Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[N:11][CH:12]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([F:32])=[CH:28][C:29]=2[F:31])[N:24]=[C:23]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[C:22]=1[CH3:39]>CN(C=O)C.O>[F:31][C:29]1[CH:28]=[C:27]([F:32])[CH:26]=[C:25]2[C:30]=1[C:21]([O:13][C:9]1[CH:8]=[C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH:12]=[N:11][CH:10]=1)=[C:22]([CH3:39])[C:23]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1)=[N:24]2
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Reactant: Oc1cncc(N2CCOCC2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Oc1cncc(N2CCOCC2)c1
Temperature: 23 °C
Reaction time: 0.25 h

Procedure:
To a vial containing 5-morpholinopyridin-3-ol (67.3 mg, 0.37 mmol) in DMF (3 mL) was added cesium carbonate (0.26 g, 0.8 mmol) in portions. The mixture was stirred at 23° C. for 15 minutes, then 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (90.7 mg, 0.31 mmol) was added in portions. Upon complete addition, the mixture was warmed to 100° C. After 18 h, the reaction mixture was diluted with water then subsequently extracted five times with EtOAc. The organic extractions were then washed one time with brine and dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on silica gel (0-45% of a premixed solution of 89:9:1 DCM:methanol:ammonium hydroxide in DCM) to afford light yellow film that was further purified with HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution.) The desired fractions were concd then diluted with EtOAc. After washing twice with satd aq. sodium bicarbonate solution and once with brine, the solvent was removed under reduced pressure to yield a light yellow solid as 4-(5-(5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-yloxy)pyridin-3-yl)morpholine. 1H NMR (500 MHz, CDCl3) δ ppm 8.74 (1H, d, J=4.6 Hz), 8.12 (1H, d, J=2.4 Hz), 7.98 (2H, m), 7.68 (1H, dd, J=9.4, 1.3 Hz), 7.59 (1H, d, J=2.2 Hz), 7.43 (1H, sxt, J=4.4 Hz), 7.02 (1H, ddd, J=11.4, 8.9, 2.4 Hz), 6.87 (1H, s), 3.93 (4H, m), 3.29 (4H, m), 2.41 (3H, s). Mass Spectrum (pos.) m/e: 435.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([C:16]([OH:18])=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])([CH3:4])[CH3:3].Cl.[CH2:20]([O:27][C:28](=[O:34])[C@@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>ClCCl>[CH2:20]([O:27][C:28]([C@@H:29]1[CH2:33][CH2:32][CH2:31][N:30]1[C:16](=[O:18])[C@H:9]([NH:8][C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:34])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Boc-D-α-phenylglycine (2 mmol), L-proline benzyl ester hydrochloride (2.2 mmol), and DIPEA (5 mmol) in dry dichloromethane (10 mL) was added TBTU (2.2 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated under vacuum and the residue was passed through a SCX-2 column and further chromatographied to yield compound 2a. 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.40 (s, 9H), 1.76-1.82 (m, 1H), 1.92-2.07 (m, 3H), 3.09-3.15 (m, 1H), 3.70-3.77 (m, 1H), 4.47-4.51 (m, 1H), 5.16 (d, J=12.35 Hz, 1H), 5.23 (d, J=12.35 Hz, 1H), 5.43 (d, J=7.20 Hz, 1H), 6.12 (d, J=7.20 Hz, 1H), 7.27-7.41 (m, 10H); and MS (ESI, EI+) m/z=439 (MH+).
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[H+].[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[F:1][B-:2]([F:5])([F:4])[F:3].[NH+:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: c1ccncc1
Agent: F[B-](F)(F)F
Agent: [H+]
Product: c1cc[nH+]cc1
Reaction time: 0.5 h

