Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][NH:6][C:7]1[N:8]([CH2:22][CH2:23][CH3:24])[C:9](=[O:21])[C:10]2[NH:11][C:12]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[N:13][C:14]=2[N:15]=1)C.C1COCC1.[OH-].[Na+].Cl>O.C(O)C>[CH:16]1([C:12]2[NH:11][C:10]3[C:9](=[O:21])[N:8]([CH2:22][CH2:23][CH3:24])[C:7]([NH:6][CH2:5][C:4]([OH:25])=[O:3])=[N:15][C:14]=3[N:13]=2)[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CCCn1c(NCC(=O)OCC)nc2nc(C3CCCC3)[nH]c2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CCCn1c(NCC(=O)O)nc2nc(C3CCCC3)[nH]c2c1=O
Temperature: 55 °C
Yield: 13 %

Procedure:
To a solution of (8-cyclopentyl-6-oxo-1-propyl-6,7-dihydro-1H-purin-2-ylamino)-acetic acid ethyl ester (0.05 g, 0.144 mmol) prepared in the previous step in a mixture of water (5 ml), THF (5 ml) and ethanol (5 ml) was added sodium hydroxide (0.017 g, 0.425 mmol) and the resulting reaction mixture was heated at 50-60° C. overnight. The solvent was evaporated under reduced pressure and the residue was dissolved in 2 ml of water. The solution obtained was neutralized with 1N HCl. The solid formed was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous sodium sulphate and concentrated under vacuum. The crude product was purified by crystallization with dichloromethane/ether/methanol mixture to give the product (0.006 g, 13%) as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:15])=O>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(F)cc1Br
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(F)cc1Br

Procedure:
A suspension of 2-bromo-4-fluorobenzoic acid (6.87 g, 31.37 mmol) in dichloromethane (70 mL) containing a few drops of dimethylformamide was treated dropwise under nitrogen with a 2M solution of oxalyl chloride in dichloromethane (1.16 equivalents). After gas evolution subsided, the reaction mixture was refluxed for an additional 25 minutes and then the solution was evaporated to dryness in vacuo. The crude acid chloride was used as such in the next step.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=2)=[CH:5][CH:4]=1.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CC(O)C>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:22][C:21]3[CH:24]=[CH:25][C:18]([F:17])=[CH:19][CH:20]=3)[CH:10]=2)=[CH:7][CH:8]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: NCc1cccc(-c2ccc(Cl)cc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: Fc1ccc(CNCc2cccc(-c3ccc(Cl)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
To a solution of (4′-chlorobiphenyl-3-yl)methanamine HCl salt (Chem-Impex International, Inc., 0.6 g, 2.36 mmol) in CH2Cl2 (6 mL) and 2-propanol (6.00 mL) was added 4-fluorobenzaldehyde (0.28 mL, 2.60 mmol). The resulting reaction mixture was stirred at rt for 1 h. and sodium triacetoxyborohydride (0.75 g, 3.54 mmol) was added under N2. After stirring at rt for 3 h, the reaction mixture was quenched with saturated aqueous NaHCO3, stirred for 10 minutes and concentrated in vacuo. The residue was diluted with ethyl acetate and saturated aqueous NaHCO3 solution. The organic layer was separated, washed with brine, dried over MgSO4, filtered and the filtrate solution was concentrated in vacuo. The residue was purified by flash silica gel chromatography eluting with 0-10% ethyl acetate in CH2Cl2 to afford the desired compound (0.63 g, 73%) as a colorless oil. 1H NMR (CDCl3) δ 7.62-7.41 (m, 6H), 7.37-7.32 (m, 3H), 7.09-7.01 (m, 3H), 3.92 (s, 2H), 3.83 (s, 2H). MS (ESI): 326.0 (M+H)+.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[N:10]1[CH2:14][CH2:13][N:12]([C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17](S(C3C=CC(C)=CC=3)(=O)=O)[CH:16]=2)[C:11]1=[O:34].CO>C(O)C.C(Cl)(Cl)Cl>[NH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]([N:12]2[CH2:13][CH2:14][N:10]([C:5]3[CH:6]=[N:7][CH:8]=[CH:9][C:4]=3[CH3:3])[C:11]2=[O:34])=[CH:16]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(N3CCN(c4cnccc4C)C3=O)c3ccccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1ccncc1N1CCN(c2c[nH]c3ccccc23)C1=O
Temperature: 90 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
LCMS purity: 92.68%, m/z=446.9 (M+1) 10% NaOH solution (10 mL) was added to a solution of 1-(4-methyl-pyridin-3-yl)-3-[1-(toluene-4-sulfonyl)-1H-indol-3-yl]-imidazolidin-2-one (110 mg, 0.0002 mol) in ethanol (10 mL) and the resulting mixture was stirred at 90° C. for 1 hour. The reaction was monitored by TLC (10% MeOH in CHCl3). The reaction mixture was partitioned between ethylacetate and ice water. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (2% MeOH in CHCl3) afforded 50 mg of the product (86.2% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:17][CH:18]([CH3:20])[CH3:19])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:29][C:30](Br)=[O:31].[NH2:33][C@H:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][CH2:35]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:17][CH:18]([CH3:20])[CH3:19])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:29][C:30]([NH:33][C@H:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][CH2:35]1)=[O:31]
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC(C)C)cc32)cc1OC
Reactant: O=C(Br)CBr
Reactant: N[C@@H]1CCc2ccccc21
Product: COc1ccc(CC2c3cc(OC(C)C)c(OC)cc3CCN2CC(=O)N[C@@H]2CCc3ccccc32)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with (1R)-1-amino-indane
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][O:10][C:9]2(O)[CH2:12][CH2:13][CH:14]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH2:15][CH:8]2[CH2:7]1)=O)C.C([O-])(=O)C.[NH4+:30]>CO>[OH:10][CH2:11][CH:6]1[CH2:7][C:8]2[CH2:15][CH:14]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH2:13][CH2:12][C:9]=2[NH:30][C:4]1=[O:3]
Reactant: [NH4+]
Reactant: CCOC(=O)C1COC2(O)CCC(Cc3ccc(OC)cc3)CC2C1
Agent: CC(=O)[O-]
Solvent: CO
Product: COc1ccc(CC2CCC3=C(C2)CC(CO)C(=O)N3)cc1

