Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([CH3:14])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[C:12]#[N:13].C[O-].[Na+].CN(C)[CH:20]=[O:21]>CO>[C:12]([C:11]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4]([CH3:14])=[N:3][C:2]=1[O:21][CH3:20])#[N:13]
Reactant: CN(C)C=O
Reactant: Cc1nc(Cl)c(C#N)c2c1CCCC2
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(C)c2c(c1C#N)CCCC2

Procedure:
3-Chloro-4-cyano-1-methyl-5,6,7,8-tetrahydroisoquinoline (10.0 g) was refluxed with sodium methoxide (1.1 equiv) in a mixture of methanol (150 ml) and anhydrous dimethylformamide (20 ml) for 24 hr. The bulk of the solvent was evaporated under reduced pressure, water was added to the residue and the resulting mixture was extracted with ether. The dried (MgSO4) organic fraction was evaporated and the residue was purified by column chromatography over silica gel with dichloromethane elution to give 4-cyano-3-methoxy-1-methyl-5,6,7,8-tetrahydroisoquinoline as white crystals, mp 116° C. Pmr spectrum (CDCl3 ; δ in ppm): 1.81 (4H,m); 2.39 (3H,s); 2.50-2.94 (4H,m); 3.98 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([NH:15][CH3:16])=[C:10]2[N:13]=O)=[CH:5][CH:4]=1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.[ClH:27]>C(OCC)C>[ClH:27].[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]3[N:15]([CH3:16])[C:23]([C:22]4[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[CH:20][CH:21]=4)=[N:13][C:10]=32)=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CNc1ccc2ccc(OC)cc2c1N=O
Agent: Cl
Solvent: CCOCC
Product: COc1ccc(-c2nc3c4cc(OC)ccc4ccc3n2C)cc1
Yield: 40 %

Procedure:
The compound of the title, as the free base, is prepared by following essentially the same procedure described in example 2 but using 7-methoxy-2-methylamino-1-nitrosonaphthalene instead of 2-methylamino-1-nitrosonaphthalene and 4-methoxybenzaldehyde instead of 4-ethoxybenzaldehyde. By addition of HCl to a diethyl ether solution of the free base, the corresponding hydrochloride precipitates. Yield 40%. M.p. 265° C. dec. (from methanol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)([O-:18])=[O:17]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:23](=[O:24])[C:22]3[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:27][CH:26]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Product: O=C(NC1CCCc2c1[nH]c1ccc(Br)cc21)c1ccc([N+](=O)[O-])cc1

Procedure:
N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-4-nitrobenzamide was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and 4-nitrobenzoyl chloride in a similar manner as described above to give an orange solid (32% yield). 1H-NMR (DMSO-d6): δ 11.11 (s, 1H), 9.24 (d, 1H), 8.36 (d, 2H), 8.19 (d, 2H), 7.62 (m, 1H), 7.29 (d, 1H), 7.18 (dd, 1H), 5.41 (m, 1H), 2.69 (m, 2H), 2.10 (m, 2H), 1.89 (m, 2H); MS m/z 414 (M−1).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[NH:10][NH2:11].C(Cl)Cl.[OH-].[Na+].C(O[CH:20]=[C:21]([C:24]#[N:25])[C:22]#[N:23])C>CO>[NH2:25][C:24]1[N:10]([C:4]2[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:3]=2[Cl:2])[N:11]=[CH:20][C:21]=1[C:22]#[N:23]
Reactant: CCOC=C(C#N)C#N
Reactant: NNc1ccc(F)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: N#Cc1cnn(-c2ccc(F)cc2Cl)c1N
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
2-Chloro-4-fluorophenyl hydrazine hydrochloride (CAS 497959-29-2) (25.0 g, 126.9 mmol) was partitioned between DCM (250 mL) and 2M NaOH (100 mL). The organic phase was separated and washed sequentially with water (2×150 mL) and brine (150 mL), dried over MgSO4 and evaporated to give the free base. This oil was dissolved in MeOH (200 mL) under nitrogen at −5° C. and 2-(ethoxymethylene)malononitrile (15.5 g, 127 mmol) was added portionwise. The resulting mixture was stirred at 0° C. for 2 hours then at reflux for a further 2 hours. After cooling, the mixture was evaporated to provide 5-amino-1-(2-chloro-4-fluorophenyl)-1H-pyrazole-4-carbonitrile (28.9 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][C:14]=1[Cl:20])[O:8][CH:7]([C:21]([F:24])([F:23])[F:22])[C:6]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH2:41](B(CC)CC)[CH3:42]>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.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:41][CH3:42])=[CH:15][C:14]=1[Cl:20])[O:8][CH:7]([C:21]([F:24])([F:23])[F:22])[C:6]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:5]2
Reactant: CCB(CC)CC
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(Oc3ccc(Br)cc3Cl)cc2OC1C(F)(F)F
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: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(Cl)c(Oc3ccc(CC)cc3Cl)cc2OC1C(F)(F)F
Temperature: 110 °C
Reaction time: 5 h
Yield: 84.5 %

