Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([CH:12]2[CH2:14][CH2:13]2)=[O:11])=[CH:4][C:3]=1[C:15]1[NH:19][C:18](=[O:20])[N:17]([C:21]2[CH:30]=[CH:29][C:24]([C:25](OC)=[O:26])=[CH:23][CH:22]=2)[N:16]=1.[F:31][C:32]([F:41])([F:40])[C:33]1[CH:34]=[C:35]([CH:37]=[CH:38][CH:39]=1)[NH2:36].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([CH:12]2[CH2:14][CH2:13]2)=[O:11])=[CH:4][C:3]=1[C:15]1[NH:19][C:18](=[O:20])[N:17]([C:21]2[CH:30]=[CH:29][C:24]([C:25]([NH:36][C:35]3[CH:37]=[CH:38][CH:39]=[C:33]([C:32]([F:31])([F:40])[F:41])[CH:34]=3)=[O:26])=[CH:23][CH:22]=2)[N:16]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3cc(CNC(=O)C4CC4)ccc3Cl)[nH]c2=O)cc1
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1ccc(-n2nc(-c3cc(CNC(=O)C4CC4)ccc3Cl)[nH]c2=O)cc1
Yield: 7.5 %

Procedure:
The title compound was prepared by following the procedure as described for Example-31 by using methyl 4-(3-(2-chloro-5-(cyclopropane carboxamidomethyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzoate (Intermediate-42, 0.100 g, 0.24 mmol), 3-(trifluoromethyl)aniline (0.050 g, 0.36 mmol), trimethyl aluminium (2M solution in toluene) (1 mL) and dry toluene (8.0 mL). The reaction mass was quenched in water, extracted with DCM and the organic layer was concentrated to afford 0.010 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 0.70 (s, 4H), 1.62 (m, 1H), 4.33 (d, J=6.3 Hz, 2H), 7.44-7.67 (m, 4H), 8.10-8.26 (m, 6H), 8.68 (m, 1H), 10.53 (s, 1H), 12.68 (br s, 1H); MS (m/z): 554.30 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=3)[CH:8]=2)=[CH:4][CH:3]=1.C1([O:30][C:31](=O)[NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([S:39]([CH3:42])(=[O:41])=[O:40])[CH:34]=2)C=CC=CC=1.C(OCC)(=O)C.O>CS(C)=O>[CH3:42][S:39]([C:35]1[CH:34]=[C:33]([NH:32][C:31]([NH:1][C:2]2[CH:23]=[CH:22][C:5]([O:6][C:7]3[CH:8]=[C:9]([NH:13][C:14]4[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=4)[N:10]=[CH:11][N:12]=3)=[CH:4][CH:3]=2)=[O:30])[CH:38]=[CH:37][CH:36]=1)(=[O:40])=[O:41]
Reactant: CS(=O)(=O)c1cccc(NC(=O)Oc2ccccc2)c1
Reactant: CSc1ccc(Nc2cc(Oc3ccc(N)cc3)ncn2)cc1
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CSc1ccc(Nc2cc(Oc3ccc(NC(=O)Nc4cccc(S(C)(=O)=O)c4)cc3)ncn2)cc1
Yield: 94.8 %

Procedure:
N-(6-(4-Aminophenoxy)pyrimidin-4-yl)-4-methylsulfanylphenylamine (194 mg, 0.600 mmol) and (3-methylsulfonylphenyl)carbamic acid phenyl ester (192 mg, 0.660 mmol) were heated and stirred in dimethyl sulfoxide (2 ml) at 85° C. for 18 hours. The reaction solution was distributed between ethyl acetate and water, the organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was distilled off under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (eluent—ethyl acetate), the fraction containing the target substance was concentrated and suspended in ethyl acetate, the suspension was diluted with hexane and the crystals were filtered out, washed with hexane and blow-dried to obtain the title compound (297 mg, 0.569 mmol, 95%) as colorless crystals.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:3][CH2:2]1.Cl[CH2:13][CH2:14][CH2:15][N:16]1[C:21]2[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=2[O:19][CH2:18][C:17]1=[O:27].C([O-])([O-])=O.[K+].[K+]>>[CH:1]1([CH2:4][O:5][CH:6]2[CH2:11][CH2:10][N:9]([CH2:13][CH2:14][CH2:15][N:16]3[C:21]4[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=4[O:19][CH2:18][C:17]3=[O:27])[CH2:8][CH2:7]2)[CH2:2][CH2:3]1
Reactant: O=C1COc2cc(F)ccc2N1CCCCl
Reactant: C1CC(OCC2CC2)CCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1COc2cc(F)ccc2N1CCCN1CCC(OCC2CC2)CC1
Yield: 50.1 %

