Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(O[CH:12]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>>[I:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][CH:3]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccc(I)cc1
Product: CCOC(=O)C(=CNc1ccc(I)cc1)C(=O)OCC
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 4-iodoaniline (208 g) (available from Aldrich) and diethyl (ethoxymethylene)malonate (210 ml) (available from Aldrich) was heated to ca. 60° C., whereupon the mixture set solid. Heating was continued to 100° C., and then the mixture was removed from heating and broken up. Heating was continued at 100° C. for 1 h, and the solid was collected, washed with cyclohexane (1 L) and ethanol (2×500 ml), and dried in vacuo at 40° C. overnight to give the title compound as a white solid (356 g).
Reaction SMILES: Cl.[CH:2]1[C:14]2[CH:13]([CH2:15][O:16][C:17]([N:19]3[CH2:24][C@H:23]([C:25](=[O:48])[N:26]([CH:45]4[CH2:47][CH2:46]4)[C:27]4[CH:28]=[CH:29][C:30]5[O:35][C:34]([CH3:37])([CH3:36])[C:33](=[O:38])[N:32]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[C:31]=5[CH:44]=4)[CH2:22][C@H:21]([NH2:49])[CH2:20]3)=[O:18])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:50]([C:52]1([C:55](O)=[O:56])[CH2:54][CH2:53]1)#[N:51].CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH:11]1[C:12]2[CH:13]([CH2:15][O:16][C:17]([N:19]3[CH2:24][C@H:23]([C:25](=[O:48])[N:26]([CH:45]4[CH2:47][CH2:46]4)[C:27]4[CH:28]=[CH:29][C:30]5[O:35][C:34]([CH3:36])([CH3:37])[C:33](=[O:38])[N:32]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[C:31]=5[CH:44]=4)[CH2:22][C@H:21]([NH:49][C:55]([C:52]4([C:50]#[N:51])[CH2:54][CH2:53]4)=[O:56])[CH2:20]3)=[O:18])[C:14]3[C:6](=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: N#CC1(C(=O)O)CC1
Reactant: COCCCN1C(=O)C(C)(C)Oc2ccc(N(C(=O)[C@@H]3C[C@H](N)CN(C(=O)OCC4c5ccccc5-c5ccccc54)C3)C3CC3)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCCN1C(=O)C(C)(C)Oc2ccc(N(C(=O)[C@@H]3C[C@H](NC(=O)C4(C#N)CC4)CN(C(=O)OCC4c5ccccc5-c5ccccc54)C3)C3CC3)cc21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of (3S,5R)-3-Amino-5-{cyclopropyl-[4-(3-methoxy-propyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamoyl}-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester hydrochloride salt (100 mg, 0.152 mmol) and 1-Cyano-cyclo-propanecarboxylic acid (20 mg, 0.182 mmol) in DMF (10 mL) is added EDC-HCl (45 mg, 0.227 mmol), HOAt (31 mg, 0.227 mmol) and diisopropylethylamine (0.04 mL, 0.227 mmol) at 0° C. The mixture is stirred for 14 h at r.t. and diluted with ethyl acetate, and washed with H2O. The organic layer is dried over MgSO4 and evaporated in vacuo. The residue is purified by silica-gel column chromatography to afford the title compound as a white solid. MS: 746 [M+H]+; tR (CombiScreen ODS-AM, 50×4.6 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 2 min, flow 2.0 ml/min): 2.14 min.
Reaction SMILES: [OH:1][CH:2]([C:9]1[C:19]([OH:20])=[CH:18][C:12]2[C:13]([C:15]([OH:17])=[O:16])=[CH:14][C:11]=2[CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl>[C:2]([C:9]1[C:19]([OH:20])=[CH:18][C:12]2[C:13]([C:15]([OH:17])=[O:16])=[CH:14][C:11]=2[CH:10]=1)(=[O:1])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)C1=Cc2cc(C(O)c3ccccc3)c(O)cc21
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C(O)C1=Cc2cc(C(=O)c3ccccc3)c(O)cc21
Reaction time: 7 h

Procedure:
3.0 g of 4-(α-hydroxybenzyl)-5-hydroxybenzocyclobutene-1-carboxylic acid are dissolved in 30 ml of dichloromethane and over a period of 10 minutes, while stirring, 30 g of pyridinium dichromate in 100 ml of dichloromethane are added dropwise thereto. Stirring is then carried out for 7 hours at room temperature, and the mixture is decanted off from the black residue, filtered over silica gel, concentrated to dryness by evaporation and crystallised from ether/hexane. 4-benzoyl-5-hydroxybenzocyclobutene-1-carboxylic acid is obtained having a melting point of 167°-169°.
