Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[OH:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH:27]=O.[BH3-]C#N.[Na+]>CO.CN1C(=O)N(C)CC1>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([NH:1][CH2:27][C:26]4[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:24]([OH:23])[CH:25]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Reactant: COc1ccc(C=O)cc1O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CN1CCN(C)C1=O
Product: COc1ccc(CNc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1O

Procedure:
Analogously to Example 21, 1.00 mmol of 3-amino-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine in 26 ml of methanol, 13 ml of DMEU and 3.0 mmol of acetic acid are first reacted with 3-hydroxy-4-methoxy-benzaldehyde and then reduced with 7.00 mmol of NaCNBH3 (5-7 days). 4-(3-Chloro-phenylamino)-3-(3-hydroxy-4-methoxy-benzylamino)-1H-pyrazolo[3,4-d]pyrimidine is obtained; m.p. 225-227° C.; HPLC: TRet (Grad5-40)=17.6.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH:8]([NH2:16])[CH2:9]2.[C:17](=[O:20])([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]Br.Cl>C(#N)C>[ClH:1].[ClH:1].[CH3:2][O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH:8]([NH:16][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:16][CH:8]1[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:13]([O:20][CH3:17])[C:4]=3[O:3][CH3:2])[CH2:9]1)[CH2:9]2
Reactant: O=C([O-])[O-]
Reactant: COc1ccc2c(c1OC)CCC(N)C2
Reactant: BrCCCCCCBr
Agent: Cl
Agent: [K+]
Solvent: CC#N
Product: COc1ccc2c(c1OC)CCC(NCCCCCCNC1CCc3c(ccc(OC)c3OC)C1)C2
Reaction time: 24 h
Yield: 20.2 %

Procedure:
1,2,3,4-Tetrahydro-5,6-dimethoxy-2-naphthalenamine hydrochloride (4.87 g) in acetonitrile (100 ml) was added slowly to a stirred suspension of potassium carbonate (3.0 g) in a refluxing solution of 1,6-dibromohexane (2.44 g) in acetonitrile (100 ml) over a period of 1 hour. When the addition was complete, reflux was continued for 24 hours, the solution filtered to remove inorganic salts, and the filtrate evaporated in vacuo to give an oil. Chromatography on silica, eluting with chloroform: methanol 95:5 , gave, following trituration with ethereal hydrogen chloride, the title compound 1.15 g (20%), mp 275° (decomp)
Reaction SMILES: [CH3:1][S-:2].[Na+].[Br:4][C:5]1[CH:10]=[C:9](I)[CH:8]=[CH:7][C:6]=1[OH:12].Cl.CCOC(C)=O>CN(C=O)C.[Cu-]=O>[Br:4][C:5]1[CH:10]=[C:9]([S:2][CH3:1])[CH:8]=[CH:7][C:6]=1[OH:12]
Reactant: C[S-]
Reactant: Oc1ccc(I)cc1Br
Agent: O=[Cu-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1ccc(O)c(Br)c1
Temperature: 80 °C
Yield: 48.4 %

