Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][CH2:14][CH2:13][C:12]=3[CH:16]=2)=[N:6][N:7]=1.[F:17][C:18]1[CH:19]=[C:20]([SH:24])[CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[O:15]1[C:11]2[CH:10]=[CH:9][C:8]([C:5]3[O:4][C:3]([CH2:2][S:24][C:20]4[CH:21]=[CH:22][CH:23]=[C:18]([F:17])[CH:19]=4)=[N:7][N:6]=3)=[CH:16][C:12]=2[CH2:13][CH2:14]1
Reactant: Fc1cccc(S)c1
Reactant: ClCc1nnc(-c2ccc3c(c2)CCO3)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1cccc(SCc2nnc(-c3ccc4c(c3)CCO4)o2)c1
Yield: 14.3 %

Procedure:
A solution of 2-(chloromethyl)-5-(2,3-dihydro-1-benzofuran-5-yl)-1,3,4-oxadiazole (0.16 g, 0.68 mmol), 3-fluorothiophenol (57 μL, 0.68 mmol) and potassium carbonate (0.10 g, 0.75 mmol) in N,N-dimethylformamide (5 mL) was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) and recrystallized from hexane/ethyl acetate to give the title compound (32 mg, yield 14%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:19][CH:18]3[CH:14]([CH2:15][N:16]([CH3:20])[CH2:17]3)[CH2:13]2)=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[OH-].[Li+].[CH2:23](OC(OCC)OCC)C>CO>[CH3:7][N:6]1[C:4](=[O:5])[C:3]2[C:2](=[CH:11][CH:10]=[C:9]([N:12]3[CH2:13][CH:14]4[CH:18]([CH2:17][N:16]([CH3:20])[CH2:15]4)[CH2:19]3)[CH:8]=2)[N:1]=[CH:23]1
Reactant: CCOC(OCC)OCC
Reactant: CNC(=O)c1cc(N2CC3CN(C)CC3C2)ccc1N
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CN1CC2CN(c3ccc4ncn(C)c(=O)c4c3)CC2C1
Temperature: 160 °C
Reaction time: 8 h

Procedure:
2-Amino-N-methyl-5-(5-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)benzamide (Intermediate 8A) (100 mg, 0.36 mmol) was dissolved in triethoxymethane (1 mL) and sealed in a microwave vial. Heated at 160° C. for 10 minutes. Reaction allowed to cool to room temperature and lithium hydroxide solution added (0.5 mL, 1M in methanol) and reaction stirred overnight. Organic layer loaded onto a 1 g SCX cartridge. The crude material was purified by SCX, and the solvent removed under reduced pressure. The crude material was then re-dissolved in methanol (1 mL) and purified by preparative-HPLC. Purified sample was free-based using 500 mg SCX cartridge to afford 3-methyl-6-(5-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)quinazolin-4(3H)-one (56 mg, 0.2 mmol).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[CH:4][CH:3]=1.[CH2:13]([O:15][C:16](=[O:19])[CH2:17][SH:18])[CH3:14].[H-].[Na+]>CN(C=O)C>[CH2:13]([O:15][C:16]([C:17]1[S:18][C:2]2[CH:3]=[CH:4][N:5]=[CH:6][C:7]=2[C:8]=1[OH:10])=[O:19])[CH3:14]
Reactant: CCOC(=O)CS
Reactant: CCOC(=O)c1cnccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc2ccncc2c1O
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
To a cooled (5° C.) stirred solution of ethyl 4-chloro-nicotinate (1.55 g, 8.4 mmol) and mercapto-acetic acid ethyl ester (2.6 ml, 23.4 mmol) in anhydrous DMF (30 ml), under an argon atmosphere, was added sodium hydride (21.7 mmol; 60% dispersion in oil, 868 mg) in portions over 20 minutes. Stirring was continued at 5° C. for 10 minutes, followed by 1.5 hours at room temperature. The reaction mixture was then quenched by the addition of water (5 ml), acidified by the addition of acetic acid (1 ml), and subsequently concentrated to provide a residue. The residue was partitioned between ethyl acetate (150 ml) and water (100 ml). The layers were separated and aqueous phase was extracted with DCM (100 ml). The combined organic phase was dried over sodium sulphate, filtered and evaporated to give a solid. The solid was triturated with diethyl ether:pentane (1:1, 15 ml) to afford the title compound as a yellow solid (1.5 g, 81%). LCMS (method B): RT=2.21 min, M+H+=224.
Reaction SMILES: [CH2:1]([C:4]1[C:13]([CH3:14])=[C:12]2[C:7]([C:8]([CH3:17])([CH3:16])[CH2:9][C:10](=[O:15])[O:11]2)=[C:6]([CH3:18])[C:5]=1[OH:19])[CH:2]=[CH2:3].CCN(C(C)C)C(C)C.[CH3:29][O:30][CH2:31]Cl>C(Cl)Cl>[CH2:1]([C:4]1[C:13]([CH3:14])=[C:12]2[C:7]([C:8]([CH3:16])([CH3:17])[CH2:9][C:10](=[O:15])[O:11]2)=[C:6]([CH3:18])[C:5]=1[O:19][CH2:29][O:30][CH3:31])[CH:2]=[CH2:3]
Reactant: C=CCc1c(C)c2c(c(C)c1O)C(C)(C)CC(=O)O2
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCc1c(C)c2c(c(C)c1OCOC)C(C)(C)CC(=O)O2
Yield: 89.4 %

