Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:7]([NH:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=2)[C:8]2[S:16][C:11]3=[CH:12][N:13]=[CH:14][CH:15]=[C:10]3[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:29]([O:31][C:32](=[O:36])[CH2:33][CH2:34][NH2:35])[CH3:30].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl-].[NH4+]>CN(C)C=O.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([NH:35][CH2:34][CH2:33][C:32]([O:31][CH2:29][CH3:30])=[O:36])=[O:25])=[CH:26][CH:27]=2)[C:8]2[S:16][C:11]3=[CH:12][N:13]=[CH:14][CH:15]=[C:10]3[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)sc2cnccc12
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCNC(=O)c1ccc(NC(c2sc3cnccc3c2C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
To a mixture of 4-{[cyclohexyl(3-methylthieno[2,3-c]pyridin-2-yl)methyl]amino}benzoic acid (201 mg) synthesized in Example A136(4), β-alanine ethyl ester hydrochloride (122 mg), 1-hydroxybenzotriazole monohydrate (121 mg), triethylamine (220 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (152 mg), and the mixture was stirred overnight at room temperature. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (60-100% ethyl acetate/hexane) to give the title object compound (209 mg, 83%) as a pale-yellow oil.
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:12]([C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:15]=1[C:16](O)=[O:17])[CH3:13]>>[CH2:12]([C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:15]=1[C:16]([NH:11][C@@H:7]1[CH2:8][CH2:9][CH2:10][C@@H:6]1[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:17])[CH3:13]
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Reactant: CCc1cccc(C)c1C(=O)O
Product: CCc1cccc(C)c1C(=O)N[C@@H]1CCC[C@@H]1N1CCCC1

Procedure:
The title compound, white solid, MS: m/e=301.3 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2-ethyl-6-methylbenzoic acid (CAS 106976-50-5).
Reaction SMILES: Cl.N(OC(C)(C)C)=O.[NH:9]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C@H:10]([C:17]([NH:19][C@H:20]([C:27]([NH:29]N)=[O:28])[CH2:21][O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:18])[CH2:11][O:12][C:13]([CH3:16])([CH3:15])[CH3:14].N[C@H:42]([C:47]([NH:49][C@H:50]([C:52]([O:54][CH3:55])=[O:53])[CH3:51])=[O:48])[CH2:43][C:44](=[O:46])[NH2:45].C(N1CCOCC1)C>C(OCC)(=O)C.CN(C)C=O>[NH:9]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C@H:10]([C:17]([NH:19][C@H:20]([C:27]([NH:29][C@H:42]([C:47]([NH:49][C@H:50]([C:52]([O:54][CH3:55])=[O:53])[CH3:51])=[O:48])[CH2:43][C:44](=[O:46])[NH2:45])=[O:28])[CH2:21][O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:18])[CH2:11][O:12][C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](COC(C)(C)C)C(=O)NN
Reactant: COC(=O)[C@H](C)NC(=O)[C@@H](N)CC(N)=O
Agent: CC(C)(C)ON=O
Agent: CCN1CCOCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](COC(C)(C)C)NC(=O)[C@H](COC(C)(C)C)NC(=O)OCc1ccccc1
Reaction time: 15 h

