Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([CH2:13][CH3:14])=[C:9]([F:12])[CH:10]=2)[NH:5][C:4]=1[C:15]1[N:20]=[CH:19][C:18]([S:21]([NH:24][C@@H:25]([CH3:30])[C:26]([F:29])([F:28])[F:27])(=[O:23])=[O:22])=[CH:17][CH:16]=1)#[N:2].Br[C:32]1[N:37]=[CH:36][CH:35]=[CH:34][N:33]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu]I.CN(C=O)C>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([CH2:13][CH3:14])=[C:9]([F:12])[CH:10]=2)[N:5]([C:32]2[N:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[C:4]=1[C:15]1[N:20]=[CH:19][C:18]([S:21]([NH:24][C@@H:25]([CH3:30])[C:26]([F:29])([F:27])[F:28])(=[O:22])=[O:23])=[CH:17][CH:16]=1)#[N:2]
Reactant: CCc1cc2[nH]c(-c3ccc(S(=O)(=O)N[C@@H](C)C(F)(F)F)cn3)c(C#N)c2cc1F
Reactant: Brc1ncccn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cc2c(cc1F)c(C#N)c(-c1ccc(S(=O)(=O)N[C@@H](C)C(F)(F)F)cn1)n2-c1ncccn1
Temperature: 110 °C
Reaction time: 70 h

Procedure:
A mixture of (S)-6-(3-cyano-6-ethyl-5-fluoro-1H-indol-2-yl)-N-(1,1,1-trifluoropropan-2-yl)pyridine-3-sulfonamide (0.22 g, 0.5 mmol), prepared as above, 2-bromopyrimidine (0.167 g, 1.0 mmol), potassium carbonate (0.212 g, 1.5 mmol) and copper (I) iodide (20 mg, 0.1 mmol) were mixed with DMF (2.5 mL). The system was evacuated and replaced with an argon atmosphere. The reaction mixture was stirred at 110° C. for 70 hr, then cooled to 0° C., diluted with ethyl acetate and neutralized with 1N HCl. The ethyl acetate layer was washed with water, brine, dried over Na2SO4, filtrated through silica gel pad and evaporated. The crude product was triturated with CH2Cl2 and hexane and was further recrystallized from ethyl acetate and hexane. After air drying, the off-white solid (S)-6-(3-cyano-6-ethyl-5-fluoro-1-(pyrimidin-2-yl)-1H-indol-2-yl)-N-(1,1,1-trifluoropropan-2-yl)pyridine-3-sulfonamide was obtained. Melting point: 195-198° C.; MS m/z 519.1 M-1-H+; 1H NMR (500 MHz, acetone-d6): □ 8.90 (1H, dd, J=2.5, 1.0 Hz), 8.83 (2H, d, J=4.5 Hz), 8.49 (1H, dd, J=8.0, 2.5 Hz), 8.16 (1 H, t, J=6.5 Hz), 8.15 (1 H, d, J=9.0 Hz), 7.68 (1 H, br s), 7.57-7.54 (2H, m), 4.32 (1 H, br s), 2.85 (2 H, q, J=7.5 Hz), 1.29 (3 H, t, J=7.5 Hz), 1.28 (3 H, d, J=7.2 Hz).
Reaction SMILES: [F:1][C:2]1[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]2[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]4[CH:38]=[C:37]5[C:32]([CH2:33][CH2:34][N:35](C(=O)C(F)(F)F)[CH2:36]5)=[CH:31][CH:30]=4)[N:23]=3)=[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]3[N:14]=2)[CH:10]=[CH:9][C:8]=1[O:45][CH3:46])=[O:5].C1COCC1.[Li+].[OH-]>O>[F:51][C:47]1[CH:48]=[CH:49][CH:50]=[C:2]([F:1])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]2[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]4[CH:38]=[C:37]5[C:32]([CH2:33][CH2:34][NH:35][CH2:36]5)=[CH:31][CH:30]=4)[N:23]=3)=[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]3[N:14]=2)[CH:10]=[CH:9][C:8]=1[O:45][CH3:46])=[O:5]
Reactant: COc1ccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CN(C(=O)C(F)(F)F)CC4)n2)cc1NC(=O)c1c(F)cccc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)cc1NC(=O)c1c(F)cccc1F
Temperature: 50 °C
Yield: 73.6 %

