Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:19])[CH2:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:7][C:6]=1[O:20][CH3:21])[CH:2]=[CH2:3].[H][H].CCCCCC.C(OCC)(=O)C>C(O)C.[Pd]>[CH3:21][O:20][C:6]1[CH:7]=[C:8]([C:11](=[O:19])[CH2:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH:9]=[CH:10][C:5]=1[O:4][CH2:1][CH2:2][CH3:3]
Reactant: C=CCOc1ccc(C(=O)CC(=O)C(C)(C)C)cc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCOc1ccc(C(=O)CC(=O)C(C)(C)C)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
Into a 50 ml egg plant type flask equipped with a magnetic stirrer, a dropping funnel, a reflux condenser, and a nitogen-inlet tube, were charged 250 mg of 5% palladium/carbon and 5.0 gm (24 mmol) of 1-(4-allyloxy-3-methoxyphenyl)- 4,4-dimethylpentane-1,3-dione which had been dispersed in 25 ml of ethanol. After completely replacing the reaction atmosphere by hydrogen, the mixture was stirred for 2 hours at room temperature. Palladium/carbon was removed by filtration and the solvent was evaporated to obtain pale yellow oily product. The oil was submitted to silica gel column chromatography using a hexane-ethyl acetate (10:1-5:1) mixed solvent as an eluent to produce 4.0 gm (yield: 80%) of the title compound as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[N:18](C=O)CCOC3)=[CH:9][CH:8]=2)[N:5]=[C:4]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:3]=1.B.[CH2:26]1[CH2:30][O:29][CH2:28][CH2:27]1>>[C:21]([C:4]1[CH:3]=[C:2]([NH2:1])[N:6]([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][N:18]3[CH2:26][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:11][CH:12]=2)[N:5]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(C3COCCN3C=O)cc2)n1
Reactant: C1CCOC1
Agent: B
Product: CC(C)(C)c1cc(N)n(-c2ccc(CN3CCOCC3)cc2)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 490 mg 5-[4-(5-amino-3-tert-butyl-pyrazol-1-yl)-phenyl]-morpholin-4-yl-methanone (1.49 mmol) in 13 mL THF, 3 mL (2.98 mmol) of borane (1M solution in THF) are added at rt. The reaction is stirred at rt for 12 h, concentrated, taken up in MeOH and concentrated again (3×). The residual crude product is purified by flash chromatography (SiO2, CH2Cl2/MeOH, gradient 0-5% MeOH) to give the title compound as a yellow solid. 1H-NMR (CDCl3): 7.50 (d, J=7.2 Hz, 2H), 7.40 (d, J=7.2 Hz, 2H), 5.52 (s, 1H), 3.73-3.70 (m, 5H), 3.51 (s, 2H), 2.47-2.44 (m, 3H), 1.32 (s, 9H).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C@@H:6]([CH:10]([CH3:12])[CH3:11])[C:7]([OH:9])=[O:8])=[O:4].[OH:13][CH2:14][CH2:15][N:16]1[C:21](=[O:22])[CH2:20][CH2:19][CH:18]([N:23]2[C:31](=[O:32])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]2=[O:33])[C:17]1=[O:34].C(NCC)C>C(Cl)Cl>[CH2:15]([N:16]([CH2:17][CH3:18])[CH2:2][C:3]([NH:5][C@@H:6]([CH:10]([CH3:12])[CH3:11])[C:7]([OH:9])=[O:8])=[O:4])[CH3:14].[OH:13][CH2:14][CH2:15][N:16]1[C:21](=[O:22])[CH2:20][CH2:19][CH:18]([N:23]2[C:24](=[O:33])[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]2=[O:32])[C:17]1=[O:34]
Reactant: CC(C)[C@H](NC(=O)CBr)C(=O)O
Agent: O=C1CCC(N2C(=O)c3ccccc3C2=O)C(=O)N1CCO
Solvent: CCNCC
Solvent: ClCCl
Product: CCN(CC)CC(=O)N[C@H](C(=O)O)C(C)C

