Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1Br)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1B(O)O>>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[C:17]1[S:16][CH:20]=[CH:19][CH:18]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1Br
Reactant: OB(O)c1cccs1
Product: CCOC(=O)c1[nH]c2ccccc2c1-c1cccs1

Procedure:
3-Thiophene-2-yl-1H-indole-2-carboxylic acid ethyl ester was prepared from 3-bromo-1H-indolecarboxylic acid ethyl ester and 2-thiopheneboronic acid followed the procedure of Example 11 Step 2 as a light yellow powder: 1H NMR (DMSO-d6) δ 1.27 (t, J=7.2 Hz, 3H), 4.30 (q, J=7.2 Hz, 2H), 7.12-7.16 (m, 1H), 7.17-7.20 (m, 1H), 7.31-7.34 (m, 1H), 7.36(dd, J=5.1, 1.5 Hz, 1H), 7.51 (d, J=8.3 Hz, 1H), 7.63 (d, J=6.3 Hz, 1H), 7.71 (d, J=8.2 Hz, 1H), 12.02 (br s, 1H); MS (ESI) m/z 272 (MH+); 270 ([M−H]−).
Reaction SMILES: [CH:1]([CH:4]1[C:9]2=[CH:10][C:11]3[CH:12]=[CH:13][C:14]([S:17][CH3:18])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6][NH:5]1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:29]1[N:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[C:32]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:31][N:30]=1>CC(O)C>[CH:1]([CH:4]1[C:9]2=[CH:10][C:11]3[CH:12]=[CH:13][C:14]([S:17][CH3:18])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6][N:5]1[C:29]1[N:34]=[C:33]([C:35]([F:37])([F:38])[F:36])[C:32]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:31][N:30]=1)([CH3:3])[CH3:2]
Reactant: CSc1ccc2cc3n(c2c1)CCNC3C(C)C
Reactant: CCOC(=O)c1cnc(Cl)nc1C(F)(F)F
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc(N2CCn3c(cc4ccc(SC)cc43)C2C(C)C)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
To a solution of 1-isopropyl-7-(methylthio)-1,2,3,4-tetrahydropyrazino[1,2-a]indole (100 mg, 0.38 mmol) and DIPEA (248.3 mg, 1.921 mmol) in i-PrOH (3 mL) was added ethyl 2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxylate (196 mg, 0.77 mmol). The reaction mixture was stirred at rt overnight. The mixture was concentrated and purified by preparative TLC on silica gel eluting with PE/EtOAc 1:1 to afford ethyl 2-(1-isopropyl-7-(methylthio)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylate (60 mg, 32.6% yield) as a colorless oil. LC-MS MS (ESI) m/z 478.7 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:21])=[CH:3][CH2:4][C@@H:5]([OH:20])[C:6]1[C:16](=[O:17])[C:15]2[C:14]([OH:18])=[CH:13][CH:12]=[C:11]([OH:19])[C:10]=2[C:8](=[O:9])[CH:7]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:37](O)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C)C1C=CN=CC=1.ClCCl>[C:37]([O:20][CH:5]([C:6]1[C:16](=[O:17])[C:15]2[C:10]([C:8](=[O:9])[CH:7]=1)=[C:11]([OH:19])[CH:12]=[CH:13][C:14]=2[OH:18])[CH2:4][CH:3]=[C:2]([CH3:21])[CH3:1])(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)=CC[C@@H](O)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)=CCC(OC(=O)c1ccccc1)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reaction time: 0.5 h
Yield: 29.8 %

Procedure:
288 mg (1 mmole) of shikonin, 226 mg (1.1 mmole) of dicyclohexylcarbodiimide and 30 mg (0.25 mmole) of 4-dimethylaminopyridine were dissolved in 3 ml of dry dichloromethane. To the resulting solution was added 122 mg (1 mmole) of benzoic acid at 0° C. under nitrogen gas, and the mixture was stirred for 30 minutes and then at room temperature for further 3 hours. The resulting product was separated and purified according to the procedures as described in Example 1 to obtain 117 mg (Yield: 30%) of the title compound having the following structure as a red precipitate.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]([OH:14])=O)=[CH:9][C:8]=1[CH3:15])[CH2:4][CH3:5])[CH3:2].[NH2:16][C:17]1[C:26]([CH3:27])=[CH:25][C:20]([C:21]([NH:23]O)=[NH:22])=[CH:19][C:18]=1[Cl:28]>>[Cl:28][C:18]1[CH:19]=[C:20]([C:21]2[N:23]=[C:12]([C:10]3[S:11][C:7]([CH2:6][N:3]([CH2:1][CH3:2])[CH2:4][CH3:5])=[C:8]([CH3:15])[CH:9]=3)[O:14][N:22]=2)[CH:25]=[C:26]([CH3:27])[C:17]=1[NH2:16]
Reactant: CCN(CC)Cc1sc(C(=O)O)cc1C
Reactant: Cc1cc(C(=N)NO)cc(Cl)c1N
Product: CCN(CC)Cc1sc(-c2nc(-c3cc(C)c(N)c(Cl)c3)no2)cc1C
Yield: 11.6 %

