Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:15]([F:16])=[C:14](F)[C:13]([F:18])=[CH:12][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH2:19]([O:21][C:22]([N:24]([CH2:26][CH:27]1[O:32][CH2:31][CH2:30][NH:29][CH2:28]1)[CH3:25])=[O:23])[CH3:20].C(=O)([O-])O.[Na+]>C(#N)C>[CH2:19]([O:21][C:22]([N:24]([CH2:26][CH:27]1[CH2:28][N:29]([C:14]2[C:13]([F:18])=[CH:12][C:3]([C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])=[C:2]([F:1])[C:15]=2[F:16])[CH2:30][CH2:31][O:32]1)[CH3:25])=[O:23])[CH3:20]
Reactant: CCOC(=O)N(C)CC1CNCCO1
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)c(F)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)CC(=O)c1cc(F)c(N2CCOC(CN(C)C(=O)OCC)C2)c(F)c1F
Yield: 72.7 %

Procedure:
A suspension of 26.4 g of ethyl 2,3,4,5-tetrafluorobenzoylacetate, 18.7 g of 2-(N-ethoxycarbonyl-N-methylaminomethyl)morpholine and 8.4 g of sodium hydrogen carbonate in 130 ml of acetonitrile is refluxed for 7 hours. The reaction mixture is concentrated under reduced pressure, to the obtained residue is added 100 ml of chloroform and the solution is washed with water. After drying over anhydrous magnesium sulfate, the chloroform is distilled off under reduced pressure and the residue is purified by chromatography on silica gel to give 30.0 g of ethyl 4-[2-(N-ethoxycarbonyl-N-methylaminomethyl)morpholino]-2,3,5-trifluorobenzoylacetate in 67% yield, as an oily substance.
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:15]=[C:14]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:13]=1)[C:3]([O:5]C)=[O:4].[OH-].[K+]>C(O)C>[CH3:1][C:2]([CH3:30])([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:15]=[C:14]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:13]=1)[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(C)(C)CCCCOc1cc(-c2ccccc2)cc(-c2ccccc2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(CCCCOc1cc(-c2ccccc2)cc(-c2ccccc2)n1)C(=O)O

Procedure:
The procedure in Example 6 is followed but using methyl 2,2-dimethyl-6-[(4,6-diphenyl-2-pyridyl) oxy]hexanoate (5 g), potassium hydroxide pellets (1.1 g) and ethanol (100 cc). The reaction mixture is refluxed for 24 hours. The product is purified by chromatography under pressure on silica gel (30-60 mm; eluent: n-hexane-ethyl acetate 8-2), white crystals (m.p.=115° C.)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH2:6]/[C:5]/2=[CH:12]\[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH3:24])=[C:17]([OH:25])[CH:16]=1.[S:26]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[OH:25][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][CH2:22][CH2:23][CH3:24])[CH2:14][NH:13]/[CH:12]=[C:5]1\[CH2:6][N:7]=[CH:8][C:9]2[C:4]\1=[CH:3][C:2]([C:28]1[CH:29]=[CH:30][S:26][CH:27]=1)=[CH:11][CH:10]=2
Reactant: CCCOc1ccc(CN/C=C2\CN=Cc3ccc(Br)cc32)cc1O
Reactant: OB(O)c1ccsc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1ccc(CN/C=C2\CN=Cc3ccc(-c4ccsc4)cc32)cc1O

Procedure:
An amount of (4Z)-6-bromo-4-{[(3-hydroxy-4-propoxybenzyl)amino]methylene}isoquinoline}-1,3(2H,4H)-dione (135.0 mg, 0.32 mmol) is dissolved in 80% mixture of N,N dimethylformamide/water (4 mL). Tetrakistriphenylphosphine (44.0 mg, 0.04 mmol) is added followed by 3-thiopheneboronic acid (48.4 mg, 0.38 mmol) along with sodium carbonate (67.8 mg, 0.64 mmol). The reaction mixture is heated to 150° C.-180° C. for 3 minutes under microwave irradiation. The solvent is concentrated and the reaction mixture is partitioned between ethyl acetate (50 ml) and water (50 ml). The crude solid is then purified by high performance liquid chromatography to give 25.0 mg of a white solid. MS (ESI) m/z 549.8 (M+1).
Reaction SMILES: C([NH:4][C:5]1[C:6]([C:18]([OH:20])=[O:19])=[CH:7][C:8]2[C:13]([C:14]=1[N+:15]([O-:17])=[O:16])=[CH:12][CH:11]=[CH:10][CH:9]=2)(=O)C>Cl>[NH2:4][C:5]1[C:6]([C:18]([OH:20])=[O:19])=[CH:7][C:8]2[C:13]([C:14]=1[N+:15]([O-:17])=[O:16])=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: CC(=O)Nc1c(C(=O)O)cc2ccccc2c1[N+](=O)[O-]
Agent: Cl
Product: Nc1c(C(=O)O)cc2ccccc2c1[N+](=O)[O-]

