Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.[C:20]([C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1)#[N:21].CO.[BH3-]C#N.[Na+]>O1CCCC1.C(O)(=O)C>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([C:20]#[N:21])=[CH:23][CH:24]=2)[N:13]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: N#Cc1ccc(CNCCNc2nc(Cl)nc3c2ncn3C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.9 %

Procedure:
The operation is carried out as in Stage 2 of Example 7 starting from 280 mg of the product obtained in Stage 1 of Example 7, 184 mg of 4-cyano-benzaldehyde in place of the benzaldehyde, 4 ml of methanol and 0.2 ml of acetic acid and 0.5 ml of tetrahydrofuran then the reaction medium is agitated at ambient temperature for approximately 5 hours. then 100 mg of NaBH3CN is added and agitation is carried out at ambient temperature for 1 hour. 10 ml AcOET is added, followed by washing with 2×5 ml H2O, then 5 ml of a saturated aqueous solution of NaCl, drying and evaporating the solvent. After purification by chromatography on silica eluting with methylene chloride/methanol/hydroxylamine in a proportion of 95/05/0.33, 347 mg of expected product is obtained in the form of white crystals.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[S:4][CH:5]=[C:6]([C:8](=[O:11])[CH2:9][Br:10])[N:7]=1.[BH4-].[Na+].Cl.N>CO>[F:13][C:2]([F:1])([F:12])[C:3]1[S:4][CH:5]=[C:6]([CH:8]([OH:11])[CH2:9][Br:10])[N:7]=1
Reactant: O=C(CBr)c1csc(C(F)(F)F)n1
Agent: Cl
Agent: N
Agent: [BH4-]
Solvent: CO
Product: OC(CBr)c1csc(C(F)(F)F)n1
Temperature: 10 °C

Procedure:
6 g (0.022 mol) of 2-Trifluoromethyl-4-bromoacetylthiazole are dissolved in 150 ml of methanol, and the solution is cooled to 10° C. and 0.63 g of sodium borohydride is added. After 15 minutes ice is added, and the mixture is acidified with hydrochloric acid, made alkaline with ammonia and extracted by shaking with methylene chloride. The organic phase is dried over sodium sulphate, filtered and concentrated. An oil is obtained and is reacted further as the crude product.
Reaction SMILES: [Na].[NH2:2][C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:4]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.[C:21]([CH2:23][C:24](OCC)=[O:25])#[N:22].Cl>C(O)C.O>[NH2:22][C:21]1[N:7]2[N:6]=[C:5]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=3)[C:4]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[C:3]2[N:2]=[C:24]([OH:25])[CH:23]=1
Reactant: CCOC(=O)CC#N
Reactant: Nc1[nH]nc(-c2ccc(F)cc2)c1-c1ccncc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: Nc1cc(O)nc2c(-c3ccncc3)c(-c3ccc(F)cc3)nn12
Yield: 84.1 %

Procedure:
To a solution of sodium (23 mg) in dry ethanol (3 ml) was added 5-amino-3-(4-fluorophenyl)-4-(pyridin-4-yl)pyrazole (254 mg) and ethyl cyanoacetate (113 mg). The mixture was refluxed for 5 hours and cooled. To the reaction mixture were added 1N-hydrochloric acid (2 ml) and water (5 ml). The separated solid was collected, washed with water and dried to give 7-amino-2-(4-fluorophenyl)-5-hydroxy-3-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine (270 mg).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[C:8]([O:17][CH3:18])[C:7]=1[OH:19])[CH:2]=[C:3]([CH3:5])[CH3:4].C1C=CC=CC=1>CCCCCC>[CH2:13]([O:12][C:9]1[C:8]([O:17][CH3:18])=[C:7]2[C:6]([CH:1]=[CH:2][C:3]([CH3:4])([CH3:5])[O:19]2)=[CH:11][CH:10]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: COc1c(OCC(C)C)ccc(CC=C(C)C)c1O
Solvent: CCCCCC
Solvent: c1ccccc1
Product: COc1c(OCC(C)C)ccc2c1OC(C)(C)C=C2
Yield: 79.7 %

