Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:10][NH:11][C:3]=12.[CH2:18]([NH2:21])[CH:19]=[CH2:20]>C1(C)C(C)=CC=CC=1>[CH2:18]([NH:21][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:10][NH:11][C:3]=12)[CH:19]=[CH2:20]
Reactant: Cc1cc(Cl)c2[nH]nc(-c3ccccc3)c2n1
Reactant: C=CCN
Solvent: Cc1ccccc1C
Product: C=CCNc1cc(C)nc2c(-c3ccccc3)n[nH]c12
Reaction time: 48 h

Procedure:
A mixture of 7-chloro-5-methyl-3-phenyl-1H-pyrazolo[4,3-b]pyridine (D9) (1 g), xylene (80 ml) and allylamine (20 ml) was placed in a Parr pressure vessel and heated at 142° rising to 162° for 2 days during which time the internal pressure rose to 75 psi. The vessel was then allowed to cool, the pressure released and the contents evaporated to dryness. The residue was chromotographed on basic alumina eluting with ether and then a rising percentage of methanol (to 25%). Approximately 90% of the starting material was recovered. The fractions containing the required product were combined, evaporated to dryness and recrystallised from ether/pentane with charcoal decolourisation to give the title compound as an off-white crystalline solid, m.p. 92°-105° followed by resolidification and melting 171°-177°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:24]CC2C=CC(OC)=CC=2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2>FC(F)(F)C(O)=O.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([OH:24])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:21])([F:22])[F:23])=[CH:15][CH:14]=1)[CH2:7]2
Reactant: COc1ccc(COc2cc(Cl)c3c(c2)CN(Cc2ccc(OC(F)(F)F)cc2)C3=O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1c2c(Cl)cc(O)cc2CN1Cc1ccc(OC(F)(F)F)cc1
Yield: 50 %

Procedure:
7-Chloro-5-(4-methoxy-benzyloxy)-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (5.0 mg) was dissolved in a 1:1 mixture of trifluoroacetic acid and dichloromethane. The reaction was stirred over the weekend. The mixture was then washed with water, brine, dried over sodium sulfate, filtered and concentrated to provide the title compound (1.87 mg). 1H NMR (300 MHz, CDCl3): δ 7.36 (d, 2H), 7.20 (d, 2H), 6.94 (s, 1H), 6.76 (s, 1H), 4.76 (s, 2H), 4.19 (s, 2H).
Reaction SMILES: C([C@@H]1COC(=O)N1[C:14](=[O:36])[C@H:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:22][C:21]=1[Cl:35])[CH2:16][CH:17]=O)C1C=CC=CC=1.[NH:37]1[C:45]2[CH2:44][CH:43]([NH2:46])[CH2:42][CH2:41][C:40]=2[CH:39]=[N:38]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(#N)C>[CH2:28]([O:27][C:23]1[CH:22]=[C:21]([Cl:35])[C:20]([CH2:19][C@@H:15]2[CH2:16][CH2:17][N:46]([CH:43]3[CH2:44][C:45]4[NH:37][N:38]=[CH:39][C:40]=4[CH2:41][CH2:42]3)[C:14]2=[O:36])=[C:25]([Cl:26])[CH:24]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=CC[C@@H](Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: NC1CCc2cn[nH]c2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: O=C1[C@H](Cc2c(Cl)cc(OCc3ccccc3)cc2Cl)CCN1C1CCc2cn[nH]c2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
Add a solution of (R)-4-((R)-4-benzyl-2-oxo-oxazolidin-3-yl)-3-(4-benzyloxy-2,6-dichloro-benzyl)-4-oxo-butyraldehyde, Preparation 38, (8.17 g, 15.5 mmol) in CH2Cl2 (100 mL) to a solution of 4,5,6,7-tetrahydro-1H-indazol-6-ylamine (2.13 g, 15.5 mmol) in acetonitrile (200 mL) and stir for 30 minutes at room temperature under N2. Add sodium triacetoxyborohydride (9.89 g, 46.7 mmol) to the reaction and stir for 18 hours. Remove the solvent in vacuo and extract solid with ethyl acetate, water and saturated NaHCO3. Dry the organic layer (Na2SO4), filter and concentrate under vacuum. Purify the residue by silica gel chromatography with a gradient of 0 to 10% methanol in CH2Cl2 to afford 3.93 g (54%) of the title compound. MS (m/z): 470 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:29])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[C@H:25]([CH2:26][OH:27])[CH2:24][O:23][C:22]3=[O:28])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30]I>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:29])[C:15]2[CH:16]=[CH:17][C:18]([N:21]3[C@H:25]([CH2:26][O:27][CH3:30])[CH2:24][O:23][C:22]3=[O:28])=[CH:19][CH:20]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3CO)cc2)CC1
Reactant: CI
Product: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Yield: 71.2 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 93 and using (R)-4-[4-(4-hydroxymethyl-2-oxooxazolidin-3-yl)benzoyl]piperazine-1-carboxylic acid tert-butyl ester (739 mg) described in Preparation Example 163 and methyl iodide (259 mg), the title compound (544 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[O:15]=[C:13]1[NH:12][C:8]2=[N:9][CH:10]=[CH:11][C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:19](=[O:26])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:18]=[CH:17][CH:16]=3)=[C:7]2[NH:14]1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Reactant: O=C(Cl)c1ccccc1
Product: O=C(Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1)c1ccccc1
Yield: 82 %

