Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(#N)C.[CH3:4][C:5]([C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=[O:18])([CH3:14])[CH2:6][C@:7]1([C:10]([F:13])([F:12])[F:11])[CH2:9][O:8]1.Cl([O-])=[O:24].[Na+].S(=O)(=O)(O)N>[Cl-].[Na+].O>[CH3:14][C:5]([C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[C:17]([OH:24])=[O:18])([CH3:4])[CH2:6][C@:7]1([C:10]([F:12])([F:13])[F:11])[CH2:9][O:8]1
Reactant: CC(C)(C[C@]1(C(F)(F)F)CO1)c1ccccc1C=O
Reactant: [O-][Cl+][O-]
Agent: NS(=O)(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C[C@]1(C(F)(F)F)CO1)c1ccccc1C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a stirred, ice-cooled, acetonitrile (250 mL) solution of 2-[1,1-dimethyl-2-((R)-2-trifluoromethyloxiranyl)ethyl]benzaldehyde (20 g, 73.5 mmol) was added a solution of sodium chlorite (7.4 g, 73.5 mmol in 100 mL water) followed immediately by a solution of sulfamic acid (7.13 g, 73.5 mmol in 100 mL water). After 30 minutes, the ice-cooled reaction mixture was treated with 500 mL of brine and extracted with three 300 mL portions of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate, and the solvent evaporated in vacuo to give 2-[1,1-dimethyl-2-((R)-2-trifluoromethyloxiranyl)ethyl]benzoic acid as a colorless thick oil (18 g, 85%).
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14](Cl)=[O:15])[S:13][C:6]=12.[NH2:24][CH:25]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26]1>C(Cl)Cl>[F:1][C:2]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]([NH:24][CH:25]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26]3)=[O:15])[S:13][C:6]=12
Reactant: O=C(Cl)c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
A solution of 40 (shown in the scheme 7, 600 mg, 1.54 mmol), tert-butyl 3-aminopyrrolidine-1-carboxylate (369 mg, 2.0 mmol) in DCM (15 mL) was stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography, eluents EtOAc and EtOAc/MeOH (10:1), to afford the title compound 289 (160mg, 20%) as an off-white solid. MS (m/z): 503.3 (M+H) (found).
Reaction SMILES: COC1C=C[C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([C:16]3[N:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:18][C:17]=3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])[CH:12]=[CH:13][C:14]=2[Cl:15])=[CH:5]C=1.Cl.ClC1C=CC([C:43]2[N:48]=[C:47](C(O)=O)C=CC=2C2C=CC=CC=2Cl)=CC=1OCCCN(C)C>>[Cl:15][C:14]1[CH:13]=[CH:12][C:11]([C:16]2[N:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:18][C:17]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])=[CH:10][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][N:48]([CH3:43])[CH3:47]
Reactant: CN(C)CCCOc1cc(-c2nc(C(=O)O)ccc2-c2ccccc2Cl)ccc1Cl
Reactant: COC(=O)c1ccc(-c2ccccc2Cl)c(-c2ccc(Cl)c(OCc3ccc(OC)cc3)c2)n1
Agent: Cl
Product: COC(=O)c1ccc(-c2ccccc2Cl)c(-c2ccc(Cl)c(OCCCN(C)C)c2)n1

Procedure:
According to the debenzylation/O-alkylation/saponification sequence described in Examples 1.7, 1.8 and 1.9, respectively, starting with 665 mg (1.35 mmol) of methyl 6-[3-[(4-methoxybenzyl)oxy]-4-chlorophenyl]-5-(2-chlorophenyl)pyridine-2-carboxylate, 181 mg of 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chlorophenyl)pyridine-2-carboxylic acid hydrochloride are obtained in the form of a gum.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3](=O)[CH2:4][CH3:5].Cl.[NH2:10][OH:11].[OH-].[Na+]>O>[F:1][C:2]([F:8])([F:7])/[C:3](=[N:10]/[OH:11])/[CH2:4][CH3:5]
Reactant: CCC(=O)C(F)(F)F
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC/C(=N\O)C(F)(F)F
Temperature: 25 °C
Yield: 44.4 %

