Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:10][CH3:11])[CH2:5][C:6]([O:8][CH3:9])=[O:7].[CH2:12]([Li])[CH2:13][CH2:14]C.C(Br)C=C.Cl.[BH4-].[Na+]>O1CCCC1>[CH3:11][CH:10]([CH2:14][CH:13]=[CH2:12])[CH:4]([OH:3])[CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: [Li]CCCC
Reactant: CCC(=O)CC(=O)OC
Agent: Cl
Agent: [BH4-]
Agent: [H-]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCC(C)C(O)CC(=O)OC
Reaction time: 0.17 h

Procedure:
Sodium hydride (>63% oil, 1.64 g, 43.1 mmol) was added to a tetrahydrofuran solution (50 mL) of methyl 3-oxopentanoate (5.10 g, 39.2 mmol) under ice cooling, and the mixture was stirred in this state for 10 minutes. To the reaction solution, n-butyllithium (1.66 M hexane solution, 25.9 mL, 43.1 mmol) was added dropwise, and the mixture was further stirred for 10 minutes under ice cooling. Then, allyl bromide (5.18 g, 43.1 mmol) was added thereto, and the mixture was stirred in this state for 30 minutes and then further stirred overnight at room temperature. To the reaction solution, 1 N hydrochloric acid and saturated saline were added, followed by extraction with diethyl ether. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in methanol (100 mL). To the solution, sodium borohydride (1.89 g, 50 mmol) was added under ice cooling, and the mixture was stirred in this state for 1.5 hours. 2 N hydrochloric acid (50 mL) was added thereto, and the mixture was stirred for 30 minutes. Then, saturated saline was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the compound of interest as a pale yellow oil substance (5.72 g, 85%, mixture of diastereomers).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[C:9]([C@@H:11]3[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]3)=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C@@H:30]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31][C:32](O)=[O:33])=[CH:25][CH:24]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C@@H:30]([NH:35][C:36](=[O:37])[O:38][C:39]([CH3:41])([CH3:40])[CH3:42])[CH2:31][C:32]([N:13]2[CH2:14][CH2:15][CH2:16][C@@H:11]([C:9]3[N:8]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[C:7]4[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=4[N:10]=3)[CH2:12]2)=[O:33])=[CH:25][CH:24]=1
Reactant: COCCCn1c([C@@H]2CCCNC2)nc2cccc(Cl)c21
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COCCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc(Br)cc3)NC(=O)OC(C)(C)C)C2)nc2cccc(Cl)c21

Procedure:
((R)-7-Chloro-1-(3-methoxypropyl)-2-(piperidin-3-yl)-1H-benzo[d]imidazole (30E) (0.111 mmol, crude oil) prepared according to the procedure described in Example 30, Steps A-E was added to a 15 mL round-bottomed flask equipped for stirring under nitrogen. DMF (2 mL), (R)-4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoic acid (0.122 mmol, 0.032 g) and N-methylmorpholine (0.555 mmol, 0.061 mL) were then added and the solution was allowed to stir at rt for 5 min. HATU (0.122 mmol, 0.046 g) was added and the resultant solution was stirred at room temperature for 3 hrs. The reaction solution was then directly purified by preparative LC/MS (20-85% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording tert-butyl (R)-1-(4-bromophenyl)-4-((R)-3-(7-chloro-1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutan-2-ylcarbamate (31A) as a clear oil that was used directly onto the next step. EST-MS: m/z 647.3 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[C:5]([NH:7][C@@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=1)[CH3:9])=[O:6].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[C:63]1([SH:69])[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1.C(N(C(C)C)C(C)C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:20][C:19]1[CH:18]=[CH:17][C:4]([C:5]([NH:7][C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[CH3:9])=[O:6])=[CH:3][C:2]=1[S:69][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1
Reactant: Sc1ccccc1
Reactant: C[C@@H](NC(=O)c1ccc(Cl)c(Br)c1)c1cccc(Cl)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[C@@H](NC(=O)c1ccc(Cl)c(Sc2ccccc2)c1)c1cccc(Cl)c1
Reaction time: 18 h
Yield: 92.3 %

