Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Br)=[CH:17][CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:23]=[N+:24]=[N-:25].[Li+]>>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:23]=[N+:24]=[N-:25])=[CH:17][CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(CN=[N+]=[N-])cc1
Yield: 74 %

Procedure:
Reaction of [2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl bromide (from Step D) with lithium azide was carried out according to the procedure of Example 9, Step A. The crude product was purified by flash chromatography on silica gel (elution with 10% EtOAc in hexane) to give a 74% yield of the title compound as a white solid; satisfactory purity (by TLC in 9:1 hexane-EtOAc) for use in the next step.
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:23])=[C:6]([CH2:20][CH2:21][CH3:22])[C:7]2[S:12][C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][C:9](=[O:18])[C:8]=2[CH:19]=1)(=[O:3])[CH3:2].[C:24](OCC)(=O)[C:25]([O:27][CH2:28][CH3:29])=[O:26].CCOCC.Cl>CN(C)C=O.O.C(O)C>[O:3]=[C:1]1[C:4]2[CH:19]=[C:8]3[C:9](=[O:18])[CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:12][C:7]3=[C:6]([CH2:20][CH2:21][CH3:22])[C:5]=2[O:23][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:2]1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCCc1c(O)c(C(C)=O)cc2c(=O)cc(C(=O)OCC)sc12
Agent: Cl
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1c2oc(C(=O)OCC)cc(=O)c2cc2c(=O)cc(C(=O)OCC)sc12

Procedure:
The product of step (f) (7.5 g) and diethyl oxalate (24.4 mls) in dry dimethylformamide (200 mls) were added to ether washed 50% sodium hydride (4.3 g) in dry dimethylformamide (250 mls) with stirring under nitrogen. The whole was stirred for a further 24 hours after addition, then poured into ice/water and extracted into ethyl acetate which was dried, filtered and the solvent evaporated to afford a red solid. This was added to ethanol (100 mls) previously saturated with hydrogen chloride gas and refluxed for 15 minutes. The reaction mixture was poured into water, extracted with chloroform, dried and the solvent evaporated to give 4.9 g of the desired product. Structure confirmed by MS and NMR.
Reaction SMILES: [ClH:1].[NH2:2][CH:3]1[CH2:17][C:6]2[C:7]3[NH:8][C:9](=[O:16])[C:10](=[O:15])[NH:11][C:12]=3[CH:13]=[CH:14][C:5]=2[CH2:4]1.[N+:18]([O-])([OH:20])=[O:19]>FC(F)(F)C(O)=O>[ClH:1].[NH2:2][CH:3]1[CH2:17][C:6]2[C:7]3[NH:8][C:9](=[O:16])[C:10](=[O:15])[NH:11][C:12]=3[CH:13]=[C:14]([N+:18]([O-:20])=[O:19])[C:5]=2[CH2:4]1
Reactant: O=[N+]([O-])O
Reactant: NC1Cc2ccc3[nH]c(=O)c(=O)[nH]c3c2C1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: NC1Cc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The parent quinoxalinedione (Example 33) was mixed with 50 mL trifluoroacetic acid and 1 mL fuming nitric acid at 0° C. and stirred for 3 h, then warmed to room temperature for 2 h. The solvent was evaporated, the residue taken up in acetone, and the solid collected by filtration. After washing with water and then tetrahydrofuran, the material was dried to give 1.3 g of the compound as the hydrochloride salt. CHN calc'd for C11H10N4O4.HCl.0.5H2O; C, 38.39; H, 3.52; N, 16.28; found-C, 38.54; H, 3.57; N, 17.39. CI MS m/e (M+1) 263. H-NMR (400 MHz, dmso) 1H, s, 12.2; 1H, s, 12.12; 2H, br s, 8.1; 1H, s, 7.9; 1H, br s, 4.2: 1H, dd, 3.7; 2H, m, 3.4; 1H dd, 3.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=O)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[F:17][C:18]([F:27])([F:26])[C:19]1[N:23]=[C:22]([CH2:24][NH2:25])[O:21][N:20]=1>>[Br:1][C:2]1[C:7]([O:8][CH2:9][C:10]([F:11])([F:12])[F:13])=[N:6][CH:5]=[C:4]([CH:3]=1)[C:14]([NH:25][CH2:24][C:22]1[O:21][N:20]=[C:19]([C:18]([F:27])([F:26])[F:17])[N:23]=1)=[O:16]
Reactant: NCc1nc(C(F)(F)F)no1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(Br)c1
Product: O=C(NCc1nc(C(F)(F)F)no1)c1cnc(OCC(F)(F)F)c(Br)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-bromo-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAN 1211586-75-2) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) as starting materials; LC-MS (UV peak area/ESI) 97%, 448.9532 (M−H)−.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:15][CH2:16][CH3:17])=[C:7]([O:12][CH2:13][CH3:14])[CH:8]=2)[N:3]=1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([NH:25][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:15][CH2:16][CH3:17])=[C:7]([O:12][CH2:13][CH3:14])[CH:8]=2)[N:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOc1cc2ncc(Cl)nc2cc1OCC
Reactant: NCc1ccccc1
Product: CCOc1cc2ncc(NCc3ccccc3)nc2cc1OCC
Yield: 87.6 %

