Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([N:13]([CH2:15][CH:16]=C)[CH3:14])=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[O:18]=[O+][O-].CSC.[K+].[Br-]>O.ClCCl.CO>[C:1]([C:5]1[O:9][N:8]=[C:7]([N:10]2[CH:16]([OH:18])[CH2:15][N:13]([CH3:14])[C:11]2=[O:12])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCN(C)C(=O)Nc1cc(C(C)(C)C)on1
Reactant: O=[O+][O-]
Agent: [Br-]
Agent: [K+]
Solvent: CSC
Solvent: CO
Solvent: ClCCl
Product: CN1CC(O)N(c2cc(C(C)(C)C)on2)C1=O
Reaction time: 1 h

Procedure:
To a 100 ml. round bottom flask equipped with a magnetic stirring bar and a gas dispersion tube were added 8.89 g. of 1-(5-t-butylisoxazol-3-yl)-3-allyl-3-methylurea, 38 ml. of methanol and 38 ml. of dichloromethane. The solution was cooled to -10°, and approximately 40 millimoles of ozone was introduced into the mixture through the gas dispersion tube in a stream of dry air with good mixing over 1 hour. The temperature of the mixture gradually warmed to about 3° as the reaction went on. When all of the ozone had been added, 5 ml. of dimethyl sulfide was added, and the cooling bath was removed. The temperature of the mixture rose to 32°, and then returned to ambient temperature after 1 hour of stirring. The solvent was then removed from the reaction mixture under vacuum at 35°, reducing the volume to about 15 ml. To the semi-solid was added 100 ml. of water, and the mixture was stirred for 15 minutes and filtered. The filter cake was washed with two 50 ml. portions of additional water, and the solids were dried under vacuum to obtain 8.06 g. of product, m.p. 173°-177°. It contained 0.1% water by Karl Fischer analysis, and its nuclear magnetic resonance spectrum, determined in CDCl3 on a 60 mHZ instrument, showed features at δ 6.60 (s, 1H); 5.82 (1H, X of ABX, JAX =7.8 Hz, JBX =2.2 Hz); 4.50 (bs, 1H, exchanges with D2O), 3.83-3.23 (2H, AB of ABX, JAB =3 Hz); 2.90 (s, 3H); 1.32 (s, 9H). Its infra-red spectrum (KBr pellet) showed bands at 3411 (m), 1699 (s), 1599 (m), 1517 (m), 1500 (m), 1479 (m), 1443 (m), 1402 (m) and 1277 (m) cm-1. A 5 g. sample of the above product was recrystallized from 25 ml. of boiling denatured ethanol to obtain 4.2 g. of purified product, m.p. 176°-179°. Its calculated elemental analysis was 55.22% C, 7.16% H, 17.56% N; the actual analysis was 55.49% C, 7.27% H, 17.28% N.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.[N:28]1([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.CCN(C(C)C)C(C)C>C1COCC1>[F:26][CH:25]([F:27])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([N:31]3[CH2:30][CH2:29][N:28]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33][CH2:32]3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
A mixture of 1.98 g (5 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole, 1.16 g (6.25 mmol) of tert-butyl 1-piperazinecarboxylate, and 1.29 g (10 mmol) of DIPEA in 100 mL of THF was stirred at room temperature for 1 hr, and the solution was concentrated under vacuum. The residue was diluted with water (100 mL) containing 1 mL of acetic acid. The resulting precipitate was collected, washed with water, and dried to give 2.71 g (99% yield) of tert-butyl 4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinecarboxylate: mp (MeOH) 221-223° C.; 1H NMR (CDCl3) δ 7.88 (dd, J=8.4, 0.6 Hz, 1H), 7.47 (t, J=53.5 Hz, 1H), 7.35 (t, J=8.2 Hz, 1H), 6.81 (d, J=7.7 Hz, 1H), 4.05 (s, 3H), 3.87 (m, 8H), 3.78 (m, 4H), 3.53 (m, 4H), 1.50 (s, 9H); Anal. Calcd. for C25H32F2N8O4: C, 54.9; H, 5.9; N, 20.5. Found: C, 54.9; H, 5.9; N, 20.5%.
Reaction SMILES: [NH:1]1[C:5]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=2)=[N:4][N:3]=[N:2]1.O>CS(C)=O>[NH:4]1[C:5]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]=[O:14])=[CH:9][CH:8]=2)=[N:1][N:2]=[N:3]1
Reactant: OCc1ccc(Cc2nnn[nH]2)cc1
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1ccc(Cc2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
IBX (0.437 g, 1.562 mmol) was dissolved in anhydrous DMSO (5 mL) and [4-(1H-tetrazol-5-ylmethyl)-phenyl]-methanol (0.270 g, 1.562 mmol) was added. The reaction mixture was stirred at room temperature under nitrogen for 4 hours. Water (20 mL) was added. The white precipitate was filtered off, washed with water, and dried under vacuum. The crude compound was mixed with methanol (20 mL) and stirred for 30 minutes, before being filtered. The filtrate was concentrated to give 4-(1H-tetrazol-5-ylmethyl)-benzaldehyde as a white solid. Yield: 0.267 g (99%). To a solution of 2-amino-4,6-dimethoxybenzamide (0.157 g, 0.8 mmol) in N,N-dimethyl acetamide (5 mL) were added 4-(1H-tetrazol-5-ylmethyl)-benzaldehyde (0.260 g, 1.4 mmol), sodium hydrogen sulfite (58.5%, 0.159 g, 0.88 mmol) and p-toluenesulfonic acid (19 mg, 0.08 mmol). The reaction mixture was stirred at 150° C. for 3 h, then cooled to room temperature. Water (40 mL) was then added. A yellow precipitate was formed and filtered off, washed with water, and small amount of methanol. It was triturated with 10% methanol in ether to give 0.107 g of solid, which was further purified by preparative HPLC, to give the title compound (0.082 g, 28%) as a white solid. MS (ES) m/z: 365.1 (M+1). MP 295-296° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[N:20][N:21]([C@H:23]2[CH2:28][CH2:27][C@H:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25][CH2:24]2)[CH:22]=1.[Cl:37][C:38]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[C:40]([Cl:53])[C:39]=1[OH:54]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:19]=[N:20][N:21]([C@H:23]4[CH2:24][CH2:25][C@H:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])[CH2:27][CH2:28]4)[CH:22]=2)=[CH:3][C:2]([C:42]2[CH:43]=[C:38]([Cl:37])[C:39]([OH:54])=[C:40]([Cl:53])[CH:41]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](n2cc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)CC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](n2cc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)cc34)cn2)CC1

