Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[Cl:59][C:60]1[N:68]=[CH:67][CH:66]=[CH:65][C:61]=1[C:62](Cl)=[O:63]>>[CH3:55][O:54][C:52](=[O:53])[C@@H:51]([N:46]1[CH2:45][C:44]2[C:48](=[CH:49][C:41]([C:38]3[CH:37]=[CH:36][C:35]([NH:34][C:62](=[O:63])[C:61]4[CH:65]=[CH:66][CH:67]=[N:68][C:60]=4[Cl:59])=[CH:40][CH:39]=3)=[CH:42][CH:43]=2)[C:47]1=[O:50])[CH:56]([CH3:58])[CH3:57]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: O=C(Cl)c1cccnc1Cl
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4cccnc4Cl)cc3)cc2C1=O
Yield: 96 %

Procedure:
The compound of example 208 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 2-chloro nicotinoyl chloride.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([SH:11])[N:8]2[N:12]=[C:13]([CH3:15])[N:14]=[C:7]2[N:6]=1)=[O:4].CC(O[CH2:20][C:21]1[CH2:30][S:29][C@@H:24]2[C@H:25]([NH2:28])[C:26](=[O:27])[N:23]2[C:22]=1[C:31]([OH:33])=[O:32])=O.B(F)(F)F.CCOCC.ClCCl>S1(CCCC1)(=O)=O.ClCCl>[NH2:28][C@@H:25]1[C:26](=[O:27])[N:23]2[C@@H:24]1[S:29][CH2:30][C:21]([CH2:20][S:11][C:9]1[N:8]3[N:12]=[C:13]([CH3:15])[N:14]=[C:7]3[N:6]=[C:5]([C:3](=[O:4])[NH:2][OH:1])[CH:10]=1)=[C:22]2[C:31]([OH:33])=[O:32]
Reactant: Cc1nc2nc(C(=O)NO)cc(S)n2n1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: O=S1(=O)CCCC1
Product: Cc1nc2nc(C(=O)NO)cc(SCC3=C(C(=O)O)N4C(=O)[C@@H](N)[C@H]4SC3)n2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.4 %

Procedure:
N-Hydroxy-7-mercapto-2-methyl-s-triazolo[1,5-a]pyrimidine-5-carboxamide (250 mg) (1.1 mmol) and 275 mg (1.0 mmol) of 7-amino-cephalosporanic acid are suspended in 15 ml of sulpholane/dichloromethane (1:1 v/v) and treated at 0° C. with 3.5 ml of boron trifluoride diethyl etherate. The mixture is stirred at 0°-5° C. for 2 hours and at room temperature for 3 hours. Subsequently, 60 ml of dichloromethane are added. Insoluble material is filtered off under suction, dissolved in water and treated with saturated sodium bicarbonate solution until pH value 3 has been reached. The precipitated product is filtered off under suction and washed in succession with water and diethyl ether. There are obtained 295 mg of (6R,7R)-7-amino-3-[[[5-(hydroxycarbamoyl)-2-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a beige powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11]Br.[C:22]([OH:30])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-:32].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([O:14][C:15](=[O:32])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][O:29][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccccc1
Reactant: Clc1cc(OCc2ccccc2)cc(Cl)c1OCCCBr
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCCCOc1c(Cl)cc(OC(=O)c2ccccc2)cc1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.5 %

Procedure:
A reaction vessel was charged with 4.24 g of 3,5-dichloro-4-(3-bromopropyl-oxy)-1-(benzyloxy)benzene, 1.33 g of benzoic acid, 1.65 g of potassium carbonate and 20 ml of N,N-dimethylformamide. After stirring at room temperature for 24 hours, the reaction mixture was poured into water, and extracted twice with 150 ml of diethyl ether. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 3.75 g of 3,5-dichloro-4-(3-benzoyloxy-propyloxy)-1-(benzoyloxy)benzene (80% yield).
Reaction SMILES: C(O[C:4](=[O:13])[C:5]1[CH:10]=[C:9]([NH2:11])[N:8]=[C:7]([NH2:12])[CH:6]=1)C.[CH3:14][NH2:15]>CO>[NH2:11][C:9]1[CH:10]=[C:5]([CH:6]=[C:7]([NH2:12])[N:8]=1)[C:4]([NH:15][CH3:14])=[O:13]
Reactant: CCOC(=O)c1cc(N)nc(N)c1
Reactant: CN
Solvent: CO
Product: CNC(=O)c1cc(N)nc(N)c1
Temperature: 70 °C
Reaction time: 24 h

