Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:19]=[CH:18][C:17]3[O:16][C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[S:9][C:8]=3[CH:7]=2)=[N:4][N:3]=[N:2]1.ClC1C=C(C=CC=1)C(OO)=[O:25]>CC(C)=O.O>[NH:1]1[C:5]([C:6]2[CH:19]=[CH:18][C:17]3[O:16][C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[S:9](=[O:25])[C:8]=3[CH:7]=2)=[N:4][N:3]=[N:2]1
Reactant: c1ccc2c(c1)Oc1ccc(-c3nnn[nH]3)cc1S2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: CC(C)=O
Product: O=S1c2ccccc2Oc2ccc(-c3nnn[nH]3)cc21

Procedure:
2-(5-Tetrazolyl)phenoxathiin (0.70g) and m-chloroperoxybenzoic acid (0.45g) were stirred for 2 hours at room temperature in acetone (20 ml.) and water (5 ml.). The reaction mixture was diluted with water, and the solid filtered, dried, washed with ether and re-dried to give 2-(5-tetrazolyl)phenoxathiin-10-oxide m.p. 267°-8° C. Recrystallisation from glacial acetic acid raised the melting point to 280°-1° C.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]3[C:22]([C:23]#[N:24])=[C:21]([CH3:25])[NH:20][C:19]([CH3:26])=[C:18]3[C:27]#[N:28])=[CH:14][CH:15]=2)[C:10]([NH:29][CH2:30][CH2:31][N:32]2C(=O)C3C(=CC=CC=3)C2=O)=[N:9]1)=O)(C)(C)C.O.NN>C(O)C>[NH2:32][CH2:31][CH2:30][NH:29][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([CH:17]3[C:22]([C:23]#[N:24])=[C:21]([CH3:25])[NH:20][C:19]([CH3:26])=[C:18]3[C:27]#[N:28])[CH:12]=2)[NH:8][N:9]=1
Reactant: CC1=C(C#N)C(c2ccc3c(c2)c(NCCN2C(=O)c4ccccc4C2=O)nn3C(=O)OC(C)(C)C)C(C#N)=C(C)N1
Agent: NN
Solvent: CCO
Solvent: O
Product: CC1=C(C#N)C(c2ccc3[nH]nc(NCCN)c3c2)C(C#N)=C(C)N1
Yield: 58.4 %

Procedure:
A mixture of crude 5-(3,5-dicyano-2,6-dimethyl-1,4-dihydro-pyridin-4-yl)-3-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethylamino]-indazole-1-carboxylic acid tert-butyl ester (110 mg), hydrazine hydrate (80%, 0.039 mL, 0.62 mmol) and ethanol (1 mL), was heated at reflux for 2 hours. On cooling the reaction mixture was concentrated and the residue taken up in THF and aqueous HCl (4M) and heated at reflux for 1 hour. On cooling the reaction mixture was concentrated and the residue purified by preparative reverse phase HPLC to give 4-[3-[(2-aminoethyl)amino]-1H-indazol-5-yl]-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarbonitrile (38 mg) (Cpd. No. 308, Table 8). 1H-NMR (DMSO-D6, 300 MHz): δ=11.38 (br s, 1H), 9.46 (br s, 1H), 7.52 (s, 1H), 7.20 (d, 1H), 7.12 (dd, 1H), 5.93 (t, 1H), 4.34 (s, 1H), 3.21 (m, 2H), 2.75 (t, 2H), 2.01 (s, 6H) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:22])[C:6]=1[O:23][CH3:24])[CH3:2].Br[C:27]1[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=1>>[CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:27]3[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=3)[C:13]=2[CH3:22])[C:6]=1[O:23][CH3:24])[CH3:2]
Reactant: Cn1cc(Br)cn1
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1OC
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnn(C)c3)c3cc(Cl)ccc23)c1OC

Procedure:
Prepared according to the procedure described in Example 42, Step 4, using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-2-methoxy-benzoic acid ethyl ester and 4-bromo-1-methylpyrazole.
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[C:9]([C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[Cl:51][C:52]1[CH:64]=[CH:63][CH:62]=[CH:61][C:53]=1[O:54][CH:55]1[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]1>CN(C=O)C.O>[Cl:51][C:52]1[CH:64]=[CH:63][CH:62]=[CH:61][C:53]=1[O:54][CH:55]1[CH2:60][CH2:59][N:58]([C:16](=[O:18])[CH2:15][NH:14][C:12]([C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:11][N:10]=2)=[O:13])[CH2:57][CH2:56]1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: Clc1ccccc1OC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2Cl)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 8 h
Yield: 90.6 %