Reaction SMILES: C([CH2:5][O:6][C:7]1[CH:29]=[CH:28][C:10]([C:11]2[O:12][C:13]3[C:18]([C:19](=[O:21])[CH:20]=2)=[C:17]([O:22]C)[C:16]([O:24][CH3:25])=[C:15]([O:26][CH3:27])[CH:14]=3)=[CH:9][CH:8]=1)(OC)=O.OC1C(O)=C(OC)C=C2C=1C(=O)C=C(C1C=CC(OC)=CC=1)O2.BrC[C:55]([O:57][CH2:58][CH3:59])=[O:56].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:55]([CH2:25][O:24][C:16]1[C:17]([OH:22])=[C:18]2[C:13](=[CH:14][C:15]=1[O:26][CH3:27])[O:12][C:11]([C:10]1[CH:9]=[CH:8][C:7]([O:6][CH3:5])=[CH:29][CH:28]=1)=[CH:20][C:19]2=[O:21])([O:57][CH2:58][CH3:59])=[O:56]
Reactant: COC(=O)COc1ccc(-c2cc(=O)c3c(OC)c(OC)c(OC)cc3o2)cc1
Reactant: CCOC(=O)CBr
Agent: COc1ccc(-c2cc(=O)c3c(O)c(O)c(OC)cc3o2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1c(OC)cc2oc(-c3ccc(OC)cc3)cc(=O)c2c1O

Procedure:
Similar to the preparation of 4′-(carbmethoxymethoxy)-5,6,7-trimethoxyflavone, the title compound is prepared from a suspension of 5,6-dihydroxy-4′,7-dimethoxyflavone (628 mg, 2 mmol), ethyl bromoacetate (367 mg, 2.2 mmol), and anhydrous potassium carbonate (0.5 g) in acetone (50 ml).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[CH:8]=2)[CH:2]=1.C([O-])([O-])=O.[K+].[K+].Br[C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[CH3:30].CNCCNC.N.[Na+].[Cl-]>[Cu]I.O1CCOCC1>[CH3:30][C:22]1[CH:21]=[CH:26][C:25]([N+:27]([O-:29])=[O:28])=[CH:24][C:23]=1[NH:13][C:9]1[CH:8]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:12]=[CH:11][N:10]=1
Reactant: Nc1cc(-c2cccnc2)ccn1
Reactant: Cc1ccc([N+](=O)[O-])cc1Br
Agent: [Cu]I
Agent: CNCCNC
Agent: N
Solvent: C1COCCO1
Product: Cc1ccc([N+](=O)[O-])cc1Nc1cc(-c2cccnc2)ccn1
Temperature: 25 °C

Procedure:
4-(Pyridine-3-yl)pyridine-2-amine (8.60 g, 0.05 mol), CuI (2.39 g, 0.0125 mmol), anhydrous K2CO3 (14.0 g, 0.1 mol), KI (2.08 g, 0.0125 mol) were added to a Schlenk-type three-neck flask fitted with a thermometer, magnetic stirbar, and septum. The flask was evacuated and back filled with N2 three times. Dioxane (250 mL) and 2-bromo-4-nitrotoluene (9.82 g, 0.045 mol) were added to the flask. Finally, N,N′-dimethylethylenediamine (1.10 g, 0.0125 mol) was added by syringe at room temperature with stirring. The reaction mixture was stirred at 110° C. under N2 for 24 hours and then cooled to room temperature. Ammonia (30%, 100 mL) and saturated NaCl (400 mL), were added to the reaction mixture which was then extracted with ethyl acetate (500 mL×3). The organic phase was dried over Na2SO4 and a yellow solid was obtained after the solvent was removed under reduced pressure. The crude product was purified by column chromatography (biotage: DMC/Methanol, 1-8%, 20 CV). The desired product was obtained as a yellow solid (8.3 g, yield: 60%); NMR (500 MHz, CDCl3) δ 2.49 (s, 3H), 7.36 (m, 1H), 7.15 (br., 1H), 7.35 (d, 1H), 7.38 (d, 1H), 7.52 (m, 1H), 7.88 (d, 1H), 8.55 (d, 1H), 8.60 (d, 1H), 8.76 (d, 1H), 9.28 (s, 1H), 9.50 (s, 1H). LC-MS (m/z) calculated, 307.3. found, 308.3 [M+H]+.