Procedure:
To 0.3 g (1.19 mmol) of 2-chloro-6,7-diethoxyquinoxaline is added 2 mL of benzylamine. This mixture is heated under nitrogen overnight to 120° C. The resulting mixture is partitioned between CH2Cl2 and saturated NaHCO3 solution. The organic layer is concentrated, and the residue chromatographed (30:1 CH2Cl2; EtOH) to provide 0.337 g of the product as a yellow solid in 87.6% yield (m.p. 136° C.). Anal. Calcd for C19H21N3O2: C, 70.57; H, 6.54; N, 12.99. Found: C, 70.54; H, 6.66; N, 12.80.
Reaction SMILES: CC(=[N:4][N:5]=[C:6]1[N:10]([CH3:11])[C:9]([CH3:12])=[CH:8][S:7]1)C.[ClH:13]>>[ClH:13].[CH3:11][N:10]1[C:9]([CH3:12])=[CH:8][S:7][C:6]1=[N:5][NH2:4]
Reactant: CC(C)=NN=c1scc(C)n1C
Agent: Cl
Product: Cc1csc(=NN)n1C

Procedure:
3.5 g (19 mmol) of 3,4-dimethyl-2(3H)-thiazolone-(1-methylethylidene)hydrazone from step A in 60 mL of 6M hydrochloric acid was heated at 50° C. for 30 minutes. The reaction mixture was then concentrated, and the crude product was recrystallized from ethanol. This gave 2 g (60% of the theoretical) of a pink powder.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:18])([F:20])[F:19])=[CH:10][C:9]2[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cccnc3)c1)=N2

Procedure:
The title compound was prepared from {5-dimethylamino-2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M1) (306 mg, 0.56 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (162 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[C:26](I)=[N:25][C:24]4[C:19]3=[N:20][CH:21]=[N:22][C:23]=4[NH:28][CH3:29])=[CH:14][CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:30]([F:33])([F:32])[F:31].[CH3:34][OH:35]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[C:26]([O:35][CH3:34])=[N:25][C:24]4[C:19]3=[N:20][CH:21]=[N:22][C:23]=4[NH:28][CH3:29])=[CH:14][CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:30]([F:33])([F:32])[F:31]
Reactant: CO
Reactant: CNc1ncnc2c1nc(I)n2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Product: CNc1ncnc2c1nc(OC)n2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be prepared from 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-[4-(8-iodo-6-(methylamino)purin-9-yl)phenyl]urea and methanol by using the same technique as in Example 136.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=[O:12].[N+]([O-])([O-])=[O:14].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[Tl+3]>>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][CH:6]([C:5]([OH:12])=[O:14])[C:4]=2[CH:3]=1
Reactant: O=C1CCOc2ccc(F)cc21
Reactant: O=[N+]([O-])[O-]
Agent: [Tl+3]
Product: O=C(O)C1COc2ccc(F)cc21

Procedure:
The title compound was prepared from 6-fluoro-4-chromanone (D12) (9.96 g, 0.06 mole) and thallium trinitrate (0.083 mole) on K10 clay (84 g) by the method of Description 1, as a yellow solid, (1.66 g, 15%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][C@H:16]([CH3:18])[NH:15][CH2:14][C@@H:13]2[CH3:19])=[N:4][N:3]=1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C.C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[C@@H:13]([CH3:19])[CH2:14][N:15]([C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:27])[C@@H:16]([CH3:18])[CH2:17]2)=[N:4][N:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@H]1CN(c2nnc(Cl)c3ccccc23)[C@@H](C)CN1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@H]1CN(c2nnc(Cl)c3ccccc23)[C@@H](C)CN1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-chloro-4-((2S,5S)-2,5-dimethylpiperazin-1-yl)phthalazine (496 mg, 1.79 mmol) was dissolved in DMF (5 mL) and N,N-diisopropylethylamine (0.5 mL). Benzoyl chloride (0.23 mL, 2.02 mmol) was added and the mixture stirred at rt for 16 hours. The reaction was taken up in ethyl acetate (80 mL) and washed with aqueous K2CO3 (10%), water, and saturated sodium chloride. The organics were dried (MgSO4) and evaporated to give a yellow oil. Chromatography over silica gel with a gradient of hexanes/0-70% ethyl acetate gave off-white foam. MS (M+H)+=381.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][S:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Cl)(=[O:29])=[O:28]>C(N(C(C)C)C(C)C)C>[OH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][S:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N:12]1[CH2:11][CH2:10][N:9]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:14][CH2:13]1)(=[O:29])=[O:28]
Reactant: O=S(=O)(CCCCCCCl)NCCCCO
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(CCCCCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1)NCCCCO
Yield: 95 %

