Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:5]=2[N:4]([CH3:20])[C:3]1=[O:21].[N:22]([C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[CH:27][C:26]=1[CH3:37])=[C:23]=[S:24]>CC(N(C)C)=O>[F:19][C:16]1[CH:17]=[CH:18][C:5]2[N:4]([CH3:20])[C:3](=[O:21])[CH:2]([NH:1][C:23]([NH:22][C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[CH:27][C:26]=3[CH3:37])=[S:24])[N:8]=[C:7]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:6]=2[CH:15]=1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2cc(F)ccc21
Reactant: Cc1cc(N2CCOCC2)ccc1N=C=S
Solvent: CC(=O)N(C)C
Product: Cc1cc(N2CCOCC2)ccc1NC(=S)NC1N=C(c2ccccc2)c2cc(F)ccc2N(C)C1=O
Temperature: 70 °C
Yield: 100.5 %

Procedure:
As illustrated in the scheme above, a solution of 3-amino-7-fluoro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (0.0056 g, 0.020 mmol) and 4-(4-isothiocyanato-3-methylphenyl)morpholine (0.0048 g, 0.020 mmol) in DMA (0.5 mL) was heated at 70° C. for 16 h. The reaction was cooled and concentrated in vacuo, and the residue was lyophilized to provide the title compound (0.0104 g, quantitative). 1H-NMR (CDCl3): δ 7.63-7.58 (m, 2H), 7.50-7.45 (m, 1H), 7.44-7.36 (m, 4H), 7.36-7.26 (m, 3H), 7.09 (dd, J=2.4 Hz, J=8.4 Hz, 1H), 6.85-6.78 (m, 2H), 6.09-6.05 (m, 1H), 3.90-3.83 (br m, 4H), 3.41 (s, 3H), 3.21-3.15 (br s, 4H), 2.36 (s, 3H). MS (ESI) (M+H)+=518.HRMS calculated for (C28H28FN5O2S+H) (M+H)+: 518.2026. Found (ESI): 518.2117.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=O)=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[Br-].[C:18]1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:19]=1>C1OCCOC1>[C:3]1([O:2][CH3:1])[CH:4]=[CH:5][C:6]([CH:9]=[CH:18][CH3:19])=[CH:7][CH:8]=1
Reactant: COc1ccc(C=O)cc1
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC=Cc1ccc(OC)cc1

Procedure:
Anethole is synthesized starting from anisaldehyde in the presence of potassium carbonate and ethyle triphenyl phosphonium bromide in dioxane-1,4.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([O:16][C:17]([NH:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([C:26]#[N:27])[CH:21]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:10]=[C:1]1[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[S:4][C:26]([C:22]2[CH:21]=[C:20]([NH:19][C:17](=[O:18])[O:16][C:12]([CH3:14])([CH3:13])[CH3:15])[CH:25]=[CH:24][N:23]=2)=[N:27]1
Reactant: CC(C)(C)OC(=O)Nc1ccnc(C#N)c1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Yield: 45.6 %

Procedure:
A mixture of methyl thiosalicylate (0.61 g, 3.7 mmol), 4-tert-butoxycarbonylamino-2-cyanopyridine (0.80 g, 3.7 mmol), triethylamine (0.80 ml, 5.7 mmol) and toluene (2.0 ml) was refluxed for 9 hrs. After cooling, the precipitated crystals were collected by filtration and dried to give the titled compound (0.60 g, 49%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[O:18][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[CH:28]=[C:27]([O:32][CH:33]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:34]([O:36]C)=[O:35])[CH:26]=[CH:25]4)=[CH:20][N:21]=2)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[O:18][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[CH:28]=[C:27]([O:32][CH:33]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:34]([OH:36])=[O:35])[CH:26]=[CH:25]4)=[CH:20][N:21]=2)=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(Cc1ccccc1)Oc1ccc2cc(-c3cnc(-c4cn(Cc5ccccc5)c5ccccc45)o3)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C(Cc1ccccc1)Oc1ccc2cc(-c3cnc(-c4cn(Cc5ccccc5)c5ccccc45)o3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