Procedure:
Following general procedure M, tert-butyl (trans-4-(4-((6-bromo-3-(cyclopropanecarbonyl)quinolin-4-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)carbamate (45 mg, 0.081 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (43 mg, 0.15 mmol) to afford the desired product (23 mg, 45%) as a yellow-brown solid. ESI MS m/z 636 [C33H35Cl2N5O4+H]+
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:9]1[C:20]([O:22]CC)=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[OH-].[Na+]>CO>[CH2:1]([N:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[C:9]1[C:20]([OH:22])=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(-c2ccc(Cl)cc2)ccn1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1c(-c2ccc(Cl)cc2)ccn1Cc1ccccc1

Procedure:
Ethyl 1-benzyl-3-(4-chlorophenyl)-1H-pyrrole-2-carboxylate (8 g, 23.54 mmol) was dissolved in MeOH (33.4 mL) and THF (33.4 mL) followed by addition of aqueous 6M NaOH (33.4 mL, 200 mmol) and the reaction mixture was stirred at reflux for 18 h. The volatile solvents were evaporated under reduced pressure. The remaining aqueous phase was acidified with aqueous 1M HCl until pH=4 and a solid precipitated. The solid was filtered off and washed with cold H2O. The collected solid was dissolved in EtOAc, dried over Na2SO4, filtered and the solution evaporated to dryness to give 6.69 g (91%) of ACI-01.
Reaction SMILES: COC1C=CC(C([NH:11][C:12]([C:14]2[C@@H:23]([C:24]3[CH:29]=[C:28]([O:30][CH2:31][CH3:32])[C:27]([OH:33])=[C:26]([Br:34])[CH:25]=3)[C:22]3[C:21](=[O:35])[CH2:20][C@@H:19]([CH2:36][CH2:37][CH3:38])[CH2:18][C:17]=3[NH:16][C:15]=2[CH3:39])=O)C)=CC=1>C(O)(C(F)(F)F)=O>[Br:34][C:26]1[CH:25]=[C:24]([C@H:23]2[C:22]3[C:21](=[O:35])[CH2:20][C@@H:19]([CH2:36][CH2:37][CH3:38])[CH2:18][C:17]=3[NH:16][C:15]([CH3:39])=[C:14]2[C:12]#[N:11])[CH:29]=[C:28]([O:30][CH2:31][CH3:32])[C:27]=1[OH:33]
Reactant: CCC[C@@H]1CC(=O)C2=C(C1)NC(C)=C(C(=O)NC(C)c1ccc(OC)cc1)[C@H]2c1cc(Br)c(O)c(OCC)c1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@@H]1CC(=O)C2=C(C1)NC(C)=C(C#N)[C@H]2c1cc(Br)c(O)c(OCC)c1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
A solution of (4S,7S)-4-(3-Bromo-5-ethoxy-4-hydroxy-phenyl)-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydro-quinoline-3-carboxylic acid [1-(4-methoxy-phenyl)ethyl]-amide (Example 72d, 1.43 g) was dissolved in TFA (30 mL) and stirred at 75° C. for 1 hr. The TFA was evaporated in vacuo and the residue was then dissolved in dichloromethane (30 ml). Triethylamine (1.04 g) and trifluoroacetic acid anhydride (0.95 g) were added dropwise at 0° C. for 15 minutes. The reaction was stirred for 1 hr and the reaction mixture was washed with water (20 ml). The organic layer was dried (MgSO4), filtered, concentrated in vacuo and concentrated. The residue was purified by chromatography on silicagel in heptane/ethyl acetate 1/0->0/1 (v/v) as eluent.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:38]([O:39][CH3:40])=[CH:37][C:15]2[NH:16][C:17](=[O:36])[C:18]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[C:27]([O:34][CH3:35])[CH:26]=4)=[CH:21][C:19]=3[NH:20][C:14]=2[CH:13]=1)(C)(C)C.[N+](CC)(CC)(CC)CC.[F-].O>C1COCC1>[OH:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:38]([O:39][CH3:40])=[CH:37][C:15]2[NH:16][C:17](=[O:36])[C:18]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[C:27]([O:34][CH3:35])[CH:26]=4)=[CH:21][C:19]=3[NH:20][C:14]=2[CH:13]=1
