Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=O)[CH:15]=2)[NH:10][N:9]=1)([CH3:3])[CH3:2].[NH2:19][C:20]([CH:24]([F:26])[F:25])=[CH:21][C:22]#[N:23]>C(O)(=O)C.C1COCC1>[F:25][CH:24]([F:26])[C:20]1[NH:19][C:20]([CH:24]([F:26])[F:25])=[C:21]([C:22]#[N:23])[CH:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][N:9]=[C:8]3[O:7][CH2:6][CH2:5][O:4][CH:1]([CH3:2])[CH3:3])[C:21]=1[C:22]#[N:23]
Reactant: N#CC=C(N)C(F)F
Reactant: CC(C)OCCOc1n[nH]c2ccc(C=O)cc12
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)OCCOc1n[nH]c2ccc(C3C(C#N)=C(C(F)F)NC(C(F)F)=C3C#N)cc12
Temperature: 25 °C

Procedure:
80 mg (0.32 mmol) 3-(2-isopropoxyethoxy)-1H-indazole-5-carbaldehyde (Example 32A), 84 mg (0.71 mmol) 3-amino-4,4-difluorobut-2-enenitrile [obtainable by Thorpe reaction of acetonitrile with 2,2-difluoroacetonitrile, cf. Org. React. 15, 1 (1967), ibid. 31, 1 (1984)] and a small amount of powdered 4 Å molecular sieve in acetic acid (310 μl) were heated to 115° C. for 1 h. After cooling to room temperature, the reaction mixture was diluted with THF and filtered. The filtrate was directly purified by preparative RP-HPLC (acetonitrile/water+0.05% TFA gradient) to give 85 mg (59% of th.) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:20][C:21]([F:24])([F:23])[F:22])[S:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[C:4]([F:25])[CH:3]=1.[N:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[F:25][C:4]1[CH:3]=[C:2]([C:29]2[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=2)[CH:7]=[CH:6][C:5]=1[CH2:8][N:9]([CH2:20][C:21]([F:24])([F:23])[F:22])[S:10]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:12])=[O:11]
Reactant: OB(O)c1ccncc1
Reactant: O=S(=O)(Cc1ccccc1)N(Cc1ccc(Br)cc1F)CC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=S(=O)(Cc1ccccc1)N(Cc1ccc(-c2ccncc2)cc1F)CC(F)(F)F
Temperature: 80 °C
Reaction time: 16 h
Yield: 92.9 %

Procedure:
N-[(4-bromo-2-fluoro-phenyl)methyl]-1-phenyl-N-(2,2,2-trifluoroethyl)methanesulfonamide (Example 2, Step 2) (2 g, 4.54 mmol), 4-pyridylboronic acid (931 mg, 6.81 mmol) dichlorobis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) (161 mg, 0.23 mmol) potassium acetate (669 mg, 6.81 mmol) and sodium carbonate (722 mg, 6.81 mmol) were combined and the reaction was purged with nitrogen. Acetonitrile (15 mL) and water (4.5 mL) were then added and the reaction was stirred at 80° C. for 16 hours. The reaction was filtered through diatomaceous earth, concentrated and purified by silica gel column chromatography (20-100% EtOAc in heptane) to give N-[[2-fluoro-4-(4-pyridyl)phenyl]methyl]-1-phenyl-N-(2,2,2-trifluoroethyl)methanesulfonamide (1.85 g, 93% yield). 1H NMR (400 MHz, DMSO) δ 8.69-8.62 (m, 2H), 7.79-7.74 (m, 2H), 7.74-7.66 (m, 2H), 7.57 (t, J=8.1 Hz, 1H), 7.50-7.36 (m, 5H), 4.68 (s, 2H), 4.53 (s, 2H), 4.04 (q, J=9.3 Hz, 2H); LCMS (m/z) ES+ 439.0 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[C:10]([CH3:21])=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][N:15]=[C:14]([NH:19][CH3:20])[CH:13]=3)=[CH:4][C:3]=1[NH:22][C:23](=[O:28])OC(C)=C.[CH3:29][C:30]([CH3:35])([CH3:34])[CH2:31][CH2:32][NH2:33].CN1CCCC1>O1CCOCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[C:10]([CH3:21])=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][N:15]=[C:14]([NH:19][CH3:20])[CH:13]=3)=[CH:4][C:3]=1[NH:22][C:23]([NH:33][CH2:32][CH2:31][C:30]([CH3:35])([CH3:34])[CH3:29])=[O:28]
Reactant: CC(C)(C)CCN
Reactant: C=C(C)OC(=O)Nc1cc(-c2cc3cnc(NC)cc3nc2C)c(F)cc1F
Agent: CN1CCCC1
Solvent: C1COCCO1
Product: CNc1cc2nc(C)c(-c3cc(NC(=O)NCCC(C)(C)C)c(F)cc3F)cc2cn1
Temperature: 25 °C
Yield: 88.7 %

