Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].[Br:14]Br>C(O)(=O)C.O>[Br:14][C:9]1[NH:10][C:11]2[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=2[N:8]=1
Reactant: BrBr
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(=O)c2[nH]c(Br)nc2n(C)c1=O
Yield: 70 %

Procedure:
One mole of theophylline is dissolved in 2.5 liters of acetic acid containing one liter of water, and kept at 50° C., until the theophylline is dissolved and the medium becomes homogeneous. 1.1 mole of bromine is then added, drop by drop, and the bromine derivative, 8-bromotheophylline precipitates in the medium. The solution is then ccoled to room temperature , and the product filtered and washed with water, and then dried to give 70-85% yield of 8-bromo-theophylline.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][NH2:19])=[S:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][N:24]=[C:25]=[O:26].CCOCC>C1COCC1>[CH3:23][NH:24][C:25]([NH:19][NH:18][C:16]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]1[CH:20]=[CH:21][CH:22]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:9]=1)=[S:17])=[O:26]
Reactant: NNC(=S)NCCCOc1cccc(CN2CCCCC2)c1
Reactant: CN=C=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CNC(=O)NNC(=S)NCCCOc1cccc(CN2CCCCC2)c1
Reaction time: 8 h

Procedure:
1.62 g (5 mmol) of N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]hydrazine carbothioamide are dissolved in 30 ml of THF, 0.40 g (6 mmol) of methylisocyanate are added and the reaction mixture is left to stand overnight at room temperature. Ether is added to complete the precipitation, and the precipitate is suction filtered, washed with ether and recrystallised from ethanol. The analytical values are summarized in Table I.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[CH3:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([CH3:25])[C:23]=1[OH:24])[CH:19]=O.C([O-])([O-])=O.[K+].[K+].II>CN(C=O)C>[OH:24][C:23]1[C:22]([CH3:25])=[CH:21][C:18]([C:19]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)=[CH:17][C:16]=1[CH3:15]
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(O)c(C)c3)nc2c1
Temperature: 80 °C
Yield: 51.1 %

Procedure:
2-Amino-4,6-dimethoxy-benzamide (1.06 g, 5.4 mmol), 3,5-dimethyl-4-hydroxybenzaldehyde (0.810 g, 5.4 mmol), K2CO3 (0.747 g, 5.4 mmol) and I2 (1.645 g, 6.5 mmol) were mixed in DMF (20 mL) and the reaction mixture was heated at 80° C., for 12 h. It was cooled to room temperature and poured into crushed ice. The solid was collected and purified by column chromatography to give 2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.9 g, 51%) as a white solid. Selected data: MP 291-293° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[CH:4]([CH:11]([O:14][CH3:15])[O:12][CH3:13])[CH2:5][CH2:6]S([O-])(=O)=O.C(OCC)(=O)C.O.CC#[N:27]>[C-]#N.C([N+](CC)(CC)CC)C>[CH3:1][O:2][CH:3]([O:16][CH3:17])[CH:4]([CH:11]([O:14][CH3:15])[O:12][CH3:13])[CH2:5][C:6]#[N:27]
Reactant: COC(OC)C(CCS(=O)(=O)[O-])C(OC)OC
Reactant: CC#N
Agent: CC[N+](CC)(CC)CC
Agent: [C-]#N
Solvent: CCOC(C)=O
Solvent: O
Product: COC(OC)C(CC#N)C(OC)OC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Tetraethylammonium cyanide (142.3 g, 910.8 mmol) was added portionwise over 10 minutes to a solution of [2-(dimethoxymethyl)-3,3-dimethoxypropyl]methanesulfonate (124 g, 455.4 mmol) in MeCN (1.24 L). The reaction mixture was stirred at room temperature for 72 h, then portioned between ethyl acetate (1.24 L) and water (1.24 L). The layers were separated and the organic layer was isolated, washed with brine. The organics were dried over MgSO4, filtered and evaporated to give 3-(dimethoxymethyl)-4,4-dimethoxybutanenitrile 11 as a dark brown oil (86.1 g).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]1[O:14][CH2:13]1)[CH:2]1[O:4][CH2:3]1.[CH2:15]([OH:18])[C:16]#[CH:17]>>[CH2:15]([O:18][CH2:13][CH:12]([OH:14])[CH2:11][O:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:1][CH:2]([OH:4])[CH2:3][O:4][CH2:3][C:2]#[CH:1])[C:16]#[CH:17]
Reactant: C#CCO
Reactant: C(CCOCC1CO1)COCC1CO1
Product: C#CCOCC(O)COCCCCOCC(O)COCC#C