Procedure:
Tetrafluoroboric acid (250 ml, 2.00 mol) was added to cool (0° C.) pyridine (157.7 ml, 1.95 mol) within 25 min obtaining a colorless precipitate. After the acid was completely added the mixture was further stirred for 30 min at the same temperature. Then the reaction mixture was filtered. The residue was washed twice with cold ethanol and dried 12 h at high vacuum to yield 201.9 g (60%) pyridinium tetrafluoroborate as colorless crystals.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[CH3:28][S:29]([CH2:32][C:33](O)=[O:34])(=[O:31])=[O:30]>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:33](=[O:34])[CH2:32][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: CS(=O)(=O)CC(=O)O
Agent: Cl
Product: CS(=O)(=O)CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (22.6 mg, 61.4%), MS (ISP) m/z=452.1 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and 2-(methylsulfonyl)acetic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[C:11]1[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]1=[O:20])[O:6][CH2:5]2.C(N(CC)C(C)C)(C)C.[C:30](Cl)(=[O:32])[CH3:31]>C1COCC1>[O:20]=[C:12]1[C:11](=[C:7]2[C:8]3[C:4](=[CH:3][C:2]([NH:1][C:30](=[O:32])[CH3:31])=[CH:10][CH:9]=3)[CH2:5][O:6]2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13]1
Reactant: CC(=O)Cl
Reactant: Nc1ccc2c(c1)COC2=C1C(=O)Nc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc2c(c1)COC2=C1C(=O)Nc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.9 %

Procedure:
To a solution of 3-(5-Amino-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one (50.0 mg, 0.189 mmol) and N,N-diisopropylethylamine (98.8 μL, 0.567 mmol) in 2.0 mL THF was added acetyl chloride (13.4 μL, 0.189 mmol). After stirring at room temperature for 3 h, the mixture was concentrated in vacuo and the solid triturated with MeOH. Filtering the mixture and rinsing with MeOH and hexanes/EtOAc (7:3) afforded the title compound (42.2 mg, 73%) as a yellow solid.
Reaction SMILES: [SH:1][C:2]1[N:12]2[C:13]3[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=1.Cl.[N:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1>C(O)C>[N:15]1[CH:20]=[CH:19][C:18]([CH2:21][S:1][C:2]2[N:12]3[C:13]4[C:8]([CH2:9][CH2:10][CH2:11]3)=[CH:7][CH:6]=[CH:5][C:4]=4[N:3]=2)=[CH:17][CH:16]=1
Reactant: ClCc1ccncc1
Reactant: Sc1nc2cccc3c2n1CCC3
Agent: Cl
Solvent: CCO
Product: c1cc2c3c(c1)nc(SCc1ccncc1)n3CCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.5 %

Procedure:
To a suspension of 5,6-dihydro-2-mercapto-4H-imidazo [4,5,1-ij]quinoline (1.9 g) in ethanol was added 4-picolyl chloride HCl (1.68 g) and the mixture was stirred at ambient temperature for 16 hours and at reflux for 2 hours. The solvent was removed by evaporation and the residue dissolved in water. The solution was washed with EtOAc and then basified (aqueous NaOH) and extracted with CHCl3. Following short column chromatography (SiO2 /CHCl3) the residue was crystallised from EtOAc to give the title compound (1.25 g, 44%). mp 105°-7° C. (Found: C,68.20; H,5.50; N,15.30. C16H15N3S requires C,68.30; H,5.40; N,14.90).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1CCCC1.[CH3:20][C:21]([C:23]1[CH:28]=[C:27]([Br:29])[CH:26]=[CH:25][C:24]=1O)=[O:22]>CO>[Br:29][C:27]1[CH:28]=[C:23]2[C:24](=[CH:25][CH:26]=1)[O:14][C:11]1([CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]1)[CH2:20][C:21]2=[O:22]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: C1CCNC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(Br)ccc1O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
60 mL of MeOH, 7.97 g of N-Boc-piperidin-4-one, and 3.34 mL of pyrrolidine were added to 8.60 g of 5-bromo-2-hydroxyacetophenone put in a 200-mL flask equipped with a condenser, and the mixture was overnight heated under reflux. The reaction mixture was cooled to room temperature, and concentrated. The residue was purified through silica gel column chromatography (eluted with n-hexane/EtOAc=6/1) to obtain the intended compound as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[C:10]([NH:11][CH2:12][CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:9][C:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])=[N:7][C:6]=12.C[Si]([N:30]=[C:31]=[O:32])(C)C>ClCCl>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[C:10]([NH:11][CH2:12][CH:13]3[CH2:14][CH2:15][N:16]([C:31]([NH2:30])=[O:32])[CH2:17][CH2:18]3)=[CH:9][C:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])=[N:7][C:6]=12
Reactant: C[Si](C)(C)N=C=O
Reactant: Clc1ccccc1-c1cc(NCC2CCNCC2)n2ncc(Br)c2n1
Solvent: ClCCl
Product: NC(=O)N1CCC(CNc2cc(-c3ccccc3Cl)nc3c(Br)cnn23)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 85.1 %