Procedure:
Compound C (8.26 g, 31.65 mmol) and DIPEA (57.2 mL, 317.7 mmol) were dissolved in 160 mL of methylene chloride. The mixture was cooled in an ice-water bath and stirred under N2. Methoxymethyl chloride (12.2 mL, 159 mmol) was added dropwise. After the addition, the mixture was stirred at room temperature under N2 overnight. The mixture was diluted with 140 mL of methylene chloride and washed with 10% HCl solution (2×50 mL) and water (3×50 mL) and dried over MgSO4. Filtration and solvent evaporation gave a yellow residue, which was purified on a silica gel column (hexanes and ethyl acetate, 3/1, v/v) to give 8.61 g (87%) of a solid product. 1H NMR (CDCl3) δ5.96 (m, 1H), 5.07-4.95 (m, 2H), 4.90 (s, 2H), 3.63 (s, 3H), 3.47 (d, J=5.7 Hz, 2H), 2.58 (s, 2H), 2.40 (s, 3H), 2.22 (s, 3H), 1.47 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.[NH2:10][C:11]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:12]=1[C:13]([NH2:15])=[O:14]>>[NH2:15][C:13]([C:12]1[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:11]=1[NH:10][C:7]([C:5]1[N:6]=[C:2]([Br:1])[S:3][CH:4]=1)=[O:9])=[O:14]
Reactant: O=C(O)c1csc(Br)n1
Reactant: Cc1ccc(C(N)=O)c(N)c1
Product: Cc1ccc(C(N)=O)c(NC(=O)c2csc(Br)n2)c1

Procedure:
2-Bromo-4-thiazolecarboxylic acid and 2-amino-4-methylbenzamide are reacted in analogy to the synthesis of intermediate VI.1 to give N-[2-(aminocarbonyl)-5-methylphenyl]-2-bromo-4-thiazolecarboxamide.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:5]=[N:6][C:7]([CH2:13][S+:14]([O-:26])[C:15]2[NH:16][C:17]3[CH:18]=[CH:19][C:20]([O:24][CH3:25])=[CH:21][C:22]=3[N:23]=2)=[C:8]([CH3:12])[C:9]=1[O:10][CH3:11].C1(C(C2C=CC=CC=2)(O)[C@H](C2C=CC=CC=2)O)C=CC=CC=1.C(O)(=O)C>C(O)C>[CH3:3][C:4]1[C:9]([O:10][CH3:11])=[C:8]([CH3:12])[C:7]([CH2:13][S@@:14]([C:15]2[NH:23][C:22]3[CH:21]=[C:20]([O:24][CH3:25])[CH:19]=[CH:18][C:17]=3[N:16]=2)=[O:26])=[N:6][CH:5]=1
Reactant: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Agent: O[C@@H](c1ccccc1)C(O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc2nc([S@@](=O)Cc3ncc(C)c(OC)c3C)[nH]c2c1
Reaction time: 4 h

