Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.CCN(C(C)C)C(C)C.[NH2:21][C:22]1[CH:34]=[CH:33][C:25]2[O:26][C:27]([CH3:32])([CH3:31])[C:28](=[O:30])[NH:29][C:24]=2[CH:23]=1>CS(C)=O.C(OC(=O)C)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:34]=[CH:33][C:25]3[O:26][C:27]([CH3:31])([CH3:32])[C:28](=[O:30])[NH:29][C:24]=3[CH:23]=2)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Reactant: CC1(C)Oc2ccc(N)cc2NC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC1(C)Oc2ccc(Nc3nc(Cl)nc4[nH]ccc34)cc2NC1=O
Temperature: 100 °C
Yield: 48.5 %

Procedure:
To a solution of 2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine (0.056 g, 0.30 mmol) in dimethylsulfoxide (1 mL) was added DIPEA (0.12 mL, 0.60 mmol) and 6-amino-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (0.085 g, 0.44 mmol). After heating at 100° C. for 15 h, the mixture was diluted with ethylacetate and sequentially washed with saturated NaHCO3 and brine. The organic extracts were dried over Na2SO4 and concentrated to give 6-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (0.05 g).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH:20]=[C:19]([O:21][CH2:22][C@@H:23]([NH:25][C:26](=[O:32])[O:27][C:28](C)(C)C)[CH3:24])[CH:18]=[CH:17][C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:33])[CH2:3][CH2:2]1.ClC(OC)=O>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH:20]=[C:19]([O:21][CH2:22][C@@H:23]([NH:25][C:26](=[O:32])[O:27][CH3:28])[CH3:24])[CH:18]=[CH:17][C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:33])[CH2:2][CH2:3]1
Reactant: C[C@@H](COc1ccc2nc(-c3ccc(OCC4CC4)c(F)c3)oc2c1)NC(=O)OC(C)(C)C
Agent: COC(=O)Cl
Product: COC(=O)N[C@@H](C)COc1ccc2nc(-c3ccc(OCC4CC4)c(F)c3)oc2c1

Procedure:
Using tert-butyl ((2S)-1-((2-(4-(cyclopropylmethoxy)-3-fluorophenyl)-1,3-benzoxazol-6-yl)oxy)propan-2-yl)carbamate and methyl chloroformate, and in the same manner as in Example 10, the title compound was obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:14]2[CH:19]=[CH:18][C:17]([N:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=2)(C)[C:10](O)=O)=[CH:5][CH:4]=1.[Pb](=O)=O>C1C=CC=CC=1>[CH3:22][N:20]([CH3:21])[C:17]1[CH:16]=[CH:15][C:14]([C:9]([C:6]2[CH:5]=[CH:4][C:3]([N:2]([CH3:1])[CH3:23])=[CH:8][CH:7]=2)=[CH2:10])=[CH:19][CH:18]=1
Reactant: CN(C)c1ccc(C(C)(C(=O)O)c2ccc(N(C)C)cc2)cc1
Agent: O=[Pb]=O
Solvent: c1ccccc1
Product: C=C(c1ccc(N(C)C)cc1)c1ccc(N(C)C)cc1
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
Into 400 ml of benzene was dissolved 10 g of 2,2-bis(4-dimethylaminophenyl)propionic acid. Thereto was added 10 g of lead dioxide and the mixture was reacted at room temperature with stirring for 30 minutes. The lead compound was removed by filtration and the benzene layer was washed with 200 ml of 5% aqueous solution of sodium hydroxide. Benzene was removed by distillation at a reduced pressure. The residue was recrystallized from methanol to obtain 6.3 g (yield 74%) of 1,1-bis(4-dimethylaminophenyl)ethylene, having a melting point of 123°~123.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:22]=[C:21]3[C:16]([CH:17]=[CH:18][CH:19]=[N:20]3)=[C:15](OS(C(F)(F)F)(=O)=O)[N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[NH2:31][CH2:32][C:33]1[O:37][C:36](=[O:38])[NH:35][N:34]=1.C(NC(C)C)(C)C>CC(N(C)C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:22]=[C:21]3[C:16]([CH:17]=[CH:18][CH:19]=[N:20]3)=[C:15]([NH:31][CH2:32][C:33]3[O:37][C:36](=[O:38])[NH:35][N:34]=3)[N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: NCc1n[nH]c(=O)o1
Reactant: COc1cc(-c2cc3ncccc3c(OS(=O)(=O)C(F)(F)F)n2)cc(OC)c1OC
Solvent: CC(C)NC(C)C
Solvent: CC(=O)N(C)C
Product: COc1cc(-c2cc3ncccc3c(NCc3n[nH]c(=O)o3)n2)cc(OC)c1OC
Temperature: 70 °C
Reaction time: 6 h

