Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:5][C@:4]1([CH2:12][N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH-].[Na+]>C(Cl)Cl.CC(O)(C)C.C(OCC)C>[CH:2]([C@@H:3]1[CH2:5][C@:4]1([CH2:12][N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:1]
Reactant: CN(C[C@]1(c2ccccc2)C[C@H]1CO)C(=O)OC(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: CN(C[C@]1(c2ccccc2)C[C@H]1C=O)C(=O)OC(C)(C)C
Yield: 84.6 %

Procedure:
1,1-dimethylethyl {[(1R,2R)-2-(hydroxymethyl)-1-phenylcyclopropyl]methyl}methylcarbamate (3.8 g, 13.0 mmol), accessed via the method of Preparation 13B, was dissolved in 35 mL DCM with 1.1 mL 2-methylpropan-2-ol and treated with Dess-Martin Periodinane (8.8 g, 20.8 mmol, 1.6 eq) in 35 mL DCM at ambient temperature for 2 h. The reaction mixture was diluted with 50 mL diethyl ether and treated with 50 mL 1N NaOH at ambient temperature for 15 min. The organic phase was separated, the aqueous phase extracted twice with diethyl ether, the organic phases combined, washed with brine, dried over MgSO4, filtered and concentrated to a colorless oil. The crude material was purified by flash chromatography (SiO2, eluted EtOAc/hexanes (3:7)) to give the title compound (3.2 g, 11.0 mmol, 84%). 1H NMR (400 MHz, CDCl3) δ 8.49-8.47 (m, 1H), 7.29-7.24 (m, 5H), 3.62-3.58 (m, 1H), 3.33-3.22 (m, 1H), 2.72-2.58 (m, 3H), 1.84-1.81 (m, 1H), 1.71-1.53 (m, 1H), 1.34-1.25 (m, 10H). ES-LCMS m/z 312.2 (M+Na).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[N:7][C:6]([OH:9])=[CH:5][CH:4]=1.[Br:12]N1C(=O)CCC1=O>C(O)(=O)C.C(#N)C.ClCCl>[Br:12][C:5]1[CH:4]=[C:3]([C:2]([F:1])([F:10])[F:11])[N:8]=[N:7][C:6]=1[OH:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: Oc1ccc(C(F)(F)F)nn1
Solvent: ClCCl
Solvent: CC#N
Solvent: CC(=O)O
Product: Oc1nnc(C(F)(F)F)cc1Br
Temperature: 60 °C
Reaction time: 16 h
Yield: 95.2 %

Procedure:
A mixture of 6-trifluoromethyl-pyridazin-3-ol (9.0 g, 54.9 mmol) (D3) and N-bromosuccinimide (12.7 g, 71.4 mmol) in a mixture of acetic acid (15 ml) and acetonitrile (350 ml) was stirred at 60° C. for 6 h. and at room temperature for a further 16 h. After this period, the reaction mixture was diluted with dichloromethane and extracted with a 10% solution of sodium thiosulfite. The organic layer was separated, dried (MgSO4) and the solvent evaporated in vacuo to yield D4 (12.7 g, 95%) as a yellow solid. C5H2BrF3N2O requires 243; Found 244 (MH+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[CH2:15]([N:17](CC)CC)[CH3:16].O1CCCC1.C(N)C>C(OCC)(=O)C.CCCCCCC>[CH2:11]([O:10][C:8]([C:7]1[C:2]([NH:17][CH2:15][CH3:16])=[N:3][C:4]([S:13][CH3:14])=[N:5][CH:6]=1)=[O:9])[CH3:12]
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: CCN(CC)CC
Agent: CCN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CCNc1nc(SC)ncc1C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A 22-L, 4-necked round-bottomed flask was equipped with a mechanical stirrer, a dropping funnel, and a thermometer. The flask was charged with the ethyl 4-chloro-2-(methylthio)-5-pyrimidinecarboxylate (1.53 kg, 6.56 mol), triethylamine (2.74 L, 19.7 mol, 3 eq), and 7.5 L of tetrahydrofuran to give a solution. The aqueous ethylamine (0.53 L, 6.56 mol, 1 eq) was added via the dropping funnel over 20 minutes. The reaction temperature rose to 35° C. during the addition. The reaction was stirred at ambient temperature for 2 hours. The reaction was checked for completion using TLC (SiO2; 7:3/heptane:ethyl acetate). The precipitate (triethylamine hydrochloride) was filtered off and washed 2 times with tetrahydrofuran, combining the washes with the original filtrate. The tetrahydrofuran was stripped to near dryness on a rotary evaporator. The residue was partitioned between saturated aqueous sodium bicarbonate (500 mL) and ethyl acetate (1 L). Note that there is carbon dioxide gas evolution from the bicarbonate both during the partitioning and the subsequent washes. The layers were separated and the organic layer washed 2 times with saturated aqueous sodium bicarbonate and 1 time with brine. The solution was dried over magnesium sulfate, filtered, and stripped to give the titled compound as an off-white solid. Yield: 95%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[H-].[Na+].F[C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-])=O)=[CH:34][CH:33]=1>C(Cl)Cl.CC(N(C)C)=O>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:17]1[O:11][CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N(CCOC1CCCCO1)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25.3 %