Procedure:
To a solution of 2,6-difluoro-N-{2-(methyloxy)-5-[3-(2-{[2-(trifluoroacetyl)-1,2,3,4-tetrahydro-7-isoquinolinyl]amino}-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}benzamide (50 mg, 0.072 mmol) in 10:1 THF:H2O (10 mL) was added 1M LiOH (0.43 ml, 0.43 mmol) and the reaction mixture was heated at 50° C. overnight. The reaction was washed with brine (10 mL), organic layer removed, adsorbed to silica gel and purified by column chromatography (0-10% MeOH/DCM+1% NH4OH) to afford the title compound (32 mg, 74%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 2.75 (t, 2H, J=5.86 Hz), 3.13 (t, 2H, J=5.86 Hz), 3.93 (s, 3H), 3.97 (s, 2H), 6.64 (d, 1H, J=5.31 Hz), 6.86-6.89 (m, 1H), 6.94-7.03 (m, 4H), 7.24-7.44 (m, 5H), 8.16 (d, 1H, J=5.31 Hz), 8.32-8.38 (m, 2H), 8.50 (d, 1H, J=6.96 Hz), 8.98 (m, 1H); ESIMS (M+H)+=604.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:25]=[C:24]([O:26][C@H:27]3[C@H:31]4[O:32][CH2:33][C@@H:34]([OH:35])[C@H:30]4[O:29][CH2:28]3)[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=1.Br[C:45]1[CH:50]=[CH:49][C:48]([N:51]=[S:52]([CH3:57])([N:54]([CH3:56])[CH3:55])=[O:53])=[CH:47][CH:46]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)C>[OH:35][C@H:34]1[C@H:30]2[O:29][CH2:28][C@@H:27]([O:26][C:24]3[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:5]4=[N:6][C:7]([C:8]5[CH:9]=[CH:10][C:11]([C:45]6[CH:46]=[CH:47][C:48]([N:51]=[S:52]([CH3:57])([N:54]([CH3:55])[CH3:56])=[O:53])=[CH:49][CH:50]=6)=[CH:12][CH:13]=5)=[C:2]([Cl:1])[CH:3]=[C:4]4[N:25]=3)[C@H:31]2[O:32][CH2:33]1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)OC1(C)C
Reactant: CN(C)S(C)(=O)=Nc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)S(C)(=O)=Nc1ccc(-c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)cc1
Temperature: 70 °C

Procedure:
A mixture of (3R,3aR,6R,6aR)-6-(6-chloro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol (1.00 g), N′-(4-bromophenyl)-N,N-dimethyl-methanesulfonimidamide (484 mg), Na2CO3 (2 M aqueous solution, 1.98 mL), and ethanol (8 mL) is purged for 5 minutes with argon. [1,1′-Bis(diphenylphosphino)-ferrocene]-dichloropalladium(II)-CH2Cl2-complex (PdCl2(dppf)×CH2Cl2) (130 mg) is added and the mixture is stirred over night at 70° C. The reaction mixture concentrated in vacuo and the residue is purified by preparative HPLC to give the title compound. LC (method 1): tR=1.13 min; Mass spectrum (ESI+): m/z=700 [M+H]+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]([O:14][CH3:15])=[C:7]([C@H:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)[CH:8]=1.Br[C:17]1[CH:22]=[CH:21][N:20]2[N:23]=[CH:24][C:25]([C:26]([O:28]CC)=[O:27])=[C:19]2[C:18]=1[F:31]>>[F:31][C:18]1[C:19]2[N:20]([N:23]=[CH:24][C:25]=2[C:26]([OH:28])=[O:27])[CH:21]=[CH:22][C:17]=1[N:10]1[CH2:11][CH2:12][CH2:13][C@@H:9]1[C:7]1[CH:8]=[C:3]([F:2])[CH:4]=[CH:5][C:6]=1[O:14][CH3:15]
Reactant: COc1ccc(F)cc1[C@H]1CCCN1
Reactant: CCOC(=O)c1cnn2ccc(Br)c(F)c12
Agent: Cl
Product: COc1ccc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2c1F

