Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[CH:14](OCC)(OCC)OCC.[N-:24]=[N+:25]=[N-:26].[Na+]>C(O)(=O)C.O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N:13]2[CH:14]=[N:26][N:25]=[N:24]2)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(N)ccc1OC
Reactant: CCOC(OCC)OCC
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc(-n2cnnn2)ccc1OC
Temperature: 70 °C
Reaction time: 20 h

Procedure:
Combine methyl 2-methoxy-5-aminobenzoate (3.94 g, 21.7 mmol) and triethyl orthoformate (12.8 g, 86.7 mmol) in glacial acetic acid (20 mL). After 20 hours, concentrate the reaction mixture in vacuo to remove ethanol. Add glacial acetic acid (20 mL) and sodium azide (5.64 g, 86.7 mmol). Heat to 70° C. After 1 hour, add glacial acetic acid (10 mL) and continue to heat to 70° C. After an additional hour, cool the reaction mixture to ambient temperature, dilute with water (500 mL). Collect the solid by filtration, rinse with water, and dry to give methyl 2-methoxy-5-(1H-tetrazol-1-yl)benzoate.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[H][H].[CH2:15](Br)[CH:16]=[CH2:17]>CN(C=O)C>[CH2:17]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=2)[CH:6]=[CH:7]1)[CH:16]=[CH2:15]
Reactant: [H][H]
Reactant: C=CCBr
Reactant: Brc1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1ccc2ccc(Br)cc21
Reaction time: 2 h
Yield: 98 %

Procedure:
To a room temperature solution of 10.0 g (51.0 mmol) of 6-bromoindole in DMF was added 1.4 g (58.0 mmol) of 60% NaH in mineral oil. Once evolution of hydrogen ceased, allyl bromide was added. After 2 hours, the reaction was quenched with water and was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford 11.8 g (98%) of 1-allyl-6-bromo-1H-indole. MS m/z 237.11 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Br:9])=[CH:4][C:3]=1[OH:10].[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.[C:36](OC)(OC)(OC)[CH3:37]>CCO>[Br:9][C:5]1[C:6]([Cl:8])=[CH:7][C:2]2[N:1]=[C:36]([CH3:37])[O:10][C:3]=2[CH:4]=1
Reactant: COC(C)(OC)OC
Reactant: Nc1cc(Cl)c(Br)cc1O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCO
Product: Cc1nc2cc(Cl)c(Br)cc2o1
Temperature: 90 °C
Yield: 80.2 %

Procedure:
A mixture of 2-amino-5-bromo-4-chlorophenol (29) (865 mg, 3.89 mmol), trifluoromethanesulfonic acid Ytterbium (III) salt (24 mg, 1% mol) and trimethyl orthoacetate (610 μl, 1.2 eq.) in 3 ml EtOH was heated at 90° C. for 1 h. After cooling down to r.t., off-white needles fell off, which were filtered, washed with MeOH, water and dried to give 791 mg title compound as off-white crystalline solid. Yield: 80.2%; purity>95%.
Reaction SMILES: [SH:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.CI.[C:13](=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:13][S:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Sc1nc2ccccc2o1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CSc1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.9 %

