Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]1(=[O:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.Cl>O>[OH:7][C:1]1[CH:6]=[CH:5][C:4]([C:1]2([C:11]3[CH:12]=[CH:13][C:8]([OH:14])=[CH:9][CH:10]=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:3][CH:2]=1
Reactant: O=C1CCCCC1
Reactant: Oc1ccccc1
Agent: Cl
Solvent: O
Product: Oc1ccc(C2(c3ccc(O)cc3)CCCCC2)cc1
Temperature: 36 °C
Reaction time: 72 h
Yield: 28.1 %

Procedure:
A mixture of 188 g (2 moles) of phenol, 98 g (1 mole) of cyclohexanone and 32 g of concentrated hydrochloric acid was heated at 36° C. with stirring for 72 hours. At the end of this time water (1000 ml) was added to the solid red mass and the mixture was extracted with ether (3000 ml). The ethereal extract was washed with water and dried over anhydrous magnesium sulfate. The dried extract was filtered and the filtrate was evaporated to dryness. The residue was recrystallized from monochlorobenzene to give 75.4 g (53 percent theoretical yield) of 1,1-bis(p-hydroxyphenyl)cyclohexane in the form of a crystalline solid having a melting point of 181° to 182.5° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[CH:7]([CH:10]([C:16](OCC)=[O:17])[C:11](OCC)=[O:12])([CH3:9])[CH3:8].C(N(CCCC)CCCC)CCC>[OH-].[Na+]>[OH:12][C:11]1[C:10]([CH:7]([CH3:9])[CH3:8])=[C:16]([OH:17])[N:3]2[N:4]=[CH:5][N:6]=[C:2]2[N:1]=1
Reactant: CCOC(=O)C(C(=O)OCC)C(C)C
Reactant: Nc1nc[nH]n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCN(CCCC)CCCC
Product: CC(C)c1c(O)nc2ncnn2c1O
Temperature: 180 °C
Reaction time: 6 h
Yield: 82.4 %

Procedure:
A mixture of 14 g (0.17 mol) of 3-amino-1,2,4-triazole, 34.3 g (0.17 mol) of diethyl 2-isopropylmalonate and 50 ml of tributylamine were stirred at 180° C. for 6 h. The reaction mixture was then cooled to 70° C., an aqueous solution of sodium hydroxide (21 g/200 ml of water) was added and the mixture was stirred for 30 min. The organic phase was separated and the aqueous phase was extracted with diethyl ether. The aqueous phase was then acidified using conc. hydrochloric acid and the resulting precipitate was collected by filtration. Drying gave 27 g (0.14 mol) of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH:34]1[CH2:39][CH2:38][S:37][CH2:36][CH2:35]1>>[NH:2]=[C:1]([N:34]1[CH2:39][CH2:38][S:37][CH2:36][CH2:35]1)[C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: C1CSCCN1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Product: N=C(c1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1)N1CCSCC1
Yield: 28 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 1.1 equivalents of thiomorpholine as secondary amine. The product was purified by preparative TLC (eluent DCM/MeOH 8:2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][C:11]([Cl:15])=[CH:12][C:13]=2Cl)=[CH:4][CH:3]=1.[OH2:16].[OH-].[Na+]>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][C:11]([Cl:15])=[CH:12][C:13]=2[OH:16])=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2nnc(Cl)cc2Cl)cc1
Reactant: O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Oc1cc(Cl)nnc1-c1ccc(F)cc1
Yield: 67.5 %

