Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Sn]([N:14]=[N+:15]=[N-:16])(CCCC)CCCC)CCC.[Cl:17][C:18]1[CH:27]=[C:26]2[C:21]([CH:22]=[CH:23][C:24]([CH:28]3[CH2:30][CH:29]3[C:31]3[CH:32]=[C:33]([CH:39]=[CH:40][CH:41]=3)[O:34][CH:35]([CH3:38])[C:36]#[N:37])=[N:25]2)=[CH:20][CH:19]=1>CCOC(C)=O.C1(C)C=CC=CC=1.CC(O)=O>[Cl:17][C:18]1[CH:27]=[C:26]2[C:21]([CH:22]=[CH:23][C:24]([CH:28]3[CH2:30][CH:29]3[C:31]3[CH:32]=[C:33]([CH:39]=[CH:40][CH:41]=3)[O:34][CH:35]([C:36]3[NH:16][N:15]=[N:14][N:37]=3)[CH3:38])=[N:25]2)=[CH:20][CH:19]=1
Reactant: CC(C#N)Oc1cccc(C2CC2c2ccc3ccc(Cl)cc3n2)c1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(Oc1cccc(C2CC2c2ccc3ccc(Cl)cc3n2)c1)c1nnn[nH]1

Procedure:
A mixture of tributyltin azide (1.603 g, 1.5 eg.) and the nitrile (Step 4) (1.115 g, 3.20 mmoles) was heated at 120° C. for 4 hours. Flash chromatography of this reaction mixture using EtOAc: toluene AcOH 20:80:1 and 40:60:1 yielded the title compound.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:12]1[CH:17]=[N:16][CH:15]=[CH:14][N:13]=1.[C:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])[CH2:19][CH3:20]>C1(C)C=CC=CC=1>[N:13]1[CH:14]=[CH:15][N:16]=[CH:17][C:12]=1[CH:19]([CH3:20])[C:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: Clc1cnccn1
Reactant: CCC(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C(=O)OC(C)(C)C)c1cnccn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of NaHMDS (1M in toluene, 349 mL, 349 mmol) was added over 5 minutes to a toluene (200 mL) solution containing chloropyrazine (20 g, 175 mmol) and t-butyl propionate (22.73 g, 175 mmol) cooled to 0° C. The solution was stirred at 0° C. for 2 hours and then at room temperature for 4 hours. The reaction was then quenched with saturated aqueous NH4Cl. The mixture was extracted with ethyl acetate and the organic layer concentrated. The residue was purified by silica gel chromatography using a hexanes/EtOAc gradient to give the indicated product. m/z=209.3 (M+H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:7][CH:8]=1.CC1(C)C(C)(C)[O:19][B:18]([C:23]2[CH:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=2)[O:17]1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C(=O)C>[F:13][C:2]([F:1])([F:14])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([NH:29][C:26]2[N:27]=[CH:28][C:23]([B:18]([OH:19])[OH:17])=[CH:24][CH:25]=2)=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CN1CCOCC1
Product: O=C(Cc1cccc(C(F)(F)F)c1)Nc1ccc(B(O)O)cn1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A 250 mL round-bottomed flask was charged with 2-(3-(trifluoromethyl)phenyl)acetic acid (2.319 g, 11.36 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (2.5 g, 11.36 mmol), 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (2.178 g, 11.36 mmol), 1-hydroxybenzotriazole hydrate (1.740 g, 11.36 mmol), N-methylmorpholine (5.00 mL, 45.4 mmol) and N,N-dimethylacetamide (50 mL). The reaction was stirred at 50° C. for 16 hours. The reaction was then quenched by the addition of ethyl acetate (50 mL) and water (50 mL). The layers were separated, and the organic was washed with water (3×50 mL) and brine (1×50 mL). The organic was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC using a 15% water (0.1% trifluoroacetic acid) to 95% acetonitrile (0.1% trifluoroacetic acid) gradient to give the boronic acid as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.88 (s, 2H), 7.54-7.66 (m, 3H), 7.72 (s, 1H), 7.96 (d, J=8.5 Hz, 1H), 8.12 (dd, J=1.7 and 8.1 Hz, 1H), 8.4 (br s, 1H), 10.94 (s, 1H).
Reaction SMILES: [CH3:1][C@H:2]([NH:20]C(=O)OC(C)(C)C)[C:3](=[O:19])[NH:4][C:5]1[CH:18]=[CH:17][C:8]2[O:9][C:10]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[C:7]=2[CH:6]=1.ClCCl.O1CCO[CH2:33][CH2:32]1>Cl>[CH:6]1[C:7]2[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:10]=3[O:9][C:8]=2[CH:17]=[CH:18][C:5]=1[NH:4][C:3](=[O:19])[C@@H:2]1[CH2:1][CH2:33][CH2:32][NH:20]1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc2oc3c(c2c1)CCCCC3
Reactant: C1COCCO1
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1ccc2oc3c(c2c1)CCCCC3)[C@@H]1CCCN1