Procedure:
The title compound was prepared by a method substantially similar to that mentioned in step-5 and step-6 of example-3 using (R)-2-(5-Fluoro-2-methoxyphenyl)pyrrolidine hydrochloride (step-1) and Ethyl 5-bromo-4-fluoropyrazolo[1,5-a]pyridine-3-carboxylate (step-4 of example-248) to afford the product as white solid. MS (ESI): m/z 374.12 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:13])([CH3:12])[CH2:10][OH:11])=[CH:5][CH:4]=1.[I:14]I>CCO.[O-]S([O-])(=O)=O.[Ag+].[Ag+]>[I:14][C:4]1[CH:5]=[C:6]([C:9]([CH3:13])([CH3:12])[CH2:10][OH:11])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(C(C)(C)CO)cc1
Reactant: II
Agent: [Ag+]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: COc1ccc(C(C)(C)CO)cc1I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(4-methoxyphenyl)-2-methylpropan-1-ol (661.7 mg, 3.68 mmol) (2-(4-methoxyphenyl)-2-methylpropan-1-ol has been described in the literature. See Helv. Chim. Acta. 1971, 54, p. 868-897.) in EtOH (40 mL) was added Ag2SO4 (1.15 g, 3.68 mmol) followed by I2 (934 mg, 3.68 mmol). The reaction was stirred at room temperature for 2 hours, and then the solids were filtered off through a pad of Celite. The filtrate was concentrated to ˜10 mL and then diluted with EtOAc (50 mL). The organic solution was washed with water, aq. NaHSO3, and brine (15 mL each). The organic layer was then diluted with 50 mL of hexanes and filtered through a short plug of silica gel with (50/50 EtOAc/hexanes). The filtrate was concentrated to afford 2-(3-iodo-4-methoxyphenyl)-2-methylpropan-1-ol. 1H NMR (CDCl3, 500 MHz) δ 7.76 (d, J=2.3 Hz, 1H), 7.32 (dd, J=8.7, 2.3 Hz, 1H), 6.79 (d, J=8.7 Hz, 1H), 3.87 (s, 3H), 3.57 (s, 2H), 1.30 (s, 6H).
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:7]=[CH:8][C:9]([C:20]([F:23])([F:22])[F:21])=[C:10]2[C:14]=1[NH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11]2)[CH2:3][CH2:4][OH:5].C(N(CC)CC)C.O1CCCC1.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>O>[CH3:1][N:2]([C:6]1[CH:7]=[CH:8][C:9]([C:20]([F:23])([F:22])[F:21])=[C:10]2[C:14]=1[NH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11]2)[CH2:3][CH2:4][O:5][S:37]([CH3:36])(=[O:39])=[O:38]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1cc2c(C(F)(F)F)ccc(N(C)CCO)c2[nH]1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc2c(C(F)(F)F)ccc(N(C)CCOS(C)(=O)=O)c2[nH]1

Procedure:
A mixture of ethyl 7-[N-methyl-N-(2-hydroxyethyl)amino]-4-trifluoromethyl-1H-indole-2-carboxylate (0.37 g, 1.12 mmol)., triethylamine (0.25 g, 2.46 mmol) and tetrahydrofuran (20 ml) was cooled to -19° C., after which methanesulfonyl chloride (0.14 g, 1.23 mmol) was added dropwise with stirring. The reaction mixture was stirred at -18° C. to -13° C. for 1 hour, poured into cold water, and then extracted three times with ethyl acetate. The extract solution was washed with a 5% aqueous sodium hydrogencarbonate solution and a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain an oil of ethyl 7-[N-methyl-N-(2-methanesulfonyloxyethyl)amino]-4-trifluoromethyl-1H-indole-2-carboxylate.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH2:3][CH2:2]1.C1([CH:20]=[CH:21][C:22]([OH:24])=[O:23])C2NC3C(=CC=CC=3)SC=2C=CC=1.C=CC1C=CN=CC=1.Cl>>[C:22]([O:24][CH:5]1[CH2:4][CH2:3][CH2:2][O:1]1)(=[O:23])[CH:21]=[CH2:20]
Reactant: C1=COCC1
Reactant: O=C(O)C=Cc1cccc2c1Nc1ccccc1S2
Agent: C=Cc1ccncc1
Agent: Cl
Product: C=CC(=O)OC1CCCO1
Temperature: 25 °C

