Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([OH:15])([C:11]([NH:13][NH2:14])=[O:12])[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][C:17]([CH3:19])=O>>[CH3:16][C:17](=[N:14][NH:13][C:11](=[O:12])[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([OH:15])[C:8]([NH2:10])=[O:9])[CH3:19]
Reactant: CC(C)=O
Reactant: NNC(=O)C(O)(C(N)=O)c1ccccc1
Product: CC(C)=NNC(=O)C(O)(C(N)=O)c1ccccc1

Procedure:
20 g of phenylhydroxymalonic acid amide hydrazide in 100 ml of acetone were heated under reflux for 3 hours. The crystals were filtered off under suction and recrystallized from ethanol. 15 g of phenylhydroxymalonic acid amide (2-propylidene)-hydrazide (m.p. 199°-201° C.) were obtained.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:40]([NH2:42])=[O:41])[CH:24]=[C:25](C4C=CC=C(C5CNCCN5)C=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].Cl[C:44]1[CH:45]=[C:46]([CH:50]2CNC[CH2:52][NH:51]2)[CH:47]=[CH:48][CH:49]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:40]([NH2:42])=[O:41])[CH:24]=[C:25]([C:45]4[CH:44]=[CH:49][CH:48]=[CH:47][C:46]=4[CH2:50][NH:51][CH3:52])[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:11])=[O:12])[CH3:9]
Reactant: Clc1cccc(C2CNCCN2)c1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C5CNCCN5)c4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccccc4CNC)cc23)CC1
Yield: 19.8 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(2-piperazinyl)phenyl]-1H-indole-7-carboxamide trifluoroacetate, substituting 1-(2-bromophenyl)-N-methylmethanamine (65 mg, 0.325 mmol) for 2-(3-chlorophenyl)piperazine to afford 14.6 mg of the title compound (19.8%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][N:14]1[CH2:20][C@H:19]3[C@H:16]([CH2:17][C@H:18]3O)[CH2:15]1)=[N:9][C:8]([O:22][CH3:23])=[CH:7][CH:6]=2.CCOC(/N=N/C(OCC)=O)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:55]1(=[O:65])[NH:59][C:58](=[O:60])[C:57]2=[CH:61][CH:62]=[CH:63][CH:64]=[C:56]12>C1COCC1.C1COCC1.O1CCOCC1>[F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][N:14]1[CH2:20][C@H:19]3[C@H:16]([CH2:17][C@@H:18]3[N:59]3[C:55](=[O:65])[C:56]4[C:57](=[CH:61][CH:62]=[CH:63][CH:64]=4)[C:58]3=[O:60])[CH2:15]1)=[N:9][C:8]([O:22][CH3:23])=[CH:7][CH:6]=2
Reactant: COc1ccc2ncc(F)c(CCN3C[C@H]4C[C@@H](O)[C@H]4C3)c2n1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COc1ccc2ncc(F)c(CCN3C[C@H]4C[C@H](N5C(=O)c6ccccc6C5=O)[C@H]4C3)c2n1
Reaction time: 12 h
Yield: 42 %

Procedure:
To a solution of (±)-(1S,5R,6R)-3-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-azabicyclo[3.2.0]heptan-6-ol (230 mg, 0.73 mmol) in THF (2 mL) as added DEAD (0.11 mL, 0.76 mmol), followed by dropwise addition of a preformed solution of PPh3 (190 mg, 0.72 mmol) and phthalimide-(107 mg, 0.73 mmol) in THF-dioxane (4 mL, 1:1). The resulting solution was heated at reflux. After 12 h, the solution was concentrated and the residue purified via a column chromatography (silica, 1% MeOH in DCM (1% NH4OH)) yielding the title compound (137 mg, 42%) as a yellow oil: LC/MS (ES) m/e 448 (M+H)+.
Reaction SMILES: [CH:1](=[C:8]([CH2:12][OH:13])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N.O.[H][H]>CO.[C].[Pd]>[OH:13][CH2:12][CH:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]([OH:11])=[O:10]
Reactant: [H][H]
Reactant: O=C(O)C(=Cc1ccccc1)CO
Agent: [Pd]
Agent: N
Solvent: O
Solvent: CO
Product: O=C(O)C(CO)Cc1ccccc1
Yield: 93 %