Procedure:
To aqueous sodium hydroxide (2.03 ml, 1.5 M, 3.04 mmol) at ambient temperature was added omeprazole (1 g, 2.90 mmol) in 5 portions over 10 min. On complete dissolution, ethanol (35 ml) and (S)-1,1,2-triphenyl-1,2-ethanediol (1.26 g, 4.34 mmol) were added. To the resulting colourless solution at ambient temperature was added a solution of aqueous acetic acid (3.04 ml, 1 M, 3.04 mmol) dropwise over 1 h and, on complete addition, stirring was continued for 4 h. The solid was filtered, was washed with ethanol (3×15 ml) and was dried in vacuo to afford (S)-omeprazole.2[(S)-1,1,2-triphenyl-1,2-ethanediol] (925 mg, 69%, 96.4% ee) as a white powder.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([CH2:8]Cl)=[O:7])(=[O:3])[CH3:2].[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([SH:17])=[CH:13][CH:12]=1.C(N(CC)CC)C>COC(C)(C)C>[C:1]([O:4][CH2:5][C:6]([CH2:8][S:17][C:14]1[CH:15]=[CH:16][C:11]([CH3:10])=[CH:12][CH:13]=1)=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)CCl
Reactant: Cc1ccc(S)cc1
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: CC(=O)OCC(=O)CSc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
To a solution of 1-acetoxy-3-chloroacetone (5.0 g, 33.2 mmol) and 4-methylthiophenol (4.12 g, 33.2 mmol) in tert-butyl methyl ether (100 ml) was slowly added triethylamine (5.1 ml, 36.6 mmol) under ice-cooling. The solution was stirred at room temperature for 30 minutes. The reaction solution was washed with water, saturated aqueous sodium hydrogen carbonate solution, then saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3) to give 7.72 g of 1-acetoxy-3-(4-methylphenylthio)acetone (yield: 97%) as oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:18][C@H:19]1[CH2:24][O:23][CH2:22][CH2:21][NH:20]1>CC(O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][C@@H:19]2[CH3:18])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: C[C@H]1COCCN1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1COCCN1c1ccnc(Cl)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a solution of 2,4-dichloropyrimidine (5.00 g, 0.034 mol) and DIPEA (8.00 mL, 0.046 mol) in 2-propanol (60 mL) at 0° C. was added (S)-3-methylmorpholine (3.73 g, 0.037 mol) dropwise. The reaction mixture was stirred at 0° C. for 30 min and then allowed to warm to RT and stirred for a further 16 h. Solvent was removed in vacuo and the residue was then partitioned between water and EtOAc. The phases were separated and the organic layer washed with brine, dried over magnesium sulfate, filtered and the solvent removed in vacuo to yield a yellow oil (6.54 g, 91%).
Reaction SMILES: [CH2:1]([C:3]1C=C(C=C(C)C=1O)C=O)[CH3:2].C(C1C=CC=C(C)C=1O)C.[CH2:23]([C:25]1[CH:26]=[C:27]([CH:32]=[C:33]([CH3:36])[C:34]=1[OH:35])[C:28]([NH:30][OH:31])=[NH:29])[CH3:24]>>[CH2:3]([O:35][C:34]1[C:33]([CH3:36])=[CH:32][C:27]([C:28]([NH:30][OH:31])=[NH:29])=[CH:26][C:25]=1[CH2:23][CH3:24])[CH:1]=[CH2:2]
Reactant: CCc1cc(C(=N)NO)cc(C)c1O
Reactant: CCc1cc(C=O)cc(C)c1O
Agent: CCc1cccc(C)c1O
Product: C=CCOc1c(C)cc(C(=N)NO)cc1CC

Procedure:
The title compound is prepared by allylating 3-ethyl-4-hydroxy-5-methyl-benzaldehyde which is prepared from 2-ethyl-6-methyl-phenol following literature procedures (see 3-ethyl-4,N-dihydroxy-5-methyl-benzamidine). The aldehyde is then transformed into the corresponding hydroxyamidine according to literature procedures (see 3-ethyl-4,N-dihydroxy-5-methyl-benzamidine); LC-MS: tR=0.72 min; [M+1]+=235.09; 1H NMR (CD3OD): δ 7.31 (s, 1H), 7.29 (s, 1H), 6.10 (m, 1H), 5.43 (dd, J=17.0, 1.5 Hz, 1H), 5.27 (dd, J=10.3, 1.2 Hz, 1H), 4.81 (s br, 3H), 4.31 (d, J=5.6 Hz, 2H), 2.67 (q, J=7.6 Hz, 2H), 2.30 (s, 3H), 1.23 (t, J=7.6 Hz, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(N)(=[S:12])C.Cl>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]([NH2:7])=[S:12])=[CH:4][CH:3]=1
Reactant: CC(N)=S
Reactant: N#Cc1ccc(Cl)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: NC(=S)c1ccc(Cl)cc1
Yield: 70.4 %

