Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][N:5]([CH3:7])[CH:6]=1.C1COCC1.B.C1COCC1.[Cl:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[C:25]([O:30][CH3:31])[C:24]=1[C@H:32]([C:34]1[C:42]2[C:37](=[N:38][CH:39]=[C:40](B3OC(C)(C)C(C)(C)O3)[CH:41]=2)[NH:36][CH:35]=1)[CH3:33].C([O-])([O-])=O.[K+].[K+].O>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O1CCOCC1>[Cl:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[C:25]([O:30][CH3:31])[C:24]=1[C@H:32]([C:34]1[C:42]2[C:37](=[N:38][CH:39]=[C:40]([C:2]3[C:3]([CH2:8][OH:10])=[N:4][N:5]([CH3:7])[CH:6]=3)[CH:41]=2)[NH:36][CH:35]=1)[CH3:33]
Reactant: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: Cn1cc(Br)c(C(=O)O)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: B
Solvent: C1CCOC1
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(-c3cn(C)nc3CO)cc12
Temperature: 60 °C

Procedure:
To a solution of 4-bromo-1-methyl-1H-pyrazole-3-carboxylic acid (20.0 mg, 0.0976 mmol) in THF (3 mL, 40 mmol) was added 1.0 M of BH3.THF in THF (0.49 mL, 0.49 mmol), and the resulting solution was heated to 60° C. overnight. The material was extracted with EtOAc and washed with sat. NaHCO3 (3×) to remove carboxylic acid starting material. The organic layer was concentrated in vacuo. 3-[(S)-1-(2-Chloro-3-fluoro-6-methoxyphenyl)-ethyl]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (15.0 mg, 0.0348 mmol), (1,1′bis-(diphenylphosphino)-ferrocene) palladium dichloride (3.57 mg, 0.00488 mmol), K2CO3 (20.2 mg, 0.146 mmol) and 4:1 dioxane:H2O (1 mL, 10 mmol) were added, and the mixture was heated to 95° C. for 30 min. The solution was used directly for HPLC purification, and the fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.80 (d, J=7.1 Hz, 3H), 3.68 (br. s., 3H), 3.90 (s, 3H), 4.45-4.55 (m, 2H), 5.10-5.16 (m, 1H), 6.89 (dd, J=9.1, 4.3 Hz, 1H), 7.07 (t, J=8.8 Hz, 1H), 7.31 (d, J=1.3 Hz, 1H), 7.65 (s, 1H), 7.68 (s, 1H), 8.27 (br. s., 1H). MS (ES+): m/z=415.12/417.13 (100/50) [MH+]. HPLC: tR=1.35 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].N1C=CC=CC=1>ClCCl.C(#N)C>[CH3:32][S:33]([O:1][CH2:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1)(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(CO)c3ccccc32)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CC#N
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(COS(C)(=O)=O)c3ccccc32)cc1
Reaction time: 2 h

Procedure:
5-Hydroxymethyl-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.70 g) is dissolved in a mixture (30 ml) of dichloromethane/acetonitrile (1:1) and thereto are added methanesulfonyl chloride (0.8 ml) and pyridine (1.0 ml), and the mixture is refluxed with stirring for 2 hours. After cooling, the reaction solution is evaporated under reduced pressure and to the resulting residue is added water and then extracted with ethyl acetate. The extract is washed successively with diluted hydrochloric acid and saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is recrystallized from ethyl acetate/n-hexane to give 5-methanesulfonyloxymethyl-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.72 g) as white powder, m.p. 189-190° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])=[CH:5][CH:4]=1.C(=O)(O)[O-:18].[Na+].O>CS(C)=O>[CH:2]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])=[CH:5][CH:4]=1)=[O:18]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccccc1-c1ccc(C=O)cc1
Temperature: 120 °C
Yield: 63.1 %

