Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:21][C:22]2[CH:23]=[C:24]([C:29]3[C:34]([CH3:35])=[CH:33][C:32]([O:36][CH2:37][C:38]4([OH:46])[CH2:43][CH2:42][S:41](=[O:45])(=[O:44])[CH2:40][CH2:39]4)=[CH:31][C:30]=3[CH3:47])[C:25]([CH3:28])=[CH:26][CH:27]=2)S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[CH:5]=[CH:4][C:3]=1[CH2:48][CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51].SCC(O)=O.O.[OH-].[Li+]>CN(C)C=O.[Cl-].[Na+].O>[F:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:21][C:22]2[CH:23]=[C:24]([C:29]3[C:30]([CH3:47])=[CH:31][C:32]([O:36][CH2:37][C:38]4([OH:46])[CH2:39][CH2:40][S:41](=[O:44])(=[O:45])[CH2:42][CH2:43]4)=[CH:33][C:34]=3[CH3:35])[C:25]([CH3:28])=[CH:26][CH:27]=2)[CH:5]=[CH:4][C:3]=1[CH2:48][CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51]
Reactant: CCOC(=O)CCc1ccc(N(Cc2ccc(C)c(-c3c(C)cc(OCC4(O)CCS(=O)(=O)CC4)cc3C)c2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Agent: O=C(O)CS
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1ccc(NCc2ccc(C)c(-c3c(C)cc(OCC4(O)CCS(=O)(=O)CC4)cc3C)c2)cc1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 92.7 %

Procedure:
To a solution of ethyl 3-(2-fluoro-4-{({4′-[(4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy]-2′,6,6′-trimethylbiphenyl-3-yl}methyl)[(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (189 mg, 0.24 mmol) and mercaptoacetic acid (50.1 μL, 0.72 mmol) in N,N-dimethylformamide (2 mL) was added lithium hydroxide monohydrate (60.4 mg, 1.44 mmol), and the mixture was stirred at room temperature for 2 days. Brine was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1-hexane/ethyl acetate=1/2) to give the title compound (133 mg, yield 93%) as a colorless oil.
Reaction SMILES: [I-].[Na+].[Br:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7].[C:13](#[N:15])C>>[Br:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([C:13]#[N:15])=[O:7]
Reactant: O=C(Cl)c1ccccc1Br
Reactant: CC#N
Agent: [I-]
Agent: [Na+]
Product: N#CC(=O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The reaction was carried out under Argon. Cuprous cyanide (6.52q, 72.8 mmol) and anhydrous sodium iodide (20.25g, 135 mmol) were stirred for 2 minutes in anhydrous acetonitrile (100 ml). The resulting solution was mixed with o-bromo benzoyl chloride (15.0q, 68 mmol) whereupon an orange precipitate formed. The mixture was stirred for 30 minutes at room temperature, filtered and concentrated in vacuo. The residue was taken up in dichloromethane and the resulting precipitate was filtered off. Concentration of the filtrate under reduced pressure gave a yellow solid. Recrystallisation from 60°-80° C. b.p.t. petroleum ether afforded o-bromo benzoyl cyanide as yellow crystals (7.14q, 50%), meltinq point 64° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:14]=[N:15][CH:16]=[C:17]([F:19])[CH:18]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:14]=[N:15][CH:16]=[C:17]([F:19])[CH:18]=2)=[C:6]([CH:10]=1)[C:7]([NH:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23])=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1COc1cncc(F)c1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2COc2cncc(F)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 6 of Example 1 from 5-chloro-2-{[(5-fluoropyridin-3-yl)oxy]methyl}benzoic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 5 of Example 1):
Reaction SMILES: Cl.O.[F:3][CH:4]([F:14])[C:5]([NH2:13])([CH2:9][CH2:10][CH2:11][NH2:12])[C:6]([OH:8])=[O:7].Br.C([NH+:18]=[C:19]([NH2:21])S)C.Cl>[OH-].[Na+]>[F:3][CH:4]([F:14])[C:5]([NH2:13])([CH2:9][CH2:10][CH2:11][NH:12][C:19]([NH2:21])=[NH:18])[C:6]([OH:8])=[O:7]
Reactant: NCCCC(N)(C(=O)O)C(F)F
Reactant: CC[NH+]=C(N)S
Agent: Br
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N=C(N)NCCCC(N)(C(=O)O)C(F)F

