Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]([NH:11][CH2:12][CH:13]([OH:16])[CH2:14][OH:15])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[C:18]1([CH:17]2[N:11]([CH:9]([CH3:10])[CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH:13]([CH2:14][OH:15])[O:16]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(CCc1ccccc1)NCC(O)CO
Reactant: O=Cc1ccccc1
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(CCc1ccccc1)N1CC(CO)OC1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of 94 (24 g, 0.108 mol), toluene, benzaldehyde (40 ml) and benzoic acid (0.5 g) was heated at reflux with a Dean-Stark trap. After 1 hour, the theoretical amount of H2O was collected, the reaction cooled to room temperature and saturated Na2CO3 added. The aqueous layer was separated and washed with CHCl3 (3×). The combined extracts were dried, filtered and concentrated to dryness to yield 34 g (100%) of 95.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:34])[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)=[CH:24][CH:23]=3)[CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.ClC1C=CC=C(C(OO)=[O:43])C=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:22]3[CH:23]=[CH:24][C:25]([C:28]4[CH:33]=[CH:32][N+:31]([O-:43])=[CH:30][CH:29]=4)=[CH:26][CH:27]=3)=[O:34])[CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: O=C(c1ccc(-c2ccncc2)cc1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(c1ccc(-c2cc[n+]([O-])cc2)cc1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a solution of 1-(6-chloronaphthalene-2-sulfonyl)-4-[4-(4-pyridyl)benzoyl]piperazine (200 mg) in dichloromethane (25 ml) was added m-chloroperbenzoic acid (140 mg) and the solution was stirred at room temperature for 2 hours. The reaction solution was diluted with dichloromethane, washed with 1 N sodium hydroxide solution and sodium chloride solution, dried and concentrated. The residue was crystallized with dichloromethane/hexane to give a colorless solid of the title compound (188 mg).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH:17]([OH:19])[CH3:18])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:20]([NH2:22])=[O:21].[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](Cl)=O)=[CH:26][CH:25]=1>>[OH:19][CH:17]([CH:7]([N:6]1[C:2]2[N:1]=[C:31]([CH2:30][C:27]3[CH:28]=[CH:29][C:24]([CH3:23])=[CH:25][CH:26]=3)[NH:22][C:20](=[O:21])[C:3]=2[CH:4]=[N:5]1)[CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:18]
Reactant: Cc1ccc(CC(=O)Cl)cc1
Reactant: CC(O)C(CCCc1ccccc1)n1ncc(C(N)=O)c1N
Product: Cc1ccc(Cc2nc3c(cnn3C(CCCc3ccccc3)C(C)O)c(=O)[nH]2)cc1

Procedure:
Starting from 400 g (1.32 mmol) of 5-amino-1-[1-(1-hydroxy-ethyl)-4-phenyl-butyl]-1H-pyrazole-4-carboxamide and 578 mg (3.44 mmol) of 4-methylphenylacetylchloride, the title compound is prepared analogously to the protocol of Example 13. This gives 117 mg (21%) of the diastereomer which elutes more rapidly, M.p.: 133° C., and 75 mg (13.6%) of the diastereomer which elutes more slowly, M.p.: 136° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[CH:13])[CH:10]=2)[S:5][CH2:4][CH2:3]1.Br[C:16]1[O:20][C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:18][CH:17]=1>>[CH2:24]([O:23][C:21]([C:19]1[O:20][C:16]([C:13]#[C:12][C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[S:5][CH2:4][CH2:3][C:2]3([CH3:14])[CH3:1])=[CH:17][CH:18]=1)=[O:22])[CH3:25]
Reactant: CCOC(=O)c1ccc(Br)o1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCS2
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCS3)o1

