Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.Br[C:10]1[S:18][C:17]2[C:16]([NH:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][CH:24]=[CH:23]4)=[N:15][CH:14]=[N:13][C:12]=2[CH:11]=1>>[NH:25]1[C:26]2[C:22](=[CH:21][C:20]([NH:19][C:16]3[C:17]4[S:18][C:10]([C:3]5[CH:4]=[CH:5][S:1][CH:2]=5)=[CH:11][C:12]=4[N:13]=[CH:14][N:15]=3)=[CH:28][CH:27]=2)[CH:23]=[CH:24]1
Reactant: OB(O)c1ccsc1
Reactant: Brc1cc2ncnc(Nc3ccc4[nH]ccc4c3)c2s1
Product: c1nc(Nc2ccc3[nH]ccc3c2)c2sc(-c3ccsc3)cc2n1

Procedure:
The title compound was prepared from thiophene-3-boronic acid and (6-bromo-thieno[3,2-d]pyrimidin-4-yl)-(1H-indol-5-yl)-amine by a procedure analogous to example 2. 1H NMR (400 MHz, DMSO) d 11.4 (s, 1H), 11.2 (s, 1H), 8.86 (s, 1H), 8.10 (s, 1H), 7.70 (m, 3H), 7.46 (m, 3H), 7.21 (d, 1H), 6.49 (s, 1H), M.P. 178-189° C.; LC-MS: 349 (MH+); HPLC RT 4.05 minutes.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][N:2]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[CH3:18][C:19]1[CH:23]=[CH:22][S:21][C:20]=1[CH:24]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(O)(=O)C.CN(C)C=O>[CH3:18][C:19]1[CH:23]=[CH:22][S:21][C:20]=1[CH2:24][N:8]1[CH2:7][CH2:6][C:5]2([CH2:1][N:2]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3][CH2:4]2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Reactant: Cc1ccsc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1ccsc1CN1CCC2(CC1)CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 15 h
Yield: 61.1 %

Procedure:
To a 1% acetic acid-dimethylformamide (10 mL) solution of tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (1.28 g) and 3-methylthiophene-2-carboaldehyde (700 mg), sodium triacetoxyborohydride (1.96 g) was added. The reaction solution was stirred at room temperature for 15 hours. To the reaction solution, an aqueous 5N sodium hydroxide solution (10 mL) was added. The aqueous layer was washed twice with dichloromethane (100 mL) The combined organic layer was washed with saturated sodium chloride solution (50 mL) and then dried over anhydrous magnesium sulfate. After removing the anhydrous magnesium sulfate by filtration, the filtrate was concentrated. The residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:1→1:3) to obtain the title compound (1.14 g) having the following physical properties.
Reaction SMILES: [Cl:1][C:2]1[S:28][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]4[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=4)[C:21]([O:23]C)=[O:22])[CH2:13][CH2:12]3)[C:4]=2[CH:3]=1.O[Li].O>CO.O>[Cl:1][C:2]1[S:28][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]4[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=4)[C:21]([OH:23])=[O:22])[CH2:13][CH2:12]3)[C:4]=2[CH:3]=1
Reactant: COC(=O)c1cccc(CN2CCC(Nc3ncnc4sc(Cl)cc34)CC2)c1
Agent: [Li]O
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc(CN2CCC(Nc3ncnc4sc(Cl)cc34)CC2)c1
Yield: 79 %

Procedure:
Methyl 3-((4-(6-chlorothieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)benzoate (127 mg, 0.3 mmol) was heated in a 25% MeOH—H2O solution at 90° C. for 3 h in the presence of LiOH—H2O (12.7 mg, 0.3 mmol). The solvent was removed under reduced pressure; the residue was dissolved in MeOH and filtered. The filtrate was evaporated to collect product in 79% yield (97 mg). 1H NMR (400 MHz, CD3OD) δ 8.27 (s, 1H), 7.92 (s, 1H), 7.85 (d, 1H), 7.50 (s, 1H), 7.42 (d, 1H), 7.33 (t, 1H), 4.11 (m, 1H), 3.59 (s, 2H), 2.98 (d, 2H), 2.20 (t, 2H), 2.00 (d, 2H), 1.68 (m, 2H); MS (ESI) m/z: Calculated for C19H20ClN4O2S, 403.1; Observed: 403.2 (M++1).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[CH2:15]([OH:18])[CH:16]=[CH2:17]>C1C=CC=CC=1>[CH:4]1[C:5]2[CH:6]3[CH2:17][CH:16]([CH2:15][OH:18])[CH:13]([C:12]4[C:7]3=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:14]=2[CH:1]=[CH:2][CH:3]=1
Reactant: C=CCO
Reactant: c1ccc2cc3ccccc3cc2c1
Solvent: c1ccccc1
Product: OCC1CC2c3ccccc3C1c1ccccc12
Temperature: 210 °C

