Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH:18]([CH3:20])[CH3:19])[N:11]=[C:10](OS(C(F)(F)F)(=O)=O)[N:9]=2)=[CH:4][CH:3]=1.[CH3:29][NH:30][S:31]([CH3:34])(=[O:33])=[O:32].C(=O)([O-])[O-].[K+].[K+].C(OCCCC)(=O)C>CC(C)=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH:18]([CH3:20])[CH3:19])[N:11]=[C:10]([N:30]([CH3:29])[S:31]([CH3:34])(=[O:33])=[O:32])[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(-c2ccc(F)cc2)nc(OS(=O)(=O)C(F)(F)F)nc1C(C)C
Reactant: CNS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Temperature: 123.5 °C
Yield: 78.7 %

Procedure:
In a 50 mL-volume glass flask equipped with a stirrer, a thermometer and a reflux condenser were placed 3.0 g (7 mmol.) of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-trifluoromethanesulfonyloxypyrimidine, 1.13 g (10.5 mmol.) of N-methylmethanesulfonamide, 1.45 g (10.5 mmol.) of potassium carbonate (available from Wako Junyaku Co., Ltd., special grade), and 14 mL of butyl acetate. The mixture was heated to 122-125° C. for 3 hours under refluxing, to carry out reaction. After the reaction was complete, the reaction mixture was cooled to room temperature. To the reaction mixture were added 10 mL of water and 7 mL of acetone, and the organic liquid portion was separated. The organic liquid portion was washed with a saturated aqueous sodium chloride solution and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (column: Wako Gel C-200, eluent: hexane/ethyl acetate (5:1, volume ratio)). There was obtained 2.1 g of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesul-fonylamino)pyrimidine as a white crystalline product. The yield was 78% (based on the amount of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-trifluoromethanesulfonyloxypyrimidine).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12](=[O:15])[CH2:13][CH2:14][C:5]=3[C:4]=2[CH:3]=1.N12CCCN=C1CCCCC2.[CH3:27][N:28]=[C:29]=[O:30]>C(Cl)Cl>[CH3:27][NH:28][C:29]([O:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12](=[O:15])[CH2:13][CH2:14][C:5]=3[C:4]=2[CH:3]=1)=[O:30]
Reactant: CN=C=O
Reactant: Cn1c2c(c3cc(O)ccc31)CCC2=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CNC(=O)Oc1ccc2c(c1)c1c(n2C)C(=O)CC1
Reaction time: 8 h

Procedure:
7-Chloroacetyloxy-1,4-dihydro-4-methylcyclopent[b]indol- 3(2H)-one (5.0 g) was suspended in EtOH (100 ml), and thereafter 10% NaOH solution (50 ml) was added and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated in vacuo, CH2Cl2 (100 ml) was added followed by 10% HCl until the aqueous layer was neutralized. The layers were separated and the aqueous phase extracted with CH2Cl2 (2×100 ml). The organic portion was dried (Na2SO4) and concentrated and the residue was recrystallized from 95% EtOH to provide 1,4-dihydro-7-hydroxy-4-methylcyclopent[b]indol-3(2H)-one as an off-white solid. The phenol was dissolved in CH2Cl2 (100 ml), and thereafter 1,8-diazabicyclo[5.4.0]undec-7-ene (0.4 g) was added followed by methyl isocyanate (1.4 g) and the mixture was stirred overnight. The mixture was concentrated in vacuo to afford an oily solid which was crystallized from EtOH to provide 1,4-dihydro-7 -methylaminocarbonyloxy-4-methylcyclopent[b]indol-3(2H)-one (1.1 g).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[NH:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[C:21]([C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Br)#[N:22]>>[C:21]([C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][N:7]1[C:8]([C:9](=[O:18])[C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:20])[NH:5][C:6]1=[O:19])#[N:22]
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: N#Cc1ccccc1CBr
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(Cc2ccccc2C#N)c(=O)[nH]c1=O
Yield: 51.4 %