Procedure:
A mixture of 55.03 g of 4-chlorobenzonitrile, 75.13 g of thioacetamide and 600 ml of dimethylformamide was saturated with dry hydrogen chloride gas while being chilled in an ice bath. The mixture was then distilled slowly on an oil bath at 100° C. When the liquid had been removed, aqueous sodium bicarbonate was added. The solid was collected and recrystallized from toluene, giving 48.35 g of 4-chlorothiobenzamide as yellow crystals.
Reaction SMILES: [F:1][CH:2]([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH2:12][N:13]([CH3:15])[CH3:14])[CH:11]=1)[C:6]([OH:8])=O.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[NH:48]1[CH2:53][CH2:52][CH:51]([N:54]2[CH2:57][C:56]([CH2:80][C:81]#[N:82])([N:58]3[CH:62]=[C:61]([C:63]4[C:64]5[CH:71]=[CH:70][N:69](COCC[Si](C)(C)C)[C:65]=5[N:66]=[CH:67][N:68]=4)[CH:60]=[N:59]3)[CH2:55]2)[CH2:50][CH2:49]1>O1CCCC1>[F:16][CH:2]([F:1])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH2:12][N:13]([CH3:15])[CH3:14])[CH:11]=1)[C:6]([N:48]1[CH2:49][CH2:50][CH:51]([N:54]2[CH2:55][C:56]([CH2:80][C:81]#[N:82])([N:58]3[CH:62]=[C:61]([C:63]4[C:64]5[CH:71]=[CH:70][NH:69][C:65]=5[N:66]=[CH:67][N:68]=4)[CH:60]=[N:59]3)[CH2:57]2)[CH2:52][CH2:53]1)=[O:8]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCNCC5)C4)c3)ncnc21
Reactant: CN(C)Cc1cc(C(=O)O)cc(C(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)Cc1cc(C(=O)N2CCC(N3CC(CC#N)(n4cc(-c5ncnc6[nH]ccc56)cn4)C3)CC2)cc(C(F)F)c1
Reaction time: 0.25 h

Procedure:
A mixture of 3-(difluoromethyl)-5-[(dimethylamino)methyl]benzoic acid (14.0 mg, 0.0609 mmol, from Step D), Triethylamine (28.3 μL, 0.203 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (21.2 mg, 0.0558 mmol) in tetrahydrofuran (0.56 mL) was stirred for 15 minutes. {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (25.0 mg, 0.0507 mmol, prepared as described in Example 1, Step H, except worked up to provide the free base) was added and the reaction was stirred for two hours. The reaction mixture was partitioned between ethyl acetate and water. The organic portion was washed with water, 0.1N NaOH and sat. NaCl, dried over sodium sulfate, filtered and concentrated. The residue was stirred in 1:1 DCM:TFA for 1 hour, solvents were removed in vacuo, and the resulting residue stirred in methanol (1 mL) containing ethylenediamine (0.2 mL) until deprotection was complete. Purification via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) afforded product as a white powder. Yield: 0.012 g (40%); LC-MS: 574.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ 12.09 (br s, 1H), 8.82 (s, 1H), 8.69 (s, 1H), 8.42 (s, 1H), 7.61 (d, 1H), 7.56 (s, 1H), 7.46-7.41 (m, 2H), 7.07 (t, 1H), 7.07 (d, 1H), 4.17-4.03 (m, 1H), 3.75 (d, 2H), 3.62-3.25 (m, 7H), 3.22-3.03 (m, 2H), 2.58-2.51 (m, 1H), 2.15 (s, 6H), 1.85-1.55 (m, 2H), 1.33-1.12 (m, 2H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2([NH2:13])[CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:32]([CH:33]3[CH2:35][CH2:34]3)[C:31](=[O:36])[N:30]([CH2:37][C:38](O)=[O:39])[N:29]=2)=[CH:24][CH:23]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O>[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2([NH:13][C:38](=[O:39])[CH2:37][N:30]3[C:31](=[O:36])[N:32]([CH:33]4[CH2:34][CH2:35]4)[C:28]([C:25]4[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=4)=[N:29]3)[CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: NC1(c2cccc(Cl)c2)CCC1
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O)NC1(c2cccc(Cl)c2)CCC1
Reaction time: 0.17 h