Procedure:
Method A, Part A. A solution of 2-mercapto-1H-benzoxazole (5.85 g, 38.7 mmol), methyl iodide (2.70 mL, 43.4 mmol), and potassium carbonate (7.39 g, 53.5 mmol) in tetrahydrofuran (100 mL) was heated to reflux for 18 hours. After stirring at room temperature for an additional 24 hours, the solution was poured into (2×150 mL). The extracts were combined, dried over anhydrous magnesium sulfate, filtered and evaporated to afford sufficiently pure 2-methylthio-1-H-benzoxazole (6.27 g, 37.9 mmol, 98%) as a pale yellow oil. This material was dissolved in methylene chloride (100 mL), cooled to 0° C., and treated with a solution of m-chloroperben-zoic acid (7.20 g, 41.7 mmol) in methylene chloride (40 mL). Sodium bicarbonate (about 10 g) was added, and the mixture was stirred for 18 hours. This mixture was diluted slightly with methylene chloride, then washed with aqueous sodium carbonate solution (1M, 2×150 mL) and water (150 mL). The aqueous phases were back-extracted in sequence with methylene chloride (150 mL). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and evaporated to afford the product, 2-methylsulfonyl-1H-benzoxazole (7.04 g, 35.7 mmol, 94%), as a waxy solid. 1H NMR (CDCl3): 8.03-7.40 (4H, m); 3.22 (3H, s).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:10][CH:11]([CH2:16][CH3:17])[CH2:12][C:13]([OH:15])=[O:14]>>[CH3:10][CH:11]([CH:12]([C:1]([OH:3])([CH3:2])[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)[C:13]([OH:15])=[O:14])[CH2:16][CH3:17]
Reactant: CC(=O)c1ccncc1
Reactant: CCC(C)CC(=O)O
Product: CCC(C)C(C(=O)O)C(C)(O)c1ccncc1

Procedure:
The reaction of 4-acetylpyridine (24.1 grams, 0.2 mole) with the dianion of 3-methylvaleric acid (from 23.2 grams of acid, 0.2 mole) is carried out as described in Example III.
Reaction SMILES: [CH2:1]([N:4]([CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C:5](=[O:34])[C:6]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:14][CH2:13]2)[CH:9]=[CH:8][C:7]=1F)[CH:2]=[CH2:3].F[C:42]1[CH:50]=CC([N+]([O-])=O)=C[C:43]=1C(O)=O.C(NC1CCCCC1)C=C>>[CH2:1]([N:4]([CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C:5](=[O:34])[C:6]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:14][CH2:13]2)[CH:9]=[CH:8][C:7]=1[CH:42]([CH3:50])[CH3:43])[CH:2]=[CH2:3]
Reactant: C=CCN(C(=O)c1cc(N2CCN(CCC(c3ccccc3)c3ccccc3)CC2)ccc1F)C1CCCCC1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Agent: C=CCNC1CCCCC1
Product: C=CCN(C(=O)c1cc(N2CCN(CCC(c3ccccc3)c3ccccc3)CC2)ccc1C(C)C)C1CCCCC1

Procedure:
Steps (a) and (b) of Example 59 were repeated, except that the compound prepared just above in step (a) was used instead of 2-fluoro-5-nitrobenzoic acid. Step (d) of Example 1 was then repeated, except that N-allylcyclohexylamine was used instead of N-methylbenzylamine. Thus, the title compound was prepared.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=O)[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2].Cl.[CH3:14][NH:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCOC(C)=O>ClC(Cl)C>[C:9]([O:8][CH2:7][CH:6]([N:15]([CH3:14])[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:5][O:4][C:1](=[O:3])[CH3:2])(=[O:11])[CH3:10]
Reactant: CC(=O)OCC(=O)COC(C)=O
Reactant: CNCC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: CC(=O)OCC(COC(C)=O)N(C)CC(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 17 %