Procedure:
5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 2-cyanobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (199 mg, yield: 51.4%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=2)[CH:4]=[CH:3]1.Cl.[CH2:15](N=C=NCCCN(C)C)[CH3:16].C(O)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:15]([O:12][C:11]([C:8]1[CH:9]=[C:10]2[C:5]([CH:4]=[CH:3][N:2]2[CH3:1])=[CH:6][CH:7]=1)=[O:13])[CH3:16]
Reactant: Cn1ccc2ccc(C(=O)O)cc21
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1ccc2ccn(C)c2c1
Reaction time: 15 h
Yield: 88.6 %

Procedure:
A solution of 1.05 g (6.0 mmol) of 1-methyl-1H-indole-6-carboxylic acid in 15 mL of methylene chloride was added to a stirring solution of 1.905 g (10 mmole) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1.20 g (10 mmole) of 4-dimethylaminopyridine in 20 mL of methylene chloride at room temperature. Ethanol was added and the reaction stirred for 15 h. The reaction mixture was extracted with ethyl acetate, the organic phase was washed with brine and dried on anhydrous magnesium sulfate. Chromatographic purification of this material gave 1.08 g (89%) of 1-methyl-1H-indole-6-carboxylic acid ethyl ester as a pale yellow oil.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1(=[O:12])[O:11][C:9](=[O:10])[CH2:8][CH2:7][CH2:6]1.C[O:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:18]=[CH:19][CH:20]=1.Cl>ClC(Cl)C.O>[OH:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:18]=[CH:19][C:20]=1[C:9](=[O:10])[CH2:8][CH2:7][CH2:6][C:5]([OH:11])=[O:12]
Reactant: COc1cccc(-c2ccccc2)c1
Reactant: O=C1CCCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CC(Cl)Cl
Product: O=C(O)CCCC(=O)c1ccc(-c2ccccc2)cc1O
Reaction time: 0.25 h

Procedure:
24 g aluminium chloride are added at 0° C. to a solution of 10 g glutaric acid anhydride in 300 ml dichloroethane. After stirring for 15 mins. at 0° to 5° C., 15 g 3-methoxy-biphenyl in 50 ml dichloroethane are added rapidly at ca. 0° C. The reaction mixture is stirred for 24 hours at room temperature, poured onto a mixture of ice and conc. HCl and diluted with water. The organic phase is separated off and the aqueous phase extracted 3×with methylene chloride. The combined organic phases are washed thoroughly with water, dried over MgSO4 and clarified with activated charcoal. The solvent is evaporated off and the obtained oil crystallised from ether to yield the title compound: m.p.=168°-170° C.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[F:7][C:8]1[C:9](B(O)O)=[CH:10][C:11]([O:14][CH3:15])=[N:12][CH:13]=1.[Cl:19][C:20]1[N:25]=[C:24](Cl)[CH:23]=[CH:22][N:21]=1.O1CCOCC1.O>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:19][C:20]1[N:25]=[C:24]([C:9]2[C:8]([F:7])=[CH:13][N:12]=[C:11]([O:14][CH3:15])[CH:10]=2)[CH:23]=[CH:22][N:21]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: COc1cc(B(O)O)c(F)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-c2ccnc(Cl)n2)c(F)cn1
Temperature: 80 °C
Yield: 100 %

Procedure:
Sodium carbonate (1.6 g, 15 mmol) was added to 5-fluoro-2-methoxypyridin-4-ylboronic acid (1.0 g, 6.0 mmol) and 2,4-dichloropyrimidine (0.75 g, 5.0 mmol) in 4:1 dioxane/water (25 mL), and the suspension was purged with argon. PdCl2(dppf)*DCM (0.21 g, 0.25 mmol) was added, and the mixture was heated at 80° C. under argon overnight. The reaction mixture was diluted with water, and the resulting solid was collected by vacuum filtration, washed with water, and dried to provide the desired 2-chloro-4-(5-fluoro-2-methoxypyridin-4-yl)pyrimidine (1.2 g, 5.0 mmol, 99% yield) as a solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[C:16]([O:17][CH3:18])=[N:15][C:14]2[C:9](=[CH:10][C:11]([CH3:22])=[C:12]([CH3:21])[C:13]=2[CH2:19]O)[N:8]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:3][CH2:19][C:13]1[C:12]([CH3:21])=[C:11]([CH3:22])[CH:10]=[C:9]2[C:14]=1[N:15]=[C:16]([O:17][CH3:18])[C:7]([O:6][CH3:5])=[N:8]2
Reactant: COc1nc2cc(C)c(C)c(CO)c2nc1OC
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COc1nc2cc(C)c(C)c(CCl)c2nc1OC
Reaction time: 0.33 h
Yield: 33.7 %

