Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:20]=[N:21][C:22](OS(C(F)(F)F)(=O)=O)=[C:23]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:24]=3)[CH:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[F:38][C:39]([F:51])([F:50])[O:40][C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=1.C(=O)([O-])[O-].[Na+].[Na+].O>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.C(OCC)(=O)C>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:20]=[N:21][C:22]([C:44]4[CH:43]=[CH:42][C:41]([O:40][C:39]([F:38])([F:50])[F:51])=[CH:46][CH:45]=4)=[C:23]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:24]=3)[CH:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)CC(c1cccc(COc2cnc(OS(=O)(=O)C(F)(F)F)c(CC(C)(C)C)c2)c1)C1CC1
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: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)Cc1cc(OCc2cccc(C(CC(=O)O)C3CC3)c2)cnc1-c1ccc(OC(F)(F)F)cc1
Temperature: 100 °C
Yield: 23.5 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(3-(((5-neopentyl-6-(((trifluoromethyl)sulfonyl)oxy)pyridin-3-yl)oxy)methyl)phenyl)propanoate (65.2 mg) in toluene (1.5 mL) were added (4-(trifluoromethoxy)phenyl)boronic acid (24.7 mg), 2M aqueous sodium carbonate solution (720 μL), and tetrakis(triphenylphosphine)palladium(0) (13.8 mg), and the mixture was heated in a microwave synthesizer (Anton Parr, Synthos3000) at 100° C. for 90 min. Water (1 mL) and ethyl acetate (3 mL) were added to the reaction solution and the mixture was stirred. The organic layer was passed through a phase separation filter, and the solvent was evaporated by an air blowing apparatus. The residue was purified by HPLC (column: YMC Triart C18, mobile phase: acetonitrile/10 mM aqueous ammonium hydrogen carbonate solution) and the solvent was evaporated by an air blowing apparatus. To the residue were added ethanol (1 mL) and 2M aqueous lithium hydroxide solution (180 μL), and the mixture was stirred at 60° C. for 1 hr. 1M Hydrochloric acid (360 μL) was added and the obtained solution was purified by HPLC (column: YMC Triart C18, mobile phase: acetonitrile/10 mM aqueous ammonium hydrogen carbonate solution), and the solvent was evaporated by an air blowing apparatus to give the title compound (14.9 mg).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1)(=O)=O.[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C)C=O.C(OCC)(=O)C>[N:20]([CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1)=[N+:21]=[N-:22]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](COS(C)(=O)=O)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H](CN=[N+]=[N-])C1
Temperature: 80 °C
Reaction time: 4 h
Yield: 84.2 %

Procedure:
To a solution of 10.50 g of {(3S)-1-(tert-butoxycarbonyl)-3-piperidyl}methyl methanesulfonate in 100 ml of N,N-dimethylformamide, 4.9 g of sodium azide was added at room temperature, followed by 4 hours' stirring at 80° C. under heating. The reaction liquid was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and resulting residue was purified by means of silica gel column chromatography (eluting solvent: from hexane to hexane/ethyl acetate=15/1) to provide 7.24 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:8][NH2:9])=[CH:6][CH:7]=1.[C:10](Cl)(=O)[CH:11]([CH3:13])[CH3:12].O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:4]([C:10]([CH:11]([CH3:13])[CH3:12])=[N:9][N:8]=2)[N:3]=1
Reactant: CC(C)C(=O)Cl
Reactant: NNc1ccc(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)c1nnc2ccc(Cl)nn12
Temperature: 90 °C
Yield: 94 %

Procedure:
A mixture of 3-chloro-6-hydrazinylpyridazine (200 g, 1.38 mol) and isobutyryl chloride (175 mL, 1.66 mol) in 1,4-dioxane (2 L) was heated at about 90° C. overnight. The suspension was cooled to about 5° C. in an ice bath and then water (2 L) was added followed by slow addition of Na2CO3 (275 g, 2.59 mol). The resulting solution was extracted with DCM (3×1 L). The combined organic extracts were dried over MgSO4, concentrated under reduced pressure, and dried under vacuum overnight to give the title compound (255 g, 94%): LC/MS (Table 1, Method a) Rt=2.04 min; MS m/z: 197.1 (M+H)+.
Reaction SMILES: O=[C:2]([CH:8]([CH3:18])[CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5].[CH2:19]([NH2:22])[CH:20]=[CH2:21].[C:23](Cl)(=[O:25])[CH3:24]>CO>[C:23]([C:3](=[C:2]([NH:22][CH2:19][CH:20]=[CH2:21])[CH:8]([CH3:18])[CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4]([O:6][CH3:7])=[O:5])(=[O:25])[CH3:24]
Reactant: COC(=O)CC(=O)C(C)COCc1ccccc1
Reactant: C=CCN
Reactant: CC(=O)Cl
Solvent: CO
Product: C=CCNC(=C(C(C)=O)C(=O)OC)C(C)COCc1ccccc1
Temperature: 40 °C
Reaction time: 12 h