Procedure:
Sodium thiomethoxide (8.64 g) and copper (I) oxide (8.79 g) were mixed with 2-bromo-4-iodophenol (XX, 14.72 g) in anhydrous DMF (100 mL). The mixture was stirred and heated at 80° C. for 48 h under nitrogen atmosphere. Then, the resultant slurry was treated with concentrated HCl (5 mL) and EtOAc (200 mL), and was filtered and rinsed with EtOAc (200 mL). The organic layers were partitioned with 1N HCl (150 mL), water (150 mL) and brine (150 mL) and dried over MgSO4, filtered and solvent removed in vacuo. Product was purified by silica gel column chromatography, the product eluted with dichloromethane/hexane (2:3), to give the desired product (5.22 g, 39%) as a light brown oil.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].C1(S([C:25]2[O:26][CH:27]=[C:28]([CH3:30])[N:29]=2)=O)CCCCC1.O>CN1CCCC1=O.CCOCC>[CH2:1]([N:5]([C:25]1[O:26][CH:27]=[C:28]([CH3:30])[N:29]=1)[C:6](=[O:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1coc(S(=O)C2CCCCC2)n1
Reactant: CCCCNC(=O)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: CCCCN(C(=O)Cc1ccccc1)c1nc(C)co1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
N-Butyl-phenylacetamide (1.80 g, 0.0094 m) in N-methyl pyrrolidone (10 ml) was stirred at 80° C. under nitrogen during the portionwise addition of a 50% sodium hydride/oil dispersion (0.75 g, 0.0094 m). After the addition, the mixture was warmed to 100° C. and 2-cyclohexylsulphinyl-4-methyloxazole (2.0 g, 0.0094 m) in dry N-methyl pyrrolidone (10 ml) was added. The mixture was stirred at 100° C. for 5 hours and then hydrolysed with water. The solvent was removed in vacuo and the product isolated by column chromatography on silica using ether. Distillation gave the title product as a colourless oil. b.p. 126°-130° C./0.2 mm.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11](=[O:16])[CH2:12][CH:13](O)[CH:14]=1)([OH:3])=[O:2].[SH:17][CH2:18][CH2:19][OH:20].C[O-].[Na+]>CO>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11](=[O:16])[CH2:12][CH:13]([S:17][CH2:18][CH2:19][OH:20])[CH:14]=1)([OH:3])=[O:2]
Reactant: O=C(O)CCCCCCC1=CC(O)CC1=O
Reactant: OCCS
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CCCCCCC1=CC(SCCO)CC1=O

Procedure:
In the manner of Example 281 a methanol solution of 2-(6-carboxyhexyl)-4-hydroxycyclopent-2-en-1-one [Prostaglandins, 3, 921 (1973)] and β-mercaptoethanol is treated with sodium methoxide solution, acidified, concentrated, and extracted to provide the subject compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.Cl[C:11]1[C:16]([C:17](OCC)=[O:18])=[CH:15][N:14]=[C:13]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:12]=12>C(O)CCC>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17](=[O:18])[C:16]3[C:11]([C:12]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:13]=4[NH:14][CH:15]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc2c(c1Cl)CCCCC2
Reactant: NNc1ccc(Cl)cc1
Solvent: CCCCO
Product: Cl
Product: O=c1c2c[nH]c3c(c-2nn1-c1ccc(Cl)cc1)CCCCC3
Temperature: 25 °C

Procedure:
A mixture of 2.6 g of p-chlorophenylhydrazine and 3.9 g of ethyl 4-chloro-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylate (Example 2c) in 100 mL of n-butanol is refluxed overnight under nitrogen atmosphere, then cooled to room temperature. The solid precipitate is collected, triturated with ether, dissolved in hot ethanol and decolorized with charcoal. The ethanolic solution is acidified with hydrogen chloride, then concentrated to a smaller volume and diluted with ether to precipitate a yellow solid, which is collected, washed with ether and dried at 90° in vacuum overnight, obtaining 2-p-chlorophenyl-2,3,5,6,7,8,9,10-octahydrocyclohepta[b]pyrazolo[3,4-d]pyridin-3-one hydrochloride, m.p. 272°-275°.
Reaction SMILES: [C:1](=[O:6])([O:3][CH2:4][CH3:5])[NH2:2].[CH:7]12[CH2:13][CH:10]([CH2:11][CH2:12]1)[CH:9]=[CH:8]2>C(O)C>[C:7]12([NH:2][C:1](=[O:6])[O:3][CH2:4][CH3:5])[CH2:13][CH:10]([CH2:11][CH2:12]1)[CH2:9][CH2:8]2
Reactant: CCOC(N)=O
Reactant: C1=CC2CCC1C2
Solvent: CCO
Product: CCOC(=O)NC12CCC(CC1)C2
Temperature: 70 °C
Reaction time: 7 h
Yield: 85.8 %

