Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([O:11][CH3:12])=[O:10])=[C:4]([NH:13][C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)[N:3]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32].C(N(C(C)C)C(C)C)C.O>CN(C=O)C>[C:31]([O:30][C:29]([NH:28][CH2:27][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][N:21]1[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([O:11][CH3:12])=[O:10])=[C:4]([NH:13][C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)[N:3]=1)=[O:35])([CH3:34])([CH3:32])[CH3:33]
Reactant: COC(=O)c1c(Cl)nc(Cl)nc1Nc1cccc(C)c1
Reactant: CC(C)(C)OC(=O)NCC1CCCCN1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1c(Cl)nc(N2CCCCC2CNC(=O)OC(C)(C)C)nc1Nc1cccc(C)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 32.9 %

Procedure:
A mixture of methyl 2,4-dichloro-6-(m-tolylamino)pyrimidine-5-carboxylate (600.6 mg, 1.924 mmol), tert-butyl piperidin-2-ylmethylcarbamate (500.9 mg, 2.337 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.4 mL, 2.296 mmol) in DMF (10 mL) was stirred at 0° C. for 3 h. Water (50 mL) was added to the mixture, which was extracted with EtOAc (2×40 mL). The organic layers were washed with saturated aq NaHCO3 (20 mL), water (20 mL) and brine (20 mL), were dried over anhydrous Na2SO4, and then filtered (DM1020). The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (SiO2, hexanes/EtOAc=4/1) to give the title compound as a clear oil (310.5 mg). 1H NMR (500 MHz, CDCl3) δ ppm 1.34-1.74 (m, 15H), 2.35-2.37 (m, 3H), 3.03-3.21 (m, 2H), 3.60-3.71 (m, 1H), 3.90 (s, 3H), 4.43-5.04 (m, 3H), 6.94-6.98 (m, 1H), 7.23-7.46 (m, 3H), 10.13-10.43 (m, 1H). [M+H] calc'd for C24H33ClN5O4, 490; found, 490.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[N+:21]([O-:23])=[O:22])[CH2:10][C@@H:9]1[CH2:24][OH:25])=O)(C)(C)C.[ClH:26]>ClCCl.O1CCOCC1>[ClH:26].[Br:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C@H:11]2[CH2:12][NH:8][C@@H:9]([CH2:24][OH:25])[CH2:10]2)=[C:15]([N+:21]([O-:23])=[O:22])[CH:16]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](Nc2ccc(Br)cc2[N+](=O)[O-])C[C@@H]1CO
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cc(Br)ccc1N[C@H]1CN[C@@H](CO)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
To a solution of (2R,4R)-4-(4-bromo-2-nitro-phenylamino)-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (125.5 g, 0.301 mol) in dichloromethane (400 mL) add 4 N hydrochloric acid in dioxane (800 mL) and stir for 4 h at room temperature. Collect the precipitate by filtration, wash with ether and dry at 20 mm Hg/60° C. to obtain the title compound (105.2 g, 99%). [α]D20−89.6 (c=1.0 in methanol). 1H NMR (400 MHz, DMSO-d6) δ 1.80-1.85 (m, 1H), 2.54-2.59 (m, 1H), 3.43-3.51 (m, 3H), 3.56-3.63 (m, 1H), 3.69-3.72 (m, 2 H), 4.50-4.51 (m, 1H), 5.60 (br s, 1H), 7.10 (d, 1H), 7.65 (dd, 1H), 8.14 (d, 1H), 8.95 (br s, 1H), 9.91 (br s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[NH:14][C:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=2[C:21]=1[CH2:22][CH2:23][C:24](O)=[O:25].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[NH:14][C:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=2[C:21]=1[CH2:22][CH2:23][C:24]([NH:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1)=[O:25]
Reactant: NCCN1CCOCC1
Reactant: O=C(O)CCc1c(C=C2C(=O)Nc3ccc(Br)cc32)[nH]c2c1CCCC2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCc1c(C=C2C(=O)Nc3ccc(Br)cc32)[nH]c2c1CCCC2)NCCN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
3-[2-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-propionic acid (12.3 g) was dissolved in 150 mL of dimethylformamide. Carbonyldiimidazole (6.3 g) was added and the mixture stirred at ambient temperature for 1 hour. 4-(2-Aminoethyl)morpholine (7.7 g) and 30 mL of dimethylformamide were added and the stirring continued overnight at room temperature. Fifty mL of water was added to the mixture and stirring was continued for 10 minutes. The precipitate was collected by vacuum filtration, washed with 20 mL of water and then 20 mL of ethanol. The solid was slurry-washed in 30 mL of refluxing ethanol for 5 minutes and cooled to room temperature. The solid was collected by vacuum filtration, washed with 20 mL of ethanol and vacuum dried to give 12.5 g (80%) of 3-[2-(5-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-N-(2-morpholin-4-ylethyl)-propionamide.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5](=[O:10])[CH2:6][CH2:7][C:8]#[CH:9].O>CO>[CH:17]1([C:4]([OH:3])([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:5](=[O:10])[CH2:6][CH2:7][C:8]#[CH:9])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C#CCCC(=O)C(O[Si](C)(C)C)(c1ccccc1)C1CCCCC1
Solvent: CO
Solvent: O
Product: C#CCCC(=O)C(O)(c1ccccc1)C1CCCCC1