Procedure:
57.2 mg (0.262 mmol) of 1-(3-chlorophenyl)cyclobutanamine hydrochloride are placed in 2 ml of dimethylformamide and treated with 26.5 mg (0.262 mmol) of triethylamine. After 10 mins' stirring, 70.0 mg (0.238 mmol) of [3-(4-chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-acetic acid from Example 88A and 38.7 mg (0.286 mmol) of HOBt are added. After a further 10 mins' stirring, the mixture is treated with 59.4 mg (0.310 mmol) of EDC hydrochloride and stirred overnight at room temperature. For the workup, the reaction mixture is partitioned between dichloromethane and water, and the organic phase is separated, dried over sodium sulphate and concentrated. The residue is purified by flash chromatography on silica gel (eluent: dichloromethane/methanol first 200:1, then 100:1) and thus yields 66 mg (61% of theory) of the target compound.
Reaction SMILES: [N+:1]([CH:4]([CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[O:8]1)[CH2:5][CH3:6])([O-:3])=[O:2].[C:17](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:17][O:8][C:9](=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=1[CH:7]=[C:4]([N+:1]([O-:3])=[O:2])[CH2:5][CH3:6]
Reactant: CCC(C1OC(=O)c2ccccc21)[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: CCC(=Cc1ccccc1C(=O)OC)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.9 %

Procedure:
A suspension of 1,3-dihydro-3-(1-nitropropyl)-isobenzofuran-1-one (53 g, described in Example 27), potassium carbonate (64 g) and dimethyl sulfate (45.4 g) in acetone (1.5 l) is stirred at room temperature for 18 hr and filtered. The filtrate is evaporated and the residue is chromatographed on silica gel using hexane-diethyl ether (4:1). The eluates are evaporated to give the title compound (49 g), nmr (CDCl3) δ1.15(t), 2.65(q), 3.94(s), 7.55(m), 8.2(m) and 8.45(s).
Reaction SMILES: [C:1]1([C:7]2[C:16]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:23]([O:25][CH3:26])=[O:24])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[CH3:36][S:37]([N:20]1[CH2:19][CH2:18][N:17]([C:16]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][C:9]3[C:14]([N:15]=2)=[CH:13][C:12]([C:23]([O:25][CH3:26])=[O:24])=[CH:11][CH:10]=3)[CH2:22][CH2:21]1)(=[O:39])=[O:38]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCNCC3)nc2c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCN(S(C)(=O)=O)CC3)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of methyl 2-phenyl-3-(piperazin-1-yl)quinoxaline-6-carboxylate (150 mg, 0.43 mmol, 1.00 equiv), DIEA (3 mL) in DCM (15 mL). This was followed by the addition of methanesulfonyl chloride (0.5 mL) at 0° C. The resulting solution was stirred overnight at room temperature. The reaction was washed by sat. NaCl and concentrated under vacuum. This resulted in 0.17 g (93%) of methyl 3-(4-(methylsulfonyl)piperazin-1-yl)-2-phenylquinoxaline-6-carboxylate as a brown yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:12](O)=[O:13])=[N:9][C:8]([C@@H:15]([NH:17][C:18]1[N:26]=[CH:25][N:24]=[C:23]3[C:19]=1[N:20]=[CH:21][N:22]3[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[CH3:16])=[CH:7]2.CN(C=O)C.C(Cl)(=O)C([Cl:44])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:12]([Cl:44])=[O:13])=[N:9][C:8]([C@@H:15]([NH:17][C:18]1[N:26]=[CH:25][N:24]=[C:23]3[C:19]=1[N:20]=[CH:21][N:22]3[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[CH3:16])=[CH:7]2
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(C(=O)O)n4)ncnc32)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(C(=O)Cl)n4)ncnc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-8-chloro-3-(1-((9-(4-methoxybenzyl)-9H-purin-6-yl)amino)ethyl)isoquinoline-1-carboxylic acid 10 (160 mg, 0.327 mol, 1 eq) and DMF (0.1 mL) in DCM (10 mL), oxalyl chloride (83.1 mg, 0.654 mmol, 2 eq) was added and the resulting mixture was stirred at RT for 1 h. The mixture was concentrated in vacuo to afford the product (S)-8-chloro-3-(1-((9-(4-methoxybenzyl)-9H-purin-6-yl)amino)ethyl) isoquinoline-1-carbonyl chloride 11. The product obtained was used directly in the next step without purification.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:11][O:12]C(Cl)Cl>[Ti](Cl)(Cl)(Cl)Cl>[CH:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[CH2:1][CH2:2][CH2:3][CH2:4]2)=[O:12]
Reactant: COC(Cl)Cl
Reactant: c1ccc2c(c1)CCCC2
Agent: Cl[Ti](Cl)(Cl)Cl
Product: O=Cc1ccc2c(c1)CCCC2

