Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](=[O:40])[NH:19][C@H:20]([C:36]([O:38][CH3:39])=[O:37])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[C:29]=3[CH3:35])=[CH:24][CH:23]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:41][CH2:42][C@H:43]([C:45]4[CH:50]=[CH:49][CH:48]=[C:47]([OH:51])[CH:46]=4)[O:44][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:52]1([CH2:57]O)[CH2:56][CH2:55][CH2:54][CH2:53]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC(C)C)=O)=NC(OCC(C)C)=O>C(Cl)Cl.CCOC(C)=O.CO>[C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](=[O:40])[NH:19][C@H:20]([C:36]([O:38][CH3:39])=[O:37])[CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[C:29]=3[CH3:35])=[CH:26][CH:27]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:41][CH2:42][C@H:43]([C:45]4[CH:50]=[CH:49][CH:48]=[C:47]([O:51][CH2:57][CH:52]5[CH2:56][CH2:55][CH2:54][CH2:53]5)[CH:46]=4)[O:44][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1cccc(O)c1)CO3
Reactant: OCC1CCCC1
Agent: CC(C)COC(=O)N=NC(=O)OCC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1cccc(OCC2CCCC2)c1)CO3
Temperature: 0 °C
Reaction time: 4 h
Yield: 85.8 %

Procedure:
(3S,8S)-8-{(S)-2-[4-(2,3-Dimethyl-pyridin-4-yl)-phenyl]-1-methoxycarbonyl-ethyl-carbamoyl}-3-(3-hydroxy-phenyl)-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester (25 mg), cyclopentyl methanol (11 mg), triphenyl phosphine (38 mg) were taken in 1 mL of anhydrous DCM and cooled to 0° C. Diisobutyl azodicarboxylate (22 mg) was added and reaction was warned to room temperature and stirred for 4 hours. After the completion of the reaction, the reaction mixture was loaded onto a silica gel column (1:1 EtOAc:hexanes to 4% MeOH in 1:1 EtOAc:hexanes) to give (3S,8S)-3-(3-cyclopentylmethoxy-phenyl)-8-{(S)-2-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-1-methoxycarbonyl-ethylcarbamoyl}-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester (24 mg). This was taken up in 2 mL anhydrous DCM and cooled 0° C., HCl (0.5 mL, 4N in dioxane) was added and stirred at room temperature for 1 hour. All volatiles are evaporated and residue was precipitated from DCM/hexanes to get (S)-2-{[(3S,8S)-3-(3-cyclopentylmethoxy-phenyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester dihydrochloride (22 mg).
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].Cl.Cl.[CH3:17][N:18]([CH3:27])[C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1.C(N(CC)CC)C>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:24][CH2:23][C:22]1[CH:25]=[CH:26][C:19]([N:18]([CH3:27])[CH3:17])=[CH:20][CH:21]=1)#[N:2]
Reactant: CN(C)c1ccc(CN)cc1
Reactant: CC(C)OC(=NC#N)c1cccnc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CN(C)c1ccc(CN=C(NC#N)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.5 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (5 ml), and a solution of p-(dimethylamino)benzylamine dihydrochloride (0.65 g, 2.9 mmol) and triethylamine (0.64 g, 6.4 mmol) in methanol (5 ml) were added. The mixture was stirred at room temperature for 6 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrated residue thus obtained was extracted with ethyl acetate (50 ml×3). The ethyl acetate layer was washed with water (50 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residual concentrate thus obtained was subjected to chromatography on a silica gel column (WAKO GEL C-200, 30 g) eluting with chloroformmethanol (100:1). The eluted fractions were concentrated under reduced pressure and then crystallized from methanol-diethyl ether to give the title compound (0.63 g, 2.3 mmol, yield: 85%) as colorless powder.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:12][O:13][CH2:14][CH2:15][CH2:16][NH2:17].C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:17][CH2:16][CH2:15][CH2:14][O:13][CH3:12])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: COCCCN
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: COCCCNc1ccc2ncc(Br)n2n1

