Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:38])[CH:10]([CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[N:11]1[C:15]2[CH:16]=[C:17]([F:21])[C:18]([F:20])=[CH:19][C:14]=2[N:13]=[C:12]1[C:22]1[C:23]([O:30][CH3:31])=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.C(OC(=O)C)(=O)C.[N:50]([O-])=[O:51].[Na+]>>[CH2:1]([N:8]([N:50]=[O:51])[C:9](=[O:38])[CH:10]([CH:32]1[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1)[N:11]1[C:15]2[CH:16]=[C:17]([F:21])[C:18]([F:20])=[CH:19][C:14]=2[N:13]=[C:12]1[C:22]1[C:23]([O:30][CH3:31])=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2nc3cc(F)c(F)cc3n2C(C(=O)NCc2ccccc2)C2CCCCC2)c(OC)n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(-c2nc3cc(F)c(F)cc3n2C(C(=O)N(Cc2ccccc2)N=O)C2CCCCC2)c(OC)n1
Temperature: 25 °C

Procedure:
To an ice-cold solution of 15 g (28.81 mmol) N-benzyl-2-cyclohexyl-2-[2-(2,6-dimethoxy-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-acetamide in 94 ml (1642 mmol) acetic acid and 198 ml (3486 mmol) acetic anhydride were added in 5 portions over 30 min. 9.94 g (144 mmol) sodium nitrite. The resulting solution was allowed to warm to room temperature overnight. The resulting yellow suspension was evaporated and the yellow slurry was taken up in 500 ml saturated aqueous sodium bicarbonate solution and 1500 ml ethyl acetate. The aqueous layer was extracted twice with 1500 ml ethyl acetate and once with 500 ml ethyl acetate. The combined organic layers were washed with water and brine. The remaining unsoluble material was filtered off and the filtrate dried over magnesium sulfate, filtered and evaporated until a suspension has formed. This suspensions was filtered and the filter cake washed twice with 50 ml ice-cold ethyl acetate and dried in high vacuum. Light yellow solid. MS (Turbo Spray): m/z=550.3 [M+H].
Reaction SMILES: [CH2:1]([N:8]([CH2:15][C:16]1[C:21](Cl)=[N:20][C:19]([N:23]([CH3:27])[CH2:24][CH2:25][CH3:26])=[CH:18][N:17]=1)[CH2:9][C@@H:10]([OH:14])[CH2:11][O:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].O>CN(C=O)C>[CH2:1]([N:8]1[CH2:15][C:16]2[N:17]=[CH:18][C:19]([N:23]([CH3:27])[CH2:24][CH2:25][CH3:26])=[N:20][C:21]=2[O:14][C@@H:10]([CH2:11][O:12][CH3:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCN(C)c1cnc(CN(Cc2ccccc2)C[C@@H](O)COC)c(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN(C)c1cnc2c(n1)O[C@@H](COC)CN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.9 %