Procedure:
To a solution of 2-difluoromethyl-2,5-diamino-pentanoic acid monohydrate monohydrochloride (5 g or 21.13 mmole) in NaOH 2M (8.5 ml) is added at once ethylthiouronium hydrobromide (7.82 g or 42.26 mmole). The pH of the solution is adjusted to 10.5 with NaOH 2M and maintained to that value for 4 days. The reaction mixture is then neutralized to pH=7 with 1M HCl and concentrated under reduced pressure. The residue is passed on an Amberlite IR 120 H+ form column. Elution with NH4OH 2M affords 2-difluoromethyl-2-amino-5-guanidinopentanoic acid which is recrystallized from H2O/EtOH (2.3 g) m.p. 257° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH:15]([F:17])[F:16])[CH2:13][O:12][CH2:11][C:10]([NH2:14])=[N:9]2)[CH:7]=1.[C:19]([C:21]1[CH:22]=[C:23]([CH3:30])[C:24]([C:27]([NH2:29])=[O:28])=[N:25][CH:26]=1)#[N:20].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>[Cu]I.O1CCOCC1>[NH2:14][C:10]1[CH2:11][O:12][CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:29][C:27]([C:24]3[C:23]([CH3:30])=[CH:22][C:21]([C:19]#[N:20])=[CH:26][N:25]=3)=[O:28])[CH:3]=[CH:4][C:5]=2[F:18])([CH:15]([F:17])[F:16])[N:9]=1
Reactant: NC1=N[C@@](c2cc(Br)ccc2F)(C(F)F)COC1
Reactant: Cc1cc(C#N)cnc1C(N)=O
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cc(C#N)cnc1C(=O)Nc1ccc(F)c([C@]2(C(F)F)COCC(N)=N2)c1
Temperature: 23 °C
Reaction time: 23 h
Yield: 48.1 %

Procedure:
50 mg of (R)-5-(5-bromo-2-fluoro-phenyl)-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine, 30 mg of 5-cyano-3-methyl-pyridine-2-carboxylic acid amide, 3.0 mg CuI and 65 mg K3PO4 was charged to the reactor under N2 atomosphere. 1.0 ml of dioxane was added. Followed by 3.0 mg of N1,N2-dimethylethane-1,2-diamine. The resulting reaction mixture was heated to reflux and hold for 23 h. Cooled down to 23° C. then dilute with 15 ml IPAc. The organic phase was washed with water (5 ml×2), concentrated to dry under reduced pressure, Purification via column chromatography on silica gel (IPAc-Heptane 2:1 to 3:1) gave 30 mg of white solid. ESIMS: [M+H]+=403.9, 1H NMR (400 MHz, DMSO-d6): 10.72 (s, 1H), 8.96 (s, 1H), 8.38 (s, 1H), 7.99 (dd, 1H), 7.81 (m, 1H), 7.18 (d, 1H), 6.17 (br s, 2H), 6.15 (t, 1H), 3.98 (m, 4H), 2.53 (s, 3H).
Reaction SMILES: CC(C)(C)C(NC1C(C(OC)=O)=C2C(C=CCO2)=CC=1)=O.C(OC([N:29]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C:30]1[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH2:41][C:42]#[C:43][CH3:44])[C:31]=1[C:32]([O:34][CH3:35])=[O:33])=O)(C)(C)C>>[CH3:44][C:43]1[C:37]2[C:36](=[C:31]([C:32]([O:34][CH3:35])=[O:33])[C:30]([NH:29][C:45]([O:47][C:48]([CH3:51])([CH3:49])[CH3:50])=[O:46])=[CH:39][CH:38]=2)[O:40][CH2:41][CH:42]=1
Reactant: CC#CCOc1cccc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1C(=O)OC
Agent: COC(=O)c1c(NC(=O)C(C)(C)C)ccc2c1OCC=C2
Product: COC(=O)c1c(NC(=O)OC(C)(C)C)ccc2c1OCC=C2C