Procedure:
2-Benzylidene-3-hydroxypropionic acid (490.4 mg, 2.752 mmols) was dissolved in 7 ml of methanol, and 0.5 ml of 28% aqueous ammonia and 2 ml of water were added thereto. Then, 38 mg (water content 52.7%) of 5% palladium-carbon were added thereto, and catalytic reduction was conducted in a hydrogen atmosphere for 160 minutes. After the completion of the reaction, the reaction solution was filtered with Celite to remove the palladium-carbon. The resulting filtrate was subjected to the HPLC analysis. As a result, the filtrate contained 461 mg (2.558 mmols) of the above title compound (yield 93.0%).
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:29][O:30][C:31]1[N:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>O1CCOCC1.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>[CH:14]([N:12]([CH3:13])[C:11]1[C:2]([C:34]2[CH:35]=[N:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=2)=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:6][CH:5]=2)([CH3:16])[CH3:15]
Reactant: COc1ccc(B(O)O)cn1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccc(OC)nc3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
To a solution of methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (Scheme I, 120 mg, 0.41 mmol) in dioxane (3 mL) was added K3PO4 (257 mg, 1.22 mmol), 6-methoxypyridin-3-ylboronic acid (187 mg, 1.22 mmol) and Pd(PPh3)4 (23.54 mg, 0.02 mmol) with stirring for 1 h at 90° C. in an oil bath with an inert atmosphere of nitrogen. The reaction mixture was concentrated under vacuum to get a residue, which was purified by a silica gel column with 1%-2% ethyl acetate in petroleum ether to afford methyl 3-(isopropyl(methyl)amino)-2-(6-methoxypyridin-3-yl)quinoxaline-6-carboxylate as a light yellow solid (120 mg, 80%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([F:21])=[C:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[N:14]=2)[C:9](=[O:22])[C:8]([C:23]([O:25]CC)=[O:24])=[CH:7]1.[Li+].[OH-]>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([F:21])=[C:13]([N:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)[N:14]=2)[C:9](=[O:22])[C:8]([C:23]([OH:25])=[O:24])=[CH:7]1
Reactant: CCOC(=O)c1cn(Cc2ccc(OC)cc2OC)c2nc(N3CCCC3)c(F)cc2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(Cn2cc(C(=O)O)c(=O)c3cc(F)c(N4CCCC4)nc32)c(OC)c1
Reaction time: 1.5 h

Procedure:
A solution of Example 51B (17.9 g) in THF (750 mL) and methanol (70 mL) was treated with 1M LiOH (196 mL), stirred for 1.5 hours, and filtered. The filtrant was dissolved in 2:1 methanol/water (1.5 L), and this solution was treated with 1M HCl and water (500 mL total) and filtered.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[CH:16]=[CH:15][C:9]([O:10][CH2:11][CH:12]3[CH2:14][O:13]3)=[CH:8][CH:7]=2)[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2.[Cl:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][NH2:25]>C(O)C>[S:1]1[CH:5]=[C:4]([C:6]2[CH:16]=[CH:15][C:9]([O:10][CH2:11][C@H:12]([OH:13])[CH2:14][NH:25][CH2:24][C:23]3[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=3[Cl:21])=[CH:8][CH:7]=2)[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2
Reactant: c1ccc2c(-c3ccc(OCC4CO4)cc3)csc2c1
Reactant: NCc1ccccc1Cl
Solvent: CCO
Product: O[C@H](CNCc1ccccc1Cl)COc1ccc(-c2csc3ccccc23)cc1

Procedure:
The title compound is prepared from a mixture of 2-(4-benzo[b]thiophen-3-yl-phenoxymethyl)-oxirane, 2-chlorobenzylamine and ethanol essentially as described above in Example 94. Purity by LC/MS=99%, [M+H]+=424.
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][C:8]([O:9][CH2:10][C@H:11]2[O:15][C:14]([NH2:16])=[N:13][CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:19](OCC)(=[O:22])[C:20]#[CH:21]>C(O)C>[C:1]([C:5]1[CH:18]=[CH:17][C:8]([O:9][CH2:10][C@H:11]2[O:15][C:14]3=[N:16][C:19](=[O:22])[CH:20]=[CH:21][N:13]3[CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(OC[C@@H]2CN=C(N)O2)cc1
Reactant: C#CC(=O)OCC
Solvent: CCO
Product: CC(C)(C)c1ccc(OC[C@@H]2Cn3ccc(=O)nc3O2)cc1
Temperature: 25 °C
Yield: 50.9 %

