Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:6])(=O)[C:2](O)=[O:3].S(=O)(=O)(O)O.[CH:12]12[CH2:21][CH:16]3C[CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2>>[CH:16]12[CH2:21][CH:12]3[CH2:13][CH:14]([CH2:20][CH:2]([CH2:19]3)[C:1]1=[O:6])[CH2:15]2.[OH:6][C:1]12[CH2:21][CH:12]3[CH2:13][CH:14]([CH2:20][CH:18]([CH2:19]3)[C:2]1=[O:3])[CH2:15]2
Reactant: O=C(O)C(=O)O
Reactant: C1C2CC3CC1CC(C2)C3
Agent: O=S(=O)(O)O
Product: O=C1C2CC3CC(C2)CC1(O)C3
Product: O=C1C2CC3CC(C2)CC1C3
Yield: 2 %
Yield: 8 %

Procedure:
The reaction was conducted in the same manner as Example 1 except using 1 mmol of oxalic acid instead of 98% by weight of sulfuric acid, the pH of the mixture was 3.7, and as a result, adamantane was converted into adamantanone (yield 8%) and 1-hydroxyadamantanone (yield 2%) with a conversion of 99%. Incidentally, excepting the above, 1-adamantanol (yield 26%), 1,3-adamantanediol (yield 33%) and other products (polyol such as adamantanetriol) (yield 30%) were formed.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[N:17]3[C:18]([N+:21]([O-])=O)=[CH:19][N:20]=[C:16]3[CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3]>C(Cl)Cl.[H][H].[C].[Pd]>[NH2:21][C:18]1[N:17]2[C:12]([O:11][CH:8]3[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH2:7]3)=[CH:13][CH:14]=[CH:15][C:16]2=[N:20][CH:19]=1
Reactant: [H][H]
Reactant: CS(=O)(=O)N1CCC(Oc2cccc3ncc([N+](=O)[O-])n23)CC1
Agent: [Pd]
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(Oc2cccc3ncc(N)n23)CC1
Yield: 132.6 %

Procedure:
To a solution of 5-[1-(methylsulfonyl)-4-piperidyloxy]-3-nitroimidazo[1,2-a]pyridine (70 mg, 0.226 mmole) in methylene chloride (10 ml) was added 10% palladium-carbon (50 ml) and the mixture was stirred in hydrogen atmosphere at room temperature for 1.5 hours. After the reaction mixture was treated with Cellite, the solvent was distilled off. To the residue was added chloroform, which was washed in turn with an aqueous saturated sodium bicarbonate solution and water and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography [eluent:chloroform/methanol (15:1)] to obtain 93 mg of the desired product (30.0%, brown oily product).
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][C:11](Cl)=[O:12])=[N:5][N:4]=[N:3]1.N1C=CC=CC=1.[SH2:20]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][C:11]([OH:12])=[S:20])=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1SCCCC(=O)Cl
Reactant: S
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cn1nnnc1SCCCC(O)=S
Reaction time: 1 h