Procedure:
To a mixture of (R)-3-bromo-4-chloro-N-(1-(3-chlorophenyl)ethyl)benzamide 32 (0.634 g, 1.7 mmol), Pd2(dba)3 (0.100 g, 0.11 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.125 g, 0.22 mmol) was added benzenethiol (0.173 mL, 1.7 mmol), dioxane (4.5 mL) and N-ethyl-N-isopropylpropan-2-amine (0.590 mL, 3.4 mmol). The reaction mixture was degassed and heated to reflux. After 18 h, the reaction mixture was diluted with EtOAc, washed with water (1×), brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 5% to 30% EtOAc in hexanes) gave (R)-4-chloro-N-(1-(3-chlorophenyl)ethyl)-3-(phenylthio)benzamide 33 (0.631 g, 92% yield) as a white solid. Mass spectrum: calculated for C21H17Cl2NOS 401.0. found 402.1 (M++1).
Reaction SMILES: C(OC(C([O:8][C:9](=[O:40])[C@H:10]([C:33]1[CH:34]=[C:35]([CH3:39])[CH:36]=[CH:37][CH:38]=1)[CH2:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[N:14]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[N:13]=1)C)=O)C.Cl>C(O)(=O)C>[Cl:24][C:19]1[CH:18]=[C:17]([C:15]2[N:14]([C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[N:13]=[C:12]([CH2:11][C@@H:10]([C:33]3[CH:34]=[C:35]([CH3:39])[CH:36]=[CH:37][CH:38]=3)[C:9]([OH:40])=[O:8])[CH:16]=2)[CH:22]=[CH:21][C:20]=1[Cl:23]
Reactant: CCOC(=O)C(C)OC(=O)[C@@H](Cc1cc(-c2ccc(Cl)c(Cl)c2)n(-c2ccc(OC)cc2)n1)c1cccc(C)c1
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc(-n2nc(C[C@H](C(=O)O)c3cccc(C)c3)cc2-c2ccc(Cl)c(Cl)c2)cc1
Temperature: 85 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
A 500-mL, 1-necked round-bottomed flask equipped with a magnetic stirring bar was charged with (S)-3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionic acid 1-ethoxycarbonyl-ethyl ester from Example 503 (18.5 g. 0.0318 mol), as a 4:1 mixture of regioisomers, in 150 mL of acetic acid. After the addition of 2 N HCl (25 mL), the reaction mixture was heated at 85° C. using an oil bath. After 4 h, when TLC indicated complete hydrolysis of the lactate ester, the heating source was removed and reaction flask cooled to rt. The mixture was concentrated under reduced pressure to remove most of acetic acid, and then 250 mL of EtOAc was added. The EtOAc solution was then washed with H2O (50 mL) and brine (50 mL), and then dried over Na2SO4. The solvents were removed under reduced pressure to obtain the crude acid as a brown oil (15 g, 98%). HPLC (Method E) indicated the product to be a mixture of 2 regioisomers in a 4:1 ratio. Chiral HPLC (Method S): Rt (S isomer)=8.1 min (enantiomeric ratio of 1:9 R/S). This mixture was subjected to the next step without any additional purification. MS (ES+): mass calculated for C26H22Cl2N2O3, 480.10; m/z found, 480.8 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.31-7.09 (m, 8H), 6.91-6.86 (m, 3H), 6.21 (s, 1H), 4.12-4.08 (dd, J=5.8, 9.6 Hz, 1H), 3.82 (s, 3H), 3.54-3.49 (dd, J=9.6, 14.9 Hz, 1H), 3.13-3.08 (dd, J=5.8, 14.9 Hz, 1H), 2.35 (s, 3H).
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=CC=1.[CH3:50][N:51]([CH3:55])[CH2:52][CH2:53][NH2:54]>>[NH2:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[C:16]3[CH2:29][CH2:28][N:27]([C:30]4[CH:38]=[CH:37][C:33]([C:34]([NH:54][CH2:53][CH2:52][N:51]([CH3:55])[CH3:50])=[O:35])=[CH:32][CH:31]=4)[C:17]=3[N:18]=[C:19]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[N:20]=2)=[CH:11][N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3)cn2)cc1
Reactant: CN(C)CCN
Product: CN(C)CCNC(=O)c1ccc(N2CCc3c(-c4cnc(N)nc4)nc(N4CCOCC4)nc32)cc1
Yield: 55 %

