Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@@H:5]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:8]=2[NH:7][C:6]1=S.O.[NH2:28][NH2:29].CCN(CC)CC.[C:37](Cl)([CH3:39])=[O:38]>C1COCC1>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@@H:5]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:8]=2[N:7]=[C:6]1[NH:28][NH:29][C:37](=[O:38])[CH3:39]
Reactant: NN
Reactant: CC(=O)Cl
Reactant: COC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(OC)ccc2NC1=S
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(OC)ccc2N=C1NNC(C)=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a suspension of methyl[(3S)-5-(4-chlorophenyl)-7-(methyloxy)-2-thioxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]acetate (for a preparation see Intermediate 4) (30.2 g, 77.7 mmol) in THF (800 mL) at 0° C. was added hydrazine monohydrate (11.3 mL, 233 mmol) dropwise. The reaction mixture was stirred for 4 h between 0° C. and 15° C. before being cooled at 0° C. Et3N (32.4 mL, 230 mmol) was then added slowly and AcCl (16.3 mL, 230 mmol) was added dropwise. The mixture was allowed to warm to RT and stir for 1 h then quenched with water and concentrated under reduced pressure. The resulting aqueous layer was then extracted with DCM and the organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give the crude title compound (34 g, 100% yield) which was used without further purification. LC/MS: m/z 429 [M(35Cl)+H]+, Rt 2.83 min.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([NH:7][CH2:8][C:9]([OH:11])=[O:10])[CH3:6].[CH2:12](O)[CH3:13]>>[ClH:3].[CH2:12]([O:10][C:9](=[O:11])[CH2:8][NH:7][CH2:5][CH3:6])[CH3:13]
Reactant: CCO
Reactant: O=S(Cl)Cl
Reactant: CCNCC(=O)O
Product: CCNCC(=O)OCC
Product: Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To ethanol (30 mL) was added dropwise thionyl chloride (2.6 mL) at −10° C., and the mixture was stirred for 15 min. N-ethylglycine (1.0 g) was added to this solution at −10° C., and the mixture was allowed to warm to room temperature while stirring for 17 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (1.63 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:12]([CH2:22][C:23](O)=[O:24])[C:13]2[C:18]([C:19](=[O:21])[N:20]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.[CH3:26][C:27]([N:34]1[CH2:39][CH2:38][CH:37]([NH:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]3[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:50][CH:49]=3)=[CH:44][CH:43]=2)[CH2:36][CH2:35]1)([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:12]([CH2:22][C:23]([N:40]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]3[CH:49]=[CH:50][C:51]([C:54]([F:56])([F:55])[F:57])=[CH:52][CH:53]=3)=[CH:44][CH:43]=2)[CH:37]2[CH2:36][CH2:35][N:34]([C:27]([CH3:26])([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:39][CH2:38]2)=[O:24])[C:13]2[C:18]([C:19](=[O:21])[N:20]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: CCOC(=O)C(C)(C)N1CCC(NCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)CC1
Reactant: O=C(O)Cn1c(CCc2ccc(F)cc2F)nc(=O)c2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)N1CCC(N(Cc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)C(=O)Cn2c(CCc3ccc(F)cc3F)nc(=O)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.1 %

