Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9]3[C:15](=O)[N:14]([CH3:17])[C:13]4[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=4[O:11][C:10]=3[C:5]2=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:28][N:29]([CH3:34])[CH2:30][CH2:31][CH2:32][NH2:33]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[N:8][C:9]3[C:10]=2[O:11][C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[N:14]([CH3:17])[C:15]=3[NH:33][CH2:32][CH2:31][CH2:30][N:29]([CH3:34])[CH3:28])[CH:7]=1
Reactant: CN1C(=O)c2[nH]c3cc(Cl)ccc3c2Oc2ccccc21
Reactant: CN(C)CCCN
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CN(C)CCCNC1=C2N=c3cc(Cl)ccc3=C2Oc2ccccc2N1C

Procedure:
In the same way as described in example 1, 3-chloro-7-methyl-7H-indolo[3,2-b][1,5]benzoxazepine-6(5H)-one, phosphorous pentachloride and 3-dimethylaminopropylamine were reacted and the crude product recrystallized from acetonitrile for analysis, mp. 156°-7°.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([O:14]CC)=[O:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH2:17][CH2:18][S:19][C:3]1=2>Cl>[O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH2:17][CH2:18][S:19][C:3]1=2
Reactant: CCOC(=O)c1ccc2nc3c(c(=O)n2c1)SCC3
Agent: Cl
Product: O=C(O)c1ccc2nc3c(c(=O)n2c1)SCC3

Procedure:
A suspension of ethyl 3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxylate (5.0 g., 0.018 mol) in 2N hydrochloric acid (60 ml) is refluxed for 3 hours. The reaction mixture is cooled in an ice-bath. The precipitate is filtered, washed with water, with acetone and dried to give the product (3.5 g.), mp 325° C. (dec).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:24]([CH3:26])[CH3:25])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([O:16]CC1C=CC=CC=1)=[O:15])=[O:8])=[O:4].C1COCC1>CCCCCCC>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:24]([CH3:26])[CH3:25])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([OH:16])=[O:15])=[O:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)C(C)C
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
(S)-Benzyl 1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidine-2-carboxylate (40 g) and 5% Pd/alumina were charged to a Parr® reactor followed by THF (160 mL). The reactor was sealed and purged with nitrogen (6×20 psig) followed by a hydrogen purge (6×30 psig). The reactor was pressurized to 30 psig with hydrogen and agitated at room temperature for approximately 15 hours. The resulting slurry was filtered through a GF/F filter and concentrated to approximately 135 g solution. Heptane (120 mL) was added, and the solution was stirred until solids formed. After an addition 2-3 hours, additional heptane (240 mL) was added drop-wise, the slurry was stirred for approximately 1 hour, then filtered. The solids were dried to afford the title compound (S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidine-2-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.C([O:22][C:23]([C:25]1[N:30]2[C:31]([C:34](=[O:39])C(Cl)(Cl)Cl)=[CH:32][N:33]=[C:29]2[CH:28]=[CH:27][CH:26]=1)=O)C>C(#N)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:23](=[O:22])[C:25]3[N:30]4[C:31](=[CH:32][N:33]=[C:29]4[CH:28]=[CH:27][CH:26]=3)[C:34]2=[O:39])=[CH:4][CH:3]=1
Reactant: NCCc1ccc(N)cc1
Reactant: CCOC(=O)c1cccc2ncc(C(=O)C(Cl)(Cl)Cl)n12
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccc(CCn2c(=O)c3cccc4ncc(c2=O)n43)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.6 %

Procedure:
To a solution of 1.63 g (12.0 mmol) of 2-[4-(amino)phenyl]ethylamine and 1.68 g (13 mmol) of N,N-diisopropylethylamine in 40 ml of acetonitrile was added a solution of 3.50 g (10.0 mmol) of 5-ethoxycarbonyl-3-trichloroacetylimidazo[1,2-a]pyridine in 10 ml of acetonitrile. The mixture was stirred for one hour at room temperature. The resulting crystalline precipitates were collected by filtration, washed with acetonitrile and dried to afford 1.03 g of the desired compound (33.6%, a yellow crystals). The filtrate was concentrated. The residne was crystallized from acetonitrile-methylene chloride. Crystalline precipitatse were collected by filtration, washed with acetonitrile to afford 1.60 g of the desired compound (52.1%, a yellow crystals).
Reaction SMILES: [O-]CC.[Na+].[OH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:18])[N:14]([O:16][CH3:17])[CH3:15])=[CH:8][CH:7]=1.[CH3:19][O:20][C:21]1[CH:29]=[CH:28][C:24]([CH2:25][CH2:26]Br)=[CH:23][CH:22]=1>CN(C)C=O>[CH3:19][O:20][C:21]1[CH:29]=[CH:28][C:24]([CH2:25][CH2:26][O:5][C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:18])[N:14]([O:16][CH3:17])[CH3:15])=[CH:8][CH:7]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc(CCBr)cc1
Reactant: CON(C)C(=O)Nc1ccc(O)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CCOc2ccc(NC(=O)N(C)OC)cc2)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 28.5 %