Procedure:
Anthracene (45.4 gm) was combined with allyl alcohol (90.8 gm) and benzene (260 ml) in a Parr bomb and heated to 210° C. for 12 hours. The benzene was removed on a rotary evaporator and the residue was recrystallized from n-heptane to provide the product as a white solid (mp=104-105° C.).
Reaction SMILES: S(=O)(=O)(O)O.C([C:9]1[CH:21]=[CH:20][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][C:11]=2[CH:10]=1)(=O)C.[C:22]([O:25]C(=O)C)(=[O:24])[CH3:23].OO>O.C(O)=O>[C:22]([O:25][C:9]1[CH:21]=[CH:20][C:19]2[C:14]3[C:13](=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][C:11]=2[CH:10]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)c1ccc2c(c1)Cc1ccccc1-2
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Agent: OO
Solvent: O=CO
Solvent: O
Product: CC(=O)Oc1ccc2c(c1)Cc1ccccc1-2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
Sulfuric acid (40 mL) was added to a mixture of 2-acetylfluorene (165 g), formic acid (320 g), acetic anhydride (120 g) and dicholoromethane (1 L), and then aqueous hydrogen peroxide (120 mL) was dropwise added thereto. The solution was stirred for 30 minutes at a room temperature, and it was heated up to 40° C. and further stirred for 5 hours. Water (1 L) was added to the reaction mixture, and the dichloromethane layer was separated. The dichloromethane layer was washed in order with a saturated sodium carbonate aqueous solution, a sodium hydrogensulfite aqueous solution and water, and then it was dried on anhydrous magnesium sulfate and concentrated to obtain a solid matter. This was recrystallized from a mixed solvent of heptane-ethyl acetate (1:1) to obtain 2-acetoxyfluorene (149 g) of colorless needle crystal. The melting point was 130 C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[CH2:7][CH2:6][CH2:5]2.C([Li])CCC.[Br:26][C:27]1[CH:28]=[CH:29][C:30]([Cl:35])=[C:31]([CH:34]=1)[CH:32]=[O:33]>C1COCC1>[Br:26][C:27]1[CH:28]=[CH:29][C:30]([Cl:35])=[C:31]([CH:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:7][CH2:6][CH2:5]3)[OH:33])[CH:34]=1
Reactant: O=Cc1cc(Br)ccc1Cl
Reactant: COc1ccc(CN2CCCc3cc(Br)ccc32)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(CN2CCCc3cc(C(O)c4cc(Br)ccc4Cl)ccc32)cc1
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
To a cooled solution of 6-bromo-1-(4-methoxy-benzyl)-1,2,3,4-tetrahydro-quinoline (2.5 g, 7.5 mmol) in THF (30 mL) was added 1.6 M n-butyl lithium in hexanes (4.7 mL, 7.5 mmol) at −78° C., stirred for 30 min. This was transferred to a stirred solution of 5-bromo-2-chlorobenzaldehyde (1.73 g, 7.9 mmol) in THF (30 mL) at −78° C. After stirring for 30 min, reaction was quenched by the addition of saturated aqueous solution of ammonium chloride and extracted with ethyl acetate (2×50 mL). The ethyl acetate layer was washed with water, brine, dried over sodium sulphate, and concentrated. The resulting residue was purified by silica gel column chromatography to give (5-bromo-2-chloro-phenyl)-[1-(4-methoxy-benzyl)-1,2,3,4-tetrahydro-quinolin-6-yl]-methanol (2.31 g).
Reaction SMILES: [O:1]=[C:2]([C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[CH2:27][CH2:26]2)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9](C2C=CC(OCC)=CC2=C=O)[CH2:8][CH2:7]1.[OH-:34].[Na+].[ClH:36]>CO>[ClH:36].[O:1]=[C:2]([C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[CH2:27][CH2:26]2)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:7][CH2:8][N:9]([C:30]2[CH:25]=[CH:24][C:23]([C:2]([OH:1])=[O:34])=[CH:32][CH:31]=2)[CH2:10][CH2:11]1
Reactant: [OH-]
Reactant: CCOC1=CC(=C=O)C(N2CCN(CCCC(=O)c3ccc4c(c3)CCC(=O)N4)CC2)C=C1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C1CCc2cc(C(=O)CCCN3CCN(c4ccc(C(=O)O)cc4)CC3)ccc2N1