Procedure:
A solution of tert-butyl [(1S)-1-methyl-2-oxo-2-(7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylamino)ethyl]carbamate (0.10 g) in 4 N HCl in dioxane (3 mL) and dichloromethane (3 mL) was stirred at room temperature for 30 min and then concentrated to provide N-7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-yl-L-prolinamide (46 mg) as its hydrochloric acid salt. MS (ESI) m/z 299 ([M+H]+).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].B(O)(O)[C:16]1[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.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>[CH3:22][C:19]1[CH:20]=[CH:21][C:16]([C:2]2[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=2)=[CH:17][CH:18]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: COC(=O)c1cc(I)cc([N+](=O)[O-])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: [Cs+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cc(-c2ccc(C)cc2)cc([N+](=O)[O-])c1

Procedure:
To a stirred solution of methyl 3-iodo-5-nitrobenzoate (7.76 g, 24 mmol) and p-tolylboronic acid (3.94 g, 28 mmol) in toluene (576 mL) was added cesium carbonate (9.4 g, 28 mmol) in water (7.8 mL). The mixture was purged with nitrogen, and then tetrakis(triphenylphosphine)palladium(0) (860 mg, 0.74 mmol) was added at room temperature. The reaction mixture was heated to reflux for 3 days. After cooling, the mixture was filtered through Celite and the filtrate was concentrated. The residue was purified by flash chromatography to afford a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([Cl:11])[C:3]=1[N:12]1[CH:29]=[C:15]2[C:16]([NH:21][C:22]3[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24][N:23]=3)=[N:17][CH:18]=[C:19]([F:20])[C:14]2=[N:13]1.C1COCC1.O.[Cl-].[NH4+]>C(O)C.[Fe]>[NH2:8][C:6]1[CH:5]=[C:4]([Cl:11])[C:3]([N:12]2[CH:29]=[C:15]3[C:16]([NH:21][C:22]4[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24][N:23]=4)=[N:17][CH:18]=[C:19]([F:20])[C:14]3=[N:13]2)=[C:2]([Cl:1])[CH:7]=1
Reactant: Cc1cc(Nc2ncc(F)c3nn(-c4c(Cl)cc([N+](=O)[O-])cc4Cl)cc23)ncn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(Nc2ncc(F)c3nn(-c4c(Cl)cc(N)cc4Cl)cc23)ncn1
Temperature: 70 °C
Yield: 74.2 %

