Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].Cl.[CH3:7][O:8][CH:9]([O:12][CH3:13])[CH2:10][NH2:11]>>[CH3:7][O:8][CH:9]([O:12][CH3:13])[CH2:10][NH:11][C:1](=[O:4])[CH:2]=[CH2:3]
Reactant: COC(CN)OC
Reactant: C=CC(=O)Cl
Agent: Cl
Product: C=CC(=O)NCC(OC)OC
Yield: 92 %

Procedure:
The round bottom flask was suspended in a dry ice-isopropanol bath. When the contents reached 0° C., the acryloylchloride solution was allowed to slowly drip into the flask. Temperature was maintained at 0° to 3° C. over a 40 minute period during which all the acryloylchloride solution had been added. Voluminous white crystals of aminoacetaldehyde dimethylacetal hydrochloride were present in the product. These crystals were removed via filtration. Methoxyhydroquinone (0.1 gram) was added and the filtrate was concentrated by evaporation of the ethyl ether to yield 189 grams of N-(2,2 dimethoxyethyl)acrylamide (92% yield).
Reaction SMILES: C(OC(=O)[CH2:5][CH2:6][C:7]1[C:12]([C:13]([O:15]C)=O)=[CH:11][N:10]=[CH:9][CH:8]=1)C.[H-].[Na+].CO>O1CCCC1>[CH:11]1[C:12]2[C:13](=[O:15])[CH2:5][CH2:6][C:7]=2[CH:8]=[CH:9][N:10]=1
Reactant: CCOC(=O)CCc1ccncc1C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C1CCc2ccncc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.4 %

Procedure:
A solution of methyl 4-(3-ethoxy-3-oxopropyl)nicotinate (4.80 g, 20.2 mmol) in tetrahydrofuran (100 mL) was added to a suspension of 60% sodium hydride (3.73 g, 93.3 mmol) in tetrahydrofuran (50 mL) at room temperature. Methanol (100 μL) was added to the mixture at room temperature, and the mixture was heated under reflux for 4 hr. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was added to 12M hydrochloric acid (50 mL) at 0° C., and the mixture was stirred at 110° C. for 30 min. The mixture was alkalified with sodium hydrogen carbonate, the insoluble material was filtered off, and the filtrate was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with hexane to give the title compound (1.57 g, yield 58%).
Reaction SMILES: [ClH:1].Cl.C[O:4][C:5]([C:7]1([NH:19][S:20]([C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][N:29]([C:33](=[NH:35])[NH2:34])[CH2:30]3)=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)=[O:6].Cl>>[ClH:1].[ClH:1].[C:33]([N:29]1[CH2:28][CH2:27][C:26]2[C:31](=[CH:32][C:23]([S:20]([NH:19][C:7]3([C:5]([OH:6])=[O:4])[CH2:12][CH2:11][N:10]([C:13]4[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=4)[CH2:9][CH2:8]3)(=[O:22])=[O:21])=[CH:24][CH:25]=2)[CH2:30]1)(=[NH:34])[NH2:35]
Reactant: COC(=O)C1(NS(=O)(=O)c2ccc3c(c2)CN(C(=N)N)CC3)CCN(c2ccncc2)CC1
Agent: Cl
Product: N=C(N)N1CCc2ccc(S(=O)(=O)NC3(C(=O)O)CCN(c4ccncc4)CC3)cc2C1
Yield: 179.6 %

Procedure:
To 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylamino)-1-(pyridin-4-yl)piperidine-4-carboxylic acid methyl ester dihydrochloride (415 mg) was added 6N hydrochloric acid (2 ml), and the mixture was stirred under reflux for 4 hours. After completion of the reaction, insoluble material was removed and the solvent was evaporated. Diethyl ether was added and the resultant solid was collected by filtration and dried under reduced pressure to give the title compound (363 mg).
Reaction SMILES: [CH:1]([C:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]2[CH2:12][CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15][CH2:16][C:4]=12)=[O:2].Cl>CO>[CH2:16]1[C:4]2=[C:3]([CH:1]=[O:2])[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]2[CH2:12][CH2:13][NH:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCc2c(C=O)c3ccccc3n2CC1
Agent: Cl
Solvent: CO
Product: O=Cc1c2n(c3ccccc13)CCNCC2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 76.5 %