Procedure:
Method H was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and benzoyl chloride to afford the title compound as an off-white solid (37 mg, 82%). 1H-NMR (□, ppm, DMSO-d6): 6.49 (d, 1H, HPy,5, J=6.0 Hz), 6.90 (d, 1H, Harom, J=8.0 Hz), 7.42 (ps t, 1H, Harom, J=8.0 Hz), 7.51-7.68 (m, 5H, Harom), 7.81 (d, 1H, HPy,6, J=6.0 Hz), 7.93 (d, 2H, Harom, J=7.5 Hz), 10.35 (s, 1H, NHamide), 11.20 (s, 1H, NHPy3), 11.40 (s, 1H, NHPy2). 13C-NMR (□, ppm, DMSO-d6): 106.56, 110.71, 114.34, 116.20, 127.64, 128.37, 129.32, 130.13, 131.69, 134.68, 140.88, 141.26, 144.65, 147.10, 154.19, 154.69, 165.72. HRMS (EI): m/z [M+H] calcd for C19H15N4O3: 347.1144; found: 347.1140.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.S(=O)(=O)(O)O.[I:18]I.[OH-].[Na+].Cl>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][C:12]=1[I:18]
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Reactant: II
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C1OC(=O)c2cc(I)c(Br)cc21
Temperature: 110 °C
Reaction time: 4 h
Yield: 22 %

Procedure:
To a 100 ml three-necked flask were added 6.42 g (28.3 mmol) of 4-bromophthalic anhydride (manufactured by Tokyo Chemical Industry Co. Ltd.), 25 ml of 10% fuming sulfuric acid, and 3.60 g (14.2=mol) of iodine. The mixture was heated to 110° C. and the reaction was carried out for 4 hours. After cooling at room temperature, the reaction mixture was poured into ice to quench the reaction. After the mixture was treated with a cold 20% aqueous sodium hydroxide solution, hydrochloric acid was added to adjust the pH of the solution to 6 to 7. Insoluble matter was removed by means of a filter paper and hydrochloric acid was added portionwise to adjust the pH to 1 or lower. After the resulting slurry was stirred overnight, the formed precipitate was filtrated and dried. The resulting solid was washed with toluene and the residue was treated with a cold 20% aqueous sodium hydroxide solution and dissolved therein. The pH of the solution was adjusted to 3.5 with acetic acid and the formed precipitate was removed by filtration. After the precipitate was treated with hydrochloric acid, the precipitate was further treated with toluene and acetic anhydride to obtain 1.10 g of 4-bromo-5-iodophthalic anhydride (yield 11%).
Reaction SMILES: [C:1]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[CH:32]=[CH:31][C:29]([NH2:30])=[N:28][C:26]2=[O:27])[CH2:22][C@@H:21]1[OH:33])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(OC([N:41](C(OC(C)(C)C)=O)[C@H:42]([C:48](O)=[O:49])[CH2:43][CH2:44][CH2:45][CH2:46][NH2:47])=O)(C)(C)C.C1(N=C=NC2CCCCC2)CCCCC1>CC(N(C)C)=O>[NH2:41][C@H:42]([C:48]([NH:30][C:29]1[CH:31]=[CH:32][N:25]([C@@H:23]2[O:24][C@H:20]([CH2:19][O:18][C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C@@H:21]([OH:33])[CH2:22]2)[C:26](=[O:27])[N:28]=1)=[O:49])[CH2:43][CH2:44][CH2:45][CH2:46][NH2:47]
Reactant: CCCCCCCCCCCCCCCC(=O)OC[C@H]1O[C@@H](n2ccc(N)nc2=O)C[C@@H]1O
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H](CCCCN)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(=O)N(C)C
Product: CCCCCCCCCCCCCCCC(=O)OC[C@H]1O[C@@H](n2ccc(NC(=O)[C@@H](N)CCCCN)nc2=O)C[C@@H]1O
Temperature: 4 °C
Reaction time: 90 h