Procedure:
4-Cyclopropylmethoxypiperidine (0.042 g, 0.27 mmol), 4-(3-chloropropyl)-7-fluoro-4H-benzo[1,4]oxazin-3-one (0.08 g, 0.32 mmol), K2CO3 (0.075 g, 0.54 mmol) and KI (0.081 g, 0.54 mmol) were mixed according to GP3. Purified by prep TLC (SiO2; heptanes/EtOAc 1:1) to give the title compound (0.049 g, 42%). Rf=0.47 (CH2Cl2/MeOH 10:1); 1H NMR (CDCl3) δ 7.09-7.04 (m, 1H), 6.75-6.69 (m, 2H), 4.57 (s, 2H), 3.95 (t, J=7.2 Hz), 3.34-3.25 (m, 3H), 2.77-2.70 (m, 2H), 2.36 (t, J=6.8 Hz, 2H), 2.11-2.02 (m, 2H), 1.93-1.76 (m, 4H), 1.64-1.54 (m, 2H), 1.09-0.98 (m, 1H), 0.55-0.49 (m, 2H), 0.21-0.16 (m, 2H); 13C NMR (CDCl3) δ 163.6, 158.9 (d, J=243.7 Hz), 146.3 (d, J=11.6 Hz), 125.2 (d, J=3.1 Hz), 115.8 (t, J=11.2 Hz), 109.2 (d, J=22.3 Hz), 105.2 (dd, J=25.7 Hz, J=3.8 Hz), 75.0, 72.8, 67.8 (t, J=8.1 Hz), 55.4, 51.6 (J=9.2 Hz), 39.9 (t, J=12.3 Hz), 31.7, 24.9, 11.1, 3.2.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][NH:27][CH3:28])=[CH:24][CH:23]=1.O>CS(C)=O>[F:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][N:27]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[CH:3]=2)[CH3:28])=[CH:24][CH:23]=1
Reactant: CC(C)Oc1cc(F)ccc1[N+](=O)[O-]
Reactant: CNCc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)Oc1cc(N(C)Cc2ccc(F)cc2)ccc1[N+](=O)[O-]
Temperature: 90 °C

Procedure:
4-Fluoro-2-isopropoxy-1-nitrobenzene (1.0 g) was dissolved in dry dimethylsulfoxide (25 mL). Potassium carbonate (1.4 g) and (4-fluorobenzyl)-(methyl)-amine (0.84 g) were added. The resulting mixture was heated to 90° C. over night. After cooling to room temperature, water (75 mL) was added, and the resulting mixture was extracted with ethyl acetate (3×75 mL). The organic phase was dried over sodium sulfate, filtered, and evaporated in vacuo to yield the title compound as slightly yellow solid (1.6 g, 100%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[C@H:19]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:18][CH2:17]3)=[N:7][CH:8]=1)#[N:2].[SH2:29].C(NCC)C>CN(C=O)C>[NH2:2][C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[C@H:19]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:18][CH2:17]3)=[N:7][CH:8]=1)=[S:29]
Reactant: S
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(C#N)cn3)ccc21
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(C(N)=S)cn3)ccc21
Reaction time: 0.33 h
Yield: 86 %

