Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrBr.[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])[CH3:4].C[OH:13].Br>O>[OH:13][CH2:4][C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: CC(=O)c1ccccc1
Reactant: CO
Agent: Br
Agent: BrBr
Solvent: O
Product: O=C(CO)c1ccccc1
Temperature: 60 °C

Procedure:
About 13 parts of bromine was added with stirring to a mixture of 474.6 parts of acetophenone in about 640 parts of methanol, while the mixture was stirred and maintained at a temperature between 5°-10° C. Hydrogen bromide gas was then introduced into the mixture until bromine coloration disappeared, at which point an additional amount of bromine was added over a 2 hour period to make a total of 631.3 parts. There was then added 71 parts of water while the mixture was stirred and externally cooled for a period of about 30 minutes. An excess of about 2700 parts of water was then slowly added to effect the precipitation in the form of crystals of α-bromo acetophenone from the mixture. The crystals were decanted by means of a vacuum siphon, washed, then neutralized with a 20% sodium hydroxide solution and decanted to dryness. There was then added about 940 parts water, 1600 parts of methanol, 333 parts of sodium bicarbonate and a sodium formate solution prepared from 161 parts of 90% formic acid and sufficient sodium hydroxide to neutralize the acid. The mixture was heated at 60° C. with vigorous stirring for 7 hours after which time it was cooled to ambient temperature and filtered. Based on method of preparation and gas chromatographic analysis of the mixture there was produced α-hydroxy acetophenone in quantitative yields.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]([CH2:28][O:29][Si](C(C)(C)C)(C)C)[CH2:11][O:12][C:13]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[CH:17][C:14]=1[CH:15]=[O:16])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[OH:8][CH2:9][CH:10]([CH2:28][OH:29])[CH2:11][O:12][C:13]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[CH:17][C:14]=1[CH:15]=[O:16]
Reactant: COc1cc(OCC(CO[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C)c(C=O)cc1-c1cccs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(OCC(CO)CO)c(C=O)cc1-c1cccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
Ex-13E: To a solution of 2-[3-(tert-butyldimethylsilanyloxy)-2-(tert-butyldimethylsilanyloxymethyl)propoxy]-4-methoxy-5-thien-2-ylbenzaldehyde (Ex-13D, 0.78 g, 1.41 mmol) in tetrahydrofuran (5 mL) was added tetrabutylammonium fluoride (1 M in tetrahydrofuran, 3.0 mL, 2.9 mmol) and the mixture was stirred at room temperature for 30 min. The reaction was diluted with ethyl acetate (50 mL) and washed sequentially with a 50% ammonium chloride solution (30 mL), water (2×30 mL), brine (30 mL), dried over sodium sulfate and concentrated to a crude yellow solid. Silica gel chromatography afforded 0.37 g (99%) of 2-(3-hydroxy-2-hydroxymethylpropoxy)-4-methoxy-5-thien-2-ylbenzaldehyde as a pale yellow solid, mp 144–145° C. 1H-NMR (300 MHz, CDCl3) δ 10.33 (s, 1H), 8.10 (s, 1H), 7.38 (dd, 1H, J=3.6, 1.5 Hz), 7.30 (dd, 1H, J=5.1, 1.5 Hz), 7.07 (dd, 1H, J=5.1, 3.6 Hz), 6.59 (s, 1H), 4.35 (d, 2H, J=6.0 Hz), 4.02 (t, 4H, J=4.8 Hz), 3.96 (s, 3H), 2.33 (pentet, 1H, J=6.0 Hz), 1.89 (t, 2H, J=4.8 Hz). Anal. Calcd. for C16H18O5S: C, 59.61; H, 5.63; S, 9.95; Found: C, 59.34; H, 5.75; S, 9.82.
