Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[C:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:14][CH:13]=[CH:12][C:11]=1[CH:25]([OH:29])[C:26]([OH:28])=[O:27].C(OC(=O)C)(=O)C>CS(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[C:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:14][CH:13]=[CH:12][C:11]=1[C:25](=[O:29])[C:26]([OH:28])=[O:27]
Reactant: O=C(O)C(O)c1cccc(OCc2ccccc2Cl)c1OCc1ccccc1Cl
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)C(=O)c1cccc(OCc2ccccc2Cl)c1OCc1ccccc1Cl
Reaction time: 3 h
Yield: 96 %

Procedure:
To a stirred solution of Example 1 Part B compound (400 mg, 0.867 mmol) in DMSO (1 mL) at 90° C. was added acetic anhydride (0.1 mL, 1 mmol) over 1 h. After an additional 3 h, the reaction mixture was cooled, diluted with water and extracted three times with ether. The organic extracts were combined, washed with brine, dried (Na2SO4) and evaporated. Purification by flash chromatography on silica gel provided the title compound, 382 mg (96% yield). LC/MS gave the correct molecular ion [(M+Na)+=481] for the desired compound.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1>>[CH3:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:1]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[O:8])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: O=C(Cl)c1cccnc1
Product: COc1ccc(NC(=O)c2cccnc2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared from nicotinoyl chloride and 4-methoxy-2-nitroaniline and was obtained as an orange solid as described in Example 1. 1H NMR (DMSO-d6): 10.74 (s, 1H), 9.10 (d, J=2.4, 1H), 8.80-8.78 (m, 1H), 7.62-7.54 (m, 3H), 7.39-7.35 (m, 1H), 3.87 (s, 3H).
Reaction SMILES: [OH:1][C:2]1([C:14]2[S:15][C:16]([C:19]3[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([NH:26][C:27]4[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][N:28]=4)[N:20]=3)=[CH:17][N:18]=2)[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]#[N:13])[CH:5]=[CH:4][C:3]1=2.[N-:37]=[N+:38]=[N-:39].[Na+]>[Br-].[Zn+2].[Br-].CN(C=O)C>[CH3:25][C:23]1[CH:22]=[C:21]([NH:26][C:27]2[CH:32]=[C:31]([C:33]([F:35])([F:34])[F:36])[CH:30]=[CH:29][N:28]=2)[N:20]=[C:19]([C:16]2[S:15][C:14]([C:2]3([OH:1])[C:3]4[C:8](=[CH:7][C:6]([C:12]5[N:37]=[N:38][NH:39][N:13]=5)=[CH:5][CH:4]=4)[CH2:9][CH2:10][CH2:11]3)=[N:18][CH:17]=2)[CH:24]=1
Reactant: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cnc(C3(O)CCCc4cc(C#N)ccc43)s2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Br-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: CN(C)C=O
Product: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cnc(C3(O)CCCc4cc(-c5nn[nH]n5)ccc43)s2)c1
Temperature: 125 °C
Yield: 12.9 %

Procedure:
To a microwave vial was added 5-hydroxy-5-(5-(4-methyl-6-((4-(trifluoromethyl)pyridin-2-yl)amino)pyridin-2-yl)thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (250 mg, 0.493 mmol), sodium azide (32.0 mg, 0.493 mmol), zinc bromide (111 mg, 0.493 mmol) and DMF (2463 μl). The tube was sealed and heated to 125° C. for 16 h. The reaction was cooled to rt and filtered, then purified by reverse phase HPLC using a C18 column with a solvent system containing MeCN and H2O modified with 0.1% TFA. Product containing fractions were lyophilyzed to give 1-(5-(4-methyl-6-((4-(trifluoromethyl)pyridin-2-yl)amino)pyridin-2-yl)thiazol-2-yl)-6-(2H-tetrazol-5-yl)-1,2,3,4-tetrahydronaphthalen-1-ol (35 mg, 13%) as a white powder. MS ESI calcd for C26H21F3N8OS [M+H]+ 551, found 551. 1H NMR (600 MHz, dmso) δ 10.17 (s, 1H), 8.63 (s, 1H), 8.46 (d, J=4.8, 1H), 8.22 (s, 1H), 7.81 (s, 1H), 7.75 (d, J=7.8, 1H), 7.41 (d, J=8.1, 1H), 7.34 (s, 1H), 7.18 (d, J=4.0, 1H), 7.07 (s, 1H), 6.62 (s, 1H), 2.90 (d, J=4.3, 2H), 2.42-2.33 (m, 1H), 2.28 (s, 3H), 2.19-2.07 (m, 1H), 2.07-1.90 (m, 2H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH2:24][CH3:25])[CH:6]=1.[C:27]([C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1)(=[O:29])[CH3:28]>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=2[CH2:22][N:23]([S:36]([C:33]2[CH:32]=[CH:31][C:30]([C:27](=[O:29])[CH3:28])=[CH:35][CH:34]=2)(=[O:38])=[O:37])[CH2:24][CH3:25])[CH:6]=1
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCNCc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)OC)c1
Product: CCN(Cc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)OC)c1)S(=O)(=O)c1ccc(C(C)=O)cc1