Procedure:
Thionyl chloride (0.44 mL, 6.0 mmol) was added dropwise to a solution of 2,3-dimethoxy-6,7-dimethyl-5-hydroxymethylquinoxaline (0.50 g, 2.0 mmol) in toluene (30 mL) and pyridine (0.81 mL, 10.0 mmol) under nitrogen at 5° C. After 20 minutes, water (20 mL), and the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic solutions were washed with 2M hydrochloric acid, dried (MgSO4) and concentrated under reduced pressure. Purification of the residue by flash chromatography (eluting with dichloromethane) gave 5-(chloromethyl)-2,3-dimethoxy-6,7-dimethylquinoxaline (0.18 g, 34%) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH:10]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=2[Cl:20])[CH3:11])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:21][N:22](C=O)C>O.[C-]#N.[C-]#N.[Zn+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[NH2:8][C:5]1[C:4]([O:9][CH:10]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=2[Cl:20])[CH3:11])=[CH:3][C:2]([C:21]#[N:22])=[CH:7][N:6]=1
Reactant: CC(Oc1cc(Br)cnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: CC(Oc1cc(C#N)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 100 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a solution of 5-bromo-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine (5.00 g, 13.15 mmol) in DMF (73 mL) and water (1 mL) was added Zn(CN)2 (4.50 g, 26.3 mmol), Pd2(dba)3 (0.602 g, 0.65 mmol), and DPPF (0.86 g, 1.55 mmol). The mixture was degassed and charged with nitrogen for three time, and then stirred under nitrogen at 100° C. for 3 hr. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with a solution of sat. NH4Cl-conc. NH4OH-water (4:1:4), then dried over MgSO4. The crude product was purified on a silica gel column eluting with ethyl acetate-hexanes (1:4) to provide 6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-nicotinonitrile as a white solide (4.15 g, 97% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:29][C:30]([C@@H:32]2[CH2:36][CH2:35][CH2:34][N:33]2C(OC(C)(C)C)=O)=[O:31])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:29][C:30]([C@@H:32]2[CH2:36][CH2:35][CH2:34][NH:33]2)=[O:31])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2NS(C)(=O)=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Nc1ccccc1C1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2CCCN2)CC1
Reaction time: 0.5 h