Procedure:
A mixture of 5.8 g (22 millimoles) of 2-prenyl-5-isobutoxy-6-methoxy-phenol, a molar equivalent amount of methyl-trialkyl (C8 -C10)-ammonium dichromane and 100 ml of benzene is refluxed for 10 hours. The reaction mixture is diluted with hexane, washed with 20% sodium thiosulfate, the organic phase is dried, evaporated and the residue is purified by column chromatography (see Example 3). Thus 4.6 g of the desired compound are obtained in the form of a colorless oil, yield 80%.
Reaction SMILES: [C:1]1([B:7]([OH:9])[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:11]([C:14](O)([CH3:16])[CH3:15])([CH3:13])[CH3:12]>C1(C)C=CC=CC=1>[C:1]1([B:7]2[O:9][C:14]([CH3:16])([CH3:15])[C:11]([CH3:13])([CH3:12])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(O)C(C)(C)O
Reactant: OB(O)c1ccccc1
Solvent: Cc1ccccc1
Product: CC1(C)OB(c2ccccc2)OC1(C)C
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Phenyl boronic acid (100 g, 0.82 mol, 1 equiv.) and pinacol (96.92 g, 0.82 mol, 1 equiv.) were dissolved in toluene (500 mL) at room temperature. The cloudy solution was then placed on to a rotary evaporator and stirred for 2 hours at 60° C. After this period the solid had dissolved, concurrent with the formation of water (ca. 29.5 mL) as a second layer. The water was then removed in a separating funnel and the crude reaction filtered through Celite. Evaporation of the solvent yielded a clear pale yellow oil which solidified on cooling in a refrigerator to give the title compound in a near-quantitative yield as a white solid (ca. 167 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][C:31]1[S:35][C:34]([C:36](O)=[O:37])=[CH:33][CH:32]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:36]([C:34]4[S:35][C:31]([CH3:30])=[CH:32][CH:33]=4)=[O:37])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: Cc1ccc(C(=O)O)s1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2ccc(C)s2)c1

Procedure:
Prepared as described in Example 105 using (1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-(3-methoxyphenyl)propan-2-amine (6a, 39 mg, 100 μmol) and 5-methyl-2-thiophenecarboxylic acid (28 mg, 200 μmol). Yield 42 mg (81%).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([O:12]COCCOC)[C:9]2[C:4](=[CH:5][C:6]([Cl:19])=[CH:7][CH:8]=2)[N:3]=1.[NH:20]1[CH:24]=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:22]=[N:21]1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>Cl>[CH2:28]([O:27][C:25]([C:23]1[CH:24]=[N:20][N:21]([C:2]2[NH:11][C:10](=[O:12])[C:9]3[C:4](=[CH:5][C:6]([Cl:19])=[CH:7][CH:8]=3)[N:3]=2)[CH:22]=1)=[O:26])[CH3:29]
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: COCCOCOc1nc(Cl)nc2cc(Cl)ccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(-c2nc3cc(Cl)ccc3c(=O)[nH]2)c1
Temperature: 120 °C
Yield: 49.9 %

Procedure:
A mixture of 2,7-dichloro-4-(2-methoxy-ethoxymethoxy)-quinazoline (0.68 g, 2.2 mmol), ethyl pyrazole-4-carboxylate (0.34 g, 2.4 mmol), Cs2CO3 (1.2 g, 3.6 mmol) and anhydrous DMF (10 mL) was heated to 120° C. for 20 min, and then was cooled to 0° C. The mixture was carefully diluted with 1 M aq. HCl (30 mL). The mixture was allowed to warm to rt and the precipitate was collected by filtration to provide the titled compound (0.35 g, 50%). MS (Cl): mass calcd. for C14H11ClN4O3, 318.7; m/z found, 317.0 [M−H]−. 1H NMR (400 MHz, DMSO-d6): 13.04 (br s, 1H), 8.99 (s, 1H), 8.32 (s, 1H), 8.11 (d, J=8.5 Hz, 1H), 7.75 (s, 1H), 7.54 (dd, J=8.5, 2.1 Hz, 1H), 4.30 (q, J=7.1 Hz, 2H), 1.33 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([CH2:28][OH:29])[CH:25]=[C:24]([Br:30])[CH:23]=2)[C:10]=1[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH3:2].[CH3:39][S:40](Cl)(=[O:42])=[O:41].CO.CCOC(C)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:3][C:4](=[O:38])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([CH2:28][O:29][S:40]([CH3:39])(=[O:42])=[O:41])[CH:25]=[C:24]([Br:30])[CH:23]=2)[C:10]=1[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(CO)c2)c1CCC(=O)OCC
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(COS(C)(=O)=O)c2)c1CCC(=O)OCC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 74 %