Procedure:
Analogous to Example 1, 475 g 1,4-diglycidyloxybutane was reacted with 528 g of propargyl alcohol to give 1,4-bis(3-propargyloxy-2-hydroxypropyl) oxybutane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:12]=[C:13]([CH3:28])[C:14]3[C:18]4[N:19]=[C:20]([CH2:24][CH2:25][CH3:26])[NH:21][C:22](=O)[C:17]=4[S:16][C:15]=3[N:27]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O=P(Cl)(Cl)[Cl:31]>>[Cl:31][C:22]1[C:17]2[S:16][C:15]3[N:27]=[C:11]([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:12]=[C:13]([CH3:28])[C:14]=3[C:18]=2[N:19]=[C:20]([CH2:24][CH2:25][CH3:26])[N:21]=1
Reactant: CCCc1nc2c(sc3nc(-c4ccc(OC)c(OC)c4)cc(C)c32)c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: CCCc1nc(Cl)c2sc3nc(-c4ccc(OC)c(OC)c4)cc(C)c3c2n1
Temperature: 0 °C
Yield: 100.1 %

Procedure:
0.57 g (1.4 mmol) 7-(3,4-dimethoxyphenyl)-9-methyl-2-propyl-pyrido[3′,2′:4,5]thieno-[3,2-d]pyrimidin-4-one is refluxed in 8 ml (86.4 mmol) phosphoroxychloride for 9 h. Then, the product is poured onto about 50 g ice water. The precipitate is sucked off, washed with about 250 ml water, suck dried and dried in vacuo at 50° C. 0.58 g (96%) 4-chloro-7-(3,4-dimethoxyphenyl)-9-methyl-2-propyl-pyrido[3′,2′:4,5]-thieno[3,2-d]pyrimidine is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]3[CH2:7][CH2:8][CH2:9][N:10]([C:14]([NH:16]C(=O)CCl)=[O:15])[C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1.O.NN>C(O)C>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]3[CH2:7][CH2:8][CH2:9][N:10]([C:14]([NH2:16])=[O:15])[C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1
Reactant: O=C(CCl)NC(=O)N1CCCC2=C1CCc1cc(Cl)ccc12
Agent: NN
Solvent: O
Solvent: CCO
Product: NC(=O)N1CCCC2=C1CCc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 11.85 g (0.035 mol) of 8-chloro-N -(chloroacetyl)-2,3,5,6-tetrahydrobenzo[f]quinoline-4(1H)carboxamide and 4.4 ml (0.091 mol) of hydrazine hydrate in 250 ml of ethanol is stirred at room temperature for 3 hours, concentrated in a vacuum and extracted with methylene chloride/water. Drying with magnesium sulfate and distillation of the solvent in a vacuum yields 8-chloro-2,3,5,6-tetrahydrobenzo[f]quinoline-4(1H)-carboxamide as white crystals which exhibit a melting point of 169-171° after recrystallization from methylene chloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([F:15])=[CH:13][N:12]=[C:11]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:18]=2)[N:10]=1.[F:28][C:29]1[CH:30]=[C:31]([CH2:35][OH:36])[CH:32]=[CH:33][CH:34]=1>>[F:15][C:14]1[C:9]([C:3]2[CH:4]=[CH:5][C:6]([O:36][CH2:35][C:31]3[CH:32]=[CH:33][CH:34]=[C:29]([F:28])[CH:30]=3)=[CH:7][C:2]=2[F:1])=[N:10][C:11]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][S:24]([CH3:27])(=[O:25])=[O:26])[CH:18]=2)=[N:12][CH:13]=1
Reactant: OCc1cccc(F)c1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncc(F)c(-c3ccc(F)cc3F)n2)c1
Product: CS(=O)(=O)Cc1cccc(Nc2ncc(F)c(-c3ccc(OCc4cccc(F)c4)cc3F)n2)c1

