Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[C:7]2[N:14]([CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[C:15](=[O:27])[C:16]1[C:21](OC)=[C:20]([O:24][CH3:25])[CH:19]=[CH:18][C:17]=1I)([O-:3])=[O:2].C(Cl)(=O)[C:34](Cl)=[O:35].COC1C=C(C(I)=CC=1OC)C(O)=O.[N+](C1C=C2C(=CC=1)N=CC=C2NCCN(C)C)([O-])=O.C(N(CC)CC)C>C(Cl)Cl>[CH3:25][O:24][C:20]1[C:19]([O:35][CH3:34])=[CH:18][C:17]2[C:8]3[C:7](=[C:6]4[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=[CH:12][C:11]4=[N:10][CH:9]=3)[N:14]([CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[C:15](=[O:27])[C:16]=2[CH:21]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(I)c(C(=O)N(CCN(C)C)c2ccnc3ccc([N+](=O)[O-])cc23)c1OC
Agent: CN(C)CCNc1ccnc2ccc([N+](=O)[O-])cc12
Agent: COc1cc(I)c(C(=O)O)cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(=O)n(CCN(C)C)c3c4cc([N+](=O)[O-])ccc4ncc3c2cc1OC
Yield: 78 %

Procedure:
N-(6-Nitroquinolin-4-yl)-N-(N,N-dimethylaminoethyl)-2-iodo-5,6-dimethoxybenzamide (8c). Oxalyl chloride (1.5 g, 12.0 mmol) was added to a solution of 3,4-dimethoxy-6-iodobenzoic acid (985 mg, 3.2 mmol) in anhydrous methylene chloride (20 mL), and the stirred mixture was refluxed for 3 hours. The mixture was then concentrated to dryness under reduced pressure. The acid chloride was redissolved in 20 mL of anhydrous methylene chloride, and this solution was added to a solution of 7c (700 mg, 2.7 mmol) and triethylamine (2.0 g, 20.0 mmol) in methylene chloride (30 mL), and the resulting mixture was stirred at reflux for 2 hours. The reaction mix was cooled and washed with saturated sodium bicarbonate (3×75 mL), and extracted with 5% aqueous HCl (4×100 mL). The combined aqueous extracts were basified with 30% NaOH and then extracted with chloroform (3×100 mL). Combined organic extracts were then dried (MgSO4) and evaporated to give 1.15 g of the amide, in 78% yield; 1H NMR (CDCl3) δ 2.23 (s, 6H), 2.63 (m, 2H), 3.35 (s, 3H), 3.71 (s, 3H), 3.96 (m, 1H), 4.29 (m, 1H), 6.50 (s, 1H), 6.94 (s, 1H), 7.79 (d, 1H, J=5.2), 8.22 (d, 1H, J=9.2), 8.48 (d, 1H, J=9.2), 9.0 (d, 1H, J=5.2), 9.28 (s, 1H); 13C NMR (CDCl3) δ 45.5, 48.0, 55.6, 56.1, 56.8, 82.3, 110.7, 120.9, 121.5, 122.9, 123.4, 125.5, 132.2, 133.7, 145.9, 148.4, 149.1, 149.8, 151.5, 154.1, 169.7; IR (CHCl3) 1345, 1535, 1655.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:15][C:14]1[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[CH:12][CH:13]=1
Reactant: Oc1ccccc1Br
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(COc2ccccc2Br)cc1
Yield: 70.3 %

Procedure:
A stirred mixture of 2-bromophenol (5.19 g), 4-methoxybenzyl chloride (4.70 g), potassium carbonate (4.15 g) and acetone (30 ml) is heated under reflux for 8 hours. The cool mixture is evaporated under reduced pressure, and the residue is mixed with water (60 ml) and ether (60 ml) and shaken. The aqueous layer is extracted with ether (2×60 ml), and the combined extracts washed with 2M sodium hydroxide solution (20 ml) and water (20 ml), dried (MgSO4) and evaporated to give a solid residue which is recrystallized from ethanol to give 6.18 g of 1-bromo-2-(4-methoxybenzyloxy)benzene, mp 87-90° C.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1[O:32][CH3:33].Cl>C(O)C>[CH:16]1([N:7]2[CH2:8][C:9]([CH3:15])([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: Cl
Solvent: CCO
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C
Yield: 52 %

