Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:17]3[C:18]([CH3:28])=[N:19][N:20]4[CH:25]=[CH:24][C:23]([CH2:26][NH2:27])=[CH:22][C:21]=34)[S:10][C:11]=2[C:12]2[NH:16][CH:15]=[N:14][N:13]=2)=[CH:4][CH:3]=1.[N:31]1[CH:36]=[CH:35][N:34]=[CH:33][C:32]=1[C:37](Cl)=[O:38].C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:17]3[C:18]([CH3:28])=[N:19][N:20]4[CH:25]=[CH:24][C:23]([CH2:26][NH:27][C:37]([C:32]5[CH:33]=[N:34][CH:35]=[CH:36][N:31]=5)=[O:38])=[CH:22][C:21]=34)[S:10][C:11]=2[C:12]2[NH:16][CH:15]=[N:14][N:13]=2)=[CH:29][CH:30]=1
Reactant: O=C(Cl)c1cnccn1
Reactant: Cc1nn2ccc(CN)cc2c1-c1nc(Cc2ccc(Cl)cc2)c(-c2nnc[nH]2)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nn2ccc(CNC(=O)c3cnccn3)cc2c1-c1nc(Cc2ccc(Cl)cc2)c(-c2nnc[nH]2)s1
Temperature: 25 °C
Reaction time: 22 h
Yield: 2.5 %

Procedure:
A mixture of 1-{3-[4-(4-chlorobenzyl)-5-(4H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-2-methylpyrazolo[1,5-a]pyridin-5-yl}methanamine (0.0222 g, 0.0491), pyrazine-2-carboxylic acid chloride (8.0 mg, 0.056 mmol) and N,N-diisopropylethylamine (10 mg, 0.08 mmol) in dry Methylene chloride (5.0 mL) in dry N,N-dimethylformamide (1.0 mL) was sonicated for 2 min. The mixture was stirred at rt for 22 hours. N,N-diisopropylethylamine (13 mg, 0.10 mmol) and pyrazine-2-carboxylic acid chloride (9.11 mg, 0.0639 mmol) were added and the mixture was stirred at rt for 3 days. The mixture was quenched with water, then extracted with DCM (3×30 mL). The combined DCM solutions were washed with water, brine, dried over Na2SO4, filtered, and evaporated to give a crude product (80 mg). The crude product was purified by HPLC to give a solid product (0.0007 g, yield 3%). LCMS: (AA) ES+ 542, 544. 1H NMR (400 MHz, d6-DMSO) δ: 9.72-9.74 (d, J=6.53 Hz, 1H), 9.23 (s, 1H), 8.87 (s, 1H), 8.75 (s, 1H), 8.67-8.69 (d, J=6.53 Hz, 1H), 8.63 (s, 1H), 8.22 (s, 1H), 7.24-7.30 (m, 4H), 7.03-7.05 (d, J=7.28 Hz, 1H), 4.62-4.64 (d, J=6.78 Hz, 2H), 4.47 (s, 2H), 2.63 (s, 3H).
Reaction SMILES: C[Si:2]([O:9][CH2:10][CH3:11])([O:6][CH2:7][CH3:8])[O:3][CH2:4][CH3:5].C=C[Si](ON=C(CC)C)(ON=C(CC)C)ON=C(CC)C.C[Si](ON=C(C)C)(ON=C(C)C)ON=C(C)C.C[Si](OC(=C)C)(OC(=C)C)[O:52][C:53](=C)[CH3:54]>>[Si:2]([O:52][CH2:53][CH3:54])([O:9][CH2:10][CH3:11])([O:6][CH2:7][CH3:8])[O:3][CH2:4][CH3:5]
Reactant: C=C(C)O[Si](C)(OC(=C)C)OC(=C)C
Reactant: CCO[Si](C)(OCC)OCC
Agent: C=C[Si](ON=C(C)CC)(ON=C(C)CC)ON=C(C)CC
Agent: CC(C)=NO[Si](C)(ON=C(C)C)ON=C(C)C
Product: CCO[Si](OCC)(OCC)OCC

