Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([CH:8]1[NH:12][CH:11]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:10]2([C:25]3[C:20](=[C:21]([F:27])[C:22]([Cl:26])=[CH:23][CH:24]=3)[NH:19][C:18]2=[O:28])[CH:9]1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=1[F:36])=[O:7])(C)(C)C.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[Cl:26][C:22]1[C:21]([F:27])=[C:20]2[NH:19][C:18](=[O:28])[C:10]3([CH:9]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=4[F:36])[CH:8]([C:6]([OH:7])=[O:5])[NH:12][CH:11]3[CH2:13][C:14]([CH3:16])([CH3:15])[CH3:17])[C:25]2=[CH:24][CH:23]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C12C(=O)Nc1c2ccc(Cl)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1c2ccc(Cl)c1F
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-7-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid tert-butyl ester (0.91 g, 1.7 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (5 mL). The reaction mixture was stirred at room temperature for 20 h, then concentrated. The residue was then triturated with ethyl ether hexanes, concentrated, dried in vacuo to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-7-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid as a off white solid (0.95 g, 94%).
Reaction SMILES: [Br:1][C:2]1[N:18]=[C:5]2[CH:6]=[C:7]([NH:10]C(=O)OC(C)(C)C)[CH:8]=[CH:9][N:4]2[N:3]=1.Cl>ClCCl>[Br:1][C:2]1[N:18]=[C:5]2[CH:6]=[C:7]([NH2:10])[CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ccn2nc(Br)nc2c1
Agent: Cl
Solvent: ClCCl
Product: Nc1ccn2nc(Br)nc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.6 %

Procedure:
A suspension of tert-butyl 2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamate (5.19 g, 16.6 mmol) in dichloromethane (150 ml) and hydrochloric acid (5N in ether, 150 ml, 750 mmol) was stirred for 18 hours at 25° C. The solvents were evaporated, the residue was suspended in water (200 ml) and adjusted to pH=14 using sodium hydroxide 32%. The precipitated solid was filtered off, washed with water 4 times and dried in vacuo affording 2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-ylamine (2.39 g, 67.7&) as a light yellow solid. MS: m/z=213.0/215.1 (M+H+).
Reaction SMILES: Cl.[CH3:2][N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]1=[N:12][NH2:13].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=O)[CH:15]=1.[OH-].[Na+]>C(O)(=O)C>[CH3:2][N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5]/[C:4]/1=[N:12]/[N:13]=[CH:20][C:16]1[CH:17]=[CH:18][CH:19]=[N:14][CH:15]=1
Reactant: O=Cc1cccnc1
Reactant: Cn1c(=NN)sc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cn1/c(=N\N=Cc2cccnc2)sc2ccccc21