Procedure:
A solution of 1 g of the compound obtained in Step 1 in 18 ml of hydrochloric acid is refluxed for 4 hours and then poured onto ice. The precipitate formed is filtered off, washed with water until the pH is 5-6 and then dried, allowing the expected product to be isolated.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([Si:15]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)([CH:17](Cl)[CH3:18])[CH3:16])=[CH:11][CH:10]=1.FC1C=CC([Si](C2C=CC(F)=CC=2)(CCCl)C)=CC=1>CN(C)C=O.O.ClCCl.CO>[F:26][C:23]1[CH:24]=[CH:25][C:20]([Si:15]([C:12]2[CH:11]=[CH:10][C:9]([F:8])=[CH:14][CH:13]=2)([CH3:16])[CH:17]([N:3]2[CH:7]=[N:6][CH:5]=[N:4]2)[CH3:18])=[CH:21][CH:22]=1
Reactant: c1nc[nH]n1
Reactant: CC(Cl)[Si](C)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: C[Si](CCCl)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC(n1cncn1)[Si](C)(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 1 h
Yield: 12 %

Procedure:
A mixture of 1.78 g (37 mmol) of 50% sodium hydride, 30 ml of dimethylformamide, and 2.56 g (37 mmol) of 1H-1,2,4-triazole was stirred at 50° for one hour, and a solution of 10 g (33.7 mmol) of a 1:1 mixture of bis(4-fluorophenyl)-1-chloroethyl(methyl)silane and bis(4-fluorophenyl)-2-chloroethyl(methyl)silane in 10 ml of dimethylformamide was added. The mixture was stirred at 50° for 64 hours, cooled, diluted with water, and extracted with ether. The ether extracts were washed with water and brine, dried over sodium sulfate, and evaporated to leave a viscous oil. Chromatography over silica gel eluting with dichloromethane followed by 3% methanol in dichloromethane provided 1.37 g (12%) of the title compound as a viscous oil: nmr (CDCl3) 0.7 (3H, s), 1.6 (3H, d, J=7 Hz), 4.5 (1H, q, J=7 Hz), 6.9-7.7 (8H, m), 7.9 (1H, s), and 8.0 (1H, s).
Reaction SMILES: C([NH:5][C:6]([NH:8][CH:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=1)[CH2:10]O)=[S:7])(C)(C)C.[ClH:19]>>[ClH:19].[Br:18][C:14]1[CH:13]=[C:12]([CH:9]2[CH2:10][S:7][C:6]([NH2:5])=[N:8]2)[CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)NC(=S)NC(CO)c1cccc(Br)c1
Agent: Cl
Product: NC1=NC(c2cccc(Br)c2)CS1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A suspension of 0.5 g of N-(tert-butyl)-N′-[2-hydroxy-1-(3-bromophenyl)ethyl]thiourea in 3.8 cm3 of 6N hydrochloric acid is heated with stirring at a temperature in the region of 100° C. for 5 hours 30 minutes. The reaction medium is then cooled to a temperature in the region of 20° C. A white precipitate forms, which is filtered off after stirring for 30 minutes. The filter cake is rinsed with diethyl ether and then dried in an oven under reduced pressure (10 Pa) at a temperature in the region of 60° C., after which it is purified by chromatography, under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-63μ; diameter 1.5 cm; height 20 cm), eluting with a dichloromethane/methanol mixture (90/10 by volume). The fractions containing the expected product are collected. These fractions are combined and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 0.1 g of (4RS)-4-(3-bromophenyl)-4,5-dihydro-1,3-thiazol-2-ylamine hydrochloride is obtained in the form of a white solid. (Rf=0.26 in a 90/10 by volume dichloromethane/methanol mixture, on a Merck 60F254R silica plate). [1H NMR spectrum (250 MHz, d6-(CD3)SO, δ in ppm): 3.45 (dd, J=14 and 8 Hz: 1H); 3.97 (dd, J=14 and 8.5 Hz : 1H); 5.42 (dd, J=8.5 and 8 Hz: 1H); from 7.35 to 7.55 (mt: 2H); from 7.55 to 7.75 (mt: 2H); from 9.10 to 10.90 (broad unres. mult.: 1H)].
Reaction SMILES: FC(F)(F)C(O)=O.Cl[C:9]1[N:14]=[C:13]([F:15])[C:12]2[O:16][C:17]3[C:22]([C@@:23]4([C:27]5[CH:28]=[N:29][CH:30]=[CH:31][C:26]=5[C:25]([NH2:32])=[N:24]4)[C:11]=2[CH:10]=1)=[CH:21][C:20]([C:33]1[C:34]([F:39])=[N:35][CH:36]=[CH:37][CH:38]=1)=[CH:19][CH:18]=3.[O:40]1[CH2:45][CH2:44][CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH2:41]1.C(O)(C(F)(F)F)=O>>[O:40]1[CH2:45][CH2:44][CH:43]=[C:42]([C:9]2[N:14]=[C:13]([F:15])[C:12]3[O:16][C:17]4[C:22]([C@@:23]5([C:27]6[CH:28]=[N:29][CH:30]=[CH:31][C:26]=6[C:25]([NH2:32])=[N:24]5)[C:11]=3[CH:10]=2)=[CH:21][C:20]([C:33]2[C:34]([F:39])=[N:35][CH:36]=[CH:37][CH:38]=2)=[CH:19][CH:18]=4)[CH2:41]1
Reactant: NC1=N[C@]2(c3cc(-c4cccnc4F)ccc3Oc3c2cc(Cl)nc3F)c2cnccc21
Reactant: CC1(C)OB(C2=CCCOC2)OC1(C)C
Solvent: O=C(O)C(F)(F)F
Product: NC1=N[C@]2(c3cc(-c4cccnc4F)ccc3Oc3c2cc(C2=CCCOC2)nc3F)c2cnccc21

