Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[Cl:9].[Cl:10][S:11](O)(=[O:13])=[O:12]>>[Br:1][C:2]1[C:3]([Cl:9])=[CH:4][C:5]([F:8])=[C:6]([S:11]([Cl:10])(=[O:13])=[O:12])[CH:7]=1
Reactant: O=S(=O)(O)Cl
Reactant: Fc1ccc(Br)c(Cl)c1
Product: O=S(=O)(Cl)c1cc(Br)c(Cl)cc1F
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 4-bromo-3-chloro-1-fluorobenzene (10 g, 47.6 mmol) and chlorosulfonic acid (20 mL) was heated at 90° C. with stirring for 2 hrs. After cooling to rt, the mixture was poured into ice water (200 mL). The resulting precipitate was filtered, washed with water, and dried to yield 5-bromo-4-chloro-2-fluoro-benzenesulfonyl chloride as a white solid (13.2 g).
Reaction SMILES: Br[CH:2]([C:5]([C:7]1[CH:8]=[N:9][N:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:11]=1)=O)[C:3]#[N:4].[NH2:21][C:22]([NH2:24])=[S:23]>CCO>[NH2:24][C:22]1[S:23][C:2]([C:3]#[N:4])=[C:5]([C:7]2[CH:8]=[N:9][N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:11]=2)[N:21]=1
Reactant: COc1ccc(Cn2cc(C(=O)C(Br)C#N)cn2)cc1
Reactant: NC(N)=S
Solvent: CCO
Product: COc1ccc(Cn2cc(-c3nc(N)sc3C#N)cn2)cc1
Temperature: 25 °C
Yield: 87 %

Procedure:
According to Scheme 7, Step 3: To a solution of 2-bromo-3-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-3-oxopropanenitrile (25.3 mmol, 8.44 g) in EtOH (120 mL) was added thiourea (26.5 mmol, 2.06 g). The resulting mixture was stirred at reflux for 2 hours. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was purified by silica column on combi-flash EtOAc/PE (1:10 to ˜1:1) to give 2-amino-4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazole-5-carbonitrile as a yellow solid (22.0 mmol, 6.83 g, 87%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[CH3:9][O:10][C:11]([C:13]1[CH:22]=[CH:21][C:16]2[C:17](=[O:20])[NH:18][S:19][C:15]=2[CH:14]=1)=[O:12].[Na]>O1CCCC1>[CH3:9][O:10][C:11]([C:13]1[CH:22]=[CH:21][C:16]2[C:17](=[O:20])[N:18]([C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[O:7])[S:19][C:15]=2[CH:14]=1)=[O:12]
Reactant: COC(=O)c1ccc2c(=O)[nH]sc2c1
Reactant: O=C(Cl)c1ccco1
Agent: [Na]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(=O)n(C(=O)c3ccco3)sc2c1

Procedure:
A mixture of 2-furoyl chloride (0.1 mole) and 3-oxo-1,2-benzisothiazoline-6-carboxylic acid methyl ester, 1,1-dioxide, sodium salt, from example 3C, above, is refluxed in 100 ml of tetrahydrofuran for 3 hours. The reaction mixture is filtered hot and the filtrate is concentrated to give the product. The product is triturated with ether and air dried to give 2-(2-furoyl)-3-oxo-1,2-benzisothiazoline-6-carboxylic acid methyl ester, 1,1-dioxide.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.[BH4-].[Na+].C(O)(=O)C>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][OH:21])=[CH:22][CH:23]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CO)cc1
Temperature: 0 °C
Yield: 97.9 %

Procedure:
To a solution of 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzaldehyde (7.0 g) in ethanol (100 ml) was added, under ice-cooling, sodium borohydride (0.473 g), and the mixture was stirred for 2 hours at room temperature. To the reaction mixture was added acetic acid (2 ml), which was poured into ice-water, then resulting crystalline precipitate was collected by filtration, followed by recrystallization from ethyl acetate--hexane to yield 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl alcohol (6.9 g, 88%) as colorless plates, m.p.112°-113° C.
Reaction SMILES: Cl.Cl.[NH2:3][NH2:4].[C:5]1(=[O:12])[O:11][C:9](=[O:10])[CH:8]=[C:6]1[CH3:7]>O>[C:5]([NH:3][NH2:4])(=[O:12])/[C:6](=[CH:8]\[C:9]([OH:11])=[O:10])/[CH3:7]
Reactant: CC1=CC(=O)OC1=O
Reactant: NN
Agent: Cl
Solvent: O
Product: C/C(=C/C(=O)O)C(=O)NN
Temperature: 10 °C

