[CH:5]=[C:4]([C:1](=[C:39]2[S:35][C:36](=[O:41])[NH:37][C:38]2=[O:40])[CH3:2])[CH:33]=[CH:32][C:7]=1[O:8][CH2:9][CH2:10][O:11][C:12]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH3:23])[C:13]=1[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=1
Reactant: CC(=O)c1ccc(OCCOc2c(-c3ccc(F)c(F)c3)n(C)c3ccccc3c2=O)c(Cl)c1
Reactant: O=C1CSC(=O)N1
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CC(=C1SC(=O)NC1=O)c1ccc(OCCOc2c(-c3ccc(F)c(F)c3)n(C)c3ccccc3c2=O)c(Cl)c1
Temperature: 25 °C

Procedure:
A mixture of compound 3-[2-(4-Acetyl-2-chloro-phenoxy)-ethoxy]-2-(3,4-difluoro-phenyl)-1-methyl-1H-quinolin-4-one (97 g, 200 mmol), thiazolidine-2,4-dione (141 g, 1200 mmol), benzoic acid (44 g, 361 mmol) and piperidine (35 g, 411.7 mmol) were taken a single neck round bottomed flask, to this toluene (1000 mL) was added. The round-bottomed flask 20 was fitted with dean stark apparatus, which was connected to a reflux condenser. The reaction mixture was heated to reflux for 48 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25° C. and was allowed to pass through a silica gel column. The product was eluted by using 0.3-0.9% MeOH/CHCl3 to afford the title compound, 37 g (32%) as off white solid.
Reaction SMILES: [CH:1]12[CH2:11][CH:7]3[CH:8](C[CH2:10]1)[CH:3]([CH2:4][CH2:5][CH2:6]3)[CH2:2]2.F[C:13](F)(F)S(O)(=O)=O>>[CH3:13][C:5]12[CH2:4][CH:3]3[CH2:2][CH:1]([CH2:11][CH:7]([CH2:8]3)[CH2:6]1)[CH2:10]2
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: C1CC2CC3CCC2C(C1)C3
Product: CC12CC3CC(CC(C3)C1)C2
Temperature: 80 °C
Yield: 90.5 %

Procedure:
A mixture of 7.5 g (0.05 mole) of tricyclo[5.3.1.03,8 ]-undecane (II) and 76 g (0.5 mole) of trifluoromethanesulfonic acid was heated at 80°C. for 30 hours under agitation. The reaction mixture was allowed to cool and then poured over 200 ml of ice water. The organic layer was separated and the water layer was extracted with methylene chloride. The methylene chloride extract was combined with the organic layer, and the mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with water, and dried over anhydrous sodium sulfate. Methylene chloride was distilled off and the residue was sublimed to obtain 6.8 g (yield: 90 wt.%) of 1-methyladamantane (II). All of the IR, NMR and MS spectra of the product were in agreement with those of the authentic sample.
Reaction SMILES: [OH-].[K+].[C:3](=[S:5])=S.[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[C:8]=1[OH:14]>CCO.O>[NH2:6][C:7]1[C:8]2[O:14][C:3](=[S:5])[NH:13][C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: Nc1cccc(N)c1O
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cccc2[nH]c(=S)oc12
Yield: 49.7 %

Procedure:
A solution of KOH (0.875 g, 15.6 mmol) in EtOH (14.3 mL) and water (2.6 mL) was treated with carbon disulfide (0.828 g, 10.9 mmol), followed by of 2,6-diaminophenol (1.50 g, 12.1 mmol). The mixture was heated at reflux temperature for 3 h, concentrated, neutralized with 1M HCl to pH 7, and extracted with EtOAc. The extracts were combined, dried over Na2SO4 and concentrated in vacuo to afford the title compound (0.90 g, 45%), characterized by NMR and mass spectral analyses.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][C:5]1[CH:6]=[C:7]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:8]([N:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[O:25][CH3:26])[CH3:11])=[O:9].[S:34](N)([NH2:37])(=[O:36])=[O:35]>C(OC(=O)C)(C)C>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N:10]([CH3:11])[C:8](=[O:9])[C:7]2[CH:27]=[C:28]([C:30]([F:32])([F:33])[F:31])[CH:29]=[C:5]([S:4][CH2:3][CH2:2][NH:1][S:34](=[O:36])(=[O:35])[NH2:37])[CH:6]=2)=[C:19]([O:25][CH3:26])[CH:20]=1
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(SCCN)cc(C(F)(F)F)c1
Reactant: NS(N)(=O)=O
Solvent: CC(=O)OC(C)C
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(SCCNS(N)(=O)=O)cc(C(F)(F)F)c1

