Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1B(O)O.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:13]1[C:12]([F:11])=[CH:17][CH:16]=[CH:15][C:14]=1[F:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(N)C(=O)OC(C)(C)C
Reactant: OB(O)c1c(F)cccc1F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CN(Nc1c(F)cccc1F)C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 9.5 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 1.00 g, 6.8 mmol), 2,6-difluorophenylboronic acid (Aldrich; 1.07 g, 6.8 mmol), copper(II) acetate (1.24 g, 6.8 mmol) and triethylamine (960 μL, 6.8 mmol) in 1,2-dichloroethane (15 mL) was heated in an oil bath at 50° C. overnight. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 120 g column, eluting with 20-25% ethyl acetate/hexanes, to give N′-(2,6-difluoro-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (167 mg, 9%) as a colorless oil.
Reaction SMILES: O1CCCCC1[O:7][C@H:8]1[C@H:12]2[O:13][CH2:14][C@@H:15]([O:16][C:17](=[O:31])[CH2:18][CH2:19][CH2:20][C@H:21]([O:27][N+:28]([O-:30])=[O:29])[CH2:22][O:23][N+:24]([O-:26])=[O:25])[C@H:11]2[O:10][CH2:9]1.C(O)C>>[OH:7][C@H:8]1[C@H:12]2[O:13][CH2:14][C@@H:15]([O:16][C:17](=[O:31])[CH2:18][CH2:19][CH2:20][C@H:21]([O:27][N+:28]([O-:30])=[O:29])[CH2:22][O:23][N+:24]([O-:26])=[O:25])[C@H:11]2[O:10][CH2:9]1
Reactant: O=C(CCC[C@@H](CO[N+](=O)[O-])O[N+](=O)[O-])O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2OC1CCCCO1
Solvent: CCO
Product: O=C(CCC[C@@H](CO[N+](=O)[O-])O[N+](=O)[O-])O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Temperature: 45 °C
Reaction time: 4 h

Procedure:
To a solution of (5S)-((3R,3aR,6R,6aR)-6-(tetrahydro-2H-pyran-2-yloxy)-hexahydrofuro[3,2-b]furan-3-yl)5,6-bis(nitrooxy)hexanoate (2.27 g, 5.04 mmol) in ethanol (40 mL) pyridinium p-toluensulfonate (127 mg, 0.504 mmol) was added The reaction mixture was stirred at 45° C. for 4 hrs. The reaction mixture was filtered, concentrated under reduced pressure. The crude residue was purified by flash chromatography (Biotage SP1, EtOAc/n-hexane from 10 to 60%), affording the title product as pale yellow oil. 1H-NMR (300 MHz, CDCl3); δ 5.30 (1H, dd), 5.16 (1H, q), 4.77 (1H, d), 4.71 (1H, t), 4.50 (2H, m), 4.26 (1H, m), 4.12 (1H, dd), 3.94 (1H, dd), 3.85 (1H, dd), 3.58 (1H, dd), 2.61 (1H, d), 2.47 (2H, m), 1.83 (4H, m).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Na+].[C:12]1(=[O:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH:1](=[C:13]1[CH2:14][CH2:15][CH2:16][CH2:17][C:12]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1CCCCC1=Cc1ccccc1
Yield: 25.8 %

Procedure:
A 500-ml four-necked flask equipped with a thermometer was charged with 53 g of benzaldehyde, 25 ml of water and 1 g of sodium hydroxide, to which 68 g of cyclohexanone were added dropwise at 30° C. over 30 minutes. The resultant mixture was stirred for 1 hour at the same temperature. After neutralizing the reaction mixture to separate liquid layers from each other, the resultant reaction product was dissolved in 500 ml of toluene. To the solution, 0.5 g of PTS (p-toluenesulfonic acid) was added to conduct azeotropic dehydration for 3 hours in a 1-liter four-necked flask equipped with a Dean-Stark trap and a thermometer. After cooling, the residue was neutralized and washed with water, and the resultant organic layer was dried and concentrated, thereby obtaining 119 g of a crude product. This product was purified by column chromatography to obtain 24 g (yield: 28%) of 2-benzylidenecyclohexanone.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]=[C:24]=[S:25]>CN(C=O)C>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24]([NH:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[S:25]
Reactant: S=C=Nc1ccccc1Cl
Reactant: NCC(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: S=C(NCC(c1ccccc1)c1ccccc1)Nc1ccccc1Cl