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and 3-methoxypropylamine according to general procedure 1 providing the intermediate (43 mg, 54%) as a clear oil: Rf=0.55 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CD3OD) δ 7.53 (d, J=9.6 Hz, 1H), 7.39 (s, 1H), 6.68 (d, J=9.7 Hz, 1H), 3.53 (t, J=6.2 Hz, 2H), 3.44 (t, J=6.9 Hz, 2H), 3.36 (s, 3H), 1.95 (quin, J=6.5 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][N:7]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[C@H:6]([C:19]2[NH:20][C:21]([C:24]3[CH:29]=[CH:28][C:27](B4OC(C)(C)C(C)(C)O4)=[CH:26][CH:25]=3)=[CH:22][N:23]=2)[CH2:5]1.Br[C:40]1[CH:45]=[CH:44][C:43]([C:46](=[O:56])[CH2:47][NH:48][C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:42][CH:41]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:51]([O:50][C:49]([NH:48][CH2:47][C:46]([C:43]1[CH:42]=[CH:41][C:40]([C:27]2[CH:28]=[CH:29][C:24]([C:21]3[NH:20][C:19]([C@@H:6]4[CH2:5][C@H:4]([CH2:3][O:2][CH3:1])[CH2:8][N:7]4[C:9]([O:11][CH2:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)=[O:10])=[N:23][CH:22]=3)=[CH:25][CH:26]=2)=[CH:45][CH:44]=1)=[O:56])=[O:55])([CH3:54])([CH3:52])[CH3:53]
Reactant: COC[C@H]1C[C@@H](c2ncc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)[nH]2)N(C(=O)OCc2ccccc2)C1
Reactant: CC(C)(C)OC(=O)NCC(=O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC[C@H]1C[C@@H](c2ncc(-c3ccc(-c4ccc(C(=O)CNC(=O)OC(C)(C)C)cc4)cc3)[nH]2)N(C(=O)OCc2ccccc2)C1
Temperature: 85 °C
Yield: 58.9 %

Procedure:
(2S,4S)-benzyl 4-(methoxymethyl)-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (500 mg, 0.97 mmol), tert-butyl 2-(4-bromophenyl)-2-oxoethylcarbamate (364 mg, 1.16 mmol), Pd(PPh3)4 (112 mg, 0.097 mmol), and K2CO3 (2M in H2O, 1.6 mL, 3.2 mmoL) were combined in DME (10 mL). The mixture was degassed with bubbling N2 for 10 min the heated to 85° C. for 18 h. After cooling, the reaction mixture was diluted with EtOAc, and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (0% to 30% MeOH/EtOAc) to afford product (357 mg, 56%).
Reaction SMILES: [CH:1]1[C:6]2[NH:7][C:8]3[C:9](=[CH:10][CH:11]=[C:12]4[C:20]=3[NH:19][C:18]3[C:13]4=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[I:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30](Cl)(=[O:32])=[O:31]>C1COCC1>[I:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([C:1]1[CH:2]=[CH:3][CH:4]=[C:5]2[C:6]=1[NH:7][C:8]1[C:9]2=[CH:10][CH:11]=[C:12]2[C:20]=1[NH:19][C:18]1[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:32])=[O:31]
Reactant: c1ccc2c(c1)[nH]c1c2ccc2c3ccccc3[nH]c21
Reactant: O=S(=O)(Cl)c1ccccc1I
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1I)c1cccc2c1[nH]c1c2ccc2c3ccccc3[nH]c21
Temperature: 40 °C
Reaction time: 12 h