Procedure:
To a mixture of N-t-butoxycarbonylethanolamine (7.7 ml, 50 mmol) and 3,4-dihydropyran (5.7 ml, 62.5 mmol) in DCM (125 ml) was added 4-toluenesulphonic acid (100 mg, 0.5 mmol) and the mixture stirred at ambient temperature for 3 h. The solution was washed with saturated sodium hydrogen carbonate solution, dried and evaporated to dryness. The residue was filtered through a short pad of basic alumina with 10% EtOAc in hexane, the solvent evaporated to dryness, the residue dissolved in dimethylacetamide (5 ml) and added to a suspension of sodium hydride (400 mg of 50% dispersion in mineral oil, 10 mmol) in dimethylacetamide (5 ml). The mixture was heated at 50° C. for 1 h, cooled to ambient temperature and added to a solution of 1-fluoro-4-nitrobenzene (1.06 g, 7.5 mmol) in dimethylacetamide (5 ml) and heated at 50° C. for 4 h. The cooled mixture was poured onto water (150 ml), the aqueous solution was extracted with EtOAc, the EtOAc extracts were washed with brine, dried and evaporated. The residue was dissolved in ethanol (50 ml) and hydrogenated over 10% Pd/C for 4 h at ambient temperature. The catalyst was removed by filtration, the ethanol evaporated and the residue purified by column chromatography using 30% EtOAc in hexane to yield the title compound (640 mg, 1.9 mmol). NMR: 1.2-1.6 (m, 15H), 3.4-3.8 (m, 6H), 6.6 (d, 2H), 7.0 (d, 2H(; MS: 337 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1Cl)=[N:15][C:14]([Cl:19])=[CH:13][CH:12]=2)=[O:7])(=[O:3])[CH3:2].[CH3:20][N:21]([CH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26][CH2:25]1)[CH3:22]>>[C:1]([O:4][CH2:5][C:6]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[NH:30][C@H:27]1[CH2:28][CH2:29][C@H:24]([CH2:23][N:21]([CH3:22])[CH3:20])[CH2:25][CH2:26]1)=[N:15][C:14]([Cl:19])=[CH:13][CH:12]=2)=[O:7])(=[O:3])[CH3:2]
Reactant: CN(C)C[C@H]1CC[C@H](N)CC1
Reactant: CC(=O)OCC(=O)c1cnc2ccc(Cl)nc2c1Cl
Product: CC(=O)OCC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](CN(C)C)CC1

Procedure:
Following general procedure I, 2-(4,6-dichloro-1,5-naphthyridin-3-yl)-2-oxoethyl acetate (101 mg, 0.33 mmol) was reacted with trans-4-[(dimethylamino)methyl]cyclohexan amine (67 mg, 0.43 mmol) to afford the desired product (90 mg, 65%) as an off-white solid. ESI MS m/z 419 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19]([OH:21])=O)[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:22]([F:25])([F:24])[F:23])([O-:3])=[O:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[Cl:55][C:56]1[CH:57]=[CH:58][C:59]2[O:63][CH:62]([C:64]([N:66]3[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]3)=[O:65])[CH2:61][C:60]=2[CH:72]=1>ClCCl>[Cl:55][C:56]1[CH:57]=[CH:58][C:59]2[O:63][CH:62]([C:64]([N:66]3[CH2:67][CH2:68][N:69]([C:19](=[O:21])[CH2:18][O:17][CH:14]4[CH2:13][CH2:12][CH:11]([NH:10][C:7]5[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:22]([F:24])([F:25])[F:23])[CH:6]=5)[CH2:16][CH2:15]4)[CH2:70][CH2:71]3)=[O:65])[CH2:61][C:60]=2[CH:72]=1
Reactant: O=C(O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reactant: O=C(C1Cc2cc(Cl)ccc2O1)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCN(C(=O)C2Cc3cc(Cl)ccc3O2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.4 %