Reactant: COc1cc2c(cc1OCCCCO[Si](C)(C)C(C)(C)C)Nc1cc(-c3ccc([N+](=O)[O-])c(OC)c3)ccc1C(=O)N2
Agent: CC[N+](CC)(CC)CC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2c(cc1OCCCCO)Nc1cc(-c3ccc([N+](=O)[O-])c(OC)c3)ccc1C(=O)N2
Yield: 28 %

Procedure:
A mixture of Example 500A, Et4NF.H2O (10 equiv.) and THF was heated overnight at 65° C., concentrated under vacuum, diluted with ethyl acetate, washed with water and brine, dried (MgSO4), filtered and concentrated under vacuum. The residue was purified by preparative HPLC to provide 50 mg (28%) of the desired product. MS (ESI) m/e 480 (M+H)+; 1H NMR (400 MHz, DMSO-d6) □ 9.63 (s, 1H), 8.01 (d, J=8.6 Hz, 1H), 7.78 (d, J=8.3 Hz, 1H), 7.71 (s, 1H), 7.53 (d, J=1.2 Hz, 1H), 7.35 (dd, J=1.5, 8.6 Hz, 1H), 7.28-7.30 (m, 2H), 6.70 (s, 1H), 6.65 (s, 1H), 4.03 (s, 3H), 3.89 (t, J=6.6 Hz, 2H), 3.67 (s, 3H), 3.44 (t, J=6.4 Hz, 2H), 1.69-1.76 (m, 2H), 1.51-1.58 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]2)=[N:6][C:7]=1[NH2:8].[CH:20]1([C:23]2[N:28]=[C:27]([CH:29]=O)[CH:26]=[CH:25][CH:24]=2)[CH2:22][CH2:21]1.[S].C(O)(=O)C>C(O)C>[CH:20]1([C:23]2[N:28]=[C:27]([C:29]3[NH:8][C:7]4=[N:6][C:5]([N:9]5[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]5)=[CH:4][CH:3]=[C:2]4[N:1]=3)[CH:26]=[CH:25][CH:24]=2)[CH2:22][CH2:21]1
Reactant: O=Cc1cccc(C2CC2)n1
Reactant: CCOC(=O)[C@@H]1CCCN(c2ccc(N)c(N)n2)C1
Agent: [S]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)[C@@H]1CCCN(c2ccc3nc(-c4cccc(C5CC5)n4)[nH]c3n2)C1
Temperature: 80 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
To a solution of (R)-ethyl 1-(5,6-diaminopyridin-2-yl)piperidine-3-carboxylate (250 mg, 0.686 mmol) in ethanol (15 mL) was added 6-cyclopropylpicolinaldehyde (55 mg, 0.823 mmol), sulfur (43 mg, 1.372 mmol) and acetic acid (1.5 mL) at room temperature. The reaction mixture was stirred at 80° C. for 18 h. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organics were concentrated under reduced pressure and the crude material was purified via preparative TLC (80% ethyl acetate in petroleum ether) to afford (R)-ethyl 1-(2-(6-cyclopropylpyridin-2-yl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidine-3-carboxylate (180 mg). MS (ES+APCI) (M+H) 392.2; LCMS retention time 3.757 min (Method J).
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7](=[O:15])[CH2:6]1)([OH:3])=[O:2].[O-:16][Mn](=O)(=O)=O.[K+]>O.[OH-].[Na+]>[C:1]([CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7](=[O:15])[C:6]1=[O:16])([OH:3])=[O:2]
Reactant: O=C(O)CN1CC(=O)Nc2ccccc21
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)Cn1c(=O)c(=O)[nH]c2ccccc21
Yield: 55.7 %