Procedure:
14 grams of 5′-O-palmitoyl-deoxycytidine is dissolved in 100 ml dimethylacetamide, 1 molar equivalent of di-tert-butoxycarbonyl-lysine is added, and the mixture is cooled in an ice bath. 1.2 molar equivalents (7.4 g) of dicyclohexylcarbodiimide are added and the mixture is stirred at 4° C. for 90 hours. The precipitate (dicyclohexylurea) is removed by filtration. 100 ml of water is added to the filtrate, followed by 1 liter of ethyl acetate. N4-(di-N-tert-butoxycarbonyl-lysyl)-5′-O-palmitoyl-deoxycytidine is separated from unreacted reagents by chromatography over silica gel. The t-butoxycarbonyl protecting groups are removed by the standard methods of treatment with an acid, such as trifluoroacetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[NH:6][C:7]1[NH:8][C:9](=[O:18])[C:10]([C:13]([O:15]CC)=[O:14])=[CH:11][N:12]=1.[OH-].[Na+].O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[NH:6][C:7]1[NH:8][C:9](=[O:18])[C:10]([C:13]([OH:15])=[O:14])=[CH:11][N:12]=1
Reactant: CCOC(=O)c1cnc(Nc2cccc(OC)c2)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COc1cccc(Nc2ncc(C(=O)O)c(=O)[nH]2)c1
Reaction time: 1 h
Yield: 66.4 %

Procedure:
Ethyl 1,6-dihydro-2-(3-methoxyanilino)-6-oxo-5-pyrimidinecarboxylate (3 g) and sodium hydroxide (1 g) are added to water (50 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the reaction mixture is acidified with acetic acid, and the resulting solid is collected by filtration and recrystallized from DMF. The precipitate is collected by filtration and added to water (60 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the resulting product is collected by filtration and dried at 80° C. under reduced pressure to give 1,6-dihydro-2-(3-methoxyanilino)-6-oxo-5-pyrimidinecarboxylic acid (1.8 g). M.p. 247°-249° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3](=[O:16])[C:4]#[C:5][Si:6]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:12])[CH3:11])[CH:7]([CH3:9])[CH3:8].[CH2:19]1[CH2:23]OC[CH2:20]1.C1([Mg]Br)CC1.[NH4+].[Cl-]>C(Cl)Cl>[CH:20]1([C:3]([OH:16])([C:4]#[C:5][Si:6]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:11])[CH3:12])[CH:7]([CH3:8])[CH3:9])[C:2]([F:1])([F:17])[F:18])[CH2:19][CH2:23]1
Reactant: CC(C)[Si](C#CC(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: C1CCOC1
Agent: Br[Mg]C1CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CC(C)[Si](C#CC(O)(C1CC1)C(F)(F)F)(C(C)C)C(C)C
Reaction time: 1.5 h

Procedure:
To a solution of 1,1,1-trifluoro-4-(triisopropylsilyl)but-3-yn-2-one (2.01 g, 7.22 mmol) in CH2Cl2 (50 mL) at 0° C. was added a THF solution of cyclopropylmagnesium bromide (0.5 M, 21.7 mL, 10.8 mmol). After 1.5 h, a saturated solution of NH4Cl was added. The aqueous layer was extracted with CHCl3 (3×), and the combined organic layers were washed with H2O and brine, dried (Na2SO4) and concentrated under vacuum at 30° C. affording the title compound. 1H NMR (500 MHz, acetone-d6): 5.97 (s, 1H), 1.36 (m, 1H), 1.10 (m, 21H), 0.74 (m, 1H), 0.65 (m, 2H), 0.60 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[N:16]=[C:17]3[N:21]([CH:22]=2)[CH:20]=[CH:19][S:18]3)[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Br:23]Br>C(Cl)Cl>[Br:23][C:22]1[N:21]2[C:17]([S:18][CH:19]=[CH:20]2)=[N:16][C:15]=1[C:5]1[CH:6]=[CH:7][C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc(-c2cn3ccsc3n2)ccc1-c1ccccn1
Reactant: BrBr
Solvent: ClCCl
Product: COc1cc(-c2nc3sccn3c2Br)ccc1-c1ccccn1

