Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)OCC(OCC)=O.ClC1C=CC=CC=1O[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].O(CC(OCC)=O)C1C=CC=CC=1>>[C:2]1([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:3]=[CH:4][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)COc1cccc(Cl)c1
Reactant: CCOC(=O)COc1ccccc1Cl
Agent: CCOC(=O)COc1ccccc1
Product: CCOC(=O)Cc1ccccc1

Procedure:
Following Example 15 but using ethyl 3-chlorophenoxyacetate, ethyl 2-chlorophenoxyacetate or ethyl phenoxyacetate, respectively, in place of ethyl phenylacetate, the final compounds obtained were the PGE2 analogs of Example 15 wherein R (of structure IV) is 3-chlorophenoxymethyl, 2-chlorophenoxymethyl or phenoxymethyl.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:10]2[CH:15]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:13]=[C:12]([N:25]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:11]=2)=[CH:5][CH:4]=1.[Br:46][C:47]1[CH:56]=[CH:55][C:54]2[C:49](=[CH:50][CH:51]=[C:52](Br)[CH:53]=2)[CH:48]=1.C([O-])([O-])=O.[K+].[K+].C1COCC1>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>[Br:46][C:47]1[CH:48]=[C:49]2[C:54](=[CH:55][CH:56]=1)[CH:53]=[C:52]([C:14]1[CH:15]=[C:10]([N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:11]=[C:12]([N:25]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:13]=1)[CH:51]=[CH:50]2
Reactant: COc1ccc(N(c2ccccc2)c2cc(B3OC(C)(C)C(C)(C)O3)cc(N(c3ccccc3)c3ccc(OC)cc3)c2)cc1
Reactant: Brc1ccc2cc(Br)ccc2c1
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: C1CCOC1
Solvent: O
Product: COc1ccc(N(c2ccccc2)c2cc(-c3ccc4cc(Br)ccc4c3)cc(N(c3ccccc3)c3ccc(OC)cc3)c2)cc1

Procedure:
13.42 g of a product (yield: 66%) was obtained in the same manner as described in the synthesis method of intermediate 2-3 except that N1,N3-bis(4-methoxyphenyl)-N1,N3-diphenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene-1,3-diamine (17.76 g, 30 mmol), 2,6-dibromonaphthalene (9.44 g, 33 mmol), Pd(PPh3)4 (1.04 g, 0.9 mmol), K2CO3 (12.44 g, 90 mmol), THF (90 mL), and water (45 mL) were used.
Reaction SMILES: [N:1]1[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[C:4](=[O:10])[NH:3][CH:2]=1.[Cl:11][S:12](O)(=[O:14])=[O:13].S(Cl)(Cl)=O>>[Cl:11][S:12]([C:8]1[S:7][C:6]2[N:1]=[CH:2][NH:3][C:4](=[O:10])[C:5]=2[CH:9]=1)(=[O:14])=[O:13]
Reactant: O=S(=O)(O)Cl
Reactant: O=c1[nH]cnc2sccc12
Solvent: O=S(Cl)Cl
Product: O=c1[nH]cnc2sc(S(=O)(=O)Cl)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3,4-Dihydrothieno [2,3-d] pyrimidin-4-one (50 g) was added portionwise to chlorosulphonic acid (243 ml), maintaining the temperature below 0° C. Thionyl chloride (121 ml) was added dropwise, and the mixture stirred for a further 30 minutes at room temperature; then two hours at reflux. It was then cooled, and poured carefully on to ice. The precipitate was washed and dried to give 6-chlorosulphonylthieno[2,3-d]pyrimidin-4-one (84 g). This compound (30 g) and dimethylamine (450 ml) were mixed at -10°, then allowed to stir at room temperature for two hours. The mixture was poured into water and acidified with hydrochloric acid. The precipitate was washed with water and ethanol, and dried to give the 6-dimethylsulphonamido-4-one (23.8 g). This material was converted into the 4-chloro derivative as described in Example 19 above and thence into the title compounds by treatment with amines basically as described in Example 5.
Reaction SMILES: [NH2:1][CH2:2][P:3](=[O:6])([OH:5])[OH:4].O.[C:8]([OH:12])(=[O:11])[CH:9]=O.[H][H]>>[CH2:9]([NH:1][CH2:2][P:3]([OH:5])([OH:4])=[O:6])[C:8]([OH:12])=[O:11]
Reactant: [H][H]
Reactant: NCP(=O)(O)O
Reactant: O=CC(=O)O
Solvent: O
Product: O=C(O)CNCP(=O)(O)O
Yield: 96 %