Procedure:
Prepared by proceeding in a similar manner to Intermediate 45, starting from methyl 2-[bis-(tert-butyoxycarbonyl)amino]-6-(but-2-ynyloxy)benzoate (Intermediate 54).
Reaction SMILES: [NH2:1][C:2]1[CH2:3][C:4]([C:14]([N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])=[O:15])=[CH:5][C:6]2[CH:12]=[CH:11][C:10](Br)=[CH:9][C:7]=2[N:8]=1.[CH3:23][O:24][C:25]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)=[O:26].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[CH2:3][C:4]([C:14](=[O:15])[N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])=[CH:5][C:6]2[CH:12]=[CH:11][C:10]([C:30]3[CH:31]=[CH:32][C:27]([C:25]([O:24][CH3:23])=[O:26])=[CH:28][CH:29]=3)=[CH:9][C:7]=2[N:8]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CCCN(CCC)C(=O)C1=Cc2ccc(Br)cc2N=C(N)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCN(CCC)C(=O)C1=Cc2ccc(-c3ccc(C(=O)OC)cc3)cc2N=C(N)C1
Temperature: 100 °C
Yield: 23 %

Procedure:
(1E,4E)-2-amino-8-bromo-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide (75.0 mgs, 0.206 mmol), 4-(methoxycarbonyl)phenylboronic acid (55.6 mgs, 0.309 mmol, tetrakis(triphenylphosphine)palladium(0) (23.8 mgs, 0.021 mmol), 2M aqueous potassium carbonate (0.309 ml, 0.618 mmol) were combined in 2 mls of acetonitrile in a microwave reaction vial. This mixture was heated in a microwave to 100° C. for 30 minutes. The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. Preparative thin layer chromatography (2×0.5 mm plates, 7% MeOH/DCM) afforded 20 mgs (23%) of methyl 4-((1E,4E)-2-amino-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-8-yl)benzoate. 1H NMR (400 MHz, CDCl3) δ 8.08-8.13 (m, 2H), 7.68-7.74 (m, 2H), 7.52-7.56 (m, 1H), 7.33-7.39 (m, 2H), 6.84 (s, 1H), 3.94 (s, 3H), 3.60-3.68 (m, 2H), 3.37-3.51 (m, 4H), 2.86 (s, 2H), 1.60-1.72 (m, 4H), 0.88-0.98 (m, 6H); m/z (APCI-pos) M+1=420.2.
Reaction SMILES: [C:1]([NH:4][C:5](=S)[NH:6][NH:7][C:8]1[N:13]([CH2:14][CH2:15][CH2:16][CH3:17])[C:12](=[O:18])[N:11]([CH2:19][CH2:20][CH3:21])[C:10](=[O:22])[CH:9]=1)(=[O:3])[CH3:2]>CN(C)C=O>[C:1]([NH:4][C:5]1[C:9]2[C:10](=[O:22])[N:11]([CH2:19][CH2:20][CH3:21])[C:12](=[O:18])[N:13]([CH2:14][CH2:15][CH2:16][CH3:17])[C:8]=2[NH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: CCCCn1c(NNC(=S)NC(C)=O)cc(=O)n(CCC)c1=O
Solvent: CN(C)C=O
Product: CCCCn1c(=O)n(CCC)c(=O)c2c(NC(C)=O)n[nH]c21
Yield: 81.5 %

Procedure:
6-(4-Acetylthiosemicarbazido)-1-butyl-3-propylpyrimidine-2,4(1H,3H)-dione (6.0 g) was heated in dimethylformamide (DMF) (60 ml) at 110°-120° C. for 60 hours. The reaction mixture was concentrated to dryness to give a crystalline product, which were recrystallized from aqueous methanol to afford colorless crystals (4.4 g, 61%),
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].[CH2:36](Br)[CH2:37][CH2:38][CH3:39]>>[CH2:36]([O:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:37][CH2:38][CH3:39]
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)cc1O
Reactant: CCCCBr
Product: CCCCOc1cc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)ccc1OC

Procedure:
prepared by reaction of 2-[1-(3-hydroxy-4-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with butyl bromide
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[CH:10]1[C:22]2[CH:21]([CH2:23][O:24][C:25](Cl)=[O:26])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1.C(N(C(C)C)CC)(C)C>>[NH:1]([C:25]([O:24][CH2:23][CH:21]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]2[C:22]1=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:26])[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5]
Reactant: NC(=O)C[C@H](N)C(=O)O
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Temperature: 25 °C

