Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH3:17])[CH2:11][CH2:10]2)[CH:5]=[CH:4][C:3]=1[OH:18].C(OCC)C.[F:24][C:25]1[C:33]([F:34])=[C:32]([O:35][CH2:36][CH3:37])[CH:31]=[CH:30][C:26]=1[C:27](O)=[O:28]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:36]([O:35][C:32]1[CH:31]=[CH:30][C:26]([C:27]([O:18][C:3]2[CH:4]=[CH:5][C:6]([C@H:9]3[CH2:10][CH2:11][C@H:12]([CH2:15][CH2:16][CH3:17])[CH2:13][CH2:14]3)=[C:7]([F:8])[C:2]=2[F:1])=[O:28])=[C:25]([F:24])[C:33]=1[F:34])[CH3:37]
Reactant: CCOc1ccc(C(=O)O)c(F)c1F
Reactant: CCC[C@H]1CC[C@H](c2ccc(O)c(F)c2F)CC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCC[C@H]1CC[C@H](c2ccc(OC(=O)c3ccc(OCC)c(F)c3F)c(F)c2F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 500 mL three-neck flask, 3.20 g of 2,3-difluoro-4-ethoxybenzoic acid (a) and 3.84 g of 2,3-difluoro-4-(trans-4-propylcyclohexyl)phenol (1) were dissolved in 230 mL of methylene chloride. 0.70 g of 4-dimethylaminopyridine was added thereto and stirred at room temperature for 1 hour. A solution in which 3.54 g of N,N-dicyclohexylcarbodiimide was dissolved in 90 mL of methylene chloride was added thereto and stirred overnight. Diethyl ether was added and urea precipitated was filtered off. Saturated aqueous solution of sodium chloride was added and stirred for 1 hour. After organic layer was separated, the organic layer was washed with 3N hydrochloric acid and saturated aqueous solution of sodium bicarbonate, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 6.60 g of 2,3-difluoro-4-(trans-4-propylcyclohexyl)phenyl 4-ethoxy-2,3-difluorobenzoate (m).
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:13]([CH3:17])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[ClH:24]>>[ClH:24].[CH3:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:9][NH:8][CH2:16]2
Reactant: Cc1cc2c(cc1N1CCOCC1)CN(C(=O)OC(C)(C)C)C2
Agent: Cl
Product: Cc1cc2c(cc1N1CCOCC1)CNC2

Procedure:
Prepared in analogy to Example A3(e) from 5-methyl-6-morpholin-4-yl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and hydrochloric acid. Brown solid. MS (m/e): 219.3 ([M+H]+, 100%).
Reaction SMILES: [C:1]([CH:4]([N:6]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]([NH:13][CH:14]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]1=[O:28])[CH3:5])([OH:3])=[O:2].Cl.[CH2:30](O)[CH3:31]>>[CH2:30]([O:2][C:1]([CH:4]([N:6]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]([NH:13][CH:14]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]1=[O:28])[CH3:5])=[O:3])[CH3:31]
Reactant: CCOC(=O)C(CCc1ccccc1)N[C@H]1CCCCN(C(C)C(=O)O)C1=O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C(CCc1ccccc1)N[C@H]1CCCCN(C(C)C(=O)OCC)C1=O
Reaction time: 8 h

Procedure:
A solution of 1-(1-carboxyethyl)-3-(S)-[(1-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazepin-2-one (2.94 g.), a diastereoisomeric mixture prepared as in Example 13 from Isomer A of Example 12, with 40 ml. of ethanol was cooled to 0° and saturated with hydrogen chloride. After standing overnight at room temperature the solution was concentrated under vacuum. Dissolution in water, adjustment to pH 7, extraction with ether and concentration gave product as a colorless oil, weight 2.87 g. Tlc on silica gel indicated the presence of two diastereomers. If desired, the isomers may be separated by chromatography on silica gel and elution with hexane-ethyl acetate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26].Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[OH:26][CH2:25][C:24]([NH:23][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1)([CH3:28])[CH3:27]
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(Br)c1
Reactant: CC(C)(N)CO
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: CC(C)(CO)Nc1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Temperature: 120 °C
Reaction time: 16 h
Yield: 2.2 %