Procedure:
The title compound (20 mg) is prepared starting from 5-diethylaminomethyl-4-methyl-thiophene-2-carboxylic acid (100 mg, 440 μmol) and 4-amino-3-chloro-N-hydroxy-5-methyl-benzamidine (97 mg, 484 μmol) according to Method A; LC-MS: tR=0.61 min; [M+1]+=391.08; 1H NMR (CDCl3): δ1.11 (t, J=7.0 Hz, 6H), 2.25 (s, 3H), 2.29 (s, 3H), 2.57-2.70 (m, 4H), 3.72 (s, 2H), 7.65 (s, 1H), 7.78 (s, 1H), 7.98 (d, J=1.5 Hz, 1H).
Reaction SMILES: C[Si](I)(C)C.C[O:7][C:8]1[CH:9]=[C:10]2[C:13]([CH3:22])([C:14]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH2:12][C:11]2=[CH:23][CH:24]=1>C(Cl)Cl>[OH:7][C:8]1[CH:9]=[C:10]2[C:13]([CH3:22])([C:14]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH2:12][C:11]2=[CH:23][CH:24]=1
Reactant: COc1ccc2c(c1)C(C)(C(=O)N1CCCCC1)C2
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: CC1(C(=O)N2CCCCC2)Cc2ccc(O)cc21

Procedure:
Trimethylsilyliodide (46.4 ml) is added dropwise to a stirred solution of the 5-methoxy compound of Step 3. above (42.1 g) in methylene chloride (100 ml) under nitrogen and the mixture is refluxed for 48 hours. The reaction mixture is diluted with methylene chloride, washed with 10% aq. sodium sulphite, water, dried, filtered, and evaporated in vacuo. The residue is triturated with acetonitrile affording a white solid. The filtrate is evaporated in vacuo affording a viscous liquid which is chromatographed on silica gel. The purified fractions are washed with sat'd sodium bicarbonate, sat'd sodium chloride, dried, filtered and evaporated in vacuo affording the desired product as a yellow solid.
Reaction SMILES: [CH3:1][S:2][C:3]([CH3:19])([CH3:18])[CH2:4][CH2:5][CH2:6][CH:7]([CH3:17])[CH2:8][CH:9]=[CH:10][C:11]([CH3:16])=[CH:12][C:13]([OH:15])=O.[CH3:20][CH2:21]OCC.C([Li])C.Cl>C1C=CC=CC=1>[CH3:1][S:2][C:3]([CH3:19])([CH3:18])[CH2:4][CH2:5][CH2:6][CH:7]([CH3:17])[CH2:8][CH:9]=[CH:10][C:11]([CH3:16])=[CH:12][C:13](=[O:15])[CH2:20][CH3:21]
Reactant: CSC(C)(C)CCCC(C)CC=CC(C)=CC(=O)O
Reactant: CCOCC
Agent: Cl
Agent: [Li]CC
Solvent: c1ccccc1
Product: CCC(=O)C=C(C)C=CCC(C)CCCC(C)(C)SC
Reaction time: 3 h

Procedure:
To a stirred solution of 2.5 g. of 11-methylthio-3,7,11-trimethyldodeca-2,4-dienoic acid in 20 ml. of dry ether is added slowly at 0°, 23 ml. of a one molar solution of ethyl lithium in benzene. After about 3 hours at 20°, the mixture is poured into iced 1N hydrochloric acid (100 ml.) with vigorous stirring. The ether layer is separated, combined with ethereal washings of the aqueous phase, washed with water, saturated potassium bicarbonate and then saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to yield 13-methylthio-5,9,13-trimethyltetradeca-4,6-dien-3-one, which can be purified by chromatography.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:15]2[CH:16]=[N:17][S:18][C:14]=2[CH:13]=[CH:12][C:11]=1[C:19]([OH:21])=O.C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:41][O:42][CH2:43][C@@H:44]([OH:46])[CH3:45].CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(=O)C>[OH:46][C@@H:44]([CH3:45])[CH2:43][O:42][NH:41][C:19]([C:11]1[CH:12]=[CH:13][C:14]2[S:18][N:17]=[CH:16][C:15]=2[C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])=[O:21]
Reactant: C[C@H](O)CON
Reactant: O=C(O)c1ccc2sncc2c1Nc1ccc(I)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@H](O)CONC(=O)c1ccc2sncc2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 26 %