Procedure:
61.8 ml of 2.32 N-hydrochloric acid in ethyl acetate and 7.3 ml of tert.butyl nitrite are added to 25.95 g of Z-Ser(But)-Ser(But)-NH-NH2 in 200 ml of dimethylformamide at -10°. After 10 minutes a solution of 14.8 g of HCl.H-Asn-Ala-OMe and 36.16 ml of N-ethyl morpholine in 150 ml of dimethylformamide is added dropwise and the mixture is then kept for one hour at -10° and 15 hours at 0°. The solution is freed from the solvent by evaporation, the residue is taken up in chloroform and washed with sodium bicarbonate, dilute hydrochloric acid and with water. The Z-Ser(But)-Ser(But)-Asn-Ala-OCH3 obtained after evaporation of the solvent is reprecipitated from chloroform-petroleum ether. The Rf-value on silicagel in the system chloroform-methanol 9:1 is 0.35.
Reaction SMILES: [C@@H:1]12[CH2:7][NH:6][C@@H:5]1[CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:2]2.[Br:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23](Br)[CH:24]=1>>[Br:18][C:19]1[CH:24]=[C:23]([N:6]2[CH2:7][C@@H:1]3[C@H:5]2[CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:2]3)[CH:22]=[N:21][CH:20]=1
Reactant: Brc1cncc(Br)c1
Reactant: O=C(OCc1ccccc1)N1C[C@@H]2CN[C@@H]2C1
Product: O=C(OCc1ccccc1)N1C[C@@H]2CN(c3cncc(Br)c3)[C@@H]2C1
Yield: 47 %

Procedure:
The product of Example 52D (230 mg, 1.0 mmol) and 3,5-dibromopyridine were processed as described in Example 1E. The crude product was purified by chromatography (SiO2,ethyl acetate, Rf. 0.2) to provide the title compound (180 mg, 47% yield). 1H NMR (MeOH-d4, 300 MHz) δ3.20(dd, J=12.5, 4.0 Hz, 1H), 3.30 (m, 2H), 3.40 (m, 1H), 3.64 (dd, J=7.8, 3.4 Hz, 1H), 3.95-4.10 (m, 3H), 4.75 (m, 1H), 5.15 (m, 2H), 3.40 7.05 (t, J=2.1 Hz, 1H), 7.24 (m, 3H), 7.35 (m, 2H), 7.70 (d, J=2.3 Hz, 1H), 7.93 (d, J=1.7 Hz, 1H); MS (DCI/NH3) m/z 390 (M+2+H)+, 388 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.Br[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[F:34]>>[F:34][C:28]1[C:29]([F:33])=[CH:30][CH:31]=[CH:32][C:27]=1[O:26][CH2:25][CH2:24][CH2:23][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][CH:2]2[OH:1])=[CH:13][CH:12]=1
Reactant: Fc1cccc(OCCCBr)c1F
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3cccc(F)c3F)cc2)C(O)C1

Procedure:
Analogously to Method I, 0.750 g of tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 0.776 g of 1-(3-bromopropoxy)-2,3-difluorobenzene are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.11 (1:2 EtOAc-heptane); Rt=5.13.
Reaction SMILES: Cl.[OH:2][C:3]1[N:7]([CH3:8])[N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[O:16]1[CH2:20][CH2:19][C:18]([C:21]2[C:22]([CH3:34])=[C:23]([CH:27]=[CH:28][C:29]=2[S:30]([CH3:33])(=[O:32])=[O:31])[C:24](Cl)=[O:25])=[N:17]1.CC(C)(O)C#N>C(Cl)(Cl)Cl>[O:16]1[CH2:20][CH2:19][C:18]([C:21]2[C:22]([CH3:34])=[C:23]([CH:27]=[CH:28][C:29]=2[S:30]([CH3:33])(=[O:32])=[O:31])[C:24]([C:4]2[CH:5]=[N:6][N:7]([CH3:8])[C:3]=2[OH:2])=[O:25])=[N:17]1
Reactant: Cn1nccc1O
Reactant: Cc1c(C(=O)Cl)ccc(S(C)(=O)=O)c1C1=NOCC1
Agent: CC(C)(O)C#N
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)c2cnn(C)c2O)ccc(S(C)(=O)=O)c1C1=NOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.5 %