Procedure:
To a solution of 4-[3-[6-(3-Bromo-5-hydroxymethyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (2.99 g, 5.05 mmol) in DCM (100 mL), TEA (3.52 mL, 25.26 mmol), DMAP (62 mg, 0.505 mmol) were added, followed by MsCl (0.60 mL, 7.58 mmol), and stirred at room temperature for 2.5 h. MeOH (4 mL) was added to quench the reaction. The solvent was removed under reduced pressure. Flash column chromatography (40% EtOAc/Hex) provided a colorless oil (2.51 g, 74% yield). 1H NMR (CDCl3): δ 7.11-7.05 (m, 3H), 6.86 (s, 1H), 6.77 (d, 1H), 6.68 (d, 1H), 5.14 (s, 2H), 4.17-4.08 (m, 4H), 4.01-3.91 (m, 4H), 2.99-2.93 (m, 5H), 2.63 (dd, 2H), 2.56-2.46 (m, 4H), 2.17-0.89 (m, 16H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[N:6]1[C:11](=[O:12])[C:10]([F:13])=[CH:9][NH:8][C:7]1=[O:14].ClC1C(=O)NC(=O)NC=1.CC1C=CC(S(O[CH:35]([I:38])[C:36]#[CH:37])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>>[I:38][C:35]#[C:36][CH2:37][C:9]1[NH:8][C:7](=[O:14])[N:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[C:11](=[O:12])[C:10]=1[F:13]
Reactant: C#CC(I)OS(=O)(=O)c1ccc(C)cc1
Reactant: O=c1[nH]cc(F)c(=O)n1-c1ccco1
Agent: O=C([O-])[O-]
Agent: O=c1[nH]cc(Cl)c(=O)[nH]1
Agent: [K+]
Product: O=c1[nH]c(CC#CI)c(F)c(=O)n1-c1ccco1

Procedure:
The procedure in Example 1 was repeated, except that 2.0477 g of 3N-(2-furanyl)-5-fluorouracil (ftorafur) (10.23 mmole) available from Aldrich Chemical Co. was used instead of 5-chlorouracil and 3.6089 g of iodopropargyl 4-methylbenzenesulfonate (10.741 mmole) and 1.060 g (7.67 mmole) of potassium carbonate were used.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@H:11]3[C@@H:15]4[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]4[C@@H:13]([CH2:21]O)[CH2:12]3)[C:4]=2[N:5]=[CH:6][N:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(OP(OC2C=CC=CC=2)([N:51]=[N+:52]=[N-:53])=O)=CC=1>C1COCC1>[N:51]([CH2:21][C@@H:13]1[C@H:14]2[O:18][C:17]([CH3:19])([CH3:20])[O:16][C@H:15]2[C@H:11]([N:8]2[C:4]3[N:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]=3[CH:10]=[CH:9]2)[CH2:12]1)=[N+:52]=[N-:53]
Reactant: CC1(C)O[C@@H]2[C@@H](CO)C[C@@H](n3ccc4c(Cl)ncnc43)[C@@H]2O1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)O[C@@H]2[C@@H](CN=[N+]=[N-])C[C@@H](n3ccc4c(Cl)ncnc43)[C@@H]2O1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.6 %