Reaction SMILES: [Li]CCCC.C[Si](C#N)(C)C.[C:12]([Si](C)(C)C)(=[O:14])[CH3:13].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.Cl>C1COCC1.CCOCC>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]([OH:25])[C:12]([CH3:13])=[O:14])=[CH:22][CH:21]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(=O)[Si](C)(C)C
Agent: C[Si](C)(C)C#N
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)C(O)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A suspension of ground LaCl3 (26 mg, 0.104 mmol) in dry THF (7.8 mL) under N2 was cooled to −78° C. and stirred for 15 min. A solution of n-BuLi (1.6 M in hexanes, 195 μL, 0.312 mmol) was added and stirring was continued for 15 min. The reaction was warmed to 0° C. and stirred for 30 min. Trimethylsilyl cyanide (31 mg, 42 μL, 0.312 mmol) was added and the reaction was stirred for 30 min at 0° C. and warmed to room temperature over 30 min. A solution of acetyltrimethylsilane (Cunico, R. F., Kuan, C.-P., J. Org. Chem., 1985, 50, 5410-5413) (121 mg, 1.04 mmol) and 4-fluorobenzaldehyde (142 mg, 1.14 mmol) in dry THF (19 mL) was added by cannula and the reaction was stirred at room temperature for 2 h. After this time 1N HCl (24 mL) was added and the reaction was stirred for 1 h. Et2O (25 mL) was added and the organic layer was separated and washed with H2O (2×25 mL). The combined aqueous layers were extracted with Et2O (3×50 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 25×160 mm, 0-50% EtOAc in hexanes gradient) to give 1-(4-fluorophenyl)-1-hydroxyacetone as a colorless solid. Rf=0.31 (20% EtOAc/hexanes). 1H NMR (CDCl3, 500 MHz) δ 7.29 (m, 2H), 7.08-7.04 (m, 2H), 5.06 (d, J=3.6 Hz, 1H), 4.35 (t, J=6.5 Hz, 1H), 2.05 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(N(CC)CC)C.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[C:23]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1[nH]c2ccccc2c1N
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1[nH]c2ccccc2c1NC(=O)c1ccccc1

Procedure:
To a mixture of 3-Amino-2-carboethoxyindole (572 mg) and triethylamine (400 mg) in methylene chloride (100 mL) was added benzoyl chloride (450 mg). After 30 min at room temperature the reaction mixture was washed with 0.1N HCl, dried over magnesium sulfate and the solvent was removed in vacuo. The residue was triturated with ether to afford 3-Benzamido-2-carboethoxyindole as a white solid.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:14][CH:15]=2)[CH2:10]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(Cl)[Cl:34]>>[ClH:34].[NH2:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:14][CH:15]=2)[CH2:10]1
Reactant: CCOC(=O)COc1ccc2c(c1)C[C@@H](NC(=O)OC(C)(C)C)CC2
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)COc1ccc2c(c1)C[C@@H](N)CC2
Product: Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 1 g of (S)-2-[N-(tert-butoxycarbonyl)amino]-7-carbethoxymethoxytetraline, EXAMPLE 5, in 15 ml of methylene chloride is cooled to 0° C. A solution of 2.2 ml of trifluoroacetic acid in 15 ml of methylene chloride is added thereto and the reacting mixture is left under stirring 30 minutes at a temperature of 0°-5° C. and afterwards 4 hours at room temperature. By operating as described in EXAMPLE 4, the (S)-2-amino-7-carbethoxymethoxytetraline hydrochloride is obtained; /alpha/=-52° (methanol, c=1%).