Procedure:
4.95 g (37.5 mmoles) of finely ground asparagine (Chemical Dynamics Corp.) was placed in a 250 mL round bottom flask (oven dried) which was fitted with a condenser (oven dried). A nitrogen gas line was attached at the top of the condenser. The solid was suspended in 87.5 mL of dry N,N-dimethylacetamide and stirred vigorously. 19.04 mL (150 mmoles) of Tms-Cl was injected in one portion. The mixture was stirred for 1 hour and cooled in an ice bath. 9-Fluorenylmethyoxycarbonyl chloride (6.47 g, 25 mmoles) and 19.78 mL (175 mmoles) of diisopropylethylamine were added. The solution was stirred in ice for 20 minutes and warmed to room temperature for 1-1.5 hrs. The mixture was concentrated on a rotary evaporator and then distributed between 200 mL diethyl ether and 250 mL 2.5% sodium bicarbonate. The phases were separated and the aqueous layer was extracted with 2×50 mL diethyl ether. The ether layers were backwashed with 2×25 mL H2O. The combined aqueous layers were acidified to pH 2 with 1.0N HCl. The white precipitate was filtered and washed with cold H2O. The product was then dried overnight. Appropriate solvents were used to recrystallize the product. The product was found to be homogeneous (Table II).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[C@H:10]([C:22]([N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH2:25]2)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.C(O)(=O)C>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[C@@H:10]([CH2:22][N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)[CH2:25]2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](N[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(=O)N1CCC[C@@H](Cc2ccc(F)cc2)C1)c1ccccc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: C[C@@H](N[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1CN1CCC[C@@H](Cc2ccc(F)cc2)C1)c1ccccc1
Reaction time: 20 h
Yield: 68.6 %

