Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][CH2:6][C:7]1([CH3:19])[CH2:11][CH2:10][CH2:9][N:8]1C(OC(C)(C)C)=O)=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][CH2:2][C:3]([NH:5][CH2:6][C:7]1([CH3:19])[CH2:11][CH2:10][CH2:9][NH:8]1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCCC1(C)CNC(=O)CCl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(CNC(=O)CCl)CCCN1
Yield: 32.8 %

Procedure:
A solution of tert-butyl 2-((2-chloroacetamido)methyl)-2-methylpyrrolidine-1-carboxylate (0.7 g, 4.8 mmol) and TFA (3 mL) in DCM was stirred at room temperature for about 3 h. Then the solution was concentrated to give 300 mg of the crude product, which was directly used for the next step. MS (ESI): 191, 193 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][CH2:8][C:9]1[C:10]2[C:15]([CH:16]=[C:17]3[C:22]=1[CH:21]=[CH:20][CH:19]=[CH:18]3)=[CH:14][CH:13]=[CH:12][CH:11]=2.C([O-])([O-])=O.[K+].[K+].[CH2:29](Br)[CH3:30]>C(#N)C>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]([CH2:8][C:9]1[C:10]2[C:15]([CH:16]=[C:17]3[C:22]=1[CH:21]=[CH:20][CH:19]=[CH:18]3)=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:29][CH3:30]
Reactant: OCCCCCNCc1c2ccccc2cc2ccccc12
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(CCCCCO)Cc1c2ccccc2cc2ccccc12
Yield: 3.3 %

Procedure:
9-((5-hydroxypentyl)aminomethyl)anthracene (1.00 g, 3.41 mol) and K2CO3 (0.518 g, 3.75 mmol) were taken up in 25 mL acetonitrile. Ethyl bromide (11.14 g, 102 mmol) was added and the mixture was refluxed under nitrogen for 24 h. The mixture was filtered on a sintered-glass frit and the solvent and excess ethyl bromide was removed under reduced pressure. Removal of the solvent afforded 1.07 g (98% yield) of 6 as a yellow solid; 1H NMR (300.13 MHz, CD3CN) δ 1.15 (m, 2H), 1.38 (m, 5H), 1.81 (m, 2H), 3.05 (m, 4H), 3.49 (t, 2H), 5.21 (s, 2H), 7.45 (m, 2H), 7.62 (m, 2H), 8.05 (d, 2H), 8.44 (m, 3H); 13C—{1H} NMR (75.4 MHz, CDCl3) δ 131.8, 131.3, 130.8, 129.6, 128.0, 125.6, 124.0, 61.7, 53.1, 49.4, 48.7, 31.4, 23.9, 23.3, 10.0.
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:7][N:6]=[CH:5][N:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:18][C:19]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:20]=1[S:27](Cl)(=[O:29])=[O:28].[Cl-].[NH4+]>O1CCCC1>[F:18][C:19]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:20]=1[S:27]([N:2]([CH3:1])[C:3]1[S:7][N:6]=[CH:5][N:4]=1)(=[O:29])=[O:28]
Reactant: CNc1ncns1
Reactant: O=S(=O)(Cl)c1cc(F)c(F)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(c1ncns1)S(=O)(=O)c1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of N-methyl-1,2,4-thiadiazol-5-amine (0.64 g, 5.5 mmol) in tetrahydrofuran (15 mL) at −78° C. was added lithium bis(trimethylsilyl)amide (1 M solution in tetrahydrofuran, 6.1 mL, 6.1 mmol). The reaction mixture was allowed to warm to ambient temperature and was stirred for 1 hr. The mixture was cooled to −78° C., and a solution of 2,4,5-trifluorobenzenesulfonyl chloride (0.85 mL, 6.1 mmol) in tetrahydrofuran (5 mL) was added. The reaction mixture was allowed to warm to ambient temperature, stirred for 1 h and saturated aqueous ammonium chloride (10 mL) was added. The mixture was extracted with ethyl acetate (4×20 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with a 10-30% gradient of ethyl acetate in hexanes to afford 2,4,5-trifluoro-N-methyl-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide as a colorless solid in 50% yield (0.864 g): 1H NMR (300 MHz, CDCl3) δ8.28-8.18 (m, 1H), 7.97-7.84 (m, 1H), 7.20-7.07 (m, 1H), 3.61 (s, 3H); MS (ES+) m/z 309.7 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[CH3:19][O:20][CH2:21][CH2:22][NH2:23]>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:23][CH2:22][CH2:21][O:20][CH3:19])[N:3]=1
Reactant: COCCN
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Product: COCCNc1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile and 2-methoxyethylamine in DME. EI-MS m/e (%): 259 (M+, 15), 214 ([M—MeOCH2]+, 100), 201 ([M—MeOCH═CH2]+, 78).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:18][CH:19]([CH3:23])[C:20](Cl)=[O:21]>ClCCl.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:20](=[O:21])[CH:19]([CH3:23])[CH3:18])[CH:5]=[CH:6][CH:7]=1
Reactant: NCCc1cccc(Br)c1
Reactant: CC(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)NCCc1cccc(Br)c1
Reaction time: 3 h