Procedure:
Heat a solution of prop-1-en-2-yl 2,4-difluoro-5-(2-methyl-7-(methylamino)-1,6-naphthyridin-3-yl)phenylcarbamate (1.449 g, 3.77 mmol), 3,3-dimethylbutylamine (0.572 g, 5.65 mmol), and 1-methylpyrrolidine (0.080 g, 0.942 mmol) in dioxane (30 mL) at 80° C. overnight. Cool to RT, collect the precipitate via filtration and dry. Concentrate the filtrate, treat with DCM, sonicate for 0.5 h, collect the solid via filtration and combine with the solid above to afford the title compound (1.43 g, 89%). 1H NMR (400 MHz, DMSO-d6): δ 8.86 (s, 1H), 8.35 (s, 1H), 8.13 (t, 1H), 8.00 (s, 1H), 7.40 (t, 1H), 8.85-8.82 (m, 1H), 6.52-6.49 (m, 2H), 3.07-3.04 (m, 2H), 2.82 (d, 3H), 2.38 (s, 3H), 1.34-1.30 (m, 2H), 0.87 (s, 9H); MS (ESI) m/z: 428.2 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:16][CH3:17])[C:5]([O:14][CH3:15])=[C:6]([CH:8]2[O:13][CH2:12][CH2:11][CH2:10][O:9]2)[CH:7]=1.[Li]C(C)(C)C.[C:23]1([CH3:31])[CH:28]=[CH:27][C:26]([CH:29]=[O:30])=[CH:25][CH:24]=1.O>C1COCC1>[O:9]1[CH2:10][CH2:11][CH2:12][O:13][CH:8]1[C:6]1[CH:7]=[C:2]([CH:29]([C:26]2[CH:27]=[CH:28][C:23]([CH3:31])=[CH:24][CH:25]=2)[OH:30])[CH:3]=[C:4]([O:16][CH3:17])[C:5]=1[O:14][CH3:15]
Reactant: Cc1ccc(C=O)cc1
Reactant: COc1cc(Br)cc(C2OCCCO2)c1OC
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(O)c2ccc(C)cc2)cc(C2OCCCO2)c1OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(5-Bromo-2,3-dimethoxy-phenyl)-[1,3]dioxane (2 g, 6.6 mmol) in 13 mL dry THF cooled to −78° C., t-BuLi (1.5M solution in pentane, 2.5 eq.) was added dropwise via a syringe and the resulting dark red suspension was stirred 30 min. at −78° C. p-Tolualdehyde (1.2 g, 10 mmol, 1.5 eq.) was added dropwise to the mixture and the resulting clear solution was stirred 30 min at −78° C., then 30 min at 0° C. H2O (25 mL) was slowly added and the resulting solution was extracted with EtOAc (3×25 mL). The pooled organic fractions were dried over MgSO4 and evaporated in vacuo. The crude product was purified using flash chromatography (silica gel, hexane/EtOAc 3:2) to yield the desired compound as a colorless solid.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH2:14][CH3:15].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[F:35][C:36]([F:46])([F:45])[C:37]1[CH:44]=[CH:43][C:40]([CH2:41]Br)=[CH:39][CH:38]=1.O>CN(C=O)C>[CH2:14]([C:6]1[N:7]([CH2:41][C:40]2[CH:39]=[CH:38][C:37]([C:36]([F:35])([F:45])[F:46])=[CH:44][CH:43]=2)[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:13]2[C:5]=1[CH2:4][C:3]([OH:2])=[O:16])[CH3:15]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCc1[nH]c2ncccc2c1CC(=O)OC
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: O
Solvent: CN(C)C=O
Product: CCc1c(CC(=O)O)c2cccnc2n1Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To an ice-cooled stirring solution of (2-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester (80 mg, 0.37 mmol) in DMF (1 ml) is added BEMP (171 μl, 0.59 mmol). The solution is stirred at room temperature for 40 minutes and then re-cooled. 4-(Trifluoromethyl)benzyl bromide ((91 μl, 0.59 mmol) is added and stirring continues while the reaction mixture gradually warmed up to room temperature overnight. The resulting mixture is poured into water (30 ml) and extracted with 1:1 EtOAc/ether. The organic layer is washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue is loaded on a pre-packed Isolute™ silica column and eluted with DCM to yield the titled compound as a pale yellow oil. (MH+ 377)
Reaction SMILES: [OH:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([C:8]2[CH:28]=[CH:27][C:11]([CH2:12][S:13][C:14]3[N:23]([CH3:24])[C:22](=[O:25])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[CH3:26])[N:15]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.Cl.[Cl:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[ClH:32].[CH3:24][N:23]1[C:22](=[O:25])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[CH3:26])[N:15]=[C:14]1[S:13][CH2:12][C:11]1[CH:27]=[CH:28][C:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[CH:30][CH:29]=2)=[CH:9][CH:10]=1
Reactant: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(O)cc4)cc3)n(C)c(=O)c12
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(OCCN5CCOCC5)cc4)cc3)n(C)c(=O)c12
Yield: 67.7 %