Procedure:
Into a solution of 8.8 g of sodium ethoxide in 200 ml of N,N-dimethylformamide is added 27 g of N'-(4-hydroxyphenyl)-N-methoxy-N-methylurea. To the mixture is added dropwise a solution of 27 g of 4-methoxyphenethyl bromide in 100 ml of N,N-dimethylformamide. The mixture is then gradually heated to 100° C., kept at the same temperature for 5 hours and then poured into ice water. The precipitated crystals are filtered, washed with water, ethanol and ether in this order and air-dried. The product is recrystallized from ethanol to obtain 11.8 g of N'-[4-(4-methoxyphenethyloxy)phenyl]-N-methoxy-N-methylurea as white needles, M.P. 100°-101° C.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]([F:26])([F:25])[O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][CH2:17][C:16]3([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:15]2=[O:24])=[CH:10][CH:9]=1.[CH3:27][N:28]1[CH:32]=[C:31]([S:33](Cl)(=[O:35])=[O:34])[N:30]=[CH:29]1>>[CH3:27][N:28]1[CH:32]=[C:31]([S:33]([N:21]2[CH2:20][CH2:19][C:16]3([C:15](=[O:24])[N:14]([C:11]4[CH:12]=[CH:13][C:8]([O:7][C:6]([F:5])([F:25])[F:26])=[CH:9][CH:10]=4)[CH2:18][CH2:17]3)[CH2:23][CH2:22]2)(=[O:35])=[O:34])[N:30]=[CH:29]1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Solvent: CC(=O)O
Product: Cn1cnc(S(=O)(=O)N2CCC3(CCN(c4ccc(OC(F)(F)F)cc4)C3=O)CC2)c1

Procedure:
The title compound was prepared in analogy to example 180 step D from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one acetic acid salt (described in example 180 step C) and 1-methyl-1H-imidazole-4-sulfonyl chloride. Off-white solid. MS (ESI): 459.3 (MH+)
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]1[C:15]([C:16](Cl)=[O:17])=[C:14]([CH3:19])[N:13]=[C:8]12.[OH-].[NH4+:21]>>[C:16]([C:15]1[N:7]2[CH:6]=[CH:5][C:4]3[C:9]([C:8]2=[N:13][C:14]=1[CH3:19])=[CH:10][CH:11]=[CH:12][C:3]=3[Cl:2])(=[O:17])[NH2:21]
Reactant: Cc1nc2c3cccc(Cl)c3ccn2c1C(=O)Cl
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Product: Cc1nc2c3cccc(Cl)c3ccn2c1C(N)=O

Procedure:
To 28% ammonium hydroxide (50 ml) was added 7-chloro-3-chloroformyl-2-methylimidazo[2,1-a]isoquinoline hydrochloride (1.3 g) and the mixture was stirred under ice-cooling for 40 minutes. The resulting precipitate was collected by filtration, washed with water and recrystallized from a mixture of chloroform and methanol to give 3-carbamoyl-7-chloro-2-methylimidazo[2,1-a]isoquinoline (0.75 g).
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[C:14]([CH2:15][OH:16])=[CH:13][CH:12]=[CH:11][N:10]=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[CH3:17][S:18]([O:16][CH2:15][C:14]1[C:9]([Br:8])=[N:10][CH:11]=[CH:12][CH:13]=1)(=[O:20])=[O:19]
Reactant: OCc1cccnc1Br
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cccnc1Br
Reaction time: 1.5 h