Procedure:
To a 100 mL 3-neck round bottom flask equipped with a stir bar, condenser, and addition funnel was added 39 mL of dihydrofuran (FW 70.09, d=0.927), and 0.18 g of phenothiazine Acrylic acid (19 mL, FW 72.06, d=1.05) was added dropwise slowly with stirring. A mild exotherm (55° C.) occurred. After cooling to room temperature, 0.415 g of poly(4-vinylpyridine hydrochloride) was added and the reaction was stirred overnight. The acid catalyst was then filtered off and 0.2 g each of calcium hydride and potassium carbonate was added to the filtrate. After removal of excess dihydrofuran on a rotovap, 10 mg of DPPH (2,2-diphenyl-1-picrylhydrazyl hydrate) was added and the slurry was vacuum distilled at 200 mtorr at 26° C. to give 26.0 g of 2-tetrahydrofuranyl acrylate.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)=[N+]=[N-].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[NH2:1][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][CH:10]=1
Reactant: [N-]=[N+]=NCCCCCc1ccc(Oc2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCCCCCc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 84 h

Procedure:
To a solution of the product from Step 2 (360 mg, 1.28 mmol) in 10 mL of THF at room temperature was added water (0.025 mL), followed by triphenylphosphine (364 mg, 1.41 mmol). The solution was stirred at room temperature. After 84 hours, the reaction was concentrated in vacuo to provide the titled compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]=2[CH:11]=[O:12])[CH:7]=1.[BH4-].[Na+]>CO>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]=2[CH2:11][OH:12])[CH:7]=1
Reactant: Cc1cnc2c(C=O)c(-c3ccccc3)nn2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cnc2c(CO)c(-c3ccccc3)nn2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
To a solution of 6-methyl-2-phenylpyrazolo[1,5-a]pyrimidine-3-carbaldehyde x26 (3.37 mmol, 1 eq, 0.8 g) in MeOH (20 ml) maintained at 0° C. is added sodium borohydride (3.7 mmol, 1.1 eq, 0.14 g) and the resulting solution is stirred at room temperature during 0.5 hour. After this time, the solvent is removed under reduced pressure. The solid residue is washed with water, filtered and dried (under vacuum) to give 0.58 g of pure (6-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methanol x143.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH:4][N:5]=[C:6]1[C:10](=O)[CH2:9][CH2:8][S:7]1(=[O:13])=[O:12]>O.CO>[OH:4][N:5]=[C:6]1[C:10](=[N:2][OH:3])[CH2:9][CH2:8][S:7]1(=[O:13])=[O:12]
Reactant: O=C1CCS(=O)(=O)C1=NO
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CO
Product: O=S1(=O)CCC(=NO)C1=NO
Yield: 49.7 %

Procedure:
5.4 g (77 mmol) of hydroxylamine hydrochloride, dissolved in 15 ml of water, are added to a solution of 11.4 g (70 mmol) of 2-hydroxyimino-3-oxotetrahydrothiophene dioxide in 100 ml of methanol. After 2 hours at room temperature the batch is completely concentrated and the residue is recrystallised from ethanol. 6.2 g (50%) of 2,3-dihydroxyiminotetrahydrothiophene dioxide, m.p. 181° C., are obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2=[N:14][NH:15][CH:16]=[C:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:18]1[N:28]=[CH:27][CH:26]=[CH:25][C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2=[N:14][N:15]([C:18]3[N:28]=[CH:27][CH:26]=[CH:25][C:19]=3[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:16]=[C:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCc3n[nH]cc3C2)cc1
Reactant: CCOC(=O)c1cccnc1Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccnc1-n1cc2c(n1)CCN(Cc1ccccc1)C2
Temperature: 140 °C
Yield: 130 %