Procedure:
To a solution of 1,1,1-trifluorobutan-2-one (5.0 g, 39.9 mmol) and hydroxylamine hydrochloride (3.22 g, 46.3 mmol) in water (28 mL) was added a solution of sodium hydroxide (1.84 g, 46.0 mmol) in water (14 mL), then the mixture was brought to reflux for 4 hr. After cooling to room temperature, the mixture was extracted with dichloromethane (3×50 mL) and the combined organic layers were washed with water, brine, then dried over anhydrous sodium sulfate. Filtration and concentration then distillation using a 10 cm Vigreux column (b.p. 123-124° C.) afforded (E)-1,1,1-trifluorobutan-2-one oxime (2.50 g, 44.5% yield) as a clear liquid. 1H NMR (400 MHz, CDCl3): 9.18 (br s, 1H), 2.52 (q, 2H), 1.21 (t, 3H).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[H-].[Na+].[SH:13][CH2:14][C:15]([O:17][CH3:18])=[O:16]>>[F:10][C:8]1[CH:7]=[CH:6][C:3]2[CH:4]=[C:14]([C:15]([O:17][CH3:18])=[O:16])[S:13][C:2]=2[CH:9]=1
Reactant: O=Cc1ccc(F)cc1F
Reactant: COC(=O)CS
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cc2ccc(F)cc2s1
Yield: 67.3 %

Procedure:
Using 2.00 g (14.07 mmol) of 2,4-difluorobenzaldehyde, 0.84 g (21.11 mmol) of sodium hydride (60% pure) and 1.64 g (15.48 mmol) of methyl mercaptoacetate, 1.99 g of the desired product are obtained. The product is obtained in a purity which permits further reaction and is reacted without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]([S:15]([CH3:18])(=[O:17])=[O:16])([CH3:14])[CH3:13])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[OH:19][CH2:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[CH3:18][S:15]([C:12]([C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([C:25]3[CH:26]=[C:21]([CH2:20][OH:19])[CH:22]=[CH:23][CH:24]=3)[CH:3]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)([CH3:14])[CH3:13])(=[O:17])=[O:16]
Reactant: OCc1cccc(B(O)O)c1
Reactant: CC(C)(c1cc(Br)c2ncccc2c1)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(c1cc(-c2cccc(CO)c2)c2ncccc2c1)S(C)(=O)=O
Temperature: 95 °C
Reaction time: 3 h

Procedure:
A mixture of the 8-Bromo-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline from Step 2 above (26 g, 79 mmol), 3-(hydroxymethyl)phenyl-boronic acid (14 g, 92 mmol), sodium carbonate (120 mL, 2M, H2O), PdCl2(Ph3P)2 (2 g) in DME (300 mL) was heated at 90-100° C. for 8 h. The resulting reaction mixture was filtered on a large plug/column of silica gel and the eluted with EtOAc. The organic extracts were concentrated and the resulting suspension diluted with Et2O and stirred vigorously for 3 h. The desired {3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-methanol was isolated as a white solid by filtration.
Reaction SMILES: Cl.[I:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([C@H:13]1[CH2:17][CH2:16][NH:15][CH2:14]1)[CH:8]=[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:6]2=[O:23].C=O.O.[C:27]([BH3-])#N.[Na+]>CO>[I:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([C@H:13]1[CH2:17][CH2:16][N:15]([CH3:27])[CH2:14]1)[CH:8]=[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:6]2=[O:23]
Reactant: CCOC(=O)c1cn([C@H]2CCNC2)c2ccc(I)cc2c1=O
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)c1cn([C@H]2CCN(C)C2)c2ccc(I)cc2c1=O
Temperature: 23 °C
Reaction time: 16 h
Yield: 82.3 %

