Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8](B(O)O)[CH:9]=[CH:10][CH:11]=1)(=[O:4])=[O:3].I[C:16]1[C:24]2[C:19](=[N:20][CH:21]=[N:22][C:23]=2[NH2:25])[N:18]([CH:26]([CH3:28])[CH3:27])[N:17]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[NH2:25][C:23]1[N:22]=[CH:21][N:20]=[C:19]2[N:18]([CH:26]([CH3:28])[CH3:27])[N:17]=[C:16]([C:8]3[CH:7]=[C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:11]=[CH:10][CH:9]=3)[C:24]=12
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
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: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CC(C)n1nc(-c2cccc(NS(C)(=O)=O)c2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 54 %

Procedure:
A solution of 3-Methanesulfonylaminophenylboronic acid (32 mg, 0.15 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (40 mg, 0.13 mmol) in DME (12 ml). Pd(PPh3)4 (16 mg, 0.014 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA38 (24.3 mg, 54% yield). ESI-MS (M+H)+ m/z calcd 347.1, found 347.0.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=[CH:7]1.[C:15]([O-:18])(=[S:17])[CH3:16].[K+]>CC(C)=O>[C:15]([S:17][CH2:2][CH2:3][O:4][CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=[CH:7]1)(=[O:18])[CH3:16]
Reactant: ClCCOCn1cnc2cccnc21
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)SCCOCn1cnc2cccnc21
Yield: 45.8 %

Procedure:
A suspension of 0.7 g (3.3 mmol) 3-(2-Chloro-ethoxymethyl)-3H-imidazo[4,5-b]pyridine and 378 mg (3.3 mmol) potassium thioacetate in 15 ml acetone was heated to reflux for 12 hours. The orange suspension was concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, gradient of 0 to 10% methanol in DCM) to afford 380 mg (46%) of the desired product MS(ISP): 252.1 [MH]+; 1H-NMR (CDCl3): 2.28 (s, 3H), 3.05 (t, 2H), 3.69 (t, 2H), 5.72 (s, 2H), 7.27 (m, 1H), 8.09 (dd, 1H), 8.20 (s, 1H), 8.43 (dd, 1H).
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:8]([C:10]1[C:11](=[O:25])[NH:12][C:13](=[O:24])[N:14]([CH:23]=1)[C@@H:15]1[O:22][C@H:19]([CH2:20][OH:21])[C@@H:17]([OH:18])[CH2:16]1)#[CH:9].C(Cl)Cl>N1C=CC=CC=1.C(Cl)Cl.CO>[C:1]([O:18][C@@H:17]1[C@@H:19]([CH2:20][O:21][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])[O:22][C@@H:15]([N:14]2[CH:23]=[C:10]([C:8]#[CH:9])[C:11](=[O:25])[NH:12][C:13]2=[O:24])[CH2:16]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)Cl
Reactant: C#Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CO
Product: C#Cc1cn([C@H]2C[C@H](OC(=O)C(C)(C)C)[C@@H](COC(=O)C(C)(C)C)O2)c(=O)[nH]c1=O
Temperature: 25 °C

Procedure:
Pivaloyl chloride (0.3 ml, 2.56 mmoles) was added to a cooled, stirred solution of 2'-deoxy-5-ethynyluridine (0.5 g, 1.98 mmols) in dry pyridine (5 ml) and stirring was maintained at room temperature for 3 hours. TLC in CH2Cl2 /MeOH (19:1) revealed complete reaction. The mixture was poured onto ice/water, methylene chloride added, the organic layer separated and washed with water, dried with sodium sulphate and evaporated to dryness. The residue was chromatographed on silica gel eluted with CH2Cl2 /MeOH. The first product was triturated with hexane to give 2'-deoxy-3',5'-di-O-pivaloyl-5-ethynyluridine. M.p. 151° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:32]1(=[O:42])[NH:36][C:35](=[O:37])[C:34]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:33]12.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:36]2[C:32](=[O:42])[C:33]3[C:34](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:35]2=[O:37])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCCCCCc1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCCCCc1ccccc1
Temperature: 0 °C
Yield: 77.3 %

