Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:8](OC)=[O:9])([C:4]([O:6][CH3:7])=[O:5])[CH2:3][CH2:2]1.CC(C[AlH]CC(C)C)C.[Cl-].[NH4+].Cl>ClCCl>[CH:8]([C:1]1([C:4]([O:6][CH3:7])=[O:5])[CH2:3][CH2:2]1)=[O:9]
Reactant: COC(=O)C1(C(=O)OC)CC1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)C1(C=O)CC1
Temperature: -78 °C
Reaction time: 6.5 h

Procedure:
Dimethyl cyclopropane-1,1-dicarboxylate (6.90 ml, 50 mmol) was dissolved in dichloromethane (100 mL) and cooled to −78° C. DIBAL (1.0 M in DCM, 100 ml, 100 mmol) was added slowly over a period of 30 minutes. The reaction mixture was stirred for 6.5 hours at −78° C. then treated carefully with an aqueous saturated solution of ammonium chloride (16 mL) followed by HCl (1.0 M, 20 mL). The reaction was allowed to warm to room temperature over the weekend. The solids were filtered off and washed with DCM. The filtrate was washed with brine, dried over magnesium sulfate and the solvent removed under reduced pressure (200 mbar at rt). The crude product was purified on silica gel by flash column chromatography to afford the desired compound as a 45% w/w solution in EtOAc/DCM/ether as judged by 1H NMR (3.295 g).
Reaction SMILES: CN1CCOCC1.[C:8]([C:11]1[CH:27]=[CH:26][C:14]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](=[S:24]=[O:25])[C:21]([OH:23])=O)=[C:13]([CH2:28][CH:29]=[CH2:30])[C:12]=1[OH:31])(=[O:10])[CH3:9].ClC(OCC(C)C)=O.[CH3:40][N:41]([CH3:45])[CH2:42][CH2:43][NH2:44].Cl>O.ClCCl.O1CCCC1>[CH3:40][N:41]([CH3:45])[CH2:42][CH2:43][NH:44][C:21](=[O:23])[C:20](=[S:24]=[O:25])[CH2:19][CH2:18][CH2:17][CH2:16][O:15][C:14]1[CH:26]=[CH:27][C:11]([C:8](=[O:10])[CH3:9])=[C:12]([OH:31])[C:13]=1[CH2:28][CH:29]=[CH2:30]
Reactant: CN(C)CCN
Reactant: C=CCc1c(OCCCCC(=S=O)C(=O)O)ccc(C(C)=O)c1O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=CCc1c(OCCCCC(=S=O)C(=O)NCCN(C)C)ccc(C(C)=O)c1O
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
0.31 g. (3 mmol) N-methylmorpholine is added to a suspension of 1.06 g. (3 mmol) 3-[3-(4-acetyl-2-allyl-3-hydroxyphenoxy)-propyl]-sulphinylpropionic acid in 20 ml. dichloromethane and 10 ml. tetrahydrofuran, the reaction mixture is cooled to -10° C. and, at this temperature, 0.43 g. (3 mmol) isobutyl chloroformate, dissolved in 5 ml. dichloromethane, is added dropwise thereto. Subsequently, the reaction mixture is stirred for 15 minutes at -10° C. and then 0.26 g. (3 mmol) N,N-dimethylethylenediamine, dissolved in 5 ml. dichloromethane, is added dropwise thereto in such a manner that the temperature does not exceed -10° C. The reaction mixture is stirred for 1 hour at -10° C. and for 2 hours at 0° C. and then allowed to warm up to ambient temperature. The reaction mixture is mixed with water, acidified with 2N hydrochloric acid and the aqueous phase separated off and extracted twice with dichloromethane. The aqueous phase is then rendered alkaline with 2N aqueous sodium hydroxide solution, extracted three times with dichloromethane and the extracts washed neutral with water, dried and evaporated. The crude product is dissolved in methanol/dichloromethane and, by the addition of ethereal hydrochloric acid, 3-[3-(4-acetyl-2-allyl-3-hydroxyphenoxy)-propyl]-sulphinylpropionic acid (2-dimethylaminoethyl)-amide precipitated out as the hydrochloride. Yield 0.85 g. (67% of theory) as deliquescent crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:14][CH2:15][C@@H:16]([NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[CH2:17]([C@H:16]([NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH2:15][NH:14][C:11](=[O:13])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:10])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NC[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)NC[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 15 h
Yield: 99 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-D-alanine (595 mg, 3.14 mmol) in DMF (20 mL) was added benzyl [(1S)-2-amino-1-benzylethyl]carbamate (Tet. Lett. 2005, 46(41), 7069) (968 mg, 3.30 mmol), HBTU (1.43 g, 3.77 mmol) and triethylamine (1.8 ml, 12.6 mmol) at room temperature. After stirring the reaction mixture for 15 hours, water (20 mL) was added to the mixture. The mixture was extracted with ethyl acetate/heptane 5/1 (2×20 mL) and the combined extracts were washed with 1N citric acid (20 mL), saturated aqueous sodium bicarbonate (20 mL) and brine (20 mL). The organic layer was dried over sodium sulfate, and concentrated under reduced pressure to afford the title compound as a white solid in 99% yield, 1.42 g. 1H NMR (400 MHz, CDCl3) : 1.24 (d, 3H), 1.43 (s, 9H), 2.59-2.86 (m, 4H), 3.13-3.25 (m, 2H), 3.34-3.44 (m, 1H), 3.89-4.05 (m, 2H), 4.90-5.05 (m, 2H), 7.11-7.36 (m, 10H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:33]=[CH:32][C:15]3[N:16]([CH2:20][C:21]4[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=4[C:23]([O:25]CC)=[O:24])[CH2:17][CH2:18][O:19][C:14]=3[CH:13]=2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].CO>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:33]=[CH:32][C:15]3[N:16]([CH2:20][C:21]4[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=4[C:23]([OH:25])=[O:24])[CH2:17][CH2:18][O:19][C:14]=3[CH:13]=2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1ccccc1CN1CCOc2cc(NC(=O)c3nc(Cl)c(CC)[nH]3)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1[nH]c(C(=O)Nc2ccc3c(c2)OCCN3Cc2ccccc2C(=O)O)nc1Cl
Yield: 101.7 %