Procedure:
1-[(4-Chlorophenyl)phenylmethyl]piperazine (479.8 mg, 1.67 mmol) and N-(4-hydroxybutyl)-6-chlorohexanesulfonamide (500.0 mg, 1.84 mmol) prepared in Preparation Example 22 were refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (20:1), to give N-(4-hydroxybutyl)-6-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulfonamide (828.6 mg) as a pale yellow oil (yield based on 1-[(4-chlorophenyl)phenylmethyl]piperazine: 94.9%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:17][CH2:16][C@@H:15]3[C@H:10]([O:11][CH2:12][C:13](=[O:18])[NH:14]3)[CH2:9]2)=[CH:6][C:5]([C:19]#[N:20])=[CH:4][C:3]=1[NH:21]C1N=C(N(CC)CC2C=CC(OC)=CC=2)C2=NC=C(C#N)N2N=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O.[Cl:60]CCCl>>[NH2:21][C:3]1[C:2]([Cl:1])=[C:7]([N:8]2[CH2:17][CH2:16][C@@H:15]([NH:14][C:13](=[O:18])[CH2:12][Cl:60])[C@H:10]([OH:11])[CH2:9]2)[CH:6]=[C:5]([C:19]#[N:20])[CH:4]=1
Reactant: ClCCCl
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(Nc2cc(C#N)cc(N3CC[C@H]4NC(=O)CO[C@@H]4C3)c2Cl)nn2c(C#N)cnc12
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: N#Cc1cc(N)c(Cl)c(N2CC[C@@H](NC(=O)CCl)[C@H](O)C2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(+/−)-2-((2-chloro-5-cyano-3-((4aR,8aR)-2-oxohexahydro-1H-pyrido[3,4-b][1,4]oxazin-6(7H)-yl)phenyl)amino)-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile was taken up in DCE (0.8 mL), anisole (0.043 mL, 0.391 mmol) and TFA (0.5 mL, 6.49 mmol). The mixture stirred 2 h at 25° C. and solvent was removed. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 20-mM ammonium acetate; Gradient: 25-65% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford (+/−)-N-((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-hydroxypiperidin-4-yl)-2-chloroacetamide (2.2 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][N:5]1[CH2:17][C:16](=O)[C:15]2[C:14]3[C:13]([C:19]([O:21]C)=O)=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7]=2[CH2:6]1.O.NN.C1C2NC3C=CC=C4C(=O)[NH:41][N:42]=C(C=2C=34)CC1>>[CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][N:5]1[CH2:6][C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:21])[NH:41][N:42]=[C:16]([C:15]=2[C:14]=34)[CH2:17]1
Reactant: O=C1NN=C2CCCc3[nH]c4cccc1c4c32
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CN(CCN(C)C)C3
Agent: NN
Solvent: O
Product: CN(C)CCN1CC2=NNC(=O)c3cccc4[nH]c(c2c34)C1

Procedure:
Compound 60 was prepared from methyl 2-(2-(dimethylamino)ethyl)-4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate and hydrazine hydrate according to the procedure similar to that for Compound 1. 1H NMR δ 9.92 (s, 1H), 7.60 (d, 1H, J=8.4 Hz), 7.46 (d, 1H, J=7.8 Hz), 7.13 (dd, 1H, J=8.4, 7.8 Hz), 4.20-4.22 (m, 2H), 4.03 (s, 2H), 3.41 (s, 2H), 2.51-2.54 (m, 2H), and 2.18 (s, 6H). MS (ESI) m/e [M+1]+ 298.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[C:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:13].N1C=CC=CC=1>C(Cl)Cl>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:1][C:12](=[O:13])[O:14][C:15]1[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=1
Reactant: Nc1nc2ccccc2s1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1nc2ccccc2s1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97.5 %