Procedure:
The compound was prepared substantially in accordance with the procedure detailed in Example 1, using 2,2-diphenylethylamine (1.61 g, 8.1 mmol) and 2-chlorophenyl isothiocyanate (1.1 ml, 8.2 mmol) in 30 ml of DMF. The crude material was purified by recrystallization (hexanes/EtOAc).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:7]=1[O:13][CH3:14].[CH3:15][O:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20].Cl>ClCCCl.CCCCCC>[Cl:12][C:11]1[C:6]([Cl:5])=[C:7]([O:13][CH3:14])[CH:8]=[CH:9][C:10]=1[C:19]([C:18]1[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=1[O:16][CH3:15])=[O:20]
Reactant: COc1cccc(Cl)c1Cl
Reactant: COc1ccccc1C(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCC
Solvent: ClCCCl
Product: COc1ccccc1C(=O)c1ccc(OC)c(Cl)c1Cl
Temperature: 5 °C
Reaction time: 2.5 h

Procedure:
To a mixture of 3.9 g of AlCl3 and 4.67 g of 2,3-dichloroanisole in 70 ml of 1,2-dichloroethane at -10° C., 5 g of o-methoxybenzoyl chloride is added dropwise. The mixture is stirred for 2.5 hours and is gradually warmed to 5° C. The reaction mixture is poured into concentrated HCl and ice. The mixture is stirred one half hour to decompose the complex. The aqueous layer is extracted with additional organic solvent. The combined organic layers are washed until neutral, dried over Na2SO4 and evaporated to give an oil which solidifies on trituration with hexane. The crude product is recrystallized from 95% ethanol giving 2,3-dichloro-2',4-dimethoxybenzophenone, mp 94°-96° C.
Reaction SMILES: [NH2:1][CH:2]1[C:15](=[O:16])[N:4]2[CH:5]([C:10]3[NH:14][N:13]=[N:12][N:11]=3)[C:6]([CH3:9])([CH3:8])[S:7][C@H:3]12.C(N(CC)CC)C.Cl.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([NH:35][C:36](=[O:42])[NH:37][CH2:38][C:39](Cl)=[O:40])=[NH:34])=[CH:28][CH:27]=1>CN(C)C=O>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:32][C:33]([NH:35][C:36](=[O:42])[NH:37][CH2:38][C:39]([NH:1][CH:2]2[C:15](=[O:16])[N:4]3[CH:5]([C:10]4[NH:11][N:12]=[N:13][N:14]=4)[C:6]([CH3:8])([CH3:9])[S:7][C@H:3]23)=[O:40])=[NH:34])=[CH:30][CH:31]=1
Reactant: CC1(C)S[C@@H]2C(N)C(=O)N2C1c1nnn[nH]1
Reactant: N=C(Cc1ccc(Cl)cc1)NC(=O)NCC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)S[C@@H]2C(NC(=O)CNC(=O)NC(=N)Cc3ccc(Cl)cc3)C(=O)N2C1c1nnn[nH]1
Reaction time: 1 h

Procedure:
To a stirred solution of 480 mg. of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam and 404 mg. of triethylamine, in 6 ml. of N,N-dimethylformamide, is added 650 mg. of 2-(3-[2-(p-chlorophenyl)acetimidoyl]ureido)acetyl chloride hydrochloride. Stirring is continued for 1 hour, and then the reaction mixture is filtered. The filtrate is added to 300 ml. of ether, and the solid which precipitates is filtered off. The solid is washed thoroughly with methylene chloride, and dried, giving 585 mg. of the title compound, m.p. 150°-162° C. IR spectrum (Nujol mull): 1780 cm-1 (β-lactam). NMR spectrum (DMSO-d6): 8.90 ppm (d, 1H), 8.00-7.20 ppm (m, 8H), 5.80-5.20 ppm (m, 3H), 4.10-3.60 ppm (m, 4H), 1.65 ppm (s, 3H), 1.10 ppm (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25]([OH:27])=O)=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH2:28][C:29]1[N:34]=[CH:33][C:32]([C:35]([NH:37]O)=[NH:36])=[CH:31][N:30]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25]4[O:27][N:37]=[C:35]([C:32]5[CH:31]=[N:30][C:29]([NH2:28])=[N:34][CH:33]=5)[N:36]=4)=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: N=C(NO)c1cnc(N)nc1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)c(F)c3)nc12
Product: Nc1ncc(-c2noc(-c3cnn4c(C(F)(F)F)cc(-c5ccc(C(F)(F)F)c(F)c5)nc34)n2)cn1