Procedure:
The same operation as in Example (91d) was performed using methyl 2-[(7-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-2,3-dihydro-4H-1,4-benzoxazin-4-yl)methyl]benzoate obtained in Example (104c) (0.13 g, 0.29 mmol), 2 N lithium hydroxide (3 mL, 6 mmol), methanol (3 mL) and tetrahydrofuran (3 mL), to obtain 0.13 g of the title compound as a light brown solid (92%).
Reaction SMILES: [C:1](O)(=O)C.O.[CH:6](=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>C=O>[CH2:1]=[C:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:6]=[O:13]
Reactant: CCCCCCC=O
Reactant: CC(=O)O
Agent: C=O
Solvent: O
Product: C=C(C=O)CCCCC
Temperature: 50 °C

Procedure:
A 3-liter three-neck flask fitted with an overhead stirrer and condenser was charged with di-N-butyl amine (33 g, 0.25 mol) and acetic acid (31 g, 0.5 mol). Roughly 500 ml of 33% formaldehyde solution in water (178 g formaldehyde, 5.9 mol) was then added and the resulting solution was heated to 50° C. with stirring. After this temperature was reached heptanal (500 g, 4.3 mol) was fed in over about 1.5 h. A slight exotherm was noticed during the feed. Monitoring by GC showed the consumption of heptanal and the production of 2-methylene heptanal, finally reaching roughly 95% conversion after the addition was complete. The reaction mixture was allowed to cool to room temperature, poured into a separatory funnel, and washed once with 5% HCl solution. The organic layer was then washed once with saturated sodium carbonate, then taken directly on to the next step.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][CH2:24][CH2:25][C:26]1[CH:27]=[C:28]([CH2:31][N:32]2[CH2:50][CH2:49][C:35]3([O:40][CH2:39][CH2:38][N:37]([C:41]([C:43]4[S:44][C:45]([CH3:48])=[CH:46][CH:47]=4)=[O:42])[CH2:36]3)[CH2:34][CH2:33]2)[S:29][CH:30]=1.FC(F)(F)C(O)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[CH3:48][C:45]1[S:44][C:43]([C:41]([N:37]2[CH2:36][C:35]3([CH2:49][CH2:50][N:32]([CH2:31][C:28]4[S:29][CH:30]=[C:26]([CH2:25][CH:24]=[O:23])[CH:27]=4)[CH2:33][CH2:34]3)[O:40][CH2:39][CH2:38]2)=[O:42])=[CH:47][CH:46]=1
Reactant: Cc1ccc(C(=O)N2CCOC3(CCN(Cc4cc(CCO)cs4)CC3)C2)s1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)N2CCOC3(CCN(Cc4cc(CC=O)cs4)CC3)C2)s1
Reaction time: 1 h