Procedure:
104 mg Trifluoro-methanesulfonic acid 7-(3,4,5-trimethoxy-phenyl)-[1,6]naphthyridine-5-yl ester (6.1), 30 mg (0.261 mmol) of 5-aminomethyl-3H-[1,3,4]oxadiazole-2-one (2.33) and 0.132 mL (0.782 mL) N,N-diisopropylamine were placed in dimethylacetamide at ambient temperature. The reaction was then heated to 70° C. where it was maintained overnight and then cooled to ambient temperature. After this time 0.132 mL (0.782 mL) N,N-diisopropylamine was added and the reaction was heated to 90° C. where it was left for 6 h. The reaction was then cooled to ambient temperature and partitioned between water and ethyl acetate. The organic layer was separated and the aqueous phase was extracted with additional ethyl acetate (×2). The combined organic fractions were dried over sodium sulfate, filtered and the solvent was removed from the filtrate under reduced pressure. Purification by silica gel chromatography (ethyl acetate/methanol: 100:0 to 90:10) and then a second purification by silica gel chromatography (dichloromethane/methanol: 100:0 to 95:5) gave the title compound.
Reaction SMILES: [Br:1]Br.[O:3]([CH2:10][C:11]([NH:13][CH:14]1[CH2:17][N:16]([CH:18]([C:35]([CH3:37])=[CH2:36])[C:19]([O:21][CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[C:15]1=[O:38])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(=O)(O)[O-].[Na+]>O1CCCC1.O>[O:3]([CH2:10][C:11]([NH:13][CH:14]1[CH2:17][N:16]([C:18](=[C:35]([CH3:37])[CH2:36][Br:1])[C:19]([O:21][CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20])[C:15]1=[O:38])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C=C(C)C(C(=O)OC(c1ccccc1)c1ccccc1)N1CC(NC(=O)COc2ccccc2)C1=O
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(CBr)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1CC(NC(=O)COc2ccccc2)C1=O
Reaction time: 0.33 h
Yield: 77 %

Procedure:
To a solution of 4.1 ml of 1,5-diazabicyclo[5.4.0]undecene-5 (DBU) and 1.6 ml of bromine in 90 ml of tetrahydrofuran (THF) at -78° was added 4.36 g (9.0 mmol) of benzhydryl 2-(3-phenoxyacetamido-2-oxoazetidin-1-yl)-3-methyl-3-butenoate in 20 ml of THF. The reaction mixture was placed in an ice bath and stirred for 20 minutes. Sodium bisulfite (3 g) in 30 ml of water was then added. After 10 min. the THF was removed under reduced pressure. Ethyl acetate was added to the resulting aqueous mixture. The organic layer was washed with dilute acid, sodium bicarbonate solution and brine (2X), dried, and evaporated in vacuo to provide 3.6 g (77%) of the title product: nmr (CDCl3) δ 2.13 and 2.28 (s, 3, CH3), 4.2 (m, 2, --CH2Br), 3.67 (m, 2, C4 --H), 4.97 (m, 1, C3 --H), 4.50 (s, 2, side chain CH2), and 7.2 (b, ArH).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:19](OCC)=[O:20])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH:19]=[O:20])=[N:11][C:12]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ccc(-c2ccccc2)c(-c2ccccc2)n1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: O=Cc1ccc(-c2ccccc2)c(-c2ccccc2)n1
Reaction time: 1 h