Reaction SMILES: [F-:1].[K+].C1OCCOCCOCCOCCOCCOC1.Cl[C:22]1[N:31]2[CH:32]=[C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[F:41])[N:34]=[C:30]2[C:29]2[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=2[N:23]=1.O>CN(C=O)C>[F:1][C:22]1[N:31]2[CH:32]=[C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[F:41])[N:34]=[C:30]2[C:29]2[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=2[N:23]=1
Reactant: Fc1ccccc1-c1cn2c(Cl)nc3c(c2n1)CCCC3
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccccc1-c1cn2c(F)nc3c(c2n1)CCCC3
Temperature: 25 °C

Procedure:
To a solution of 700 mg of potassium fluoride and 200 mg 18-crown-6 in 10 mL of DMF was added 5-Chloro-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline (200 mg). This mixture was refluxed for 1.5 h, cooled to room temperature and poured into water. The aqueous solution was extracted with ethyl acetate, the organic layer was separated and dried, and the solvent removed in vacuo to yield 5-Fluoro-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline (Compound 41), m.p. 154°-155° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16](=[O:26])[NH:17][C@@H:18]([C:20]2C=CC=CC=2)C)=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:36]=[CH:37][C:38]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[C@H:14]([O:15][C:16](=[O:26])[NH:17][CH2:18][CH3:20])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:6][CH:7]=3)=[CH:39][CH:40]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1COC(=O)N[C@H](C)c1ccccc1
Product: CCNC(=O)O[C@H](c1ccccc1)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using ((R)-1-phenyl-ethyl)-carbamic acid 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylmethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH2:26]>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH:26][C:17]([C:15]1[CH:16]=[C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])[CH:12]=[N:13][CH:14]=1)=[O:19]
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Reactant: COc1cccc(CN)c1
Product: CCc1cc(-c2cncc(C(=O)NCc3cccc(OC)c3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and 3-methoxy-benzylamine to afford the title compound. MS: m/e=378 (M+H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH2:2].C1C=CC(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC1(C)C(C)(C)OB[O:49]1.B(O[O-])=O.[Na+]>C1COCC1>[OH:49][CH2:2][CH2:1][C:3]1[CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: C=Cc1cc(C(=O)OC)c2ccccc2c1
Reactant: CC1(C)OBOC1(C)C
Agent: O=BO[O-]
Agent: [Na+]
Agent: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(CCO)cc2ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Methyl 3-ethenyl-1-naphthalenecarboxylate (1 eq.) from the previous step, [Ir(COD)Cl]2 (0.025 eq.) and DPPB (0.05 eq.) were combined in THF (0.12 M). To this solution was then added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.2 eq.) and the resulting red solution was stirred at RT for 16 h. Finally, sodium perborate (0.1 M aqueous solution, 2 eq.) was added and the now black biphasic solution was vigorously stirred at RT for another 12 h. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were then washed further with 1 N aq. NaOH, water and brine. This was then dried over Na2SO4, filtered and the filtrate concentrated in vacuo to afford a pale yellow oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→1:1 (v/v) EtOAc:Hex) afforded the title compound as a pale yellow oil.