Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:19])[C:6]=1[C:7]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:8]=1[O:16][CH2:17][CH3:18].O.O.Cl[Sn]Cl.CCO>>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:19])[C:6]=1[C:7]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:8]=1[O:16][CH2:17][CH3:18]
Reactant: CCOc1ccc([N+](=O)[O-])cc1-c1c(Br)cnn1C
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: CCOc1ccc(N)cc1-c1c(Br)cnn1C

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-ethoxy-phenylamine was prepared in a similar manner as described in Example 1.1 using 4-bromo-5-(2-ethoxy-5-nitro-phenyl)-1-methyl-1H-pyrazole, SnCl2.2H2O in EtOH [0.225 g, 0.76 mmol, 81% for three steps from 2-(2-methyl-2H-pyrazol-3-yl)-4-nitro-phenol]. LCMS m/z (%)=296 (M+H79Br, 100), 298 (M+H81Br, 98). 1H NMR (400 MHz, CDCl3) δ: 7.52 (s, 1H), 6.86 (d, J=8.7 Hz, 1H), 6.77 (dd, J=2.2, 8.5 Hz, 1H), 6.62 (d, J=2.3 Hz, 1H), 3.82-4.00 (m, 2H), 3.73 (s, 3H), 3.24-3.58 (broad s, 2H), 1.24 (t, J=6.8 Hz, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][CH2:30][O:31][C:24]=3[CH:23]=2)[C:10]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][CH2:30][O:31][C:24]=4[CH:23]=3)[C:10]3[C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=4[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: Clc1nc(NCc2ccc3c(c2)OCCO3)c2c3c(sc2n1)CCCC3
Product: c1cnn(-c2nc(NCc3ccc4c(c3)OCCO4)c3c4c(sc3n2)CCCC4)c1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-5,6,7,8-tetrahydro-4-(3,4-ethylendioxybenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5,6,7,8-tetrahydro-4-(3,4-ethylendioxybenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Br[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25]>C(OCC)(=O)C>[CH2:23]([O:12][C:11](=[O:13])[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH3:14])[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25]
Reactant: O=C(CBr)c1ccccc1
Reactant: CN(CCC(=O)O)C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN(CCC(=O)OCC(=O)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 88.6 %

Procedure:
To a mixture of N-t-butoxycarbonyl-N-methyl-β-alanine (6.097 g) and triethylamine (4.18 ml) in ethyl acetate (60 ml) was added 2-bromoacetophenone (5.972 g) portionwise at 0°-5° C. After being stirred over night at ambient temperature, the solvent was evaporated and the resulting residue was dissolved in ethyl acetate (200 ml). The solution was washed with 0.5N hydrochloric acid (200 ml), water (200 ml) aqueous sodium bicarbonate (200 ml), water (200 ml) and brine (200 ml) successively, and dried over magnesium sulfate. Evaporation of the solvent gave N-t-butoxycarbonyl-N-methyl-β-alanine phenacyl ester (8.54 g) as an oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([CH2:16][NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])(=[O:20])=[O:19])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[CH2:31]([N:33]([CH2:38][CH3:39])[C:34](=[O:37])[CH2:35]Cl)[CH3:32].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH2:31]([N:33]([CH2:38][CH3:39])[C:34](=[O:37])[CH2:35][N:17]([CH2:16][C:14]1[S:15][C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=2)=[CH:12][CH:13]=1)[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([F:30])([F:28])[F:29])(=[O:20])=[O:19])[CH3:32]
Reactant: CS(=O)(=O)c1cccc(-c2ccc(CNS(=O)(=O)c3ccccc3C(F)(F)F)s2)c1
Reactant: CCN(CC)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CCN(CC)C(=O)CN(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)S(=O)(=O)c1ccccc1C(F)(F)F