Procedure:
A mixture of 25.26 g (0.0818 mole) 2-chloro-9-cyclopentyl-5,7,7-trimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-38), 15.35 g (0.0900 mole) of 4-amino-3-methoxy-benzoic acid, 300 mL of ethanol and 1200 mL of 1M hydrochloric acid was heated at reflux for 17 hours. The mixture was cooled, and the precipitate which formed was collected by filtration to give 18.7 g of 4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-38) as white solid.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1(C)C=CC=C[CH:18]=1.OS(O)(=O)=O.O>CCO.CCOC(C)=O>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([O:10][CH2:17][CH3:18])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Reactant: Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C(c1ccccc1)c1ccccc1

Procedure:
To a solution of diphenylacetic acid (20 g, 0.094 mol) in EtOH (70 mL), was added toluene (70 mL). Next, H2SO4 (3 mL) was added dropwise and the reaction mixture was refluxed for 18 h. Then, H2O and EtOAc were added, the layers were separated, and the organic phase was washed with saturated NaHCO3 solution (3×), dried and concentrated to a white solid (23.2 g), which was directly used in the next step as obtained.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([CH:12]=O)=[C:8]2[C:3]=1[C:4](=[O:15])[CH:5]=[C:6]([CH3:14])[O:7]2.[C:16]([CH:18]=[C:19]([O-])[CH3:20])#[N:17].[Na+].[NH2:23][C:24]([CH3:33])=[CH:25][C:26]([O:28][CH:29]1[CH2:32][CH2:31][CH2:30]1)=[O:27].C(O)(=O)C>CC(O)C>[C:16]([C:18]1[CH:12]([C:9]2[CH:10]=[CH:11][C:2]([F:1])=[C:3]3[C:8]=2[O:7][C:6]([CH3:14])=[CH:5][C:4]3=[O:15])[C:25]([C:26]([O:28][CH:29]2[CH2:32][CH2:31][CH2:30]2)=[O:27])=[C:24]([CH3:33])[NH:23][C:19]=1[CH3:20])#[N:17]
Reactant: CC(N)=CC(=O)OC1CCC1
Reactant: CC([O-])=CC#N
Reactant: Cc1cc(=O)c2c(F)ccc(C=O)c2o1
Agent: [Na+]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC1=C(C#N)C(c2ccc(F)c3c(=O)cc(C)oc23)C(C(=O)OC2CCC2)=C(C)N1

Procedure:
A solution of 100 mg (0.49 mmol) of 5-fluoro-2-methyl-4-oxo-4H-chromene-8-carbaldehyde in 5 ml of 2-propanol is mixed with 50.96 mg (0.49 mmol) of sodium 1-cyanoprop-1-en-2-olate, 75.28 mg (0.49 mmol) of cyclobutyl 3-aminobut-2-enoate and 0.04 ml (0.73 mmol) of acetic acid and stirred under reflux for 3 h. After cooling, the mixture is concentrated. The residue is taken up in dichloromethane and washed with water. The organic phase is dried over sodium sulfate and concentrated. The resulting residue is crystallized from diethyl ether. The beige-colored crystals are filtered off with suction and dried at 40° C. in a vacuum drying oven. 120.5 mg (60.8% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:11](=[O:13])[NH:10][C:9](=[O:14])[NH:8][C:7]=2[N:6]=[CH:5]1)[CH:2]=[CH2:3].C([O-])([O-])=O.[K+].[K+].[CH2:21](I)[CH2:22][CH2:23][CH3:24]>CN(C=O)C>[CH2:21]([N:8]1[C:7]2[N:6]=[CH:5][N:4]([CH2:1][CH:2]=[CH2:3])[C:12]=2[C:11](=[O:13])[NH:10][C:9]1=[O:14])[CH2:22][CH2:23][CH3:24]
Reactant: CCCCI
Reactant: C=CCn1cnc2[nH]c(=O)[nH]c(=O)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCn1cnc2c1c(=O)[nH]c(=O)n2CCCC
Reaction time: 48 h
Yield: 68.7 %

Procedure:
A stirred solution of 7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (10 g, 52 mmol) in anhydrous DMF (100 ml) was treated with K2CO3 (7.91 g, 57.2 mmol) and, after 10 minutes, BuI (6.51 ml, 57.2 mmol). After reacting for 2 days the reaction mixture was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated in vacuo to give an off-white solid. This was washed with hot cyclohexane and dried under vacuum to give the title compound (8.87 g, 68%); m/z 249.3[MH+].
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][C:10]2[C:12]([N+:18]([O-:20])=[O:19])=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:9]=2[O:8][CH2:7]1)=[O:5])C>C(O)C.[OH-].[Na+]>[CH3:17][O:16][C:15]1[C:9]2[O:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][C:10]=2[C:12]([N+:18]([O-:20])=[O:19])=[CH:13][CH:14]=1
Reactant: CCOC(=O)C1COc2c(OC)ccc([N+](=O)[O-])c2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc([N+](=O)[O-])c2c1OCC(C(=O)O)C2
Yield: 92.2 %