Procedure:
Dess-Martin periodinane (0.35 g) was added to a stirred solution of (9-((4-(2-hydroxyethyl)thiophen-2-yl)methyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(5-methylthiophen-2-yl)methanone (example 27, step d) (0.19 g) and trifluoroacetic acid (0.052 mL) in DCM (5 mL). After 1 h, ethyl acetate (30 mL) was added followed by a mixture of saturated sodium thiosulphate solution (5 mL) and saturated sodium bicarbonate solution (5 mL). The reaction mixture was shaken well and separated. The ethyl acetate solution was washed with saturated sodium bicarbonate solution, water and brine. Acetic acid (0.07 mL) was added, the solution dried over sodium sulphate, filtered and evaporated in vacuo (bath temperature ˜30° C.) to give the subtitled compound as a gum. Yield 0.19 g. Used directly.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26]([CH3:33])[N:25]=[C:24]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[N:23]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[CH:42](OC)[N:43]([CH3:45])[CH3:44].O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26](/[CH:33]=[CH:42]/[N:43]([CH3:45])[CH3:44])[N:25]=[C:24]([N:34]4[CH2:35][CH2:36][O:37][CH2:38][CH2:39]4)[N:23]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1c(C)nc(N2CCOCC2)nc1Nc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: COC(OC)N(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(/C=C/N(C)C)nc(N2CCOCC2)nc1Nc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 130 °C

Procedure:
Ethyl 4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)phenylamino)-6-methyl-2-morpholinopyrimidine-5-carboxylate (350 mg, 0.64 mmol) was dissolved in DMF (5 mL), dimethyl formamide dimethyl acetal (0.26 mL) was added and the mixture was heated to 130° C. for 12 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with water, dried over Na2SO4 and evaporated to give the desired product (0.23 g). 1H NMR (400 MHz, DMSO-d6): δ 10.44 (s, 1H), 7.94 (d, J=12.2 Hz, 1H), 7.55 (d, J=8.8 Hz, 2H), 7.22 (d, J=8.8 Hz, 2H), 5.89 (d, J=12.2 Hz, 1H), 4.30 (q, J=6.8 Hz, 2H), 3.80 (s, 2H), 3.75-3.65 (m, 8H), 3.33 (m, 4H), 3.32 (m, 6H), 2.41 (m, 4H), 1.38 (s, 9H), 1.32 (t, J=6.8 Hz, 3H); MS m/z 596.4 (M+1).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[CH:14][C:15]=2[Br:17])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CCOCC.O.[OH-].[Na+]>CO.CCOCC>[Br:17][C:15]1[CH:14]=[C:13]([O:18][CH3:19])[CH:12]=[C:11]2[C:16]=1[NH:8][CH2:9][CH2:10]2
Reactant: COc1cc(Br)c2c(c1)CCN2C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: COc1cc(Br)c2c(c1)CCN2
Temperature: 55 °C
Yield: 85 %