Procedure:
To a solution of 2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]acetic acid (100 mg, 0.28 mmol) in dichloromethane (20 ml) was added EDAC.HCl (80 mg, 0.42 mmol 1.5 eq), HOBt (56 mg, 0.41 mmol, 1.5 eq), triethylamine (84 mg, 0.83 mmol, 3 eq) and 1-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)carbonyl]piperazine (74 mg, 0.28 mmol, 1 eq). The resulting solution was stirred overnight at room temperature and then concentrated under vacuum. The crude residue was purified by silica gel chromatography using 5-20% ethyl acetate in dichloromethane to elute. The product-containing fractions were combined and concentrated under vacuum to afford 1-[4-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)carbonyl]piperazin-1-yl]-2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethan-1-one as a yellow solid (34.9 mg, 19%). (ES, m/z): [M+H]+ 611.25; 1H NMR (300 MHz, CDCl3): δ 8.00 (d, J=9.0 Hz, 1H), 7.18 (s, 1H), 7.07 (d, J=8.4 Hz, 1H), 6.85 (d, J=2.1 Hz, 1H), 6.70 (d, J=8.7 Hz, 1H), 6.63 (dd, J=2.1 Hz, 9.0 Hz, 1H), 5.42 (dd, J=7.5 Hz, 9.0 Hz, 1H), 4.23 (s, 2H), 3.82-3.98 (m, 4H), 3.30-3.70 (m, 8H), 2.10-2.20 (m, 4H), 1.42-1.58 (m, 2H), 1.20-1.40 (m, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([Cl:10])[N:7]=[CH:6][C:5]=1[NH:11]S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O)(=[O:3])[CH3:2].[CH3:24]CN(C(C)C)C(C)C.C1(S)C=CC=CC=1>CN(C=O)C>[Cl:10][C:8]1[CH:9]=[C:4]2[C:5](=[CH:6][N:7]=1)[N:11]=[CH:24][CH:2]=[C:1]2[OH:3]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(=O)c1cc(Cl)ncc1NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Sc1ccccc1
Solvent: CN(C)C=O
Product: Oc1ccnc2cnc(Cl)cc12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of N-(4-acetyl-6-chloropyridin-3-yl)-4-nitrobenzenesulfonamide (1.0 equiv.), dimethylformamidedimethylacetal (4.8 equiv.) and DIEA (4.8 equiv.) in DMF (0.15 M) was heated under Ar at 110° C. for 96 hours. Upon cooling, thiophenol (4.9 equiv.) was added and the solution was stirred at rt for 15 hours. The volatiles were removed in vacuo and following silica gel purification (0-1.5-3-5% MeOH/CH2Cl2) 6-chloro-1,7-naphthyridin-4-ol was obtained (55%). LC/MS=180.9/182.9 (M+H), LC=1.41 min
Reaction SMILES: Cl[C:2]1[C:3]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Br:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21].CN(C)C(=O)C.O>Cl.CC(O)C>[Br:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH:21][C:2]1[C:3]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COc1ccc2[nH]c3ncnc(Cl)c3c2c1
Reactant: Nc1cccc(Br)c1
Agent: Cl
Solvent: CC(C)O
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1ccc2[nH]c3ncnc(Nc4cccc(Br)c4)c3c2c1
Temperature: 120 °C
Yield: 28.5 %