Procedure:
2-(1-(2-hydroxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (S)-2-(2-bromoacetamido)-3-methylbutanoate (120 mg) was dissolved in DCM (8 mL). The mixture was stirred and diethylamine solution was added slowly dropwise (0.04 mL). The reaction mixture was stirred additionally for 2 hrs at room temperature. The solvent and the residual diethylamine were removed by rotary evaporation in vacuo. 101 mg of white solid were obtained after purification of the crude product by silica gel column chromatography (eluted with acetic ether:petroleum ether=3:1). 1H NMR (CDCl3, ppm) δ 7.94 (d, 1H, J=8.4 Hz), 7.87-7.91 (m, 2H), 7.76-7.79 (m, 2H), 4.97-5.08 (m, 1H), 4.38-4.43 (m, 1H), 4.05-4.30 (m, 3H), 3.25 (dd, 1H, J=4.8, 13.2 Hz), 3.05 (s, 2H), 2.95-3.05 (m, 1H), 2.80-2.95 (m, 2H), 2.45-2.58 (m, 4H), 2.10-2.20 (m, 1H), 1.90-2.10 (m, 2H), 1.00-1.20 (m, 7H), 0.95-0.98 (m, 3H), 0.87-0.91 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]2=[C:6]3[C:11](=[C:12]([NH2:14])[N:13]=[C:4]2[CH:3]=1)[N:10]=[CH:9][C:8](/[CH:15]=[CH:16]/[CH3:17])=[CH:7]3.[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH3:1][C:2]1[CH:19]=[CH:18][C:5]2=[C:6]3[C:11](=[C:12]([NH2:14])[N:13]=[C:4]2[CH:3]=1)[N:10]=[CH:9][C:8]([CH2:15][CH2:16][CH3:17])=[CH:7]3
Reactant: [H][H]
Reactant: C/C=C/c1cnc2c(N)nc3cc(C)ccc3c2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCc1cnc2c(N)nc3cc(C)ccc3c2c1
Reaction time: 3 h

Procedure:
To a solution of (E)-8-methyl-2-(prop-1-enyl)benzo[f][1,7]naphthyridin-5-amine (from the previous step) in ethyl acetate/methanol (1:4, 0.05 M) was added 10% wt palladium on carbon (0.2 eq.). Hydrogen gas was introduced via a balloon, and the reaction was stirred for 3 hours. The mixture was filtered through a pad of celite, washing with dichloromethane. The filtrate was concentrated en vaccuo and purified by a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give 8-methyl-2-propylbenzo[f][1,7]naphthyridin-5-amine as offwhite solid. 1H NMR (CDCl3): δ 8.59 (d, 1H), 8.41 (d, 1H), 8.10 (d, 1H), 7.43 (s, 1H), 7.13 (dd, 1H), 5.94 (bs, 2H), 2.78 (t, 2H), 2.44 (s, 3H), 1.75 (m, 2H), 0.95 (t, 3H). LRMS [M+H]=252.1
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.[H-].[Na+]>CN(C)C=O>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:2]2[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:14][CH:13]=1
Reactant: COc1ccc(O)cc1
Reactant: N#Cc1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ncccc2C#N)cc1

Procedure:
2-Chloro-3-cyanopyridine is reacted with 4-methoxyphenol in the presence of sodium hydride in dimethylformamide to give 2-(4-methoxyphenoxy)-3-cyanopyridine, which is subjected to Grignard reaction with 2-bromothiophene in a mixed solvent of ether and benzene, followed by treatment with hydrochloric acid to give 2-(4-methoxyphenoxy)-3-(2-thenoyl)pyridine. The thus obtained compound is subjected to demethylation reaction with the use of aluminium chloride and 1-butanethiol in dichloromethane to give 2-(4-hydroxyphenoxy)-3-(2-thenoyl)pyridine.
Reaction SMILES: C(O[C:5](=[O:16])[NH:6][C:7]1[CH:8]([O:13][CH2:14][CH3:15])[O:9][C:10](=[O:12])[CH:11]=1)C=C.C([SiH2][O:22][C:23](C)(C)[C:24]1[CH2:30][N:29]([CH2:31]C(O)=O)[C:28](=[O:35])[CH:27]([NH:36][C:37]([C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH:42]=[CH:41][N:40]=2)=[O:38])[CH2:26][CH:25]=1)(C)(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.C(Cl)Cl.CN(C=O)C.CCOC(C)=O.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>[OH:22][CH2:23][C:24]1[CH2:30][N:29]([CH2:31][C:5](=[O:16])[NH:6][CH:7]2[CH2:11][C:10](=[O:12])[O:9][CH:8]2[O:13][CH2:14][CH3:15])[C:28](=[O:35])[CH:27]([NH:36][C:37]([C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH:42]=[CH:41][N:40]=2)=[O:38])[CH2:26][CH:25]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)C1=CCC(NC(=O)c2nccc3ccccc23)C(=O)N(CC(=O)O)C1
Reactant: C=CCOC(=O)NC1=CC(=O)OC1OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC1OC(=O)CC1NC(=O)CN1CC(CO)=CCC(NC(=O)c2nccc3ccccc23)C1=O
Reaction time: 5 h