Procedure:
A solution of 2-(3-bromophenyl)ethylamine (3.0 g) in dichloromethane (180 mL) at room temperature was treated sequentially with triethylamine (7.0 mL), DMAP (10 mg), and a solution of 2-methylpropanoyl chloride(1.52 mL) in dichloromethane (30 mL). The mixture was stirred for 3 hours, quenched with N1,N2-dimethyl-1,2-ethanediamine, washed sequentially with 0.5M HCl, water, and brine, dried (MgSO4), filtered, and concentrated to provide the desired product.
Reaction SMILES: [CH2:1]([N:8]1[C:14](=O)[CH:13]2[N:16]([CH3:17])[CH:10]([CH2:11][CH2:12]2)[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>O1CCOCC1>[CH2:1]([N:8]1[CH2:14][CH:13]2[N:16]([CH3:17])[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1C2CCC1C(=O)N(Cc1ccccc1)C2=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1COCCO1
Product: CN1C2CCC1CN(Cc1ccccc1)C2
Reaction time: 18 h

Procedure:
To a solution of 3-benzyl-8-methyl-3,8-diazabicyclo[3.2.1]octane-2,4-dione (28.3 g; 0.116 mol) in 200 ml of absolute dioxane LiAlH4 (7.6 g; 0.2 mol) was added and the mixture boiled under argon for 18 hours. Then a mixture of water (7.5 ml) and dioxane (40 ml) was added drop-wise to the reaction mixture. The suspension was mixed for 20 minutes and filtered trough a dense glass filter. The filtrate was evaporated and the residue was distilled on Büchi oven for distillation at 120° C. and 0.1 mbar. Yield 17.6 g (70%).
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[CH3:13][O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>C(O)C>[CH3:13][O:14][C:15]1[CH:21]=[CH:20][C:18]([N:19]2[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]2=[O:11])=[CH:17][CH:16]=1
Reactant: COc1ccc(N)cc1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Solvent: CCO
Product: COc1ccc(N2CCC(C(=O)O)C2=O)cc1
Yield: 15.9 %

