Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[CH:14]=[C:15]([C:18]([NH:20][NH2:21])=[O:19])[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)=[CH:5][CH:4]=1.[F:22][C:23]([F:36])([F:35])[C:24]1[CH:25]=[C:26]([CH2:30][CH2:31][C:32](O)=O)[CH:27]=[CH:28][CH:29]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:19][C:32]([CH2:31][CH2:30][C:26]5[CH:27]=[CH:28][CH:29]=[C:24]([C:23]([F:22])([F:35])[F:36])[CH:25]=5)=[N:21][N:20]=4)[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)=[CH:7][CH:8]=1
Reactant: O=C(O)CCc1cccc(C(F)(F)F)c1
Reactant: COc1ccc(-n2cnc3ccc(C(=O)NN)cc32)cc1
Product: COc1ccc(-n2cnc3ccc(-c4nnc(CCc5cccc(C(F)(F)F)c5)o4)cc32)cc1
Yield: 50 %

Procedure:
In the same manner as in Example 14 and using 1-(4-methoxyphenyl)-1H-benzimidazole-6-carbohydrazide instead of 1H-benzotriazole-5-carbohydrazide and 3-[3-(trifluoromethyl)phenyl]propionic acid instead of 3-(3-cyanophenyl)propionic acid, the title compound (yield 50%) was obtained as colorless crystals.
Reaction SMILES: [CH3:1][C@:2]12[C@@H:11]3[CH2:12][CH2:13][C@@:14]4([O:19][C@@H:20]5[O:25][C@H:24]([CH2:26]O)[C@@H:23]([OH:28])[C@H:22]([OH:29])[C@H:21]5[O:30][C@@H:31]5[O:36][C@H:35]([CH2:37][OH:38])[C@@H:34]([OH:39])[C@H:33]([O:40][C@@H:41]6[O:46][C@H:45]([CH2:47][OH:48])[C@@H:44]([OH:49])[C@H:43]([OH:50])[C@H:42]6[OH:51])[C@H:32]5[OH:52])[C:16]([CH2:18][C@@:10]3([CH2:15]4)[CH2:9][CH2:8][C@@H:7]1[C@@:6]([C:54]([O:56][C@@H:57]1[O:62][C@H:61]([CH2:63][OH:64])[C@@H:60]([OH:65])[C@H:59]([OH:66])[C@H:58]1[OH:67])=[O:55])([CH3:53])[CH2:5][CH2:4][CH2:3]2)=[CH2:17].[OH-].[K+].OS(O)(=O)=O>CO>[CH3:26][C@H:24]1[O:25][C@@H:20]([O:19][C@:14]23[C:16](=[CH2:17])[CH2:18][C@:10]4([CH2:15]2)[C@H:11]([C@@:2]2([CH3:1])[C@H:7]([CH2:8][CH2:9]4)[C@@:6]([C:54]([O:56][C@@H:57]4[O:62][C@H:61]([CH2:63][OH:64])[C@@H:60]([OH:65])[C@H:59]([OH:66])[C@H:58]4[OH:67])=[O:55])([CH3:53])[CH2:5][CH2:4][CH2:3]2)[CH2:12][CH2:13]3)[C@@H:21]([O:30][C@@H:31]2[O:36][C@H:35]([CH2:37][OH:38])[C@@H:34]([OH:39])[C@H:33]([O:40][C@@H:41]3[O:46][C@H:45]([CH2:47][OH:48])[C@@H:44]([OH:49])[C@H:43]([OH:50])[C@H:42]3[OH:51])[C@H:32]2[OH:52])[C@@H:22]([OH:29])[C@@H:23]1[OH:28]
Reactant: C=C1C[C@@]23CC[C@H]4[C@@](C)(CCC[C@@]4(C)C(=O)O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)[C@@H]2CC[C@]1(O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H]1O)C3
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C=C1C[C@@]23CC[C@H]4[C@@](C)(CCC[C@@]4(C)C(=O)O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)[C@@H]2CC[C@]1(O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O)[C@@H]1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H]1O)C3
Yield: 78.9 %