Procedure:
To a solution of (S)-5-(4-tert-butyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (4.53 g, 18.3 mmol) in ethanol (35 mL) was added ethyl propiolate (2.32 g, 23.7 mmol). The reaction mixture was stirred at reflux for 6 hours. The mixture was stirred at 30° C. for a few minutes and subsequently cooled to room temperature. The resulting crystals were collected and washed twice with hexane. The solid was dried under high vacuum at 65° C. for 18 hours to afford 2.8 g (50%) of (S)-2-(4-tert-butyl-phenoxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one. [α]D25 −54.04 (c 0.503, CHCl3).
Reaction SMILES: [C:1](O)(=O)[CH:2]([CH:4]([C:6](O)=O)[OH:5])[OH:3].[NH2:11][C:12]1[CH:13]=[C:14]([CH3:19])[CH:15]=[CH:16][C:17]=1[NH2:18].Cl.P(=O)(O)(O)O>O.C(O)C>[CH3:19][C:14]1[CH:15]=[CH:16][C:17]2[N:18]=[C:1]([CH:2]([OH:3])[CH:4]([OH:5])[C:6]3[NH:11][C:12]4[CH:13]=[C:14]([CH3:19])[CH:15]=[CH:16][C:17]=4[N:18]=3)[NH:11][C:12]=2[CH:13]=1
Reactant: Cc1ccc(N)c(N)c1
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: Cl
Agent: O=P(O)(O)O
Solvent: O
Solvent: CCO
Product: Cc1ccc2nc(C(O)C(O)c3nc4ccc(C)cc4[nH]3)[nH]c2c1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
A mixture of 15.0 g (0.10 mole) tartaric acid, 29.32 g (0.24 mole) 3,4-diaminotoluene, 25 ml water, 15 ml ethanol, 25 ml hydrochloric acid (conc.) and 10 ml 85% phosphoric acid was heated at 120° C. for 40 hours, poured into water and the mixture acidified with concentrated hydrochloric acid. After extraction with chloroform and making the aqueous phase alkaline with sodium hydroxide, a precipitate formed and was collected by filtration. The solid was washed with a small amount of acetone and held in vacuo for 18 hours. The residual moisture was removed by azeotropic distillation of its mixture with benzene.
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]([CH2:42][CH2:43][CH2:44][NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C:12](=[O:41])[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][C@H:18]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:19][C:20](=[O:32])[NH:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])C1C=CC=CC=1>C(O)(=O)C.O.[Pd]>[C:49]([O:48][C:46](=[O:47])[NH:45][CH2:44][CH2:43][CH2:42][C@H:11]([NH2:10])[C:12](=[O:41])[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][C@H:18]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:19][C:20](=[O:32])[NH:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:30])[CH3:28])([CH3:50])([CH3:51])[CH3:52]
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)NCCCC[C@@H](CC(=O)NCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCC[C@H](N)C(=O)NCCCC[C@@H](CC(=O)NCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reaction time: 15 h

Procedure:
290 mg (0.390 mmol) of benzyl((1S,8S)-8-[(tert-butoxycarbonyl)amino]-1-{3-[(tert-butoxycarbonyl)amino]propyl}-17,17-dimethyl-2,10,15-trioxo-16-oxa-3,11,14-triazaoctadec-1-yl)carbamate (Example 226A) are dissolved in 10 ml of a 4/1 glacial acetic acid/water mixture. 75 mg of palladium on activated carbon (10%) are added thereto, and the mixture is then hydrogenated under atmospheric pressure for 15 h. The reaction mixture is filtered through a Millipore filter and the filtrate is concentrated and dried under high vacuum. The crude product is reacted without further purification.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].P(Cl)(Cl)(Cl)=O.[CH3:17][S:18](C)=O>Cl(O)(=O)(=O)=O>[CH3:17][S:18][C:9]1[CH:10]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[CH:6]=[CH:7][C:8]=1[OH:11]
Reactant: CS(C)=O
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O=P(Cl)(Cl)Cl
Product: CSc1cc(C(C)(C)C)ccc1O
Temperature: 20 °C
Reaction time: 16 h