Procedure:
To a solution of 210 g of hydrazine dihydrochloride in 2 liters of water there was added, in one portion, 224 g of citraconic anhydride. When the mixture was heated to boiling with stirring, a homogeneous solution was first obtained and then a white precipitate started to form in the mixture. After 30 minutes at reflux, the mixture was allowed to cool with stirring. It was then cooled to 10° C. and the solid was separated by filtration and dried in a vacuum oven overnight to give citraconic hydrazide melting at about 281-283.5° C. with decomposition.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:3]=12.[C-:18]#[N:19].[Na+].[C-]#N>CN(C=O)C.C(O)C.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:18]([C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:3]=12)#[N:19]
Reactant: [C-]#N
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cnc2c(cnn2CC)c1C#N
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 40 %

Procedure:
To a solution of 4-chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester (10.0 g, 39.5 mmol) in DMF (50 mL) and ethanol (10 mL) was added either sodium cyanide (3.9 g, 80.0 mmol) or tetrabutylarimonium cyanide (11.8 g, 1.1 eq) or tetrabutylammonium chloride (14.7 g, 1.0 eq) and sodium cyanide (2.4 g, 1.2 eq) together. This solution or suspension was warmed up to 60° C. until reaction was completed as judged by TLC. The reaction mixture was then diluted with water (200 mL) and stirred gently at rt for 10 min. A large amount of precipitate formed. The solid was filtered and rinsed thoroughly with water to afford the title compound as an off-white solid after drying: 40-80% yield. This material was >95% pure as judged by HPLC and was used directly without further purification.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][C:18]([NH2:20])=S)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].O.O.O.C([O-])(=O)C.[Pb+2].C([O-])(=O)C.[OH-].[K+]>O>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][C:18]#[N:20])[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1cccc(-c2ccccc2NC(N)=S)c1
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CS(=O)(=O)c1cccc(-c2ccccc2NC#N)c1

Procedure:
A mixture of N-(3'-methanesulphonyl-2-biphenylyl)-thiourea (6.1 g), lead acetate trihydrate (7.6 g), potassium hydroxide (11.2 g) and water (30 ml) was heated at 90°-95° C. for 30 minutes to give N-(3'-methanesulphonyl-2-biphenylyl)cyanamide as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:15][CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[N:11]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]#[N:34])=[CH:23][CH:22]=2)[C:10]1=[O:35])=[O:7])([CH3:4])([CH3:3])[CH3:2].N>C(O)C.[Ni]>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:15][CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[N:11]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH2:33][NH2:34])=[CH:25][CH:26]=2)[C:10]1=[O:35])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3C#N)cc2)C1=O
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3CN)cc2)C1=O
Yield: 74.4 %

Procedure:
To a solution of 200 mg (0.43 mmol) of the intermediate obtained in Step B in 5 mL of ethanol was added 5 mL of liquid ammonia and the resulting mixture hydrogenated at 200-400 psi and 80° C. for 6 hours over 60 mg of Raney nickel. The reaction mixture was cautiously vented and all volatiles removed by a steady stream of nitrogen. The residue was redissolved in chloroform, filtered through Celite and the filtrate concentrated under vacuum to give 149 mg (0.32 mmol, 74%) of the product as a white foam which was used without purification.
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]1=[O:20])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[CH3:21][N:22]([CH3:36])[CH2:23][CH2:24][S:25]([NH:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)(=[O:27])=[O:26]>>[CH3:21][N:22]([CH3:36])[CH2:23][CH2:24][S:25]([NH:28][C:29]1[CH:35]=[CH:34][C:32]([NH:33]/[C:4](=[C:11]2\[C:12](=[O:20])[NH:13][C:14]3[C:19]\2=[CH:18][CH:17]=[CH:16][CH:15]=3)/[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[CH:31][CH:30]=1)(=[O:27])=[O:26]
Reactant: CCOC(=C1C(=O)Nc2ccccc21)c1ccccc1
Reactant: CN(C)CCS(=O)(=O)Nc1ccc(N)cc1
Product: CN(C)CCS(=O)(=O)Nc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 39 from 3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 4-(2-dimethylamino-ethylsulphonylamino)-aniline.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([CH3:15])[C:5]2=[C:4]([CH3:19])[N:3]=1)=[C:11]([F:16])[CH:10]=[C:9]([O:17][CH3:18])[CH:8]=3.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[NH2:28])=[CH:23][C:22]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([NH2:28])=[O:29])=[CH:23][C:22]=1[C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([CH3:15])[C:5]2=[C:4]([CH3:19])[N:3]=1)=[C:11]([F:16])[CH:10]=[C:9]([O:17][CH3:18])[CH:8]=3
Reactant: NC(=O)c1ccc(F)c(B(O)O)c1
Reactant: COc1cc(F)c2nc(C)c3c(C)nc(Br)n3c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(F)c2nc(C)c3c(C)nc(-c4cc(C(N)=O)ccc4F)n3c2c1
Yield: 10.5 %