Procedure:
920 mg of 4-(1-methyltetrazol-5-ylthio)-butyric acid chloride are dissoved in 1.4 ml of absolute methylene chloride and added dropwise at 0° to 5.54 ml of a pyridine/H2S solution in methylene chloride (30 ml of absolute pyridine and 6 g of H2S in 100 ml of methylene chloride). The whole is then stirred for one hour at 0° under a nitrogen atmosphere. The reaction mixture is taken up in chloroform, the aqueous phase is acidified to a pH of 2 using 2N H2SO4 and extraction is carried out twice with chloroform. The combined organic phases are washed twice with 5 ml of 10% NaHCO3 solution. The pH is then adjusted to 3 using 2N H2SO4 and the title compound is extracted several times with chloroform. The title compound is obtained after drying over sodium sulphate and concentrating.
Reaction SMILES: [CH2:1]([S:8]([NH:11][C@@H:12]([C:17]([NH:19][C@H:20]([C:25]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([NH2:37])=[NH:36])=[CH:31][CH:30]=1)=[O:26])[CH2:21][CH2:22][S:23][CH3:24])=[O:18])[C@@H:13]([CH2:15][CH3:16])[CH3:14])(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:45](=O)([O:51]C(C)(C)C)[O:46][C:47]([CH3:50])([CH3:49])[CH3:48].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([S:8]([NH:11][C@@H:12]([C:17]([NH:19][C@H:20]([C:25]([NH:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32](/[C:35](/[NH2:37])=[N:36]\[C:45]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:51])=[CH:33][CH:34]=1)=[O:26])[CH2:21][CH2:22][S:23][CH3:24])=[O:18])[C@@H:13]([CH2:15][CH3:16])[CH3:14])(=[O:9])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](C)[C@@H](NS(=O)(=O)Cc1ccccc1)C(=O)N[C@@H](CCSC)C(=O)NCc1ccc(C(=N)N)cc1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC[C@@H](C)[C@@H](NS(=O)(=O)Cc1ccccc1)C(=O)N[C@@H](CCSC)C(=O)NCc1ccc(/C(N)=N\C(=O)OC(C)(C)C)cc1
Reaction time: 16 h
Yield: 75 %

Procedure:
N-(Benzylsulfonyl)-D-isoleucyl-N1-{4-[amino(imino)-methyl]benzyl}-L-methioninamide (20 mg, 0.032 mmol) was dissolved in dimethylformamide (0.5 ml), to which triethylamine (0.018 ml, 0.13 mmol) and di-t-butyl carbonate (14 mg, 0.065 mnol) were then added and stirred for 16 hours. After addition of ethyl acetate to the reaction mixture, the organic layer was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by preparative TLC (dichloromethane:methanol=10:1) to give N-(benzylsulfonyl)-D-isoleucyl-N1-[4-((E)-amino-[[(t-butyloxy)carbonyl]imino]methyl)benzyl]-L-methioninamide (16 mg, 0.024 mmol; yield 76%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[C:17]1[C:18]([CH3:23])=[N:19][CH:20]=[CH:21][CH:22]=1)[C:11]([OH:13])=O.[F:24][C:25]1[CH:26]=[CH:27][C:28]([O:35][CH3:36])=[C:29]([C:31](=[N:33]O)[NH2:32])[CH:30]=1.CCN(C(C)C)C(C)C>>[F:24][C:25]1[CH:26]=[CH:27][C:28]([O:35][CH3:36])=[C:29]([C:31]2[N:32]=[C:11]([C:10]3[CH:14]=[CH:15][C:16]([C:17]4[C:18]([CH3:23])=[N:19][CH:20]=[CH:21][CH:22]=4)=[C:8]([CH3:7])[CH:9]=3)[O:13][N:33]=2)[CH:30]=1
Reactant: Cc1cc(C(=O)O)ccc1-c1cccnc1C
Reactant: COc1ccc(F)cc1C(N)=NO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(F)cc1-c1noc(-c2ccc(-c3cccnc3C)c(C)c2)n1

