Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]3[S:28][C:27]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)=[N:26][C:25]=3[CH2:35][N:36]3[CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][CH2:37]3)[CH2:19][CH2:18]2)=[O:14])[CH:3]=1.[F:49][C:50]([F:55])([F:54])[C:51]([OH:53])=[O:52]>ClCCl>[F:49][C:50]([F:55])([F:54])[C:51]([OH:53])=[O:52].[F:49][C:50]([F:55])([F:54])[C:51]([OH:53])=[O:52].[F:49][C:50]([F:55])([F:54])[C:51]([OH:53])=[O:52].[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:15][CH2:16][CH:17]2[CH2:18][CH2:19][N:20]([CH2:23][C:24]3[S:28][C:27]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)=[N:26][C:25]=3[CH2:35][N:36]3[CH2:37][CH2:38][NH:39][CH2:40][CH2:41]3)[CH2:21][CH2:22]2)=[O:14])[CH:3]=1
Reactant: CCOc1nc(C(=O)NCC2CCN(Cc3sc(-c4ccccn4)nc3CN3CCN(C(=O)OC(C)(C)C)CC3)CC2)cc(N)c1C#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1nc(C(=O)NCC2CCN(Cc3sc(-c4ccccn4)nc3CN3CCNCC3)CC2)cc(N)c1C#N

Procedure:
A solution of the compound prepared in Example 159 (100 mg) in dichloromethane (1 mL)-trifluoroacetic acid (228 mL) was stirred for 30 minutes. The reaction was concentrated and the excess trifluoroacetic acid was removed via azeotropic distillation from toluene and hexane to obtain the title compound (110 mg) having the following physical data.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C@H:17]2[C:21]#[N:22])=[O:15])[C@H:12]2[CH2:23][C@@H:9]1[C@H:10]([O:24][CH2:25][C:26](O)=[O:27])[CH2:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[NH4+].O[N:32]1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[NH2:32][C:26](=[O:27])[CH2:25][O:24][C@H:10]1[C@H:9]2[CH2:23][C@H:12]([C@@H:13]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[C:21]#[N:22])=[O:15])[N:8]2[C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:11]1
Reactant: On1nnc2cccnc21
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@H]2OCC(=O)O)[C@H]1C(=O)N1CCC[C@H]1C#N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@H]2OCC(N)=O)[C@H]1C(=O)N1CCC[C@H]1C#N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of [((1R,3S,4S,6R)-2-(tert-butoxycarbonyl)-3-{[(2S)-2-cyano-1-pyrrolidinyl]carbonyl}-2-azabicyclo[2.2.1]hept-6-yl)oxy]acetic acid obtained in Example 51-2 (260 mg) in dimethylformamide (3.0 mL), was added 28% ammonium hydroxide (0.08 mL), 1-hydroxy-7-azabenzotriazole (117 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (165 mg). The mixture was stirred at room temperature for 12 hrs.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]2)=[N:22][CH:23]=1.[Cl:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[C:41]([O:54][CH3:55])[C:40]=1[OH:56]>>[NH2:30][C@@H:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:21]2[N:22]=[CH:23][C:18]([NH:17][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:43]5[CH:42]=[C:41]([O:54][CH3:55])[C:40]([OH:56])=[C:39]([Cl:38])[CH:44]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12]([CH:14]3[CH2:15][CH2:16]3)=[O:13])=[CH:19][CH:20]=2)[CH2:25]1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(Nc4ccc(N5CCC[C@@H](N)C5)nc4)c3c2)cc(Cl)c1O
Yield: 32.4 %

Procedure:
Following general procedure D, (R)-tert-butyl 1-(5-(6-bromo-3-(cyclopropanecarbonyl)quinoline-4-ylamino)pyridin-2-yl)piperidin-3-ylcarbamate (100 mg, 0.17 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (74 mg, 0.26 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (30 mg, 32% over 2 steps) as an orange-yellow solid: 1H NMR (500 MHz, MeOD+TFA-d) δ 9.40 (br s, 1H), 8.28-8.20 (m, 2H), 8.10 (br s, 1H), 8.00 (d, J=8.8 Hz, 1H), 7.65 (dd, J=9.1, 2.8 Hz, 1H), 7.05 (d, J=9.1 Hz, 1H), 6.99 (s, 1H), 6.83 (br s, 1H), 4.55-4.49 (d, J=11.6 Hz, 1H), 4.04-3.95 (m, 1H), 3.91 (s, 3H), 3.28-3.18 (m, 3H), 2.87 (br s, 1H), 2.22-2.14 (m, 1H), 1.96-1.87 (m, 1H), 1.76-1.62 (m, 2H), 1.28-1.16 (m, 4H).; ESI MS m/z 544 [C30H30ClN5O3+H]+; HPLC>99.0% (AUC), tR=10.74 min.
Reaction SMILES: Br[C:2]1[S:3][C:4]([Br:8])=[CH:5][C:6]=1[Br:7].CCCCCC.[Li]CCCC.[CH3:20][C:21]([CH3:23])=[O:22]>CCOCC>[Br:7][C:6]1[CH:5]=[C:4]([Br:8])[S:3][C:2]=1[C:21]([OH:22])([CH3:23])[CH3:20]
Reactant: Brc1cc(Br)c(Br)s1
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)(O)c1sc(Br)cc1Br
Reaction time: 0.17 h