Procedure:
Aminomethylphosphonic acid and glyoxylic acid hydrate were reacted under catalytic hydrogenation conditions in the manner described in Example 2, except prior to introduction of hydrogen, the pH was adjusted to 8.0. A 96% yield of glyphosate was obtained.
Reaction SMILES: [CH3:1][C:2]([NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[F:15])([CH3:5])[C:3]#[CH:4].N1C2C(=CC=CC=2)C=CC=1>CO.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH3:5][C:2]([NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[F:15])([CH3:1])[CH:3]=[CH2:4]
Reactant: C#CC(C)(C)NC(=O)c1ccc(F)cc1F
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Solvent: c1ccc2ncccc2c1
Product: C=CC(C)(C)NC(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.7 %

Procedure:
Five percent Pd/BaSO4 (100 mg) was added to a solution of N -(1,1-dimethyl-2-propynyl)-2,4-difluorobenzamide obtained in Example 36 (1.0 g, 4.5 mmol) and quinoline (100 mg) in methanol (20 ml), and stirred under a hydrogen atmosphere at room temperature for 1.5 hours. The catalyst was removed by filtration and the filtrate was concentrated under a reduced pressure. The residue was diluted with ethyl acetate and washed with 1N hydrochloric acid (×3), saturated aqueous NaHCO3 and brine and dried over Na2SO4. The solvent was evaporated and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=15/1) to give the title compound (0.95 g; 94%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH2:26]([NH2:36])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].C(N(CC)CC)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:36][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:20]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Reactant: CCCCCCCCCCN
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCNC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), decylamine (0.520 g, 3.31 mmol), triethylamine (0.310 g, 3.06 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-decyl-3,4,5,6-tetrahydrophthalamide as white crystals (1.06 g, 73.8% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])(C)C)=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[Br-].[CH2:22]([Zn+])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH2:30]1COC[CH2:31]1>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>[CH2:22]([C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][CH2:17][CH2:20][CH2:30][CH3:31])=[O:15])[CH2:12][CH2:13]2)=[N:4][CH:3]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: [Zn+]Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cn2)CC1
Reactant: C1CCOC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: CCOC(C)=O
Product: CCCCOC(=O)N1CCN(c2ncc(Cc3ccccc3)cn2)CC1
Temperature: 70 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
To a solution of tert-butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (12.0 g, 35.0 mmol) and tetrakis(triphenylphosphine)palladium (2.0 g, 1.7 mmol) in THF (200 mL, dry) was added dropwise a solution of benzylzinc(II) bromide in THF (140 mL, 0.5 M, 70 mmol). The reaction mixture was stirred at 70° C. for 4 h under N2, cooled to RT, then diluted with ethyl acetate (300 mL), filtered and concentrated. The residue was purified by silica gel chromatography, eluting with ethyl acetate/petroleum ether=1/20˜1/10, to give -butyl 4-(5-benzylpyrimidin-2-yl)piperazine-1-carboxylate (7.5 g, yield 60%) as a white solid, MS (ES+) C20H26N4O2 requires: 354, found: 355 [M+H]+.
Reaction SMILES: [NH:1]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C@H:2]([C:7]([NH:9][C@H:10]([C:18]([NH:20][C@H:21]([C:25]([NH:27][C@H:28]([C:33]([NH:35][C@H:36]([C:39](OC)=[O:40])[CH2:37][OH:38])=[O:34])[CH2:29][C:30](=[O:32])[NH2:31])=[O:26])[C@@H:22]([CH3:24])[OH:23])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O)[C@H:3]([CH2:5][CH3:6])[CH3:4].[OH2:50].[NH2:51][NH2:52]>CN(C=O)C.CO>[NH:1]([C:43]([O:45][C:46]([CH3:49])([CH3:47])[CH3:48])=[O:44])[C@H:2]([C:7]([NH:9][C@H:10]([C:18]([NH:20][C@H:21]([C:25]([NH:27][C@H:28]([C:33]([NH:35][C@H:36]([C:37]([NH:51][NH2:52])=[O:38])[CH2:39][OH:40])=[O:34])[CH2:29][C:30](=[O:32])[NH2:31])=[O:26])[C@@H:22]([CH3:24])[OH:23])=[O:19])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:50])[C@H:3]([CH2:5][CH3:6])[CH3:4]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@H](C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)OC)[C@@H](C)O
Reactant: O
Reactant: NN
Solvent: CO
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@H](C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)NN)[C@@H](C)O
Yield: 78.8 %