Procedure:
Rebaudioside A (0.2 mmol, 183 mg) was transferred to a 15 ml flask. Four ml each of 10% KOH and methanol were added and the resultant mixture heated to yield a homogeneous solution which was refluxed for 11/2 h. Reaction was than judged complete by TLC analysis. After cooling to 0°; the reaction mixture was acidified to pH3 with 10% H2SO4. The resultant mixture (primarily rebaudioside C) was then concentrated to dryness and the residue recrystallized from water to give 150 mg (99%) of pure rebaudioside C.
Reaction SMILES: CC1N=C(N2C(=O)N(CC3C=CC(C(F)(F)F)=CC=3)N=C2)SC=1C(OCC)=O.[F:29][CH:30]([F:56])[O:31][C:32]1[CH:55]=[CH:54][C:35]([CH2:36][N:37]2[C:41](=[O:42])[N:40]([C:43]3[S:44][C:45]([C:49]([O:51]CC)=[O:50])=[C:46]([CH3:48])[N:47]=3)[CH:39]=[N:38]2)=[CH:34][CH:33]=1>>[F:56][CH:30]([F:29])[O:31][C:32]1[CH:55]=[CH:54][C:35]([CH2:36][N:37]2[C:41](=[O:42])[N:40]([C:43]3[S:44][C:45]([C:49]([OH:51])=[O:50])=[C:46]([CH3:48])[N:47]=3)[CH:39]=[N:38]2)=[CH:34][CH:33]=1
Reactant: CCOC(=O)c1sc(-n2cnn(Cc3ccc(OC(F)F)cc3)c2=O)nc1C
Agent: CCOC(=O)c1sc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)nc1C
Product: Cc1nc(-n2cnn(Cc3ccc(OC(F)F)cc3)c2=O)sc1C(=O)O
Yield: 91 %

Procedure:
Following the procedure as described in Example 20, making variation as required to replace ethyl 4-methyl-2-(5-oxo-1-(4-(trifluoromethyl)benzyl)-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylate with ethyl 2-(1-(4-(difluoromethoxy)benzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained as a white solid in 91% yield: MS (ES−) m/z 381.1 (M−1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:14][C:13]([NH2:15])=[N:12][C:11]2[C:7]=1[N:8]=[CH:9][N:10]=2.[C:16]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17].CCN(CC)CC>C1COCC1.CN(C=O)C.O>[C:16]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:10]2[CH:9]=[N:8][C:7]3[C:11]2=[N:12][C:13]([NH2:15])=[N:14][C:6]=3[C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nc2ncnc-2c(-c2ccco2)[nH]1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(S(=O)(=O)n2cnc3c(-c4ccco4)nc(N)nc32)cc1
Temperature: 60 °C
Yield: 53.3 %

Procedure:
A solution of 6-(2-furyl)-1H-purine-2-amine (100 mg, 0.5 mmol) in THF (2 mL) and DMF (0.5 mL) was treated with 4-tert-butylbenzenesulphonyl chloride (116 mg, 0.5 mmol) and Et3N (69 μL, 0.6 mmol), heated at 60° C. for 2 h, cooled, diluted with water and the resulting solid filtered and washed with EtOAc to give the title compound (106 mg, 53%) as a cream solid.
Reaction SMILES: C(OC(COC1C=CC(F)=CC=1)CCCNS(C)(=O)=O)(=O)C.C(OC(COC1C=CC(F)=CC=1)/C=C/CNS(C)(=O)=O)(=O)C.C([O:48][CH:49]([CH2:68][O:69][C:70]1[CH:75]=[CH:74][C:73]([F:76])=[CH:72][CH:71]=1)/[CH:50]=[CH:51]/[CH2:52][N:53]([CH2:58][C:59]#[C:60][CH2:61][CH2:62][CH2:63][C:64]([O:66]C)=[O:65])[S:54]([CH3:57])(=[O:56])=[O:55])(=O)C>>[OH:48][CH:49]([CH2:68][O:69][C:70]1[CH:75]=[CH:74][C:73]([F:76])=[CH:72][CH:71]=1)/[CH:50]=[CH:51]/[CH2:52][N:53]([CH2:58]/[CH:59]=[CH:60]\[CH2:61][CH2:62][CH2:63][C:64]([OH:66])=[O:65])[S:54]([CH3:57])(=[O:56])=[O:55]
Reactant: COC(=O)CCCC#CCN(C/C=C/C(COc1ccc(F)cc1)OC(C)=O)S(C)(=O)=O
Agent: CC(=O)OC(/C=C/CNS(C)(=O)=O)COc1ccc(F)cc1
Agent: CC(=O)OC(CCCNS(C)(=O)=O)COc1ccc(F)cc1
Product: CS(=O)(=O)N(C/C=C\CCCC(=O)O)C/C=C/C(O)COc1ccc(F)cc1