Procedure:
The title compound was prepared from 5-(3-fluoro-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C. 18) (197 mg, 0.5 mmol) and 2-amino-N-hydroxy-pyrimidine-5-carboxamidine (example B.5) (115 mg, 0.75 mmol) according to general procedure II. Obtained after flash chromatography on silica gel (ethyl acetate/heptane) and further purification by crystallization (dichloromethane/hexane) as a yellow solid (130 mg, 51%). MS (EI) 510.1 [(M)+]; mp 270° C.
Reaction SMILES: [CH:1]1[C:11]2[C:10](=[O:12])[NH:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>C(#N)C>[N:29]1([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][N:6]2[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10](=[O:12])[NH:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]2=3)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: BrCCCCCCN1CCCCC1
Reactant: O=C1Nc2ccccc2Nc2ccccc21
Agent: [Li]CCCC
Solvent: CC#N
Product: O=C1Nc2ccccc2N(CCCCCCN2CCCCC2)c2ccccc21
Yield: 46 %

Procedure:
Prepared analogously to Example 6 from 5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, n-butyl-lithium and 1-bromo-6-(1-piperidinyl)-hexane in a yield of 46% of theory. Colourless crystals, m.p. 124°-125° C. (from acetonitrile using activated charcoal).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:19])[CH2:9][O:10][C:11]2[C:12](=[O:18])[N:13]([CH3:17])[N:14]=[CH:15][CH:16]=2)[CH2:4][CH2:3]1.[F:20][C:21]([F:31])([F:30])[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1O>>[CH3:17][N:13]1[C:12](=[O:18])[C:11]([O:10][CH2:9][C:8](=[O:19])[N:5]2[CH2:4][CH2:3][CH:2]([O:1][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][C:21]([F:20])([F:31])[F:30])[CH2:7][CH2:6]2)=[CH:16][CH:15]=[N:14]1
Reactant: Cn1nccc(OCC(=O)N2CCC(O)CC2)c1=O
Reactant: Oc1ccccc1OC(F)(F)F
Product: Cn1nccc(OCC(=O)N2CCC(Oc3ccccc3OC(F)(F)F)CC2)c1=O
Yield: 20 %

Procedure:
Compound 21 is prepared from intermediate 5c and 2-trifluoromethoxy-phenol following synthesis method 3 (yield: 20%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[N:11]=[N:12][N:13]([CH3:15])[N:14]=2)[CH:3]=1.[ClH:16]>C(O)C.[Pd]>[ClH:16].[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([C:10]2[N:11]=[N:12][N:13]([CH3:15])[N:14]=2)[CH:3]=1
Reactant: Cn1nnc(-c2cc(F)ccc2C#N)n1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cn1nnc(-c2cc(F)ccc2CN)n1
Reaction time: 3 h
Yield: 91 %

Procedure:
A solution of intermediate 58, 4-fluoro-2-(2-methyl-2H-tetrazol-5-yl)-benzonitrile, (330 mg, 1.62 mmol) in ethanol (15 mL) was mixed with 6N HCl (1 mL) and 10% Pd—C (200 mg) under nitrogen. The mixture was then stirred under hydrogen (1 atm) for 3 hrs. After removing the catalyst, the filtrate was concentrated in vacuo to provide 360 mg (Yield 91%) of the title compound as an off-white solid; 1H NMR (500 MHz, DMSO-D6) δ ppm: 4.42 (2H, d, J=2.75 Hz) 4.49 (3H, s) 7.48-7.56 (1H, m) 7.78 (1H, dd, J=8.7, 5.7 Hz) 7.86 (1H, dd, J=9.8, 2.8 Hz) 8.45 (3H, s); LC/MS m/z 208.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[N+:12]([C:15]1[C:16]([N:24]2[CH2:29][C@H:28]([C:30]([F:33])([F:32])[F:31])[CH2:27][C@H:26]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:25]2)=[C:17]2[CH2:23][CH2:22][CH2:21][C:18]2=[N:19][CH:20]=1)([O-:14])=[O:13].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[N+:12]([C:15]1[C:16]([N:24]2[CH2:29][C@H:28]([C:30]([F:33])([F:32])[F:31])[CH2:27][C@H:26]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:38])([CH3:40])[CH3:39])[CH2:25]2)=[C:17]2[CH2:23][CH2:22][CH2:21][C:18]2=[N+:19]([O-:9])[CH:20]=1)([O-:14])=[O:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(c2c([N+](=O)[O-])cnc3c2CCC3)C1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(c2c([N+](=O)[O-])c[n+]([O-])c3c2CCC3)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.5 %