Procedure:
Prepared according to the procedure described in Example 22, Step 1, using the following starting materials: [3-(2-ethylaminomethyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid methyl ester and 4-acetylbenzenesulfonyl chloride.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:18])[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[C:9]([O:16][CH3:17])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[C:19](NC(=O)C1C=CC(N)=C(OC)C=1)(C)(C)C>>[C:1]([NH:5][C:6](=[O:18])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([O:16][CH3:17])[CH:8]=1)([CH2:4][CH3:19])([CH3:3])[CH3:2]
Reactant: COc1cc(C(=O)NC(C)(C)C)ccc1N
Reactant: COc1cc(C(=O)NC(C)(C)C)ccc1[N+](=O)[O-]
Product: CCC(C)(C)NC(=O)c1ccc(N)c(OC)c1

Procedure:
In the same way, from the compound N-tert-butyl-3-methoxy-4-nitrobenzamide, N-tert-butyl-3-methoxy-4-aminobenzamide is prepared; M.p.=160° C.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[NH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][CH2:18]1.O>CO>[C:10]1([CH:8]([OH:9])[CH:7]([NH:16][CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)[C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Solvent: O
Solvent: CO
Product: OC(c1ccccc1)C(NC1CCN(Cc2ccccc2)CC1)c1ccccc1
Temperature: 145 °C
Yield: 95.2 %

Procedure:
A mixture of trans-stilbene oxide (1.96 g, 0.010 mol) and 4-amino-1-benzylpiperidine (5.70 g, 0.030 mol) was heated at 145° C. in an oil bath for 15 hours. The cooled mixture was then dissolved in methanol (20 mL) and the solution poured into water (200 mL). The product separated as an oil that solidified on standing. The solid was collected and dried under ambient conditions for 18 hours to obtain 3.68 g (95%) of material. Recrystallization from toluene-isooctane gave 2.31 g of the product as a tan solid; mp 128°-130° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:18][O:19][C:20]([C:22]12[C:30]([CH3:37])([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:29][CH:28]=[C:27](I)[CH:26]1[CH2:25][N:24]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:23]2)=[O:21]>CO.C1(C)C=CC=CC=1.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>[CH3:18][O:19][C:20]([C:22]12[C:30]([CH3:37])([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:29][CH:28]=[C:27]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:26]1[CH2:25][N:24]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:23]2)=[O:21]
Reactant: COc1ccc(B(O)O)cc1
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(I)=CCC2(C)c1ccccc1
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: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C12CN(Cc3ccccc3)CC1C(c1ccc(OC)cc1)=CCC2(C)c1ccccc1
Yield: 51.7 %

