Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH:6]1([O:12][N:13]2[C:18]([CH3:20])([CH3:19])[CH2:17][CH:16]([OH:21])[CH2:15][C:14]2([CH3:23])[CH3:22])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)CC)C>C(Cl)Cl>[CH:6]1([O:12][N:13]2[C:14]([CH3:23])([CH3:22])[CH2:15][CH:16]([O:21][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:17][C:18]2([CH3:19])[CH3:20])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: CC1(C)CC(O)CC(C)(C)N1OC1CCCCC1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)OC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1.6 ml of acryloyl chloride in 20 ml of methylene chloride is added to a stirred solution of 5.11 grams of 1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-ol and 3.10 ml of triethylamine in 20 ml of methylene chloride at 0° C. After stirring at room temperature for 2 hours, the solvent is removed under reduced pressure. The residue is then purified by liquid chromatography to afford the title compound as a white solid with a melting point of 49°-52° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]([O:21][C@H:22]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH:40]([F:42])[F:41])=[C:35]([O:43][CH2:44][CH:45]3[CH2:47][CH2:46]3)[CH:34]=1)[CH2:23][C:24]1[C:29]([Cl:30])=[CH:28][N+:27]([O-:31])=[CH:26][C:25]=1[Cl:32])=[O:20])[CH:13]=[CH:12]2)C1C=CC=CC=1>[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[Cl:32][C:25]1[CH:26]=[N+:27]([O-:31])[CH:28]=[C:29]([Cl:30])[C:24]=1[CH2:23][C@@H:22]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH:40]([F:42])[F:41])=[C:35]([O:43][CH2:44][CH:45]2[CH2:47][CH2:46]2)[CH:34]=1)[O:21][C:19](=[O:20])[CH2:18][N:14]1[C:15]2[C:11](=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=2)[CH:12]=[CH:13]1
Reactant: O=C(Cn1ccc2cc(OCc3ccccc3)ccc21)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Product: O=C(Cn1ccc2cc(O)ccc21)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reaction time: 5 h
Yield: 30.8 %

Procedure:
A mixture of (S)-4-(2-(2-(5-(benzyloxy)-1H-indol-1-yl)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (155 mg, 0.227 mmol) and 5% Pd/BaSO4 dry powder (type D1863 Chimet spa) (290 mg, 0.136 mmol) in 20 ml of EtOH was hydrogenated for 5 hours at 50 psi. The catalyst was filtered off, solvent was evaporated and the crude was purified by flash chromatography on silica gel (DCM/MeOH from 99.5:0.5 to 99:1) affording (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5-hydroxy-1H-indol-1-yl)acetoxy)ethyl)pyridine 1-oxide (41.8 mg, 0.070 mmol, 31% yield). MS/ESI+ 593.18 [MH]+, [αD]=+30.50, c=0.6 in DCM; 1H NMR (300 MHz, DMSO-d6) δ ppm 8.67 (s, 1H) 8.54 (s, 2H) 7.12-7.19 (m, 2H) 6.99 (d, 1H) 6.93 (d, 1H) 6.91 (dd, 1H) 6.85 (d, 1H) 7.05 (t, 1H) 6.61 (dd, 1H) 6.24 (dd, 1H) 6.01 (dd, 1H) 5.13 (d, 1H) 4.94 (d, 1H) 3.84 (d, 2H) 3.42 (dd, 1H) 3.20 (dd, 1H) 1.11-1.31 (m, 1H) 0.51-0.66 (m, 2H) 0.27-0.44 (m, 2H)
Reaction SMILES: [CH3:1][C@@:2]([S:31]([CH3:34])(=[O:33])=[O:32])([CH2:13][CH2:14][N:15]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[O:27][CH:28]=[CH:29][N:30]=3)=[CH:22][CH:21]=2)[CH:17]=[N:16]1)[C:3]([NH:5][O:6]C1CCCCO1)=[O:4].Cl>CCO>[OH:6][NH:5][C:3](=[O:4])[C@:2]([CH3:1])([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:13][CH2:14][N:15]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[O:27][CH:28]=[CH:29][N:30]=3)=[CH:22][CH:21]=2)[CH:17]=[N:16]1
Reactant: C[C@@](CCn1cc(-c2ccc(-c3ncco3)cc2)cn1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: CCO
Product: C[C@@](CCn1cc(-c2ccc(-c3ncco3)cc2)cn1)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.5 %