Procedure:
[2-(2,6-Dichloro-4-nitrophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridin-4-yl]-(6-methylpyrimidin-4-yl)-amine (173 mg, 0.40 mmol) was dissolved in ethanol (10 mL) and THF (4.0 mL) and water (1.0 mL) were added, followed by iron powder (325 mesh, 112 mg, 2.0 mmol) and ammonium chloride (86 mg, 1.6 mmol). The reaction mixture was heated at 70° C. for 4 hours. More iron powder (112 mg) and ammonium chloride (100 mg) were added and the mixture was heated at 70° C. for another 5 hours. The resultant mixture was cooled and filtered through Celite®. The filtrate was concentrated under reduced pressure and the residue was triturated with water. The solid obtained was dried under reduced pressure and purified by silica gel flash chromatography (0-5% methanol in DCM) to afford the title compound as an off-white solid (120 mg, 74% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.62 (s, 1H), 9.13 (d, J=2.6 Hz, 1H), 8.71 (d, J=1.2 Hz, 1H), 8.42 (s, 1H), 7.96 (d, J=3.5 Hz, 1H), 6.83 (s, 2H), 6.30 (s, 2H), 2.46 (s, 3H). LCMS (Method B): RT=3.00 min, m/z: 404 [M+H+].
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=1>C(O)C>[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]2[NH:1][CH:2]([C:5]([OH:7])=[O:6])[CH2:3][S:4]2)[CH:9]=1
Reactant: N[C@@H](CS)C(=O)O
Reactant: O=Cc1cccnc1
Solvent: CCO
Product: O=C(O)C1CSC(c2cccnc2)N1
Temperature: 100 °C
Yield: 80855 %

Procedure:
Cysteine (24.2 g, 0.2 mole) and 3-pyridine carboxaldehyde (21.4 g, 0.2 mmole) were suspended in 60% aqueous ethanol (400 mL) and the mixture was heated at 100° C. for 5 hours. The reaction mixture was then cooled and most of the solvent was removed in vacuo. The resulting slurry was washed with ethanol and filtered. This material was dried overnight in vacuo at 50° C. to afford the thiazolidine acid (34 g, 81%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C@@:10]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].[C:35]1([C:41]2([C:47]([OH:49])=[O:48])[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH3:34][O:33][C:29]1[CH:28]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C@:10]([CH2:13][CH2:14][N:44]2[CH2:43][CH2:42][C:41]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)([C:47]([OH:49])=[O:48])[CH2:46][CH2:45]2)([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CC[C@](CCOS(C)(=O)=O)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Product: COc1cc(C(=O)N2CC[C@](CCN3CCC(C(=O)O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Alternately prepare by a method similar to Example 5.4.1 using (S)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine and 4-phenylpiperidine-4-carboxylic acid to give the title compound.
Reaction SMILES: [C:1]([O-])([O-])=O.[K+].[K+].[C:7]([O:11][C:12](=[O:46])[N:13]([CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:14][CH2:15][NH:16][S:17]([C:20]1[C:21]2[CH:22]=[CH:23][N:24]=[CH:25][C:26]=2[CH:27]=[CH:28][CH:29]=1)(=[O:19])=[O:18])([CH3:10])([CH3:9])[CH3:8].CI>CN(C=O)C.CCOC(C)=O>[C:7]([O:11][C:12](=[O:46])[N:13]([CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[CH2:14][CH2:15][N:16]([S:17]([C:20]1[C:21]2[CH:22]=[CH:23][N:24]=[CH:25][C:26]=2[CH:27]=[CH:28][CH:29]=1)(=[O:19])=[O:18])[CH3:1])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N(CCNS(=O)(=O)c1cccc2cnccc12)CCOc1ccccc1Cc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: CN(CCN(CCOc1ccccc1Cc1ccccc1)C(=O)OC(C)(C)C)S(=O)(=O)c1cccc2cnccc12
Yield: 75.3 %

Procedure:
Powdered K2CO3 (50.4 mg, 0.365 mmol) is added to a stirred solution of [2-(2-benzyl-phenoxy)-ethyl]-[2-(isoquinoline-5-sulfonylamino)-ethyl]-carbamic acid tert-butyl ester (82.0 mg, 0.146 mmol) and CH3I (18.2 μL, 0.292 mmol) in anhydrous DMF (1 mL) at ambient temperature under nitrogen. The resultant solution is stirred for 2 hours. The mixture is diluted with EtOAc (10 mL), washed with water (5 mL×3), dried over MgSO4, filtered and concentrated. The crude product is chromatographed on silica (gradient 0-5% CH3OH in CH2Cl2) to give 65 mg (0.11 mmol, 77% yield) of the title compound as a gum. ESIMS: m/z 576 (M+H)+.
Reaction SMILES: CO[C:3](OC)(OC)[CH2:4][CH2:5][CH2:6][CH3:7].[NH2:12][C:13]1[CH:14]=[N:15][C:16]2[C:21]([C:22]=1[NH:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:20][CH:19]=[CH:18][CH:17]=2>C1(C)C=CC=CC=1>[CH2:4]([C:3]1[N:23]([CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:12]=1)[CH2:5][CH2:6][CH3:7]
Reactant: CCCCC(OC)(OC)OC
Reactant: CC(C)(C)OC(=O)NCCNc1c(N)cnc2ccccc12
Solvent: Cc1ccccc1
Product: CCCCc1nc2cnc3ccccc3c2n1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 50.8 %