Procedure:
3-(4'-Fluorophenyl)-4,6-dichloropyridazine (145.84 g, 0.600 mol) was dissolved in dioxane (800 ml) at 60° C., water (300 ml) was added, and the solution was refluxed. Sodium hydroxide solution (48 g of solid NaOH, dissolved in 300 ml of water) was then added dropwise in the course of half an hour, and the mixture was kept under reflux for a further 5 hours. The mixture was then evaporated to dryness in vacuo, the residue was dissolved in hot water (5 l), insoluble particles were filtered off, and the solution was brought to pH 1 using concentrated hydrochloric acid. The solid obtained was isolated, washed with water and dissolved in dilute ammonia (8 l of water, pH 9-10) for further purification. Small amounts of 3-(4'-fluorophenyl)-4-chloro-6-pyridazinone were then selectively precipitated by carefully adding hydrochloric acid and then removed (by filtration), and the main bulk was then precipitated out (up to pH 1). The solid product obtained was isolated, washed with water and dried to constant weight. 91.0 g (0.4051 mol) of 3-(4'-fluorophenyl)-4-hydroxy-6-chloropyridazine of m.p.=254°-260° C. (point of decomposition) were obtained, which corresponds to a yield of 67.5% of theory.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH:7]=[C:6]2[CH3:14].S(Cl)([Cl:18])(=O)=O>C(O)(=O)C>[CH3:1][O:2][C:3]1[C:4]([Cl:18])=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH:7]=[C:6]2[CH3:14]
Reactant: COc1ccc2[nH]c(=O)cc(C)c2c1
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: COc1ccc2[nH]c(=O)cc(C)c2c1Cl
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
In a 250 ml, three-necked round bottom flask equipped with a mechanical stirrer, thermowatch, and addition funnel was placed glacial acetic acid (125 ml) and 6-methoxy-4-methyl-2-quinolone (15.78 g, 0.0834 moles). This was heated to 70° C., then a solution of sulfuryl chloride (13.5 g, 0.100 moles) and glacial acetic acid (10 ml) was added over 50 minutes. Reaction temperature held between 70-75° C. and product precipitated from solution about one third through the addition. The slurry was stirred for 15 minutes , then cooled to ambient temperature. Product was isolated by suction filtration followed by two 20 ml washes with acetic acid and one 50 ml wash with ethanol. Air dried yield is 17.9 g; purity by HPLC is 76.6 area % (contains 9.8% starting material and 12.8% over chlorinated product)
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][C@@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl.O>[CH3:1][C:2]1([CH3:9])[O:6][C@@H:5]([CH2:7][O:8][S:18]([CH3:17])(=[O:20])=[O:19])[CH2:4][O:3]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)OC[C@H](CO)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC1(C)OC[C@H](COS(C)(=O)=O)O1
Reaction time: 8 h
Yield: 100.6 %

Procedure:
((S)-2,2-Dimethyl-[1,3]dioxolan-4-yl)-methanol (2.0 g, 15.13 mmol) and triethylamine (2.53 ml, 18.16 mmol) were dissolved in dichloromethane (60 mL) followed by the addition of methanesulfonyl chloride (1.35 ml, 17.40 mmol) at 0° C. The reaction was warmed to ambinet temperature, stirred overnight, and then diluted with water. The organic layer was washed with saturated aqueous sodium bicarbonate solution, brine and dried over sodium sulfate. Removal of solvents gave methanesulfonic acid (R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester as an oil (3.2 g, 100%).
Reaction SMILES: N(CCC[C@@]1(C2C=CC=CC=2)N(C(=O)[C@@H](O[Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)C)N=C(C2C=C(F)C=CC=2F)S1)=[N+]=[N-].[NH2:48][CH2:49][CH2:50][CH2:51][C@:52]1([C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)[N:56]([C:57](=[O:62])[C@@H:58]([O:60][CH3:61])[CH3:59])[N:55]=[C:54]([C:63]2[CH:68]=[C:67]([F:69])[CH:66]=[CH:65][C:64]=2[F:70])[S:53]1>>[NH2:48][CH2:49][CH2:50][CH2:51][C@@:52]1([C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)[N:56]([C:57](=[O:62])[C@@H:58]([O:60][CH3:61])[CH3:59])[N:55]=[C:54]([C:63]2[CH:68]=[C:67]([F:69])[CH:66]=[CH:65][C:64]=2[F:70])[S:53]1
Reactant: CO[C@@H](C)C(=O)N1N=C(c2cc(F)ccc2F)S[C@@]1(CCCN)c1ccccc1
Agent: C[C@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)N1N=C(c2cc(F)ccc2F)S[C@]1(CCCN=[N+]=[N-])c1ccccc1
Product: CO[C@@H](C)C(=O)N1N=C(c2cc(F)ccc2F)S[C@]1(CCCN)c1ccccc1