Procedure:
To a solution of 3-(acetyloxy)-2-oxopropyl acetate (4.54 g, 26 mmol) in dichloroethane (75 ml) was added tert-butyl 2-(methylamino)acetate HCl. After stirring for 10 minutes sodium triacetoxyborohydride (8.3 g, 39 mmol) was added and stirring was continued for 18 hours and monitored by TLC (1:1heptane:EtOAc). The reaction was quenched by the addition of saturated sodium hydrogen carbonate solution and the crude product was extracted into dichloromethane. The organic phase was separated, dried over MgSO4, filtered and concentrated in vacuo. The title compound was purified by silica column chromatography eluting with 0-20% EtOAc:Hept to yield the title compound (1.32 g, 17% yield). 1H NMR (250 MHz, CHLOROFORM-d) δ 4.07-4.33 (4H, m), 3.34 (2H, s), 3.23 (1H, t, 5.9 Hz), 2.49 (3H, s), 1.99-2.19 (6H, m), 1.33-1.55 (9H, m).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([S:8]([CH3:10])=[O:9])[N:5]=[C:4]([NH:11][C:12]2[NH:16][N:15]=[C:14]([CH3:17])[CH:13]=2)[CH:3]=1.[OH:18]OS([O-])=O.[K+]>CO.O>[Cl:1][C:2]1[N:7]=[C:6]([S:8]([CH3:10])(=[O:18])=[O:9])[N:5]=[C:4]([NH:11][C:12]2[NH:16][N:15]=[C:14]([CH3:17])[CH:13]=2)[CH:3]=1
Reactant: O=S([O-])OO
Reactant: Cc1cc(Nc2cc(Cl)nc(S(C)=O)n2)[nH]n1
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1cc(Nc2cc(Cl)nc(S(C)(=O)=O)n2)[nH]n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a stirred suspension of 6-chloro-N-(3-methyl-1H-pyrazol-5-yl)-2-(methylsulfinyl)pyrimidin-4-amine (8 g, 31.2 mmol) in Methanol (200 ml) at 0° C. was added a suspension of Oxone (44 g, 71.7 mmol) in water (100 ml) portionwise over 10 minutes. The mixture was stirred for 30 minutes at 0° C. then warmed to ambient and stirred for an additional 2 hours. The reaction mixture was filtered and the resulting solid slurried in aqueous sodium bicarbonate. The mixture was filtered and the solid washed with water, then diethyl ether. The solid was slurried in ethyl acetate, filtered and dried. This gave the title product as an off-white solid (7.9 g, 88%); 1H NMR (d6-DMSO) δ 2.24 (3H, s), 3.35 (3H, s), 5.85 (0.5H, brs), 6.50 (0.5H, brs), 6.95 (0.5H, brs), 8.00 (0.5H, brs), 10.95 (1H, s), 12.28 (1H, s); MS ES+288.07, ES−286.25.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH2:29][CH3:30])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].CN(C)C=O.[CH:36](N(CC)C(C)C)([CH3:38])[CH3:37].C(I)(C)C>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH2:29][CH3:30])[C:16]3[CH2:22][CH2:21][N:20]([CH:36]([CH3:38])[CH3:37])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4CC)n2)CCNC3)cc1
Reactant: CCN(C(C)C)C(C)C
Solvent: CC(C)I
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4CC)n2)CCN(C(C)C)C3)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Step 2—Synthesis of compound xc: (S)-1-ethyl-3-(4-(4-(3-ethylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.097 g, 0.24 mmol) in dry N,N-Dimethylformamide (1.30 mL, 16.8 mmol) was added N,N-Diisopropylethylamine (0.1270 mL, 0.7291 mmol) followed by Isopropyl iodide (0.0488 mL, 0.488 mmol). The reaction mixture was heated at 50° C. and stirred overnight. The reaction mixture was purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.62 (s, 1H), 8.15 (d, J=8.7, 2H), 7.46 (d, J=8.7, 2H), 6.16 (t, J=5.5, 1H), 3.97 (s, 1H), 3.85 (d, J=10.7, 1H), 3.77 (d, J=11.4, 1H), 3.68 (t, J=13.3, 3H), 3.60-3.49 (m, 2H), 3.40 (t, J=11.0, 1H), 3.18-3.04 (m, 2H), 2.91-2.64 (m, 3H), 2.57 (d, J=15.4, 1H), 1.89-1.63 (m, 2H), 1.06 (t, J=7.5, 9H), 0.94 (t, J=6.3, 1H), 0.82 (t, J=7.4, 3H). LC/MS-m/z+453.2 (M+H)+
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>>[N:13]1([C:2]2[CH:11]=[C:10]3[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]3)=[CH:4][CH:3]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: O=c1[nH]cnc2cc(F)ccc12
Reactant: C1COCCN1
Product: O=c1[nH]cnc2cc(N3CCOCC3)ccc12
Temperature: 90 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
20.0 g (0.122 mol) of 7-fluoro-3H-quinazolin-4-one were suspended in 80 ml of morpholine and stirred at an internal temperature of 90° C. for 16 h. Conventional work-up gave 14.1 g (Y=50%) of 7-morpholin-4-yl-3H-quinazolin-4-one (as described in Example 2.2, reaction step 1a).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]3[C:21]([OH:29])=[C:22]([C:26](=[O:28])[CH3:27])[CH:23]=[CH:24][CH:25]=3)=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:30](OCC)(=O)[C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[O:28]=[C:26]1[C:22]2[CH:23]=[CH:24][CH:25]=[C:20](/[CH:19]=[CH:18]/[C:15]3[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:13][CH:14]=3)[C:21]=2[O:29][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:27]1
Reactant: CC(=O)c1cccc(/C=C/c2ccc(OCCCCc3ccccc3)cc2)c1O
Reactant: CCOC(=O)C(=O)OCC
Product: CCOC(=O)c1cc(=O)c2cccc(/C=C/c3ccc(OCCCCc4ccccc4)cc3)c2o1
Yield: 66 %