Procedure:
A mixture of 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.500 g; 2.94 mmol) and 4-methoxyaniline (1.09 g; 8.82 mmol) in ethanol (3 mL) was irradiated in a microwave oven for 3 minutes at 100° C. The mixture was concentrated under reduced pressure and the residue was dissolved in a solution of sodium hydroxide 6N, washed with dichloromethane, acidified with a solution of hydrochloric acid 6N to pH=2, extracted with ethyl acetate dried and concentrated under reduced pressure to yield 0.11 g (16%) of a pale pink solid, which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:12]=[C:11]([C:13]([OH:15])=O)[O:10][N:9]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C.C([O:47][C:48](=[O:68])[C@H:49]([OH:67])[CH2:50][C@H:51]([NH2:66])[CH2:52][C:53]1[CH:58]=[CH:57][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([Cl:65])[CH:60]=2)=[CH:55][CH:54]=1)C.CCN(C(C)C)C(C)C.CO.O>>[Cl:65][C:61]1[CH:60]=[C:59]([C:56]2[CH:55]=[CH:54][C:53]([CH2:52][C@@H:51]([NH:66][C:13]([C:11]3[O:10][N:9]=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[CH:12]=3)=[O:15])[CH2:50][C@@H:49]([OH:67])[C:48]([OH:68])=[O:47])=[CH:58][CH:57]=2)[CH:64]=[CH:63][CH:62]=1
Reactant: O=C(O)c1cc(-c2ccccc2F)no1
Reactant: CCOC(=O)[C@H](O)C[C@H](N)Cc1ccc(-c2cccc(Cl)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: O
Solvent: CO
Product: O=C(N[C@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C[C@@H](O)C(=O)O)c1cc(-c2ccccc2F)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
To a mixture of 3-(2-fluorophenyl)isoxazole-5-carboxylic acid (14.3 mg, 69 μmol) and HATU (26.2 mg, 69 μmol) in DMF (0.5 mL, 6 mmol) at room temperature, was added (2R,4R)-4-amino-5-(3′-chlorobiphenyl-4-yl)-2-hydroxypentanoic acid ethyl ester (20.0 mg, 58 μmol) and DIPEA (20.0 μL, 115 μmol). The mixture was stirred at room temperature overnight. MeOH (2.0 mL, 49 mmol), water (1.0 mL, 56 mmol), and LiOH monohydrate (9.7 mg, 230 μmol) was added, and the resulting mixture was stirred at room temperature for 1 hour. The resulting solids were filtered and rinsed with MeCN and water to yield the title compound (17.1 mg). MS m/z [M+H]+ calc'd for C27H22ClFN2O5, 509.12. found 509.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4]1[N:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[C:6]([CH3:13])[N:5]=1)[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.O[NH:48][C:49](=[NH:59])[C:50]1[CH:55]=[CH:54][C:53]([CH2:56][CH2:57][OH:58])=[CH:52][CH:51]=1>CN(C=O)C.CCOC(C)=O.O1CCOCC1>[CH2:14]([N:3]([CH2:1][CH3:2])[C:4]1[N:9]=[C:8]([C:10]2[O:12][N:59]=[C:49]([C:50]3[CH:55]=[CH:54][C:53]([CH2:56][CH2:57][OH:58])=[CH:52][CH:51]=3)[N:48]=2)[CH:7]=[C:6]([CH3:13])[N:5]=1)[CH3:15]
Reactant: CCN(CC)c1nc(C)cc(C(=O)O)n1
Reactant: N=C(NO)c1ccc(CCO)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCN(CC)c1nc(C)cc(-c2nc(-c3ccc(CCO)cc3)no2)n1
Reaction time: 1 h
Yield: 58.6 %

Procedure:
To a suspension of 2-diethylamino-6-methylpyrimidine-4-carboxylic acid (1.31 g, 6.28 mmol) in DMF (20 mL) is added DIPEA (3.23 mL, 18.8 mmol) followed by TBTU (2.62 g, 8.17 mmol). The mixture is stirred at rt for 10 min before N-hydroxy-4-(2-hydroxy-ethyl)-benzamidine (1.24 g, 6.91 mmol) is added. After stirring for 1 h, the reaction mixture is diluted with EtOAc and the solution is washed with sat. aq. NaHCO3. The aq. phase is extracted with EtOAc and the combined org. extracts are dried over MgSO4, filtered and concentrated to give the crude hydroxyamidine ester intermediate (3.56 g). This material is dissolved in dioxane (50 mL) and the resulting solution is stirred at 85° C. for 16 h. The solvent is evaporated and the crude product is purified by CC (eluting with EtOAc/Heptane 1:4) to give 2-{4-[5-(2-diethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-ethanol as a yellow solid (1.30 g); LC-MS: tR=1.07 min; [M+H]+=354.07. 1H NMR (CDCl3): δ 1.25 (t, J=7.0 Hz, 6H), 1.45 (m, 1H), 2.47 (s, 3H), 2.98 (t, J=6.5 Hz, 2H), 3.75 (q, J=7.0 Hz, 4H), 3.95 (m, 2H), 7.23 (s, 1H), 7.41 (d, J=7.8 Hz, 2H), 8.15 (d, J=7.5 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:11]2([CH2:13][CH2:12]2)[CH2:10][C@H:9]1[C:16](O)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].B.C1COCC1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:11]2([CH2:13][CH2:12]2)[CH2:10][C@H:9]1[CH2:16][OH:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)C[C@H]1C(=O)O
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC2)C[C@H]1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of (S)-6-aza-spiro[2.5]octane-5,6-dicarboxylic acid 6-tert-butyl ester (intermediate 17, 35 g, 0.122 mol) in anhydrous THF (300 ml) was added BH3/THF (1M, 360 ml, 0.365 mol) under nitrogen at 0° C. After the addition was completed, the reaction mixture was warmed to room temperature and stirred at room temperature for overnight. The resulting mixture was evaporated to obtain a crude that was purified by silica gel chromatography (petroleum ether/ethyl acetate from 10/1 to 5/1). (S)-5-Hydroxymethyl-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester was obtained as colourless oil (31 g), yield:86%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[C:10]([O:14]C(=O)CC)(=[O:13])[CH2:11][CH3:12].C([O-])(=O)CC.[Na+].[OH-].[K+]>>[CH3:12][C:11](=[CH:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=1)[C:10]([OH:14])=[O:13]
Reactant: O=Cc1cccc(F)c1
Reactant: CCC(=O)OC(=O)CC
Agent: CCC(=O)[O-]
Agent: [K+]
Agent: [Na+]
Product: CC(=Cc1cccc(F)c1)C(=O)O
Yield: 71.5 %