Procedure:
A mixture of 0.270 g 2,6-diaminoisonicotinic acid ethyl ester and 5 ml of a 2M solution of methylamine in methanol was stirred at 70° C. for 24 h. The solvent were evaporated and the residue was triturated with ethyl acetate to yield 0.214 g of the title compound as light brown solid. MS (ISP) M+H+=167.4
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2C=C[C:17]([CH3:20])=[CH:16][CH:15]=2)[O:6][C:7]=1[C:8]1C=CC=CC=1.C/C(/C(C)=O)=N\[OH:24].CC1OC(C=O)=CC=1>>[I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[O:24][C:17]([CH3:20])=[CH:16][CH:15]=2)[O:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Reactant: CC(=O)/C(C)=N/O
Agent: Cc1ccc(C=O)o1
Product: Cc1ccc(-c2nc(CI)c(C)o2)o1

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, diacetylmonoxime and 5-methylfuran-2-carbaldehyde gave 4-iodomethyl-5-methyl-2-(5-methylfuran-2-yl)oxazole.
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13](=O)[N:14]([CH2:16][C:17](=[O:22])[NH:18][CH2:19][CH:20]=[CH2:21])C)(C)(C)C.C(Cl)[Cl:25]>>[ClH:25].[CH2:19]([NH:18][C:17](=[O:22])[CH2:16][NH:14][CH3:13])[CH:20]=[CH2:21]
Reactant: ClCCl
Reactant: C=CCNC(=O)CN(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: C=CCNC(=O)CNC
Product: Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid (7 ml) was added to a solution of the resulting allylcarbamoylmethyl-methyl-carbamic acid tert-butyl ester in methylene chloride (14 ml), and the mixture was stirred at room temperature for three hours. The reaction solution was concentrated under reduced pressure, and 4 N hydrochloric acid-dioxane was then added to the resulting residue. The mixture was concentrated under reduced pressure again to give N-allyl-2-methylamino-acetamide hydrochloride (577 mg). This was used in the next reaction without complete purification.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[C:16]([CH3:18])([CH3:17])[C:15]2[C:10](=[CH:11][C:12]([CH2:19][CH3:20])=[CH:13][CH:14]=2)[C:9]1=[O:21])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[C:16]([CH3:18])([CH3:17])[C:15]2[C:10](=[CH:11][C:12]([CH2:19][CH3:20])=[CH:13][CH:14]=2)[C:9]1=[O:21]
Reactant: O=[O+][O-]
Reactant: CC=CCC1C(=O)c2cc(CC)ccc2C1(C)C
Solvent: CO
Solvent: ClCCl
Product: CCc1ccc2c(c1)C(=O)C(CC=O)C2(C)C
Reaction time: 0.67 h
Yield: 97 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted for 40 minutes while stirring through a solution, cooled to -70°, of 8.2 g of (RS)-2-(2-buten-1-yl)-6-ethyl-3,3-dimethyl-1-indanone in 120 ml of anhydrous dichloromethane and 30 ml of anhydrous methanol. Subsequently, the mixture was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 3.72 ml of dimethyl sulfide, the mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated in a vacuum. The residue was treated with 100 ml of dichoromethane and, after the addition of 15 ml of water and 15 ml of trifluoroacetic acid, stirred at room temperature for 2 hours. The mixture was subsequently poured into 100 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 50 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 100 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. 7.55 g (97%) of (RS)-2-(2-oxoethyl)-6-ethyl-3,3-dimethyl1-indanone were obtained as a light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12]C)=[C:8]2[C:4]=1[CH2:5][CH2:6][CH2:7]2.B(Br)(Br)Br.O>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]2[CH2:5][CH2:6][CH2:7][C:8]=2[C:9]([OH:12])=[CH:10][CH:11]=1
Reactant: COc1ccc(OC)c2c1CCC2
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: COc1ccc(O)c2c1CCC2
Temperature: 5 °C
Reaction time: 2 h