Procedure:
The procedure of Borthakur, N. et at., Ind. J. Chem. 20B:822 (1981) was adapted. To a stirred solution of 1-carboxymethyl-1,2,3,4-tetrahydroquinoxaline-3-one (15.400 g, 0.075 mol) and sodium hydroxide (5.20 g, 0.13 mol) in water (250 mL), was added gradually, a solution of KMnO4 (20.800 g 0.132 mol) in aq. NaOH (4% w/v, 120 mL) and the dark purple colored solution was refluxed for 4 h, cooled and filtered. The clear filtrate was acidified (pH~2) with concentrated HCl. Filtration under vacuum (water aspirator) afforded 9.200 g (56%, pure by 1H NMR) of 1-carboxymethyl-1,4-dihydro-2,3-quinoxalinedione as a cream colored powder, m.p.>300° C. (decomposes) (lit. m.p.>300° C., Borthakur et al., supra). It was sufficiently pure for use in the next reaction; 1H NMR: δ4.84 (s, 2H), 7.13-7.27 (m, 4H), 12.16 (s, 1H); IR (KBr, cm-1): 3431, 1743, 1687, 1481, 1406, 1393, 1250.
Reaction SMILES: [C:1]([CH2:5]P(=O)(OCC)OCC)([O:3][CH3:4])=[O:2].CN(C)C=O.[H-].[Na+].[CH3:21][C:22]([CH2:30][CH3:31])=[CH:23][CH2:24][CH2:25][CH2:26][C:27](=O)[CH3:28]>O>[CH3:28][C:27]([CH2:26][CH2:25][CH2:24][CH:23]=[C:22]([CH3:21])[CH2:30][CH3:31])=[CH:5][C:1]([O:3][CH3:4])=[O:2]
Reactant: CCOP(=O)(CC(=O)OC)OCC
Reactant: CCC(C)=CCCCC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)=CCCCC(C)=CC(=O)OC

Procedure:
A mixture of 11.2 g. of diethyl carbomethoxymethylphosphonate in 100 ml. of dimethylformamide is treated with 2.4 g. of sodium hydride. The mixture is stirred until the evolution of gas ceases and then 10 g. of 7-methyl-6-nonen-2-one is added slowly with stirring, maintaining temperature below 30°. The mixture is stirred for about one hour, then diluted with water and then extracted with ether. The ethereal phase is washed with water, dried over sodium sulfate and evaporated under reduced pressure to yield methyl 3,8-dimethyldeca-2,7-dienoate as a mixture of isomers (trans,cis; trans,trans; cis,cis and cis,trans) which are separated by chromatography.
Reaction SMILES: [N:1]1([C:5]([CH:7]2[CH2:12][CH2:11][N:10]([CH:13]3[CH2:16][N:15](C(C4C=CC=CC=4)C4C=CC=CC=4)[CH2:14]3)[CH2:9][CH2:8]2)=[O:6])[CH2:4][CH2:3][CH2:2]1.C([O-])=O.[NH4+]>C(O)C.[OH-].[OH-].[Pd+2]>[NH:15]1[CH2:14][CH:13]([N:10]2[CH2:11][CH2:12][CH:7]([C:5]([N:1]3[CH2:2][CH2:3][CH2:4]3)=[O:6])[CH2:8][CH2:9]2)[CH2:16]1
Reactant: O=C(C1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)CC1)N1CCC1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: O=C(C1CCN(C2CNC2)CC1)N1CCC1
Temperature: 120 °C
Yield: 101.8 %