Procedure:
3,4,4a,5,6,7,8,8a-Octahydro-3-ethoxycarbonyl-8a-hydroxy-6-(4-methoxyphenyl)methyl-2H-benzo[b]pyran (21 g) in methanol (100 ml) was heated under reflux with ammonium acetate (40 g) for 18 hours. The mixture was evaporated to dryness and the residue partitioned between water and chloroform. The chloroform extract was dried (Na2SO4), treated with charcoal and evaporated to give an oil. This was crystallised from ethylacetate to give the title compound mp 165°-168° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[Br:25][C:26]1[CH:27]=[CH:28][C:29]([Cl:35])=[C:30]([CH:34]=1)[C:31](Cl)=[O:32].C(NC1C=CC(N2C(=O)CC(=O)NC3C4C(C=CC2=3)=CC=CC=4)=CC=1)(=O)C1C=CC=CC=1>>[Br:25][C:26]1[CH:27]=[CH:28][C:29]([Cl:35])=[C:30]([CH:34]=1)[C:31]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:32]
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: O=C(Cl)c1cc(Br)ccc1Cl
Agent: O=C1CC(=O)N(c2ccc(NC(=O)c3ccccc3)cc2)c2ccc3ccccc3c2N1
Product: O=C1CC(=O)N(c2ccc(NC(=O)c3cc(Br)ccc3Cl)cc2)c2ccc3ccccc3c2N1
Yield: 23.7 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (20 mg, 0.063 mmol) obtained in Example 1, (3), and 5-bromo-2-chlorobenzoyl chloride (0.0945 mmol), the title compound (8 mg, yield 24%) was obtained as pale yellow crystals in the same manner as that of Example 1, (4).
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[Cl:18])[N:9]=[C:8]1[CH2:19]Cl.O.[SH:28][C:29]1[N:37]=[CH:36][N:35]=[C:34]2[C:30]=1[NH:31][CH:32]=[N:33]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:1]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[Cl:18])[N:9]=[C:8]1[CH2:19][S:28][C:29]1[N:37]=[CH:36][N:35]=[C:34]2[C:30]=1[N:31]=[CH:32][NH:33]2
Reactant: Sc1ncnc2nc[nH]c12
Reactant: O=c1c2c(Cl)cccc2nc(CCl)n1-c1ccccc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2c(Cl)cccc2nc(CSc2ncnc3[nH]cnc23)n1-c1ccccc1-c1ccccc1
Yield: 84.1 %