Procedure:
[3-Bromo-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-yl]piperidin-4-ylmethylamine (57 mg, 0.136 mmoles) (prepared as described in Example 460, Step B above) was dissolved in anhydrous dichloromethane (1.2 mL) and trimethylsilylisocyanate (0.091 mL, 0.679 mmoles) was added. The mixture was stirred at 25° C. for 2.5h. The mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic layer was dried (MgSO4), filtered and evaporated to dryness. The residue was chromatographed on a silica gel column (30×2.5 cm) using 3% (10% conc. ammonium hydroxide in methanol)-dichloromethane as the eluant to give 4-{[3-bromo-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino]methyl}piperidine-1-carboxylic acid amide (53.7 mg, 86%): FABMS: m/z 463.1 (MH+); HRFABMS: m/z 463.0647 (MH+). Calcd. for C19H21N6OBrCl: m/z 463.0649; δH (d6-DMSO) 1.09 (2H, m, CH2), 1.63 (2H, m, CH2), 1.87 (1H, m, CH), 2.60 (2H, m, CH2), 3.53 (2H, bm, CONH2), 3.91 (2H, d, CH2), 6.52 (1H, s, H6), 7.50 (2H, m, Ar—H), 7.62 (2H, m, Ar—H), 8.33 (1H, s, H2) and 8.52 ppm (1H, m, NH); δC (d6-DMSO) CH2: 30.1, 30.1, 44.2, 44.2, 47.7; CH: 36.4, 88.2, 128.1, 130.7, 131.4, 132.1, 147.9; C: 82.1, 132.1, 139.4, 145.7, 147.9, 158.1, 158.8.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([OH:13])=O)=[CH:9][N:10]=[C:4]2[CH:3]=1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:25][C:26]1[CH:27]=[C:28]([C:33]2[N:37]=[C:36]([CH:38]3[CH2:41][N:40]([C:42]([O:44][CH3:45])=[O:43])[CH2:39]3)[O:35][N:34]=2)[CH:29]=[CH:30][C:31]=1[CH3:32]>ClCCl.N1C=CC=CC=1>[CH3:32][C:31]1[CH:30]=[CH:29][C:28]([C:33]2[N:37]=[C:36]([CH:38]3[CH2:39][N:40]([C:42]([O:44][CH3:45])=[O:43])[CH2:41]3)[O:35][N:34]=2)=[CH:27][C:26]=1[NH:25][C:11]([C:8]1[N:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]2=[N:10][CH:9]=1)=[O:13]
Reactant: Cc1ccn2c(C(=O)O)cnc2c1
Reactant: COC(=O)N1CC(c2nc(-c3ccc(C)c(N)c3)no2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)N1CC(c2nc(-c3ccc(C)c(NC(=O)c4cnc5cc(C)ccn45)c3)no2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirring suspension of 7-methylimidazo[1,2-a]pyridine-3-carboxylic acid (24i) (100 mg, 0.568 mmol) in anhydrous dichloromethane (5 mL) at 0° C. under Argon was added dropwise oxalyl chloride (53 uL, 0.624 mmol). Then, a drop of anhydrous N,N-dimethylformamide was added and the reaction mixture was stirred at 0° C. for 1 hour. The solvent was concentrated. A stirring mixture of the acid chloride and methyl 3-(3-(3-amino-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (31) (82 mg, 0.283 mmol) in anhydrous pyridine (2 mL) was stirred at room temperature for 2 hour. The solvent was concentrated and the crude product was purified by silica chromatography to give methyl 3-(3-(4-methyl-3-(7-methylimidazo[1,2-a]pyridine-3-carboxamido)phenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (F61). 1H NMR (400 MHz, d6-DMSO) δ 9.97 (s, 1H), 9.33 (d, J=7.2 Hz, 1H), 8.52 (s, 1H), 8.09 (d, J=1.6 Hz, 1H), 7.83 (dd, J=1.6, 7.6 Hz, 1H), 7.58 (s, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.03 (dd, J=1.6, 7.2 Hz, 1H), 4.39-4.33 (m, 2H), 4.31-4.24 (m, 1H), 4.22-4.16 (m, 2H), 3.59 (s, 3H), 2.43 (s, 3H), 2.36 (s, 3H). MS m/z 447.17 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[N:30](C(OC(C)(C)C)=O)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([OH:25])=O.[NH:43]1[CH2:48][CH2:47][S:46](=[O:49])[CH2:45][CH2:44]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[NH:30][C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([N:43]1[CH2:48][CH2:47][S:46](=[O:49])[CH2:45][CH2:44]1)=[O:25]
Reactant: O=S1CCNCC1
Reactant: CC(C)(C)OC(=O)n1c(C(CCC(=O)O)Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)nc2cc(Cl)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CC#N
Product: O=C(CCC(Nc1ncnc2cc(C(=O)N3CCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1)N1CCS(=O)CC1