Procedure:
A stirred mixture of 178 g of ethyl carbamate, 94 g of norbornene, 5 g of ethanol and 20 g of ®LEWASORB AC-10 was heated to 70° C. in a stirred reactor, and stirring was continued at this temperature for 7 hours. Thereafter, the catalyst was filtered off and the mixture was distilled under reduced pressure. 157 g (86% of theory) of ethyl N-norbornylcarbamate of boiling point 148°-150° C./20 mbar and melting point 50° C. (from pentane) were obtained. No substantial amount of norbornene oligomers was detected.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:31])[CH:14]([CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7])(C)(C)C.FC(F)(F)[C:34]([OH:36])=[O:35].[CH2:39](N(CC)CC)C.ClC(=O)C([O-])=O>C(Cl)Cl>[CH3:39][O:36][C:34](=[O:35])[C:6](=[O:7])[N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:31])[CH:14]([CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)C(CCc1ccccc1)CCc1ccccc1
Reactant: O=C(O)C(F)(F)F
Reactant: CCN(CC)CC
Agent: O=C([O-])C(=O)Cl
Solvent: ClCCl
Product: COC(=O)C(=O)N1CCCC1C(=O)C(CCc1ccccc1)CCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
To a solution of 0.18 g (0.40 mmol) of 11a in CH2Cl2 (3 mL) was added dropwise 10 mL (8.77 mmol) of trifluoroacetic acid, and the mixture was allowed to stir for 2 hours. The solution was diluted with CH2Cl2 (10 mL) and cooled to 0° C. followed by dropwise addition of 0.7 g (10.00 mmol) of triethylamine. After 5 minutes, to the solution was added dropwise 0.06 g (0.5 mmol) of chlorooxoacetate, and the mixture was stirred for 2 hours. The solution was quenched with H2O and extracted with CH2Cl2 (2×200 mL). The organic phase was dried (MgSO4) and evaporated to a clear oil which was subject to column chromatography (EtOAc/Hexanes, 1:1) to yield 0.16 g (98.2%) of 12a as a clear oil. TLC Rf=0.6 (EtOAc/Hexanes, 1:3)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C([Sn](CCCC)(CCCC)C1C=CC(C(F)(F)F)=CC=1[N+]([O-])=O)CCC.FC(F)(F)S(O[C:47]1[CH2:56][CH2:55][C:54]2[C:49](=[CH:50][CH:51]=[C:52]([O:57][CH3:58])[CH:53]=2)[CH:48]=1)(=O)=O>>[CH3:58][O:57][C:52]1[CH:53]=[C:54]2[C:49]([CH:48]=[C:47]([C:2]3[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=3[N+:12]([O-:14])=[O:13])[CH2:56][CH2:55]2)=[CH:50][CH:51]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Br
Reactant: COc1ccc2c(c1)CCC(OS(=O)(=O)C(F)(F)F)=C2
Agent: CCCC[Sn](CCCC)(CCCC)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Product: COc1ccc2c(c1)CCC(c1ccc(C(F)(F)F)cc1[N+](=O)[O-])=C2

Procedure:
Synthesized from 1-bromo-2-nitro-4-trifluoromethylbenzene according to an analogous synthetic method to Preparation Example 76, tributyl(2-nitro-4-trifluoromethylphenyl)tin (7.4 and 6-methoxy-3,4-dihydronaphthalen-2-yl trifluoromethanesulfonate (2.2 g) were used according to an analogous synthetic method to Preparation Example 77 to provide 7-methoxy-3-(2-nitro-4-trifluoromethylphenyl)-1,2-dihydronaphthalene (1.5 g). The total amount of this compound was used according to an analogous synthetic method to Example 30 to provide the title compound (1.0 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([O:10]CC)=[O:9])=[C:5]([CH3:7])[N:6]=1.O1CCCC1.[OH-].[Na+]>O>[NH2:1][C:2]1[S:3][C:4]([C:8]([OH:10])=[O:9])=[C:5]([CH3:7])[N:6]=1
Reactant: CCOC(=O)c1sc(N)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(N)sc1C(=O)O
Temperature: 25 °C
Yield: 75 %