Procedure:
Triethylamine (8.90 mL) is added to a round bottom flask containing a solution of (2-bromopyridin-3-yl)methanol (8 g, 42.55 mmol) in dichloromethane (212 mL) at 0° C., then methanesulfonyl chloride (3.95 mL) is added and the mixture is stirred at that temperature for 1.5 h. After that time the mixture is washed with water and organic layer is decanted, dried over magnesium sulfate and solvent evaporated under reduced pressure to yield 10.4 g of the title compound used without further purification. MS (m/z): 266, 268 (M+1; M+3).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:11]([C:12](=[O:14])[CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:15])=[O:4].[CH2:16](O)[CH:17]([OH:19])[CH3:18].C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[CH3:13][C:12]1([C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:15])[C:6]=2[NH:5][C:3](=[O:4])[CH2:2][Cl:1])[O:19][CH:17]([CH3:18])[CH2:16][O:14]1
Reactant: CC(=O)c1cccc(C)c1NC(=O)CCl
Reactant: CC(O)CO
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Product: Cc1cccc(C2(C)OCC(C)O2)c1NC(=O)CCl

Procedure:
N-chloroacetyl-2-methyl-6-acetylaniline (from Example 1), 4.51 g, 1,2-propanediol, 3.7 ml, and a dash of toluene sulfonic acid were combined in 50 ml toluene and refluxed. The distilled water by-product was collected in a Dean-Stark trap. After water ceased to distil, methylene chloride was added and the mixture was extracted successively with bicarbonate solution and water, then dried (MgSO4) and evaporated to yield 3.3 g brown oil. The oil was purified on a silica gel column (Hexane:ethyl acetate eluant) to yield the title product (Compound No. 2 in Table A).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:4]=1[O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.Br[CH:20]([CH3:25])[C:21]([O:23][CH3:24])=[O:22]>C(O)C>[Cl:2][C:3]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:4]=1[O:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH:20]([CH3:25])[C:21]([O:23][CH3:24])=[O:22])=[CH:11][CH:12]=1
Reactant: COC(=O)C(C)Br
Reactant: Oc1ccc(COc2ccc(Cl)cc2Cl)cc1
Agent: [Na]
Solvent: CCO
Product: COC(=O)C(C)Oc1ccc(COc2ccc(Cl)cc2Cl)cc1
Reaction time: 3 h

Procedure:
2.3 gm of sodium were dissolved in 100 ml of absolute ethanol, 26.9 gm of 4-(2,4-dichlorophenoxy-methyl)-phenol and 16.7 gm of methyl 2-bromo-propionate were added to the solution, and the mixture was boiled for 3 hours. Thereafter, the reaction solution was evaporated, and the residue was worked up as usual with water and chloroform, yielding 80% of theory of the desired compound named in the heading, which had a melting point of 64° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:26])[CH2:10][N:11]([CH2:22][C@H:23]([OH:25])[CH3:24])[C:12](=[O:21])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.CN(C1C=CC=CN=1)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>ClCCl>[CH3:45][S:46]([O:25][C@H:23]([CH3:24])[CH2:22][N:11]([C:12]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:21])[CH2:10][C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH3:26])(=[O:48])=[O:47]
Reactant: C[C@@H](O)CN(C[C@H](C)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H](CN(C[C@H](C)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a stirred solution of benzyl {(2S)-2-[(tert-butoxycarbonyl)amino]propyl}[(2R)-2-hydroxypropyl]carbamate (1.95 g, 5.32 mmol) and diisopropylethylamine (1.85 mL, 10.64 mmol) in anhydrous dichloromethane (110 mL) was added dimethylaminopyridine (135 mg) and methane sulfonyl chloride (0.535 mL, 6.92 mmol). The mixture was stirred at room temperature for 1 hour. Reaction was complete as determined by TLC. The reaction mixture was concentrated and purified using flash column chromatography. (1R)-2-([(benzyloxy)carbonyl]{(2S)-2-[(tert-butoxycarbonyl)amino]propyl}amino)-1-methylethyl methanesulfonate was obtained in 97.0% yield (2.29 g) as light yellow oil.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.CCN(CC)CC.[N:15]([CH2:18][CH2:19][OH:20])=[N+:16]=[N-:17]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[N:15]([CH2:18][CH2:19][O:20][C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])=[N+:16]=[N-:17]
Reactant: O=C1CCC(=O)O1
Reactant: [N-]=[N+]=NCCO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: [N-]=[N+]=NCCOC(=O)CCC(=O)O
Temperature: 40 °C