Procedure:
Methyl 3-oxo-4-methyl-5-benzyloxypentanoate (1.11 g; 4.43 mmole) was dissolved in dry methanol (5 ml), allylamine (1.26 g) and molecular sieve 3A (0.6 g) were added thereto and then a solution of acetyl chloride (1.04 g; 13.3 mmole) in dry methanol (2 ml) was added thereto with icecooling, followed by stirring at 40° C. for 12 hours. The molecular sieve was removed by filtration, and the filtrate was diluted with ethyl acetate. The reaction mixture was washed successively with a saturated sodium bicarbonate solution and an aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in toluene (5 ml), and gaseous ketene was introduced therein at room temperature. After completion of the reaction, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give methyl 2-acetyl-3-allylamino-4-methyl-5-benzyloxy-2-pentenoate.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:18]4=[N:19][S:20](=[O:24])(=[O:23])[CH2:21][CH2:22][N:17]4[CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)=[CH:4][C:3]=1[O:27][CH3:28]>C1COCC1.CO.[Pt](=O)=O>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([CH:13]3[C:18]4=[N:19][S:20](=[O:24])(=[O:23])[CH2:21][CH2:22][N:17]4[CH2:16][CH2:15][CH2:14]3)=[CH:11][CH:12]=2)=[CH:4][C:3]=1[O:27][CH3:28]
Reactant: COc1cc(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)ccc1Cl
Agent: O=[Pt]=O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(Oc2ccc(C3CCCN4CCS(=O)(=O)N=C34)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.2 %

Procedure:
Platinum(IV) oxide (30 mg) was added to a solution of 9-[4-(4-chloro-3-methoxyphenoxy)phenyl]-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (262.3 mg) in THF (dry) (60 mL) and MeOH (30 mL). The mixture was stirred at room temperature under hydrogen for 3 hr. Platinum(IV) oxide (30 mg) was added and the mixture was stirred at room temperature under hydrogen for 4 hr. The insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc) and the filtrate was concentrated in vacuo. MeCN (13 mL) was adde and this mixture was purified by preparative HPLC (C18, eluted with water in acetonitrile containing 0.1% TFA). The desired fractions were neutralized with sat. NaHCO3 aq. and the mixture was extracted with EtOAc. The combined organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was crystallized from THF/IPE to give the title compound (80.1 mg) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH:12](O)([CH3:14])[CH3:13]>C[Si](Cl)(C)C.C(OCC)C>[CH:12]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([CH3:11])[C:2]([Cl:1])=[N:3][CH:4]=1)([CH3:14])[CH3:13]
Reactant: CC(C)O
Reactant: Cc1cc(C(=O)O)cnc1Cl
Agent: C[Si](C)(C)Cl
Solvent: CCOCC
Product: Cc1cc(C(=O)OC(C)C)cnc1Cl
Temperature: 70 °C
Reaction time: 18 h

Procedure:
To a solution of 6-chloro-5-methyl-nicotinic acid (21.64 g, 126 mmol) in isopropanol (450 mL), trimethylsilyl chloride (160 mL) is added dropwise. Upon completion of the addition, the mixture is heated to 70° C. and stirring is continued for 18 h. The mixture is diluted with diethyl ether (500 mL) and washed with sat. aq. NaHCO3 solution (5×50 mL). The washings are extracted back with diethyl ether (100 mL). The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 6:1 to give 6-chloro-5-methyl-nicotinic acid isopropyl ester (6.09 g) as a colourless oil; LC-MS: tR=0.97 min, [M+1]+=214.03. 1H NMR (D6-DMSO): δ 1.34 (d, J=6.3 Hz, 6H), 2.41 (s, 3H), 5.11-5.22 (m, 1H), 8.27 (s, 1H), 8.73 (s, 1H).
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C-:12]#[N:13].[Na+].[NH4+:15].[Cl-]>N.CO>[NH2:15][C:8]1([C:12]#[N:13])[CH2:9][CH2:10][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:6][CH2:7]1
Reactant: [C-]#N
Reactant: [NH4+]
Reactant: CC(C)(C)N1CCC(=O)CC1
Agent: N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)N1CCC(N)(C#N)CC1
Reaction time: 2 h