Procedure:
A mixture of 8-methoxy-5-nitro-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid ethyl ester (5.8 g, 21 mmol) in ethanol (150 mL) and 2 M NaOH (15 mL) was heated to reflux for 30 min. The solvent was evaporated in vacuo the residue dissolved in water. Acidification to pH 2 and extraction with ethyl acetate followed by evaporation of the solvent in vacuo gave 4.9 g (94 % yield) of the title compound: mp 181-183° C.; EIMS (70 eV) m/z (relative intensity) 253 (55, M+).
Reaction SMILES: [Cl:1][CH2:2][C:3](=O)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:11]1([CH:18]=CC=[C:14](O)[CH:13]=1)[OH:12].O>S(=O)(=O)(O)O>[Cl:1][CH2:2][C:3]1[C:9]2[C:8](=[CH:18][C:11]([OH:12])=[CH:13][CH:14]=2)[O:7][C:5](=[O:6])[CH:4]=1
Reactant: Oc1cccc(O)c1
Reactant: CCOC(=O)CC(=O)CCl
Agent: O=S(=O)(O)O
Solvent: O
Product: O=c1cc(CCl)c2ccc(O)cc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
Ethyl 4-chloroacetoacetate (14.0 g, 85.0 mmol) was dissolved in conc. sulfuric acid (30 mL) under ice-cooling and resorcinol (8.81 g, 80.0 mmol) was added by small portions, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into iced water. The resulting solid was collected by filtration, washed with water and air dried to give the title compound (14.1 g, 84%).
Reaction SMILES: FC1C=C(N[N:9]=[C:10]([C:13]#[N:14])[C:11]#[N:12])C=CC=1.[F:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].C(#N)CC#N.O.[NH2:29][NH2:30]>>[F:15][C:16]1[CH:17]=[C:18]([NH:19][N:9]=[C:10]2[C:11]([NH2:12])=[N:30][N:29]=[C:13]2[NH2:14])[CH:20]=[CH:21][CH:22]=1
Reactant: NN
Reactant: Nc1cccc(F)c1
Reactant: N#CC(C#N)=NNc1cccc(F)c1
Solvent: O
Solvent: N#CCC#N
Product: NC1=NN=C(N)C1=NNc1cccc(F)c1

Procedure:
4-[(3-fluorophenyl)hydrazono]-4H-pyrazole-3,5-diamine was prepared using 94 mg (0.5 mmol) of 2-[(3-fluorophenyl)hydrazono]malononitrile, which was derived from 3-fluoroaniline (96 μL, 1.0 mmol) and malononitrile (1.5 mmol) and hydrazine hydrate. Precipitate formed in the reaction tube approximately 5 minutes after the addition of hydrazine hydrate. The resulting solid was isolated by filtration, washed with ethanol, and dried to yield 41 mg (37%) of the compound as a yellow solid. 1H NMR (ppm, DMSO-d6): 6.2 (br s, 4H), 7.0 (t, 1H), 7.35-7.62 (m, 3H), 10.80 (s, 1H).
Reaction SMILES: [I:1]I.[C:3]1([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>O.C(O)C>[I:1][C:6]1[CH:7]=[CH:8][C:3]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:5]=1
Reactant: II
Reactant: c1ccc(N2CCCC2)cc1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Ic1ccc(N2CCCC2)cc1
Reaction time: 1 h
Yield: 19.6 %

Procedure:
Iodine (6.09 g) was added slowly to a stirred solution of phenylpyrrolidine (3.21 g) and sodium bicarbonate (2.75 g) in water (30 ml). The reaction was stirred for 1 h and then left to stand overnight. The solid was isolated by filtration, dissolved in ethanol (50 ml) and discoloured with aqueous sodium thiosulfate. The product was then isolated by filtration and recrystalised from ethanol to give the desired product as a brown/red powder (1.17 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:7]=1[NH:13][C:14](=[O:20])[CH:15]=[CH:16][C:17](O)=[O:18])=[O:5])[CH3:2].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:43][C:44]([NH2:46])=[S:45]>CN(C)C=O.C(OCC)(=O)C>[NH2:46][C:44]1[S:45][CH:16]([CH2:15][C:14]([NH:13][C:7]2[S:8][C:9]([CH3:12])=[C:10]([CH3:11])[C:6]=2[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:20])[C:17](=[O:18])[N:43]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)c1c(NC(=O)C=CC(=O)O)sc(C)c1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(NC(=O)CC2SC(N)=NC2=O)sc(C)c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.6 %