Procedure:
A mixture of 49.6 g. (0.4 mole) of meta-fluorobenzaldehyde, 66 ml. (0.51 mole) of propionic anhydride and 38.4 g. (0.4 mole) of sodium propionate were heated at 135°C for 19 hours. The reaction was cooled and to it was added a liter of 1 normal potassium hydroxide and the mixture was extracted with ether. The aqueous phase was freed of residual ether and acidified to pH 2 with hydrochloric acid. The product which crystallized was filtered and dried to give 51.5 grams of α-methyl-3-fluorocinnamic acid, melting point 95°-97°C.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].[CH2:17]([O:19][CH:20]([C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1)[C:21](N(OC)C)=[O:22])[CH3:18]>>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][C:12]([C:21](=[O:22])[CH:20]([O:19][CH2:17][CH3:18])[C:27]3[CH:28]=[CH:29][C:30]([N:33]4[CH2:34][CH2:35][O:36][CH2:37][CH2:38]4)=[CH:31][CH:32]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: CCOC(C(=O)N(C)OC)c1ccc(N2CCOCC2)cc1
Reactant: COc1cc(-c2ccco2)cc(OC)c1Br
Product: CCOC(C(=O)c1ccc(-c2cc(OC)c(Br)c(OC)c2)o1)c1ccc(N2CCOCC2)cc1

Procedure:
1-(5-(4-Bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-ethoxy-2-(4-morpholinophenyl)ethanone was prepared from 2-(4-bromo-3,5-dimethoxyphenyl)furan and 2-ethoxy-N-methoxy-N-methyl-2-(4-morpholinophenyl)acetamide according to the procedure used in Example 30. Purification by chromatography (50% EtOAc/hexanes) gave the product as a yellow solid (0.129 g, 34% yield). MS: m/z 530.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:14]3[C:9]([CH2:10][CH2:11][CH2:12][CH2:13]3)=[C:8]([CH:15]=[CH:16][N+:17]([O-:19])=[O:18])[C:7]=2[N:20]=1.C(Cl)(Cl)Cl.[BH4-].[Na+].C(O)(=O)C>C(O)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:14]3[C:9]([CH2:10][CH2:11][CH2:12][CH2:13]3)=[C:8]([CH2:15][CH2:16][N+:17]([O-:19])=[O:18])[C:7]=2[N:20]=1
Reactant: COc1ccc2c(n1)c(C=C[N+](=O)[O-])c1n2CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COc1ccc2c(n1)c(CC[N+](=O)[O-])c1n2CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon and in an anhydrous medium, 650 mg (2.38 mmol) of the compound obtained in Step D are suspended in 10 ml of isopropanol and 30 ml of chloroform in the presence of 1.5 g of 230-400 mesh silica; 450 mg (11.90 mmol) of sodium borohydride are added slowly. After stirring for 30 minutes at room temperature, acetic acid is added and the reaction mixture is filtered over a glass frit. After removal of the solvents by evaporation, the residue is diluted in dichloromethane and washed with water. The organic phase is then dried over magnesium sulphate, filtered and concentrated to yield the title compound in the form of a yellow solid.
Reaction SMILES: [OH-].[Li+].[C:3]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([O:18]CCCC)=[O:17])=[CH:13][CH:14]=2)[C@H:9]([NH:23][C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[CH2:8][C@@H:7]1[CH3:30])(=[O:5])[CH3:4]>O.C(O)C>[C:3]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([OH:18])=[O:17])=[CH:13][CH:14]=2)[C@H:9]([NH:23][C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[CH2:8][C@@H:7]1[CH3:30])(=[O:5])[CH3:4]
Reactant: CCCCOC(=O)c1ccc2c(c1)[C@H](NC(=O)OC(C)C)C[C@H](C)N2C(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)N1c2ccc(C(=O)O)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reaction time: 16 h
Yield: 85 %