Procedure:
Following the general Suzuki coupling procedure, reaction of bromide 6A (65 mg, 0.2 mmol), 2-fluoro-5-carbamoylphenylboronic acid (55 mg, 0.3 mmol), K2CO3 (82 mg, 0.6 mmol) and Pd(PPh3)4 (5 mg, 0.004 mmol) provided the coupling product as an off-white powder (8 mg, 11% yield). EIMS 383.1 [M+H]+.
Reaction SMILES: C([NH:4][C:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])([CH2:11][O:12]C(=O)C)[CH2:6][O:7]C(=O)C)(=O)C.[OH-].[Na+].[ClH:38]>CO>[ClH:38].[NH2:4][C:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])([CH2:6][OH:7])[CH2:11][OH:12]
Reactant: CCCCCCCCCCCCCCCCCCCCC(COC(C)=O)(COC(C)=O)NC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCCCC(N)(CO)CO

Procedure:
2-Acetamido-1,3-diacetoxy-2-icosylpropane (1.5 g) was dissolved in 40 ml of methanol and 9.6 ml of a 1N aqueous sodium hydroxide solution was added thereto. The mixture was refluxed under heating for 6 hours. The mixture was neutralized with a 1N aqueous hydrochloric acid solution and the reaction mixture was concentrated under reduced pressure. The concentrate was washed with water and ethyl acetate:hexane=1:1 in order to give 817 mg of 2-amino-2-icosyl-1,3-propanediol hydrochloride.
Reaction SMILES: C(OC([N:11]1[CH2:25][CH2:24][C:14]2([C:18](=[O:19])[N:17]([N:20]([CH3:22])[CH3:21])[C:16](=[O:23])[CH2:15]2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[ClH:26]>>[ClH:26].[CH3:21][N:20]([CH3:22])[N:17]1[C:16](=[O:23])[CH2:15][C:14]2([CH2:24][CH2:25][NH:11][CH2:12][CH2:13]2)[C:18]1=[O:19]
Reactant: CN(C)N1C(=O)CC2(CCN(C(=O)OCc3ccccc3)CC2)C1=O
Agent: Cl
Product: CN(C)N1C(=O)CC2(CCNCC2)C1=O
Temperature: 100 °C

Procedure:
To the 8-benzyloxycarbonyl-2-dimethylamino-2,8-diazaspiro[4,5]decane-1,3-dione (0.4 g) which was obtained in Example 18 was added 6N hydrochloric acid (20 ml), and was followed by heating at 100° C. for 3 hours. The solvent was then evaporated; the resulting residual solid was recrystallized from ethanol-ethyl acetate to obtain 0.3 g of a colorless crystal having a melting point of from 257° to 260° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2].[CH3:24][Mg]Cl>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])([CH3:24])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1=O
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1(C)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 38 %