Procedure:
A catalytic amount of Pd(Ph3P)4 is added to a solution of (2-Ethoxy-5-oxo-furan-3-yl)-carbamic acid allyl ester (0.24 g, 1.0 mmol) and N,N-dimethylbarbituric acid (0.38 g, 2.4 mmol) in CH2Cl2 (5 mL). The solution is stirred for 15 minutes at room temperature after which {6-(tert-butyl-dimethyl-silanyloxymethyl)-3-[(isoquinoline-1-carbonyl)amino]-2-oxo-2,3,4,7-tetrahydro-azepin-1-yl}-acetic acid, 22, (0.15 g) is added as a solution in CH2Cl2/DMF (2 mL, 1:1), followed by HOBt (0.126 g, 0.93 mmol) and EDCl (0.18 g, 0.93 mmol). The solution is stirred for 5 hours, diluted with EtOAc, washed with saturated NaHCO3 and brine, dried (Na2SO4), and concentrated in vacuo. The resulting residue us purified over silica (EtOAc/hexane) to afford the desired compound.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH3:20])[CH:14]=3)[CH:10]=[C:9]([C:21]([F:24])([F:23])[F:22])[N:8]=2)[CH:6]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[CH:10]=[C:9]([C:21]([F:24])([F:23])[F:22])[N:8]=[C:7]([N:5]3[CH:6]=[C:2]([C:29]4[CH:30]=[CH:31][C:26]([NH2:25])=[N:27][CH:28]=4)[N:3]=[CH:4]3)[N:12]=2)=[CH:14][C:15]=1[CH3:20]
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(Br)c3)n2)ccc1Cl
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(-c4ccc(N)nc4)c3)n2)ccc1Cl

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-(4-chloro-3-methyl-phenyl)-6-trifluoromethyl-pyrimidine (example E.40) (0.21 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as a yellow solid (0.096 g, 45%). MS (ISP) 431.2 [(M+H)+]; mp 276° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[C:4](N)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].N([O-])=O.[Na+].[BrH:16]>O>[Br:16][C:4]1[CH:5]=[C:6]([Cl:9])[C:7]([F:8])=[C:2]([Cl:1])[C:3]=1[F:11]
Reactant: Nc1cc(Cl)c(F)c(Cl)c1F
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Fc1c(Cl)cc(Br)c(F)c1Cl
Reaction time: 2 h
Yield: 48 %

Procedure:
To a solution of 3,5-dichloro-2,4-difluorobenzenamine (9.9 g, 50.0 mmol) in HBr (200 mL) was added a solution of NaNO2 (3.45 g, 50.0 mmol) in H2O (80 mL) slowly under salt ice-bath, then the mixture was stirred for 2 h, and CuBr (7.15 g, 50.0 mmol) was added at 0° C. The mixture was stirred for additional 2 h, and then poured into water (100 mL), extracted with DCM, dried over NaSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by chromatography over silica gel eluted with PE to give compound 1-bromo-3,5-dichloro-2,4-difluorobenzene (6.2 g, yield 48%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.49 (t, J=7.2 Hz, 1H) ppm.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([Si:19]([CH3:22])([CH3:21])[CH3:20])=[C:15]([F:23])[C:14]=2[F:24])=[C:9]([F:25])[CH:8]=1.[I:26]CCI.O>C1COCC1.C(OC)(C)(C)C>[CH3:20][Si:19]([CH3:22])([CH3:21])[C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:11]=[CH:12][C:7]([I:26])=[CH:8][C:9]=2[F:25])=[C:14]([F:24])[C:15]=1[F:23]
Reactant: ICCI
Reactant: C[Si](C)(C)c1ccc(-c2ccc(Br)cc2F)c(F)c1F
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)c1ccc(-c2ccc(I)cc2F)c(F)c1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84 %