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[NH:29][C:10]2=[N:11][C:12]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[N:14]=[C:9]2[CH:8]=1)(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44].O>CN(C=O)C>[C:1]([O:4][CH2:5][CH2:6][C:7]1[N:29]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[C:10]2=[N:11][C:12]([C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[N:14]=[C:9]2[CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCc1cc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2[nH]1
Reactant: CCOC(=O)CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCCCn1c(CCOC(C)=O)cc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(2,3-Dip-tolyl-5H-pyrrolo[2,3-b]pyrazin-6-yl)ethyl acetate (step 3) (12 mg, 0.031 mmol) was dissolved in dry DMF (1 ml) at RT and treated with K2CO3 (12.91 mg, 0.093 mmol) and ethyl 7-bromoheptanoate (0.012 ml, 0.062 mmol). The resulting brown suspension was stirred at RT for 16 hours. The mixture was then heated at 60° C. for 5 hours and after cooling to RT, stirred overnight. The mixture was added to water (30 ml) and extracted with DCM (×3). The combined organic extracts were passed through a phase separating column and concentrated under reduced pressure to afford the title compound;
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]#[N:8].Cl.[NH2:10][OH:11].C(N(CC)CC)C>CO>[OH:11][N:10]=[C:7]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=1)[NH2:8]
Reactant: Cn1ccnc1C#N
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: Cn1ccnc1C(N)=NO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Methyl-2-cyanoimidazole (0.85 g, 8.0 mmol) (J. Chem. Soc. Perkin Trans. I 1994, 239) was dissolved in methanol (20 mL), then hydroxylamine hydrochloride (0.66 g, 9.6 mmol) and triethylamine (1.3 mL, 9.6 mmol) were added and the mixture was stirred at room temperature for 1 hour. The mixture was chilled in an ice-bath, then the solid was collected by filtration, washed with methanol and dried to give the title compound as a white crystalline solid which was contaminated with triethylamine hydrochloride (0.90 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:23]3[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=3)[CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:39][O:40][C:41](=[O:46])[C@H:42]([OH:45])[CH2:43][NH2:44].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:39][O:40][C:41](=[O:46])[C@H:42]([OH:45])[CH2:43][NH:44][C:27](=[O:28])[C:26]1[CH:25]=[CH:24][C:23]([CH:18]([O:17][C:14]2[CH:15]=[CH:16][C:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:10][CH:9]=3)=[CH:12][CH:13]=2)[CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:31][CH:30]=1
Reactant: COC(=O)[C@H](O)CN
Reactant: CC(C)CC(Oc1ccc(-c2ccc(C(C)(C)C)cc2)cc1)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](O)CNC(=O)c1ccc(C(CC(C)C)Oc2ccc(-c3ccc(C(C)(C)C)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.2 %

Procedure:
To a mixture of 4-[1-(4′-tertbutyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoic acid (120 mg) in methylene chloride (3 mL) are added triethyl amine (0.12 mL, 0.87 mmol), DMAP (5 mg), 3-Amino-2(R)-hydroxy-propionic acid methyl ester (67.3 mg, 0.43 mmol) and EDCI (166 mg, 0.87 mmol) at room temperature. The reaction mixture is stirred at room temperature overnight, loaded on silica gel, eluted with eluted with hexanes with a gradient from 0% of ethyl acetate to 100% of ethyl acetate giving 3-{4-[1-(4′-tert-butyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylamino}-2(R)-hydroxy-propionic acid methyl ester (60 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10]C1CCCCO1.[CH3:17][CH2:18][CH2:19]CC>CS(C)=O>[CH2:9]([OH:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:19][C:18]#[CH:17]