Procedure:
To a solution of ethyl 2-amino-4-methylthiazole-5-carboxylate (2.19 g, 11.8 mmol) in a 1:1 mixture of tetrahydrofuran (20 mL) and water (10 mL) was added sodium hydroxide (1.80 g, 45.0 mmol). The reaction mixture was refluxed for 18 hours and allowed to cool down to ambient temperature. The organic solvent was removed in vacuo. The aqueous solution was acidified with 10% aqueous hydrochloric acid solution. The colorless solid was collected and dried to afford 2-amino-4-methylthiazole-5-carboxylic acid (1.40 g, 75%): 1H NMR (300 MHz, DMSO-d6) δ 11.95 (s, 1H), 7.26 (s, 2H), 2.01 (s, 3H); MS (ES+) m/z 159.3 (M+1).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:14](O)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:14]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Prepared in the same manner as intermediate 18. To a solution of tert-butyl 1-piperazinecarboxylate (15.0 g. 80.5 mmol) and benzoic acid (8.94 g, 73.2 mmol) in CH2Cl2 (500 mL), was added DMAP (9.84 g, 80.5 mmol) and EDC (15.39 g, 80.5 mmol). The reaction mixture was stirred at rt for 17 h, and then washed with excess hydrochloric acid (5×250 mL, 1 N aq.) and water (350 mL). The organic layer was dried (MgSO4) and evaporated in vacuo to give N-Benzoyl-N′-Boc piperazine as an off white solid (21 g, 99%). 1H NMR (300 MHz, CD3OD) δ 7.46 (m, 5H), 3.80-3.30 (b m, 8H), 1.47 (s, 9H); LC/MS (ES+) m/z (M+H)+=291, (2M+H)+=581, HPLC Rt=1.430.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(Cl)Cl.CO>C(O)(=O)C>[C:14]1([CH:13]2[C:5]3[NH:6][C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:4]=3[CH2:3][CH2:2][NH:1]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: NCCc1c[nH]c2ccccc12
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: c1ccc(C2NCCc3c2[nH]c2ccccc32)cc1
Yield: 661.9 %

Procedure:
A mixture of 1.0 g (6.24 mmol) of tryptamine and 0.73 g (0.87 mmol) of benzaldehyde in 10 ml of acetic acid was refluxed for 3 hours. After completion of the reaction, the solvent was distilled off, and the residue was made alkaline by the addition of a saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and then the solvent was removed by evaporation under reduced pressure to give 1.82 g of a crude mixture. The resulting residue was subjected to column chromatography using 35 g of silica gel with a 9:1 by volume mixture of methylene chloride and methanol as the eluent, to yield 1.43 g (92%) of the title compound. The product was subsequently recrystallized from dichloroethane and hexane to yield 0.72 g of pale yellowish brown crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20](Cl)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][C:36]1[CH:41]=[CH:40][N:39]2[N:42]=[CH:43][C:44](B3OC(C)(C)C(C)(C)O3)=[C:38]2[CH:37]=1.C(=O)([O-])[O-].[K+].[K+].C(N[C@H](C(O)=O)CS)(=O)C>O.CC(N(C)C)=O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:44]2[CH:43]=[N:42][N:39]3[CH:40]=[CH:41][C:36]([CH3:35])=[CH:37][C:38]=23)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccn2ncc(B3OC(C)(C)C(C)(C)O3)c2c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: CC(=O)N[C@@H](CS)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1ccn2ncc(-c3nc(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)c(F)c4c3C(=O)N(C(=O)OC(C)(C)C)C4)c2c1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 46.1 %

Procedure:
To a 25 mL reaction flask equipped with magnetic stir bar and thermometer was added tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (200 mg, 0.401 mmol) and 5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (124 mg, 0.481 mmol), followed by potassium carbonate (325 mesh powder) (111 mg, 0.802 mmol), DMA (6 mL), and water (0.400 mL). The mixture was stirred at room temperature for 3 min before degassing with vacuum and N2 back-fill (5×). To the resulting deep purple mixture was added Pd-118 (10.93 mg, 0.016 mmol). The reaction mixture was degassed again with vacuum and N2 back-fill (5×). The flask was wrapped tightly with plastic film, placed in an oil bath, and the reaction mixture was stirred at 80° C. for 18 hours. Solid N-acetyl cysteine (65.4 mg, 0.401 mmol) was added and the mixture was stirred at 70° C. for 2 h. The mixture was subsequently diluted with water and extracted with EtOAc (200 mL). The organic layer was dried and concentrated to give a residue, which was purified by preparative HPLC, eluting with a gradient of 55-80% ACN (0.035% TFA) and water (0.05% TFA). The fractions were collected to give, upon basic work-up, the title compound as a light yellow solid (110 mg, 46%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]#[N:14].[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=O.[OH-:24].[NH4+]>O>[Cl:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]2[C:3]=1[CH2:12][C:13](=[O:24])[NH:14][CH:18]2[C:17]1[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=1[Cl:15]
Reactant: [OH-]
Reactant: O=Cc1ccccc1Cl
Reactant: N#CCc1ccc2ccccc2c1Cl
Agent: [NH4+]
Solvent: O
Product: O=C1Cc2c(cc3ccccc3c2Cl)C(c2ccccc2Cl)N1
Temperature: 130 °C
Reaction time: 0.5 h