Procedure:
Prepared according to Procedure C using Intermediate 2i (400 mg, 1.05 mmol), 6-mercaptopurine monohydrate (196 mg, 1.15 mmol), K2CO3 (159 mg, 1.15 mmol), and DMF (5 mL). The crude product was chromatographed in MeOH/CH2Cl2 and subsequently recrystallized from EtOH to provide 439 mg of a pale yellow crystalline solid (84%), mp 222.0-222.5° C. (dec). 1H NMR (DMSO-d6) δ: 13.56 (br s, 1H); 8.55 (s, 1H); 8.45 (s, 1H); 7.73 (t, J=8.0 Hz, 1H); 7.64 (d, J=7.7 Hz, 1H); 7.50-7.59 (m, 4H); 7.41-7.48 (m, 1H); 7.25-7.38 (m, 5H); 4.41 (d, J=16 Hz, 1H); 4.16 (d, J=16 Hz, 1H). 13C NMR (DMSO-d6) ppm: 160.2, 157.0, 153.7, 151.5, 149.7, 149.3, 143.5, 139.9, 137.8, 135.1, 134.1, 133.3, 131.5, 130.5, 130.3, 130.1, 129.1, 128.9, 128.4, 128.4, 126.9, 117.5, 32.3. MS (ES): m/z 497.0 (M+). Anal. calcd. for C26H17ClN6OS: C, 62.84; H, 3.45; Cl, 7.13; N, 16.91; S, 6.45. Found: C, 62.60; H, 3.47; Cl, 7.15; N, 16.65; S, 6.41.
Reaction SMILES: CN(C)C.[CH3:5][O:6][CH2:7][CH:8]1[O:29][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][C:11]=2[O:10][CH:9]1[CH2:30][O:31][CH3:32])[N:18]=[CH:17][N:16]=[C:15]3[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24](I)[CH:23]=1.[CH3:33][Si:34]([CH3:38])([CH3:37])[C:35]#[CH:36]>[Cu](I)I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:5][O:6][CH2:7][CH:8]1[O:29][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][C:11]=2[O:10][CH:9]1[CH2:30][O:31][CH3:32])[N:18]=[CH:17][N:16]=[C:15]3[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:36]#[C:35][Si:34]([CH3:38])([CH3:37])[CH3:33])[CH:23]=1
Reactant: COCC1Oc2cc3ncnc(Nc4cccc(I)c4)c3cc2OC1COC
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN(C)C
Product: COCC1Oc2cc3ncnc(Nc4cccc(C#C[Si](C)(C)C)c4)c3cc2OC1COC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3 ml of trimethylamine was mixed with the titled compound of Example 45 (40 mg, 0.075 mmol), 1-trimethylsilylacetylene (15 mg, 0.15 mmol), copper iodide (16 mg, 0.084 mmol) and tetrakis(triphenylphosphine)palladium (26 mg, 0.022 mmol), followed by stirring for 12 hours at a room temperature. Then, the reaction mixture was filtered to obtain a filtrate, which was then concentrated and purified by a column chromatography (mobile phase: hexane:ethylacetate=2:3(v:v)) to prepare the titled compound (33 mg, 97%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH:10]=[C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]3=[CH:7][C:6]=2[C:5](Cl)=[N:4][N:3]=1>C(N)CCC>[ClH:1].[CH2:2]([NH:3][C:2]1[C:11]2[CH:10]=[C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]3=[CH:7][C:6]=2[C:5]([NH:4][CH2:5][CH2:6][CH2:7][CH3:8])=[N:4][N:3]=1)[CH2:11][CH2:10][CH3:9]
Reactant: Clc1nnc(Cl)c2cc3ccccc3cc12
Solvent: CCCCN
Product: CCCCNc1nnc(NCCCC)c2cc3ccccc3cc12
Product: Cl
Temperature: 130 °C
Yield: 112.9 %