Procedure:
5-Phenylpentan-1-ol (0.50 g, 3 mmol), triphenylphosphine (0.45 g, 3 mmol), and phthalimide (0.80 g, 3 mmol) were vigorously stirred in dry THE (5 mL) while cooling to 0° C. A solution of DEAD (0.62 g, 3 mmol) in 5 mL of dry THF was added dropwise to the cooled mixture. After stirring at room temperature for 12 his, the solvent was removed by reduced pressure. The crude was purified by column chromatography using a Teledyne ISCO apparatus (cyclohexane:EtOAc 90:10) to afford the title compound (0.68 g, 76%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 1.22-1.34 (m, 2H), 1.49-1.69 (m, 4H), 2.52-2.58 (m, 2H), 3.56 (t, J=7.06 Hz, 2H), 7.06-7.27 (m, 5H), 7.75-7.95 (m, 4H). MS (ESI) m/z: 334 [M-H]−.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:21]=[O:22])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8](F)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23]1([CH2:29][O:30][C:31]([N:33]2[CH2:37][CH2:36][CH:35]([C:38]([OH:40])=[O:39])[NH:34]2)=[O:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:21]=[O:22])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]([N:34]2[CH:35]([C:38]([OH:40])=[O:39])[CH2:36][CH2:37][N:33]2[C:31]([O:30][CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:32])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)N1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)F)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)N1C(C(=O)O)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl fluoride (3.24 g, 10.55 mmol) in DMF (30 mL) was added 1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid (2.2 g, 8.79 mmol) followed by DIPEA (3.07 mL, 17.58 mmol). The reaction was stirred at 25° C. for 18 hrs. The reaction was concentrated and purified by reverse-phase HPLC to afford 2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid as a mixture of diastereomers. LC-MS (ES) m/e 538.8 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:7][N:6]([CH3:8])[C:5]2[CH:9]=[CH:10][CH:11]=[C:12]([C:13]([OH:15])=O)[C:4]=2[O:3]1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[NH2:31][CH:32]1[CH:37]2[CH2:38][CH2:39][N:34]([CH2:35][CH2:36]2)[CH2:33]1>C(OCC)(=O)C>[CH3:16][C:2]1([CH3:1])[CH2:7][N:6]([CH3:8])[C:5]2[CH:9]=[CH:10][CH:11]=[C:12]([C:13]([NH:31][CH:32]3[CH:37]4[CH2:38][CH2:39][N:34]([CH2:35][CH2:36]4)[CH2:33]3)=[O:15])[C:4]=2[O:3]1
Reactant: CN1CC(C)(C)Oc2c(C(=O)O)cccc21
Reactant: NC1CN2CCC1CC2
Agent: CC(C)(C)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN1CC(C)(C)Oc2c(C(=O)NC3CN4CCC3CC4)cccc21
Temperature: 25 °C

Procedure:
To a solution of 1.0 g of 2,2,4-trimethyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid in 30 ml of ethyl acetate was added 1.2 ml of triethylamine, and 0.55 g of pivaloyl chloride was added dropwise thereto at -10° to -5° C. under cooling. After stirring for 15 minutes at the same temperature, 0.57 g of 3-aminoquinuclidine was added at -10° to -5° C. and the mixture was stirred at room temperature for an hour. The resultant mixture was washed with water, dried over magnesium sulfate and concentrated. The precipitated crystals were collected by filtration and recrystallized from a mixed solvent of isopropyl ether and ethanol to give 2,2,4-trimethyl-N-(3-quinuclidinyl)-3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide as white crystals, melting at 114°-116° C.
Reaction SMILES: [CH3:1][CH:2]1[NH:6][C:5](=[O:7])[CH2:4][CH2:3]1.Br[C:9]1[N:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH:30]4[CH2:32][CH2:31]4)=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:11][CH:10]=1>>[CH:30]1([C:26]2[CH:27]=[C:28]([CH3:29])[C:23]([N:20]3[CH2:21][CH2:22][N:17]([C:15]([C:12]4[CH:11]=[CH:10][C:9]([N:6]5[CH:2]([CH3:1])[CH2:3][CH2:4][C:5]5=[O:7])=[N:14][CH:13]=4)=[O:16])[CH2:18][CH2:19]3)=[N:24][CH:25]=2)[CH2:31][CH2:32]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)nc2)CC1
Reactant: CC1CCC(=O)N1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)CCC3C)nc2)CC1
Yield: 24.4 %