Procedure:
43 g (169 mmol) of 11,12-dihydroindolo[2,3-a]carbazole are initially introduced in 1000 ml of THF, and 8.9 g (223.3 mmol) of NaH (60% in oil) are added at 0° C. 24 g (80 mmol) of 2-iodobenzenesulfonyl chloride are subsequently added to the mixture, which is then stirred at 40° C. for 12 h. The organic phase is dried over MgSO4, and the solvent is removed in vacuo. The residue is recrystallised from acetone and finally sublimed in a high vacuum. Yield: 29 g (574 mmol), 72% of theory, purity according to HPLC 99.9%.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[F:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=1)[NH2:13].C(N(CC)CC)C>C(Cl)Cl>[F:9][C:10]1[CH:11]=[C:12]([NH:13][C:6]([C:2]2[NH:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[CH:14]=[CH:15][CH:16]=1
Reactant: Nc1cccc(F)c1
Reactant: O=C(Cl)c1ccc[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(F)c1)c1ccc[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.7 %

Procedure:
To a solution of 1H-pyrrole-2-carbonyl chloride (1.3 g, 10 mmol) (from Example 30) in DCM (20 mL) was added 3-fluoroaniline (1.2 g, 10.7 mmol) and triethylamine (1.5 mL). The mixture was stirred at room temperature for overnight. The reaction was washed with NaOH, water, brine, dried and concentrated to give 750 mg (37%) of 1H-pyrrole-2-carboxylic acid (3-fluoro-phenyl)-amide.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:10][C:11]1[CH:12]=[C:13]([CH:21]=[CH:22][CH:23]=1)[O:14][CH2:15][C:16](OCC)=[O:17])(=O)C>O1CCCC1>[OH:17][CH2:16][CH2:15][O:14][C:13]1[CH:12]=[C:11]([OH:10])[CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)COc1cccc(OC(C)=O)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCOc1cccc(O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of lithium aluminum hydride (455 mg, 12 mmol) in tetrahydrofuren was dropped ethyl [3-(acetyloxy)phenoxy]acetate (1.19 g, 5 mmol) in tetrahydrofuran (20 ml) at room temperature, and the mixture was stirred for 2 hours at room temperature. The reaction was quenched by 10% hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed with water, 10% hydrochloric acid, an aqueous saturated sodium hydrogencarbonate solution and an aqueous saturated sodium chloride solution. The organic layer was dried over sodium sulfate. The solvent was removed under reduced pressure to give 3-(2-hydroxyethoxy)phenol (864 mg, quantitatively).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][CH3:23])=[C:14]([CH2:24][OH:25])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:29][CH:30]1[CH2:32][CH2:31]1>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][CH3:23])=[C:14]([CH2:24][O:25][CH2:29][CH:30]2[CH2:32][CH2:31]2)[CH:13]=3)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: BrCC1CC1
Reactant: CCc1nc2c(cc1CO)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Agent: [H-]
Agent: [Na+]
Product: CCc1nc2c(cc1COCC1CC1)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21

Procedure:
This compound was prepared in analogy to example 1, intermediate d) from (4R,9aR)-6-ethyl-7-hydroxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester, sodium hydride and (bromomethyl)cyclopropane.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([N:9](C=O)[CH2:10][C@@H:11]2[O:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C:24]4=[O:29])=[CH:19][CH:18]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1.ClCCl.CS(O)(=O)=O>CO>[CH:19]1[C:20]([N:23]2[C:24](=[O:29])[CH2:25][O:26][CH2:27][CH2:28]2)=[CH:21][CH:22]=[C:17]([N:13]2[C:14](=[O:16])[O:15][C@@H:11]([CH2:10][NH:9][C:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:8])[CH2:12]2)[CH:18]=1
Reactant: O=CN(C[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)C(=O)c1ccc(Cl)s1
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: CO
Product: O=C(NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)c1ccc(Cl)s1