Procedure:
A suspension of tert-butyl 11-formyl-1,2,4,5-tetrahydro-3H-[1,4]diazepino[1,7-a]indole-3-carboxylate (225 mg, 0.72 mmol) in methanol (5 mL) is cooled to 0° C. and treated with a solution of saturated hydrochloric acid in methanol (3 mL). After 15 min, the yellow homogenous solution is treated with an additional portion of the hydrochloric acid solution and warmed to rt. After 1 hr, the reaction is concentrated under reduced pressure, diluted with 2M sodium hydroxide (15 mL), and extracted twice with dichloromethane (20 mL). The combined organics are washed once with brine (20 mL), dried over MgSO4, filtered, and concentrated to give 165 mg of a crude solid. This material is purified by LC (230-400) silica gel eluting with 10% methanol/dichloromethane to afford 118 mg of 2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indole-11-carbaldehyde as an off-white solid. This material is recrystallized form ethyl acetate/heptane to give a light yellow solid, mp 167-168° C. IR (drift) 3307, 2941, 1636, 1464, 1429, 1391, 1367, 1350, 1269, 1205, 1124, 1052, 775, 750, 731 cm−1.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH3:42])[C:38]2=[N:43][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:49][CH2:48][C:16]([CH3:50])([O:17][CH2:18][CH:19]=[CH:20][CH2:21][C@H:22]([CH3:47])[O:23][C:24]2[CH:25]=[C:26]([F:46])[CH:27]=[C:28]([F:45])[C:29]=2[C:30]2[CH:44]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=CN2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=C(F)C=CC=2C2C=C3C=CC=2)CC1)C(OC)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH3:42])[C:38]2=[N:43][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:50])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:47])[O:23][C:24]2[CH:25]=[C:26]([F:46])[CH:27]=[C:28]([F:45])[C:29]=2[C:30]2[CH:44]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:48][CH2:49]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C)c2nc3cn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(F)cc(F)c1-c1cccc-3c1
Agent: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C)c2nc3cn2c1N1CCC(C)(CC1)OC/C=C\C[C@H](C)Oc1cc(F)cc(F)c1-c1cccc-3c1
Agent: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(F)ccc1-c1cccc-3c1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(F)cc(F)c1-c1cccc-3c1
Yield: 69.8 %

Procedure:
Prepared in 69.8% yield from methyl(2S)-2-(tert-butoxy)-2-[(22S,24Z)-16,18-difluoro-4,5,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18,24-undecaen-3-yl]acetate following the procedure for methyl(2S)-2-(tert-butoxy)-2-[(22S)-18-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate. LCMS (ESI, M+1): 690.30.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[C:5]([N+:17]([O-])=O)[CH:4]=1.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]2)=[C:5]([CH:4]=1)[NH2:17]
Reactant: COc1ccc(CN2CCN(C)CC2)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1ccc(CN2CCN(C)CC2)c(N)c1
Yield: 75 %

