Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[NH2:24][CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][NH:24][CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5]
Reactant: CC(C)(CN)CO
Reactant: O=Cc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(CO)CNCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Yield: 18.5 %

Procedure:
Prepared according to the method described in Example 2 from 2-chloro-5-formyl-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.150 g, Example 1b), 3-amino-2,2-dimethylpropanol (0.093 g) and sodium triacetoxyborohydride (0.134 g) in 1,2-dichloroethane (6 ml). After work-up, the resiude was purified by NPHPLC eluting with a gradient of 0-10% ethanol in dichloromethane to give the title compound as a white powder (0.035 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][S:5]([O-:8])(=[O:7])=[O:6].[Na+].[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH:11]1[C:16]([OH:18])=[O:17]>[OH-].[Na+]>[C:16]([CH:11]1[CH2:12][N:13]([CH2:2][CH2:3][CH2:4][S:5]([OH:8])(=[O:7])=[O:6])[CH2:14][CH2:15][NH:10]1)([OH:18])=[O:17]
Reactant: O=S(=O)([O-])CCCBr
Reactant: O=C(O)C1CNCCN1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1CN(CCCS(=O)(=O)O)CCN1

Procedure:
Sodium 3-bromo-propane-1-sulphonate (2.25 g, 0.01 mole) was added to a solution of piperazine-2-carboxylic acid (1.3 g, 0.01 mole) in aqueous sodium hydroxide (0.9 g NaOH/30 ml H2O). The resulting solution was maintained at 60°-65° for 12 h. The product, 3((±)-2-carboxypiperazin-4-yl)-propane-1-sulphonic acid, was isolated by passage of the reaction mixture through Dowex-AG-1-acetate resin. Evaporation of the column filtrate and aqueous washings and recrystallization of the crude product from a 50% aqueous ethanol solution yielded 3-((±)-2-carboxy-piperazin-4-yl)-propane-1-sulphonic acid (500 mg) as a white crystalline solid, m.p. 190°-191°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([OH:19])=O)[CH:14]=[CH:15][CH:16]=3)[N:12]=2)=[CH:3][CH:2]=1.Cl.Cl.[NH2:22][C@H:23]1[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1>>[N:25]12[CH2:24][C@@H:23]([NH:22][C:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:10]4[O:9][C:8]([NH:7][C:4]5[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=5)=[N:12][C:11]=34)=[O:19])[CH:28]([CH2:29][CH2:30]1)[CH2:27][CH2:26]2
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: O=C(O)c1cccc2oc(Nc3ccncc3)nc12
Agent: Cl
Product: O=C(N[C@@H]1CN2CCC1CC2)c1cccc2oc(Nc3ccncc3)nc12

Procedure:
Following general procedure GP-C1, a mixture of 2-(pyridin-4-ylamino)benzoxazole-4-carboxylic acid and (S)-(−)-3-aminoquinuclidine dihydrochloride were coupled to provide (S)—N-(quinuclidine-8-yl)-2-(pyridin-4-ylamino)benzoxazole-4-carboxamide, which was converted to the dihydrochloride salt following general procedure GP-D1. 1H NMR and MS consistent.
Reaction SMILES: [N:1]1([NH:7][C:8]([C:10]2[N:11]=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])[N:13]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[C:14]=2[CH3:15])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:38]([S:40](Cl)(=[O:42])=[O:41])[CH3:39].O>C(Cl)Cl>[Cl:30][C:24]1[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=1[C:12]1[N:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])=[CH:20][CH:21]=2)[C:14]([CH3:15])=[C:10]([C:8](=[O:9])[NH:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:11]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(O)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)Oc1ccc(-n2c(-c3ccc(Cl)cc3Cl)nc(C(=O)NN3CCCCC3)c2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
A solution of 2-(2,4-dichlorophenyl)-1-(4-hydroxyphenyl)-5-methyl-1H-imidazole-4-carboxylic acid piperidin-1-ylamide, from Ex. 2, Step 1 (321 mg, 0.72 mmol) in 10 ml CH2Cl2 was cooled to 0° C. Triethylamine (101 μl, 0.72 mmol) was added followed by ethanesulfonyl chloride (69 μl, 0.72 mmol) and the reaction mixture was stirred at room temperature overnight. Water was added, the mixture extracted with CH2Cl2 (3×20 ml), dried (Na2SO4), filtered and concentrated. Flash chromatography (silica, hexane:EtOAc 1:3) afforded 230 mg (60%) of the title compound as a white solid.
Reaction SMILES: CS([O:5][CH:6]1[CH2:9][N:8]([C:10]([C:12]2[O:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][N:16]=2)=[O:11])[CH2:7]1)(=O)=O.[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1O)[CH:27]=[O:28]>>[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:5][CH:6]1[CH2:9][N:8]([C:10]([C:12]2[O:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][N:16]=2)=[O:11])[CH2:7]1)[CH:27]=[O:28]
Reactant: CS(=O)(=O)OC1CN(C(=O)c2nnc(-c3ccccc3)o2)C1
Reactant: O=Cc1ccc(O)c(Cl)c1
Product: O=Cc1ccc(OC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)c(Cl)c1
Yield: 45.4 %