Procedure:
CH3Si (OCH3)3; CH3Si(OC2H5)3; (C2H5O)3Si(OCH3); CH2═CHSi (OCH3)3; CH3(CH2═CH)Si (OCH3)2; CH2═CHSi (OC2H5)3; CH2═CHSi[ON═C(CH3)C2H5]3; CH3Si[ON═C(CH3)2]3; CH3Si[O—C(CH3)═CH2]3; methyltris (N-methylacetamido-silane); methyltris (cyclohexylaminosiloxane).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.[CH2:19]([N:26]1[CH2:31][CH2:30][CH2:29][C:28](=O)[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([BH3-])#N.[Na+]>CO>[CH2:19]([N:26]1[CH2:31][CH2:30][CH2:29][CH:28]([NH:11][C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[NH2:1])[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)n1nc(N)c2cc(N)ccc21
Reactant: O=C1CCCN(Cc2ccccc2)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Nc1n[nH]c2ccc(NC3CCCN(Cc4ccccc4)C3)cc12

Procedure:
Reaction of tert-butyl 3,5-diamino-1H-indazole-1-carboxylate with 1-benzylpiperidin-3-one using the method of Example 8, with the modification that sodium cyanoborohydride was used as the reductant and methanol was used as the solvent, followed by deprotection using the method of Example 4 afforded the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:10]=[C:6]([CH2:7][OH:8])[CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cncc(Br)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: OCc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.7 %

Procedure:
To a solution of 5-bromonicotinic acid (20.00 g, 97.00 mmol) in anhydrous THF (250 mL) was added a solution of BH3 (1 M in THF, 197 mL) slowly at rt over a period of 1 h. The reaction mixture was stirred for 1 h at rt and then was heated at reflux temperature for 5 h. The reaction mixture was cooled to rt and treated with 1 M HCl (100 mL) drop-wise. The resulting mixture was stirred for 1 h and treated with 10% aq. NaOH until pH 10. The solution was then extracted with ethyl acetate (4×200 mL). The combined organic extracts were washed with H2O, dried over anhydrous Na2SO4, filtered and concentrated to yield the crude alcohol (10.71 g). Purification of the crude compound (SiO2: 0-5% 2 M NH3 in MeOH/DCM) gave (5-bromo-pyridin-3-yl)-methanol (4.14 g, 22%).
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([CH3:15])[C:5]2=[C:4]([CH3:17])[N:3]=1)=[CH:11][CH:10]=[C:9]([F:16])[CH:8]=3.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>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>[Cl:18][C:19]1[CH:24]=[C:23]([C:2]2[N:6]3[C:7]4[C:12]([N:13]=[C:14]([CH3:15])[C:5]3=[C:4]([CH3:17])[N:3]=2)=[CH:11][CH:10]=[C:9]([F:16])[CH:8]=4)[CH:22]=[CH:21][CH:20]=1
Reactant: Cc1nc(Br)n2c1c(C)nc1ccc(F)cc12
Reactant: OB(O)c1cccc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nc(-c2cccc(Cl)c2)n2c1c(C)nc1ccc(F)cc12
Yield: 95.8 %

Procedure:
Following the general Suzuki coupling procedure, reaction of bromide 5A (75 mg, 0.25 mmol), 3-chlorophenylboronic acid (48 mg, 0.30 mmol), K2CO3 (105 mg, 0.75 mmol) and Pd(PPh3)4 (5.8 mg, 0.005 mmol) provided the coupling product as a white powder (78 mg, 96% yield). EIMS 326.0 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].C(=O)([O-])[O-].[K+].[K+].Br[CH2:58][C:59]([O:61][CH3:62])=[O:60]>>[OH:24][C@H:22]1[C@:21]2([O:25][CH3:26])[C@@:8]([OH:45])([C:9](=[O:44])[C:10]3[C:19]([C:20]2=[O:27])=[C:18]([OH:28])[C:17]2[C:16](=[O:29])[CH:15]=[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)[C:13](=[O:43])[C:12]=2[CH:11]=3)[C:7]2[C:2]([O:1][CH2:58][C:59]([O:61][CH3:62])=[O:60])=[C:3]([C:47]([O:49][CH3:50])=[O:48])[C:4]([CH3:46])=[CH:5][C:6]=2[CH2:23]1
Reactant: COC(=O)CBr
Reactant: COC(=O)c1c(C)cc2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)COc1c(C(=O)OC)c(C)cc2c1[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Yield: 18 %