Procedure:
A mixture of [2-[2-(2,4-difluorophenyl)ethyl]-4-oxo-1(4H)-quinazolinyl]acetic acid (Int. C3) (120 mg, 1 equiv), ethyl 2-methyl-2-[4-({[4′-(trifluoromethyl)-4-biphenylyl]methyl}amino)-1-piperidinyl]propanoate (Int. B2) (204 mg, 1.3 equiv), DMF (1.4 ml) and DIPEA (0.183 ml, 3 equiv) was shaken at room temperature, then HATU (206 mg, 1.5 equiv) was added with vigorous agitation and shaking continued for 1.5 h. A further portion of Intermediate D5 (12 mg, 0.1 equiv) was added then shaking was continued for 2 days. Reverse phase HPLC (Preparative Method B) gave ethyl 2-[4-({[2-[2-(2,4-difluorophenyl)ethyl]-4-oxo-1(4H)-quinazolinyl]acetyl}{[4′-(trifluoromethyl)-4-biphenylyl]methyl}amino)-1-piperidinyl]-2-methylpropanoate as a white solid (173 mg).
Reaction SMILES: [F:1][C:2]([F:42])([C:38]([F:41])([F:40])[F:39])[CH2:3][CH2:4][CH2:5][S:6][CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C@@H:18]1[CH2:35][C:34]2[CH:33]=[C:32]([OH:36])[CH:31]=[CH:30][C:29]=2[C@@H:28]2[C@@H:19]1[C@H:20]1[C@@:24]([CH2:26][CH2:27]2)([CH3:25])[C@@H:23]([OH:37])[CH2:22][CH2:21]1.C(OC(=O)C)(=O)C.B1([O-])OO1.[OH2:54].[OH2:55].O.O.[Na+]>>[F:42][C:2]([F:1])([C:38]([F:39])([F:40])[F:41])[CH2:3][CH2:4][CH2:5][S:6]([CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C@@H:18]1[CH2:35][C:34]2[CH:33]=[C:32]([OH:36])[CH:31]=[CH:30][C:29]=2[C@@H:28]2[C@@H:19]1[C@H:20]1[C@@:24]([CH2:26][CH2:27]2)([CH3:25])[C@@H:23]([OH:37])[CH2:22][CH2:21]1)(=[O:55])=[O:54]
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCN4CCC[C@H]4CSCCCC(F)(F)C(F)(F)F)[C@H]3[C@@H]1CC[C@@H]2O
Reactant: O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)OC(C)=O
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCN4CCC[C@H]4CS(=O)(=O)CCCC(F)(F)C(F)(F)F)[C@H]3[C@@H]1CC[C@@H]2O

Procedure:
Under the conditions of Example 3, 76 mg of 7α-{5-[(2S)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)-pyrrolidin-1-yl]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol (Example 26f) is acetylated with acetic anhydride, and the crude product is oxidized, as described in Example 4, with sodium perborate tetrahydrate, worked up and chromatographed. 31 mg of the title compound is obtained as oil. [α]D22 =30.6° (c=0.515 in methanol).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[CH:6]=[CH:7][CH:8]=1)=O.[S:16]1[CH2:20][C:19](=[O:21])[NH:18][C:17]1=[O:22].N1CCCCC1.C(O)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1.O>[Cl:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH:1]=[C:20]1[S:16][C:17](=[O:22])[NH:18][C:19]1=[O:21]
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1cccc(-c2ccccc2Cl)c1
Agent: O=C(O)c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(=Cc2cccc(-c3ccccc3Cl)c2)S1

Procedure:
To a solution of 3-formyl-(2′-chloro-1,1′-biphenyl) (0.12 g, 0.55 mmol) and 2,4-thiazolidinedione (0.08 g, 0.65 mmol) in toluene (10 mL) were added piperidine (0.008 mL, 0.073 mMol) and benzoic acid (0.011 mg, 0.08 mmol), and the reaction was refluxed for 4 h with continuous removal of water. The solvent was then distilled off and the oily residue obtained was purified by chromatography on silica-gel using hexane: ethyl acetate (3:1) as the eluent to yield titled product.
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][CH:5]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:20][CH2:21][CH2:22][Cl:23])(=[O:3])[CH3:2]>C(O)C.C(NCC)C>[ClH:23].[C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][CH:5]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:20][CH2:21][CH2:22][N:4]([CH2:5][CH3:13])[CH2:1][CH3:2])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccccc2SC1c1ccccc1OCCCCl
Solvent: CCO
Solvent: CCNCC
Product: CCN(CC)CCCOc1ccccc1C1Sc2ccccc2N1C(C)=O
Product: Cl
Yield: 161.5 %

