Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:30]=[CH:29][C:6]([C:7]([NH:9][C:10]2[CH:15]=[C:14]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)[CH:13]=[CH:12][C:11]=2[NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:8])=[CH:5][CH:4]=1.[CH3:31][O:32][CH2:33][C@@H:34]1[CH2:38][CH2:37][CH2:36][NH:35]1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>C(Cl)Cl.CC(C)=O>[CH3:31][O:32][CH2:33][C@@H:34]1[CH2:38][CH2:37][CH2:36][N:35]1[CH2:2][C:3]1[CH:30]=[CH:29][C:6]([C:7]([NH:9][C:10]2[CH:15]=[C:14]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)[CH:13]=[CH:12][C:11]=2[NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:8])=[CH:5][CH:4]=1
Reactant: COC[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: COC[C@@H]1CCCN1Cc1ccc(C(=O)Nc2cc(-c3cccs3)ccc2NC(=O)OC(C)(C)C)cc1
Yield: 91.1 %

Procedure:
To a solution of chloride 74 (0.30 g, 0.68 mmol) in DCM (7 mL) was added (S)-2-(methoxymethyl)pyrrolidine (86 mg, 0.75 mmol), K2CO3 (0.31 g, 2.24 mmol) and NaI (12 mg, 0.075 mmol). Acetone (3 mL) was added and the reaction mixture was heated to reflux for 3 days then concentrated. The residue was taken up in AcOEt, washed with H2O, brine, dried over MgSO4, filtered and concentrated to give title compound 75 (0.323 g, 91% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][CH2:11]O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:20]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:20][CH2:11][CH2:10][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCO)C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCBr)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.6 %

Procedure:
A mixture of 5.00 g (18.2 mmol) tert-butyl N-(tert-butoxycarbonyl)-L-homoserinate (prepared according to J. Org. Chem. 1988, 53, 1900-1903), 3.23 g N-bromo succinimide (18.2 mmol), and 6.16 g polymer bound triphenylphosphine (loading approx. 3 mmol/g, approx. 18.5 mmol) in dichloromethane (60 mL) was stirred overnight at room temperature. All solids were removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (2.5→25% ethyl acetate in hexane) to give 2.56 g of the title compound (38% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19](Cl)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:21]1[CH:26]=[CH:25][C:24]([CH2:27][OH:28])=[CH:23][CH:22]=1.C(C(CCC)[O-])(C)(C)C.[K+].C(O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([O:28][CH2:27][C:24]3[CH:25]=[CH:26][N:21]=[CH:22][CH:23]=3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Reactant: OCc1ccncc1
Agent: CCCC([O-])C(C)(C)C
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCc2ccncc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.2 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (7.89 g, 26.4 mmol, 1.0 eq.), pyridin-4-yl-methanol (3.74 g, 34.3 mmol, 1.3 eq) and 1M potassium tert-butyl butoxide in t-butanol (72 ml, 72 mmol, 2.7 eq). The reaction was then stirred overnight at room temperature after which the solvent was removed. The solid was then diluted with EtOAc, washed 3× with water, 2×NaHCO3, 2× with brine, and dried over NaSO4. Purification was then accomplished on column chromatography with the eluent being 1:2 ethyl acetate/hexane and 2% TEA. Removal of the solvent resulted in the title compound as a cream solid (6.98 g, 33% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[CH2:17]([S:19](Cl)(=[O:21])=[O:20])[CH3:18].N1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:19]([CH2:17][CH3:18])(=[O:21])=[O:20])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)Cl
Reactant: CCOC(=O)c1oc2cccc(N)c2c1C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1oc2cccc(NS(=O)(=O)CC)c2c1C
Temperature: 25 °C
Yield: 69 %