Procedure:
Prepared as previously described in Example 71 using (S)-1-((R)-2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-(tert-butyldiphenylsilyloxy)propan-1-one from Step C. MS ESI (+) m/z 420 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 7.51 (m, 1H), 7.44 (m, 2H), 7.36 (m, 2H), 7.29 (m, 1H), 7.12 (m, 2H), 4.71 (q, 1H, J=6 Hz), 3.32 (s, 3H), 3.23 (m, 1H), 2.84 (m, 2H), 2.43 (m, 1H), 1.93 (m, 1H), 1.50 (d, 3H, J=6 Hz), 1.44 (m, 2H), 1.34 (m, 1H). Stereochemistry was assigned by inference from (S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CS(O[CH2:24][C@H:25]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH3:26])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[C:31]([O:30][C:28]([NH:27][C@H:25]([CH3:26])[CH2:24][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: C[C@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1ccc(-c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2ccc(OC[C@@H](C)NC(=O)OC(C)(C)C)cc2)cc1
Temperature: 50 °C
Reaction time: 21 h
Yield: 109 %

Procedure:
A suspension of ethyl 4′-hydroxybiphenyl-4-carboxylate (1.63 g), (R)-(+)-2-(tert-butoxycarbonylamino)propyl methanesulfonate (1.93 g), and cesium carbonate (2.70 g) in N,N-dimethylformamide (18 mL) was stirred at 50° C. for 21 hrs. The reaction mixture was diluted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by aminopropyl silica gel flash column chromatography (eluent: n-hexane/ethyl acetate=1/1) to afford ethyl 4′-[(R)-2-(tert-butoxycarbonylamino)propyloxy]biphenyl-4-carboxylate (2.93 g).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2[O:15][N:14]=[C:13]([CH3:16])[CH:12]=2)=[C:9]([Cl:17])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[OH:18][C:19]1[N:23]([CH3:24])[N:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC>[Cl:1][C:2]1[C:10]([C:11]2[O:15][N:14]=[C:13]([CH3:16])[CH:12]=2)=[C:9]([Cl:17])[CH:8]=[CH:7][C:3]=1[C:4]([C:20]1[CH:21]=[N:22][N:23]([CH3:24])[C:19]=1[OH:18])=[O:5]
Reactant: Cn1nccc1O
Reactant: Cc1cc(-c2c(Cl)ccc(C(=O)Cl)c2Cl)on1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: Cc1cc(-c2c(Cl)ccc(C(=O)c3cnn(C)c3O)c2Cl)on1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 73 %

Procedure:
At 0 to 5° C., the 2,4-dichloro-3-(3-methylisoxazol-5-yl)benzoyl chloride obtained above (step e) in 40 ml of dimethoxyethane was added to 0.7 g (7.35 mmol) of 5-hydroxy-1-methyl-1H-pyrazole in 30 ml of dimethoxyethane and 2.0 g (14.7 mmol) of potassium carbonate. The mixture was stirred at room temperature for 3.5 hours, heated under reflux for 1 hour and stirred at room temperature for 12 hours. The precipitate that had formed was filtered off with suction and introduced into 50 ml of water. The mixture is acidified to pH=1 and the solid is filtered off with suction and dried. Likewise, the first-mentioned filtrate was taken up in 400 ml of water, washed with methyl t-butyl ether, adjusted to pH 3 and extracted with methylene chloride. The combined organic phases were dried and concentrated. 1.9 g (73% of theory) of 4-[2,4-dichloro-3-(3-methylisoxazol-5-yl)benzoyl]-5-hydroxy-1-methyl-1H-pyrazole were obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:32])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[N:16][N:15]3[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([N:27]5[CH:31]=[CH:30]C=N5)[CH:22]=4)=[CH:19][N:20]=[C:14]3[CH:13]=2)=[CH:8][CH:7]=1.C(O[C:36](=O)[C:37]1C=CC(C2C=NN3C(C4C=CN=C(C5C=CC=CC=5)C=4)=CN=C3C=2)=C[CH:38]=1)C>>[OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:32])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[N:16][N:15]3[C:18]([C:21]4[CH:30]=[CH:31][N:27]=[C:23]([C:24]5[CH:38]=[CH:37][CH:36]=[CH:26][CH:25]=5)[CH:22]=4)=[CH:19][N:20]=[C:14]3[CH:13]=2)=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1ccc(-c2cnn3c(-c4ccnc(-c5ccccc5)c4)cnc3c2)cc1
Reactant: O=C(NCCO)c1ccc(-c2cnn3c(-c4cccc(-n5cccn5)c4)cnc3c2)cc1
Product: O=C(NCCO)c1ccc(-c2cnn3c(-c4ccnc(-c5ccccc5)c4)cnc3c2)cc1