Procedure:
A mixture of 1,4-dichlorobenzo[g]phthalazine (9.23 mmol) and n-butylamine (20 mL) was heated in an autoclave at 130° C. for 12 h. After cooling to room temperature, the excess of n-butyl amine was evaporated to dryness under vacuum. When the residue was treated with acetone (100 mL) a yellow solid was formed. After being filtered off and dried it afforded 1.87 g (55% yield) of 1,4-bis(n-butylamino)benzo[g]phthalazine monohydrochloride. m.p. 195°-197° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17]([CH2:26][CH2:27][CH3:28])=[N:18][C:19]3[N:20]([N:23]=[CH:24][CH:25]=3)[C:21]=2O)=[CH:11][CH:10]=1)#[N:2].O=P(Cl)(Cl)[Cl:31]>ClCCl>[Cl:31][C:21]1[N:20]2[N:23]=[CH:24][CH:25]=[C:19]2[N:18]=[C:17]([CH2:26][CH2:27][CH3:28])[C:16]=1[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])=[CH:10][CH:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCc1nc2ccnn2c(O)c1Cc1ccc(-c2ccccc2C#N)cc1
Solvent: ClCCl
Product: CCCc1nc2ccnn2c(Cl)c1Cc1ccc(-c2ccccc2C#N)cc1

Procedure:
27 g of 6-[(2'-cyanobiphenyl-4-yl)methyl]-7-hydroxy-5-propylpyrazolo[1,5-a]pyrimidine, prepared in Example 18, are added in portions to 540 ml of POCl3. The mixture is refluxed for 3 h. It is concentrated under vacuum. The oil obtained is taken up in dichloromethane and washed twice with a solution of water and ice. The organic phase is decanted, dried and concentrated. The yellow oil is taken up in ether to give 25.6 g of crystals of 7-chloro-6-[(2'-cyanobiphenyl-4-yl)methyl]-5-propylpyrazolo[1,5-a]pyrimidine.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][O:12][C:13]1[C:18]2[C:19](=[O:37])[N:20]3[CH2:35][C@H:34]([OH:36])[CH2:33][C@H:21]3[C:22](=[O:32])[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:17]=2[CH:16]=[CH:15][C:14]=1[O:38][CH3:39]>C(Cl)Cl.O>[CH3:11][O:12][C:13]1[C:18]2[C:19](=[O:37])[N:20]3[CH2:35][C:34](=[O:36])[CH2:33][C@H:21]3[C:22](=[O:32])[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:29])[CH3:30])[C:17]=2[CH:16]=[CH:15][C:14]=1[O:38][CH3:39]
Reactant: COc1ccc2c(c1OC)C(=O)N1C[C@H](O)C[C@H]1C(=O)N2COCC[Si](C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1ccc2c(c1OC)C(=O)N1CC(=O)C[C@H]1C(=O)N2COCC[Si](C)(C)C
Temperature: 25 °C
Yield: 73.7 %