Procedure:
To a solution of (2R)-2-methyl-2-(methylsulfonyl)-4-{4-[4-(1,3-oxazol-2-yl)phenyl]-1H-pyrazol-1-yl}-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (0.031 g, 0.063 mmol) in EtOH (20 mL) was added 6M HCl (5 mL). The reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was concentrated and was purified via reverse-phase chromatography, using 5%-95% acetonitrile/water with 0.1% formic acid modifier. The target fractions were combined and evaporated to give (2R)—N-hydroxy-2-methyl-2-(methylsulfonyl)-4-{4-[4-(1,3-oxazol-2-yl)phenyl]-1H-pyrazol-1-yl}butanamide (6 mg, 20% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 1.22-1.30 (m, 3H), 2.44-2.59 (m, 1H), 2.76-2.92 (m, 1H), 2.94-3.11 (m, 3H), 4.19-4.45 (m, 2H), 7.23 (s, 1H), 7.45-7.56 (m, 2H), 7.66-7.74 (m, 2H), 7.80-7.86 (m, 1H), 7.93-8.06 (m, 2H). LC-MS M+H+405.1.
Reaction SMILES: [C:1]1([PH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C[O:17]CC1.[Li]CCCC.ClC/C=C1\C(=C)[C@@H](O[Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)C[C@@H](O[Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)C\1>O>[C:8]1([PH:7](=[O:17])[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C1CCOC1
Reactant: c1ccc(Pc2ccccc2)cc1
Agent: C=C1/C(=C\CCl)C[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C[C@@H]1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: [Li]CCCC
Solvent: O
Product: O=[PH](c1ccccc1)c1ccccc1
Reaction time: 1.25 h

Procedure:
847 μl (10.2 mmol) of diphenylphosphine in 16 ml of abs. THF was deprotonated at -10° with 3.05 ml nBuLi (1.5M, hexane). The solution was then cooled to -75° and 2.76 g (4.15 mmol) of (Z)-(3S,5S)-1-(2-chloro-ethylidene)-3,5-bis-(tert-butyl-diphenyl-silanyloxy)-2-methylene-cyclohexane, dissolved in 16 ml of abs. THF, was added dropwise. 10 Minutes later, 190 μl of water was injected and the reaction mixture allowed to reach room temperature. All solvents were then removed i.V., the residue taken up in 33 ml of CH2Cl2 and treated with 81 ml of 5% H2O2. After stirring for 75 minutes, the layers were separated, the queous phase extracted with AcOEt, the organic layers washed with sodium pyrosulfite, dried over sodium sulfate and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=45/55) afforded 2.534 g of (Z)-(3S,5S)-[2 t-3,5-bis-(tert-butyl-diphenyl-silanyloxy)-2-methylene-cyclohexylidene]-ethyl]-diphenyl-phosphine oxide as colorless foam.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.FC1[C:18]([C:23]#[N:24])=[N:19][CH:20]=[CH:21][CH:22]=1.[CH3:25]S(C)=O>C(Cl)(Cl)Cl>[C:23]([C:18]1[C:1]([NH:2][CH2:3][CH2:4][N:5]([CH3:25])[C:6](=[O:15])[O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:22][CH:21]=[CH:20][N:19]=1)#[N:24]
Reactant: CS(C)=O
Reactant: N#Cc1ncccc1F
Reactant: CNCCNC(=O)OCc1ccccc1
Solvent: ClC(Cl)Cl
Product: CN(CCNc1cccnc1C#N)C(=O)OCc1ccccc1