Procedure:
To the mixture of 0.3g (0.59 mmol, 1.0 eqv) of ethyl 6-chloro-7-(2-chloro-4-bromophenoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylate, 0.32 g (2.3 mmol) of potassium carbonate, 68 mg (0.059 mmol ) of tetrakistriphenyl-phosphinepalladium (0), and 2.5 mL of anhydrous DMF under nitrogen was added 0.83 mL (0.83 mmol, 1.0 M in THF) of triethylborane. The mixture was heated to 110° C. and shaken for five hrs. LC-MS indicated that the reaction was completed. After cooling to room temperature, the reaction was added to 50 mL of ethyl acetate. The resulting organic phase was washed with brine three times, and dried over anhydrous magnesium sulfate. After removing the volatiles, the residue was purified on silica gel column with 1:9 EtOAc/hexane to afford 0.23 g (84.7%) of a light yellow solid. The product was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:25]1[CH2:29][CH2:28][C@@H:27]([OH:30])[CH2:26]1>>[Br:1][C:2]1[C:3]([N:25]2[CH2:29][CH2:28][C@@H:27]([OH:30])[CH2:26]2)=[N:4][CH:5]=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(C(F)(F)C(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: O[C@@H]1CCNC1
Product: O=C(Nc1ccc(C(F)(F)C(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 33.1 using 5-bromo-6-chloro-N-(4-(perfluoroethyl)phenyl)nicotinamide (Stage 208.2) and (R)-pyrrolidin-3-ol to afford an off-white crystalline solid. HPLC (Condition 4) tR=5.96 min, UPLC-MS (Condition 3) tR=1.20 min, m/z=480.2 [M+H]+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(N(CC)CC)C>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:10]([C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1)#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: C#CCCCCCCCCCC
Reactant: O=Cc1cccc(Br)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCC#Cc1cccc(C=O)n1
Temperature: 40 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
To a solution of 6-bromo-2-pyridinecarboxaldehyde (3.0 g) in tetrahydrofuran (10 ml), was added sequentially bis(triphenylphosphine)palladium(II) chloride (0.178 g), copper(I)iodide (0.024 g), 1-dodecyne (3.25 ml), and triethylamine (2.12 ml). The solution was stirred at 40° C. overnight. The reaction mixture was cooled to room temperature, charged again with bis(triphenylphosphine)palladium (11) chloride (0.024 g), copper (I) iodide (0.024 g), and triethylamine (2.12 ml), and 1-dodecyne (3.25 ml), and tetrahydrofuran (5.0 ml), and heated at 40° C. for 5 hrs. The reaction mixture was again cooled and recharged as above, and heated at 40° C. for 24 hrs. The cooled mixture was concentrated, taken up in ethyl acetate (100 ml), washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was taken up in ethyl acetate (100 ml) and filtered. The filtrate wets combined with material from a similar reaction run 1.43 g of the carboxaldehyde and proportionate amounts of the catalysts, 1-dodecyne, and solvent. The filtrate was concentrated. The residue was purified by flash chromatography using 1.5% ethyl acetate/hexane followed by 1% ethyl acetate/hexane as eluents. The appropriate fractions were collected and concentrated to yield 2.24 g (29%) of product, as an oil.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[CH2:5]([O:7][C:8](=[O:25])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=1[O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:6].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:5]([O:7][C:8](=[O:25])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:3][CH:2]=[CH2:1])=[CH:13][C:12]=1[O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:6]
Reactant: C=CCBr
Reactant: CCOC(=O)COc1ccc(O)cc1OCC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccc(OCC(=O)OCC)c(OCC(=O)OCC)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Allyl bromide (25.53 ml; 302 mmol) was added slowly to a mixture of the compound of example 65b (75 g; 251.4 mmol), K2CO3 (52.04 g; 377 mmol) and KI (˜1 g) in DMF (150 ml) under vigorous stirring for 15 min at room temperature. The reaction mixture was stirred overnight (˜16 h), treated with water (1 lit.), and extracted with EtOAc. The EtOAc layer was washed with water, brine, dried (Na2SO4), concentrated and purified using flash chromatography (silica gel, 3% CH3CN in chloroform) to obtain the title compound as an oil. Yield, 76 g (89.7%); MS (EI): 337 (M+), 136.
Reaction SMILES: C(O)C.[Cl:4][C:5]1[CH:6]=[C:7]([S:12]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)(=[O:14])=[O:13])[CH:8]=[N:9][C:10]=1Cl.[NH2:23][NH2:24]>O>[Cl:4][C:5]1[CH:6]=[C:7]([S:12]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)(=[O:14])=[O:13])[CH:8]=[N:9][C:10]=1[NH:23][NH2:24]
Reactant: O=S(=O)(Nc1cccc(O)c1)c1cnc(Cl)c(Cl)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNc1ncc(S(=O)(=O)Nc2cccc(O)c2)cc1Cl
Yield: 80.3 %