Procedure:
Through a solution of ethyl ((1S)-5-{3-[(5-cyano-2-pyridinyl)oxy]propoxy}2,3-dihydro-1H-inden-1-yl)acetate (Example 258) (600 mg, 1.58 mmol) in DMF (8 mL) was passed H2S, gently at rt for 20 min. Diethylamine (0.24 mL, 2.37 mmol) was added in one portion and the resultant light-green solution was heated at 60° C. for 3 h (TLC in 2:1 hexanes/EtOAc indicated that the reaction was complete). The darkgreen solution was purged with a strong flow of argon, and then concentrated under reduced pressure. The product (0.56 g, 86%) was isolated by column chromatography (1:1 hexanes/EtOAc) as a bright yellow solid. 1H NMR (400 MHz, CD2Cl2) δ 8.65 (dd, 1H), 8.16 (dd, 1H), 7.56 (b, 1H), 7.19 (b, 1H), 7.04 (d, 1H), 6.80-6.72 (m, 2H), 6.69 (dd, 1H), 4.56 (t, 2H), 4.16 (q, 2H), 4.12 (t, 2H), 3.50 (qt, 1H), 2.90-2.78 (m, 2H), 2.70 (dd, 1H), 2.45-2.32 (m, 2H), 2.30-2.22 (m, 2H), 1.80-1.70 (m, 1H), 1.28 (t, 3H).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([S:14]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH:9]=[C:8]2[I:24])[NH2:4].CCN(CC)CC.[Cl:32][C:33]([Cl:38])([Cl:37])[C:34](Cl)=O.O>C1COCC1>[I:24][C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[C:5]([C:3]3[N:4]=[C:34]([C:33]([Cl:38])([Cl:37])[Cl:32])[O:1][N:2]=3)[CH:6]=2)[N:10]([S:14]([C:17]2[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:9]=1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C(N)=NO)ccc32)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4noc(C(Cl)(Cl)Cl)n4)ccc32)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.5 %

Procedure:
To a suspension of N′-hydroxy-3-iodo-1-tosyl-1H-indole-5-carboximidamide (950 mg, 2.09 mmol) in dry THF (10 mL) was added Et3N (1.4 mL, 10.10 mmol) and O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate (HBTU) (1.6 g, 4.18 mmol) at 0° C. Trichloroacetyl chloride (0.48 mL, 2.51 mmol) was added portion wise at 0° C. and the reaction was stirred for 16 h at RT. The mixture was treated with H2O (10 mL) and extracted with EtOAc (2×25 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was further with basic alumina chromatography (eluent: 5% EtOAc in petroleum ether) to afford 3-(3-iodo-1-tosyl-1H-indol-5-yl)-5-(trichloromethyl)-1,2,4-oxadiazole (250 mg, 20.8%) as an off white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.26 (s, 1H), 8.21 (d, J=8.8 z, 1H), 8.10 (t, J=1.2 Hz, 1H), 7.99-7.95 (m, 3H), 7.44 (d, J=8.4 Hz, 1H), 2.32 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[C:16]([CH2:18][O:19][CH2:20][C:21]3([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)[C:15]3[C:11](=[CH:12][N:13](COCC[Si](C)(C)C)[N:14]=3)[CH:10]=2)=[CH:5][CH:4]=1)#[N:2]>FC(F)(F)C(O)=O>[C:34]1([C:21]2([CH2:20][O:19][CH2:18][C:16]3[CH:17]=[C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=4)[CH:10]=[C:11]4[C:15]=3[NH:14][N:13]=[CH:12]4)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(-c3ccc(C#N)cc3)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(-c2cc(COCC3(c4ccccc4)CCNCC3)c3[nH]ncc3c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl 4-(((5-(4-cyanophenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (391 mg, 0.60 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 10 mL) and stirred at room temperature for 2 h. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was washed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 241 mg (95%) as an amorphous solid. 1H-NMR (CDCl3, 500 MHz) δ 8.02 (s, 1H), 7.79 (s, 1H), 7.64 (m, 4H), 7.22-7.50 (m, 7H), 4.73 (s, 2H), 3.57 (s, 2H), 3.41 (s, 1H), 2.90 (m, 2H), 2.75 (m, 2H), 2.19 (m, 2H), 1.88 (m, 2H); 13C-NMR (CDCl3, 126 MHz) δ 145.9, 144.1, 138.6, 134.9, 132.7, 132.0, 129.0, 127.9, 127.1, 126.8, 124.4, 123.7, 121.8, 119.1, 119.0, 110.4, 80.6, 72.0, 42.6, 41.7, 33.6. Mass spec.: 423.18 (MH)+. Accurate mass spec.: m/z 423.2206 [MH]+, Δ=5.0 ppm.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[C:14]([CH:15]=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=1.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>ClCCl>[CH:15]([C:14]1[C:9]([NH:8][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:16]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ncccc1C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ncccc1C=O
Temperature: 0 °C
Reaction time: 63 h
Yield: 90 %