Procedure:
To 4-amino-3-methyl-benzofuran-2-carboxylic acid ethyl ester (563 mg, 2.57 mmol, 1 eq., prepared according to Example 60, Step 1), CH2Cl2 (12 mL) was added under argon and the reaction was cooled to <0° C. Then ethanesulfonyl chloride (243 uL, 2.57 mmol, 1 eq.), and pyridine (623 uL, 7.70 mmol, 3 eq.) were added and the reaction was stirred while slowly warming to room temperature. After work-up and flash column chromatography, 4-ethanesulfonylamino-3-methyl-benzofuran-2-carboxylic acid ethyl ester was obtained in 69% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.3 (m, 6 H) 2.8 (s, 3 H) 3.2 (q, J=7.3 Hz, 2 H) 4.4 (m, J=7.1, 7.1, 7.1 Hz, 2 H) 7.2 (d, J=7.6 Hz, 1 H) 7.5 (m, 1 H) 7.6 (m, 1 H) 9.6 (s, 1 H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH2:24][C@@H:25]5[CH2:27][O:26]5)=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>CN(C=O)C>[OH:26][C@@H:25]([CH2:27][N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)[CH2:24][O:23][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([O:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][CH:2]=[CH:3]4)=[N:12][CH:13]=[N:14]2)=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@@H]1CO1
Reactant: C1CCNC1
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@@H](O)CN1CCCC1
Temperature: 75 °C
Reaction time: 3 h
Yield: 93.7 %

Procedure:
A mixture of (2S)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline (100 mg, 0.28 mmol), and pyrrolidine (60 mg, 0.84 mmol) in DMF (5 ml) was stirred at 75° C. for 3 hours under an atmosphere of nitrogen and then allowed to cool to ambient temperature. The solvents were removed in vacuo and the residue purified on silica gel, gradient elution with dichloromethane, dichloromethane/methanol (95/5), dichloromethane/methanolic ammonia (7M) (98/2 to 90/10), to give (2S)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline (114 mg, 92%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH:21]1([NH:24][CH2:25][C:26]2[O:27][C:28]([CH3:31])=[N:29][N:30]=2)[CH2:23][CH2:22]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:21]1([N:24]([CH2:25][C:26]2[O:27][C:28]([CH3:31])=[N:29][N:30]=2)[C:12]([C:10]2[CH:9]=[CH:8][C:7]([N:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])[CH2:22][CH2:23]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: Cc1nnc(CNC2CC2)o1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nnc(CN(C(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)C2CC2)o1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with cyclopropyl-(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-amine in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=420.6 [MH+].
Reaction SMILES: N#N.[Cl:3][CH2:4][C:5]1[O:6][CH:7]=[C:8]([C:10]([OH:13])([CH3:12])[CH3:11])[N:9]=1.[CH3:14]I>>[Cl:3][CH2:4][C:5]1[O:6][CH:7]=[C:8]([C:10]([O:13][CH3:14])([CH3:11])[CH3:12])[N:9]=1
Reactant: CI
Reactant: CC(C)(O)c1coc(CCl)n1
Agent: N#N
Product: COC(C)(C)c1coc(CCl)n1
Temperature: 40 °C
Reaction time: 26 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-(2-(chloromethyl)oxazol-4-yl)propan-2-ol (200 mg, 1.14 mmol) in MeI (3.5 mL) was treated with Ag2O (396 mg, 1.71 mmol) and the resulting mixture (protected from light) was stirred for 26 h at 40° C. The reaction mixture was filtered and the MeI was removed under reduced pressure. Purification of the residue by FC (7:3 hept-EA) gave the title compound as a colorless oil: TLC: rf (7:3 hept-EA)=0.33. LC-MS-conditions 06: tR=0.64 min, [M+H]+=190.17.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9]([C:11]2[C:12]([NH:18][CH2:19][CH3:20])=[N:13][CH:14]=[C:15]([Br:17])[CH:16]=2)=[O:10])=[CH:6][CH:5]=[C:4]([Cl:21])[N:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].O1CCCC1>N1C=CC=CC=1>[Br:17][C:15]1[CH:14]=[N:13][C:12]2[N:18]([CH2:19][CH3:20])[C:2]3[N:3]=[C:4]([Cl:21])[CH:5]=[CH:6][C:7]=3[NH:8][C:9](=[O:10])[C:11]=2[CH:16]=1
Reactant: CCNc1ncc(Br)cc1C(=O)Nc1ccc(Cl)nc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCN1c2nc(Cl)ccc2NC(=O)c2cc(Br)cnc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92.4 %