Procedure:
To a solution of (2R)-1-[benzyl({3-chloro-5-[methyl(propyl)amino]pyrazin-2-yl}methyl)amino]-3-methoxypropan-2-ol (574 mg) in DMF (15 mL) was added potassium tert-butoxide (197 mg), and the mixture was stirred at room temperature for 1.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient: 10→33% ethyl acetate/hexane) to give the title compound (468 mg, 90%).
Reaction SMILES: C(N(CC)CC)C.[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[S:18][C:17]([S:19](Cl)(=[O:21])=[O:20])=[CH:16][CH:15]=2)[CH:9]=1.Cl.[NH2:24][C@H:25]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:40]=[C:39]3[C:34]([CH:35]=[CH:36][N:37]=[C:38]3[Cl:41])=[CH:33][CH:32]=2)[C:26]1=[O:42]>CC#N>[Cl:41][C:38]1[C:39]2[C:34](=[CH:33][CH:32]=[C:31]([CH2:30][N:27]3[CH2:28][CH2:29][C@H:25]([NH:24][S:19]([C:17]4[S:18][C:14]([C:10]5[CH:9]=[N:8][CH:13]=[CH:12][CH:11]=5)=[CH:15][CH:16]=4)(=[O:21])=[O:20])[C:26]3=[O:42])[CH:40]=2)[CH:35]=[CH:36][N:37]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2cccnc2)s1
Reactant: N[C@H]1CCN(Cc2ccc3ccnc(Cl)c3c2)C1=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1[C@@H](NS(=O)(=O)c2ccc(-c3cccnc3)s2)CCN1Cc1ccc2ccnc(Cl)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
Triethylamine (0.35 mL, 2.5 mmol) is added dropwise to a solution of 5-pyridin-3-yl-thiophene-2-sulfonyl chloride (0.22 g, 0.85 mmol) and 3-(S)-amino-1-(1-chloro-isoquinolin-7-ylmethyl)-pyrrolidin-2-one hydrochloride (0.22 g, 0.71 mmol) in CH3CN (5 mL). The suspension is stirred at room temperature overnight then concentrated to dryness. The residue is diluted with methylene chloride and washed with saturated NaHCO3 solution and brine. The organic layer is dried over MgSO4, filtered, concentrated, and then purified by column chromatography eluting with a gradient of 1% MeOH/CH2Cl2 to 5% MeOH/CH2Cl2 to give the product (0.23 g, 0.45 mmol) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[N:3]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.Cl[CH2:32][C:33]1[S:34][CH:35]=[C:36]([CH3:38])[N:37]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:38][C:36]1[N:37]=[C:33]([CH2:32][N:7]2[C:6]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[S:10][C:5]=3[C:4](=[O:17])[N:3]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:2]2=[O:1])[S:34][CH:35]=1
Reactant: Cc1csc(CCl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1csc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)n1

Procedure:
According to GP1 tert-butyl 4-(2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (855 mg; compound B50) is reacted with 2-(chloromethyl)-4-methyl-1,3-thiazole (368 mg; compound D13) in the presence of potassium carbonate (276 mg) in DMF (15 ml). Using WU1 a solid is obtained which is purified by flash chromatography [silica gel, eluation gradient: DCM/MeOH, 100/0 to 95/5 (v/v)] to give the title compound as a solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH3:9].CC1(C)C(C)(C)OB([C:18]2[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])O1.C1(C)C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:18]2[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=[CH:27][CH:28]=2)=[C:3]([CH3:9])[CH:4]=1
Reactant: Cc1cc(Cl)ccc1Br
Reactant: CCOC(=O)c1ccccc1B1OC(C)(C)C(C)(C)O1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1ccccc1-c1ccc(Cl)cc1C
Temperature: 25 °C
Yield: 99 %

Procedure:
Under an argon atmosphere, a mixture of 2-bromo-5-chloro-toluene (20.55 g), ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (55.23 g), toluene (200 ml), water (125 ml), tripotassium phosphate (53.07 g) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride-dichloromethane complex (1.633 g) was stirred with heating under reflux for 1 hr. The reaction mixture was cooled to room temperature, activated carbon (1 g) was added and the mixture was stirred for 10 min at room temperature. The insoluble material was filtered off, and the filtrate was partitioned in a separatory funnel. The organic layer was washed twice with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=98/2) to give the title compound (27.20 g, 99%).
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([CH:19]=[CH:20][CH3:21])=[C:6]([CH:22]([CH3:24])[CH3:23])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[C:7]([CH2:19][CH2:20][CH3:21])=[C:6]([CH:22]([CH3:23])[CH3:24])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(1-propenyl)pyridine (Example 21) according to the procedure described in Example 1, Step H. 1H NMR (300 MHz, CDCl3): δ7.15 (m, 4 H), 4.33 (s, 2 H), 3.41 (sept, J=6.6 Hz, 1 H), 3.23 (sept, J=6.6 Hz, 1 H), 2.25 (m, 2 H), 1.33 (d, J=6.6 Hz, 6 H), 1.30 (d, J=6.6 Hz, 6 H), 1.27 (m, 1 H), 1.19 (m, 1 H), 0.76 (t, J=7 Hz, 3 H). FAB-MS: calculated for (C21H20FNO) 329, found 330 (M+H). Anal. Calcd for C21H28FNO: C, 76.56; H, 8.57; N, 4.25. Found: C, 76.55; H, 8.48; N, 4.11. mp 49-54°C. Rf=0.4 (20% ethyl acetate/hexane).
Reaction SMILES: N[C@H](C([NH:12][C@H:13]([C:19]([N:21]1[CH2:35][CH2:34][CH2:33][C@H:22]1[C:23]([N:25]1[CH2:32][CH2:31][CH2:30][C@H:26]1[C:27]([OH:29])=[O:28])=[O:24])=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])=O)CCCNC(=N)N.[NH2:36][C@H:37](C(N[C@H](C(N1CCC[C@H]1C(N1CCC[C@H]1C(O)=O)=O)=O)CCCNC(=N)N)=O)CCCCN>>[NH2:12][C@H:13]([C:19]([NH:21][C@H:22]([C:23]([N:25]1[CH2:32][CH2:31][CH2:30][C@H:26]1[C:27]([OH:29])=[O:28])=[O:24])[CH2:33][CH2:34][CH2:35][CH2:37][NH2:36])=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][NH2:18]
Reactant: N=C(N)NCCC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Reactant: N=C(N)NCCC[C@H](NC(=O)[C@@H](N)CCCCN)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Product: NCCCC[C@H](NC(=O)[C@@H](N)CCCCN)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
Arg-Lys-Pro-Pro; or Lys-Arg-Pro-Pro,
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([NH:22][C:23](=[O:29])[C:24](OCC)=[O:25])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:30][NH2:31]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([NH:22][C:23](=[O:29])[C:24]([NH:30][NH2:31])=[O:25])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)C(=O)OCC
Reactant: NN
Solvent: CO
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)C(=O)NN
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.5 %