Procedure:
(S)-Ethyl 6-iodo-4-oxo-1-(pyrrolidin-3-yl)-1,4-dihydroquinoline-3-carboxylate hydrochloride (Intermediate 136, 484 mg, 1.08 mmol) was suspended in methanol (15 mL) then 37% formaldehyde in water (405 μl, 5.4 mmol) and sodium cyanoborohydride (612 mg, 9 7 mmol) were added. The reaction was stirred at 23° C. for 16 h. The volume of the reaction was reduced by half and water (25 mL) was added. The suspension was extracted with 2:1 ethyl acetate: tetrahydrofuran (3×, 10 mL). The organic phases were combined, dried over sodium sulfate, and the solvent was removed in vacuo. The residue was passed through a plug of silica gel (2 g) eluting with 10% methanol in dichloromethane to remove any remaining borohydride. The solid was then dried in a vacuum oven at 50° C. for 18 h to give 379 mg (82% yield) of (S)-ethyl 6-iodo-1-(1-methylpyrrolidin-3-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate as an off white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]([C:17]([O:19][CH3:20])=[O:18])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[I-:21].[Na+]>CC(C)=O>[I:21][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]([C:17]([O:19][CH3:20])=[O:18])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: COC(=O)C(CCCCCCCBr)C(=O)OC(C)(C)C
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)C(CCCCCCCI)C(=O)OC(C)(C)C

Procedure:
t-Butyl methyl 7-bromoheptylmalonate (8.81 g, 25.1 mmol) is dissolved in acetone (50 ml). Sodium iodide (3.7 g, 25.1 mmol) is added and the mixture is stirred at reflux for 2 hours. The reaction mixture is filtered and the filtrate is concentrated to dryness. The residue is dissolved in methylene chloride and filtered again. The filtrate is concentrated to dryness to give t-butyl methyl 7-iodoheptylmalonate as an oil.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[CH3:25][C:26]([CH3:31])=[CH:27][C:28](O)=[O:29].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:25][C:26]([CH3:31])=[CH:27][C:28]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:29]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: CC(C)=CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=C(C)C
Yield: 76.3 %

Procedure:
The same procedures as in Example 146 were carried out from methyl L-tryptophanate hydrochloride (3.0 g), triethylamine (2.0 mL), 3-methylcrotonic acid (1.4 g), WSC.HCl (2.7 g), and methylene chloride (80 mL), to give the captioned compound (2.7 g, 77%) as crystals.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[N:21]1[C:30]2[C:25](=[CH:26][C:27]([CH:31]([NH2:33])[CH3:32])=[CH:28][CH:29]=2)[N:24]=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:20][C:17]1[CH:18]=[CH:19][C:12]([N:10]2[CH2:9][CH2:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:33][CH:31]([C:27]4[CH:26]=[C:25]5[C:30](=[CH:29][CH:28]=4)[N:21]=[CH:22][CH:23]=[N:24]5)[CH3:32])[C:3]=3[CH2:11]2)=[C:13]([CH:16]=1)[C:14]#[N:15]
Reactant: CC(N)c1ccc2nccnc2c1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(N2CCc3ncnc(NC(C)c4ccc5nccnc5c4)c3C2)c(C#N)c1
Yield: 15.3 %

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (200 mg, 0.70 mmol) and 1-(quinoxalin-6-yl)ethanamine (150 mg, 0.87 mmol) in acetonitrile (2 mL) and N,N-diisopropylethylamine (734 μL, 4.2 mmol) was subjected to microwave irradiation at 185° C. for 3.5 h. The reaction mixture was concentrated and the residue was purified by preparative HPLC (100×20.2 mm, C18 column; 30-60% acetonitrile-water [10 mM Et2NH]) to afford a light brown solid (45 mg).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O.[NH2:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1>COCCOC.C(=O)([O-])[O-].[Na+].[Na+].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>[NH2:11][C:12]1[CH:17]=[C:16]([C:2]2[C:3]([C:4]#[N:5])=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: N#Cc1ccccc1Br
Reactant: Nc1cccc(B(O)O)c1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: N#Cc1ccccc1-c1cccc(N)c1
Temperature: 80 °C
Yield: 97.8 %