Procedure:
General Procedure L. To a solution of ethyl 5,6-diphenylpyridine-2-carboxylate (Compound 21, 145 mg, 0.48 mmol) in CH2Cl2 (5 ml) at −78° C. was added DIBAL-H (0.72 ml, 0.72 mmol, 1.0 M in Toluene) and the mixture was stirred between −78° C. and −60° C. for 1 hour under argon. The reaction was quenched with aq, NH4Cl, diethyl ether and 400 mg Celite were added, and the mixture was stirred at room temperature 30 min. The solid was filtered off and rinsed with ether, and the combined filtrate was concentrated in vacuo, and the residue was purified by column chromatography (silica gel, 15% ethyl acetate in hexane) to produce the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][N:14]([CH3:22])[C:15]([C@H:17]2[CH2:21][CH2:20][CH2:19][O:18]2)=[O:16])[N:12]=1)(C)(C)C.C(O)(C(F)(F)F)=O>>[NH2:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][N:14]([CH3:22])[C:15]([C@H:17]2[CH2:21][CH2:20][CH2:19][O:18]2)=[O:16])[N:12]=1
Reactant: CN(Cc1csc(NC(=O)OC(C)(C)C)n1)C(=O)[C@H]1CCCO1
Solvent: O=C(O)C(F)(F)F
Product: CN(Cc1csc(N)n1)C(=O)[C@H]1CCCO1

Procedure:
The product from Step 1 was treated with TFA to cleave the BOC group (Method 1) to afford (R)-tetrahydro-furan-2-carboxylic acid (2-amino-thiazol-4-ylmethyl)-methyl-amide.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[CH3:27][C:28]1[CH:32]=[C:31]([C:33](O)=[O:34])[O:30][N:29]=1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:33]([C:31]5[O:30][N:29]=[C:28]([CH3:27])[CH:32]=5)=[O:34])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: Cc1cc(C(=O)O)on1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: Cc1cc(C(=O)N[C@H]2CC[C@H](CCN3CCC(c4cccc5c4CCO5)CC3)CC2)on1

Procedure:
The title compound, off-white solid (89 mg, 82%), MS (ISP) m/z=438.3 [(M+H)+], mp 215° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 3-methyl-isoxazole-5-carboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][S:13]([C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[C:18]([N+:23]([O-:25])=[O:24])[C:17]=1Cl)(=[O:15])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[OH2:29]>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][S:13]([C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[C:18]([N+:23]([O-:25])=[O:24])[C:17]=1[OH:29])(=[O:15])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: O
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)NCCCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Yield: 58.1 %

Procedure:
Following the general hydrolysis procedure outlined in example 15, N-[3-(tert-butoxycarbonylamino)propyl]-2,6-dichloro-3-nitrobenzenesulfonamide (450 mg, 1.05 mmol), 60% NaH (168 mg, 4.2 mmol) and water (21 μL, 1.15 mmol) were reacted to form the desired product (250 mg, 58%). EI-MS (m/z) 408.1, 410.1 (M-H)−.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[NH:21][C:22]4[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=4)=[CH:15][CH:14]=3)[N:10]=[C:9]([NH:29][CH:30]3[CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31]3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:32]1[CH2:31][CH:30]([NH:29][C:9]2[N:8]=[C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:12]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:20]([NH:21][C:22]4[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=4)=[O:28])=[CH:17][CH:18]=3)[N:10]=2)[CH2:33]1
Reactant: CC(C)(C)OC(=O)N1CC(Nc2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CCOCC3)n2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccncc1)Nc1ccc(-c2nc(NC3CNC3)nc(N3CCOCC3)n2)cc1
Reaction time: 24 h

Procedure:
To a stirred solution of tert-butyl 3-[(4-morpholin-4-yl-6-{4-[(pyridine-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)amino]azetidine-1-carboxylate 40 mg (0.073 mmoles) in DCM, (20 ml) TFA (1.5 ml) was added at room temperature and stirred for 24 hours. At the end, reaction mixture was concentrated and purified by Gilson HPLC, using ACN/water and TFA. Yield: 26 (81%); (M+H) 448.5.
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-])=O)=[CH:5][CH:4]=[C:3]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:2]=1.CS(O)(=O)=O>O.CO.[Pd]>[CH:17]1[C:16]([NH2:19])=[CH:15][CH:14]=[C:13]([S:10]([C:3]2[CH:2]=[CH:1][C:6]([NH2:7])=[CH:5][CH:4]=2)(=[O:12])=[O:11])[CH:18]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: O
Solvent: CO
Product: Nc1ccc(S(=O)(=O)c2ccc(N)cc2)cc1
Temperature: 50 °C
Reaction time: 0.29 h
Yield: 69.5 %