Procedure:
A solution of 2,3,5-tribromothiophene (8.17 g, 25 mmol) in Et2O (N2 atmosphere) was cooled to −78° C. and treated with a 1.6 M hexane solution of nBuLi (15.6 mL, 25 mmol). The mixture was then stirred for 10 minutes, then treated with acetone (1.84 mL, 25 mmol). The mixture was then stirred for 30 minutes and quenched with H2O. The mixture was extracted with Et2O; the organic layers were combined, dried (MgSO4), and the solvent removed in vacuo. The residue was filtered through a plug of silica gel (gradient elution from hexanes to EtOAc) to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=2)[CH2:3]1.N1C=CC=CC=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>ClCCl>[CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:17]=[C:18]([NH:22][S:37]([C:34]3[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=3)(=[O:39])=[O:38])[CH:19]=[CH:20][CH:21]=2)[CH2:3]1
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(C(F)(F)F)cc21
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)CC(c2cccc(NS(=O)(=O)c3ccc(F)cc3)c2)Nc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
To a stirred solution of 3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (100 mg, 0.31 mmol) in pyridine (49 mg, 0.62 mmol) and dichloromethane (1.5 mL) at 0° C. was added dropwise a solution of 4-fluoro-benzenesulfonyl chloride (73 mg, 0.37 mmol) in dichloromethane (0.5 mL). The mixture was stirred at room temperature overnight. The mixture was quenched with water (5 mL) and extracted with dichloromethane (5 mL×2). The combined organic layers were dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography on silica gel to afford N-[3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-4-fluoro-benzenesulfonamide (121 mg, 81.3%) as a white solid. MS (ESI+APCI) M+1=479.1.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([CH3:12])[C:8]2=[O:11])=[CH:4][C:3]=1[O:13][CH3:14].Cl[C:16]1[N:21]=[C:20]([NH:22][CH3:23])[C:19]([C:24]([F:27])([F:26])[F:25])=[CH:18][N:17]=1.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1.C(Cl)Cl>[CH3:14][O:13][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[NH:1][C:16]1[N:21]=[C:20]([NH:22][CH3:23])[C:19]([C:24]([F:27])([F:25])[F:26])=[CH:18][N:17]=1)[C:8](=[O:11])[N:7]([CH3:12])[CH2:6]2
Reactant: COc1cc2c(cc1N)C(=O)N(C)C2
Reactant: CNc1nc(Cl)ncc1C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNc1nc(Nc2cc3c(cc2OC)CN(C)C3=O)ncc1C(F)(F)F
Temperature: 100 °C
Yield: 13 %

Procedure:
A mixture of impure 6-amino-5-methoxy-2-methylisoindolin-1-one (<0.57 mmol), 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (66 mg, 0.31 mmol) and pTSA (59 mg, 0.31 mmol) in dioxane (4 mL) was heated to 100° C. for 4 h. DCM (10 mL) and saturated aqueous NaHCO3 (10 mL) were added and the organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo. Purification of the residue via reversed phase preparative HPLC gave 5-methoxy-2-methyl-6-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)isoindolin-1-one (15 mg, 13%) as an off-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN): [M+H]+=368 at 2.89 min. 1H NMR (400 MHz, CDCl3): δ 9.04 (s, 1H), 8.17 (s, 1H), 7.80 (s, 1H), 6.93 (s, 1H), 5.26 (br s, 1H), 4.31 (s, 2H), 3.97 (s, 3H), 3.20 (d, J 4.7, 3H), 3.18 (s, 3H).
Reaction SMILES: BrCCO.FC1C=CC=CC=1C1C2C=C([N+]([O-])=O)C=CC=2N(C)C(=O)C(C)(C)N=1.[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]1[C:43]2[CH:44]=[C:45]([N+:48]([O-:50])=[O:49])[CH:46]=[CH:47][C:42]=2[N:41](CCO)[C:40](=[O:54])[C:39]([CH3:56])([CH3:55])[N:38]=1>CCOCC.CCCCCC>[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]1[C:43]2[CH:44]=[C:45]([N+:48]([O-:50])=[O:49])[CH:46]=[CH:47][C:42]=2[NH:41][C:40](=[O:54])[C:39]([CH3:56])([CH3:55])[N:38]=1
Reactant: CC1(C)N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2N(CCO)C1=O
Agent: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc21
Agent: OCCBr
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1(C)N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2NC1=O