Procedure:
To 2-(3-Carboxy-acryloylamino)-4,5-dimethyl-thiophene-3-carboxylic acid ethyl ester (2.97 g, 10.0 mmol) in 50 mL of N,N-dimethyl-formamide was added N-hydroxy-benzotriazole (1.48 g, 11.0 mmol) and 1-[3-(dimethylamino) propyl]-3-ethyl-carbodiimide hydrochloride (2.88 g, 15.0 mmol). The reaction mixture was stirred at room temperature for 10 minutes and thiourea (0.84 g, 11.0 mmol) was added. The reaction mixture was stirred at room temperature for another 30 minutes and was heated at 60° C. for 12 hours. The reaction mixture was diluted with 250 mL of ethyl acetate and was washed with 100 mL of water and 100 mL of brine. The organic layer was collected, dried over sodium sulfate and concentrated. The residue was load on a 120 g silica gel column and purified by flash chromatography (eluted with a gradient of 0 to 10% ethyl acetate/hexanes). Ethyl 2-{[(2-amino-4-oxo-4,5-dihydro-1,3-thiazol-5-yl) acetyl]amino}-4,5-dimethylthiophene-3-carboxylate (1.80 g, 51% yield) was produced.
Reaction SMILES: C([O:5][C:6](=O)[NH:7][C@H:8]([CH2:24][C:25]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:26]=1[F:33])[CH2:9][C:10]([NH:12][NH:13][C:14]1[N:19]2[N:20]=[C:21]([CH3:23])[N:22]=[C:18]2[CH2:17][CH2:16][N:15]=1)=O)(C)(C)C.[C:35](O)(=O)C>>[CH3:23][C:21]1[N:22]=[C:18]2[N:19]([C:14]3[N:15]([C:10]([CH2:9][C@H:8]([NH:7][C:6](=[O:5])[CH3:35])[CH2:24][C:25]4[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:26]=4[F:33])=[N:12][N:13]=3)[CH2:16][CH2:17]2)[N:20]=1
Reactant: Cc1nc2n(n1)C(NNC(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)=NCC2
Reactant: CC(=O)O
Product: CC(=O)N[C@H](Cc1cc(F)c(F)cc1F)Cc1nnc2n1CCc1nc(C)nn1-2

Procedure:
The crude residue from Step A was dissolved in 5 mL of glacial acetic acid, and the resulting solution was stirred at reflux for 60 h. The cooled solution was concentrated, and the residue was partitioned between 1:1 ethyl acetate:tetrahydrofuran and saturated sodium carbonate aqueous solution. The organic phase was dried over magnesium sulfate, filtered, and concentrated to dryness. Purification of the residue by preparative thin-layer chromatography on silica gel (three successive developments in 95:5, 92.5:7.5, and 90:10 dichloromethane:methanol) afforded the title compound as a stiff foam. LC-MS 406 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[OH:10][C:11]1[C:30](=[O:31])[N:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]([NH:21][C@@H:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH3:23])[C:14]2=[N:13][C:12]=1[C:32](OC)=[O:33]>CO>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:32]([C:12]2[N:13]=[C:14]3[CH:20]([NH:21][C@@H:22]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH3:23])[CH2:19][CH2:18][CH2:17][CH2:16][N:15]3[C:30](=[O:31])[C:11]=2[OH:10])=[O:33])=[CH:4][CH:3]=1.[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH3+:7])=[CH:4][CH:3]=1
Reactant: COC(=O)c1nc2n(c(=O)c1O)CCCCC2N[C@H](C)c1ccccc1
Reactant: NCc1ccc(F)cc1
Solvent: CO
Product: C[C@@H](NC1CCCCn2c1nc(C(=O)NCc1ccc(F)cc1)c(O)c2=O)c1ccccc1
Product: [NH3+]Cc1ccc(F)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
p-Fluorobenzylamine (3 eq.) was added to the methyl 3-hydroxy-4-oxo-10-{[(1R)-1-phenylethyl]amino}-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepine-2-carboxylate (prepared as described in Step 5 or Step 5A) dissolved in methanol. The mixture was stirred at 70° C. overnight, then cooled to room temperature for use directly in Step 7. In an alternative procedure (Step 6A), the solvent was removed and the crude product crystallized from acetonitrile several times to obtain a single diasteroisomer of the title compound as the 4-fluorobenzylammonium salt with d.e.>95%
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH:6]2[O:8][CH:5]2[CH2:4]1)[CH3:2].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[SH:16]>Cl.C(Cl)Cl>[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16][C@@H:5]1[CH2:4][N:3]([CH2:1][CH3:2])[CH2:7][C@H:6]1[OH:8]
Reactant: CCN1CC2OC2C1
Reactant: Sc1ccccc1Cl
Agent: Cl
Solvent: ClCCl
Product: CCN1C[C@@H](O)[C@H](Sc2ccccc2Cl)C1