Procedure:
Succinic anhydride (23.0 g, 0.230 mol) was added into a three-neck round-bottom flask equipped with a condenser and a dropping funnel. Under nitrogen atmosphere and magnetic stirring, freshly distilled methylene chloride (150 mL), DMAP (2.3 g, 19 mmol) and freshly distilled Et3N (46.46 g, 0.460 mol) was sequentially added. After the flask was immersed into an ice-water bath, 2-azidoethanol (20.0 g, 0.230 mol) was added dropwise into the previous solution. The solution was later heated at 40° C. for 48 h, and the reaction mixture was washed successively with 1 M HCl solution (5×100 mL) and deionized water (2×100 mL). The organic phase was dried over anhydrous MgSO4 overnight. After filtering and removal of methylene chloride under reduced pressure, the final product was obtained as a yellow viscous liquid. The yield was: 38.4 g, 90%. 1H NMR (CDCl3, δ, ppm): 4.20 (t, 2H, N3CH2CH2), 3.42 (t, 2H, N3CH2), and 2.61 (m, 4H, CH2CH2COOH).
Reaction SMILES: [CH2:1]1[C:5]2([CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][CH:2]1[CH2:12][OH:13].C(O)C.[H][H]>O1CCCC1.[C].[Pd]>[CH2:1]1[C:5]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][CH:2]1[CH2:12][OH:13]
Reactant: OCC1CCC2(CCC=CCC2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: OCC1CCC2(CCCCCC2)C1
Yield: 96.6 %

Procedure:
A suspension of spiro[4.6]undec-8-ene-2-methanol (44 mg) obtained in Step 6 and 5% palladium carbon (4 mg) in tetrahydrofuran (1 mL)-ethanol (1 mL) was stirred in an atmosphere of hydrogen for 3 hours. Then, the reaction mixture was filtered through Celite and the filtrate was concentrated. The residue was purified by column chromatography on silica gel to give spiro[4.6]undecane-2-methanol (43 mg).
Reaction SMILES: FC1C(NC2C=C(C)NN=2)=NC([NH:8][C@H:9]([C:11]2[N:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=2)[CH3:10])=NC=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:37]=[N+:38]=[N-].[Na+]>C(Cl)Cl>[N:8]([CH:9]([C:11]1[N:12]=[CH:13][C:14]([F:17])=[CH:15][N:16]=1)[CH3:10])=[N+:37]=[N-:38]
Reactant: Cc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)ncc2F)n[nH]1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(N=[N+]=[N-])c1ncc(F)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 64.7 %

Procedure:
A round-bottom flask containing 1-(5-fluoropyrimidin-2-yl)ethanol (Method 4, 0.79 g, 5.55 mmol) was charged with triethylamine (0.67 g, 6.66 mmol) and anhydrous DCM (10 ml). The solution was cooled to 0° C., and methanesulfonyl chloride (0.70 g, 4.1 mmol) was added dropwise. The resulting mixture was allowed to stir at room temperature for 2 hours, at which point the volatile components were removed using a rotary evaporator. The residue was dissolved in DMF (15 ml) and treated with sodium azide (0.72 g, 11.1 mmol). The resulting mixture was stirred at room temperature for 60 hours. It was then partitioned between EtOAc and brine. The organic layer was obtained, dried (Na2SO4), and evaporated to dryness. The crude material was purified by silica gel chromatography (by ISCO Combiflash with gradient EtOAc and hexanes) to afford the title compound as a colourless oil (0.60 g, 65% yield over two steps). GC-MS, 167 (M), 138 (M-N2), 125 (M-N3); 1H NMR (CDCl3) δ 8.60 (s, 2H), 4.60 (m, 1H), 1.65 (d, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[C@H:3]([NH:11][CH2:12][CH2:13][NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C1C(=O)N(OC(ON2C(=O)CCC2=O)=O)[C:27](=[O:28])C1.C(N(CC)CC)C>ClCCCl>[CH3:1][C:2]([CH3:24])([CH3:23])[C@H:3]([N:11]1[CH2:12][CH2:13][N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=2)[C:27]1=[O:28])[C:4]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:5]
Reactant: Cc1cccc(CNCCN[C@H](C(=O)OC(C)(C)C)C(C)(C)C)n1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(CN2CCN([C@H](C(=O)OC(C)(C)C)C(C)(C)C)C2=O)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.1 %