Procedure:
To 500 ml ethanol was added 5,6-dichloro-3'-hydroxy-3-pyridinesulfonanilide (10.4 g, 42 mmol) and 95 percent hydrazine (60 mmol). The reaction mixture was refluxed overnight. The completely reacted mixture was chilled, and the precipitate was filtered off and washed with ethanol. The filtrate was concentrated so as to obtain a second crop, yielding a total of 16.5 g. The solid was stirred in 250 ml of water to remove any salts. The product was filtered, washed with water, and dried under vacuum at 50° C. to give 10.61 g (80 percent) of pure product.
Reaction SMILES: [I:1][C:2]1[C:7](CC(O)=O)=[C:6]([I:12])[C:5](CC(O)=O)=[C:4]([I:17])[C:3]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24](O)=[O:25])=[C:20]([N+:27]([O-:29])=[O:28])[CH:19]=1.[C:30]([O:33][CH:34]1[O:48][C@H:47]([CH2:49][O:50][C:51](=[O:53])[CH3:52])[C@@H:42]([O:43][C:44](=[O:46])[CH3:45])[C@H:37]([O:38][C:39](=[O:41])[CH3:40])[C@H:35]1[NH2:36])(=[O:32])[CH3:31].Cl.CN(C)CCCN=C=NCC>>[N+:27]([C:20]1[CH:19]=[C:18]([C:3]2[C:2]([I:1])=[C:7]([C:30]([OH:33])=[O:32])[C:6]([I:12])=[C:5]([C:39]([OH:41])=[O:38])[C:4]=2[I:17])[CH:23]=[CH:22][C:21]=1[C:24]([C:34]1([O:48][C@H:47]([CH2:49][O:50][C:51](=[O:53])[CH3:52])[C@@H:42]([O:43][C:44](=[O:46])[CH3:45])[C@H:37]([O:38][C:39](=[O:41])[CH3:40])[C@H:35]1[NH2:36])[O:33][C:30](=[O:32])[CH3:31])=[O:25])([O-:29])=[O:28]
Reactant: O=C(O)Cc1c(I)c(CC(=O)O)c(I)c(-c2ccc(C(=O)O)c([N+](=O)[O-])c2)c1I
Reactant: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](N)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: CC(=O)OC[C@H]1OC(OC(C)=O)(C(=O)c2ccc(-c3c(I)c(C(=O)O)c(I)c(C(=O)O)c3I)cc2[N+](=O)[O-])[C@H](N)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
2′,4′,6′-triiodo-3′,5′-bis(carboxymethyl)-3-nitrobiphenyl-4-carboxylic acid (18) is coupled with 1,3,4,6-tetra-O-acetyl-D-glucosamine in the presence of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride and N-hydrosuccinamide to yield 2-nitro-4-[3′,5′-bis(carboxy)-2′,4′,6′-triiodophenyl]-benzoyl-1,3,4,6-tetra-O-acetyl-D-glucosamine. The protecting acetyl groups on the glucosamine moiety are removed by reaction with sodium hydroxide in methanol to yield 2-nitro-4-[3′,5′-bis(carboxy)-2′,4′,6′-triiodophenyl]-benzoyl-D-glucosamine (19).
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:13]1([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:1]([N:22]1[CH2:23][CH2:24][CH:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:20][CH2:21]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)N1CCC(c2ccccc2)CC1