Procedure:
1-t-Butyl-4-piperidone (1.3 g, 8.4 mmol, 1.0 equiv), NaCN (0.61 g, 12.6 mmol, 1.5 equiv), and NH4Cl (0.67 g, 12.6 mmol, 1.5 equiv) were combined in 34 mL of 2 M NH3 in MeOH. The mixture was refluxed for 2 h at which time an additional 34 mL of 2 M NH3 in MeOH was added followed by another 2 h at reflux. The mixture was cooled and filtered. The filtrate was concentrated in vacuo and the residue was triturated with CH2Cl2 and filtered again. The solution was concentrated to a thick red oil which was used without further purification; MS, m/z 182=M+1.
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.[F:59][C:60]1[CH:68]=[C:67]([C:69]([F:72])([F:71])[F:70])[CH:66]=[CH:65][C:61]=1[C:62](Cl)=[O:63]>>[F:59][C:60]1[CH:68]=[C:67]([C:69]([F:70])([F:71])[F:72])[CH:66]=[CH:65][C:61]=1[C:62]([NH:34][C:35]1[CH:36]=[CH:37][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:39][CH:40]=1)=[O:63]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1F
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
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)c4ccc(C(F)(F)F)cc4F)cc3)cc2C1=O
Yield: 73 %

Procedure:
The compound of example 191 was prepared was prepared analogous to compound of example 97 by reaction of compound of example 6 with 2-fluoro-4-trifluoromethyl benzoyl chloride.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH2:7][CH2:6]1.[C:17]12[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=1)[NH:22]C(=O)O[C:18]2=[O:19].C(OCC)(=O)C>CN(C)C=O.O>[N:16]1[CH:15]=[CH:14][CH:13]=[N:12][C:11]=1[N:8]1[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:18](=[O:19])[C:17]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[NH2:22])[CH2:10][CH2:9]1
Reactant: NCCCN1CCN(c2ncccn2)CC1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccccc1C(=O)NCCCN1CCN(c2ncccn2)CC1
Reaction time: 1 h

Procedure:
0.02 mol of 1-(3-aminopropyl)-4-(2-pyrimidinyl)piperazine is dissolved in 100 ml of absolute dimethylformamide, 0.02 mol of isatoic anhydride is added, and the mixture is stirred for 1 hour. It is diluted with 50 ml of water, shaken with ethyl acetate and the organic phase is evaporated. Purification is by column chromatography over silica gel 60. After elution with methylene chloride/methanol 93:7, the resulting oil can be crystallised from ethyl acetate with isopropyl ether.
Reaction SMILES: N1C2C(=NC=CC=2)N([N:10]2[C:14](/[CH:15]=[C:16]3\[C:17](=[O:26])[NH:18][C:19]4[C:24]\3=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)=[C:13]([CH3:27])[C:12]([C:28]([O-])=[O:29])=[C:11]2[CH3:31])N=1.CCN(C(C)C)C(C)C.[NH2:41][C@H:42]1[CH2:47][CH2:46][CH2:45][CH2:44][C@@H:43]1[OH:48]>CN(C=O)C>[OH:48][C@H:43]1[CH2:44][CH2:45][CH2:46][CH2:47][C@@H:42]1[NH:41][C:28]([C:12]1[C:13]([CH3:27])=[C:14](/[CH:15]=[C:16]2\[C:17](=[O:26])[NH:18][C:19]3[C:24]\2=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[NH:10][C:11]=1[CH3:31])=[O:29]
Reactant: N[C@H]1CCCC[C@@H]1O
Reactant: Cc1c(C(=O)[O-])c(C)n(-n2nnc3cccnc32)c1/C=C1\C(=O)Nc2ccc(F)cc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)N[C@H]1CCCC[C@@H]1O
Temperature: 25 °C
Yield: 73.4 %