Procedure:
Using a similar protocol as described in Example 53C employing 53B (1.0 g, 3.10 mmol) and 3-chloro-4-hydroxybenzaldehyde (0.50 g, 3.19 mmol) as starting materials afforded 0.54 g (45%) of 57A as a solid. 1H NMR (500 MHz, CD3OD): δ 4.34 (m, 1H), 4.77 (m, 2H), 5.25 (m, 1H), 5.36 (m, 1H), 7.05 (d, 1H), 7.62 (m, 3H), 7.7-8.1 (m, 2H), 8.14 (d, 2H), 9.87 (s, 1H), MS (APCI+) m/z 384 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]([CH2:4][CH3:5])[CH3:3].[P:6](Cl)([Cl:9])([Cl:8])=[S:7]>CCOCC>[CH:2]([NH:1][P:6]([Cl:9])([Cl:8])=[S:7])([CH2:4][CH3:5])[CH3:3]
Reactant: S=P(Cl)(Cl)Cl
Reactant: CCC(C)N
Solvent: CCOCC
Product: CCC(C)NP(=S)(Cl)Cl
Temperature: 25 °C
Yield: 34.9 %

Procedure:
A solution of 2-aminobutane (45 mL, 0.449 mol) in 45 mL of anhydrous ether was added dropwise to a solution of 93 mL (0.915 mol) of thiophosphoryl chloride in 200 mL of anhydrous ether at 0° C. under an argon atmosphere. The resultant slurry was stirred while slowly warmed to room temperature. After filtering to remove sec-butylamine hydrochloride (40.6 g), the filtrate was concentrated at reduced pressure to provide 32.3 g (69.7%) of a yellow oil.
Reaction SMILES: [NH2:1][C@H:2]([CH2:24][CH3:25])[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:11]=1)=[O:4].C(N(CC)CC)C.Cl[C:34](Cl)([O:36]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>ClCCl>[CH3:23][C:20]1([CH3:22])[CH2:19][C:18]2[C:13]([O:12][C:9]3[N:8]=[CH:7][C:6]([N:5]4[C:3](=[O:4])[C@@H:2]([CH2:24][CH3:25])[NH:1][C:34]4=[O:36])=[CH:11][CH:10]=3)=[CH:14][CH:15]=[CH:16][C:17]=2[O:21]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC[C@@H](N)C(=O)Nc1ccc(Oc2cccc3c2CC(C)(C)O3)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H]1NC(=O)N(c2ccc(Oc3cccc4c3CC(C)(C)O4)nc2)C1=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
((2R)-2-amino-N-{6-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}butanamide) (Intermediate 209, 10 mg, 0.029 mmol) was dissolved in dry dichloromethane (1 ml). The reaction mixture was cooled down in an ice bath. Triethylamine (0.024 ml, 0.176 mmol) was added at 0° C. Then 0.5 ml of a solution of triphosgene in dry dichloromethane (4.78 mg, 0.016 mmol in 0.5 ml) was added dropwise. The reaction mixture was stirred under argon during 20 min at 0° C. A saturated aqueous solution of NaHCO3 was added (3 ml). The aqueous layer was extracted with dichloromethane 4 times (4×4 mL). Combined organic layers were dried over Na2SO4 and evaporated. the residue was purified by flash chromatography (Companion system) on silica gel using a 4 g silica cartridge and cyclohexane/ethyl acetate from 100:0 to 60:40 as eluents affording the title compound (7 mg).
Reaction SMILES: B(F)(F)F.CSC.C[O:9][C:10]1[CH:11]=[C:12]([C:17]2[N:21]([CH2:22][C:23]#[N:24])[N:20]=[CH:19][C:18]=2[C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:36]=[CH:35][C:34]([C:37](=[O:39])[CH3:38])=[CH:33][CH:32]=3)[CH:26]=2)[CH:13]=[C:14]([CH3:16])[CH:15]=1>ClCCl>[OH:9][C:10]1[CH:11]=[C:12]([C:17]2[N:21]([CH2:22][C:23]#[N:24])[N:20]=[CH:19][C:18]=2[C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:32]=[CH:33][C:34]([C:37](=[O:39])[CH3:38])=[CH:35][CH:36]=3)[CH:26]=2)[CH:13]=[C:14]([CH3:16])[CH:15]=1
Reactant: COc1cc(C)cc(-c2c(-c3ccnc(-c4ccc(C(C)=O)cc4)c3)cnn2CC#N)c1
Agent: FB(F)F
Solvent: CSC
Solvent: ClCCl
Product: CC(=O)c1ccc(-c2cc(-c3cnn(CC#N)c3-c3cc(C)cc(O)c3)ccn2)cc1
Reaction time: 24 h