Procedure:
Trimethylorthovalerate (5.9 g, 36.4 mmol) was added with stirring to a solution of 1,1-dimethylethyl N-{2-[(3-aminoquinolin-4-yl)amino]ethyl}carbamate (10.0 g, 33.1 mmol) in anhydrous toluene (100 mL). The reaction mixture was heated to reflux. A 10 mL portion of toluene was removed using a Dean Stark trap and the reaction mixture was maintained for 36 hours. An additional 40 mL of toluene was removed and then the reaction was allowed to cool to ambient temperature with continued stirring. The resulting precipitate was isolated by filtration and dried to provide 6.2 g of 1,1-dimethylethyl N-[2-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate as a tan solid. Thin layer chromatography (silica gel; 10% methanol in dichloromethane) analysis indicated that the material was pure.
Reaction SMILES: CN([CH:4]=[C:5]1[CH2:11][C:10](=[O:12])[NH:9][C:8]2[CH:13]=[CH:14][C:15]([I:17])=[CH:16][C:7]=2[C:6]1=O)C.C([O-])([O-])=O.[K+].[K+].[CH3:25][O:26][C:27]1[CH:28]=[C:29]([NH:35][C:36]([NH2:38])=[NH:37])[CH:30]=[CH:31][C:32]=1[O:33][CH3:34].Cl>CCO.O>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([NH:35][C:36]2[N:38]=[CH:4][C:5]3[CH2:11][C:10](=[O:12])[NH:9][C:8]4[CH:13]=[CH:14][C:15]([I:17])=[CH:16][C:7]=4[C:6]=3[N:37]=2)[CH:30]=[CH:31][C:32]=1[O:33][CH3:34]
Reactant: COc1ccc(NC(=N)N)cc1OC
Reactant: CN(C)C=C1CC(=O)Nc2ccc(I)cc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1ccc(Nc2ncc3c(n2)-c2cc(I)ccc2NC(=O)C3)cc1OC
Temperature: 80 °C

Procedure:
To a solution of 4-dimethylaminomethylene-7-iodo-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-a) (1.64 g, 4.6 mmol) in 50 mL EtOH was added K2CO3 (1.82 g, 11.04 mmol) and 1-(3,4-dimethoxyphenyl)guanidine (1.31 g, 5.06 mmol), and the reaction was heated to 80° C. for 12 h. The reaction was then cooled to 22° C., diluted with H2O, and treated with 1 M HCl to pH 3. The resulting solid was filtered and washed with H2O, followed by EtOH and Et2O. The crude product was dried in vacuo to give I-26 (1.8 g, 81%): HRMS Calcd. for C20H17IN4O3: 489.0423, Found 489.0431.
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=3)[N:13]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=O>>[CH3:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][N:4]1[CH2:5][CH2:6][CH2:7][N:1]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:18])([F:19])[F:20])=[N:15][N:16]=3)[N:13]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccccc1C=O
Reactant: FC(F)(F)c1nnc2ccc(N3CCCNCC3)nn12
Product: Cc1ccccc1CN1CCCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1