Procedure:
To the solution of 3.48 g of 3-acetyl-2-[2-(3-chloropropoxy)-phenyl]benzothiazoline in 20 ml of ethanol, 10.3 ml of diethylamine is added and the mixture is refluxed for 2 hours. After removal of ethanol and excess amount of diethylamine in vacuo, ethyl acetate and water are added to the residue. The organic layer is extracted with N-hydrochloric acid, the acidic layer is alkalinized with N-sodium hydroxide solution and extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is removed off in vacuo and the resulting oil is dissolved in methanol. To the solution hydrochloric acid in ethyl acetate is added to give 3.4 g (80%) of the titled compound.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[Na].CCO.[Cl:20][C:21]1[CH:26]=[C:25]([CH2:27]Cl)[CH:24]=[C:23]([C:29]([F:32])([F:31])[F:30])[C:22]=1[NH2:33]>O1CCOCC1.O>[C:1]([NH:4][C:5]([CH2:27][C:25]1[CH:24]=[C:23]([C:29]([F:31])([F:32])[F:30])[C:22]([NH2:33])=[C:21]([Cl:20])[CH:26]=1)([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: Nc1c(Cl)cc(CCl)cc1C(F)(F)F
Agent: [Na]
Solvent: O
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)C(Cc1cc(Cl)c(N)c(C(F)(F)F)c1)(NC(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
24.11 g (0.11 mol) diethyl 2-acetylamino-malonate was added to a freshly prepared solution of 2.55 g (0.11 mol) sodium in 200 mL abs. EtOH under a nitrogen atmosphere and the mixture was stirred for 15 minutes at RT. A solution of 27.00 g (0.11 mol) 2-chloro-4-chlormethyl-6-trifluoromethyl-phenylamine (Intermediate product 55) in 100 mL 1,4-dioxane was rapidly added dropwise and the mixture was stirred for 4 hours at RT. 500 mL water were added and the mixture was stirred for a further 16 hours. The precipitate formed was filtered off, washed with water and dried i. vac.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Br:6][C:7]1[CH:8]=[C:9]([NH2:14])[C:10]([CH3:13])=[N:11][CH:12]=1.Cl.C(Cl)Cl>N1C=CC=CC=1>[Br:6][C:7]1[CH:8]=[C:9]([NH:14][S:2]([CH3:1])(=[O:4])=[O:3])[C:10]([CH3:13])=[N:11][CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ncc(Br)cc1N
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ncc(Br)cc1NS(C)(=O)=O

Procedure:
Methanesulfonyl chloride (97 μl) was added dropwise to 5-bromo-2-methyl-3-pyridinamine (Chempacific) (200 mg) in pyridine (5 ml). The reaction was stirred at room temperature for 20 min before addition of 2M HCl (aq) (5 ml) and extraction into DCM. The DCM was passed through a hydrophobic frit then dried under a stream of nitrogen. The residue was dissolved in DCM and washed through an aminopropyl cartridge (preconditioned with DCM) with DCM to give title compound, 77 mg.
Reaction SMILES: CN[C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].[OH-:19].[K+].Cl.[CH3:22][Si](Cl)(C)C>C(O)C.O>[CH3:22][O:19][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: C[Si](C)(C)Cl
Reactant: [OH-]
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Temperature: 90 °C
Reaction time: 48 h
Yield: 41.6 %

Procedure:
A mixture of 4-(4-Aminophenoxy)pyridine-2-carboxylic acid methylamide (15.0 g, 61.7 mmol) and potassium hydroxide (34.6 g, 617 mmol) in ethanol (400 mL) and water (40 mL) was stirred at 90° C. for 48 h. After cooling to RT, 2.0 N hydrochloric acid was slowly added to the reaction mixture until pH=5. The solvent was removed completely and the residue redissolved in MeOH (400 mL). After slow addition of trimethylsilylchloride (178 mL, 140 mmol, 2.27 eq) at 0° C., the reaction mixture was stirred at reflux for 24 h and cooled to RT. The mixture was filtered, and the filtrate concentrated under reduced pressure and then partitioned between DCM and water. The organic layer was then washed with 1M aqueous sodium bicarbonate solution, dried over Na2SO4, filtered, and evaporated under reduced pressure. The resulting residue was washed further with H2O and reextracted with EtOAc/Hex (1:2 v/v) to afford the desired ester (6.27 g, 42%) as a light brown solid. 1H-NMR (DMSO-d6) δ 8.51 (d, J=5.7 Hz, 1H), 7.35 (d, J=2.4 Hz, 1H), 7.10 (dd, J=5.7, 2.7 Hz, 1H), 6.86 (dt, J=9.0, 2.4 Hz, 2H), 6.63 (dt, J=8.7, 2.4 Hz, 2H), 5.18 (br s, 2H), 3.86 (s, 3H); MS LC-MS [M+H]+=245, RT=1.04 min; TLC (75% EtOAc/hex), Rf=0.20.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:29]=[CH:28][C:8]([O:9][CH:10]([C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[O:12])=[CH:7][CH:6]=1)([OH:4])=[O:3].[CH3:30]O>>[C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH:10]([C:22](=[O:27])[C:23]([CH3:24])([CH3:25])[CH3:26])[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[O:12])=[CH:28][CH:29]=1)([O:4][CH3:30])=[O:3]
Reactant: CO
Reactant: CC(C)(C)C(=O)C(Oc1ccc(C(=O)O)cc1)C(=O)Nc1ccc(Cl)cc1Cl
Agent: Cl
Product: COC(=O)c1ccc(OC(C(=O)Nc2ccc(Cl)cc2Cl)C(=O)C(C)(C)C)cc1
Temperature: 25 °C
Yield: 68 %