Procedure:
In analogy to example 10, step 3, N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-trifluoromethyl-benzenesulfonamide (example 27, step 1) was reacted with N,N-diethylchloro acetamide and cesium carbonate in N,N-dimethylacetamide for 1 day at r.t., for 18 h at 50° C. and for 6 h at 100° C. to give N,N-diethyl-2-[[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-(2-trifluoromethyl-benzenesulfonyl)-amino]-acetamide as a light yellow oil. MS: 588.8 ([M+NH4]+)
Reaction SMILES: [I-].[CH:2](P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:4])[CH3:3].C([Li])CCC.[CH3:29][C:30]1[CH:35]=[C:34]([C:36]#[C:37][CH:38]=O)[N:33]=[C:32]([O:40][C:41]2[N:45]([CH3:46])[N:44]=[C:43]([C:47]([F:50])([F:49])[F:48])[CH:42]=2)[CH:31]=1>C1COCC1>[CH3:29][C:30]1[CH:35]=[C:34]([C:36]#[C:37][CH:38]=[C:2]([CH3:4])[CH3:3])[N:33]=[C:32]([O:40][C:41]2[N:45]([CH3:46])[N:44]=[C:43]([C:47]([F:50])([F:49])[F:48])[CH:42]=2)[CH:31]=1
Reactant: CC(C)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1cc(C#CC=O)nc(Oc2cc(C(F)(F)F)nn2C)c1
Agent: [I-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)=CC#Cc1cc(C)cc(Oc2cc(C(F)(F)F)nn2C)n1
Temperature: -70 °C
Reaction time: 0.75 h
Yield: 44.7 %

Procedure:
A mixture of isopropyltriphenylphosphine iodide (0.43 g, 1 mmol) in a dry THF (15 ml) is cooled to −70° C. under an inert gas atmosphere. A 2.5 M solution of butyl lithium (0.44 ml) is added and after stirring at −70° C. for 45 min the mixture is heated at 0° C. for 1 h. Then the mixture is cooled to −70° C. and 4-methyl-6-for-mylethynyl-2-(1-methyl-3-trifluoromethylpyrazol-5-yloxy)pyridine 0.3 g, 1 mmol) is added. After stirring for 30 min at −70° C. the reaction mixture is stirred at ambient temperature for 2 days. The mixture is quenched with water, evaporated and to the water containing residue is added ethyl acetate. The mixture is washed with diluted hydrochloric acid and with water. After drying and evaporation, the product (0.15 g) is obtained by flash chromatogy as nearly colorless crystals of mp 85° C.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1)#[N:2].[Cl:11][C:12]1[CH:13]=[C:14]([CH2:34][CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:15]=[C:16]2[C:20]=1[C:19](=[O:21])[N:18]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1)[CH2:17]2.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[Cl:11][C:12]1[CH:13]=[C:14]([CH2:34][CH:35]2[CH2:40][CH2:39][N:38]([CH2:7][C:6]3[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[CH2:37][CH2:36]2)[CH:15]=[C:16]2[C:20]=1[C:19](=[O:21])[N:18]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:32])([F:33])[F:31])=[CH:25][CH:24]=1)[CH2:17]2
Reactant: O=C1c2c(Cl)cc(CC3CCNCC3)cc2CN1Cc1ccc(OC(F)(F)F)cc1
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: N#Cc1ccc(CN2CCC(Cc3cc(Cl)c4c(c3)CN(Cc3ccc(OC(F)(F)F)cc3)C4=O)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 117.3 %

Procedure:
To a mixture of 4-Cyano-benzyl bromide (12 mg, 0.06 mmol), 7-chloro-5-piperidin-4-ylmethyl-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (30.0 mg, 0.06 mmol) and potassium carbonate (42 mg, 0.3 mmol) was added acetonitrile (3.0 mL). The mixture was allowed to stir at room temperature overnight. Water (2.0 mL) was added and the product was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated. Column chromatography provided the title compound as a brown oil (39.0 mg, 99%). 1H NMR (300 MHz, CDCl3): δ 7.60 (d, 2H), 7.27-7.59 (m, 4H), 7.17-7.20 (m, 3H), 7.05 (s, 1H), 4.77 (s, 2H), 4.22 (s, 2H), 3.53 (s, 2H), 2.80-2.84 (m, 2H), 2.58-2.60 (m, 2H), 1.91 (t, 21, 1.56-1.62 (m, 3H), 1.27-1.34 (m, 2H).
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[CH:4]=[N:3][CH:2]=1.[I:10]N1C(=O)CCC1=O.C(#N)C>O>[I:10][C:9]1[C:5]2[CH:4]=[N:3][CH:2]=[N:1][C:6]=2[NH:7][CH:8]=1
Reactant: c1ncc2cc[nH]c2n1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Solvent: O
Product: Ic1c[nH]c2ncncc12
Reaction time: 3 h
Yield: 85 %