Procedure:
To a solution of 4-(2-fluoro-4-iodo-phenylamino)-benzo[d]iso-thiazole-5-carboxylic acid (150 mg, 0.362 mmol), diisopropylethylamine (0.25 mL, 1.45 mmol), HOBt (98 mg, 0.724 mmol) and (S)-1-aminooxy-propan-2-ol (92 mg, 0.724 mmol in DMF (2 mL) was added EDCI (139 mg, 0.724 mmol). The reaction mixture was stirred for 16 hours at room temperature, diluted with ethyl acetate, and washed with water, a saturated aqueous solution of sodium hydrogen carbonate, then brine before being dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—PPC, gradient 30% to 80%, EtOAc in cyclohexane) to afford the title compound as a solid (45 mg, 26%). LCMS (method A): RT=10.26 min, [M+H]+=488. 1H NMR (DMSO-d6, 400 MHz) 11.72 (1 H, s), 9.22 (1 H, s), 8.69 (1 H, s), 7.86-7.81 (1 H, m), 7.64-7.55 (2 H, m), 7.30 (1 H, dd, J=8.47, 1.83 Hz), 6.63 (1 H, t, J=8.72 Hz), 4.73 (1 H, s), 3.76-3.68 (1 H, m), 3.53 (2 H, d, J=5.78 Hz), 0.99 (3 H, d, J=6.33 Hz).
Reaction SMILES: Br[C:2]1[C:3]([F:21])=[C:4]([F:20])[C:5]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].N(C(C)C)C(C)C.[Si:29]([C:33]#[CH:34])([CH3:32])([CH3:31])[CH3:30]>C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[NH:12][C:5]1[C:4]([F:20])=[C:3]([F:21])[C:2]([C:34]#[C:33][Si:29]([CH3:32])([CH3:31])[CH3:30])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1cc(Br)c(F)c(F)c1Nc1ccccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)c1cc(C#C[Si](C)(C)C)c(F)c(F)c1Nc1ccccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.1 %

Procedure:
To an oven dried flask charged with a solution of methyl 5-bromo-2-(2-fluorophenylamino)-3,4-difluorobenzoate (21.68 mmol, 8.1 g) in THF (116 ml), was added CuI (2.16 mmol, 0.4 g) and iPr2NH (43.36 mmol, 6.1 ml). After addition is completed, reaction was purged with Argon and Pd(PPh3)2Cl2 (3.73 mmol, 2.62 g) and TMS-acetylene (26.88 mmol, 3.7 ml) are added. The reaction mixture was stirred at room temperature for 16 h, concentrated and taken up in EtOAc. The organic fraction was washed with sat NH4Cl, brine, dried over MgSO4 and conc. The crude was purified by flash chromatography using 5% to 20% EtOAc in Hexane to afford the desired product 6.96 g (85%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[NH2:17][C:18]1[CH:19]=[C:20]([NH:24][C:25](=[O:29])[CH2:26][CH2:27][CH3:28])[CH:21]=[CH:22][CH:23]=1.N1C=CC=CC=1>CN(C)C=O.ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25](=[O:29])[CH2:26][CH2:27][CH3:28])[CH:19]=1)=[O:6]
Reactant: O=C(O)c1ccccc1Br
Reactant: CCCC(=O)Nc1cccc(N)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC(=O)Nc1cccc(NC(=O)c2ccccc2Br)c1
Reaction time: 18 h
Yield: 94.4 %