Procedure:
Anhydrous DMSO (3.28 g, 41.94 mmol) in dry DCM (20 mL) was added dropwise over 5 minutes to a stirred solution of oxalyl chloride (10.48 mL of a 2 N solution in DCM, 20.97 mmol) under a nitrogen atmosphere at −50° C. After stirring for 5 minutess, a solution 7 (5.90 g, 13.98 mmol), in dry DCM (45 mL) was added dropwise over 45 minutes to the reaction mixture, which was then stirred for a further 45 minutes at −50° C. TEA (9.89 g; 97.87 mmol) was added dropwise to the mixture over 15 minutes followed by stirring for a further 15 minutes. The reaction mixture was left to warm to room temperature, diluted with H2O (150 mL) and DCM (100 mL). The organic phase was washed with 1 N HCl (2×100 mL), water (2×100 mL), brine (2×100 mL) and dried over MgS evaporation afforded the crude product (8), which was purified by flash column chromatography using 50:50 petroleum ether (40-60°):EtOAc as eluent. Evaporation of the pure fractions in vacuo afforded the product (4.33 g, 10.3 mmol, 74%). 1HNMR (270 MHz, CDCl3) δ 7.30 (s, 1H, ArH), 7.24 (s, 1H, ArH), 5.60 (d, 1H, J=9.89 Hz, SEM amino acetal CH2), 4.69 (d, 1H, J=9.89 Hz, SEM amino acetal CH2), 4.62 (dd, 1H, J=9.89, 3.12 Hz, 11a), 4.26-4.19 (m, 1H, 3), 3.95 (s, 3HOHe), 3.94 (s, 3H, OMe), 3.81-3.49(m, 4H, SEM 1=CH2+1+3), 2.82-2.71 (m, 1H, 1), 0.95 (t, 2H, J=2.01 Hz, SEM 2=CH2), −0.04 (s, 9H, SEM CH3); 13C NMR (67.8 MHz, CDCl3) δ206.8, 168.8, 165.9, 152.4, 147.5, 134.0, 120.4, 111.1, 105.6, 78.2, 67.2, 56.2, 54.8, 52.3, 37.3, 18.3, −1.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=[CH:41][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH3:40])S(C4C=CC=CC=4[N+]([O-])=O)(=O)=O)[O:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(#N)C.C1(S)C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=[CH:41][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@H:20]4[C@H:19]([O:23][C:22]([CH3:25])([CH3:24])[O:21]4)[C@@H:18]([CH2:26][NH:27][CH3:40])[O:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN(C)S(=O)(=O)c3ccccc3[N+](=O)[O-])[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [Cs+]
Solvent: CC#N
Product: CNC[C@H]1O[C@@H](n2ccc3c(NCc4ccc(OC)cc4OC)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
A suspension of N-(((3aR,4R,6R,6aR)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-N-methyl-2-nitrobenzenesulfonamide (0.82 g, 1.2 mmol) and cesium carbonate (0.82 g, 2.5 mmol) in acetonitrile (23 mL, 440 mmol) was degassed by sparging with nitrogen gas for 10 minutes. The solution was treated dropwise with benzenethiol (0.26 mL, 2.5 mmol) and the mixture was allowed to stir at room temperature overnight. After 22 h, LCMS indicated the reaction was complete. The reaction mixture was partitioned between 60 mL 1N NaOH and 120 mL CH2Cl2, the layers separated and the aqueous phase was washed with three 25 mL portions of CH2Cl2. The combined organic phase was dried over MgSO4, filtered, and concentrated to an oil. The material was purified by flash chromatography (80 g silica gel, 0-5% 7N NH3 in CH3OH/CH2Cl2) to yield the title compound (320 mg, 54%) as a foam: MS (ESI+) for C24H31N5O6 m/z 470.1 (M+H)+; (ESI−) for C24H31N5O6 m/z 468.0 (M−H)−; HPLC purity 99% (ret. time, 2.67 min).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3O[C:36]([CH3:40])=[C:37]([CH3:39])[N:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[CH2:41]([NH:43]C=O)[CH3:42].C(N)C>>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:43]([CH2:41][CH3:42])[C:36]([CH3:40])=[C:37]([CH3:39])[N:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3nc(C)c(C)o3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: CCNC=O
Agent: CCN
Product: CCCc1nc2c(C)cc(-c3nc(C)c(C)n3CC)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 146 from tert.butyl 4'-[[2-n-propyl-4-methyl-6-(4,5-dimethyl-oxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and N-ethylformamide/ethylamine.
Reaction SMILES: C([O:3][C:4](=[O:16])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]([OH:15])[CH:8]=1)C.[OH-].[Na+]>C(O)C.O>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C:4]([OH:16])=[O:3])=[CH:8][C:9]=1[OH:15])#[N:14]
Reactant: CCOC(=O)CCc1ccc(C#N)c(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(CCC(=O)O)cc1O
Yield: 9.8 %