Procedure:
The title compound was prepared according to the procedure described in Example 3, Step (b) from tert-butyl 2-{N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-(2-[(methylsulfonyl)-amino]-phenyl)-piperidyl)-2-oxoethyl]carbamoyl}(2S)pyrrolidinecarboxylate (Step a) (315 mg, 0.5 mmol) and 50% TFA in CH2Cl2 (20 mL). Purification by preparative reverse phase HPLC [Phenomenex; 5 μm 250×21.2 mm, 5% to 95% CH3CN (0.1% TFA) in H2O (0.1% TFA) over 30 min, then 100% CH3CN (0.1% TFA) for 2 min] provided the title compound (TFA salt) as a white foam (101 mg). MS (ESI, pos. ion) m/z: 533 (M+1); (ESI, neg. ion) m/z: 531 (M−1). Calc'd for C26H33ClN4O4S: 532.19. Anal. Calcd for C26H33ClN4O4S.1.2C2HF3O2: C, 50.92; H, 5.15; N, 8.36. Found: C, 50.82; H, 5.32; N, 8.38.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[F:12][C:13]([F:44])([F:43])[C:14]1[CH:15]=[C:16]([CH:40]=[CH:41][CH:42]=1)[CH2:17][NH:18][C:19](=[O:39])[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([C:26]2[CH:31]=[C:30]([N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[CH:29]=[CH:28][C:27]=2[NH2:38])[CH:21]=1.C(N(C(C)C)CC)(C)C.ClCCl>C1COCC1>[Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:38][C:27]1[CH:28]=[CH:29][C:30]([N:32]2[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]2)=[CH:31][C:26]=1[C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][N:23]=1)[C:19]([NH:18][CH2:17][C:16]1[CH:40]=[CH:41][CH:42]=[C:14]([C:13]([F:44])([F:12])[F:43])[CH:15]=1)=[O:39])=[O:7]
Reactant: Nc1ccc(N2CCCCC2)cc1-c1cc(C(=O)NCc2cccc(C(F)(F)F)c2)ccn1
Reactant: O=C(Cl)c1cccc(CCl)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CCl)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-(Chloromethyl)benzoyl chloride was added dropwise to a 0° C. solution of 900 mg of N-(3-(trifluoromethyl)benzyl)-2-(2-amino-5-(piperidin-1-yl)phenyl)isonicotinamide 4.1c 1.02 g of diisopropylethylamine in 10 mL of a 1:1 mixture of dichloromethane and THF. The mixture was warmed to 25° C. and stirred for 1 h, after which it was washed five times with aqueous hydrochloric acid, once with a saturated aqueous solution of sodium bicarbonate, and once with water. The solution was dried and the solvent was evaporated to give 1.24 g of product as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][C:24]3[C:29]([Cl:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=3[Cl:32])=[CH:16][CH:15]=2)[C@@H:10]([C:33]([N:35]([CH2:39][C:40]2[CH:41]=[C:42]([CH:51]=[C:52]([CH2:54][CH2:55][CH2:56][O:57][CH3:58])[CH:53]=2)[O:43][CH2:44][C@@H:45]2[CH2:47][C@H:46]2[C:48]([OH:50])=[O:49])[CH:36]2[CH2:38][CH2:37]2)=[O:34])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH2:74]1[C:82]2[C:77](=[CH:78][C:79](O)=[CH:80][CH:81]=2)[CH2:76][CH2:75]1.[H-].[Na+]>C(Cl)Cl.C1COCC1>[CH:36]1([N:35]([CH2:39][C:40]2[CH:53]=[C:52]([CH2:54][CH2:55][CH2:56][O:57][CH3:58])[CH:51]=[C:42]([O:43][CH2:44][C@@H:45]3[CH2:47][C@H:46]3[C:48]([O:50][C:79]3[CH:78]=[C:77]4[C:82](=[CH:81][CH:80]=3)[CH2:74][CH2:75][CH2:76]4)=[O:49])[CH:41]=2)[C:33]([C@@H:10]2[C@@H:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][C:24]4[C:29]([Cl:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=4[Cl:32])=[CH:16][CH:15]=3)[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9]2)=[O:34])[CH2:37][CH2:38]1
Reactant: Oc1ccc2c(c1)CCC2
Reactant: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OC[C@@H]2C[C@H]2C(=O)O)c1
Agent: CC(C)COC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OC[C@@H]2C[C@H]2C(=O)Oc2ccc3c(c2)CCC3)c1
Temperature: -20 °C
Reaction time: 0.75 h

Procedure:
To a solution of (1R,2R)-2-{[3-{[[((3R,4S)-1-(tert-butoxycarbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidin-3-yl)carbonyl](cyclopropyl)-amino]methyl}-5-(3-methoxypropyl)phenoxy]methyl}cyclopropanecarboxylic acid (1 eq.) from Example 4/Step 1 in DCM (0.1 M) at −20° C. was added N-methylmorpholine (1.3 eq.) and isobutylchloroformate (1.3 eq.). The reaction was stirred at −20° C. for 45 min. Meanwhile, a solution of indan-5-ol (2 eq) in THF (0.2) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 1 eq.), stirred for 30 min at rt, and added to the reaction at −15° C. The reaction was stirred at rt for 18 h and then quenched with saturated aqueous NaHCO3 solution. The aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 35% EtOAc in Hex) to afford the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[BH4-].[Na+]>O1CCCC1.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([OH:18])[CH3:17])=[CH:12][CH:11]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(F)cc1-c1ccc(C(C)=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ncc(F)cc1-c1ccc(C(C)O)cc1
Yield: 51.2 %