Procedure:
mCPBA (0.16 g, 0.93 mmol) was added to a solution of tert-butyl [(3S,5R)-1-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate (0.16 g, 0.37 mmol) (second peak, pure product resolved on chiral HPLC from previous step) in DCM (2.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The mixture was treated with aq. Na2S2O3, then 1 M NaOH, and extracted with EtOAc. The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CombiFlash® apparatus (20 g column) eluting with 0-100% EtOAc in hexanes followed by MeOH/EtOAc (0-30%) to give 0.10 g (60%) of the sub-title compound as a reddish solid. 0.033 g of unreacted starting material was recovered. LCMS calc. for C19H26F3N4O5 (M+H)+ m/z=447.2. found: 446.9.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[CH3:3].C(O)(C)C.CS(O)(=O)=O.[CH3:24][N:25]=[C:26](SC)[S:27][CH3:28]>O>[CH3:24][NH:25][C:26](=[N:14][CH2:13][CH2:12][S:11][CH2:10][C:8]1[N:9]=[C:5]([CH2:4][N:2]([CH3:1])[CH3:3])[S:6][CH:7]=1)[S:27][CH3:28]
Reactant: CN=C(SC)SC
Reactant: CN(C)Cc1nc(CSCCN)cs1
Agent: CS(=O)(=O)O
Solvent: CC(C)O
Solvent: O
Product: CNC(=NCCSCc1csc(CN(C)C)n1)SC

Procedure:
Ten g. of 2-dimethylaminomethyl-4-(2-aminoethyl)thiomethylthiazole was dissolved in 100 ml. of isopropanol, and 2.8 ml. of methanesulfonic acid was added, followed by 6.5 g. of methylcarbonimidodithioic acid, dimethyl ester. The mixture was stirred under reflux for 16 hours, and was evaporated under vacuum to obtain a residue, which was taken up in 100 ml. of water. The solution was extracted with two 25 ml. portions of dichloromethane, and the aqueous layer was cooled. Fifty ml. of dichloromethane and 15 ml. of 50% aqueous sodium hydroxide were added. The layers were separated, and the solution was extracted again with 50 ml. of dichloromethane. The organic layers were combined, dried over potassium carbonate and evaporated under vacuum to obtain 10.3 g. of product, substantially identical to that of Example 1, which was 96.7% pure by HPLC analysis.
Reaction SMILES: [F:1][C:2]1([F:8])[CH2:4][CH:3]1[C:5](O)=[O:6].C(N1C=CN=C1)(N1C=CN=C1)=O.O[N:22]=[C:23]([C:25]1[CH:26]=[CH:27][C:28]([CH3:43])=[C:29]([NH:31][C:32]([C:34]2[N:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]3=[N:36][CH:35]=2)=[O:33])[CH:30]=1)[NH2:24]>CN1C(=O)CCC1>[F:1][C:2]1([F:8])[CH2:4][CH:3]1[C:5]1[O:6][N:22]=[C:23]([C:25]2[CH:26]=[CH:27][C:28]([CH3:43])=[C:29]([NH:31][C:32]([C:34]3[N:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]4=[N:36][CH:35]=3)=[O:33])[CH:30]=2)[N:24]=1
Reactant: O=C(O)C1CC1(F)F
Reactant: Cc1ccc(C(N)=NO)cc1NC(=O)c1cnc2ccccn12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN1CCCC1=O
Product: Cc1ccc(-c2noc(C3CC3(F)F)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 120 °C
Reaction time: 0.05 h