Procedure:
A solution of 20.1 g (0.132 mol) of 4-methoxyphenylboronic acid in 580 cm3 of methanol and 1170 cm3 of a 2N aqueous sodium carbonate solution were successively added to a solution of 58.6 g (0.12 mol) of methyl(3aRS,4SR,7aRS)-2-benzyl-7-iodo-4-methyl-4-phenyl-2,3,3a,4,5,7a-hexahydro-1H-isoindole-3a-carboxylate and of 7 g of tetrakis(triphenylphosphine)palladium in 30 cm3 of toluene and then the mixture was brought to reflux for twenty-four hours. After returning to a temperature in the region of 20° C., the reaction mixture was extracted with ethyl acetate, washed with distilled water, dried over magnesium sulphate and then concentrated under reduced pressure. The residue obtained was purified by flash chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (98/02 by volume) mixture. 29 g (52%) of methyl(3aRS,4SR,7aRS)-2-benzyl-7-(4-methoxyphenyl)-4-methyl-4-phenyl-2,3,3a,4,5,7a-hexahydro-1H-isoindole-3a-carboxylate were thus obtained in the form of a brown powder, the characteristics of which were as follows:
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[C:6]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][C:7]=2[S:8][CH:9]=1)=O.[NH:16]1[CH2:20][CH2:19][NH:18][C:17]1=[S:21].C(O)C>C(O)(=O)C>[BrH:1].[S:21]1[CH:2]=[C:3]([C:5]2[C:6]3[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][C:7]=3[S:8][CH:9]=2)[N:18]2[CH2:19][CH2:20][N:16]=[C:17]12
Reactant: N#Cc1ccc2scc(C(=O)CBr)c2c1
Reactant: S=C1NCCN1
Solvent: CC(=O)O
Solvent: CCO
Product: Br
Product: N#Cc1ccc2scc(C3=CSC4=NCCN34)c2c1
Yield: 73.2 %

Procedure:
A mixture of 3-(bromoacetyl)benzo[b]thiophen-5-carbonitrile (1.05 g), 2-imidazolidinethione (0.4 g), ethanol (31.5 ml), and acetic acid (21 ml) was heated under reflux under nitrogen for 24 hours, then cooled in ice. The resulting precipitate was collected by filtration, washed with ether, and dried in vacuo at 65° C. to give 3-(5,6-dihydroimidazo[2,1-b]thiazol-3-yl)benzo[b]thiophen-5-carbonitrile monohydrobromide as a white solid (1 g), m.p. 303°-305° C.
Reaction SMILES: [Cl-:1].[Al+3].[Cl-].[Cl-].[CH3:5][CH:6]([CH3:10])[C:7](Cl)=[O:8].[Cl:11][CH:12]=[CH2:13]>ClC(Cl)Cl>[Cl:11][CH:12]([Cl:1])[CH2:13][C:7](=[O:8])[CH:6]([CH3:10])[CH3:5]
Reactant: CC(C)C(=O)Cl
Reactant: [Cl-]
Reactant: C=CCl
Agent: [Al+3]
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)CC(Cl)Cl
Reaction time: 0.67 h

Procedure:
Anhydrous aluminium chloride (27.2 g) was added to a stirred solution of 2-methylpropionyl chloride (23.4 g) in dry trichloromethane (100 ml) with external cooling to between 0° C. and 15° C. Over a period of 1 hour chloroethene (20 g) was passed through the mixture held at 24°-26° C., after which stirring was continued for a further 40 minutes. The reaction mixture was then poured onto crushed ice, the organic layer was separated, dried over magnesium sulphate and distilled under reduced pressure to obtain a colourless liquid of 1,1-dichloro-4-methyl-3-pentanone. Yield 23 g.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]([F:22])([F:21])[C:15]([CH3:20])=[CH:16][C:17](O)=[O:18].[CH3:23][S:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=1>C1COCC1.O>[F:13][C:14]([F:22])([F:21])[C:15]1[CH:20]=[C:29]([C:28]2[CH:31]=[CH:32][C:25]([S:24][CH3:23])=[CH:26][CH:27]=2)[NH:30][C:17](=[O:18])[CH:16]=1
Reactant: CSc1ccc(C#N)cc1
Reactant: CC(=CC(=O)O)C(F)(F)F
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: CSc1ccc(-c2cc(C(F)(F)F)cc(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43.7 %