Procedure:
A mixture of 3-bromo-5-fluoro-2-methoxy-pyridine (1.0 g, 4.9 mmol), 4-acetylphenylboronic acid (1.59 g, 9.7 mmol), tetrakis(triphenylphosphine)palladium (0) (0.28 g, 0.24 mmol), 2M aqueous sodium carbonate solution (2.4 ml) and 1,2-dimethoxyethane (5 ml) was heated in a microwave oven at 150° C. for 20 min. The solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic phase was washed with water, brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue chromatographed on silica gel eluting with 3:1 heptane/ethyl acetate to give 1-[4-(5-fluoro-2-methoxy-pyridin-3-yl)-phenyl]-ethanone (1.0 g, 4.0 mmol, 82%). 1-[4-(5-fluoro-2-methoxy-pyridin-3-yl)-phenyl]-ethanone (1.0 g, 4.1 mmol) was treated with sodium borohydride (4.0 eq) in tetrahydrofuran and dichloromethane at room temperature. The solvent was evaporated to give 1-[4-(5-fluoro-2-methoxy-pyridin-3-yl)-phenyl]-ethanol (0.51 g, 2.1 mmol, 51%). To a solution 1-[4-(5-fluoro-2-methoxy-pyridin-3-yl)-phenyl]-ethanol (0.5 g, 2.0 mmol) in tetrahydrofuran (5 ml) was added triphenylphosphine (0.63 g, 2.4 mmol) and pthalimide (0.35 g, 2.4 mmol). The reaction was cooled to below 5° C. before adding diethylazodicarboxylate (0.42 g, 2.4 mmol) in a dropwise manner maintaining the temperature below 5° C. The reaction mixture was stirred for 24 h at room temperature. The solvent was evaporated and the residue partitioned between ethyl acetate and water.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([CH3:22])[CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]#[N:32]>CN(C=O)C>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:30][C:31]#[N:32])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([CH3:22])[CH:13]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc2c(c1)c1c(O)cccc1n2Cc1ccccc1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(OCC#N)cccc1n2Cc1ccccc1
Yield: 92.1 %

Procedure:
A mixture 9-benzyl-6-methyl-9H-carbazol-4-ol (1.4172 g, 0.0049 mol), potassium carbonate (0.8184 g, 0.0059 mol), bromoacetonitrile (0.75mL, 0.011 mol) and DMF (18 mL) is stirred at room temperature for 3 h. The mixture is then partitioned between water and dichloromethane and the combined organic layers are dried over sodium sulfate and concentrated to a residue. Water is added to the residue and solids precipitated. The solids are collected by filtration and washed with water, followed by a little hexane, and then vacuum dried at room temperature. The solids are chromatographed on silica gel (150 mL) using dichloromethane (100%) to give 1.4723 g (91%) of the title compound. An aliquot is recrystallized from ethyl acetate/hexane, chromatographed on silica gel (50 mL) using ethyl acetate/hexane (20/80) and then recrystallized again from ethyl acetate/dichloromethane/hexane; mp 188-188.25° C.; MS (ESI+) for C22H18N2O m/z 327.2 (M+H)+; IR (drift) 1497, 1467, 1447, 1365, 1340, 1305, 1264, 1237, 1152, 1126, 1053, 799, 781, 754, 711 cm−; 1H NMR (CDCl3) δ2.54, 5.06, 5.49, 6.73, 7.10, 7.25, 7.36, 8.10. Anal. Calcd for C22H18N2O: C, 80.96; H, 5.56; N, 8.58. Found: C, 80.62; H, 5.68; N, 8.55.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]([F:20])([F:19])[F:18])[CH2:13][CH2:12]2)=[CH:4][C:5]([NH:9][CH3:10])=[C:6]([CH:8]=1)[NH2:7].[N:21]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[C:32]([F:35])([F:34])[F:33])[C:27]#[N:28])=[C:22]=S.CC(C)N=C=NC(C)C>CN(C=O)C>[Cl:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]([F:19])([F:18])[F:20])[CH2:13][CH2:12]2)=[CH:4][C:5]2[N:9]([CH3:10])[C:22]([NH:21][C:24]3[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=3[C:32]([F:35])([F:34])[F:33])[C:27]#[N:28])=[N:7][C:6]=2[CH:8]=1
Reactant: N#Cc1ccc(C(F)(F)F)c(N=C=S)c1
Reactant: CNc1cc(N2CCC(C(F)(F)F)CC2)c(Cl)cc1N
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: Cn1c(Nc2cc(C#N)ccc2C(F)(F)F)nc2cc(Cl)c(N3CCC(C(F)(F)F)CC3)cc21