Procedure:
The title compound was synthesized by procedures and steps analogous to those described in Example 14 above, but using (S)-3-Chloro-1-fluoro-7-(2-fluoropyridin-3-yl)spiro[chromeno[2,3-c]pyridine-5,3′-pyrrolo[3,4-c]pyridin]-1′-amine 2,2,2-trifluoroacetate (14d-2) and 2-(5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in step 5. MS m/z=496.0 [M+H]+. Calculated for: C28H19F2N5O2.O2HF3O2: 609.50 (TFA salt)
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][C:6]2([CH3:15])[CH3:14].BrB(Br)Br>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][C:6]2([CH3:15])[CH3:14]
Reactant: COc1ccc2c(c1)C(C)(C)CCC2=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1(C)CCC(=O)c2ccc(O)cc21
Reaction time: 8 h
Yield: 32 %

Procedure:
To a solution of 6-methoxy-4,4-dimethyl-3,4-dihydronaphthalen-1(2H)-one (1.0 g, 4.90 mmol) in dichloromethane (50 mL) at 0° C. was slowly added tribromoborane (1.0 M in dichloromethane) (24.5 mL, 24.5 mmol), resulting in a dark solution. The ice-bath was removed, and the reaction mixture was stirred overnight. The reaction mixture was diluted with dichloromethane (100 mL) and washed with water (2×25 mL). The aqueous layer was extracted with dichloromethane (2×25 mL), and the combined organic layers were dried over anhydrous sodium sulfate and concentrated to give a red, viscous oil. The residue was purified by flash silica gel chromatography using a mixture of ethyl acetate in hexane (5%-12.5%-20%) to give 6-hydroxy-4,4-dimethyl-3,4-dihydronaphthalen-1(2H)-one (0.299 g, 1.57 mmol, 32% yield) as an orange solid. The product had an HPLC ret. time=1.68 min. (condition A); LC/MS M+1=190.9.
Reaction SMILES: [O:1]=[C:2]1[NH:6][N:5]=[C:4]([C:7]2[N:8]=[C:9]([O:17][C@H:18]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]3)[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[NH:3]1.[ClH:30]>O1CCOCC1>[ClH:30].[NH:20]1[CH2:21][CH2:22][C@H:18]([O:17][C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:16]=[C:7]([C:4]3[NH:3][C:2](=[O:1])[NH:6][N:5]=3)[N:8]=2)[CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(-c3n[nH]c(=O)[nH]3)cc3ccccc23)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1[nH]nc(-c2cc3ccccc3c(O[C@H]3CCNC3)n2)[nH]1
Temperature: 25 °C