Procedure:
A solution of 2-[4-(4-hydroxybenzoyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (366 mg), 4-(2-chloroethyl)morpholine hydrochloride (192 mg) and potassium carbonate (356 mg) in DMF (5 ml) was stirred at 60° C. for 62 hours. This reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, and dried. Then, hydrogen chloride/ethyl acetate was added and the precipitated hydrochloride was collected by filtration to provide the title compound as colorless solid (337 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C@H:6]([C:7]([O-:9])=[O:8])[N:5]2[C:10](=[O:17])[C@@H:11]([NH:12][Si](C)(C)C)[C@H:4]2[S:3]1.C1OC1C.ClC(Cl)C([O:27][N:28]=[C:29]([C:33]1[O:34][CH:35]=[CH:36][CH:37]=1)[C:30](Cl)=[O:31])=O.CS(C)=O>ClCCl>[CH3:1][C:2]1([CH3:18])[C@H:6]([C:7]([OH:9])=[O:8])[N:5]2[C:10](=[O:17])[C@@H:11]([NH:12][C:30](=[O:31])[C:29](=[N:28][OH:27])[C:33]3[O:34][CH:35]=[CH:36][CH:37]=3)[C@H:4]2[S:3]1
Reactant: O=C(Cl)C(=NOC(=O)C(Cl)Cl)c1ccco1
Reactant: CC1(C)S[C@@H]2[C@H](N[Si](C)(C)C)C(=O)N2[C@H]1C(=O)[O-]
Agent: CC1CO1
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC1(C)S[C@@H]2[C@H](NC(=O)C(=NO)c3ccco3)C(=O)N2[C@H]1C(=O)O