Procedure:
Again using the general procedure of Example 11, but using instead 4,4-dimethyl-6-ethynylthiochroman and ethyl 5-bromo-2-furate, the title compound was synthesized.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:28]=[CH:27][C:26]([CH:29]([CH3:33])[C:30](O)=[O:31])=[CH:25][CH:24]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[O:36]1[CH2:40][CH2:39][CH2:38][C@H:37]1[CH2:41][NH2:42]>>[O:36]1[CH2:40][CH2:39][CH2:38][C@H:37]1[CH2:41][NH:42][C:30](=[O:31])[CH:29]([C:26]1[CH:25]=[CH:24][C:23]([C:21]2[CH:20]=[N:19][N:18]3[C:14]([C:10]4[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:35])([F:34])[F:1])=[O:6])[CH:9]=4)=[CH:15][N:16]=[C:17]3[CH:22]=2)=[CH:28][CH:27]=1)[CH3:33]
Reactant: NC[C@@H]1CCCO1
Reactant: CC(C(=O)O)c1ccc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cc1
Product: CC(C(=O)NC[C@@H]1CCCO1)c1ccc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cc1

Procedure:
This compound was prepared by using procedure analogous to those described for the synthesis of Example 98, Step 9 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}phenyl)propanoic acid and 1-[(25)-tetrahydrofuran-2-yl]methanamine. LCMS (M+H)+: m/z=567.3
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:31])OC3C=CC=CC=3)=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:7]=1)[CH3:2].[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([NH2:42])(=[O:41])=[O:40])=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([S:39]([NH:42][C:23]([NH:22][CH2:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([N:4]3[CH:5]=[C:6]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=4)[N:7]=[C:3]3[CH2:1][CH3:2])=[CH:15][CH:16]=2)=[O:31])(=[O:40])=[O:41])=[CH:37][CH:38]=1
Reactant: CCc1nc(-c2ccccn2)cn1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Product: CCc1nc(-c2ccccn2)cn1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from phenyl 2-{4-[2-ethyl-4-(2-pyridinyl)-1H-imidazol-1-yl]phenyl}ethylcarbamate and 4-chlorobenzenesulfonamide. MS (ESI) m/z 510 [M+H]+, 508 [M−H]−, 1H-NMR (CDCl3) □1.17 (3H, t, J=7.3 Hz), 2.65 (2H, q, J=7.7 Hz), 2.80-2.88 (2H, m), 3.42-3.55 (2H, m), 6.78 (1H, br), 7.15-7.28 (4H, m),7.42 (2H, d, J=8.4 Hz), 7.58 (1H, s), 7.71 (1H, t, J=6.0 Hz), 7.80-7.89 (3H, m), 8.51 (1H, d, J=6.0 Hz).
Reaction SMILES: [C:1]1([C:7](=[N:9][OH:10])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][O:12][C:13]([C:15]1([CH3:26])[O:20][CH2:19][CH:18]([CH2:21][CH2:22][CH2:23][CH2:24]Cl)[CH2:17][O:16]1)=[O:14].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:11][O:12][C:13]([C:15]1([CH3:26])[O:16][CH2:17][CH:18]([CH2:21][CH2:22][CH2:23][CH2:24][O:10][N:9]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])[CH2:19][O:20]1)=[O:14]
Reactant: CC(=NO)c1ccccc1
Reactant: COC(=O)C1(C)OCC(CCCCCl)CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)C1(C)OCC(CCCCON=C(C)c2ccccc2)CO1
Temperature: 60 °C
Reaction time: 18 h
Yield: 85.6 %