Procedure:
This material was prepared in a similar manner to that described in Acta Chimica Academie Scientarum Hungaricae, Tomus 108(3), 255, (1981). Thus a mixture of 1-chloro-2-naphthylacetonitrile (25 g) and polyphosphoric acid (100 g) was heated and stirred at 80° for 30 min. 2-Chlorobenzaldehyde (8.7 g) was added with stirring over 30 min. The mixture was heated at 130° C. for 3 hours, cooled and poured into water. 0.88 Ammonium hydroxide was added and the mixture left overnight. The precipitate was filtered off and refluxed in 5% sodium hydroxide. The mixture was filtered hot after 2 hours and the product chromatographed (silica gel, chloroform as eluant) to give 5-chloro-1-(2'-chlorophenyl)-1,4-dihydrobenzo[g]isoquinol-3-one (5.3 g) m.p. 252°-254° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:20]=[C:19](I)[C:9]2[N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]=[N:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[C:22]([NH:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)(=[O:24])[CH3:23].C(O)CCO.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.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>[C:22]([NH:25][C:26]1[CH:31]=[C:30]([C:19]2[C:9]3[N:10]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH:11]=[N:12][C:8]=3[CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:20]=2)[CH:29]=[CH:28][CH:27]=1)(=[O:24])[CH3:23]
Reactant: CCOC(=O)c1cc(I)c2c(c1)ncn2-c1ccccc1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCCO
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1cc(-c2cccc(NC(C)=O)c2)c2c(c1)ncn2-c1ccccc1

Procedure:
A mixture of 5-ethoxycarbonyl-7-iodo-1-phenylbenzimidazole (0.70 g, 1.8 mmol), 3-acetamidophenylboronic acid (0.48 g, 2.7 mmol), 1,3-propanediol (0.65 ml, 8.9 mmol), potassium carbonate (1.23 g, 8.9 mmol) and bis(triphenylphosphin)palladium dichloride (50 mg, 0.07 mmol) in a mixture of dimethoxyethane (10 ml) and water (5 ml) was stirred at reflux for 1 hour. The cooled reaction mixture was concentrated under reduced pressure, and the concentrate was partitioned between water and ethyl acetate. The organic phase was dried and concentrated under reduced pressure, and the concentrate was triturated in ethyl acetate leaving the product as an off-white solid (0.48 g, 67%) m/z, 400.2 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4].[C:7](Cl)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.O>CN(C=O)C>[C:8]1([C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: NC(CO)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: OCC(CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 91.3 %

Procedure:
Part A: Serinol (24 g) was added to a solution of trityl chloride (65 g) and triethylamine (51.0 g) in 600 mL of dry DMF. After stirring at room temperature for 48 h, the reaction was poured into water and extracted several times with diethyl ether. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated to dryness to afford N-triphenylmethylserinol (71.0 g).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].C(N(CC)CC)C.[OH:16][CH2:17][C:18]([CH3:35])([CH3:34])[C@@H:19]([O:26][Si:27]([CH3:33])([CH3:32])[C:28]([CH3:31])([CH3:30])[CH3:29])/[CH:20]=[CH:21]/[C:22]([O:24][CH3:25])=[O:23]>ClCCl.CN(C1C=CN=CC=1)C>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:16][CH2:17][C:18]([CH3:35])([CH3:34])[C@@H:19]([O:26][Si:27]([CH3:33])([CH3:32])[C:28]([CH3:30])([CH3:29])[CH3:31])/[CH:20]=[CH:21]/[C:22]([O:24][CH3:25])=[O:23])(=[O:7])=[O:6]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: COC(=O)/C=C/[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)CO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)COS(=O)(=O)CCCCl
Yield: 84.3 %