Procedure:
To a solution of 1-(4-methoxy-2-nitrobenzyl)-4-methylpiperazine (6 g; 25.5 mmol; 1 eq) in methanol (100 mL) was added palladium on charcoal (0.6 g; 10%) and the mixture is hydrogenated under atmospheric pressure of hydrogen for 3 h. The catalyst is filtered off and the filtrate is evaporated under vacuum. The crude residue is purified via column chromatography (eluent chloroform/methanol [9/1]) to afford 4.5 g (84%) of the title compound as a viscous liquid. 1H NMR (CDCl3, 400 MHz) δ 6.90-6.88 (m, 1H), 6.24-6.22 (m, 2H), 5.32 (br s, 2H), 3.82 (s, 3H), 3.47 (s, 2H), 2.46-2.30 (m, 8H), 2.25 (s, 3H). HPLC (max plot) 99%. LC/MS(ES+): 236.0.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:16]1[C:24]([OH:25])=[CH:23][C:19]3[O:20][CH2:21][O:22][C:18]=3[CH:17]=1)([CH2:14]O)[C:5](=[O:13])[N:6]2CO.C(P(CCCC)CCCC)CCC.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C.[OH-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:16]3=[CH:17][C:18]4[O:22][CH2:21][O:20][C:19]=4[CH:23]=[C:24]3[O:25][CH2:14]1)[C:5](=[O:13])[NH:6]2
Reactant: O=C1N(CO)c2cccc(Cl)c2C1(CO)c1cc2c(cc1O)OCO2
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C1Nc2cccc(Cl)c2C12COc1cc3c(cc12)OCO3
Temperature: 0 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
To a solution of 4-chloro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-bis(hydroxymethyl)-1,3-dihydro-2H-indol-2-one (3.63 g, 10.0 mmol) in anhydrous tetrahydrofuran (100.0 mL) was added tributylphosphine (2.53 g, 12.5 mmol) at 0° C. followed by the solution of di-tert-butylazodicarboxylate (2.88 g, 12.5 mmol) in anhydrous tetrahydrofuran (25.0 mL). The reaction solution was stirred at 0° C. for 1 h followed by the addition of ammonium hydroxide (100.0 mL). The reaction mixture was continued to stir for another 2 h. The reaction was quenched with 10% aqueous solution of hydrochloric acid (100.0 mL). The reaction solution was extracted with ethyl acetate (3×100 mL). The combined organic solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was purified by flash chromatography with ethyl acetate in hexanes to afford 4′-chlorospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.98 g, 31%) as a colourless solid: mp 175-185° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.81 (s, 1H), 7.24 (t, J=8.0 Hz, 1H), 6.94 (d, J=8.2 Hz, 1H), 6.86 (d, J=7.1 Hz, 1H), 6.59 (s, 1H), 6.28 (s, 1H), 5.90 (d, J=2.5 Hz, 2H), 4.74 (ABq, J=9.5 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ 178.4, 157.0, 148.8, 144.2, 141.9, 130.9, 130.3, 129.2, 123.0, 117.5, 109.4, 103.3, 101.9, 93.3, 77.8, 58.9; MS (ES+) m/z 318.3 (M+1), 316.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][NH2:11].C(O[CH:15]=[C:16]([C:23]#[N:24])[C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])C>C(O)CCC>[NH2:24][C:23]1[N:10]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([Br:8])=[CH:5][C:4]=2[Cl:9])[N:11]=[CH:15][C:16]=1[C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18]
Reactant: NNc1c(Cl)cc(Br)cc1Cl
Reactant: C=CCOC(=O)C(C#N)=COCC
Solvent: CCCCO
Product: C=CCOC(=O)c1cnn(-c2c(Cl)cc(Br)cc2Cl)c1N

Procedure:
20.5 parts by weight of 2,6-dichloro-4-bromophenylhydrazine and 14.5 parts by weight of allyl ethoxymethylene-2-cyanoacetate in 100 parts by volume of n-butanol were refluxed for 4 hours. The butanol was evaporated off, the oily residue was dissolved in 150 parts by volume of ether, and dry halogen chloride gas was passed in, with ice-cooling. The hydrochloride which had precipitated was stirred with saturated sodium bicarbonate solution, and the precipitate was filtered off with suction and dried under reduced pressure to give 24.8 parts by weight of allyl 5-amino-1-(2,6-dichloro-4-bromophenyl)-pyrazole-4-carboxylate of melting point 85° C. (active ingredient No.6).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]#[N:10].N.CO.[H][H]>[Ni]>[F:11][C:2]([F:1])([F:12])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH2:9][NH2:10]
Reactant: N#Cc1cnccc1C(F)(F)F
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1cnccc1C(F)(F)F
Reaction time: 16 h
Yield: 108.4 %