Procedure:
A mixture of 11.3 g. (0.1 mole) of crude 1-ethyl-3,4-epoxypyrrolidine, 14.4 g. (0.1 mole) of 2-chlorothiophenol and 1 drop concentrated hydrochloric acid on a steam bath overnight. The reaction mixture was dissolved in methylene chloride and the solution was washed with two 100-ml portions of 5% sodium hydroxide and once with water. The methylene chloride layer was dried over anhydrous sodium sulfate and concentrated to give 23.8 g. of dark oil as residue which solidified when scratched with petroleum ether. The solid was collected by filtration and recrystallized from cyclohexane to yield 10 g. (39%) of tan solid, m.p. 90.5°-92.5°.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([O:23]C)[N:13]2[CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][O:19][CH2:18]2)=[C:9]([NH2:25])[N:8]=1)[CH3:2].Cl.[OH-].[Na+]>CO.O1CCOCC1.O>[NH2:25][C:9]1[N:8]=[C:7]([O:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2])[N:15]=[C:14]2[C:10]=1[NH:11][C:12](=[O:23])[N:13]2[CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][O:19][CH2:18]1
Reactant: CCOCCOc1nc(N)c2nc(OC)n(CC3CCCOC3)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: CCOCCOc1nc(N)c2[nH]c(=O)n(CC3CCCOC3)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(2-ethoxyethoxy)-8-methoxy-9-(tetrahydro-2H-pyran-3-ylmethyl)-9H-purin-6-amine (245 mg) in dry methanol (10 ml) at room temperature and under nitrogen was added 4.0M hydrogen chloride in 1,4-dioxane (4.0 ml). The reaction was left to stir at room temperature for 1 hour. The reaction was concentrated in vacuo and the resulting residue purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluant (10-45%) to afford a white solid. This was taken up in water (15 ml) and neutralised by the addition of 2.0M sodium hydroxide solution. The solid was filtered and dried on the rotary evaporator (60° C.) for 30 minutes (90 mg).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)[C:26](O)=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:58][C:59]1[CH:60]=[C:61]([CH:64]=[C:65]([Cl:67])[CH:66]=1)[CH2:62][NH2:63]>ClCCl>[Br:58][C:59]1[CH:60]=[C:61]([CH2:62][NH:63][C:26]([C:25]2[CH:29]=[CH:30][CH:31]=[C:23]([C:21]([NH:20][CH2:19][C:10]3[C:11]([NH:12][CH:13]4[CH2:14][CH2:15][O:16][CH2:17][CH2:18]4)=[C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]4=[N:8][C:9]=3[CH2:32][CH3:33])=[O:22])[CH:24]=2)=[O:27])[CH:64]=[C:65]([Cl:67])[CH:66]=1
Reactant: NCc1cc(Cl)cc(Br)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(Cl)cc(Br)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-[({[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoic acid (677 mg, 1.5 mmol) was suspended in dichloromethane (DCM) (50 ml), and HBTU (569 mg, 1.5 mmol) was added, followed sequentially by 3-bromo-5-chlorobenzylamine (331 mg, 1.5 mmol), and TEA (0.418 mL, 3.0 mmol). The reaction mixture was stirred overnight under argon at room temperature to give a clear-colorless solution. The solvent was removed on a rotovap and the residue was partitioned between ethyl acetate (100 mL) and 1N NaOH (20 mL). The phases were separated and the organic phase was washed 2× with 1N NaOH (20 mL), and then 1× with brine (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. The crude product was taken up in dichloromethane and absorbed on Isolute® Sorbent and purified by CombiFlash on a 40 g silica column eluted with 0-10% DCM/MeOH to give the title compound as white solid. LC-MS m/z 652.9 (M+H)+, 2.08 min (ret time); mp 109-112° C.; analytical HPLC shows 97.6% purity, (ret time 13.921 min).
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH2:19][CH2:18][CH2:17][CH:16]([C:21](=[O:23])[NH2:22])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][C:13]=2[O:24][CH2:25][C:26]([O:28]C)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.CO>[CH2:1]([N:8]1[C:20]2[CH2:19][CH2:18][CH2:17][CH:16]([C:21](=[O:23])[NH2:22])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][C:13]=2[O:24][CH2:25][C:26]([OH:28])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)COc1cccc2c1c1c(n2Cc2ccccc2)CCCC1C(N)=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)C1CCCc2c1c1c(OCC(=O)O)cccc1n2Cc1ccccc1
Reaction time: 18 h
Yield: 86.9 %