Procedure:
A solution containing the product from Example 10A (1.76 g, 5.25 mmol) in 1,2-dichloroethane (210 mL) was treated with N,N-disuccinimidyl carbonate (1.61 g, 6.28 mmol) and triethylamine (0.75 mL, 5.38 mmol), stirred at 25° C. for 16 hours, and partitioned with 10% Na2CO3. The aqueous phase was extracted with additional dichloromethane. The combined organic phase was dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-25% methyl tert-butyl ether/dichloromethane to give the title compound (1.33 g, 70% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:18]3[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=3)=[N:10][N:11]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH2:30][C:31](Cl)=[O:32]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:18]3[CH:19]=[C:20]([NH:24][C:31](=[O:32])[CH2:30][C:26]4[S:25][CH:29]=[CH:28][CH:27]=4)[CH:21]=[CH:22][CH:23]=3)=[N:10][N:11]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc2c(-c3ccnc(Cl)n3)c(-c3cccc(N)c3)nn2c1
Reactant: O=C(Cl)Cc1cccs1
Solvent: C1CCOC1
Product: Cc1ccc2c(-c3ccnc(Cl)n3)c(-c3cccc(NC(=O)Cc4cccs4)c3)nn2c1
Reaction time: 16 h
Yield: 89.3 %

Procedure:
{3-[3-(2-Chloro-4-pyrimidinyl)-6-methylpyrazolo[1,5-a]pyridin-2-yl]phenyl}amine (0.57 g, 1.68 mmol) and 2-thienylacetyl chloride (0.25 mL, 2.00 mmol) were stirred in THF (30 mL) and stirred for 16 h. Additional 2-thienylacetyl chloride was added until reaction was complete by LC/MS. The mixture was concentrated to dryness and partitioned between aqueous NaHCO3 (saturated) and DCM. The organic layers were concentrated and purified by column chromatography to afford N-{3-[3-(2-chloro-4-pyrimidinyl)-6-methylpyrazolo[1,5-a]pyridin-2-yl]phenyl}-2-(2-thienyl)acetamide as a yellow solid (0.69 g, 89%). ES-LC/MS m/z=460 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH3:10])[C:3]=1[C:11]([F:14])([F:13])[F:12].[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH:16]=[CH2:17].C(N(CC)CC)C>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C)C=O>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2](/[CH:17]=[CH:16]/[C:15]([O:19][CH2:20][CH3:21])=[O:18])=[C:3]([C:11]([F:14])([F:13])[F:12])[C:4]=1[CH3:10]
Reactant: C=CC(=O)OCC
Reactant: COc1ccc(Br)c(C(F)(F)F)c1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(OC)c(C)c1C(F)(F)F
Temperature: 110 °C
Reaction time: 8 h

Procedure:
Into a 10-mL sealed tube (1 atm) purged and maintained with an inert atmosphere of nitrogen, was placed 1-bromo-4-methoxy-3-methyl-2-(trifluoromethyl)benzene (300 mg, 1.12 mmol, 1.00 equiv), ethyl prop-2-enoate (560 mg, 5.59 mmol, 5.02 equiv), P(Tol)3 (61 mg, 0.20 mmol, 0.18 equiv), Pd(OAc)2 (30 mg, 0.13 mmol, 0.12 equiv), triethylamine (566 mg, 5.59 mmol, 5.02 equiv), N,N-dimethylformamide (2.0 mL). The resulting solution was stirred overnight at 110° C. in an oil bath. The reaction progress was monitored by GCMS. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×15 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×20 mL of H2O. The mixture was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:6). This resulted in 0.16 g (50%) of ethyl (2E)-3-[4-methoxy-3-methyl-2-(trifluoromethyl)phenyl]prop-2-enoate as a yellow solid.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:22]([CH2:31][CH3:32])[CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[CH3:21]>C(OCC)(=O)C>[CH2:31]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][CH:25]1[CH2:26][CH2:27][N:28]([C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)=[O:3])[CH2:29][CH2:30]1)[CH3:32]
Reactant: CCN(CC)CCC1CCNCC1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Solvent: CCOC(C)=O
Product: CCN(CC)CCC1CCN(C(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1
Yield: 34 %