Procedure:
2.0 Grams of 6-{1-oxo-4-[4-(4-ethoxy-carbonylphenyl)-1-piperazinyl]butyl}-3,4-dihydrocarbostyril and 0.6 g of sodium hydroxide were mixed in 70 ml of methanol and refluxed by heating for 2 hours. To the reaction mixture was added 5 ml of concentrated hydrochloric acid and the mixture was concentrated under a reduced pressure to dryness. The residue was recrystallized from ethanol-water to obtain 0.6 g of 6-{1-oxo-4-[4-(4-carboxyphenyl)-1-piperazinyl]butyl}-3,4-dihydrocarbostyril monohydrochloride in colorless needle-like crystals.
Reaction SMILES: O1CCCC1.[CH3:6][O:7][C:8](=[O:24])[C@H:9]([CH:21]([CH3:23])C)[NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].C(Br)[C:26]1[CH:31]=[CH:30]C=[CH:28][CH:27]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[CH3:6][O:7][C:8](=[O:24])[C@H:9]([CH2:21][C:23]1[CH:30]=[CH:31][CH:26]=[CH:27][CH:28]=1)[NH:10][C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12]
Reactant: COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a tetrahydrofuran solution (1 ml) of the compound prepared in Example 6 (174 mg, 0.5 mmol), were succcessively added dropwise at 0° C. in a nitrogen atmosphere benzyl bromide (0.119 ml, 1.0 mmol) and a tetrahydrofuran solution of tetrabutyl ammonium fluoride (0.5 ml, 0.5 mmol). After the mixture was stirred for 1 hour at 0° C., it was poured into water and extracted with ether. The ether layer was dried over anhydrous magnesium sulfate and concentrated under vacuum. The resulting reaction mixture was subjected to column chromatography on silica gel and eluted with a 3:7 mixture of ether and hexane to give the titled compound in an amount of 122 mg (yield, 78% based on the starting materials used in Example 6)
Reaction SMILES: Cl[CH:2]1[C:6]2=[N:7][C:8]3[N:9]([CH2:21][CH3:22])[CH:10]=[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:12](=[O:15])[C:13]=3[CH:14]=[C:5]2[O:4][CH2:3]1.C1CCN2C(=NCCC2)CC1>CN(C)C=O>[CH2:21]([N:9]1[C:8]2[N:7]=[C:6]3[CH:2]=[CH:3][O:4][C:5]3=[CH:14][C:13]=2[C:12](=[O:15])[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10]1)[CH3:22]
Reactant: CCOC(=O)c1cn(CC)c2nc3c(cc2c1=O)OCC3Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC)c2nc3ccoc3cc2c1=O
Reaction time: 1 h
Yield: 81 %

Procedure:
To a solution of 3.2 g of ethyl 3-chloro-5-ethyl-8-oxo-2,3,5,8-tetrahydrofuro[3,2-b]-1,8-naphthyridine-7-carboxylate (Compound XII where R1 =R3 =C2H5, X=Cl) dissolved in 50 ml of dimethylformamide, 3.2 g of 1,8-diazabicyclo[5,4,0]-7-undecene was slowly added dropwise and the mixture was stirred at 40° to 45° C. for 1 hour. After removal of the solvent, the residue was dissolved in dilute hydrochloric acid and extracted with chloroform. The chloroform layer separated out was washed with water, dried and evaporated in vacuo to obtain 2.3 g of ethyl 5,8-dihydro-5-ethyl-8-oxofuro[3,2-b]-1,8-naphthyridine-7-carboxylate.
Reaction SMILES: [OH:1][CH2:2][C:3]1O[CH:5]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:7](=[O:9])[CH:8]=1.[CH2:29]([NH2:32])[CH2:30][CH3:31]>C(O)C.O>[OH:1][CH2:2][C:3]1[N:32]([CH2:29][CH2:30][CH3:31])[CH:5]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:7](=[O:9])[CH:8]=1
Reactant: CCCCCCCCCCCCCCCCCCOc1coc(CO)cc1=O
Reactant: CCCN
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCOc1cn(CCC)c(CO)cc1=O