Procedure:
To the solution of A4 (100 mg, 0.24 mmol) and DIEA (140 mg, 0.96 mmol) in 10 mL of DMF, was added (1S,2S)-2-Amino-cyclohexanol (45 mg, 0.29 mmol). The reaction mixture was stirred at room temperature for several hours. LC/MS was applied to determine completion of the reaction. DMF was evaporated under reduced pressure and the residue was precipitated with 5% diethylamine/methanol (25 mL) under sonication. The solid was collected by filtration and washed with methanol), dried under vacuum to provide to provide title compound (70 mg, 74% yield) as orange solid. 1H NMR (300 MHz, DMSO-d6): δ=13.62 (s, 1H), 10.88 (s, 1H), 7.71-7.77 (m, 2H), 7.36-7.39 (d, 1H), 6.81-6.95 (m, 2H), 4.58-4.60 (d, 1H), 3.48-3.60 (m, 1H), 3.30-3.35 (m, 1H), 2.41-2.44 (ds, 6H), 1.88-1.90 (t, 2H), 1.62 (S, 2h), 1.23 (s, 4H). LC/MS: 398.1 [M+H]+.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CC(OC([N:13]1[CH:22]([C:23]([N:25]2[CH2:29][CH2:28][CH2:27][CH:26]2[C:30]([NH2:32])=O)=[O:24])[CH2:21][C:20]2[C:15](=[CH:16][C:17]([O:35][CH3:36])=[C:18]([O:33][CH3:34])[CH:19]=2)[CH2:14]1)=O)(C)C.N1C=CN=C1>N1C=CC=CC=1>[CH3:34][O:33][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][C:17]=1[O:35][CH3:36])[CH2:14][NH:13][CH:22]([C:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[C:30]#[N:32])=[O:24])[CH2:21]2
Reactant: COc1cc2c(cc1OC)CN(C(=O)OC(C)(C)C)C(C(=O)N1CCCC1C(N)=O)C2
Agent: c1c[nH]cn1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1cc2c(cc1OC)CC(C(=O)N1CCCC1C#N)NC2
Reaction time: 1.75 h
Yield: 108.3 %

Procedure:
Phosphorus oxychloride (239 mg, 0.15 mL, 1.56 mmol) was added to a solution of the title D compound of Example 6, 3-(2-aminocarbonyl-1-pyrrolidinyl)carbonyl-3,4-dihydro-6,7-dimethoxy-2(1H)-isoquinolinecarboxylic acid 2-(1,1-dimethylethyl) ester (259 mg, 0.6 mmol; diastereomer B) and imidazole (53 mg, 0.78 mmol) in pyridine (6 mL) at −45° C. The reaction was stirred for 1.75 hours, then allowed to stand at 8° C. overnight, after which the mixture was concentrated under vacuum. The residue was purified by flash chromatography on silica gel using 2% methanol in methylene chloride as eluent to give 205 mg of the title compound as a yellowish white solid.
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3][OH:4].CN(C=O)C.[H-].[Na+].F[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:20]1[O:21][C:22]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:23]=2[CH:24]=1>O>[F:1][CH:2]([F:5])[CH2:3][O:4][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:20]1[O:21][C:22]2[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][C:23]=2[CH:24]=1
Reactant: OCC(F)F
Reactant: Fc1cnccc1-c1cc2cc(C(F)(F)F)ccc2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)COc1cnccc1-c1cc2cc(C(F)(F)F)ccc2o1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.9 %