Procedure:
Lithium hydroxide (0.365 g, 15.23 mmol) in water (5 mL) was added to a solution of butyl (2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinecarboxylate (for a preparation, see Intermediate 65) (1.982 g, 5.08 mmol) in ethanol (5 ml) and the mixture was stirred for 16 h at this temperature then concentrated in vacuo. The aqueous residue was diluted with water (5 mL) and the aqueous phase was washed with Et2O (10 mL). The aqueous layer was acidified with a 2M HCl aqueous solution (pH<2) and extracted with EtOAc (2×10 mL). The combined organic phases were dried over MgSO4 and concentrated in vacuo to give (2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinecarboxylic acid (1.45 g, 4.34 mmol, 85% yield) as a colourless crystalline solid
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]([O:10]CC)=[O:9])[N:6]=1.[OH-].[Na+].CO.Cl>O1CCCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)C(=NOCc1ccccc1)c1csc(N)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nc(C(=NOCc2ccccc2)C(=O)O)cs1
Temperature: 25 °C
Reaction time: 12 h
Yield: 36.2 %

Procedure:
A mixture of ethyl 2-(2-aminothiazol-4-yl)-2-benzyloxyiminoacetate (syn isomer, 35 g.), 1 N aqueous sodium hydroxide (172 ml.), methanol (150 ml.) and tetrahydrofuran (150 ml.) was stirred at 35° to 40° C. for 9 hours and at room temperature for 12 hours. After adjusted the resultant solution to pH 6.5 with conc. hydrochloric acid, the solution was concentrated to about 2/3 volume of the initial. The concentrate was adjusted to pH 3.5 with conc. hydrochloric acid under ice cooling, and the precipitates were collected by filtration, washed with water and acetone in turn and then dried over phosphorus pentoxide under reduced pressure to give 2-(2-aminothiazol-4-yl)-2-benzyloxyiminoacetic acid (syn isomer, 11.5 g.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:17][C:18]2[N:23]=[CH:22][N:21]=[C:20]3[NH:24][N:25]=[C:26]([O:27][CH2:28][CH2:29][OH:30])[C:19]=23)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>N1C=CC=CC=1>[CH3:31][S:32]([O:30][CH2:29][CH2:28][O:27][C:26]1[C:19]2[C:20](=[N:21][CH:22]=[N:23][C:18]=2[NH:17][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:24][N:25]=1)(=[O:34])=[O:33]
Reactant: COc1cc(Nc2ncnc3[nH]nc(OCCO)c23)ccc1OCc1ccccn1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COc1cc(Nc2ncnc3[nH]nc(OCCOS(C)(=O)=O)c23)ccc1OCc1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
2-[(4-{[3-methoxy-4-(pyridin-2-ylmethoxy)phenyl]amino}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)oxy]ethanol (prepared as described in Example 7/500 mg, 1.22 mmol) was dissolved in dry pyridine (12 ml) and methanesulfonyl chloride (142 μl, 1.84 mmol) was added drop-wise under argon. The mixture was stirred for 1 hour at room temperature then partitioned between water and methylene chloride. The organic layer was washed with water, dried over MgSO4 and evaporated under vacuum. The residue was triturated in ether, filtered and dried to give the title compound as a tan solid (462 mg, 78%); NMR Spectrum: 3.28 (s, 3H), 3.80 (s, 3H), 4.58 (d, 2H), 4.69 (d, 2H), 5.16 (s, 2H), 7.03 (d, 2H), 7.37 (m, 3H), 7.55 (d, 1H), 7.85 (td, 1H), 8.13 (s, 1H), 8.29 (s, 1H), 8.58 (d, 1H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][C@:13]([CH3:49])([CH2:47][OH:48])[C:14](=[O:46])[C@@H:15]([NH:23][C:24](=[O:45])[C@@H:25]([NH:29][C:30](=[O:44])[C@@H:31]([NH:35][C:36]([C:38]1[S:42][C:41]([CH3:43])=[N:40][CH:39]=1)=[O:37])[CH2:32][O:33][CH3:34])[CH2:26][O:27][CH3:28])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:48][CH2:47][C@:13]([OH:12])([CH3:49])[C:14](=[O:46])[C@@H:15]([NH:23][C:24](=[O:45])[C@@H:25]([NH:29][C:30](=[O:44])[C@@H:31]([NH:35][C:36]([C:38]2[S:42][C:41]([CH3:43])=[N:40][CH:39]=2)=[O:37])[CH2:32][O:33][CH3:34])[CH2:26][O:27][CH3:28])[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@](C)(O)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@](C)(O)COS(=O)(=O)c1ccc(C)cc1