Procedure:
A mixture of 2-(3-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (360 mg, 1 mmol), 2-amino-2-methyl-propan-1-ol (0.48 mL, 5 mmol), copper(I) iodide (115 mg, 0.6 mmol), N,N-dimethylglycine hydrochloride (112 g, 0.8 mmol) and potassium carbonate (415 mg, 3 mmol) in dimethyl sulfoxide (5 mL) was stirred at 120° C. for 16 h. Then the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2×150 mL), washed with water (2×50 mL) and saturated aqueous ammonium chloride solution (2×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-[3-(2-hydroxy-1,1-dimethyl-ethylamino)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (8 mg, 2%) as a white powder: LC/MS m/e calcd for C22H28N2O3 (M+H)+: 369.48, observed: 369.1.
Reaction SMILES: Br[C:2]1[C:3]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:35])[C@H:18]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH2:13][CH2:12]2)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[C:36]1(B(O)O)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][C@@H:18]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[C:17](=[O:35])[N:14]2[CH2:15][CH2:16][N:11]([C:3]3[C:2]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:7][N:6]=[C:5]4[NH:8][CH:9]=[CH:10][C:4]=34)[CH2:12][CH2:13]2)=[CH:25][CH:24]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2c(Br)cnc3[nH]ccc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]ccc23)CC1
Temperature: 80 °C
Yield: 10 %

Procedure:
(R)-tert-Butyl 1-(4-(5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-3-(4-chlorophenyl)-1-oxopropan-2-ylcarbamate (0.180 g, 0.320 mmol, see Example 1), phenylboronic acid (0.0468 g, 0.384 mmol), Pd(PPh3)4 (0.0185 g, 0.0160 mmol) and 10% K2CO3 (aq., 0.66 mL, 0.47 mmol) were added to an Ar degassed solution of 2:1 toluene:EtOH (3 mL). The reaction was then heated to 80° C. overnight. The reaction was then cooled to room temperature, diluted with water, and extracted with DCM. The organic fractions were dried, filtered, concentrated, and purified (500:10-500:15) to give (R)-tert-butyl 3-(4-chlorophenyl)-1-oxo-1-(4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)propan-2-ylcarbamate (0.018 g, 10.0% yield).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:25]([O:29][C:30]([C@@:32]1([CH2:47]CO)[CH:36]([F:37])[C:35](=[O:38])[N:34]([C@@H:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH3:40])[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>ClCCl>[C:25]([O:29][C:30]([C@@:32]1([CH2:47][CH2:1][Br:5])[CH:36]([F:37])[C:35](=[O:38])[N:34]([C@@H:39]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH3:40])[CH2:33]1)=[O:31])([CH3:26])([CH3:27])[CH3:28]
Reactant: BrC(Br)(Br)Br
Reactant: C[C@H](c1ccccc1)N1C[C@@](CCO)(C(=O)OC(C)(C)C)C(F)C1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@H](c1ccccc1)N1C[C@@](CCBr)(C(=O)OC(C)(C)C)C(F)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 110.5 %

Procedure:
Carbon tetrabromide (1.88 g, 5.68 mmol) and triphenylphosphine (1.49 g, 5.68 mmol) were sequentially added to a solution of (3S)-4-fluoro-3-(2-hydroxyethyl)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (1.66 g, 4.74 mmol) in dichloromethane (20 mL) in a nitrogen atmosphere at 0° C. After heating to room temperature, the reaction solution was stirred for one hour and concentrated to about 5 mL. The residue was purified by silica gel column chromatography (dichloromethane→hexane:ethyl acetate=2:1) to give 2.17 g (91%) of the title compound as a white solid.
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[CH3:12][C:13]([CH3:29])([C:26](=[O:28])[CH3:27])[CH2:14]OS(C1C=CC(C)=CC=1)(=O)=O.O>CO>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]([CH3:29])([CH3:14])[C:26](=[O:28])[CH3:27])=[CH:7][CH:6]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(=O)C(C)(C)COS(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=O)C(C)(C)COc1ccc(Cl)cc1
Yield: 55.5 %