Procedure:
To the clear solution of 4,7-Dimethoxyindane (22.5 gm, 0.126 mole) in Methylene chloride (400 ml), added Boron tribromide (12.27 ml, 0.13 mole) at 0° C. After 2 hours stirring at 0-10° C., water (100 ml) was added and then the reaction mixture was extracted with Methylene chloride. The Methylene chloride layer was dried over Sodium sulphate and distilled off to give a crude mass which was purified by column chromatography using 7% Ethyl acetate in Hexane (9.0 gm).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[N+:31]([C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH:36]=[O:37])([O-:33])=[O:32]>O1CCCC1>[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]([CH:26]([CH:36]([OH:37])[C:35]2[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=2[N+:31]([O-:33])=[O:32])[C:27]([O:29][CH3:30])=[O:28])[CH2:22][CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)CC1CCN(Cc2ccccc2)CC1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C(C1CCN(Cc2ccccc2)CC1)C(O)c1ccccc1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
Diisopropylamine (3.50 mL, 24.9 mmol) was dissolved in tetrahydrofuran (30 mL). The mixture was cooled to −78° C. Butyllithium (2.5 M in pentane, 9.8 mL, 24.5 mmol) was added to the mixture dropwise, and the reaction stirred at −78° C. for 15 min. A solution of methyl 2-(1-benzylpiperidin-4-yl)acetate (5.50 g, 22.2 mmol) in THF (8 mL) was then added to the mixture dropwise over 20 minutes. The reaction was stirred at −78° C. for 45 minutes. A solution of 2-nitrobenzaldehyde (3.70 g, 24.5 mmol) in THF (5 mL) was then added to the mixture dropwise over 15 minutes. The reaction was stirred at −78° C. for 30 minutes and quenched by the addition of saturated aqueous ammonium chloride. The resulting mixture was warmed to room temperature, extracted with ethyl acetate (2×). The combined organics were dried (magnesium sulfate), filtered, and concentrated. Silica gel chromatography afforded the desired product in 89% yield as light yellow foam. Mass spec.: 399.3 (MH)+.
Reaction SMILES: [S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][C:9]=2[NH:8][CH:7]=1>C(O)(=O)C.[Pd]>[S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[N:6]1[C:10]2[CH2:11][CH2:12][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:14][C:9]=2[NH:8][CH:7]=1
Reactant: COC(=O)c1ccc2nc[nH]c2c1
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COC(=O)C1CCc2nc[nH]c2C1
Yield: 101 %

Procedure:
In 600 ml of acetic acid was dissolved 40.0 g of methyl 5-benzimidazole carboxylate sulfate in a 1 l-volume autoclave, and 11 g of 10% palladium-on-carbon was added to the solution as a catalyst to conduct hydrogenation at 80° C. at a pressure of 60 atm for 5 hours. The catalyst was separated by filtration, and the mother liquor was concentrated under reduced pressure to obtain 41.0 g of methyl 4,5,6,7-tetrahydrobenzimidazole-5-carboxylate sulfate as an oil. ##STR10##
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:3]1=[O:21].[CH2:22]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([CH2:38][CH2:39][CH2:40][CH2:41][CH:42](OS(C)(=O)=O)[C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:34][CH2:33]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(OCC)(=O)C>[CH2:22]([O:29][C:30]([N:32]1[CH2:33][CH2:34][CH:35]([CH2:38][CH2:39][CH2:40][CH2:41][CH:42]([NH:1][CH:2]2[CH2:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=3[N:4]([CH2:13][C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[C:3]2=[O:21])[C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:36][CH2:37]1)=[O:31])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)C(CCCCC1CCN(C(=O)OCc2ccccc2)CC1)OS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(N)CCc2ccccc21
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CCCCC1CCN(C(=O)OCc2ccccc2)CC1)NC1CCc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Temperature: 90 °C
Yield: 51 %