Procedure:
This example is prepared by an analogous method to N-(2-Hydroxy-ethyl)-4-[3-(3-pyrazol-1-yl-phenyl)-imidazo-[1,2-b]-pyridazin-7-yl]-benzamide (Ex. 49) by replacing 4-[3-(3-Pyrazol-1-yl-phenyl)-imidazo[1,2-b]pyridazin-7-yl]-benzoic acid ethyl ester (Ex. 34) with 4-[3-(2-Phenylpyridin -4-yl)-imidazo[1,2-b]pyridazin-7-yl]-benzoic acid ethyl ester (Ex. 48).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:10]=1[CH2:11][NH:12][C:13]1[N:18]=[N:17][C:16]([C:19]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:20])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:41](Br)[CH:42]=[CH2:43].O>C1COCC1>[CH2:43]([N:12]([C:13]1[N:18]=[N:17][C:16]([C:19]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:20])=[CH:15][CH:14]=1)[CH2:11][C:10]1[CH:26]=[C:27]([Br:30])[CH:28]=[CH:29][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:42]=[CH2:41]
Reactant: CCCCOC(=O)c1ccc(NCc2cc(Br)ccc2OCc2ccccc2)nn1
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCN(Cc1cc(Br)ccc1OCc1ccccc1)c1ccc(C(=O)OCCCC)nn1
Reaction time: 2 h

Procedure:
To a mixture of butyl 6-[N-(2-benzyloxy-5-bromobenzyl)amino]pyridazine-3-carboxylate (CF3CO2H salt) (1.2 g) in THF (100 ml) under argon, was added potassium di-(trimethylsilyl)amide [7.0 ml of 0.67M solution in toluene] to give a yellow solution. To the solution was added allyl bromide (0.5 ml). The mixture was stirred for 2 hours, poured into water and extracted with diethyl ether. The organic solution was dried (MgSO4), evaporated and the residue purified by HPLC, eluting with dichloromethane, to give butyl 6-[N-allyl-N-(2-benzyloxy-5-bromobenzyl)amino]pyridazine-3-carboxylate (460 mg) as a gum.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH2:15])=[O:14])[CH:8]=2)=[CH:4][CH:3]=1.ClC1C=CN=[C:21]([C:25]([NH:27][CH3:28])=[O:26])C=1>>[CH3:28][NH:27][C:25]([CH2:21][NH:15][C:13]([C:9]1[CH:8]=[C:7]([O:6][C:5]2[CH:16]=[CH:17][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH:12]=[CH:11][N:10]=1)=[O:14])=[O:26]
Reactant: CNC(=O)c1cc(Cl)ccn1
Reactant: NC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Product: CNC(=O)CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1

Procedure:
The title compound was prepared in the same manner described for 4-(4-aminophenoxy)-pyridine-2-carboxamide, substituting of 4-chloropyridine-2-carboxylic acid N-methylcarbamoylmethylamide for 4-chloro-N-methyl-pyridine-2-carboxamide.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH2:6]([O:8][C:9]([C:11]1([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH:14]=[CH:13][CH2:12]1)=[O:10])[CH3:7].CN([CH:24]=[O:25])C>>[CH2:6]([O:8][C:9]([C:11]1([C:16]2[S:17][C:18]([CH:24]=[O:25])=[CH:19][CH:20]=2)[CH2:15][CH:14]=[CH:13][CH2:12]1)=[O:10])[CH3:7]
Reactant: CN(C)C=O
Reactant: CCOC(=O)C1(c2cccs2)CC=CC1
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)C1(c2ccc(C=O)s2)CC=CC1
Temperature: 105 °C
Reaction time: 0.5 h