Procedure:
Following the general procedure for the preparation of neopentyl sulfonylester intermediates of Description 10, 25.7 mL (37.4 g, 211.4 mmol) of 3-chloropropylsulfonyl chloride in 500 mL of anhydrous dichloromethane (DCM) in the presence of 25.8 g (211.4 mmol) of 4-(N,N-dimethylamino)pyridine (DMAP) and 29.5 mL (21.4 g, 211.4 mmol) of triethylamine (Et3N, TEA) was reacted at ca. 0° C. with 40.5 g (133.9 mmol) of methyl (2E)(4S)-6-hydroxy-5,5-dimethyl-4-(1,1,2,2-tetramethyl-1-silapropoxy)hex-2-enoate (4). After work-up and isolation, the crude material was purified by silica gel column chromatography using methyl tert-butyl ether (MTBE) and hexane (Hxn) mixtures (MTBE/Hxn=1:6 MTBE/Hxn=1:5→MTBE/Hxn=1:4) as eluent to provide 50.0 g (84% yield) of the title compound (15a) as a pale-yellow oil. Rf=0.46 (MTBE/Hxn=1:4). 1H NMR (400 MHz, CDCl3): δ=0.01 (s, 3H), 0.09 (s, 3H), 0.93 (s, 9H), 0.97 (s, 3H), 0.98 (s, 3H), 2.30-2.38 (m, 2H), 3.27-3.33 (m, 2H), 3.68-3.73 (m, 2H), 3.77 (s, 3H), 3.98 (d, J=9.6 Hz, 1H), 4.10 (d, J=9.2 Hz, 1H), 4.11 (dd, superimposed, J=6.4, 1.6 Hz, 1H), 5.97 (dd, J=15.6, 1.2 Hz, 1H), 6.90 (dd, J=15.6, 6.8 Hz, 1H) ppm. MS (ESI) m/z 442.9 (M+H)+, 464.9 (M+Na)+. The analytical data was consistent the proposed structure.
Reaction SMILES: Cl.[NH:2]1[CH2:10][CH2:9][CH2:8][C@@H:3]1[CH2:4][C:5]([OH:7])=[O:6].S(Cl)([Cl:13])=O.[CH3:15]O>>[ClH:13].[CH3:15][O:6][C:5](=[O:7])[CH2:4][C@H:3]1[CH2:8][CH2:9][CH2:10][NH:2]1
Reactant: O=S(Cl)Cl
Reactant: CO
Reactant: O=C(O)C[C@H]1CCCN1
Agent: Cl
Product: COC(=O)C[C@H]1CCCN1
Reaction time: 8 h

Procedure:
To a solution of 2.0 g (0.012 mole) of D-beta-homoproline hydrochloride in 20 mL of methanol was added slowly 1.8 mL (0.024 mole) of thionyl chloride at 0 degrees. The mixture was stirred overnight, then concentrated under reduced pressure. The solid was slurried in ether, and collected by filtration to give 2.2 g of (2R)-pyrrolidin-2-yl-acetic acid methyl ester hydrochloride as a white solid. A solution of 2.2 g (0.012 mole) of (2R)-pyrrolidin-2-yl-acetic acid methyl ester hydrochloride in 3 mL of chloroform was added over 5 minutes to a cooled (0 degrees) mixture of 2.34 g (0.012 mole) of 2,4-dichloro-5-nitro-pyrimidine, 5.1 g (0.060 mole) of sodium bicarbonate and 25 mL of ethyl acetate. The cooling bath was removed and the mixture stirred for 17 hours at room temperature. Activated charcoal was added and after stirring briefly, the mixture was filtered through a pad of Celite, washing the filter pad with ethyl acetate. The filtrate was concentrated under reduced pressure. Purification of the residue by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-70:30) gave 3.3 g of [(R)-1-(2-chloro-5-nitro-pyrimidin-4-yl)-pyrrolidin-2-yl]-acetic acid methyl ester (IV-102) as a yellow thick oil.