Procedure:
A mixture of 4-chloro-6-methoxyindolo[2,3-d]pyrimidine (107 mg, 0.37 mmol, 80% pure), 3-bromoaniline (0.15 mL, 1.4 mmol), N,N-dimethylacetamide (1 mL), and 1 drop of a solution of 2-propanol that is 8.5 molar in HCl is heated under N2 at 120° C. for 5 h. The solution is concentrated in vacuo to an oily solid that is triturated in 5% aqueous sodium bicarbonate. The solids are collected by filtration, then washed successively with H2 O and EtOAc. The solids are warmed in a small volume of N,N-dimethylformamide and filtered. The filtrate is purified by thick layer silica gel chromatography eluting with 3:2 dichloromethane:EtOAc. The product band is collected and sonicated in EtOAc. The mixture is filtered and the filtrate is concentrated to a solid that is sonicated in MeOH. The solids are collected, washed with MeOH, and dried to give pure 4-(3-bromoanilino)-6-methoxyindolo[2,3-d]pyrimidine (39 mg, 28%) hydrated with 0.7 equivalent of H2O. 1H NMR (DMSO): δ11.99 (1H, br s, exchanges with D2O), 8.97 (1H, br s, exchanges with D2 O), 8.44 (1H, s), 8.02 (1H, s), 7.91 (1H, d, J=2.4 Hz), 7.76 (1H, d, J=8.0 Hz), 7.42 (1H, d, J=8.7 Hz), 7.36-7.24 (2H, m), 7.08 (1H,dd, J=8.7, 2.2 Hz), 3.87 (3H, s).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[S:21]1[CH2:25][CH:24]([C:26]([NH2:28])=[O:27])[NH:23][CH2:22]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CS(C)=O>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:23]3[CH:24]([C:26]([NH2:28])=[O:27])[CH2:25][S:21][CH2:22]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: NC(=O)C1CSCN1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)C1CSCN1C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with and 4-thiazolidinecarboxamide (CAN 103749-87-7) in the presence of TBTU and DIEA. The mixture of enantiomers was separated by chiral HPLC (Reprosil Chiral NR). The (−) enantiomer was isolated as white solid; MS (EI): m/e=399.4 [MH+]; αD20 (DMSO)=−547.6°.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([CH3:27])[CH3:26])[C:20]=1[N:28]=[C:29]=[O:30])([CH3:18])[CH3:17]>C(Cl)(Cl)Cl>[CH:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([CH3:26])[CH3:27])[C:20]=1[NH:28][C:29](=[O:30])[N:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])([CH3:17])[CH3:18]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CCCCCCCNCCCCCCO
Solvent: ClC(Cl)Cl
Product: CCCCCCCN(CCCCCCO)C(=O)Nc1c(C(C)C)cccc1C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
Lithium aluminum hydride (189 mg, 5 mmols) was added to an anhydride THF solution (7 ml) of the above amide (454 mg, 2 mmols), and the resulting mixture was refluxed for 2 hours under argon atmosphere. The reaction mixture was diluted with ether (30 ml), and an aqueous saturated solution of ammonium chloride (0.4 ml) was added to the mixture, and stirred for 30 minutes at room temperature, and dried with anhydrous potassium carbonate. And the mixture solution was filtered through a pad of Cerite. The filtrate was concentrated to obtain the residue, which was crystallized from ether and hexane, and 6-heptylamino-1-hexanol 223 mg (yield 52%) was obtained as colorless crystals. This amine (213 mg, 1 mmol) was added to a chloroform solution (2 ml) of 2,6-diisopropylphenylisocyanate (207 mg, 1 mmol), and stirred for 2 hours at room temperature. The solvent was evaporated, and the obtained residue was purified through silica gel column chromatography (silica gel 15 g, developer: chloroform:methanol=98:2). The resulting crystals were recrystallized from acetone-hexane to obtain 370 mg of N′-(2,6-diisopropylphenyl)-N-heptyl-N-(6-hydroxyhexyl)urea (yield: 88%) as colorless crystals.
Reaction SMILES: [F:1][CH:2]([F:23])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH3:22])[CH:15]=2)[CH:4]=1.Br[C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1>>[F:23][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:25]3[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH3:22])[CH:15]=2)[CH:4]=1
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3cccc(OCC)c3)nc12
Product: CCOc1cccc(-c2cc(C(F)F)n3ncc(C#Cc4ccc(S(N)(=O)=O)cc4)c3n2)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(3-ethoxy-phenyl)-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.19) (313 g, 1.0 mmol) and commercially available 4-bromobenzenesulfonamide (230 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (190 mg, 41%). MS (ISN) 467.1 [(M−H)−]; mp 245° C.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:13])[CH:6]([NH2:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:3].C(N(CC)CC)C.[CH3:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26].O>ClCCl>[CH2:10]([O:9][C:7](=[O:8])[CH:6]([NH:12][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][CH:30]=[C:22]([CH3:21])[CH:23]=1)[C:5]([O:4][CH2:2][CH3:3])=[O:13])[CH3:11]
Reactant: CCOC(=O)C(N)C(=O)OCC
Reactant: Cc1cccc(C(=O)Cl)c1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(NC(=O)c1cccc(C)c1)C(=O)OCC
Reaction time: 2 h
Yield: 94.9 %

