Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:18]=[O:19])=[C:13]2[C:17]=1[NH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:27](OC(=O)C)(=[O:29])[CH3:28]>CN(C)C1C=CN=CC=1.ClCCl>[C:27]([N:16]1[C:17]2[C:13](=[C:12]([CH:18]=[O:19])[CH:11]=[CH:10][C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:14]=[CH:15]1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1ccc(OCc2ccccc2)c2[nH]ccc12
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)n1ccc2c(C=O)ccc(OCc3ccccc3)c21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
500 mg of 7-benzyloxy-4-formylindole is combined with 50 mg of 4-dimethylaminopyridine, 0.7 ml of triethylamine, 0.5 ml of acetic anhydride, and 10 ml of dichloromethane and agitated for 24 hours at room temperature. The reaction mixture is then diluted with 50 ml of dichloromethane, washed with concentrated sodium bicarbonate solution; the organic phase is dried and concentrated. The residue is recrystallized from isopropanol, thus obtaining 400 mg of 1-acetyl-7-benzyloxy-4-formylindole, mp 77°-78° C.
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:5]=[C:4](Cl)[N:3]=1.[CH3:15][NH:16][CH3:17].[OH-].[Na+]>C(O)C.O>[NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:5]=[C:4]([N:16]([CH3:17])[CH3:15])[N:3]=1
Reactant: CNC
Reactant: CCCCNc1cc(Cl)nc(N)[n+]1[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCNc1cc(N(C)C)nc(N)[n+]1[O-]
Yield: 39 %

Procedure:
1.5 g of 2-amino-4-butylamino-6-chloropyrimidine 3-oxide are placed in 10 ml of ethanol. 5 ml of dimethyl-amine are added as 33% solution in ethanol. The reaction mixture is refluxed for 4 hours and is then evaporated to dryness. The precipitate obtained is taken up in 20 ml of water. The pH is adjusted to 8 by adding sodium hydroxide. The mixture is extracted with 3×50 ml of butanol. The butanol phase is evaporated to dryness. The precipitate is recrystallized from 10 ml of acetonitrile. 610 mg of 2-amino-4-butylamino-6-dimethylaminopyrimidine 3-oxide are obtained.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13]CC)=[O:12])=[CH:8][CH:9]=2)[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:3]1.O[Li].O>C1COCC1.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:3]1
Reactant: CCOC(=O)c1ccc2c(c1)c(-c1ccccc1)nn2C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cn1nc(-c2ccccc2)c2cc(C(=O)O)ccc21
Yield: 140.8 %

Procedure:
A solution compound 54b (230 mg, 0.58 mmol), and LiOH.H2O (98 mg, 2.33 mmol) in THF/H2O (10/10 mL) was stirred at 45° C. for 8 h. The resulting mixture was concentrated and diluted with water. The water layer was acidified with 1N aqueous HCl to pH˜4 and extracted with CH2Cl2. The organic solution was dried over Na2SO4 and concentrated to give 54c (206 mg), which was used in the next reaction without further purification. MS m/z (M+H+) 253.1.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:20][C:19]2[CH:18]=[C:17]([O:21][CH3:22])[CH:16]=[CH:15][C:14]=2[C@@H:13]2[C@@H:4]1[C:5]1[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C@@H:8]([OH:23])[CH2:7][CH:6]=1)[CH3:2].[Li].N.CC(O)C>O1CCCC1>[CH2:1]([C@@H:3]1[CH2:20][C:19]2[CH2:18][C:17]([O:21][CH3:22])=[CH:16][CH2:15][C:14]=2[C@@H:13]2[C@@H:4]1[C:5]1[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C@@H:8]([OH:23])[CH2:7][CH:6]=1)[CH3:2]
Reactant: CC[C@@H]1Cc2cc(OC)ccc2[C@H]2CC[C@@]3(C)C(=CC[C@@H]3O)[C@H]12
Agent: N
Agent: [Li]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC[C@@H]1CC2=C(CC=C(OC)C2)[C@H]2CC[C@@]3(C)C(=CC[C@@H]3O)[C@H]12
Temperature: -35 °C
Reaction time: 4.5 h