Procedure:
This compound is prepared by the procedure described in Example 2, Step I, except that the N-[4-acetoxy-5-(4-fluorophenoxy)pentyl]methanesulfonamide is replaced by an equimolar amount of N-[4-acetoxy-5-(4-fluorophenoxy)trans-2-pentenyl]methanesulfonamide (Example 6, Step G). This product is thus methyl 7-{N-[4-acetoxy-5-(4-fluorophenoxy)trans-2-pentenyl]methanesulfonamido}hept-5-ynoate. The subsequent hydrolysis is carried out as described in Example 2, Step J and affords 7-{N-[4-fluorophenoxy)trans-2-pentenyl]methanesulfonamido}hept-5-ynoic acid. The hydrogenation is carried out by the procedure described in Example 3 and affords the subject compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:20][NH2:21])=O)[N:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:23][C:24]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=1)([CH3:28])[C:25](=N)[NH2:26].C[O-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]3[NH:26][C:25]([C:24]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:36])([F:38])[F:37])[CH:30]=4)([CH3:28])[CH3:23])=[N:21][N:20]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C(=N)N)c1cccc(C(F)(F)F)c1
Reactant: NNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(c1cccc(C(F)(F)F)c1)c1nnc(Cn2nc(-c3ccc(Cl)cc3)n(C3CC3)c2=O)[nH]1
Temperature: 180 °C
Reaction time: 2 h

Procedure:
42 mg (0.14 mmol) of the compound from Example 21A were dissolved in 1.2 ml of DMF, 40 mg (0.15 mmol) of 2-methyl 2-[3-(trifluoromethyl)phenyl]propaneimidamide hydrochloride and 9 mg (0.16 mmol) of sodium methoxide were added and the mixture was stirred in a microwave reactor at 180° C. for 2 h. After cooling to RT, the mixture was purified directly by preparative HPLC [Method 19]. This gave 2 mg (3% of theory) of the target compound as a colorless foam.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][C:9]2=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[N:1]1([CH2:6][CH2:7][N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][CH2:9]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C1CCc2ccccc2N1CCN1CCCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: c1ccc2c(c1)CCCN2CCN1CCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.2 %

Procedure:
A solution of 1-(2-(pyrrolidin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one (700 mg, 2.87 mmol) in 12 mL anhydrous THF was treated with LiAlH4 (218 mg, 5.73 mmol) portionwise. The suspension was stirred at room temperature for 1 day. After this time, the mixture was cooled to 0° C. and treated with 2 mL 1N NaOH dropwise with rapid stirring. After stirring for 30 minutes, the suspension was treated with Na2SO4 and filtered. The filter cake was rinsed with CH2Cl2 (150 mL total). The filtrate was concentrated and the residue was subjected to flash chromatography on silica gel using 5% 2M NH3 in MeOH/CH2Cl2 to give a light yellow oil (563 mg, 85.1%). 1H-NMR (CDCl3) δ: 7.06-7.01 (m, 1H), 6.93 (d, J=7.2 Hz, 1H), 6.63-6.52 (m, 2H), 3.44 (t, J=7.5 Hz, 2H), 3.31 (t, J=5.7 Hz, 2H), 2.76-2.56 (m, 8H), 1.97-1.90 (m, 2H), 1.83-1.78 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[CH3:13].[C:17]([NH2:20])(=[S:19])[CH3:18]>>[CH3:1][O:2][C:3]([C:4]1[N:20]=[C:17]([CH3:18])[S:19][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[CH3:13])=[O:16]
Reactant: COC(=O)C(=O)C(Cl)c1cccc(F)c1C
Reactant: CC(N)=S
Product: COC(=O)c1nc(C)sc1-c1cccc(F)c1C

