Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]([C:11]1[CH:20]=[CH:19][C:14]([C:15](OC)=[O:16])=[CH:13][CH:12]=1)=[CH:8][CH2:9][CH3:10].O.[OH-].[Na+]>C(OCC)C>[CH:7](/[C:11]1[CH:12]=[CH:13][C:14]([CH2:15][OH:16])=[CH:19][CH:20]=1)=[CH:8]\[CH2:9][CH3:10]
Reactant: CCC=Cc1ccc(C(=O)OC)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CC/C=C/c1ccc(CO)cc1
Temperature: 0 °C
Yield: 89.1 %

Procedure:
To a suspension of lithium aluminum hydride (1.2 g) in diethyl ether (100 mL) was added a solution of methyl 4-(but-1-en-1-yl)benzoate (2.5 g) in diethyl ether (20 mL) at 0° C., and the mixture was heated under reflux for 30 mixture. After the reaction mixture was cooled to 0° C., to the mixture were added water (1.2 mL), an aqueous sodium hydroxide solution (15%, 1.2 mL) and water (3.6 mL), and the mixture was stirred at room temperature for 5 minutes. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=2/1) to give (E)-4-(but-1-en-1-yl)benzyl alcohol (1.9 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[N:9]=1.[NH2:30][C:31]1[C:32]([C:38](O)=[O:39])=[N:33][C:34]([Br:37])=[CH:35][CH:36]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[NH2:30][C:31]1[C:32]([C:38]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[N:9]=2)=[O:39])=[N:33][C:34]([Br:37])=[CH:35][CH:36]=1
Reactant: Cc1cc(-c2ccncc2N)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Reactant: Nc1ccc(Br)nc1C(=O)O
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1cc(-c2ccncc2NC(=O)c2nc(Br)ccc2N)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Yield: 12 %

Procedure:
Method 27 was followed using 4-(3-aminopyridin-4-yl)-N,N-di-BOC-6-methylpyrimidin-2-amine (1.0 equiv.), 3-amino-6-bromopicolinic acid (1.0 equiv), EDC (1.0 equiv.), and HOAt (1.0 equiv.) in DMF yielding 3-amino-6-bromo-N-(4-(2-(di-BOC-amino)-6-methylpyrimidin-4-yl)pyridin-3-yl)picolinamide in 12% yield. LCMS (m/z): 602.2 (MH+); LC Rt=3.60 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][C:6]1([CH3:22])[CH2:15][CH2:14][C:13]2[C:8](=[C:9]3[CH:20]4[CH2:21][CH:17]([CH2:18][CH2:19]4)[C:10]3=[C:11]([OH:16])[CH:12]=2)[O:7]1.C(N(C(C)C)CC)(C)C.[CH3:33][O:34][CH2:35]Cl>C(Cl)Cl.[Cl-].[Na+].O>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][C:6]1([CH3:22])[CH2:15][CH2:14][C:13]2[C:8](=[C:9]3[CH:20]4[CH2:21][CH:17]([CH2:18][CH2:19]4)[C:10]3=[C:11]([O:16][CH2:33][O:34][CH3:35])[CH:12]=2)[O:7]1
Reactant: COCCl
Reactant: COC(=O)CCC1(C)CCc2cc(O)c3c(c2O1)C1CCC3C1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cc2c(c3c1C1CCC3C1)OC(C)(CCC(=O)OC)CC2
Yield: 74.3 %

Procedure:
To a solution of 3-(6-hydroxy-2-methyl-3,4,7,8,9,10-hexahydro-7,10-methano-2H-benzo[h]chromen-2-yl)-propionic acid methyl ester from Example 13 (400 mg, 1.27 mmol) and diisopropyl ethylamine (DIPEA) (0.90 ml, 5 mmol) in 4 mL of DCM was slowly added chloromethyl methyl ether (0.30 mL, 3.8 mmol) at room temperature. The reaction was left over night. After the completion of reaction shown by TLC, the mixture was poured into brine and the organic layer was separated and dried over MgSO4. After the removal of solvents the residue was purified through flash column chromatography on silica gel (25% of ethyl acetate in hexane) to afford 340 mg of 3-(6-methoxymethoxy-2-methyl-3,4,7,8,9,10-hexahydro-7,10-methano-2H-benzo[h]chromen-2-yl)-propionic acid methyl ester. 