Procedure:
A mixture of 2-(4-bromomethylphenyl)benzonitrile (12 g) and sodium bicarbonate (26 g) in dimethyl sulfoxide (150 ml) was heated at 120° C. for 5 hours with stirring. After addition of water, the mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated to dryness. The residue was purified by column chromatography on silica gel to give crystals. Recrystallization from chloroform-isopropyl ether gave colorless needles (5.77 g, 63%).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][C:9]#[CH:10])=[CH:3]1.N1C=CN=C1.[CH2:16]([Si:18](Cl)([CH2:21][CH3:22])[CH2:19][CH3:20])[CH3:17]>CN(C)C=O.O>[CH2:8]([C:4]1[C:5](=[O:7])[CH2:6][CH:2]([O:1][Si:18]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:16][CH3:17])[CH:3]=1)[C:9]#[CH:10]
Reactant: C#CCC1=CC(O)CC1=O
Reactant: CC[Si](Cl)(CC)CC
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: C#CCC1=CC(O[Si](CC)(CC)CC)CC1=O
Yield: 80.3 %

Procedure:
A solution of 250 mg (1.84 mmole) of the title compound of Example B in 4 ml of dimethylformamide was treated successively with 200 mg (3 mmole) of imidazole and 300 mg (2 mmole) of triethylsilyl chloride. After stirring for thirty minutes, the reaction mixture was diluted with water, washed with diethyl ether, dried over sodium sulfate, filtered, and concentrated to dryness. The crude material was chromatographed on silica gel to give 0.37 g of the title compound as an oil. Structure assignment was confirmed by the proton nmr spectrum: 2.13 (t, J=2 Hz, ≡C--H), 3.08 (mult, --CH2 --C≡), 4.90 (mult C-11), ##STR9##
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)[CH2:10][C:11]([OH:13])=O)=O)(C)(C)C.[Cl:25][C:26]1[C:45]([Cl:46])=[CH:44][C:29]2[N:30]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[C:31]([C@@H:33]3[CH2:38][CH2:37][CH2:36][NH:35][CH2:34]3)=[N:32][C:28]=2[CH:27]=1>>[NH2:8][C@H:9]([CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)[CH2:10][C:11]([N:35]1[CH2:36][CH2:37][CH2:38][C@@H:33]([C:31]2[N:30]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[C:29]3[CH:44]=[C:45]([Cl:46])[C:26]([Cl:25])=[CH:27][C:28]=3[N:32]=2)[CH2:34]1)=[O:13]
Reactant: COCCCn1c([C@@H]2CCCNC2)nc2cc(Cl)c(Cl)cc21
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc2ccccc2c1
Product: COCCCn1c([C@@H]2CCCN(C(=O)C[C@H](N)Cc3ccc4ccccc4c3)C2)nc2cc(Cl)c(Cl)cc21

Procedure:
The title compound was prepared according to the procedure outlined in Example DI, Steps A-F, using reagents (R)-3-(tert-butoxycarbonylamino)-4-(naphthalen-2-yl)butanoic acid and (R)-5,6-dichloro-1-(3-methoxypropyl)-2-(piperidin-3-yl)-1H-benzo[d]imidazole in Step E. ESI-MS: m/z 553.4 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.35-1.52 (m, 1H) 1.65-1.89 (m, 3H) 1.91-2.10 (m, 2H) 2.60-2.82 (m, 2H) 2.89-3.18 (m, 7H) 3.18-3.44 (m, 3H) 3.69-3.99 (m, 2H) 4.07-4.21 (m, 1H) 4.23-4.53 (m, 2H) 7.40-7.57 (m, 3H) 7.75-8.00 (m, 6H).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[CH2:7]([O:9][C:10]1[C:11]([F:20])=[C:12]2[C:18]([NH2:19])=[CH:17][NH:16][C:13]2=[N:14][CH:15]=1)[CH3:8]>N1C=CC=CC=1>[CH2:7]([O:9][C:10]1[C:11]([F:20])=[C:12]2[C:18]([NH:19][C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])=[CH:17][NH:16][C:13]2=[N:14][CH:15]=1)[CH3:8]
Reactant: O=C(Cl)C1CC1
Reactant: CCOc1cnc2[nH]cc(N)c2c1F
Solvent: c1ccncc1
Product: CCOc1cnc2[nH]cc(NC(=O)C3CC3)c2c1F
Reaction time: 2 h
Yield: 55.6 %