Procedure:
prepared by reaction of 3-chloro-3-(3-fluoro-2-methyl-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.93 min; [M+H]+=266.3.
Reaction SMILES: BrB(Br)Br.[Br:5][C:6]1[CH:11]=[C:10]([O:12]C)[CH:9]=[CH:8][C:7]=1[CH2:14][C:15]([OH:17])=[O:16]>ClCCl>[Br:5][C:6]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:7]=1[CH2:14][C:15]([OH:17])=[O:16]
Reactant: COc1ccc(CC(=O)O)c(Br)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)Cc1ccc(O)cc1Br
Temperature: 25 °C
Yield: 72.8 %

Procedure:
A dichloromethane solution (1.0 M, 150 mL) of tribromoborane was added dropwise to a solution of (2-bromo-4-methoxyphenyl)acetic acid (15.0 g) in dichloromethane (160 mL) at room temperature, and the reaction mixture was refluxed for 3 hr, allowed to cool to room temperature, and poured into ice water. The mixture was extracted with ethyl acetate, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained yellow solid was collected by filtration and washed with hexane-diethyl ether to give the title compound (10.3 g).
Reaction SMILES: C(O[C:4]([O:13]CC)([CH3:12])[CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])C.[CH:16](OCC)=[O:17].[Na].O>C1C=CC=CC=1>[CH:16]([CH:6]([CH2:5][C:4]([CH3:12])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:17]
Reactant: CCOC(=O)CCC(C)(OCC)OCC
Reactant: CCOC=O
Agent: [Na]
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C(C=O)CC(C)=O
Reaction time: 3 h

Procedure:
A mixture of 106.3 g (0.489 mol) of ethyl 4,4-diethoxypentanoate and 80 ml (73.6 g, 0.99 mol) of ethyl formate was added dropwise to a vigorously stirred suspension of 12.7 g (0.55 gram atom) of sodium (shavings) in 300 ml of anhydrous benzene at 10-15° C. over 3 h. Stirring was continued for a further 3 h, and the reaction mixture was left to stand overnight. 250 ml of water were added with vigorous stirring, and this was continued for a further 15 min. The water layer was separated off, and the benzene layer was extracted with 70 ml of water. The combined aqueous extracts were acidified to pH 2 and extracted with ethyl acetate (5×50 ml), and the organic extracts were dried over calcium chloride.
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7][C:8]1[CH:19]=[CH:18][CH2:17][C:16]2[C:9]=1[CH:10]=[C:11]1[C:15]=2[CH:14]=[N:13][N:12]1[CH2:20][C@H:21](O)[CH3:22].C(N(CC)CC)C.[N-:31]=[N+:32]=[N-:33].[Na+].[Cl-].[Na+]>ClCCl.CN(C)C=O>[N:31]([C@@H:21]([CH3:22])[CH2:20][N:12]1[C:11]2=[CH:10][C:9]3[C:16]([CH2:17][CH:18]=[CH:19][C:8]=3[O:7][CH3:6])=[C:15]2[CH:14]=[N:13]1)=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=[N-]
Reactant: COC1=C2C=c3c(cnn3C[C@@H](C)O)=C2CC=C1
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC1=C2C=c3c(cnn3C[C@H](C)N=[N+]=[N-])=C2CC=C1
Yield: 91.1 %