Procedure:
To a stirring solution of 2,2-difluorocyclopropanecarboxylic acid (325 mg, 2.66 mmol) in anhydrous NMP (7 mL) was added 1,1′-carbonyldiimidazole (CDI) (432 mg, 2.66 mmol). The reaction was stirred for 3 minutes. N-(5-(N′-hydroxycarbamimidoyl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (9) (825 mg, 2.66 mmol) was added and the reaction was stirred for 25 minutes. Then, the reaction was heated at 120° C. for minutes. The crude product was purified on silica gel using 10% MeOH in dichloromethane to give N-(5-(5-(2,2-difluorocyclopropyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (F64). 1H NMR (400 MHz, d6-DMSO) δ 9.60 (d, J=7.2 Hz, 1H), 8.56 (d, J=1.6 Hz, 1H), 8.51 (s, 1H), 8.12 (bs, 1H), 7.87 (dd, J=2.0, 7.8 Hz, 1H), 7.82 (d, J=9.2 Hz, 1H), 7.58-7.53 (m, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.16 (td, J=0.8, 6.8 Hz, 1H), 3.19-3.12 (m, 1H), 2.48 (s, 3H), 2.45-2.36 (m, 1H), 2.27-2.18 (m, 1H). MS m/z 396.1 (M+1)+.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:10][S:11](O)(=[O:13])=[O:12].ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:1][N:2]([CH3:9])[C:3]1[CH:8]=[CH:7][C:6]([S:11]([Cl:10])(=[O:13])=[O:12])=[CH:5][CH:4]=1
Reactant: O=S(=O)(O)Cl
Reactant: CN(C)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CN(C)c1ccc(S(=O)(=O)Cl)cc1

Procedure:
N,N-Dimethylaniline (8 ml) was dissolved in 20 ml of chloroform, and chlorosulfonic acid (20 ml) was slowly added with cooling. The reaction mixture was refluxed for 6 hr. The reaction mixture was cooled and poured on ice (100 g). Dichloromethane (120 ml) was added and aqueous layer was neutralized by concentrated sodium carbonate solution with keeping temperature below 4 ° C. Organic layer was again washed with ice-cold 0.1N sodium bicarbonate solution, and dried over anhydrous magnesium sulfate. Organic layer was concentrated under reduced pressure. Residual material was crystallized from ethyl ether-heptane to give yellowish green solid. p-(Dimethylamino)benzenesulfonyl chloride (4.2 g) was obtained. M. P. 108-13 111° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:26])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)[O:11][C:6]=2[C:5]([F:27])=[CH:4][C:3]=1[F:28].[H-].[Na+].I[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].[Cl-].[Na+]>CN(C)C=O>[F:28][C:3]1[CH:4]=[C:5]([F:27])[C:6]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)=[CH:9][C:8](=[O:26])[C:7]=2[C:2]=1[NH:1][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Reactant: CCCCCCCI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCNc1c(F)cc(F)c2oc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)cc(=O)c12
Reaction time: 2 h
Yield: 73 %