Procedure:
Following General Procedure: Method A using (6R,6aS,14aR)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (50 mg, 0.072 mmol), potassium carbonate (30 mg, 0.22 mmol) and methyl bromoacetate (20 μL, 0.22 mmol), the product was purified by preparative TLC (silica gel, 95:5 dichloromethane/methanol) and semi-preparative HPLC (45:55 acetonitrile/water with 0.05% TFA) to afford (6R,6aS,14aR)-methyl 6,8,14a-trihydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-1-(2-methoxy-2-oxoethoxy)-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (10 mg, 20%) as a red solid: 1H NMR (500 MHz, CDCl3) δ 14.19 (s, 1H), 8.27 (s, 1H), 6.89 (d, J=9.0 Hz, 1H), 6.86 (s, 1H), 5.88 (s, 1H), 4.96 (d, J=6.6 Hz, 1H), 4.69 (d, J=8.7 Hz, 1H), 4.54 (d, J=15.1 Hz, 1H), 4.43 (d, J=15.1 Hz, 1H), 3.91 (br s, 3H), 3.79 (s, 3H), 3.76-3.67 (m, 3H), 3.73 (s, 3H), 3.64-3.55 (m, 1H), 3.60 (s, 3H), 3.39 (s, 3H), 3.36-3.29 (m, 3H), 3.13 (t, J=9.2 Hz, 1H), 2.60 (br s, 1H), 2.19 (s, 3H), 1.36 (d, J=6.2 Hz, 3H); MS (ESI+) m/z 770 (M+H); HPLC 96.4% (AUC), tR 15.46 min.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][CH:8]2[CH2:13][NH:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])#[N:2].CCN(CC)CC.[Cl:32][CH2:33][C:34](Cl)=[O:35]>C(Cl)Cl>[Cl:32][CH2:33][C:34]([N:14]([CH2:13][CH:8]1[C:9]2[C:4](=[C:3]([C:1]#[N:2])[CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH2:7]1)[CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:35]
Reactant: CC(C)(C)OC(=O)NCCNCC1CCCc2c(C#N)cccc21
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCN(CC1CCCc2c(C#N)cccc21)C(=O)CCl
Reaction time: 8 h

Procedure:
A solution of tert-Butyl (2-{[(5-cyano-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]amino}ethyl)carbamate (0.20 g, 0.61 mmol) in DCM (5 mL) was added Et3N (74 mg, 7.2 mmol), followed by chloro-acetyl chloride (81 mg, 7.2 mmol). The reaction mixture was stirred overnight. The product was purified by prep-TLC (Pet Ether:EtOAc=1:1) to give the title product. MS m/z: 406 [M+1]+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:36])([F:35])[C:5]1[CH:6]=[C:7]([C@H:15]([O:17][C@@H:18]2[C@@H:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:22]([C@H:30]3CCN3C)[CH2:21][CH2:20][O:19]2)[CH3:16])[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1.[N:37]1([C:42]([O-:44])=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38]1.O>O1CCCC1.C(OCC)(=O)C>[F:13][C:11]([F:12])([F:14])[C:9]1[CH:8]=[C:7]([C@H:15]([O:17][C@@H:18]2[C@@H:23]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:22]([CH:30]3[O:43][C:42](=[O:44])[N:37]4[CH2:41][CH2:40][CH2:39][CH:38]34)[CH2:21][CH2:20][O:19]2)[CH3:16])[CH:6]=[C:5]([C:4]([F:36])([F:35])[F:3])[CH:10]=1
Reactant: C[C@@H](O[C@H]1OCC[C@@H]([C@H]2CCN2C)[C@@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C([O-])N1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H](O[C@H]1OCC[C@@H](C2OC(=O)N3CCCC23)[C@@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 82 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 15 mg, 0.36 mmol) was added to a solution of 1,1-dimethylethyl (2R or S)-2-[(R or S)-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)hydroxymethyl]-1-pyrrolidinecarboxylate (Example 41, Isomer A; 75 mg, 0.12 mmol) in tetrahydrofuran (2 mL) and the mixture was stirred at room temperature for 15 hours. Water (2 mL) was added slowly, then ethyl acetate (10 mL). The layers were separated and the organic layer was washed with brine (5 mL). The combined aqueous layers were extracted with ethyl acetate (10 mL). The combined organic layers were dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane/EtOAc (80:20 increasing to 60:40), to give the title compound (Single diastereoisomer; Stereochemistry unassigned) as a colorless foam (54 mg, 82%).
Reaction SMILES: CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH3:23][O:24][C:25](=[O:41])[CH:26]([NH:30][C:31](=[O:40])[C:32]1[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=1[Cl:39])[CH2:27][CH:28]=[CH2:29].I[C:43]1[CH:48]=[CH:47][C:46]([C:49]2([OH:55])[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)=[CH:45][CH:44]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[CH3:23][O:24][C:25](=[O:41])[CH:26]([NH:30][C:31](=[O:40])[C:32]1[C:33]([Cl:39])=[CH:34][CH:35]=[CH:36][C:37]=1[Cl:38])[CH2:27]/[CH:28]=[CH:29]/[C:43]1[CH:44]=[CH:45][C:46]([C:49]2([OH:55])[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)=[CH:47][CH:48]=1
Reactant: OC1(c2ccc(I)cc2)CCOCC1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(C/C=C/c1ccc(C2(O)CCOCC2)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 80 °C
Reaction time: 6 h
Yield: 58.6 %