Procedure:
To a solution of N-(2,6-dichloro-3-pyridinyl)-5-bromo-2-ethylamino-3-pyridinecarboxamide (5.9 g, 15 mmol) in 30 mL of pyridine at 50° C. under argon was added by syringe a 1.0M solution of sodium hexamethyldisilazide in tetrahydrofuran (31.5 mL, 31.5 mmol). After 10 min, the reaction mixture was diluted with ice water and allowed to stir for 2 hours. The resultant orange-yellow precipitate was collected by suction filtration and air-dried to give 4.9 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[SH:11].[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O>[CH2:14]([S:11][C:3]1[CH:4]=[CH:5][C:6]([O:9][CH3:10])=[C:7]([Cl:8])[C:2]=1[Cl:1])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccc(S)c(Cl)c1Cl
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(SCc2ccccc2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87.5 %

Procedure:
A solution of 6.23 g of 2,3-dichloro-4-methoxythiophenol in 60 ml of sieved-dried dimethylformamide is added to 0.75 g of sodium hydride over a period of 2-3 minutes. After stirring at room temperature for 20 minutes, the yellowish solution is treated with 5.10 g of benzyl bromide at a rate so that the temperature does not rise above 40°. Stirring is continued for an additional 30 minutes. The cloudy mixture is poured onto 200 g of crushed ice with caution and the white precipitate is collected on a filter after 1 hour at 10° C. The air-dried product is recrystallized from acetone-hexane to give 7.8 g of 4-benzylthio-2,3-dichloroanisole as white needles, mp 116°-117° C.
Reaction SMILES: Cl[C:2]([C:22]1[CH:27]=[N:26][CH:25]=[CH:24][N:23]=1)([CH3:21])[CH2:3][N:4]1[C:16]2[CH2:15][CH2:14][N:13]3[CH2:17][CH2:18][CH2:19][CH:12]3[C:11]=2[C:10]2[CH:9]=[C:8]([CH3:20])[CH:7]=[CH:6][C:5]1=2.[CH3:28][NH:29][CH3:30]>O>[CH3:28][N:29]([CH3:30])[C:2]([CH3:21])([C:22]1[CH:27]=[N:26][CH:25]=[CH:24][N:23]=1)[CH2:3][N:4]1[C:16]2[CH2:15][CH2:14][N:13]3[CH2:17][CH2:18][CH2:19][CH:12]3[C:11]=2[C:10]2[CH:9]=[C:8]([CH3:20])[CH:7]=[CH:6][C:5]1=2
Reactant: Cc1ccc2c(c1)c1c(n2CC(C)(Cl)c2cnccn2)CCN2CCCC12
Reactant: CNC
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(c2cnccn2)N(C)C)CCN2CCCC12
Temperature: 25 °C

Procedure:
6-(2-Chloro-2-pyrazin-2-yl-propyl)-9-methyl-2,3,4,5,6,10c-hexahydro-1H-3a,6-diaza-cyclopenta[c]fluorene (500 mg, 1.31 mmol) in 40% dimethylamine in water (30 mL) was heated at 100° C. for 3 h. The reaction mixture was cooled at RT and extracted with EtOAc (3×50 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by reverse phase chromatography to obtain 62 mg of dimethyl-[1-methyl-2-(9-methyl-1,2,3,4,5,10c-hexahydro-3a,6-diaza-cyclopenta[c]fluoren-6-yl)-1-pyrazin-2-yl-ethyl]-amine. 1H NMR (CD3OD, TFA salt): δ (ppm): 8.06 (s, 1H), 7.48 (s, 1H), 7.21 (s, 1H), 7.17 (d, 1H),7.00 (d, 1H), 4.98 (t, 1H), 4.28 (d, 2H), 3.6 (m, 3H), 3.39 (m, 2H), 3.2 (m, 1H), 3.15 (s, 6H), 2.8 (m, 1H), 2.7 (m, 1H), 2.39 (s, 3H), 2.17 (m, 3H). Chiral HPLC separated the racemate into diastereomers II-6a-d.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:20]#[N:21])[CH2:16][C:17]([OH:19])=[O:18])=[C:11]([O:22][CH3:23])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24]S(O)(=O)=O>CO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:20]#[N:21])[CH2:16][C:17]([O:19][CH3:24])=[O:18])=[C:11]([O:22][CH3:23])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(OCc2ccccc2)ccc1C(C#N)CC(=O)O
Reactant: CS(=O)(=O)O
Solvent: CO
Product: COC(=O)CC(C#N)c1ccc(OCc2ccccc2)cc1OC
Temperature: 65 °C
Yield: 100 %