A mixture of methyl 2-({6-[2-(1-benzyl-1H-indol-3-yl)-1,3-oxazol-5-yl]-2-naphthyl}oxy)-3-phenylpropanoate (117 mg 0.202 mmol), prepared in the previous step, and 1 N NaOH (400 μL, 0.4 mmol) in 20 mL of THF was stirred at room temperature for 16 hr (overnight). The reaction was acidified by the addition of 500 μL of 1N HCl and then concentrated under reduced pressure to remove the THF. The yellow solid that formed was collected by filtration, rinsed with water and dried under reduced pressure to give the title compound (102 mg, 90%) as a dark yellow solid, mp 125-127° C. Elemental Analysis for C37H28N2O4+0.17 mole of H2O Calc'd: C, 78.28; H, 5.03; N, 4.93. Found: C, 76.56; H, 5.59; N, 4.37.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[O:30]1[CH2:35][CH2:34][CH:33]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:39]4[CH2:40][CH2:41][N:36]([CH:33]5[CH2:34][CH2:35][O:30][CH2:31][CH2:32]5)[CH2:37][CH2:38]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: C1CN(C2CCOCC2)CCN1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C4CCOCC4)CC3)n(C)c2n1
Reaction time: 18 h
Yield: 87.4 %

Procedure:
A solution of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (360 mg, 0.92 mmol), 1-(tetrahydropyran-4-yl)piperazine (250 mg, 1.47 mmol) and molecular sieves (4 Å, powdered, 1.5 g) in DCE (10 mL) was stirred at ambient temperature for 6 h. Sodium triacetoxyborohydride (530 mg, 2.50 mmol) was added and the mixture stirred for 18 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, EtOAc: MeOH; gradient from 100:0 to 70:30) followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 80:20 to 2:98) to afford 495 as a cream foam (439 mg, 87%). LCMS (Method I): RT=2.50 min, M+H+=546. 1H NMR (CDCl3, 400 MHz) δ 8.01 (m, 1 H); 7.76 (m, 1 H); 7.27 (m, 2 H); 4.35 (m, 4 H); 4.03 (d, J=11.3 Hz, 2 H); 3.87 (m, 7 H); 3.78 (s, 2 H); 3.42-3.29 (m, 4 H); 2.64 (m, 8 H); 1.79 (m, 3 H); 1.62 (m, 2 H) and 1.45 (t, J=7.5 Hz, 3 H)
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[N:6][C:7]=1Cl.[Cl:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1.Cl>CCO.O>[Cl:9][C:3]1[N:4]=[CH:5][N:6]=[C:7]([NH:15][C:14]2[CH:16]=[CH:17][C:11]([Cl:10])=[CH:12][CH:13]=2)[C:2]=1[NH2:1]
Reactant: Nc1ccc(Cl)cc1
Reactant: Nc1c(Cl)ncnc1Cl
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1c(Cl)ncnc1Nc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
5-amino-4,6-dichloropyrimidine (5.0 g, 30.49 mmol) and 4-chloroaniline (5.1 g, 40.0 mmol) were added to the solution of hydrochloric acid (1.3 mL, 15.24 mmol) in EtOH/H2O (8:1 v/v) (100 ml). The resulting reaction mixture was stirred for overnight at 80° C. The resulting mixture was filtered with NaHCO3(aq)/H2O. The collected solid was dried under reduced pressure to obtain the title compound (6.8 g, 88%) as white solid.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:16](=[O:26])[NH:17][C:18]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=1[F:25])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C@@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[C:16]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=1[F:25])=[O:26]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccn1)C(=O)Nc1ccc(I)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](Cc1ccccn1)C(=O)Nc1ccc(I)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
To a solution of (S)-[1-(2-fluoro-4-iodo-phenylcarbamoyl)-2-pyridin-2-yl-ethyl]-carbamic acid tert-butyl ester (1.2 g, 2.47 mmol) in dichloromethane (5 mL) at 0° C. was added trifluoroacetic acid (5 mL) and the mixture stirred at 0° C. for 1 hour. The reaction mixture was concentrated in vacuo and the residue suspended in ice cold water. The aqueous suspension was neutralized with saturated aqueous sodium carbonate solution to basic then extracted with dichloromethane (three times). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography over silica gel gradient eluted from 100% hexane up to 100% ethyl acetate in 40 minutes. Concentration of the product containing fractions gave (S)-2-amino-N-(2-fluoro-4-iodo-phenyl)-3-pyridin-2-yl-propionamide as a yellow solid (806 mg, 85%).