Procedure:
To a mixture of 4-(trifluoromethyl)-3-pyridinecarbonitrile (9.5 g, 55 mmol, 1.0 equiv) and 5 M NH3 in methanol (600 mL, 3.0 mol, 54 equiv) was added Raney-Ni (3.0 g, 52 mmol, 0.95 equiv). The flask was fitted with a hydrogen balloon, and the mixture was stirred for 16 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by HPLC to afford 10.5 g (47%) of the title compound as the bis-trifluoroacetate salt. MS (ES+): m/e 177.1 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[N:8][N:9]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:19]([F:28])([C:24]([F:27])([F:26])[F:25])[C:20]([F:23])([F:22])[F:21])[CH:16]=3)[NH:11][C:10]2=[O:29])[CH:2]=1.[H-].[Na+].[C:32](Cl)(=[O:34])[CH3:33]>CN(C)C=O>[C:32]([N:11]1[C:12]2[C:17](=[CH:16][C:15]([C:19]([F:28])([C:24]([F:25])([F:26])[F:27])[C:20]([F:22])([F:21])[F:23])=[CH:14][CH:13]=2)[CH2:18][N:9]([N:8]=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C:10]1=[O:29])(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: O=C1Nc2ccc(C(F)(C(F)(F)F)C(F)(F)F)cc2CN1N=Cc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N1C(=O)N(N=Cc2cccnc2)Cc2cc(C(F)(C(F)(F)F)C(F)(F)F)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.2 %

Procedure:
In 10 ml of dimethylformamide was dissolved 0.84 g (2.0 mmol) of 3-(3-pyridylmethylideneamino)-3,4-dihydro-6-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-2(1H)-quinazolinone, and to the resulting solution was added 0.09 g (2.3 mmol) of sodium hydride (purity: 62.4%). The reaction was carried out at room temperature for 30 minutes, after which 0.19 g (2.4 mmol) of acetyl chloride was added and the reaction was carried out for 4 hours. After completion of the reaction, the reaction solution was poured into ice water and the desired compound was extracted with ethyl acetate (20 ml×3). The extract solution was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated in vacuo. The crude product thus obtained was purified by silica gel column chromatography (ethyl acetate−methanol 10:1) to obtain 0.51 g of the desired compound.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](Cl)(=[O:13])=[O:12])(=[O:4])=[O:3].[NH2:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[N:20]=[C:19]2[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>N1C=CC=CC=1.O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:30])[CH3:31])[N:20]=[C:19]2[CH2:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)(=[O:13])=[O:12])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Reactant: C[Si](C)(C)CCOCn1nc(CCc2ccccc2)c2cc(N)ccc21
Solvent: O
Solvent: c1ccncc1
Product: C[Si](C)(C)CCOCn1nc(CCc2ccccc2)c2cc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
2-Methylsulfonyl-N-[3-phenethyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazol-5-yl]benzenesulfonamide can be obtained in the following way: 0.6 g 2-methylsulfonylbenzenesulfonyl chloride is added portionwise to a solution, at a temperature in the region of 0° C. and under argon, of 0.83 g of 5-amino-3-phenethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole in 13 ml of pyridine. The reaction mixture is then stirred for 0.5 hours at a temperature in the region of 0° C. then 2 hours at a temperature in the region of 20° C., and is then diluted with 13 ml of water. After settling out, the aqueous phase is extracted with 3 times 30 ml of ethyl acetate. The organic extracts are pooled, washed with 2 times 15 ml of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue thus obtained is purified by chromatography under argon pressure (50 kPa), on a cartridge of 70 g of silice (particle size 20-40 μm), eluting successively with pure cyclohexane then with a cyclohexane/ethyl acetate (80/20 by volume) mixture. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 25° C. 0.56 g of 2-methylsulfonyl-N-[3-phenethyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazol-5-yl]benzenesulfonamide are obtained in the form of a brown-colored paste (Rf=0.32, silica gel thin layer chromatography, eluent: cyclohexane/ethyl acetate (70/30 by volume)).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[CH:9][C:8]([CH3:19])=[CH:7][C:6]=2[CH3:20].[C:21]([C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])[C:33]=1[OH:34])[C:28](O)=[O:29])([CH3:24])([CH3:23])[CH3:22].C(P(C#N)(CC)=O)C.C(N(CC)CC)C>CN(C=O)C.O>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]1[C:10]2[C:5](=[C:6]([CH3:20])[CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=[CH:3][C:2]=1[NH:1][C:28](=[O:29])[C:27]1[CH:31]=[C:32]([C:35]([CH3:36])([CH3:37])[CH3:38])[C:33]([OH:34])=[C:25]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:26]=1
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Reactant: Cc1cc(C)c2ncc(N)c(-c3ccccc3Cl)c2c1
Agent: CCP(=O)(C#N)CC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)c2ncc(NC(=O)c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)c(-c3ccccc3Cl)c2c1
Temperature: 0 °C
Yield: 24.2 %