Procedure:
To 1-(tert-butoxycarbonyl)-7-bromo-5-methoxyindoline (1.16 g) in methanol (28 mL) was added HCl/ether (1.0 M, 14.1 mL, 4 eq.). The reaction was heated at 55° C. for 4 hours and then cooled to room temperature. Water (25 mL) was added and the pH was adjusted to 9 with NaOH (1 N, aq.). The mixture was extrated with ether, which was washed with brine, dried over MgSO4, and concentrated to give 7-bromo-5-methoxyindoline (685 mg).
Reaction SMILES: F[B-](F)(F)F.[F:6][S:7]([F:19])([F:18])([F:17])([F:16])[C:8]1[CH:13]=[CH:12][C:11]([N+]#N)=[CH:10][CH:9]=1.[CH2:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CCO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:6][S:7]([F:19])([F:18])([F:17])([F:16])[C:8]1[CH:13]=[CH:12][C:11](/[CH:20]=[CH:21]/[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:10][CH:9]=1
Reactant: C=Cc1ccccc1
Reactant: N#[N+]c1ccc(S(F)(F)(F)(F)F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: F[B-](F)(F)F
Solvent: CCO
Product: FS(F)(F)(F)(F)c1ccc(/C=C/c2ccccc2)cc1
Temperature: 70 °C
Yield: 76.7 %

Procedure:
EtOH as Solvent: A solution of 1 (10.0 mg, 0.0315 mmol) in 0.4 mL of 95% aqueous ethanol was added dropwise to a solution of styrene (6.5 mg, 0.062 mmol) and palladium(II) acetate (0.5 mg, 0.002 mmol) in 0.11 g of 95% aqueous ethanol. The reaction mixture was heated by an oil bath at 70° C. for 15 h. After cooling, the mixture was filtered through a pad of Celite 545 and purified by SiO2 column chromatography (9:1 hexane/CH2Cl2) to give 2a (7.4 mg, 77% yield) as colorless crystals; m.p. 121.6-122.0° C. IR (ATR): {tilde over (v)}=3028, 1593, 1499, 1450, 1096, 964 cm−1. MS (GC, EI): m/z=306 [M+], 179. 1H NMR (500 MHz, CDCl3): δ=7.73 (d, J=8.5 Hz, 2H), 7.56 (d, J=8.5 Hz, 2H), 7.53 (d, J=7.4 Hz, 2H), 7.39 (t, J=7.4 Hz, 2H), 7.31 (t, J=7.4 Hz, 1H), 7.19 (d, J=16.4 Hz, 1H), 7.09 (d, J=16.4 Hz, 1H) ppm. 13C NMR (125 MHz, CDCl3): δ=152.5 (C), 140.6 (C), 136.4 (C), 132.0 (CH), 128.8 (2CH), 128.5 (CH), 126.8 (2CH), 126.3 (5CH) ppm. 19F NMR (470 MHz, CDCl3): δ=89.9 (quint, J=150.2 Hz, 1 F), 61.0 (d, J=150.2 Hz, 4 F) ppm.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:12]([N:13]=[C:14]=[O:15])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[C@@:16]12([OH:25])[N:23]([CH3:24])[C@@H:20]([CH2:21][CH2:22]1)[CH2:19][CH:18]=[CH:17]2>C(#N)C>[C:12]1([NH:13][C:14]([O:25][C@@:16]23[N:23]([CH3:24])[C@@H:20]([CH2:21][CH2:22]2)[CH2:19][CH:18]=[CH:17]3)=[O:15])[C:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C=Nc1ccccc1-c1ccccc1
Reactant: CN1[C@@H]2CC=C[C@@]1(O)CC2
Solvent: CC#N
Product: CN1[C@@H]2CC=C[C@@]1(OC(=O)Nc1ccccc1-c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5.0 g (0.026 mol) of 2-biphenylisocyanate is placed in 10 mL acetonitrile, and a solution of 3.619 g (0.026 mol) tropenol in 5 mL acetonitrile is added dropwise, then stirred for 24 hours at ambient temperature. The solution is concentrated by evaporation and the residue is distributed between dichloromethane and water. The organic phase is dried over sodium sulfate and evaporated to dryness. Yield: 7.4 g yellowish-orange oil (85% of theory).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH3:11])=O)=[CH:4][C:3]=1[CH3:12].Br[C:14]1[CH:15]=[C:16]([CH3:21])[C:17](C)=[CH:18]C=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[K+]>C(O)C.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:15][C:16]([CH3:21])=[C:17]([CH3:18])[CH:11]=2)=[CH:4][C:3]=1[CH3:12]
Reactant: CC(=O)Nc1ccc(C)c(C)c1
Reactant: Cc1ccc(Br)cc1C
Agent: [Cu+2]
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(Nc2ccc(C)c(C)c2)cc1C
Temperature: 25 °C
Yield: 70.6 %