Procedure:
Borontrifluoride-dimethylsulfide (0.25 mL, 2.37 mmol) was dropwise added to a solution of the methoxy compound (0.1 g, 0.24 mmol) prepared in Example 37 in dichloromethane (4 mL) at room temperature under nitrogen atmosphere, and stirred for 24 hours. The reaction mixture was concentrated by vacuum distillation. The residue was treated in ethyl acetate (100 mL) and brine (50 mL), and the organic layer was dried over anhydrous magnesium sulfate and distilled under vacuum. Purification through column chromatography (silica gel, ethyl acetate) afforded pure hydroxy products (21 mg, 42%).
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[C:8]([O:13][CH2:14][CH3:15])(=[O:12])[C:9]([CH3:11])=O>O.C(O)C>[CH3:15][CH2:14][O:13][C:8]([C:9]1([CH3:11])[NH:1][CH:2]([C:5]([OH:7])=[O:6])[CH2:3][S:4]1)=[O:12]
Reactant: N[C@@H](CS)C(=O)O
Reactant: CCOC(=O)C(C)=O
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1(C)NC(C(=O)O)CS1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
Under an argon atmosphere, L-cysteine (10 g) was dissolved in pure water (150 ml), and ethyl pyruvate (19.7 ml) dissolved in ethanol (10 ml) at room temperature was gradually added to the solution. The mixture was stirred overnight at room temperature, and concentrated under reduced pressure. The obtained solid was dissolved in pure water, and the solution was extracted with chloroform. The extract was dried over magnesium sulfate, and concentrated under reduced pressure to give an oil. The oil was recrystallized from chloroform/hexane to give 2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (diastereomer mixture) (12.7 g, yield 70%).
Reaction SMILES: S(Br)([Br:3])=O.N1C=CC=CC=1.[C:11]1([C:17]2[C:18]([O:20][C:21](=[O:23])[CH:22]=2)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[Br:3][C:22]1[C:21](=[O:23])[O:20][C:18](=[O:19])[C:17]=1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C1C=C(c2ccccc2)C(=O)O1
Reactant: O=S(Br)Br
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=C1OC(=O)C(c2ccccc2)=C1Br
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
At 10° C., first 40.2 g (193 munol) of thionyl bromide and then 15.3 g (193 mmol) of pyridine were added dropwise with stirring to 16.8 g (97 mmol) of phenylmaleic anhydride in 200 ml of toluene. The mixture was stirred at 10° C. for 30 min, heated at 75° C. for 30 min using a preheated heating bath and allowed to cool, and excess thionyl bromide was removed at 65° C. under reduced pressure. The mixture was then stirred with 150 ml of toluene and filtered, and the residue was washed twice with in each case 200 ml of toluene, and the filtrate was concentrated under reduced pressure. The crude product (9.3 g) still contained 25% of unreacted starting material and was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7](Br)=[C:6]([O:11][C:12]([F:15])([F:14])[F:13])[CH:5]=1.[CH3:17][O:18][C:19](=[O:54])[NH:20][C@H:21]([C:25]([N:27]1[CH2:31][C@@H:30]([S:32][CH3:33])[CH2:29][C@H:28]1[C:34]1[NH:35][CH:36]=[C:37]([C:39]2[CH:44]=[CH:43][C:42](B3OC(C)(C)C(C)(C)O3)=[CH:41][CH:40]=2)[N:38]=1)=[O:26])[CH:22]([CH3:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>O>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]([C:42]2[CH:43]=[CH:44][C:39]([C:37]3[N:38]=[C:34]([C@@H:28]4[CH2:29][C@H:30]([S:32][CH3:33])[CH2:31][N:27]4[C:25](=[O:26])[C@@H:21]([NH:20][C:19]([O:18][CH3:17])=[O:54])[CH:22]([CH3:24])[CH3:23])[NH:35][CH:36]=3)=[CH:40][CH:41]=2)=[C:6]([O:11][C:12]([F:15])([F:14])[F:13])[CH:5]=1)=[O:16]
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](SC)C[C@H]1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c[nH]1)C(C)C
Reactant: COC(=O)c1ccc(Br)c(OC(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](SC)C[C@H]1c1nc(-c2ccc(-c3ccc(C(=O)OC)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Temperature: 100 °C