Reactant: CCCCC
Reactant: BrCCCCCCCCOC1CCCCO1
Solvent: CS(C)=O
Product: C#CCCCCCCCCCO
Temperature: 25 °C
Reaction time: 18 h
Yield: 48 %

Procedure:
(Method G) A solution of commercially available 2-[(8-bromooctyl)oxy]tetrahydro-2H-pyran (1.0 g, 3.4 mmol, 1 equiv.) in DMSO (5 ml), was added, slowly, dropwise, at r.t., under N2, to a stirred suspension of lithium acetylide ethylenediamine complex (350 mg, 3.8 mmol, 1.1 equiv.) in DMSO (5 ml). The reaction mixture was stirred at r.t. for 18 h and diluted with n-pentane (50 ml). The organic phase was washed with 1N HCl solution (2×20 ml) and water (2×20 ml), dried (Na2SO4) and evaporated to dryness under reduced pressure. The residue (colourless liquid, 570 mg, yield 70%) was dissolved in 95% EtOH (20 ml) together with p-toluenesulfonic acid (150 mg) and the mixture was heated under reflux for 2.5 h. After being cooled, the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with EtOAc/hexane (10%-30% gradient), to give the desired compound as a colourless oil (240 mg, overall yield 48%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][N:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.[BH4-].[Na+]>C1COCC1.CO>[CH3:1][O:2][C:3](=[O:15])[CH2:4][NH:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=1
Reactant: COC(=O)CN=Cc1ccc(OC)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CNCc1ccc(OC)cc1
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
To a solution of 91.3 g (0.441 mol) of [(4-methoxy-benzylidene)-amino]-acetic acid methyl ester in 500 ml of THF and 1000 ml of MeOH, 20 g (0.529 mol) of sodium borohydride is added portionwise at −10 to 0° C. The reaction mixture is stirred for 30 min. at −10 to 0° C. and quenched with sat. NH4Cl. After adding of ice-water, the mixture is concentrated to ¼ of whole volume and extracted with AcOEt. The combined extracts are washed with H2O and brine, dried over MgSO4 and concentrated under reduced pressure to give (4-methoxybenzylamino)-acetic acid methyl ester; NMR (CDCl3): 1.87 (br s, 1H), 3.41 (s, 2H), 3.73 (s, 3H), 3.74 (s, 2H), 3.8 (s, 3H), 6.86 (d, 2H, J=8.56 Hz), 7.24 (d, 2H, J=8.56 Hz).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[C:8]([Cl:11])[CH:9]=2)[CH2:4][CH:3]1[CH2:17][CH3:18].[Br:19]Br>Br.C(O)(=O)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[C:8]([Cl:11])[CH:9]=2)[CH2:4][C:3]1([Br:19])[CH2:17][CH3:18]
Reactant: BrBr
Reactant: CCC1Cc2cc(OCC(=O)O)c(Cl)cc2C1=O
Agent: Br
Solvent: CC(=O)O
Product: CCC1(Br)Cc2cc(OCC(=O)O)c(Cl)cc2C1=O

Procedure:
(1-Oxo-2-bromo-2-ethyl-6-chloro-5-indanyloxy)acetic acid is prepared by following substantially the same procedure as described in Example 1, Step B, using the following reagents: (1-oxo-2-ethyl-6-chloro-5-indanyloxy)acetic acid (13.44 g., 0.05 mole), bromine (8.79 g., 0.055 mole), acetic acid (135 ml.) and 48% hydrobromic acid (2 drops). The crude yield of the product is 17.38 g. (100%), m.p. 157°-159° C. Recrystallization from benzene gives (1-oxo-2-bromo-2-ethyl-6-chloro-5-indanyloxy)acetic acid as white needles, m.p. 159.5°-160.5° C.