Procedure:
To a cold (0°-5° C.) suspension of 4-(1,1-dimethylethyl)phenol (7.5 g., 0.05 mole) and phosphorous oxychloride (8 ml.) in 70% perchloric acid (10 ml.) is added dimethylsulfoxide (3.9 g., 0.05 mole) dropwise with vigorous stirring. The resulting reaction mixture is stirred at 0°-5° C. for 1 hour and at 20° C. for 16 hours and then poured onto crushed ice whereupon a gum separates. Upon warming to 20° C. with vigorous stirring there is obtained a white solid which is collected, washed with cold water, air dried at 20° C. with aspiration and washed with ether. The white solid (10 g., m.p. 160° C.) is added to saturated aqueous potassium chloride (100 ml.) and the resulting mixture, heated at reflux for 4 hours. After standing at 20° C. for 12 hours, the reaction mixture is extracted with ether. The ethereal extract is washed with water and saturated brine, dried over sodium sulfate and filtered. Evaporation of the filtrate in vacuo leaves 2-methylthio-4-(1,1-dimethylethyl)phenol as an analytically pure, colorless oil (5.7 g., 58%).
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:11]=[C:12]([CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=2[OH:22])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH2:27](O)[CH2:28][CH2:29][CH2:30][CH2:31][CH:32](C)[CH3:33].C([Sn](=O)CCCC)CCC>>[N:1]1[N:2]([C:10]2[CH:11]=[C:12]([CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=2[OH:22])[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:16])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC(C)CCCCCO
Reactant: COC(=O)CCc1cc(-n2nc3ccccc3n2)c(O)c(C(C)(C)C)c1
Agent: CCCC[Sn](=O)CCCC
Product: CCCCCCCCOC(=O)CCc1cc(-n2nc3ccccc3n2)c(O)c(C(C)(C)C)c1
Temperature: 175 °C
Reaction time: 0.5 h

Procedure:
Methyl 3-(2H-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyhydrocinnamate (353 g, 1 mol), isooctanol (260 g, 2 mol, from Exxon) and dibutyltin oxide (0.5 g, 0.002 mol) are charged to a reaction flask and heated to 175° C. While heating to 175° C., a 300 mm Hg vacuum is applied. After holding at 175° C. for 30 minutes, the excess isooctanol is distilled by slowly reducing the pressure to <5 mm Hg. The desired product is cooled and discharged. The title compound is obtained in a yield of 451 g (100%) as a light yellow oil whose structure is verified by 1Hnmr and mass spectroscopy. The non-distilled product is analyzed by ICP (Inductively Coupled Plasma) for tin and is found to contain 170 ppm of tin.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:10]=[C:11]([OH:18])[CH:12]=[CH:13][C:14]=2[N+:15]([O-:17])=[O:16])=[CH:4][CH:3]=1.[CH3:19][O:20][C:21](=[O:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br>>[CH3:19][O:20][C:21](=[O:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:18][C:11]1[CH:12]=[CH:13][C:14]([N+:15]([O-:17])=[O:16])=[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[CH:10]=1
Reactant: COC(=O)CCCCCBr
Reactant: Cc1ccc(Nc2cc(O)ccc2[N+](=O)[O-])cc1
Product: COC(=O)CCCCCOc1ccc([N+](=O)[O-])c(Nc2ccc(C)cc2)c1