Procedure:
x)—The alcohol obtained in the previous step (1.5 g) in dry tetrahydrofuran (24 ml) was added to a refluxing solution of lithium (2.12 g) in liquid ammonia (98 ml). After 4.5 h stirring at −35° C., 2-propanol was added in 30 min. and the ammonia was allowed to evaporate. Water was added and the product was extracted into ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure, to give (7α,17β)-7-ethyl-3-methoxyestra-2,5(10),14-trien-17-ol (1.65 g). The product was used in the following step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:11](=[CH:14]/[C:15]2[S:16][C:17]([N:20]3[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]3)=[CH:18][CH:19]=2)/[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Na+].[CH2:28]([N:30]([CH2:35][CH3:36])[CH2:31][C:32]([O-])=[O:33])[CH3:29].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>N1C=CC=CC=1>[CH2:28]([N:30]([CH2:31][C:32]([O:26][CH:23]1[CH2:22][CH2:21][N:20]([C:17]2[S:16][C:15](/[CH:14]=[C:11](\[C:12]#[N:13])/[C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:19][CH:18]=2)[CH2:25][CH2:24]1)=[O:33])[CH2:35][CH3:36])[CH3:29]
Reactant: CCN(CC)CC(=O)[O-]
Reactant: COc1ccc(/C(C#N)=C/c2ccc(N3CCC(O)CC3)s2)cc1OC
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Solvent: c1ccncc1
Product: CCN(CC)CC(=O)OC1CCN(c2ccc(/C=C(\C#N)c3ccc(OC)c(OC)c3)s2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
Compound 6 (3.70 g) was dissolved in pyridine (100 mL), and N,N-diethylglycin sodium salt (7.66 g) was added to the solution, followed by stirring at room temperature for 1 hour. Subsequently, p-toluenesulfonyl chloride (9.43 g) was added to the mixture, followed by stirring under reflux for 12 hours. After completion of reaction, the solvent was evaporated under reduced pressure. Chloroform (1,000 mL) was added to the residue, and the mixture was washed with water three times. The pH of the aqueous layer was checked by use of a pH testpaper, and adjusted to 4 to 5 with 1N aqueous hydrochloric acid. The organic layer was dried over sodium sulfate anhydrate, and the solvent was evaporated to dryness. The residue was purified by silica gel column chromatography (CHCl3-Hexane), to thereby yield the target product (yield: 3.62 g, 75%).
Reaction SMILES: C([O:3][C:4](=[O:28])[CH:5]([N:13]1[CH2:17][C:16]([O:18][C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])=[CH:15][C:14]1=[O:27])[CH2:6][C:7]1([F:12])[CH2:11][CH2:10][CH2:9][CH2:8]1)C.O.[OH-].[Li+].O>O1CCCC1.O>[F:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([F:25])[C:19]=1[O:18][C:16]1[CH2:17][N:13]([CH:5]([CH2:6][C:7]2([F:12])[CH2:8][CH2:9][CH2:10][CH2:11]2)[C:4]([OH:28])=[O:3])[C:14](=[O:27])[CH:15]=1
Reactant: CCOC(=O)C(CC1(F)CCCC1)N1CC(Oc2c(F)cccc2F)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(CC1(F)CCCC1)N1CC(Oc2c(F)cccc2F)=CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
To a solution of 2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(1-fluoro-cyclopentyl)-propionic acid ethyl ester (0.440 g, 1.11 mol) in tetrahydrofuran:water (1:1, 10 mL) was added lithium hydroxide monohydrate (0.140 g 3.34 mmol). The mixture was stirred at room temperature for 2 h. The reaction mixture was poured into water and washed with diethyl ether and the diethyl ether layer discarded. The aqueous phase was acidified with 1N aqueous hydrochloric acid (pH <2), and extracted with ethyl acetate (2×30 mL). The combined ethyl acetate layers were dried over magnesium sulfate, filtered and concentrated to afford 2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(1-fluoro-cyclopentyl)-propionic acid, (0.358 g, 88%) as a yellow solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.64 (br. s., 8H), 2.34 (dd, J=22.6, 6.9 Hz, 2H), 4.23 (d, J=18.4 Hz, 1H), 4.31 (d, J=18.4 Hz, 1H), 4.84 (t, J=6.9 Hz, 1H), 5.05 (s, 1H), 7.26-7.55 (m, 3H), 13.05 (br. s., 1H).
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:41][C:42]([N:44]([CH3:52])[CH2:45][CH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1)=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:33]=[CH:34][C:35]([O:38][CH2:41][CH2:42][N:44]([CH3:52])[CH2:45][CH:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)=[CH:36][CH:37]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CN(CC1CCOCC1)C(=O)CCl
Product: CCN(Cc1ccc(OCCN(C)CC2CCOCC2)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 23.7 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (16 mg) and 2-chloro-N-methyl-N-(tetrahydropyran-4-ylmethyl)acetamide (11 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (4.2 mg) was obtained.
Reaction SMILES: [C:1]1([CH2:11][CH:12]([CH2:16][C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.Cl.[CH3:27][O:28][C:29](=[O:38])[C@H:30]([CH2:32][C:33]1[N:37]=[CH:36][NH:35][CH:34]=1)[NH2:31].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[CH3:27][O:28][C:29](=[O:38])[C@H:30]([CH2:32][C:33]1[N:37]=[CH:36][NH:35][CH:34]=1)[NH:31][C:13](=[O:14])[CH:12]([CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH2:16][C:17]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:18]
Reactant: O=C(O)C(CC(=O)N1CCOCC1)Cc1cccc2ccccc12
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(CC(=O)N1CCOCC1)Cc1cccc2ccccc12
Yield: 19.2 %