Procedure:
In autoclave at room temperature 4,4′-dinitrodiphenylsulfone (0.0649 mol, 20.0 g), 5% palladium on 50% wet carbon (1.4 g), 70% methanesulfonic acid in water (0.130 mol, 17.8 g), water (10 ml) and methanol (70 ml) are loaded. The mixture is left to react under hydrogen pressure (4-5 atm) at a temperature of 55-60° C. for about 8 hours. The mixture is filtered on a Perlite layer washing with methanol (10 ml for 2 times), subsequently with water (80 ml). The solution is concentrated under reduced volume to remove the organic phase. The aqueous phase is extracted with ethyl acetate (50 ml for 3 times) and the organic washings are discarded. Discolouring carbon (1.0 g) is added under vigorous stirring and after 15-20 minutes the mixture is filtered on a Perlite layer. To the aqueous solution heated at about 50° C. a aqueous solution of 30% sodium hydroxide is slowly added to reach a pH higher than 10. After about 30 minutes the mixture is cooled to 0-5° C. and then filtered, washing the solid with water cooled at 0-5° C. (20 ml for three times). After oven-drying at 50° C., 11.2 g of crude Dapsone are obtained that are then crystallized from a mixture of isopropanol (35 ml) and water (25 ml) to obtain 10.2 g of dry Dapsone, having a chemical purity evaluated by HPLC equal to about 98.5%.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:15]2[CH:16]=[N:17][CH:18]=[C:19]([O:20][CH:21]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)[C:14]=2[C:13]2[CH:34]=[C:35]([Br:38])[CH:36]=[N:37][C:12]1=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O.ClCCl>[CH2:1]([O:8][C:9]([N:11]1[C:15]2[CH:16]=[N:17][CH:18]=[C:19]([O:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:14]=2[C:13]2[CH:34]=[C:35]([Br:38])[CH:36]=[N:37][C:12]1=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cncc3c2c2cc(Br)cnc2n3C(=O)OCc2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(OCc1ccccc1)n1c2cncc(OC3CCNCC3)c2c2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41.6 %

Procedure:
A solution of 3-bromo-5-(1-tert-butoxycarbonyl-piperidin-4-yloxy)dipyrido[2,3-b;4′,3′-d]pyrrole-9-carboxylic acid benzyl ester (0.34 g, 0.59 mmol) in triflouroacetic acid (2 mL) and dichloromethane (4 mL) was allowed to stir at ambient temperature for 15 minutes. The solvent was evaporated and the resultant residue was treated with saturated sodium hydrogen carbonate solution (20 mL) and extracted with dichloromethane (3×30 mL). The combined organic phase was dried (Na2SO4), filtered and evaporated to afford a residue. The resultant residue was purified by flash chromatography (silica, 12 g cartridge, ISCO, 0-10% methanol in dichloromethane then 10% 2M NH3 in methanol in dichloromethane). The appropriate fractions were combined and evaporated to afford the title compound as a yellow solid (118 mg, 42%). LCMS (Method B): RT=3.13 min, M+H+=481/483. 1H NMR (400 MHz, CDCl3): 9.22 (s, 1H), 8.77 (d, J=2.3 Hz, 1H), 8.62 (d, J=2.4 Hz, 1H), 8.31 (s, 1H), 7.60-7.59 (m, 2H), 7.40-7.40 (m, 3H), 5.63 (s, 2H), 4.86-4.82 (m, 1H), 3.26-3.25 (m, 2H), 2.95-2.94 (m, 2H), 2.29-2.25 (m, 2H), 1.99-1.97 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].CC([O-])=O.[Na+].[Br:17]Br>CC(O)=O>[Br:17][C:10]1[C:2]([CH3:1])=[C:3]([C:7]([CH3:11])=[CH:8][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: BrBr
Reactant: Cc1cccc(C)c1C(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1ccc(Br)c(C)c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,6-dimethylbenzoic acid (25.00 g, 166 mmol) in HOAc (432 mL) was added NaOAc (16.39 g, 200 mmol) followed by bromine (11.2 mL, 216 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was poured onto ice water (800 mL) and stirred for 20 minutes. The solid was filtered off, washed with H2O and dried at 50° C. under vacuum to give INT 34.
Reaction SMILES: Br[C:2]1[C:3](=[O:13])[N:4]([CH2:8][CH2:9][CH2:10][CH2:11][Cl:12])[CH:5]=[CH:6][CH:7]=1.[F:14][C:15]1[N:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:12][CH2:11][CH2:10][CH2:9][CH2:8][N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:18]2[CH:19]=[N:20][C:15]([F:14])=[CH:16][CH:17]=2)[C:3]1=[O:13]
Reactant: OB(O)c1ccc(F)nc1
Reactant: O=c1c(Br)cccn1CCCCCl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=c1c(-c2ccc(F)nc2)cccn1CCCCCl
Yield: 82 %