Procedure:
0.85 ml (10.7 mmol) of methanesulfonyl chloride was added dropwise while stirring to a solution, cooled to 0°, of 1.3 g (5.3 mmol) of (R)-1-(7-methoxy-1,4-dihydro-indeno[2,1-c]pyrazol-1-yl)-propan-2-ol and 3.05 ml (21.4 mmol) of triethylamine in 50 ml of dichloromethane and the mixture was stirred at this temperature for a further 1.5 hours. The reaction mixture was subsequently diluted with 150 ml of dichloromethane, washed twice with 70 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 70 ml of dichloromethane. The combined organic phases were washed with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The yellow oil obtained was dissolved in 40 ml of anhydrous dimethylformamide, treated with 0.83 g (12.5 mmol) of sodium azide and the reaction mixture was heated to 70° for 15 hours while stirring. After cooling, the solution was poured into 100 ml of semi-saturated sodium chloride solution and extracted twice with 100 ml of diethyl ether each time. The combined organic phases were washed once with 100 ml of water and once with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 1.3 g (90%) of (S)-1-(2-azido-propyl)-7-methoxy-1,4-dihydro-indeno[2,1-c]pyrazole were obtained as a light yellow oil.
Reaction SMILES: [N+]1([O-:7])C=CC=CC=1.[CH2:8]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[N:15]=1)=[O:12])[CH3:9].ClC1C=CC=C(C(OO)=O)C=1>C(Cl)(Cl)Cl>[CH2:8]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[N+:15]=1[O-:7])=[O:12])[CH3:9]
Reactant: [O-][n+]1ccccc1
Reactant: CCOC(=O)Nc1cccc(Br)n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Nc1cccc(Br)[n+]1[O-]
Yield: 62 %

Procedure:
The procedure of Example 3 was repeated except that Step 2 relating to the oxidation to the pyridine-oxide was changed, whereby a chloroform solution of 2-ethoxycarbonylamino-6-bromopyridine was treated with m-chloroperbenzoic acid as the oxidizing agent for 9 days at room temperature, giving a 62% yield of 2-ethoxycarbonylamino-6-bromopyridine-1-oxide.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[NH:16][C:15]3[C:14](=[O:17])[N:13]([CH2:18][CH2:19][CH3:20])[C:12](=[O:21])[N:11]([CH2:22][CH2:23][CH3:24])[C:10]=3[CH:9]=2)=[CH:4][CH:3]=1>CN(C)CCN.CCO>[CH3:12][N:11]([CH3:22])[CH2:10][CH2:15][NH:16][C:2]1[N:7]=[CH:6][C:5]([C:8]2[NH:16][C:15]3[C:14](=[O:17])[N:13]([CH2:18][CH2:19][CH3:20])[C:12](=[O:21])[N:11]([CH2:22][CH2:23][CH3:24])[C:10]=3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCCn1c(=O)c2[nH]c(-c3ccc(Cl)nc3)cc2n(CCC)c1=O
Agent: CN(C)CCN
Solvent: CCO
Product: CCCn1c(=O)c2[nH]c(-c3ccc(NCCN(C)C)nc3)cc2n(CCC)c1=O
Temperature: 167.5 °C
Reaction time: 2 h
Yield: 116 %

Procedure:
8a (135 mg) was suspended in N,N-dimethylethylenediamine (1.5 g) in EtOH (4 ml) in quartz tube and stirred at 160-175° C. under microwave (400 w) (CEM Mars) for 2 hrs. After cooling to room temperature, the solvent was removed and the solid was purified by column (26 g silica gel, RT Scientific) (CH2Cl2: MeOH=100:0 to 90:10). The fractions was evaporated and washed with ether to give the product (9c) (90 mg). HPLC condition: MeOH 40%-95% gradient in 10 minutes then MeOH 95%. Retention Time=5.32 min. 1H NMR (DMSO, d6): 0.83-0.93 (m, 6H), 1.53-1.71 (m, 4H), 2.21 (s, 6H), 2.45 (t, 2H, J=6.6 Hz), 3.38 (m, 2H), 3.85 (m, 4H), 6.55 (m, 2H), 6.73 (t, 1H, J=5.4 Hz), 7.86 (dd, 1H, J1=8.7 Hz, J2=2.4 Hz), 8.54 (d, 1H, J=2.4 Hz), 12.22 (s, 1H). MS: m/z 399 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N+:26]([O-])([N+]([O-])=O)=[O:27]>>[Cl:1][CH2:2][CH2:3][N:4]([N:26]=[O:27])[C:5]([N:7]([CH2:19][CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1)[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=C(NCCCl)N(CC1CCCCC1)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: O=[N+]([O-])[N+](=O)[O-]
Product: O=NN(CCCl)C(=O)N(CC1CCCCC1)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 68.5 %