Procedure:
A solution of 5 g of Boc-Ile-Phe-Thr-Asn-Ser-OMe (7.2 mM) in 40 ml of DMF and 200 ml of methanol cooled on an ice bath has 3.6 ml of an 80% solution of hydrazine hydrate added thereto. After 21 hours of reaction at ambient temperature, 0.9 ml of the same solution of hydrazine hydrate are added. After 3 more hours, the gel obtained is filtered, washed with methanol and dried in vacuo. 3.94 g of product are obtained.
Reaction SMILES: [OH2:1].[C:2]1([CH3:12])[CH:7]=[CH:6][C:5](S(O)(=O)=O)=[CH:4][CH:3]=1.[CH3:13][O:14][CH2:15][O:16]C>C(Cl)Cl>[CH3:13][O:14][CH2:15][O:16][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[CH:12]=[O:1]
Reactant: O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COCOC
Solvent: ClCCl
Product: COCOc1cccc(C=O)c1

Procedure:
In a preferred embodiment of the invention, m-hydroxybenzaldehyde and dimethoxymethane are dissolved in methylene chloride and p-toluenesulfonic acid monohydrate is added. The mixture is refluxed overnight using a Soxhlet extractor containing type 3A molecular sieves, and the product, m-methoxymethoxybenzaldehyde, is isolated and purified by standard procedures. For example, after the reaction mixture cools, triethylamine is added to neutralize the acid catalyst and the mixture is washed with dilute sodium hydroxide solution and water, dried over sodium sulfate and evaporated. The residue is purified by distillation.
Reaction SMILES: [CH3:1][N:2]1[CH2:10][C:9]2[C:4](=[C:5]([N+:11]([O-])=O)[CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:14]>C(Cl)Cl.C(O)C.[Pd]>[NH2:11][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[C:3](=[O:14])[N:2]([CH3:1])[CH2:10]2
Reactant: CN1Cc2cccc([N+](=O)[O-])c2C1=O
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: CN1Cc2cccc(N)c2C1=O
Yield: 88.5 %

Procedure:
A solution of 2-methyl-7-nitro-2,3-dihydro-1H-isoindol-1-one (6.09 g, 31 mmol) in DCM:ethanol (8:2) was hydrogenated under 40 psi of H2 in the presence of 5% Pd/C (500 mg) until cessation of H2 uptake. The reaction mixture was filtered, and the filtrate dried (Na2SO4) and concentrated in vacuo to afford 4.45 g of 7-amino-2-methyl-2,3-dihydro-1H-isoindol-1-one (XXXVIII, yield: 73%). 1H NMR (CDCl3, 400 MHz): δ 3.11 (s, 3H), 4.27 (s, 2H), 5.19 (bs, 2H), 5.5 (d, 1H, J=7.8 Hz), 6.71 (d, 1H, J=7.2 Hz).
Reaction SMILES: F[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])[C:3]=1[C:15]([F:18])([F:17])[F:16].[C-:19]#[N:20].[Na+].O.C(OCC)C>C(#N)C>[C:19]([C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])[C:3]=1[C:15]([F:18])([F:17])[F:16])#[N:20]
Reactant: [C-]#N
Reactant: Cn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1F
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CC#N
Product: Cn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1C#N

