Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)O)[CH:5]=[C:6]([O:13][CH3:14])[C:7]=1[O:8][CH2:9][CH2:10][O:11][CH3:12].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:15][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:5]=[C:6]([O:13][CH3:14])[C:7]=1[O:8][CH2:9][CH2:10][O:11][CH3:12]
Reactant: COCCOc1c(Br)cc(C(O)c2ccccc2)cc1OC
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COCCOc1c(Br)cc(Cc2ccccc2)cc1OC
Reaction time: 2 h
Yield: 77 %

Procedure:
To a 500 mL round bottomed flask with a stirring bar and a nitrogen inlet was added of 1-(3-bromo-4-(2-methoxyethoxy)-5-methoxyphenyl)-1-phenylmethanol (12.83 g, 34.94 mmol), dry methylene chloride (200 mL) and triethylsilane (13.87 mL, 87.34 mmol). This solution was cooled in an ice bath and borontrifluoride etherate (4.43 mL, 34.94 mmol) was added with a syringe over 5 min. The mixture was aged 2 h at 0° C. The reaction was quenched with saturated aqueous sodium bicarbonate solution and the mixture was extracted with chloroform. The chloroform fraction was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. This material was chromatographed on 400 g of silica gel using 20/80 EtOAc-hexane as eluant to give 9.45 g of 1-(3-bromo-4-(2-methoxyethoxy)-5-methoxyphenyl)-1-phenylmethane as an oil. 1H NMR (CDCl3): δ3.44 (s, 3H); 3.74 (t, j=4 Hz, 2H); 3.77 (s, 3H); 3.88 (s, 2H); 4.13 (t, j=4 Hz, 2H); 6.64 (d, j=2Hz, 1H); 6.94 (d, j=2Hz, 1H); 7.26 (m, 5H).
Reaction SMILES: C1(P(Cl)Cl)C=CC=CC=1.[C:10]1([P:16]([OH:18])[OH:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[N+:19]([O-])([OH:21])=[O:20]>>[N+:19]([C:12]1[CH:11]=[C:10]([P:16]([OH:18])[OH:17])[CH:15]=[CH:14][CH:13]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])O
Reactant: OP(O)c1ccccc1
Agent: ClP(Cl)c1ccccc1
Product: O=[N+]([O-])c1cccc(P(O)O)c1

Procedure:
According to my invention phenylphosphorus dichloride is converted to benzenephosphonous acid (B), which is nitrated (I) with nitric acid at a temperature around 0° C. to form m-nitrobenzenephosphonous acid (E) which, to my knowledge, is a compound not previously described in the literature. Compound E is conveniently oxidized by heating (II) the reaction mixture in the presence of additional nitric acid to form m-nitrobenzenephosphonic acid (C), and then compound (D) by subsequent reduction. My contribution, then, includes the nitration of benzenephosphonous acid (B), which is considerably less costly than benzenephosphonic acid (A), to form the novel compound m-nitrobenzenephosphonous acid (E), followed by oxidation to form m-nitrobenzene phosphonic acid (C) which is converted by conventional reduction to form the desired m-aminobenzenephosphonic acid (D).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([CH2:18][CH:19]([OH:30])[CH2:20][NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)[C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][C:12]([Br:17])=[CH:11][CH:10]=3.[CH3:31]I>CN(C=O)C.C(OCC)(=O)C>[Br:17][C:12]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:18][CH:19]([O:30][CH3:31])[CH2:20][NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)[C:7]3[C:15]([C:14]=2[CH:13]=1)=[CH:16][C:4]([Br:3])=[CH:5][CH:6]=3
Reactant: CI
Reactant: COc1cccc(NCC(O)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cccc(NCC(Cn2c3ccc(Br)cc3c3cc(Br)ccc32)OC)c1
Reaction time: 2.5 h