Procedure:
Cyclopropanecarbonyl chloride (63.1 μL, 0.676 mmol) was added dropwise to 5-ethoxy-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (120 mg, 0.615 mmol) in pyridine (5 mL) at 0° C. The reaction was stirred at about 0 to about 5° C. for 2 hours and then concentrated to dryness. Water (10 mL) was added and extracted with CHCl3/IPA (3:1). The combined organic phases were dried over MgSO4 and concentrated to yield N-(5-ethoxy-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide (90 mg, 55% yield) as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=O)[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2].[Na]>C(O)CCC>[CH2:1]([O:3][C:4]1[C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1cccc2c(=O)c3ccccc3sc12
Agent: [Na]
Solvent: CCCCO
Product: CCOc1cccc2c1Sc1ccccc1C2

Procedure:
A solution of 4-ethoxythioxanth-9-one (4.4 g.) in n-butanol (100 ml.) is heated under reflux and sodium (6.0 g.) is added in portions to the boiling solution. Heating is continued until all the sodium has reacted, and the solvent is then removed by evaporation in vacuo. The residue is slurried with water, extracted with ether (3 × 50 ml.), the extracts dried and evaporated to give 4-ethoxythioxanthene, m.p. 95°-98° C. on recrystallisation from ethanol.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]2[C:4](=[C:5]([C:16]([NH:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[O:17])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(Cl)Cl.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:25]1([C:2]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]3[C:4](=[C:5]([C:16]([NH:18][C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)=[O:17])[CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(Nc1cccnc1)c1cccc2cc(C(F)(F)F)c(Cl)nc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: O=C(Nc1cccnc1)c1cccc2cc(C(F)(F)F)c(-c3ccccc3)nc12
Yield: 40.4 %

Procedure:
A mixture of 2-chloro-N-(pyridin-3-yl)-3-(trifluoromethyl)quinoline-8-carboxamide (136 mg, 0.39 mmol), phenylboronic acid (62 mg, 0.51 mmol), Pd(dppf)Cl2.CH2Cl2 (39 mg, 0.048 mmol), K2CO3 (167 mg, 1.2 mmol) in dioxane/H2O (4:1, 3 ml) was heated (85° C.×2 hours) under a blanket of Nitrogen. The reaction mixture was evaporated, and the residue was triturated with ethyl acetate. The mixture was filtered, concentrated and the residue was purified by prep. HPLC to give 2-phenyl-N-(pyridin-3-yl)-3-(trifluoromethyl)quinoline-8-carboxamide as a white powder (62 mg, 41% yield). MS (ESI) calcd for C22H14F3N3O (m/z): 393.11. found: 394 [M+1].
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1.O[CH2:12][C@@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:18]([O:17][C:16]([NH:15][C@@H:13]([CH3:14])[CH2:12][O:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1)=[O:22])([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)c1cc(O)no1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(OC[C@H](C)NC(=O)OC(C)(C)C)no1
Temperature: 25 °C
Yield: 59.6 %

Procedure:
To a solution of methyl 3-hydroxyisoxazole-5-carboxylate (20 g), tert-butyl [(1S)-2-hydroxy-1-methylethyl]carbamate (25 g) and triphenylphosphine (55.1 g) in THF (800 mL) was added dropwise a toluene solution (1.9 M, 110 mL) of diisopropyl azodicarboxylate, and the mixture was refluxed for 5 hr. The reaction mixture was allowed to cool to room temperature, and ethyl acetate was added thereto. The mixture was washed with water and saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (25 g).
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][CH:6]([CH3:9])[CH:5]1[C:10]1[C:15](F)=[CH:14][C:13]([NH:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=O)=[C:12]([N+:26]([O-])=O)[CH:11]=1)(=[O:3])[CH3:2].[CH3:29][S:30]([C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1)(=[O:32])=[O:31]>>[C:1]([N:4]1[CH2:8][CH2:7][CH:6]([CH3:9])[CH:5]1[C:10]1[C:15]([O:39][C:36]2[CH:35]=[CH:34][C:33]([S:30]([CH3:29])(=[O:32])=[O:31])=[CH:38][CH:37]=2)=[CH:14][C:13]2[NH:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[N:26][C:12]=2[CH:11]=1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: CC(=O)N1CCC(C)C1c1cc([N+](=O)[O-])c(NC(=O)c2ccccn2)cc1F
Product: CC(=O)N1CCC(C)C1c1cc2nc(-c3ccccn3)[nH]c2cc1Oc1ccc(S(C)(=O)=O)cc1