Procedure:
990 mg of 3-(4-methylphenyl)amino-4-nitrophenol was reacted with 6-bromohexanoic acid methyl ester according to general operating instructions 2. 1.5 g was obtained.
Reaction SMILES: C(O[C:4]([C:6]1[S:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2[N:14]=1)=[O:5])C.[CH:15]([O:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22])([CH3:17])[CH3:16].C[Al](C)C.CCCCCC>ClCCl>[CH:15]([O:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH:22][C:4]([C:6]1[S:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2[N:14]=1)=[O:5])([CH3:17])[CH3:16]
Reactant: CC(C)Oc1ccccc1CN
Reactant: CCOC(=O)c1nc2ccncc2s1
Agent: C[Al](C)C
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)Oc1ccccc1CNC(=O)c1nc2ccncc2s1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of thiazolo [5,4-c]pyridine-2-carboxylic acid ethyl ester (34 mg, 0.16 mmol) and 2-isopropoxy benzyl amine (67 mg, 0.41 mmol)in dichloromethane(1.7 mL) was added a solution of trimethylaluminum in hexane(0.203 mL, 2.0 M., 0.41 mmol). The solution was then stirred for 5 hours at room temperature. After usual work-up, the product was purified by flash chromatography (CH2Cl2/EtOAc 2:1) to give 30 mg of the thiazolo derivative.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[CH3:12][NH:13][C:14]1[CH:19]=[CH:18][C:17](B2OC(C)(C)C(C)(C)O2)=[CH:16][CH:15]=1>>[CH3:12][NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][CH:6]=[CH:5]3)=[CH:16][CH:15]=1
Reactant: CNc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Brc1ccc2ncccc2c1
Product: CNc1ccc(-c2ccc3ncccc3c2)cc1

Procedure:
N-Methyl-4-(quinolin-6-yl)aniline T514 was prepared using general procedure A from 6-bromoquinoline (41 mg, 0.2 mmol) and N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (46 mg, 0.2 mmol). The product T514 was obtained as a black solid (20 mg, 43%). 1H NMR (400 MHz, CDCl3): δ 8.86 (dd, J=4.4, 1.6 Hz, 1H), 8.18 9m, 1H), 8.13 (d, J=9.2 Hz, 1H), 7.96 (dd, J=8.8, 2.4 Hz, 1H), 7.92 (d, J=2.0 Hz, 1H), 7.59 (m, 2H), 7.40 (dd, J=8.4, 4.4 Hz, 1H), 6.74 (m, 2H), 2.91 (s, 3H); MS (ESI): 235 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Br)=[C:6]([O:12][CH3:13])[CH:5]=1.[N-:15]=[N+:16]=[N-:17].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:15]=[N+:16]=[N-:17])=[C:6]([O:12][CH3:13])[CH:5]=1
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN=[N+]=[N-])c(OC)c1
Yield: 96.8 %

Procedure:
A solution of 4-(bromomethyl)-3-methoxybenzoic acid methyl ester (8 g; 31 mmol) and NaN3 (2 g; 31 mmol) in DMF (90 mL) was stirred overnight at room temperature. The volatiles were removed under vacuum and the crude product was dissolved in EtOAc (50 mL). The solution was washed with water (2×50 mL) and dried. The volatiles were evaporated to provide 4-(azidomethyl)-3-methoxybenzoic acid methyl ester (6.68 g; 30 mmol). Yield 97%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[C@:9]([CH3:27])([C:23]([F:26])([F:25])[F:24])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[C:29]([C:31]1[CH:32]=[C:33]([CH3:40])[C:34]([C:37](O)=[O:38])=[N:35][CH:36]=1)#[N:30].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[C@:9]([CH3:27])([C:23]([F:26])([F:25])[F:24])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:37]([C:34]3[C:33]([CH3:40])=[CH:32][C:31]([C:29]#[N:30])=[CH:36][N:35]=3)=[O:38])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)ccc2F)CO[C@@]1(C)C(F)(F)F
Reactant: Cc1cc(C#N)cnc1C(=O)O
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1cc(C#N)cnc1C(=O)Nc1ccc(F)c([C@]2(C)CO[C@@](C)(C(F)(F)F)C(NC(=O)OC(C)(C)C)=N2)c1