Procedure:
POCl3 (275 mg, 1.8 mmol) was added to 1 ml DMF at ambient temperature and stirred for 30 minutes. The product of Step 1, above (2) (208 mg, 0.93 mmol), was dissolved in 1 ml DMF, added to the reaction mixture and stirred for 1 hour at ambient temperature. The reaction mixture was heated to 105° C. for 3 hours, cooled to ambient temperature, quenched with saturated sodium acetate solution and extracted (2×10 ml, EtOAc). The organics were washed with brine and dried over MgSO4, filtered and concentrated to yield the title compound (3).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[H][H]>CO>[C:8]([NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: [H][H]
Reactant: CCOC(=O)C1=C(N)CCCC1
Solvent: CO
Product: CCOC(=O)[C@H]1CCCC[C@H]1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a 10 mL test tube were charged diacetato{(S)-2,2′-bis[bis(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-1,1′-binaphthyl}ruthenium (II) (12.9 mg), and ethyl 2-aminocyclohexene-1-carboxylate (50 mg), and the mixture was set on a pressurization apparatus. Argon substitution was performed, and dehydrated methanol for organic synthesis (2.5 ml) was injected with pressure. Thereafter, hydrogen (1 MPa) was charged in and the mixture was stirred at 25° C. for 18 hr. After completion of the reaction, the reaction mixture was analyzed by HPLC.
Reaction SMILES: [C:1]([OH:6])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH:7](O)([CH3:9])[CH3:8].C1C=CC=CC=1.OS(O)(=O)=O>C1(C)C=CC(S(O)(=O)=O)=CC=1.CCOCC.O>[CH:7]([O:5][C:1](=[O:6])/[CH:2]=[CH:3]/[CH3:4])([CH3:9])[CH3:8]
Reactant: C/C=C/C(=O)O
Reactant: CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOCC
Solvent: c1ccccc1
Product: C/C=C/C(=O)OC(C)C
Yield: 56.9 %

Procedure:
40.0 g (465 mmol) of crotonic acid (Fluka 28010), 25.1 g (418 mmol) of isopropanol (Merck 1.09634.2500), 200 mL of benzene, 4.2 g of conc. H2SO4 and 2.1 g of para-toluene sulfonic acid was charged to a 500 mL flask equipped with a magnetic stirrer bar and Dean-Stark water separator. The mixture was refluxed until water formation ceased. 200 mL of ether was added to the mixture, and then washed with several portions of NaHCO3 (aq., sat.) until the the acid was neutralized. Organic phase was separated, dried with MgSO4 and filtered. Solvent was removed under reduced pressure and the remainder distilled at 95° C. to give 30.5 g of isopropylcrotonate. Yield 57%. 1H-NMR (CDCl3): 6.95 (dq, 1H), 5.82 (d, 1H), 5.05 (sept, 1H), 1.88 (d, 3H), 1.25 (d, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]([CH3:17])[C:11]2[CH2:15][O:14][C:13](=[O:16])[CH:12]=2)[CH:5]=[N:6][C:7]=1Cl.C(#N)CC.Cl[Si](C)(C)C.[I-:27].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]([CH3:17])[C:11]2[CH2:15][O:14][C:13](=[O:16])[CH:12]=2)[CH:5]=[N:6][C:7]=1[I:27]
Reactant: [I-]
Reactant: CN(Cc1cnc(Cl)c(Cl)c1)C1=CC(=O)OC1
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Solvent: CCC#N
Product: CN(Cc1cnc(I)c(Cl)c1)C1=CC(=O)OC1
Yield: 29.9 %

Procedure:
150 mg (0.55 mmol) of 4-[[(5,6-dichloropyridin-3-yl)methyl](methyl)amino]furan-2(5H)-one (10), 1.2 ml of propionitrile, 140 μl of chlorotrimethylsilane (1.10 mmol) and 247 mg of sodium iodide (1.65 mmol) are heated under reflux for 2 hours. Concentration under reduced pressure and purification of the residue by column chromatography on silica gel (silica gel 60-Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture ethyl acetate:cyclohexane (5:1) gives 60 mg (29% of theory) of 4-[[(5-chloro-6-iodopyridin-3-yl)methyl](methyl)amino]furan-2(5H)-one.
Reaction SMILES: C(OC(=O)[N:10]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26]2[S:27][C:28]([C:34]3[C:39]([F:40])=[CH:38][C:37]([C:41]([OH:44])([CH3:43])[CH3:42])=[CH:36][C:35]=3[F:45])=[CH:29][C:30]=2[C:31]([NH2:33])=[O:32])[N:20]=1)[CH2:11][C:12]([NH:14][CH:15]([CH3:17])[CH3:16])=[O:13])C1C=CC=CC=1.[H][H]>CO.[Pd]>[F:40][C:39]1[CH:38]=[C:37]([C:41]([OH:44])([CH3:43])[CH3:42])[CH:36]=[C:35]([F:45])[C:34]=1[C:28]1[S:27][C:26]([NH:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([CH2:18][NH:10][CH2:11][C:12]([NH:14][CH:15]([CH3:17])[CH3:16])=[O:13])[N:20]=2)=[C:30]([C:31]([NH2:33])=[O:32])[CH:29]=1
Reactant: CC(C)NC(=O)CN(Cc1cccc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)n1)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)NC(=O)CNCc1cccc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)n1
Reaction time: 3 h