Procedure:
To a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (0.038 g, 0.00013 mol) in DMF (2 mL) was added DIPEA (0.0872 g, 0.00067 mol), HOBt (0.023 g, 0.00017 mol) and EDCI.HCl (0.0325 g, 0.00017 mol) at ambient temperature. After 2 minutes 4-(2-chlorophenoxy)-piperidine hydrochloride (0.03347 g, 0.00013 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water. The resulting precipitate was isolated by filtration and dried to afford 0.0517 g (87%) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-chloro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 439.15 (M+1)+, 98.84%, 1H NMR (DMSO-d6): δ 13.7 (s, 1H), 8.1 (s, 1H), 7.8 (d, 2H), 7.42 (m, 3H), 7.32 (m, 1H), 7.24 (m, 2H), 7.1 (s, 1H), 7.0 (t, 1H), 4.7 (m, 1H), 4.1 (d, 2H), 3.7 (m, 2H), 3.4 (m, 2H), 1.9 (m, 2H), 1.6 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([N+:35]([O-])=O)=[C:7]([NH:9][C:10]2[N:15]=[C:14]3[N:16]([C@@H:27]([C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)[CH3:28])[C:17](=[O:26])[N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:13]3=[CH:12][CH:11]=2)[CH:8]=1)#[N:2].[O-]S(S([O-])=O)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C1COCC1.O.C(OCC)(=O)C>[NH2:35][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][C:7]=1[NH:9][C:10]1[N:15]=[C:14]2[N:16]([C@@H:27]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[CH3:28])[C:17](=[O:26])[N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])[C:13]2=[CH:12][CH:11]=1
Reactant: C[C@H](c1cccnc1)n1c(=O)n(C(=O)OC(C)(C)C)c2ccc(Nc3cc(C#N)ccc3[N+](=O)[O-])nc21
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@H](c1cccnc1)n1c(=O)n(C(=O)OC(C)(C)C)c2ccc(Nc3cc(C#N)ccc3N)nc21

Procedure:
A solution of (R)-tert-butyl 5-(5-cyano-2-nitrophenylamino)-2-oxo-3-(1-(pyridin-3-yl)ethyl)-2,3-dihydroimidazo[4,5-b]pyridine-1-carboxylate (70) (100 mg) in THF (5 mL) was treated with an aqueous solution comprised of 0.5 g of Na2S2O4 and 0.25 g NaHCO3 in 5 mL of water. The mixture went quickly from a red color to a slightly yellow color, which indicated reduction of the nitro group. The mixture was diluted with ethyl acetate and washed with saturated sodium chloride solution. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated to provide the intermediate (R)-tert-butyl 5-(2-amino-5-cyanophenylamino)-2-oxo-3-(1-(pyridin-3-yl)ethyl)-2,3-dihydroimidazo[4,5-b]pyridine-1-carboxylate (71). The intermediate was dissolved in THF (5 mL), DMF (1 mL), and trimethylorthoformate (2 mL). The mixture was treated with 10 mg of p-toluenesulfonic acid and stirred for 20 h. The mixture was diluted with ethyl acetate and washed once with saturated sodium bicarbonate and twice with saturated NaCl solution. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated. Column chromatography (2% MeOH in methylene chloride) provided 57 mg tert-Butyl 5-(6-cyano-1H-benzo[d]imidazol-1-yl)-2-oxo-3-((R)-1-(pyridin-3-yl)ethyl)-2,3-dihydroimidazo[4,5-b]pyridine-1-carboxylate (72).
Reaction SMILES: C[O:2][C:3](=[O:36])[CH:4]=[CH:5][CH2:6][CH2:7][N:8]([C:13]1[N:18]=[C:17]2[O:19][C:20]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)=[C:21]([C:22](=[O:25])[NH:23][CH3:24])[C:16]2=[CH:15][C:14]=1[CH:33]1[CH2:35][CH2:34]1)[S:9]([CH3:12])(=[O:11])=[O:10].[CH3:37][NH:38][CH3:39].[Li+].[OH-].Cl>C(Cl)Cl.C1COCC1.O.CO>[CH:33]1([C:14]2[CH:15]=[C:16]3[C:21]([C:22](=[O:25])[NH:23][CH3:24])=[C:20]([C:26]4[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=4)[O:19][C:17]3=[N:18][C:13]=2[N:8]([S:9]([CH3:12])(=[O:11])=[O:10])[CH2:7][CH2:6][CH:5]([N:38]([CH3:39])[CH3:37])[CH2:4][C:3]([OH:2])=[O:36])[CH2:35][CH2:34]1
Reactant: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(N(CCC=CC(=O)OC)S(C)(=O)=O)c(C3CC3)cc12
Reactant: CNC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(N(CCC(CC(=O)O)N(C)C)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 21.7 %