Procedure:
505 mg (1.29 mmol) of 5-amino-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one obtained in Example 66 was dissolved in 15 ml of dimethylformamide under argon atmosphere, 156 mg of sodium hydride (60% oil dispersion) and 0.42 ml of 1-iodoheptane were added under ice-cooling and the mixture was stirred for 2 hours. An aqueous saturated solution of sodium chloride was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1) to give 460 mg (73%) of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-heptylamino-4H-1-benzopyran-4-one.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH:10]=[CH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C1C=C(Cl)C=C(C(OO)=[O:22])C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[O:22]1[C:10]2[CH2:9][CH2:8][C:7]3[C:12]([C:11]1=2)=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3
Reactant: O=[N+]([O-])c1ccc2c(c1)C=CCC2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2c(c1)C1=C(CC2)O1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
A solution of 7-nitro-3,4-dihydronaphthalene (9.18 g; 0.052 mol) (from Preparation 2) in CH2Cl2 (600 ml) was cooled to 0° C. and treated with m-CPBA, 57-85%, (13.86 g, approx. 0.056 mol, approx. 1.1 equiv). The reaction mixture was allowed to stir for 48 h, slowly warming to room temperature. The mixture was treated with aqueous NaHCO3 (300 ml) and the organic layer was separated. The organic layer was extracted with additional aqueous NaHCO3, washed with aqueous NaCl, dried (Na2SO4), filtered and concentrated under reduced pressure to give 1,2-epoxy-7-nitro-3,4-dihydronaphthalene (9.94, 100%) as a white solid which was used in the next step without further purification. Rf (silica gel): 0.56(70% hexane: 30% EtOAc); 1H NMR (300 MHZ, CDCl3) 8.24 (s, 1H), 8.08 (dd, J=1.8 and 8.1 H 1H), 7.23 (d, J=8.1 Hz, 1H), 3.92 (d, J=4.2 Hz, 1H), 3.77 (s, 1H), 2.87-2.62 (m, 2H), 2.47 (dd, J=6.6 and 14.4 Hz, 1H), 1.78 (dt, J=5.7 and 14.1 Hz, 1H), 13C NMR (75 MHZ, CDCl3) 146.5, 144.7, 134.5, 129.4, 124.4, 123.4, 54.7, 51.8, 24.5, 21.0.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH2:15][CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[C:6]=2[N:22]=1.[C:23](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:23])[C:10](=[O:12])[C:9]([F:13])([F:14])[CH2:8][N:7]([CH2:15][CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[C:6]=2[N:22]=1
Reactant: O=C1Nc2cnc(Cl)nc2N(CCc2cccs2)CC1(F)F
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)C(F)(F)CN(CCc2cccs2)c2nc(Cl)ncc21
Reaction time: 4 h
Yield: 102.2 %

Procedure:
To a solution of 0.51 g (0.0015 mole) of 2-chloro-7,7-difluoro-9-(2-thiophen-2-yl-ethyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-269) in 12 mL of dimethylformamide was added 0.58 g (0.0023 mole) of cesium carbonate, followed by 0.28 mL (0.0045 mole) of iodomethane. After stirring four hours, the mixture filtered and then concentrated under reduced pressure. Ice water and dichloromethane were added. The mixture was extracted with dichloromethane twice. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 0.55 g of 2-chloro-7,7-difluoro-5-methyl-9-(2-thiophen-2-yl-ethyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-269) as a sticky solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])=[CH:5][C:4]=1[C:14]([F:17])([F:16])[F:15].C(O)C>[Pd].O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:5][C:4]=1[C:14]([F:15])([F:17])[F:16]
Reactant: COc1ccc(C=CC(=O)O)cc1C(F)(F)F
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(CCC(=O)O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
A mixture of 3-[4-methoxy-3-(trifluoromethyl)phenyl]acrylic acid (2.90 g, 11.8 mmol), 10% palladium on carbon (250 mg), ethanol (60 mL) and tetrahydrofuran (40 mL) was stirred under a hydrogen atmosphere (1 kg/cm2) at room temperature overnight. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-0/1) to give the title compound (2.40 g, yield 83%) as colorless crystals.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[C:5]([C:12]1[CH:21]=[CH:20][C:15]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[H-].[Na+].[CH3:30][CH2:31][O:32][C:33]([CH2:35]Br)=[O:34]>O1CCCC1>[CH2:31]([O:32][C:33](=[O:34])[CH2:35][O:19][CH2:18][CH2:17][O:16][C:15]1[CH:14]=[CH:13][C:12]([C:5]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[C:4]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:3][CH2:2][Cl:1])=[CH:21][CH:20]=1)[CH3:30]
Reactant: OCCOc1ccc(C(=C(CCCl)c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COCCOc1ccc(C(=C(CCCl)c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2-[4-(4-Chloro-1,2-diphenyl-but-1-enyl)-phenoxy]-ethanol (Compound II) (0.3 g, 0.79 mmol) was dissolved in tetrahydrofuran (5 ml) under a nitrogen atmosphere. Sodium hydride (0.058 g, 1.21 mmol) was added in THF (5 ml) to the solution and the mixture was stirred at room temperature for an hour. Then the mixture was cooled to 0° C., ethyl bromo acetate (0.4 g, 2.38 mmol) was added and the stirring was continued for 5 hours at 0-5° C. The mixture was allowed to warm up to room temperature and stirring was continued overnight. Then the reaction is quenched with water and ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate. The organic phase was washed with water, dried with sodium sulphate and evaporated to dryness. The residue was used in the next reaction step without further purification.