Procedure:
A solution of 6-(3-methoxy-4-pyridin-2-ylphenyl)-imidazo[2,1-b][1,3]thiazole (100 mg, 0.33 mmol) in CH2Cl2 (3 mL) was treated with a solution of bromine (0.017 mL, 0.33 mmol) in CH2Cl2 (1 mL) over 1 h at 0° C. The reaction mixture was diluted with CH2Cl2 (25 mL) and was washed with a solution of saturated aqueous sodium bicarbonate (25 mL). The organic layer was dried (MgSO4) and concentrated to afford 5-bromo-6-(3-methoxy-4-pyridin-2-ylphenyl)imidazo[2,1-b][1,3]thiazole. 1H NMR (CD3OD, 500 MHz) δ 7.29 (d, 1H), 7.12 (dt, 1H), 6.82 (d, 1H), 6.47 (dd, 1H), 6.36 (s, 1H), 6.35 (dd, 1H), 6.27 (m, 2H), 5.83 (d, 1H), 2.49 (s, 3H) ppm. MS (ESI) 388 (M)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:21])=[N:15][CH:16]=[C:17]([C:19]#[CH:20])[CH:18]=1)[CH3:11].C(N(C(C)C)CC)(C)C.[C:31]1([CH:37]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[N:38]2[CH2:41][CH:40]([N:42]=[N+:43]=[N-:44])[CH2:39]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CO.[Cu](I)I>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:21])=[N:15][CH:16]=[C:17]([C:19]2[N:44]=[N:43][N:42]([CH:40]3[CH2:41][N:38]([CH:37]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[CH2:39]3)[CH:20]=2)[CH:18]=1)[CH3:11]
Reactant: C#Cc1cnc(N)c(OC(C)c2c(Cl)ccc(F)c2Cl)c1
Reactant: [N-]=[N+]=NC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: I[Cu]I
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Oc1cc(-c2cn(C3CN(C(c4ccccc4)c4ccccc4)C3)nn2)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound 3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-ethynyl-2-aminopyridine (4.2 g, 12.62 mmol) was dissolved in methanol (40 mL), and diisopropylethylamine (8.36 g, 64.78 mmol), copper iodide (62 mg, 0.33 mmol) and 1-(diphenylmethyl)-3-azidoazetidine (3.34 g, 12.62 mmol) were added successively. The reaction was stirred overnight at room temperature. TLC test showed that the raw materials were completely reacted. The resultant mixture was concentrated under reduced pressure;
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]([F:36])([F:35])[C:7]([N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19]C)[CH:15]=2)[CH:10]1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:23][CH:22]=1)=[O:8].CO>C(Cl)Cl>[F:35][C:6]([F:5])([F:36])[C:7]([N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=2)[CH:10]1[C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][N:30]2[CH2:31][CH2:32][CH2:33][CH2:34]2)=[CH:25][CH:26]=1)=[O:8]
Reactant: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)C2c1ccc(OCCN2CCCC2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: O=C(N1CCc2cc(O)ccc2C1c1ccc(OCCN2CCCC2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 21 h
Yield: 31 %

Procedure:
A 1M solution of BBr3 in CH2Cl2 (35.0 ml, 35.0 mmol) was added slowly to a solution of 2,2,2-trifluoro-1-{6-methoxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-3,4-dihydro-1H-isoquinolin-2-yl}ethanone (6.26 g, 14.0 mmol) in anhydrous CH2Cl2 (400 ml) at 0° C. under N2. The reaction mixture was warmed to rt and stirred at rt for 21 hr. MeOH (100 ml) was slowly added with stirring and the resulting solution was concentrated in vacuo to a red oil. Purification by flash chromatography, eluting with EtOAc:MeOH (8:2), gave 1.886 g (31% yield) of yellow solid.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH3:21])=[CH:11][C:10]=2[CH:22]=1)=[O:5].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([Mg]Br)[CH:29]=[CH:30][CH:31]=1>>[CH3:24][O:25][C:26]1[CH:31]=[C:30]([C:4]([C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([CH2:14][CH2:15][N:16]4[CH2:20][CH2:19][CH2:18][C@H:17]4[CH3:21])=[CH:11][C:10]=3[CH:22]=2)=[O:5])[CH:29]=[CH:28][CH:27]=1
Reactant: COc1cccc([Mg]Br)c1
Reactant: CON(C)C(=O)c1ccc2oc(CCN3CCC[C@H]3C)cc2c1
Product: COc1cccc(C(=O)c2ccc3oc(CCN4CCC[C@H]4C)cc3c2)c1