Procedure:
From 25 g (0.073 mol) of 5-(o-chlorophenyl)-1,3-dihydro-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one and 2-bromoethanol there is obtained, in analogy to the details in paragraph (c) of Example 1, with a reaction period of 7 days, 5-(o-chlorophenyl)-1,3-dihydro-1-(2-hydroxyethyl)-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one of melting point 124°-125° (ether/n-hexane).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([N:5]1[CH:9]=[CH:8][C:7]([C:10]2[CH:17]=[C:16]([F:18])[C:13]([C:14]#[N:15])=[C:12]([F:19])[CH:11]=2)=[N:6]1)[CH3:4].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:30]=[C:29]([C:31](O)=[O:32])[NH:28][N:27]=2)[CH:21]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[C:14]([C:13]1[C:16]([F:18])=[CH:17][C:10]([C:7]2[CH:8]=[CH:9][N:5]([C@@H:3]([CH3:4])[CH2:2][NH:1][C:31]([C:29]3[NH:28][N:27]=[C:26]([C:22]4[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=4)[CH:30]=3)=[O:32])[N:6]=2)=[CH:11][C:12]=1[F:19])#[N:15]
Reactant: C[C@@H](CN)n1ccc(-c2cc(F)c(C#N)c(F)c2)n1
Reactant: O=C(O)c1cc(-c2cccnc2)n[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](CNC(=O)c1cc(-c2cccnc2)n[nH]1)n1ccc(-c2cc(F)c(C#N)c(F)c2)n1

Procedure:
The title compound was synthesized from (S)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2,6-difluorobenzonitrile (0.277 g, 1.06 mmol), 3-(pyridin-3-yl)-1H-pyrazole-5-carboxylic acid (0.2 g, 1.06 mmol), HOBt (0.17 g, 1.27 mmol), DIPEA (0.22 mL, 1.27 mmol) and EDCI (0.243 g, 1.27 mmol) using DCM as the solvent using the method of Example 34(d). Yield 0.13 g. 1H NMR (400 MHz; d6-DMSO): δ 1.50 (d, 3H), 3.66 (m, 2H), 4.72 (m, 1H), 7.00 (d, 1H), 7.20 (s, 1H), 7.48 (m, 1H), 7.78 (m, 2H), 7.93 (d, 1H), 8.13 (m, 1H), 8.55 (dd, 1H), 8.97 (s, 1H).
Reaction SMILES: Br[C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:3]=1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.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>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:4]2[N:3]=[C:2]([C:21]3[CH:20]=[N:19][C:18]([C:17]([F:28])([F:27])[F:16])=[CH:23][CH:22]=3)[C:7]([OH:8])=[CH:6][CH:5]=2)=[CH:10][CH:11]=1
Reactant: OB(O)c1ccc(C(F)(F)F)nc1
Reactant: Oc1ccc(-c2ccc(Cl)cc2)nc1Br
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: O
Solvent: COCCOC
Product: Oc1ccc(-c2ccc(Cl)cc2)nc1-c1ccc(C(F)(F)F)nc1
Temperature: 80 °C
Yield: 59.6 %