Procedure:
To 2.75 g of 3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonyl-2-methylbenzoic acid were added 30 ml of benzene, then 1.7 ml of thionyl chloride and a drop of pyridine to heat at reflux for 3 hours. The reaction solution was cooled down. The solvent was distilled out under reduced pressure to give 2.90 g of 3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonyl-2-methylbenzoyl chloride. Separately 0.93 g of 5-hydroxy-1-methylpyrazole hydrochloride was dissolved in 20 ml of chloroform, and 1.60 g of triethylamine was added, while cooling with ice. Into the obtained solution was added dropwise 10 ml of a chloroform solution containing 1.90 g of 3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonyl-2-methylbenzoyl chloride to stir at room temperature for 30 minutes, and 0. 76 g of triethylamine and 0.16 g of acetone cyanohydrin were added to further stir overnight. The reaction solution was washed with dilute hydrochloric acid, then with a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled out under reduced pressure. Methanol was added to the residue. The obtained crystals were separated by filtration to give 1.59 g of the title compound as white crystals. m.p. 224~226° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=3)[C:14]([OH:16])=O)=[C:8]([CH3:20])[C:6]=2[N:7]=1.[CH2:27]([CH2:29][NH2:30])[OH:28]>>[Cl:1][C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=3)[C:14]([NH:30][CH2:29][CH2:27][OH:28])=[O:16])=[C:8]([CH3:20])[C:6]=2[N:7]=1
Reactant: Cc1c(-c2cccc(C(=O)O)c2)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: NCCO
Product: Cc1c(-c2cccc(C(=O)NCCO)c2)sc2c(N3CCOCC3)nc(Cl)nc12

Procedure:
3-(2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzoic acid (60 mg) was reacted with ethanolamine via General Procedure B to yield 3-(2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-(2-hydroxyethyl)benzamide. Crude 3-(2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-(2-hydroxyethyl)benzamide (74 mg) was coupled to 7-azaindole-5-boronic acid pinacol ester via General Procedure A. The product was purified by reverse phase HPLC to yield 2.6 mg of 426. MS (Q1) 515.2 (M)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]=1/[CH:17]=[CH:18]/[CH:19]([OH:28])[CH2:20][CH:21]([OH:27])[CH2:22][C:23]([O:25]C)=[O:24].[OH-].[Na+].C(O)C.Cl>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]=1/[CH:17]=[CH:18]/[CH:19]([OH:28])[CH2:20][CH:21]([OH:27])[CH2:22][C:23]([OH:25])=[O:24]
Reactant: COC(=O)CC(O)CC(O)/C=C/c1c(Cl)cc(Cl)cc1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CC(O)CC(O)/C=C/c1c(Cl)cc(Cl)cc1OCc1ccccc1
Yield: 99 %

Procedure:
A solution of methyl (E)-7-(2,4-dichloro-6-phenylmethoxyphenyl)-3,5-dihydroxy-6-heptenoate (34.8 g, 81.8 mmole), 1 N sodium hydroxide (82 ml, 82 mmole) and ethanol (200 ml) was stirred at 25° C. for 15 min. The reaction solution was acidified with 6 N hydrochloric acid, diluted with water (400 ml) and extracted with ether (3×200 ml). The combined organic extracts were washed with brine (3×100 ml), dried over magnesium sulfate and filtered. The filtrate was evaporated in vacuo, leaving the title compound as an orange oil (33.3 g, 99%): pmr (CDCl3) δ2.47 (2H, d), 4.30 (2H, br m), 4.98 (2H, s), 7.30 (5H, s).
Reaction SMILES: O1[CH2:6][CH2:5][N:4]([CH:7]=[CH:8][N+:9]([O-:11])=[O:10])CC1.NC1C=[C:15]2[C:19](=[CH:20][C:21]=1[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:29])[CH2:18][CH2:17][CH2:16]2.Cl.CC(C)=O>O>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:22]([C:21]1[CH:20]=[C:19]2[C:18]([CH2:17][CH2:16][CH2:15]2)=[CH:6][C:5]=1[NH:4][CH:7]=[CH:8][N+:9]([O-:11])=[O:10])=[O:30]
Reactant: O=[N+]([O-])C=CN1CCOCC1
Reactant: Nc1cc2c(cc1C(=O)c1ccccc1Cl)CCC2
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: O=C(c1ccccc1Cl)c1cc2c(cc1NC=C[N+](=O)[O-])CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
1-Morpholino-2-nitroethene (3.93 g) was added to a mixture of 5-amino-6-(2-chlorobenzoyl)indan (4.50 g), 6N HCl (15 ml) and acetone (45 ml) and the whole mixture was stirred at room temperature for one hour. To this reaction mixture was added water to give crystals of 6-(2-chlorobenzoyl)-5-(2-nitroethenylamino)indan (5.40 g, 95.2%). Recrystallization from ethanol gave yellow needles, mp. 225°-226° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].Cl.Cl[CH2:12][CH2:13][N:14]([CH3:16])[CH3:15].C(=O)(O)[O-].[Na+]>>[CH3:15][N:14]([CH3:16])[CH2:13][CH2:12][NH:5][C:4]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=1
Reactant: CN(C)CCCl
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CN(C)CCNc1ccc(Cl)c(Cl)c1