Procedure:
The same procedures as in Example 1 were carried out using (E)-2-decenoic acid and 4-phenylpiperidine as starting raw materials, to produce an intended compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([CH2:15][CH2:16][CH3:17])[C:9]2=[O:18])=[N:5][N:4]=1.[CH:19]1([N:25]=[C:26]=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(N(CC)CC)C>[CH3:1][S:2][C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][C:26](=[O:27])[NH:25][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:12][CH2:11][N:10]([CH2:15][CH2:16][CH3:17])[C:9]2=[O:18])=[N:5][N:4]=1
Reactant: O=C=NC1CCCCC1
Reactant: CCCN1CCC(O)N(c2nnc(SC)s2)C1=O
Solvent: CCN(CC)CC
Product: CCCN1CCC(OC(=O)NC2CCCCC2)N(c2nnc(SC)s2)C1=O
Reaction time: 1 h

Procedure:
Tetrahydro-1-(5-methylthio-1,3,4-thiadiazol-2-yl)-3-propyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole) and cyclohexyl isocyanate (3.5 ml; 0.06 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer. The mixture is stirred and triethylamine (1 drop) is added thereto. After the addition is completed the reaction mixture is allowed to stand for a period of about 1 hour. The mixture is then washed with hexane and is dried to yield the desired product tetrahydro-1-(5-methylthio-1,3,4-thiadiazol-2-yl)-3-propyl-6-(N-cyclohexylcarbamoyloxy)-2(1H)-pyrimidinone.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]2[N:9]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:10]([C@@H:12]([NH:14][C:15]3[N:23]=[CH:22][N:21]=[C:20]4[C:16]=3[N:17]=[CH:18][N:19]4C3CCCCO3)[CH3:13])=[N:11][C:7]=2[CH:6]=[CH:5][C:4]=1[F:36]>O1CCOCC1.CO>[Cl:2][C:3]1[C:8]2[N:9]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:10]([CH:12]([NH:14][C:15]3[N:23]=[CH:22][N:21]=[C:20]4[C:16]=3[N:17]=[CH:18][NH:19]4)[CH3:13])=[N:11][C:7]=2[CH:6]=[CH:5][C:4]=1[F:36]
Reactant: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c(Cl)c2n1-c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2ccc(F)c(Cl)c2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
4N HCl in dioxane (0.5 mL) was added to a solution of [(S)-1-(7-chloro-6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]-[9-(tetrahydropyran-2-yl)-9H-purin-6-yl]amine (166 mg, 0.34 mmol) in MeOH (5 mL) and the mixture was stirred at RT for 1 h. The volatiles were removed in vacuo and the resulting residue was purified by HPLC (Phenomenex Gemini 5 μm C18 on a 25 min gradient 10-90%, 0.1% HCO2H in acetonitrile/water) to afford 179 (96 mg, 69%). LCMS (Method K): RT 3.80 min [M+H]+ 408.0/409.9/411.08. 1H NMR (DMSO-d6, 400 MHz): δ 8.22-7.83 (3H, m), 7.69-7.34 (6H, m), 7.33-7.24 (1H, t, J=9.50 Hz), 5.25 (1H, s), 1.56 (3H, d, J=6.88 Hz)
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:12]([CH3:23])([CH3:22])[C:4]=2[N:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.C(N(CC)C(C)C)(C)C.[F:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1>C1COCC1>[F:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([NH:1][C:2]2[C:3]3[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:12]([CH3:22])([CH3:23])[C:4]=3[N:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=2)=[O:39])=[CH:36][CH:35]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCOC(=O)n1nc(N)c2c1C(C)(C)N(C(=O)OC(C)(C)C)C2
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)n1nc(NC(=O)c2ccc(F)cc2)c2c1C(C)(C)N(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.9 %