Procedure:
The title compound was prepared in 82% yield using a similar procedure as set out earlier in Prep8 starting from 3-bromo-1-(4-chlorobutyl)-2(1H)-pyridinone (Prep7) (400 mg, 1.51 mmol), (6-fluoro-3-pyridinyl)boronic acid (commercial Alfa Aesar) (426 mg, 3.02 mmol), K2CO3 (627 mg, 4.54 mmol), triphenylphosphine (200 mg, 0.75 mmol) and palladium (II) acetate (68 mg, 0.30 mmol) dissolved in dioxane (5 ml).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N:10]2[CH2:16][CH2:15][CH2:14][N:13]([CH2:17][C:18]3[S:22][C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:20][CH:19]=3)[CH2:12][CH2:11]2)=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1.[N+]([C:32]1[CH:33]=C(S([O-])(=O)=O)C=C[CH:37]=1)([O-])=O.[Na+].OCC(CO)O.[OH-].[Na+]>CS(O)(=O)=O.O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:4]([N:10]2[CH2:16][CH2:15][CH2:14][N:13]([CH2:17][C:18]3[S:22][C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:20][CH:19]=3)[CH2:12][CH2:11]2)=[C:5]2[C:6]([CH:37]=[CH:32][CH:33]=[N:9]2)=[CH:7][CH:8]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Reactant: COc1cccc(N)c1N1CCCN(Cc2cnc(-c3ccccc3)s2)CC1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: OCC(O)CO
Product: COc1ccc2cccnc2c1N1CCCN(Cc2cnc(-c3ccccc3)s2)CC1
Temperature: 130 °C
Yield: 87.2 %