Procedure:
1.50 g (6.42 mmol) of 2,3-dihydro-3-methyl-2-benzothiazolone hydrazone hydrochloride and 0.69 g (6.42 mmol) of 3-pyridinecarboxaldehyde in 10% acetic acid were stirred at room temperature for 30 minutes. The mixture was then made slightly alkaline with 2N sodium hydroxide solution and the precipitate was suction-filtered off, washed with water and dried under vacuum.
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:9][CH:8]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:7]1)=[O:5].[H-].C([Al+]CC(C)C)C(C)C.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[CH3:12][C:11]([CH3:14])([CH3:13])[CH2:10][CH:8]1[CH2:7][CH:6]([CH:4]=[O:5])[CH2:9]1
Reactant: CON(C)C(=O)C1CC(CC(C)(C)C)C1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)(O)O
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC(C)(C)CC1CC(C=O)C1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of N-methoxy-N-methyl-3-(2,2-dimethylpropyl)cyclobutanecarboxamide (95.2 g) in toluene (330 mL) was added diisobutylaluminum hydride (1.0M in toluene) (486 mL) dropwise at −78° C. After the mixture was stirred at −78° C. for 3 hr, 1.5 M sulfuric acid (648 mL) was added dropwise to the mixture at ice temperature. The mixture was extracted with toluene and the combined organic layer was washed with 1 M sulfuric acid, water and brine, then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate comprising the title compound was used in the next step.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[C:12]([O:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[C:28]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[N:27][N:26]=4)=[CH:20][CH:19]=3)=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH3:41][N:42]([CH3:49])[CH2:43][C:44]([CH3:48])([CH3:47])[CH2:45][NH2:46]>CS(C)=O>[CH3:41][N:42]([CH3:49])[CH2:43][C:44]([CH3:48])([CH3:47])[CH2:45][NH:46][C:5]1[N:10]=[C:9]([C:11]2[C:12]([O:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]4[C:40]5[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=5)[C:28]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[N:27][N:26]=4)=[CH:20][CH:19]=3)=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:8]=[CH:7][N:6]=1
Reactant: CS(=O)(=O)c1nccc(-c2cccnc2Oc2ccc(Nc3nnc(-c4ccccc4)c4ccccc34)cc2)n1
Reactant: CN(C)CC(C)(C)CN
Solvent: CS(C)=O
Product: CN(C)CC(C)(C)CNc1nccc(-c2cccnc2Oc2ccc(Nc3nnc(-c4ccccc4)c4ccccc34)cc2)n1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A resealable pressure vial was charged with N-(4-(3-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-phenylphthalazin-1-amine (100 mg, 0.180 mmol) and N1,N1,2,2-tetramethylpropane-1,3-diamine (0.12 ml, 0.73 mmol) and DMSO (1.2 ml, 0.15 M). The reaction vessel was sealed and the mixture was stirred at 70° C. for 16 hrs. The reaction was cooled to RT and diluted with 3 ml of DMSO. The solution was purified by Gilson reverse phase chromatography (10% to 90% CH3CN/H2O/0.1% TFA). The product-containing fractions were combined, basified by addition of aq. NaHCO3 and extracted with ethyl acetate. The organic portion was dried with Na2SO4, filtered, and concentrated to afford pure N-(4-(3-(2-(3-(dimethylamino)-2,2-dimethylpropylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)4-phenylphthalazin-1-amine as a yellow solid. MS m/z=597 [M+H]+. Calc'd for C36H36N8O: 596.72.
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([OH:11])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].O[C:13]1[C:14]([C:30]([F:33])([F:32])[F:31])=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([C@:23]1([CH3:29])[CH2:27][O:26][C:25](=[O:28])[NH:24]1)[CH:17]=[CH:16]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:13]2[C:14]([C:30]([F:32])([F:33])[F:31])=[C:15]3[C:20](=[CH:21][CH:22]=2)[CH:19]=[C:18]([C@:23]2([CH3:29])[CH2:27][O:26][C:25](=[O:28])[NH:24]2)[CH:17]=[CH:16]3)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@]1(c2ccc3c(C(F)(F)F)c(O)ccc3c2)COC(=O)N1
Reactant: CC(C)(C)[C@H]1CC[C@@H](O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2C(F)(F)F)CC1

Procedure:
The mixture of cis-4-tert-butylcyclohexanol (30.4 mg, 0.000195 mol), (R)-4-(6-hydroxy-5-(trifluoromethyl)naphthalen-2-yl)-4-methyloxazolidin-2-one (50.5 mg, 0.000162 mol) and triphenylphosphine (51.1 mg, 0.000195 mol) in tetrahydrofuran (2 mL, 0.02 mol) was heated to reflux, and diisopropyl azodicarboxylate (0.0383 mL, 0.000195 mol) was added dropwise and was stirred and refluxed for 3 hours. The mixture was taken up into methylene chloride and subjected to chromatography purification with EtOAc/hexane (10:90 to 80:20) to give product (R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)-4-methyloxazolidin-2-one (22.2 mg, 30%). LCMS: Rf=2.41 min (450.46, M+1, 70%; 491.47, M+ACN, 100%). 1H NMR (400 MHz, CHLOROFORM-d) δ=8.25 (dd, J=8.7, 1.4 Hz, 1 H), 7.91 (d, J=9.0 Hz, 1 H), 7.79 (d, J=2.0 Hz, 1 H), 7.52 (dd, J=9.3, 2.3 Hz, 1 H), 7.34 (d, J=9.3 Hz, 1 H), 5.98 (br. s., 1 H), 4.45 (d, J=8.6 Hz, 1 H), 4.41 (d, J=8.6 Hz, 1 H), 4.38-4.26 (m, 1 H), 2.19 (d, J=13.1 Hz, 2 H), 1.89 (d, J=10.0 Hz, 2 H), 1.87 (s, 3 H), 1.59-1.48 (m, 2 H), 1.21-1.05 (m, 3 H), 0.89 (s, 9 H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:11]2[NH:10][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N+:18]([O-:20])=[O:19])=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1>CC#N.C(Cl)Cl.[O-2].[O-2].[Mn+4]>[N+:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:9]1[NH:10][C:11]2[C:3]([CH:2]=[O:1])=[CH:4][CH:5]=[CH:6][C:7]=2[N:8]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccccc1-c1nc2cccc(CO)c2[nH]1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: CC#N
Product: O=Cc1cccc2nc(-c3ccccc3[N+](=O)[O-])[nH]c12
Temperature: 25 °C
Yield: 82.3 %