Procedure:
The title compound 4-nitrophenyl benzo[d]thiazol-2-ylcarbamate (19) was prepared by the following procedure: To 2-aminobenzothiazole (5.0 g, 30 mmol) was added DCM (36 mL) and the reaction mixture was stirred at 0° C. for 15 minutes. Then, p-nitrophenyl chloroformate (6.64 g, 33 mmol) in DCM (60 mL) was added, followed by pyridine (2.66 mL, 33 mmol) in DCM (36 mL). The reaction mixture was stirred and allowed to warm to rt overnight. The reaction mixture was filtered, washed with DCM, and dried to provide 9.22 g (90%) of the desired product 4-nitrophenyl benzo[d]thiazol-2-ylcarbamate (19): LC/MS (APCI): m/z 316.0 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[S:10][C:9]([C:14]([OH:16])=[O:15])=[CH:8][C:7]2=[O:17])[CH3:2].C(=O)(O)[O-].[Na+:22]>O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[S:10][C:9]([C:14]([O-:16])=[O:15])=[CH:8][C:7]2=[O:17])[CH3:2].[Na+:22]
Reactant: CCOc1ccc2sc(C(=O)O)cc(=O)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCOc1ccc2sc(C(=O)[O-])cc(=O)c2c1

Procedure:
To part of 6-ethoxy-1thiachromone-2-carboxylic acid in water was added 0.336 parts of sodium bicarbonate. The mixture was stirred for several minutes and the resulting solution was filtered and freeze-dried to give sodium 6-ethoxy-1-thiachromone-2-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](Br)[CH:7]=1.[CH3:9][O-:10].[Na+].O>CO>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:10][CH3:9])[CH:7]=1
Reactant: Brc1cncc(Br)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cncc(Br)c1
Temperature: 25 °C

Procedure:
3,5-Dibromopyridine (30.0 g) was added to a stirred solution of sodium methoxide (prepared from 11.6 g of sodium) in methanol (120 ml) and heated to reflux for 70 hours under an atmosphere of nitrogen. The mixture was cooled to ambient temperature, poured into water (1000 ml), extracted with diethyl ether and the extracts combined, washed with water and dried over magnesium sulphate. The solvent was evaporated to give 3-bromo-5-methoxypyridine as a colourless liquid, which slowly crystallised on storing (19.3 g).
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:13][C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=2[CH3:22])=[N:4][C:5]([CH3:12])=[CH:6][C:7]=1[CH:8]([NH2:11])[CH2:9][CH3:10].[CH3:23][N:24]=[C:25]=[O:26]>ClC(Cl)C>[CH3:1][C:2]1[C:3]([O:13][C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=2[CH3:22])=[N:4][C:5]([CH3:12])=[CH:6][C:7]=1[CH:8]([NH:11][C:25]([NH:24][CH3:23])=[O:26])[CH2:9][CH3:10]
Reactant: CN=C=O
Reactant: CCC(N)c1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C
Solvent: CC(Cl)Cl
Product: CCC(NC(=O)NC)c1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C

Procedure:
A mixture of 1-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-propylamine (26.5 mg), methyl isocyanate (0.05 ml), in dichloroethane (1 ml) was heated at reflux overnight. The mixture was quenched with water and extracted with chloroform. The organic layer was separated, dried and concentrated to give 27.1 mg of white solid. The solid was purified by preparative thin layer chromatography using 5% methanol in chloroform as solvent to give the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3].[Cl:23]N1C(=O)CCC1=O.O>CN(C)C=O>[NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)=[C:8]([Cl:23])[C:9]=1[C:10]([NH2:12])=[O:11])=[O:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: NC(=O)Nc1[nH]c(-c2ccc3ccccc3c2)cc1C(N)=O
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)Nc1[nH]c(-c2ccc3ccccc3c2)c(Cl)c1C(N)=O
Yield: 45 %