Procedure:
To a suspension of 0.89 g of 2-(1-naphthylmethyl)3-(morpholinocarbonyl)propionic acid and 0.79 g of L-histidine methyl ester dihydrochloride in 23 ml of N,N-dimethylformamide were added 0.70 ml of diphenylphosphoryl azide and 1.50 ml of triethylamine with stirring under ice-cooling, and then the mixture was additionaly stirred for 16 hours. The reaction mixture was evaporated under reduced pressure, and to the residue was added a 5% aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=20/1, by volume) to obtain 0.25 g of N-[2-(1-Naphthylmethyl)-3-(morpholinocarbonyl)propionyl]-L-histidine methyl ester having an Rf2 value of 0.56 as a white powder.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([NH:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[C:16]([O:18]CC)=[O:17])[CH:7]=[CH:8][CH:9]=1.Cl>O1CCOCC1>[F:3][C:4]1[CH:5]=[C:6]([NH:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[C:16]([OH:18])=[O:17])[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C1CCCC1Nc1cccc(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)C1CCCC1Nc1cccc(F)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Sodium hydroxide (96 mL, 478 mmol, 5 M in water, 5 equiv.) was added to a mixture of ethyl 2-[(3-fluorophenyl)amino]cyclopentanecarboxylate (reported by Micovic et al., Synthesis, 1991, 1043-1045) (24.0 g, 96 mmol, 1 equiv) in dioxane (95 mL). The reaction was heated to 100° C. and stirred for one hour. The reaction mixture was then cooled to 23° C. and acidified to pH=3 with 2N HCl. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, and the washed solution was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated to afford 6A as a mixture of cis and trans isomers. [M+H]+: 224.1.
Reaction SMILES: C[O:2][C:3](=[O:34])[C@H:4]([CH2:30][CH:31]([CH3:33])[CH3:32])[NH:5][C:6](=[O:29])[C@H:7]([CH2:23][C:24]1[N:28]=[CH:27][NH:26][CH:25]=1)[NH:8][C:9](=[O:22])[CH2:10][NH:11][C:12]([O:14]CC1C=CC=CC=1)=O.Br.[C:36]([OH:39])(=O)[CH3:37]>>[OH:39][C:36]1[CH:37]=[CH:31][C:30]([C:12](=[O:14])[NH:11][CH2:10][C:9]([NH:8][C@H:7]([C:6]([NH:5][C@H:4]([C:3]([OH:2])=[O:34])[CH2:30][CH:31]([CH3:32])[CH3:33])=[O:29])[CH2:23][C:24]2[N:28]=[CH:27][NH:26][CH:25]=2)=[O:22])=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)CNC(=O)OCc1ccccc1
Agent: Br
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)CNC(=O)c1ccc(O)cc1)C(=O)O
Reaction time: 1 h