Procedure:
To a solution of (R)-ethyl 4-(3′-chlorobiphenyl-4-yl)-3-(2-ethoxy-2-oxoacetamido)butanoate (450 mg, 1.08 mmol) in MeOH (24 mL) is added a solution of 50% wt hydrazine (0.068 ml, 1.08 mmol) in MeOH (10 mL) at −20° C. After stirring for 18 hours at room temperature, the reaction mixture is concentrated under reduced pressure to give (R)-ethyl 4-(3′-chlorobiphenyl-4-yl)-3-(2-hydrazinyl-2-oxoacetamido)butanoate (412 mg). HPLC retention time=1.76 minutes (condition A); MS (m+1)=404.1
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([N:10]([CH2:12][C:13]1[S:17][CH:16]=[C:15]([C:18]2[CH:19]=[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=2)[NH:23][CH:22]=[C:21]3[CH:30]2[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:38])=[O:37])[CH2:32][CH2:31]2)[CH:14]=1)[CH3:11])[CH3:9].[CH3:41][NH:42][CH2:43][CH3:44]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:39]([S:36]([N:33]1[CH2:34][CH2:35][CH:30]([C:21]2[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=[C:18]([C:15]4[CH:14]=[C:13]([CH2:12][N:10]([CH3:11])[CH2:8][C:9]5[CH:2]=[CH:41][N:42]=[CH:43][CH:44]=5)[S:17][CH:16]=4)[CH:19]=3)[NH:23][CH:22]=2)[CH2:31][CH2:32]1)(=[O:37])=[O:38])[CH3:40]
Reactant: CCNC
Reactant: CCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)Cc5ccncc5)c4)cc23)CC1
Yield: 46.6 %

Procedure:
The title compound was prepared according to the general procedure of 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting methyl(4-pyridinylmethyl)amine (122 mg, 1.0 mmol) for N-methylethanamine to afford 31.0 mg of the title compound (46.6%).
Reaction SMILES: Br[CH:2]([CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([SH:20])=[CH:16][CH:15]=1>>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([S:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1)[CH2:8][CH2:9][CH2:10][CH3:11])[CH3:7]
Reactant: CCCCC(Br)C(=O)OCC
Reactant: COc1ccc(S)cc1
Product: CCCCC(Sc1ccc(OC)cc1)C(=O)OCC
Yield: 98 %