Procedure:
A mixture of 2-bromobenzonitrile (9.1 g, 50 mmol), 3-aminobenzeneboronic acid monohydrate (11.6 g, 75 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.73 g, 1.5 mmol) in 1,2-dimethoxyethane (50 ml) and 2 M aqueous sodium carbonate (25 ml) was heated at 80° C. for 20 h. After cooling to ambient temperature the reaction was partitioned between ethyl acetate (400 ml) and water (400 ml). The organic layer was washed with brine (400 ml), dried (Na2SO4), and evaporated in vacuo. Purification of the residue by flash chromatography (silica gel, 0-25% EtOAc/isohexane) gave 9.5 g (98%) of 3′-aminobiphenyl-2-carbonitrile as a colourless oil that solidified on standing to afford a white solid: 1H NMR (400 MHz, CDCl3) δ 3.79 (2H, br), 6.75 (1H, ddd, J 8, 3, 1 Hz), 6.84 (1H, dd, J 3, 3 Hz), 6.92 (1H, dd, J δ, 3 Hz), 7.25 (1H, dd, J 8, 8 Hz), 7.40 (1H, ddd, J 8, 8, 1 Hz), 7.50 (1H, dd, J 8, 1 Hz), 7.62 (1H, ddd, J 8, 8, 1 Hz), 7.73 (1H, dd, J 8, 1 Hz).
Reaction SMILES: [CH3:1][C@H:2]1[C@H:30]([CH3:31])[C@@H:29]2[C@@:5]([C:33]([OH:35])=[O:34])([CH2:6][CH2:7][C@@:8]3([CH3:32])[C@:13]4([CH3:28])[CH2:14][CH2:15][C@H:16]5[C@@:21]([CH2:23][OH:24])([CH3:22])[C@@H:20]([OH:25])[C@H:19]([OH:26])[CH2:18][C@:17]5([CH3:27])[C@H:12]4[CH2:11][CH:10]=[C:9]32)[CH2:4][CH2:3]1.[N+](=[CH2:38])=[N-].CCOCC>CO>[CH3:1][C@H:2]1[C@H:30]([CH3:31])[C@@H:29]2[C@@:5]([C:33]([O:35][CH3:38])=[O:34])([CH2:6][CH2:7][C@@:8]3([CH3:32])[C@:13]4([CH3:28])[CH2:14][CH2:15][C@H:16]5[C@@:21]([CH2:23][OH:24])([CH3:22])[C@@H:20]([OH:25])[C@H:19]([OH:26])[CH2:18][C@:17]5([CH3:27])[C@H:12]4[CH2:11][CH:10]=[C:9]32)[CH2:4][CH2:3]1
Reactant: C=[N+]=[N-]
Reactant: C[C@H]1[C@H](C)CC[C@]2(C(=O)O)CC[C@]3(C)C(=CC[C@@H]4[C@@]5(C)C[C@@H](O)[C@H](O)[C@@](C)(CO)[C@@H]5CC[C@]43C)[C@H]12
Solvent: CO
Solvent: CCOCC
Product: COC(=O)[C@]12CC[C@@H](C)[C@H](C)[C@H]1C1=CC[C@@H]3[C@@]4(C)C[C@@H](O)[C@H](O)[C@@](C)(CO)[C@@H]4CC[C@@]3(C)[C@]1(C)CC2
Temperature: 0 °C
Yield: 95 %

Procedure:
Asiatic acid (500 mg) was dissolved in methanol (25 ml), and the solution was cooled to 0° C. An excess amount of diazomethane/ether solution was added, and the resultant mixture was stirred at room temperature for 1 hour. The solvent was removed by evaporation under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane/methanol=30:1) to give 490 mg of white solid(yield: 95%). The product was recrystallized from ethyl acetate to obtain needle-like crystals.
Reaction SMILES: [CH2:1]([C:3]1[CH:14]=[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:12]=[CH:11][C:4]=1[O:5][CH2:6][CH:7]([OH:10])[CH2:8][OH:9])[CH3:2].[C:29](Cl)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[CH:14]=[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:12]=[CH:11][C:4]=1[O:5][CH2:6][CH:7]([OH:10])[CH2:8][O:9][C:29]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[CH3:2]
Reactant: CCCCCCCCCCCCCCc1ccc(OCC(O)CO)c(CC)c1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCc1ccc(OCC(O)COC(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC)c1
Reaction time: 72 h
Yield: 95.3 %