Procedure:
Using 5-methylpyrrolidin-2-one (64 mg) and (6-bromopyridin-3-yl) [4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (260 mg) described in Preparation Example 144 and by the reaction and treatment in the same manner as in Example 1, the title compound (66 mg) was obtained.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:18])[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[CH2:1]([NH:8][C:9](=[O:18])[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:11][C:19](=[O:21])[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(NCc1ccccc1)C(O)c1ccccc1
Product: CC(=O)OC(C(=O)NCc1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
N-benzyl mandelic amide 100 g is suspended in 250 ml of acetic anhydride and the mixture is heated to 60 degrees C. After all the solid materials have been dissolved in acetic anhydride concentrated sulfuric acid 0.5 ml is added to the solution. Acetylation takes place instantly with exothermic reaction and the reaction mixture turns reddish in color. After the initial exothermic reaction has subsided the mixture is heated to 90-100 degrees C. for 5 hours to complete the acetylation. The reaction mixture is then evaporated at 70-80 degrees C. in vacuum to remove acetic acid, water and the like. The residue is mixed with 300 ml of chloroform. The chloroform layer is washed with 300 ml of 5% aqueous sodium bicarbonate solution, water and dried over anhydrous sodium sulfate. On evaporation of chloroform solution crystalline product 113 g is obtained.
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].C([Li])CCC.[C:12]1(=[O:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>O1CCCC1>[OH:6][C:2]([CH3:3])([CH3:1])[C:4]#[C:5][C:12]1([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C#CC(C)(C)O
Reactant: O=C1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(O)C#CC1(O)CCCCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 36.9 %

Procedure:
A solution of 2-methyl-3-butyne-2-ol (25 g, 0.297 mol) in tetrahydrofuran (250 ml) is cooled to −78° C. under a nitrogen atmosphere and to this solution, n-butyl lithium (1.6 molar solution in hexanes, 410 ml, 0.65 mol) is added slowly over 1.5-2.0 hours. The reaction mixture is stirred for 1 hour at −78° C. and a solution of cyclohexanone (46.2 ml, 0.44 mol) in tetrahydrofuran (46 ml) is added. The reaction mixture is stirred at −78° C. for one hour and allowed to come to ambient temperature and stirred at ambient temperature for 2-3 hours. The reaction mixture is cooled to 10° C. and quenched with ice cold water. The mixture is extracted with dichloromethane (3×250 ml), the organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 1-(3-hydroxy-3-methylbut-1-ynyl)cyclohexanol (20 g) as a colourless oil.
Reaction SMILES: [Li+].[F:2][C:3]([F:30])([F:29])[C:4]1[CH:28]=[CH:27][C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]([O-])=[O:25])[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.Cl.[N+:65]([C:68]1[CH:73]=[CH:72][C:71]([NH:74][CH:75]2[CH2:80][CH2:79][NH:78][CH2:77][CH2:76]2)=[CH:70][C:69]=1[C:81]([F:84])([F:83])[F:82])([O-:67])=[O:66]>CN(C)C=O.ClCCl.O1CCCC1>[N+:65]([C:68]1[CH:73]=[CH:72][C:71]([NH:74][CH:75]2[CH2:76][CH2:77][N:78]([C:24](=[O:25])[CH2:23][CH2:22][N:19]3[CH2:20][CH2:21][N:16]([C:13]4[CH:14]=[CH:15][C:10]([O:9][CH2:8][C:7]5[CH:6]=[CH:5][C:4]([C:3]([F:2])([F:30])[F:29])=[CH:28][CH:27]=5)=[CH:11][CH:12]=4)[CH2:17][CH2:18]3)[CH2:79][CH2:80]2)=[CH:70][C:69]=1[C:81]([F:84])([F:82])[F:83])([O-:67])=[O:66]
Reactant: O=C([O-])CCN1CCN(c2ccc(OCc3ccc(C(F)(F)F)cc3)cc2)CC1
Reactant: O=[N+]([O-])c1ccc(NC2CCNCC2)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(CCN1CCN(c2ccc(OCc3ccc(C(F)(F)F)cc3)cc2)CC1)N1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reaction time: 0.08 h