Procedure:
41.1 g of aminomalonic acid diethyl ester hydrochloride were dissolved in 200 ml of dichloromethane, and 80.7 ml of triethylamine were added with cooling in an ice bath. A solution of 30 g of 3-methyl-benzoyl chloride in 200 ml of dichloromethane was slowly added dropwise. After 2 h at 0° C., 100 ml of water were added dropwise. The phases were separated, and the aqueous phase was extracted with 100 ml of dichloromethane. The combined organic phases were dried with sodium sulfate, filtered and evaporated to give 54 g of the crude title compound.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=1[CH2:6][N:7]1[C:11](=[O:12])[CH2:10][CH2:9][C@@H:8]1[C:13]([OH:15])=O.[NH2:22][CH:23]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:24]([OH:28])[C:25]([NH2:27])=[O:26].O[NH-].O=[N-]>>[NH2:27][C:25](=[O:26])[C:24](=[O:28])[CH:23]([NH:22][C:13]([C@H:8]1[CH2:9][CH2:10][C:11](=[O:12])[N:7]1[CH2:6][C:5]1[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=1[O:3][C:2]([F:1])([F:21])[F:20])=[O:15])[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Reactant: O=C(O)[C@H]1CCC(=O)N1Cc1ccccc1OC(F)(F)F
Agent: [N-]=O
Agent: [NH-]O
Product: NC(=O)C(=O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1OC(F)(F)F

Procedure:
Coupling of (R)-1-(2-trifluoromethoxy-benzyl)-5-oxo-pyrrolidine-2-carboxylic acid with 3-amino-2-hydroxy-4-phenylbutanamide and oxidation of the resulting hydroxyamide intermediate to the corresponding ketoamide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10](=[O:12])[CH3:11])=[C:4]([CH3:13])[CH:3]=1.[F:14][C:15]([F:25])([F:24])[C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.O>C(O)C>[CH3:8][C:6]1[CH:7]=[C:2]([NH:1][CH2:20][C:19]2[CH:18]=[CH:17][C:16]([C:15]([F:14])([F:24])[F:25])=[CH:23][CH:22]=2)[CH:3]=[C:4]([CH3:13])[C:5]=1[NH:9][C:10](=[O:12])[CH3:11]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CC(=O)Nc1c(C)cc(N)cc1C
Solvent: CCO
Solvent: O
Product: CC(=O)Nc1c(C)cc(NCc2ccc(C(F)(F)F)cc2)cc1C
Reaction time: 0.25 h
Yield: 30 %