Procedure:
A mixture of 11.68 g of 3-(2-ethyl-4-tetradecylphenoxy)-1,2-propanediol, 14.95 g of trityl chloride and ml pyridine was stirred for 72 hours, then diluted with chloroform, washed with two 100 ml portions of aqueous sodium bicarbonate, then water and dried. The solvents were evaporated under reduced pressure and the residue evaporated with toluene. This residue was then diluted with hexane and the solid which formed collected giving 18 g of the desired compound.
Reaction SMILES: C(OC([N:8]([C:16]1[O:17][CH2:18][C:19]2([C:29]3[C:24](=[CH:25][CH:26]=[C:27](B4OC(C)(C)C(C)(C)O4)[CH:28]=3)[O:23][CH2:22][C:21]32[CH2:40][CH2:39]3)[N:20]=1)C(OC(C)(C)C)=O)=O)(C)(C)C.Br[C:42]1[CH:43]=[C:44]2[CH:50]=[CH:49][NH:48][C:45]2=[N:46][CH:47]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[NH:48]1[C:45]2=[N:46][CH:47]=[C:42]([C:27]3[CH:28]=[C:29]4[C:19]5([CH2:18][O:17][C:16]([NH2:8])=[N:20]5)[C:21]5([CH2:39][CH2:40]5)[CH2:22][O:23][C:24]4=[CH:25][CH:26]=3)[CH:43]=[C:44]2[CH:50]=[CH:49]1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=NC2(CO1)c1cc(B3OC(C)(C)C(C)(C)O3)ccc1OCC21CC1
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: NC1=NC2(CO1)c1cc(-c3cnc4[nH]ccc4c3)ccc1OCC21CC1
Temperature: 100 °C
Reaction time: 7 h
Yield: 48.5 %

Procedure:
The mixture of di-tert-butyl[6′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)dispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]oxazol]-2″-yl]imidodicarbonate (140 mg, 0.25 mmol), 5-bromo-1H-pyrrolo[2,3-b]pyridine (87 mg, 0.44 mmol), Pd(PPh3)4 (58 mg, 0.050 mmol), and Na2CO3 (80 mg, 0.76 mmol) in 1,4-dioxane-H2O (2.8 ml, 4:1) was stirred for 7 hours at 100° C. After dilution with EtOAc and H2O, the organic layer was washed with H2O, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (CHCl3:MeOH=100:0-85:15) to give white solid. The solid was washed by diisopropyl ether to give 6′-(1H-pyrrolo[2,3-b]pyridin-5-yl)dispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]oxazol]-2″-amine (42 mg).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:15][CH:14]([O:16][CH3:17])[CH:13]([O:18][CH3:19])[CH2:12]3)[C:8]2=[O:11])=[CH:4][CH:3]=1.[C:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)#[N:21].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:19][O:18][CH:13]1[CH:14]([O:16][CH3:17])[CH2:15][C:7]2([CH2:6][C:5]3[C:9](=[CH:10][C:2]([C:26]4[CH:27]=[C:22]([CH:23]=[CH:24][CH:25]=4)[C:20]#[N:21])=[CH:3][CH:4]=3)[C:8]2=[O:11])[CH2:12]1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: COC1CC2(Cc3ccc(Br)cc3C2=O)CC1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COC1CC2(Cc3ccc(-c4cccc(C#N)c4)cc3C2=O)CC1OC
Temperature: 110 °C
Yield: 73 %