Procedure:
4-(Azetidin-1-ylcarbonyl)-1-[1-(diphenylmethyl)azetidin-3-yl]piperidine (0.42 g, 1.1 mmol) was dissolved in ethanol and to the resultant solution was added palladium hydroxide on carbon (0.15 g) and ammonium formate (0.28 g, 4.4 mmol). The reaction mixture was heated for 4 min at 120° C. using microwave single node heating. The catalyst was filtered off by means of a phase separator and the filter cake washed with ethanol. The solvent was removed by evaporation and the residue was dissolved in methanol (1 mL) and THF (10 mL). The solution was loaded on a cation exchange sorbent (Isolute® SCX-2; 10 g). The column washed with THF and the product was then eluted with ammonia saturated methanol. The solvent was removed by evaporation and there was obtained 0.25 g of the title compound as colourless oil. 1H NMR (500 MHz, CD3OD): 2.0-2.2 (m, 4H), 2.3-2.4 (m, 2H), 2.6-2.8 (m, 3H), 3.2-3.3 (d, 2H), 3.8 (qn, 1H), 4.3 (t, 2H), 4.4 (m, 2H), 4.5 (m, 2H), 4.6 (t, 2H); LCMS: m/z 224 (M+1)+.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=1>C(Cl)(Cl)Cl>[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N+:18]=1[O-:9]
Reactant: Cc1cccc(-c2ccco2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1cccc(-c2ccco2)[n+]1[O-]
Temperature: 0 °C
Reaction time: 12 h
Yield: 52 %

Procedure:
4.90 g of metachioroperbenzoic acid are added in portions to a solution of 2.20 g of 2-furan-2-yl-6-methylpyridine (13.8 mmol) in 50 ml of chloroform cooled to 0° C. The mixture is stirred for 12 hours at room temperature and then the precipitate is removed by filtration and the filtrate is washed with a 5% aqueous solution of sodium bicarbonate. After drying over magnesium sulfate, filtration and evaporation, the title product is isolated by chromatography on a silica column (eluent: chloroform/methanol; 99:1). 1.25 g of a white powder are recovered.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.O>CN(C)C(=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:3][CH:4]=1
Reactant: C1CNCCN1
Reactant: Clc1ccc(Cl)nc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: Clc1ccc(N2CCNCC2)nc1
Yield: 50.2 %

Procedure:
Following the general procedure of Example 33, Step 1, and making non-critical variations, 2,5-dichloropyridine (Aldrich; 5.10 g), piperazine (14.8 g), water (50 mL), and N,N-dimethylacetamide (2 mL) give 3.42 g of 1-(5-chloropyridin-2-yl)piperazine; mp 92-107° C.; IR 1480, 1244, 1390, 1589 815 cm-1 ; 1H NMR (CDCl3) δ2.98, 3.47, 6.58, 7.42, 8.11.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1([NH:15][C:16]2[C:17](=[O:35])[N:18]([C:22]3[CH:23]=[C:24]([CH:31]=[CH:32][C:33]=3[CH3:34])[C:25]([NH:27][CH:28]3[CH2:30][CH2:29]3)=[O:26])[CH:19]=[CH:20][N:21]=2)[CH2:14][CH2:13][CH2:12]1.[CH3:36][NH2:37]>>[CH:28]1([NH:27][C:25](=[O:26])[C:24]2[CH:31]=[CH:32][C:33]([CH3:34])=[C:22]([N:18]3[CH:19]=[CH:20][N:21]=[C:16]([NH:15][C:11]4([C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=5[O:4][CH2:3][CH2:2][NH:37][CH3:36])[CH2:14][CH2:13][CH2:12]4)[C:17]3=[O:35])[CH:23]=2)[CH2:30][CH2:29]1
Reactant: CN
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OCCCl)CCC2)c1=O
Product: CNCCOc1ccccc1C1(Nc2nccn(-c3cc(C(=O)NC4CC4)ccc3C)c2=O)CCC1