1H-NMR (300 MHz, CDCl3) δ (ppm)): 6.25 (s, 1H), 4.29 (s, 1H), 3.63 (s, 3H), 3.48 (s, 1H), 3.40 (s, 1H), 2.66-2.64 (m, 2H), 2.47-2.43 (m, 2H), 1.83-1.50, (m, 12H) 1.18 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]([C:20]4([CH:46]([OH:48])[CH3:47])[CH2:24][CH2:23][N:22]([CH2:25][C:26](=[O:45])[N:27]5[CH2:32][CH2:31][N:30]([C:33]6[CH:38]=[CH:37][C:36]([C:39]7[N:44]=[CH:43][CH:42]=[CH:41][N:40]=7)=[CH:35][CH:34]=6)[CH2:29][CH2:28]5)[CH2:21]4)=[O:19])[CH:15]=3)[N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:9]=2)=[CH:4][CH:3]=1.CCOC(C)=O>C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]([C:20]4([CH:46]([OH:48])[CH3:47])[CH2:24][CH2:23][N:22]([CH2:25][C:26](=[O:45])[N:27]5[CH2:32][CH2:31][N:30]([C:33]6[CH:38]=[CH:37][C:36]([C:39]7[N:40]=[CH:41][CH:42]=[CH:43][N:44]=7)=[CH:35][CH:34]=6)[CH2:29][CH2:28]5)[CH2:21]4)=[O:19])[CH:15]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(O)C1(C(=O)Nc2ccc3c(c2)c(-c2ccc(F)cc2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)cc3)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CC(O)C1(C(=O)Nc2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)cc3)CC2)C1

Procedure:
Stirred 3-(1-Hydroxy-ethyl)-1-{2-oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1-yl]-ethyl}-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1Trityl-indazol-5-yl]-amide (7N) (65 mg, 0.073 mmol) in 85% TFA (2 ml) at room temperature overnight. Evaporated solvent. Added EtOAc (50 ml) H2O (20 ml) 2M NaOH (3 ml). Separated organic layer, dried over MgSO4, filtered and solvent evaporated yielding a residue which purified on silica gel eluting with 5% v/v MeOH:EtOAc yielding two diastereomeric racemates.
Reaction SMILES: Cl[CH:2]([C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][CH3:16])=[CH:10][C:9]=1[CH3:17])[C:3]([O:5][CH2:6][CH3:7])=[O:4]>CC(O)=O.CCOC(C)=O.[Fe]>[Cl:14][C:12]1[C:11]([O:15][CH3:16])=[CH:10][C:9]([CH3:17])=[C:8]([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:13]=1
Reactant: CCOC(=O)C(Cl)c1cc(Cl)c(OC)cc1C
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)Cc1cc(Cl)c(OC)cc1C
Temperature: 60 °C
Reaction time: 17 h
Yield: 45.3 %

Procedure:
Iron powder (193 mg, 3.46 mmol) was added to a stirred solution of ethyl 2-chloro-2-(5-chloro-4-methoxy-2-methylphenyl)acetate (Intermediate 3-5; 480 mg, 1.73 mmol) in AcOH (2 mL) under nitrogen, and the resulting mixture was stirred at 60° C. for 17 hours. The reaction mixture was allowed to cool to ambient temperature, diluted with EtOAc (50 mL), filtered through celite and washed with saturated brine (3×25 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford ethyl 2-(5-chloro-4-methoxy-2-methylphenyl)acetate (190 mg, 45.2%) as a colourless gum.