Procedure:
HCl gas was bubbled into a suspension of N-[2-[4-carboxyphenoxy]-4,4-dimethyl-3-oxopentanoyl]-2,4-dichloroaniline (12.0 g, 28.3 mmol, available from Eastman Kodak, Rochester, N.Y.) in absolute methanol (175 mL) for 30 minutes. The mixture was heated to reflux for 2 hrs during which complete solution was obtained. Upon cooling to room temperature, white crystals of the product began to form. The reaction mixture was cooled in an ice bath, and the solids were collected by filtration, washed with fresh methanol and air-dried to provide N-[2-[4-carbomethoxyphenoxy]-4,4-dimethyl-3-oxopentanoyl]-2,4-dichloroaniline (8.4 g, 68% yield). The structure of this compound was confirmed by mass spectroscopy and by 1H and 13C NMR spectroscopy.
Reaction SMILES: [CH3:1][C:2]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O-:10])=[O:9].[OH-].[Na+].CCO.CCOCC>O>[CH3:1][C:2]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: Cc1cc(C)c(C)c(OCCCC(=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: Cc1cc(C)c(C)c(OCCCC(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.8 %

Procedure:
A mixture of 4-(2,3,5-trimethylphenoxy)butyrate (9.09 g), 1N NaOH (58 ml), and EtOH (80 ml) was stirred at room temperature overnight. The reaction mixture was poured into a mixture of Et2O and water. The separated water phase was washed with Et2O, and was acidified by 6N HCl. After extraction by AcOEt, the AcOEt was washed with water and brine, and dried over MgSO4, and then evaporated. The resulting precipitate was collected by filtration, and dried to give 4-(2,3,5-trimethylphenoxy)butyric acid (4.91 g).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][C:14]([O:16]C)=O)=[CH:10][CH:11]=2)[CH:6]=[CH:5]1)(=O)C.C(OCC)(=O)C.[OH-].[NH4+:25]>CO>[NH:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][C:14]([NH2:25])=[O:16])=[CH:10][CH:11]=2)[CH:6]=[CH:5]1
Reactant: COC(=O)Cc1ccc2c(ccn2C(C)=O)c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: NC(=O)Cc1ccc2[nH]ccc2c1

Procedure:
A solution of 1-acetyl-1H-indole-5-acetic acid, methyl ester (1.46 g) in methanol (10 ml) and conc. ammonium hydroxide (20 ml) was stirred at ambient temperature for 48 h. The resulting solution was poured into ethyl acetate (100 ml). The layers were separated and the aqueous layer was washed with ethyl acetate (3×50 ml) and chloroform (3×50 ml). The organic layers were dried (MgSO4) and the solvent was evaporated to give a solid (0.72 g). Crystallisation from ethyl acetate gave the title compound as a white solid, (0.3 g) m.p. 146°-7°.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.C(=O)(O)[O-].[Na+].O>CN(C)C=O.C(O)C>[C:10]1(=[O:11])[N:6]([CH2:5][CH2:4][C:3]2[N:18]=[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]3[CH:2]=2)[C:7](=[O:16])[C:8]2=[CH:15][CH:14]=[CH:13][CH:12]=[C:9]12
Reactant: O=C(CBr)CCN1C(=O)c2ccccc2C1=O
Reactant: Nc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1CCc1cn2ccccc2n1
Yield: 57.7 %