Procedure:
A solution of tirmethylsily 2,2-dimethyl-6β-trimethylsilylaminopenam-3α-carboxylate [prepared from the corresponding amino-acid (0.648 g.)] and propylene oxide (0.75 ml.) in dichloromethane (15 ml) was cooled to 0° and treated dropwise with a solution of 2-dichloroacetoxyimino(fur-2-yl)acetyl chloride [syn-isomer; prepared from the corresponding acid (0.579 g)] in dichloromethane (12 ml.). The resulting solution was maintained at 0° for 1 hour and was then evaporated to small volume and partitioned between ethylacetate and saturated sodium bicarbonate solution. The aqueous phase was washed with ethyl acetate, acidified with 2N=hydrochloric acid and extracted with ethyl acetate. The dried organic solution was evaporated to a small bulk and added dropwise to stirred petroleum spirit (b.p. 40°-60°). The resulting precipitate was collected, washed and dried to give the title acid (0.56 g., 55% based on amine), [α]D + 243° (c 0.93, DMSO), λmax. (pH 6 buffer) 275 nm (ε 9,600) νmax. (Nujol), 1778 (β-lactam), 1740 and 2600 (CO2H), 1670 and 1528 cm.-1 (CONH), τ (d6 -DMSO) values include 0.44 (d, J 6 Hz; NH) 2.18 and 3.34 (multiplets; aromatic protons), 5.70 (s; C-3H), 8.36 and 8.46 (2s; CH3 groups).
Reaction SMILES: [Cl:1][C:2]([CH2:13][CH2:14][CH2:15][C:16]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]2[C:17]=1[CH:18]=[CH:19][C:20](=[O:29])[N:21]2[CH3:28])(C(OCC)=O)[C:3]([O:5]CC)=[O:4].C(O)(=O)C.Cl>O>[Cl:1][CH:2]([CH2:13][CH2:14][CH2:15][C:16]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]2[C:17]=1[CH:18]=[CH:19][C:20](=[O:29])[N:21]2[CH3:28])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(Cl)(CCCc1ccc(OC)c2c1ccc(=O)n2C)C(=O)OCC
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(CCCC(Cl)C(=O)O)c2ccc(=O)n(C)c12
Temperature: 25 °C
Yield: 74.9 %

Procedure:
Diethyl 2-chloro-2-[3-(8-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-5-yl)propyl]malonate (4.02 g) was added to a mixture of acetic acid (15 ml) and 6N hydrochloric acid (20 ml), followed by heating under reflux for 24 hours. After cooling to room temperature, water was added to the reaction mixture, followed by cooling with ice. The precipitated solid was collected by filtration, washed with water and dried to thereby obtain 2.30 g (yield: 75%) of 2-chloro-5-(8-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-5-yl)valeric acid as a light yellow powder.
Reaction SMILES: [NH2:1][C:2]1[C:19]([Br:20])=[CH:18][C:5]([C:6]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:7][C:8]([OH:10])=O)=[CH:4][C:3]=1[Br:21].ClC(OCC)=O.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>C(N(CC)CC)C>[NH2:1][C:2]1[C:3]([Br:21])=[CH:4][C:5]([C:6]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:7][C:8]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:10])=[CH:18][C:19]=1[Br:20]
Reactant: Nc1c(Br)cc(C(=CC(=O)O)c2ccc(Cl)cc2)cc1Br
Reactant: C1COCCN1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Product: Nc1c(Br)cc(C(=CC(=O)N2CCOCC2)c2ccc(Cl)cc2)cc1Br

Procedure:
This compound was prepared from 4-amino-β-(4'-chlorophenyl)-3,5-dibromo-cinnamic acid (isomer ratio A:B=5:1), ethyl chloroformate, triethylamine and morpholine analogous to Example 1(c).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:33][CH3:34])[C:23]=3[O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:18]2=[O:35])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[OH-].[Pd+2].[OH-].[C].C(O)(=O)C>[CH3:34][O:33][C:22]1[C:23]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[C:24]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:35])[N:17]([CH2:16][CH2:15][CH:12]1[CH2:13][CH2:14][C:9](=[O:8])[CH2:10][CH2:11]1)[CH2:26][CH2:25]2
Reactant: [H][H]
Reactant: CCCCCOc1c(OC)ccc2c(=O)n(CCc3ccc(OCc4ccccc4)cc3)ccc12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCCCCOc1c(OC)ccc2c1CCN(CCC1CCC(=O)CC1)C2=O
Temperature: 25 °C
Yield: 82.6 %