Procedure:
The product from Example 71E and 3-methoxyphenylmagnesium bromide were processed as described in Example 71F to provide the title compound. 1HNMR (300 MHz, CD3OD) δ 1.42 (d, 3H), 1.72 (m, 1H), 2.10 (m, 2H), 2.35 (m, 1H), 3.30 (m, 4H), 3.55 (m, 1H), 3.80 (m, 2H), 3.83 (s, 3H), 6.83 (s, 1H), 7.2 (m, 1H), 7.30 (m, 2H), 7.45 (m, 1H), 7.60 (m, 2H), 7.80 (dd, 1H), 8.02 (d, 1H); MS (ESI) m/z 364 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:7]([CH2:9]Cl)=[N:8][C:4]=2[CH:3]=1.[CH3:19][S:20]([C:23]1[C:31]2[C:26](=[CH:27][N:28]=[CH:29][CH:30]=2)[NH:25][N:24]=1)(=[O:22])=[O:21]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:7]([CH2:9][N:25]3[C:26]4=[CH:27][N:28]=[CH:29][CH:30]=[C:31]4[C:23]([S:20]([CH3:19])(=[O:21])=[O:22])=[N:24]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)c1n[nH]c2cnccc12
Reactant: ClCc1nc2cc(Cl)ccc2n1C1CCOCC1
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2C2CCOCC2)c2cnccc12

Procedure:
The title compound was prepared in analogy to Example 2-1 by using 5-chloro-2-chloromethyl-1-(tetrahydro-pyran-4-yl)-1H-benzoimidazole and 3-methanesulfonyl-1H-pyrazolo[3,4-c]pyridine instead of 5-chloro-2-chloromethyl-1-((S)-1,1-dioxo-tetrahydro-1λ6-thiophen-3-yl)-1H-benzoimidazole and 3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:17])=[C:4]([C:8]([N:10]2[CH2:15][CH2:14][NH:13][C:12](=O)[CH2:11]2)=[O:9])[CH:5]=[CH:6][CH:7]=1.F[B-](F)(F)F.C[O+](C)C.[CH3:27][C:28]1[S:32][CH:31]=[N:30][C:29]=1[C:33]([NH:35][NH2:36])=O>ClCCl>[Cl:1][C:2]1[C:3]([CH3:17])=[C:4]([C:8]([N:10]2[CH2:15][CH2:14][N:13]3[C:33]([C:29]4[N:30]=[CH:31][S:32][C:28]=4[CH3:27])=[N:35][N:36]=[C:12]3[CH2:11]2)=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1scnc1C(=O)NN
Reactant: Cc1c(Cl)cccc1C(=O)N1CCNC(=O)C1
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: Cc1scnc1-c1nnc2n1CCN(C(=O)c1cccc(Cl)c1C)C2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-[(3-Chloro-2-methylphenyl)carbonyl]-2-piperazinone (I131)(250 mg, 0.989 mmol) was suspended in dry Dichloromethane (DCM) (3 mL) before treating with trimethyloxonium tetrafluoroborate (185 mg, 1.187 mmol) and stirring for 16 hours at RT under argon before adding 5-methyl-1,3-thiazole-4-carbohydrazide (I123) (233 mg, 1.484 mmol) and stirring for a further 3 hours. DCM was removed by evaporation and the residue was dissolved in 1-butanol (3.00 mL) before heating at 110° C. for 4 hours then cooled to RT overnight. The reaction was worked up by diluting with DCM (50 ml) and washing with saturated sodium bicarbonate solution (50 ml). The aqueous layer was extracted with DCM (2×30 ml), the combined extracts were washed with brine (30 ml), dried (MgSO4), filtered and evaporated to afford a pale yellow cloudy gum as crude product. The product was purified on 50 g Isolera column, eluting with DCM (3CV) then 0-10% MeOH/DCM over 10CV. The desired fractions were isolated, the solvent evaporated and the residue was further purified by MDAP (formic acid method). The desired fraction was identified and the solvent evaporated to afford a white foam of desired product in 130 mg.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[C@H:14]([CH2:15][C:16](OC)=[O:17])[CH2:13][CH2:12][C@H:11]1[O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.[OH-].[Al+3].[OH-].[OH-].S([O-])([O-])(=O)=O.[Mg+2]>C1(C)C=CC=CC=1.CO>[CH2:1]([O:8][CH2:9][C@@H:10]1[C@H:14]([CH2:15][CH2:16][OH:17])[CH2:13][CH2:12][C@H:11]1[O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C[C@@H]1CC[C@@H](OC2CCCCO2)[C@@H]1COCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: Cc1ccccc1
Solvent: CO
Product: OCC[C@@H]1CC[C@@H](OC2CCCCO2)[C@@H]1COCc1ccccc1
Reaction time: 2 h
Yield: 78.6 %