Procedure:
To a 200 mL round-bottom flask charged with crude (S)-tert-butyl 3-((3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate (5.47 g) and dioxane (27.5 mL) was added 4M HCl in dioxane (13.76 mL, 55.1 mmol). The suspension was stirred at RT with periodic monitoring by HPLC. Upon completion, the reaction mixture was concentrated in vacuo to give an HCl salt of the title compound as a light tan powder that was dried and used without further purification. ESI-MS m/z [M+H]+ 298.6.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:6][N:7]=[CH:8][C:9]1[S:19][C:12]2[N:13]=[CH:14][N:15]=[C:16]([S:17][CH3:18])[C:11]=2[CH:10]=1.CO[C:27]1[CH:28]=[C:29]([CH:42]=[CH:43][C:44]=1OC)[CH2:30][N:31]=[CH:32]C1SC2N=CN=CC=2C=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:6][N:7]1[C:8]([C:9]2[S:19][C:12]3[N:13]=[CH:14][N:15]=[C:16]([S:17][CH3:18])[C:11]=3[CH:10]=2)=[C:30]([C:29]2[CH:42]=[CH:43][CH:44]=[CH:27][CH:28]=2)[N:31]=[CH:32]1
Reactant: COc1ccc(CN=Cc2cc3c(SC)ncnc3s2)cc1OC
Reactant: COc1ccc(CN=Cc2cc3cncnc3s2)cc1OC
Product: COc1ccc(Cn2cnc(-c3ccccc3)c2-c2cc3c(SC)ncnc3s2)cc1OC
Yield: 55 %

Procedure:
The title compound was prepared in 55% yield using a procedure similar to the one described for example 6 above but starting from N-(3,4-dimethoxybenzyl)-N-{[4-(methylthio)thieno[2,3-d]pyrimidin-6-yl]methylidene}amine (intermediate 18) (76 mg), in place of N-(3,4-dimethoxybenzyl)-N-[thieno[2,3d]pyrimidin-6-ylmethylidene]amine (intermediate 14);
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:14][C:15](=[O:19])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:1][O:2][C:3]1[C:4]([NH:14][C:15]([N:31]2[CH2:32][CH2:33][N:28]([C:22]3[C:23]([CH3:27])=[CH:24][CH:25]=[CH:26][C:21]=3[CH3:20])[CH2:29][CH2:30]2)=[O:19])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2
Reactant: Cc1cccc(C)c1N1CCNCC1
Reactant: CCOC(=O)Nc1nc2ccc(C)cc2nc1OC
Product: COc1nc2cc(C)ccc2nc1NC(=O)N1CCN(c2c(C)cccc2C)CC1
Yield: 83 %

Procedure:
Ethyl N-(3-methoxy-6-methylquinoxalin-2-yl)carbamate and 1-(2,6-dimethylphenyl)piperazine were reacted by the same way with the example 127 to obtain the titled compound (yield, 83%). 1H NMR (300 MHz, CDCl3): δ 2.33-2.50 (m, 9H), 3.14-2.20 (m, 4H), 3.70-3.75 (m, 4H), 4.14 (s, 3H), 7.00 (s, 3H), 7.09-7.78 (m, 3H).
Reaction SMILES: C([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12]CC)[C:7]#[N:8])C.COC1C=C(C=CC=1O)C#N.[Br-].[Li+]>>[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[C:7]#[N:8]
Reactant: CCOc1ccc(C#N)cc1OCC
Agent: COc1cc(C#N)ccc1O
Agent: [Br-]
Agent: [Li+]
Product: N#Cc1ccc(O)c(O)c1
Yield: 79 %