Procedure:
A solution of benzyl 2-(methylamino)ethylcarbamate (prepared as described in example 7, 14 g, 72.1 mmol) in DMSO (20 mL) was reacted with 3-fluoro-2-cyanopyridine (see example 2, 8 g, 65.5 mmol) in a pressure vessel at 85° C. overnight. The resulting mixture was diluted with CHCl3 (100 mL) and added to the top of a silica gel column (150 mm by 7 inches) packed with 20% EtOAc/Hexanes. The column was eluted with a gradient of 20% EtOAc/Hexanes to 100% EtOAc and the clean fractions combined and evaporated to give the product as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:39][CH2:40][CH3:41])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH:20]([C:21]3[CH:26]=[CH:25][C:24]([CH:27]([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])=[CH:23][CH:22]=3)[C:19](=O)[C:18]3[C:17]([C:35](OC)=[O:36])=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12]2)=[CH:7][CH:6]=1)[CH3:2].C(OC(OCC)C1C=CC(C2C(C3C=CC(C(OCC)OCC)=CC=3)C(=O)C3C(C(OCC)=O)=CC=CC=3N2)=CC=1)C.O.[NH2:85][NH2:86]>CO>[CH2:40]([O:39][CH:4]([O:3][CH2:1][CH3:2])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[NH:12][C:13]3[C:18]4[C:19](=[N:85][NH:86][C:35](=[O:36])[C:17]=4[CH:16]=[CH:15][CH:14]=3)[CH:20]2[C:21]2[CH:26]=[CH:25][C:24]([CH:27]([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])=[CH:23][CH:22]=2)=[CH:7][CH:6]=1)[CH3:41]
Reactant: NN
Reactant: CCOC(OCC)c1ccc(C2Nc3cccc(C(=O)OC)c3C(=O)C2c2ccc(C(OCC)OCC)cc2)cc1
Agent: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(C(OCC)OCC)cc1)C(c1ccc(C(OCC)OCC)cc1)N2
Solvent: CO
Solvent: O
Product: CCOC(OCC)c1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(C(OCC)OCC)cc2)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
A mixture of methyl 2,3-bis(4-(diethoxymethyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate and ethyl 2,3-bis(4-(diethoxymethyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (240 mg, 0.43 mmol) in hydrazine monohydrate (5 mL) and methanol (5 mL) was stirred at 40° C. for 2 hr. The mixture was cooled to room temperature and filtered to give the 8,9-bis(4-(diethoxymethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (120 mg, yield 52%) as a light yellow solid. LC-MS (ESI) m/z: 544 (M+1)+. MS (ESI) m/e 381 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[CH2:22]([O:25][C:26](Cl)=[O:27])[CH2:23][CH3:24]>C1C=CC=CC=1>[C:26](=[O:27])([O:25][CH2:22][CH2:23][CH3:24])[O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1
Reactant: CCCOC(=O)Cl
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCCOC(=O)Oc1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
0.390 G. of 4'-cyano-4-hydroxy-biphenyl are dissolved in 4.0 ml. of absolute pyridine and reacted with 0.293 g. of chloroformic acid n-propyl ester as in Example 1. The 0.546 g. of brownish crystals obtained according to the procedure described in Example 1 are dissolved in benzene and chromatographed on 40 g. of silica gel. Benzene elutes 0.528 g. of yellowish crystals which are recrystallized from ether-hexane up to constant melting point and clearing point. The pure 4'-cyano-4-biphenylyl n-propyl carbonate obtained melts at 70.2°-70.9° and is liquid crystalline (monotrope) upon cooling to 68.2°. UV (EtOH): ε270 = 26,000.
Reaction SMILES: [CH:1]1([CH:7]2[CH2:13][CH2:12][C:11](OC)=[N:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-:16].[NH4+:17]>CO>[ClH:16].[CH:1]1([CH:7]2[CH2:8][CH2:9][NH:10][C:11](=[NH:17])[CH2:12][CH2:13]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC1=NCCC(C2CCCCC2)CC1
Reactant: [Cl-]
Reactant: [NH4+]
Solvent: CO
Product: Cl
Product: N=C1CCC(C2CCCCC2)CCN1