Procedure:
29.7 g (0.55 mole) of sodium methylate were dissolved in 500 ml of methanol, and 70.4 g (0.55 mol) of 4-chlorophenol were added, while stirring. After stirring the mixture for 10 minutes, the solvent was distilled off under reduced pressure and the residue was taken up in 100 ml of glycol. This solution was added to a solution of 135 g (0.5 mole) of 2,2-dimethyl-1-tosyloxy-butan-3-one in 200 ml of glycol. The reaction mixture was stirred at 100° to 120° C. for 48 hours, cooled and stirred into 2,000 ml of water. The mixture was extracted twice with 250 ml of diethyl ether each time and the combined organic phases were washed three times with 100 ml of water each time, once with 100 ml of 10% strength sodium hydroxide solution and once more with 100 ml of water, dried over sodium sulphate and distilled, 62.9 g (55.7% of theory) of 1-(4-chlorophenoxy)-2,2-dimethyl-butan-3-one of boiling point 135°-140° C./0.4 mm Hg were obtained.
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH3:31])[CH2:14][C:15]2[S:19][C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[N:17][C:16]=2[CH3:30])=[CH:9][C:8]=1[CH2:32][CH2:33][CH2:34][O:35][CH3:36])C.[OH-].[Na+]>C1COCC1.CCO>[CH3:36][O:35][CH2:34][CH2:33][CH2:32][C:8]1[CH:9]=[C:10]([N:13]([CH3:31])[CH2:14][C:15]2[S:19][C:18]([C:20]3[CH:21]=[CH:22][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:24][CH:25]=3)=[N:17][C:16]=2[CH3:30])[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:37])=[O:3]
Reactant: CCOC(=O)COc1ccc(N(C)Cc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1CCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COCCCc1cc(N(C)Cc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1OCC(=O)O
Reaction time: 0.5 h

Procedure:
0.280 g (0.52 mmol) of the above prepared (2-(3-methoxy-propyl)-4-{methyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-phenoxy)-acetic acid ethyl ester was dissolved in 3.3 ml of THF/EtOH=1/1, treated with 1.56 ml (3 eq.) of 1N NaOH, and kept at ambient temperature for 0.5 h. The reaction mixture was then poured onto crashed ice/HCl dil., extracted twice with EtOAc, the organic layer washed with water and brine, dried over sodium sulfate, and evaporated to dryness. Crystallization from hexane/EtOAc afforded finally 0.209 g of the title compound as off-white crystals of mp. 142-143° C., MS: 507.5 (M-H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:58]=[C:57]([O:59][CH3:60])[CH:56]=[CH:55][C:4]=1[CH2:5][N:6]([CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[N:28](S(C3C=CC(C)=CC=3)(=O)=O)[C:29]([C:31]3[C:39]4[C:34](=[CH:35][C:36]([O:42][CH3:43])=[C:37]([O:40][CH3:41])[CH:38]=4)[N:33]([CH3:44])[CH:32]=3)=[CH:30][C:23]=12)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)(=[O:9])=[O:8].[OH-].[K+]>>[CH3:1][O:2][C:3]1[CH:58]=[C:57]([O:59][CH3:60])[CH:56]=[CH:55][C:4]=1[CH2:5][N:6]([CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][C:29]([C:31]3[C:39]4[C:34](=[CH:35][C:36]([O:42][CH3:43])=[C:37]([O:40][CH3:41])[CH:38]=4)[N:33]([CH3:44])[CH:32]=3)=[CH:30][C:23]=12)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:18])[F:19])=[CH:12][CH:11]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(Cc2ccnc3c2cc(-c2cn(C)c4cc(OC)c(OC)cc24)n3S(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(OC(F)(F)F)cc2)c(OC)c1
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(CN(Cc2ccnc3[nH]c(-c4cn(C)c5cc(OC)c(OC)cc45)cc23)S(=O)(=O)c2ccc(OC(F)(F)F)cc2)c(OC)c1
Yield: 52.2 %