Procedure:
To a solution of [(2R,5R)-5-(5-amino-2-fluoro-phenyl)-2,5-dimethyl-2-trifluoromethyl-5,6-di-hydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (2.2 g, 5.43 mmol) in DMF (20 ml) was added at 0-5° C. 5-cyano-3-methyl-pyridine-2-carboxylic acid (0.968 g, 5.97 mmol), EDC (1.095 g, 7.05 mmol), HOAt (1.182 g, 8.68 mmol) and the reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was added to cold saturated NaHCO3 solution and the product was extracted with TBME. Combined TBME layers were washed with H2O and brine, dried over MgSO4, filtered and concentrated to obtain after crystallization from diisopropylether the title compound as colorless crystals: UPLC RtH5=1.472 min); ESIMS: 550; [(M+H)+]; 1H NMR (400 MHz, CDCl3): δ 11.11 (s, 1H), 10.11 (s, 1H), 8.79 (br s, 1H), 8.01 (s, 1H), 7.84 (m, 1H), 7.68 (dd, 1H), 7.21 (dd, 1H), 4.49 (d, 1H), 4.16 (d, 1H), 1.76 (s, 3H), 1.64 (s, 3H), 1.62 (s, 9H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[F:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[CH:48][C:47]([S:50]([N:53]([CH2:62][CH2:63][C:64]([O:66][CH3:67])=[O:65])[C:54]3([C:59]([OH:61])=O)[CH2:58][CH2:57][CH2:56][CH2:55]3)(=[O:52])=[O:51])=[CH:46][CH:45]=2)=[CH:40][CH:39]=1.Cl.[CH2:69]([O:76][NH2:77])[C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1>CN(C)C=O>[CH3:67][O:66][C:64](=[O:65])[CH2:63][CH2:62][N:53]([C:54]1([C:59](=[O:61])[NH:77][O:76][CH2:69][C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[CH2:55][CH2:56][CH2:57][CH2:58]1)[S:50]([C:47]1[CH:48]=[CH:49][C:44]([C:41]2[CH:40]=[CH:39][C:38]([F:37])=[CH:43][CH:42]=2)=[CH:45][CH:46]=1)(=[O:51])=[O:52]
Reactant: NOCc1ccccc1
Reactant: COC(=O)CCN(C1(C(=O)O)CCCC1)S(=O)(=O)c1ccc(-c2ccc(F)cc2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CCN(C1(C(=O)NOCc2ccccc2)CCCC1)S(=O)(=O)c1ccc(-c2ccc(F)cc2)cc1
Reaction time: 4 h
Yield: 85.7 %

Procedure:
Diisopropylethylamine (4.3 mL, 24.6 mmole) and (benzotriazol-1-yloxy)tris-(dimethylamino)phosphonium hexafluorophosphate (11.0 grams, 24.9 mmole) were added sequentially to a solution of 1-[(4'-fluorobiphenyl-4-sulfonyl)-(2-methoxycarbonylethyl)-amino]cyclopentane-1-carboxylic acid (10.1 grams, 22.4 mmole) in N,N-dimethylformamide (170 mL). The mixture was stirred for 4 hours. Additional diisopropylethylamine (7.8 mL, 44.6 mmole) and O-benzylhydroxylamine hydrochloride (4.64 grams, 29.1 mmole) were then added and the resulting mixture was stirred at 60° C. for 16 hours. After concentration under vacuum, the residue was taken up in water and acidified with 1 N aqueous hydrogen chloride solution. The mixture was extracted with ethyl acetate and the extract was washed sequentially with water, saturated aqueous sodium bicarbonate solution and brine. The solution was dried over magnesium sulfate and concentrated to give a solid which upon trituration with 7:3:1 hexane/ethyl acetate/methylene chloride provided 3-[(1-benzyloxycarbamoylcyclopentyl)-(4'-fluorobiphenyl-4-sulfonyl)amino]propionic acid methyl ester as a white crystalline solid (10.65 grams, 86%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]2[N:20]=[C:19]([NH2:21])[C:18]([C:22](=[O:31])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[CH:17][N:16]=2)[CH2:9]1)=O)(C)(C)C.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>ClCCl>[NH2:21][C:19]1[C:18]([C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])=[O:31])=[CH:17][N:16]=[C:15]([NH:14][CH:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)[N:20]=1.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]
Reactant: COc1ccccc1C(=O)c1cnc(NC2CCCN(C(=O)OC(C)(C)C)C2)nc1N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccccc1C(=O)c1cnc(NC2CCCNC2)nc1N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-[4-Amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (76 mg, Example 52) was dissolved in dichloromethane (4 mL), cooled to 0° C. and treated with trifluoroacetic acid (1 mL). After stirred 30 minutes at 0° C., the reaction mixture was concentrated in vacuo to give [4-amino-2-(piperidin-3-ylamino)-pyrimidin-5-yl]-(2-methoxy-phenyl)-methanone as a trifluoroacetic acid salt. A portion of this material was partitioned between ethyl acetate and aqueous sodium carbonate to give the free base. (129.5 mg). MS (M+H)+, 328.