Procedure:
3-{4-[4-(4-Trifluoromethyl-benzyloxy)-phenyl]-piperazin-1-yl}-propionic acid lithium salt (134 mg; 0.32 mmol, prepared in accordance with Example 13), diisopropylethyl amine (174 μL; 1.0 mmol) and tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (133 mg; 0.35 mmol) are diluted in a 2 to 1 mixture of dimethylformamide and tetrahydrofuran (1.5 mL) and the resulting solution is stirred for 5 minutes. A solution of (4-nitro-3-trifluoromethyl-phenyl)-piperidin-4-yl-amine hydrochloride (114 mg; 0.30 mmol, prepared in accordance with Example 8) in dimethylformamide (0.5 mL) is added and the reaction is then stirred for 2 hours at room temperature. Following dilution with dichloromethane (10 mL), the organic layer is sequentially washed with water (5 mL), aq. sat. sodium hydrogen carbonate (3×5 mL), is dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained is finally purified by preparative HPLC to deliver the desired product in pure form (34 mg; 0.05 mmol). The structure was confirmed using Protocol II-A. Calculated mass=680; observed mass=680; HPLC retention time=3.84 min.
Reaction SMILES: [CH:1]1[C:6](N=C=S)=[CH:5][C:4]2[C:10]([O:12][C:13]3([C:23]4[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:22]=4[O:21][C:15]4[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:14]3=4)[C:3]=2[CH:2]=1)=[O:11].C1COC(CCCCN)CO1>N1C=CC=CC=1>[CH:1]1[CH:6]=[CH:5][C:4]([C:10]([OH:12])=[O:11])=[C:3]([C:13]2[C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[O:21][C:22]3[C:23]=2[CH:24]=[CH:25][C:26]([CH:27]=3)=[O:28])[CH:2]=1
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Agent: NCCCCC1COCCO1
Solvent: c1ccncc1
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Temperature: 23 °C
Reaction time: 1 h
Yield: 11.8 %

Procedure:
A mixture of 10.8 mg (0.28 mmoles) of fluorescein isothiocyanate and 23 mg (0.14 mmoles) of 6-ethylenedioxy-1-hexylamine in 1.5 ml of dry pyridine was stirred at 23° C. for one hour. After concentrating the solution under reduced pressure, the crude product was purified by flash chromatography using 10% methanol in methylene chloride to afford 11 mg (72%) of fluorescein-linker acetal. This was quantitatively converted to the aldehyde by treatment with 80% aqueous acetic acid at 37° C. for 3 hours followed by lyophilization.
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:2]([C:4]([OH:6])=O)[CH3:3].C(N1CCOCC1)C.C(OC(Cl)=O)C(C)C.[CH2:30]([O:37][C:38](=[O:41])[CH2:39][NH2:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O>O1CCCC1.CN(C=O)C>[NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:2]([C:4]([NH:40][CH2:39][C:38]([O:37][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:41])=[O:6])[CH3:3]
Reactant: NCC(=O)OCc1ccccc1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Reaction time: 0.08 h

Procedure:
1.9 g of Boc-(D)Ala-OH and 1.3 ml of N-ethylmorpholine are dissolved in 50 ml of absolute tetrahydrofuran and 1.3 ml of chloroformic acid iso-butyl ester added dropwise at a temperature of -15°. After 5 minutes, a solution of 3.4 g of glycine-benzylester-tosylate and 1.3 ml of N-ethylmorpholine in 50 ml of DMF is added. After 1 hour's stirring at -10°, the reaction mixture is evaporated and the residue taken up in acetic acid. The solution is repeatedly washed with dilute citric acid and potassium bicarbonate. The title compound is crystallised from ether. M.P. 88°.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:11][CH2:12][C:13](Cl)=[O:14]>C1COCC1>[Cl:11][CH2:12][C:13]([NH:8][C:7]1[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:14]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: O=C(CCl)Nc1ccc([N+](=O)[O-])cc1
Reaction time: 0.71 h