Procedure:
A mixture of 20.0 g (51 mMole) 2-hydroxymethyl-5-octadecyloxy-4-pyranone and 30 mL of a 40% solution of propylamine in ethanol is heated in an autoclave at 100°-110° C. for 5 hours. After cooling, the crystallizate formed is taken up in water, stirred, filtered off, dried and recrystallized from ethyl acetate, colorless crystals thereby being obtained; m.p 120°-121° C.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])=[C:9]([O:23][CH3:24])[C:8]([Cl:25])=[C:7]([CH3:26])[C:6]=1[C:27](=[O:29])[CH3:28].[CH3:30][NH:31][CH3:32].C1COCC1>>[Cl:25][C:8]1[C:7]([CH3:26])=[C:6]([C:27](=[O:29])[CH3:28])[C:5]([O:4][CH2:3][CH2:2][N:31]([CH3:32])[CH3:30])=[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])[C:9]=1[O:23][CH3:24]
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(OCCBr)c1OCCC(C)c1ccc(F)cc1
Reactant: CNC
Solvent: C1CCOC1
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCN(C)C)c1OCCC(C)c1ccc(F)cc1
Yield: 56 %

Procedure:
Example 8a (50 mg, 0.10 mmol) was reacted with 1.0 M solution of dimethylamine in THF (1 mL, 1 mmol) at 55° C. at for 24 h. The solvent was removed under vacuum and the crude mixture was suspended in Et2O (910 mL) and 2N HCl (10 mL). The ethereal layer was separated, dried over MgSO4 and evaporated to dryness. The isolated white solid was again suspended in mixture of Et2O and hexane (1/9) sonicated for 1 minute and solid was filtered and dried. The isolated solid was suspended in DCM and washed with NaHCO3 (aq) solution. The organic layer was dried over MgSO4 and evaporated to dryness to afford the title compound as a pale yellow oil (26 mg, 56%). 1H NMR (300 MHz, CDCl3) δ 7.20-7.15 (m, 2H), 7.00-6.95 (m, 2H), 4.05 (t, J=6.0 Hz, 2H), 3.96 (t, J=6.6 Hz, 2H), 3.82 (s, 3H), 3.03-2.96 (m, 1H), 2.57 (t, J=6.0 Hz, 2H), 2.49 (s, 3H), 2.27 (s, 6H), 2.18 (s, 3H), 2.03-1.98 (m, 2H), 1.29 (d, J=6.9 Hz, 3H). MS (ES+) m/z 452.2.2 (M+H+).
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[S:8][C:9]([Cl:12])=[CH:10][CH:11]=1)=[O:6])[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:21])C=1>ClCCl>[Cl:12][C:9]1[S:8][C:7]([C:5]([NH:4][CH2:1][CH:2]2[CH2:3][O:21]2)=[O:6])=[CH:11][CH:10]=1
Reactant: C=CCNC(=O)c1ccc(Cl)s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(NCC1CO1)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An ice-cooled solution of 2.0 g (9.92 mmol) of N-allyl-5-chloro-2-thiophenecarboxamide in 10 ml of dichloromethane is admixed with metachloroperbenzoic acid (3.83 g, about 60% strength). The mixture is stirred overnight, during which it is allowed to warm to room temperature, and is then washed with 10% sodium hydrogen sulphate solution (three times). The organic phase is washed with saturated sodium bicarbonate solution (twice) and with saturated sodium chloride solution, dried over magnesium sulphate and concentrated. The product is purified by silica gel chromatography (cyclohexane/ethyl acetate 1:1).
Reaction SMILES: F[C:2]1[C:7]([CH:8]=O)=[C:6]([I:10])[CH:5]=[CH:4][N:3]=1.[CH3:11][NH:12][NH2:13]>>[I:10][C:6]1[CH:5]=[CH:4][N:3]=[C:2]2[N:12]([CH3:11])[N:13]=[CH:8][C:7]=12
Reactant: CNN
Reactant: O=Cc1c(I)ccnc1F
Product: Cn1ncc2c(I)ccnc21