Procedure:
5-tert-Butyl 1-ethyl 3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate (2.0 g, 6.16 mmol) was dissolved in THF (40 ml), treated first with N,N-diisopropylethylamine (5.4 ml, 30.80 mmol) and then, at 0° C., with 4-fluorobenzoyl chloride (800 μl, 6.77 mmol) dissolved in THF (8 ml) dropwise. The reaction mixture was stirred at room temperature for 5 hours, concentrated and dissolved in DCM, washed with saturated sodium hydrogencarbonate aqueous solution and with brine. The organic phase was dried over sodium sulfate, evaporated and purified by flash chromatography (eluent hexane/EtOAc 80/20) to afford 2.5 g of the title compound in 90% yield.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.Br[CH:14]([CH3:18])[C:15]([NH2:17])=[O:16].O>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:14]([CH3:18])[C:15]([NH2:17])=[O:16])[CH:8]=[CH:7]2
Reactant: CC(Br)C(N)=O
Reactant: Clc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C(N)=O)n1ccc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A dispersion of 60% NaH (6.85 g, 0.17 mol) was added to an ice-cooled solution of 5-chloroindole (20 g, 0.13 mol) in 250 ml of dry DMF. The stirring was continued for 20 minutes at room temperature, and the mixture was cooled again with an ice bath. After portionwise addition of solid 2-bromopropanamide (24.1 g, 0.15 mol), the reaction mixture was stirred for 1 h 30 at room temperature, then poured into cold water and extracted 3 times with AcOEt. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography (AcOEt/hexane 50/50) to give pure 2-(5-chloro-1H-indol-1-yl)propanamide 25 as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:5][C:4](=[O:14])[CH:3]=1.[CH:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[S:25]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:17])[CH3:16].C(N(CC)CC)C>C(O)C>[OH:1][C:2]1[CH2:7][CH:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:5][C:4](=[O:14])[C:3]=1[S:25][C:19]1[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:18]=1[CH:15]([CH3:17])[CH3:16]
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)ccc2C(C)C)cc1
Reactant: O=C1C=C(O)CC(c2ccccc2)N1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccc(C(C)C)c(SC2=C(O)CC(c3ccccc3)NC2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared as described in General Method III using 95.6 mg of 5,6-dihydro-4-hydroxy-6-phenyl-2(1H)-pyridinone, 180 mg of toluene-4-thiosulfonic acid S-(2-isopropyl-5-methylphenyl) ester (prepared as per Ranasinghe and Fuchs, Synthetic Communications 18: 227, (1988)) and 0.08 ml of triethylamine in 5 ml of absolute ethanol. The solution was stirred overnight at room temperature. Purification by flash chromatography using CH2Cl2 /isopropanol (99/1 to 95/5) as eluent gave a solid (m.p. 184°-186° C.). 1H NMR (CDCl3) δ1.28 (d, 3H), 1.29 (d, 3H), 2.23 (s, 3H), 2.98 (d, 2H), 3.52 (qn, 1H), 4.85 (t, 1H), 5.63 (s, 1H), 6.78 (s, 1H), 6.96 (m, 1H), 7.14 (d, 1H), 7.35-7.44 (m, 5H), 7.55 (s, 1H).
Reaction SMILES: Br.Br.[N:3]1([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(O)C.C(=O)([O-])O.[Na+].[CH3:24][S:25](Cl)(=[O:27])=[O:26]>O>[OH:15][C:12]1[CH:11]=[CH:10][C:9]([N:3]2[CH2:4][CH2:5][N:6]([S:25]([CH3:24])(=[O:27])=[O:26])[CH2:7][CH2:8]2)=[CH:14][CH:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: Oc1ccc(N2CCNCC2)cc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)N1CCN(c2ccc(O)cc2)CC1
Reaction time: 8 h