Procedure:
30 ml (48 mmol) of 1.6 M BuLi are added dropwise at −78° C. to a solution of 15.8 g (44 mmol) of 7 in 132 ml of dry THF. After 15 minutes, 16 g (57.2 mmol) of 1,2-diiodoethane are added as solid, and the mixture is allowed to warm to room temperature over the course of 1 hour. Water and methyl tert-butyl ether are subsequently added. The organic phase is washed with water, sat. Na2S2O5 and sat. NaCl, dried over MgSO4 and filtered through SiO2. The solvent is removed under reduced pressure, petroleum ether is added to the oily residue, and the product is recrystallised at −25° C. (yield: 84%, m.p. 76.0° C.).
Reaction SMILES: [N+:1]1([O-:10])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH3:9].[N+:11]([O-])([OH:13])=[O:12].C(Cl)(Cl)Cl>OS(O)(=O)=O>[CH3:9][C:2]1[C:3]([CH3:8])=[C:4]([N+:11]([O-:13])=[O:12])[C:5]([CH3:7])=[CH:6][N+:1]=1[O-:10]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(C)c(C)[n+]([O-])c1
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: Cc1c[n+]([O-])c(C)c(C)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 24 h
Yield: 97 %

Procedure:
A suspension of 2,3,5-collidine-N-oxide (3.77 g, 28 mmol) in conc. H2SO4 (8 mL) was cooled to 0° C. and fuming HNO3 (5 mL, 100 mmol) was added dropwise. The resulting transparent solution was stirred at 100° C. for 24 h, cooled to r.t., poured onto ice, and the pH was adjusted to 10. Work-up (CHCl3), drying (MgSO4), and evaporation gave the title compound, (97% yield, 97% purity). Rf (MeOH/EtOAc 1:9): 0.7. HPLC Rt: 4.756 min. 1H-NMR (CDCl3): δ 8.08 (s, 1H), 2.50 (s, 3H), 2.27 (s, 3H), 2.23 (s, 3H). m/z (%) 183.1 (M+1, 100%).
Reaction SMILES: [C:1]([O:7][CH2:8][C@@H:9]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:10]1[C:25]([CH3:26])=[CH:24][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](Cl)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:39]([C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1)#[N:40].C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:7][CH2:8][C@@H:9]([O:34][C:35]([CH3:38])([CH3:36])[CH3:37])[C:10]1[C:25]([CH3:26])=[CH:24][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:45]4[CH:44]=[CH:43][CH:42]=[C:41]([C:39]#[N:40])[CH:46]=4)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Cc1cc2nc(-c3ccnc(Cl)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc2nc(-c3ccnc(-c4cccc(C#N)c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 110 °C

Procedure:
(S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)ethyl pivalate (19.7 mg, 0.034 mmol), 3-cyanophenylboronic acid (6.1 mg, 0.041 mmol), Pd(PPh3)4, and K2CO3 (14.3 mg, 0.103 mmol) were placed in a microwave vial and the vial was vacuum pumped and flushed with argon three times. To this mixture was added degassed 1,4-dioxane (0.4 mL) and degassed water (0.1 mL). The reaction mixture was heated at 110° C. for 1.5 h, cooled, diluted with ethyl acetate, filtered through Celite (ethyl acetate eluent), and concentrated. Purification by flash column chromatography on silica gel (hexanes/ethyl acetate eluent) provided the product. LCMS-ESI+: calc'd for C37H37ClN3O3S: 638.2 (M+H+); Found: 637.9 (M+H+).
Reaction SMILES: [C:1]([C:9]1[C:10]([F:20])=[C:11]([C@H:16]([NH2:19])[CH2:17][CH3:18])[CH:12]=[CH:13][C:14]=1[Cl:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[C:24]([NH2:28])(=[O:27])[CH:25]=[CH2:26]>CO>[C:1]([C:9]1[C:10]([F:20])=[C:11]([C@H:16]([NH:19][CH2:26][CH2:25][C:24]([NH2:28])=[O:27])[CH2:17][CH3:18])[CH:12]=[CH:13][C:14]=1[Cl:15])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](N)c1ccc(Cl)c(C(=O)c2ccccc2)c1F
Reactant: C=CC(N)=O
Solvent: CCO
Solvent: CO
Product: CC[C@@H](NCCC(N)=O)c1ccc(Cl)c(C(=O)c2ccccc2)c1F
Temperature: 100 °C
Yield: 38.1 %