Procedure:
A mixture of 2-bromo-6-(4-chlorophenyl)pyridin-3-ol (0.319 g, 1.12 mmol), 2-(trifluoromethyl)pyridine-5-boronic acid [purchased from Frontier Scientific] (277.8 mg, 1.46 mmol) and potassium carbonate (386.7 mg, 2.798 mmol) in dimethoxyethane (15 mL) and water (5 mL) was purged with nitrogen for 20 minutes. Tetrakis(triphenylphosphine)palladium(0) (64.7 mg, 0.056 mmol) was added and the reaction mixture heated to 80° C. in a sealed vial for 15 hours. The cooled reaction mixture was partitioned between ethyl acetate (50 mL) and saturated aqueous ammonium chloride solution (50 mL), the organic phase separated, washed with water (50 mL) and saturated brine (50 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give a yellow solid. The crude product was purified by chromatography on silica eluting with a solvent gradient of 0 to 50% ethyl acetate in hexanes to give 6-(4-chlorophenyl)-6′-(trifluoromethyl)-[2,3′-bipyridin]-3-ol (0.234 g, 60% yield) as a cream solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](O)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:13]1[C:12]2[C:17](=[CH:18][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:10]([O:20][CH3:21])[CH:11]=2)[N:16]=[CH:15][CH:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2c(O)ccnc2cc1OCc1ccccc1
Product: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1

Procedure:
7-Benzyloxy-6-methoxy-quinolin-4-ol (WO2006108059) (1 g) was refluxed with POCl3 (8 ml) for 3 hours. The reaction was evaporated and dissolved into DCM (80 ml) that was washed with ice water followed by brine. The organic layer was dried with Na2SO4 and evaporated to dryness to give a dark yellow solid as 4-chloro-7-benzyloxy-6-methoxy-quinoline that was mixed with 6-Hydroxy-N-methyl-1-naphthamide (600 mg), DMAP (1.5 eq) in dioxane (40 ml). The reaction was refluxed for three days and diluted with EtOAc, water and extracted with EtOAc three times. The combined organic layer was washed with water, brine and dried. The solution was evaporated and purified with silica gel column to give 6-(7-(benzyloxy)-6-methoxyquinolin-4-yloxy)-N-methyl-1-naphthamide (210 mg). This product was mixed with Pd/C (120 mg, 10%), HCONH4 (210 mg) in EtOH (20 ml). The mixture was refluxed for 1 hour and evaporated then mixed with water (2 ml). The solid was filtered and washed with water twice and cold MeOH as 6-(7-hydroxy-6-methoxyquinolin-4-yloxy)-N-methyl-1-naphthamide for next step without further purification.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH:36]([O:39][C:40]([N:42]1[C:51]2[C:46](=[N:47][C:48]([O:52][CH3:53])=[CH:49][CH:50]=2)[C@H:45]([N:54]([CH2:60][C:61]2[CH:66]=[C:65]([C:67]([F:70])([F:69])[F:68])[CH:64]=[C:63]([C:71]([F:74])([F:73])[F:72])[CH:62]=2)[C:55]2[N:56]=[N:57][NH:58][N:59]=2)[CH2:44][C@@H:43]1[CH2:75][CH3:76])=[O:41])([CH3:38])[CH3:37]>ClCCl>[CH:36]([O:39][C:40]([N:42]1[C:51]2[C:46](=[N:47][C:48]([O:52][CH3:53])=[CH:49][CH:50]=2)[C@H:45]([N:54]([CH2:60][C:61]2[CH:66]=[C:65]([C:67]([F:68])([F:69])[F:70])[CH:64]=[C:63]([C:71]([F:72])([F:73])[F:74])[CH:62]=2)[C:55]2[N:56]=[N:57][N:58]([CH3:1])[N:59]=2)[CH2:44][C@@H:43]1[CH2:75][CH3:76])=[O:41])([CH3:38])[CH3:37]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC[C@H]1C[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nn[nH]n2)c2nc(OC)ccc2N1C(=O)OC(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: CO
Solvent: ClCCl
Product: CC[C@H]1C[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2nc(OC)ccc2N1C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 66 %