Procedure:
In a flow of argon, to a solution cooled to -15° C., of 14.2 g of (1R,2S,3S)-2-benzyloxymethyl-3-methoxycarbonylmethyl-1-(2-tetrahydropyranyloxy)cyclopentane (prepared in Reference Example 3) in 100 ml of dry toluene, 42 ml of a 25% solution of DIBAL (diisobutyl aluminium hydride) in toluene was added dropwise. The mixture was stirred for 2 hrs, and then 20 ml of methanol was added thereto at the same temperature. The solution was stirred at room temperature and, after deposition of aluminum hydroxide, magnesium sulphate was added thereto. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (2:1) as eluent to give 10.3 g of the title compound having the following physical characteristics.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12].Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:19][CH:18]=1.[Cl-].[Na+]>O1CCCC1>[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:19][CH:18]=1)[S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: CCCCCCCCCCCCCCOc1ccc(CBr)cc1
Reactant: CS(=O)(=O)NCc1ccccn1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1ccc(CN(Cc2ccccn2)S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 38.3 %

Procedure:
To a room temperature slurry of 0.391 g of 50% sodium hydride in 20 ml of dry tetrahydrofuran is added, via cannula, 1.27 g of product from Example 121 in 30 ml of dry tetrahydrofuran. The reaction is stirred at room temperature for 1.5 hours. Two and one half grams of product from Example 20 in 30 ml of dry tetrahydrofuran is added via cannula. The reaction is stirred at room temperature for 20 hours followed by heating at reflux temperature for 2 hours. The cooled reaction is poured into half saturated sodium chloride and extracted with methylene chloride. The combined organic layers are washed with saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by chromatography (silica gel: 40% ethyl acetate/hexane) to give 1.22 g of the desired product as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:45]2[CH:49]=[N:48][N:47]=[N:46]2)=[C:6](/[CH:8]=[CH:9]/[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[C:22](=[O:28])[NH:23][CH2:24][CH2:25][O:26][CH3:27])[CH:13]2[C:29]([NH:31][C:32]2[CH:44]=[CH:43][C:35]([C:36]([O:38]C(C)(C)C)=[O:37])=[CH:34][CH:33]=2)=[O:30])=[O:11])[CH:7]=1.COCCN.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:45]2[CH:49]=[N:48][N:47]=[N:46]2)=[C:6](/[CH:8]=[CH:9]/[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[C:22](=[O:28])[NH:23][CH2:24][CH2:25][O:26][CH3:27])[CH:13]2[C:29]([NH:31][C:32]2[CH:33]=[CH:34][C:35]([C:36]([OH:38])=[O:37])=[CH:43][CH:44]=2)=[O:30])=[O:11])[CH:7]=1
Reactant: COCCNC(=O)c1cccc2c1CCN(C(=O)/C=C/c1cc(Cl)ccc1-n1cnnn1)C2C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: COCCN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCNC(=O)c1cccc2c1CCN(C(=O)/C=C/c1cc(Cl)ccc1-n1cnnn1)C2C(=O)Nc1ccc(C(=O)O)cc1
Reaction time: 24 h

Procedure:
(E)-tert-Butyl 4-(2-(3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(2-methoxyethylcarbamoyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido)benzoate: To 3A (46 mg, 0.073 mmol), 2-methoxyethanamine (5.49 mg, 0.073 mmol), BOP (32.3 mg, 0.073 mmol) in DMF (1 mL) was added DIEA (12.77 μL, 0.073 mmol). After 24 h, the reaction was quenched with H2O (10 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (10 mL) and dried (MgSO4). MS (ESI) m/z: 686.0 (M+H)+.