Procedure:
Prepared analogously to Example 4 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 4-[2-(diethylamino)ethyl]piperidine in a yield of 34% of theory. Colourless crystals, m.p. 154° C. (ethyl acetate).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]([N+:13]([O-])=O)[CH:8]=[C:9]([CH3:12])[C:10]=1[F:11])(=[O:4])=[O:3].C(O)C.[Cl-].[NH4+]>[Fe].O>[NH2:1][S:2]([C:5]1[CH:6]=[C:7]([CH:8]=[C:9]([CH3:12])[C:10]=1[F:11])[NH2:13])(=[O:4])=[O:3]
Reactant: Cc1cc([N+](=O)[O-])cc(S(N)(=O)=O)c1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1cc(N)cc(S(N)(=O)=O)c1F
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a heterogeneous solution of 3-aminosulfonyl-4-fluoro-5-methylnitrobenzene (27) (0.5 g, 2 mmol) in of ethanol:water (50 mL, each) were added iron powder (1.08 g, 20 mmol), and ammonium chloride (1.08 g, 20 mmol) at room temperature. The resulting heterogeneous mixture was then stirred at 60° C. for 2 hours, filtered through celite (when hot), washed with ethanol (2×50 mL) and then the solvent was removed under reduced pressure. The residue upon dilution with water was extracted with ethyl acetate (3×50 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated under a reduced pressure to obtain 3-aminosulfonyl-4-fluoro-5-methylaniline (28). LCMS: purity: 85%; MS (m/z): 205 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:15]([O:17]CC)=[O:16])[C:5]2[CH:6]=[CH:7][N:8]([CH:11]3[CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.[OH-].[Na+]>CO.C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=[O:16])[C:5]2[CH:6]=[CH:7][N:8]([CH:11]3[CH2:12][CH2:13][CH2:14]3)[C:9]=2[CH:10]=1
Reactant: CCOC(=O)c1cc(Br)cc2c1ccn2C1CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc(Br)cc2c1ccn2C1CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55 %

Procedure:
To a solution of ethyl 6-bromo-1-cyclobutyl-1H-indole-4-carboxylate (0.3 g, 0.973 mmol) (crude residue from above) in MeOH (8 mL) and THF (2 mL) was added 3M NaOH (1.298 mL, 3.89 mmol). The reaction was stirred at RT for 16 h, at which time the volatiles were removed in vacuo. The residue was diluted with water and slowly acidified with 1N HCl to pH 3-4. The solids were filtered and dried on hivac for 16 h to give 6-bromo-1-cyclobutyl-1H-indole-4-carboxylic acid (0.21 g, 0.535 mmol, 55.0% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.79-1.89 (m, 2H) 2.34-2.46 (m, 2H) 3.84 (s, 1H) 5.08 (t, J=8.21 Hz, 1H) 6.99 (d, J=3.03 Hz, 1H) 7.75-7.79 (m, 1H) 7.81 (d, J=3.03 Hz, 1H) 8.01-8.05 (m, 1H) 13.03 (br. s., 1H). MS(ES) [M+H]+ 294.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:6]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.C(N(CC)CC)C.Cl[S:21]([C:24]1[N:28]=[CH:27][NH:26][N:25]=1)(=[O:23])=[O:22]>O1CCCC1>[CH3:1][C:2]1([CH3:12])[C:6]2[CH:7]=[C:8]([O:11][S:21]([C:24]3[N:28]=[CH:27][NH:26][N:25]=3)(=[O:23])=[O:22])[CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: CC1(C)COc2ccc(O)cc21
Reactant: O=S(=O)(Cl)c1nc[nH]n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)COc2ccc(OS(=O)(=O)c3nc[nH]n3)cc21

Procedure:
5.4 g of 3,3-dimethyl-5-hydroxy-2,3-dihydrobenzofuran was dissolved in 30 ml of tetrahydrofuran, and then 4.6 ml of triethylamine was added while stirring the solution. Then, 5.0 g of 3-chlorosulfonyl-1,2,4-triazole was gradually added while cooling with ice and stirring the solution. Then, this was stirred for 14 hours. Tetrahydrofuran was evaporated, and 2N hydrochloric acid was added and extracted with ethyl acetate. The organic layer was washed with brine, dried with magnesium sulfate, and the solvent was removed, so that coarse crystals were obtained. This was then recrystallized from n-hexane/ethyl acetate, so that 2.7 g of the titled compound was obtained.