Procedure:
Add triphenylphosphine (27 mg, 0.104 mmol), methanol (17 mg, 0.52 mmol), and diisopropylazodicarboxylate (0.018 mL, 0.104 mmol) to a solution of (+/−)-cis-4-[(3,5-bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester in dry dichloromethane (1 mL) and stir the mixture for 15 h at room temperature. Remove the solvent in vacuo and purify the residue by silica gel chromatography, eluting with ethyl acetate/hexanes to afford the title compound (41 mg, 66%). MS (ES+): 602 (M+H).
Reaction SMILES: O=[C:2]1[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH:3]1[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl.[NH2:21][OH:22]>N1C=CC=CC=1>[OH:22][N:21]=[C:2]1[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH:3]1[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CC1CN(c2ccccc2)C(=O)C1=O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)CC1CN(c2ccccc2)C(=O)C1=NO
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of product of Example 62 in pyridine is treated with an excess of hydroxylamine hydrochloride and the reaction is stirred at room temperature for 2 d. The solution is concentrated in vacuo and the residue is chromatographed on silica gel to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[CH:13]=[N:14][C:15]([C:16](O)=[O:17])=[C:11]3[CH2:10][N:9]=[C:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:7]=2[CH:25]=1)#[CH:2].[ClH:26].[CH2:27]([N:29]=C=NCCCN(C)C)[CH3:28].N1(O)C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.C(N)C>CN(C=O)C>[ClH:26].[ClH:26].[CH2:27]([NH:29][C:16]([C:15]1[N:14]=[CH:13][N:12]2[C:6]3[CH:5]=[CH:4][C:3]([C:1]#[CH:2])=[CH:25][C:7]=3[C:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:9][CH2:10][C:11]=12)=[O:17])[CH3:28]
Reactant: CCN=C=NCCCN(C)C
Reactant: C#Cc1ccc2c(c1)C(c1ccccc1)=NCc1c(C(=O)O)ncn1-2
Agent: CCN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C#Cc1ccc2c(c1)C(c1ccccc1)=NCc1c(C(=O)NCC)ncn1-2
Reaction time: 0.25 h

Procedure:
8-Ethynyl-6-phenyl-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylic acid (82 mg, 0.251 mmol) was dissolved in DMF (6 ml) and then N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (48 mg, 0.251 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (33.8 mg, 0.251 mmol), and triethylamine (70 μL, 0.501 mmol) were added. The solution was stirred for 15 min and then ethylamine hydrochloride (20.4 mg, 0.251 mmol) was added. The solution was stirred at room temperature for 3 days. The DMF was removed in vacuo. The residue was dissolved in ethyl acetate and extracted with water twice, then dried with brine. The ethyl acetate layer was then condensed with a stream of nitrogen, and dried in vacuo. The residue was dissolved in methylene chloride, and applied to a silica gel column. The product was eluted with ethyl acetate. The product fractions were concentrated in vacuo. The oily residue was dissolved in acetonitrile and several drops of concentrated HCl were added to give the HCl salt. The acetonitrile was removed in vacuo and the HCl salt was dried under high vacuum to give a yellow powder (75 mg, 77%).
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:8]([N:9]=[N+:10]=[N-:11])[CH2:7][N:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[N:9]([C@@H:8]1[C@@H:4]([NH2:1])[CH2:5][N:6]([CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:7]1)=[N+:10]=[N-:11]
Reactant: [N-]=[N+]=N[C@H]1CN(Cc2ccccc2)C[C@@H]1N=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: [N-]=[N+]=N[C@H]1CN(Cc2ccccc2)C[C@@H]1N
Temperature: 25 °C
Yield: 81.3 %

Procedure:
To a solution of the product from Step 4 (38.4 g, 158 mmol) in tetrahydrofuran (430 mL) was added triphenylphosphine (35.2 g, 134 mmol) and water (5.69 g, 316 mmol). The solution was stirred at room temperature until gas evolution had ceased and stirred at reflux for one hour. The reaction was cooled to RT and concentrated and the residue was dissolved in 4.0 N aqueous HCl (300 mL). The resultant mixture was extracted with chloroform (2×200 mL) and the aqueous phase was basified to pH 10 with concentrated aqueous ammonium hydroxide. This mixture was extracted with chloroform (3×300 mL) and the combined organic extracts were dried over sodium sulfate and concentrated to afford the 27.9 g (96%) of the product as an oil. MS m/z 218.3 (AP+100).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[Cl:5][C:6]1[C:7](I)=[C:8]([OH:13])[CH:9]=[C:10]([Cl:12])[CH:11]=1>N1C=CC=CC=1>[Cl:5][C:6]1[C:7]2[CH:3]=[C:2]([CH2:1][OH:4])[O:13][C:8]=2[CH:9]=[C:10]([Cl:12])[CH:11]=1
Reactant: C#CCO
Reactant: Oc1cc(Cl)cc(Cl)c1I
Solvent: c1ccncc1
Product: OCc1cc2c(Cl)cc(Cl)cc2o1
Yield: 56.4 %