Procedure:
The mixture of 5-benzyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine (1.0 g, 4.69 mmol), ethyl 2-chloronicotinate (1.55 g, 8.35 mmol), K2CO3 (1.7 g, 12.30 mmol), 18-CROWN-6 (0.2 g, 0.757 mmol) and KI (0.13 g, 0.783 mmol) in N,N-dimethylformamide (15 mL) was heated to 140° C. under stirring. After completion of the reaction the mixture was concentrated, the remainder dissolved in 250 mL of dichloromethane, washed subsequently with water (3×30 mL) and brine, dried (MgSO4), filtered and concentrated to give 2.21 g of a brown oil, which was purified by chromatography over silica gel (eluent CH2Cl2/methanol). 200 mg of the title compound was obtained as a white amorphous solid; ESI-MS [M+H]+: 363.2.
Reaction SMILES: Cl[S:2]([C:5]1[C:6]([O:16][CH3:17])=[CH:7][C:8]([O:14][CH3:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].[NH3:18].Cl>>[NH2:18][S:2]([C:5]1[C:6]([O:16][CH3:17])=[CH:7][C:8]([O:14][CH3:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3]
Reactant: N
Reactant: COc1cc(OC)c(S(=O)(=O)Cl)cc1C(=O)O
Agent: Cl
Product: COc1cc(OC)c(S(N)(=O)=O)cc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 1.00 g portion of 5-chlorosulfonyl-2,4-dimethoxybenzoic acid was added to 5 ml of saturated aqueous ammonia, followed by stirring at room temperature for 1 hour. Then, 6N hydrochloric acid aqueous solution was added to the reaction solution, and the thus precipitated product of interest was collected by filtration, washed with water and then dried under a reduced pressure to give 0.81 g of 5-aminosulfonyl-2,4-dimethoxybenzoic acid.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:4]2[C:9]([N:10]=1)=[C:8]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)[N:7]=[C:6]([NH2:17])[N:5]=2.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Br[C:77]1[CH:82]=[C:81]([Cl:83])[CH:80]=[CH:79][C:78]=1[N+:84]([O-:86])=[O:85]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:83][C:81]1[CH:80]=[CH:79][C:78]([N+:84]([O-:86])=[O:85])=[C:77]([NH:17][C:6]2[N:5]=[C:4]3[C:9]([N:10]=[C:2]([CH3:1])[N:3]3[CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:8]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[N:7]=2)[CH:82]=1
Reactant: Cc1nc2c(-c3ccncc3)nc(N)nc2n1C1CCOCC1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1nc2c(-c3ccncc3)nc(Nc3cc(Cl)ccc3[N+](=O)[O-])nc2n1C1CCOCC1
Temperature: 170 °C
Reaction time: 0.17 h
Yield: 21.5 %

Procedure:
To an oven-dried vial was added 8-methyl-6-(pyridin-4-yl)-9-(tetrahydro-2H-pyran-4-yl)-9H-purin-2-amine (56 mg, 0.18 mmol, 1 equiv.) in anhydrous toluene (1 mL), then freshly grounded cesium carbonate (82 mg, 0.25 mmol, 1.4 equiv.) with stirring at room temperature under Ar. After 10 min, Pd(OAc)2 (13.5 mg, 0.02 mmol, 0.1 equiv.), racemic BINAP (17 mg, 0.03 mmol, 0.15 equiv.) and 1-bromo-5-chloro-2-nitrobenzene (WO 02/053545 A1) (55 mg, 0.23 mmol, 1.3 equiv.) were added as solids. The vial was purged with Ar for 3 min, then closed and heated in a microwave oven at 170° C. for 2 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate/methylene chloride, filtered through a Nylon 0.45 μm filter, and the filtrate was concentrated in vacuo. The resulting residue was purified using preparative TLC (silica gel, 7.5% methanol in methylene chloride) to give the desired product as a yellow solid (18 mg, 21% yield). 1H NMR (300 MHz, CDCl3+CD3OD) δ, ppm: 9.30 (s, 1H), 8.77 (br m, 2H), 8.64 (br m, 2H), 8.26 (d, J=8.9 Hz, 1H), 7.05 (d, J=7.9 Hz, 1H), 4.60-4.56 (m, 1H), 4.26-4.22 (m, 2H), 3.64 (app t, J=11.9 Hz, 2H), 2.94-2.90 (m, 2H), 2.76 (s, 3H), 1.91 (br d, J=11.2 Hz, 2H); MS (EI) m/z 466.3 (MH)+.
Reaction SMILES: N1C[CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([NH:12]C(N3CC(C4C=NC=CC=4)C3)=O)=CC=2)C1.[NH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[CH:28][CH:27]=1.C[C@@H](CC)C(O)=O>>[NH2:25][C:26]1[CH:27]=[CH:28][C:29]([C:30]([NH:12][CH2:9][CH:10]2[CH2:11][CH2:6][O:5][CH2:3]2)=[O:32])=[CH:33][CH:34]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C(Nc1ccc(OC2CNC2)cc1)N1CC(c2cccnc2)C1
Agent: CC[C@H](C)C(=O)O
Product: Nc1ccc(C(=O)NCC2CCOC2)cc1