Procedure:
A mixture of 1.75 g of tert-butyl 3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetate and 1.1 g of ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-methanesulfonyloxyhexanoate is heated at 90° C. for 24 hours. After cooling, the reaction solution is diluted with 200 ml of ethyl acetate, and the resulting solution is washed with 30 ml of 5% aqueous phosphoric acid and water, successively, and dried over anhydrous magnesium sulfate. After the solvent is distilled off under reduced pressure, the residue is separated and purified by silica gel column chromatography (hexane:ethyl acetate=2:1), whereby the first fraction yields 0.8 g of tert-butyl 3(RS)-[5-(1-benzyloxycarbonyl-4-piperidyl)-1(SR)-ethoxycarbonylpentyl]amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetate as a colorless oil.
Reaction SMILES: [Si]([C:5]#[N:6])(C)(C)C.[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.[Br:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>CO.S(=O)(=O)(O)N>[Br:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][CH:12]([C:11]2[CH:14]=[CH:15][C:8]([Cl:7])=[CH:9][CH:10]=2)[C:5]#[N:6])=[CH:19][CH:18]=1
Reactant: C[Si](C)(C)C#N
Reactant: Nc1ccc(Br)cc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: NS(=O)(=O)O
Solvent: CO
Product: N#CC(Nc1ccc(Br)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 83.2 %

Procedure:
TMSCN (19.9 mL, 149 mmol) was added to a solution of 4-chlorobenzaldehyde (20.0 g, 142 mmol), 4-bromoaniline (25.1 g, 146 mmol), and sulfamic acid (0.691 g, 7.11 mmol) in MeOH (56.9 mL), and the reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was filtered, and the filter cake was washed with ethanol, affording 2-(4-bromophenylamino)-2-(4-chlorophenyl)acetonitrile as a solid (38.0 g, 83%). 1H NMR (400 MHz, d6-DMSO) δ 7.53 (d, J=8.2 Hz, 2H), 7.44 (d, J=8.6 Hz, 2H), 7.37 (d, J=9.0 Hz, 2H), 6.64 (d, J=9.0 Hz, 2H), 5.38 (d, J=9.0 Hz, 1H), 4.06 (d, J=9.0 Hz, 1H).
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[OH:1][NH:2][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[CH:17]=[CH:16][N:15]=1
Reactant: NO
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(-c2ccc(C)cc2)ccn1
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1ccc(-c2ccnc(N(CCCCCCC(=O)NO)c3ccccn3)c2)cc1
Reaction time: 17 h
Yield: 38 %

Procedure:
HONH2 (50% aqueous, 2 mL) was added to III (43 mg, 0.10 mmol) in DMF (0.5 mL) and MeOH (2 mL) at rt. The reaction mixture was stirred for 17 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×2 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:4 to 100:7) to furnish IV as a colourless oil (16 mg, 38%).
Reaction SMILES: [CH:1]1([C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=2[O-:6])[CH2:3][CH2:2]1.[Na+].C1(O)CCCCC1.[OH:20][C:21]1[CH:26]=[C:25]([Cl:27])[N:24]=[N:23][C:22]=1Cl.C1(C2C=CC=C(C)C=2O)CC1>C1(C)C=CC=CC=1.O>[Cl:27][C:25]1[N:24]=[N:23][C:22]([O:6][C:5]2[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:4]=2[CH:1]2[CH2:3][CH2:2]2)=[C:21]([OH:20])[CH:26]=1
Reactant: Oc1cc(Cl)nnc1Cl
Reactant: Cc1cccc(C2CC2)c1[O-]
Agent: Cc1cccc(C2CC2)c1O
Agent: [Na+]
Solvent: OC1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
To a mixture of 25.0 g (147 mmol) of sodium 2-cyclopropyl-6-methylphenoxide and 12.5 g of cyclohexanol was added 2.5 g (purity: 98.5%; 14.7 mmol) of 4-hydroxy-3,6-dichloropyridazine at room temperature. Then, the resultant mixture was heated from room temperature to 140° C. to effect a reaction for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and 80.0 g of pure water and 90.0 g of toluene were added to the cooled mixture, and stirred for 30 minutes, and an organic phase containing 2-cyclopropyl-6-methylphenol added in an excess amount was separated. Then, the resultant aqueous phase containing a sodium salt of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol was quantitatively determined by an HPLC internal standard analysis method, which showed that 3.64 g of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 89.9%) and 10.0 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.3%) were obtained.
Reaction SMILES: C[O-].[Na+].C([O:7][C@@H:8]1[C@@H:17]([O:18]C(=O)C)[C@@H:16]([O:22]C(=O)C)[C@@H:15]([CH2:26][O:27]C(=O)C)[O:14][C@H:9]1[O:10][CH2:11][CH2:12][Br:13])(=O)C>CO>[O:10]([CH2:11][CH2:12][Br:13])[C@@H:9]1[O:14][C@H:15]([CH2:26][OH:27])[C@H:16]([OH:22])[C@H:17]([OH:18])[C@H:8]1[OH:7]
Reactant: CC(=O)OC[C@H]1O[C@@H](OCCBr)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: OC[C@H]1O[C@@H](OCCBr)[C@H](O)[C@@H](O)[C@H]1O
Reaction time: 4 h
Yield: 91.7 %