Procedure:
A solution of 3-(4-Cyano-3-hydroxy-phenyl)-propionic acid ethyl ester (2.2 g, 10 mmol) in ethanol (10 mL) and water (40 mL) was treated with aqueous sodium hydroxide solution (2.5 M, 44 mL) at room temperature overnight. The solvent was removed under vacuum and the residue was dissolved in water (150 mL). The pH of the aqueous solution was adjusted to 2–4 by the addition of 3N HCl (aqueous) and the precipitate was then filtered and washed with water to give the title compound as white solid (1.88 g, 0.98 mmol, 98.4% yield). ESMS m/z: 192 [M+H]+.
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:30])/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=CC=1)([O-])=O.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][CH2:38][CH2:39][CH2:40][NH2:41])[CH:32]=1>O1CCCC1>[Cl:29][C:25]1[CH:24]=[C:23]([C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:41][CH2:40][CH2:39][CH2:38][CH2:37][C:33]2[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH:28]=[CH:27][CH:26]=1
Reactant: O=C(/C=C/C=C(c1cccc(Cl)c1)c1cccc(Cl)c1)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCCCCc1cccnc1
Solvent: C1CCOC1
Product: O=C(/C=C/C=C(c1cccc(Cl)c1)c1cccc(Cl)c1)NCCCCc1cccnc1
Yield: 77.7 %

Procedure:
As in Example 134, a solution of (E)-5,5-bis(3- chlorophenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (6.4 g) and 3-pyridinebutanamine (2.7 g) in tetrahydrofuran (75 mL) was stirred for 40 minutes at 40° C. and was worked up in the usual manner. The crude amide was purified by HPLC (ethyl acetate) and then crystallized from ethyl acetate-hexane to yield 5.1 g of (E)-5,5-bis(3-chlorophenyl)-N-[4-(3-pyridinyl)butyl]-2,4-pentadienamide, mp 100°-102° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC(F)(F)C(O)=O.[CH3:56][C:57]1([OH:61])[CH2:60][NH:59][CH2:58]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([N:59]4[CH2:60][C:57]([OH:61])([CH3:56])[CH2:58]4)=[O:24])=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Reactant: CC1(O)CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC1(O)CN(C(=O)c2cnn3ccc(N4CCC[C@@H]4c4cncc(F)c4)nc23)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 81.5 %

Procedure:
To a DMF (1.0 mL) solution of (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation I, 85 mg, 0.26 mmol) was added HATU (118 mg, 0.31 mmol) and 3-methylazetidin-3-ol 2,2,2-trifluoroacetate (63 mg, 0.31 mmol) at ambient temperature, followed by addition of DIEA (0.14 mL, 0.78 mmol) at 0° C. After stirring for 5 minutes at ambient temperature, the reaction was directly purified by reverse-phase chromatography (5 to 45% acetonitrile/water) to yield the final product as white solid (84 mg, 82%). LCMS (apci) m/z=397.1 (M+H).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[C:10]([F:12])[C:9]([C:13]2[CH:14]=[N:15][C:16]([C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=3)=[N:17][CH:18]=2)=[C:8]([F:27])[CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH:28]([N-:31]C(C)C)(C)C.[Li+].C1(C)C=CC(S(C#N)(=O)=O)=CC=1.C(O)C>CCCCCC.C1COCC1>[CH2:1]([C:6]1[CH:11]=[C:10]([F:12])[C:9]([C:13]2[CH:18]=[N:17][C:16]([C:19]3[CH:24]=[C:23]([F:25])[C:22]([C:28]#[N:31])=[C:21]([F:26])[CH:20]=3)=[N:15][CH:14]=2)=[C:8]([F:27])[CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1cc(F)c(-c2cnc(-c3cc(F)cc(F)c3)nc2)c(F)c1
Reactant: CC(C)[N-]C(C)C
Agent: Cc1ccc(S(=O)(=O)C#N)cc1
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCCc1cc(F)c(-c2cnc(-c3cc(F)c(C#N)c(F)c3)nc2)c(F)c1
Temperature: -50 °C
Reaction time: 2 h

Procedure:
A mixture of 44 mmol of 1B and 80 ml of THF is added dropwise at -78° C. to a solution of 48 mmol of lithium diisopropylamide in hexane. The mixture is stirred at -50° C. for 2 hours and then re-cooled to -78° C., and a mixture of 48 mmol of p-toluenesulphonyl cyanide in 20 ml of THF is slowly added dropwise. After warming to room temperature and conventional work-up, the pure product is obtained by recrystallization from ethanol. C 85 N (75) I, Δε=71.3, Δn=0.232 (extrapolated from ZLI-4792)