Procedure:
A mixture of 1-Phenyl-ethanone oxime (1.13 g), Methyl-5-(4-chloro-butyl)-2-methyl-[1,3]dioxane-2-carboxylate (prepared by processes known) (2.5 g) and cesium carbonate (4.0 g) in anhydrous dimethyl formamide was stirred at 60° C. for 18 hours in an inert atmosphere. The reaction mixture was cooled to ambient temperature, poured into ice cold water and extracted with ethyl-acetate. The combined organic extract was washed with water, brine solution, dried over sodium sulphate and evaporated under reduced pressure. Crude product was flash chromatographed over silica gel using 7% ethyl acetate in petroleum ether as eluent to obtain 2.5 g of pure product.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:12][C:13](N)=[O:14]>O>[Br:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:2]=1[NH:1][C:13](=[O:14])[NH:12][C:4]2=[O:5]
Reactant: NC(N)=O
Reactant: Nc1c(Br)cccc1C(=O)O
Solvent: O
Product: O=c1[nH]c(=O)c2cccc(Br)c2[nH]1
Temperature: 195 °C
Reaction time: 3 h
Yield: 95.7 %

Procedure:
To a 100 mL round bottom flask, 2-amino-3-bromo-benzoic acid (5 g, 0.0234 mol) and urea (7.33 g, 0.122 mol) were added. The reaction mixture was stirred at 195° C. for 3 h. The reaction mixture was allowed to reach 80° C. and water was added. The aqueous reaction mixture was stirred for 5-10 min and filtered to afford the title compound [5.4 g, 97%]. This material was taken to the next step without any further purification.
Reaction SMILES: [OH:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[C:29]([F:41])=[CH:30][C:31]([F:40])=[C:32]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:33]=2)[CH2:24][CH2:23]1>>[F:40][C:31]1[CH:30]=[C:29]([F:41])[C:28]([CH:25]2[CH2:24][CH2:23][N:22]([CH2:21][CH2:20][CH2:19][NH:18][C:3](=[O:5])[C:2]([OH:1])([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:27][CH2:26]2)=[CH:33][C:32]=1[NH:34][C:35](=[O:39])[CH:36]([CH3:37])[CH3:38]
Reactant: O=C(O)C(O)(c1ccccc1)c1ccccc1
Reactant: CC(C)C(=O)Nc1cc(C2CCN(CCCN)CC2)c(F)cc1F
Product: CC(C)C(=O)Nc1cc(C2CCN(CCCNC(=O)C(O)(c3ccccc3)c3ccccc3)CC2)c(F)cc1F

Procedure:
Example 155 was prepared from hydroxy(diphenyl)acetic acid and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2,4-difluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 12: 1H NMR (400 MHz, CDCl3) δ 8.96 (s, 1 H), 8.39 (t, 1 H, J=8.4 Hz), 7.62–7.45 (m, 4 H), 7.38–7.18 (m, 7 H), 6.85–6.74 (m, 1 H), 5.43–5.14 (br, 1 H), 3.59–3.39 (m, 2 H), 3.11–2.97 (m, 2 H), 2.97–2.79 (m, 1 H), 2.59–2.45 (m, 2 H), 2.45–2.29 (m, 1 H), 2.14–1.86 (m, 4 H), 1.81–1.56 (m, 4 H), 1.01 (d, 6 H, J=7.2 Hz); ESMS m/e: 550.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=2[Cl:15])[CH2:5][C:4](=[O:16])[CH:3]=1.[OH-].[K+]>C(O)C.C1(C)C=CC=CC=1>[Cl:15][C:9]1[C:10]([Cl:14])=[CH:11][CH:12]=[CH:13][C:8]=1[CH:6]1[CH2:7][C:2]2[N:1]=[CH:7][CH:2]=[C:3]([CH3:4])[C:3]=2[C:4](=[O:16])[CH2:5]1
Reactant: NC1=CC(=O)CC(c2cccc(Cl)c2Cl)C1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccnc2c1C(=O)CC(c1cccc(Cl)c1Cl)C2
Temperature: 115 °C
Yield: 117.1 %