Procedure:
In four neck round bottom flask charge 5-chloro-N-formyl-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide (120 g), dichloromethane(2400 ml) and 70% methanesulphonic acid (120 ml) at 25-30° C. Obtained reaction mixture is heated to reflux for 4 to 5 h. After completion of reaction, concentrate reaction mass under reduced pressure to obtain residue. Added Dichloromethane (120 ml) and slowly added Methanol (600 ml) to the residue. The precipitated solid is filtered off and washed by methanol (240 ml)
Reaction SMILES: [C:1]1(=[O:32])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:13]([O:25][CH3:26])[CH:12]=2)[CH2:7][C:8](O)=[O:9])[C:4](=[O:27])[C:3]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:2]12.C(N1C=CN=C1)([N:35]1C=CN=C1)=O.CN(C1C=CC=CN=1)C.[OH-].[NH4+]>>[C:1]1(=[O:32])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:13]([O:25][CH3:26])[CH:12]=2)[CH2:7][C:8]([NH2:35])=[O:9])[C:4](=[O:27])[C:3]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:2]12
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1cc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)ccc1OCc1ccccc1
Agent: CN(C)c1ccccn1
Agent: [NH4+]
Agent: [OH-]
Product: COc1cc(C(CC(N)=O)N2C(=O)c3ccccc3C2=O)ccc1OCc1ccccc1
Reaction time: 0.25 h
Yield: 64.6 %

Procedure:
A mixture of 3-phthalimido-3-(4-benzyloxy-3-methoxyphenyl)propionic acid (1.00 g, 2.32 mmol), carbonyldiimidazole (0.406 g, 2.50 mmol) and a catalytic amount of dimethylaminopyridine in 20 mL of dry tetrahydrofuiran under nitrogen was stirred for 1 hour. To the reaction solution was then added 0.25 mL of concentrated ammonium hydroxide. After 15 minutes, the reaction mixture was concentrated in vacuo to an oil which was diluted with 20 mL of water and stirred overnight. The resulting slurry was filtered and the solid dried to afford 0.645 g (65%) of 3-phthalimido-3-(4-benzyloxy-3-methoxyphenyl)propionamide as a white powder: 1H NMR (DMSO-d6) δ7.84 (m, 4 H, Ar), 7.60-7.25 (m, 5H), 7.53 (br s, 1H, CONH), 7.15-6.8 (m, 4H), 5.67 (t, 1H, J=7.8 Hz), 5.04 (s, 2H, OCH2), 3.75 (s, 3H, OMe), 3.19 (d, 2H, J=9, 16.5 Hz);13C NMR (DMSO-d6) δ171.1, 167.6, 148.8, 147.2, 137.0, 134.5, 132.0, 131.2, 128.3, 127.7, 127.6, 123.0, 119.3, 113.2, 111.4, 69.8, 55.5, 50.3, 36.9. Anal. Calcd for C25H22N2O5. Theory: C, 69.76; H, 5.15; N, 6.51. Found: C, 69.54; H, 5.13; N, 6.28.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:25])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=O.COC(C1NN=C(OCC2C(C3C=CC=CC=3)=NOC=2C)C=1)=O.[CH3:49][N:50]([CH3:52])[NH2:51]>>[CH3:49][N:50]([CH3:52])[NH:51][C:3]([C:5]1[N:6]([CH3:25])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:2]
Reactant: CN(C)N
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2C)nn1C
Agent: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)n[nH]1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)NN(C)C)n(C)n1
Yield: 96 %