Procedure:
1-Bromo-4-phthalimidobutan-2-one (23.6 g.) was added to a solution of 2-aminopyridine (7.6 g.) and sodium bicarbonate (6.8 g.) in dimethylformamide (100 ml.) and the mixture was heated at 100° for 1 hour. Cooling followed by addition to water and recrystallisation from ethanol afforded 2-(2-phthalimidoethyl)imidazo [1,2-a]-pyridine (13.4 g.) m.p. 181° - 181.5°.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([NH:17][S:18]([C:21]1[S:25][C:24]2[S:26](=[O:33])(=[O:32])[CH:27]([C:29]([OH:31])=[O:30])[CH2:28][C:23]=2[CH:22]=1)(=[O:20])=[O:19])([CH3:16])([CH3:15])[CH3:14]>C(Cl)CCC>[C:13]([NH:17][S:18]([C:21]1[S:25][C:24]2[S:26](=[O:32])(=[O:33])[CH:27]([C:29]([O:31][CH3:1])=[O:30])[CH2:28][C:23]=2[CH:22]=1)(=[O:20])=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)NS(=O)(=O)c1cc2c(s1)S(=O)(=O)C(C(=O)O)C2
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCCCCl
Product: COC(=O)C1Cc2cc(S(=O)(=O)NC(C)(C)C)sc2S1(=O)=O
Reaction time: 1 h
Yield: 74 %

Procedure:
Carbonyldiimidazole (5.3 g, 32.7 mmol) was added at room temperature to a stirred solution of product from Step A (7.7 g, 21.8 mmol) in dry, degassed DMF under an N2 atmosphere. After 1 h, methanol (150 mL) was added and the reaction stirred for 30 min. The solvents were removed under high vacuum, and the residue taken up in ethyl acetate. This solution was extracted with water and saturated brine, dried over MgSO4, filtered, and the filtrate evaporated to dryness to give a foam. This foam was treated with n-butyl-chloride and the resulting solid filtered and dried in the air to give the title compound (5.7, 74%). 1H NMR (300 MHz,DMSO-d6) 1.20(s,9H), 3.53(d,2H), 3.80(s,3H), 5.30(t,1H), 7.60(s,1H, 8.20(s,1H,exch.).
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[CH:11]1([CH2:14][N:15]2[CH2:21][CH2:20][CH:19]3[CH2:22][NH:23][CH2:24][CH2:25][N:18]3[C:17]3[N:26]=[CH:27][CH:28]=[CH:29][C:16]2=3)[CH2:13][CH2:12]1.C(N(CC)CC)C>C(Cl)Cl>[CH:11]1([CH2:14][N:15]2[CH2:21][CH2:20][CH:19]3[CH2:22][N:23]([C:2]([C:3]4[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=4)=[O:9])[CH2:24][CH2:25][N:18]3[C:17]3[N:26]=[CH:27][CH:28]=[CH:29][C:16]2=3)[CH2:12][CH2:13]1
Reactant: O=C(Cl)c1cccnc1
Reactant: c1cnc2c(c1)N(CC1CC1)CCC1CNCCN21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cccnc1)N1CCN2c3ncccc3N(CC3CC3)CCC2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Nicotinoyl chloride hydrochloride (58.2 mg, 0.317 mmol) was added at room temperature to a solution of the product of Example 74A (82 mg, 0.317 mmol) in CH2Cl2 (4 mL) and triethylamine (0.111 mL, 0.793 mmol). The mixture was stirred at room temperature for 30 minutes and then concentrated under vacuum. The residue was purified by HPLC (30×100 mm, C18, Waters XBridge™ column eluted with 0.1 Maqueous (NH4)2CO3-methanol, 40:60-0:100 over 15 minutes) to provide the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 0.16-0.21 (m, 2H), 0.45-0.54 (m, 2H), 0.93-1.03 (m, 1H), 1.61-1.75 (m, 1H), 1.79-1.91 (m, 1H), 2.90-3.05 (m, 2H), 3.19-3.30 (m, 2H), 3.34-3.50 (m, 4H), 3.54-3.64 (m, 1H), 3.71-3.92 (m, 2H), 6.74 (dd, J=7.8, 4.7 Hz, 1H), 7.00 (dd, J=7.9, 1.5 Hz, 1H), 7.45 (ddd, J=7.9, 4.9, 0.9 Hz, 1H), 7.65 (dd, J=4.6, 1.5 Hz, 1H), 7.83 (ddd, J=8.1, 2.0, 1.8 Hz, 1H), 8.58-8.67 (m, 2H); MS (ESI) m/z 364 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:22]=[CH:21][C:12]([O:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16](Cl)[CH:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=O.C[CH2:28][N:29](C(C)C)C(C)C.CN>C1COCC1>[CH2:1]([O:8][C:9]1[CH:22]=[CH:21][C:12]([O:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:29][CH3:28])[CH:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cc(Oc2ccc(OCc3ccccc3)cc2)ccn1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CNc1cc(Oc2ccc(OCc3ccccc3)cc2)ccn1
Temperature: 100 °C