Procedure:
Example 18 was prepared under similar conditions as described in the preparation of Example 16 using 4-(2,4-difluorophenyl)-5-fluoro-N-{3-[(methylsulfonyl)methyl]phenyl}pyrimidin-2-amine (Intermediate 16.2) and (3-fluorophenyl)methanol (ABCR GmbH & CO. KG). The batch was purified by preparative HPLC.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([C@H:40]([CH3:43])[CH2:41]O)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>C(Cl)Cl>[I:25][CH2:41][C@H:40]([CH:37]1[CH2:38][CH2:39][N:34]([C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:33])[CH2:35][CH2:36]1)[CH3:43]
Reactant: II
Reactant: C[C@H](CO)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@H](CI)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
A solution of 1.57 g (6.0 mmol) of triphenylphosphine and 0.41 g (6.0 mmol) of imidazole in 40 mL of CH2Cl2 was treated with 1.52 g (6.0 mmol) of iodine and stirred at rt for 30 min. A solution of 1.15 g (4.7 mmol) of 2-(S)-((t-butoxycarbonyl)piperidin-4-yl)propanol (from EXAMPLE 30, Step D) in 10 mL of CH2Cl2 was added and the resulting mixture was stirred at rt for 20 h. The reaction mixture was partitioned between 200 mL of ether and 100 mL of H2O and the layers were separated. The organic layer was washed with 100 mL of sat'd NaHCO3, 100 mL of 5% Na2SO3, 100 mL of sat'd NaCl, dried over MgSO4 and concentrated. Flash chromatography on 60 g of silica gel using 10:1 v/v hexanes/ether as the eluant afforded 1.57 g (95%) of the title compound: 1H NMR (500 MHz) δ 0.98 (d, J=6.5, 3H), 1.10-1.20 (m, 2H), 1.26-1.36 (m, 1H), 1.40-1.50 (m, 1H), 1.45 (s, 9H), 1.64 (app d, J=11.0, 11H), 2.67 (br s, 2H), 3.19-3.28 (m, 2H), 4.13 (br s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][N:6]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:4].[C:25](Cl)([O:27][CH2:28][C:29]([Cl:32])([Cl:31])[Cl:30])=[O:26]>C(Cl)Cl>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([N:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:25]([O:27][CH2:28][C:29]([Cl:32])([Cl:31])[Cl:30])=[O:26])[CH2:7][N:6]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:4]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: COC(=O)C1CC(NCc2ccccc2)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Product: COC(=O)C1CC(N(Cc2ccccc2)C(=O)OCC(Cl)(Cl)Cl)CN1C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
To a solution of a corresponding 4-[(benzylamino)]-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester in DCM, cooled to 0 degree is added TrocCl and TEA. The mixture is stirred overnight, washed with Na2CO3, brine, dried and concentrated in vacuo to give 4-[(benzyl)-(2,2,2-trichloro-ethoxycarbonyl)-amino]-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester 2-methyl ester (19).
Reaction SMILES: [NH2:1][C:2]1[C:6]([Br:7])=[C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])[O:4][N:3]=1.[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1.ClCCl>[Br:7][C:6]1[C:2]([NH:1][S:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:20])=[O:19])=[N:3][O:4][C:5]=1[C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)c1onc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1onc(NS(=O)(=O)c2ccccc2)c1Br
Temperature: 50 °C
Reaction time: 6 h

Procedure:
3-Amino-4-bromo-5-tert-butylisoxazole (21 9 mg, 1.0 mmol) was dissolved in dry pyridine (1 ml). Benzenesulfonyl chloride (0.14 ml, 1.1 mmol) and 4-dimethylamino-pyridine (5 mg) were added and the solution was stirred at 50° C. for 6 h. The reaction mixture was diluted with dichloromethane (75 ml), washed with 1N HCl (50 ml) and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography (9:1 hexanes/ethyl acetate). A crystalline solid was obtained after recrystallization from ethyl acetate/hexanes, m.p. 139°-141° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][C:3]=1[NH2:4].[C:15]1(=O)[O:20][C:18](=[O:19])[C:17]2[CH2:21][CH2:22][CH2:23][CH2:24][C:16]1=2.O>C(O)(=O)C>[F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][C:3]=1[N:4]1[C:18](=[O:19])[C:17]2[CH2:21][CH2:22][CH2:23][CH2:24][C:16]=2[C:15]1=[O:20]
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: COC(=O)Oc1cc(N)c(F)cc1Cl
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 79.1 %

