Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CS(O[CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]2[O:25][N:24]=[C:23]([CH:26]([CH3:28])[CH3:27])[N:22]=2)[CH2:17][CH2:16]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[O:25][N:24]=[C:23]([CH:26]([CH3:28])[CH3:27])[N:22]=3)[CH2:17][CH2:16]2)=[CH:6][N:7]=1
Reactant: CC(C)c1noc(N2CCC(COS(C)(=O)=O)CC2)n1
Reactant: Oc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1noc(N2CCC(COc3ccc(Br)nc3)CC2)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
A mixture of 6-bromo-3-pyridinol (1 g, 5.75 mmol), {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl methanesulfonate (prepared as in Example 100, Steps 1-4, 1.74 g, 5.75 mmol), potassium carbonate (1.59 g, 11.49 mmol), and DMF (15 mL) stirred at 80° C. overnight. The mixture was cooled to room temperature, charged with water (100 mL), and was extracted with EtOAc. The organics were dried over MgSO4, filtered, and concentrated. The crude product was purified by chromatography on a silica gel column using 0 to 50% EtOAc/hexane to give 1.76 g (80%) of 2-bromo-5-[({1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]pyridine as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.03 (d, 1H, J=3.1 Hz), 7.36 (d, 1H, J=8.7 Hz), 7.07 (dd, 1H, Ja=8.7 Hz, Jb=3.1 Hz), 4.21 (dd, 2H, Ja=11.0 Hz, Jb=2.1 Hz), 3.84 (d, 2H, J=6.3 Hz), 3.09 (m, 2H), 2.94-2.83 (m, 1H), 2.12-1.98 (m, 1H), 1.92 (d, 2H, J=12.2 Hz), 1.36-1.53 (m, 2H), 1.28 (d, 6H, J=7.0 Hz); LRMS (ESI), m/z 381/383 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[C:6]([OH:8])=O.[NH2:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1O>O>[Cl:25][C:23]1[CH:22]=[CH:21][C:20]2[O:8][C:6]([C:5]3[CH:9]=[CH:10][C:11]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=4)=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:18][C:19]=2[CH:24]=1
Reactant: COc1cc(C(=O)O)ccc1-c1ccccn1
Reactant: Nc1cc(Cl)ccc1O
Solvent: O
Product: COc1cc(-c2nc3cc(Cl)ccc3o2)ccc1-c1ccccn1

Procedure:
3-Methoxy-4-pyridin-2-yl benzoic acid (500 mg, 2.2 mmol), 2-amino-4-chlorophenol (620 mg, 4.3 mmol) and trimethyl silylpolyphosphate (2 mL) was heated to 180° C. overnight under argon. To the cooled reaction mixture, water (100 mL) was added and extracted with EtOAc (4×20 mL). Set aside organic layer. Filtered aqueous layer through Celite pad and basified filtrate to pH 9 (solid NaHCO3). Extracted with EtOAc (2×30 mL), combined all organic layers and concentrated in vacuo. The resulting orange oil was purified by flash chromatography using a gradient elution of 15:85 ethyl acetate:hexane to 1:1 ethyl acetate:hexane to give the desired intermediate, 5-chloro-2-(3-methoxy-4-pyridin-2-ylphenyl)-1,3-benzoxazole as a colorless solid.
Reaction SMILES: [H-].[Na+].[C:3]([N:13]1[CH2:17][CH2:16][C@H:15]([NH:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:14]1)([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].Br[CH2:26][C:27]([O:29][CH3:30])=[O:28]>C1COCC1>[C:3]([N:13]1[CH2:17][CH2:16][C@H:15]([N:18]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH2:14]1)([O:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:4]
Reactant: COC(=O)CBr
Reactant: O=C(OCc1ccccc1)N1CC[C@H](NC2CCCCC2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CN(C1CCCCC1)[C@H]1CCN(C(=O)OCc2ccccc2)C1
Reaction time: 0.5 h
Yield: 90 %