Procedure:
A mixture of 75 mg of 2,2-difluoroethanol and 0.5 ml of DMF was added to a mixture of 36 mg of sodium hydride (60%, oil-based) and 3 ml of DMF under ice-cooling. This mixture was stirred at room temperature for 15 minutes, and then ice-cooled. Subsequently, 0.20 g of 3-fluoro-4-[5-(trifluoromethyl)benzofuran-2-yl]pyridine was added thereto, and the mixture was stirred at room temperature for 3.5 hours. Thereto was added a mixture of 29 mg of 2,2-difluoroethanol, 0.5 ml of DMF and 14 mg of sodium hydride (60%, oil-based), and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.20 g of 3-(2,2-difluoroethoxy)-4-[5-(trifluoromethyl)benzofuran-2-yl]pyridine (hereinafter, referred to as “Present Active Compound 10”).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=[O:2].[C:13]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29]CCCC(OCC)=O)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)#[N:14].[NH:38]1[CH2:43][CH2:42][CH2:41][CH:40]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:39]1>O1CCCC1>[C:13]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH2:28][C:29]([N:38]3[CH2:43][CH2:42][CH2:41][CH:40]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:39]3)=[O:2])=[CH:25][CH:26]=2)=[CH:19][CH:20]=1)#[N:14]
Reactant: CCOC(=O)CCCCCOc1ccc(-c2ccc(C#N)cc2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)C1CCCNC1
Solvent: C1CCOC1
Product: CCOC(=O)C1CCCN(C(=O)COc2ccc(-c3ccc(C#N)cc3)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5.35 g of carbonyldiimidazole are added to a solution of 7.6 g of 4-(carboxymethyloxy)-4'-cyanobiphenyl (prepared from 4-cyano-4'-hydroxy-biphenyl and tert.butyl bromoacetate according to Example 13, but with potassium tert.butoxide as base, and subsequent ester cleaving with trifluoroacetic acid) in 30 ml of tetrahydrofuran and the resulting mixture is stirred for 0.5 hours at ambient temperature. 5.1 ml of ethyl piperidine-3-carboxylate are added and the mixture is stirred for 22 hours at ambient temperature. The tetrahydrofuran is evaporated off, the residue is taken up in ethyl acetate and washed successively with saturated sodium bicarbonate solution, 0.1N hydrochloric acid and water. After evaporation of the organic phase the residue remains as an oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11](SC)=[C:12]([S:15]([CH3:18])(=[O:17])=[O:16])[C:13]#[N:14])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:21][C:22]([NH2:26])([CH3:25])[CH2:23][CH3:24]>C(#N)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]([NH:26][C:22]([CH3:25])([CH3:21])[CH2:23][CH3:24])=[C:12]([S:15]([CH3:18])(=[O:17])=[O:16])[C:13]#[N:14])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CSC(Nc1ccc2c(c1)OCO2)=C(C#N)S(C)(=O)=O
Reactant: CCC(C)(C)N
Solvent: CC#N
Product: CCC(C)(C)NC(Nc1ccc2c(c1)OCO2)=C(C#N)S(C)(=O)=O

Procedure:
A mixture of 3-(benzo[1,3]dioxol-5-ylamino)-2-methanesulfonyl-3-methylsulfanyl-2-propenenitrile(0.800 g, 2.5 mmol) and 1,1-dimethylpropylamine (2.92 ml) in 10 ml of acetonitrile was stirred and refluxed for one week under nitrogen. The reaction mixture was concentrated and the residue dissolved in dichloromethane, washed twice with 1N aqueous HCl, once with brine, and trice with water. The organic phase was dried (sodium sulphate) and evaporated to afford the title compound as white crystals. Mp 86-88° C. 1H NMR (200 MHz, DMSO-d6): δ=0.90 (t, 3H), 1.34 (s, 6H), 1.70 (q, 2H), 3.04 (s, 3H), 6.66 (s, 2H), 6.66 (dd, 1H), 6.74 (d, 1H), 6.88 (d, 1H), 7.21 (s, 1H). 8.19 (s, 1H).
Reaction SMILES: ClC1C=CC2[C:6]3[N:7](C=C(I)N=3)CCOC=2N=1.Cl[C:18]1[CH:19]=[CH:20][C:21]2[C:22]3[N:23]([CH:29]=[C:30]([C:32]4[N:36]([CH:37]([CH3:39])[CH3:38])[N:35]=[CH:34][N:33]=4)[N:31]=3)[CH2:24][CH2:25][O:26][C:27]=2[N:28]=1.[Cl-].C[NH3+].C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[CH:37]([N:36]1[C:32]([C:30]2[N:31]=[C:22]3[C:21]4[CH:20]=[CH:19][C:18]([NH:7][CH3:6])=[N:28][C:27]=4[O:26][CH2:25][CH2:24][N:23]3[CH:29]=2)=[N:33][CH:34]=[N:35]1)([CH3:39])[CH3:38]
Reactant: Clc1ccc2c(n1)OCCn1cc(I)nc1-2
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Cl)nc1OCC2
Agent: C[NH3+]
Agent: [Cl-]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CNc1ccc2c(n1)OCCn1cc(-c3ncnn3C(C)C)nc1-2