Reaction SMILES: C([Li])CCC.[CH:6]([NH:9]C(C)C)(C)C.C(CC[C:20]([O:41]CC)([O:38][CH2:39][CH3:40])[CH2:21][S:22][CH2:23][C:24]([O:35][CH2:36][CH3:37])([O:32][CH2:33][CH3:34])CCC(OCC)=O)(OCC)=O.O.[CH3:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]>O1CCCC1>[CH2:36]([O:35][CH:24]([O:32][CH2:33][CH3:34])[CH2:23][S:22][CH:21]([CH2:45][C:46]#[C:47][CH2:48][CH2:49][CH2:50][C:6]#[N:9])[C:20]([O:38][CH2:39][CH3:40])=[O:41])[CH3:37]
Reactant: CCCCCC
Reactant: CC(C)NC(C)C
Reactant: CCOC(=O)CCC(CSCC(CCC(=O)OCC)(OCC)OCC)(OCC)OCC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(CC#CCCCC#N)SCC(OCC)OCC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The starting material is prepared as follows: To the solution, made by adding dropwise 132 ml of n-butyl lithium in hexane to 21.2 g of diisopropylamine in 500 ml of tetrahydrofuran while stirring under nitrogen at -30° for 15 minutes, and cooling it to -70°, 49.5 g of carboethoxyethyl-2,2-diethoxy ethylsulfide are added dropwise over a period of 4 minutes. After stirring at -70° for 1 hour, 49.2 g of 7-iodo-5 -heptynoic acid nitrile are added dropwise during 10 minutes. The mixture is stirred at -70° for 6 hours and allowed to warm up to room temperature overnight. It is poured into water, extracted with diethyl ether, the extract washed with water, dried and evaporated, to yield the ethyl 2-(2,2-diethoxyethylmercapto)-8 cyano-4-octynoate.
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([C:17]#[CH:18])[CH:16]=1)[C:10]([O:12]C)=[O:11])=[O:6])[CH2:2][CH3:3].[OH-].[K+]>CO.O.C(Cl)(Cl)Cl>[CH2:19]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([C:17]#[CH:18])[CH:16]=1)[C:10]([OH:12])=[O:11])=[O:6])[CH2:20][CH3:21]
Reactant: C#Cc1cc(C(=O)OC)cc(C(=O)N(CCC)CCC)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C#Cc1cc(C(=O)O)cc(C(=O)N(CCC)CCC)c1
Reaction time: 4 h

Procedure:
To a stirred mixture of the protected methyl 3-[(dipropylamino)carbonyl]-5-ethynylbenzoate (XXXII, Step 1, 185.3 mg, 0.49 mmol) in methanol (2.5 mL) is added a mixture of potassium hydroxide (2.9 mL of a 1 M mixture in water, 2.9 mmol). The reaction mixture is stirred for 4 hours diluted with chloroform (40 mL), the phases are separated and the organic phase is concentrated under reduced pressure to give 3-[(dipropylamino)carbonyl]-5-ethynylbenzoic acid, NMR (300 MHz, CDCl3): □ 8.22, 8.05, 7.71, 3.48, 3.17, 3.16, 1.71, 1.55, 1.00 and 0.78.
Reaction SMILES: [CH2:1]([OH:6])[CH:2]([OH:5])[CH2:3][CH3:4].[C:7]1([C:13](Cl)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>N1C=CC=CC=1.CCOC(C)=O.O>[C:13]([O:6][CH2:1][CH:2]([OH:5])[CH2:3][CH3:4])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCC(O)CO
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 36.2 %

Procedure:
To a solution of 1,2-butandiol (2 g) in anh. pyridine (15 mL) was added triphenylmethyl chloride (8 g). The dark reaction mixture was heated at 100° C. for 8 hr and stirred at r.t. for 18 hr. The mixture was then poured in EtOAc/H2O, the phases were separated and the organic layer was washed with sat. aq. NaCl and dried over Na2SO4. The solids were filtered and the solvent evaporated. The residual pyiridine was eliminated by filtration through a pad of silica gel (cHex/EtOAc 8:2). The solvent was evaporated and the residue was purified by flash chromatography (silica gel, cHex/EtOAc 95:5) to give the title compound as a yellow oil (2.67 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([CH3:28])[S:8][C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[N:18]([CH3:27])[S:19]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)(=[O:21])=[O:20])=[N:6][CH2:5]1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38].O>O1CCCC1>[CH3:36][S:37]([O:1][CH2:2][CH2:3][C:4]1([CH3:28])[S:8][C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[N:18]([CH3:27])[S:19]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)(=[O:21])=[O:20])=[N:6][CH2:5]1)(=[O:39])=[O:38]