Procedure:
To a mixture of 4-bromo-3-trifluoromethoxy-benzoic acid methyl ester (184 mg, 0.62 mmol), [(S)-2-methyl-1-((2S,4S)-4-methylsulfanyl-2-{4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (300 mg, 0.55 mmol) and potassium carbonate (344 mg, 2.49 mmol) at RT was added toluene (1.35 mL) followed by water (0.69 mL). The reaction mixture was purged with nitrogen, Pd(dppf)Cl2CH2Cl2 (27.4 mg, 0.034 mmol) was added under an atmosphere of nitrogen. The reaction vial was capped and heated at 100° C. overnight, cooled to RT and partitioned between EtOAc (10 mL) and water (2 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to give a brownish oil which was purified by silica gel chromatography (12 g silica gel, 0-100% EtOAc/Hexanes). Desired fractions were combined and concentrated to give the title intermediate as an orange oil. (m/z): [M+H]+ calcd for C30H33F3N4O6S 635.21. found 635.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]3=[O:19])=[CH:8]2)=[N:3]1.[Br:20][C:21]1[N:22]=[C:23]([CH2:26]O)[S:24][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[Br:20][C:21]1[N:22]=[C:23]([CH2:26][O:18][C:15]2[CH:16]=[CH:17][N:12]([C:7]3[CH:6]=[CH:5][C:4]4[C:9](=[C:10]([CH3:11])[N:2]([CH3:1])[N:3]=4)[CH:8]=3)[C:13](=[O:19])[CH:14]=2)[S:24][CH:25]=1
Reactant: OCc1nc(Br)cs1
Reactant: Cc1c2cc(-n3ccc(O)cc3=O)ccc2nn1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1c2cc(-n3ccc(OCc4nc(Br)cs4)cc3=O)ccc2nn1C
Reaction time: 3 h
Yield: 53.3 %