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-yl)-benzoic acid (53.4 mg) obtained in Step A in Example 1-D-19 and N,N-dimethyl ethylenediamine (18 μl) instead of 3-(aminomethyl)pyridine, in the same manner as Step B in Example 1-D-19, 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-N-(2-dimethylamino-ethyl)-benzamide was obtained as a crude product. Then the PMB groups were removed according to Deprotection method 3, to obtain the desired compound (D-41) as a colorless solid (21.7 mg, 55%).
Reaction SMILES: [C:1]1([N:7]2[C:15](=[O:16])[C:14]3[C:9]([C:10]4[C:11](=[CH:17][NH:18][CH:19]=4)[NH:12][CH:13]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[CH3:29][N:30]=[C:31]=[O:32]>CN(C=O)C>[CH3:29][NH:30][C:31]([N:18]1[CH:19]=[C:10]2[C:11]([NH:12][CH:13]=[C:14]3[C:15](=[O:16])[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=[C:9]32)=[CH:17]1)=[O:32]
Reactant: CN=C=O
Reactant: O=c1c2c[nH]c3c[nH]cc3c-2nn1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)n1cc2[nH]cc3c(=O)n(-c4ccccc4)nc-3c2c1
Reaction time: 8 h

Procedure:
One equivalent of pyrrolo-pyridine 12a was dissolved in DMF (0.1 M) under an atmosphere of nitrogen. 3 equivalents of di-iso-propylethylamine was added, followed by 1.5 equivalents of methylisocyanate and stirred overnight. The crude reaction mixture was concentrated to dryness and purification by column chromatography afforded the compound 13a. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.84 (d, J=3.52 Hz, 3H) 7.02-7.18 (m, 1H) 7.30-7.47 (m, 2H) 7.57-7.78 (m, 1H) 7.90-8.04 (m, 1H) 8.05-8.20 (m, 2H) 8.32-8.50 (m, 1H) 8.52-8.68 (m, 1H) 12.28-12.49 (m, 1H)
Reaction SMILES: [NH2:1][C:2]1[C:32]([C:33]([F:36])([F:35])[F:34])=[CH:31][C:5]([CH2:6][CH:7]([CH2:10][C:11](=[O:30])[N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:24][CH2:23][C:22]4[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=4[NH:20][C:19]3=[O:29])[CH2:14][CH2:13]2)[CH:8]=O)=[CH:4][C:3]=1[Cl:37].[NH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[NH:45][CH2:46][CH:47]1[CH2:52][CH2:51][N:50](C(OC(C)(C)C)=O)[CH2:49][CH2:48]1.C(O)(C(F)(F)F)=O>CN(C=O)C.ClCCl>[NH2:1][C:2]1[C:32]([C:33]([F:34])([F:36])[F:35])=[CH:31][C:5]([CH2:6][CH:7]([C:8]2[N:45]([CH2:46][CH:47]3[CH2:48][CH2:49][NH:50][CH2:51][CH2:52]3)[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=3[N:38]=2)[CH2:10][C:11]([N:12]2[CH2:13][CH2:14][CH:15]([N:18]3[CH2:24][CH2:23][C:22]4[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=4[NH:20][C:19]3=[O:29])[CH2:16][CH2:17]2)=[O:30])=[CH:4][C:3]=1[Cl:37]
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2ccccc2N)CC1
Reactant: Nc1c(Cl)cc(CC(C=O)CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Nc1c(Cl)cc(CC(CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)c2nc3ccccc3n2CC2CCNCC2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 537 mg (1.000 mmol) 2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-butyraldehyde (Intermediate product 36) in 10 mL DMF was added tert. butyl 4-[(2-amino-phenylamino)-methyl]-piperidin-1-carboxylate (Intermediate product 34) and the mixture was stirred for 16 hours in an atmosphere of air at RT. The reaction mixture was poured onto ice water, the precipitate formed was filtered off, washed with water and dried i. vac. (Yield: 790 mg, 96% of theory). 1 mL of TFA was added to a solution of 580 mg (0.705 mmol) of the crude product in 10 mL dichloromethane and the mixture was stirred for 16 hours at RT. The reaction mixture was diluted with dichloromethane, the org. phase was washed with sat. aqueous sodium bicarbonate solution, dried over sodium sulphate and evaporated i. vac. The residue was dissolved in 3.5 mL DMF and purified by HPLC-MS (Zorbax Bonus C18 amide-phase 5 μm, gradient 0.15% formic acid in water/acetonitrile 10/90→90/10 v/v) and then lyophilised.
Reaction SMILES: Cl[C:2]1[CH:7]=C[C:5]([C@@H:8](CNC(C)C)[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]4[NH:23][CH:24]=[C:25]([NH:26]C(=O)CCC)[C:18]=34)[CH2:13][CH2:12]2)=O)=[CH:4][CH:3]=1.[C:37]([OH:45])(=O)[C:38]1[CH:43]=[CH:42][CH:41]=[N:40][CH:39]=1.C(N(CC)CC)C.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CO.[Li+].[OH-]>[CH2:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[NH:23][CH:24]=[C:25]([NH:26][C:37](=[O:45])[C:38]4[CH:43]=[CH:42][CH:41]=[N:40][CH:39]=4)[C:18]=23)[CH2:13][CH2:12]1)[C:8]1[CH:7]=[CH:2][CH:3]=[CH:4][CH:5]=1
Reactant: CCCC(=O)Nc1c[nH]c2nccc(N3CCN(C(=O)[C@H](CNC(C)C)c4ccc(Cl)cc4)CC3)c12
Reactant: O=C(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Li+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(Nc1c[nH]c2nccc(N3CCN(Cc4ccccc4)CC3)c12)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.6 %