Procedure:
((3aR,4R,6R,6aS)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol (2.68 g, 8.28 mmol) was dissolved in THF (32 mL), treated with PPh3 (3.05 g, 11.6 mmol), and the reaction vessel was cooled in an ice-brine bath. Diisopropyl azodicarboxylate[DIAD] (2.3 mL, 12 mmol) was added dropwise via syringe and the mixture was stirred for 10 min. A solution of diphenylphosphonic azide [DPPA] (2.50 mL, 11.6 mmol) in THF (7.8 mL) was added dropwise via syringe to afford a off-white mixture, which was stirred for 21 h, allowing the ice bath to warm to RT; HPLC/LC MS indicated complete consumption of starting material and formation of product. At 22.5 h the reaction mixture was concentrated in vacuo and purified by column chromatography (4×22 cm silica; 0-25% EtOAc/Hex) to afford the title compound (2.27 g, 78%) as a clear, colorless oil: MS (ESI+) for C15H17ClN6O2 m/z 349.2 (M+H)+; MS (ESI−) for C15H17ClN6O2 m/z 393.2 (M+HCO2)−; HPLC purity >95% (ret. time, 4.169 min).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][CH2:16][CH:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1.Cl[CH:27]([O:29]C)Cl>C(Cl)Cl>[CH:27]([C:21]1[CH:20]=[C:19]2[C:24](=[CH:23][CH:22]=1)[CH2:25][CH:17]([CH2:16][NH:15][S:12]([C:9]1[CH:8]=[CH:7][C:6]([Cl:5])=[CH:11][CH:10]=1)(=[O:14])=[O:13])[CH2:18]2)=[O:29]
Reactant: O=S(=O)(NCC1Cc2ccccc2C1)c1ccc(Cl)cc1
Reactant: COC(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=Cc1ccc2c(c1)CC(CNS(=O)(=O)c1ccc(Cl)cc1)C2
Temperature: -20 °C
Reaction time: 1 h
Yield: 21.4 %

Procedure:
5.33 g (40.0 mmol) of anhydrous aluminum chloride was suspended in 20 ml of methylenechloride and added with 1.61 g (5.00 mmol) of 2-[(4-chlorophenyl)sulfonylaminomethyl]indan, followed by cooling at -20° C. 10 ml of methylene chloride containing as dissolved 0.68 ml (7.5 mmol) of dichloromethylmethylether was slowly added dropwise thereto, followed by stirring for 1 hour at the same temperature. The reaction solution was poured into ice-water and stirred for 1 hour. Thereafter, the organic phase was collected, washed, dried, and the solvent was removed. The residue was purified by silica gel column chromatography (chloroform), followed by recrystallizing from a solvent mixture of ethylacetate and hexane to obtain 375 mg of colorless crystals. Yield: 22%
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([NH:11][C:12](=[O:40])[CH2:13][CH2:14][CH:15]([N:22]1[CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:29]=2)[N:24]=[C:23]1[NH2:39])[CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH2:5][O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[BH4-].[Na+]>CO>[NH2:39][C:23]1[N:22]([C@H:15]([CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:14][CH2:13][C:12]([NH:11][C@H:4]([CH2:5][O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:3][OH:2])=[O:40])[CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:29]=2)[N:24]=1
Reactant: COC(=O)C(COC(C)(C)C)NC(=O)CCC(C1CCCCC1)N1Cc2cc(Oc3ccccc3)ccc2N=C1N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC[C@H](CO)NC(=O)CC[C@@H](C1CCCCC1)N1Cc2cc(Oc3ccccc3)ccc2N=C1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-[4-(2-amino-6-phenoxy-4H-quinazolin-3-yl)-4-cyclohexyl-butyrylamino]-3-tert-butoxy-propionic acid methyl ester (TFA salt, 50 mg) in methanol (5 mL), NaBH4 (0.04 g) was added slowly over a 30 minute period. The resulting solution was then stirred at room temperature overnight. LC/MS indicated very little product formed and most of the starting material remained. Additional NaBH4 (0.04 g) was added at room temperature, and the solution was stirred for an additional 8 hrs. Additional NaBH4 (0.08 g) was added over a 4 day period. LC/MS then indicated that most of the starting material was converted. The crude reaction mixture was purified by Gilson HPLC to yield the title compound as a white solid.
Reaction SMILES: Br[CH2:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=O.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>C(O)C>[C:11]([N:8]1[CH2:9][CH2:10][CH:5]([C:3]2[N:19]=[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]3[CH:2]=2)[CH2:6][CH2:7]1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccn1
Reactant: O=C(CBr)C1CCN(C(=O)c2ccccc2)CC1
Solvent: CCO
Product: O=C(c1ccccc1)N1CCC(c2cn3ccccc3n2)CC1
Yield: 49.5 %