Reaction SMILES: CS(C)=O.[C:5]([C:9]1[C:10](=[O:30])[CH2:11][CH:12]([C:16]2[CH:17]=[CH:18][C:19]3[O:24][CH2:23][C:22](=[O:25])[N:21]([CH2:26][C:27]#[CH:28])[C:20]=3[CH:29]=2)[CH2:13][C:14]=1[OH:15])(=O)[CH2:6][CH3:7].Cl.[CH2:32]([O:34][NH2:35])[CH3:33].C([O-])(=O)C.[Na+]>Cl>[CH2:32]([O:34][N:35]=[C:5]([C:9]1[C:10](=[O:30])[CH2:11][CH:12]([C:16]2[CH:17]=[CH:18][C:19]3[O:24][CH2:23][C:22](=[O:25])[N:21]([CH2:26][C:27]#[CH:28])[C:20]=3[CH:29]=2)[CH2:13][C:14]=1[OH:15])[CH2:6][CH3:7])[CH3:33]
Reactant: C#CCN1C(=O)COc2ccc(C3CC(=O)C(C(=O)CC)=C(O)C3)cc21
Reactant: CCON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: C#CCN1C(=O)COc2ccc(C3CC(=O)C(C(CC)=NOCC)=C(O)C3)cc21
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To 50 mL of methyl sulfoxide were added in sequence 2.2 g (6.2 mmol ) of 2-propionyl-3-hydroxy-5-(N-(2-propynyl)-3-oxo-(2H)-1,4-benzoxazin-6-yl)cyclohex-2-en-1-one, 0.70 g (7.4 mmol) of ethoxyamine hydrochloride and 0.60 g (7.3 mmol) of anhydrous sodium acetate. The resulting mixture was stirred at ambient temperature for 3.5 hours. The reaction mixture was then diluted with 400 mL of 0.2N HCl and extracted four times with 20 mL portions of dichloromethane. The extracts were combined, washed with aqueous NaCl, dried over MgSO4 and filtered through a short pad of silica gel. Evaporation off of the solvent gave the crude product as a light yellow glass, which solidified upon standing. The solid was triturated in ether and the product isolated by filtration which afforded the above-named product as a white solid which melted at 100°-102° C. in a yield of 1.3 g (53 percent of theoretical). 1H NMR (CDCl3): d1.08-1.47 (m, 6H, both --CH2CH3 's), 2.31 (t, J=2 Hz, 1H,--C--CH), 2.62-3.64 (m, 7H), 4.17 (q, J=7 Hz, 2H, OCH2CH3), 4.67 (s, 2H, --OCH2C=O), 4.74(d, J=2 Hz, 2H,--NCH2), 6.87-7.12 (m, 3H, aromatic H's), 15.10 (broad s, 1H, enol H); (Compound 11).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[S:5][C:4]2[CH:13]=[C:14]([CH:17]([CH3:21])[C:18](N)=[O:19])[CH:15]=[CH:16][C:3]1=2.S(=O)(=O)(O)O.[CH2:27]([OH:29])[CH3:28]>>[O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[S:5][C:4]2[CH:13]=[C:14]([CH:17]([CH3:21])[C:18]([O:29][CH2:27][CH3:28])=[O:19])[CH:15]=[CH:16][C:3]1=2
Reactant: CCO
Reactant: CC(C(N)=O)c1ccc2c(c1)Sc1ccccc1CC2=O
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(C)c1ccc2c(c1)Sc1ccccc1CC2=O

Procedure:
To 300 mg of 2-(10,11-dihydro-11-oxo dibenzo[b,f]thiepin-3-yl)-propionamide in 3 ml of ethanol was added 0.3 ml of conc. sulfuric acid and the mixture was refluxed for 3.5 hours. The solvent was distilled off to obtain the residue, to which was added pieces of ice, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain brown oil, which was chromatographed over silica gel, eluted with chloroform, and there was obtained 277 mg of ethyl 2-(10,11-dihydro-11-oxo dibenzo[b,f]thiepin-3-yl)-propionate as pale brown oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[N:25]([CH:27]=[C:28]([C:30](O)=[O:31])[N:29]=2)[CH:26]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:30]([C:28]1[N:29]=[C:24]2[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][N:25]2[CH:27]=1)=[O:31]
Reactant: O=C(O)c1cn2cc(Cl)ccc2n1