Procedure:
The title compound was prepared as described in Example 1E, substituting (tetrahydrofuran-3-yl)methanamine for N-(4-(azetidin-3-yloxy)phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide and 4-aminobenzoic acid for (S)-2-methylbutanoic acid.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([O:15][C:16]1[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1)C.[CH3:24][C:25]1[O:29][C:28]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[S:37][CH:38]=[CH:39][CH:40]=3)=[CH:32][CH:31]=2)=[N:27][C:26]=1[CH2:41][CH2:42][O:43]S(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>C(O)C>[CH3:14][C:5]([O:15][C:16]1[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=1)([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:43][CH2:42][CH2:41][C:26]2[N:27]=[C:28]([C:30]3[CH:31]=[CH:32][C:33]([C:36]4[S:37][CH:38]=[CH:39][CH:40]=4)=[CH:34][CH:35]=3)[O:29][C:25]=2[CH3:24])=[CH:9][CH:8]=1)[C:4]([OH:23])=[O:3]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1cccc(C)c1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4cccs4)cc3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc(OC(C)(Cc2ccc(OCCc3nc(-c4ccc(-c5cccs5)cc4)oc3C)cc2)C(=O)O)c1

Procedure:
A mixture of 2-(m-tolyloxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethyl ester (0.095 g, 0.030 mmol) (see Ex. 48, Part C), toluene-4-sulfonic acid 2-(5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl)ethyl ester (0.030 mmol) and 325 mesh K2CO3 (0.084 g, 0.60 mmol) in ethanol (2 mL) was heated to reflux for 24 h under N2. Aqueous 5N NaOH (0.5 mL) and additional ethanol (1 mL) was added to the reaction mixture and it was heated at reflux for an additional 2 h. The reaction was cooled and the solvent removed in vacuo. The residue was acidified with aqueous 1 N HCl (5 mL), extracted with water and CH2Cl2 and the organic layer dried by passing it through a Varian Chem Elut 1003 cartridge. The solvent was removed in vacuo to give 2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-2-m-tolyloxy-propionic acid. 1H NMR (400 MHz, CDCl3) δ 7.97 (d, 2H, J=8.60 Hz), 7.68 (d, 2H, J=8.60 Hz), 7.40 (d, 1H, J=3.52 Hz), 7.34 (d, 1H, J=4.69 Hz), 7.18 (d, 2H, J=8.21 Hz), 7.15–7.09 (m, 2H), 6.87–6.82 (m, 3H), 6.72–6.69 (m, 2H), 4.22 (t, 2H, J=6.26 Hz), 3.23 (d, 1H, J=14.08 Hz), 3.13 (d, 1H, J=14.08 Hz), 3.03 (t, 2H, J=6.26 Hz) 2.41 (s, 3H), 2.29 (s, 3H), 1.42 (s, 3H); HRMS (ES+) m/z exact mass calcd for C33H32NO5S 554.2001, found 554.2022.
Reaction SMILES: [C:1]([NH:4][C:5]([NH:7][C:8]1[C:13]([F:14])=[CH:12][C:11]([Br:15])=[CH:10][C:9]=1F)=[S:6])(=[O:3])[CH3:2].[H-].[Na+].O>CN(C=O)C>[Br:15][C:11]1[CH:12]=[C:13]([F:14])[C:8]2[N:7]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][C:9]=2[CH:10]=1
Reactant: CC(=O)NC(=S)Nc1c(F)cc(Br)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1nc2c(F)cc(Br)cc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.1 %