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH3:25])[C:10]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:14]=[CH:13]2)=[O:11])[CH2:5][CH2:4]1)#[N:2].C([Sn](CCCC)=O)CCC.[N:36]([Si](C)(C)C)=[N+:37]=[N-:38]>C1(C)C=CC=CC=1>[N:2]1[NH:36][N:37]=[N:38][C:1]=1[N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH3:25])[C:10]([N:12]2[CH:16]=[C:15]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[N:14]=[CH:13]2)=[O:11])[CH2:5][CH2:4]1
Reactant: COc1ccc(-c2cn(C(=O)N(C)C3CCN(C#N)CC3)cn2)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cn(C(=O)N(C)C3CCN(c4nn[nH]n4)CC3)cn2)cc1
Yield: 58.8 %

Procedure:
To a suspension of N-(1-cyanopiperidin-4-yl)-4-(4-methoxyphenyl)-N-methyl-1H-imidazole-1-carboxamide (151 mg, 0.445 mmol) in toluene (10 mL) was added dibutylstannanone (13.84 mg, 0.056 mmol) followed by azidotrimethylsilane (0.207 mL, 1.557 mmol). The reaction mixture was heated at reflux for 5 h, whereupon it was filtered still hot and the resulting pink solid was washed sequentially with toluene, dichloromethane and then finally ether. The solid was recrystallised from methanol to give the product as a light pink solid, (100 mg, 56%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH:11]([C:13]([OH:15])=O)[CH2:10][NH:9][C:8]=2[CH:16]=1.[C:19](=[O:36])([O:34][CH3:35])[O:20][C:21]1[CH:26]=[C:25]([NH2:27])[C:24]([Br:28])=[CH:23][C:22]=1[CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.N1C=CC=CC=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CC1CCCO1>[C:19](=[O:36])([O:34][CH3:35])[O:20][C:21]1[CH:26]=[C:25]([NH:27][C:13]([CH:11]2[O:12][C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:18])[F:17])=[CH:16][C:8]=3[NH:9][CH2:10]2)=[O:15])[C:24]([Br:28])=[CH:23][C:22]=1[CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=C(O)C1CNc2cc(OC(F)(F)F)ccc2O1
Reactant: COC(=O)Oc1cc(N)c(Br)cc1C1CCCC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CC1CCCO1
Solvent: c1ccncc1
Product: COC(=O)Oc1cc(NC(=O)C2CNc3cc(OC(F)(F)F)ccc3O2)c(Br)cc1C1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
6-(Trifluoromethoxy)-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid (490 mg, 1.86 mmol) and (5-amino-4-bromo-2-cyclopentyl-phenyl) methyl carbonate (585 mg, 1.86 mmol) were dissolved in 2-methyltetrahydrofuran (13 mL). Pyridine (376 μL, 4.65 mmol) and T3P (2960 mg, 2.8 mL of 50% w/w solution, 4.66 mmol) were added and the reaction was stirred for 1 h at room temperature. Purification by silica gel chromatography (10-75% ethyl acetate/hexanes) yielded 4-bromo-2-cyclopentyl-5-(6-(trifluoromethoxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamido)phenyl methyl carbonate (802 mg, 77% yield). LC/MS m/z 560.2 [M+H]+.