Procedure:
4-Hydroxymethyl-2-(2-nitrophenyl)-benzimidazole 3 (2.69 g, 10 mmol) was dissolved in a mixture of CH3CN/CH2Cl2 (500 mL, v/v=4:1), and then manganese dioxide (10 g, 120 mmol) was added. The solution was stirred at room temperature and monitored by TLC. Once the reaction was complete, the reaction mixture was filtered through a pad of celite. The filtrate was washed with NaHCO3, and the water phase was extracted with CH2Cl2. The combined organic layer was washed with brine and dried over Na2SO4. Concentration by rotary evaporation and subsequent column chromatography on silica gel using hexane/ethyl acetate (1:1) as the eluent afforded 2-(2-nitrophenyl)-benzimidazole-4-carboxaldehyde (2.2 g, 82%) as a light-yellow solid. Rf=0.38 (hexane/ethyl acetate=1:1); 1H NMR (200 MHz, CDCl3) δ 7.47 (t, J=7.6 Hz, 1H), 7.63-7.82 (m, 3H), 7.94 (d, J,=7.5 Hz, J2=1.5 Hz, 1H), 8.05 (d, J1=7.7 Hz, J2=1.6 Hz, 1H), 8.10 (d, J=8.1 Hz, 1H), 10.11 (s, 1H), 11.21 (broad s, 1H); HRMS: Calcd. for C14H9N3O3 267.0644, found 267.0648.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:9][N:10]=2)[N:7]=1.C([O-])([O-])=O.[Na+].[Na+].CCO[C:29]([CH3:31])=O>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][C:8]2[N:6]3[N:7]=[C:2]([C:29]4[CH:31]=[N:7][N:6]([CH3:8])[CH:5]=4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)=[CH:13][CH:14]=1
Reactant: CCOC(C)=O
Reactant: COc1ccc(Cc2cnc3ccc(Cl)nn23)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc(Cc2cnc3ccc(-c4cnn(C)c4)nn23)cc1
Temperature: 180 °C

Procedure:
The compound 6-chloro-3-(4-methoxy-benzyl)-imidazo-[1,2-b]-pyridazine (Stage 4.1, 100 mg, 0.36 mmol) was introduced in a microwave reactor with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazole (75 mg, 0.36 mmol) and dissolved in 1 mL of 2-dimethoxyethane. An aqueous solution of 2 M Na2CO3 (660 μL, 1.3 mmol) was added to this mixture and also tetrakis-(triphenylphosphine)-palladium (21 mg, 0.02 mmol). The RM was heated at 180° C. for 30 min under microwave irradiations. The reaction was taken up with EtOAc and washed with 10% Na2CO3 and brine. The organic layer was dried over Na2SO4 and the solvent was removed. The residue was purified by preparative HPLC with acetonitrile and water (+0.1% TFA). The white solid the title compound was obtained (tR 1.0 min (conditions 2), MH+=320).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]1[C:7](=[O:12])[N:8]([CH3:11])[CH2:9][CH:10]=1.CO.[NH2:16][O:17][K].C(O)(=O)C>CO.C(Cl)(Cl)Cl>[OH:17][NH:16][C:3](=[O:2])[CH2:4][CH2:5][C:6]1[C:7](=[O:12])[N:8]([CH3:11])[CH2:9][CH:10]=1
Reactant: NO[K]
Reactant: COC(=O)CCC1=CCN(C)C1=O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: CO
Product: CN1CC=C(CCC(=O)NO)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.8 %