Procedure:
In a 250 mL round-bottomed flask, 7H-pyrrolo[2,3-d]pyrimidine (4.34 g, 36.4 mmol, Eq: 1.00) and N-iodosuccinimide (8.61 g, 38.3 mmol, Eq: 1.05) were combined with acetonitrile (60 ml) to give a light brown suspension. The reaction mixture was stirred for 3 h. The reaction mixture was poured into 100 mL H2O and extracted with EtOAc (3×50 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was triturated with diethyl ether (2×25 mL) to give 5-iodo-7H-pyrrolo[2,3-d]pyrimidine (7.58 g, 85%) as orange solid.
Reaction SMILES: CO[CH:3]([Cl:12])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].O.[BH4-].[Na+].[O:16]1CCOC[CH2:17]1>>[Cl:12][CH2:3][CH:4]([OH:5])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[O:16][CH3:17]
Reactant: C1COCCO1
Reactant: COC(Cl)C(=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: COc1ccccc1C(O)CCl

Procedure:
1.7 g of 2-methoxy-α-chloroacetophenone are dissolved in 30 ml of dioxane, and 12 ml of water are added thereto. 600 mg of sodium borohydride are added gradually to the solution at 10° to 20° C. Then, the mixture is treated in the same manner as described in Example 2-(1). 1.4 g of α-chloromethyl-2-methoxybenzylalcohol are obtained as a crude oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=1)=[CH:12][CH:11]=[C:10]([Cl:23])[CH:9]=2)=[O:5])[CH3:2].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:8]2[C:13]([C:14]=1[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=1)=[CH:12][CH:11]=[C:10]([Cl:23])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2cc(Cl)ccc2c1Sc1cccc(Br)c1
Reactant: BrCc1ccccc1
Product: CCOC(=O)c1c(Sc2cccc(Br)c2)c2ccc(Cl)cc2n1Cc1ccccc1

Procedure:
Prepared according to the procedure described in Example 4, Step 1, using the following starting materials: 3-(3-bromo-phenylsulfanyl)-6-chloro-1H-indole-2-carboxylic acid ethyl ester and benzyl bromide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[CH:17][S:18][C:11]=12)[NH2:5].C(N(C(C)C)CC)(C)C.[CH2:28]([O:35][CH2:36][C:37](Cl)=[O:38])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[CH2:28]([O:35][CH2:36][C:37]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[CH:16]=[CH:17][S:18][C:11]=23)=[C:2]([F:1])[CH:3]=1)=[O:38])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(COCc1ccccc1)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Reaction time: 1 h

Procedure:
To a stirred solution of 3-fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)aniline (Example 1-B; 67 mg, 0.258 mmol) in 1 mL CH2Cl2 at room temperature under nitrogen was added diisopropylethylamine (68 μL, 0.387 mmol) followed by 2-(benzyloxy)acetyl chloride (41 μL, 0.258 mmol). After 1 hour, the reaction was diluted to 30 mL with CH2Cl2 and washed 2×30 mL with 10% citric acid and 2×30 mL with saturated NaHCO3. The organics were isolated, dried (MgSO4), filtered and concentrated. The crude product was loaded onto a Biotage 12S column with 2/3 EtOAc/hexanes and eluted. The fractions containing the product were pooled and concentrated to a yellow oil (68 mg, 64%). 1H NMR (400 MHz, CDCl3) δ 8.51 (d, 1H), 8.44 (br s, 1H), 7.74 (d, 1H), 7.57 (d, 1H), 7.39 (m, 5H), 7.24 (m, 3H), 6.50 (d, 1H), 4.68 (s, 2H), 4.13 (s, 2H). LRMS (ESI pos) m/e 409.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[CH3:17][O:18][C:19]1[C:29]([O:30][CH3:31])=[C:28]([O:32][CH3:33])[CH:27]=[CH:26][C:20]=1[CH:21]=[CH:22][C:23](O)=O>>[CH2:13]([N:4]1[C:3](=[O:16])[C:2]2[NH:1][C:23](/[CH:22]=[CH:21]/[C:20]3[CH:26]=[CH:27][C:28]([O:32][CH3:33])=[C:29]([O:30][CH3:31])[C:19]=3[O:18][CH3:17])=[N:8][C:7]=2[N:6]([CH2:9][CH2:10][CH3:11])[C:5]1=[O:12])[CH2:14][CH3:15]
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: COc1ccc(C=CC(=O)O)c(OC)c1OC
Product: CCCn1c(=O)c2[nH]c(/C=C/c3ccc(OC)c(OC)c3OC)nc2n(CCC)c1=O
Yield: 48.5 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 2.00 g (8.85 mmol) of 5,6-diamino-1,3-dipropyluracil and 2.32 g (9.73 mmol) of 2,3,4-trimethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from 2-propanol/water to give 1.84 g (yield 49%) of Compound 21 as pale yellow needles.
Reaction SMILES: N1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:5]=2[N:4]=[C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])N=1.C(O)(=O)[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)N.C(ON=O)CC(C)C>O1CCOCC1.C(OCC)C>[CH2:7]1[C:6]2[C:5](=[N:4][C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:17]3[C:18]=2[CH:20]=[CH:21][CH:22]=[CH:23]3)[CH2:10][CH2:9][CH2:8]1
Reactant: Nc1ccccc1C(=O)O
Reactant: CCOC(=O)c1nnc2c(n1)CCCC2
Agent: CC(C)CCON=O
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCOC(=O)c1nc2c(c3ccccc13)CCCC2