Procedure:
Oxalyl chloride (84 mg; 0.66 mmol; 3 eq.), Intermediate 37 (50 mg; 0.22 mmol; 1 eq.), Intermediate 23 (41 mg; 0.22 mmol, 1 eq.) and DIEA (85 mg; 0.66 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography c-hexane/ethyl acetate, 90/10 then 85/15) afforded the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][CH3:44])=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>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.O>[CH2:42]([O:41][CH2:40][CH2:39][O:38][C:35]1[CH:34]=[CH:33][C:32]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:37][CH:36]=1)[CH2:43][CH3:44]
Reactant: CCCOCCOc1ccc(OB([O-])[O-])cc1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2S(=O)(=O)CC1
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: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
To methyl 7-bromo-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (6.5 g) was added toluene/ethanol/water (10/1/1,188 ml) and then were added 4-(2-propoxyethoxy)phenyl borate (5.3 g) and potassium carbonate (6.0 g), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (0.9 g), and the mixture was refluxed for 14 hours and cooled to room temperature. The mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=3/2) to give methyl 7-[4-(2-propoxyethoxy)phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (6.5 g).
Reaction SMILES: [NH2:1][C:2]1([CH2:17][CH3:18])[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5](=[O:15])[NH:4][C:3]1=[O:16].[F:19][C:20]1[C:21]([F:33])=[C:22]([F:32])[C:23]([F:31])=[C:24]2[C:29](=O)[O:28][C:26](=[O:27])[C:25]=12>C(O)(=O)C>[CH2:17]([C:2]1([N:1]2[C:29](=[O:28])[C:24]3=[C:23]([F:31])[C:22]([F:32])=[C:21]([F:33])[C:20]([F:19])=[C:25]3[C:26]2=[O:27])[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5](=[O:15])[NH:4][C:3]1=[O:16])[CH3:18]
Reactant: CCC1(N)C(=O)NC(=O)N(c2ccccc2)C1=O
Reactant: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Solvent: CC(=O)O
Product: CCC1(N2C(=O)c3c(F)c(F)c(F)c(F)c3C2=O)C(=O)NC(=O)N(c2ccccc2)C1=O
Yield: 60.1 %

Procedure:
A mixture of about 250 mg (about 1 mmol) of 5-amino-5-ethyl-1-phenylbarbituric acid, about 260 mg (about 1.2 mmol) of tetrafluorophthalic anhydride, and about 7 mL of acetic acid was refluxed for about 3 hours. The solvent was evaporated to dryness under reduced pressure of from about 200 to about 15 mbar. The residue was recrystallized from ethyl alcohol to yield about 270 mg 5-ethyl-1-phenyl-5-(tetrafluorophthalimido)barbituric acid (a 60% yield) having a melting point of about 218° to about 220° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[CH2:29][CH2:30][NH2:31])=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[CH2:29][CH2:30][NH:31][CH2:11][C:10]1[CH:13]=[CH:14][CH:15]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:9]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCN
Product: CC(C)(C)OC(=O)N1CCCCC1CCNCc1cccc(-c2ccnc(Cl)n2)c1

Procedure:
Intermediate 1 was coupled with 2-(2-Amino-ethyl)-piperidine-1-carboxylic acid tert-butyl ester following procedure B. LC-MS showed the product had the expected M+H+ of 431.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[C:4]=1[CH2:5][Br:6].[C:17]1([P:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[Br-:6].[F:1][C:2]([F:16])([F:15])[C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[C:4]=1[CH2:5][P+:23]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: FC(F)(F)c1cccc(C(F)(F)F)c1CBr
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cccc(C(F)(F)F)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2,6-bis(trifluoromethyl)benzyl bromide (0.400 g, 1.30 mmol) in toluene (5 mL) was added triphenylphosphine (0.375 g, 1.43 mmol). The mixture was heated to reflux for 24 h. After cooling to room temperature, hexanes (10 mL) was added and the mixture was stirred for 1 h. The solid was collected by filtration and rinsed with hexanes to give 2,6-bis(trifluoromethyl)benzyltriphenylphosphonium bromide as a white solid. Yield (0.446 g, 60%): 1H NMR (400 MHz, DMSO-d6) δ 8.02 (d, J=8.0 Hz, 2H), 7.57-7.87 (m, 16H), 5.17 (d, J=15.2 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:4]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=2[Cl:20])[N:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[N+:34]([O-])([O-:36])=[O:35].[NH4+].C(=O)([O-])[O-].[K+].[K+]>FC(F)(F)C(O)=O>[CH3:1][C:2]1[C:6]([N+:34]([O-:36])=[O:35])=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:4]([C:12]2[C:13]([Cl:20])=[CH:14][C:15]([Cl:19])=[CH:16][C:17]=2[Cl:18])[N:3]=1
Reactant: O=[N+]([O-])[O-]
Reactant: CCOC(=O)c1cc(C)nn1-c1c(Cl)cc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [NH4+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c([N+](=O)[O-])c(C)nn1-c1c(Cl)cc(Cl)cc1Cl
Yield: 65.5 %