Procedure:
To a mixture of 3-amino-4-(2-chlorophenyl)-6,8-dimethylquinoline (1.02 g), 3,5-di-tert-butyl-4-hydroxy benzoic acid (750 mg), diethylphosphoryl cyanide (DEPC) (587 mg) and N,N-dimethylformamide (100 mg) was dropwise added a solution of triethylamine (0.51 ml) in DMF (2 ml) under stirring at 0° C. The mixture was stirred at 0° C. for 30 minutes and at room temperature for one night. Then, the mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was concentrated after being washed with water and dried (MgSO4). The residue was purified by a silica gel column chromatography with hexane-ethyl acetate (85:15,V/V), and then crystallized from methanol to give 4-(2-chlorophenyl)-3-(3,5-di-tert-butyl-4-hydroxybenzamido)-6,8-dimethylquinoline (373 mg, 24.2%). Recrystallization from methanol gave colorless prisms of mp 127°-129° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=O)[CH:5]=[CH:6][CH:7]=1.O.[NH2:20][NH2:21]>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:21][N:20]=[C:8]2[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1
Reactant: COc1ccc(C(=O)c2cccc(Cl)c2F)cc1
Reactant: NN
Agent: CN(C)c1ccncc1
Solvent: O
Product: COc1ccc(-c2n[nH]c3c(Cl)cccc23)cc1
Yield: 90.6 %

Procedure:
Prepared as in Example 104 from (3-chloro-2-fluoro-phenyl)-(4-methoxy-phenyl)-methanone (0.84 g, 3.2 mmol), hydrazine hydrate (1.0 mL, 32 mmol) and DMAP (0.39 g, 3.2 mmol) to give the product (0.75 g) as a white solid.
Reaction SMILES: O[CH2:2][C:3]1[C:8]([C:9]([NH2:11])=O)=[CH:7][CH:6]=[CH:5][N:4]=1.P(Cl)(Cl)([Cl:14])=O.[OH-].[Na+]>O>[C:9]([C:8]1[C:3]([CH2:2][Cl:14])=[N:4][CH:5]=[CH:6][CH:7]=1)#[N:11]
Reactant: NC(=O)c1cccnc1CO
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#Cc1cccnc1CCl
Temperature: 25 °C