Procedure:
A solution of 2-aminocarbonylamino-5-(2-naphthyl)pyrrole-3-carboxamide (Compound No. 1-1, 92 mg, 0.31 mmol) and N-chlorosuccinimide (46 mg, 0.34 mmol) in anhydrous N,N-dimethylformamide (2 mL) was stirred at 60° C. for 2 hours. After cooling, water (10 mL) was added thereto, the precipitated solid was filtered off, and washed with water (10 mL) and acetone (10 mL). The obtained solid was dried at 50° C. under reduced pressure to give the target compound (46 mg) as a pale brown solid (Yield 45%).
Reaction SMILES: [C:1](=[O:41])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH:3]1[CH2:7][CH2:6][CH:5]([N:8]2[C:12]3[N:13]=[CH:14][N:15]=[C:16]([NH2:17])[C:11]=3[C:10]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)=[CH:9]2)[CH2:4]1.[O:42]1[CH2:47][CH2:46][N:45]([CH2:48][CH2:49][NH2:50])[CH2:44][CH2:43]1>ClCCl.C(OCC)(=O)C>[O:42]1[CH2:47][CH2:46][N:45]([CH2:48][CH2:49][NH:50][C:1](=[O:41])[O:2][CH:3]2[CH2:7][CH2:6][CH:5]([N:8]3[C:12]4[N:13]=[CH:14][N:15]=[C:16]([NH2:17])[C:11]=4[C:10]([C:18]4[CH:19]=[CH:20][C:21]([O:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[CH:22][CH:23]=4)=[CH:9]3)[CH2:4]2)[CH2:44][CH2:43]1
Reactant: NCCN1CCOCC1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC(OC(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC(OC(=O)NCCN2CCOCC2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentyl (4-nitrophenyl) carbonate (0.052 mmol) in dichloromethane (1 ml) was added to 2-morpholinoethylamine (0.2 ml). The resulting mixture was stirred under nitrogen at ambient temperature for 24 hours. The reaction mixture was diluted with ethyl acetate and washed, dried (MgSO4), filtered and evaporated. The solid was purified by preparative HPLC to give 3-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentyl N-(2-morpholinoethyl)carbamate. The structure was confirmed by 1H NMR and LC/MS (MH+=543).
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([N:10]=[C:11]=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]([O:26][CH2:27][CH2:28][CH2:29][OH:30])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:26][CH2:27][CH2:28][CH2:29][O:30][C:11](=[O:12])[NH:10][C:8](=[O:9])[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OCCCOCc1ccccc1
Reactant: O=C=NC(=O)C(c1ccccc1)c1ccccc1
Product: O=C(NC(=O)C(c1ccccc1)c1ccccc1)OCCCOCc1ccccc1

Procedure:
The title compound, colorless oil, MS: m/e=403.5 (M+H+) was prepared in accordance with the general method of example 1 from diphenylacetyl isocyanate and 3-benzyloxy-propan-1-ol.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[Cl:11].[CH2:12]1[C@H:21]2[C@H:16]([CH2:17][CH2:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=32)[NH:15][CH2:14][CH2:13]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:15]2[C@@H:16]3[C@@H:21]([C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[CH2:18][CH2:17]3)[CH2:12][CH2:13][CH2:14]2)=[O:8])=[CH:4][C:3]=1[Cl:11]
Reactant: Nc1ccc(C(=O)O)cc1Cl
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Nc1ccc(C(=O)N2CCC[C@@H]3c4ccccc4CC[C@@H]32)cc1Cl
Yield: 52 %

Procedure:
The title compound is prepared from 4-amino-3-chloro-benzoic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 52% of theory; LC (method 4): tR=1.99 min; Mass spectrum (ESI+): m/z=341/343 (Cl) [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH:20]3[CH2:21][CH2:22][CH:23]([CH2:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:19]3[C:18](=O)[CH2:17][O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]2[CH:20]3[CH2:21][CH2:22][CH:23]([CH2:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:19]3[CH2:18][CH2:17][O:16]2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1COC(c2ccc(OCc3ccccc3)cc2)C2CCC(CCc3ccccc3)N12
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(CCC2CCC3C(c4ccc(OCc5ccccc5)cc4)OCCN23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.7 %

Procedure:
A solution of (1RS,6RS,8aSR)-1-(4-Benzyloxy-phenyl)-6-phenethyl-tetrahydro-pyrrolo[2, 1-c][1,4]oxazin-4-one (0.12 g, 0.28 mmol) in THF (1 ml) was added dropwise to a 0° C. suspension of LiAlH4 (0.021 g, 0.56 mmol) in THF (1 ml). Reaction mixture was stirred at room temperature for 2 hours then cooled to 0° C. and treated successively with H2O (25 ml), 5N NaOH (25 ml), H2O (75 ml). Reaction mixture was stirred at room temperature for 30 min. and Na2SO4 was added. After filtration, evaporation of the solvent provided (1RS,6RS,8aSR)-1-(4-benzyloxy-phenyl)-6-phenethyl-hexahydro-pyrrolo[2,1-c][1,4]oxazine (90 mg, 78%) as a colorless oil. MS: m/e=414.5 (M+H+). Following the general method of example 40 the compound of example 41 was prepared.