Procedure:
To a solution of 5-[(5-cyclopropyl-3-methylcarbamoyl-2-p-tolyl-furo[2,3-b]pyridin-6-yl)-methanesulfonyl-amino]-pent-2-enoic acid methyl ester (26 mg, 0.051 mmol, 1.0 equiv) in DCM (0.5 mL) was added dimethyl amine (0.10 mL, 2.0 M in THF, 0.2 mmol, 4.0 equiv) and LiClO4 (10.8 mg, 0.1 mmol, 2.0 equiv). The mixture was stirred at room temperature for 24 hours. The reaction mixture was then diluted with THF (0.3 mL), water (0.3 mL), MeOH (0.3 mL) and to the solution was added LiOH (4.9 mg, 0.2 mmol, 5.0 equiv). The mixture was heated at 55° C. for 20 minutes. The solution was neutralized to pH=7 by addition of 1.0 N HCl aq. solution. The mixture was extracted with CH2Cl2. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by reverse phase HPLC with ammonium hydroxide as modifier to give product 6.0 mg. MS (ESI) m/z 543.6 (M+1). Retention time=1.09 min, Method A. 1H NMR (400 MHz, MeOD) d ppm 0.77-0.92 (m, 2H) 1.09-1.20 (m, 2H) 1.61-1.75 (m, 1 H) 2.00-2.11 (m, 1H) 2.37-2.47 (m, 4H) 2.48-2.58 (m, 2H) 2.68 (s, 6H) 2.93 (s, 3 H) 3.17 (s, 3H) 3.51-3.62 (m, 1H) 3.82-3.94 (m, 1H) 3.94-4.04 (m, 1H) 7.35 (d, J=8.03 Hz, 2H) 7.59 (s, 1H) 7.79 (d, J=8.53 Hz, 2H)
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[N:6]#[O+].[CH:8]([C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1)=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCOCC>C(#N)C>[F:1][B-:2]([F:5])([F:4])[F:3].[CH:8]([C:16]1[CH:17]=[CH:18][C:19]([N+:22]#[N:6])=[CH:20][CH:21]=1)=[CH:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: N#[O+]
Reactant: Nc1ccc(C=Cc2ccccc2)cc1
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCOCC
Product: N#[N+]c1ccc(C=Cc2ccccc2)cc1
Temperature: -30 °C
Yield: 324.3 %

Procedure:
To a 25 mL round bottom in a drybox was added nitrosonium tetrafluoroborate (0.11 g, 0.95 mmol). Acetonitrile (2 mL) was added and the flask was cooled down to −30° C. A solution of 4-STYRYLPHENYLAMINE (0.17 g, 0.86 mmol) and BHT (0.19 g, 0.86 mmol) in acetonitrile (5 mL) was added dropwise via syringe. The reaction was allowed to warm to −5° C. over 20 min. Ether (10 mL) was then added and the precipitate was filtered. The title compound was purified by re-precipitating from acetonitrile (3 mL) with ether (15 mL) to yield 0.82 g (34%) of the desired compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].CCN(C(C)C)C(C)C.[C:20](Cl)(=[O:24])[CH2:21][CH2:22][CH3:23]>ClCCl>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][C:20](=[O:24])[CH2:21][CH2:22][CH3:23])[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: CCCC(=O)Cl
Reactant: Nc1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(=O)Nc1cccc([N+](=O)[O-])c1
Yield: 100 %