Procedure:
227 mg of 2-fluoro-4-iodo-pyridine-3-carbaldehyde (0.9 mmol, 1 eq.; prepared as described in J. Org. Chem. 1993, 58, 7832) were dissolved in 3.6 mL 1-PrOH, treated with 72 μL methyl hydrazine (1.36 mmol, 1.5 eq.) and heated to 100° C. for 30 min (Biotage Initiator 60®). The reaction mixture was concentrated in vacuo, the residue was partioned between water and ethyl acetate, the aq. layer was extracted with ethyl acetate, the combined organic layers were dried and concentrated in vacuo to provide the crude target compound.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Br:7][C:8]1[CH:16]=[CH:15]C(C(O)=O)=[CH:10][C:9]=1[F:17].CN(C=O)C>C(Cl)Cl>[Br:7][C:8]1[CH:16]=[CH:15][C:1]([C:2]([Cl:4])=[O:3])=[CH:10][C:9]=1[F:17]
Reactant: O=C(O)c1ccc(Br)c(F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalyl dichloride (6.1 g, 48 mmol) was added to a solution of 4-bromo-3-fluoro-benzoic acid (7 g, 32 mmol) in DCM (80 mL) at 0° C. followed by DMF (0.2 mL) and the reaction mixture was stirred at RT for 2 h and then concentrated under vacuum to provide crude 4-bromo-3-fluoro-benzoyl chloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[O:13])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[CH3:19][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1>[O:13]=[C:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@H:9]([C:14]([O:16][CH3:19])=[O:15])[CH2:10]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)[C@@H]1CC(=O)CN1C(=O)OC(C)(C)C

Procedure:
A solution of (2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid (1 g, 4.3 mmol) in a 1:1 mixture of methanol and toluene (60 ml) was made. Trimethylsilyl diazomethane (6.5 ml of a 2M solution in hexanes, 13 mmol) was then added dropwise to the stirred solution at room temperature under nitrogen. After completion of the evolution of nitrogen gas, the resulting yellow solution was evaporated in vacuo, and the residue filtered through a pad of silica gel, eluting with ethyl acetate. Removal of solvent from the filtrate gave a yellow oil (1.05 g, near quantitative yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[N:15]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[N:14]=[C:13]([OH:23])[CH2:12]2)=[O:10])=[C:4]([C:24](=[O:31])[NH:25][CH:26]([CH:28]2[CH2:30][CH2:29]2)[CH3:27])[CH:3]=1.[H-].[Na+].[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1.Cl>CN(C)C=O>[CH3:44][C:34]1[CH:39]=[CH:38][C:37]([S:40]([O:23][C:13]2[CH2:12][CH:11]([C:9](=[O:10])[NH:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[C:24](=[O:31])[NH:25][CH:26]([CH:28]3[CH2:29][CH2:30]3)[CH3:27])[N:15]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[N:14]=2)(=[O:42])=[O:41])=[CH:36][CH:35]=1
Reactant: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(O)=NN1c1ncccc1Cl)C1CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)OC2=NN(c3ncccc3Cl)C(C(=O)Nc3ccc(Cl)cc3C(=O)NC(C)C3CC3)C2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
A mixed liquid comprising 2.0 g of N-(4-chloro-2-(1-cyclopropylethylcarbamoyl)phenyl)-1-(3-chloropyridin-2-yl)-3-hydroxy-4,5-dihydro-1H-pyrazole-5-carboxamide and 41 ml of N,N-dimethylformamide was cooled to 0° C., and 0.2 g of sodium hydride (60% oil suspension) was added. After stirring for one hour, 1.2 g of p-toluenesulfonyl chloride was added at 0° C. After stirring for 1.5 hours, the reaction liquid was poured to 120 ml of a 1 M HCl aqueous solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/0 to 1/1) to obtain 2.45 g of the desired product in the form of a paste.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:22][OH:23])=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([C:29]3[N:30]=[CH:31][N:32]([CH3:34])[CH:33]=3)[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[Mn]([O-])(=O)(=O)=[O:36].[K+]>[OH-].[Na+]>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:36])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([C:29]3[N:30]=[CH:31][N:32]([CH3:34])[CH:33]=3)[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCCc1nc2c(C)cc(-c3cn(C)cn3)cc2n1Cc1ccc(-c2ccccc2CO)cc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Product: CCCc1nc2c(C)cc(-c3cn(C)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4′-[(2-n-propyl-4-methyl-6-(1-methylimidazol-4-yl)-benzimidazol-1-yl)methyl]-2-hydroxymethylbiphenyl (0.2 g, 0.4 mmol) in 7 ml of 4 N sodium hydroxide solution, 0.252 g of potassium permanganate (1.5 mmol) is added. Reaction mixture is then stirred overnight at room temperature and finally quenched with 30 ml of saturated solution of Na2CO3. The obtained mixture is filtered, clear filtrate acidified with acetic acid to pH 4-5 and precipitated solid isolated and dried. Yield: 0.08 g.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]([OH:16])=O)=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])=[O:4].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[C:58]([Si:62]([CH3:73])([CH3:72])[O:63][C:64]1[CH:65]=[C:66]([CH:69]=[CH:70][CH:71]=1)[CH2:67][NH2:68])([CH3:61])([CH3:60])[CH3:59]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14](=[O:16])[NH:68][CH2:67][C:66]2[CH:69]=[CH:70][CH:71]=[C:64]([O:63][Si:62]([C:58]([CH3:61])([CH3:60])[CH3:59])([CH3:72])[CH3:73])[CH:65]=2)=[CH:8][C:9]=1[C:10]([F:11])([F:12])[F:13])=[O:4]
Reactant: COC(=O)c1sc(C(=O)O)cc1C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(CN)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1sc(C(=O)NCc2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 20.2 %