Procedure:
1-(Trimethylsilyloxy)-1-cyclohexyl-1-phenylhex-5-yn-2-one is dissolved in methanol containing 1% concentrated hydrochloric acid at 25° C. Water is added and the solution transferred to a separatory funnel. The solution is washed with ether and the ether layer dried over sodium sulfate. Upon evaporation of the ether under vacuum and vacuum distillation of the crude product a pale yellow oil is isolated.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17](O)=[O:18])=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].C(O[C:25]([CH:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[NH:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:26])C.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[O-]CC.[Na+].C(O)C>CN(C)C=O.C(O)(=O)C>[CH2:33]([N:32]1[C@@H:28]2[C@@H:27]([CH2:31][CH2:30][CH2:29]2)[C:25]([OH:26])=[C:16]([C:11]2[NH:10][C:9]3[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][C:8]=3[S:13](=[O:14])(=[O:15])[N:12]=2)[C:17]1=[O:18])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCOC(=O)C1CCCC1NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CC[O-]
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Solvent: CN1CCOCC1
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3CCC[C@@H]3N(Cc3ccccc3)C1=O)N2
Temperature: 25 °C
Reaction time: 4 h
Yield: 30.3 %

Procedure:
A solution of (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.100 g, 0.300 mmol) and 2-benzylamino-cyclopentanecarboxylic acid ethyl ester (0.074 g, 0.300 mmol) in N,N-dimethylformamide (1.5 mL) was treated with N-methylmorpholine (63.7 mg, 0.63 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (60.4 mg, 0.315 mmol) and stirred at 25° C. for 4 h. The solvent was removed in vacuo. The crude material was redissolved in ethyl acetate (75 mL) and washed twice with 1.0 M aqueous hydrochloric acid solution (50 mL). The organic layer was then dried over sodium sulfate, filtered and concentrated in vacuo. The crude intermediate was redissolved in ethanol (5 mL) and treated with a 21% w/w solution of sodium ethoxide in ethanol (448 μL, 1.2 mmol) and stirred for 2 h at 60° C. The reaction was allowed to cool to 25° C., treated with glacial acetic acid (0.4 mL), the solvents were removed in vacuo, and the residue was purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 50×21.2 mm, 5 micron, 30%-90% in 7 min @ 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, cis-N-[3-(1-benzyl-4-hydroxy-2-oxo-2,4a,5,6,7,7a-hexahydro-1H-[1]pyrindin-3-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl]-methanesulfonamide (47.0 mg, 0.091 mmol, 30.3%), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.43-1.61 (3H, m), 1.93-2.15 (3H, m), 3.06 (3H, s), 3.80-3.90 (1H, m), 4.40-4.52 (1H, m), 4.96 (1H, d, J=14.8 Hz), 7.27-7.34 (5H, m), 7.50-7.60 (3H, m), 10.18 (1H, s). LC-MS (ESI) calcd for C23H24N4O6S2 516.11, found 517.2 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][CH3:21])=[S:19])=[CH:13][CH:12]=3)[N:10]=[C:4]2[CH:3]=1.[Br:22]Br>C(Cl)(Cl)Cl>[Br:22][C:8]1[N:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]2=[N:10][C:9]=1[C:11]1[CH:12]=[CH:13][C:14]2[N:17]=[C:18]([NH:20][CH3:21])[S:19][C:15]=2[CH:16]=1
Reactant: BrBr
Reactant: CNC(=S)Nc1ccc(-c2cn3ccc(C)cc3n2)cc1
Solvent: ClC(Cl)Cl
Product: CNc1nc2ccc(-c3nc4cc(C)ccn4c3Br)cc2s1
Temperature: 82.5 °C
Yield: 15 %