Procedure:
N-(2,4-Dimethoxybenzyl)-N-[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]-4-trifluoromethoxybenzenesulfonamide is prepared as described in Example 179a starting with 0.070 g of N-(2,4-dimethoxybenzyl)-N-[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]-4-trifluoromethoxybenzenesulfonamide instead of the [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl](4-trifluoromethylsulfanylbenzyl)amine used in Example 179a and 0.40 cm3 of 5N potassium hydroxide. 0.030 g of N-(2,4-dimethoxybenzyl)-N-[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]-4-trifluoromethoxybenzenesulfonamide is obtained, the characteristics of which are as follows:
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:24])=[C:8]2[CH:14]=[CH:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[C:9]2=[CH:10][N:11]=1)=[O:5])C.[NH2:25][CH2:26][C:27]([OH:29])=[O:28].C[O-].[Na+].CO>>[OH:24][C:7]1[C:6]([C:4]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:5])=[N:11][CH:10]=[C:9]2[N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH:13]=[CH:14][C:8]=12
Reactant: CCOC(=O)c1ncc2c(ccn2Cc2ccccc2OC)c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1Cn1ccc2c(O)c(C(=O)NCC(=O)O)ncc21

Procedure:
Prepared in analogy to that of Example 1(e) from 1-(2-methoxy-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 356 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([C:8]1[CH:9]=[C:10]([N+:14]([O-])=O)[CH:11]=[CH:12][CH:13]=1)[CH2:5][CH2:6][Cl:7].O.O.[Sn](Cl)Cl.N>Cl.O>[ClH:1].[Cl:1][CH2:2][CH2:3][N:4]([CH2:5][CH2:6][Cl:7])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=1
Reactant: O=[N+]([O-])c1cccc(N(CCCl)CCCl)c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: N
Solvent: O
Product: Nc1cccc(N(CCCl)CCCl)c1
Temperature: 25 °C
Yield: 192.1 %

Procedure:
3-[N,N-Bis(2-chloroethyl)amino]nitrobenzene (2.0 g; 7.6 mmol) was dissolved in 35 ml of concentrated hydrochloric acid, followed by the addition of 6.9 g (30.6 mmol; 4.0 equivalents) of tin(II) chloride dihydrate. The resultant mixture was stirred under heating for 1 hour over an oil bath controlled at 100° C. The reaction mixture was allowed to cool down to room temperature and then diluted with water. The resulting mixture was basified with concentrated aqueous ammonia and then extracted twice with ethyl acetate. The extracts were combined, dried over sodium sulfate and then concentrated under reduced pressure. The residue was added with 4N hydrochloric acid/dioxane, followed by concentration. The residue was crystallized from a mixed solvent of a small amount of methanol and ethyl ether, whereby 1.97 g (7.3 mmol) of the title compound were obtained as yellow crystals (yield: 96.1%).
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]1([CH3:13])[CH3:12].[CH3:14][O:15][C:16](=[O:19])[CH2:17]Br>C(OCC)C>[CH3:14][O:15][C:16](=[O:19])[CH2:17][NH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]1([CH3:13])[CH3:12]
Reactant: CC1(C)CCc2ccccc2C1N
Reactant: COC(=O)CBr
Solvent: CCOCC
Product: COC(=O)CNC1c2ccccc2CCC1(C)C
Temperature: 25 °C
Reaction time: 70 h