Procedure:
To a solution of 3-(2-aminoethylthio)-N-(4-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)-N-methyl-5-(trifluoromethyl)benzamide (0.1 g, 209 μmol, example 237) in isopropylacetate (2 mL) was added sulfamide (80.2 mg, 834 μmol) and the mixture was heated at reflux for 23 hours while the solvent was vaporized. The product was purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.1% formic acid) (20:80 to 98:2). Colorless foam (0.067 g; 57%). MS (ESI): m/z=559.11 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:24])([CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)[CH2:10][C:11](=[O:17])[NH:12][CH2:13][CH2:14][S:15][CH3:16].ClC1C=CC=C(C(OO)=[O:33])C=1>C(O)(C)C.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:24])([CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)[CH2:10][C:11](=[O:17])[NH:12][CH2:13][CH2:14][S:15]([CH3:16])=[O:33]
Reactant: CSCCNC(=O)CC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CC(C)O
Solvent: ClCCl
Product: CS(=O)CCNC(=O)CC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl

Procedure:
2-(2,4-Dichlorophenyl)-1-[N-(2-[methylthio]ethyl)carbamoyl]-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (0.8 g) and m-chloroperbenzoic acid (85%, 0.35 g, 1 equiv.) were stirred at room temperature in a mixture of isopropanol and methylene chloride (1:1, v/v, 40 ml) for two days. The solvents were then removed under reduced pressure, and the residue was chromatographed on silica (Merck, "Kieselgel 60 ", 25 g), eluting with a mixture of chloroform, methanol and ammonia (sp. gr. 0.880) (160:20:5, v/v). A portion of the isomer which was eluted first was obtained pure, 116 mg, m.p. 168°-170° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[NH:8][C:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:10]([CH3:12])[CH:11]=1)=[O:6].[CH3:20]I>CN(C=O)C>[CH3:3][O:4][C:5]([C:7]1[N:8]([CH3:20])[C:9]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[C:10]([CH3:12])[CH:11]=1)=[O:6]
Reactant: COC(=O)c1cc(C)c(-c2ccc(Cl)cc2)[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c(-c2ccc(Cl)cc2)n1C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 81.9 %

Procedure:
To a stirred solution of sodium hydride (60% suspension in mineral oil) (0.529 g, 13.22 mmol) in DMF (5 ml) at 0° C. was added a solution of methyl-5-(4-chlorophenyl)-4-methyl-1H-pyrrole-2-carboxylate (prepared according to the procedure reported in J. org. Chem., 2009, 74(2), 903-905, Org. Lett. 2007, 9(25), 5191-5194, 2.20 g, 8.81 mmol) in DMF (10 ml), which was then followed by the addition of methyl iodide (1.88 g, 0.83 ml, 13.22 mmol). The resulting reaction mixture was stirred at room temperature for 45 minutes. The progress of the reaction was monitored by TLC. The reaction mixture was then quenched with water (10 ml). The mixture so obtained was then extracted with ethyl acetate (2×50 ml). The combined organic layer was dried over anhydrous Na2SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product, which was then purified by column chromatography over silica gel (100-200 mesh) using 15-20% ethyl acetate in hexanes as an eluent to obtain the title compound (1.9 g, 81.9%)
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:13]=[C:12]([CH2:14][C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:22])[N:11]=[C:10]([NH:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=2)[N:9]=1.[Cl:32][CH2:33][C:34](Cl)=[O:35]>C(Cl)Cl>[Cl:32][CH2:33][C:34]([NH:7][C:8]1[CH:13]=[C:12]([CH2:14][C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:22])[N:11]=[C:10]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]#[N:29])=[CH:30][CH:31]=2)[N:9]=1)=[O:35]
Reactant: O=C(Cl)CCl
Reactant: N#Cc1ccc(Nc2nc(N)cc(Cc3c(Cl)cccc3Cl)n2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1ccc(Nc2nc(Cc3c(Cl)cccc3Cl)cc(NC(=O)CCl)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.5 %

Procedure:
Pyridine (1 ml) was added to a mixture of 4-[[4-amino-6-[(2,6-dichlorophenyl)-methyl]-2-pyrimidinyl]amino]benzonitrile (0.00135 mol) in CH2Cl2 (19 ml). A solution of chloroethanoyl chloride (0.001375 mol) in CH2Cl2 (0.5 ml) was added dropwise on an ice bath. The mixture was stirred at room temperature for 2 hours. More chloroethanoyl chloride (0.00625 mol) in CH2Cl2 (0.5 ml) was added. The mixture stood in the refrigerator overnight. The solvent was evaporated. The residue was treated with a saturated Na2CO3 solution and the mixture was extracted with CH2Cl2. The separated organic layer was dried, filtered and concentrated. The residue was purified by flash column chromatography over silica gel (eluent: CH2Cl2CH3OH/NH4OH 99/110.1). The desired fractions were collected and the solvent was evaporated, yielding 0.22 g (36.5%) of 2-chloro-N-[6-[(2,6-dichloro-phenyl)methyl]-2-[(4-cyano-phenyl)amino]-4-pyrimidinyl]acetamide (interm. 13).