Procedure:
N-(4-Amino-2,6-dimethyl-phenyl)-acetamide (1.2 g) and 4-trifluoromethyl-benzaldehyde (1.3 g) were dissolved in ethanol (100 mL) and refluxed for 16 h. The reaction mixture was poured into water (3 L) and the precipitate collected by filtration. Sodium cyanoborohydride (2 g) and acetic acid (2 mL) were added to the precipitate dispersed in methanol (50 mL) and stirred for 15 minutes. The reaction mixture was filtered, water (100 mL) was added and the organic solvent was removed in vacuo. The product was allowed to precipitate at 25° C. and collected by filtration and washed with water (200 mL) to furnish 0.68 g (30% yield) of the title compound as a pale yellow solid. LC-MS (m/z) 337 (MH+); tR=2.39, (UV, ELSD) 99%, 99%. 1H NMR (500 MHz, DMSO-d6): 1.95 (s, 3H), 1.96 (s, 6H), 4.34 (d, 2H), 6.18 (t, 1H), 6.25 (s, 2H), 7.55 (d, 2H), 7.69 (d, 2H), 8.81 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[NH2:18][C:19]1[C:24]([O:25][CH3:26])=[CH:23][C:22]([N:27]2[CH2:32][CH2:31][CH:30]([N:33]([CH3:35])[CH3:34])[CH2:29][CH2:28]2)=[C:21]([CH3:36])[CH:20]=1>>[Cl:17][C:5]1[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[N:7][C:2]([NH:18][C:19]2[CH:20]=[C:21]([CH3:36])[C:22]([N:27]3[CH2:28][CH2:29][CH:30]([N:33]([CH3:35])[CH3:34])[CH2:31][CH2:32]3)=[CH:23][C:24]=2[O:25][CH3:26])=[N:3][CH:4]=1
Reactant: Clc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Reactant: COc1cc(N2CCC(N(C)C)CC2)c(C)cc1N
Product: COc1cc(N2CCC(N(C)C)CC2)c(C)cc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1

Procedure:
Starting materials: 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (INTERMEDIATE 2) and 1-(4-amino-5-methoxy-2-methylphenyl)-N,N-dimethylpiperidin-4-amine (INTERMEDIATE 30).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14](B(O)O)=[CH:13][C:12]=2[CH:19]=1.C([O-])(=O)C.[K+].Br[C:26]1[CH:41]=[CH:40][C:29]([CH2:30][N:31]2[CH2:34][CH:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:32]2)=[CH:28][C:27]=1[F:42]>CCO>[F:42][C:27]1[CH:28]=[C:29]([CH2:30][N:31]2[CH2:34][CH:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:32]2)[CH:40]=[CH:41][C:26]=1[C:14]1[O:15][C:11]2[CH:10]=[CH:9][C:8]([CH2:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:19][C:12]=2[CH:13]=1
Reactant: CCOC(=O)C1CN(Cc2ccc(Br)c(F)c2)C1
Reactant: OB(O)c1cc2cc(Cc3ccccn3)ccc2o1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C1CN(Cc2ccc(-c3cc4cc(Cc5ccccn5)ccc4o3)c(F)c2)C1
Temperature: 80 °C

Procedure:
In a sealed flask, a mixture of 5-(pyridin-2-ylmethyl)benzofuran-2-ylboronic acid (214 mg, 846 μmol) and potassium acetate (166 mg, 1691 μmol) was set under argon, treated with bis{di(tbutyl)phenyl}palladium(II) dichloride (32 mg, 51 μmol), followed by a solution of ethyl 1-(4-bromo-3-fluorobenzyl)azetidine-3-carboxylate (267 mg, 846 μmol) in EtOH (5 mL). The resulting suspension was degassed again and heated to 80° C. for 2.5 h. The mixture was cooled to ˜10° C. and dropwise treated with H2O (15 mL). The mixture was extracted 2× with EtOAc. The combined organic layers were dried over MgSO4 and evaporated. Purification by flash chromatography (DCM to DCM/MeOH=4:1) gave ethyl 1-((3-fluoro-4-(5-(pyridin-2-ylmethyl)benzofuran-2-yl)phenyl)methyl)azetidine-3-carboxylate as a yellow foam.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]3[CH2:20][CH2:19][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([NH2:18])=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCOCC1.N1C=CC=CC=1>[Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]3[CH2:20][CH2:19][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[N:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Cl)cccc1-2
Solvent: C1COCCO1
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#Cc1ncn2c1[C@@H]1CCN1C(=O)c1c(Cl)cccc1-2
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
A suspension of 11.9 g (0.0394 mol) of (S)-8-chloro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamide in a mixture of 85 ml of dioxan and 6.8 ml of pyridine was treated dropwise at 0° with 7.1 ml (0.051 mol) of trifluoroacetic anhydride. The suspension was stirred at 50° for 3 hrs., cooled and poured on to ice-water. After stirring for 11/2 hr. the suspension was suction filtered. There were obtained 11.2 g (100%) of (S)-8-chloro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carbonitrile as white crystals; m.p. 130° (dec.).