Reaction SMILES: Br[C:2]1[C:3]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:21][C:20]=2[N+:32]([O-:34])=[O:33])=[C:4]([Cl:17])[CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][CH:7]2[C:12]([O:14][CH2:15][CH3:16])=[O:13].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P([CH:56]2[CH2:61][CH2:60]CCC2)C2CCCCC2)CCCCC1.C1(B(O)O)CC1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[C:28]([O:27][C:25]([C:22]1[CH:23]=[CH:24][C:19]([O:18][C:3]2[C:2]([CH:60]3[CH2:61][CH2:56]3)=[C:11]3[C:6]([CH:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8][CH2:9][O:10]3)=[CH:5][C:4]=2[Cl:17])=[C:20]([N+:32]([O-:34])=[O:33])[CH:21]=1)=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Reactant: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)OC(C)(C)C)cc1[N+](=O)[O-])c2Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)OC(C)(C)C)cc1[N+](=O)[O-])c2C1CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 128.7 %

Procedure:
To a stirred solution of ethyl 8-bromo-7-(4-(tert-butoxycarbonyl)-2-nitrophenoxy)-6-chlorochroman-4-carboxylate (0.59 g, 1.05 mmol) in toluene (6 mL) was added successively water (0.3 mL), potassium phosphate (0.67 g, 3.2 mmol), tricyclohexylphosphine (0.12 g, 0.42 mmol), and cyclopropylboronic acid (0.18 g, 2.1 mmol). The resulting mixture was stirred and a balloon of nitrogen with a three-way purge valve was attached, and the flask was evacuated and refilled five times with nitrogen. Palladium(II) acetate (0.047 g, 0.21 mmol) was added, and again the flask was evacuated and refilled five times with nitrogen. The mixture was stirred in an oil bath set to 100° C. under the nitrogen balloon for 1.5 hours. The mixture was cooled to ambient temperature, and diluted with ethyl acetate (25 mL) and water (15 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel, eluting with 85/15 hexanes/ethyl acetate, to afford ethyl 7-(4-(tert-butoxycarbonyl)-2-nitrophenoxy)-6-chloro-8-cyclopropylchroman-4-carboxylate as a yellow oil (0.28 g, 51%).
Reaction SMILES: F[C:2]1[C:16]([CH:17]=[O:18])=[CH:15][C:5]2[C:6]([C:9]3[N:13]([CH3:14])[N:12]=[CH:11][N:10]=3)=[N:7][O:8][C:4]=2[C:3]=1[F:19].[CH3:20][C@H:21]1[O:26][C@H:25]([CH3:27])[CH2:24][NH:23][CH2:22]1>>[CH3:27][C@@H:25]1[CH2:24][N:23]([C:2]2[C:16]([CH:17]=[O:18])=[CH:15][C:5]3[C:6]([C:9]4[N:13]([CH3:14])[N:12]=[CH:11][N:10]=4)=[N:7][O:8][C:4]=3[C:3]=2[F:19])[CH2:22][C@@H:21]([CH3:20])[O:26]1
Reactant: C[C@@H]1CNC[C@@H](C)O1
Reactant: Cn1ncnc1-c1noc2c(F)c(F)c(C=O)cc12
Product: C[C@@H]1CN(c2c(C=O)cc3c(-c4ncnn4C)noc3c2F)C[C@@H](C)O1

Procedure:
Starting materials: 6,7-difluoro-3-(1-methyl-1H-1,2,4-triazol-5-yl)benzo[d]isoxazole-5-carbaldehyde (Intermediate 404) and (2R,6R)-2,6-dimethylmorpholine.
Reaction SMILES: [CH2:1]([C:8]1[C:13](Br)=[CH:12][N:11]=[C:10]([O:15][CH2:16][C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([C@:24]1([OH:32])[CH:29]2[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]2)[CH2:25]1)#[CH:23].C(N(CC)CC)C>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.CN(C)C=O>[CH2:1]([C:8]1[C:13]([C:23]#[C:22][C@:24]2([OH:32])[CH:29]3[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]3)[CH2:25]2)=[CH:12][N:11]=[C:10]([O:15][CH2:16][C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cnc(OCc2ccco2)nc1Cc1ccccc1
Reactant: C#C[C@@]1(O)CN2CCC1CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O[C@]1(C#Cc2cnc(OCc3ccco3)nc2Cc2ccccc2)CN2CCC1CC2
Temperature: 90 °C
Reaction time: 4 h
Yield: 47.3 %

Procedure:
A mixture of 50.9 mg of 4-benzyl-2-(2-furylmethoxy)-5-bromopyrimidine, 26.8 mg of (3R)-3-ethynyl-3-quinuclidinol, 8.5 mg of tetrakis(triphenylphosphine)palladium(0), 0.3 mg of cuprous iodide, 61.5 μl of triethylamine and 1 ml of N,N-dimethylformamide was stirred at 90° C. for 4 hours in a nitrogen atmosphere. NH-silica gel was added to the reaction solution and the solvent was removed. The residue was subjected to NH-silica gel column chromatography using 3% methanol/ethyl acetate, to give 29.0 mg of the target compound.