Procedure:
165.5 g (0.98 mol) of 2-hydroxymethyl-3-pyridinecarboxamide are heated together with 270 ml of phosphorus oxychloride to 90-100° C. for 1 hour. The reaction mixture is cooled to room temperature and subsequently added dropwise to approx. 800 ml of water at 50-60° C. After the phosphorus oxychloride has been hydrolyzed, the mixture is neutralized with sodium hydroxide solution with cooling, in the course of which the product precipitates out. It is filtered off, washed with 300 ml of water and subsequently dried at 35-40° C.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]3C(=O)C4C(=CC=CC=4)C3=O)([CH3:16])[C:4]=2[CH:3]=1.O.NN.Cl.ClCCl>C(O)C>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5]([CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])([CH3:16])[C:4]=2[CH:3]=1
Reactant: CC1(CCCCN2C(=O)c3ccccc3C2=O)c2cc(Br)ccc2-c2ccc(Br)cc21
Agent: Cl
Agent: NN
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: CC1(CCCCN)c2cc(Br)ccc2-c2ccc(Br)cc21
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
2-(4-(2,7-dibromo-9-methyl-9H-fluoren-9-yl)butyl)iso indo line-1,3-dione (3.08, 5.71 mmol) was dissolved in ethanol (250 mL) under nitrogen. To the mixture was added hydrazine monohydrate (2.77 mL, 57.1 mmol), and the reaction was refluxed at 80° C. for 3.0 hours. The reaction was cooled to room temperature, and added 1M HCl (˜100 mL). The mixture was stirred for 30 minutes or until all solids were dissolved. Dichloromethane was added to the solution and the organic layer was extracted with saturated NaHCO3 three times, and washed with water. The organic layers were collected and removed solvent by vacuo to give an yellow oil (2.33 g, 100%). 1H NMR (500 MHz, CD2Cl2): δ=7.57 (d, 2H), 7.52 (d, 2H), 7.46-7.48 (dd, 2H), 2.39-2.42 (t, 2H), 1.95-1.98 (t, 2H), 1.44 (s, 3H), 1.17-1.23 (m, 2H), 0.59-0.65 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH2:9][OH:10])[CH:3]=1.[Mn]([O-])(=O)(=O)=[O:12].[K+]>O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([OH:12])=[O:10])[CH:3]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1cc(C)nc(CO)c1
Agent: [K+]
Solvent: O
Product: Cc1cc(C)nc(C(=O)O)c1
Temperature: 2.5 °C
Yield: 122.3 %

Procedure:
4,6-Dimethyl-2-pyridinemethanol (7.5 g, 29.2 mmol) was added to 100 mL of water and stirred at 0-5° C. A solution of 5.3 g (32.1 mmol) of potassium permanganate in 100 mL of water was added portion-wise over 30 min while maintaining the temperature at 5-10° C. This resulted in the formation of a black solid. The mixture was stirred at 5-10° C. for an additional 30 min and then allowed to stir at room temperature for 30 min. The mixture was filtered and the manganese dioxide washed with methanol. The methanol washings were combined with the water extracts and the solvent was removed. The resulting tan solid was redissolved in water and washed with chloroform. The water layer was separated and the water removed to yield 5.4 g of 4,6-dimethyl-2-pyridinecarboxylic acid. The product was characterized by HPLC/MS.
Reaction SMILES: [Si:1]([O:18][C:19]1[CH:20]=[C:21]([CH2:25][CH2:26][C:27]([C:29]2[O:30][C:31]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[C:32]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:33]=2)=[O:28])[CH:22]=[CH:23][CH:24]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49].C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C.O>CN(C)C=O>[Si:1]([O:18][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=1)[CH2:25][CH:26]([C:27]([C:29]1[O:30][C:31]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[C:32]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:33]=1)=[O:28])[CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)[Si](Oc1cccc(CCC(=O)c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CC(Cc1cccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1)C(=O)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.6 %

Procedure:
A mixture of 3-[3-(tert-butyldiphenylsilyloxy)phenyl]-1-(4,5-diphenyl-2-oxazolyl)-1-propanone (526 mg), ethyl bromoacetate (1.61 g), and K2CO3 (1.34 g) in N,N-dimethylformamide (2.0 ml) was stirred at room temperature for 5 hours and poured into ethyl acetate—water. The organic layer was separated, washed with water (three times) and brine, dried over MgSO4, and evaporated in vacuo. The residue was chromatographed over silica gel to afford ethyl 3-[3-(tert-butyldiphenylsilyloxy)benzyl]-4-(4,5-diphenyl-2-oxazolyl)-4-oxobutyrate (436 mg) as an oil.