Procedure:
To a solution of ethyl 3-methyl-1-(2,4,6-trichlorophenyl)-1H-pyrazole-5-carboxylate (500 mg, 1.50 mmol) in trifluoroacetic acid (2.54 ml) was added trifluoroacetic anhydride (1.48 ml) followed by an addition of ammonium nitrate (240 mg, 3.00 mmol). The mixture was stirred for 20 h at room temperature and neutralized with aqueous potassium carbonate. The aqueous solution was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under vacuum. The residue was purified by silica gel chromatography eluting with 3% ethyl acetate/n-hexane to give the title compound (372 mg, 66%).
Reaction SMILES: O.[NH2:2][C:3]1[N:8]=[C:7]([OH:9])[CH:6]=[C:5](Cl)[N:4]=1.[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH2:16][NH2:17].C(N(CC)CC)C.C(O)(=O)C>COC(O)C>[NH2:2][C:3]1[N:8]=[C:7]([OH:9])[CH:6]=[C:5]([NH:17][CH2:16][C:12]2[S:11][CH:15]=[CH:14][CH:13]=2)[N:4]=1
Reactant: Nc1nc(O)cc(Cl)n1
Reactant: NCc1cccs1
Agent: COC(C)O
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1nc(O)cc(NCc2cccs2)n1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
2-Amino-6-chloro-4-pyrimidinol, monohydrate (85%, 100 g, 0.5197 mol) was suspended in methoxyethanol (700 ml) and 2-thienylmethylamine (96%, 61.3 g, 0.5197 mol) was added to the suspension. The mixture was heated under reflux for two hours and then 73 ml (d =0.726; 0.52 mol) of triethylamine was added and the refluxing continued for an additional 18 hours. The reaction mixture was poured into ice water (1000 ml), acidified with acetic acid (ph 4.0) and the precipitated solid was filtered, washed, and dried. Yield: 110 g (72.6%). This was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[C:3](=[O:21])[N:4]([C:9]2[CH:10]=[C:11]([CH:16]=[C:17]([F:20])[C:18]=2[CH3:19])[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([Br:8])[N:7]=1.[NH2:22][C@@H:23]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@@H:24]([CH3:27])[CH2:25][OH:26].CCN(C(C)C)C(C)C>C1COCC1.C(OCC)(=O)C>[Br:8][C:6]1[N:7]=[C:2]([NH:22][C@@H:23]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@@H:24]([CH3:27])[CH2:25][OH:26])[C:3](=[O:21])[N:4]([C:9]2[CH:10]=[C:11]([CH:16]=[C:17]([F:20])[C:18]=2[CH3:19])[C:12]([O:14][CH3:15])=[O:13])[CH:5]=1
Reactant: C[C@@H](CO)[C@@H](N)c1ccccc1
Reactant: COC(=O)c1cc(F)c(C)c(-n2cc(Br)nc(Br)c2=O)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(F)c(C)c(-n2cc(Br)nc(N[C@@H](c3ccccc3)[C@@H](C)CO)c2=O)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To methyl 3-(3,5-dibromo-2-oxopyrazin-1(2H)-yl)-5-fluoro-4-methylbenzoate (Example 252g, 0.9 g) in THF (3 mL) was added (2R,3R)-3-amino-2-methyl-3-phenylpropan-1-ol (Example 328a, 0.389 g) and Hunig's Base (0.374 mL) and the reaction stirred at 50° C. for 8 h. The reaction mixture was diluted with ethyl acetate and washed with aqueous NaHCO3. The organics were dried (MgSO4) and concentrated in vacuo to leave the crude product which was triturated overnight in 2:1 isohexane/diethyl ether to give the subtitle compound. Purification of the filtrate (SiO2 chromatography eluting with 50-100% diethyl ether in isohexane) to give further subtitle compound (total 0.820 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([C:13]3[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=3)[C:6]=2[CH:19]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][N:25]2C1CCCCO1.CCN(C(C)C)C(C)C.Cl.O1CCOCC1>CC(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:12][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:11])[N:7]([C:13]3[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=3)[C:6]=2[CH:19]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1cnn(C)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CC(C)O
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1cnn(C)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 63.1 %