Procedure:
In a mixture of ethanol (30 ml) and toluene (90 ml) was dissolved 1-amino-5-(2, 3-dichlorophenyl)cyclohexen-3-one (1.5 g), and to the solution were added 3-oxobutylaldehydedimethylacetal (2 g) and granulated potassium hydroxide (330 mg). The mixture was stirred at 115° C. (bath temperature), and to the mixture was added granulated potassium hydroxide (70 mg), 30 minutes later; 1 hour later; and 1.5 hours, respectively. The reaction solution was stirred at the same temperature for 1 hour, cooled and concentrated under reduced pressure, and to the residue were added ethyl acetate (50 ml) and water (20 ml). The mixture was shaken and separated ethyl acetate layer was washed with brine. Under reduced pressure, ethyl acetate was evaporated, and the residue was purified with silica gel column chromatography (EtOAc/hexane) and eluted with ethyl acetate/hexane to give 7-(2,3-dichlorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (1.05 g) as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:6][N:7]([C:30]1[N:35]=[CH:34][C:33](Br)=[CH:32][N:31]=1)[CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=1[O:28][CH3:29].CS(C)=[O:48]>>[F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:6][N:7]([CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=1[O:28][CH3:29])[C:30]1[N:35]=[CH:34][C:33]([OH:48])=[CH:32][N:31]=1
Reactant: CS(C)=O
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(O)cn1
Temperature: 80 °C
Reaction time: 0.75 h

Procedure:
(3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amine (1.06 g) is dissolved in dimethylsulfoxide (5 ml), and the mixture is degassed and thereto are added [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloride (61 mg), potassium acetate (442 mg) and bis(pinacolato)diboron (571 mg). The mixture is degassed and heated to 80° C. under nitrogen flow and stirred for 45 minutes. The reaction solution is allowed to cool to room temperature, and thereto is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed twice with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is dissolved in tetrahydrofuran (5 ml), and thereto is added dropwise a 30% aqueous hydrogen peroxide solution (1.5 ml) under ice-cooling and stirred at the same temperature for 1 hour and a half. To the reaction mixture is added dropwise saturated aqueous sodium thiosulfate solution under ice-cooling, and thereto is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=4:1→3:1) to give 2-[(3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-ol (866 mg). MS (m/z): 644 [M+H]+
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][C:6]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)([CH3:22])[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)=[O:8].[Br:29][C:30]([CH3:35])([CH3:34])[C:31](Br)=[O:32]>ClCCl>[Br:29][C:30]([CH3:35])([CH3:34])[C:31]([C:19]1[CH:20]=[CH:21][C:16]([O:15][C:12]2[CH:13]=[CH:14][C:9]([C:7](=[O:8])[C:6]([CH3:5])([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[CH3:22])=[CH:10][CH:11]=2)=[CH:17][CH:18]=1)=[O:32]
Reactant: CC(C)(Br)C(=O)Br
Reactant: CC(C)(C(=O)c1ccc(Oc2ccccc2)cc1)N1CCOCC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(Br)C(=O)c1ccc(Oc2ccc(C(=O)C(C)(C)N3CCOCC3)cc2)cc1
Yield: 100 %

Procedure:
21.59 (0.162 mol) of AlCl3 were added in portion to a solution of 12 g (0.0369 mol) of 2-methyl-2-morpholin-yl-1-(4-phenoxy-phenyl)-propan-1-one and 9.57 g of (0.0406 mol) of α-bromoisobutyrylbromide (97.5% w/w) in 240 ml of dichloromethane, between 0 and 5° C. under stirring. At the end of the addition the temperature was brought to 25° C. then after 2.5 h the reaction was quenched with 500 ml of water and ice. The organic phase was separated and washed with water and 5% NaOH, dried on sodium sulphate, filtered and evaporated obtaining 17.5 g of a reddish oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([C:11]2([CH3:17])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:7][C:4]=1[CH:5]=[O:6].F[B-](F)(F)F.[O:23]=[N+:24]=[O:25].O>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:10]([N+:24]([O-:25])=[O:23])=[CH:9][C:8]([C:11]2([CH3:17])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:7][C:4]=1[CH:5]=[O:6]
Reactant: COc1ccc(C2(C)CCOCC2)cc1C=O
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Product: COc1c(C=O)cc(C2(C)CCOCC2)cc1[N+](=O)[O-]
Temperature: -40 °C
Reaction time: 2 h
Yield: 75.1 %