Procedure:
In a microwave vial was placed 6′-bromo-3,4-dimethoxyspiro[cyclopentane-1,2′-inden]-1′(3′H)-one 1st isomer (51 mg, 0.157 mmol), 3-cyanobenzeneboronic acid (30 mg, 0.204 mmol), PdCl2(PPh3)2 (11 mg, 0.016 mmol) and cesium carbonate (128 mg, 0.393 mmol). This solid mixture was dissolved in a Dioxane/water mixture (2.0 mL, 6:1 ratio, respectively). The solution was purged with a N2 stream for 30 seconds. The vessel was placed in the μwave and heated to 110° C. for 30 minutes. After that time, the mixture was filtered through a Celite plug. The plug was rinsed with dichloromethane (4 mL) and water (4 mL). The phases in the filtrate were separated. The aqueous phase was back-extracted with dichloromethane (2 mL). The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated under reduce pressure. The crude material was purified by flash chromatography (ISCO, 12 g SiO2 cartridge, ethyl acetate/hexanes as the eluents). The corresponding fractions were combined and concentrated under reduce pressure yielding 3-(3,4-dimethoxy-1′-oxo-1′,3′-dihydrospiro[cyclopentane-1,2′-indene]-6′-yl)benzonitrile 1st isomer (40 mg, 0.115 mmol, 73% yield).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][NH:4][C@@H:3]1[C:7]([O:9]C)=[O:8].[CH:11](=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17]>>[CH2:17]([N:4]1[CH2:5][CH2:6][C@H:2]([CH3:1])[C@H:3]1[C:7]([OH:9])=[O:8])[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=[CH2:11]
Reactant: COC(=O)[C@H]1NCC[C@@H]1C
Reactant: C=CCCCCC=O
Product: C=CCCCCCN1CC[C@H](C)[C@H]1C(=O)O
Yield: 80 %

Procedure:
Following the procedure described above for Compound 19 Steps 1-2, treatment of methyl (3S)-3-methyl-L-prolinate with hept-6-enal afforded the title compound 125 (80%) as an oil. 1H NMR (400 MHz, DMSO-d6, 300 K) δ 5.78 (m, 1H), 5.03-4.92 (m, 2H), 3.58-3.48 (m, 2H), 3.19-3.01 (m, 2H), 3.07-2.95 (m, 1H), 2.34-2.22 (m, 1H), 2.12-2.00 (m, 3H), 1.69-1.55 (m, 3H), 1.41-1.22 (m, 4H), 1.18 (d, J 8.8, 3H).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1.CO.Cl.[O-:16][C:17]#[N:18].[K+]>O>[CH3:1][N:2]([CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1)[C:17]([NH2:18])=[O:16]
Reactant: CNC1CCCc2ccccc21
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: CN(C(N)=O)C1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of 8.05 grams (0.05 mole) of 1,2,3,4-tetrahydro-N-methyl-1-naphthylamine in 10 ml. of methanol is added a solution of 4.2 ml. of 12N hydrochloric acid (0.05 mole) in 35 ml. of water. The mixture is cooled in an ice-water bath while a solution of 4.46 grams (0.055 mole) of potassium cyanate in 15 ml. is added dropwise. After the addition is complete, the reaction mixture is stirred at room temperature for 45 minutes and then at 70°C. to 75°C. for 30 minutes. The mixture is cooled to 25°C., and the solid product filtered off, washed with water and then with cold ethyl acetate. The dried product weighs 7.1 grams and has melting point 160°-163°C. Recrystallization from acetone-hexane gives the analytical sample, melting point 161°C. to 163°C. Recrystallization from acetone-hexane gives the analytical sample, melting point 161°C. to 163°C. Analysis Calculated for C 12 H16N2O: C, 70.56; H, 7.90; N, 13,72. Found: C, 70.60; H, 7.94; N, 13.75.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:7]2[N:21]=[CH:22][C:23]([C:24]#[N:25])=[C:6]12)=[O:4].S(=O)(=O)(O)[OH:27]>>[Cl:1][CH2:2][C:3]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:7]2[N:21]=[CH:22][C:23]([C:24]([NH2:25])=[O:27])=[C:6]12)=[O:4]
Reactant: N#Cc1cnn2c1N(C(=O)CCl)CC=C2c1cccc(C(F)(F)F)c1
Reactant: O=S(=O)(O)O
Product: NC(=O)c1cnn2c1N(C(=O)CCl)CC=C2c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2 g of 4-(chloroacetyl)-4,5-dihydro-7-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile and 20 ml of concentrated sulfuric acid was stirred at room temperature for 2 hours, then poured into ice water, stirred, and filtered. The product was washed with water and dried giving 2 g of the desired intermediate,. mp 174°-176°.