Procedure:
2-(4-Methoxy-phenylsulfanyl)-hexanoic acid ethyl ester was prepared according to the general method as outlined in Example 1. Starting from ethyl 2-bromo,hexanoate (7 g, 32 mmol) and 4-methoxybenzenethiol (4.2 g, 30 mmol), 8.3 g of the product was isolated. Yield 98%; Light yellow oil; MS: 283 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:6](=[O:7])[CH2:5][C:4]([CH3:9])([CH3:8])[O:3]1.C[O-].[Na+].[Br:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:23][CH3:24])=[C:19]([CH:22]=1)[CH:20]=O>COCCOC.C(OCC)C>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:23][CH3:24])=[C:19]([CH:22]=1)[CH:20]=[C:5]1[C:4]([CH3:9])([CH3:8])[O:3][C:2]([CH3:10])([CH3:1])[C:6]1=[O:7]
Reactant: CC1(C)CC(=O)C(C)(C)O1
Reactant: CCc1ccc(Br)cc1C=O
Agent: C[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOCC
Product: CCc1ccc(Br)cc1C=C1C(=O)C(C)(C)OC1(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 94.9 %

Procedure:
To an ice-cold solution of dihydro-2,2,5,5-tetramethyl-3(2H)-furanone (13.4 g, 94.34 mmol) in anhydrous 1,2-dimethoxyethane (32 ml) is added sodium methoxide (5.6 g, 103.8 mmol) in one portion, and the reaction mixture is stirred at this temperature for 5 minutes. To the resulting slurry is then added a solution of 5-bromo-2-ethyl-benzaldehyde (20 g, 94.34 mmol) in 1,2-dimethoxyethane (32 ml) dropwise over 10 minutes. The solution is next stirred at 0° C. for 1 hour, then diluted with diethyl ether and washed with 2M hydrochloric acid (×2). Organic fractions are combined, dried over magnesium sulphate, filtered and the filtrate evaporated in vacuo to afford 4-(5-bromo-2-ethylbenzylidene)-2,2,5,5-tetramethyldihydrofuran-3-one (30.2 g) as a yellow liquid.
Reaction SMILES: [CH3:1][CH:2]([CH:4]1[CH2:8][O:7][C:6](=[O:9])[NH:5]1)[CH3:3].C([Li])CCC.CCCCCC.[CH3:21][CH:22]([CH3:28])[CH2:23][CH2:24][C:25](Cl)=[O:26]>O1CCCC1>[CH3:21][CH:22]([CH3:28])[CH2:23][CH2:24][C:25]([N:5]1[C@@H:4]([CH:2]([CH3:3])[CH3:1])[CH2:8][O:7][C:6]1=[O:9])=[O:26]
Reactant: CC(C)CCC(=O)Cl
Reactant: CC(C)C1COC(=O)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)CCC(=O)N1C(=O)OC[C@@H]1C(C)C
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 4-(2-propyl)-oxazolidine-2-one in anhydrous tetrahydrofuran (250 ml) under a nitrogen atmosphere at -78° C. was added in a dropwise fashion a solution of n-butyllithium in hexane (50 ml, 77.4 mmol) over 5 to 10 min. After stirring an additional 20 min at -78° C., 4-methylpentanoyl chloride (85.2 mmol) was added neat. The reaction was warmed to room temperature and stirred 1 to 2 h at the temperature. The reaction was quenched by adding 100 ml of saturated aqueous ammonium chloride and the volatiles were removed by rotary evaporation. The resulting aqueous residue was extracted three times with ether and the combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. Recrystallization from hexanes/ethyl acetate provided the desired compound.
Reaction SMILES: [C:1]1([N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17]1([NH2:20])[CH2:19][CH2:18]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:17]1([NH:20][C:8]([N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])[CH2:19][CH2:18]1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Reactant: NC1CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(NC1CC1)N(c1ccccc1)c1ccccc1