Procedure:
18 mg of 3-(1-methyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-propionic acid methyl ester (2g) prepared by the above Step 2 was dissolved in methanol solution (0.1 mmol) and then 1.7 M methanolic suspension solution containing NH2OK (0.09 ml, 0.15 mmol) was added thereto at 0° C. and the resulting mixture was stirred for 1 hr at room temperature. The resulting mixture was neutralized with 0.03 ml of acetic acid, diluted with 10% methanol/chloroform solution, filtered and concentrated in vacuo. The resulting compound was purified by Silica gel column chromatography with a solvent mixture mixed with EtOAc and methanol (5:2) as an eluant to give 11 mg of N-hydroxy-3-(1-methyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-propionamide (2h) (yield: 59%).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:29][C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36]C)=[O:35])=[CH:32][CH:31]=2)[C:7](/[CH:10]=[C:11]2\[N:12]([CH2:22][C:23]3[N:24]=[C:25]([CH3:28])[S:26][CH:27]=3)[C:13](=[O:21])[N:14]([CH2:17][CH2:18][CH2:19][CH3:20])[C:15]\2=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].Cl.C([O-])(=O)C.[Na+]>O>[CH2:1]([C:5]1[N:6]([CH2:29][C:30]2[CH:31]=[CH:32][C:33]([C:34]([OH:36])=[O:35])=[CH:38][CH:39]=2)[C:7](/[CH:10]=[C:11]2\[N:12]([CH2:22][C:23]3[N:24]=[C:25]([CH3:28])[S:26][CH:27]=3)[C:13](=[O:21])[N:14]([CH2:17][CH2:18][CH2:19][CH3:20])[C:15]\2=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(/C=C2/C(=O)N(CCCC)C(=O)N2Cc2csc(C)n2)n1Cc1ccc(C(=O)OC)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCCCc1ncc(/C=C2/C(=O)N(CCCC)C(=O)N2Cc2csc(C)n2)n1Cc1ccc(C(=O)O)cc1

Procedure:
A mixture of methyl Z-4-[[2-butyl-5-[[1-butyl-3-[(2-methyl-4-thiazolyl)methyl]-2,5dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoate (0.428 g, 0.65 mmol) and 2N HCl (12 mL) is refluxed for 1 hour in which time all the solid dissolved. Solvents are removed in vacuo and the mixture is evaporated from ethanol (5 mL) three times. The solid that results is treated with 5% aqueous sodium acetate (10 mL) and water (10 mL) to precipitate a gummy solid which is dissolved in methylene chloride (30 mL). The organic layer is dried over Na2SO4 and then evaporated in vacuo. The residue is recrystallized from hot ethyl acetate/hexane.
Reaction SMILES: [ClH:1].[CH:2]1([NH:5][CH2:6][CH2:7][NH:8][C:9]([N:11]2[CH2:16][CH2:15][N:14]3[C:17](=[O:32])[O:18][C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:13]3[CH2:12]2)=[O:10])[CH2:4][CH2:3]1.[CH2:33](N(CC)CC)[CH3:34].C(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[ClH:1].[CH:2]1([N:5]([CH2:33][CH3:34])[CH2:6][CH2:7][NH:8][C:9]([N:11]2[CH2:16][CH2:15][N:14]3[C:17](=[O:32])[O:18][C:19]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:13]3[CH2:12]2)=[O:10])[CH2:4][CH2:3]1
Reactant: O=C(NCCNC1CC1)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Reactant: CCN(CC)CC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: Cl
Solvent: O
Solvent: ClCCCl
Product: CCN(CCNC(=O)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1)C1CC1
Temperature: 25 °C
Reaction time: 13 h
Yield: 33.7 %