Procedure:
3.8 g of 1-(2-chloroethyl)-3-cyclohexylmethyl-3-(D-galactopyranosyl)urea and 5 g of nitrogen tetroxide gas are treated in the same manner as described in Example 23-(2). 2.8 g of 1-(2-chloroethyl)-1-nitroso-3-cyclohexylmethyl-3-(D-galactopyranosyl)urea are thereby obtained as pale yellow poder.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:5]2[C:14]3[C:19]([C:20](=[O:21])[C@@H:4]2[CH2:3]1)=[CH:18][CH:17]=[CH:16][CH:15]=3.[BH4-].[Na+].Cl>C(O)C.C1COCC1>[OH:21][C@@H:20]1[C@H:4]2[C@H:5]([N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C:2](=[O:1])[CH2:3]2)[C:14]2[C:19]1=[CH:18][CH:17]=[CH:16][CH:15]=2
Reactant: CC(C)(C)OC(=O)N1C(=O)C[C@H]2C(=O)c3ccccc3[C@H]21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C(=O)C[C@@H]2[C@H]1c1ccccc1[C@@H]2O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (3aR,8bS)-2,4-dioxo-3a,8b-dihydro-3H-indeno[1,2-b]pyrrole-1-carboxylate F 26 (1.60 g, 5.56 mmol) in ethanol (20 mL) and THF (20 mL) was added at 0° C. NaBH4 (0.316 g, 8.15 mmol). The solution was stirred for 2 h at 0° C. 1M HCl was carefully added and the solution was concentrated in vacuo. The residue was partitioned between ethyl acetate and water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by flash chromatography (2/1 cyclohexane/ethyl acetate) to give tert-butyl (3aR,4R,8bS)-4-hydroxy-2-oxo-3,3a,4,8b-tetrahydroindeno[1,2-b]pyrrole-1-carboxylate F27 (800 mg, 50%). LCMS (method E): 0.78 min; ES+: 601 (2M+Na+).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[C:11](=[O:22])[NH:10][C:8]=2[N:9]=1.I[CH2:24][CH:25]([CH3:27])[CH3:26]>CN(C)C=O>[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[C:15]([Cl:21])=[CH:16][CH:17]=[CH:18][C:19]=3[Cl:20])[C:11](=[O:22])[N:10]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:8]=2[N:9]=1
Reactant: CC(C)CI
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(N)nc21
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 50.5 %

Procedure:
To a suspension of NaH (60% in mineral oil, 36 mg) in 8 mL of dimethylformamide was added 2-amino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidin-7(8H)-one (205 mg, 0.67 mmol). The mixture was heated at 60° C. for 20 minutes resulting in a clear solution. 1-Iodo-2-methylpropane (110 μL, 0.94 mmol) was added, and the solution was stirred at 50° C. for 30 minutes. An additional amount of 1-iodo-2-methylpropane (40 μL, 0.34 mmol) was added, and the solution was stirred at 50° C. for 40 minutes, then cooled to room temperature and poured onto 40 mL of ice water. The resulting precipitate was removed by filtration and washed with water. The gummy residue was dissolved in ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was purified by flash chromatography, eluting with 1:1 hexane:ethyl acetate to provide 123 mg (51%) of 2-amino-6-(2,6-dichlorophenyl)-8-isobutyl-8H-pyrido[2,3-d]pyrimidin-7-one; mp 193°-195° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]([O:14][CH3:15])=[C:7]([C@H:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)[CH:8]=1.Br[C:17]1[CH:22]=[CH:21][N:20]2[N:23]=[CH:24][C:25]([C:26]([O:28]CC)=[O:27])=[C:19]2[CH:18]=1>>[F:2][C:3]1[CH:4]=[CH:5][C:6]([O:14][CH3:15])=[C:7]([C@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:17]2[CH:22]=[CH:21][N:20]3[N:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[C:19]3[CH:18]=2)[CH:8]=1
Reactant: COc1ccc(F)cc1[C@H]1CCCN1
Reactant: CCOC(=O)c1cnn2ccc(Br)cc12
Agent: Cl
Product: COc1ccc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2c1