Procedure:
3-Nitroaniline (6.00 g, 43.4 mmol) was sealed in a flask with stir bar under nitrogen and dissolved with dichloromethane (DCM, 145 mL). The solution was cooled on ice before (i-Pr)2NEt (8.35 ml, 47.8 mmol) and butyryl chloride (5.00 ml, 47.8 mmol) were added. The flask was removed from the ice and stirred for 16 h. The reaction was then diluted with DCM and aq. 1 M HCl, the layers were separated, and the combined organics were washed again with 1 M aq. HCl, then twice with half-saturated aq. NaHCO3, then brine. The organic phase was dried over MgSO4, filtered, and concentrated, yielding a yellow oil (9.04 g, 100%). LRMS (ESI−) (M−H): 207.06. The crude oil was used without further purification in the subsequent reaction.
Reaction SMILES: [C:1]([C:3]([CH3:16])([CH3:15])[CH2:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10]C)=[O:9])#[N:2].O1CCCC1.[OH-].[Na+].Cl>CO>[C:1]([C:3]([CH3:16])([CH3:15])[CH2:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([OH:10])=[O:9])#[N:2]
Reactant: COC(=O)c1cccc(CC(C)(C)C#N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C#N)Cc1cccc(C(=O)O)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
To a solution of methyl 3-(2-cyano-2-methylpropyl)benzoate (260 mg, 1.20 mmol) in methanol (6 mL)/tetrahydrofuran (2 mL) was added 2N aqueous sodium hydroxide solution (1.20 mL, 2.39 mmol), and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was neutralized with 6N hydrochloric acid (600 μL), 1N hydrochloric acid (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL, 10 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (230 mg, 95%) as a white solid.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:7][CH:8]=[CH:9][N:10]=1)CCC.[C:19]([C:22]1[CH:37]=[CH:36][C:25]2[N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31](Br)[CH:30]=3)[CH:27]=[N:28][C:24]=2[CH:23]=1)(=[O:21])[CH3:20]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:19]([C:22]1[CH:37]=[CH:36][C:25]2[N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:6]4[S:7][CH:8]=[CH:9][N:10]=4)[CH:30]=3)[CH:27]=[N:28][C:24]=2[CH:23]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)c1ccc2c(c1)ncn2-c1cccc(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(c1)ncn2-c1cccc(-c2nccs2)c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 97.8 %

Procedure:
To a solution of (50) from Example 17 (3.6 g, 9.7 mmol) in dry THF (20 ml) was added 5-acetyl-1-(3-bromophenyl)benzimidazole (52) (1.5 g, 4.8 mmol) and (PPh3)2PdCl2 (340 mg, 0.48 mmol) under argon. The reaction mixture was stirred at 80° C. for 24 hr in a 50 ml sealed tube. After cooling the mixture was concentrated, triturated with water (100 ml) and extracted with CH2Cl2 (200 ml×3). The extract was washed with brine, dried and concentrated under reduced pressure. The residue was washed with ether to afford crystalline (51) (1.5 g, 89%).
Reaction SMILES: Cl.[CH:2]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:4])[CH3:3].[F:32][C:33]([F:40])([F:39])[CH2:34][S:35](Cl)(=[O:37])=[O:36]>>[CH:2]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:24]([N:26]1[CH2:27][CH2:28][N:29]([S:35]([CH2:34][C:33]([F:40])([F:39])[F:32])(=[O:37])=[O:36])[CH2:30][CH2:31]1)=[O:25])([CH3:3])[CH3:4]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCNCC2)n3C(C)C)CC1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Agent: Cl
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCN(S(=O)(=O)CC(F)(F)F)CC2)n3C(C)C)CC1

Procedure:
The title compound was prepared in analogy to example 51, from [1-isopropyl-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone hydrochloride and 2,2,2-trifluoro-ethanesulfonyl chloride. Off-white solid. MS (m/z): 559.4 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:30]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)#[N:31]>>[CH:18]1([N:13]2[C:12]([C:35]3[CH:36]=[CH:37][C:32]([C:30]#[N:31])=[CH:33][CH:34]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19][CH2:20][CH2:21]1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Product: N#Cc1ccc(-c2c3c(nn2C2CCC2)CCNCC3)cc1
Yield: 24.5 %