Procedure:
As described for example 1b, 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (110 mg, 0.32 mmol), instead of 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester, was converted, using N,N-dimethylhydrazine instead of morpholine, to the title compound (114 mg, 96%) which was obtained as a white foam. MS: m/e=374.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][CH2:8][CH2:9][C:10](O)=[S:11])=[N:5][N:4]=[N:3]1.N1C=CC=CC=1.BrC(OC)=O.[CH3:24][CH:25]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1>O1CCCC1>[CH3:24][CH:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:10](=[S:11])[CH2:9][CH2:8][CH2:7][C:6]2[N:2]([CH3:1])[N:3]=[N:4][N:5]=2)[CH2:27][CH2:26]1
Reactant: Cn1nnnc1CCCC(O)=S
Reactant: CC1CCC(N)CC1
Agent: COC(=O)Br
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC1CCC(NC(=S)CCCc2nnnn2C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
To tetrahydrofuran (50 ml) are added 4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyric acid (45 mmole) and pyridine (50 mmole), and thereto is added dropwide with stirring methyl bromoformate (50 mmole) with keeping the inner temperature at 5°-15° C. by ice-cooling, and thereafter, the mixture is stirred at room temperature for one hour. To the mixture is added 4-methylcyclohexylamine (55 mmole), and the mixture is further stirred for 3 hours. After the reaction, the solvent is distilled off under reduced pressure, and the residue is dissolved in chloroform. The chloroform layer is washed with dilute aqueous sodium hydroxide solution, diluted hydrochloric acid and water in order, and dried over sodium sulfate. Inorganic materials are filtered off and the mother liquor is concentrated. The resulting residue is subjected to column chromatography (Wakogel C-200, eluting solvent, benzene:chloroform=4:1, V/V) to isolate N-(4-methylcyclohexyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide (yield: 45%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:27][C:28](=[O:39])[C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:31][CH:30]=2)=[C:6]([CH:26]=1)[C:7]([NH:9][C:10]1[CH:18]=[C:17]2[C:13]([CH:14]=[N:15][N:16]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:12][CH:11]=1)=[O:8].N1C=CC=CC=1.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>ClCCl.C1COCC1>[C:19]([N:16]1[C:17]2[C:13](=[CH:12][CH:11]=[C:10]([NH:9][C:7](=[O:8])[C:6]3[CH:26]=[C:2]([NH:1][S:47]([CH3:46])(=[O:49])=[O:48])[CH:3]=[CH:4][C:5]=3[NH:27][C:28](=[O:39])[C:29]3[CH:30]=[CH:31][C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:33][CH:34]=3)[CH:18]=2)[CH:14]=[N:15]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]
Reactant: CC(C)(C)OC(=O)n1ncc2ccc(NC(=O)c3cc(N)ccc3NC(=O)c3ccc(C(C)(C)C)cc3)cc21
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)n1ncc2ccc(NC(=O)c3cc(NS(C)(=O)=O)ccc3NC(=O)c3ccc(C(C)(C)C)cc3)cc21
Reaction time: 24 h
Yield: 83 %

Procedure:
To a stirring solution of 5-amino-N-(1-Boc-6-indazolyl)-2-[(4-t-butylbenzoyl)amino]benzamide (144 mg, 0.27 mmol) and pyridine (0.066 mL, 0.82 mmol) in dichloromethane (5 mL) and THF (5 mL) was added methanesulfonyl chloride (0.023 mL, 0.30 mL). After stirring for 24 h, the solvent was removed in vacuo and the residue was dissolved in ethyl acetate and washed with 1 M citric acid, water, satd aq NaHCO3, and brine. The organic phase was then dried with MgSO4, filtered and concentrated in vacuo and the resulting solid was recrystallized from dichloromethane/hexanes to give 137 mg (83%) of tan solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][CH:14]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:37]1([CH2:43][CH2:44][S:45][CH:46]([C:50](O)=[O:51])[C:47](O)=[O:48])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C1COCC1>[OH:51][C:50]1[CH:20]=[C:19]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)=[CH:14][CH:15]=2)[O:21][C:47](=[O:48])[C:46]=1[S:45][CH2:44][CH2:43][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CC(=O)c1ccc(OCc2ccc3ccccc3c2)cc1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2ccc(OCc3ccc4ccccc4c3)cc2)cc(O)c1SCCc1ccccc1