Procedure:
2-Bromobenzoic acid (259 mg, 1.29 mmol) was sealed in a flask with stir bar under nitrogen, then dissolved with dichloromethane (7.5 mL) and cooled on ice. Oxalyl chloride (113 μL, 1.29 mmol) and N,N-dimethylformamide (4 μL, 0.06 mmol) were added, then the reaction was removed from the ice bath and stirred for 3 h with a vent to an oil bubbler. N-(3-Aminophenyl)butyramide (200 mg, 1.12 mmol) was then added, followed by pyridine (209 μL, 2.58 mmol). After 18 h, LC-MS analysis showed complete consumption of the amine reactant. The reaction was diluted with ethyl acetate (40 mL) and 1 M aqueous HCl (40 mL), then the layers were separated and the organic phase was washed again with aqueous HCl, then twice with half-saturated aqueous NaHCO3, then brine. The organics were dried over Na2SO4, filtered, and concentrated to a colorless oil. The oil was redissolved with dichloromethane, then hexane was added to induce the precipitation of an amorphous solid. The suspension was concentrated and dried under hi-vacuum to yield the title compound (382 mg, 94%). LRMS (ESI+) (M+H): 361.12.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[NH:23][C:22](=[O:24])[O:21][C:20]([CH3:26])([CH3:25])[C:19]=3[CH:27]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:28]O>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[NH:23][C:22](=[O:24])[O:21][C:20]([CH3:25])([CH3:26])[C:19]=3[CH:27]=2)=[O:28])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OO
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccc(Cl)c(Cl)c3)cc21
Product: CC1(C)OC(=O)Nc2ccc(OCCCCS(=O)c3ccc(Cl)c(Cl)c3)cc21

Procedure:
Prepared analogously to Example 2 from 6-[4-(3,4-dichloro-phenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[CH:6])[CH3:2].[Li]CCCC.C([O:17][C:18](=O)[C:19]([F:22])([F:21])[F:20])C>C1COCC1>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[C:6][C:18](=[O:17])[C:19]([F:22])([F:21])[F:20])[CH3:2]
Reactant: C#CC(OCC)OCC
Reactant: CCOC(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(C#CC(=O)C(F)(F)F)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3,3-Diethoxy-propyne (0.98 g, 7.64 mmol) in THF (20 ml) was cooled to −78 C under Ar. A solution of n-BuLi (2.0M in cyclohexane, 4.2 ml, 8.40 mmol) was added. After 30 min., Trifluoroacetic acid ethyl ester (1.19 g, 8.40 mmol) was added. After 1 h, the reaction was quenched by dilution with 1N HCl, warmed to room temperature and extracted into EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography (0-40% EtOAc in Hexanes) to give product, 0.51 g (30%).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([O:17][CH2:18][CH:19]=[C:20]([Cl:22])[Cl:21])[CH:14]=[C:13]([Cl:23])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8]S(C)(=O)=O.C(=O)([O-])[O-].[K+].[K+].O[C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[C:37](=[O:41])[CH2:36][CH2:35][CH2:34]2.O>CN(C)C=O>[Cl:1][C:2]1[CH:16]=[C:15]([O:17][CH2:18][CH:19]=[C:20]([Cl:22])[Cl:21])[CH:14]=[C:13]([Cl:23])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[C:37](=[O:41])[CH2:36][CH2:35][CH2:34]2
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: CS(=O)(=O)OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCCc2cc(OCCCOc3c(Cl)cc(OCC=C(Cl)Cl)cc3Cl)ccc21

Procedure:
1.1 g of methanesulfonic acid 3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propyl ester, 1.1 g of potassium carbonate and 0.45 g of 6-hydroxy-1-tetralone are stirred in 10 ml of dimethylformamide at 50° C. for 17 hours. The reaction mixture is poured into water and extracted with ethyl acetate. After concentration of the organic phases and purification over silica gel, 6-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-3,4-dihydro-2H-naphthalen-1-one is obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([C:30](O)=[O:31])[CH2:8][CH2:7][N:6]([CH2:9][C:10](=[O:29])[N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[N:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)[CH2:5]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[F:55][C:56]1[CH:61]=[CH:60][C:59]([C:62]2[C:70]3[C:65](=[CH:66][CH:67]=[C:68]([NH2:71])[CH:69]=3)[NH:64][N:63]=2)=[CH:58][CH:57]=1>CN(C=O)C>[F:55][C:56]1[CH:57]=[CH:58][C:59]([C:62]2[C:70]3[C:65](=[CH:66][CH:67]=[C:68]([NH:71][C:30]([C:4]4([CH2:3][O:2][CH3:1])[CH2:8][CH2:7][N:6]([CH2:9][C:10](=[O:29])[N:11]5[CH2:12][CH2:13][N:14]([C:17]6[CH:18]=[CH:19][C:20]([C:23]7[N:28]=[CH:27][CH:26]=[CH:25][N:24]=7)=[CH:21][CH:22]=6)[CH2:15][CH2:16]5)[CH2:5]4)=[O:31])[CH:69]=3)[NH:64][N:63]=2)=[CH:60][CH:61]=1
Reactant: Nc1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Reactant: COCC1(C(=O)O)CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)cc3)CC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COCC1(C(=O)Nc2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)cc3)CC2)C1
Reaction time: 8 h
Yield: 28.8 %