Procedure:
To a solution of 4-nitroaniline 37b (6.9 g, 50 mmol) in THF (50 mL) was added dropwise a solution of chloroacetyl chloride (100 mmol) in dry THF (50 mL) at room temperature. The reaction mixture was stirred for additional 40-45 minutes and then evaporated in vacuo to dryness. The solid residue was triturated with saturated NaHCO3 solution (aqueous) and then collected by filtration. The solid product was washed with water, followed by hexane, and dried to give 2-chloro-N-(4-nitrophenyl)acetamide, 10.02 g (94%); mp 182-183° C. (Lit. 181-183° C.58). 1H NMR (DMSO-d6) δ: 4.34 (2H, s, CH2), 7.83-7.85 (2H, d, J=9.1 Hz, Ar—H), 8.23-8.26 (2H, d, J=9.1 Hz, Ar—H), 10.88 (1H, brs, NH).
Reaction SMILES: [C:1]([C:4]1[C:9]([Br:10])=[CH:8][C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][N:5]=1)(=[O:3])[CH3:2].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>C1(C)C=CC=CC=1>[Br:10][C:9]1[C:4]([C:1](=[O:3])[CH:2]=[CH:17][N:18]([CH3:20])[CH3:19])=[N:5][CH:6]=[C:7]([C:11]([F:13])([F:14])[F:12])[CH:8]=1
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ncc(C(F)(F)F)cc1Br
Solvent: Cc1ccccc1
Product: CN(C)C=CC(=O)c1ncc(C(F)(F)F)cc1Br
Yield: 98.7 %

Procedure:
728 mg of 2-acetyl-3-bromo-5-(trifluoromethyl)pyridine and 466 mg of N,N-dimethylformamide dimethyl acetal were reacted in 5 mL of toluene at 100° C. for 16 hours. The reaction liquid was concentrated under reduced pressure to obtain 866 mg of 1-(3-bromo-5-(trifluoromethyl)pyridin-2-yl)-3-(dimethylamino)-2-propen-1-one (after-mentioned intermediate No. IV-7).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C@H:14]([O:18][CH3:19])[C:15]([OH:17])=[O:16])=[CH:9][CH:8]=1.O[C:21]1[CH:34]=[CH:33][C:24]([C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:26])=[CH:23][CH:22]=1>>[C:25]([C:27]1[CH:32]=[CH:31][C:30]([O:1][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]2[CH:8]=[CH:9][C:10]([CH2:13][C@H:14]([O:18][CH3:19])[C:15]([OH:17])=[O:16])=[CH:11][CH:12]=2)=[CH:29][CH:28]=1)(=[O:26])[C:24]1[CH:33]=[CH:34][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: CO[C@@H](Cc1ccc(C#CCCCO)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(C#CCCCOc2ccc(C(=O)c3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(5-hydroxy-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid (Example 21, Step A) and 4-hydroxybenzophenone via the standard Mitsunobu coupling-hydrolysis procedure (Standard Procedure A) to produce a white oily solid. 1H-NMR (200.15 MHz, CDCl3): δ 7.82–7.70 (m, 3H), 7.54–7.43 (m, 4H), 7.31–7.23 (m, 2H), 7.14 (d, 2H, J=8.1), 6.95 (d, 2H, J=8.8), 4.19 (d, 2H, J=5.9), 3.96 (dd, 1H, J=7.7, 4.4), 3.34 (s, 3H), 3.09 (dd, 1H, J=14.3, 4.4), 2.95 (dd, 1H, J=14.3, 7.7), 2.61 (t, 2H, J=7.0), 2.08 (qn, 2H, J=0.6).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:12]=[C:11]([NH2:13])[N:10]([CH3:14])[N:9]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:12]=[C:11]([NH:13][C:15](=[O:17])[CH3:16])[N:10]([CH3:14])[N:9]=1
Reactant: Cn1nc(-c2ccccc2Cl)cc1N
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(-c2ccccc2Cl)nn1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.2 %