Procedure:
A solution of NaOMe (0.104 M, 0.8 mL) was added to a solution of 4j (See FIG. 7) (778 mg, 1.71 mmol) in MeOH (10 mL) under N2. After 4 hours, the reaction solution was passed through a Dowex 50W(H+) plug (3×1 cm, eluant MeOH) and the solvent removed to give 2-bromoethyl β-D-galactopyranoside (4e) (See FIG. 7) (450 mg, 92%) (The synthesis of unstable 4e has been described previously. Dahmén et al., “2-Bromoethyl Glycosides .4.2-Bromoethyl Glycosides in Glycoside Synthesis—Preparation of Glycoproteins Containing Alpha-L-Fuc-(1−>2)-D-Gal and Beta-D-Gal-(1>4)-D-Glcnac,” Carbohydr. Res., 125:237-245 (1984), which is hereby incorporated by reference) as a white solid which was used directly in the next step. NaSSO2CH3 (180 mg, 1.34 mmol) was added to a solution 4e (See FIG. 7) (290 mg, 1.01 mmol) in DMF (12 mL) under N2 and warmed to 50° C. After 15 hours, the solution was cooled and the solvent removed. The residue was purified by flash chromatography (MeOH:EtOAc, 1:9) to give 1e (See FIG. 7) (229 mg, 71%) as a white foam; [α]27D=+2.9 (c 0.58, H2O); IR (film) 3358 cm−1 (br, O—H), 1306, 1120 cm−1 (S—SO2); 1H NMR (500 MHz, D2O, COSY) δ 3.29-3.33 (m, 2H, —CH2S—), 3.30 (dd, J1,2 7.7 Hz, J2,3 10.0 Hz, 1H, H-2), 3.35 (s, 3H, CH3SO2—), 3.43 (dd, J2,3 10.0 Hz, J3 4 3.6 Hz, 1H, H-3), 3.48 (ddd, J4,5 0.9Hz, J5,6 4.3 Hz, J5,6′ 7.9 Hz, 1H, H-5), 3.52 (dd, J5,6 4.3 Hz, J6,6 11.7 Hz, 1H, H-6), 3.57 (dd, J5,6′ 7.9 Hz, J6,6 11.7 Hz, 1H, H-6′), 3.70 (dd, 3,4 3.6 Hz, J4,5 0.9 Hz, 1H, H-4), 3.80 (dt, Jd 11.2 Hz, Jt 6.1 Hz, 1H, —OCHH′—), 4.01 (dt, Jd 11.4 Hz, Jt 5.8 Hz, 1H, —OCHH′—), 4.24 (d, J1,2 7.7 Hz, 1H, H-1); 13C NMR (100 MHz, D2O) δ 36.7 (—CH2S—), 50.8 (CH3SO2—), 61.9 (—OCH2—), 69.2, 69.6, 71.7, 73.7, 76.2 (C-2, C-3, C-4, C-5, C-6), 104.0 (C-1); HRMS m/z (FAB+): Found 319.0523 (M+H+); C9H19O8S2 requires 319.0521.
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][C:4]1[S:8][C:7]([CH:9]=O)=[N:6][CH:5]=1.[BH4-].[Na+]>>[CH3:1][NH:2][CH2:9][C:7]1[S:8][C:4]([CH3:3])=[CH:5][N:6]=1
Reactant: Cc1cnc(C=O)s1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Product: CNCc1ncc(C)s1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 80 %