Procedure:
Sodium hydride (9.0 mg, 0.23 mmol) was added to a stirring solution of 1-(3,6-dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol (99.3 mg, 0.20 mmol) in DMF 0.5 ml, 0.39 M). The solution was stirred at room temperature for about 70 minutes before the dropwise addition of a solution of methyl iodide (14 ml. 0.22 mol) in DMF (1.0 ml). The reaction was monitored by 1 c/ms for the consumption of SM and the appearance of O and N-methyl products. After 2.5 hours of stirring at r.t, conversion was about 30% and about 5% N-methyl product had formed. The reaction was stopped when an increase of N-Me to O-Me had been observed and conversion was about 50%. The brown solution was diluted with ethyl acetate and washed several times with water and finally brine. The organic layer was dried over Na2SO4, filtered and condensed. The mixture was purified by preparative TLC 30% EtOAc/hexanes.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[C:9](Br)=[N:10][CH:11]=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[O:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[CH:29]=[C:28]1B(O)O>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[C:9]([C:28]2[O:27][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[CH:29]=2)=[N:10][CH:11]=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccnc1Br
Reactant: OB(O)c1cc2ccccc2o1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccnc1-c1cc2ccccc2o1

Procedure:
By carrying out the operation analogously to example 1, starting from 2-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation III, and 2-benzofuranboronic acid, the desired product is obtained and is used directly in the deacetylation stage.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].I[C:8]1[C:13]2[N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:15]=[N:16][C:12]=2[CH:11]=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=1.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(#N)C>[CH3:6][O:5][C:1](=[O:4])[CH:2]=[CH:3][C:8]1[C:13]2[N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:15]=[N:16][C:12]=2[CH:11]=[C:10]([C:23]([F:25])([F:26])[F:24])[CH:9]=1
Reactant: C=CC(=O)OC
Reactant: FC(F)(F)c1cc(I)c2c(c1)ncn2-c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C=Cc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12
Yield: 92.4 %

Procedure:
Methyl acrylate (2.7 ml, 30 mmol), 7-iodo-1-phenyl-5-trifluoromethylbenzimidazole (3.48 g, 10 mmol), triethylamine (2.79 ml, 20 mmol), palladium acetate (45 mg, 0.2 mmol), tri-o-tolylphosphine (161 mg, 0.53 mmol) and acetonitrile (50 ml) were combined and the mixture heated at reflux under an argon atmosphere for 17 h. The mixture was cooled, filtered through Dicalite and the filtrate was concentrated under reduced pressure. Crystals formed and were isolated by filtration and dried to give the title compound (3.2 g, 92%), m/z 347.0 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[CH2:6]1[O:8][CH2:7]1.C1OC1.[N-:12]=[N+:13]=[N-:14].[Na+].C1C(N)=NC(=O)N(CCOCCP(O)(O)=O)C=1.[OH-].[Na+]>CC(N(C)C)=O>[CH2:1]([N:12]=[N+:13]=[N-:14])[CH:3]1[O:5][CH2:4]1.[CH2:7]1[O:8][CH2:6]1
Reactant: [N-]=[N+]=[N-]
Reactant: ClCC1CO1
Agent: Nc1ccn(CCOCCP(=O)(O)O)c(=O)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CO1
Solvent: CC(=O)N(C)C
Product: [N-]=[N+]=NCC1CO1