Procedure:
Triethlyamine (7.6 mL, 54 mmol), was added to a solution of 2-aminopyridine-3-carboxaldehyde (4.45 g, 36 mmol) in dichloromethane (70 mL). Mixture was cooled to 0° C. A solution of pivaloyl chloride (5.3 mL, 43 mmol) in dichloromethane (30 mL) was added to the mixture. Reaction was warmed to room temperature. Mixture stirred at room temperature for 63 hours. Mixture was washed successively with water (2×50 mL) and brine (30 mL). Organic layer was dried (magnesium sulfate), filtered and concentrated in vacuo. Silica gel chromatography afforded the title compound as off-white solid in 90% yield. (M+H)+=207.1.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:7]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=O)=[CH:5][N:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH3:1][C:2]1[S:3][C:4]([CH2:7][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:5][N:6]=1
Reactant: Cc1ncc(C(=O)N2CCCC2)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: Cc1ncc(CN2CCCC2)s1
Temperature: 25 °C

Procedure:
A solution of 2-methyl-5-(pyrrolidinocarbonyl)thiazole in dry ether was added dropwise to a suspension of lithium aluminium hydride and the mixture was stirred at room temperature to give the title compound as a colourless liquid, b.p. 61-62°C.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8](=[O:16])[NH:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]1[CH:17]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([C:26](O)=[O:27])[C:20]=2[CH2:19][CH2:18]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[CH3:58][NH2:59].Cl>C(Cl)Cl.O>[CH3:58][NH:59][C:26]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:20]=1[CH2:19][CH2:18][CH:17]2[N:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([NH:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[O:16])[C:2]1=[O:1])=[O:27]
Reactant: O=C(O)c1cccc2c1CCC2n1cccc(C(=O)Nc2ccncc2)c1=O
Reactant: CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)c1cccc2c1CCC2n1cccc(C(=O)Nc2ccncc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
To a mixture of 1-(2-oxo-3-(pyridin-4-ylcarbamoyl)pyridin-1(2H)-yl)-2,3-dihydro-1H-indene-4-carboxylic acid (45 mg, 1.0 eq) in DCM (4 mL) was added EDC.HCl (1.5 eq), HOBt (1.5 eq), Et3N (3.0 eq) and MeNH2.HCl (1.1 eq) The mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with DCM. The combined organic layer was washed with brine and dried over MgSO4, evaporated the filtrate to give the crude product, which was purified by HPLC to afford 1-(4-(methylcarbamoyl)-2,3-dihydro-1H-inden-1-yl)-2-oxo-N-(pyridin-4-yl)-1,2-dihydropyridine-3-carboxamide (18 mg, 39%). 389.2 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 12.97 (s, 1H), 8.73 (d, J=3.6 Hz, 2H), 8.51 (dd, J=1.2 Hz, 4.2 Hz, 1H), 8.31 (d, J=2.8 Hz, 1H), 8.20 (d, J=3.6 Hz, 2H), 7.74 (d, J=4.2 Hz, 1H), 7.60 (d, J=4.2 Hz, 1H), 7.35 (t, J=4.2 Hz, 1H), 7.27 (d, J=4.2 Hz, 2H), 6.65 (t, J=4.2 Hz, 1H), 6.55 (t, J=4.2 Hz, 1H), 3.37 (overlap with DMSO-d6, 2H), 2.60-2.75 (m, 1H), 2.05-2.15 (m, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][CH:27]=[C:28]4[C:32]=3[N:31]([CH3:33])[CH:30]=[C:29]4[CH2:34][CH2:35][C:36]([O:38]C(C)(C)C)=[O:37])[N:20]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH:16]([CH3:18])[CH3:17]>ClCCl>[Cl:8][C:9]1[CH:10]=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][CH:27]=[C:28]4[C:32]=3[N:31]([CH3:33])[CH:30]=[C:29]4[CH2:34][CH2:35][C:36]([OH:38])=[O:37])[N:20]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH:16]([CH3:17])[CH3:18]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC(=O)OC(C)(C)C)cn(C)c34)no2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC(=O)O)cn(C)c34)no2)cc1Cl
Reaction time: 1 h
Yield: 63.4 %