Procedure:
The product of EXAMPLE 73 in MeOH is reacted with ammonium chloride by the method of EXAMPLE 27 to generate the title material.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:11]1[N:15]=[C:14]([NH2:16])[O:13][N:12]=1)([CH3:10])[CH3:9])(C)(C)C.[ClH:18].O1CCOCC1>C(O)C>[ClH:18].[NH2:7][C:8]([C:11]1[N:15]=[C:14]([NH2:16])[O:13][N:12]=1)([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1noc(N)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CC(C)(N)c1noc(N)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of [1-(5-amino-[1,2,4]oxadiazol-3-yl)-1-methyl-ethyl]carbamic acid tert-butyl ester (1.6 g, 6.6 mmol) in ethanol (30 mL) was added HCl in dioxane (4 M, 6.6 ml, 26.4 mmol) and the reaction mixture was stirred 16 hours at room temperature. The reaction mixture was concentrated in vacuo and dried by applying high vacuum at 40° C. for 4 hours to give the title compound as off-white solid (1.2 g, quant.); LC-MS (UV peak area/ESI) 99.9%, 143.0927 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:18]2[C:23](=[O:24])[NH:22][C:21](=[O:25])[CH:20]=[N:19]2)[CH:5]=[C:6]([CH3:17])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.[C:26]1([S:32](O)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:18]2[C:23](=[O:24])[NH:22][C:21](=[O:25])[CH:20]=[N:19]2)[CH:5]=[C:6]([CH3:17])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([S:32]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:34])=[O:33])[CH:10]=1
Reactant: O=S(=O)(O)c1ccccc1
Reactant: COc1ccc(Oc2c(C)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)cc1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: COc1ccc(Oc2c(C)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)cc1S(=O)(=O)c1ccccc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-{3-chloro-4-[4-methoxy-phenoxy]-5-methyl-phenyl}-2H-[1,2,4]triazine-3,5-dione (1.0 g) and benzenesulfonic acid (0.9 g) in Eaton's reagent (5 mL) was heated at 80° C. for 8 h. The reaction was poured over ice, stirred for 30 min, solids filtered, dried and flash chromatographed on silica gel (30-100% THF/hexanes) to afford the title compound of Step A, 0.66 g.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[C:8]([F:10])[CH:7]=[C:6](F)[N:5]=1.[CH2:12]([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[NH2:3][C:4]1[N:9]=[C:8]([F:10])[CH:7]=[C:6]([O:19][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]=1
Reactant: OCc1ccccc1
Reactant: Nc1nc(F)cc(F)n1
Agent: [H-]
Agent: [Na+]
Product: Nc1nc(F)cc(OCc2ccccc2)n1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
1.14 g (0.0382 mol) of 80% sodium hydride were added at 25° C. under nitrogen to 70 ml of benzyl alcohol, and this mixture was stirred at 100° C. for 30 minutes. After it had been cooled to 40° C., 5.0 g (0.0382 mol) of 2-amino-4,6-difluoropyrimidine were added, and the mixture was then stirred at 100° C. for 5 hours. After the reaction was complete, a little precipitate was filtered off, and the filtrate was concentrated under 1 mbar at a bath temperature of 150° C. The viscous residue obtained in this way was induced to crystallize by trituration with cyclohexane. 6.3 g (75.2% of theory) of the title compound of melting point 96°-98° C. were obtained after filtering off, washing with water and drying.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[C:5]([Cl:8])=[CH:6][CH:7]=1.[CH:14]([N:18]=[C:19]=[O:20])([CH2:16][CH3:17])[CH3:15]>CN(C)C=O>[NH2:12][S:9]([C:4]1[C:3]([OH:13])=[C:2]([NH:1][C:19]([NH:18][CH:14]([CH2:16][CH3:17])[CH3:15])=[O:20])[CH:7]=[CH:6][C:5]=1[Cl:8])(=[O:11])=[O:10]
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Reactant: CCC(C)N=C=O
Solvent: CN(C)C=O
Product: CCC(C)NC(=O)Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Yield: 53.9 %

Procedure:
A solution of 3-amino-6-chloro-2-hydroxybenzenesulfonamide (200 mg, 0.90 mmol) and sec-butyl isocyanate (102 μL, 0.90 mmol) in 1.5 mL of N,N-dimethyl-formamide was stirred at room temperature for 20 hours. Purification upon column chromatograph on silica gel, eluting with ethyl acetate/hexane (40/60, v/v), gave the desired product (156 mg, 54%). LC-MS 322.2 (M+).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][O:22][CH2:23][C:24]([NH2:26])=[NH:25])=[CH:16][CH:15]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH:26][C:24](=[NH:25])[CH2:23][O:22][CH2:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=1)=[O:6]
Reactant: N=C(N)COCCc1ccc(F)cc1
Reactant: O=C(O)c1cc(Cl)cnc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: N=C(COCCc1ccc(F)cc1)NC(=O)c1cc(Cl)cnc1Cl