Procedure:
A mixture of (S)-1-[6-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-1H-benzoimidazol-2-yl]ethylamine, (0.055 g, 0.21 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (0.070 g, 0.30 mmol) and DIPEA (0.07 mL, 0.38 mmol) in IPA (1.5 mL) was stirred at 80° C. in a sealed tube for 16 h. After cooling, the reaction mixture was concentrated in vacuo and the residue purified by chromatography (SiO2, 0-10% (2M ammonia in methanol) in DCM). The product was dissolved in methanol (4 mL) and treated with HCl/dioxane (4M, 0.5 mL, 2.0 mmol) then stirred for 15 minutes. The resulting mixture was concentrated in vacuo and the residue loaded onto an Isolute® SCX-2 cartridge and washed with MeOH then the product eluted with 2M NH3/MeOH and concentrated in vacuo to give 419 as a white solid (0.050 g, 63%). LCMS (Method K): RT 2.65 min [M+H]+ 378.0. 1H NMR (DMSO-d6, 400 MHz): δ 12.90 (1H, s), 8.22-8.03 (3H, m), 7.89-7.81 (1H, m), 7.76 (1H, s), 7.66-7.62 (1H, m), 7.09-7.05 (1H, m), 7.00-6.91 (1H, m), 5.61-5.42 (1H, m), 3.86 (3H, s), 1.57 (3H, d, J=6.84 Hz)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:14]=[C:13]([C:23](=O)[CH3:24])[C:12]=2[OH:26])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:27]([C:29]([NH:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=1)=[S:30])[NH2:28].CN(C)C=O>Cl.O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:15]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:14]=[C:13]([C:23](=[N:28][NH:27][C:29]([NH:31][C:32]3[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=3)=[S:30])[CH3:24])[C:12]=2[OH:26])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Reactant: CC(=O)c1nn(Cc2ccccc2)c(-c2ccc(C(C)(C)C)cc2)c1O
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)cc1)c1nn(Cc2ccccc2)c(-c2ccc(C(C)(C)C)cc2)c1O
Yield: 70.3 %

Procedure:
1-[5-(4-tert-Butylphenyl)-1-benzyl-4-hydroxy-1H-pyrazol-3-yl]ethanone (0.218 mmol, 76 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.218 mmol, 46 mg) were stirred with dimethylformamide (3.5 mL) and three drops of concentrated hydrochloric acid at room temperature for 22 hours. After addition of water, the precipitated yellow solid was recovered by filtration, washed with water and dried by means of a vacuum pump. The resulting solid was stirred with chloroform/n-hexane for a while, then recovered by filtration and dried by means of a vacuum pump to give the desired product as a pale yellow solid (83 mg, yield 70%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][C:10]2[C:11]3[N:34]([CH3:35])[CH:33]=[CH:32][C:12]=3[N:13]=[C:14]([N:16]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[N:15]=2)=[C:4]([CH3:36])[CH:3]=1.[N:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1.C1COCC1.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=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>[CH3:36][C:4]1[CH:3]=[C:2]([C:40]2[CH:41]=[CH:42][N:37]=[CH:38][CH:39]=2)[CH:7]=[C:6]([CH3:8])[C:5]=1[S:9][C:10]1[C:11]2[N:34]([CH3:35])[CH:33]=[CH:32][C:12]=2[N:13]=[C:14]([N:16]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[N:31])=[CH:28][CH:29]=2)[C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[N:15]=1
Reactant: OB(O)c1ccncc1
Reactant: Cc1cc(Br)cc(C)c1Sc1nc(N(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)nc2ccn(C)c12
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: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccncc2)cc(C)c1Sc1nc(N(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)nc2ccn(C)c12
Temperature: 80 °C
Reaction time: 10 h