Procedure:
To a suspension of 1-(2,3-dimethyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (50 mg), (4-bromo-1,3-thiazol-2-yl)methanol (76 mg) and triphenylphosphine (154 mg) in tetrahydrofuran (6 ml) was added bis(2-methoxyethyl)azodicarboxylate (138 mg) at room temperature, and the mixture was stirred at the same temperature for 3 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate/methanol) and recrystallized from ethanol-hexane to give the title compound (45 mg).
Reaction SMILES: ClC(N(C)C)=C(C)C.[C:9]([O:13][C:14]([NH:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([Cl:27])=[C:22]([CH:26]=1)[C:23]([OH:25])=O)=[O:15])([CH3:12])([CH3:11])[CH3:10].N1C=CC=CC=1.C([O:36][C:37](=[O:50])[C:38]1[CH:43]=[C:42]([NH2:44])[CH:41]=[CH:40][C:39]=1[O:45][CH2:46][CH2:47][O:48][CH3:49])C>CC#N>[C:9]([O:13][C:14]([NH:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([Cl:27])=[C:22]([CH:26]=1)[C:23]([NH:44][C:42]1[CH:41]=[CH:40][C:39]([O:45][CH2:46][CH2:47][O:48][CH3:49])=[C:38]([CH:43]=1)[C:37]([OH:50])=[O:36])=[O:25])=[O:15])([CH3:10])([CH3:11])[CH3:12]
Reactant: CCOC(=O)c1cc(N)ccc1OCCOC
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c(C(=O)O)c1
Agent: CC(C)=C(Cl)N(C)C
Solvent: CC#N
Solvent: c1ccncc1
Product: COCCOc1ccc(NC(=O)c2cc(CNC(=O)OC(C)(C)C)ccc2Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1-Chloro-N,N,2-trimethylpropenylamine (166 μL; 1.25 mmol) was added to a mixture of 5-(tert-butoxycarbonylamino)methyl-2-chloro benzoic acid (263 mg; 0.92 mmol) in MeCN (10 mL) and stirred at rt for 15 min. Pyridine (198 μL; 2.51 mmol) and 5-amino-2-(2-methoxyethoxy)-benzoic acid ethyl ester (200 mg; 0.84 mmol) was added and it was stirred at rt overnight. The mixture was filtered through a pad of Alox B, washed with DMF/MeOH 9/1 and concentrated i. vac. The residue was mixed with 15 mL MeOH and 15 mL 2 M aq NaOH and stirred for 3 days at rt. After concentration, the residue was diluted with 10 mL 4M aq. HCl, extracted with EtOAc, dried with Na2SO4 and concentrated i. vac. The crude was mixed with 50 mL Dioxan; 5 mL H2O and di-tert-butyldicarbonate (200 mg), stirred at rt for 2 h and concentrated. Yield: 380 mg (95%); MS: [M+H]+=479 (Cl isotope pattern); HPLC: Rt=2.01 min (Method CC-4)
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([Cl:13])[C:11]=1[NH2:12])[C:6]([O-:8])=[O:7].[C:14](CC(=O)C)(=O)[CH3:15].[CH2:21](O)C>>[Cl:13][C:10]1[C:11]2[NH:12][C:14]([CH3:15])=[N:2][C:3]=2[CH:4]=[C:5]([C:6]([O:8][CH3:21])=[O:7])[CH:9]=1
Reactant: CCO
Reactant: Nc1cc(C(=O)[O-])cc(Cl)c1N
Reactant: CC(=O)CC(C)=O
Agent: Cl
Product: COC(=O)c1cc(Cl)c2[nH]c(C)nc2c1
Yield: 59 %

Procedure:
Add 2N hydrochloric acid (8 mL) to a solution of 3,4-diamino-5-chlorobenzoate (from acid preparation 1, 435 mg, 2.17 mmol) in ethanol (20 mL). Heat the mixture to reflux then add acetylacetone (437 mg, 4.37 mmol) to the yellow solution. The yellow solution turned purple upon addition. Stir at reflux for 1 hour and the solution turned back to yellow. Stir at reflux for an additional 1 hour. Concentrate the solvent to a colorless residue. Add water (20 mL). Extract the suspension with ethyl acetate (20 mL). Basify the aqueous layer with 2N sodium hydroxide (˜8 mL) to pH˜10. Extract with ethyl acetate (3×15 mL). Wash combined organics from the basic extraction with brine (5 mL). Dry over magnesium sulfate, to filter, concentrate, and dry under high vacuum to yield methyl 7-chloro-2-methyl-1H-benzo[d]imidazole-5-carboxylate (290 mg, 59%) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ ppm 2.68 (s, 3H), 3.93 (s, 3H), 7.25 (s, 1H), 7.96 (s, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[Cl:9].[CH3:10][C:11]1[N:16]=[C:15]([SH:17])[N:14]=[C:13]([OH:18])[CH:12]=1.C(N(CC)CC)C>C(O)C>[Cl:9][C:4]1[S:5][C:6]([Cl:8])=[CH:7][C:3]=1[CH2:2][S:17][C:15]1[N:14]=[C:13]([OH:18])[CH:12]=[C:11]([CH3:10])[N:16]=1
Reactant: Clc1cc(CBr)c(Cl)s1
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(O)nc(SCc2cc(Cl)sc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
A mixture of 3-(bromomethyl)-2,5-dichlorothiophene (125 mg, 0.51 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (60 mg, 0.42 mmol), and triethylamine (180 μL, 1.3 mmol) in absolute ethanol (5 mL) was stirred at room temperature overnight. The mixture was recovered and evaporated. The solid residue was treated with water (100 mL). The solid product was recovered by filtration, washed with water (1×15 mL), diethyl ether (2×15 mL), and hexanes (2×15 mL), and then dried in vacuo, affording 2-{[(2,5-dichlorothiophen-3-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (91 mg, 71% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.21 (s, 3H), 4.27 (s, 2H), 6.02 (s (br), 1H), 7.17 (s 1H); M+308.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[CH:16]=2)=[CH:7][CH:6]=1.[OH-].[Na+]>CO.O1CCCC1.O>[O:25]=[C:4]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[CH:16]=2)=[CH:9][CH:10]=1)[C:3]([OH:26])=[O:2]
Reactant: COC(=O)C(=O)c1ccc(OCCOc2ccc3c(c2)CCCC3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OCCOc2ccc3c(c2)CCCC3)cc1
Yield: 77.7 %