Procedure:
Benzyl{[6-({3-(aminocarbonyl)-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-thienyl}amino)pyridin-2-yl]methyl}[2-(isopropylamino)-2-oxoethyl]carbamate (83 mg, 0.13 mmol) was dissolved in methanol. Palladium on carbon (0.68 mg, 6.4 μmol) was added and a hydrogen balloon was placed on top. The solution was evacuated and then charged with hydrogen several times. The reaction was stirred for 3 hours. The solution was filtered through celite and concentrated. The crude residue was purified by reverse phase HPLC (10-100% acetonitrile/water+0.05% TFA modifier) to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[CH2:7][CH:6]([O:8][C:9](=[O:36])[CH2:10][CH:11]([C:24]2[C:29]([CH3:30])=[CH:28][C:27]([OH:31])=[C:26]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:25]=2)[C:12]2[C:17]([CH3:18])=[CH:16][C:15]([OH:19])=[C:14]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:13]=2)[CH2:5][C:4]([CH3:38])([CH3:37])[NH:3]1.[C:40](O)(=[O:42])[CH3:41]>C(OC(=O)C)(=O)C>[C:40]([N:3]1[C:2]([CH3:39])([CH3:1])[CH2:7][CH:6]([O:8][C:9](=[O:36])[CH2:10][CH:11]([C:24]2[C:29]([CH3:30])=[CH:28][C:27]([OH:31])=[C:26]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:25]=2)[C:12]2[C:17]([CH3:18])=[CH:16][C:15]([OH:19])=[C:14]([C:20]([CH3:21])([CH3:22])[CH3:23])[CH:13]=2)[CH2:5][C:4]1([CH3:38])[CH3:37])(=[O:42])[CH3:41]
Reactant: Cc1cc(O)c(C(C)(C)C)cc1C(CC(=O)OC1CC(C)(C)NC(C)(C)C1)c1cc(C(C)(C)C)c(O)cc1C
Reactant: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1C(C)(C)CC(OC(=O)CC(c2cc(C(C)(C)C)c(O)cc2C)c2cc(C(C)(C)C)c(O)cc2C)CC1(C)C
Temperature: 25 °C

Procedure:
10 g of 2,2,6,6-tetramethyl-4-[3,3-bis-(3-tert.-butyl-6-methyl-4-hydroxyphenyl)-propionyloxy]-piperidine are stirred in 25 ml of acetic anhydride at 110° for 6 hours. The acetic acid formed and excess anhydride are then distilled off under vacuum as completely as possible. The residue is cooled down to room temperature, 100 ml of water are added and are mixed in efficiently, and the precipitate is filtered off, is washed with water and is dried. Crystallising from acetonitrile gives 1-acetyl-2,2,6,6-tetramethyl-4-[3,3-bis-(3-tert.-butyl-6-methyl-4-hydroxyphenyl)-propionyloxy]-piperidine having a melting point of 270° (optical stabiliser No. 2).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([S:13][C:14]3[CH:15]=[C:16]([C:20]4([C:26](OC)=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH:17]=[CH:18][CH:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>Cl>[CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([S:13][C:14]3[CH:15]=[C:16]([C:20]4([CH:26]=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH:17]=[CH:18][CH:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1
Reactant: COC(=O)C1(c2cccc(Sc3ccc(-n4ccnc4C)cc3)c2)CCOCC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Product: Cc1nccn1-c1ccc(Sc2cccc(C3(C=O)CCOCC3)c2)cc1
Temperature: 25 °C
Yield: 67.8 %

Procedure:
To a stirred solution of methyl 4-[3-[4-(2-methylimidazol-1-yl)phenylthio]phenyl]-3,4,5,6-tetrahydro-2H-pyran-4-carboxylate (359 mg, 0.9 mmol) was added LAH (80 mg, 2.0 mmol) at 0° C. After completion of addition, the mixture was allowed to warm to room temperature. To the reaction mixture was carefully added water (1 ml), and the resulting solids were dissolved in 1 N aqueous HCl and the aqueous solution was basified with 1 N aqueous NaOH. The aqueous mixture was extracted with ethyl acetate (30 ml×3), and the combined extracts were washed with water (50 ml) and brine (50 ml), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography {LiChroprep NH2 (Merck), 20 g; eluted with ethyl acetate} to afford 231 mg (69%) of the desired compound as white solids.