Procedure:
Prepared analogously to Example 61 from 6-chloro-4-[1-(1-tert.-butyloxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl-amino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and thiomorpholine-1-oxide with TBTU in acetonitrile/tetrahydrofuran and subsequent reaction with trifluoroacetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([Cl:9])[N:6]=[C:5]([C:10]([OH:12])=O)[CH:4]=1.C1N=C[N:15](C(N2C=NC=C2)=O)C=1.[NH4+].[OH-].O>CN(C=O)C.C(Cl)Cl>[Cl:9][C:7]1[N:6]=[C:5]([C:10]([NH2:15])=[O:12])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(Cl)nc(C(=O)O)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(Cl)nc(C(N)=O)c1
Reaction time: 0.08 h
Yield: 61 %

Procedure:
To a solution of 4-methoxy-6-chloro picolinic acid (25 mmol) in anhydrous DMF (48 mL) was added CDI (27.5 mmol) at 0° C. The reaction mixture was stirred for 5 min in an ice-bath and then stirred at room temperature. After the reaction was completed, NH4OH (190 mL) was added and the reaction mixture was stirred at room temperature for 6 hrs. The mixture was partioned between H2O (200 mL) and DCM (300 mL). The organic layer was washed with H2O and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude was purified by silica gel chromatography (eluent: DCM/CH3OH) to give compound 18 as a beige solid in 61% yield. MS (ESI, EI+): m/z=187.14 (MH+).
Reaction SMILES: [CH3:1][CH:2](O)C=C.[C:6]([O:9][C:10](=O)[CH3:11])(=[O:8])[CH3:7].N1C=CC=C[CH:14]=1>>[CH3:14][CH:11]([CH:1]=[CH2:2])[CH2:10][O:9][C:6](=[O:8])[CH3:7]
Reactant: c1ccncc1
Reactant: CC(=O)OC(C)=O
Reactant: C=CC(C)O
Product: C=CC(C)COC(C)=O
Temperature: 50 °C