Procedure:
The entitled compound was obtained as a white solid in the same method as in Example 338 (step 5) or in accordance with the method or by combining it with an ordinary method but using N-(4-(1-acetyl-3-methylpyrrolidin-2-yl)-5-fluoro-2-nitrophenyl)pyridine-2-carboxamide and 4-(methanesulfonyl)phenol.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.S(Cl)([Cl:26])=O>>[Cl:26][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(O)ncnc2cc1OCCCN1CCOCC1
Product: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Yield: 87 %

Procedure:
A mixture of 4-hydroxy-6-methoxy-7-(3-morpholinopropoxy)quinazoline (638 mg, 2 mmol) and thionyl chloride (8 ml) was heated at reflux for 30 minutes. Excess thionyl chloride was removed by evaporation and by azeotroping with toluene (x2). The residue was suspended in methylene chloride and a 10% aqueous solution of sodium hydrogen carbonate (50 ml) was added to the mixture. The organic layer was separated, dried (MgSO4) and the solvent removed by evaporation. The residue was triturated with ether, the solid was collected by filtration, washed with ether and dried under vacuum to give 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (590 mg, 87%).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:19]=O)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:21]=1.[C:23]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)(=[O:25])[CH3:24]>>[C:23]([N:26]1[CH2:31][CH2:30][N:29]([CH2:19][C:13]2[N:8]3[CH:9]4[CH2:12][CH:11]([C:5]5[CH:4]=[C:3]([F:22])[C:2]([Br:1])=[CH:21][C:6]=5[C:7]3=[N:15][C:14]=2[C:16]([NH2:18])=[O:17])[CH2:10]4)[CH2:28][CH2:27]1)(=[O:25])[CH3:24]
Reactant: CC(=O)N1CCNCC1
Reactant: NC(=O)c1nc2n(c1C=O)C1CC(C1)c1cc(F)c(Br)cc1-2
Product: CC(=O)N1CCN(Cc2c(C(N)=O)nc3n2C2CC(C2)c2cc(F)c(Br)cc2-3)CC1

Procedure:
10-bromo-9-fluoro-3-formyl-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide (75 mg) was reacted with N-acetylpiperazine similarly to as described in the synthesis of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-3-[(4-methylpiperazin-1-yl)methyl]-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide to afford 3-((4-acetylpiperazin-1-yl)methyl)-10-bromo-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide which was directly reacted with 2-Methyl-3-butyne-ol via General Procedure E to afford 41 mg (41%) of 3-[(4-acetylpiperazin-1-yl)methyl]-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide. M+1=480.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([CH3:31])[O:11][C@H:10]1[CH2:32][CH2:33][CH2:34][OH:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>C(Cl)Cl>[CH3:45][S:46]([O:35][CH2:34][CH2:33][CH2:32][C@@H:10]1[O:11][C@@H:12]([CH3:31])[C@@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:9]1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:48])=[O:47]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H]1O[C@@H](CCCO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1O[C@@H](CCCOS(C)(=O)=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reaction time: 1 h
Yield: 102.3 %