Procedure:
65.2 g of 1-amino-2,2-dimethyl-1,2,3,4-tetrahydronaphthalene are solved in 250 ml of diethyl ether. To this solution is dropwise added a solution of 28.5 g of bromoacetic acid methyl ester in 150 ml of diethyl ether. The mixture is stirred at room temperature for 70 hours. The precipitate is separated and the solution is concentrated to dryness, yielding N-(2,2-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl) glycine methyl ester quantitatively.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH:7]=[CH:8][N+:9]([O-])=O)=[CH:5][CH:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C(OCC)C>[CH3:1][C:2]1[S:3][C:4]([CH2:7][CH2:8][NH2:9])=[CH:5][CH:6]=1
Reactant: Cc1ccc(C=C[N+](=O)[O-])s1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: Cc1ccc(CCN)s1
Reaction time: 8 h
Yield: 20.3 %

Procedure:
Add 2-methyl-5-(2-nitrovinyl)thiophene (483 mg crude, 2.855 mmol, 1 eq) as a solution in diethyl ether (15 mL) to a solution of lithium aluminum hydride (227 mg, 5.995 mmol, 2.1 eq) in diethyl ether (5.995 mL) at a rate such as to maintain gentle reflux of the solution. Stir reaction for 5 minutes. Cautiously add water followed by several small portions of potassium sodium tartrate. Stir reaction vigorously for 1 hour and then let stand overnight. Separate organics, dry with magnesium sulfate, and concentrate on rotovap to give 360 mg of crude product as an oil. Perform column chromatography to give 82 mg (20% yield) of 2-(5-methylthiophen-2-yl)ethylamine. MS (m/e): 142.0 (MH+).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[N:9]=[C:8]([NH2:10])[CH:7]=[C:6]([Cl:11])[N:5]=1.Cl[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]([N+:22]([O-:24])=[O:23])=[CH:15][C:14]=1[C:25]([F:28])([F:27])[F:26].Cl>O1CCCC1>[N+:22]([C:16]1[CH:17]=[C:18]([N+:19]([O-:21])=[O:20])[CH:13]=[C:14]([C:25]([F:26])([F:27])[F:28])[C:15]=1[N:5]1[C:6]([Cl:11])=[CH:7][C:8]([NH2:10])=[N:9][CH:4]1[Cl:3])([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Reactant: Nc1cc(Cl)nc(Cl)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC1=NC(Cl)N(c2c([N+](=O)[O-])cc([N+](=O)[O-])cc2C(F)(F)F)C(Cl)=C1
Temperature: 0 °C