Procedure:
6-Methoxy-1-oxo-3-phenyl-1H-indene-2-carboxylic acid ethyl ester (300 mg, 0.974 mmol) obtained in Example 1 was dissolved in THF and 1.2 equivalents of methylmagnesium chloride were added thereto, followed by stirring for 3 hrs at 0° C. The resulting mixture washed with saturated saline and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4, and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 126 mg of the titled compound (yield: 38%).
Reaction SMILES: C[O:2][C:3]1[CH:34]=[CH:33][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][C:28]([O:31]C)=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)=[O:17])=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>O>[OH:31][C:28]1[CH:27]=[CH:26][C:25]([O:24][C:21]2[CH:20]=[CH:19][C:18]([C:16]([C:14]([C:11]3[CH:12]=[CH:13][C:8]([O:7][C:6]4[CH:33]=[CH:34][C:3]([OH:2])=[CH:4][CH:5]=4)=[CH:9][CH:10]=3)=[O:15])=[O:17])=[CH:23][CH:22]=2)=[CH:30][CH:29]=1
Reactant: COc1ccc(Oc2ccc(C(=O)C(=O)c3ccc(Oc4ccc(OC)cc4)cc3)cc2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(C(=O)c1ccc(Oc2ccc(O)cc2)cc1)c1ccc(Oc2ccc(O)cc2)cc1
Temperature: 220 °C
Yield: 81 %

Procedure:
In a 250 ml round-bottom flask with a stirbar were placed 4,4'-bis(4-methoxyphenoxy)benzil (7.81 g, 20 mmol) and pyridine hydrochloride (13.87 g, 120 mmol). The mixture was heated under nitrogen in a 220° C. oil bath for 45 mins after which time deprotection was complete. The mixture was cooled to 80° C. and diluted to a volume of 250 ml by dropwise addition of water. The crude product was isolated by suction filtration, washed with water and then recrystallized from acetic acid to give the product (6.91 g, 81%). (mp=220°-221° C.).
Reaction SMILES: [CH3:1][C:2]([C:5]#[C:6][CH:7]([OH:16])[C:8]#[C:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])[CH3:3]>ClCCl.[O-2].[O-2].[Mn+4]>[CH3:4][C:2]([C:5]#[C:6][C:7](=[O:16])[C:8]#[C:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)C#CC(O)C#Cc1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(C)(C)C#CC(=O)C#Cc1ccccc1
Yield: 95 %

Procedure:
(C15H14O), FW=210.27 g/mol. 1-(1,1-dimethylethyl)-5-phenyl-1,4-pentadiyn-3-ol (5.46 g, 25.6 mmol) was dissolved in dichloromethane (134 mL). Manganese dioxide (13.42 g, 154 mmol) was added and the reaction was heated to reflux for 45 minutes. The reaction mixture was cooled and filtered through celite and concentrated. The orange liquid was obtained in 95% yield. Rf 0.72 (DCM) 1H NMR (500 MHz, CDCl3, ppm) d 7.59 (d, 2H, J=7.3 Hz), 7.46 (t, 1H, J=7.3 Hz), 7.38 (t, 2H, J=7.3 Hz) 1.32 (s, 9H); 13C NMR (75 MHz, CDCl3, ppm) d 161.3, 133.2, 131.0, 128.6, 119.6, 102.6, 90.3, 89.4, 80.8, 29.8, 27.9; HRMS(EI) m/z calculated 210.104465, found 210.103678.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[C:11](=[N:14][NH2:15])[C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])=[N:9]1.[I:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1.[H-].[Na+].[Cl-].[NH4+]>CN(C)C=O.O>[I:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:15][N:14]=[C:11]2[C:12](=[O:13])[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[N:9]=[C:10]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])=[CH:26][CH:25]=1
Reactant: BrCc1ccc(I)cc1
Reactant: NN=C1C(=O)N(c2ccccc2F)N=C1c1ccccc1F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1C(=NNCc2ccc(I)cc2)C(c2ccccc2F)=NN1c1ccccc1F
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
1,3-Bis(2-fluorophenyl)-1H-pyrazole-4,5-dione-4-hydrazone (57 mg, 0.19 mmol) and 4-iodobenzylbromide (56 mg, 0.19 mmol, 1.0 equiv) were dissolved in degassed N,N-dimethylformamide (3 mL), cooled to 0° C. and treated with sodium hydride (17 mg, 0.43 mmol, 2.2 equiv). After stirring at 0° C. for 1.5 hours, the mixture was treated with ammonium chloride (3 mL, aqueous saturated), poured into water (15 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 1:1; hexanes:ethyl acetate), providing the titled compound as a light yellow solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:6]S[CH2:4][C:3]1([CH3:9])[C:7]#[N:8].C1C=C(Cl)C=C(C(OO)=O)C=1.[S:21]([O-:25])([O-])(=[O:23])=S.[Na+].[Na+]>C(Cl)Cl>[OH:1][CH:2]1[CH2:6][S:21](=[O:25])(=[O:23])[CH2:4][C:3]1([CH3:9])[C:7]#[N:8]
Reactant: O=S([O-])([O-])=S
Reactant: CC1(C#N)CSCC1O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C#N)CS(=O)(=O)CC1O
Temperature: 25 °C