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([C:7](=[O:17])[CH2:8][N:9]2[CH2:16][CH2:15][CH2:14][C@H:10]2[C:11](O)=[O:12])=[CH:3][CH:2]=1.C(N1CCOCC1)C.ClCCl.[CH2:35]([NH:42][C:43](=[O:50])[C@H:44]([CH2:46][CH2:47][S:48][CH3:49])[NH2:45])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(#N)C>[C:1]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:2]=[CH:3][C:4]([C:7](=[O:17])[CH2:8][N:9]2[CH2:16][CH2:15][CH2:14][C@H:10]2[C:11]([N:42]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:43](=[O:50])[C@H:44]([CH2:46][CH2:47][S:48][CH3:49])[NH2:45])=[O:12])=[CH:5][CH:6]=1
Reactant: O=C(CN1CCC[C@H]1C(=O)O)c1ccc(-c2ccccc2)cc1
Reactant: CSCC[C@H](N)C(=O)NCc1ccccc1
Agent: CCN1CCOCC1
Solvent: CC#N
Solvent: ClCCl
Product: CSCC[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)c1ccc(-c2ccccc2)cc1
Yield: 38.9 %

Procedure:
A solution of N-[2-(biphenyl-4-yl)-2-oxoethyl] L-proline (54 mg, 0.17 mmol, 1.0 eq), N-ethylmorpholine (133 uL, 1.04 mmol, 6 eq) in acetonitrile (0.5 mL) was cooled to 0° C. and treated with a 50% solution of 1-n-propylphosphonic acid cyclic anhydride in dichloromethane (180 uL, 0.27 mmol, 1.6 eq) followed by the L-methionine benzylamide (71.36 mg, 0.30 mmol, 1.7 eq). Purification by HPLC provided 35 mg (38%) of L-methionine, N-[1-(2-(biphenyl-4-yl)-2-oxoethyl)-L-prolyl] benzylamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([OH:16])=O)=[C:12]([CH2:17][O:18][CH3:19])[NH:11][C:10](=[O:20])[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[C:21]1([CH2:27][CH2:28][CH2:29][NH2:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C.Cl>ClCCl>[C:21]1([CH2:27][CH2:28][CH2:29][NH:30][C:14]([C:13]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[NH:9][C:10](=[O:20])[NH:11][C:12]=2[CH2:17][O:18][CH3:19])=[O:16])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COCC1=C(C(=O)O)C(c2cccc(Cl)c2)NC(=O)N1
Reactant: NCCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COCC1=C(C(=O)NCCCc2ccccc2)C(c2cccc(Cl)c2)NC(=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
60.0 mg (0.225 mmol) of 4-(3-chlorophenyl)-6-methoxymethyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid and 36.5 mg (0.270 mmol) of 3-phenylpropylamine were dissolved in 10 ml of dichloromethane. 64.7 mg (0.338 mmol) of WSC hydrochloride was added to the obtained solution under cooling with ice, and they were stirred at room temperature overnight. After the concentration under reduced pressure, the reaction mixture was diluted with ethyl acetate and then washed with 1 N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (dichloromethane/methanol=100/1 to 10/1) to obtain the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[S:7][C:8]([CH:11]=[O:12])=[CH:9][N:10]=2)[CH:3]=[N:2]1.[CH2:13]([Mg]Br)[CH3:14].C(OCC)C>C1COCC1>[NH:2]1[CH:3]=[C:4]([C:6]2[S:7][C:8]([CH:11]([OH:12])[CH2:13][CH3:14])=[CH:9][N:10]=2)[CH:5]=[N:1]1
Reactant: O=Cc1cnc(-c2cn[nH]c2)s1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(O)c1cnc(-c2cn[nH]c2)s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
A solution of 2-(1H-pyrazol-4-yl)thiazole-5-carbaldehyde (245 mg, 1.3 mmol) in THF (15 mL) was cooled to 0° C., a 3M solution of ethyl magnesium bromide in diethyl ether (0.9 mL, 2.7 mmol) slowly added at 0° C., and the reaction mixture stirred for 2 hours at 0° C. The reaction mixture was quenched with saturated NH4Cl solution (10 mL) and extracted with ethyl acetate (2×200 mL). The combined extracts were washed with brine solution (20 mL), dried over Na2SO4, filtered and the organic solvent was concentrated under reduced pressure to obtain crude product. The crude product was purified by flash chromatography (60-120μ; 3% methanol in dichloromethane) to afford 1-(2-(1H-pyrazol-4-yl)thiazol-5-yl)propan-1-ol as pale yellow liquid (180 mg, 63% yield). 