Procedure:
Trifluoroacetic acid (0.62 mL) was added to a solution of 1,1-dimethylethyl 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]propanoate (D8) (80 mg) in dichloromethane (1 mL) at RT. The resulting solution was stirred for 1 hour. The reaction mixture was concentrated. The residue was recrystallized from ether/hexane to afford 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]propanoic acid (E2) (45 mg) as a pale yellow solid. δH (DMSO-d6, 400 MHz): 1.36 (6H, d), 2.65 (2H, q), 2.96 (2H, t), 3.63 (3H, s), 4.89 (1H, m), 7.18 (1H, t), 7.20 (1H, s), 7.45 (2H, m), 7.81 (1H, dd), 8.14 (1H, dd), 8.21 (1H, d), 12.14 (1H, br s). MS (ES): C23H22ClN3O4 requires 439; found 440.0 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[F:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:11]=1[CH:12]=O.[OH-].[Na+]>[Cl-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.[Cl-].[Na+].O>[F:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:11]=1[CH:12]=[C:4]1[C:5](=[O:8])[C:6](=[CH:12][C:11]2[C:10]([F:9])=[CH:17][CH:16]=[CH:15][C:14]=2[F:18])[CH2:7][N:2]([CH3:1])[CH2:3]1
Reactant: CN1CCC(=O)CC1
Reactant: O=Cc1c(F)cccc1F
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CN1CC(=Cc2c(F)cccc2F)C(=O)C(=Cc2c(F)cccc2F)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.2 %

Procedure:
To a solution of 1.0 g (8.84 mmol) of 1-methylpiperidine-4-one and 2.57 g (18.09 mmol) of 2,6-difluoro benzaldehyde in 90 mL of a 0.25M solution of aqueous NaOH (22.59 mmol) was added 1.16 mL (0.88 mmol) of a 25% w/w aqueous solution of cetyltrimethylammonium chloride. The mixture was allowed to stir vigorously at room temperature for 12 hours, diluted with 100 ml of brine and extracted with three 40 mL portions of methylene chloride. The organic phase was dried over anhydrous MgSO4 and concentrated in vacuo. The residue was slurried in 100 ml of boiling ethyl acetate and the insolubles were removed by rapid suction filtration. The filtrate was concentrated in vacuo and recrystallized from ethyl acetate to provide 3.01 g (94%) of a bright yellow solid.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)=[N:11][N:10](COCC[Si](C)(C)C)[C:7]=3[C:8]=2[CH:9]=1.Cl>CO>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]2[C:6]3[CH2:5][C:4]4[S:3][C:2]([C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=5)=[CH:9][C:8]=4[C:7]=3[NH:10][N:11]=2)=[CH:18][CH:17]=1
Reactant: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(Br)cc2-3)cc1
Agent: Cl
Solvent: CO
Product: COc1ccc(-c2n[nH]c3c2Cc2sc(-c4ccccc4)cc2-3)cc1
Temperature: 100 °C
Yield: 88 %

Procedure:
2-Bromo-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.12 g, 0.25 mmol) was dissolved in MeOH and treated with concentrated HCl (0.08 mL, 2.5 mmol). The reaction mixture was heated at 100° C. for 4 hr. The solution was cooled to room temperature and the resultant precipitate was filtered, washed with MeOH and concentrated under reduced pressure to provide the corresponding 6-(4-Methoxy-phenyl)-2-phenyl-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.04 g, 0.11 mmol) as white solid in 46% yield.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][N:8]1[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[N:11]=[C:10]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]1=[O:26].C([O-])([O-])=O.[K+].[K+]>C(Cl)(Cl)Cl>[Cl:3][CH2:6][CH2:7][N:8]1[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[N:11]=[C:10]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]1=[O:26]
Reactant: O=S(Cl)Cl
Reactant: O=c1c(CCc2ccccc2)nc2c(n1CCO)CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: O=c1c(CCc2ccccc2)nc2c(n1CCCl)CCCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Thionylchloride (2.05 ml) was added dropwise under ice-cooling to compound 645 (6.49 g, 22.1 mM) dissolved in chloroform (25 ml), and stirred at room temperature for 2 hours. Dilute aqueous K2CO3 was added to the reaction mixture, which mixture was then extracted twice with chloroform. The extract was dried with anhydrous sodium sulfate and concentrated in vacuo to obtain compound 647, which was used without further purification in the following reactions.
Reaction SMILES: C([S:4][CH2:5][CH:6]1[CH2:10][S:9][C:8]2([CH2:14][CH2:13][CH:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11]2)[S:7]1)(=O)C.[O-]CC.[Na+].OS([O-])(=O)=O.[K+]>C(O)C>[SH:4][CH2:5][CH:6]1[CH2:10][S:9][C:8]2([CH2:14][CH2:13][CH:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11]2)[S:7]1
Reactant: CCOC(=O)CC1CCC2(C1)SCC(CSC(C)=O)S2
Agent: CC[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)CC1CCC2(C1)SCC(CS)S2