Procedure:
The preparation was carried out according to the process of Example 2a except that 3,4-diethoxybenzonitrile was used as the starting material instead of 3-methoxy-4-hydroxybenzonitrile, and 2-fold of lithium bromide (162.6 g, 1.88 mole) were added to form the reaction mixture. 3,4-Dihydroxybenzonitrile was obtained as a white solid with a yield of 79% and a purity of greater than 92% as indicated by HPLC analysis.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([Cl:15])[N:12]=[C:11]([NH:16][CH:17]([CH3:19])[CH3:18])[C:10]=1[NH2:20])[CH2:2]2.[CH3:21][N:22]([CH3:28])[CH2:23][CH2:24][C:25]([O-])=[O:26].CN(C)CCC(O)=O.C(OC1C=CC2C(=CC=CC=2)N1C(OCC(C)C)=O)C(C)C>CN(C)C=O>[CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[C:10]([NH:20][C:25](=[O:26])[CH2:24][CH2:23][N:22]([CH3:28])[CH3:21])=[C:11]([NH:16][CH:17]([CH3:18])[CH3:19])[N:12]=[C:13]([Cl:15])[N:14]=1)[CH2:2]2
Reactant: CN(C)CCC(=O)[O-]
Reactant: CC(C)Nc1nc(Cl)nc(N2CC3CCC(C2)O3)c1N
Agent: CC(C)COC(=O)N1c2ccccc2C=CC1OCC(C)C
Agent: CN(C)CCC(=O)O
Solvent: CN(C)C=O
Product: CC(C)Nc1nc(Cl)nc(N2CC3CCC(C2)O3)c1NC(=O)CCN(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
6-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-2-chloro-N4-isopropylpyrimidine-4,5-diamine 3-(dimethylamino)propanoate (48, 0.500 g, 1.68 mmoles) was dissolved in dimethylformamide and 3-dimethylaminopropionic acid (0.310 g, 2.02 mmoles) and isobutyl 2-isobutoxyquinoline-1(2H)-carboxylate (IIDQ, 0.699 mL, 2.35 mmoles) were added. The reaction mixture was allowed to stir at room temperature for 18 hours, concentrated, and purified by silica gel column chromatography (5-10% ethanol in dichloromethane) to provide N-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-2-chloro-6-(isopropylamino)pyrimidin-5-yl)-3-(dimethylamino)propanamide (49) as a tan solid. Yield: 0.350 g (53%). LCMS (Waters walk-on); 2.43 min., 397.2, M+H.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:24])[NH:6][C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH:9]=1)(=[O:3])[CH3:2].[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH:29]=[O:30].C[O-].[Na+]>C1COCC1.CO.CCOC(C)=O>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:7]1[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:9][CH:4]([C:1](=[O:3])[CH2:2][CH:29]([C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([F:25])[CH:27]=2)[OH:30])[C:5](=[O:24])[N:6]=1
Reactant: CC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)[nH]c1=O
Reactant: O=Cc1cccc(F)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(CC(O)c1cccc(F)c1)C1C=C(c2ccc(Cl)cc2)C(c2ccccc2Cl)=NC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the product of Example 4, Step A (0.5 g, 1.4 mmol) in THF (3 mL) and MeOH (1.5 mL) was added 3-fluorobenzaldehyde (0.6 mL, 2.8 mmol) and NaOMe (0.2 g, 0.56 mmol). The reaction was stirred at rt overnight, followed by heating at 50° C. for an additional day. The reaction was diluted with EtOAc and washed with saturated aq NaHCO3, brine, dried (Na2SO4), filtered and concentrated The residue was purified by flash chromatography on silica gel gradient eluted with 0-30% EtOAc in hexane to afford the product.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][N:7]1[C:11]([CH3:12])=[C:10]([C:13]([N:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]([CH3:25])[CH2:17][C:16]2([CH3:27])[CH3:26])=[O:14])[C:9]([CH3:28])=[N:8]1>>[CH3:6][N:7]1[C:11]([CH3:12])=[C:10]([C:13]([NH:15][C:24]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:19]=2[CH:18]([CH3:25])[CH2:17][C:16]3([CH3:26])[CH3:27])=[O:14])[C:9]([CH3:28])=[N:8]1
Reactant: Cc1nn(C)c(C)c1C(=O)N1c2ccccc2C(C)CC1(C)C
Agent: O=S(=O)(O)O
Product: Cc1nn(C)c(C)c1C(=O)Nc1cccc2c1C(C)CC2(C)C
Temperature: 0 °C
Reaction time: 24 h
Yield: 54.8 %