Procedure:
(3R,4S and 3S,4R)-4-Hydroxy-3-methyltetrahydrothiophene-3-carbonitrile (140 mg, 0.98 mmol) was dissolved in DCM (4.9 mL) and was stirred vigorously at ambient temperature. m-CPBA (340 mg, 2.0 mmol) was added in three portions and the resulting mixture was maintained at ambient temperature for 18 hours. The mixture was then diluted with 1M aqueous sodium thiosulfate and extracted with EtOAc. The organic layer was again washed with 1M aqueous sodium thiosulfate, saturated aqueous NaHCO3, brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-100% EtOAc/hexanes) to afford the title compound. 1H NMR (600 MHz, CD3OD): δ 4.40 (t, J=6.5 Hz, 1H); 3.70 (d, J=13.6 Hz, 1H); 3.56 (dd, J=13.8, 6.2 Hz, 1H); 3.29-3.30 (m, 1H); 3.23 (dd, J=13.7, 6.8 Hz, 1H); 1.60 (s, 3H).
Reaction SMILES: [CH2:1]([N:4]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:5]1)[CH2:2][CH3:3].[F:15][CH2:16][C@H:17]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)[CH3:18]>C(Cl)Cl.N1C=CC=CC=1>[F:15][CH2:16][C@H:17]([C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:14][C:11]2[CH:10]=[CH:9][C:8]([CH:6]3[CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH2:7]3)=[CH:13][CH:12]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1)[CH3:18]
Reactant: CCCN1CC(c2ccc(N)cc2)C1
Reactant: C[C@H](CF)c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCN1CC(c2ccc(NS(=O)(=O)c3ccc([C@H](C)CF)cc3)cc2)C1
Yield: 22.5 %

Procedure:
Following the same procedure as described in example 55, 4-(1-propyl-azetidin-3-yl)phenylamine (110 mg, 0.57 mmol) in CH2Cl2/pyridine 1:1 (12 ml) was treated with 4-((S)-2-fluoro-1-methyl-ethyl)-benzenesulfonyl chloride (178 mg, 0.75 mmol). Purification of the crude product by flash column chromatography (CH2Cl2:methanol, 95:5) provided the title compound (50 mg, 22%) as a gum.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([OH:8])=[N:6][CH:7]=1.[CH3:12]I>C(Cl)(Cl)Cl.[Al]>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([O:8][CH3:12])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1O
Reactant: CI
Agent: [Al]
Solvent: ClC(Cl)Cl
Product: COc1ncc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 44.8 %

Procedure:
In a 1 L, round-bottomed, single-necked flask equipped with a magnetic stirring bar was placed 5-bromo-3-nitropyridin-2-ol (50.0 g, 0.23 mol) in CHCl3 (500 mL) under nitrogen in the dark (wrapped in aluminum foil.) To this solution was added Ag2CO3 (75.5 g, 0.28 mol) and MeI (142.0 mL, 2.3 mol). After the mixture was stirred for 48 h at room temperature, it was filtered through a pad of Celite, washed with CH2Cl2, and concentrated. The crude mixture was purified by column chromatography (EtOAc:Hexane, 1:4) to give 24.0 g (45%) of 5-bromo-2-methoxy-3-nitropyridine (15) as a solid.
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH2:12][CH3:13])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:11])[CH2:9][CH3:10].[OH:14][C:15]1[CH:23]=[CH:22][C:18]2[CH2:19][CH2:20][O:21][C:17]=2[CH:16]=1>>[CH2:12]([C:4]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:11])[CH2:9][CH3:10])=[CH:3][CH2:2][O:14][C:15]1[CH:23]=[CH:22][C:18]2[CH2:19][CH2:20][O:21][C:17]=2[CH:16]=1)[CH3:13]
Reactant: Oc1ccc2c(c1)OCC2
Reactant: CCC(C)=CCCC(=CCBr)CC
Product: CCC(C)=CCCC(=CCOc1ccc2c(c1)OCC2)CC