Procedure:
A mixture of 3-methoxy-2-[4-(2-phenylthiazol-5-ylmethyl)-[1,4]diazepan-1-yl]-phenylamine (210 mg, 0.53 mmol, 1 equiv), sodium 3-nitrophenylsulfonate (78 mg, 0.65 equiv), FeSO4.7H2O (7.5 mg, 0.05 equiv) and glycerol (122 mg, 2.5 equiv) in 2 mL of methanesulfonic acid was heated at 130° C. for 2 hours. After cooling down to room temperature, the mixture was diluted with water, neutralized with 10 N NaOH to pH ˜10. Ethyl acetate was added and the mixture was filtered through celite. The organic layer was subjected to reverse phase HPLC purification. The combined fractions with the desired product were evaporated to remove acetonitrile, treated with saturated sodium bicarbonate and extracted with ethyl acetate to give the pure title compound (130 mg, 56%). 1H NMR (400 MHz, CDCl3) δ 8.85 (dd, 1H, J=4.1, 2 Hz), 8.05 (dd, 1H, J=7.8, 2 Hz), 7.95 (d, 1H, J=2 Hz), 7.90 (d, 1H, J=2 Hz), 7.50 (d, 1H, 8.6 Hz), 7.42-7.35 (m, 3H), 7.30-7.20 (m, 3H), 7.20 (dd, 1H, J=7.8, 4.1 Hz), 4.08 (s, 2H), 3.85 (s, 3H), 3.62-3.50 (m, 4H), 3.10-3.00 (m, 2H), 3.00-2.80 (m, 2H), 2.20-2.00 (m, 2H). MS (ES) m/z 431.1 (M+H+).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([NH:12][CH:13]([C:22]1[N:23](C(OC(C)(C)C)=O)[CH:24]=[C:25]([CH2:27][C:28]([CH3:32])([CH3:31])[CH2:29][CH3:30])[N:26]=1)[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:47][N:48]([CH3:53])[S:49](Cl)(=[O:51])=[O:50]>CO.C(Cl)Cl.O>[Br:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH:13]([NH:12][C:10](=[O:11])[O:9][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:22]2[N:23]([S:49]([N:48]([CH3:53])[CH3:47])(=[O:51])=[O:50])[CH:24]=[C:25]([CH2:27][C:28]([CH3:31])([CH3:32])[CH2:29][CH3:30])[N:26]=2)=[CH:20][CH:19]=1
Reactant: CCC(C)(C)Cc1cn(C(=O)OC(C)(C)C)c(C(Cc2ccc(Br)cc2)NC(=O)OCc2ccccc2)n1
Reactant: CN(C)S(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(Cc2ccc(Br)cc2)NC(=O)OCc2ccccc2)n1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Hydrogen chloride (4 M in 1,4-dioxane) (2 mL, 8 mmol) was added to an ambient temperature solution of tert-butyl 2-[1-{[(benzyloxy)carbonyl]amino}-2-(4-bromophenyl)ethyl]-4-(2,2-dimethylbutyl)-1H-imidazole-1-carboxylate (for synthesis see Example 37) (600 mg, 1.03 mmol) in methanol (4 mL). After stirring at 70° C. for 1 h, volatiles were removed in vacuo. The residue was partitioned between methanol/ethyl acetate and 10% aqueous sodium hydroxide. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Triethylamine (0.43 mL, 3.09 mmol) followed by dimethylsulfamoyl chloride (0.22 mL, 2.06 mmol) were added to an ambient temperature solution of the crude residue in methylene chloride (10 mL). After stirring at ambient temperature overnight, the reaction mixture was diluted with water and extracted with ethyl acetate and methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo to afford benzyl {2-(4-bromophenyl)-1-[1-[(dimethylamino)sulfonyl]-4-(2,2-dimethylbutyl)-1H-imidazol-2-yl]ethyl}carbamate which was used in the subsequent step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:20][CH3:21])=[CH:11][C:12]([N+:17]([O-])=O)=[C:13]([CH:16]=1)[C:14]#[N:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.S(S([O-])=O)([O-])=O.[Na+].[Na+].[OH-].[Na+]>ClCCl.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[NH2:17][C:12]1[CH:11]=[C:10]([O:20][CH3:21])[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: COc1cc([N+](=O)[O-])c(C#N)cc1OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S([O-])S(=O)[O-]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COc1cc(N)c(C#N)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-benzyloxy-4-methoxy-2-nitro-benzonitrile (35.0 g, 0.12 mol) in dichloromethane (500 ml) was added tetra-n-butylammonium chloride (20.3 g, 0.074 mol) followed by a solution of sodium dithionite hydrate (118.0 g, 0.61 mol) in H2O (400 ml) and the mixture was stirred vigorously for 2 hours at room temperature. A further quantity of sodium dithionite hydrate (47.2 g) was then added and stirring continued for 1 hour. The reaction mixture was then basified with 2N aqueous sodium hydroxide and the phases separated. The aqueous layer was extracted twice more with dichloromethane and the combined organic layers dried over MgSO4 and concentrated under reduced pressure to a volume of 60 ml. Treatment with excess ethereal hydrogen chloride led to the precipitation of an orange solid which was washed with diethyl ether and then dissolved in a mixture of dichloromethane and 2N aqueous sodium hydroxide. The phases were separated and the organic layer concentrated under reduced pressure and then dissolved in ethyl acetate and passed through a 5 cm plug of silica gel, eluting with ethyl acetate. On evaporation and drying under reduced pressure, the subtitle compound was obtained as a yellow solid (26.7 g, 85%). Rf 0.76 (0.880 aqueous ammonia:methanol:dichloromethane 1:10:90, v/v). MS m/z 255 (MH)+.
Reaction SMILES: [N:1]1([CH2:6][C:7]#[C:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1>[Pd]>[N:1]1([CH2:6][CH2:7][CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C1CCc2cc(C#CCn3ccnc3)ccc2N1
Agent: [Pd]
Product: O=C1CCc2cc(CCCn3ccnc3)ccc2N1

Procedure:
A solution of 502 mg of 6-[3-(imidazol-1-yl)prop-1-yn-1-yl]-3,4-dihydrocarbostyril was stirred under hydrogen in the presence of 200 mg of a 10% palladium on charcoal catalyst as shown in Example 8, and the product was isolated in a similar fashion, giving 6-[3-(imidazol-1-yl)propyl]-3,4-dihydrocarbostyril, m.p. 139°-141° C.