Procedure:
10% Palladium hydroxide-carbon catalyst (300 mg, water content 50%) was added to a solution of 2-[2-(4-benzyloxyphenyl)ethyl]-6-methoxy-5-pentyloxy-2H-isoquinolin-1-one (1.18 g, 2.5 mmol, 1.0 eq) in acetic acid (20 ml), and the mixture was stirred with heating in a stream of hydrogen for 4 hours at 60-70° C. at 3 kgf/cm2. The reaction mixture was cooled to room temperature, and filtered through Celite. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (ethyl acetate/hexane=4/1) to give 6-methoxy-2-[2-(4-oxocyclohexyl)ethyl]-5-pentyloxy-3,4-dihydro-2H-isoquinolin-1-one (800 mg, 82.6%) as a pale-yellow oil.
Reaction SMILES: C(OC([NH:8][C:9]([C:11]1[CH:41]=[CH:40][C:14]([O:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][N:22]([CH:25]([C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:21](=[O:38])[C:20]2=[O:39])=[CH:13][CH:12]=1)=[NH:10])=O)(C)(C)C.[ClH:42]>C(OCC)(=O)C.O1CCOCC1>[ClH:42].[C:9]([C:11]1[CH:12]=[CH:13][C:14]([O:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][N:22]([CH:25]([C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:21](=[O:38])[C:20]2=[O:39])=[CH:40][CH:41]=1)(=[NH:8])[NH2:10]
Reactant: CCOC(=O)CC(c1cccnc1)N1CCN(CCCOc2ccc(C(=N)NC(=O)OC(C)(C)C)cc2)C(=O)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)CC(c1cccnc1)N1CCN(CCCOc2ccc(C(=N)N)cc2)C(=O)C1=O

Procedure:
In 2 ml of ethyl acetate was dissolved 0.45 g of ethyl 3-[4-[3-(4-tert-butoxycarbonylamidinophenoxy)-propyl]-2,3-dioxopiperazin-1-yl]-3-(pyridin-3-yl)-propionate, followed by adding thereto 4 ml of a 2.4N solution of hydrochloric acid in dioxane, and the resulting mixture was stirred at room temperature for 12 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and the resulting residue was purified by a reversed phase column chromatography (eluent: a 15% aqueous acetonitrile solution) to obtain 0.20 g of ethyl 3-[4-[3-(4-amidinophenoxy)propyl]-2,3-dioxopiperazin-1-yl]-3-(pyridin-3-yl)propionate hydrochloride as a white solid.
Reaction SMILES: C([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14](B(O)O)[CH:15]=2)[CH2:10]1)CCCCCCC.BrC1C=C2C(=CC=1)CC(CCCCCCCC)C2.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=CC=CC=1>[CH2:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1
Reactant: CCCCCCCCC1Cc2ccc(B(O)O)cc2C1
Agent: [Pd]
Agent: CCCCCCCCC1Cc2ccc(Br)cc2C1
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: c1ccccc1
Product: c1ccc2c(c1)CCC2
Temperature: 0 °C
Yield: 83 %