Procedure:
Following the procedures of Examples herein, including Examples 20-22, 9-chloro-2-iodo-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepine was converted to 9-chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepine. A mixture of 110 mg (0.33 mmol) of 9-chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepine, 87 mg (1.3 mmol) of methylammonium chloride and 0.23 ml (1.3 mmol) of N,N-diisopropylethylamine in 3.0 ml of N-methylpyrrolidinone was microwaved for 90 min at 170° C. NMP was removed under high vacuum, the residue was basified with 1 M Na2CO3 and partitioned between ethyl acetate and water. The organic extracts were washed with 5% aqueous citric acid, water, brine, dried over MgSO4 and concentrated. The residue was purified by RP HPLC (acetonitrile gradient) to give 367. Yield 12 mg. M/z 326.3, calc. 325.17. 1H NMR (400 MHz, DMSO) δ 8.37 (d, J=8.6, 1H), 7.88 (s, 1H), 7.77 (s, 1H), 6.96 (s, 1H), 6.34 (d, J=8.6, 1H), 5.88 (dt, J=13.0, 6.5, 1H), 4.46 (d, J=9.2, 4H), 2.78 (d, J=2.9, 3H), 1.46 (d, J=6.6, 6H)
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:5]([C:6]([OH:8])=[O:7])[C:4]=1[OH:13])=O.Cl.[NH2:15]O>CN(C)C=O>[C:1]([C:3]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:5]([C:6]([OH:8])=[O:7])[C:4]=1[OH:13])#[N:15]
Reactant: NO
Reactant: Cc1cc(C=O)c(O)c(C(=O)O)c1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc(C#N)c(O)c(C(=O)O)c1
Yield: 76.3 %

Procedure:
3-Formyl-5-methylsalicylic acid (3.6 g) was dissolved in dimethylformamide (20 ml) and treated with hydroxylamine hydrochloride (1.53 g). The mixture was heated at reflux for 10 minutes and then the solvent was removed in vacuo. The residue was treated with water (20 ml) and hydrochloric acid (2N; 10 ml). The precipitated solid was filtered off and recrystallized from aqueous ethanol to give 3-cyano-5-methylsalicylic acid (2.7 g), m.p. 193°-194° C.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:33])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH3:16])[CH2:6]1)(=[O:3])[CH3:2].[OH:34]N1C(=O)C2=CC=CC=C2C1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(C(C)=O)C>[C:1]([O:4][CH:5]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C:7](=[CH:8][C:9](=[O:34])[C@@H:10]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:33])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([O:17][Si:18]([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:20])[CH3:19])[CH3:16])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H](C(C)O[Si](C)(C)C(C)(C)C)[C@@]4(C)CC[C@@H]32)C1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCC(C)=O
Product: CC(=O)OC1CC[C@@]2(C)C(=CC(=O)[C@H]3[C@@H]4CC[C@H](C(C)O[Si](C)(C)C(C)(C)C)[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 3-acetoxy-20-tert-butyldimethylsilyloxy-pregn-5-ene (337 gm, 0.71 mol, product of Step 2) in methyl ethyl ketone (4 L) was added N-hydroxyphthalimide (115.8 gm, 0.71 mol) and dibenzoyl peroxide (1.1 gm, 4.4 mmol). Air was bubbled through the reaction as the reaction was refluxed for 7.5 hr. Additional N-hydroxyphthalimide (9 gm) and dibenzoyl peroxide (0.1 gm) were added and reflux continued for 5 hr. The solvent was removed by rotoevaporation and methylene chloride (0.7 L) was added and warmned to 40° C. Upon cooling to room temperature, the suspension was filtered and the filtrate washed with methylene chloride (0.2 L). The filtrate was rotoevaporated and treated with pyridine (1.35 L) and acetic anhydride (135 mL). After stirring overnight, the solvent was removed by rotoevaporation and the dark orange oil dissolved in methanol (0.6 L). The mixture was heated to 50° C. and then cooled to room temperature. The solution was allowed to stand for 3 days and then cooled in an ice bath. The precipitate was filtered, washed with methanol, and dried to yield the title compound. The filtrate was rotoevaporated to a dry gum to yield the crude product.