Procedure:
To a stirred mixture of 12.9 parts of 4-(1-piperazinyl)-phenol dihydrobromide, 40 parts of ethanol and 50 parts of water are added 12.6 parts of sodium hydrogen carbonate. Then there are added dropwise 6.4 parts of methanesulfonyl chloride at 0° C. Upon completion, stirring is continued overnight. The precipitated product is filtered off and taken up in water. The whole is alkalized with a sodium hydroxide solution and stirred for 30 minutes at room temperature. The mixture is filtered over hyflo and the filtrate is acidified with acetic acid. The precipitated product is filtered off and dried, yielding 2.8 parts of 1-(4-hydroxyphenyl)-4-(methylsulfonyl)-piperazine; mp. 204.9° C.
Reaction SMILES: Cl[C:2]1[S:6][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4](=[O:13])[C:3]=1[CH3:14].[CH3:15][N:16]([CH3:20])[C:17](=[S:19])[SH:18].[Na].[I-].[Na+]>C(O)C>[CH3:15][N:16]([CH3:20])[C:17]([S:19][C:2]1[S:6][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4](=[O:13])[C:3]=1[CH3:14])=[S:18]
Reactant: Cc1c(Cl)sn(-c2ccccc2)c1=O
Reactant: CN(C)C(=S)S
Agent: [I-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: Cc1c(SC(=S)N(C)C)sn(-c2ccccc2)c1=O

Procedure:
To a solution of 4.51 g. (0.02 mole) of 5-chloro-4-methyl-2-phenyl-4-isothiazolin-3-one in 30 ml of warm ethanol was added a solution of 3.58 g. (0.02 mole) of N,N-dimethyldithiocarbamic acid, sodium salt dihydrate in 20 ml of ethanol followed by 0.1 g. of sodium iodide. The mixture was stirred several hours, cooled and filtered. The solid was triturated with water and dried to give 5.3 g. (88%) of the named product, mp 158°-160°.
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]1[S:19][CH:20]=[C:21]([C:23](O)=[O:24])[N:22]=1.N>>[ClH:1].[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH:12][C:23]([C:21]3[N:22]=[C:18]([C:14]4[S:13][CH:17]=[CH:16][CH:15]=4)[S:19][CH:20]=3)=[O:24])[CH2:3]1)[CH2:9]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1csc(-c2cccs2)n1
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1csc(-c2cccs2)n1

Procedure:
Prepared from (4r)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and 2-(2-thienyl)-1,3-thiazole-4-carboxylic acid (Maybridge) according to methods A and C; yield 103 mg, 0.25 mmol (62%): 1H NMR (300 MHz, methanol-d4) δ 2.04-2.32 (m, 3H), 2.51 (s, 2H), 2.51 (s, 2H), 3.46-3.62 (m, 4H), 3.82 (d, J=13 Hz, 2H), 4.29 (s, 1H), 7.18 (dd, J=5, 4 Hz, 1H), 7.65 (dd, J=5, 1 Hz, 1H), 7.64 (dd, J=5, 1 Hz, 1H), 7.72 (dd, J=4, 1 Hz, 1H), 8.21 (s, 1H); MS (DCI/NH3) m/z 346 (M+H)+; Anal. C17H19N3OS2.2HCl: C, H, N.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:5]=1[O:6][C@H:7]([CH3:13])[C:8]([O:10]CC)=[O:9].Cl>O.CCO>[Cl:3][C:4]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:5]=1[O:6][C@H:7]([CH3:13])[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)[C@@H](C)Oc1ccc(Cl)cc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C[C@@H](Oc1ccc(Cl)cc1Cl)C(=O)O
Reaction time: 4 h

Procedure:
To a solution of KOH (2.48 g, 44.2 mmol, 15 eq) in H2O (12 mL) was added ethyl (R)-2-(2,4-dichlorophenoxy)propionate (compound 9a; 0.80 g, 3.05 mmol) in EtOH (12 mL) at room temperature. The solution was stirred for 4 hours, and then acidified with concentrated aqueous HCl (pH 3). The resulting solid was filtered, rinsed with water, and dried to yield a white powder which was used without further purification.