Procedure:
42.0 g (147 mmol) of 5-fluoro-1-methyl-3-pentafluoroethyl-4-trifluoromethylpyrazole [synthesis see Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya 1990, (11), 2583-9] and 11.5 g (235 mmol) of sodium cyanide are suspended in 150 ml of acetonitrile and then heated at reflux temperature under a protective gas atmosphere. After cooling, the reaction mixture is poured onto a mixture of 300 ml of distilled water and 300 ml of diethyl ether. The aqueous phase is extracted three times with diethyl ether. The combined organic phases are washed twice with water and once with saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulphate and then filtered. The solvent is removed under reduced pressure on a rotary evaporator and the residue obtained in this way is subjected to fractional distillation in vacuo. This gives 37.0 g of 5-cyano-1-methyl-3-pentafluoroethyl-4-trifluoromethylpyrazole (82%) as a colourless liquid (b.p. 74° C./10 mbar).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[CH2:17]([N:1]([C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH2:8][C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)=[O:9])[CH2:4][CH2:3]1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N[C@H]1CC[C@@H](C(=O)O)CC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(OCc1ccccc1)[C@H]1CC[C@@H](N(Cc2ccccc2)Cc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 102.8 %

Procedure:
cis-4-Aminocyclohexanecarboxylic acid (10.0 g, 67.48 mmol) was dissolved in 140 mL of dry acetonitrile. Solid potassium carbonate (28.0 g, 202.6 mmol) was added. The suspension was heated to about 80° C. To this solution, was added benzyl bromide (28.09 mL, 236.2 mmol) in 70 mL of acetonitrile, dropwise via addition funnel. The reaction mixture was stirred at about 80° C. under nitrogen for about 2 hours then about 40° C. overnight. The reaction was cooled to room temperature and the suspension was filtered. The filtrate was concentrated under reduced pressure. The compound was purified using column chromatography on silica gel (100% hexanes to remove excess benzyl bromide, then 10% ethyl acetate in hexanes). The product was isolated as a white solid (14.35 g, 51% yield): ES-MS (m/z) 414.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-]CC.[Na+].Br[CH2:13][CH2:14][CH2:15][CH3:16]>C(O)C>[CH2:13]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:14][CH2:15][CH3:16]
Reactant: Oc1ccccc1
Reactant: CCCCBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCOc1ccccc1

Procedure:
Phenol (0.5 mole) was added to a solution of sodium ethoxide in ethanol (2 N; 250 ml) and 1-bromobutane (0.5 mole) was added dropwise while stirring. The mixture was heated under reflux for three hours and most of the solvent was then distilled off. Water was added to the residue and the organic layer was separated, washed twice with 10% aqueous NaOH, water, dilute H2SO4 and water, and was then dried over MgSO4. It was distilled in vacuo to give the title compound, b.p. 88°-91° C. at 14 mm Hg pressure. The identity and purity was confirmed by thin layer chromatography (TLC) and NMR and IR spectroscopy.
Reaction SMILES: [C:1]([C:4]1[C:5]([Cl:13])=[N:6][CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([OH:3])=O.C(Cl)(=O)C(Cl)=O.[CH3:20][N:21]([CH3:24])[CH:22]=O.[CH:25]([N:28](C(C)C)CC)(C)[CH3:26]>C(Cl)Cl.C(Cl)(Cl)Cl>[Cl:13][C:5]1[C:4]([C:1]([C:26](=[CH:22][N:21]([CH3:24])[CH3:20])[C:25]#[N:28])=[O:3])=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[CH:7][N:6]=1
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc([N+](=O)[O-])cnc1Cl
Reactant: CCN(C(C)C)C(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CN(C)C=C(C#N)C(=O)c1cc([N+](=O)[O-])cnc1Cl
Reaction time: 5.5 h