Procedure:
To a solution of 7-methyl-2-[4-(3-methylthioureido)phenyl]imidazo[1,2-a]pyridine (9.0 g) in chloroform (300 ml) was added portionwise bromine (11.5 g) at ambient temperature and the mixture was refluxed for 6 hours under stirring. The reaction mixture was evaporated in vacuo. To the residue was added 5% hydrochloric acid (300 ml) and the mixture was heated at 80 to 85° C. for 5 hours. The reaction mixture was filtered and the filtrate was adjusted to pH 7.5 with 20% potassium carbonate. From the resultant aqueous solution the product was extracted with a mixture of ethyl acetate and tetrahydrofuran. The organic extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was subjected to column chromatography on silica gel eluting with a mixture of ethyl acetate and tetrahydrofuran (8:2) and the fraction containing the desired compound was evaporated in vacuo to give 6-(3-bromo-7-methyl imidazo[1,2-a]pyridin-2-yl)- 2-methylaminobenzothiazole (1.7 g). mp. 225° C. (dec.).
Reaction SMILES: C(OC(N[C@@H](C(C)C)C(O)=O)=O)(C)(C)C.C(OC(NC(C(C)(C)C)C(O)=O)=O)(C)(C)C.[NH2:32][C@@H:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][C@@H:34]1[OH:42].C(OC(=O)NC(C(=O)NC1C2C(=CC=CC=2)CC1O)C(C)(C)C)(C)(C)C.ClNC(=O)[O-].C([O:76][C:77]([C:79]1([NH:84][C:85]([CH:87]2[CH2:91][CH:90]([O:92][C:93]3[C:102]4[C:97](=[CH:98][C:99]([O:103][CH3:104])=[CH:100][CH:101]=4)[N:96]=[C:95]([C:105]4[CH:110]=[CH:109][CH:108]=[CH:107][CH:106]=4)[CH:94]=3)[CH2:89][N:88]2[C:111](=[O:131])[NH:112][CH:113]([C:118](=[O:130])NC2C3C(=CC=CC=3)CC2O)[C:114](C)([CH3:116])[CH3:115])=[O:86])[CH2:81][CH:80]1[CH:82]=[CH2:83])=[O:78])C>>[OH:42][C@H:34]1[CH2:35][C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C@H:33]1[NH:32][C:118]([C@@H:113]([NH:112][C:111]([N:88]1[CH2:89][C@H:90]([O:92][C:93]2[C:102]3[C:97](=[CH:98][C:99]([O:103][CH3:104])=[CH:100][CH:101]=3)[N:96]=[C:95]([C:105]3[CH:106]=[CH:107][CH:108]=[CH:109][CH:110]=3)[CH:94]=2)[CH2:91][C@H:87]1[C:85]([NH:84][C@:79]1([C:77]([OH:78])=[O:76])[CH2:81][C@H:80]1[CH:82]=[CH2:83])=[O:86])=[O:131])[CH:114]([CH3:116])[CH3:115])=[O:130]
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)NC(C(=O)NC1c2ccccc2CC1O)C(C)(C)C)C(=O)OCC
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Agent: CC(C)(C)OC(=O)NC(C(=O)NC1c2ccccc2CC1O)C(C)(C)C
Agent: CC(C)(C)OC(=O)NC(C(=O)O)C(C)(C)C
Agent: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)N[C@H](C(=O)N[C@@H]1c2ccccc2C[C@@H]1O)C(C)C)C(=O)O
Yield: 24 %