Procedure:
Then, 0.89 g (3.2 mM) of 2-octylindan-5-boronic acid, 1.00 g (3.2 mM) of 5-bromo-2-octylindan, 2 ml of ethanol, 4 ml of benzene, 4 ml of 2M-sodium carbonate aqueous solution and 0.12 g of tetrakis(triphenylphosphine)palladium (O) were mixed and heat-refluxed for 1.5 hours under stirring. After the reaction, the reaction mixture was poured into ice water to precipitate a crystal. The crystal was recovered by filtration under reduced pressure and purified by silica gel column chromatography (eluent: toluene) and recrystallized from a mixture solvent (toluene/methanol) to obtain 1.22 g (2.66 mM) of 5,5'-bi-2-octyl)indan (Yield: 83%). ##STR320##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH3:22])=[C:6]([NH:8][C:9]([NH:11][CH2:12][C:13](=O)C2C=CC=CC=2)=[O:10])[CH:7]=1.S(=O)(=O)(O)O.[K+].[Br-]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH3:22])=[C:6]([N:8]2[CH:13]=[CH:12][NH:11][C:9]2=[O:10])[CH:7]=1
Reactant: COc1ccc(Cl)cc1NC(=O)NCC(=O)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Br-]
Agent: [K+]
Product: COc1ccc(Cl)cc1-n1cc[nH]c1=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
N-(5-Chloro-2-methoxyphenyl)-N′-(2-oxo-2-phenylethyl) urea (4 g, 12.7 mmol) was added to cold (0° C.) concentrated sulfuric acid and stirred for 3 h. The reaction mixture was poured into ice water (2 vol), and extracted with ethyl acetate, washed with saturated NaHCO3 solution and brine before drying over MgSO4. Recrystallization from diethylether/acetonitrile gave 1.35 g (36%). mp 133-134° C.; IR(KBr, υ=cm−1) 2962, 1628, 1576, 1236, 1144, 1130; 1H NMR (300 MHz, CDCl3) δ 3.90 (3H, s), 6.77 (1H, d, J=8.6 Hz), 6.91 (1H, dd, J=8.6 Hz, 2.5 Hz), 7.16 (1H, s), 7.22-7.27 (1H, m), 7.35-7.40 (2H, m), 7.51-7.55 (3H, m), 8.29 (1H, d, J=2.5 Hz); MS(DCl)m/z: 301 (MH+); Anal. calcd. for C16H13ClN2O2: C, 63.90; H, 4.36; N, 9.31. Found: C, 63.66; H, 4.30; N, 9.21.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([O:18][CH2:17]1)[CH:10]([F:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1.C(OCC)(=O)C>O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:18])([CH2:17][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)[CH:10]([F:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: c1nc[nH]n1
Reactant: CCOC(=O)C(F)C1(c2ccc(F)cc2F)CO1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 21.4 %

Procedure:
A mixture of 2.4 g of ethyl 3-(2,4-difluorophenyl)-3,4-epoxy-2-fluorobutyrate (a mixture of diastereomers) and 6.4 g of 1,2,4-triazole was subjected to reaction at 90°-100° C. for 8 hours. To the reaction mixture were then added 10 ml of ethyl acetate and 5 ml of water. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue obtained was purified by a column chromatography (eluant: chloroform/methanol=20/1) to obtain 650 mg of ethyl 3-(2,4-difluorophenyl)-2-fluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butyrate (one of the diastereomers).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH3:25][C:26]1[CH:31]=[C:30]([C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[C:38]([C:41](O)=[O:42])[CH:39]=3)[N:34]([C:44]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:33]=2)[CH:29]=[CH:28][N:27]=1.[N:63]1([CH2:72][CH:73]2[CH2:78][CH2:77][CH2:76][CH:75]([NH2:79])[CH2:74]2)[C:71]2[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=2)[CH:65]=[N:64]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[N:63]1([CH2:72][CH:73]2[CH2:78][CH2:77][CH2:76][CH:75]([NH:79][C:41]([C:38]3[CH:39]=[C:40]4[C:35](=[CH:36][CH:37]=3)[N:34]([C:44]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:57]3[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=3)[N:33]=[C:32]4[C:30]3[CH:29]=[CH:28][N:27]=[C:26]([CH3:25])[CH:31]=3)=[O:42])[CH2:74]2)[C:71]2[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=2)[CH:65]=[N:64]1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)O)cc23)ccn1
Reactant: NC1CCCC(Cn2ncc3ccccc32)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)NC4CCCC(Cn5ncc6ccccc65)C4)cc23)ccn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (0.11 mmol) was added to a suspension of 3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxylic acid (0.1 mmol) in DMF (0.5 mL) and was stirred at room temperature for 15 minutes. A solution of 3-((1H-indazol-1-yl)methyl)cyclohexanamine (0.1 mmol) in DMF (0.5 mL) was added to the reaction and followed by diisopropyl ethyl amine (DIEA) (0.1 mL). The mixture was stirred at room temperature for an additional 30 minutes. The reaction was quenched with water (5 mL) and extracted with ethyl acetate (3×10 mL). The extracts were combined, dried using anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was progressed to the next step without purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11](/[CH:13]=[CH:14]/[C:15](OC)=[O:16])[C@H:10]([NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.[Li+].[BH4-]>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][CH2:14][CH2:15][OH:16])[C@H:10]([NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)/C=C/[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1NC(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](CCCO)[C@H](NC(=O)OCc2ccccc2)C1