Procedure:
A solution of 2-fluoro-4-chloro-5-methoxycarbonyloxyaniline (20.0 g, 91.1 mmol) and 3,4,5,6-tetrahydrophthalic anhydride (14.0 g, 92.0 mmol) in acetic acid (200 ml) was reacted for 5 hours while heating under refluxing. After completion of the reaction, the mixture was-cooled to room temperature, water (200 ml) was added thereto, and extracted with ethyl acetate (100 ml×3 times). The organic layer was washed with an aqueous solution of sodium carbonate and water, dried, and the solvent was distilled off under reduced pressure. The resulting oily substance was purified by silica gel column chromatography (development solvent: ethyl acetate/hexane=1/5) to obtain N-(2-fluoro-4-chloro-5-methoxycarbonyloxyphenyl)-3,4,5,6-tetrahydrophthalimide as a white solid (26.2 g, 72.1 mmol, 79.2% yield).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.Cl.O1CCOCC1>C(O)CCC>[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:2]2[S:3][C:4]3[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=3[N:6]=2)=[CH:15][CH:14]=1
Reactant: Nc1ccc(Br)cc1
Reactant: Clc1ccc2nc(Cl)sc2c1
Agent: Cl
Solvent: CCCCO
Solvent: C1COCCO1
Product: Clc1ccc2nc(Nc3ccc(Br)cc3)sc2c1
Temperature: 65 °C

Procedure:
A mixture of 2,6-dichlorobenzothiazole (0.71 g, 3.5 mmol) and 4-bromoaniline (0.61 g, 3.5 mmol) in n-butanol (6 mL) was heated at 60-70° C. under nitrogen to obtain a solution, to which 4 M HCl in dioxane (0.43 mL, 1.73 mmol) was then slowly added dropwise. The reaction mixture was then heated at 90° C. for 18 h. Upon cooling to rt, the reaction mixture was concentrated under reduced pressure. The resulting solid was triturated with ethanol and collected by filtration. This yielded 1.09 g (93%) of the title compound. LC/MS m/z 339 (MH+); retention time 3.98 min. 1H NMR (CD3OD) δ 7.31 (d, 1H), 7.42-7.58 (m, 5H), 7.61 (d, 1H).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:13][N:12]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[C:11](=[O:27])[C@@H:10]1[O:28]S(C)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:33][C:34]1[CH:39]=[CH:38][C:37](O)=[C:36]([F:41])[CH:35]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH2:1]([O:8][C@H:9]1[CH2:13][N:12]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[C:11](=[O:27])[C@H:10]1[O:28][C:37]1[CH:38]=[CH:39][C:34]([Br:33])=[CH:35][C:36]=1[F:41])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(N2C[C@H](OCc3ccccc3)[C@@H](OS(C)(=O)=O)C2=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(N2C[C@H](OCc3ccccc3)[C@H](Oc3ccc(Br)cc3F)C2=O)CC1
Temperature: 70 °C
Yield: 40.3 %

Procedure:
Tert-butyl 4-((3R,4S)-4-(benzyloxy)-3-(methylsulfonyloxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (620 mg, 1.32 mmol) was dissolved in dry DMSO (10 mL) and 4-bromo-2-fluorophenol (303 mg, 1.59 mmol) and K2CO3 (219 mg, 1.59 mmol) were added and the reaction heated to 70° C. under nitrogen overnight. The reaction was partitioned between water and EtOAc, extracted, dried over Na2SO4, filtered and concentrated. The residue was purified over silica gel (50 to 75% EtOAc in hexane) to afford tert-butyl 4-((3S,4S)-4-(benzyloxy)-3-(4-bromo-2-fluorophenoxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (300 mg, 0.532 mmol, 40.2% yield) as a crude material, which was taken forward without further purification.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[C:12]1([C:18]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:26]3[CH:22]([CH2:23][NH:24][CH2:25]3)[S:21][CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl.CO>[C:27]1([C:18]2([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:26]3[CH:22]([CH2:23][NH:24][CH2:25]3)[S:21](=[O:6])[CH2:20][CH2:19]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: c1ccc(C2(c3ccccc3)CCSC3CNCC32)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: O=S1CCC(c2ccccc2)(c2ccccc2)C2CNCC21
Temperature: -3 °C
Reaction time: 1 h
Yield: 51.6 %