Procedure:
1-bromo-3-ethyl-7-methyl-2,6-nonadiene and 6-hydroxy2,3-dihydrobenzofuran are reacted to form 6-[(3-ethyl-7-methyl-2,6-nonadienyl)-oxy]-2,3-dihydrobenzofuran of boiling point 132° C. -134° C./0.001 mmHg; nD20 = 1.5346;
Reaction SMILES: [NH2:1][C@H:2]([CH:21]([CH3:23])[CH3:22])[C:3]([N:5]1[CH2:10][CH2:9][C@@:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)([OH:11])[C:7]([CH3:20])([CH3:19])[CH2:6]1)=[O:4].[CH3:24][N:25]1[C:29]([C@@H:30]2[CH2:35][CH2:34][CH2:33][C@H:32]([C:36](O)=[O:37])[CH2:31]2)=[N:28][N:27]=[N:26]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(CC)CC)C>C(Cl)Cl>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([C@@:8]2([OH:11])[CH2:9][CH2:10][N:5]([C:3](=[O:4])[C@H:2]([NH:1][C:36]([C@H:32]3[CH2:33][CH2:34][CH2:35][C@@H:30]([C:29]4[N:25]([CH3:24])[N:26]=[N:27][N:28]=4)[CH2:31]3)=[O:37])[CH:21]([CH3:23])[CH3:22])[CH2:6][C:7]2([CH3:19])[CH3:20])=[CH:17][CH:16]=1
Reactant: Cn1nnnc1[C@@H]1CCC[C@H](C(=O)O)C1
Reactant: CC(C)[C@@H](N)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@@H](NC(=O)[C@H]1CCC[C@@H](c2nnnn2C)C1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Yield: 98.5 %

Procedure:
(R)-2-Amino-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methylbutan-1-one (25 mg, 0.067 mmol), (±)-cis-3-(1-methyl-1H-tetrazol-5-yl)cyclohexanecarboxylic acid (17 mg, 0.080 mmol), HOBT (12 mg, 0.080 mmol), EDC (15 mg, 0.080 mmol) and triethylamine (0.019 mL, 0.133 mmol) were mixed in methylene chloride (3 mL) at 25° C. with stirring. The reaction was stirred for 20 hours then washed with sat'd sodium bicarbonate. The methylene chloride layer was dried over sodium sulfate and concentrated in vacuo to give a white glass which was purified over silica gel (1:1 Hexanes/EtOAc to 100% EtOAc to 4:1 methylene chloride) to obtain (±)-cis-N—((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)-3-(1-methyl-1H-tetrazol-5-yl)cyclohexanecarboxamide (35 mg, 0.066 mmol, 99% yield) as a white glass. MS found: (M+H)+=531.46.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]([C:10]1[CH2:19][C@@H:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[Cl:27][C:22]1[CH:21]=[C:20]([C@H:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C@@H:10]([CH:8]([NH:7][C:6](=[O:28])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH3:9])[CH2:19]2)[CH:25]=[CH:24][C:23]=1[Cl:26]
Reactant: CC(NC(=O)OC(C)(C)C)C1=Cc2ccccc2[C@H](c2ccc(Cl)c(Cl)c2)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(NC(=O)OC(C)(C)C)[C@@H]1Cc2ccccc2[C@H](c2ccc(Cl)c(Cl)c2)C1
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution of tert-butyl (S)-1-((S)-4-(3,4-dichlorophenyl)-3,4-dihydronaphthalen-2-yl)ethylcarbamate 49a (Example 21.3) (60 mg, 0.14 mmol) in ethyl acetate (8 mL) was added palladium on charcoal (30 mg, 5%). The mixture was then stirred under hydrogen (1 atm) for 1 h. The catalyst was filtered off through a pad of Celite. The filtrate was concentrated. Chiral AD column separation (ethanol/methanol/hexane/DEA=3:2:95:0.1) afforded tert-butyl 1-((2S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-2-yl)ethylcarbamate (isomer 2) (40 mg, 67%).