Procedure:
To a solution of 3-(2,3,4-tri-O-benzyl-α-L-fucopyranosyl)propanol [ML-36 step D] (10.6 g, 22.2 mmol) and Hunig's Base (4.66 mL, 26.7 mmol) in anhydrous DCM (100 mL) cooled in an ice bath was added dropwise methanesulfonyl chloride (1.9 mL, 24.5 mmol). After complete addition the mixture was stirred at ice bath temperature for 1 hour. Mixture washed with water (100 mL), sat. NaCl (50 mL); dried over Na2SO4, filtered and evaporated to give the title compound (12.6 g, 100%). 1H NMR (CDCl3) δ 7.37 (15H, m), 4.80 (2H, m), 4.68 (2H, m), 4.63 (1H, d, J=11.8 Hz), 4.53 (1H, J=11.8 Hz), 4.22 (2H, m), 4.00 (1H, d, J=9.8 Hz), 3.94 (1H, m), 2.99 (3H, s), 1.88 (1H, m), 1.75 (2H, m), 1.62 (1H, m), 1.31 (3H, d, J=6.6 Hz).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[CH2:9][C@@H:8]([O:10][C:11]2[CH:16]=[N:15][C:14]([CH:17]3[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[CH2:7][N:6]1C(OC(C)(C)C)=O)=[N+:2]=[N-:3].Cl>ClCCl.O1CCOCC1>[N:1]([CH2:4][C@H:5]1[NH:6][CH2:7][C@H:8]([O:10][C:11]2[CH:16]=[N:15][C:14]([CH:17]3[CH2:18][CH2:19]3)=[CH:13][N:12]=2)[CH2:9]1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](Oc2cnc(C3CC3)cn2)C[C@H]1CN=[N+]=[N-]
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: [N-]=[N+]=NC[C@@H]1C[C@@H](Oc2cnc(C3CC3)cn2)CN1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the product from Example 174C (440 mg, 1.221 mmol) dissolved in dichloromethane (2 mL) was added 4 M HCl in 1,4-dioxane (4 mL). The resulting mixture was stirred at ambient temperature for 30 minutes and was then partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:40]=[CH:41][CH:42]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([CH:26]5[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]5)=[CH:22][CH:21]=4)[CH:18]=3)[NH:13][CH:12]=2)[C:8]([CH3:39])=[N:7]1>C(O)(C(F)(F)F)=O.CO>[F:1][C:2]1[CH:3]=[C:4]([CH:40]=[CH:41][CH:42]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([CH:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:24][CH:25]=4)[CH:18]=3)[NH:13][CH:12]=2)[C:8]([CH3:39])=[N:7]1
Reactant: Cc1nn(Cc2cccc(F)c2)cc1-c1c[nH]c2ncc(-c3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Cc1nn(Cc2cccc(F)c2)cc1-c1c[nH]c2ncc(-c3ccc(C4CCNCC4)cc3)cc12
Yield: 6.1 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(4-(3-(1-(3-fluorobenzyl)-3-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (100 mg, 0.176 mmol) was deprotected in TFA/methanol (3/3 ml). This afforded 5 mg (152% yield) of the titled compound after purification by preparative HPLC along with one more isomer Example 91. 1H NMR (CD3OD, 300 MHz): δ 8.51 (s, 1H), 8.24 (s, 1H), 7.80 (s, 1H), 7.72-7.67 (m, 2H), 7.51 (s, 1H), 7.42-7.34 (m, 3H), 7.06-6.87 (m, 3H), 5.46 (s, 2H), 3.61-3.51 (m, 2H), 3.21-3.13 (m, 2H), 3.02-2.94 (t, 1H), 2.37 (s, 3H), 2.15-2.11 (m, 2H), 2.02-1.89 (m, 2H). MS: m/z=466.2 (M+1), HPLC: 89.39% in method B.
Reaction SMILES: C(OC(=O)[N:7]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH:8]1[CH2:13][CH2:12][C:11]([C:14]2[CH:15]=[C:16]3[C:22]([C:23](=[O:33])[CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=4[F:32])=[CH:21][NH:20][C:17]3=[N:18][CH:19]=2)=[CH:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:34]([NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:22]([C:23](=[O:33])[CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=4[F:32])=[CH:21][NH:20][C:17]3=[N:18][CH:19]=2)[CH2:10][CH2:9]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)C1CC=C(c2cnc3[nH]cc(C(=O)Cc4cccc(F)c4F)c3c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Cc1cccc(F)c1F)c1c[nH]c2ncc(C3CCC(NCc4ccccc4)CC3)cc12
Yield: 162 %