Procedure:
A solution of 15.4 g of 3-chloroperoxybenzoic acid (at 85%) in 400 cm3 of dichloromethane is added over 40 minutes to a solution, cooled to -3° C., of 25 g of (4aRS, 7aRS)-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole in 500 cm3 of dichloromethane and 100 cm3 of methanol. After stirring for one hour at -3° C., the reaction mixture is washed with 200 cm3 of a 10% aqueous solution of potassium hydrogen carbonate and again with 100 cm3 of this same solution, then dried over magnesium sulphate and concentrated to dryness at 40° C. under reduced pressure (2.7 kPa). The residue is crystallized from 50 cm3 of ethyl acetate, the crystals are taken up in 200 cm3 of dichloromethane, the solution obtained is washed with 75 cm3 of a 1N aqueous solution of sodium hydroxide and then dried over magnesium sulphate and concentrated to dryness. The residue is crystallized from 30 cm3 of ethyl acetate, the crystals are washed with ethyl acetate, drained and dried. 13.6 g of (1RS,4aRS,7aRS)-4,4-diphenylperhydrothiopyrano[2,3-c]-pyrrole 1-oxide are obtained in the form of white crystals; melting point 174° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([C:10]#[C:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([CH:19]=2)[C:17]#[N:18])[CH:6]=[CH:7][C:8]=1[F:9].[C-:20]#[N:21].[Na+]>CN(C)C=O.C(OCC)(=O)C>[C:20]([CH2:2][C:3]1[CH:4]=[C:5]([C:10]#[C:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([CH:19]=2)[C:17]#[N:18])[CH:6]=[CH:7][C:8]=1[F:9])#[N:21]
Reactant: N#Cc1cncc(C#Cc2ccc(F)c(CCl)c2)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CCc1cc(C#Cc2cncc(C#N)c2)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
Dissolve 5-(3-chloromethyl-4-fluorophenylethynyl)-nicotinonitrile, (prepared as described in PREPARATION 32), (120 mg, 0.44 mmol) in N,N-dimethylformamide (2.2 mL) and treat with sodium cyanide (86 mg, 1.8 mmol). After stirring for 30 min at room temperature, dilute with ethyl acetate and wash with an aqueous saturated solution of sodium bicarbonate and an aqueous saturated solution of sodium chloride. Dry (sodium sulfate), filter, and concentrate. Purify by silica gel chromatography, eluting with 70:30 hexanes:ethyl acetate, to give the title compound as a white crystalline solid (90 mg, 78%).
Reaction SMILES: O[C:2]1([CH3:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:11][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]=1
Reactant: CC1(O)CCc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1=CCc2ccccc21
Yield: 67 %

Procedure:
A solution of 24.64 (0.166 mol) of 1-hydroxy-1-methyl-2,3-dihydro-1H-indene and 0.30 g of p-toluenesulphonic acid monohydrate in 300 ml of toluene was heated to reflux for 3 h with water being collected by means of a Dean Stark trap. The reaction mixture was cooled, washed with water (3×100 ml), then with saturated sodium chloride solution (100 ml), dried (K2CO3) and evaporated in vacuo to leave an orange oil. This was vacuum distilled to yield 14.57 g (67%) of the title product as a colourless oil, b.p. 32°-35° C./0.3 mm of Hg. NMR δ(CDCl3) 2.17 (3H, m), 3.31 (2H, m), 6.20 (1H, m), 7.16-7.35 (3H, m), 7.45 (1H, m).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([OH:17])(=O)=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)C.S(Cl)([Cl:25])=O>CN(C=O)C>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([Cl:25])(=[O:17])=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)c1ccc(Oc2ccccc2)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=S(=O)(Cl)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C