Procedure:
To (1R)-1-(3-benzoyl-4-chloro-2-fluorophenyl)propan-1-amine (0.1 g, 0.34 mmol) in a microwave tube was added ethanol (0.4 ml) water (0.4 ml), acrylamide (0.025 g, 0.35 mmol) and MnCl2 (0.056 g, 0.28 mmol) heated 100° C., 200 W for a total of 1 hour. The reaction was diluted with MeOH and filtered and filtrate evaporated then purified by Prep HPLC to give 3-{[(1R)-1-(3-benzoyl-4-chloro-2-fluorophenyl)propyl]amino}-propanamide (0.047 g).
Reaction SMILES: Cl.[C:2]1([O:12][CH:13]2[CH2:19][CH2:18][NH:17][CH2:16][C:15]3[O:20][C:21]([CH3:23])=[CH:22][C:14]2=3)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:31](O)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[N:34][CH:33]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[C:2]1([O:12][CH:13]2[CH2:19][CH2:18][N:17]([C:31]([C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[O:38])[CH2:16][C:15]3[O:20][C:21]([CH3:23])=[CH:22][C:14]2=3)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccnc1
Reactant: Cc1cc2c(o1)CNCCC2Oc1cccc2ccccc12
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc2c(o1)CN(C(=O)c1cccnc1)CCC2Oc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 115.9 %

Procedure:
4-(Naphthalen-1-yloxy)-2-methyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepine hydrochloride (50 mg) prepared in Example 284 and 47 mg of triethylamine were dissolved in 1 mL of methylene chloride, then 39 mg of 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimidehydrochloride (WSCD.HCl), 25 mg of nicotinic acid and 27 mg of 1-hydroxybenzotriazole were dropped thereinto successively and the mixture was stirred at room temperature for 6 hours. The reaction solution was poured over 2 mL of water and the mixture was subjected to extraction with methylene chloride. The organic layer was washed with water and a saturated solution of sodium chloride successively and dried over anhydrous magnesium sulfate and the solvent was evaporated therefrom in vacuo. The resulting residue was purified by silica gel column chromatography to give 70 mg of 4-(naphthalen-1-yloxy)-2-methyl-7-(3-pyridylcarbonyl)-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepine.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:11](#[N:15])[CH2:12][C:13]#[N:14].[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[C:12]([C:11]#[N:15])[C:13]#[N:14]
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: N#CCC#N
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.7 %

Procedure:
To a solution of 2,4-dichlorobenzaldehyde (1.75 g, 10 mmol) and malononitrile (660 mg, 10 mmol) in ethanol (10 ml) was added 200 μL of 10% aqueous KOH. The mixture was stirred at room temperature for 15 min, allowed to stand for 30 min, cooled with ice-bath and then filtered to give 2-(2,4-dichloro-benzylidene)-malononitrile (1a) as a white solid (1.8 g).
Reaction SMILES: [CH2:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH2:15])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:4][CH2:3][CH2:2]1.N1CCOCC1.[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=O>C1(C)C=CC=CC=1>[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=[N:15][C:13]1[C:12]2[C:7]([N:6]=[C:5]3[C:14]=1[CH2:1][CH2:2][CH2:3][CH2:4]3)=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: Nc1c2c(nc3ccccc13)CCCC2
Reactant: O=Cc1ccccc1Cl
Solvent: C1COCCN1
Solvent: Cc1ccccc1
Product: Clc1ccccc1C=Nc1c2c(nc3ccccc13)CCCC2

Procedure:
1,2,3,4-Tetrahydro-9-acridinamine (4.0 g) was suspended in 400 ml of toluene to which morpholine (3.5 g) and 2-chlorobenzaldehyde (3.5 g) were successively added. The reaction mixture was refluxed overnight and then an additional 1.7 g of aldehyde was added. Reflux was continued for an additional sixteen (16) hours and then the reaction mixture was concentrated and purified by flash chromatography (CH2Cl2, then 20% EtOAc/CH2Cl2). Fractions containing the product were concentrated and recrystallized from Et2O/pentane to give 2.10 g of analytically pure product, m.p. 165°-166° C.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:12][C:11]2[N:10]=[CH:9][N:8]=[C:7]([N:13]3[CH2:19][C:18]4[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:17]=4[O:16][CH2:15][CH2:14]3)[C:6]=2[CH2:5][CH2:4]1)[CH3:2].[NH2:27][C:28]1[C:33]([S:34]([NH:37][CH2:38][C:39]([NH2:42])([CH3:41])[CH3:40])(=[O:36])=[O:35])=[CH:32][C:31](Br)=[CH:30][N:29]=1>>[NH2:27][C:28]1[C:33]([S:34]([NH:37][CH2:38][C:39]([NH2:42])([CH3:40])[CH3:41])(=[O:36])=[O:35])=[CH:32][C:31]([C:21]2[CH:22]=[CH:23][C:17]3[O:16][CH2:15][CH2:14][N:13]([C:7]4[C:6]5[CH2:5][CH2:4][C@H:3]([CH2:1][CH3:2])[CH2:12][C:11]=5[N:10]=[CH:9][N:8]=4)[CH2:19][C:18]=3[CH:20]=2)=[CH:30][N:29]=1
Reactant: CC[C@H]1CCc2c(ncnc2N2CCOc3ccc(B(O)O)cc3C2)C1
Reactant: CC(C)(N)CNS(=O)(=O)c1cc(Br)cnc1N
Product: CC[C@H]1CCc2c(ncnc2N2CCOc3ccc(-c4cnc(N)c(S(=O)(=O)NCC(C)(C)N)c4)cc3C2)C1