Procedure:
To a solution of but-3-en-2-ol (0.16 mL, 1.6 mmol) in pyridine (1 mL) is added acetic anhydride (0.28 mL, 1.6 mmol) and the mixture is heated at 50° C. for 18 h. Pyridine is removed by washing with Et2O and 1 N HCl solution, followed by sat. CuSO4, water and brine. The organic layer is dried with NaSO4 and concentrated to give the title compound.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:26]1[CH:27]=[CH:28][C:29]2[N:30]([N:32]=[C:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[N:34]=2)[N:31]=1.O>N1C=CC=CC=1>[C:38]([O:37][C:35]([C:33]1[N:34]=[C:29]2[N:30]([N:31]=[C:26]([NH:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][CH:9]([O:8][CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:10][CH2:11]3)[CH:27]=[CH:28]2)[N:32]=1)=[O:36])([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)c1nc2ccc(Cl)nn2n1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)c1nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2n1
Temperature: 80 °C
Reaction time: 13.5 h
Yield: 38.8 %

Procedure:
563 mg of 4-(diphenylmethoxy)-1-piperidinepropanamine and 442 mg of tert-butyl (6-chloro[1,2,4]triazolo[1,5-b]pyridazin-2-yl)carboxylate were dissolved in 5 ml of pyridine, followed by stirring at 80° C. for 13.5 hours. After cooling, water was added, followed by extraction with ethyl acetate; the extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (50:5:1). The desired fraction was collected and concentrated under reduced pressure. The residue was crystallized by the addition of ethyl acetate, collected by filtration, washed with ethyl ether and dried to yield 365 mg of the title compound.
Reaction SMILES: [OH-:1].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:12]([CH3:13])=[N:11][NH:10][C:7]2=[N:8][CH:9]=1.[O-:14][Mn](=O)(=O)=O.[K+]>O>[Br:3][C:4]1[CH:5]=[C:6]2[C:12]([C:13]([OH:14])=[O:1])=[N:11][NH:10][C:7]2=[N:8][CH:9]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: [OH-]
Reactant: Cc1n[nH]c2ncc(Br)cc12
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1n[nH]c2ncc(Br)cc12
Temperature: 90 °C
Reaction time: 0.42 h
Yield: 28.6 %

Procedure:
To a solution of NaOH (27 Kg, 675 mol) in water (617 L) was added 5-bromo-3-methyl-1H-pyrazolo[3,4-b]pyridine (XXI) (9.8 Kg, 46.2 mol). The solution was heated at 90° C. for 3 hours under nitrogen before adding a solution of KMnO4 (53.6 Kg, 339 mol) in water (870 L) slowly over 2 hours. The reaction was heated at 95° C. for 5 hours under nitrogen. The solution was cooled to 75° C. and filtered through diatomaceous earth (11 Kg) followed by washing the diatomaceous earth with water (150 L) heated at 75° C. The solution was cooled to 0° C. under nitrogen before the pH was adjusted to 1 with aqueous 35% HCl (˜75 L). The solution was warmed to room temperature before adding n-BuOH (473 L) which was stirred for 25 min and then the organic layer was separated. n-BuOH (473 L) was again added to the aqueous layer, stirred for 25 min and separated. The combined organic phases were concentrated under vacuum to a volume of ˜54 L. The n-BuOH was removed by adding to the solution 9×n-heptane (78 L) dropwise over 1 hour and then concentrating the volume to ˜54 L after each addition of n-heptane. The solid was filtered and washed 3×n-heptane (17 L). The solid was dried under vacuum at 45° C. to give 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid (XVIII) (3.2 Kg, 13.2 mol, 64.4% purity, 29.0% assay yield). 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.57 (d, J=2.4 Hz, 1H), 8.71 (d, J=2 Hz, 1H), 13.45 (brs, 1H), 14.65 (s, 1H); ESIMS found C7H4BrN3O2 m/z 243.8 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([NH:12][C@@H:13]1[CH2:18][C:17](=[O:19])[O:16][C:14]1=[O:15])([O:10][CH3:11])=[O:9].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl.C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:17](=[O:19])[CH2:18][C@@H:13]([NH:12][C:8]([O:10][CH3:11])=[O:9])[C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: COC(=O)N[C@@H]1CC(=O)OC1=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)N[C@H](CC(=O)c1ccc(Br)cc1)C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of bromobenzene (373 g) and (R)-2-carbomethoxyaminosuccinic anhydride (1) (90.51 g) in dichloromethane (260 ml) was cooled in ice, and aluminum chloride (174.34 g) was added over 1 minute (exothermic!). The dark red mixture was stirred at 0° C. for 30 minutes and at room temperature for 1 hour. The mixture was poured onto crushed ice, and concentrated hydrochloric acid was added slowly with stirring. Diethylether was added and the mixture was stirred until all of the red-brown material disappeared. The layers were separated, and the aqueous was extracted twice more with diethylether. The combined ether extracts were washed with water and extracted with aqueous sodium carbonate. The combined extracts were washed with diethylether, cooled in ice, and acidified with conc. hydrochloric acid. The acid was extracted 3 times with diethylether. The combined extracts were washed with brine and dried (MgSO4). The solvent was removed under vacuum to leave the title compound as a foam, 149.6 g. [α]D =-41° (25° C., CH3OH, c=1.0352).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][S:5][CH:6]=1.[C:7]([N:9]1[C:17]2[CH:16]=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=2[C:11]2[CH2:19][N:20]([CH3:23])[CH2:21][CH2:22][C:10]1=2)#[CH:8].O.O.O.[F-:27].C([N+](CCCC)(CCCC)CCCC)CCC>O>[F:27][C:8]([C:2]1[N:3]=[CH:4][S:5][CH:6]=1)=[CH:7][N:9]1[C:17]2[CH:16]=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=2[C:11]2[CH2:19][N:20]([CH3:23])[CH2:21][CH2:22][C:10]1=2
Reactant: Brc1cscn1
Reactant: [F-]
Reactant: C#Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2C=C(F)c2cscn2)CCN(C)C1
Temperature: 85 °C
Yield: 3.5 %