Procedure:
A mixture of alpha-oxo-4-[[2-(5,6,7,8-tetrahydro-2-naphthalenyloxy)ethyl]oxy]benzeneacetic acid methyl ester (0.75 g) in hot methanol (10 mL) plus enough tetrahydrofuran to dissolve all solids, was treated with 1N sodium hydroxide (4 mL) and diluted with water. The organic solvent was removed under vacuum and the residue was mixed with water, acidified with excess hydrochloric acid, and extracted with dichloromethane. The organic layer was dried (Na2SO4), filtered, and evaporated to give crude product. Crystallization from diethyl ether-hexane provided 0.56 g of alpha-oxo-4-[[2-(5,6,7,8-tetrahydro-2-naphthalenyloxy)ethyl]oxy]benzeneacetic acid as a colorless solid, mp 144°-145° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH:13](=[N:1]/[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2)\[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1cccc2ccc(O)cc12
Reactant: O=Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Oc1ccc2cccc(/N=C/c3ccccc3)c2c1
Temperature: 25 °C
Yield: 98.4 %

Procedure:
A mixture of 8-amino-2-naphthol 1 (8.2 g, 52 mmol), benzaldehyde (16 mL, 156 mmol) and sodium sulfate (41.3 g, 291 mmol) in THF (100 mL) was stirred at reflux over night. The mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (hexane/ethyl acetate/triethyl amine 75/23/2) to give 12.65 g of impure (E)-8-(benzylideneamino) naphthalen-2-ol (2) which was used in the next step without further purification.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([C:7]1[CH:16]=[CH:15][C:10]([NH:11][C:12](=[O:14])[CH3:13])=[CH:9][CH:8]=1)[CH3:6].O>C(OC(=O)C)(=O)C.C(O)(=O)C>[N+:1]([C:9]1[CH:8]=[C:7]([CH2:5][CH3:6])[CH:16]=[CH:15][C:10]=1[NH:11][C:12](=[O:14])[CH3:13])([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CCc1ccc(NC(C)=O)cc1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CCc1ccc(NC(C)=O)c([N+](=O)[O-])c1

Procedure:
A mixture of fuming nitric acid (1.4 ml.) and acetic acid (2 ml.) was added portionwise to a stirred 0°C. solution of p-ethylacetanilide (4.0 grams) in acetic anhydride (4.2 ml.) and acetic acid (4.4 ml.). The temperature was allowed to rise slowly to 25°C. Subsequently the reaction mixture was poured into 100 ml. of water. An oil settled but did not crystallize. The mixture was extracted with ether and evaporated, leaving the 2'-nitro-4'-ethylacetanilide as a dark oil.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)=[CH:19][CH:18]=1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Reactant: OB(O)c1ccc(Cl)cc1
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(Cl)cc1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 4-chlorophenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C16H11ClN4, 296. Found, 295, 297.
Reaction SMILES: [Na].[C:2]([C:4]1[C:5](=[O:17])[NH:6][C:7](=[O:16])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:9]=1)#[N:3].ClC(Cl)(F)SCl.[Cl:24][C:25]([Cl:29])([Cl:28])[S:26]Cl>>[C:2]([C:4]1[C:5](=[O:17])[N:6]([S:26][C:25]([Cl:29])([Cl:28])[Cl:24])[C:7](=[O:16])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:9]=1)#[N:3]
Reactant: N#Cc1cn(-c2ccccc2)c(=O)[nH]c1=O
Reactant: ClSC(Cl)(Cl)Cl
Agent: FC(Cl)(Cl)SCl
Agent: [Na]
Product: N#Cc1cn(-c2ccccc2)c(=O)n(SC(Cl)(Cl)Cl)c1=O

Procedure:
The sodium salt of 5-cyano-1-phenyl-uracil is reacted with each of dichlorofluoromethane sulphenyl chloride and trichloromethane sulphenyl chloride following the foregoing procedure to yield 5-cyano-3-dichlorofluoromethane sulphenyl-1-phenyl-uracil and 5-cyano-1-phenyl-3-trichloromethane sulphenyl uracil.