Procedure:
In the manner given in Example 1, 3,4-dichloroaniline, 1-chloro-2-dimethylaminoethane hydrochloride, and sodium bicarbonate are heated to give N,N-dimethyl-N'-(3,4-dichlorophenyl)ethylenediamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[CH2:7][CH2:8][CH2:9][C@H:10](O)[CH2:11][C:5]=2[CH:4]=1.[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[CH2:7][CH2:8][CH2:9][C@@H:10]([N:19]3[C:18](=[O:20])[C:17]4=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]4[C:15]3=[O:25])[CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)C[C@@H](O)CCC2
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C[C@H](N1C(=O)c3ccccc3C1=O)CCC2
Temperature: 25 °C
Reaction time: 48 h
Yield: 25.7 %

Procedure:
To a mixture of (S)-3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ol (1.00 g), phthalimide (0.77 g), and triphenylphosphine (1.36 g) in dry tetrahydrofuran, was added dropwise a solution of diethyl azodicarboxylate (0.91 g) in dry tetrahydrofuran (3 ml) at 26° C.~33° C. The mixture was stirred at ambient temperature for 2 days. The solvent was evaporated in vacuo. Diethyl ether (30 ml) was added to the residue and the mixture was stirred and the resulting precipitates (triphenyl phosphinoxide) were removed by filtration. The filtrate was evaporated in vacuo. The residue was purified by column chromatography (silica gel, n-hexane:ethyl acetate=5:1) to give (R)-N-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)phthalimide as a white powder (0.43 g).
Reaction SMILES: C([O:3][C:4]1[N:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[CH:13]=[CH:12][NH:11][C:10](=O)[C:8]=2[N:9]=1)C.P(Cl)(Cl)([Cl:30])=O>>[Cl:30][C:10]1[C:8]2[NH:9][C:4](=[O:3])[N:5]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][CH:17]=3)[C:6](=[O:15])[C:7]=2[CH:13]=[CH:12][N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOc1nc2c(=O)[nH]ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Product: O=c1[nH]c2c(Cl)nccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture of 2-ethoxy-3-[4-(2,2,2-trifluoroethoxy)phenyl]-3,7-dihydropyrido[3,4-d]pyrimidine-4,8-dione (763 mg) and phosphorus oxychloride (10 ml) was stirred at 100° C. for 5 hr, allowed to be cooled to room temperature, and concentrated under reduced pressure. To the residue was added toluene, and the mixture was again concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (437 mg).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:36]([CH2:38][NH2:39])[OH:37]>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][NH:39][CH2:38][CH2:36][OH:37])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Reactant: NCCO
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CNCCO)no1

Procedure:
Method as for preparation 5 using tert-butyl (3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (489 mg, 0.97 mmol) and ethanolamine (250 μl, 3.87 mmol) as starting materials.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[C:10](Cl)(=[O:19])/[CH:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([NH:5][C:10](=[O:19])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1ccc(N)cc1C
Reactant: O=C(Cl)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)/C=C/c2ccccc2)cc1C
Temperature: 25 °C
Yield: 57.5 %