Reactant: CS(=O)(=O)Cl
Reactant: CN(c1cccc2cc(C3=NCC(C)(CCO)S3)[nH]c12)S(=O)(=O)c1cccs1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CN(c1cccc2cc(C3=NCC(C)(CCOS(C)(=O)=O)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of N-{2-[5-(2-hydroxyethyl)-5-methyl-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (0.75 g) and triethylamine (0.50 mL) in tetrahydrofuran (10 mL) was slowly added methanesulfonyl chloride (0.20 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (0.56 g, yield 65%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (3:1, volume ratio). melting point 149-150° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11](F)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([O:21][C:22]([C:24]1[S:28][C:27]([NH2:29])=[N:26][C:25]=1[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=1)=[O:23])[CH3:20].CN(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH2:19]([O:21][C:22]([C:24]1[S:28][C:27]([NH:29][C:11]2[CH:10]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:14]=[CH:13][C:12]=2[N+:15]([O-:17])=[O:16])=[N:26][C:25]=1[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=1)=[O:23])[CH3:20]
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1F
Reactant: CCOC(=O)c1sc(N)nc1-c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(Nc2cc(OCc3ccccc3)ccc2[N+](=O)[O-])nc1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.8 %

Procedure:
To a mixture of 2.57 g (10 mmole) of 4-benzyloxy-2-fluoro-1-nitro-benzene, 2.83 g (10 mmole) of 2-amino-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid ethyl ester and 20 mL of dimethylformamide was added 16.25 g (50 mmole) of cesium carbonate. The mixture was heated at 100 degrees for 1 hour. The reaction was allowed to cool to room temperature and then 500 mL of water was added. The mixture was stirred for 15 minutes and the resulting yellow solid collected by filtration to give 5.09 g of 2-(5-benzyloxy-2-nitro-phenylamino)-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid ethyl ester (VI.25).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH:11]=[C:10]([C:21]([OH:23])=O)[CH:9]=2)=[CH:4][CH:3]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([NH2:33])[CH3:32])=[CH:27][C:26]=1[S:34]([CH3:37])(=[O:36])=[O:35].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([NH:33][C:21]([C:10]2[CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)[CH:13]=[C:12]([C:14]([N:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)=[O:15])[CH:11]=2)=[O:23])[CH3:32])=[CH:27][C:26]=1[S:34]([CH3:37])(=[O:35])=[O:36]
Reactant: CC(N)c1ccc(Cl)c(S(C)(=O)=O)c1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N3CCCC3)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)NC(C)c3ccc(Cl)c(S(C)(=O)=O)c3)cc(C(=O)N3CCCC3)c2)cc1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-methyl-5-(pyrrolidine-1-carbonyl)biphenyl-3-carboxylic acid (17 mg, 0.055 mmol) in N,N-dimethylformamide (0.5 mL) were added 1-(4-chloro-3-(methylsulfonyl)phenyl)ethanamine (50 mg, 0.21 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (80 mg, 0.21 mmol) and N,N-diisopropylethylamine (80 μL, 0.46 mmol). The reaction mixture was stirred for 16 hours at 50° C. LC-MS indicated the reaction was complete. The mixture was purified by preparative HPLC to afford the final product as an off white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([O:30]CC4C=CC=CC=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2]>[Pd].O1CCCC1.CO.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:38])[C:5]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:13][CH:14]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(OCc4ccccc4)cc3)oc2C)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(O)cc3)oc2C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.2 %