Procedure:
Crude 4-(4-benzylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-amine (0.200 g, 0.651 mmol, see Example 25), nicotinic acid (0.0961 g, 0.781 mmol) and triethylamine (0.453 mL, 3.25 mmol) were placed in DMF (3 mL) at room temperature. Triethylamine (0.453 mL, 3.25 mmol) was then added, and the reaction was stirred for 1 hour at room temperature. The reaction was then diluted with MeOH (5 mL), and 3M LiOH (0.5 mL) was added and stirred for 10 minutes. The reaction was then poured into saturated Na2CO3 and extracted into DCM. The organic fractions were combined, dried, filtered and concentrated to give a crude residue that was purified by column chromatography (500:20-500:30 DCM:MeOH) to give N-(4-(4-benzylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (0.160 g, 59.6% yield).
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:10][N:9]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])[CH2:8]2)[O:4][N:3]=1.[CH3:31][NH:32][CH3:33]>C(O)C>[CH3:31][N:32]([CH3:33])[C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:10][N:9]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])[CH2:8]2)[O:4][N:3]=1
Reactant: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(Cl)no2)C1
Reactant: CNC
Solvent: CCO
Product: CN(C)c1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1
Reaction time: 1 h

Procedure:
To a solution of 158 mg (0.355 mmol) of the oxadiazole from Example 23A in 2.5 ml of ethanol were added 2.50 ml (19.7 mmol, 40% in water) of dimethylamine solution, and then the reaction mixture was stirred in the microwave at 80 for 1 h. The solvent was removed under reduced pressure and the crude product was purified by means of preparative HPLC. Yield: 94.0 mg (58% of theory)
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=3)=[CH:9][N:8]([C@@H:25]3[CH2:28][C@H:27]([C:29](O)=[O:30])[CH2:26]3)[C:4]=2[N:5]=[CH:6][N:7]=1.F[B-](F)(F)F.O=[C:38]1C=CC=[CH:40][N:39]1OC(N(C)C)=[N+](C)C.C(N(C(C)C)CC)(C)C.CNC>CN(C)C=O>[CH3:38][N:39]([CH3:40])[C:29]([C@H:27]1[CH2:28][C@@H:25]([N:8]2[C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=3[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:12]=3)=[CH:9]2)[CH2:26]1)=[O:30]
Reactant: Nc1ncnc2c1c(-c1cccc(OCc3ccccc3)c1)cn2[C@H]1C[C@@H](C(=O)O)C1
Reactant: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: CNC
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)[C@H]1C[C@@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 45 mg (0.11 mmol) of cis-3-[4-amino-5-(3benzyloxy-phenyl)pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanecarboxylic acid in 2 ml of N,N-dimethylformamide is added 36 mg (0.12 mmol) of O-(1,2-dihydro-2-oxo-1-pyridyl)-1,1,3,3-tetramethyluronium tetrafluoroborate and 39 μl (0.23 mmol) of diisopropylethylamine. 40 μl of a 5.6 M solution of dimethylamine are added thereto. After stirring the solution for 15 min at RT, working-up is effected by partitioning between water and ethyl acetate. The organic layer is dried over magnesium sulfate and concentrated in vacuo to provide cis-3-[4-amino-5-(3-benzyloxy-phenyl)pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanecarboxylic acid dimethylamide. Analytical HPLC: tR=6.81 min (Grad 2); ES-MS: m/eo=442.0.
Reaction SMILES: Br[C:2]1[C:3]([F:14])=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2.[C:15](OCC)(=O)[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[CH2:20]([O:19][C:17](=[O:18])[C:16]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[N:10]=2)[N:5]=[CH:4][C:3]=1[F:14])=[CH2:15])[CH3:21]
Reactant: COc1ccc2ncc(F)c(Br)c2n1
Reactant: CCOC(=O)CC(=O)OCC
Product: C=C(C(=O)OCC)c1c(F)cnc2ccc(OC)nc12
Yield: 44.5 %