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1cn2cc(Cl)ccc2n1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 6-Chloro-imidazo[1,2-a]pyridine-2-carboxylic acid. MS: 438.4 (M+H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:12]([C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([N+]([O-])=O)[C:16]=1[C:17]#[N:18])([O-:14])=[O:13]>>[CH2:1]([O:8][CH2:9][CH2:10][NH:11][C:19]1[CH:20]=[CH:21][CH:22]=[C:15]([N+:12]([O-:14])=[O:13])[C:16]=1[C:17]#[N:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: NCCOCc1ccccc1
Product: N#Cc1c(NCCOCc2ccccc2)cccc1[N+](=O)[O-]
Yield: 77 %

Procedure:
Prepared as in Example 90c from 2-(benzyloxy)ethanamine and 2,6-dinitrobenzonitrile in 77% yield. 1H NMR (400 MHz, DMSO-d6) δ 3.49 (q, J=5.2 Hz, J=5.6 Hz, 2H), 3.59 (t, J=5.6 Hz, 2H), 4.49 (s, 2H), 6.47 (t, J=5.8 Hz, NH), 7.23-7.31 (m, 6H), 7.43 (d, J=8.0 Hz, 1H), 7.58 (t, J=8.4 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:24])[C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[F:23])[N:11]=[N:10][CH:9]=[C:8]2O)=[O:4].O=P(Cl)(Cl)[Cl:28]>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:24])[C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[F:23])[N:11]=[N:10][CH:9]=[C:8]2[Cl:28])=[O:4]
Reactant: COC(=O)c1cc2c(O)cnnc2c(F)c1Nc1ccc(Br)cc1F
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cc2c(Cl)cnnc2c(F)c1Nc1ccc(Br)cc1F
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
A mixture of 7-(4-bromo-2-fluorophenylamino)-8-fluoro-4-hydroxy-cinnoline-6-carboxylic acid methyl ester (1.00 equiv.) and POCl3 (excess) is stirred for 1.5 hours at 80° C. After evaporation of POCl3 under reduced pressure, the crude material is poured into ice and neutralized to pH 7 to 8 with saturated aqueous NaHCO3. The aqueous layer is extracted with EtOAc. The organic layers is dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude product that is purified by trituration or flash column chromatography to afford the desired product as necessary.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@@H:11]2[CH2:14][CH2:13][N:12]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:5]=[N:6][C:7]=1[Cl:8].[CH:22]([Sn](CCCC)(CCCC)CCCC)=[CH2:23]>C1(C)C=CC=CC=1.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:8][C:7]1[C:2]([CH:22]=[CH2:23])=[CH:3][C:4]([O:9][CH2:10][C@@H:11]2[CH2:14][CH2:13][N:12]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:5][N:6]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)cnc1Cl
Temperature: 95 °C
Yield: 84 %

Procedure:
To 5-bromo-6-chloro-3-(1-t-butyloxycarbonyl-2-(S)-azetidinylmethoxy)pyridine from Example 17 above (1.00 g, 2.65 mmol) in toluene (30 mL) was added tetrakis(triphenylphosphine)palladium(0) (93 mg, 0.081 mmol) and vinyltributyltin (0.93 mL, 3.18 mmol). The mixture heated at 95° C. overnight, then the volatile components were removed in vacuo. The residue was chromatographed (silica gel; CH2Cl2/MeOH, 100:2) to afford 2-chloro-3-vinyl-5-(1-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)pyridine as an oil (720 mg, 84%): 1H NMR (CDCl3, 300 MHz) δ1.42 (s, 9H), 2.33 (m, 2H), 3.89 (t, J=8.5 Hz, 2H), 4.14 (m, 1H), 4.36 (m, 1H), 4.52 (m, 1H), 5.50 (d, J=10.9 Hz, 1H), 5.80 (d, J=17 Hz, 1H), 6.98 (dd, J=17.6 Hz, J=11.2 Hz, 1H), 7.44 (d, J=2.7 Hz, 1H), 8.02 (d, J=2.7 Hz, 1H); MS (CI/NH3) m/z: 325 (M+H)+. This product was treated with TFA in CH2Cl2 to give, following extractive work-up, the free base of the title compound. The free amine was converted to the hydrochloride salt by treatment with a solution of HCl in diethyl ether to give the title compound as a light yellow hygroscopic solid: mp 121° C. (dec); MS (CI/NH3): m/z 225 (M+H+), 242 (M+NH4+). Anal. Calcd for C11H13ClN2O.1.1 HCl: C, 49.90; H, 5.37; N, 10.58. Found: C, 49.84; H, 5.25; N, 10.27.