Procedure:
The 3-methoxymethyl-1-{2-oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1-yl]-ethyl}-pyrrolidine-3-carboxylic acid (0.049 mmol), 1-hydroxybenztriazole (7 mg, 0.052 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) (10 mg, 0.052 mmol) were dissolved in dry DMF (1 ml). 3-(4-Fluoro-phenyl)-1H-indazol-5-ylamine (12 mg, 0.053 mmol) was added and the reaction mixture was stirred overnight and directly subjected to purification by reversed phase HPLC to obtain 9.15 mg of the title product.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH:4]1[OH:16].C1N=CN([C:22](N2C=NC=C2)=[O:23])C=1.C([O-])([O-])=O.[Na+].[Na+]>CCC(C)=O>[O:23]=[C:22]1[NH:1][CH2:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:5][CH:4]2[O:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)C(O)C1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)N1CCC2CNC(=O)OC2C1
Temperature: 60 °C
Reaction time: 3 h
Yield: 68.7 %

Procedure:
To a mixture of rac-(3R*,4R*)-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (3.39 g, 14.72 mmol; prepared according to Tetrahedron (2008), 64, 2456-2464) in MEK (40 mL) heated to 60° C. was added CDI (3.58 g, 22.08 mmol, 1.5 eq). The mixture was stirred for 3 h. Na2CO3 (5% aq., 4 mL) was added. The reaction proceeded at rt for 70 min. The two layers were decanted and the aq. layer was extracted with EA (10 mL). The combined org. layers were washed with brine (8 mL), dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by CC (DCM to DCM/MeOH 9:1) to afford the title compound as a white solid (2.59 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[C:5]([Cl:10])=[CH:4][N:3]=1.[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][C:13]=1[N+:20]([O-:22])=[O:21].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C>[Cl:10][C:5]1[C:6]([CH3:9])=[C:7]2[N:8]=[C:16]([C:15]3[CH:18]=[CH:19][C:12]([OH:11])=[C:13]([N+:20]([O-:22])=[O:21])[CH:14]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: Cc1c(Cl)cnc(N)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC#N
Product: Cc1c(Cl)cnc2[nH]c(-c3ccc(O)c([N+](=O)[O-])c3)nc12

Procedure:
2,3-Diamino-5-chloro-4-methylpyridine (prepared by a method similar to Example 206a) (3.2 g, 20.3 mmol), was dissolved in acetonitrile (150 ml). 4-Hydroxy-3-nitrobenzaldehyde (3.1 g) was added, followed by p-toluenesulfonic acid monohydrate (0.7 g) and the resulting mixture was heated to reflux overnight. The solvent was then removed in vacuo and the residue dissolved in a mixture of dichloromethane and methanol (1:1). To this solution was added silica gel and the solvents were evaporated in vacuo. The silica-supported product mixture was then applied to column chromatography, eluting with first dichloromethane and then a mixture of dichloromethane and methanol 4:1. This afforded the title compound of approx. 75% purity. This material was suspended in hot EtOAc and filtered while still hot. The collected solid was approx. 95% pure. An analytical sample was prepared by semi-preparative HPLC-C18.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]=[C:6]([C:8]1[O:12][C:11]2[C:13]([C:17]3[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:20]=[C:19]([CH:26]([CH3:28])[CH3:27])[C:18]=3[O:29][CH2:30][CH:31]([F:33])[F:32])=[CH:14][CH:15]=[CH:16][C:10]=2[CH:9]=1)[CH3:7])C.C1COCC1.[Li+].[OH-]>CO>[F:33][CH:31]([F:32])[CH2:30][O:29][C:18]1[C:19]([CH:26]([CH3:28])[CH3:27])=[CH:20][C:21]([CH:23]([CH3:25])[CH3:24])=[CH:22][C:17]=1[C:13]1[C:11]2[O:12][C:8]([C:6]([CH3:7])=[CH:5][C:4]([OH:34])=[O:3])=[CH:9][C:10]=2[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C=C(C)c1cc2cccc(-c3cc(C(C)C)cc(C(C)C)c3OCC(F)F)c2o1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=CC(=O)O)c1cc2cccc(-c3cc(C(C)C)cc(C(C)C)c3OCC(F)F)c2o1
Temperature: 25 °C