Procedure:
Compound 12 was prepared by an alternate procedure as follows: Tetralin was formylated with dichloromethyl methyl ether and titanium tetrachloride catalyst to give 6-formyltetralin. Reaction of the aldehyde with malonic acid in the presence of an amine catalyst gave the substituted acrylic acid. Catalytic hydrogenation of the double bond gave the corresponding substituted propionic acid, 3-(6-tetralyl)propionic acid. Conversion of the acid to the acid chloride with phosphorus pentachloride followed by cyclization with aluminum chloride gave the desired 2,3,5,6,7,8-hexahydro-1H-benz[f]inden-1-one.
Reaction SMILES: C(O[CH:5]1[O:27][C@H:26]([CH2:28][O:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@:6]1([CH3:38])[O:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)C.[NH2:39][C:40]1[N:45]=[CH:44][N:43]=[C:42]2[NH:46][N:47]=[C:48]([I:49])[C:41]=12.B(F)(F)F.CCOCC>[N+](C)([O-])=O>[NH2:39][C:40]1[N:45]=[CH:44][N:43]=[C:42]2[N:46]([C@@H:5]3[O:27][C@H:26]([CH2:28][O:29][C:30](=[O:37])[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C@@H:16]([O:17][C:18](=[O:25])[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C@@:6]3([CH3:38])[O:7][C:8](=[O:15])[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:47]=[C:48]([I:49])[C:41]=12
Reactant: CC(=O)OC1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@]1(C)OC(=O)c1ccccc1
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: FB(F)F
Solvent: CCOCC
Solvent: C[N+](=O)[O-]
Product: C[C@@]1(OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@H]1n1nc(I)c2c(N)ncnc21
Yield: 93.2 %

Procedure:
1-O-Acetyl-2-C-methyl-2,3,5-tri-O-benzoyl-D-ribofuranose (1.0 g, 1.72 mmol) was dissolved in anhydrous nitromethane (10.0 mL) and to this solution compound 1.2 (312 mg, 1.21 mmol) was added. The resulting suspension was brought to reflux and borontrifluoride etherate (0.23 mL, 1.78 mmol) was added. The suspension became a clear solution, which was heated at reflux for 2 hr. The mixture was cooled, the solvents were evaporated and the off-white foamy residue was dissolved in ethyl acetate and then poured with stirring into aq. sat. NaHCO3. The aqueous layer was extracted twice with ethyl acetate and the combined organic layers were dried (Na2SO4), filtered and evaporated to give an off-white solid. This material was purified by flash column chromatography on silica gel using CH2Cl2 to 2-3% MeOH in dichoromethane as eluent to give the desired compound 1.4 (811 mg) as a yellow foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:34]([NH:33][C:30]2[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)=[O:35])=[C:18]([CH3:24])[CH:17]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Solvent: ClC(Cl)Cl
Product: COc1ccc(NC(=O)Nc2cc(C)c(Oc3ccnc4cc(OC)c(OC)cc34)cc2C)cc1
Yield: 74 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethyl-aniline (100 mg) was dissolved in chloroform (4 ml), and 4-methoxyphenyl isocyanate (60 μl) was then added to the solution. The mixture was allowed to react at room temperature overnight. The solvent was removed by distillation under the reduced pressure. The residue was dissolved in a minor amount of chloroform, and a large amount of ether was added to the solution. The resultant precipitate was collected by suction filtration to give 110 mg (yield 74%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([Br:16])=[C:12]([OH:17])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].IC.[C:20]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([Br:16])=[C:12]([O:17][CH3:20])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2ccc(Br)c(O)c2c1C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1oc2ccc(Br)c(OC)c2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
To 200 mg (0.67 mmol) of 5-bromo-4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester was added 0.5 mL of iodomethane, 200 mg of K2CO3 and 2 mL of DMF. The mixture was stirred at room temperature overnight. The mixture was washed with brine and extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine. Removal of the solvent in vacuo gave 185 mg (88% yield) of 5-bromo-4-methoxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester as a white solid.