Procedure:
To a solution of N-[2-(cyclopropylamino)ethyl]-tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazine-7(1H)-carboxamide hydrochloride (0.15 g, 0.33 mmol), triethylamine (67 mg, 0.66 mmol) and 90% acetaldehyde (0.040 mL, 0.64 mmol) in 1,2-dichloroethane (5 mL) was added sodium triacetoxyborohydride (0.14 g, 0.66 mmol), and the mixture was stirred at room temperature for 13 hours. The reaction solution was diluted with water and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. The solid was filtered off, and the filtrate was concentrated. The residue was purified with amino silica gel column chromatography (hexane:ethyl acetate=1:1 to ethyl acetate) and concentrated. A 4 M hydrogen chloride/ethyl acetate solution (5 mL) was added thereto, and then concentrated. The residue was crystallized from diethyl ether to obtain the title compound (54 mg, yield 34%).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11][C:10]3[N:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[CH3:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29].C(N(CC)CC)C>ClCCl>[N:19]1[C:10]2[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=4[CH3:25])=[CH:24][CH:23]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Sc3ncccc32)cc1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3Sc3ncccc32)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 5 mmol of 5,6-dihydro-5-(4-aminobenzoyl)pyrido[2,3-b][1,4]benzothiazepine, 5.5 mmol of 2-methylbenzoyl chloride and 10 mmol of triethylamine in 15 ml of dichloromethane is stirred at room temperature for 16 hours. The mixture is diluted with 50 ml of dichloromethane and the solution washed with 20 ml each of H2O, 1M citric acid, NaHCO3, brine and dried (Na2SO4). The solvent is removed under vacuum to give a solid. The solid is purified by chromatography on silica gel with ethyl acetate-hexane as solvent to give the product as a solid.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][C:15]([OH:17])=[O:16])=[O:7])([CH3:4])[CH3:3].[CH3:18]N(C=O)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CO>[Cl-].[Na+].O>[CH3:18][O:16][C:15](=[O:17])[CH2:14][C@@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13][N:8]1[C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: COC(=O)C[C@@H]1CCCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95 %

Procedure:
Into a 250 ml round bottom flask ((2S)-1-{[(1,1-dimethylethyl)oxy]carbonyl}-2-piperidinyl)acetic acid (1.00 g, 4.11 mmol), DMF (25 ml), D1PEA (2.15 ml, 12.33 mmol) and TBTU (1.98 g, 6.17 mmol) were added. The mixture was stirred at rt for 20 min and a brown colour was formed. After this time MeOH (0.25 ml, 6.17 mmol) was added and the resulting solution stirred at rt for 30 min. Then it was transferred into e separatory funnel containing brine (20 ml) and extracted with EtOAc (20 ml×2), the combined organic layers were washed with water/ice (5×20 ml). The organic layer was dried (Na2SO4), filtered and concentrated. The crude obtained was purified by column chromatography (Biotage SP1, Cy-EtOAc from 100/0 to 85/15). Collected fractions gave the title compound (1.01 g, 3.92 mmol, 95% yield) as a colorless oil. 1H-NMR (500 MHz, CDCl3) δ(ppm): 4.67-4.75 (m, 1H), 3.96-4.05 (m, 1H), 3.67 (s, 3H), 2.79 (t, 1H), 2.61 (dd, 1H), 2.53 (dd, 1H), 1.60-1.70 (m, 6H), 1.46 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:5]2[O:9][C:8]([C:10]([N:12]([CH3:14])[CH3:13])=[O:11])=[CH:7][C:6]=2[CH:15]=1.Br[CH2:23][CH2:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([C:34](=[O:36])[CH3:35])[CH2:29][CH2:28]2>>[C:34]([N:30]1[C:31]2[C:27](=[CH:26][C:25]([CH2:24][CH2:23][N:19]3[CH2:20][CH2:21][N:16]([C:4]4[C:5]5[O:9][C:8]([C:10]([N:12]([CH3:14])[CH3:13])=[O:11])=[CH:7][C:6]=5[CH:15]=[C:2]([F:1])[CH:3]=4)[CH2:17][CH2:18]3)=[CH:33][CH:32]=2)[CH2:28][CH2:29]1)(=[O:36])[CH3:35]
Reactant: CC(=O)N1CCc2cc(CCBr)ccc21
Reactant: CN(C)C(=O)c1cc2cc(F)cc(N3CCNCC3)c2o1
Product: CC(=O)N1CCc2cc(CCN3CCN(c4cc(F)cc5cc(C(=O)N(C)C)oc45)CC3)ccc21