Procedure:
Elastomeric GEC is prepared according to the same previous procedure as in Example 1, except that commercial rubbery Epichlorohydrin-Ethylene Oxide Copolymer (PEEC) is used instead of PECH as the starting material. The copolymer contains about 70% PECH and 30% Ethylene Oxide. For this reason, a weight ratio NaN3 :PEEC of 0.55 is used in this case. Specifically, the reaction for 5 h at 120° C. of 10 g PEEC (MW~9×105) in 50 g DMA and 5 g EG with 5.5 g NaN3 and 0.9 g NaOH will yield 9.0 g (90%) of GEC azido product. This copolymer containing about 70% GAP and 30% Ethylene Oxide has a MW of about 10,000, a Tg of about -55° C. and a functionality (f) of about 3.5.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][C:22]([Br:28])=[CH:23][CH:24]=3)[CH2:19]2)[CH2:15][CH2:16][CH3:17])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Br:28][C:22]1[CH:21]=[C:20]2[C:25]([CH2:26][CH2:27][CH:18]([N:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH2:15][CH2:16][CH3:17])[CH2:19]2)=[CH:24][CH:23]=1
Reactant: CCCN(C1CCN(C(=O)OC(C)(C)C)CC1)C1CCc2ccc(Br)cc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(C1CCNCC1)C1CCc2ccc(Br)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a solution of 4-[(7-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidine-1-carboxylic acid tert-butyl ester (347 g, 0.77 mmol) in methylene chloride (30 mL) under a nitrogen atmosphere was added trifluoroacetic acid (10 mL). The reaction was stirred at room temperature for 30 min., and concentrated in vacuo. The residue was partitioned between EtOAc (50 mL) and 10% aq. KOH (50 mL). The organic layer was separated, dried over MgSO4, filtered, and concentrated to afford (7-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidin-4-yl-propyl-amine (203 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([NH:12][C@H:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1)=[N:9][C:8]([C:25]([NH:27][NH2:28])=[NH:26])=[CH:7]2.C1N=CN([C:34](N2C=NC=C2)=[O:35])C=1>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([NH:12][C@H:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:14]1)=[N:9][C:8]([C:25]1[NH:26][C:34](=[O:35])[NH:28][N:27]=1)=[CH:7]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(C(=N)NN)cc3cccc(Cl)c23)C1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3n[nH]c(=O)[nH]3)cc3cccc(Cl)c23)C1
Yield: 35.9 %

Procedure:
To a mixture of (S)-tert-butyl 3-((8-chloro-3-(hydrazinyl(imino)methyl)isoquinolin-1-yl)amino)pyrrolidine-1-carboxylate (450 mg, 1.1 mmol) in dioxane (10 mL) was added CDI (360 mg, 2.2 mmol). The resulting mixture was heated to reflux for 2 hours and was subsequently concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound (170 mg, 45%). ESI-MS m/z [M+H]+ 431.1.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[C:14](=O)[CH2:15]Br)C.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH2:30])=[O:29])=[CH:23][CH:22]=1>>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:3])=[O:18])=[C:8]([C:14]2[N:30]=[C:28]([CH2:27][C:24]3[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)[O:29][CH:15]=2)[CH:9]=1
Reactant: CCOC(=O)COc1ccc(Br)cc1C(=O)CBr
Reactant: COc1ccc(CC(N)=O)cc1
Product: COc1ccc(Cc2nc(-c3cc(Br)ccc3OCC(=O)O)co2)cc1

Procedure:
Title compound was prepared from [4-bromo-2-(2-bromoacetyl)phenoxy]acetic acid ethyl ester and 2-(4-methoxyphenyl)acetamide according to GP5 and GP3: LC/MS (an10p8) Rt 2.40 min, m/z 418 [M+H]+; 1H NMR (CDCl3): δ 3.72 (s, 3H), 4.14 (s, 1H), 4.85 (s, 1H), 6.92 (m, 2H), 7.02 (d, 1H), 7.2 (d, 1H), 7.23 (d, 1H), 7.44 (d, 1H), 8.05 (s, 1H), 8.67 (s, 1H), 13.2 (br s, 1H).
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][C:7]([N:9]1[CH2:16][C:15](=[O:17])[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=[O:3])[CH3:2].[N+](=[CH2:20])=[N-]>CCOCC>[C:1]([S:4][CH2:5][CH2:6][C:7]([N:9]1[CH2:16][C:15](=[O:17])[CH2:14][C@H:10]1[C:11]([O:13][CH3:20])=[O:12])=[O:8])(=[O:3])[CH3:2]
Reactant: C=[N+]=[N-]
Reactant: CC(=O)SCCC(=O)N1CC(=O)C[C@H]1C(=O)O
Solvent: CCOCC
Product: COC(=O)[C@@H]1CC(=O)CN1C(=O)CCSC(C)=O
Reaction time: 2 h