Procedure:
5 cc of 85% aqueous sulfuric acid was added to 0.31 g of N-(1,3,5-trimethylpyrazole-4-yl carbonyl)-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline at room temperature, followed by stirring at the same temperature for 24 hours. The reaction mixture was poured into ice water. The precipitated crystal was filtered and washed with n-hexane. After being dried, the crystal was recrystallized from n-hexane-ethyl acetate to obtain 0.17 g of the objective 1,3,5-trimethyl-N-(1,1,3-trimethylindane-4-yl)pyrazole-4-carboxamide.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[H-].[Na+].[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13]>C(O)C>[Cl:5][CH2:4][CH2:3][CH2:2][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13]
Reactant: ClCCCBr
Reactant: N#Cc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1cccc(OCCCCl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
A suspension of 1-bromo-3-chloropropane (13.9 g, 88.1 mmol) and 60% sodium hydride (oil dispersion, 3.02 g, 126 mmol) in ethanol (50 mL) was stirred at room temperature for 30 min. 3-Hydroxybenzonitrile (10.0 g, 83.9 mmol) was added to the reaction mixture at 0° C., and the mixture was stirred at 60° C. for 15 hr. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate and water. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The obtained oil was purified by silica gel column chromatography (5%-15% ethyl acetate/hexane) to give the title compound as a colorless oil (14.2 g, 86%).
Reaction SMILES: [C:1]([Si:5]([CH3:13])([CH3:12])[O:6][CH2:7][CH2:8][CH:9]1[CH2:11][O:10]1)([CH3:4])([CH3:3])[CH3:2].C([O:16][C:17](=O)[NH2:18])C.[N+](C1C=CC(C(O)=O)=CC=1)([O-])=O.[H-].[Na+]>>[C:1]([Si:5]([CH3:12])([CH3:13])[O:6][CH2:7][CH2:8][C@@H:9]1[O:10][C:17](=[O:16])[NH:18][CH2:11]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(N)=O
Reactant: CC(C)(C)[Si](C)(C)OCCC1CO1
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)[Si](C)(C)OCC[C@H]1CNC(=O)O1
Yield: 11 %

Procedure:
Starting from 2-[2-[[(tert-butyl)dimethylsilyl]oxy]ethyl]-oxirane, (7.00 g; prepared according to WO 2007/144423), carbamic acid ethyl ester (1.46 g), 4-nitrobenzoic acid (347 mg), (R,R)-(salen)CoII complex (626 mg) and NaH (1.676 g) and proceeding in analogy to Org. Letters (2005), 7, 1983-1985, the title compound was obtained as a dark orange solid (880 mg; 11% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][N:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CCO.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([OH:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][N:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(C(=O)c2ccccc2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(C(O)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
The product from step 1 (100 mg, 0.26 mmol) was dissolved in 2 ml EtOH, and NaBH4 (7.5 mg, 0.196 mmol) in 0.5 ml H2O was added and the mixture stirred at rt for 2 h. The mixture was then quenched with 3N NaOH, and 5 ml of ether was added to extract the compound, which was dried over MgSO4 and concentrated to give yellow oil (79 mg, 90.1%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:16])=[N:8][C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[CH:15]=1)=[O:5])[CH3:2].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OC(=O)C)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:16])=[N:8][C:9]2[C:10](=[CH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:11][CH2:12][CH2:13][C:14]=2[CH:15]=1)=[O:5])[CH3:2]
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)c1cc2c(nc1C)CCCC2
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1cc2c(nc1C)C(=Cc1ccccc1)CCC2

Procedure:
A solution of 5,6,7,8-tetrahydro-2-methyl-3-quinolinecarboxylic acid ethyl ester (4.4 g) and benzaldehyde (2.54 g) in acetic anhydride (13 ml) is heated at reflux temperature for 5 hours. The residue from evaporation is dissolved in aqueous tetrahydrofuran, diluted with water, and the precipitate is extracted into ethyl acetate. The extract is washed with 5 percent sodium bicarbonate solution, dried and evaporated. The residue deposited pure 5,6,7,8-tetrahydro-2-methyl-8-(phenylmethylene)-3-quinolinecarboxylic acid ethyl ester (3.0 g, m.p. 125° C.-126° C.) from ethanol solution.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].N[C@H](C(O)=O)C(C)C.N[C@@H](C(O)=O)C(C)C.N[C@H](C(O)=O)CCSC.N[C@@H](C(O)=O)CCSC>>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C[C@@H](N)C(=O)O
Agent: CC(C)[C@@H](N)C(=O)O
Agent: CC(C)[C@H](N)C(=O)O
Agent: CSCC[C@@H](N)C(=O)O
Product: CC(C)C[C@H](N)C(=O)O

Procedure:
D-Leu, Val, D-Val, Met, D-Met