Procedure:
Under an argon atmosphere, palladium acetate (4.7 mg) and tris(2-methylphenyl)phosphine (6.1 mg) were added to a suspension of 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (60.4 mg), tetrahydro-4-(4-iodophenyl)-2H-pyran-4-ol (60.8 mg) and potassium carbonate (41.5 mg) in DMF (4 ml), and the resulting mixture was stirred at 80° C. for 6 hours. After cooling the reaction solution to room temperature, ethyl acetate was added thereto and the solution was washed 3 times with water and once with saturated brine, followed by drying the organic layer over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: cyclohexane/chloroform=2/1→1/4) and thereafter by thin layer chromatography (silica gel, mobile phase: cyclohexane/ethyl acetate=1/1) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-(4-hydroxytetrahydropyran-4-yl)-phenyl]pent-4-enoic acid methyl ester (56 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:10]1(B(O)O)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.[F-].[K+]>O1CCCCO1>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([C:18]2[C:19]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: COc1cccc(Br)c1
Reactant: OB(O)c1cccc2ccccc12
Agent: C1CCOOC1
Agent: [F-]
Agent: [K+]
Product: COc1cccc(-c2cccc3ccccc23)c1
Yield: 115.2 %

Procedure:
3-Bromoanisole (75 mg, 0.40 mmol) reacted with 1-naphthylboronic acid (103 mg, 0.60 mmol) using 0.5/1.0 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and KF (70 mg, 1.20 mmol) in 1,2-dioxane at 100° C. to give the title compound (108 mg, 99%) as a colorless oil: 1H-NMR (500 MHz, CDCl3): δ 7.96 (d, 2H, J=8.49 Hz), 7.93 (d, 2H, J=7.96 Hz), 7.89 (d, 2H, J=8.20 Hz), 7.56-7.50 (m, 2H), 7.48-7.41 (m, 3H), 7.13-7.11 (m, 1H), 7.08 (m, 1H), 7.03-7.00 (m, 1H), 3.88 (s, 3H). 13C{1H}-NMR (125 MHz, CDCl3): δ 159.45, 142.15, 140.09, 133.75, 131.57, 129.20, 128.22, 127.67, 126.74, 126.04, 126.01, 125.75, 125.31, 122.57, 115.61, 112.86, 55.28. GC/MS(EI): m/z 234 (M+), 203, 189.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[N:6]=1)=[O:4].[H-].[Na+].I[CH3:17]>CN(C=O)C.[Cl-].[Na+].O>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:17])[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)=[O:4]
Reactant: CI
Reactant: COC(=O)c1nc2ccccc2[nH]1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1nc2ccccc2n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
To a solution of 1H-benzoimidazole-2-carboxylic acid methyl ester (18) (177 mg, 1.0 mmol) in dry DMF (5 mL) was added sodium hydride (applied as 60% dispersion in oil, 62 mg, 1.5 mmol)) at 0° C. under N2 atmosphere. After 0.5 h, iodomethane (284 mg, 2.0 mmol) was added slowly. The reaction mixture was stirred at RT for 4 h. The reaction was diluted with brine at 0° C. and extracted with EtOAc (3×20 mL). The combined organics were washed with water (2×15 mL), brine (20 mL), dried over sodium sulfate and filtered. The filtrate was concentrated and purified by flash column chromatography to provide the title compound (81) (180 mg, 90% yield) as a light yellow solid.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:14])[CH:12]=2)[NH:7][CH:6]=1.C=O.[C:17](O)(=O)C>C(O)C>[ClH:1].[CH2:17]1[C:6]2[NH:7][C:8]3[C:13](=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=3)[C:5]=2[CH2:4][CH2:3][NH:2]1
Reactant: CC(=O)O
Reactant: NCCc1c[nH]c2ccc(O)cc12
Agent: C=O
Agent: Cl
Solvent: CCO
Product: Oc1ccc2[nH]c3c(c2c1)CCNC3
Temperature: 25 °C