Procedure:
To a solution of 160 mg of 2-bromo-1-(1-benzoyl-4-piperidyl)-1-ethanone (prepared in analogy with Example 523, Step A) in 6 mL ethanol was added 59 mg of 2-aminopyridine. After refluxing for 18 hours, the solvent was evaporated. The mixture was partitioned between EtOAc and saturated sodium bicarbonate solution. Aqueous layer was extracted with EtOAc (3×). The combined organic phase was washed with brine, dried over MgSO4 and concentrated. The residue was purified by flash chromatography with 100% EtOAc followed by 10% MeOH in EtOAc to give 78 mg of a solid: 1H NMR (500 MHz, CDCl3) δ1.80 (d, 2H), 2.16 (d, 2H), 3.17 (m, 3H), 3.87 (br, 1H), 4.85 (br, 1H), 6.76 (t, J=6.8 Hz,1H). 7.15 (m,1H), 7.37(s, 1H), 7.42(m, 5H), 7. 55(d, J=9.1 Hz, 1H), 8.08 (d, J=6.9 Hz,1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([NH:14][C:15]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:39])[CH2:24][CH2:25][CH:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)[CH2:18]2)=[O:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[N:6][CH:7]=1.[C:40]([C:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][C:43]=1[F:51])#[N:41].[F-].[K+]>C1(C)C=CC=CC=1.C(O)C.O.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:40]([C:42]1[CH:47]=[CH:46][C:45]([C:2]2[CH:3]=[C:4]([CH:8]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:39])[CH2:24][CH2:25][CH:26]4[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:37])([CH3:38])[CH3:36])=[O:33])[CH2:28][CH2:27]4)[CH2:18]3)=[O:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[N:6][CH:7]=2)=[CH:44][C:43]=1[F:51])#[N:41]
Reactant: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(Br)c1
Reactant: N#Cc1ccc(B(O)O)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(-c2ccc(C#N)c(F)c2)c1
Temperature: 60 °C
Reaction time: 20 h
Yield: 49.3 %

Procedure:
To 300.0 mg (0.49 mmol) tert-butyl 4-{3-[(3R)-3-{[1-(5-bromopyridin-3-yl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (example 8c) in 12 ml toluene were added 11.4 mg (0.01 mmol) tetrakis(triphenylphosphine)palladium(0), 97.4 mg (0.59 mmol) (4-cyano-3-fluoro-phenyl)boronic acid in 3.0 ml ethanol and 57.2 mg (0.98 mmol) potassium fluoride in 3.0 ml water. The mixture was stirred at 100° C. for 10 hours and at 60° C. for 20 hours, diluted with water and extracted with ethyl acetate and sodium hydrogen carbonate solution. The organic phase was dried over sodium sulfate and concentrated in vacuum. Chromatography over 10 g silica gel (dichloromethane/ethanol 100/0-95/5-90/10) gave 157 mg (44%) tert-butyl 4-{3-[(3R)-3-({1-[5-(4-cyano-3-fluorophenyl)pyridin-3-yl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:22]=[CH:21][C:12]3[N:13]([CH3:20])[C:14]([NH:16][CH:17]([CH3:19])[CH3:18])=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:23](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:23])[C:9]2[CH:22]=[CH:21][C:12]3[N:13]([CH3:20])[C:14]([NH:16][CH:17]([CH3:19])[CH3:18])=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)Nc1nc2cc(Nc3ccnc(Cl)n3)ccc2n1C
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(C)Nc1nc2cc(N(C)c3ccnc(Cl)n3)ccc2n1C
Temperature: 25 °C
Yield: 46 %

Procedure:
To a solution of N2-isopropyl-1-methyl-1H-benzimidazole-2,5-diamine (1.46 g, 7.2 mmol) in THF (7 ml) and ethanol (21 ml) was added NaHCO3 (1.81 g, 21.6 mmol) and 2,4-dichloropyrimidine (2.68 g, 18 mmol) and the reaction was heated to 75° C. After 5 h, the reaction was filtered hot and concentrated to a gray foam. Ether was added and the solid was filtered and dried to give N5-(2-chloro-pyrimidin-4-yl)-N2-isopropyl-1-methyl-1H-benzimidazole-2,5-diamine as an off-white solid. N5-(2-chloro-pyrimidin-4-yl)-N2-isopropyl-1-methyl-1H-benzimidazole-2,5-diamine was dissolved in DMF (21 ml) and cesium carbonate (6.84 g, 21 mmol) was added After 15 min, iodomethane (0.70 ml, 11.2 mmol) was added, and the reaction was stirred at rt. After TLC showed the starting material to be consumed, the reaction was diluted with water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, dried over MgSO4 and concentrated to a red foam. The crude material was purified with silica gel to give the title compound as a white solid (1.10 g, 46% over two steps). 1H NMR (300 MHz, d6-DMSO) δ 7.87 (d, J=6.0 Hz, 1H), 7.22 (d, J=8.1 Hz, 1H), 7.11 (1.8 Hz, 1H), 6.82 (dd, J=8.1 and 1.8 Hz, 1H), 6.53 (d, J=7.5 Hz, 1H), 6.09 (d, J=6.0 Hz, 1H), 4.04 (m, 1H), 3.51 (s, 3H), 3.37 (s, 3H), 1.23 (d, J=6.6 Hz, 6H). MS (ESI) m/z=331 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=O)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:6]=2[CH:20]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:6]=2[CH:20]=1
Reactant: O=C1CN=C(c2ccccc2F)c2cc(Br)ccc2N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Fc1ccccc1C1=NCCNc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.2 %