1H NMR (400 MHz, DMSO-d6): δ 13.19 (br s, 1H), 8.25 (s, 1H), 7.88 (s, 1H), 7.51 (s, 1H), 5.59 (d, 1H), 4.71 (q, 1H), 1.97-1.64 (m, 2H), 0.86 (t, 3H); LC-MS m/z calculated for [M+H]+ 210.06, found 210.1.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1[OH:18].C(N(CC)CC)C>ClCCl>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1[O:18][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(Cl)c(O)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(Cl)c(OC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Benzoyl chloride (3.51 g, 25 mmol) was added dropwise to a solution of 2-chloro-5-methylphenol (3.92 g, 27.5 mmol) and triethylamine (5 mL) in dichloromethane (100 mL), The mixture was stirred for 18 hours at room temperature and concentrated under reduced pressure. Diethylether (200 mL) and water (100 mL) were added. The organic layer was separated and extracted with 2N NaOH (2×100 mL) and brine (50 mL), dried over sodium sulphate and concentrated under reduced pressure. The resulting colourless oil solidified in the freezer. Yield: 5.82 g (94%). 1H-NMR (400 MHz, CDCl3) δ 2.38 (s, 3H, —CH3), 7.05 (d, J=8.2 Hz, 1H), 7.11 (s, 1H), 7.36 (d, J=8.2 Hz, 1H), 7.51-7.56 (m, 2H), 7.64-7.7.70 (m, 1H), 8.22-8.28 (m, 2H). 13C-NMR (100 MHz, CDCl3) δ=21.41, 123.97, 124.58, 128.07, 128.85, 129.15, 130.07, 130.55, 134.01, 138.38, 146.98, 164.51.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][C:7]=1[S:15](=[O:18])(=[O:17])[NH2:16].[CH2:19]([N:21]1[C:26](=[O:27])[CH2:25][CH2:24][C:23]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:33]=3[CH2:34][C:22]1=2)[CH3:20]>ClCCl>[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([C:31]2[CH:30]=[CH:29][C:28]3[C:23]4[CH2:24][CH2:25][C:26](=[O:27])[N:21]([CH2:19][CH3:20])[C:22]=4[CH2:34][C:33]=3[CH:32]=2)=[O:11])=[CH:8][C:7]=1[S:15]([NH2:16])(=[O:18])=[O:17]
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Reactant: CCN1C(=O)CCC2=C1Cc1ccccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCN1C(=O)CCC2=C1Cc1cc(C(=O)c3ccc(Cl)c(S(N)(=O)=O)c3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.7 %

Procedure:
Under nitrogen, aluminum chloride (0.7 g, 4.9 mmol) is slurried in dichloromethane (15 mL) then 4-chloro-3-sulfamoyl-benzoyl chloride (287 mg, 1.13 mmol) is added and allowed to stir at ambient temperature for 30 minutes. Then 1-ethyl-1,3,4,9-tetrahydro-indeno[2,1-b]pyridin-2-one (240 mg, 1.13 mmol) is added in 4 mL dichloromethane. The reaction is allowed to stir at ambient temperature for 1.5 hours. The reaction mixture is poured over ice-water and extracted with dichloromethane, the organic layer is separated and concentrated to give crude title compound as a brown oil. Recrystallization from warm dichloromethane afforded the title compound as a yellow powder (125 mg, 26% yield). 1H NMR (MeOD) 1.26 (t, 2H, J=7.01 Hz), 2.76-2.83 (m, 4H), 3.6 (s, 2H), 3.77 (q, 2H, J=7.01), 5.19 (s, 2H), 7.19 (d, 1H, J=8.11 Hz), 7.68-7.73 (m, 211, 7.86 (d, 1H, J=1.09), 7.94 (dd, 1H, J=2.19, 8.11 Hz), 8.46 (d, 1H, J=1.97 Hz). MS (m/z): 431 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=O)[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>CO>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:12]([C:4]2[C:5]3[O:10][CH2:9][CH2:8][O:7][C:6]=3[CH:11]=[C:2]([NH2:1])[CH:3]=2)=[O:14])[CH2:18][CH2:17]1
Reactant: Nc1cc2c(c(C(=O)O)c1)OCCO2
Reactant: CN1CCNCC1
Solvent: CO
Product: CN1CCN(C(=O)c2cc(N)cc3c2OCCO3)CC1

Procedure:
In the same manner as described in Example 2, the 7-amino-1,4-benzodioxane-5-carboxylic acid was treated with the methanol, and then the obtained carboxylic ester was reacted with N-methyl piperazine. 5[(4-methyl-1-piperazinyl)-carbonyl]-7-amino-1,4-benzodioxane was obtained (M.P.: 170° C.)