Procedure:
A solution of the above carbamic acid tert-butyl ester (306 mg, 0.54 mmol) was dissolved in CH2Cl2 (1 ml), treated with TFA (3 ml) for 1 hour. The reaction was evaporated and the solid residue triturated with ether and hexane, and filtered to give the final desired product as a white solid (402 mg) in 80% overall yield. FIA-MS m/e=458.2 (M+H), 456.3 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]([CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:8][C:4]=2[CH:3]=1.[BH4-]>CO>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:8][C:4]=2[CH:3]=1
Reactant: CCCCCC=Cc1cc2cc(Cl)ccc2s1
Agent: [BH4-]
Solvent: CO
Product: CCCCCCCc1cc2cc(Cl)ccc2s1
Temperature: 25 °C
Yield: 48.2 %

Procedure:
To a solution of 0.36 g (1.36 mmol) of 5-chloro-2-(hepten-1-yl)benzo[b]thiophene in 50 ml methanol were added 5 g (15 mmol) of borohydride exchange resin and 375 mg (1.51 mmol) Ni(II)acetate tetrahydrate, and the mixture was refluxed for 1 h. It was cooled to room temperature and the resin removed by filtration. The resin was heated twice with 50 ml methanol, and the combined filtrates were concentrated under reduced pressure. The residue was eluted through a column of silica gel with hexane, and the eluant was evaporated to give 175 mg (48%) of the title compound as a colorless resinous oil; MS 266 (M+).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:30]12[O:37][CH:34]([CH2:35][CH2:36]1)[CH2:33][NH:32][CH2:31]2>>[CH3:28][N:26]([CH3:27])[C:25]([C:7]1[N:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:10]2[N:11]=[C:12]([NH:15][C:16]3[CH:24]=[CH:23][C:19]([C:20]([N:32]4[CH2:31][CH:30]5[O:37][CH:34]([CH2:35][CH2:36]5)[CH2:33]4)=[O:21])=[CH:18][N:17]=3)[N:13]=[CH:14][C:9]=2[CH:8]=1)=[O:29]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Reactant: C1CC2CNCC1O2
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)O5)cn3)nc2n1C1CCCC1
Yield: 32.5 %

Procedure:
Following general amide formation method 3, 6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinic acid (528 mg, 1.34 mmole) was combined with 8-Oxa-3-aza-bicyclo[3.2.1]octane (199 mg, 1.34 mmol) which gave 7-Cyclopentyl-2-[5-(8-oxa-3-aza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (213 mg, 0.435 mmol) in 32.5% yield. 1H NMR (400 MHz, CDCl3) δ ppm 1.74 (m, 8H), 2.07 (m, 5H), 2.58 (m, 2H), 3.17 (s, 7H), 4.81 (dd, 1H), 6.48 (s, 1H), 7.79 (dd, 8.30 (s, 1H), 8.39 (d, 1H), 8.56 (d, 1H), 8.77 (s, 1H) MS m/z 490.5 (M+H)+.
Reaction SMILES: [CH3:1][O:2][NH:3][C:4](=[O:7])[CH2:5][Cl:6].C(N(CC)CC)C.[CH3:15][N:16]([CH3:20])[C:17](Cl)=[O:18]>C1C=CC=CC=1>[Cl:6][CH2:5][C:4]([O:7][C:17](=[O:18])[N:16]([CH3:20])[CH3:15])=[N:3][O:2][CH3:1]
Reactant: CN(C)C(=O)Cl
Reactant: CONC(=O)CCl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CON=C(CCl)OC(=O)N(C)C
Temperature: 25 °C

Procedure:
N-Methoxychloroacetamide (12.3 grams; 0.1 mole), benzene (75 ml) and triethylamine (12 grams; 1.2 mole) are charged into a glass reaction flask equipped with a mechanical stirrer, therometer and reflux condenser. N,N-Dimethylcarbamoyl chloride (11 grams; 0.1 mole) dissolved in benzene (25 ml) is incrementally added to the reaction mixture, with stirring, at room temperature. After the addition is completed the reaction mixture is heated at reflux for a period of about 3 hours. After this time the reaction mixture is distilled to remove benzene and unreacted starting material thereby yielding the desired product 1-chloro-2-(N,N-dimethylcarbamoyloxy)-2-methoxyiminoethane.