Procedure:
NaH (60% in mineral oil, 52.0 mg, 1.30 mmol) was placed in a round-bottom flask, filled with nitrogen, and then THF (10 mL) was added. A solution of (3S)-1-Cbz-3-(cyclohexylamino)pyrrolidine (302 mg, 1.00 mmol) prepared in Intermediate 2 in THF was added dropwise at 0° C., and the reaction mixture was stirred for 30 min until no further gas evolution occurred, followed by slow addition of methyl bromoacetate. After 4 h, the reaction, mixture was quenched with water and extracted with EtOAc. The extracts were dried over MgSO4 and concentrated in vacuo, and the residue was purified by column chomatography (EtOAc/Hex=1/2) to give the title compound (227 mg, 90.0%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[F:10][C:11]([F:25])([F:24])[C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH:21]([CH3:23])[CH3:22])[C:19]#[N:20])=[CH:14][CH:13]=1.Br[CH2:27][CH2:28][CH2:29][Cl:30]>C1(C)C=CC=CC=1.O1CCCC1>[F:10][C:11]([F:24])([F:25])[C:12]1[CH:13]=[CH:14][C:15]([C:18]([CH:21]([CH3:23])[CH3:22])([CH2:27][CH2:28][CH2:29][Cl:30])[C:19]#[N:20])=[CH:16][CH:17]=1
Reactant: ClCCCBr
Reactant: CC(C)C(C#N)c1ccc(C(F)(F)F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)C(C#N)(CCCCl)c1ccc(C(F)(F)F)cc1
Yield: 89.2 %

Procedure:
To a solution consisting of a 0.5 M solution of bis(trimethylsilyl)amide in toluene (2.2 mL, (1.1 mmoles) and tetrahydrofuran (7.8 mL) stirring at −78° under an argon atmosphere was added dropwise a solution of the compound of Example 7, Step (a) (227 g, 1.00 mmole) in tetrahydrofuran (1.0 mL). After stirring for 1.0 hour at −78°, 3-bromo-1-chloropropane (236 mg, 1.50 mmoles) was added in one portion, and the resulting mixture was stirred for 30 minutes at −78° and then 2.0 hours at room temperature. The mixture was partitioned between diethyl ether and water, the aqueous layer was extracted with ether, and the combined organic extracts were washed with water and then brine. After drying over sodium sulfate, the solution was filtered and then evaporated. A compound (271 mg) was obtained as a red oil which was characterized by NMR as follows: 1H NMR(CDCl3) d 7.65(d, 2H), 7.53(d, 2H), 3.48(m, 2H), 1.19(d, 3H), 0.79(d, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[CH:47]=[CH:46][C:39]2[S:40][C:41](B(O)O)=[CH:42][C:38]=2[CH:37]=1>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])(O)=O.[Na+].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:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:41]3[S:40][C:39]4[CH:46]=[CH:47][C:36]([F:35])=[CH:37][C:38]=4[CH:42]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Reactant: OB(O)c1cc2cc(F)ccc2s1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(-c2cc3cc(F)ccc3s2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O

Procedure:
A solution of tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (33 mg, 0.066 mmol), 5-fluorobenzo[b]thiophen-2-ylboronic acid (12.91 mg, 0.066 mmol) and tetrakis(triphenylphosphine)palladium(0) (76 mg, 0.066 mmol) in toluene (3 mL) was heated to 120° C. via microwave irradiation for 30 minutes. The reaction mixture was diluted with EtOAc (50 mL) and saturated aqueous NaHCO3 (100 mL). The organic layer was separated and the aqueous layer was washed with EtOAc (50 mL). The organic layers were combined and dried over Na2SO4, and the solvent was removed in vacuo to give the intermediate, tert-butyl 6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(5-fluorobenzo[b]thiophen-2-yl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate. The intermediate was dispersed in TFA and DCM (1:1, 10 mL). The mixture was stirred at room temperature for 60 minutes and then concentrated. The resulting crude material was reconstituted in MeOH and DCM (6.0 mL) and purified via preparative HPLC, eluting with a gradient of 25-30% ACN (0.035% TFA) and H2O (0.05% TFA). The collected fractions were combined and the solvent was stripped to dryness via rotary evaporation to yield a TFA salt of the title compound (12 mg, 44%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.82 (d, J=9.76 Hz, 1H), 2.15 (d, J=8.30 Hz, 1H), 3.59-3.70 (m, 1H), 3.82 (s, 1H), 3.91 (br s, 1H), 3.98-4.11 (m, 2H), 4.38 (br s, 1H), 4.43-4.55 (m, 2H), 7.23-7.33 (m, 1H), 7.42 (d, J=4.88 Hz, 1H), 7.76 (dd, J=9.76, 2.44 Hz, 1H), 7.93-8.03 (m, 3H), 8.62-8.74 (m, 1H), 9.41 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C20H18F2N4O2S, 417. found, 417.
Reaction SMILES: O1CCOCC1.[CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=1.[C:13]1([NH:19]O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[C:7]1([NH:19][CH:13]2[CH2:18][CH2:17][CH:16]=[CH:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: ONc1ccccc1
Reactant: C1=CCCCC1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: C1=CCC(Nc2ccccc2)CC1
Yield: 95 %