Procedure:
(2S)-tert-butoxycarbonylamino-3-methylbutyric acid was attached to the resin as described for the preparation of compound 16 followed by reaction with (1R,2S)-1-amino-2-indanol as described for the preparation of 17 and removal of the Boc group as described for 18. The afforded compound was then reacted with the chlorocarbamate achieved from 12 as described for the preparation of 13 which, after purification by HPLC, gave the title compound (11 mg, 24% yield), Purity by HPLC >75% M+H+748.
Reaction SMILES: [CH:1]([NH:4][C:5]1[NH:10][C:9]2[CH:11]=[C:12]([CH2:15][C:16]([NH2:18])=O)[CH:13]=[CH:14][C:8]=2[S:7](=[O:20])(=[O:19])[N:6]=1)([CH3:3])[CH3:2].C(O)=O.C=O>C(#N)C>[CH:1]([NH:4][C:5]1[NH:10][C:9]2[CH:11]=[C:12]([CH2:15][C:16]#[N:18])[CH:13]=[CH:14][C:8]=2[S:7](=[O:19])(=[O:20])[N:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)NC1=NS(=O)(=O)c2ccc(CC(N)=O)cc2N1
Agent: C=O
Solvent: O=CO
Solvent: CC#N
Product: CC(C)NC1=NS(=O)(=O)c2ccc(CC#N)cc2N1

Procedure:
A slurry of 2-(3-isopropylamino-1,1-dioxo-1,4-dihydro-1λ6,2,4-benzothiadiazin-6-yl)acetamide (50 mg) in a mixture of 0.8 ml of acetonitrile, 0.2 ml of formic acid and 25 mg of paraformaldehyde was heated at reflux for 16 h, and then evaporated to dryness. The residue was purified on a silica column eluted with dichloromethane-methanol (95:5) to give the title compound; m.p. 195-203° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH2:12][C:13]([C:15]1[CH:26]=[CH:25][C:18]2[N:19]([CH3:24])[C:20](=[O:23])[N:21]([CH3:22])[C:17]=2[CH:16]=1)=[O:14].[CH3:27]I.O>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]([CH3:27])[C:13]([C:15]1[CH:26]=[CH:25][C:18]2[N:19]([CH3:24])[C:20](=[O:23])[N:21]([CH3:22])[C:17]=2[CH:16]=1)=[O:14]
Reactant: CI
Reactant: COc1ccc(CC(=O)c2ccc3c(c2)n(C)c(=O)n3C)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(C)C(=O)c2ccc3c(c2)n(C)c(=O)n3C)c(Cl)c1
Reaction time: 0.5 h

Procedure:
Sodium hydride (55% in mineral oil, 139 mg) was added to a solution of 5-[2-(2-chloro-4-methoxy-phenyl)-acetyl]-1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one (1 g) in DMF (16 ml) at 0° C. The mixture was stirred for 30 min, then methyl iodide (0.2 ml) was added at 0° C. Water was added to the mixture and extracted with DCM. The combined organic layers were dried over Na2SO4 and concentrated to an oil. The residue was purified by flash chromatography (SiO2, 0 to 60% EtOAc/DCM) to give the title compound (830 mg) as light yellow oil. MS (m/e)=359.0 [M+H+].
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](Cl)=[O:9])(=[O:4])=[O:3].[CH2:14]([OH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.N1C=CC=CC=1>O1CCCC1.O>[Cl:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([O:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:9])(=[O:4])=[O:3]
Reactant: OCc1ccccc1
Reactant: O=C(Cl)c1cccc(S(=O)(=O)Cl)c1
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: O=C(OCc1ccccc1)c1cccc(S(=O)(=O)Cl)c1
Reaction time: 1 h
Yield: 87.2 %