Procedure:
To a 25 mL RB flask fitted with magnetic stirrer was charged with methanol (10 mL). To the stirred solvent was added 3-[4-(benzyloxy)-2-methoxyphenyl]-3-cyanopropanoic acid (0.62 g, 2.56 mmol) and methane sulfonic acid (1 mL), it was heated at 65° C. for 2 h. The RM was concentrated, extracted with ethyl acetate (50 mL×2). The organic layer was washed with water (50 mL) and saturated brine solution (50 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as brown liquid. (0.65 g, yield: 100.0%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[F:12])[C:6](O)=O)#[N:2].[NH2:13][NH:14][C:15]([NH2:17])=[S:16].O=P(Cl)(Cl)Cl.[OH-].[Na+]>O.CC(=O)OCC>[NH2:17][C:15]1[S:16][C:6]([C:5]2[CH:9]=[CH:10][C:11]([F:12])=[C:3]([CH:4]=2)[C:1]#[N:2])=[N:13][N:14]=1
Reactant: NNC(N)=S
Reactant: N#Cc1cc(C(=O)O)ccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: N#Cc1cc(-c2nnc(N)s2)ccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
To a stirred mixture of 3-cyano-4-fluorobenzoic acid (37.3 g, 225 mmol) and thiosemicarbazide (22.6 g, 248 mmol) was added POCl3 (148 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h and then heated to 85° C. for 6 h. The resulting yellow solution was cooled to room temperature and concentrated to 50% volume. The residue was cooled to 0° C. and water was added (300 mL) drop wise. (Caution: exothermic and violent reaction with gas evolution). The mixture was heated to 90° C. for 1 h then cooled to room temperature. EA was added EA (300 mL) and the reaction mixture stirred for 10 min and before filtration. The collected solid was dispersed into water (270 mL), cooled to 0° C., and neutralized with 50% NaOH aqueous solution to pH8. The resulting solid was filtered, washed thoroughly with water, and dried under high vacuum to afford 26 g (52%) of 5-(5-amino-1,3,4-thiadiazol-2-yl)-2-fluorobenzonitrile TDZ INT-1 as pale yellow solid which was used in next experiment without purification. LCMS-ESI (m/z) calculated for C9H5FN4S: 220.0; found 221.1 [M+H]+, tR=2.44 min. 1H NMR (400 MHz, DMSO) δ 8.29 (dd, J=6.1, 2.3 Hz, 1H), 8.19 (ddd, J=8.9, 5.2, 2.4 Hz, 1H), 7.64 (t, J=9.0 Hz, 1H), 7.58 (s, 2H). 13C NMR (101 MHz, DMSO) δ 169.82, 164.25, 161.68, 133.68, 131.65, 128.96, 117.96, 113.77, 101.59.
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]3[C:11]([CH:12]=2)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=3)[CH2:3][CH2:2]1.Br[CH2:20][C:21]1[O:25][C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[N:23][CH:22]=1>>[CH:1]1([C:4]2[N:5]([CH2:20][C:21]3[O:25][C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[N:23][CH:22]=3)[C:6]3[C:11]([CH:12]=2)=[C:10]([C:13]([F:14])([F:15])[F:16])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=3)[CH2:2][CH2:3]1
Reactant: FC(F)(F)c1cccc(-c2ncc(CBr)o2)c1
Reactant: N#Cc1ccc2[nH]c(C3CC3)cc2c1C(F)(F)F
Product: N#Cc1ccc2c(cc(C3CC3)n2Cc2cnc(-c3cccc(C(F)(F)F)c3)o2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 4 using 2-cyclopropyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 165A) and 5-(bromomethyl)-2-[3-(trifluoromethyl)phenyl]-1,3-oxazole (Example 370C): MS (ES) m/z 476 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7]O)=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:28]1[C:32]2=[N:33][CH:34]=[CH:35][CH:36]=[C:31]2[CH:30]=[C:29]1[C:37]([O:39][CH2:40][CH3:41])=[O:38].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[N:1]1[CH:2]=[CH:3][C:4]([CH2:7][N:28]2[C:32]3=[N:33][CH:34]=[CH:35][CH:36]=[C:31]3[CH:30]=[C:29]2[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:5][CH:6]=1
Reactant: OCc1ccncc1
Reactant: CCOC(=O)c1cc2cccnc2[nH]1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cccnc2n1Cc1ccncc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.5 %