Procedure:
A stirred mixture containing dioxane (12 mL), 3 mL of cyclohexene, 1 g of 4A Molecular Sieves, and 0.11 mmol of (2,6-dipicolinato)(HMPA)Mo(O)(ONPh) is heated at reflux (ca. 100° C.) under a nitrogen atmosphere while a toluene solution (50 mL) of N-phenyl hydroxylamine (1.26 g, 11.6 mmol) is added dropwise over a 24 hr period. After heating an additional 12-24 hr, the mixture was allowed to cool and the volatiles were removed by evaporation at reduced pressure. Chromatography of the residue over silica gel and elution with pentane afforded phenyl 3-cyclohexenyl amine (>95% one isomer by NMR, GC/MS) in 15-25% yield based on the hydroxylamine. Later fractions contained aniline, azobenzene and azoxybenzene.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:8][CH3:9])[O:6][CH3:7].[C:12]([O-:17])(=[O:16])[C:13]([CH3:15])=[CH2:14].[K+]>C(P(CCCC)CCCC)CCC.C1C2NC3C(=CC=CC=3)SC=2C=CC=1>[C:12]([O:17][CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:8][CH3:9])[O:6][CH3:7])(=[O:16])[C:13]([CH3:15])=[CH2:14]
Reactant: C=C(C)C(=O)[O-]
Reactant: CO[Si](CCCCl)(OC)OC
Agent: CCCCP(CCCC)CCCC
Agent: [K+]
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: C=C(C)C(=O)OCCC[Si](OC)(OC)OC
Reaction time: 9 h
Yield: 91 %

Procedure:
Using a method analogous to Example 1, 198.7 g (1 mol) of 3-chloropropyltrimethoxysilane are reacted in the presence of 6.1 g (0.03 mol) of tri-n-butylphosphine and 0.1 g of phenothiazine with 130.4 g (1.05 mol) of potassium methacrylate at 90° C. The reaction is complete 9 hours after all the potassium methacrylate has been introduced. Work-up gives 226.0 g (91%) of 3-methacryloxypropyltrimethoxysilane having a purity of 98.3%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[N+:4]([O-:10])[C:3]=1[C:11]([O:13][CH3:14])=[O:12].[CH3:15][O-:16].[Na+]>CO.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:16][CH3:15])=[N+:4]([O-:10])[C:3]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1c(Cl)ccc(CCl)[n+]1[O-]
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COCc1ccc(Cl)c(C(=O)OC)[n+]1[O-]
Temperature: 25 °C
Reaction time: 144 h