Procedure:
To a stirred solution of diisopropylamine (11.5 mL, 81.8 mmol) in THF (75 mL) at 0° C. was added n-butyllithium (51.1 mL of a 1.6M solution in hexanes, 81.8 mmol). After stirring for 15 minutes, a solution of 4,4,4-trifluoro-3-methyl-2-butenoic acid (6.0 g, 38.9 mmol) in THF (10 mL) was added dropwise. The reaction was allowed to warm to room temperature and stirred for 30 minutes before being cooled to 0° C. and treated dropwise with a solution of 4-(methylthio)benzonitrile (2.91 g, 19.5 mmol) in THF (10 mL). Upon complete addition, the reaction was heated at reflux for 14 hours. After cooling, water (200 mL) was added and the mixture extracted with ethyl acetate (250 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo and the resulting residue purified by silica chromatography eluting with 1:1 ethyl acetate/cyclohexane to give the title product (2.43 g) LC retention time 3.10 mins MS m/z 286 (MH+).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:7])[C:4]([NH2:6])=[S:5].C[I:9].[C:10](OCC)(=O)C>CN(C)C=O>[IH:9].[CH3:1][O:2][N:3]([CH3:7])[C:4](=[NH:6])[S:5][CH3:10]
Reactant: CI
Reactant: CCOC(C)=O
Reactant: CON(C)C(N)=S
Solvent: CN(C)C=O
Product: CON(C)C(=N)SC
Product: I
Temperature: 25 °C
Reaction time: 15 h

Procedure:
1.76 g (14.7 mmol) of N-methoxy-N-methylthiourea was dissolved in 5 ml of N,N-dimethylformamide. 2.09 g (14.7 mmol) of methyl iodide was added thereto at room temperature, and the mixture was stirred at room temperature for 15 hours. 500 ml of ethyl acetate was added thereto, and precipitated crystals were collected by filtration and then washed with ethyl acetate to obtain 2.7 g of N-methoxy-N-methyl-S-methylisothiourea hydroiodide as pale yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][C:21]([OH:23])=O)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][C:15]([F:18])([F:17])[F:16])[CH:7]=1.[CH:24]([NH:27][NH:28][C:29]([C:31]1[CH:35]=[CH:34][O:33][CH:32]=1)=[O:30])([CH3:26])[CH3:25].C(NC(C)C)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][C:21]([N:27]([CH:24]([CH3:26])[CH3:25])[NH:28][C:29]([C:31]2[CH:35]=[CH:34][O:33][CH:32]=2)=[O:30])=[O:23])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][C:15]([F:16])([F:18])[F:17])[CH:7]=1
Reactant: O=C(O)COc1ccc(F)cc1-c1ccccc1OC(F)(F)F
Reactant: CC(C)NNC(=O)c1ccoc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CC(C)N(NC(=O)c1ccoc1)C(=O)COc1ccc(F)cc1-c1ccccc1OC(F)(F)F
Yield: 55.9 %

Procedure:
A solution of (5-fluoro-2′-trifluoromethoxy-biphenyl-2-yloxy)-acetic acid (180 mg, 0.54 mmol) and furan-3-carboxylic acid N′-isopropyl-hydrazide (110 mg, 0.65 mmol) in DMF (5 ml) was treated with diisopropyl amine (0.237 ml, 1.36 mmol) and PyBroP (381 mg, 0.82 mmol) at room temperature overnight. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was successively washed with aqueous saturated sodium bicarbonate and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate in hexanes gradient to afford the product as a solid (145 mg, 56%). MS m/e 481.35 (M+H+)
Reaction SMILES: [CH3:1][C@H:2]1[C@:27]([OH:35])(C(COC(C)=O)=O)[C@:26]2([CH3:36])[C@H:4]([C@H:5]3[C@H:23]([C@@H:24]([OH:37])[CH2:25]2)[C@:22]2([CH3:38])[C:8](=[CH:9][C:10]4[N:14]([C:15]5[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=5)[N:13]=[CH:12][C:11]=4[CH2:21]2)[C:7]([CH3:39])=[CH:6]3)[CH2:3]1.[OH-:40].[Na+].Cl.[CH3:43][OH:44]>>[OH:35][C@@:27]1([C:43]([OH:44])=[O:40])[C@:26]2([CH3:36])[C@H:4]([C@H:5]3[C@H:23]([C@@H:24]([OH:37])[CH2:25]2)[C@@:22]2([CH3:38])[CH2:21][C:11]4[CH:12]=[N:13][N:14]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)[C:10]=4[CH:9]=[C:8]2[C:7]([CH3:39])=[CH:6]3)[CH2:3][C@H:2]1[CH3:1]
Reactant: CC(=O)OCC(=O)[C@@]1(O)[C@H](C)C[C@H]2[C@@H]3C=C(C)C4=Cc5c(cnn5-c5ccccc5)C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Reactant: CO
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: CC1=C[C@@H]2[C@H]([C@@H](O)C[C@@]3(C)[C@H]2C[C@@H](C)[C@]3(O)C(=O)O)[C@@]2(C)Cc3cnn(-c4ccccc4)c3C=C12
Reaction time: 8 h