Procedure:
A solution of the product of Example 1 in ether is treated with a slight excess of diazomethane. After standing at room temperature for two hours, the solvent is evaporated to give 1-[3-(acetylthio)-1-oxopropyl]-4-oxo-L-proline, methyl ester.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:5][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:8][C:9]=2[N:10]=1.[C:18](Cl)(=[O:20])[CH3:19].O>N1C=CC=CC=1>[C:18]([NH:1][C:2]1[S:3][C:4]2[CH2:5][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:8][C:9]=2[N:10]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2nc(N)sc2C1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2c(s1)CN(C(=O)OC(C)(C)C)CC2
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
As shown in step 10-ii of Scheme 10, to Compound 1033 (10.0 g) in pyridine (80 mL) was added acetyl chloride (4.2 mL). After stirring at 50° C. for 30 min, water (200 mL) was added. The resulting solid was collected by filtration and washed with water (2×) gave tert-butyl 2-acetamido-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (Compound 1034, 10.873 g).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C[O-].[Na+].[C:9]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:14]=[CH:13][C:12]([C:15]([OH:27])([CH2:25]Cl)[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])=[CH:11][CH:10]=1>CO.CN(C)C=O>[C:9]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:10]=[CH:11][C:12]([C:15]([OH:27])([CH2:25][N:4]2[CH:3]=[N:2][N:1]=[CH:5]2)[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])=[CH:13][CH:14]=1
Reactant: c1nc[nH]n1
Reactant: OC(CCl)(Cc1ccc(Cl)cc1Cl)c1ccc(-c2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: OC(Cc1ccc(Cl)cc1Cl)(Cn1cnnc1)c1ccc(-c2ccccc2)cc1
Temperature: 70 °C
Yield: 10.4 %

Procedure:
7.6 g (0.11 mol) of 1,2,4-triazole are added to a solution of 3.5 g (0.065 mol) of a sodium methylate in 18 ml of methyl alcohol; a solution of 19.5 g (0.05 mol) of 2-(4-biphenylyl)-3-chloro-1-(2,4-dichlorophenyl)-propan-2-ol in 38 ml of dimethylformamide is then added dropwise and the mixture is heated to 70° C. for 90 minutes. The solvent is removed in vacuo in a rotary evaporator and the residue is stirred with water. The resulting crystals are washed with diethyl ether and recrystallised from acetonitrile. 2.2 g of 2-(4-biphenylyl)-1-(2,4-dichlorophenyl)-3-(1,3,4-triazol-1-yl)-propan-2-ol of melting point 260° C. are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][C@:11]([CH:17]([CH3:19])[CH3:18])([C:14]([OH:16])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20]1([C:26]2([OH:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]1[CH2:13][CH2:12][C@@:11]([C:14]([N:29]2[CH2:30][CH2:31][C:26]([OH:32])([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:27][CH2:28]2)=[O:16])([CH:17]([CH3:19])[CH3:18])[CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: OC1(c2ccccc2)CCNCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@]1(C(=O)N2CCC(O)(c3ccccc3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1S,3R)-3-[(tert-butoxycarbonyl)amino]-1-isopropylcyclopentane-carboxylic acid (200 mg, 0.7 mmol), 4-phenylpiperidin-4-ol (140 mg, 0.81 mmol), and triethylamine (0.15 g, 1.5 mmol) in methylene chloride (4 mL) was added (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (0.42 g, 0.81 mmol). After being stirred overnight at room temperature, the reaction was quenched by addition of a saturated NaHCO3 solution. The resulting solution was extracted with methylene chloride three times. The combined extracts were dried (MgSO4), filtered, and concentrated. The crude was carried on to the next step without purification. MS calculated for C25H38N2O4: (M+H) 431; found 431.2.
Reaction SMILES: [I-].[CH:2]1([CH2:7][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:37]([O:39][C:40](=[O:52])[C:41]([C:43]1[CH:48]=[CH:47][C:46]([S:49][CH3:50])=[C:45]([Cl:51])[CH:44]=1)=O)[CH3:38]>O1CCCC1.O>[CH2:37]([O:39][C:40](=[O:52])[C:41]([C:43]1[CH:48]=[CH:47][C:46]([S:49][CH3:50])=[C:45]([Cl:51])[CH:44]=1)=[CH:7][CH:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1)[CH3:38]
Reactant: c1ccc([P+](CC2CCCC2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)C(=O)c1ccc(SC)c(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(=CC1CCCC1)c1ccc(SC)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 60 %