Procedure:
A solution of the product of Example F and sodium ethoxide (prepared from 350 mg of sodium metal) in absolute ethanol (40 ml) was stirred for 1 hr under nitrogen. The reaction mixture was poured into 200 ml of 0.5N KHSO4 and extracted with ethyl acetate. After drying the organic phase over sodium sulfate, the solvent was removed on the rotary evaporator and the residue was chromatographed on silica gel using 5% ethyl acetate/hexane to give 2.1 g of the titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18]O)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N+:27]([C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](Cl)=[O:34])([O-:29])=[O:28]>C(#N)C>[N+:27]([C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]2)=[CH:4][CH:3]=1)=[O:34])([O-:29])=[O:28]
Reactant: Nc1ccc2cccc(N3CCN(CO)CC3)c2c1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3ccc(NC(=O)c4cccc([N+](=O)[O-])c4)cc23)CC1
Yield: 47.8 %

Procedure:
The title product was prepared following the procedure of example 3 from 7- amino-1-(4-methylol-piperazinyl)-naphthalene (0.15 g, 0.622 mmol) and triethylamine (0.09 mL, 0.68 mmol) and 3-nitrobenzoyl chloride (0.127 mL, 0.684 mmol) in acetonitrile (10 mL) with an overnight reflux. The product was purified by silica gel flash chromatography followed by recrystallization from ethyl acetate to yield 0.116 g (47%) of the title product: mp 182°-184° C. Analysis calculated for C22H22N4O3 : C, 67.68; H, 5.68; N, 14.35. Found: C, 67.47; H, 5.64; N, 14.08.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4]([NH:18][CH2:19][CH:20]2[CH2:22][CH2:21]2)[N:3]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24].O>CN(C)C=O>[C:23]([O:17][CH2:16][C@H:14]1[CH2:15][C@@H:11]([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][C:2]([NH2:1])=[N:3][C:4]=3[NH:18][CH2:19][CH:20]2[CH2:22][CH2:21]2)[CH:12]=[CH:13]1)(=[O:25])[CH3:24]
Reactant: Nc1nc(NCC2CC2)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OC[C@@H]1C=C[C@H](n2cnc3c(NCC4CC4)nc(N)nc32)C1

Procedure:
A solution of (%)-cis-4-(2 amino-6-(cyclopropylmethylamino)-9H-purin-9-yl)-2-cyclopentene-1-methanol from Example 7 (0.30 g, 1 mmol), acetic anhydride (0.204 g, 2 mmol), N,N-dimethylaminopyridine (0.005 g, 0.04 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature under nitrogen overnight. H2O (1 mL was added and the solution allowed to stir an additional hour, then concentrated under high vacuum. The residual oil was partitioned between saturated sodium bicarbonate solution (5 mL) and chloroform (3×50 mL). The combined chloroform extracts were dried (MgSO4), solvent evaporated and residue chromatographed on silica gel. Title compound was eluted with 4% methanol-chloroform; foamed from ethanol under high vacuum (0.330 g, 93%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:14][N:15]([C:17]([NH2:19])=[S:18])[NH2:16].O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>O1CCOCC1>[CH:5]1([N:19]=[C:17]2[N:15]([CH3:14])[N:16]=[C:9]([C:8]3[CH:12]=[CH:13][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)[S:18]2)[CH2:13][CH2:12][CH2:8][CH2:7][CH2:6]1
Reactant: CN(N)C(N)=S
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: Cn1nc(-c2ccc(S(C)(=O)=O)cc2)sc1=NC1CCCCC1
Temperature: 95 °C
Yield: 52.3 %

Procedure:
To a mixture of 4-methylsulfonyl-benzoic acid (2.5 mmol, 500 mg), 2-methylthiosemicarbazide (5a) (2.5 mmol, 468 mg) in anhydrous dioxane (5 mL) at 65° C., POCl3 (3 mmol, 280 μL) was added, and the mixture was warmed at 95° C. for 5 hours. The solvent was removed by distillation under reduced pressure to give a crude material which was basified at pH 8-7 with a saturated solution of NaHCO3. The aqueous phase was extracted with dichloromethane. The organic layer was washed with saturated solution of NaCl, dried over magnesium sulfate, filtered, and distilled to give a residue which was purified by silica gel chromatography (eluted with a gradient of cyclohexane/ethyl acetate finishing with the ratio 80:20) to afford 230 mg of the title compound. Yield: 26%.