Procedure:
In analogy to the procedure described in example 78.3, 2,5-dichloronicotinic acid was reacted with 2-[2-(4-fluoro-phenyl)-ethoxy]-acetamidine hydrochloride in the presence of TBTU and DIPEA to give 2,5-dichloro-N-{2-[2-(4-fluoro-phenyl)-ethoxy]-1-imino-ethyl}-nicotinamide as orange oil. MS: m/e=370.0 [M+H+].
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:17]3[CH2:19][CH2:18]3)[CH:15]=2)[N:10]([CH3:20])[CH:9]=1)=[O:7])C.Cl>C(O)C>[CH:17]1([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]([CH3:20])[CH:9]=[C:8]3[C:6]([OH:7])=[O:5])[CH2:18][CH2:19]1
Reactant: CCOC(=O)c1cn(C)c2ccc(C3CC3)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1cc(C(=O)O)c2cc(C3CC3)ccc21
Temperature: 70 °C
Reaction time: 12 h
Yield: 86.7 %

Procedure:
1N Aqueous solution of sodium hydroxide (16 ml) was added at room temperature to a solution of 5-cyclopropyl-1-methyl-1H-indole-3-carboxylic acid ethyl ester (802 mg) in ethanol (16 ml) and stirred at 70° C. for 12 hours. After completion of the reaction, the reaction solution was cooled to room temperature and 1N hydrochloric acid aqueous solution was added until the solution became pH 1-2. The precipitated solid was collected by filtration to give the titled compound (615 mg) as a brown solid.
Reaction SMILES: [N:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([OH:17])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18]([C:27]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)(O)[C:28]#[CH:29])[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[CH2:18]([C:27]1([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[O:17][C:9]2[CH:8]=[C:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:16]3[C:11]([C:10]=2[CH:29]=[CH:28]1)=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1
Reactant: C#CC(O)(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Reactant: Oc1cc(N2CCCCC2)c2ccccc2c1
Solvent: Cc1ccccc1
Product: COc1ccc(CC2(Cc3ccc(OC)cc3)C=Cc3c(cc(N4CCCCC4)c4ccccc34)O2)cc1
Reaction time: 1.5 h

Procedure:
1-Chloro-4-piperidino-2-naphthol (3.0 g;0.0115 mol), prepared as in 1(a) above, dissolved in 1.25M aqueous NaOH (100 ml) was stirred and heated to 75°-80° C. To the solution was added (50/50) Raney Nickel (14.0 g) portionwise over 1 hour. The mixture was stirred for 1.5 h, cooled then filtered through celite with washing (3×2M NaOH). The filtrate was neutralised with conc. HCl and extracted into CH2Cl2, dried and evaporated to yield crude 4-piperidino-2-naphthol (1.46 g;56%) as a red-orange oil. Purification by flash chromatography over silica (CH2Cl2) gave 4-piperidino-2-naphthol (of structure 4a below) as a red oil. ##STR16## (c) A mixture of 4-piperidino-2-naphthol (1.00 g; 0.0044 mol) , prepared as described in 1(b) above, 1,1-dianisylprop-2-yn-1-ol(1.18 g;0.0044 mol), acidic alumina Brockmann 1 (4 g) and toluene (40.0 ml) was heated and stirred for 1.5 h, cooled and filtered. The filtrate was washed with 2M NaOH then water, dried and evaporated to give a red gum. Purification of the gum by flash chromatography over silica (20% ethylacetate in hexane) affored an orange gum which upon trituration with pet. ether (40-60)/diethyl ether yielded 3,3-dianisyl-6-piperidino -3H-naphtho[2,1-b]pyran (of structure 5a below) as an off-white solid (5% yield), m.pt. 114°-119° C. ##STR17##
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[C:9]([NH:16][NH2:17])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>>[CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[N:17][NH:16][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][CH2:3]1
Reactant: CN1CCC(=O)CC1
Reactant: CC(C)(C)OC(=O)NN
Product: CN1CCC(=NNC(=O)OC(C)(C)C)CC1
Yield: 32 %