Procedure:
In a 50 mL round-bottomed flask was dissolved (11β,16α)-21-(Acetyloxy)-11,17-dihydroxy-6,16-dimethyl-2′-phenyl-2′H-pregna-2,4,6-trieno[3,2-c]pyrazol-20-one (also known as Cortivazol) (0.1 g, 0.19 mmol) in MeOH (10 mL) to give a colorless solution. 1M sodium hydroxide (1.2 mL, 1.20 mmol) was added, and the mixture was stirred in an open flask overnight. The solution was acidified by the addition of 1M HCl (1.3 ml), MeOH was removed in vacuo after which the product precipitated as a white solid which was filtered, washed with water and dried in air on the sinter to give 85 mg of the desired product as a white solid. APCI-MS m/z: 475 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH:23]([CH3:25])[CH3:24])[CH:20]=3)[C:15](=[O:26])[N:14]2[CH3:27])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:28]=[C:29]1[NH:34][CH2:33][CH2:32][CH2:31][N:30]1[CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH:23]([CH3:24])[CH3:25])[CH:20]=3)[C:15](=[O:26])[N:14]2[CH3:27])[CH2:10][CH2:11][N:38]2[CH2:39][CH2:40][CH:35]([N:30]3[CH2:31][CH2:32][CH2:33][NH:34][C:29]3=[O:28])[CH2:36][CH2:37]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)Oc1ccc2c(c1)C(C(CC=O)c1ccc(Cl)c(Cl)c1)N(C)C2=O
Reactant: O=C1NCCCN1C1CCNCC1
Product: CC(C)Oc1ccc2c(c1)C(C(CCN1CCC(N3CCCNC3=O)CC1)c1ccc(Cl)c(Cl)c1)N(C)C2=O
Product: Cl
Yield: 151.1 %

Procedure:
3-(3,4-Dichlorophenyl)-3-(6-isopropoxy-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (0.50 g) was coupled to 4-(2-oxoperhydropyrimidine-1-yl)piperidine (0.225 g) by a method similar to that described in Example 8. The reaction product was not purified by chromatography but converted to the corresponding hydrochloride salt as described in the Example 8 to afford the title compound (0.567 g); mp 160°-170° C. (d); MS: m/z=573(M+1); NMR(CD3 SOCD3): 1.38 (m,6), 1.83 (broad,5), 3.29 (s,3), 4.82 (m,1), 6.74-6.97 (m,2), 7.18-7.64 (m,4). Analysis for C30H38Cl2N4 O3.1.0 HCl.1.5 H2O: Calculated: C, 56.56; H, 6.64, N, 8.79; Found: C, 56.49; H, 6.40; N, 8.78.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][C@@H:8]([C:35]#[N:36])[NH:9][C:10]([C@@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:34])[CH2:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)[CH2:13]1)=[O:11])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:24]1[CH2:25][CH2:26][CH:21]([CH2:20][CH2:19][C:18]([N:14]2[CH2:15][CH2:16][CH2:17][C@@H:12]([C:10]([NH:9][C@H:8]([C:35]#[N:36])[CH2:7][C:6]([OH:37])=[O:5])=[O:11])[CH2:13]2)=[O:34])[CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)C[C@@H](C#N)NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#C[C@H](CC(=O)O)NC(=O)[C@@H]1CCCN(C(=O)CCC2CCNCC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.2 %