Procedure:
Propargyl alcohol (0.12 ml; 1.96 mmol) was added drop wise to a refluxing mixture of the product of Step D (0.55 g; 1.96 mmol) and Cu2O (0.2 g; 1.4 mmol) in anhydrous pyridine (4 ml) under N2. After refluxing for 1 h, the solvent was removed under reduced pressure and the residue was treated with EtOAc (15 ml). The insoluble material was filtered off and the filtrate was washed with 10% citric acid, H2O, brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by FCC (SiO2; CH2Cl2) to give the title compound (0.24 g; 56%) as colourless solid. 1H-NMR (CDCl3) 1.91 (tr, 1H, J=6.3 Hz); 4.75 (d, 1H, J=6.3 Hz); 6.72 (s, 1H); 7.23 (s, 1H); 7.37 (s, 1H).
Reaction SMILES: Cl.[N:2]1([CH2:8][CH:9]([N:13]2[CH:17]=[C:16]([C:18]3[C:19]4[CH:26]=[CH:25][N:24](COCC[Si](C)(C)C)[C:20]=4[N:21]=[CH:22][N:23]=3)[CH:15]=[N:14]2)[CH2:10][C:11]#[N:12])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[F:42][C:43]1[CH:44]=[C:45]([CH:49]=[CH:50][C:51]=1[O:52][CH3:53])[C:46](Cl)=[O:47].C(#N)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:42][C:43]1[CH:44]=[C:45]([CH:49]=[CH:50][C:51]=1[O:52][CH3:53])[C:46]([N:5]1[CH2:4][CH2:3][N:2]([CH2:8][CH:9]([N:13]2[CH:17]=[C:16]([C:18]3[C:19]4[CH:26]=[CH:25][NH:24][C:20]=4[N:21]=[CH:22][N:23]=3)[CH:15]=[N:14]2)[CH2:10][C:11]#[N:12])[CH2:7][CH2:6]1)=[O:47]
Reactant: COc1ccc(C(=O)Cl)cc1F
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CN4CCNCC4)c3)ncnc21
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClCCl
Product: COc1ccc(C(=O)N2CCN(CC(CC#N)n3cc(-c4ncnc5[nH]ccc45)cn3)CC2)cc1F
Reaction time: 16 h

Procedure:
To a solution of 4-piperazin-1-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile hydrochloride (125 mg, 0.211 mmol; from Example 12, Step 2) in DCM (2 mL) was added triethylamine (177 uL, 1.27 mmol) followed by 3-fluoro-4-methoxybenzoyl chloride (80 mg, 0.4 mmol). The reaction was stirred at for 16 hours. 4-Dimethylaminopyridine (5 mg, 0.04 mmol) was added. Acetonitrile (0.30 mL) was added to aid in solubility and additional 3-fluoro-4-methoxybenzoyl chloride (80 mg, 0.4 mmol) was added. When reaction was complete as evidenced by LCMS, solvent was removed in vacuo. The residue was stirred in a mixture of 1:1 DCM:TFA for 1 hour, concentrated, then stirred in MeOH (3 mL) containing ethylenediamine (0.5 mL). Preparative HPLC-MS, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH, was used to purify the product (50 mg, 48%). 1H NMR (400 MHz, d6-dmso): δ 12.12 (br s, 1H), 8.81 (s, 1H), 8.68 (s, 1H), 8.37 (s, 1H), 7.60 (d, 1H), 7.27-7.15 (m, 3H), 6.98 (d, 1H), 4.99 (tt, 1H), 3.86 (s, 3H), 3.57-3.17 (m, 6H), 2.89-2.77 (m, 2H), 2.60-2.32 (m, 4H); LCMS (M+H)+: 489.1.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH:13]([Mg]Br)([CH3:15])[CH3:14]>C1COCC1>[CH3:14][CH:13]([CH3:15])[CH:11]([CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[OH:12]
Reactant: CC(C)[Mg]Br
Reactant: O=CC1CCC2(CC1)OCCO2
Solvent: C1CCOC1
Product: CC(C)C(O)C1CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 8 h

Procedure:
To a solution of 1,4-dioxaspiro[4.5]decane-8-carbaldehyde (693 mg, 4.07 mmol, prepared as described in Pearson, et al. in J. Org. Chem. 1997, 62(16), 5284-5292) in THF (20 mL) cooled to −78° C. under argon was added a isopropylmagnesium bromide (6 mL, 12 mmol, 1 M in THF) dropwise. After the complete addition, the reaction mixture was allowed to reach room temperature overnight. It was then re-cooled to −78° C. and quenched with saturated NaHCO3 solution and warmed to room temperature. After extraction with ether, the organic layer was concentrated in vacuo and the residue purified by flash chromatography (silica gel, 0-100% ether/DCM) to afford the product.