Procedure:
The compound was prepared according to the procedure disclosed in Example 50 starting from 5-fluoro-N,N-dimethyl-7-(piperazin-1-yl)benzofuran-2-carboxamide (0.10 g, 0.35 mmol) (Example 50g) and 1-(5-(2-bromoethyl)indolin-1-yl)ethanone (0.13 g, 0.49 mmol) (Example 49b). The product was purified by preparative HPLC to give the title compound.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:12][CH:11]=2)=[O:7])[CH3:4].Cl[CH2:23][C:24]#[N:25].O>CN(C=O)C>[CH2:3]([O:5][C:6]([C:8]1[N:9]([CH2:23][C:24]#[N:25])[C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([O:17][C:18]([F:21])([F:19])[F:20])=[CH:12][CH:11]=2)=[O:7])[CH3:4]
Reactant: N#CCCl
Reactant: CCOC(=O)c1cc2cc(OC(F)(F)F)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2cc(OC(F)(F)F)ccc2n1CC#N
Temperature: 75 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a solution of sodium hydride (0.58 g in DMF (12 mL) at 0° C. was slowly added a solution of 5-trifluoromethoxy-1H-indole-2-carboxylic acid ethyl ester (2.64 g) in DMF (12 mL) keeping the temperature below 7.5° C. After gas evolution ceased, chloroacetonitrile was added, and the reaction mixture was stirred for 2 hours at 75° C. After allowing cooling down, water was added, and the reaction mixture was extracted with ethyl acetate. The combined organic phases were washed with brine then dried with magnesium sulfate, concentrated in vacuo and purified by column chromatography to yield the title compound (2.3 g, 76%). MS (EI): 312.1 (M+).
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([N:8]=[C:9](N)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.N([O-])=O.[Na+].[ClH:16]>O.O.O.[Cu](Cl)Cl>[Br:1][C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:16])[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1nc2c(Br)cccn2n1
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Clc1nc2c(Br)cccn2n1
Reaction time: 18 h

Procedure:
To a cooled, stirred suspension of 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (0.961 g, 4.51 mmol) and copper(II)chloride dihydrate (0.20 g, 1.2 mmol) in 12 M of hydrochloric acid (10.0 mL) at 5° C. was added dropwise a solution of sodium nitrite (0.37 g, 5.4 mmol) in water (2 mL). Gentle gas evolution was noted. The mixture was stirred for 30 minutes at 5° C. then at room temperature for 18 hours. The yellow mixture was diluted with water (80 mL) and the resulting precipitate was filtered, rinsed with water and dried in-the-air. 8-Bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine was isolated as a pale yellow solid (0.947 g, 90%) and was used without further purification. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.98 (d, J=6.9 Hz, 1H), 8.10 (d, J=7.8 Hz, 1H), 7.22 (t, J=7.0 Hz, 1H). MS=232, 234, 236 (MH)+.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([O:22][CH3:23])[C:14](Br)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)Cl.[Br-].[CH2:29]([Zn+])[CH2:30][CH3:31]>C1COCC1.[Cu]I>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([O:22][CH3:23])[C:14]([CH2:29][CH2:30][CH3:31])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1OC
Reactant: CCC[Zn+]
Agent: [Cu]I
Agent: [Br-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCc1ccc(CS(=O)(=O)c2ccccc2)c(C(=O)OCC)c1OC
Temperature: 160 °C

Procedure:
A mixture of ethyl 6-(benzenesulphonylmethyl)-3-bromo-2-methoxybenzoate (Intermediate 61, 0.1 g), palladium chloride dppf adduct with DCM (0.01 g), copper (I) iodide (0.003 g) and n-propyl zinc bromide (0.5M solution in THF, 0.96 ml) in THF (0.5 ml) was stirred and heated in the microwave at 160° C. for 10 minutes. After cooling, the mixture was filtered and the filtrate was evaporated to dryness. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-60% to give ethyl 6-(benzenesulphonylmethyl)-2-methoxy-3-propylbenzoate (0.034 g) as a clear gum.