Procedure:
The title product was prepared from 3-(3-(1-(2-(2-chloroethoxy)phenyl)cyclobutylamino)-2-oxopyrazin-1(2H)-yl)-N-cyclopropyl-4-methylbenzamide (Example 268 g) and methylamine using a similar method to that described for example 167f.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([OH:26])=O)=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.C(N(CC)CC)C.[Si:46]([O:63][CH2:64][CH2:65][N:66]1[C:70]([NH2:71])=[CH:69][CH:68]=[N:67]1)([C:59]([CH3:62])([CH3:61])[CH3:60])([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CN(C=O)C>[Si:46]([O:63][CH2:64][CH2:65][N:66]1[C:70]([NH:71][C:24]([C:23]2[CH:22]=[N:21][N:18]3[CH:19]=[CH:20][C:15]([N:11]4[CH2:12][CH2:13][CH2:14][C@@H:10]4[C:4]4[C:5]([O:8][CH3:9])=[N:6][CH:7]=[C:2]([F:1])[CH:3]=4)=[N:16][C:17]=23)=[O:26])=[CH:69][CH:68]=[N:67]1)([C:59]([CH3:60])([CH3:61])[CH3:62])([C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: CC(C)(C)[Si](OCCn1nccc1N)(c1ccccc1)c1ccccc1
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)Nc3ccnn3CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 46.3 %

Procedure:
To a suspension of (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (220 mg, 0.616 mmol) in DMF (5 mL) was added dropwise 2,4,6-trichlorobenzoyl chloride (106 μL, 0.677 mmol) and triethylamine (81.0 mg, 0.800 mmol). The reaction was stirred for 2 hours, and 1-(2-(tert-butyldiphenylsilyloxy)ethyl)-1H-pyrazol-5-amine (338 mg, 0.923 mmol) was added to the reaction mixture. The reaction was heated to 60° C. for 3 hours and then cooled to ambient temperature. The solvent was removed under reduced pressure and the residue was purified by silica column chromatography to afford the desired product (201 mg, 46.3% yield). MS (apci) m/z=705.1 (M+H).
Reaction SMILES: N1C2C(=CC=CC=2)C=C1C1C2C(=NC=CC=2)NN=1.[Br:19][C:20]1[CH:21]=[CH:22][C:23]([F:26])=[N:24][CH:25]=1.[Li+].CC([N-]C(C)C)C.[CH:35](N1CCCCC1)=[O:36]>>[Br:19][C:20]1[CH:25]=[N:24][C:23]([F:26])=[C:22]([CH:21]=1)[CH:35]=[O:36]
Reactant: Fc1ccc(Br)cn1
Reactant: O=CN1CCCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: c1ccc2[nH]c(-c3n[nH]c4ncccc34)cc2c1
Product: O=Cc1cc(Br)cnc1F

Procedure:
Scheme 3 describes a method for preparation of 3-(1H-indol-2-yl)-1H-pyrazolo[3,4-b]pyridine derivatives (XXVII) by first selective deprotonation at position-3 of 5-bromo-2-fluoropyridine (XVII) with LDA followed by N-formylpiperidine quench to produce 5-bromo-2-fluoronicotinaldehyde (XVIII). Aldehyde XVIII was condensed with pinacol followed by nucleophilic aromatic substitution by hydrazine to give 5-bromo-2-hydrazinyl-3-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)pyridine (XIX). XIX was then cyclized under acidic conditions to yield 5-bromo-1H-pyrazolo[3,4-b]pyridine (XX). The 1H-pyrazolo[3,4-b]pyridine NH was THP protection followed by reaction of the bromide (XXI) with bis(pinacolato)diboron to form the borate ester (XXII). Suzuki coupling with various bromides (XVIII) or chlorides yields 1H-pyrazolo[3,4-b]pyridine derivatives (XXIII). Iodization of position-3 of 1H-pyrazolo[3,4-b]pyridine (XXIII) with N-iodosuccinimide followed by Suzuki Coupling with various Boc-protected 1H-indol-2-ylboronic acids (XXV) to produce (XXVI). Final deprotection of the pyrazole and indole nitrogens yields the desired 3-(1H-indol-2-yl)-1H-pyrazolo[3,4-b]pyridine derivatives (XXVII).