Procedure:
In a 2-liter three-neck flask were placed 120 g of 3,4-dimethylacetanilide synthesized in Example 1 (1), 253 g of unpurified 4-bromo-o-xylene (purity about 70%, containing about 30% 3-bromo-o-xylene), 122 g of anhydrous potassium carbonate and 2 g of copper sulfate pentahydrate, and after carrying out the reaction for 60 hours at 200° C. under a nitrogen gas stream, the reaction mixture was cooled to room temperature. To the reaction mixture was added a solution obtained by dissolving 120 g of potassium hydroxide in 600 ml of ethanol, and the mixture was refluxed for 4 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and then, inorganic salts were removed by filtration, and the solvent was distilled off from the filtrate under reduced pressure. The remaining filtrate was recrystallized from methanol under reduced pressure (about 155° C/0.2 mmHg) to provide 117 g of 3,3',4,4'-tetramethyldiphenylamine. (Melting point 80° to 82° C., colorless crystals)
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[CH2:10]([O:13][CH2:14][CH2:15]Cl)[CH2:11][CH3:12].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>O.CN(C=O)C>[CH2:10]([O:13][CH2:14][CH2:15][O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5])[CH2:11][CH3:12]
Reactant: CCCOCCCl
Reactant: OCc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOCCOc1ccccc1CO
Temperature: 90 °C
Reaction time: 24 h

Procedure:
A mixture of 2-hydroxybenzyl alcohol (3.00 g), 2-chloroethyl propyl ether (4.0 ml), sodium iodide (4.75 g), potassium carbonate (6.68 g) and DMF (30 ml) was stirred at 90° C. for 24 hours. The reaction mixture was mixed with water and was extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated solution of sodium chloride, and was dried with magnesium sulfate. After concentration under reduced pressure, the residue was subjected to purification using column chromatography (ethyl acetate:hexane 1:2) to obtain 2-(2-propoxyethoxy)benzyl alcohol (2.35 g) as a yellow oily substance.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.C(=[NH:27])(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[Na+].Cl.[OH-].[Na+].[Cl-].[Na+]>C(OCC)(=O)C.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1>[NH2:27][C:2]1[CH:3]=[C:4]([C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)C(=O)c1cccc(I)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)c1cccc(N)c1
Temperature: 50 °C
Yield: 82 %

Procedure:
Combine 1-(3-iodo-phenyl)-2,2-dimethyl-propan-1-one (2.0 g, 8.3 mmol), benzophenone imine (1.7 mL, 1.2 equiv.), racemic BINAP (0.23 g, 4.5 mol %), NaOtBu (1.1 g, 1.4 equiv.), and THF (30 mL). De-gas thoroughly with nitrogen then add bis(dibenzylideneacetone) palladium (0.14 g, 3 mol %) and place under nitrogen. Heat the reaction at 50° C. overnight. The next morning add approximately 8 mL 5 N HCl (aq) and heat for an additional hour at 50° C. Let cool to room temperature then dilute with ethyl acetate and make basic with 1 N NaOH (aq). Wash organics with aqueous saturated sodium chloride. Dry over magnesium sulfate, filter and concentrate in vacuo. Purify by silica chromatography (Hex→9:1 Hex:EtOAc→4:1 Hex:EtOAc) to give a yellow residue (1.2 g, 82%). MS (ES), m/z 178 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([NH:27][C:28](=O)[O:29]C2C=CC=CC=2)[CH:4]=[N:3]1.[NH:37]1[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:38]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH3:1][N:2]1[C:6]([NH:7][C:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[C:5]([NH:27][C:28]([N:37]2[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:46])([CH3:48])[CH3:47])[CH2:38]2)=[O:29])[CH:4]=[N:3]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: Cn1ncc(NC(=O)Oc2ccccc2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(NC(=O)N2CC[C@H](NC(=O)OC(C)(C)C)C2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 59.9 %