Procedure:
Prepared according to procedures described above, by reacting p-toluenesulfonyl chloride with N—((S)-1-(((S)-1-(((2 S,4R)-4,5-dihydroxy-4-methyl-3-oxo-1-phenylpentan-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-2-methylthiazole-5-carboxamide. MS for C32H40N4O10S2 m/z: 705 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH:19]=[CH:18][C:17]=2[O:28][CH3:29])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:31][C:32]1[C:33]2[C:43]([F:44])=[CH:42][CH:41]=[C:40]([F:45])[C:34]=2[S:35][C:36]=1[C:37](Cl)=[O:38]>>[C:1]([O:5][C:6](=[O:30])[NH:7][CH:8]1[CH2:9][CH2:10][CH:11]([N:14]([C:37]([C:36]2[S:35][C:34]3[C:40]([F:45])=[CH:41][CH:42]=[C:43]([F:44])[C:33]=3[C:32]=2[Cl:31])=[O:38])[CH2:15][C:16]2[CH:21]=[C:20]([C:22]3[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=3)[CH:19]=[CH:18][C:17]=2[O:28][CH3:29])[CH2:12][CH2:13]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Reactant: COc1ccc(-c2ccncc2)cc1CNC1CCC(NC(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccncc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(NC(=O)OC(C)(C)C)CC1

Procedure:
Amine (297) (156 mg, 0.38 mmol) was reacted with acid chloride 8 (110 mg, 0.42 mmol) using Method D to give the title compound.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([C:7]#[CH:8])=[CH:3][CH:2]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][CH:20]([CH2:23][OH:24])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1>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.N1CCCC1>[C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([C:7]#[C:8][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][CH:20]([CH2:23][OH:24])[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)=[CH:3][CH:2]=1
Reactant: C#Cc1ccc(C)cc1
Reactant: OCC1CCC(c2ccc(Br)cc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNC1
Product: Cc1ccc(C#Cc2ccc(C3CCC(CO)CC3)cc2)cc1
Temperature: 80 °C

Procedure:
25.0 g of p-tolylacetylene and 12.71 g of tetrakis(triphenylphosphine)palladium(0) (9.2% of Pd) were introduced into 500 ml of pyrrolidine, and 65.36 g of [4-(4-bromophenyl)cyclohexyl]methanol were added quickly. The mixture was then warmed at 80° C. for 2.5 hours with stirring, cooled and subjected to conventional work-up, giving [4-(4-p-tolylethynylphenyl)cyclohexyl]methanol as a crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23].[S:31](Cl)([C:34]1[C:46]2[CH:45]=[CH:44][CH:43]=[C:39]([N:40]([CH3:42])[CH3:41])[C:38]=2[CH:37]=[CH:36][CH:35]=1)(=[O:33])=[O:32]>>[CH3:41][N:40]([CH3:42])[C:39]1[CH:43]=[CH:44][CH:45]=[C:46]2[C:38]=1[CH:37]=[CH:36][CH:35]=[C:34]2[S:31]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:23])=[O:24])(=[O:33])=[O:32]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Product: CN(C)c1cccc2c(S(=O)(=O)Nc3ccc(N4CCNCC4)cc3NS(=O)(=O)c3ccccc3)cccc12

Procedure:
5-(Dimethylamino)-N-{4-(1-piperazinyl)-2-[(phenylsulfonyl)amino]phenyl}-1-naphthalenesulfonamide was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamide and dansylchloride (64 mg, 0.239 mmol) according to general method 3 to give 60 mg of a purple solid. MS (posES-FIA) m/z=Found: 566.3; Calcd: 566.18; 1H NMR δ 8.84 (d, 1H), 8.60 (d, 1H), 8.08 (d, 2H), 7.84-7.47 (m, 7H), 6.70 (d, 1H), 6.56-6.53 (m, 1H), 6.41-6.37 (m, 1H), 3.46 (s, 6H), 3.25-3.12 (m, 8H).