Procedure:
3,4-Dimethylaniline (5.20 g, 42.9 mmol) was dissolved in 150 mL of THF and treated with trans-cinnamoyl chloride (7.5 g, 45 mmol) with vigorous stirring at room temperature. After 2 hours the mixture was quenched with 10 mL of H2O and extracted with EtOAc (3×100 mL). The combined organics were washed with saturated solution of Na2CO3, brine, dried over MgSO4 and then concentrated in vacuo to yield the title compound as a pure white crystalline solid (6.2 g, 67%). MS (ES) m/e 252 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: Nc1ccccc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: Nc1ccccc1C=O
Yield: 96.6 %

Procedure:
2-Aminobenzyl alcohol (ex. Aldrich) (2 g) was oxidised with activated manganese dioxide (2.7 g) in chloroform over 20 hours. After filtration and concentration the crude product was purified by column chromatography on silica (ethyl acetate) to give 2-aminobenzaldehyde (1.9 g) as a dark-red oil which was used directly. The latter in xylene (70 ml) was heated under reflux in a Dean-Stark apparatus with ethyl cyanoacetate (3.7 g) (ex. Aldrich) and piperidine (0.8 ml). Upon cooling the 2-hydroxy-3-cyanoquinoline was collected by filtration, washed with ether, dried and converted to the 2-chloro-3-cyanoquinoline.
Reaction SMILES: [CH:1]1([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7]([C:15]3[CH:20]=[CH:19][C:18]([S:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:36])C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:22]1([S:21]([C:18]2[CH:19]=[CH:20][C:15]([C:7]3[N:6]=[C:5]([CH:1]4[CH2:2][CH2:3][CH2:4]4)[N:9]4[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]=34)=[CH:16][CH:17]=2)=[O:36])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Nc1nccn2c(C3CCC3)nc(-c3ccc(Sc4ccccc4)cc3)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Nc1nccn2c(C3CCC3)nc(-c3ccc(S(=O)c4ccccc4)cc3)c12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-cyclobutyl-1-(4-phenylsulfanylphenyl)-imidazo[1,5-a]pyrazin-8-ylamine (15.0 mg, 0.0403 mmol) in DCM (3 mL, 0.05 mol) at 0° C. was added a solution of m-chloroperbenzoic acid (10.4 mg, 0.0604 mmol) in DCM. The mixture was stirred at 0° C. for 30 min. Sat. aq. NaHCO3 solution was added to quench, and the material was transferred to a separatory funnel. The organic layer was concentrated in vacuo and redissolved in DMF (1 mL) for Gilson HPLC separation. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3): δ=1.98-2.09 (m, 1H), 2.11-2.23 (m, 1H), 2.44-2.53 (m, 2H), 2.55-2.65 (m, 2H), 3.80 (t, J=8.5 Hz, 1H), 7.04 (d, J=5.3 Hz, 1H), 7.13 (d, J=5.3 Hz, 1H), 7.47-7.53 (m, 3H), 7.68-7.71 (m, 2H), 7.79 (s, 4H). MS (ES+): m/z 389.02 (100) [MH+]. HPLC: tR=2.17 min (Open Lynx, polar—5 min).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)([O:3][CH2:4][CH3:5])=[O:2].[Br:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25].N1C=CC=CC=1>C(O)C>[Br:21][C:22]1[CH:23]=[C:24]([NH:25][C:15]2[C:14]3[C:9](=[CH:10][C:11]([O:19][CH3:20])=[C:12]([O:17][CH3:18])[CH:13]=3)[N:8]=[CH:7][C:6]=2[C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH:26]=[CH:27][CH:28]=1
Reactant: Nc1cccc(Br)c1
Reactant: CCOC(=O)c1cnc2cc(OC)c(OC)cc2c1Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)c1cnc2cc(OC)c(OC)cc2c1Nc1cccc(Br)c1