Procedure:
tert-Butyl 4-(4-bromo-2,6-dimethylphenylthio)-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-2-yl(4-cyanophenyl)carbamate (0.729 mmol) is combined with pyridine-4-boronic acid (1.46 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.0729 mmol) in a two dram vial. The vial is sealed and flushed with argon. Degassed THF (5.0 mL) and aqueous Na2CO3 (2 M, 1.5 mL, 3.0 mmol) are injected, and the mixture agitated on a shaker at 80° C. for 10 h. The mixture is diluted with ethyl acetate and extracted with aqueous Na2CO3 (0.5 M, ×2). The organic layer is collected, concentrated, and the residue purified by chromatography (SiO2, 1:4 hexanes/EtOAc).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:20]=[CH:19][C:12]3[CH2:13][CH2:14][CH:15](C=O)[O:16][C:11]=3[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]([CH:26]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:23][CH2:24][CH3:25])=[O:22]>C1(C)C=CC=CC=1>[C:1]1([CH2:7][O:8][C:9]2[CH:20]=[CH:19][C:12]3[CH2:13][CH2:14][CH2:15][O:16][C:11]=3[CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH2:24]([O:23][C:21](=[O:22])[CH:26]=[CH2:1])[CH3:25]
Reactant: O=CC1CCc2ccc(OCc3ccccc3)cc2O1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: C=CC(=O)OCC
Product: c1ccc(COc2ccc3c(c2)OCCC3)cc1
Yield: 176.3 %

Procedure:
Using the procedure of example 30, 2.7 g (10 mmoles) of the aldehyde product from example 83 was condensed with 3.7 g (10.6 mmoles) of (carbethoxymethylene)triphenylphosphorane, in 30 ml of toluene (1.5 hours at 100° C.). After chromatography of the crude product on 50 g of silica gel (eluting with toluene), there was obtained 3.0 g (88.8%) of racemic-3,4-dihydro-7-(phenylmethoxy)-2H-1-benzopyran-2-propenoic acid ethyl ester (mixture of E- and Z-isomers), as a pale-yellow oil.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][C:13]1([CH3:41])[CH:17]([C:18]([O:20]CC2C=CC([N+]([O-])=O)=CC=2)=[O:19])[N:16]2[C:31](=[O:40])[CH:32]([NH:33][C:34]3[NH:35][CH:36]=[C:37]([CH3:39])[N:38]=3)[C@H:15]2[S:14]1>C(O)C.C(Cl)Cl.[Pd]>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([OH:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[CH3:12][C:13]1([CH3:41])[CH:17]([C:18]([OH:20])=[O:19])[N:16]2[C:31](=[O:40])[CH:32]([NH:33][C:34]3[NH:35][CH:36]=[C:37]([CH3:39])[N:38]=3)[C@H:15]2[S:14]1
Reactant: Cc1c[nH]c(NC2C(=O)N3C(C(=O)OCc4ccc([N+](=O)[O-])cc4)C(C)(C)S[C@H]23)n1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCO
Product: Cc1c[nH]c(NC2C(=O)N3C(C(=O)O)C(C)(C)S[C@H]23)n1
Reaction time: 3.5 h

Procedure:
A mixture of p-nitrobenzyl 2,2-dimethyl-6-(4-methylimidazol-2-yl)aminopenam-3-carboxylate toluene-p-sulphonate (200 mg.) and 10% w/w palladium-on-carbon in ethanol (12 ml.) and methylene chloride (3 ml.) was shaken under hydrogen at atmospheric pressure for 3.5 hours. The mixture was filtered, the filtrate evaporated to dryness and the residual gum triturated with ether to give 2,2-dimethyl-6-(4-methylimidazol-2-yl)aminopenam-3-carboxylic acid toluene-p-sulphonate as a yellow powder (118 mg.) having the following n.m.r. in d6DMSO+CD3COOD: 1.5 (s, 3H); 1.6 (s, 3H); 2.11 (s, 3H); 2.3 (s, 3H); 4.35 (s, 1H); 5.40 (d, 1H); 5.62 (d, 1H); 6.72 (s, 1H); 7.1 (d, 2H); 7.5 (d, 2H); 8.76 (s, 1H). The sample was approximately 50% pure.