Procedure:
Starting from 8-bromo-7-fluoro-2-methoxy-[1,5]naphthyridine (10 g, 38.9 mmol) and diethyl malonate (17.9 mL, 116.7 mmol), the title compound (4.8 g, 17.3 mmol) was prepared as described in WO 2007/122258 for the analogous methyl ester. The purity of the material was around 80%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1>[Pt]>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][CH:4]([C:13]([F:15])([F:14])[F:16])[CH2:3][CH2:2]2
Reactant: FC(F)(F)c1cc(Cl)c2cc(Cl)ccc2n1
Agent: [Pt]
Product: FC(F)(F)C1CCc2cc(Cl)ccc2N1

Procedure:
4,6-Dichloro-2-trifluoromethylquinoline was reduced with platinum on carbon to give 6-chloro-2-trifluoromethyltetrahydroquinoline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][N+:7]3[CH2:20][CH2:19][C:18]4[C:13](=[CH:14][C:15]5[O:23][CH2:22][O:21][C:16]=5[CH:17]=4)[C:8]=3[CH:9]=2)[C:4]=1[O:24][CH3:25].[Cl-].[C:27]([Mg]Cl)#[CH:28]>C(OCC)C>[C:27]([CH:6]1[N:7]2[CH2:20][CH2:19][C:18]3[C:13]([C:8]2=[CH:9][C:10]2[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[C:4]([O:24][CH3:25])[C:5]1=2)=[CH:14][C:15]1[O:23][CH2:22][O:21][C:16]=1[CH:17]=3)#[CH:28]
Reactant: C#C[Mg]Cl
Reactant: COc1ccc2cc3[n+](cc2c1OC)CCc1cc2c(cc1-3)OCO2
Agent: [Cl-]
Solvent: CCOCC
Product: C#CC1c2c(ccc(OC)c2OC)C=C2c3cc4c(cc3CCN21)OCO4
Temperature: 0 °C
Reaction time: 16 h
Yield: 20.2 %