Procedure:
A solution of 30 mg (0.076 mmol) of [9-benzyl-4-carbamoyl-1,2,3,4-tetrahydrocarbazole-5-yl]oxyacetic acid, methyl ester in 1.0 mL of THF and 1.0 mL of MeOH was treated with 0.2 mL of 1 N aqueous LiOH (0.2 mmol). The mixture was stirred for 18 hours. An additional 0.2 mL of 1 N aqueous LiOH (0.2 mmol) was added and stirring continued. After 1 hour, the mixture was concentrated in vacuo. The residue was dissolved in 2.0 mL of H2O and the solution acidified with 0.2 N aqueous HCl. The solid was filtered and dried to afford 25 mg of [9-benzyl-4-carbamoyl-1,2,3,4-tetrahydrocarbazole-5-yl]oxyacetic acid as a white solid. 1H NMR (DMSO-d6) δ7.36-7.12 (m, 5H), 7.05-6.83 (m, 5H), 6.71 (br s, 1H), 6.35 (d, 1H, J=7.6 Hz), 5.27 (s, 2H), 4.64 (s, 2H), 3.93-3.84 (m, 2H), 2.75-2.64 (m, 1H), 2.16-1.95 (m, 2H), 1.81-1.64 (m, 2H) and 1 proton masked by H2O peak between 2.58-2.40. IR (KBr, cm−1) 3435, 2936, 1722, 1644, 1586, 1566, 1495, 1451, 1354, 1227, 1134, 730, 716, and 698. MS (ES) m/e 377 (M−1) and 379 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]([CH:11]2[CH2:15][CH2:14][NH:13][CH2:12]2)[CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26]/[CH:27]=[C:28]1/[C:29]2[CH:42]=[C:41]([C:43]([OH:46])([CH3:45])[CH3:44])[CH:40]=[CH:39][C:30]=2[O:31][CH2:32][C:33]2[N:38]=[CH:37][CH:36]=[CH:35][C:34]/1=2>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:8][CH2:9][OH:10])[CH:11]2[CH2:15][CH2:14][N:13]([CH2:25][CH2:26][CH:27]=[C:28]3[C:34]4[CH:35]=[CH:36][CH:37]=[N:38][C:33]=4[CH2:32][O:31][C:30]4[CH:39]=[CH:40][C:41]([C:43]([OH:46])([CH3:45])[CH3:44])=[CH:42][C:29]3=4)[CH2:12]2)=[CH:16][CH:17]=1
Reactant: CC(C)(O)c1ccc2c(c1)/C(=C/CCBr)c1cccnc1CO2
Reactant: OCCN(Cc1ccc(Cl)cc1)C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCC(N(CCO)Cc3ccc(Cl)cc3)C1)c1cccnc1CO2
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of 2-[(4-chloro-benzyl)-pyrrolidin-3-yl-amino]-ethanol (0.15 g, 0.6 mmol) in acetonitrile:water (4:1) was added potassium carbonate (0.11 g, 0.8 mmol) and (E)-2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.15 g, 0.4 mmol) and the resulting mixture was stirred at 50° C. for 24 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and dried over sodium sulfate. The crude product was purified on silica. 1H-NMR (CDCl3) δ:1.40 (6H, s), 1.60 (1H, m), 1.80 (1H, m), 2.10–2.60 (8H, m), 3.20–3.40 (6H, m), 3.50 (2H, m), 5.20 (2H, br, s), 6.15 (1H, t), 6.70 (1H, t), 7.18–7.42 (7H, m), 7.70 (1H, dd), 8.50 (1H, dd). ESI-MS m/z: 548 (M+1), UV retention time: 1.26 min.