Procedure:
A solution of 10.6 g (52.5 mmol) of 3-carboxy-2-chloro-5-nitro pyridine (J. Med. Chem. 1895, 1992) and 8.86 g (69.8 mmol) of oxalyl chloride was stirred in 200 ml of methylene chloride. About 0.2 ml of N,N-dimethylformamide was added and the mixture was stirred for 5.5 hr. Solvent is removed and the resulting acid chloride was used without additional purification. The acid chloride was dissolved in 163 ml of methylene chloride containing 5.55 g (55.5 mmol) of 3-dimethylamine-acrylonitrile and 7.46 g (57.7 mmol) of diisopropylethyl amine. The solution was refluxed under nitrogen for 16 hr. The mixture was diluted with chloroform and washed with a saturated solution of sodium bicaronate. The organic layer was dried over magnesium sulfate and place on a column of silica gel. The product was eluted with a combination of chloroform and ether. Solvent was removed and the residue was treated with a mixture of ethyl acetate-hexane 1:1 at which time the mixture crystallized. The solid was collected giving 8.9 g of the title compound as an orange solid: mass spectrum (chemical ionization, m/e): M+H 281.
Reaction SMILES: [CH3:1][O-].[Na+].CI.[S:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:8]=[C:7]1[SH:19]>CO>[CH3:1][S:19][C:7]1[S:6][C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:8]=1
Reactant: C[O-]
Reactant: Sc1nc2cnc3ccccc3c2s1
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: CSc1nc2cnc3ccccc3c2s1

Procedure:
Sodium methoxide (15.8 mL of 25% in methanol, 69 mmol) and methyl iodide (3.9 mL, 63 mmol) were added to a solution of thiazolo[4,5-c]quinoline-2-thiol (13.65 g, 63 mmol) in methanol (160 mL). The reaction mixture was heated on a steam bath for 1 hour. The solvent was removed under vacuum. The resulting light green-yellow solid was slurried with water, isolated by filtration, and washed with water to provide 9.8 g of crude product. A portion (1 g) was recrystallized from methanol to provide 2-(methylthio)thiazolo[4,5-c]quinoline as a solid, m.p. 116–119° C. Analysis: Calculated for C11H8N2S2: % C, 56.87; % H, 3.47; % N, 12.06; Found: % C, 57.09; % H, 3.57; % N, 12.04.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:21]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=3)=[O:22])=[C:7]([CH:18]([CH3:20])[CH3:19])[N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[F:33].Cl[CH2:35][CH2:36][N:37]=[C:38]=[S:39]>C(Cl)Cl.CCN(CC)CC>[CH2:11]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([F:33])=[C:2]([NH:1][C:38]3[S:39][CH2:35][CH2:36][N:37]=3)[CH:10]=2)[C:6]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=2)=[O:22])=[C:7]1[CH:18]([CH3:19])[CH3:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2cc(F)c(N)cc2n1Cc1ccccc1
Reactant: S=C=NCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2cc(F)c(NC3=NCCS3)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
General Procedure AA. To a solution of 6-amino-1-benzyl-N-(3,4-difluorobenzyl)-5-fluoro-2-isopropyl-1H-indole-3-carboxamide (Compound 172, 39 mg, 0.086 mmol) in CH2Cl2 (1 ml) was added 2-chloroethyl isothiocyanate (25 μl, 0.26 mmol) and Et3N (1 drop). The reaction was stirred at room temperature for 16 h and was purified directly by chromatography on silica gel (0→60% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: Br[C:2]1[C:7]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH3:27])[N:3]=1.[CH3:28][C:29]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:30]=1[NH2:31].C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.CCOCC>[CH3:26][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([S:8]([C:7]2[C:2]([NH:31][C:30]3[CH:32]=[CH:33][C:34]([O:36][CH3:37])=[CH:35][C:29]=3[CH3:28])=[N:3][C:4]([CH3:27])=[CH:5][CH:6]=2)(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: COc1ccc(N)c(C)c1
Reactant: COc1ccccc1COc1ccc(S(=O)(=O)c2ccc(C)nc2Br)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COc1ccc(Nc2nc(C)ccc2S(=O)(=O)c2ccc(OCc3ccccc3OC)cc2)c(C)c1
Temperature: 70 °C
Yield: 15 %