Procedure:
Reductive amination of 6-(1,4-diazepan-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 2-methylbenzaldehyde was carried out according to General Synthetic Method 8. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(2-methylphenyl)methyl]-1,4-diazepan-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:35])=[C:7]2[C:12](=[C:13]([C:15]3[N:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:8]2)=[O:4].[NH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:21]([N:11]1[C:12]2[C:7](=[C:6]([OH:35])[C:5]([C:3]([NH:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:4])=[N:14][C:13]=2[C:15]2[N:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[C:9]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:10]1=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1nc(-c2cccnn2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2cccnn2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 27.7 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-8-pyridazin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (45 mg, 0.097 mmol), β-alanine (864 mg, 9.7 mmol) and NaOMe solution (15.5 mL, 7.8 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (20-100% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4, and the resulting precipitate was isolated by filtration to give 14 mg of the title compound as a yellow solid. MS: (+) m/z 522.35 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]2[C:9]3[C:14]([N:15]=[C:16]4[C:21]=2[C:20](=[O:22])[CH2:19][CH2:18][CH2:17]4)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]2[C:9]3[C:14]([N:15]=[C:16]4[C:21]=2[CH:20]([OH:22])[CH2:19][CH2:18][CH2:17]4)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:23][CH:24]=1
Reactant: O=C1CCCc2nc3ccccc3c(NCc3ccc(Cl)cc3)c21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1CCCc2nc3ccccc3c(NCc3ccc(Cl)cc3)c21
Reaction time: 1 h

Procedure:
To a cooled solution of 6.25 g of 9-(4-chlorobenzylamino)-3,4-dihydroacridin-1(2H)-one in 140 ml of tetrahydrofuran was added 10 ml of 1M LiAlH4 solution in THF. This was stirred at ice bath temperature for 1 hour.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[O:18][C:17](=[O:19])[N:16]([CH2:20][CH3:21])[N:15]=3)[CH2:10][CH2:9]2)=[C:4]([F:22])[CH:3]=1.[N+:23]([C:26]1[O:30][C:29]([CH:31]=O)=[CH:28][CH:27]=1)([O-:25])=[O:24]>CC(O)=O.CO>[CH2:20]([N:16]1[N:15]=[C:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:6]=[CH:7][C:2](/[N:1]=[CH:31]/[C:29]4[O:30][C:26]([N+:23]([O-:25])=[O:24])=[CH:27][CH:28]=4)=[CH:3][C:4]=3[F:22])[CH2:9][CH2:10]2)[O:18][C:17]1=[O:19])[CH3:21]
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: CCn1nc(C2CCN(c3ccc(N)cc3F)CC2)oc1=O
Solvent: CO
Solvent: CC(=O)O
Product: CCn1nc(C2CCN(c3ccc(/N=C/c4ccc([N+](=O)[O-])o4)cc3F)CC2)oc1=O
Yield: 87 %

Procedure:
5-[1-(4-Amino-2-fluorophenyl)-4-piperidyl]-3-ethyl-2,3-dihydro-1,3,4-oxadiazol-2-one (7 g, 0.30 g, 1 mmol) on reacting with 5-nitro2-furaldehyde in the presence of catalytic amount of CH3COOH (3 drops) in methanol at 0° C. for 10 h and the obtained solid is filtered, washed with water and re-crystallized in ethanol to obtain product 3-ethyl-5-[1-(2-fluoro-4-[(E)-1-(5-nitro-2-furyl)methylidene]aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (9 g, 373 mg, 87%).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.C1(C)C=CC(S(O[CH2:22][CH2:23][Cl:24])(=O)=O)=CC=1>O1CCCC1>[Cl:24][CH2:23][CH2:22][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: ClCCn1ccc2ccccc21
Yield: 40.8 %