Procedure:
The title compound (28 mg) was prepared according to Example 263 using 172 mg of 2-cyclobutyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 276, Step A) and 172 mg of 4-cyanophenylboronic acid. MS (ESI): exact mass calculated for C18H20N4, 292.17. found, m/z 293.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.92-7.90 (m, 2H), 7.50-7.48 (m, 2H), 4.65-4.58 (m, 1H), 3.42-3.40 (m, 2H), 3.21-3.19 (m, 2H), 2.81-2.78 (m, 2H), 2.66-2.62 (m, 2H), 2.30-2.25 (m, 2H), 1.85-1.74 (m, 2H).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:11]([N:13]1[CH2:16][CH:15]([C:17]#[N:18])[CH2:14]1)=[O:12])[CH2:9][CH3:10])(C)(C)C.[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23]>ClCCl>[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23].[NH2:7][C@H:8]([CH2:9][CH3:10])[C:11]([N:13]1[CH2:14][CH:15]([C:17]#[N:18])[CH2:16]1)=[O:12]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CC(C#N)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@@H](N)C(=O)N1CC(C#N)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [(R)-1-(3-cyano-azetidine-1-carbonyl)-propyl]-carbamic acid tert-butyl ester (200 mg, 0.67 mmol) in dichloromethane (4 ml) was added trifluoroacetic acid (1.8 ml, 23.4 mmol). The reaction mixture was stirred at room temperature for 2 h then concentrated to afford 1-((R)-2-amino-butyryl)-azetidine-3-carbonitrile trifluoroacetate as a light yellow oil which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[N:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1.[N+:17]([O-])([O-:19])=[O:18].[K+].[OH-].[Na+]>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[C:4]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[C:5]([CH3:9])[C:6]([N+:17]([O-:19])=[O:18])=[CH:7][CH:8]=1
Reactant: O=[N+]([O-])[O-]
Reactant: COc1cccc(C)c1N1CCN(C)CC1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Product: COc1ccc([N+](=O)[O-])c(C)c1N1CCN(C)CC1
Temperature: 27.5 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
A solution of 1-(2-methoxy-6-methylphenyl)-4-methylpiperazine (D29) (6.2 g, 28 mmol) in concentrated sulfuric acid (50 ml) was treated portionwise with potassium nitrate (3.3 g, 33 mmol) over 5 mins, maintaining the temperature at 25-30° C. The mixture was stirred overnight at room temperature, then added to ice, and basified with 40% sodium hydroxide solution. The mixture was extracted with dichloromethane and the organic phase was dried (Na2SO4) and evaporated under reduced pressure to give crude compound. Purification by chromatography on silica gel eluting with methanol and dichloromethane afforded the title compound (D30) (4.56 g, 61%) MH+=266.
Reaction SMILES: [OH:1][CH:2]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=[CH:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]CC[C:3]1=[O:22].OC1CCCCCCC=CCCCCCCCCC1=O>>[OH:1][CH:2]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:3]1=[O:22]
Reactant: O=C1CCCCCCCCC=CCCCCCCCCC1O
Agent: O=C1CCCCCCCCC=CCCCCCCC1O
Product: O=C1CCCCCCCCCCCCCCCCC1O

Procedure:
2-Hydroxy-11-cycloeicosenone of Synthesis Example 7 was replaced by 2-hydroxy-9-cyclooctadecenone (1.0 g, 3.54 mmol), and a hydrogenation and subsequent treatment were performed under the same conditions as in Synthesis Example 7, to yield 1.0 g of 2-hydroxycyclooctadecanone (quantitative yield).
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([CH3:26])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:24][C:23]3[CH2:22][CH2:21][NH:20][C:19](=[O:25])[C:18]=3[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].[C:27]([O-])([O-])=[O:28].[K+].[K+].C=O.CCOC(C)=O.CCO>C1COCC1>[C:1]([NH:5][C:6]1[C:7]([CH3:26])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:24][C:23]3[CH2:22][CH2:21][N:20]([CH2:27][OH:28])[C:19](=[O:25])[C:18]=3[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)(C)C
Agent: C=O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCN(CO)C4=O)c2nc1NC(C)(C)C
Temperature: 50 °C
Reaction time: 8 h
Yield: 2.8 %