Procedure:
A solution of the crude product containing 2-methoxy-5-(4-methyltetrahydro-2H-pyran-4-yl)benzaldehyde (0.719 g) in ethyl acetate (10.0 mL) was cooled to −40° C., and nitronium tetrafluoroborate (0.597 g, 4.49 mmol) was added thereto. The resulting mixture was stirred for 2 hours while raising the temperature to −10° C. Water was added to the reaction solution and the resulting solution was diluted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was then evaporated under reduced pressure, and the obtained residue was purified by column chromatography (silica gel, hexane/ethyl acetate=90/10-30/70) to obtain 0.644 g of the captioned compound (92% yield in 2 steps).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Br:23]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:23])[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCCCNc1nc(N)c2ncn(Cc3ccccc3)c2n1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCNc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
6-Amino-9-benzyl-2-butylaminopurine (101 mg, 0.34 mmol) and bromine (0.5 ml) were dissolved in 50 ml of methylene chloride and the solution was stirred at room temperature for 1 hour. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on sodium sulfate and filtered. The solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (116 mg, yield 91%).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[CH3:13][CH:14]([NH2:17])[CH2:15][CH3:16]>>[CH:14]([NH:17][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1)([CH2:15][CH3:16])[CH3:13]
Reactant: CCC(C)N
Reactant: CSc1nc(Cl)c(C=O)c(Cl)n1
Product: CCC(C)Nc1nc(SC)nc(Cl)c1C=O

Procedure:
Prepared as described above in Example 2 starting from 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde and 2-butylamine to give the title compound 4-sec-butylamino-6-chloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: δ 0.87 (m, 3H), 1.18 (m, 3H), 1.20 (m, 2H), 2.51 (s, 3H), 4.24 (m, 1H), 9.12 (br s, 1H), 10.18 (s, 1H). LC MS (m/e)=260 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[N+:21]([O-])=O)[CH:9]=2)[CH:4]=1>O1CCCC1.CO.[Pd]>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]=2)=[C:14]([NH2:21])[CH:15]=1
Reactant: COc1ccc(-c2ccc3cc(OC)ccc3c2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2ccc3cc(OC)ccc3c2)c(N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
To a solution of 2-methoxy-6-(4-methoxy-2-nitrophenyl)naphthalene (390 mg) in tetrahydrofuran (6 ml) and methanol (6 ml) was added 10% palladium-activated charcoal (100 mg), and the solution was stirred overnight at room temperature under a hydrogen atmosphere at ambient pressure. After filtration through celite pad, the solvent was evaporated in vacuo, and the resulting solid was washed with a hexane-diethyl ether system to provide the title compound (285 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][O:7][C:8]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:9]=1[CH2:10][N:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([O:22]C)=[O:21])=[CH:16][N:15]=1)[CH2:12][CH3:13].[OH-].[Na+]>CO>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][O:7][C:8]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:9]=1[CH2:10][N:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][N:15]=1)[CH2:12][CH3:13]
Reactant: CCN(Cc1cc(Br)ccc1OCc1cccs1)c1ccc(C(=O)OC)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCN(Cc1cc(Br)ccc1OCc1cccs1)c1ccc(C(=O)O)cn1
Yield: 79.7 %

Procedure:
A solution of methyl 2-[N-(2-(2-thienylmethoxy)-5-bromobenzyl)-N-ethylamino]pyridine-5-carboxylate (0.53 g, 1.15 mmol) in methanol (25 mL) was treated with aqueous sodium hydroxide (2N, 5 mL). The reaction was heated to reflux for 9 hours. The reaction mixture was cooled and evaporated and residue was diluted with water and acidified with acetic acid. The off-white solid was filtered off to give 2-[N-(2-(2-thienylmethoxy)-5-bromobenzyl)-N-ethylamino]pyridine-5-carboxylic acid (0.41 g, 91%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]1([CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]1)[O:6][CH2:5]2.[Li]CCCC.CN([CH:29]=[O:30])C>C1COCC1>[CH:29]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]1([CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]1)[O:6][CH2:5]2)=[O:30]
Reactant: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(Br)ccc12
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C=O)ccc12
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 88.2 %