Procedure:
A solution of methyl 3-chloro-6-(chloromethyl)pyridine-2-carboxylate 1-oxide (1.50 g, 6.35 mmol) in methanol (15 mL) was cooled to 0° C. A 25% solution of sodium methoxide in methanol (1.52 mL) was added and the mixture stirred at room temperature for 6 days. The reaction mixture was diluted with ethyl acetate and washed with water. To the aqueous layer was added brine solution and was extracted with ethyl acetate. The organic layers were combined, dried (MgSO4), filtered and concentrated to dryness to give crude methyl 3-chloro-6-(methoxymethyl)pyridine-2-carboxylate 1-oxide (1.14 g, 4.92 mmol) as a yellow oil; 1H NMR (CDCl3): δ 7.50 (d, 1H), 7.40 (d, 1H), 4.60 (s, 2H), 4.10 (s, 3H), 3.50 (s, 3H).
Reaction SMILES: [F:1][CH:2]([F:9])[CH:3]1[NH:8][CH2:7][CH2:6][NH:5][CH2:4]1.[CH2:10]([N:12]1[C:21]2[C:16](=[CH:17][C:18]([F:24])=[C:19](F)[C:20]=2[F:22])[C:15](=[O:25])[C:14]([C:26]([OH:28])=[O:27])=[CH:13]1)[CH3:11]>N1C=CC=CC=1>[F:1][CH:2]([F:9])[CH:3]1[NH:8][CH2:7][CH2:6][N:5]([C:19]2[C:20]([F:22])=[C:21]3[C:16]([C:15](=[O:25])[C:14]([C:26]([OH:28])=[O:27])=[CH:13][N:12]3[CH2:10][CH3:11])=[CH:17][C:18]=2[F:24])[CH2:4]1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reactant: FC(F)C1CNCCN1
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(C(F)F)C3)c(F)c21

Procedure:
The above 100 mg of 3-difluoromethylpiperazine and 200 mg of 1-ethyl-1,4-dihydro-6,7,8-trifluoro-4-oxo-3-quinolinecarboxylic acid in 5 ml of pyridine was stirred at 75° C. overnight, then cooled and the solvent- removed in vacuo. The residue was triturated in a hot methanol/chloroform mixture and then purified by chromatography on silica gel, eluting with methanol:dichloromethane (5:95), giving 90 mg of the desired product, mp 212°-227° C. (dec.)
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([O:11][CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:26]1([CH2:32]O)([CH2:30][OH:31])[CH2:29][CH2:28][CH2:27]1.OCC1CCN(CC2(C(OC)=O)CCCC2)CC1>>[OH:31][CH2:30][C:26]1([CH2:32][O:1][C:2]2[C:7]3[C:8]([O:11][CH2:12][CH:13]4[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]4)=[N:9][O:10][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:29][CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2noc3cccc(O)c23)CC1
Reactant: OCC1(CO)CCC1
Agent: COC(=O)C1(CN2CCC(CO)CC2)CCCC1
Product: CC(C)(C)OC(=O)N1CCC(COc2noc3cccc(OCC4(CO)CCC4)c23)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 4 of EXAMPLE 9 using tert-butyl 4-{[(4-hydroxy-1,2-benzisoxazol-3-yl)oxy]methyl}piperidine-1-carboxylate (EXAMPLE 17, Step 2) and cyclobutane-1,1-diyldimethanol (DE 19735574) instead of 4-[(4-methoxybenzyl)oxy]-1,2-benzisoxazol-3-ol and methyl 1-{[4-(hydroxymethyl)piperidin-1-yl]methyl}cyclopentanecarboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26](=[O:27])[NH:25][C:24](C)=[N:23]2)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[C:26](=[O:27])[N:25]([C@H:12]([CH3:13])[C@:9]3([C:3]4[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[F:1])[O:10][CH2:11]3)[CH:24]=[N:23]2)=[CH:20][CH:21]=1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: Cc1nn(-c2ccc(Cl)cc2)c(=O)[nH]1
Product: C[C@@H](n1cnn(-c2ccc(Cl)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 25.1 %