Procedure:
Ti (OiPr)4 (1.3 eq) was added with stirring to MeNH2 (2.0 M in MeOH, 3 eq) under Ar. After 5 min. 5-methylthiazole-2-carbaldehyde (1 eq) was added, and the solution was stirred for 1-2 h. The reaction was cooled to 0° C. and NaBH4 (1.3 eq) was added. The solution was stirred at 0° C. to room temperature overnight. After quenching the reaction with water the mixture was filtered through Celite to remove the white ppt. MeOH was removed in vacuo and the residue was diluted with EtOAc. The resulting solution was washed with water (×3), brine (×1), and dried over Na2SO4. The inorganic material was filtered off, and the solvent was removed in vacuo to give the crude product. Purification via column chromatography yielded N-methyl-1-(5-methylthiazol-2-yl)methanamine in 80-85% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH:12]2[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH2:8][CH2:7]1.[O-]CC.[Na+].[Na].C(O)C>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[O:5][CH:6]1[CH2:7][CH2:8][N:9]([C@H:12]2[CH2:13][CH2:14][C@H:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:17]2)[CH2:10][CH2:11]1
Reactant: CCOC(=O)C1CCC(N2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)CC1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)[C@H]1CC[C@H](N2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)CC1

Procedure:
Ethyl 4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-cyclohexanecarboxylate (method F, step a, 0.97 g) was added to a solution of sodium ethoxide prepared from sodium (1.28 g) and ethanol (100 ml). The resultant solution was heated under reflux for 18 h. Acetic acid (0.1 ml) was added and the solvent was evaporated. Ethyl acetate, water and sodium hydroxide were added to the residue and separated. The aqueous phase was extracted twice with ethyl acetate-methanol mixtures and the combined organic phases were washed with brine, dried (MgSO4), filtered and evaporated to give the subtitle compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:3]=1[NH:4][CH2:5][CH:6]=[O:7].C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1.[Cl:25][CH2:26][C:27](Cl)=[O:28]>O>[Cl:25][CH2:26][C:27]([N:4]([CH2:5][CH:6]=[O:7])[C:3]1[C:8]([CH3:12])=[CH:9][CH:10]=[CH:11][C:2]=1[CH3:1])=[O:28]
Reactant: Cc1cccc(C)c1NCC=O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: Cc1cccc(C)c1N(CC=O)C(=O)CCl
Temperature: 0 °C

Procedure:
The diethyl acetal of 2-(2,6-dimethylanilino)-acetaldehyde (13.0 grams), sodium carbonate (5.8 grams) dissolved in water (50 ml) and benzene (50 ml) were charged into a reaction vessel equipped with a mechanical stirrer, thermometer and cooling means. The mixture was cooled to about 0° C. and chloroacetyl chloride (6.2 grams) was incrementally added with stirring. After the addition was complete stirring was continued and the reaction mixture was permitted to warm to room temperature. After this time the mixture was filtered, washed with dilute hydrochloric acid and stripped of solvent under reduced pressure to yield the desired product the diethyl acetal of 2-(N-α-chloroacetyl-2,6-dimethylanilino)-acetaldehyde.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].[C:5]1([C:11]2(C(O)=O)[CH2:13][CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>S(=O)(=O)(O)O.ClCCl>[C:5]1([C:11]2([NH2:1])[CH2:13][CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)C1(c2ccccc2)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: NC1(c2ccccc2)CC1
Temperature: 50 °C
Reaction time: 17 h

Procedure:
Following the procedure described in N. W. Werner et.al., J. Org. Syn. Coll. Vol. 5, 273–276, sodium azide (0.915g, 14.1 mmol) is slowly added to a solution of 1-phenyl-cyclopropanecarboxlic acid (1.0 g, 6.1 mmol) in concentrated sulfuric acid (5 ml) and dichloromethane (10 ml). The sodium sulfate precipitated out of solution. The reaction mixture is heated to 50 degrees C. for 17 hours and then cooled to 0 degrees C. The mixture is basified to pH=11 with sodium hydroxide (1N) and extracted with dichloromethane (2×). The organic layers are combined, dried over sodium sulfate, filtered and concentrated. The residue is purified by chromatography (silica gel; isopropyl alcohol/chloroform/ammonium hydroxide 4/95/1) to give the title compound, MS (ESI+) for C9H11N m/z (M+H)+=134.