Procedure:
To a stirred solution of tert-butyl 5′-bromo-3′H-spiro[azetidine-3,1-isobenzofuran]-1-carboxylate (Intermediate 1, 2 g, 5.879 mmol, 1 eq) in dry THF (40 mL) was added n-BuLi (6.42 mL, 7.054 mmol, 1.2 eq) at −78° C. under nitrogen atmosphere. Reaction mixture was stirred for 10 minutes at −78° C. under nitrogen atmosphere. At −78° C., DMF (0.678 mL, 8.818 mmol, 1.5 eq) was added in drop wise manner over period of 10 minutes. Resulting reaction mixture was allowed to warm to −20° C. and stirred for 3 hours under nitrogen atmosphere. After complete consumption of starting material, reaction was quenched with 10% NH4Cl solution (5 mL) followed by water (70 mL) and extracted with ethyl acetate (3×30 mL). Combined organic phase was washed with brine solution (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford title compound as pale yellow thick oil (1.5 g, crude). Crude compound was used as such for next reaction. (m/z): 290.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH2:13][C:14]([O:16]C)=O)[C:6]2=[N:11]O.[H][H]>CO.C(O)(=O)C.[Pt]=O>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]1[CH2:13][C:14](=[O:16])[NH:11][CH:6]12
Reactant: COC(=O)CC1Cc2c(Cl)cccc2C1=NO
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CC(=O)O
Solvent: CO
Product: O=C1CC2Cc3c(Cl)cccc3C2N1
Yield: 40.7 %

Procedure:
Methyl 4-chloro-1-hydroxyimino-2,3-dihydro-inden-2-acetate (15 g) is hydrogenated at 40 atm of hydrogen in 200 ml of methanol plus 50 ml of acetic acid in the presence of 1.5 g of platinum oxide catalyst at 30°-50° C. for 7 hours. The catalyst is then filtered off, and the filtrate is concentrated. The residual oil is extracted with chloroform. The extract is washed with aqueous potassium carbonate solution, then with water and dried over sodium sulfate, and the solvent is distilled off. The residue is heated on an oil bath at 110°-120° C. for 2 hours. After cooling, ether is added, and the precipitated crystals are collected by filtration and recrystallized from ether to give 5 g of 5-chloro-1,2,3,3a,4,8b-hexahydro-indeno[1,2-b]pyrrol-2-one, melting at 186°-187° C.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[H-].[Na+].[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1>CN(C=O)C>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]([CH2:21][C:20]3[CH:23]=[CH:24][C:17]([F:16])=[CH:18][CH:19]=3)[C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1oc(=O)n(Cc2ccc(F)cc2)c2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
A solution of Compound 58 (5 g, 25 mmol) in DMF was added slowly to a suspension of NaH (60% in mineral oil, 1.24 g, 31 mmol) in DMF and further stirred at room temperature for 1 h. Then, neat 4-fluorobenzyl bromide (3.81 mL, 31 mmol) was added and the solution further stirred at room temperature for 3 h. The solution was poured into ice water and the solids formed were filtered, washed several times by water, and dried. The solids were suspended in hexane, sonicated briefly, filtered, and washed by hexane to yield 7.3 g (96%) of white solids. 1H NMR (DMSO-d6): δ 5.45 (s, 2H), 7.14–7.17 (m, 3H), 7.44 (m, 2H), 7.64 (dd, J=1.7, 8.2 Hz, 1H), 7.80 (d, J=1.2 Hz, 1H).