Procedure:
The thus formed solution of diphenylcarbamic acid chloride was then added dropwise upon stirring to a mixture of 114 g of cyclopropylamine, 202 g of triethylamine and 500 ml of toluene. During the addition the temperature inside the flask rose to 85° C. Subsequently the reaction mass was heated to boiling point for 15 minutes and then cooled. The precipitated triethylammoniumchloride was removed by suction and the solvent was distilled off in a vacuum. The remaining residue was subjected to recrystallization from diisopropylether. The yield in 1-cyclopropyl-3,3-diphenylurea was 440.2 g (87.2% of the theoretical value). The melting point was 98° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].C(N(C(C)C)CC)(C)C.[C:32](Cl)(=[O:42])[C:33]1[CH:41]=[CH:40][C:39]2[O:38][CH2:37][O:36][C:35]=2[CH:34]=1>C(Cl)Cl>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:32]([C:33]3[CH:41]=[CH:40][C:39]4[O:38][CH2:37][O:36][C:35]=4[CH:34]=3)=[O:42])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4ccc5c(c4)OCO5)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.16 mmol) in CH2Cl2 (60 ml), was added diisopropylethylamine (0.94 mL, 5.4 mmol) and piperonyloyl chloride (0.5 g, 2.8 mmol). The mixture was stirred at room temperature overnight and a suspension was obtained. The reaction mixture was quenched by the addition of MeOH (1 mL). The suspension was filtered, and the solid was rinsed with CH2Cl2 (10 mL) to afford benzo[1,3]dioxole-5-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide as a white solid (0.8 g, 85%): mp, 231-233° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=2.7 (99%); 1H NMR (DMSO-d6): δ 2.06-2.10 (m, 1H), 2.53-2.64 (m, 2H), 2.86-2.97 (m, 1H), 4.92 (d, J=5.6 Hz, 2H), 5.14-5.20 (dd, J=5, 12 Hz, 1H), 6.11 (s, 2H), 7.03 (d, J=8.1 Hz, 1H), 7.45-7.85 (m, 5H), 9.00 (t, J=6 Hz, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 21.97, 30.92, 38.33, 48.85, 101.68, 107.34, 107.90, 121.81, 122.35, 127.08, 127.88, 131.50, 133.01, 134.77, 139.44, 147.36, 149.87, 165.70, 166.96, 167.52, 169.82, 172.74. Anal Calcd for C22H17N3O7+0.2H2O: C, 60.19; H, 4.00; N, 9.57. Found: C, 60.15; H, 3.71; N, 9.46.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:16][CH2:15][C@H:14]([NH:17]C(=O)OC(C)(C)C)[CH2:13]2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].[ClH:26]>C(OCC)(=O)C>[ClH:26].[ClH:26].[NH2:17][C@H:14]1[CH2:15][CH2:16][N:12]([C:9]2[CH:8]=[CH:7][C:6]([S:3]([N:2]([CH3:25])[CH3:1])(=[O:4])=[O:5])=[CH:11][CH:10]=2)[CH2:13]1
Reactant: CN(C)S(=O)(=O)c1ccc(N2CC[C@H](NC(=O)OC(C)(C)C)C2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(C)S(=O)(=O)c1ccc(N2CC[C@H](N)C2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
In ethyl acetate was dissolved 8.39 g of tert-butyl [(S)-1-(4-dimethylsulfamoylphenyl)-pyrrolidin-3-yl]-carbamate, 200 ml of a solution of 4M hydrochloric acid in ethyl acetate was added thereto, and the mixture was stirred at room temperature for 3 days. The solvent was evaporated, and then, diethyl ether was added to the residue, and the precipitates were collected by filtration to obtain 4-[(S)-3-aminopyrrolidin-1-yl]-N,N-dimethyl-benzenesulfonamide dihydrochloride. To the 4-[(S)-3-aminopyrrolidin-1-yl]-N,N-dimethyl-benzenesulfonamide dihydrochloride were added a saturated aqueous sodium bicarbonate solution and chloroform, the mixture was stirred and the liquids were separated. The organic layer was dried and concentrated under reduced pressure to obtain 5.85 g of 4-[(S)-3-aminopyrrolidin-1-yl]-N,N-dimethyl-benzenesulfonamide.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:19]([C:21]4([N:47](C=O)[CH3:48])[CH2:25][CH2:24][N:23]([CH2:26][C:27](=[O:46])[N:28]5[CH2:33][CH:32]=[C:31]([C:34]6[CH:39]=[CH:38][C:37]([C:40]7[N:45]=[CH:44][CH:43]=[CH:42][N:41]=7)=[CH:36][CH:35]=6)[CH2:30][CH2:29]5)[CH2:22]4)=[O:20])[CH:16]=3)[NH:11][N:10]=2)=[CH:5][CH:4]=1.O.[OH-].[Na+]>CO>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:19]([C:21]4([NH:47][CH3:48])[CH2:25][CH2:24][N:23]([CH2:26][C:27](=[O:46])[N:28]5[CH2:29][CH:30]=[C:31]([C:34]6[CH:39]=[CH:38][C:37]([C:40]7[N:41]=[CH:42][CH:43]=[CH:44][N:45]=7)=[CH:36][CH:35]=6)[CH2:32][CH2:33]5)[CH2:22]4)=[O:20])[CH:16]=3)[NH:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: CN(C=O)C1(C(=O)Nc2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)CCN(CC(=O)N2CC=C(c3ccc(-c4ncccn4)cc3)CC2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CNC1(C(=O)Nc2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)CCN(CC(=O)N2CC=C(c3ccc(-c4ncccn4)cc3)CC2)C1