Procedure:
To a suspension of phenyl [1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]carbamate (950 mg) and tert-butyl (3S)-3-pyrrolidinylcarbamate (560 mg) in methylene chloride (20 ml) was added N-ethyldiisopropylamine (390 mg), and the mixture was stirred under reflux for 23 hours. The reaction mixture was washed successively with 10% aqueous citric acid solution, brine and saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 4% methanol/chloroform to give tert-butyl [(3S)-1-({[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}carbonyl)-3-pyrrolidinyl]carbamate (680 mg) as a solid.
Reaction SMILES: [CH2:1]([S:3]/[C:4](/[O:7][Si](C)(C)C)=[CH:5]/[CH3:6])[CH3:2].[C:12]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])(=[O:15])[CH:13]=[O:14].Cl.CO>C1(C)C=CC=CC=1>[CH2:1]([S:3][C:4](=[O:7])[CH:5]([CH3:6])[CH:13]([OH:14])[C:12]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:15])[CH3:2]
Reactant: CCCCOC(=O)C=O
Reactant: C/C=C(\O[Si](C)(C)C)SCC
Agent: Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: CCCCOC(=O)C(O)C(C)C(=O)SCC
Temperature: 0 °C
Yield: 64 %

Procedure:
0.5 ml (0.1 mmol) of (R)-1 solution prepared in the same manner as in Example 1 were cooled to 0° C., and 190 mg (1 mmol) of (E)-1-ethylthio-1-trimethylsilyloxy-1-propene (77% E) and subsequently 130 mg (1 mmol) of freshly distilled butyl glyoxylate and 0.5 ml of toluene were added thereto, followed by allowing the mixture to react at 0° C. for 0.5 hour. The resulting mixture was poured into 10% hydrochloric acid-methanol cooled at 0° C. The solution was filtered through a pad of Celite, and the filtrate was extracted three times with a 5 ml portion of diethyl ether. The combined organic layer was washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate and evaporated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=15/1 by volume) to obtain 158 mg (yield 64%) of n-butyl 4-ethylthio-2-hydroxy-3-methyl-4-oxobutyrate.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(OCC)[O:22][CH2:23][CH3:24].C(=O)([O-])O.[Na+]>C(O)CO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][CH2:9][C:10]1([CH2:12][O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[O:22][CH2:23][CH2:24][O:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(COCc1ccccc1)COCc1ccccc1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: OCCO
Product: c1ccc(COCC2(COCc3ccccc3)OCCO2)cc1
Temperature: 50 °C
Reaction time: 14 h
Yield: 81.6 %

Procedure:
The 1,3-bis(benzyloxy)acetone (30 g, 111 mmol) obtained in the step (4a) was mixed with ethylene glycol (64 ml, 1.148 mmol) and triethyl orthoformate (19 ml, 114 mmol), and p-toluenesulfonic acid monohydrate (591 mg, 3.11 mmol). The mixture was stirred at 50° C. for 14 hours. To the mixture, a saturated aqueous solution of sodium hydrogen carbonate and ethyl acetate were added. The organic layer was washed with water and a saline solution, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate=1/0-4/1 gradient) and desired fractions were concentrated to obtain the title compound (28.46 g, yield: 81.6%) as a colorless oil.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][C:6]1[CH:7]=[C:8]([NH2:13])[CH:9]=[CH:10][C:11]=1[F:12]>N1C=CC=CC=1>[F:5][C:6]1[CH:7]=[C:8]([NH:13][C:1](=[O:3])[CH3:2])[CH:9]=[CH:10][C:11]=1[F:12]
Reactant: Nc1ccc(F)c(F)c1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
1 Acetyl chloride (82.61 mL, 774.50 mmol) was added slowly to a solution of 3,4-Difluoro-phenylamine (100 g, 774.50 mmol) in pyridine (250 mL) in ice bath. The mixture was stirred at 0° C. for 45 min then was kept at room temperature for 3 hrs. Solvent was removed under reduced pressure. The residue was crystallized in acetone/water to give a solid. 1H NMR (300 MHz, CDCl3): δ 7.86 (br, 1H), 7.62-7.55 (m, 1H), 7.07 (m, 2H), 2.16 (s, 3H).