Procedure:
20 g of carbobenzoxyglycyl-L-histidyl-L-leucine methyl ester is added to 100 ml of 25% HBr solution in acetic acid and this mixture is stirred for one hour to split off the carbobenzoxy group, and then 2000 ml of absolute ether is added. The precipitate thus produced is filtered off and washed with ethyl ether and dried in a desiccator.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=2)=[O:12])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].Cl.[CH3:22][NH:23][CH3:24]>>[CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([C:13]2[CH:20]=[CH:19][C:16]([CH2:17][N:23]([CH3:24])[CH3:22])=[CH:15][CH:14]=2)=[O:12])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CNC
Reactant: CCCCN1CCN(C(=O)c2ccc(C=O)cc2)CC1
Agent: Cl
Product: CCCCN1CCN(C(=O)c2ccc(CN(C)C)cc2)CC1

Procedure:
Prepared from the product of Example 13 and dimethylamine hydrochloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.[CH2:9]([Sn](CCCC)(CCCC)C=C)[CH2:10]CC>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>[Br:1][C:2]1[CH:3]=[N:4][C:5]([CH:9]=[CH2:10])=[N:6][CH:7]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Brc1cnc(I)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=Cc1ncc(Br)cn1
Temperature: 140 °C
Yield: 68.2 %

Procedure:
5-Bromo-2-iodo-pyrimidine (9.15 g, 32.11 mmol) was dissolved in THF (150 ml) and Pd(PPh3)4 (18.85 g, 1.60 mmol) was added, followed by tributyl-vinyl-stannane (9.38 ml, 32.11 mmol). The resulting mixture was heated at 140° C. for 20 min under microwave irradiations, next filtered through a pad of celite and concentrated. The crude material was diluted with CH2Cl2 and washed with water. Separation of the layers, drying (Na2SO4) of the organic phase, filtration and evaporation in vacuo provided the crude material, which was purified by flash column chromatography (CH2Cl2) to give the title compound (4.05 g, 68%) as a volatile yellow oil crystallizing at 4° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][N:12](C(OC(C)(C)C)=O)[CH:13]=2)O1.C(=O)([O-])[O-].[K+].[K+].Br[C:29]1[CH:34]=[C:33]([N+:35]([O-:37])=[O:36])[CH:32]=[C:31]([CH3:38])[CH:30]=1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:38][C:31]1[CH:30]=[C:29]([C:9]2[CH:13]=[N:12][NH:11][CH:10]=2)[CH:34]=[C:33]([N+:35]([O-:37])=[O:36])[CH:32]=1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1cc(Br)cc([N+](=O)[O-])c1
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: C1COCCO1
Product: Cc1cc(-c2cn[nH]c2)cc([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (8.17 g, 27.8 mmol), tetrakis(triphenylphosphine)palladium(0) (2.67 g, 2.31 mmol) and potassium carbonate (12.8 g, 93.0 mmol) were added to a solution of 1-bromo-3-methyl-5-nitrobenzene (5.0 g, 23.1 mmol) in dioxane (7.5 mL). The mixture was degassed with nitrogen for 5 minutes and stirred at 100° C. for 18 h. The mixture was passed through CELITE, washed with methanol and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-50% EtOAc/Hexane) to afford 4-(3-methyl-5-nitrophenyl)-1H-pyrazole. MS ESI calc'd. for C10H10N3O2 [M+H]+ 204. found 204.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[S:15](Cl)(=[O:18])(=[O:17])[OH:16].C(N(C(C)C)C(C)C)C.C([O-])([O-])=O.[Na+].[Na+].OP(O)(O)=O>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:8][CH2:9][CH2:10][CH:11]([S:15]([OH:18])(=[O:17])=[O:16])[C:12]([OH:14])=[O:13]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)CCCSSc1ccccn1
Agent: O=C([O-])[O-]
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)C(CCSSc1ccccn1)S(=O)(=O)O
Temperature: 75 °C
Reaction time: 0.75 h
Yield: 44.2 %