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]([CH3:16])[CH3:15].[NH2:17][CH2:18][C:19]1[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=1[CH3:25].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH:17][CH2:18][C:19]3[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=3[CH3:25])=[O:13])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)c1c[nH]c2c(C(=O)O)cc(Br)cc12
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c(C(C)C)c[nH]c23)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.8 %

Procedure:
To a stirred suspension of 5-bromo-3-(1-methylethyl)-1H-indole-7-carboxylic acid (400 mg, 1.418 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (300 mg, 1.590 mmol) and HOAt (220 mg, 1.616 mmol) in DMF (15 mL) was added N-methylmorpholine (180 μL, 1.637 mmol) and EDC free base (330 mg, 2.127 mmol). The reaction was stirred for 18 h at RT. LCMS showed that the reaction was complete. The reaction was evaporated to near dryness under vacuum. Water (˜15 mL) was added and the solids which precipitated out were triturated, filtered and dried under vacuum to give 5-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-(1-methylethyl)-1H-indole-7-carboxamide (571 mg, 1.372 mmol, 97% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.52 (br. s., 1H), 11.03 (br. s., 1H), 8.58 (t, J=4.55 Hz, 1H), 7.85 (d, J=1.26 Hz, 1H), 7.82 (s, 1H), 7.12 (d, J=2.02 Hz, 1H), 5.89 (s, 1H), 4.35 (d, J=4.55 Hz, 2H), 3.13 (ddd, J=6.57, 6.69, 13.52 Hz, 1H), 2.20 (s, 3H), 2.13 (s, 3H), 1.27 (d, J=6.82 Hz, 6H). MS (ES) [M+H]+ 415.9, 418.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:6][C:7]1[N:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:9]([SH:12])=[N:10][N:11]=1.CCN(CC)CC.[F:32][C:33]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:34]=1[CH2:35]Br>C(Cl)Cl>[F:32][C:33]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:34]=1[CH2:35][S:12][C:9]1[N:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:7]([CH2:6][C:5]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:11][N:10]=1
Reactant: COc1ccc(Cc2nnc(S)n2-c2ccc(F)cc2)cc1OC
Reactant: Fc1cccc(F)c1CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Cc2nnc(SCc3c(F)cccc3F)n2-c2ccc(F)cc2)cc1OC
Reaction time: 2 h
Yield: 65.8 %

Procedure:
To a solution of 5-(3,4-dimethoxybenzyl)-4-(4-fluorophenyl)-4H-1,2,4-triazole-3-thiol (119 mg, 0.345 mmol) and Et3N (53 μL, 0.379 mmol) in CH2Cl2 (1.8 mL) was added 2,6-difluorobenzyl bromide (88 mg, 0.414 mmol). After stirring 2 h, the reaction mixture was concentrated and purified by flash chromatography (30% EtOAc/hexanes) to yield the title product (107 mg, 66%) as a white foam. 1H NMR (400 MHz, (CD3)2CO) δ 7.25 (m, 1H), 7.10 (m, 2H), 6.98 (m, 2H), 6.84 (m, 2H), 6.63 (d, J=8.2 Hz, 1H), 6.4 (d, J=2.0 Hz, 1H), 6.31 (m, 1H), 4.45 (s, 2H), 3.82 (s, 2H), 3.61 (s, 3H), 3.54 (s, 3H); MS (EI) m/z 472.3 (MH+).