Procedure:
In a 350 mL sealed tube fitted with stirring bar were combined at 0° C. 4-(4-benzyloxy-phenoxy)-2-chloro-pyridine (Step a, 2.11 g, 6.79 mmol), DMSO (10 mL), DIEA (1.3 mL, 7.47 mmol), and CH3NH2 (4.1 mL of a 2 N solution in THF, 8.15 mmol). The reaction was heated to 100° C. for 7 days. During that period, an additional amount of CH3NH2 solution was added on four separate days (for a total of 70 mL). The reaction was cooled to RT and diluted into 1N NaOH and Et2O after evaporating off THF. After separation of the layers, the organic layer was washed 3× with 1 N NaOH then with brine. The crude residue was eluted on a silica gel column with a hexanes/EtOAc gradient to yield the title compound.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:15]S(=O)O[CH2:12][C:11]([CH3:18])([CH3:17])[C:10]=2[CH:19]=1)(=[O:4])=[O:3].[Cl-].[Na+].O>CN(C)C=O>[CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:15][CH2:12][C:11]([CH3:18])([CH3:17])[C:10]=2[CH:19]=1)(=[O:4])=[O:3]
Reactant: CC1(C)COS(=O)Oc2ccc(OS(C)(=O)=O)cc21
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)COc2ccc(OS(C)(=O)=O)cc21
Yield: 84 %

Procedure:
A mixture of 4,5-dihydro-5,5-dimethyl-2-oxido-1,3,2-benzodioxathiepin-7-yl methanesulphonate (24 parts) (from Example 20) and sodium chloride (1 part) in dimethyl formamide (400 parts) was boiled under reflux for 3 hours. The mixture was then added to water and the product extracted with ether to give 2,3-dihydro-3,3-dimethylbenzofuran-5-yl methanesulphonate (16 parts, 84% yield), identical with the product of Example 37(a) above.
Reaction SMILES: [N+:1]([C:4]1[C:9]2[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])=[N:11][CH2:12][C:13](=S)[NH:14][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:24]([NH:27][NH2:28])(=O)[CH3:25]>C(O)C>[N+:1]([C:4]1[C:9]2[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])=[N:11][CH2:12][C:13]3[N:14]([C:24]([CH3:25])=[N:27][N:28]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: N#Cc1ccccc1C1=NCC(=S)Nc2cccc([N+](=O)[O-])c21
Reactant: CC(=O)NN
Solvent: CCO
Product: Cc1nnc2n1-c1cccc([N+](=O)[O-])c1C(c1ccccc1C#N)=NC2
Temperature: 250 °C

Procedure:
In the manner given in Example 2, 6-nitro-1,3-dihydro-5-(o-cyanophenyl)-2H-1,4-benzodiazepine-2-thione is heated in ethanol with acetic acid hydrazide and the resulting product heated to 250° C. to give 7-nitro-1-methyl-6-(o-cyanophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[C:8]([F:21])[CH:7]=1)(=[O:5])=[O:4])[CH3:2].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25](I)[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([F:29])=[C:27]([C:9]2[CH:10]=[CH:11][C:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])=[CH:7][C:8]=2[F:21])[CH:28]=1
Reactant: CCS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Reactant: Fc1ccc(Cl)cc1I
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: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1ccc(-c2cc(Cl)ccc2F)c(F)c1
Temperature: 80 °C
Yield: 28 %

Procedure:
A solution of 2-(4-(ethylsulfonyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation 45, 1.77 g, 5.64 mmol), 4-chloro-1-fluoro-2-iodobenzene (1.28 g, 5.00 mmol), and sodium carbonate (1.59 g, 15.00 mmol) in dioxane (40 mL) and water (10 mL) was degassed. Tetrakis(triphenylphosphine)palladium(0) (577 mg, 0.50 mmol) was added and the mixture was degassed twice more, and the reaction warmed to 80° C. for 2 hours. The reaction was cooled and diluted with EtOAc (50 mL) and water (50 mL), the layers separated and the aqueous extracted with EtOAc (2×30 mL). The combined organic layers were washed with brine (30 mL), dried over MgSO4 and the solvent removed in vacuo. The crude was purified by silica gel column chromatography eluting with EtOAc:heptane 1:19 to 1:1 to give the title compound as a colourless oil 28% yield, 443 mg.