Procedure:
0.51 g (4.73 mmol) of 4-pyridylmethanol and then 1.24 g (4.73 mmol) of triphenyl-phosphine are successively added with stirring to a solution of 0.6 g (3.15 mmol) of ethyl 1H-pyrrolo[2,3-b]pyridine-2-carboxylate, obtained according to the protocol described in step 3.2, in 40 mL of dry tetrahydrofuran, maintained under an inert atmosphere. 0.82 g (4.73 mmol) of diethyl azodicarboxylate is then added dropwise at 0° C. The reaction mixture is stirred for 24 hours at room temperature and then concentrated under reduced pressure. A mixture of water and ethyl acetate (20 mL, v/v) is added and the pH of the reaction mixture is adjusted to 5-6 by adding acetic acid. The organic phase separated out is then washed twice with 10 mL of water and once with 10 mL of saturated sodium chloride solution and then dried over magnesium sulfate. After concentrating under reduced pressure, the resulting oil is purified by chromatography on a column of silica gel. 0.66 g of expected product is isolated.
Reaction SMILES: [CH:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([O:12][CH3:13])=[O:11])=[O:2].[F:14][C:15]([F:19])([F:18])[CH2:16]I>>[CH:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]([CH2:16][C:15]([F:19])([F:18])[F:14])[C:4]=1[C:10]([O:12][CH3:13])=[O:11])=[O:2]
Reactant: FC(F)(F)CI
Reactant: COC(=O)c1[nH]c(C)c(C)c1C=O
Product: COC(=O)c1c(C=O)c(C)c(C)n1CC(F)(F)F

Procedure:
The title compound was prepared as pale brown crystals in 5.5% yeild in a similar procedure to that described in Referential Example 9 by using methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate and 1,1,1-trifluoro-2-iodoethane.
Reaction SMILES: [N:1]([CH:4]([O:16][CH2:17][CH2:18][OH:19])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11])=[N+:2]=[N-:3].[H-].[Na+].[CH2:22]([O:24][C:25](=[O:28])[CH2:26]Br)[CH3:23]>C1COCC1>[N:1]([CH:4]([O:16][CH2:17][CH2:18][O:19][CH2:26][C:25]([O:24][CH2:22][CH3:23])=[O:28])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC(COc1cccc(C(=O)O)c1)OCCO
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COCCOC(COc1cccc(C(=O)O)c1)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31.6 %