Procedure:
To a solution of 3-(2-chlorophenyl)-1-methyl-1H-pyrazol-5-amine (617 mg, 3 mmol) in pyridine (6 mL) was added acetic anhydride (425 μl, 4.5 mmol). The reaction was stirred at room temperature for 16 h. The mixture was concentrated in vacuo. The crude residue was purified by column chromatography (silica gel, gradient 0 to 100% ethyl acetate/isohexane) yielding N-(3-(2-chlorophenyl)-1-methyl-1H-pyrazol-5-yl)acetamide as a solid (526 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.OO.COC1C=C2C(=CC=1)[N+:23]([O-])=[CH:22]C=C2.C(Cl)(=O)C1C=CC=CC=1>[Ag]C#N.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:22]#[N:23])[CH:7]=[CH:6]2
Reactant: COc1ccc2ncccc2c1
Reactant: COc1ccc2c(ccc[n+]2[O-])c1
Agent: N#C[Ag]
Agent: OO
Solvent: O=C(Cl)c1ccccc1
Solvent: CC(=O)O
Product: COc1ccc2nc(C#N)ccc2c1

Procedure:
Compounds of formula II can be manufactured starting from commercially available 6-methoxy-quinoline (1) that can converted to the N-oxide 2 by reaction with hydrogen peroxide and a solvent like acetic acid under refluxing conditions. The 6-methoxy-quinoline-1-oxide is reacted with silver cyanide and benzoyl chloride to obtain the 6-methoxy-quinoline-2-carbonitrile 3 via a modification of the Reisset'sche reaction (Ber., 38, 1610 (1905). Hydrolysis of the cyano group can be affected by employing an acidic or basic medium. We find it convenient to use a base like sodium hydroxide and after acidic treatment of the mixture we obtained the corresponding 6-methoxy-quinoline-2-carboxylic acid 4. Removal of the methyl group with an acid like hydrobromic acid 48% in water gives 6-hydroxy-quinoline-2-carboxylic acid (5). The acid can be esterified with an alcohol like ethanol and an acid like sulfuric acid to yield the 6-hydroxy-quinoline-2-carboxylic acid ester II, for example 6-hydroxy-quinoline-2-carboxylic acid ethyl ester (IIa).
Reaction SMILES: [C:1]1([S:7]([O-:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH:19]=[C:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>[I-].[Na+].CO>[C:20]1(=[CH:19][CH2:18][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: BrCC=C1CCCC1
Reactant: O=S([O-])c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Product: O=S(=O)(CC=C1CCCC1)c1ccccc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 47.1 %

Procedure:
22.3 gm of sodium phenyl sulfinate, 2.2 gm of potassium carbonate and 0.2 gm of sodium iodide were introduced into 50 cc of methanol. Then 23.6 gm of 1-bromo-2-cyclopentylidene-ethane were added at a temperature of about +10° C. and under agitation and the reaction mixture was agitated for 2 hours at 20° C. Thereafter, the reaction mixture was poured into ice water and cooled to 0° C. The precipitate formed was isolated by vacuum filtering and dried under vacuum in the presence of potassium hydroxide to obtain 15 gm of (2-cyclopentylidene-ethyl)-phenyl sulfone having a melting point of 68° C. A sample of the product crystallized from isopropyl ether had a melting point of 68° C.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])[CH2:3][CH2:2]1.[Cl:17]([O-])(=O)=O.[Na+].S(=O)(O)[O-].[Na+]>Cl.C(O)(=O)C.O>[Cl:17][CH:2]1[CH2:3][CH:4]([CH2:7][C:8]([NH:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:9])[CH2:5][CH2:6][CH2:1]1
Reactant: [O-][Cl+2]([O-])[O-]
Reactant: O=C(CC1CCCCC1)Nc1ccccc1
Agent: Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(CC1CCCC(Cl)C1)Nc1ccccc1
Temperature: 25 °C

Procedure:
4-Cyclohexylacetanilide (24 g, 110 mmol) is dissolved in a mixture of concentrated HCl (25 mL) and acetic acid (75 mL). The mixture is cooled in an ice bath and a solution of sodium chlorate (NaClO3, 7.5 g, 70 mmol) in water (30 mL) is added via a dropping funnel. The reaction is allowed to warm to room temperature and then poured into saturated sodium bisulfite solution (500 mL). The solid which forms is isolated by filtration and subsequently washed first with water (500 mL) and then a mixture of hexanes/Et2O (10:1, 500 mL). The resulting solid is air dried to yield 2-chloro-4-cyclohexylacetanilide (m.p. 110–112° C.).