Procedure:
To a solution of 3-(2-amino-ethyl)-1H-indol-5-ol hydrochloride (10.0 g) in 450 mL of absolute ethanol was added 1.6 g of paraformaldehyde and 5.4 mL of glacial acetic acid. The mixture was heated to reflux for 1.5 h then allowed to cool to rt. The white precipitate so formed was collected by filtration and dried under vacuum to yield 5.9 g of 2,3,4,9-tetrahydro-1H-β-carbolin-6-ol hydrochloride.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[NH3:15]>C(O)C.C(Cl)Cl>[NH2:15][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3]
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Reactant: N
Solvent: CCO
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Yield: 843.8 %

Procedure:
A solution of 5-chlorosulphonyloxindole (2 g, 0.86 mmol) in ethanol (30 ml), methylene chloride (150 ml) and 2.8M methanolic ammonia (6.2 ml, 17 mmol) was stirred overnight at ambient temperature. The volatiles were removed by evaporation and the solid residue was purified by column chromatography eluting with methanol/methylene chloride (15/85) to give 5-aminosulphonyloxindole (1.54 g, 84%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:16][CH2:15][C:10]3(OCC[O:11]3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1>S(=O)(=O)(O)O.O1CCCC1>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:16][CH2:15][C:10](=[O:11])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1
Reactant: c1cc(N2CCC3(CC2)OCCO3)ccn1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: O=C1CCN(c2ccncc2)CC1
Yield: 49.6 %

Procedure:
A solution of 8-(4-pyridyl)-1,4-dioxa-8-azaspiro[4,5]decane (10 g) in 2N sulphuric acid (140 ml) and tetrahydrofuran (70 ml) was stirred for 72 hr. The reaction was quenched with water (700 ml) and extracted with dichloromethane (400 ml). The organic extracts were dried (MgSO4) and evaporated to give a yellow solid which was purified by flash chromatography on silica, eluting with methanol/dichloromethane (10:90 v/v) to give 1-(4-pyridyl)-4-oxopiperidine as a solid (3.97 g); m.p. 101°-104° C.; NMR (d6DMSO) δ 2.45(4H,t), 3.75(4H,t), 6.85(2H,m), 8.20(2H,m); m/e 177 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:12](N(OC)C)=[O:13])[C:5]([CH3:22])=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[N:26]=1.[C:32]([Mg]Cl)#[CH:33]>O1CCCC1>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([C:12](=[O:13])[C:32]#[CH:33])[CH:18]=[CH:19][C:20]=2[CH3:21])[C:5]([CH3:22])=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[N:26]=1
Reactant: C#C[Mg]Cl
Reactant: CON(C)C(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(F)n3)c(Cl)c2=O)c1
Solvent: C1CCOC1
Product: C#CC(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(F)n3)c(Cl)c2=O)c1