Procedure:
Alternative procedure: 4-(pyridin-2-yldisulfanyl)butanoic acid (106 mg, 0.462 mmol) was coevaporated with 1,2-dichloreoethane (2×5 ml), redissolved in 5 ml of 1,2-dichloreoethane and placed in a preheated 75° C. oil bath. To this solution, sulfurochloridic acid (154 μL, 2.311 mmol) and N-ethyl-N-isopropylpropan-2-amine (161 μL, 0.924 mmol) were added. The mixture was placed in the pre-heated 75° C. oil bath for 45 min. Another portion of sulfurochloridic acid (45 μL, 0.675 mmol) was added and the reaction was heated at 75° C. for 1 more hour until the reaction was completed (monitored by HPLC). To the mixture was added concentrated Na2CO3 until pH 11. The resulting mixture was stirred for 10 min, neutralized with H3PO4 to pH 7.5 and concentrated. The crude product was purified by HPLC on a C-18 column eluting with a gradient of 100% of water (0.5% HAc) to 80% water (0.5% HAc)/20% of MeOH to afford 4-(pyridin-2-yldisulfanyl)-2-sulfobutanoic acid (63 mg, 0.204 mmol, 44.1% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:10][CH:9]=[C:8](I)[N:7]=1.[CH3:29][O:30][C:31](=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]#[CH:39])[CH:33]=1>>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:10][CH:9]=[C:8]([C:39]#[C:38][C:34]2[CH:35]=[CH:36][CH:37]=[C:32]([C:31]([O:30][CH3:29])=[O:40])[CH:33]=2)[N:7]=1
Reactant: C#Cc1cccc(C(=O)OC)c1
Reactant: COC(=O)CCc1nc(I)ccc1OCCCC/C=C/c1ccc(OC)cc1
Product: COC(=O)CCc1nc(C#Cc2cccc(C(=O)OC)c2)ccc1OCCCC/C=C/c1ccc(OC)cc1
Yield: 79.2 %

Procedure:
Under the conditions of example 5 A, 1 g of 3-{6-iodo-3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-2-pyridyl}-propionic acid methyl ester is reacted with 320 mg of 3-ethinylbenzoic acid methyl ester, worked up, and the crude product is chromatographed on silica gel with hexane/0-15% ethyl acetate. 835 mg of 3-{6-[2-(3-methoxycarbonylphenyl)-ethinyl]-3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-2-pyridyl}-propionic acid methyl ester is obtained as oil.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([N:14]1[CH2:22][CH:21]2[CH:16]([C:17](=[O:24])[NH:18][C:19](=[O:23])[CH2:20]2)[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:7]([N:14]1[CH2:22][CH:21]2[CH:16]([C:17](=[O:24])[N:18]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:19](=[O:23])[CH2:20]2)[CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1CC2CN(Cc3ccccc3)CC2C(=O)N1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1CC2CN(Cc3ccccc3)CC2C(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 111.4 %