Procedure:
A solution of 11.2 g (99.0 mmol) of 1-methyl-piperid-4-one and 13.0 g (100 mmol) of Boc-hydrazine in 150 mL of hexanes was refluxed for 30 minutes. The hot solution was dried over MgSO4, filtered, and allowed to cool. The resulting crystals were isolated and recrystallized from Et2O to provide 7.2 g of tert-butyl N′-(1-Methyl-piperidin-4-ylidene)-hydrazinecarboxylate as a white solid.
Reaction SMILES: [O:1]=[C:2]1[N:8]2[CH2:9][C@@H:4]([CH2:5][CH2:6][C@H:7]2[C:10]([NH:12][O:13][CH:14]2[CH2:20][CH:19]3[N:21](C(OC(C)(C)C)=O)[CH:16]([CH2:17][CH2:18]3)[CH2:15]2)=[O:11])[N:3]1[O:29][S:30]([OH:33])(=[O:32])=[O:31].FC(F)(F)C(O)=O>C(Cl)Cl>[CH:16]12[NH:21][CH:19]([CH2:18][CH2:17]1)[CH2:20][CH:14]([O:13][NH:12][C:10]([C@@H:7]1[CH2:6][CH2:5][C@@H:4]3[CH2:9][N:8]1[C:2](=[O:1])[N:3]3[O:29][S:30]([OH:33])(=[O:32])=[O:31])=[O:11])[CH2:15]2
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(ONC(=O)[C@@H]1CC[C@@H]3CN1C(=O)N3OS(=O)(=O)O)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NOC1CC2CCC(C1)N2)[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 3-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]-8-azabicyclo[3.2.1]octane-8-carboxylate 48 (0.077 g, 0.17 mmol) in DCM (7 mL) was added trifluoroacetic acid (0.34 mL, 4.42 mmol) dropwise at 0° C. The reaction mixture was stirred for 1 h, then evaporated. Ether was added to the residue and the resulting white precipitate was collected by centrifugation. The solid was triturated with acetonitrile (2×) and the white solid was collected by centrifugation. The white solid was purified by HPLC and freeze-dried to give (2S,5R)-N-(8-azabicyclo[3.2.1]oct-3-yloxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide Compound 27 (Table 1) (0.003 g, 7%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH2:10])=[O:4].I[CH3:18]>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH:10][CH3:18])=[O:4]
Reactant: CI
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N
Solvent: CN(C)C=O
Product: CNc1cc(-c2ccccc2)sc1C(=O)OC
Temperature: 60 °C
Reaction time: 18 h
Yield: 32.2 %

Procedure:
To a mixture of methyl-3-amino-5-phenylthiophene-2-carboxylate (200 mg, 0.855 mmol) in anhydrous N,N-dimethylformamide (4.6 ml) were added 4.2 ml (8.55 mmol) of 2M iodomethane solution in t-buthylmethylether. The mixture was stirred at 60° C. for 18 hours, concentrated and purified using biotage technics (silica gel, hexane to hexane:ethyl acetate; 95:5 containing few drops of triethylamine) to give 68 mg (32% yield) of 3-methylamino-5-phenyl-thiophene-2-carboxylic acid methyl ester. 1H NMR (CDCl3, 400 MHz) 7.65-7.62 (m, 2H), 7.42-7.36 (m, 3H), 6.86 (broad s, 1H), 3.83 (s, 3H), 3.04 (d, 3H)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:9](=[O:21])[N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:11]([CH3:12])[C:5]2=[CH:4][N:3]=1.[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([N:8]2[C:6]3=[N:7][C:2]([NH:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[N:3][CH:4]=[C:5]3[CH:11]([CH3:12])[N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:9]2=[O:21])=[CH:23][CH:24]=1
Reactant: COc1ccc(N2C(=O)N(c3ccc(OC)cc3)C(C)c3cnc(Cl)nc32)cc1
Reactant: Nc1ccccc1
Product: COc1ccc(N2C(=O)N(c3ccc(OC)cc3)C(C)c3cnc(Nc4ccccc4)nc32)cc1
Temperature: 100 °C

Procedure:
The mixture of (±)-7-chloro-1,3-bis-(4-methoxy-phenyl)-4-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (0.30 g; 0.72 mmol) (from Example 4a supra) and aniline (0.20 mL; 2.16 mmol) (Aldrich) was heated at 100° C. for 40 minutes. The mixture was then cooled to room temperature and triturated with hexanes. The resulting solid was dissolved in dichloromethane, washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (Biotage, 12S, dichloromethane followed by 30:70 to 50:50 ethyl acetate-hexanes gradient) to give (±)-1,3-bis-(4-methoxy-phenyl)-4-methyl-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one. (Yield 0.303 g; 90.1%).