Procedure:
A mixture of 2-(4-{2-[2-(4-benzyloxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid ethyl ester (8.16 g, 15.8 mmol) and 5% palladium on carbon (1.63 g) in tetrahydrofuran (100 mL) and methanol (100 mL) was purged successively with nitrogen then hydrogen, and then stirred under a hydrogen balloon at room temperature for 18 h. The reaction mixture was filtered through hyflo and solvent was removed from the filtrate in vacuo to give an oil which was dissolved in EtOAc and dried (MgSO4). The solvent was removed in vacuo to afford 6.40 g (95%) of 2-(4-{2-[2-(4-hydroxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid ethyl ester. 1H NMR (500 MHz, CDCl3) δ 8.25 (bs, 1H), 7.32 (d, 2H, J=8.79 Hz), 6.75-6.67 (m, 4H), 6.65 (d, 2H, J=8.79 Hz), 4.17 (q, 2H, J=6.84 Hz), 4.09 (t, 2H, J=6.35 Hz), 2.88 (t, 2H, J=6.35 Hz), 2.30 (s, 3H), 1.45 (s, 6H), 1.21 (t, 3H, J=6.84 Hz); 13C (125 MHz, CDCl3) δ 174.4, 160.2, 159.0, 154.3, 148.9, 144.7, 131.5, 128.1, 122.0, 121.6, 118.7, 115.9, 115.7, 114.9, 79.8, 66.8, 61.3, 25.9, 25.2, 14.1, 10.1; IR (KBr) 2985, 2941, 2809, 2606, 1742, 1731, 1507, 1442, 1277, 1233, 1213, 1170, 1137 cm−1; UV (EtOH) λmax 285 nm (ε 21145), 219 nm (•15842); HRMS (ES+) m/z exact mass calcd for C24H28NO6 426.1917, found 426.1896; Anal. Calc'd for C24H27NO6: C, 67.75; H, 6.40; N, 3.29. Found C, 67.22; H, 6.50; N, 2.79
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15])=[CH:9][CH:8]=[CH:7][C:6]=2[Br:18].[CH2:20]([O:22][CH2:23][C:24](Cl)=O)[CH3:21].C(O)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[Br:18][C:6]1[C:5]2[N:4]=[CH:3][C:2]3[N:1]=[C:21]([CH2:20][O:22][CH2:23][CH3:24])[N:12]([CH2:13][C:14]([CH3:17])([OH:16])[CH3:15])[C:11]=3[C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(O)CNc1c(N)c(Cl)nc2c(Br)cccc12
Reactant: CCOCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CCOCc1nc2cnc3c(Br)cccc3c2n1CC(C)(C)O
Temperature: 40 °C
Reaction time: 36 h
Yield: 80.8 %

Procedure:
A solution of 1-(3-amino-8-bromo-2-chloroquinolin-4-ylamino)-2-methylpropan-2-ol (4.65 g, 14.4 mmol) and ethoxyacetyl chloride (1.9 mL, 15.8 mmol) in dichloromethane (72 mL) was stirred for one hour at ambient temperature. The solvent was removed under reduced pressure, and ethanol (43 mL), water (29 mL), and potassium carbonate (3.98 g, 28.8 mmol) were added. The reaction was stirred at 40° C. for 36 hours. The solvent was removed under reduce pressure, and the residue was diluted with water. The aqueous solution was extracted with chloroform, and the combined extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 4.4 g of 1-(6-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([OH:27])=[O:26].CCN(C(C)C)C(C)C>CC(O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:23]2[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=2[C:25]([OH:27])=[O:26])[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Reactant: Nc1ccccc1C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccccc4C(=O)O)nc(Cl)nc32)cc1
Temperature: 85 °C

Procedure:
A mixture of 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (25 g, 73.1 mmol), 2-aminobenzoic acid (10.02 g, 73.1 mmol) and DIPEA (63.8 mL, 365 mmol) in iPrOH (300 mL) was heated at 85° C. bath for 17 h. The resulting mixture was allowed to cool to rt and was concentrated to about half volume. EtOAc (400 mL) was added, followed by a 1N aqueous HCl solution (400 mL). The resulting slurry was filtered, the solids were washed with EtOAc and triturated using Et2O to obtain 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzoic acid as a yellow solid (28.44 g 88%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.36 (s, 3H), 7.11-7.23 (m, 1H), 7.47 (d. J=8.61 Hz, 2H), 7.56-7.67 (m, 1H), 7.76 (d, J=3.85 Hz, 1H), 7.95 (dd, J=7.69 Hz, 1.46 Hz, 1H), 7.97-8.02 (m, 2H), 8.29-8.36 (m, 1H), 11.36 (s, 1H); ESIMS (M+H)+=443.06.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:21][C:22]([F:26])([F:25])[CH2:23][NH2:24]>C(Cl)Cl>[F:21][C:22]([F:26])([F:25])[CH2:23][NH:24][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: NCC(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC(F)(F)F)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.7 %

Procedure:
5.0 g (24 mmol) of 4-trifluoromethylbenzoyl chloride and 5.0 ml (36 mmol) of triethylamine were dissolved in 50 ml of CH2Cl2 and 2.4 g (24 mmol) of 2,2,2-trifluoroethylamine were slowly added dropwise at RT. The mixture was stirred at RT for 4 h, then the volatile constituents were removed under reduced pressure. The residue was taken up using 100 ml of MTB and washed initially with 30 ml of a saturated aqueous Na2CO3 solution and then with 30 ml of a saturated aqueous NaHSO4 solution. Drying was effected over MgSO4 and 6.1 g (94%) of a colorless resin were obtained which crystallized when left to stand; mp: 117° C.
Reaction SMILES: Cl[Si](C)(C)C.[NH2:6][C@@H:7]([CH2:11][CH2:12][CH2:13][CH:14]1[O:18][CH2:17][CH2:16][O:15]1)[C:8]([OH:10])=[O:9].S(OC)(O[CH3:22])=O.C[O-].[K+]>CO.C(OCC)(=O)C>[NH2:6][C@@H:7]([CH2:11][CH2:12][CH2:13][CH:14]([O:18][CH3:17])[O:15][CH3:16])[C:8]([O:10][CH3:22])=[O:9]
Reactant: N[C@@H](CCCC1OCCO1)C(=O)O
Reactant: COS(=O)OC
Agent: C[O-]
Agent: C[Si](C)(C)Cl
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](N)CCCC(OC)OC
Temperature: 42.5 °C
Reaction time: 72 h
Yield: 77.8 %

Procedure:
Under nitrogen, chlorotrimethyl silane (28.0 g) was added to a slurry of (S)-α-amino-1,3-dioxolane-2-pentanoic acid (20.9 g) and dimethyl sulfite (12.0 g) in methanol (240 ml) to afford a homogeneous solution. Following the observation of an exotherm to 29° C. , the solution was heated to 40-45° C. , stirred at that temperature for 8 hours and at about 22° C. for up to 72 hours. In-process HPLC analysis showed that the reaction was complete (about 93 M% conversion to product) and the resulting solution was cooled to −5 to −10° C. With stirring, the apparent pH of the mixture was adjusted to 11.7 to 11.9 by the slow careful addition of 32% (or 4.45 M) methanolic potassium methoxide solution (70 ml) maintaining the temperature in the range of −5 to 0° C. Analysis of the product slurry (1H-NMR) indicated that the neutralizaiton was complete. The solvent of the product slurry was exchanged with ethyl acetate by first concentrating the thin slurry under vacuum at less than 30° C. to 300 ml volume followed by the addition of ethyl acetate until the removal of methanol was completed as judged by in-process GC analysis (less than 1 AP). Upon completion of the solvent exchange, the batch volume was adjusted to about 400 ml with ethyl acetate and the resulting slurry was filtered. Poly(acrylic acid co-acrylamide), potassium salt (3.0 to 3.2 g) and water (30-32 ml) were added to the filtrate. The mixture was stirred for about 35 minutes and filtered, optionally, the poly (acrylic acid co-acrylamide), potassium salt treatment can be repeated on the filtrate if the quantity of ethylene glycol exceeds 0.15 equivalents, as judged by in-process GC analysis. Following in-process HPLC analysis, 17.4 g of the title product was obtained as an ethyl acetate solution in 80.8 M% yield.