Procedure:
The sub-title compound was prepared in analogy to Example 76 using 5-chloro-2-methylamino-4-(4-trifluoromethyl-piperidin-1-yl)aniline (998 mg, 3.24 mmol), 3-isothiocyanato-4-(trifluoromethyl)benzonitrile (740 mg, 3.24 mmol), DIC (409 mg, 3.24 mmol) and DMF (7 mL).
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH2:10][CH2:9][CH:8]([NH2:11])[C:4]=2[CH:5]=[N:6][CH:7]=1.CCN(CC)CC.[C:19](Cl)(=[O:22])[CH2:20][CH3:21].O>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[C:3]2[CH2:10][CH2:9][CH:8]([NH:11][C:19](=[O:22])[CH2:20][CH3:21])[C:4]=2[CH:5]=[N:6][CH:7]=1
Reactant: CCC(=O)Cl
Reactant: NC1CCc2c(Br)cncc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCC(=O)NC1CCc2c(Br)cncc21
Reaction time: 2 h
Yield: 31.2 %

Procedure:
To a solution of 4-bromo-6,7-dihydro-5H-cyclopenta[c]pyridin-7-amine (650 mg, 3.05 mmol, 65% purity) and Et3N (400 mg, 3.97 mmol) in THF (20 mL) was added propionyl chloride (219 mg, 2.38 mmol) at 0° C. and stirring continued for 2 hours. Water (10 mL) and EtOAc (10 mL) were added and the aqueous layer was extracted with EtOAc (10 mL×3). The combined organic layers were dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was purified by column chromatography to afford the title compound (200 mg, 37.6%) as a white solid. MS: 270.9 (M+H+, 1Br).
Reaction SMILES: IC.[CH2:3]([N:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=2)[N:12]=[C:11]1[CH:22]([N:26]1[C:32](=[O:33])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[CH:23]([CH3:25])[CH3:24])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:34]CN(CC)CC>C(Cl)Cl>[CH2:3]([N:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=2)[N:12]=[C:11]1[CH:22]([N:26]1[C:32](=[O:33])[CH2:31][CH2:30][N:29]([CH3:34])[CH2:28][CH2:27]1)[CH:23]([CH3:25])[CH3:24])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCN(CC)CC
Reactant: CC(C)C(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)N1CCNCCC1=O
Solvent: ClCCl
Solvent: CI
Product: CC(C)C(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)N1CCN(C)CCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
Iodomethane (23 μL, 0.37 mmol) was added to a solution containing 3-benzyl-7-chloro-2-[2-methyl-1-(7-oxo-[1,4]diazepan-1-yl)-propyl]-3H-quinazolin-4-one and Et3N (51.4 μL, 0.37 mmol) in CH2Cl2 (5 mL). The resulting mixture was stirred at RT overnight, diluted with CH2Cl2 (5 mL), washed with brine, dried and concentrated under vacuum. Purification by flash chromatography on silica gel (1–2% CH3OH in CH2Cl2) gave the title compound (65 mg, 70%) as a pale yellow solid: MS (ES) m/e 453.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][N:13]=1)[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6].[CH3:14][S:15](Cl)(=[O:17])=[O:16]>N1C=CC=CC=1>[CH3:14][S:15]([NH:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][N:13]=1)[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6])(=[O:17])=[O:16]
Reactant: CON(C)C(=O)c1ccnc(N)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1ccnc(NS(C)(=O)=O)c1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
2-Amino-N-methoxy-N-methyl-isonicotinamide (575 mg, 3.16 mmol) was dissolved in pyridine (4 mL), followed by the addition of methanesulfonyl chloride (0.73 mL, 9.48 mmol). The reaction was subsequently warmed to 40° C. and stirred 5h. The resultant mixture was quenched with 10% HCl, diluted with EtOAc, and the organic layer washed with 10% HCl and saturated sodium bicarbonate. The combined organics were dried with sodium sulfate, concentrated in vacuo, and purified via automated silica gel chromatography to produce the desired sulfonamide.