Procedure:
In the same manner as in Reference Example 5, starting from 0.70 g of (1S)-1-[(2R)-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 0.62 g of 2-(4-chlorophenyl)-5-methyl-3(2H,4H)-1,2,4-triazolone, 0.28 g of 2-(4-chlorophenyl)-4[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3(2H,4H)-1,2,4-triazolone was obtained as a colorless oil.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:22][CH:21]=2)[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:10][CH2:9]1)=O)(C)(C)C.C(OC1C=CC([N:48]([CH2:55][CH2:56][CH:57]([CH3:59])[CH3:58])C2CCNCC2)=CC=1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:48][C@@H:55]([CH2:56][CH:57]([CH3:59])[CH3:58])[C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:24][CH:25]=2)[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:12][CH2:13]1)=[O:5]
Reactant: CC(C)CCN(c1ccc(OCc2ccccc2)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)CCN(c1ccc(OCc2ccccc2)cc1)C1CCNCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CCN(c1ccc(OCc2ccccc2)cc1)C1CCN(C(=O)[C@@H](N)CC(C)C)CC1
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
The preparation of (4-Benzyloxy-phenyl)-(3-methyl-butyl)-piperidin-4yl-amine 4-[(4-Benzyloxy-phenyl)-(3-methyl-butyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (3.27 g, 7.22 mmol) was dissolved in CH2Cl2 (25 mL), treated with TFA (25 mL), and stirred for 30 minutes. The reaction was concentrated, diluted with EtOAc (300 mL), washed twice with saturated sodium bicarbonate solution and brine, dried over Na2SO4, and concentrated to give 2.62 g of the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]2[N:22]=[CH:21][C:20]([CH:23]([OH:46])[CH2:24][CH2:25][O:26][C:27]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:19][CH:18]=2)[CH:10]=1.[C:47](OC(=O)C)(=[O:49])[CH3:48].[Cl-].C(=O)(O)O.[Na+]>N1C=CC=CC=1>[C:47]([O:46][CH:23]([C:20]1[CH:21]=[N:22][C:17]([O:16][CH2:15][C:11]2[CH:10]=[C:9]([C:3]3[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[CH:14]=[CH:13][CH:12]=2)=[CH:18][CH:19]=1)[CH2:24][CH2:25][O:26][C:27]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)(=[O:49])[CH3:48]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc(C)c1-c1cccc(COc2ccc(C(O)CCOC(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1
Agent: O=C(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)OC(CCOC(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccc(OCc2cccc(-c3c(C)cccc3C)c2)nc1
Temperature: 65 °C
Reaction time: 4 h
Yield: 79 %

Procedure:
1-{6-[(2′,6′-Dimethylbiphenyl-3-yl)methoxy]pyridin-3-yl}-3-(trityloxy)propan-1-ol (250 mg, 0.413 mmol) produced in Example 31 (31C) was dissolved in pyridine (3.0 mL), and acetic anhydride (0.116 mL, 1.24 mmol) was added thereto at 0° C., and then, the resulting mixture was stirred under a nitrogen atmosphere at 65° C. for 4 hours. To the reaction solution, a saturated sodium bicarbonate chloride solution was added, and the organic matter was extracted with ethyl acetate. The organic layer was washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, then dried over anhydrous sodium sulfate and filtered. Then, the solvent was distilled off under reduced pressure, whereby a crude product was obtained. This crude product was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 80:20 (v/v)), whereby the objective title compound was obtained (212 mg, yield: 79%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH2:16][CH2:17][O:18][Si](C(C)(C)C)(C)C)=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH3:14])[N:10]=[N:9]2)[CH:7]=1.Cl.Cl[C:28]1[N:33]=[C:32]([NH:34][C@@H:35]2[CH2:43][C@H:42]3[N:38]([CH2:39][CH2:40][CH2:41]3)[C:37]([CH3:45])([CH3:44])[CH2:36]2)[C:31]([F:46])=[CH:30][N:29]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CC(O)C>[CH3:44][C:37]1([CH3:45])[CH2:36][C@H:35]([NH:34][C:32]2[C:31]([F:46])=[CH:30][N:29]=[C:28]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([O:15][CH2:16][CH2:17][OH:18])=[C:6]([N:8]4[C:12](=[O:13])[N:11]([CH3:14])[N:10]=[N:9]4)[CH:7]=3)[N:33]=2)[CH2:43][C@H:42]2[N:38]1[CH2:39][CH2:40][CH2:41]2
Reactant: Cn1nnn(-c2cc(N)ccc2OCCO[Si](C)(C)C(C)(C)C)c1=O
Reactant: CC1(C)C[C@H](Nc2nc(Cl)ncc2F)C[C@@H]2CCCN21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: Cn1nnn(-c2cc(Nc3ncc(F)c(N[C@@H]4C[C@@H]5CCCN5C(C)(C)C4)n3)ccc2OCCO)c1=O
Yield: 20 %