Procedure:
The title compound was prepared by a method substantially similar to that mentioned in step-5 and step-6 of example-3 using (R)-2-(5-Fluoro-2-methoxyphenyl)pyrrolidine hydrochloride (step-1 of example-269) and Ethyl 5-bromo-pyrazolo[1,5-a]pyridine-3-carboxylate to afford the product as white solid. MS (ESI): m/z 356.1 (M+H).
Reaction SMILES: C1(C[O:5][C:6](=[O:31])[CH:7]([C:12]2[CH:17]=[C:16]([O:18][CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:15]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[C:14]([Cl:30])[CH:13]=2)[CH2:8][CH:9]([CH3:11])[CH3:10])CC1.[OH-].[K+]>CCO.O>[Cl:30][C:14]1[CH:13]=[C:12]([CH:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6]([OH:31])=[O:5])[CH:17]=[C:16]([O:18][CH2:19][CH:20]2[CH2:22][CH2:21]2)[C:15]=1[C:23]1[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=1
Reactant: CC(C)CC(C(=O)OCC1CC1)c1cc(Cl)c(-c2ccc(Cl)cc2)c(OCC2CC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)CC(C(=O)O)c1cc(Cl)c(-c2ccc(Cl)cc2)c(OCC2CC2)c1
Yield: 102.3 %

Procedure:
2-(2,4′-Dichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.18 g, 0.36 mmol) was dissolved in a mixture of EtOH and H2O (9 mL/1 mL) and KOH (0.2 g, 3.6 mmol) was added. The reaction mixture was refluxed for 2 h and after cooling the solvent was evaporated. Then, 6 N HCl was added to adjust the pH to 5 and the reaction mixture was extracted with EtOAc (3×10 mL). The organic phase was dried over MgSO4 and evaporated under reduced pressure to give 2-(2,4′-dichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-4-methyl-pentanoic acid as a yellowish solid (0.15 g, 93%). M.p.=52-53° C. 1H NMR (300 MHz, CDCl3/TMS): δ 10.60 (br s, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.22 (d, J=8.4 Hz, 1H), 7.07 (s, 1H), 6.83 (s, 1H), 3.75 (d, J=6.3 Hz, 2H), 3.63 (t, J=7.3 Hz, 1H), 1.99-1.93 (m, 1H), 1.74-1.65 (m, 1H), 1.59-1.51 (m, 1H), 1.11-1.00 (m, 1H), 0.94 (d, J=6.3 Hz, 6H), 0.54-0.40 (m, 2H), 0.22-0.12 (m, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 179.7, 157.2, 139.7, 134.0, 133.4, 133.1, 131.8, 128.5, 127.9, 121.6, 111.3, 73.3, 49.4, 42.0, 25.9, 22.6, 22.3, 10.0, 3.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[C:13](O)=[O:14].P(Cl)(Cl)(Cl)(Cl)[Cl:23]>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[C:13]([Cl:23])=[O:14]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(Sc2ccc(F)cc2F)c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)c1ccc([N+](=O)[O-])c(Sc2ccc(F)cc2F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 113.3 %

Procedure:
A mixture of 3-(2,4-difluorophenylthio)-4-nitrobenzoic acid (1 g) and phosphorus pentachloride (0.7 g) in benzene (10 ml) was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure to give a powder of 3-(2,4-difluorophenylthio)-4-nitrobenzoyl chloride (1.2 g).