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1([CH3:15])[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[O:7]1>S(=O)(=O)(O)O>[CH3:5][C:6]1([CH3:15])[CH2:10][C:9]2[CH:11]=[C:12]([N+:1]([O-:4])=[O:2])[CH:13]=[CH:14][C:8]=2[O:7]1
Reactant: CC1(C)Cc2ccccc2O1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC1(C)Cc2cc([N+](=O)[O-])ccc2O1
Temperature: 5 °C
Reaction time: 2.5 h

Procedure:
During a one hour period an ice cold mixture of 43 mL concentrated nitric acid and 50 mL of concentrated sulfuric acid was added dropwise to 100.0 g (0.67 mole) 2,3-dihydro-2,2-dimethylbenzofuran while maintaining the temperature of 5° C. After complete addition the mixture was stirred at 0° C. for 2.5 hours. The reaction mixture was poured into ice water and the total extracted with diethyl ether. The extract was dried over anhydrous magnesium chloride and filtered. Evaporation of the filtrate under reduced pressure produced a black oil. Purification of this oil by column chromatography on silica gel eluting with toluenen-hexane (9:1), yielded 50.0 g of 2,3-dihydro-2,2-dimethyl-5-nitrobenzofuran as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]#N)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].CN(C)C=O.[BH4-].[Na+].[CH3:21][S:22]CCl>O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][S:22][CH3:21])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CSCCl
Reactant: N#CSc1ccc(N)c([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSCSc1ccc(N)c([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
5.85 G. 1-amino-2-nitro-4-thiocyanatobenzene is treated in 20 ml. dimethylformamide under nitrogen at 20°-25° C. with 1.14 g. sodium borohydride. After 1 hour 10 ml. of methylthiomethylchloride is added and the mixture stirred overnight, diluted with water and extracted with chloroform. The dried chloroform solution is passed through a silica gel column, then evaporated to dryness leaving 1-amino-2-nitro-4-methylthiomethylthiobenzene as a red solid.
Reaction SMILES: C[O:2][C:3]1[CH:27]=[CH:26][C:6]([C:7]([C:9]2[CH:10]=[C:11]([CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:12]3[C:17]=2[CH:16]=[CH:15][CH:14]=[CH:13]3)=[O:8])=[CH:5][CH:4]=1.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[CH:10]=[C:11]([CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:12]3[C:17]=2[CH:16]=[CH:15][CH:14]=[CH:13]3)=[O:8])=[CH:26][CH:27]=1
Reactant: CCOC(=O)CCCc1cc(C(=O)c2ccc(OC)cc2)c2ccccn12
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCl
Product: CCOC(=O)CCCc1cc(C(=O)c2ccc(O)cc2)c2ccccn12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 55.9 %

Procedure:
To a mixture of ethyl 4-[1-(4-methoxybenzoyl)-indolizin-3-yl]butyrate (640 mg) and ethanethiol (2.5 ml) in dichloromethane (8 ml) was added aluminum chloride (700 mg) at 0° C. After stirred at 0° C. for 10 minutes, the solvent was evaporated and the residue was poured into a mixture of ethyl acetate and ice-water. The organic layer was separated, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel column eluting with a mixture of chloroform and ethyl acetate (4:1) to give ethyl 4-[1-(4-hydroxybenzoyl)indolizin-3-yl]butyrate (344 mg) as yellow solid.