Procedure:
Analogously to the method described by Gonsalves et al. (Tetrahedron 1992, 48, 6821) a solution of 3.90 g of ethyl 5,6,7,8-tetrahydro-benzo[1,2,4]triazin-3-carboxylate (Sagi et al., Heterocycles 1989, 29, 2253) in 20 ml dioxane is refluxed. Then 8.22 g of anthranilic acid and 7.02 g of isoamylnitrite, in each case dissolved in 20 ml dioxane, are simultaneously added dropwise within 25 minutes by means of two dropping funnels. The reaction mixture is refluxed for a further 30 minutes. For working up the cooled deep-brown reaction solution is diluted with 150 ml diethyl ether, washed with 100 ml of 2 N sodium hydroxide solution and with water, dried over magnesium sulphate and evaporated down. The brown, oily flask residue is chromatographed through a silica gel column with ethyl acetate/petroleum ether (20:80 to 50:50) as eluant. The product obtained is still somewhat contaminated, but is reacted further without any more purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15](Br)[CH:16]=[C:11]2[C:10]([C:18](=[O:34])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:20]=2[F:33])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:41]1(B(O)O)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>O1CCCC1.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:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:16]=[C:11]2[C:10]([C:18](=[O:34])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:20]=2[F:33])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Oc1cccc(C(=O)c2cn(C(=O)OC(C)(C)C)c3ncc(Br)cc23)c1F
Reactant: OB(O)c1ccccc1
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: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Oc1cccc(C(=O)c2cn(C(=O)OC(C)(C)C)c3ncc(-c4ccccc4)cc23)c1F
Temperature: 65 °C
Reaction time: 3 h

Procedure:
To 5-bromo-3-(3-tert-butoxycarbonyloxy-2-fluoro-benzoyl)-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (32, 55.0 mg, 0.10 mmol) in tetrahydrofuran (10 mL) were added 1.0 M potassium carbonate in water (3.5 mL), phenylboronic acid (18.8 mg, 0.15 mmol) and tetrakis(triphenylphosphine)palladium(0) (3.9 mg, 0.0034 mmol) under an atmosphere of nitrogen. The reaction was stirred at 65° C. for 3 hours, and then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to give crude compound 33 that was used in the next step.
Reaction SMILES: [CH:1]1([C:4]2[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.Br[C:13]1C=CC(C2CCCC2)=C[CH:14]=1.BrC1C=CC(C2CCCC=2)=CC=1.[Li]CCCC.CCCCCC.CN(C=O)C>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([CH:8]=[O:9])=[CH:10][CH:11]=2)[CH2:3][CH2:2][CH2:14][CH2:13]1
Reactant: O=Cc1ccc(C2CC2)cc1
Reactant: Brc1ccc(C2CCCC2)cc1
Agent: Brc1ccc(C2=CCCC2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: O=Cc1ccc(C2CCCC2)cc1