Procedure:
7.24 parts of 85% powdered potassium hydroxide are added to a solution of 8.2 parts of 2,6-dichloro-4-aminopyrimidine in 200 ml of absolute tetrahydrofuran. The mixture is cooled to 0° C. and then 13.5 parts of 2-chloro-3,5-dinitrobenzotrifluoride in 100 ml of absolute tetrahydrofuran are added in portions, with stirring, over half an hour. During this addition, the colour of the reaction solution turns from yellow to red. The reaction mixture is stirred for 12 hours and then poured into 500 ml of ice-water, acidified with 8 ml of hydrochloric acid, and extracted with two 200 ml portions of ethyl acetate. The combined extracts are washed with 50 ml of water, dried over sodium sulfate, filtered and concentrated. The crude product is crystallised from methanol. Melting point: 198°-200° C.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Br[CH2:30][C:31]([C:33]1[CH:43]=[CH:42][C:36]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])=[CH:35][CH:34]=1)=[O:32]>CC(C)=O>[O:32]=[C:31]([C:33]1[CH:43]=[CH:42][C:36]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])=[CH:35][CH:34]=1)[CH2:30][N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1
Reactant: c1ccc(CNCC2CCc3ccccc3C2)cc1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)CBr)cc1
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Nc1ccc(C(=O)CN(Cc2ccccc2)CC2CCc3ccccc3C2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-Benzylaminomethyl-1,2,3,4-tetrahydronaphthalene (XXXIV) (2.8 g), N,N-diisopropyl-N-ethylamine (1.44 g) and 4'-(2-bromoacetyl)methanesulfonanilide (Temple, D. L. et al., J. Med. Chem., 19(5), 626-633 (1976)) (3.27 g) were dissolved in acetone (40 ml) and stirred 18 hours at ambient temperature. The solvent was evaporated and the residue was dissolved in CH2Cl2, which was washed with H2O, dried (MgSO4) and evaporated. The HCl salt was made by dissolving the residue in MeOH/concentrated HCl, concentrating, and triturating the residue with 2-PrOH and ether. The solid product, 4'-[1-oxo-2-(N-benzyl-N-((1,2,3,4-tetrahydro-2-naphthyl)methyl)-amino)ethyl]methanesulfonanilide.HCl (XXXIII.HCl), 3 g, had NMR and mass spectra consistent with the structure indicated. It was used without further purification.
Reaction SMILES: C1([O:7][C:8](=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[CH:28][C:27]=3[F:48])[CH:22]=[CH:21][N:20]=2)C(OC2C=CC=CC=2)=O)C=CC=CC=1.Cl.Cl.[CH3:52][N:53]([CH3:60])[CH:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1.C(N(CC)CC)C>CN(C)C=O>[CH3:52][N:53]([CH3:60])[CH:54]1[CH2:59][CH2:58][N:57]([C:8]([NH:9][C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38]([NH:39][C:40]5[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=5)=[O:47])[CH2:37][CH2:36]4)=[O:34])=[CH:28][C:27]=3[F:48])[CH:22]=[CH:21][N:20]=2)=[O:7])[CH2:56][CH2:55]1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Reactant: CN(C)C1CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)C1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccn2)CC1
Reaction time: 8 h
Yield: 90.7 %

Procedure:
To a solution of [4-(2-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (66 mg) in N,N-dimethylformamide (1.0 ml) were added 4-dimethylaminopiperidine dihydrochloride (80.5 mg) and triethylamine (0.112 ml) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=98:2). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:3 to the resultant residue. The solvent was removed under reduced pressure. The solid residue was dried under reduced pressure to provide the titled compound as white powder (52.1 mg, 90%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:23])[C:9]([C:15]2[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:24])[CH:3]=1.[F:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:31]=1[C:32]([O:34][CH3:35])=[O:33]>>[CH3:35][O:34][C:32]([C:31]1[CH:30]=[CH:29][C:28]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:23])[C:9]([OH:14])([C:15]3[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:24])[CH:3]=2)=[CH:27][C:26]=1[F:25])=[O:33]
Reactant: COc1ccc(C(O)(C(C)c2ccc(Br)cc2Cl)C(F)(F)F)cn1
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Product: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3ccc(OC)nc3)C(F)(F)F)c(Cl)c2)cc1F

Procedure:
In analogy to Example 150, step 2, 3-(4-bromo-2-chloro-phenyl)-1,1,1-trifluoro-2-(6-methoxy-pyridin-3-yl)-butan-2-ol (Example 175, step 3) was reacted with 3-fluoro-4-methoxycarbonylphenylboronic acid to give the title compound as a colorless foam. MS (m/e)=498.2 [M+H+].
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1)(C)C.C([O-])([O-])=O.[K+].[K+]>CCO>[CH2:14]([O:13][C:11](=[O:12])[C:10]1[CH:16]=[CH:17][C:7]([C:6]#[CH:5])=[CH:8][CH:9]=1)[CH3:15]
Reactant: CCOC(=O)c1ccc(C#C[Si](C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C#Cc1ccc(C(=O)OCC)cc1
Reaction time: 16 h

Procedure:
Silylacetylene 29-1 (9.40 g, 38 mmol) was dissolved in 100 mL EtOH, K2CO3 (0.25 g 1.8 mmol) was added and the mixture was stirred for 16 h, concentrated, and purified by flash chromatography (silica, 5% Et2 O/hexane) provided 29-2 as a yellow oil.