Procedure:
1-acetyl-3-(4-bromo-2,6-difluorophenyl)thiourea (3.356 g, 10.86 mmol) was dissolved in DMF (100 ml) and the flask was cooled under nitrogen in an ice water bath. Then, sodium hydride (60% in mineral oil, 512.6 mg, 12.82 mmol) was added, and the reaction was warmed to room temperature and stirred for 1 hour. Then, the reaction flask was put in a preheated oil bath (130° C.) and stirred under nitrogen for an additional hour. The reaction was cooled to room temperature, poured into deionized water (300 ml), and filtered. The solid was washed with water and then dried by suction overnight to afford N-(6-bromo-4-fluorobenzo[d]thiazol-2-yl)acetamide (3.205 g, ˜100%). MS (ESI pos. ion) m/z: 289 (MH+, 79Br), 291 (MH+, 81Br). Calculated exact mass for C9H6BrFN2OS 288 (79Br), 290 (81Br).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][C@H:15]([C:18]1[N:22]([C:23]2[CH:24]=[N:25][CH:26]=[C:27]([F:29])[CH:28]=2)[C:21]2[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:20]=2[N:19]=1)[CH2:16][CH3:17])(C)(C)C>C(Cl)Cl>[F:34][C:31]1[CH:32]=[CH:33][C:20]2[N:19]=[C:18]([C@@H:15]([NH2:14])[CH2:16][CH3:17])[N:22]([C:23]3[CH:24]=[N:25][CH:26]=[C:27]([F:29])[CH:28]=3)[C:21]=2[CH:30]=1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1cncc(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@H](N)c1nc2ccc(F)cc2n1-c1cncc(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.7 %

Procedure:
TFA (0.12 mL, 1.58 mmol) was added to a solution of {(S)-1-[6-fluoro-1-(5-fluoropyridin-3-yl)-1H-benzoimidazol-2-yl]propyl}carbamic acid tert-butyl ester (123 mg, 0.33 mmol) in DCM (2 mL) and the reaction stirred at RT for 18 h. The reaction mixture was concentrated in vacuo and passed through a 2 g Isolute® SCX-2 cartridge, eluting with 2M NH3/MeOH. The basic fraction was concentrated in vacuo to give the title compound (92 mg, quant.) as brown oil. LCMS (Method J): RT=1.86 min, [M+H]+=289.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:15].[OH:16][C:17]12[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][C:19]([CH2:27][C:28](O)=[O:29])([CH2:20]3)[CH2:18]1)[CH2:24]2>>[OH:16][C:17]12[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][C:19]([CH2:27][C:28]([NH:1][N:2]4[N:11]=[C:10]([CH:12]([CH3:13])[CH3:14])[C:9]5[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=5)[C:3]4=[O:15])=[O:29])([CH2:20]3)[CH2:18]1)[CH2:24]2
Reactant: CC(C)c1nn(N)c(=O)c2ccccc12
Reactant: O=C(O)CC12CC3CC(CC(O)(C3)C1)C2
Product: CC(C)c1nn(NC(=O)CC23CC4CC(CC(O)(C4)C2)C3)c(=O)c2ccccc12

Procedure:
The product of Example 1B and 2-(3-hydroxyadamantan-1-yl)acetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 11.12 (s, 1H), 8.34 (dd, J=7.9, 1.3 Hz, 1H), 8.11 (d, J=8.1 Hz, 1H), 8.00 (ddd, J=8.3, 7.1, 1.3 Hz, 1H), 7.89 (ddd, J=8.0, 7.1, 1.0 Hz, 1H), 3.61 (p, J=6.7 Hz, 1H), 2.08-2.11 (m, 4H), 1.36-1.63 (m, 13H), 1.26 (d, J=6.7 Hz, 6H); MS (ESI) m/z 396 (M+H)+.