Procedure:
The title compound was synthesized in analogy to 4-cyclopropyl benzaldehyde (described in example S53) using 720 mg of a mixture of 1-bromo-4-cyclopentyl-benzene and 1-bromo-4-cyclopent-1-enyl-benzene (˜3.2 mmol), 2.2 ml of a 1.6 molar solution of n-BuLi in hexane (3.52 mmol) and 492 μl of DMF (6.40 mmol). 4-Cyclopentyl-benzaldehyde was isolated by flash column chromatography (5:95 EtOAc/c-hexane) as a yellow liquid (165 mg, 30%). 1H NMR (CDCl3, 300 MHz): δ 1.53-1.91 (m, 6H), 2.11 (m, 2H), 3.07 (quint, J=8.5 Hz, 1H), 7.40 (d, J=8 Hz, 2H), 7.80 (d, J=8 Hz, 2H), 9.97 (s, 1H).
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]/[C:5]([N:7]1[CH2:28][CH2:27][C:10]2[C:11]3[C:16]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=4)=[N:15][CH:14]=[N:13][C:12]=3[S:26][C:9]=2[CH2:8]1)=[O:6].[CH3:29][N:30]1[CH2:34][CH2:33][CH:32]2[CH2:35][NH:36][CH2:37][CH:31]12>CN(C=O)C>[Cl:25][C:20]1[CH:19]=[C:18]([NH:17][C:16]2[C:11]3[C:10]4[CH2:27][CH2:28][N:7]([C:5](=[O:6])/[CH:4]=[CH:3]/[CH2:2][N:36]5[CH2:35][CH:32]6[CH:31]([N:30]([CH3:29])[CH2:34][CH2:33]6)[CH2:37]5)[CH2:8][C:9]=4[S:26][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:23]=[CH:22][C:21]=1[Cl:24]
Reactant: CN1CCC2CNCC21
Reactant: O=C(/C=C/CCl)N1CCc2c(sc3ncnc(Nc4ccc(Cl)c(Cl)c4)c23)C1
Solvent: CN(C)C=O
Product: CN1CCC2CN(C/C=C/C(=O)N3CCc4c(sc5ncnc(Nc6ccc(Cl)c(Cl)c6)c45)C3)CC21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a suspension of Example 59A (80 mg, 0.16 mmol) in DMF (1 mL) was added 1-methyloctahydropyrrolo[3,4-b]pyrrole (41 mg, 0.32 mmol), and the mixture was stirred at rt for 20 h. After purification by preparative HPLC, the title compound was crystallized from dichloromethane/petroleum ether to yield 12 mg (14%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[C:10]([C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11]>>[C:10]([C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:9][C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: COc1ccc(N)cn1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cn1

Procedure:
prepared by reaction of 6-methoxy-pyridin-3-ylamine with 4-tert-butyl-benzenesulfonyl chloride
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]1[C@@H:13]([CH2:14][OH:15])[NH:12][C:10](=[O:11])[CH2:9]1.C(=O)C1C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[C:1]1([C@@H:7]2[N:12]3[C:10](=[O:11])[CH2:9][CH2:8][C@H:13]3[CH2:14][O:15]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CC[C@@H](CO)N1
Reactant: Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: O=Cc1ccccc1
Product: O=C1CC[C@H]2CO[C@H](c3ccccc3)N12
Reaction time: 0.25 h
Yield: 78.6 %

Procedure:
Toluene (36 L, 6 vol), L-pyroglutaminol (6.0 Kg, 1.0 eq), benzaldehyde (8.3 Kg, 1.5 eq) and p-toluenesulfonic acid (134 g, 1.5% mol) were charged to a reactor. The resulting mixture was heated to reflux and the water formed during the reaction was separated out by using Dean-Stark condenser. The completion of the reaction was monitored by HPLC until L-pyroglutaminol was ≦0.1%. It was cooled to 15˜20° C., added aqueous 5% NaHCO3 (3 vol), agitated for 15 min and separated the layers. 20% aqueous NaHSO3 (6 vol) was charged to the organic phase, upon stirring for 30 min, filtered through Celite and washed the cake with toluene. Separated the organic phase (this step could be skipped if there was no solid), and filtered the organic phase through a thin pad of silica gel (1.0 wt/wt) and washed the silica gel with toluene three times. Combined the organic phase and monitored by HPLC. If impurity (RRT=1.5)>1.5%, repeated the silica gel filtration procedures until the impurity (RRT=1.5)≦1.5%. Dried the filtrate with anhydrous Na2SO4 for at least 2 hrs, filtered and washed the cake with toluene for twice. Concentrated below 55° C. (bath temp) under vacuum to afford 8.30 kg (78.6% yield) of the title compound with 94.6% HPLC purity. ESI MS m/z (M+H)+ 204.11.
Reaction SMILES: [I:1]I.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][C:5]=1[I:1]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: CC(=O)c1ccc(N)c(I)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.7 %