Procedure:
To a solution of 3-Trifluoromethyl-thiophene-2,5-dicarboxylic acid 2-methyl ester (560 mg, 2.20 mmol) in anhydrous DMF (10 mL) was added triethylamine (0.92 mL, 6.6 mmol), HBTU (1.0 g, 2.64 mmol), HOBT (360 mg, 2.64 mmol), and 3-(tert-Butyl-dimethyl-silanyloxy)-benzylamine (630 mg, 2.64 mmol). The mixture was stirred at room temperature 15 h, then quenched by pouring into EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography with 0-40% EtOAc in hexane to afford the desired product (0.21 g, 20% yield).
Reaction SMILES: [C:1]1(=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl.[CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21]N)([CH3:14])[CH3:13].Cl>C(O)C>[CH:12]([C:15]1[C:16]2[NH:21][C:1]3[C:9]4[C:4]([CH2:3][C:2]=3[C:17]=2[CH:18]=[CH:19][CH:20]=1)=[CH:5][CH:6]=[CH:7][CH:8]=4)([CH3:14])[CH3:13]
Reactant: O=C1CCc2ccccc21
Reactant: CC(C)c1ccccc1NN
Agent: Cl
Solvent: CCO
Product: CC(C)c1cccc2c3c([nH]c12)-c1ccccc1C3

Procedure:
A mixture of 12.6 g (0.096 mol) of 1-indanone, 19.7 g (0.105 mol) of 2-isopropylphenylhydrazine hydrochloride, 150 ml of ethanol and 10 ml of conc. hydrochloric acid was refluxed for 2 hours. The solvent was removed by evaporation and the residue suspended in acidic water. Extraction with ether, drying (MgSO4) and evaporation gave the crude product, which was purified by column chromatography on silica gel using methylene chloride/light petroleum (2/8) as the eluant. The final purification was achieved by recrystallization from ethylacetate/light petroleum giving 14.0 g (59%) of the product. 1H NMR (CDCl3) 1.48 (6H, d), 3.37 (1H, septet), 3.77 (2H, s), 4.37 (1H, s), 7.1-7.3 (3H, m), 7.37 (1H, dd), 7.5-7.6 (3H, m), 8.03 (1H, s).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]#[N:9])[CH2:4][CH2:3]1.[CH3:10][O-:11].[Na+]>CO>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8](=[NH:9])[O:11][CH3:10])[CH2:4][CH2:3]1
Reactant: C[O-]
Reactant: CN1CCN(C#N)CC1
Agent: [Na+]
Solvent: CO
Product: COC(=N)N1CCN(C)CC1

Procedure:
In the manner given in Example 2, 4-methyl-1-piperazinecarbonitrile is treated with sodium methoxide in methanol to give methyl 4-methyl-1-piperazinecarboximidate.