Procedure:
The title compound was prepared by Method A using 4'-(2-naphthalenylmethoxy)acetophenone (1.39 g, 5.06 mmol), lithium bis(trimethylsilyl)amide (0.930 g, 5.56 mmol), chlorotrimethylsilane (0.705 mL, 5.56 mmol), THF (57 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. 152-154° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.77 (t, 2 H), 2.98 (t, 2 H), 5.38 (s, 2 H), 6.68 (s, 1 H), 7.21 (m, 7 H), 7.54 (m, 2 H), 7.60 (d, 1 H), 7.96 (m, 4 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[C:3]=1[C:16]#[N:17].O=[C:19]([CH3:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[CH2:24]([O:23][C:21]([C:20]1[C:19]([CH3:26])=[N:1][C:2]2[C:3]([C:16]=1[NH2:17])=[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)[CH:5]=[CH:6][CH:7]=2)=[O:22])[CH3:25]
Reactant: CCOC(=O)CC(C)=O
Reactant: COc1cccc(-c2cccc(N)c2C#N)c1
Product: CCOC(=O)c1c(C)nc2cccc(-c3cccc(OC)c3)c2c1N

Procedure:
Prepared as in Example 2a from 3-amino-3′-methoxy-[1,1′-biphenyl]-2-carbonitrile (Example 114b) and ethyl 3-oxobutanoate as a pale yellow solid (55%). MS 337 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH3:16])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[NH2:37])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[NH:37][C:13](=[O:15])[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH3:16])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)Nc1ccccc1NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of (S)-2-benzyloxycarbonylaminopropionic acid (230 mg, 1.03 mmol), 4-(2-aminophenylamino)piperidine-1-carboxylic acid tertbutyl ester (200 mg, 0.686 mmol), HOBt (102 mg, 0.755 mmol), 4-methylmorpholine (166 μL, 1.51 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (197 mg, 1.03 mmol) in DCM (7 mL) was stirred at RT for 3 h. The reaction mixture was then diluted with additional DCM and the organic layer was washed with water, then dried and concentrated in vacuo affording 4-[2-((S)-2-benzyloxycarbonylaminopropionylamino)phenylamino]piperidine-1-carboxylic acid tertbutyl ester as a purple/brown oil (436 mg, quantitative). LCMS: RT 3.66 min [M+H]+ 497.2.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[C:7]([O:11][C:12](=[O:32])[CH2:13][O:14][C:15]1[CH:20]=[C:19]([CH:21]=O)[CH:18]=[C:17]([O:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:16]=1)([CH3:10])([CH3:9])[CH3:8].C([BH3-])#N.[Na+].C(O)(=O)C>CO.O>[C:7]([O:11][C:12]([CH2:13][O:14][C:15]1[CH:20]=[C:19]([CH:18]=[C:17]([O:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:16]=1)[CH2:21][NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[O:32])([CH3:9])([CH3:10])[CH3:8]
Reactant: CC(C)(C)OC(=O)COc1cc(C=O)cc(OCC(=O)OC(C)(C)C)c1
Reactant: NCCC(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)COc1cc(CNCCC(=O)O)cc(OCC(=O)OC(C)(C)C)c1
Temperature: 25 °C

Procedure:
Beta-alanine (0.5 g, 5.68 mmol) was dissolved in methanol (20 mL). (3-Tert-Butoxycarbonylmethoxy-5-formylphenoxy)acetic acid tert-butyl ester (2.08 g, 5.58 mmol) was dissolved in methanol (2 mL) and added. The mixture was heated to reflux for 1 hour and allowed to cool to room temperature. Sodium cyanoborohydride (282 mg, 4.54 mmol) was added and the mixture stirred at room temperature, after 1 hour acetic acid was added (2 mL) and the mixture was stirred for an additional hour before being poured into water (50 mL) and stirred overnight. The water phase was washed with ethyl acetate (2×50 mL). The organic phase was dried (Na2SO4) and solvent removed in vacuo to yield the crude product. The crude product was used in the next step without further purification.