Procedure:
A solution of cylcopentylmethyl triphenylphosphonium iodide (prepared in Example 33, 725 mg, 1.53 mmol) in tetrahydrofuran (10 mL) cooled to 0° C. was treated with a 1.0M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (2.14 mL, 2.14 mmol). The reaction was stirred at 0° C. for 45 min. At this time, the reaction was treated with a solution of (3-chloro-4-methylsulfanyl-phenyl)-oxo-acetic acid ethyl ester (355 mg, 1.37 mmol) in tetrahydrofuran (5 mL). The reaction was then warmed to 25° C. and stirred at 25° C. for 20 h. The reaction was then diluted with water (50 mL) and extracted with diethyl ether (3×25 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 80/20 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-acrylic acid ethyl ester (267 mg, 60%, 2:1 mixture of E:Z isomers) as a yellow oil and taken on without characterization.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:14]2[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=2)[N:3]=1.[NH2:20][C@H:21]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:22]([NH2:24])=[O:23].O>CC(N(C)C)=O>[NH2:24][C:22](=[O:23])[C@H:21]([NH:20][C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:14]2[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=2)[N:3]=1)[CH2:25][CH:26]([CH3:28])[CH3:27]
Reactant: COC(=O)c1c(C#N)cc(Cl)nc1-c1cnn(C)c1
Reactant: CC(C)C[C@@H](N)C(N)=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1c(C#N)cc(N[C@H](CC(C)C)C(N)=O)nc1-c1cnn(C)c1
Temperature: 150 °C
Reaction time: 12 h
Yield: 10.5 %

Procedure:
A mixture of methyl 6-chloro-4-cyano-2-(1-methyl-1H-pyrazol-4-yl)nicotinate (82.9 mg, 0.300 mmol) and (R)-2-amino-4-methylpentanamide (39.0 mg, 0.300 mmol) in DMA (2 mL) was stirred at 150° C. for 12 h. Water was subsequently added and the mixture was extracted with EtOAc. The organic layers were washed with saturated aq NaHCO3, water, and brine, were dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, EtOAc) to give the title compound as a yellow oil (11.7 mg, 11%).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13](=[O:16])[NH:12][CH:11]=2)=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[N:3]=1.[C:24](=O)([O-])[O-].[K+].[K+].IC>CS(C)=O>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13](=[O:16])[N:12]([CH3:24])[CH:11]=2)=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cn1c(N)nc(-c2cccc(F)c2)c(-c2ccc(=O)[nH]c2)c1=O
Agent: [K+]
Solvent: CS(C)=O
Solvent: CI
Product: Cn1cc(-c2c(-c3cccc(F)c3)nc(N)n(C)c2=O)ccc1=O
Temperature: 50 °C
Reaction time: 16 h
Yield: 20.4 %

Procedure:
To a solution of 2-amino-6-(3-fluorophenyl)-3-methyl-5-(6-oxo-1,6-dihydro-3-pyridinyl)-3,4-dihydro-4-pyrimidinone (20 mg, 0.06 mmol) in dimethyl sulfoxide (1 mL) were added potassium carbonate (20 mg, 0.12 mmol) and iodomethane (20 μL, 0.30 mmol), followed by stirring at 50° C. for 16 hours. After filtering off the insoluble matters, the filtrate was purified by HPLC, to give the title compound (4 mg).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]([CH3:23])[CH3:22])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:35]([O:37][C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][CH:43]=1)[CH3:36].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.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>[CH2:35]([O:37][C:38]1[CH:43]=[C:42]([C:19]([C:11]2[N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)=[CH:20][CH:21]([CH3:22])[CH3:23])[CH:41]=[CH:40][CH:39]=1)[CH3:36]
Reactant: CCOc1cccc(B(O)O)c1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC(C)C)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOc1cccc(C(=CC(C)C)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)c1
Yield: 81.6 %