Procedure:
To a mixture of 905 mg of K2CO3 and 400 mg of the compound from step 457b in 5 mL of DMF was added 308 mg of benzyl bromide, and the reaction mixture was stirred at room temperature under N2 for 6.5 hours. The mixture was diluted with ethyl acetate, which was washed with water and brine, dried and concentrated to give 610 mg of the title compound.
Reaction SMILES: CO[C:3]1([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)[C:5]([CH3:7])([CH3:6])[O:4]1.[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>ClCCl>[CH3:6][C:5]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)([CH3:7])[C:3]([C:8]1[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=1)=[O:4]
Reactant: C1CNCCN1
Reactant: COC1(c2ccc(SC)cc2)OC1(C)C
Solvent: ClCCl
Product: CSc1ccc(C(=O)C(C)(C)N2CCNCC2)cc1
Temperature: 130 °C
Reaction time: 6 h

Procedure:
Further, in a 500 mL four-neck flask provided with a stirrer, a condenser, and a thermocouple, the compound (c) and 31 g of piperazine were added, followed by stirring at 130° C. for 6 hours. After cooling, 80 mL of dichloromethane was added, and an organic layer was washed three times with 70 mL of water. The organic layer was dried with anhydrous sodium sulfate and concentrated to produce 60.7 g of 2-methyl-1-(4-methylsulfanylphenyl)-2-piperazin-1-yl-propan-1-one (12).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][C@@H:17]([F:19])[CH2:16][C@H:12]1[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:20]1C=CC=CC=1.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.C(=O)(O)[O-].[NH4+]>O1CCOCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:18][C@@H:17]([F:19])[CH2:16][C@H:12]1[C:13]([NH2:20])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1C[C@H](F)CN1C(=O)OCc1ccccc1
Reactant: c1ccncc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: C1COCCO1
Product: NC(=O)[C@@H]1C[C@H](F)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A stirred solution of (4S)-1-[(Benzyloxy)carbonyl]-4-fluoro-L-proline in dioxane was treated with pyridine (0.7 eq.) and Boc2O (1.3 eq.), then ammonium bicarbonate (1.26 eq.) was added and the mixture was stirred at room temperature for 15 hours. Dioxane was concentrated and the residue was taken up in ethyl acetate, washed with 1 N HCl and brine, dried over Na2SO4 to give, after filtration and concentration, title compound.
Reaction SMILES: O=[C:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1.[F:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][Mg]Br)=[C:17]([CH3:24])[CH:16]=1>>[F:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][CH:2]2[C:9]3[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=3[CH2:4][CH2:3]2)=[C:17]([CH3:24])[CH:16]=1
Reactant: Cc1cc(F)ccc1C[Mg]Br
Reactant: COC(=O)c1cc2c([nH]1)CCC2=O
Product: COC(=O)c1cc2c([nH]1)CCC2Cc1ccc(F)cc1C

Procedure:
The title compound was synthesized in two steps. First, methyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate was reacted with (4-fluoro-2-methylbenzyl)magnesium bromide) according to General Procedure 3. The resulting product was then converted to the title compound by hydrogenation according to General Procedure 6.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=1)[CH3:2].[CH3:15][Si:16](Cl)([CH3:18])[CH3:17]>>[CH2:13]([N:3]([CH2:1][CH3:2])[C:4](=[O:12])[C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][C:10]=1[Si:16]([CH3:18])([CH3:17])[CH3:15])[CH3:14]
Reactant: CCN(CC)C(=O)c1cccc(C)c1
Reactant: C[Si](C)(C)Cl
Product: CCN(CC)C(=O)c1cc(C)ccc1[Si](C)(C)C
Yield: 46 %

Procedure:
These compounds were prepared from N,N-diethyl-3-methylbenzamide and 2.0 eq TMSCl according to General Method A. Purification by HPLC using 1:9 ethyl acetate/hexanes gave two products. Compound 63 was isolated as 6.0 g of a clear oil, a 46% yield. Compound 64 was isolated as 2.3 g of a clear oil, a 17% yield.