Procedure:
A mixture of 14.8 g of 3-carbethoxy-4-chloro-6,7-dimethoxylquinoline, 9.46 g of 3-bromoaniline, 4.05 ml of pyridine, and 150 ml of ethanol was refluxed for 30 min, evaporated to remove ethanol, and partitioned with dichloromethane-aq sodium bicarbonate. The organic layer was washed with water, dried, and concentrated. The residue was recrystallized from ethanol to give a white solid, mp 155-158° C.
Reaction SMILES: [CH:1]1([C:4]([NH:12][S:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])([CH3:11])[CH2:5][C:6](OCC)=[O:7])[CH2:3][CH2:2]1.CO.[NH3:21]>>[C:15]([S:13]([NH:12][C:4]([CH:1]1[CH2:3][CH2:2]1)([CH3:11])[CH2:5][C:6]([NH2:21])=[O:7])=[O:14])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCOC(=O)CC(C)(NS(=O)C(C)(C)C)C1CC1
Reactant: N
Solvent: CO
Product: CC(CC(N)=O)(NS(=O)C(C)(C)C)C1CC1
Temperature: 45 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
A solution of ethyl 3-cyclopropyl-3-(1,1-dimethylethylsulfinamido)butanoate (1.16 g, 4.21 mmol) in ammonia 7N in methanol (20 ml, 140 mmol) in a microwave sealed tube was stirred at 45° C. overnight. The volatiles were removed in vacuo and the residue was directly purified by flash chromatography on silica eluting with a gradient of dichloromethane/methanol to yield the title compound (155 mg, 15%); MS (ESI, m/z): 247.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:22][C:3]=1[C:4]([NH:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:8]=1)=[O:5].N1C=CC=CC=1.[CH3:38][N:39]([CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1)[C:40]([C:42]1[CH:43]=[C:44]([CH:48]=[CH:49][CH:50]=1)[C:45](Cl)=[O:46])=[O:41]>ClCCl>[CH3:38][N:39]([CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1)[C:40](=[O:41])[C:42]1[CH:50]=[CH:49][CH:48]=[C:44]([C:45]([NH:1][C:2]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:22][C:3]=2[C:4](=[O:5])[NH:6][C:7]2[N:11]=[CH:10][N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=3)[N:8]=2)=[O:46])[CH:43]=1
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Cl)c1
Reactant: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1ncn(-c2cccc(C(F)(F)F)c2)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2ncn(-c3cccc(C(F)(F)F)c3)n2)c1
Temperature: 2.5 °C
Yield: 14.9 %

Procedure:
Into a 100-mL round bottom flask, was placed a solution of 2-amino-5-(piperidin-1-yl)-N-(1-(3-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)benzamide (150 mg, 0.35 mmol, 1.00 equiv) in dichloromethane (20 mL), and pyridine (83 mg, 1.05 mmol, 3.01 equiv). This was followed by dropwise addition of a solution of 3-(methyl(2-morpholinoethyl)carbamoyl)benzoyl chloride (130 mg, 0.42 mmol, 1.20 equiv) in dichloromethane (10 mL) with stirring at 0-5° C. The resulting solution was stirred for 3 h at room temperature. The resulting solution was diluted with 30 mL of dichloromethane. The resulting mixture was washed with 1×20 mL of NH4Cl and 2×20 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product (200 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 36.7 mg (15%) of a yellow solid. 1H-NMR (400 MHz, DMSO, ppm): δ 11.43-11.33 (m, 2H), 9.70 (s, 1H), 9.43 (s, 1H), 8.77 (s, 1H), 8.26-8.18 (m, 3H), 8.06-7.93 (m, 2H), 7.86-7.79 (m, 2H), 7.68-7.62 (m, 2H), 7.52 (s, 1H), 7.30-7.28 (d, J=6.9 Hz, 1H), 4.59-4.57 (m, 1H), 4.18-3.83 (m, 27H), 3.44 (s, 3H), 3.27-3.26 (m, 5H), 3.18 (s, 3H), 2.96 (s, 4H), 1.69 (s, 4H), 1.59-1.52 (m, 3H). MS (ES, m/z): 705 [M+H]+.