Procedure:
4-Bromothiazole (100 mg, 0.609 mmol), 5-ethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 163 mg, 0.731 mmol), dichlorobistrifluorophosphine palladium (12 mg, 0.01 mmol) and tetrabutylammonium fluoride trihydrate (575 mg, 1.827 mmol) were charged in a microwave vial and heated to 85° C. for 5 min in microwave oven. On completion of reaction (as observed by LCMS), the reaction mixture was poured into 20 mL water and compound extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (2×50 mL) and dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (190 mg) obtained was purified by reverse phase chromatography to afford 7 mg of 5-(2-Fluoro-2-thiazol-4-yl-vinyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CDCl3, free base) δ (ppm): 8.80 (s, 1H), 7.60 (s, 1H), 7.38 (d, 1H), 7.18 (s, 1H), 7.05 (d, 1H), 6.22 (d, 1H), 3.80 (m, 2H), 3.0 (m, 4H), 3.62 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][CH:13]=O.[C:15]([O:19][C:20](=[O:28])[NH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)([CH3:18])([CH3:17])[CH3:16].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.O>[O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][CH2:13][N:25]1[CH2:24][CH2:23][CH:22]([NH:21][C:20](=[O:28])[O:19][C:15]([CH3:17])([CH3:16])[CH3:18])[CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=CCn1c(=O)ccc2cccnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3cccnc32)CC1
Reaction time: 0.17 h
Yield: 48.4 %

Procedure:
To a solution of 0.29 g of (2-oxo-1,8-naphthyridin-1(2H)-yl)acetaldehyde in 10 mL of methylene chloride, 0.30 g of tert-butyl(piperidin-4-yl)carbamate and 87 μL of acetic acid were added, the mixture was stirred for 10 minutes, and to the reaction mixture, 0.48 g of sodium triacetoxyborohydride was then added and the mixture was stirred at room temperature for 4 hours. Thereto were added water, a saturated aqueous sodium hydrogen carbonate solution and chloroform, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, and the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using an eluent of chloroform:methanol=100:1 to obtain 0.27 g of tert-butyl (1-(2-(2-oxo-1,8-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a light brown oily substance.