Procedure:
The general displacement procedure was described herein was used with 1-(5-amino-2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)phenyl)-4-methyl-1,4-dihydro-5H-tetrazol-5-one (382 mg, 1.1 mmol), (7R,8aS)-N-(2-chloro-5-fluoropyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine hydrochloride (350 mg, 1.1 mmol) and pTsOH.H2O (398 mg, 2.1 mmol) in IPA (10 mL) at reflux to give the product (113 mg, 21% yield) as a solid, after workup and purification by column chromatography on silica gel using DCM/2M NH3 in MeOH (1:0 to 95:5) as eluent.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:39]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)(=[O:41])=[O:40])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:49](C1C=CC(CS(Cl)(=O)=O)=CC=1)(=[O:52])(=[O:51])[NH2:50]>>[NH2:50][S:49]([C:46]1[CH:45]=[CH:44][C:43]([CH2:42][S:39]([NH:38][CH2:37][CH2:36][C:15]2[N:14]([CH:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:22]3[C:17]([C:16]=2[CH2:24][CH2:25][O:26][C:27]2[CH:28]=[CH:29][C:30]([C:31]([OH:33])=[O:32])=[CH:34][CH:35]=2)=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=3)(=[O:41])=[O:40])=[CH:48][CH:47]=1)(=[O:52])=[O:51]
Reactant: NS(=O)(=O)c1ccc(CS(=O)(=O)Cl)cc1
Reactant: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Product: NS(=O)(=O)c1ccc(CS(=O)(=O)NCCc2c(CCOc3ccc(C(=O)O)cc3)c3cc(Cl)ccc3n2C(c2ccccc2)c2ccccc2)cc1

Procedure:
The title compound was prepared from 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzoic acid methyl ester (Step 6, Example 1) and (4-Sulfamoyl-phenyl)-methanesulfonyl chloride according to Example 1 Step 7.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH:20]([CH3:22])[CH3:21])[N:16]=[C:17]([CH3:19])[N:18]=1)[N:7]=3.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)O1>>[CH:20]([N:15]1[C:14]([C:8]2[N:7]=[C:6]3[C:5]4[CH:23]=[CH:24][C:2]([C:33]5[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=5)=[CH:3][C:4]=4[O:13][CH2:12][CH2:11][N:10]3[CH:9]=2)=[N:18][C:17]([CH3:19])=[N:16]1)([CH3:22])[CH3:21]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Product: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cccnc4)cc2OCC3)n(C(C)C)n1

Procedure:
8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene was reacted with 3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine to give 244. MS (ESI+) 387.2
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.Cl.Cl[C:16]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[N:19]=[C:18]2[CH2:29][CH2:30][CH2:31][C:17]=12>CO.ClCCl>[Cl:28][C:24]1[CH:23]=[C:22]([C:20]2[N:19]=[C:18]3[CH2:29][CH2:30][CH2:31][C:17]3=[C:16]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=3)[CH:21]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Reactant: COC(=O)COc1ccc(N)cc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)COc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 150 °C
Yield: 43.7 %

Procedure:
An 18-mL vial was charged with methyl 2-(4-aminophenoxy)acetate (24 mg, 0.13 mmol, 2 eq.) and 4-Chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine HCl salt (20 mg, 0.066 mmol, 1 eq. See step 1 of EXAMPLE 1). The mixture was dissolved in a mixture of MeOH (1 ml) and dichloromethane (2 ml). After the volatile material was removed under reduced pressure, the residue was heated at 150° C. under argon for 1 hr. After cooling to room temperature, the reaction mixture was partitioned between NaHCO3 aq. (10 ml) and ethyl acetate (10 ml). The organics was separated and dried over MgSO4. The solvent was removed under reduced pressure to give a residue, which was purified by chromatography on silica gel using dichloromethane followed by 0.1˜0.3% methanol in dichloromethane as eluent to give the desired product methyl 2-[4-[[2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]phenoxy]acetate as white solid (11.8 mg, 44% yield).