Procedure:
A mixture of 0.450 mmol of 3-{7-[2-(2,2-difluoroethoxy)-3,5-diisopropylphenyl]-benzo[b]furan-2-yl}-but-2-enoic acid ethyl ester, 3 mL of THF, 3 mL of methanol and 1 mL of LiOH (2N aqueous) was refluxed for 2 hours. After cooling at room temperature, the mixture was acidified to pH=2 and extracted with ethyl acetate. The organic layer was dried over MgSO4 and after evaporation of the solvents, the crude acid was recrystallized from acetonitrile. 3-{7-[2-(2,2-Difluoroethoxy)-3,5-diisopropylphenyl]-benzo[b]furan-2-yl}-but-2-enoic acid was isolated as a white solid. 1H-NMR (400 MHz, CDCl3) δ 7.60 (d, J=7.1 Hz, 1H, Ar—H), 7.57 (d, J=7.4 Hz, 1H, Ar—H), 7.32 (d, J=2.3 Hz, 1H, Ar—H), 7.31 (t, J=7.6 Hz, 1H, Ar—H), 7.18 (d, J=2.2 Hz, 1H, Ar—H), 7.11 (s, 1H, furan-H), 6.58 (s, 1H, C═C—H), 5.54 (tt, J=55.3 Hz, J=4.2 Hz, 1H, O—CH2—CF2H), 3.54 (dt, J=13.6 Hz, J=4.2 Hz, 2H, O—CH2—CF2H), 3.42 (m, 1H, CH3—CH—CH3), 2.96 (m, 1H, CH3—CH—CH3), 2.57 (s, 3H, C═C—CH3), 1.32 (d, J=6.8 Hz, 6H, CH3—CH—CH3), 1.31 (d, J=6.8 Hz, 6H, CH3—CH—CH3).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][CH:16]1[CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH:29]([C@H:31]1[CH2:35][O:34][C:33]([CH3:37])([CH3:36])[N:32]1[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[O:30]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[C@H:15]([CH:16]1[CH2:17][CH2:18]1)[C@H:29]([C@H:31]1[CH2:35][O:34][C:33]([CH3:37])([CH3:36])[N:32]1[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[OH:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CC1CC1)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1[C@@H](C=O)COC1(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1[C@@H]([C@H](O)[C@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)C2CC2)COC1(C)C
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 50.5 %

Procedure:
To a −40° C. solution of (4R)-4-benzyl-3-(cyclopropylacetyl)-1,3-oxazolidin-2-one (2.0 g, 7.7 mmol) in anhydrous DCM (45 mL), a solution of 1.0 M titanium tetrachloride in DCM (9.3 mL) was added drop-wise under an atmosphere of nitrogen to form a yellow slurry. After 10 min., DIPEA (3.36 mL, 19.3 mmol) was added drop-wise, changing the color from yellow to deep purple. The reaction mixture was allowed to warm gradually to −20° C. while stirring over 1 h. The reaction mixture was again cooled to −40° C., and a solution of tert-butyl (4R)-4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (1.8 g, 7.85 mmol) (Aldrich) in anhydrous DCM (5 mL) was added drop-wise. The reaction mixture was allowed to warm gradually to 0° C. over 1 h and then allowed to stir for an additional 1.5 h at 0° C. The reaction was quenched by the addition of saturated NH4Cl (aq.) (15 mL). After separation of the two layers that resulted, the organic layer was washed with water and brine, dried over Na2SO4, concentrated under reduced pressure and purified by flash chromatography (120 g silica gel, eluting with 0-60% EtOAc/hexanes) to afford the sub-title compound (1.9 g, 50%). LC/MS (ESI) m/z calc. for C26H36N2O7Na: 511.2 [M+Na]+. found 511.1.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1>>[C:1]1([C:7]2[N:8]=[CH:9][N:10]([C:13]3[CH:20]=[CH:19][C:16]([CH2:17][OH:18])=[CH:15][CH:14]=3)[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: c1ccc(-c2c[nH]cn2)cc1
Product: OCc1ccc(-n2cnc(-c3ccccc3)c2)cc1

Procedure:
Prepared from 4-phenylimidazole and 4-fluorobenzaldehyde.