Procedure:
To a solution of benzyl (3S*,4R*)-1-(tert-butoxycarbonyl)-4-((E)-2-(methoxycarbonyl)vinyl)pyrrolidin-3-ylcarbamate (1.0 g, 2.47 mmol) in 100 mL THF, LiBH4 was added (0.2 g, 9.0 mmol) and the mixture was stirred at reflux for 9 hours. The mixture was quenched with H2O, extracted with EtOAc, the combined organic extracts were dried with Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel eluting with 10→50% EtOAc in hexane giving the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([OH:10])[CH3:9])[C:3]=1[OH:11].[CH2:12]([O:14][C:15]1[C:16](=O)[C:17](=[O:22])[C:18]=1[O:19]CC)[CH3:13]>C(O)C>[CH2:12]([O:14][C:15]1[C:18](=[O:19])[C:17](=[O:22])[C:16]=1[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([OH:10])[CH3:9])[C:3]=1[OH:11])[CH3:13]
Reactant: CC(O)c1cccc(N)c1O
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CCO
Product: CCOc1c(Nc2cccc(C(C)O)c2O)c(=O)c1=O
Temperature: 60 °C
Yield: 38 %

Procedure:
A mixture of 1.16 g (7.6 mmol, 1 eq) of 2-amino-6-(1-hydroxyethyl)phenol and 5.15 g (30.3 mmol, 4 eq) of 3,4-diethoxy-3-cyclobutene-1,2-dione in 50 ml of ethanol was heated at 60° C. for 18 hours. The reaction medium was evaporated and the residue was chromatographed on silica gel (column puriFlash IR-50SI/300G, Spot II) eluted with heptane/ethyl acetate (gradient). 800 mg of 3-ethoxy-4-[2-hydroxy-3-(1-hydroxyethyl)phenylamino]cyclobut-3-ene-1,2-dione were obtained in the form of an orange solid. Yield=38%.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[CH3:8][C:9]([CH3:11])=O.C(=O)([O-])[O-].[K+].[K+]>>[CH3:8][C:9]1([CH3:11])[N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][O:4]1
Reactant: OCCNCCO
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1(C)OCCN1CCO
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.9 %

Procedure:
To a 100 mL flask containing diethanolamine (19.2 mL, 200 mmol) was added acetone (29.4 mL, 400 mmol, 2 eq.) and potassium carbonate (pulverised and dried at 160° C., 27.6 g, 200 mmol, 1 eq.). The reaction was stirred at room temperature for one day. The mixture was filtered through a sinter funnel (no. 3) and the collected solid was washed with acetone. The filtrate and the washes were combined and the solvent evaporated. The 1H NMR indicated a conversion of 85%. Distillation at 125-132° C./20 mmHg of the crude reaction gave the title product (20.89 g, 72% yield) as a colourless oil. 1H NMR (CDCl3, 400 MHz) d?(ppm): 3.93 (t, J=6.6 Hz, 2H); 3.62 (t, J=5.3 Hz, 2H); 2.96 (t, J=6.6 Hz, 2H); 2.65 (t, J=5.3 Hz, 2H); 1.23 (s, 6H). 13C NMR (CDCl3, 129.9 MHz) d??(ppm): 94.2; 63.5; 59.3; 50.8; 49.1; 23.3 (2C).