Procedure:
To a solution of 3-(chlorosulfonyl)benzoyl chloride (1.5 g) in tetrahydrofuran (12 mL) were added benzyl alcohol (712 mg) and pyridine (370 mg) at room temperature, and the mixture was stirred for 1 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:16:1) to give benzyl 3-(chlorosulfonyl)benzoate as a colorless oil (yield 1.70 g, 87%). To a suspension of sodium hydride (60% in oil, 120 mg) in tetrahydrofuran (8 mL) were added dropwise a solution (12 mL) of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (646 mg) in tetrahydrofuran, 15-crown-5 (660 mg) and benzyl 3-(chlorosulfonyl)benzoate (684 mg) under ice-cooling and the mixture was stirred for 1 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→3:2) to give the title compound as a pale-yellow oil (yield 1.09 g, 91%).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:21])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[CH:17]=[C:16]([C:18]#[N:19])[C:15]([NH2:20])=[N:14]2)=[CH:8][CH:7]=1>O.CO>[NH2:20][C:15]1[C:16]([C:18]#[N:19])=[CH:17][N:13]([CH2:12][C:9]2[CH:10]=[CH:11][C:6]([C:5]([OH:21])=[O:4])=[CH:7][CH:8]=2)[N:14]=1
Reactant: COC(=O)c1ccc(Cn2cc(C#N)c(N)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#Cc1cn(Cc2ccc(C(=O)O)cc2)nc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
To a solution of NaOH (343 mg, 8.58 mmol) in a mixture of water (10 ml) and MeOH (20 ml) the ester 95 (732 mg, 2.86 mmol) was added. The reaction mixture was refluxed 2 min and stirred for additional 2 hrs at ambient temperature. MeOH was removed under reduced pressure and remaining aqueous solution was acidified with conc. HCl (pH 3-4) to form a precipitate which was collected by filtration to afford the title compound (96) (640 mg, 92% yield). LRMS: 242.2 (calc.), 241.1 (found).
Reaction SMILES: Cl[C:2]1[C:3]([C:18]([O:20]CC2C=CC=CC=2)=[O:19])=[N:4][CH:5]=[C:6]([C:8]([O:10]CC2C=CC=CC=2)=[O:9])[CH:7]=1.[CH3:28][S-:29].[Na+].O>CS(C)=O>[CH3:28][S:29][C:2]1[C:3]([C:18]([OH:20])=[O:19])=[N:4][CH:5]=[C:6]([C:8]([OH:10])=[O:9])[CH:7]=1
Reactant: C[S-]
Reactant: O=C(OCc1ccccc1)c1cnc(C(=O)OCc2ccccc2)c(Cl)c1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CSc1cc(C(=O)O)cnc1C(=O)O
Temperature: 140 °C
Yield: 109.4 %

Procedure:
4.6 g (12 mmol) of dibenzyl 3-chloropyridine-2,5-dicarboxylate were dissolved, at 20° C. and while stirring, in 30 ml of dimethyl sulfoxide, and after that 5.0 g (70 mmol) of sodium thiomethoxide were added, in association with which the temperature rose to 80° C. The reaction mixture was heated at 140° C. for 1 h and then cooled down, after which water was added to it; the oily layer was separated off and cone. hydrochloric acid (pH 1) was added to the aqueous DMSO phase, and the precipitated product was filtered off with suction. 2.8 g of yellow crystalline product were obtained, m.p. 223° C. (with decomposition).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][CH:8]1[CH:13]([CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])[CH:12]([CH3:19])[CH2:11][C:10](=[O:20])[CH2:9]1.O.[OH-].[Na+]>C(OCC)C>[CH3:19][CH:12]1[CH:13]([CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])[CH:8]([CH3:7])[CH2:9][CH:10]([OH:20])[CH2:11]1
Reactant: CC(C)=CCC1C(C)CC(=O)CC1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CC(C)=CCC1C(C)CC(O)CC1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
A suspension of lithium aluminum hydride (0.68 g, 0.018 mol) in anhydrous diethyl ether (50 mL) was stirred under nitrogen at 10° C. while 3,5-dimethyl-4-(3-methyl-2-butenyl) cyclohexanone (6.8 g, 0.035 mol) in anhydrous ether (15 mL) was added over a period of 30 minutes. The mixture was stirred at room temperature for 2 hours; then it was treated successively with H2O (0.7 mL), 15% NaOH (0.7 mL), and H2O (2.1 mL). The solution was filtered, dried (NaSO4), and concentrated to give the crude alcohol as a colorless oil. Kugelrohr distillation afforded 6.2 g of 3,5-dimethyl-4-(3-methyl-2-butenyl) cyclohexanol, bp 130° C./0.3 mm.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2].CN(C(ON1N=N[C:34]2[CH:35]=[CH:36][CH:37]=[N:38][C:33]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C1(CN)CCC1>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:38][CH2:37][CH:36]4[CH2:35][CH2:34][CH2:33]4)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NCC1CCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)NCC4CCC4)cn3)c2O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Combined 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (200 mg, 0.654 mmol) and HATU (372 mg, 0.98 mmol) in DMF (3 mL) was added triethylamine (198 mg, 1.961 mmol). Then cyclobutylmethanamine (0.784 mmol) was added and the reaction was stirred at room temperature for 4 h. The reaction mixture was purified by preparative HPLC to give the title compound as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.90 (s, 1H), 8.70-8.65 (m, 2H), 8.45-8.40 (m, 2H), 8.13 (d, J=7.6 Hz, 2H), 7.78 (d, J=7.6 Hz, 2H), 3.31 (m, 2H), 2.56-2.53 (m, 1H), 2.05-2.00 (m, 2H), 1.85-1.82 (m, 2H), 1.75-1.72 (m, 2H). MS m/Z [M+H]+ 374.1.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1)#[CH:2].I[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19]>>[C:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]2[O:19][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:2]=2)=[CH:4][CH:5]=1)(=[O:11])[CH3:10]
Reactant: C#Cc1ccc(C(C)=O)cc1
Reactant: Oc1ccccc1I
Product: CC(=O)c1ccc(-c2cc3ccccc3o2)cc1