Procedure:
2-Bromo-3-[4-(2-methoxybenzyloxy)-benzenesulfonyl]-6-methylpyridine from part F (75 mg, 0.167 mmol), 2-methyl-4-methoxyaniline (26 μL, 0.200 mmol), Pd(dba)3 (3 mg, 0.0033 mmol), dppp (3 mg, 0.0067 mmol), and NaOt-Bu (22 mg, 0.234 mmol) were suspended in toluene in a tightly capped conical vial. The reaction mixture was heated at 70° C. for 4.5 h. The mixture was cooled to rt, and diluted with ether. The organic layer was washed with brine (2×), dried over MgSO4, filtered, and concentrated. Purified by preparative TLC (1000 μM silica gel plate, 15% ethyl acetate in hexanes) to furnish the desired product (13 mg, 15% yield) as a pale yellow solid: mp 70–72° C.; 1H NMR (300 MHz, CDCl3) δ 8.31 (s, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.77 (d, J=9.2 Hz, 2H), 7.52 (d, J=8.4 Hz, 1H), 7.30–7.22 (m, 2H), 6.96 (d, J=8.8 Hz, 2H), 6.90 (d, J=7.6 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.68 (d, J=9.1 Hz, 2H), 6.53 (d, J=8.0 Hz, 1H), 5.23 (s, 2H), 3.78 (s, 3H), 3.73 (s, 3H), 2.27 (s, 3H), 2.10 (s, 3H); HRMS (ESI) m/z 505.1807 [(M+H)+, calcd for C28H29N2O5S, 505.1797].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:5][N:6]([CH3:14])[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:21]1(C)C=CC=CC=1.CC(C)=O.[S:32]([O:37]C)([O:35][CH3:36])(=[O:34])=[O:33]>>[CH3:36][O:35][S:32]([O-:37])(=[O:34])=[O:33].[CH3:1][O:2][C:3]1[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N+:5]([CH3:21])[N:6]([CH3:14])[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1ccccc1
Reactant: COc1c(-c2ccccc2)nn(C)c1-c1ccccc1
Reactant: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COS(=O)(=O)[O-]
Product: COc1c(-c2ccccc2)n(C)[n+](C)c1-c1ccccc1
Temperature: 130 °C

Procedure:
4-Methoxy-1-methyl-3,5-diphenylpyrazole (20 g, 0.076 mole) is suspended in dimethyl sulfate (23 g) at 20° C and the mixture is stirred and the reaction temperature raised to 130° C. At 70° C the mixture becomes a homogeneous solution and at 130° C some darkening occurs. After maintaining the reaction at 130° C for 1 hour, it is cooled and the mixture poured into toluene (250 ml). The toluene layer is decanted off and further toluene is added, decanted off, and this sequence repeated a third time. The residual oil, obtained from the above treatment, is then treated with acetone (10 ml) which has been dried over anhydrous potassium carbonate. This yields a crystalline product which is filtered off and washed with ether. The acetone filtrate is evaporated to give 27.5 g of oil, dissolved in water, and extracted with chloroform. The chloroform layer is evaporated to a small volume and then ether added. A white precipitate is obtained; combined yield 22 g (74%) of melting point 104.5°-105° C is obtained.