Reaction SMILES: C[O:2][C:3](=O)[C:4]([N:6]([C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([F:17])=[CH:12][C:11]=1[N+:18]([O-:20])=O)[CH:7]1[CH2:9][CH2:8]1)=[O:5].C(OCC)(=O)C>CO>[Cl:16][C:14]1[CH:15]=[C:10]2[C:11](=[CH:12][C:13]=1[F:17])[N:18]([OH:20])[C:3](=[O:2])[C:4](=[O:5])[N:6]2[CH:7]1[CH2:9][CH2:8]1
Reactant: COC(=O)C(=O)N(c1cc(Cl)c(F)cc1[N+](=O)[O-])C1CC1
Solvent: CCOC(C)=O
Solvent: CO
Product: O=c1c(=O)n(C2CC2)c2cc(Cl)c(F)cc2n1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.2 g (3.789 mmol) N-(5-chloro-4-fluoro-2-nitro-phenyl)-N-cyclopropyl-oxalamic acid methyl ester in 15 mL MeOH was added 120 mg Pd(C) 10% on charcoal. The reaction mixture was stirred for 2 hours under hydrogen atmosphere at 1.2 bar at room temperature. 30 mL ethyl acetate was added and the reaction mixture was filtered over Dicalite® speed plus (Acros) speed plus (Acros) and concentrated under vacuum. Light yellow solid (68%). MS (ESI): m/z=269.014 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH:10][C:11](=[O:13])[CH3:12].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=O)CC(OCC)=O)=[CH:17][CH:16]=1.P(Cl)(Cl)Cl>ClCCCl>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[NH:10][C:11](=[O:13])[CH:12]=2)=[CH:17][CH:16]=1
Reactant: COc1ccccc1NNC(C)=O
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)cc1
Solvent: ClP(Cl)Cl
Solvent: ClCCCl
Product: COc1ccccc1-n1[nH]c(=O)cc1-c1ccc(Cl)cc1
Temperature: 50 °C
Yield: 51.7 %

Procedure:
To a mixture of N′-(2-methoxyphenyl)acetohydrazide (2.90 g, 16.09 mmol) and ethyl 3-(4-chlorophenyl)-3-oxopropanoate (3.65 g, 16.09 mmol) in 10 mL of DCE was added drop wise phosphorus trichloride (1.41 mL, 16.09 mmol). The mixture was heated to 50° C. and all solids dissolved. After 2 hrs at 50° C. the mixture was cooled to RT and the ppt was collected by filtration and washed with water and EtOAc and dried to give 2.50 g (49%) of a white solid.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21](O)=[O:22])[CH:16]=3)[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:24]=[CH:25][CH:26]=[CH:27][C:4]=2[NH:3]1.[NH:28]1[C:38]2[C:39]3[CH:30]([CH2:31][C:32](=[O:40])[NH:33][C:34]=3[CH:35]=[CH:36][CH:37]=2)[CH2:29]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[O:1]=[C:2]1[NH:3][C:4]2[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=2[CH2:6][CH2:7][N:8]1[CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[CH:19][N:18]=[C:17]([C:21]([N:28]3[C:38]4[C:39]5[CH:30]([CH2:31][C:32](=[O:40])[NH:33][C:34]=5[CH:35]=[CH:36][CH:37]=4)[CH2:29]3)=[O:22])[CH:16]=2)[CH2:11][CH2:10]1
Reactant: O=C1CC2CNc3cccc(c32)N1