Procedure:
Added 2M HCl (2 ml) to a solution of 3-(Formyl-methyl-amino)-1-{2-oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-ethyl}-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1H-indazol-5-yl]-amide (8T) (11 mg, 0.017 mmol) in MeOH (5 ml) at room temperature for 4 days. Evaporated solvent Added H2O (20 ml), basified with 1N NaOH (2 ml), and extracted with MeCl2 (50 ml). Separated organic layer, dried over MgSO4, filtered and evaporated solvent, yielding residue which chromatographed on silica gel eluting with 10% MeCl2/MeOH yielding 9T (5 mg) ESMS (MH 631)
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]([CH3:14])=[C:8]([C:10]([O:12]C)=[O:11])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].Cl>C1COCC1.O>[C:1]([C:5]1[O:6][C:7]([CH3:14])=[C:8]([C:10]([OH:12])=[O:11])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1nc(C(C)(C)C)oc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(C(C)(C)C)nc1C(=O)O
Temperature: 25 °C
Reaction time: 19 h
Yield: 99.2 %

Procedure:
A mixture of methyl 2-tert-butyl-5-methyloxazole-4-carboxylate (44 mg, 0.22 mmol) and lithium hydroxide hydrate (47 mg, 1.1 mmol) in THF (1 mL) and water (1 mL) was stirred at room temperature for 19 hours. To the reaction was added 1 M HCl(aq) (1.1 mL, 1.1 mmol) and water, and the reaction was extracted with ethyl acetate. The combined extracts were washed with water, dried over sodium sulfate, and evaporated to give 2-tert-butyl-5-methyloxazole-4-carboxylic acid (40 mg, 98% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 2.61 (s, 3H), 1.38 (s, 9H) ppm.
Reaction SMILES: C(O[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:25])[C@H:18]([OH:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.ClC1[C:36]2[C:31](=[CH:32][C:33]([CH3:37])=[CH:34][CH:35]=2)[N:30]=[C:29]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[OH:44])[N:28]=1.C(N(CC)CC)C>[Pd].CO>[OH:24][C@@H:18]([C:17]([N:14]1[CH2:13][CH2:12][N:11]([C:9]2[C:36]3[C:31](=[CH:32][C:33]([CH3:37])=[CH:34][CH:35]=3)[N:30]=[C:29]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[OH:44])[N:28]=2)[CH2:16][CH2:15]1)=[O:25])[CH2:19][C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)C[C@@H](O)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)C[C@@H](O)C(=O)N1CCN(c2nc(-c3ccccc3O)nc3cc(C)ccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.2 %

Procedure:
4-((R)-2-Hydroxy-3-methoxycarbonyl-propionyl)-piperazine-1-carboxylic acid benzyl ester (0.52 g, 1.5 mmol) and MeOH (15 mL) were stirred with 10% Pd/C under an H2 atmosphere at ambient pressure overnight. After filtration and evaporation of the solvent the residue was taken up in CH2Cl2, and 2-(4-chloro-7-methylquinazolin-2-yl)phenol (0.40 g, 1.50 mmol) plus triethylamine (0.41 mL, 3.00 mmol) were added. The reaction mixture was stirred at room temperature overnight, washed with water, dried over Na2SO4, and concentrated. Purification via silica gel chromatography using 0-10% MeOH/CH2Cl2 provided (R)-methyl 3-hydroxy-4-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-oxobutanoate (0.38 g, 57%). LC/MS: m/z 451.1 (M+H)+ at 2.18 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).