Procedure:
An oil dispersion (7.2 g) of sodium hydride (0.21 mol) and tetrahydrofuran (50 ml) were placed in a 500-ml flask equipped with a stirrer and a condenser tube, and the mixture was stirred in an ice-water bath. Indole (24.60 g, 0.21 mol) dissolved in tetrahydrofuran (100 ml) was gradually added dropwise to the mixture. After completion of addition, the ice-water bath was removed, and the mixture was stirred for one hour at room temperature. Subsequently, 2-chloroethyl p-toluenesulfonate (49.29 g, 0.21 mol) was added, and the mixture was allowed to react for 15 hours while being stirred under heat-reflux conditions. After completion of reaction, insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The reaction mixture was purified by silica gel column chromatography to obtain 1-(2-chloroethyl)indole (15.4 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:17][CH3:18])(=[O:16])=[O:15])=[C:10]([F:19])[CH:9]=2)=[CH:4][N:3]=1.Cl[CH:21]([C:31]1([C:34]2[CH:35]=[C:36]3[C:41](=[CH:42][CH:43]=2)[N:40]=[CH:39][CH:38]=[CH:37]3)[CH2:33][CH2:32]1)[CH:22](N1C(=O)CCC1=O)O>C(O)C>[F:19][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[N:7][C:2]3[N:3]([C:21]([C:31]4([C:34]5[CH:35]=[C:36]6[C:41](=[CH:42][CH:43]=5)[N:40]=[CH:39][CH:38]=[CH:37]6)[CH2:33][CH2:32]4)=[CH:22][N:1]=3)[CH:4]=2)[CH:13]=[CH:12][C:11]=1[S:14]([NH:17][CH3:18])(=[O:16])=[O:15]
Reactant: O=C1CCC(=O)N1C(O)C(Cl)C1(c2ccc3ncccc3c2)CC1
Reactant: CNS(=O)(=O)c1ccc(-c2cnc(N)nc2)cc1F
Solvent: CCO
Product: CNS(=O)(=O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1F
Temperature: 105 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(2-aminopyrimidin-5-yl)-2-fluoro-N-methylbenzenesulfonamide (20 mg, 0.07 mmol) and 1-[2-chloro-1-hydroxy-2-(1-quinolin-6-ylcyclopropyl)ethyl]pyrrolidine-2,5-dione (24 mg, 0.07 mmol) in ethanol (0.4 mL) was stirred overnight at 105° C. The reaction mixture was purified by RP-HPLC (pH 10) to afford the desired product. LCMS: (M+H)=474.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:18][C:19](=[O:30])[CH2:20][C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[CH:16][S:17][C:10]=12.[CH2:31]([N:33]1[CH:37]=[C:36](C2SC3C(=NC=CC=3OC3C=CC(N)=CC=3F)C=2)[N:35]=[CH:34]1)[CH3:32]>>[CH2:31]([N:33]1[CH:37]=[C:36]([C:16]2[S:17][C:10]3[C:11](=[N:12][CH:13]=[CH:14][C:9]=3[O:8][C:7]3[CH:6]=[CH:5][C:4]([NH:18][C:19](=[O:30])[CH2:20][C:21]([NH:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[O:22])=[CH:3][C:2]=3[F:1])[CH:15]=2)[N:35]=[CH:34]1)[CH3:32]
Reactant: CCn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Reactant: O=C(CC(=O)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1)Nc1ccccc1
Product: CCn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)CC(=O)Nc5ccccc5)cc4F)c3s2)c1
Yield: 57 %

Procedure:
Following the procedure described for compound 5a (example 1, step 5) but substituting amine 9 for compound 15, title compound 5d was obtained in 57% yield. MS (m/z): 516.0 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:10](=O)[CH2:9][CH:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:7][C:6]=2[N:5]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:4]=1)[CH3:2].[C:23]([NH:26][NH2:27])([NH2:25])=[NH:24].[ClH:28].Cl.O>C(O)C>[ClH:28].[CH2:1]([C:3]1[C:11]2[C:10](=[N:27][NH:26][C:23]([NH2:25])=[NH:24])[CH2:9][CH:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:7][C:6]=2[N:5]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:4]=1)[CH3:2]
Reactant: CCc1cn(S(C)(=O)=O)c2c1C(=O)CC(c1ccccc1)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCc1cn(S(C)(=O)=O)c2c1C(=NNC(=N)N)CC(c1ccccc1)C2
Yield: 284.9 %

Procedure:
A mixture of 3-ethyl-1-methanesulfonyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.25 g), aminoguanidine hydrochloride (0.091 g), concentrated hydrochloric acid (0.039 ml), water (0.039 ml) and ethanol (30 ml) was refluxed for 1 hour. Under reduced pressure, the solvent was evaporated, and the residue was washed with ethyl acetate and water to give 3-ethyl-4-guanidinoimino-1-methanesulfonyl-6-phenyl-4,5,6,7-tetrahydroindole hydrochloride (Compound 14) (0.92 g) as colorless crystals.