Procedure:
A mixture of 2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (193) (0.2 g, 0.57 mmol), K2CO3 (0.16 g, 1.14 mmol), and formaldehyde (Sigma-Aldrich) (0.46 mL of 37% wt. in water, 5.72 mmol) in THF (5.72 mL) were combined and stirred at 50° C. overnight. The reaction mixture was directly loaded onto a biotage and purified three times (0-100% EtOAc:EtOH (3:1)/hexane; 0-40% then 40% EtOAc:EtOH (3:1)/hexanes; then 0-20% then 20% EtOAc:EtOH (3:1)/hexanes) to yield the title compound (6 mg, 3% yield). 1H NMR (300 MHz, CDCl3) d ppm 1.49-1.75 (m, 23H) 2.56 (s, 3H) 2.95-3.10 (m, 2H) 3.20-3.34 (m, 1H) 3.74-3.91 (m, 2H) 4.79-4.92 (m, 1H) 4.98-5.08 (m, 2H) 7.01-7.14 (m, 1H) 7.31-7.46 (m, 1H) 7.59-7.72 (m, 1H) 7.89-8.03 (m, 1H) 12.51-12.65 (m, 1H). m/z (ES, +ve) 380.1 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]1[NH:13][CH2:12][CH2:11][N:10]2[CH:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:16]=[C:9]12.Br[CH2:23][CH2:24][CH2:25][CH3:26].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:23]([N:13]1[CH2:12][CH2:11][N:10]2[CH:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:16]=[C:9]2[CH2:8]1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCBr
Reactant: CCOC(=O)c1cc2n(c1)CCNC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CCCCN1CCn2cc(C(=O)OCC)cc2C1
Yield: 20.9 %

Procedure:
To a solution of ethyl 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate trifluoroacetate (2.6 g, 13.4 mmol) and 1-bromobutane (3.67 g, 26.8 mmol) in acetonitrile (26 mL) was added potassium carbonate (2.45 g, 17.7 mmol). The resulting mixture was refluxed overnight. The solvent was then evaporated to give a solid residue. Purification via flash chromatography (petroleum ether:EtOAc, 10:1) afforded ethyl 2-butyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate Intermediate 11 (0.7 g, 21%). 1H NMR (CDCl3, 300 MHz) δ7.11 (s, 1 H), 6.18 (s, 1 H), 4.25 (m, 2 H), 3.99 (m, 2 H), 3.53 (s, 2 H), 2.82 (t, J=5.6 Hz, 2 H), 2.46 (t, J=7.4 Hz, 2 H), 1.46 (m, 2 H), 1.30 (m, 2 H), 1.25 (t, J=7.1 Hz, 3 H), 0.87 (t, J=7.3 Hz, 2 H).
Reaction SMILES: C([O:3][C:4](=[O:23])[CH:5]=[CH:6][C:7]1[C:8]([C:17]#[C:18][Si](C)(C)C)=[N:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=1)C.[OH-].[Na+]>C1COCC1.CO.O>[C:17]([C:8]1[C:7]([CH:6]=[CH:5][C:4]([OH:23])=[O:3])=[CH:12][CH:11]=[C:10]([C:13]([F:16])([F:14])[F:15])[N:9]=1)#[CH:18]
Reactant: CCOC(=O)C=Cc1ccc(C(F)(F)F)nc1C#C[Si](C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1nc(C(F)(F)F)ccc1C=CC(=O)O
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 117.8 %

Procedure:
To a suspension of 3-(6-trifluoromethyl-2-trimethylsilanylethynyl-pyridin-3-yl)-acrylic acid ethyl ester (68 mg, 0.169 mmol) in THF (1 ml) and CH3OH (0.5 ml) was added a solution of 1N-NaOH (0.5 ml) and the mixture was stirred for 50 min at room temperature. The resulting residue was dissolved in H2O and then washed three times with EtOAc, acidified with 1N HCl to pH 1˜2. The solution was extracted three times with methylene chloride and then dried over anhyd. Na2SO4 and concentrated in vacuo to give 3-(2-ethynyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (48 mg, 99%). To a suspension of N-(4-aminomethyl-2-ethynyl-6-fluoro-phenyl)-methanesulfonamide, HCl salt (83 mg, 0.298 mmol) in THF (3 mL) was added N-methylmorpholine (0.066 ml, 0.597 mmol). The mixture was stirred for 5 minutes, to which were added 3-(2-ethynyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (48 mg, 0.065 mmol) and 4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMTMM, 71.4 mg, 0.258 mmol). The mixture was stirred overnight at room temperature and was concentrated under reduced pressure. The residue was diluted with EtOAc and water. The organic layer was washed with saturated sodium bicarbonate, 1N HCl and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by recrystallization from CH2Cl2 to give N-(3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl)-3-(2-ethynyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide (30 mg, 32%).