Procedure:
To a solution of 3-[5-chloro-4-(6-fluoro-pyridin-2-ylmethoxy)-2-methyl-6-oxo-6H-pyrimidin-1-yl]-N-methoxy-4,N-dimethyl-benzamide from Step C (85 mg, 0.19 mmol) in tetrahydrofuran (2 mL), cooled using an ice water bath, was added ethynylmagnesium chloride, 0.5M in tetrahydrofuran, (0.57 mL, 0.28 mmol) in a drop-wise manner. Additional Grignard reagent was added as necessary to ensure full product formation. After thirty minutes, the reaction was quenched into ice cold water and extracted with ethyl acetate. The organic layer was washed with saturated ammonium chloride, water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated. The crude material was used without additional purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([B:10]([OH:12])[OH:11])[CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH2:15]1COCC1.CI>>[CH3:15][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([B:10]([OH:12])[OH:11])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: C1CCOC1
Reactant: OB(O)c1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: Cn1ccc2ccc(B(O)O)cc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of indole-6-boronic acid (0.100 g, 0.615 mmol), sodium hydride (0.07 g, 20 mmol) and THF (5 mL, 60 mmol) was stirred at rt for 20 min. then methyl iodide (100 uL, 20 mmol) was added and the mixture was allowed to stir at rt for 3 hours. The reaction was quenched with sat. NH4Cl solution, washed with brine and dried over Na2SO4, then the solvent was removed in vacuo. The crude product was purified by chromatography over silica gel eluting with 1:9 EtOAc/hexane and 1% MeOH, yielding the desired product. 1H NMR (400 MHz, CDCl3) δ ppm 3.99 (s, 3H), 6.58 (m, 1H). 7.23 (m, 1H), 7.81 (m, 1H), 8.08 (m, 1H) and 8.34 (m, 1H). MS (ES+): m/z 176.15 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:22]2([C:26]([O:28]CC)=[O:27])[CH2:25][CH2:24][CH2:23]2)[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].O.[OH-].[Li+]>CO.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:22]2([C:26]([OH:28])=[O:27])[CH2:25][CH2:24][CH2:23]2)[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11]
Reactant: CCOC(=O)C1(c2cc(Cl)c(OCC(F)(F)F)c(-c3ccc(CC)cc3)c2)CCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCc1ccc(-c2cc(C3(C(=O)O)CCC3)cc(Cl)c2OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
A mixture of ethyl 1-(5-chloro-4′-ethyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylate (350 mg, 0.84 mmol) and lithium hydroxide monohydrate (222 mg, 9.2 mmol) in a MeOH/THF/Water solvent mixture (10 ml/10 ml/10/ml) was stirred for 3 h at room temperature. After completion of the reaction, the volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with water, dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Flash Column Chromatography to give 1-(5-chloro-4′-ethyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylic acid (260 mg) as white solid. 1HNMR (CDCl3, 500 MHz): 7.42 (d, 2H), 7.38 (s, 1H), 7.22 (d, 2H) 7.20 (s, 1H), 3.85 (q, 2H); 2.82 (m, 2H), 2.71 (q, 2H), 2.52 (m, 2H), 2.15 (m, 1H), 1.91 (m, 1H); 1.27 (t, 3H).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12](S(C)(=O)=O)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:20][CH3:21])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1.O>C(O)(=O)C>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([N:22]4[CH:26]=[CH:25][N:24]=[CH:23]4)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:20][CH3:21])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1[nH]n(C2CCCC2)c2nc(S(C)(=O)=O)nc(=O)c1-2
Reactant: c1c[nH]cn1
Solvent: CC(=O)O
Solvent: O
Product: CCc1[nH]n(C2CCCC2)c2nc(-n3ccnc3)nc(=O)c1-2
Temperature: 25 °C
Yield: 80.4 %

Procedure:
A mixture of -1-cyclopentyl-3-ethyl-6-methylsulfonylpyrazolo[3,4-d]pyrimidin-4-one (3.1 g, 0.01 mol) and imidazole (2.1 g, 0.03 mol) was heated at 165°-175° C. for 3.5 hours. The mixture was cooled to room temperature and water (25 ml), followed by acetic acid (3 ml) were added. A precipitate was obtained which was collected by filtration and washed with water. The product was recrystallized from ethanol/ether to afford 2.4 g (81%) of 1-cyclopentyl-3-ethyl-6-(1-imidazolyl)pyrazolo[3,4-d]-pyrimidin-4-one as white crystals, m.p. 228°-230° C.