Procedure:
Iodine (2.82 g; 11.10 mmol) was added to a stirred mixture of silver sulphate (3.46 g; 11.10 mmol) and 1-(4-aminophenyl)ethanone (1.50 g; 11.10 mmol) in ethanol (40 mL). The reaction mixture was then stirred at room temperature for 18 hours and filtered over celite. The volatiles were removed under reduced pressure and the residue was partitioned between ethyl acetate and a saturated aqueous solution of sodium thiosulfate. The organic layer was washed with brine, dried and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (eluent 2 to 40% ethyl acetate in heptane) to afford 0.514 g (18%) of the title compound as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@@H:4]([NH:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[NH2:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1.Cl[S:27]([C:30]1[C:38]2[C:34](=[N:35][S:36][N:37]=2)[CH:33]=[CH:32][CH:31]=1)(=[O:29])=[O:28].N1C=CC=CC=1.NCCN(CCN)CCN>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:25])[C@@H:4]([NH:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[NH:23][S:27]([C:30]1[C:38]2=[N:37][S:36][N:35]=[C:34]2[CH:33]=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(Cl)c(Cl)c1)NC(=O)c1ccc(I)cc1N
Reactant: O=S(=O)(Cl)c1cccc2nsnc12
Agent: NCCN(CCN)CCN
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@H](Cc1ccc(Cl)c(Cl)c1)NC(=O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.7 %

Procedure:
To a solution of (S)-2-(2-amino-4-iodo-benzoylamino)-3-(3,4-dichloro-phenyl)-propionic acid methyl ester (39 mg, 0.079 mmol) in DCM (1 mL) was added 4-chlorosulfonyl-2,1,3-benzothiadiazole (37 mg, 0.158 mmol) and pyridine (30 μL, 0.371 mmol). The mixture was shaken overnight at rt, then polymer bound tris(2-aminoethyl)amine resin was added. The resulting mixture was shaken for 2 h, and the resin was removed by filtration and rinsed with DCM. TBD methyl polystyrene resin was then added and the mixture was shaken for 2 h. The liquid was drained and the resin was washed with DCM (3×). A solution of 10% TFA in DCM (3 mL) was added to the resin and the mixture was shaken for 1.5 h. The resin was removed by filtration, washed with 10% TFA in DCM and the filtrate was concentrated to provide the desired product as a white solid (55 mg, 99%). 1H NMR (400 MHz, CDCl3): 11.10 (s, 1H), 8.36 (dd, J=7.0, 0.8, 1H), 8.24 (dd, J=8.8, 0.8, 1H), 8.02 (d, J=1.5, 1H), 7.75 (dd, J=8.8, 7.1, 1H), 7.37-7.32 (m, 2H), 7.16 (d, J=2.0, 1H), 6.96 (d, J=8.3, 1H), 6.92 (dd, J=8.2, 2.0, 1H), 6.67 (d, J=7.3, 1H), 4.96 (q, J=5.7, 1H), 3.83 (s, 3H), 3.20-3.12 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:17])([CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH3:9])[CH:5]=[CH:4][C:3]=1[OH:18].[CH3:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH2:21].Cl(O)(=O)(=O)=O>C(Cl)Cl>[C:20]([C:4]1[CH:5]=[C:6]([C:8]([CH3:17])([CH3:9])[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:7]=[C:2]([CH3:1])[C:3]=1[OH:18])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:19])[CH3:21]
Reactant: COC(=O)CCCC(C)(C)c1ccc(O)c(C)c1
Reactant: C=C(C)c1ccccc1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Product: COC(=O)CCCC(C)(C)c1cc(C)c(O)c(C(C)(C)c2ccccc2)c1

Procedure:
5.0 Parts of 2-methyl-4-(5-methoxycarbonyl-2-methyl-pent-2-yl)-phenol, 2.4 parts of α-methylstyrene, and 0.5 parts of 70% perchloric acid in 25 parts of methylene chloride were reacted and worked up as described in Example 61. Distillation gave methyl 5-(3-cumyl-4-hydroxy-5-methyl-phenyl)5-methyl-hexanoate, b0.7 210°-4° C. as an oil with the following percentage composition by weight.