Procedure:
To a suspension of berberine hydrochloride (500 mg, 1.3 mmol) in anhydrous diethyl ether (50 mL) at 0° C. was added ethynylmagnesium chloride solution (1.1 M in tetrahydrofuran, 24 mL, 26 mmol) dropwise. After stirring at 0° C. for 16 h, the reaction was quenched by adding saturated aqueous ammonium chloride solution (20 mL). The mixture was extracted with diethyl ether (2×50 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was re-crystallized from diethyl ether to afford 8-ethynyl-9,10-dimethoxy-5,8-dihydro-6H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline (95 mg, 20%). LC/MS m/e calcd for C22H19NO4 (M+H)+: 362.40, observed: 362.2; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.78-2.88 (m, 2 H) 3.17 (d, J=2.27 Hz, 1 H) 3.21-3.30 (m, 2 H) 3.81 (d, J=4.80 Hz, 6 H) 5.45 (d, J=2.02 Hz, 1 H) 6.02 (d, J=5.81 Hz, 2 H) 6.18 (s, 1 H) 6.76-6.83 (m, 2 H) 6.93 (d, J=8.59 Hz, 1 H) 7.32 (s, 1 H).
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7](C)[CH:6](NC=O)[N:5]=2)[CH2:3][CH2:2]1.[CH2:13]([N:15](CC)[CH2:16]C)C.O=P(Cl)(Cl)Cl>C(Cl)Cl.O>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([CH2:16][N+:15]#[C-:13])[N:5]=2)[CH2:2][CH2:3]1
Reactant: CN1OC(C2CC2)=NC1NC=O
Reactant: CCN(CC)CC
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: [C-]#[N+]Cc1noc(C2CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 5-cyclopropyl-3-formylamino-methyl-1,2,4-oxadiazole (60 mmol) and triethylamine (176 mmol) in CH2Cl2 (100 ml) was charged dropwise with POCl3 (60 mmol) at 0° C. The mixture was then left for 30 minutes with stirring at 0° C., whereafter a solution of 60 mmol) in H2O (50 ml) was added. The mixture was heated to room temperature, whereafter the organic phase was separated, dried and evaporated in vacuo. The residue was treated with ether, decanted and the solution was evaporated to give the title compound as an oil. The oil was processed without any further purification. The compound was characterized by its IR absorbtion band at 2160 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([NH:12][C:13]([C:15]2[O:16][C:17]([CH:23]([CH3:25])[CH3:24])=[C:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=2)=[O:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5]>[OH-].[Na+]>[Cl:1][C:2]1[CH:11]=[C:10]([NH:12][C:13]([C:15]2[O:16][C:17]([CH:23]([CH3:25])[CH3:24])=[C:18]([CH:20]([CH3:21])[CH3:22])[CH:19]=2)=[O:14])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(NC(=O)c2cc(C(C)C)c(C(C)C)o2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)c1cc(C(=O)Nc2ccc(C(=O)O)c(Cl)c2)oc1C(C)C
Yield: 89.8 %

Procedure:
The aforementioned ester (102 mg, 0.280 mmol) was hydrolyzed with sodium hydroxide in a conventional manner, and extraction and recrystallization were performed to obtain the title compound (23, 88 mg, 90%) as pale yellow needles.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([N+:17]([O-:19])=[O:18])=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14].S(OC)(OC)(=O)=O>CC(C)=O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([N+:17]([O-:19])=[O:18])=[C:12]([CH:16]=1)[C:13]([O:15][CH3:1])=[O:14]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 99.9 %

Procedure:
Potassium carbonate (515 gm) was added to a solution of 5-chloro-2-nitro benzoic acid (500 gm) in acetone (2750 ml) at room temperature. Dimethyl sulphate (306.5 gm) was added to the reaction mixture slowly and heated to reflux for 30 minutes. The reaction mass was filtered and then concentrated to obtain a residual mass. The residual mass was poured to the ice water and extracted with methylene chloride. The solvent was distilled off under reduced pressure to obtain a residual solid of methyl 5-chloro-2-nitrobenzoate (534 gm).
Reaction SMILES: [O:1]([CH2:8][C:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C:12]2[CH:26]=[CH:27][C:28]([C:30]([OH:32])=O)=[CH:29][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)N=C=NC(C)C.[CH3:42][O:43][C:44]1[CH:51]=[CH:50][C:47]([CH2:48][NH2:49])=[CH:46][CH:45]=1>C1COCC1>[CH3:42][O:43][C:44]1[CH:51]=[CH:50][C:47]([CH2:48][NH:49][C:30]([C:28]2[CH:27]=[CH:26][C:12]3[N:13]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:17][CH:16]=4)[C:9]([CH2:8][O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[N:10][C:11]=3[CH:29]=2)=[O:32])=[CH:46][CH:45]=1
Reactant: O=C(O)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Reactant: COc1ccc(CN)cc1
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: COc1ccc(CNC(=O)c2ccc3c(c2)nc(COc2ccccc2)n3Cc2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.16 mmol of 2-phenoxymethyl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole-5-carboxylic acid were dissolved in 1 ml THF with 1 eq. DIC. After 15 min 1.5 eq of 4-methoxy-benzylamine were added and the reaction stirred at room temperature for 16 h. The crude material was purified via reversed phase preparative HPLC. MS(ISP): 562.3 (M+H)+.