Procedure:
A solution of 4-phenoxybenzenesulfonic acid (3.14 g, 12.64 mmol) in thionyl chloride (9 ml) was refluxed for 4 h in presence of DMF (2 drops). After cooling to room temperature, diethyl ether (20 ml) was added and the resulting white solid was separated by filtration. The filtered solution was evaporated in vacuo to give 4-phenoxybenzenesulfonyl chloride as a brown oil which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[Br:14]C1C=C(CC(O)=O)C=CC=1>>[Br:14][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:7][CH:2]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Product: CCOC(=O)Cc1cccc(Br)c1

Procedure:
Employing the same general procedure as for the preparation of ethyl (4-bromophenyl)acetate (Compound A), 100 g (463 mmol) of 3-bromophenylacetic acid was converted into the title compound (yellow oil) using 2 g of conc. H2SO4 and 500 ml of ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:3]=1[CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:15][CH2:16][C:17]([O:19]C)=[O:18])[C:10](=[O:21])[N:9]([CH:22]([CH3:24])[CH3:23])[C:8]=2[N:7]=[C:6]1[N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.O.[Li+].[OH-]>C(O)(=O)C>[Cl:1][C:2]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:3]=1[CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:10](=[O:21])[N:9]([CH:22]([CH3:24])[CH3:23])[C:8]=2[N:7]=[C:6]1[N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COC(=O)CCn1c(=O)c2c(nc(N3CCCCC3)n2Cc2c(F)cccc2Cl)n(C(C)C)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)n1c(=O)n(CCC(=O)O)c(=O)c2c1nc(N1CCCCC1)n2Cc1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.9 %

Procedure:
A solution of methyl 3-[7-(2-chloro-6-fluorobenzyl)-3-isopropyl-2,6-dioxo-8-piperidin-1-yl-2,3,6,7-tetrahydro-1H-purin-1-yl]propanoate (9 mg, 0.018 mmol) in 150 μTHF and 50 μL H2O was treated with 18 μL 1 N LiOH. The reaction mixture was stirred at room temperature overnight and then treated with 18 μL 1 N acetic acid. The product was extracted into EtOAc and then the solvent was removed by reduced pressure. The crude product was purified by preparative thin layer chromatography (silica gel, 1 mm plate, EM Science 20×20 cm silica gel 60 F264) eluting with 100% EtOAc to give 3 mg (13% yield) of the title compound as a clear oil: 1H NMR (CDCl3, 400 MHz) 7.23-7.17 (m, 1H), 7.15-7.12 (m, 1H), 6.99-6.94 (m, 1H), 5.52 (s, 2H), 5.16-5.07 (m, 1H), 4.21 (t, 2H, J=6.9 Hz), 3.14-3.04 (m, 4H), 2.66 (t, 2H, J=6.9 Hz), 1.56-1.51 (m, 12H); MS (ESP+) m/e 492 (MH+); TLC (EtOAc:hexanes/1:1) Rf=0.61.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=[O:19])[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[OH-:30].[Na+]>C(O)C.[N+]([O-])([O-])=O.[Ag+]>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]([OH:30])=[O:19])[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: [OH-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(=O)O)n(C)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a suspension of 2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purine-8-carbaldehyde (15 g, 38 mmol) in ethanol was added silver nitrate (8.1 g, 48 mmol) and a 1.5 M NaOH solution (150 mL). The resulting mixture was stirred at room temperature for 30 minutes prior to filtering through celite. The solution was then concentrated. To the residual solid was added water and made basic by adding 1M NaOH (cloudy mixture). The mixture was then washed with DCM. The aqueous layer was then made acidic (pH 2) by adding concentrated HCl. The acidic mixture was then concentrated under vacuum. A precipitate slowly formed during the concentration. After the volume was reduced by ⅓, the suspension was cooled in an ice-bath for 15 minutes before being filtered to collect the solid. The solid was then dried under vacuum to give 2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purine-8-carboxylic acid as a beige powder (15.2 g, 97%). LCMS m/z: 408.3 (MH+)