Reactant: O=C(O)c1cc(N2CCC(N3CCc4ccccc4NC3=O)CC2)ncn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=C1CC2CN(C(=O)c3cc(N4CCC(N5CCc6ccccc6NC5=O)CC4)ncn3)c3cccc(c32)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
63mg (0.17 mmol) 6-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid and 30 mg (0.17 mmol) 1,2,2a,5-tetrahydro-3H-pyrrolo-[4,3,2-de]quinolin-4-one in 56 μL (0.40 mmol) TEA and 1.8 mL DMF were mixed with 58 mg (0.18 mmol) TBTU and the mixture was stirred overnight at RT. Then the reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.[CH:18]1[CH:19]=CC2N(O)N=[N:24][C:22]=2[CH:23]=1.CCN(C(C)C)C(C)C.N1CCCC1.CCN=C=NCCCN(C)C>CN(C=O)C>[O:17]=[C:15]([N:24]1[CH2:19][CH2:18][CH2:23][CH2:22]1)/[CH:14]=[CH:13]/[C:8]1[CH:7]=[C:6]2[C:11](=[N:10][CH:9]=1)[NH:12][C:3](=[O:2])[CH2:4][CH2:5]2
Reactant: On1nnc2ccccc21
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1CCc2cc(/C=C/C(=O)N3CCCC3)cnc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
A 16 mL vial flask was successively charged with (2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (50 mg, 0.20 mmol), DMF (4.8 mL), HOBt (32 mg, 0.23 mmol), DIPEA (78 μL, 0.47 mmol), pyrrolidine (20 μL, 0.23 mmol) and EDAC (45 mg, 0.23 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The residue was diluted in dichloromethane and washed with water. The organic layer was concentrated to dryness and the residue was purified on preparative TLC (eluent: dichloromethane/MeOH, 95/5) to give the title compound (33 mg, 62%) as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:14][CH:15]=[C:16]([C:18]2[CH:47]=[CH:46][C:21]([O:22][C:23]3[CH:24]=[C:25]([C:29]4[NH:33][C:32]([C@@H:34]5[CH2:38][CH2:37][CH2:36][N:35]5C(OC(C)(C)C)=O)=[N:31][CH:30]=4)[CH:26]=[CH:27][CH:28]=3)=[CH:20][CH:19]=2)[N:17]=1)=O)(C)(C)C.[Cl:48]CCl>Cl>[ClH:48].[NH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:17][C:16]([C:18]2[CH:47]=[CH:46][C:21]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[N:33]=[C:32]([CH:34]5[CH2:38][CH2:37][CH2:36][NH:35]5)[NH:31][CH:30]=4)[CH:24]=3)=[CH:20][CH:19]=2)=[CH:15][N:14]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc(Oc3cccc(-c4cnc([C@@H]5CCCN5C(=O)OC(C)(C)C)[nH]4)c3)cc2)c[nH]1
Agent: Cl
Product: c1cc(Oc2ccc(-c3cnc(C4CCCN4)[nH]3)cc2)cc(-c2c[nH]c(C3CCCN3)n2)c1

Procedure:
First, to a solution of (S)-tert-butyl 2-(5-(3-(4-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-4-yl)phenoxy)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate in dichloromethane, excess HCl (1M in isopropanol) was added dropwise. The precipitated solid was filtered off and dried in the vacuum oven to afford 2-(pyrrolidin-2-yl)-5-(4-(3-(2-(pyrrolidin-2-yl)-1H-imidazol-4-yl)phenoxy)phenyl)-1H-imidazole hydrochloride.