Procedure:
Prepared according to the method of example 5 by using {4-[(7S)-7-ethyl-5,6,7,8-tetrahydroquinazolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}boronic acid (reagent preparation 23) and 2-amino-N-(2-amino-2-methylpropyl)-5-bromopyridine-3-sulfonamide (reagent preparation 25) in step 1. 1H NMR (400 MHz, d6-DMSO): 8.48 (d, 1H), 8.33 (s, 1H), 8.01 (d, 1H), 7.54 (d, 1H), 7.42 (dd, 1H), 7.01 (d, 1H), 7.72 (brs, 2H), 4.69 (dd, 2H), 4.37 (m, 1H), 4.23 (m, 1H), 3.85 (m, 2H), 2.93 (m, 2H), 2.60 (s, 2H), 2.27 (dd, 1H), 1.87 (m, 1H), 1.70 (m, 1H), 1.35 (m, 2H), 1.10 (m, 1H), 0.93 (t, 3H), 0.92 (s, 6H); MS (EI) for C28H37N7O3S: 552 (MH+).
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][CH2:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])(=O)C.[O-]CC.[Na+]>C(O)C>[OH:4][CH2:5][CH2:6][O:7][CH2:8][P:9](=[O:16])([O:10][CH2:11][CH3:12])[O:13][CH2:14][CH3:15]
Reactant: CCOP(=O)(COCCOC(C)=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOP(=O)(COCCO)OCC
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of diethyl 2-acetoxyethoxymethylphosphonate* (16 g, 63 mmol) in absolute ethanol (150 ml), was added 0.5M sodium ethoxide (12.19 ml). After standing at ambient temperature overnight, 1R-120H resin was added until pH 6.5 was reached. The solution was filtered immediately, the resin washed with ethanol and the combined filtrates evaporated under reduced pressure. The residue was chromatographed on silica gel (eluted with chloroform: methanol, 98:2) to yield the title compound as a colourless oil (9.3g, 70%). IR: νmax (film) 3420, 3000, 1450, 1395, 1240, 1170, 1130, 1030, 970 cm-1. 1H NMR: δH (CDCl3) 1.35 (6H,t,J=7Hz, (OCH2CH3)2), 3.75 (4H,br.s, OCH2CH2O), 3.90 (2H,d,J=8Hz, O--CH2P), 4.20 (4H,m,(O--CH2CH3)2), 5.20 (1H,br.s, D 2 O exchangeable, OH). Found: C,38.64; H,8.27%. C7H17PO5.0.3H2O requires: C,38.63; H,8.01%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:33]=[CH:32][C:12]([CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[CH:20]([O:24][CH3:25])[CH:19]([CH2:26][C:27]([O:29]CC)=[O:28])[CH2:18]3)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[OH-].[Na+].Cl>O1CCCC1.CO.O>[CH2:1]([O:8][C:9]1[CH:33]=[CH:32][C:12]([CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[CH:20]([O:24][CH3:25])[CH:19]([CH2:26][C:27]([OH:29])=[O:28])[CH2:18]3)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(COc2ccc3c(c2)CC(CC(=O)OCC)C3OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCOc1ccc(COc2ccc3c(c2)CC(CC(=O)O)C3OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
In 1 ml of tetrahydrofuran and 8 ml of methanol were dissolved 220 mg of ethyl 5-(p-heptyloxybenzyloxy)-1-methoxy- 2-indaneacetate obtained in Example 4. After 1 ml of a 5% aqueous sodium hydroxide solution was added to the solution, the mixture was stirred at room temperature for 8 hours. After diluting with water, the system was rendered acidic with hydrochloric acid followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried and concentrated. The obtained crystalline residue was recrystallized from ether-pentane to obtain 150 mg of 5-(p-heptyloxybenzyloxy)-1-methoxy-2-indaneacetic acid.