Procedure:
A suspension of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methyl-but-1-enyl ester (prepared as in Example 130, 3.0 g, 6.04 mmol), 3-ethoxy-phenylboronic acid (2.51 g, 15.1 mmol), bis(triphenylphosphine)palladium(II) dichloride (420 mg, 0.60 mmol) in 1,4-dioxane (30 mL) and an aqueous sodium carbonate solution (2N, 15.4 mL) was heated in a microwave at 100° C. for 2 h under nitrogen. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with a saturated aqueous sodium bicarbonate solution (2×40 mL). The organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (40 g, 11% ethyl acetate/petroleum ether) afforded 2-(1-(3-ethoxy-phenyl)-3-methyl-but-1-enyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (2.2 g, 81%) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ ppm 8.49 (d, 1H, J=4.5 Hz), 7.87 (d, 1H, J=8.4 Hz), 7.67 (d, 2H, J=4.8 Hz), 7.41 (t, 1H, J=7.5 Hz), 7.27-7.10 (m, 4H), 6.79 ((t, 2H, J=6.3 Hz), 6.52 (s, 1H), 6.14 (d, 1H, J=6.6 Hz), 3.94-3.85 (m, 2H), 2.71-2.64 (m, 1H), 1.33 (t, 3H, J=7.2 Hz), 1.14 (t, 6H, J=7.5 Hz).
Reaction SMILES: [OH:1][C@@H:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3]#[C:4][CH:5]=[O:6].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.S(=O)(=O)(O)O>O.CCOCC>[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:1][C@@H:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3]#[C:4][CH:5]=[O:6]
Reactant: C1=COCCC1
Reactant: CCCCC[C@H](O)C#CC=O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: O
Product: CCCCC[C@@H](C#CC=O)OC1CCCCO1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of (4S)-4-hydroxy-2-nonynal (41.6 g., 0.27 mole) and dihydropyran (33.6 g., 0.4 mole) is cooled to 5° by means of an ice bath and is treated with 0.2 mole of concentrated sulfuric acid. This is allowed to warm to room temperature and stand 17 hours. It is then diluted with water. The oily product is taken up in ether, washed with sodium bicarbonate solution and water and dried over sodium sulfate. Distillation affords (4S)-4-(2-tetrahydropyranyloxy)-2-nonynal as a colorless oil.
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][C:8](=[O:29])[CH:9]([N:14]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:10][CH:11]([CH3:13])[CH3:12])(=[O:6])[O:4][CH3:5].C1COCC1.[BH4-].[Na+].Cl>CO>[CH3:1][O:2][P:3]([CH2:7][CH:8]([OH:29])[CH:9]([N:14]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:10][CH:11]([CH3:13])[CH3:12])(=[O:6])[O:4][CH3:5]
Reactant: COP(=O)(CC(=O)C(CC(C)C)N(Cc1ccccc1)Cc1ccccc1)OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COP(=O)(CC(O)C(CC(C)C)N(Cc1ccccc1)Cc1ccccc1)OC
Temperature: -2.5 °C
Reaction time: 4 h
Yield: 64.9 %

Procedure:
Reaction 3: A mixture of the crude oil (3-dibenzylamino-5-methyl-2-oxohexyl)-phosphonic acid dimethyl ester, i.e., compound 3, obtained in reaction 2, was dissolved in about 10% methanol and about 90% THF (v/v) and cooled at −10° C. NaBH4 (68.58 mmol) was added to the mixture in small portions with vigorous stirring. The mixture was stirred at temperature of −10 to 5° C. for 4 h and HCl 5% (v/v) was added. The reaction mixture was concentrated under reduced pressure. The residual oil was dissolved in ethyl acetate, and washed with 30 ml portions of water. The organic phase was dried over anhydrous Na2SO4 and filtered. The solvent was evaporated off to leave (3-dibenzylamino-2-hydroxy-5-methyl-hexyl)-phosphonic acid dimethyl ester as a crude oil. 31P NMR (at 200 MHz, CDCl3) indicated an 80:20 ratio of 2R,3S (δ 34.53) to 2S,3S (δ 35.15) isomers. The diastereomeric mixture was purified by flash chromatography on silica gel using hexane/ethyl acetate as the eluent to afford compound 2R,3S-4 (20.753 g; 64.9% yield; 31P NMR at 200 MHz, CDCl3; δ 34.61).