Procedure:
A round-bottomed flask was charged with 7-bromo-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one (500 mg) and tetrahydrofuran (20 mL). To this mixture was added lithium aluminum hydride (1.8 mL of 1M solution in tetrahydrofuran). The reaction was stirred overnight at room temperature, then quenched with water and 10% sodium hydroxide. The quenched mixture was filtered through Celite and the filter was washed with ethyl acetate. The filtrate was dried over magnesium sulfate, filtered and concentrated to an oil. Silica gel purification provided 7-bromo-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine (250 mg) as a yellow powder. H1 NMR (d6-dmso): 7.43-7.50 (m, 1H), 7.40 (dt, 1H), 7.18-7.28 (m, 3H), 6.75-6.81 (m, 2H), 6.71 (d, 1H), 3.95 (m, 2H), 3.49 (m, 2H). Mass (ES+)=319.1 (100%).
Reaction SMILES: [CH3:1][CH2:2]/[CH:3]=[CH:4]\[CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:14]([CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:12](=[O:13])[CH2:11][C@H:10]1O.[OH-].[K+].Cl>C(O)C>[CH3:1][CH2:2]/[CH:3]=[CH:4]\[CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C:9]1[CH2:10][CH2:11][C:12](=[O:13])[C:14]=1[CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22]
Reactant: CC/C=C\C[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCC(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC/C=C\C[C@H](O)/C=C/C1=C(C/C=C\CCCC(=O)O)C(=O)CC1
Temperature: 10 °C

Procedure:
A solution of racemic PGE3 (200 mg.) in 100 ml. of 50% aqueous ethanol containing 10 grams of potassium hydroxide is kept at 25° C. for 10 hours under notrogen. Then, the solution is cooled to 10° C. and neutralized by addition of 3 normal hydrochloric acid at 10° C. The resulting solution is extracted repeatedly with ethyl acetate, and the combined ethyl acetate extracts are washed with water and then with saturated aqueous sodium chloride solution, dried, and evaporated to give racemic PGB3.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:9]([OH:10])=[C:8]([C:11]([CH3:13])=[O:12])[CH:7]=[CH:6][C:5]=1[OH:14].[CH2:15]=[CH:16][CH2:17][CH2:18][CH2:19][C:20](=O)[CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25].N1CCCC1>C1(C)C=CC=CC=1>[CH2:21]([C:20]1([CH2:19][CH2:18][CH2:17][CH:16]=[CH2:15])[CH2:13][C:11](=[O:12])[C:8]2[CH:7]=[CH:6][C:5]([OH:14])=[C:4]([CH2:3][CH2:2][CH3:1])[C:9]=2[O:10]1)[CH2:22][CH2:23][CH:24]=[CH2:25]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: C=CCCCC(=O)CCCC=C
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: C=CCCCC1(CCCC=C)CC(=O)c2ccc(O)c(CCC)c2O1
Yield: 84.6 %

Procedure:
A mixture of 3.93 g (20.2 mmol) of 2,4-dihydroxy-3-propylacetophenone, 3.36 g (20.2 mmol) of the title product of Example 68, 1.44 g (20.2 mmol) of pyrrolidine, and 23.5 ml of toluene was stirred at reflux under a water separator containing 3A molecular sieves for 5 hours. The mixture was then permitted to cool, and the solvent was removed under reduced pressure. Chromatography of the residue over silica gel using 25% ethyl acetate/hexane as eluant gave the title compound (5.85 g) as a dark red oil.