Procedure:
To a solution of 3-[2-azido-2-(2-hydroxy-ethoxy)-ethoxy]-benzoic acid (0.535 g, 2 mmol) in dry THF (6 ml) was added NaH (60% dispersion, 0.246 g, 6 mmol) at 0° C. After 10 minutes, ethyl-2-bromoacetate (0.488 ml, 4.4 mmol) was added. The reaction was then warmed up to room temperature and stirred for 4 hours. The reaction was quenched by pouring it into ice-cold water (50 ml). The mixture was extracted with DCM (2×50 ml) and the DCM extracts were discarded. The aqueous layer was then acidified to pH 2 with 1 N HCl, and extracted with DCM (2×50 ml). These DCM extracts were combined, dried over MgSO4 and evaporated under reduced pressure. The residue was purified by column chromatography (1×20 cm). The title compound, eluted with 2% methanol in DCM, was obtained as an oil (0.223 g, 31.6%). ES-MS, m/z 351.95 (M−1).
Reaction SMILES: C(OC([N:8]1[C@H:12]([CH2:13][CH2:14][S:15][CH2:16][CH3:17])[CH:11]([C:18]([OH:20])=[O:19])[O:10]C1(C)C)=O)(C)(C)C.[CH2:23](O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl.CN(C)CCCN=C=NCC.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1>ClCCl.ClCCl.CN(C=O)C>[NH2:8][C@H:12]([CH2:13][CH2:14][S:15][CH2:16][CH3:17])[CH:11]([OH:10])[C:18]([O:20][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:19]
Reactant: CCSCC[C@@H]1C(C(=O)O)OC(C)(C)N1C(=O)OC(C)(C)C
Reactant: OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCSCC[C@@H](N)C(O)C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
A solution of Example 22B (0.11 g, 0.33 mmol), benzyl alcohol (0.07 mL, 0.7 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.080 g, 0.41 mmol), HOAT (0.045 g, 0.33 mmol), and N-methylmorpholine (0.055 mL, 0.50 mmol) in 3:1 dichloromethane/DMF (4 mL) at room temperature was stirred for 16 hours, diluted with dichloromethane, washed sequentially with aqueous NaHCO3, brine, 0.5M citric acid, and brine, dried (MgSO4), filtered, and concentrated. The residue was dissolved in 4M HCl in dioxane (2 mL), stirred for 1 hour, treated with water (1 mL), stirred for 1 hour, concentrated, and purified by reverse phase HPLC with acetonitrile/water to provide the desired product. MS (ESI) m/e 284 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 7.43–7.37 (m, 5H), 5.20 (s, 1.4H), 5.19 (m, 0.6H), 4.44 (m, 0.3H), 4.32 (m, 0.7H), 3.53 (m, 1H), 2.63 (m, 2H), 2.43 (m, 2H), 1.90–1.75 (m, 2H), 1.20–1.12 (m, 3H).
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]([O:12][C:13]1[C:18]([Cl:19])=[CH:17][C:16]([CH2:20]O)=[CH:15][C:14]=1[Cl:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>ClCCl.C(OCC)C>[CH2:5]([O:12][C:13]1[C:18]([Cl:19])=[CH:17][C:16]([CH2:20][Br:2])=[CH:15][C:14]=1[Cl:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: BrP(Br)Br
Reactant: OCc1cc(Cl)c(OCc2ccccc2)c(Cl)c1
Solvent: ClCCl
Solvent: CCOCC
Product: Clc1cc(CBr)cc(Cl)c1OCc1ccccc1
Reaction time: 2 h

Procedure:
Phosphorous tribromide (2 mL) was added to a solution of (4-benzyloxy-3,5-dichloro-phenyl)-methanol (CAB02117, 5.50 g, 19.4 mmol) in dichloromethane (80 mL) at 0° C. The mixture was stirred at this temperature for 2 h, diluted with diethyl ether (150 mL), transferred into a separation funnel and washed with water (2×50 mL) and brine (50 mL). The organic layer was dried over magnesium sulphate and concentrated under reduced pressure. The residue was recrystallised from dichloromethane/hexane. 1H-NMR (400 MHz, CDCl3) δ 4.39 (s, 2H, —CH12Br), 5.05 (s, 2H, —CH2Ph), 7.37 (s, 2H), 7.38-7.44 (m, 3H), 7.54-7.58 (m, 2H). 13C-NMR (100 MHz, CDCl3) δ=31.48, 75.39, 128.73, 129.68, 129.70, 129.72, 130.06, 135.46, 136.27, 151.23.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][C@H:26]1[O:31][C:30]2([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[O:29][C@@H:28]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:23]([CH2:24][CH2:25][C@H:26]3[O:31][C:30]4([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[O:29][C@@H:28]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:27]3)[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C[C@H]1C[C@@H](CCN)OC2(CCCCC2)O1
Reactant: CC(C)C(=O)CC(C(=O)c1ccc(F)cc1)c1ccccc1
Product: CCOC(=O)C[C@H]1C[C@@H](CCn2c(C(C)C)cc(-c3ccccc3)c2-c2ccc(F)cc2)OC2(CCCCC2)O1

Procedure:
According to the same method as in Example 4-1, the title compound was synthesized using 1-(4-fluorophenyl)-5-methyl-2-phenyl-1,4-hexanedione and ethyl 2-((2R,4R)-4-(2-aminoethyl)-1,5-dioxaspiro[5.5]undecan-2-yl)acetate.