Procedure:
(3R,4S)-3-[(S)-3-(4-fluorobenzyl)-piperidine-1-carbonyl]-4-[(R)-1-phenyl-ethylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester (150 mg, 294 μmol) ) was treated with borane-tetrahydrofuran complex in tetrahydrofuran (1.0 M; 11.64 mL, 11.64 mmol) and stirred for 20 h . The mixture was treated slowly with 20% acetic acid in methanol (20 mL), and the resulting mixture was stirred at room temperature for 36 h . The solvents were removed, and the residue was dissolved in water, made basic (pH 11) with 50% sodium hydroxide, and extracted with dichloromethane. The combined organic phases were dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (60% ethyl acetate/hexane) to provide the product (100 mg, 68%). 1H NMR (300 mHz, CD3OD) δ7.31-7.00 (9H), 3.78 (m, 1H), 3.42 (m, 1H), 3.22-1.62 (18H), 1.39 (d, 3H), 1.34 (s, 9H); mass spec. (ES+) m/z 496.5.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[O:9]1[C:13]2([CH2:18][CH2:17][CH:16]([NH:19][C:20]3[N:21]=[CH:22][C:23]4[C:28]([CH:29]=3)=[C:27](F)[CH:26]=[CH:25][C:24]=4[CH3:31])[CH2:15][CH2:14]2)[O:12][CH2:11][CH2:10]1.C1OCCOCCOCCOCCOC1>C1COCC1.CS(C)=O>[CH:1]1([O:6][C:27]2[CH:26]=[CH:25][C:24]([CH3:31])=[C:23]3[C:28]=2[CH:29]=[C:20]([NH:19][CH:16]2[CH2:17][CH2:18][C:13]4([O:12][CH2:11][CH2:10][O:9]4)[CH2:14][CH2:15]2)[N:21]=[CH:22]3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(F)c2cc(NC3CCC4(CC3)OCCO4)ncc12
Reactant: OC1CCCC1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(OC2CCCC2)c2cc(NC3CCC4(CC3)OCCO4)ncc12
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
In a dry box, in a microwave test tube cyclopentanol (600.0 mg, 7.0 mmol) was dissolved in 5 ml of THF. To this solution was added the NaH (273.0 mg, 11.4 mmol) at room temperature and the mixture was stirred for 30 min. N-1,4-dioxaspiro[4.5]dec-8-yl-5-fluoro-8-methylisoquinolin-3-amine (1.8 g, 5.7 mmol) mixed with 15-crown-5 ether (0.13 g, 0.57 mmol) in 15 ml of DMSO was added to above solution. The microwave test tube was capped and moved out from the dry box. The tube was placed into Microwave apparatus and heated to 140° C. for 2 hours. The crude product was purified using a silica gel column to give 263.0 mg (yield 53%). 1H NMR (400 MHz, CHLOROFORM-d) ppm 0.89 (m, 1H), 1.17-1.40 (m, 2H), 1.57-2.02 (m, 10H), 2.05-2.29 (m, 2H), 2.47-2.63 (m, 3H), 3.54-3.78 (m, 1H), 3.90-4.06 (m, 4H), 4.64-5.02 (m, 2H), 6.46-6.77 (m, 1H), 6.79-6.98 (m, 2H), 7.20-7.43 (m, 1H), 8.91 (s, 1H). MS m/z, (APCI); 383.2 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:9][C:10]([CH2:13][NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1([C:24]([NH:26][CH2:27][CH:28]=[CH2:29])=[O:25])C=CN=C1.C(N(CC)C(C)C)(C)C>C(#N)C>[C:1]([O:5][C:6]([C:8]1[S:9][C:10]([CH2:13][N:14]([C:24](=[O:25])[NH:26][CH2:27][CH:28]=[CH2:29])[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCNC(=O)n1ccnc1
Reactant: CC(C)CNCc1ccc(C(=O)OC(C)(C)C)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C=CCNC(=O)N(Cc1ccc(C(=O)OC(C)(C)C)s1)CC(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
5-{[(2-Methylpropyl)amino]methyl}thiophene-2-carboxylic acid tert-butyl ester (0.55 g, 2.0 mmol) obtained in Example 24, step 1 and N-(1H-imidazol-1-ylcarbonyl)-allylamine (0.49 g, 3.2 mmol) obtained in step 1 were dissolved in acetonitrile (20 ml), N,N-diisopropylethylamine (0.56 mL, 3.2 mmol) was added, and the mixture was stirred at 60° C. overnight. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by column chromatography (hexane/ethyl acetate) to give the title compound (0.72 g, 2.0 mmol).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([NH:12][CH:13]2[CH2:19][CH:18]3[N:20]([CH3:21])[CH:15]([CH2:16][CH2:17]3)[CH2:14]2)[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH3:22][O:23][C:24]1[N:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].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>>[CH3:22][O:23][C:24]1[N:25]=[CH:26][C:27]([NH:30][C:2]2[CH:11]=[C:10]([NH:12][CH:13]3[CH2:19][CH:18]4[N:20]([CH3:21])[CH:15]([CH2:16][CH2:17]4)[CH2:14]3)[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=2)=[N:28][CH:29]=1
Reactant: COc1cnc(N)cn1
Reactant: COC(=O)c1cnc(Cl)cc1NC1CC2CCC(C1)N2C
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)c1cnc(Nc2cnc(OC)cn2)cc1NC1CC2CCC(C1)N2C
Temperature: 130 °C
Yield: 14.9 %

Procedure:
Methyl 6-chloro-4-(8-methyl-8-azabicyclo[3.2.1]octan-3-ylamino)nicotinate (26 mg, 0.084 mmol, prepared as described in Synthesis 62 and 63), 5-methoxypyrazin-2-amine (16 mg, 0.127 mmol), cesium carbonate (55 mg, 0.169 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (3.9 mg, 7 mol %), and tris(dibenzylideneacetone)dipalladium chloroform complex (3.5 mg, 3.5 mol %) were added to a vial which was flushed with nitrogen and sealed. Anhydrous toluene (0.3 mL) and DMF (0.1 mL) were added and nitrogen was bubbled through the stirred solution for 10 minutes. The mixture was heated by microwave irradiation at 130° C. for 30 minutes. The cooled solution was diluted with methanol and adsorbed onto an Isolute SCX-II column. The column was washed with methanol, then with 2M ammonia in methanol. The basic fractions concentrated. Preparative TLC, eluting with ethyl acetate-methanol-concentrated ammonia 10:1:0.2, gave methyl 6-(5-methoxypyrazin-2-ylamino)-4-(8-methyl-8-azabicyclo[3.2.1]octan-3-ylamino)nicotinate (5 mg, 15%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:17])[C:12](=[CH2:16])[C:13]([OH:15])=O)=[CH:7][CH:6]=1)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:42][C:43]1[C:48]([Br:49])=[CH:47][CH:46]=[CH:45][N+:44]=1[O-:50].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Br:49][C:48]1[C:43]([NH:42][C:13](=[O:15])[C:12](=[CH2:16])[CH:11]([C:8]2[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][CH:9]=2)[CH3:17])=[N+:44]([O-:50])[CH:45]=[CH:46][CH:47]=1
Reactant: Nc1c(Br)ccc[n+]1[O-]
Reactant: C=C(C(=O)O)C(C)c1ccc(C(=O)OC)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=C(C(=O)Nc1c(Br)ccc[n+]1[O-])C(C)c1ccc(C(=O)OC)cc1
Temperature: 23 °C
Reaction time: 1 h