Procedure:
The general procedure was used to convert 1-(4-Ethynyl-phenyl)-ethanone and 2-iodophenol to the title product. Purification by flash chromatography (10% ethyl acetate in hexanes as the eluent) gave the analytically pure product as a white solid (326 mg, 69% yield). 1H NMR (300 MHz, CDCl3) δ 8.02 (d, J=8.67, 2H), 7.92 (d, J=8.67, 2H), 7.60 (d, J=7.72, 1H), 7.52 (d, J=7.35, 1H), 7.35-7.22 (m, 2H), 7.14 (s, 1H), 2.62 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 197.33, 155.18, 154.50, 136.48, 134.55, 128.91, 128.87, 125.14, 124.75, 123.24, 121.32, 111.35, 103.65, 26.62. HRMS El calcd for C16H12O2—236.0837, Found—236.0835. mp.—168-170° C. (lit., 3168-170° C.).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]2[CH2:29][N:30]([CH2:33][C:34]3([CH3:38])[CH2:37][O:36][CH2:35]3)[C:31](=[O:32])[C:26]2=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[N:28]=[C:27]3[CH2:29][N:30]([CH2:33][C:34]4([CH3:38])[CH2:35][O:36][CH2:37]4)[C:31](=[O:32])[C:26]3=[CH:25][CH:24]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: CC1(CN2Cc3nc(Cl)ccc3C2=O)COC1
Product: CC1(CN2Cc3nc(Nc4sc(-c5c(F)cc(C(C)(C)O)cc5F)cc4C(N)=O)ccc3C2=O)COC1

Procedure:
The title compound was prepared according to the general procedure in Example 1 Step 5 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (130 mg, 0.42 mmol) and 2-chloro-6-[(3-methyloxetan-3-yl)methyl]-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (100 mg, 0.40 mmol) as the starting materials.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:23][C:24]4[CH:34]=[CH:33][C:27]5[S:28](=[O:32])(=[O:31])[CH:29]=[CH:30][C:26]=5[CH:25]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:23][C:24]4[CH:34]=[CH:33][C:27]5[S:28](=[O:31])(=[O:32])[CH2:29][CH2:30][C:26]=5[CH:25]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc5c(c4)C=CS5(=O)=O)ncnc32)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc5c(c4)CCS5(=O)=O)ncnc32)CC1
Reaction time: 3 h
Yield: 93.1 %

Procedure:
A mixture of 4-[4-(1,1-dioxo-1H-1λ6-benzo[b]thiophen-5-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 78; 531 mg, 1.1 mmol) and 10% palladium on carbon (50 mg) in ethyl acetate (40 mL) was stirred under an atmosphere of hydrogen for 3 h. The mixture was then filtered through Celite™ and the filtrate was evaporated and chromatographed, eluting with 50% ethyl acetate/hexanes to give 4-[4-(1,1-dioxo-2,3-dihydro-1H-1λ6-benzo[b]thiophen-5-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (497 mg, 93%) as a white solid.