Procedure:
To a solution of N-[(R)-1-{3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl}-3-piperidylcarbonyl]-3(S)-cyano-β-alanine tert-butyl ester (460.9 mg) in dichloromethane (5 ml) was added trifluoroacetic acid (4.6 ml). After stirring at ambient temperature for 2 hours, the mixture was concentrated in vacuo. The residue was dissolved in water and desalted by HP-20 eluting with (IPA:water=1:1). The eluting solution was concentrated in vacuo and freeze-dried to give N-[(R)-1-{3-(4-piperidyl)propionyl}-3-piperidylcarbonyl]-3(S)-cyano-β-alanine (0.12 g).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:8]([CH2:9][CH2:10][C@@H:11]([OH:19])[CH2:12][C@@H:13]([OH:18])[CH2:14][C:15]([OH:17])=[O:16])[C:7]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)=[C:6]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:5]=1[C:33]([NH:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:34])[CH3:3].[C:42](#[N:44])[CH3:43]>O>[CH:4]1[CH:5]=[CH:6][C:43]([CH2:42][NH:44][CH2:10][CH2:9][NH:8][CH2:7][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:1][CH:2]=1.[CH3:3][CH:2]([C:4]1[N:8]([CH2:9][CH2:10][C@@H:11]([OH:19])[CH2:12][C@@H:13]([OH:18])[CH2:14][C:15]([OH:17])=[O:16])[C:7]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[C:6]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:5]=1[C:33]([NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:34])[CH3:1].[C:27]1([CH2:6][CH:7]([NH2:8])[CH2:20][NH2:44])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC#N
Agent: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H](O)C[C@@H](O)CC(=O)O
Solvent: O
Product: NCC(N)Cc1ccccc1
Product: c1ccc(CNCCNCc2ccccc2)cc1

Procedure:
The benzathine salt of atorvastatin (Form B) was synthesized by preparing a stock solution of the free acid of atorvastatin (U.S. Pat. No. 5,273,995) in acetonitrile (1 g in 40 mL of ACN). A solution of N,N′-bis(phenylmethyl-1,2-ethanediamine (benzathine) was prepared by dissolving 220.64 mg (0.5 equivalents) in acetonitrile (80 mL) and water (20 mL). The stock solution of atorvastatin free acid was added to the counterion solution with stirring. After 2 days of stirring at ambient temperature, the solids were isolated by vacuum filtration using a Buchner funnel fitted with a paper filter (#2 Whatman). The solids were rinsed with acetonitrile (75 mL) to afford atorvastatin benzathine Form B. Note that this procedure is the same as above except that the sample was not oven dried.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][CH:17]([CH2:19][OH:20])[O:16][C:15]2=[O:21])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][S:11][CH2:10][CH2:9]1.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.CO.C(Cl)(Cl)Cl>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][O:20][S:28]([C:25]3[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=3)(=[O:30])=[O:29])[O:16][C:15]2=[O:21])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][S:11][CH2:12][CH2:13]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1OC(CO)CN1c1ccc(N2CCSCC2)c(F)c1
Solvent: c1ccncc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CN(c3ccc(N4CCSCC4)c(F)c3)C(=O)O2)cc1
Temperature: 0 °C
Reaction time: 7 h

Procedure:
The [3-[3-fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methanol (1.465 g, 4.69 mmol) was dissolved in pyridine (15 mL) and then cooled to 0° C. (ice bath). This solution was next treated with p-toluenesulfonyl chloride (1.34 g, 7.035 mmol) and allowed to stir at 0° C. under N2 for 7 hours. At this point, the reaction was stoppered and stored in the freezer overnight (16 hours). In the morning, the reaction showed only a trace of starting material by TLC (5% MeOH/CHCl3, UV short wave). The product was precipitated by quenching the reaction mixture with ice water (100 mL). The solid was isolated by suction filtration and washed thoroughly with water. The title compound, 2.02 g (92%), was recovered as a white solid with a melting point of 141° C. and a HRMS (M+) calculated for C21H23 N2O5FS2 466.1032, found 466.1036.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:8]=3[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:10][CH:11]([CH3:12])[C:5]2=[N:4][N:3]=1.[OH:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[Br:23][C:20]1[CH:21]=[CH:22][C:7]2[N:6]3[C:2]([N:30]4[CH2:31][CH2:32][N:27]([CH2:26][CH2:25][OH:24])[CH2:28][CH2:29]4)=[N:3][N:4]=[C:5]3[CH:11]([CH3:12])[N:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:8]=2[CH:19]=1
Reactant: OCCN1CCNCC1
Reactant: CC1N=C(c2ccccn2)c2cc(Br)ccc2-n2c(Br)nnc21
Product: CC1N=C(c2ccccn2)c2cc(Br)ccc2-n2c1nnc2N1CCN(CCO)CC1

Procedure:
In the manner given in Example 1, 1,8-dibromo-4-methyl-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is heated with excess of 1-(β-hydroxyethyl)piperazine to give 8-bromo-4-methyl-1-[4-(β-hydroxyethyl)piperazino]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.