Procedure:
A mixture of 3-(4-(methoxycarbonyl)phenyl)-2-methylenebutanoic acid (1.0 g, 4.2 mmol), HATU (1.9 g, 5.1 mmol), 2-amino-3-bromopyridine 1-oxide (0.88 g, 4.6 mmol) and diisopropyl ethylamine (2.22 mL, 12.5 mmol) in anhydrous DMF (10 mL) was stirred at 23° C. for 1 h, then concentrated. The residue was partitioned between ethyl acetate and brine (2×). The combined organic layers were dried over anhydrous sodium sulfate, and concentrated. The residue was triturated with acetonitrile (20 mL). The solid was filtered and dried under vacuum to give the title compound. MS: m/z=406.0 (M+1).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:22]=[C:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:23]5[CH:24]=[CH:25][C:26]6[N:30]=[C:29]([C@@H:31]7[C@@H:36]8[CH2:37][C@@H:33]([CH2:34][CH2:35]8)[N:32]7[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[NH:28][C:27]=6[CH:45]=5)=[CH:17][C:18]=4[CH2:19][CH2:20]3)=[CH:11][CH:10]=2)O1.Br[C:48]1[NH:52][C:51]([C@@H:53]2[CH2:57][CH2:56][CH2:55][N:54]2[C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])=[N:50][CH:49]=1.C([O-])(O)=O.[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[C:61]([O:60][C:58]([N:54]1[CH2:55][CH2:56][CH2:57][C@H:53]1[C:51]1[NH:52][C:48]([C:9]2[CH:22]=[C:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:23]5[CH:24]=[CH:25][C:26]6[N:30]=[C:29]([C@@H:31]7[C@@H:36]8[CH2:37][C@@H:33]([CH2:34][CH2:35]8)[N:32]7[C:38]([O:40][C:41]([CH3:44])([CH3:42])[CH3:43])=[O:39])[NH:28][C:27]=6[CH:45]=5)=[CH:17][C:18]=4[CH2:19][CH2:20]3)=[CH:11][CH:10]=2)=[CH:49][N:50]=1)=[O:59])([CH3:64])([CH3:62])[CH3:63]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(Br)[nH]1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1c1nc2ccc(-c3ccc4c(c3)CCc3cc(B5OC(C)(C)C(C)(C)O5)ccc3-4)cc2[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)CCc2cc(-c4ccc5nc([C@@H]6[C@H]7CC[C@H](C7)N6C(=O)OC(C)(C)C)[nH]c5c4)ccc2-3)[nH]1
Temperature: 120 °C
Yield: 88.4 %

Procedure:
To (1R,3S,4S)-tert-butyl 3-(6-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9,10-dihydrophenanthren-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (88 mg, 0.14 mmol), (S)-tert-butyl 2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (53 mg, 0.168 mmol), Pd(PPh3)4 (8 mg, 0.007 mmol). DME (1.4 mL) was added and followed by 0.56 mL 1M NaHCO3 aqueous solution. The reaction was purged with Ar and heated to 120° C. at microwave synthesizer for 0.5 hour. The reaction was cooled to room temperature and concentrated down. EtOAc was added and washed with sat. NaHCO3 aqueous (2×) and sat. NaCl aqueous (1×). The organic layer was concentrated down after drying over sodium sulfate and subject to silica gel chromatography with an eluent of ethyl acetate and hexane at a gradient of 40-100% with an ISCO column (12 g silica gel). The fractions containing product were combined and the solvent was removed under reduced pressure to provide title compound (90 mg, 86%). MS (ESI) m/z 727 [M+H]+.