Procedure:
Following the process described in example 1 (point A), starting from 3'-[(E)-2-[4-(4-phenylbutoxy)phenyl]-ethen-1-yl]-2'-hydroxyacetophenone and diethyl oxalate, the title compound was prepared, which was purified by chromatography through a silica gel column, eluting with petroleum ether:chloroform, 6:4 (66% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[CH2:6])[CH:4]=O.[CH3:7][N:8]([CH3:10])[NH2:9]>CCOCC>[CH3:1][O:2][C:3]([CH:4]=[N:9][N:8]([CH3:10])[CH3:7])=[CH2:6]
Reactant: CN(C)N
Reactant: C=C(C=O)OC
Solvent: CCOCC
Product: C=C(C=NN(C)C)OC
Yield: 66.1 %

Procedure:
6.4 g of 2-methoxyacrolein are stirred for 1 hour at 30°-35° C. with 4.4 g of N,N-dimethylhydrazine in 50 ml of ether, dried at 20° C. with Na2SO4 and then the solvent is removed. Distillation at 74°-76° C./13 mbar gives 6.2 g of pure 2-methoxy-4-dimethylamino-4-azabutadiene.
Reaction SMILES: [CH3:1][O:2][C@H:3]([C@@H:6]([C@H:9]([C@H:12]([CH3:14])[OH:13])[O:10][CH3:11])[O:7][CH3:8])[CH:4]=[O:5].O[N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22]>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C@@H:3]1[C@H:6]([O:7][CH3:8])[C@@H:9]([O:10][CH3:11])[C@H:12]([CH3:14])[O:13][C@H:4]1[O:5][N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22]
Reactant: O=C1CCC(=O)N1O
Reactant: CO[C@H]([C@@H](OC)[C@H](C=O)OC)[C@H](C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](ON2C(=O)CCC2=O)[C@@H]1OC
Reaction time: 4 h
Yield: 51.8 %

Procedure:
To a stirred solution of 2,3,4-tri-O-methyl-L-rhamnose (6.5 g, 31.5 mmol) and N-hydroxysuccinimide (5.4 g, 47 mmol) in benzene (50 mL) was added p-toluenesulfonic acid (50 mg, cat.). The solution was heated to reflux and water (H2O) was collected using a Dean-Stark trap. After 4 h, the solution was cooled and the supernatant toluene layer was separated from a small amount of insoluble gum. The organic layer was washed with a saturated solution of sodium bicarbonate (NaHCO3; 20 mL), then dried over MgSO4 and concentrated to a solid. Recrystallization from ether (Et2O)-hexanes gave the title compound (4.95 g, 52%) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH2:11])=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].COC(C1C2N=C(N)[NH:23][C:22]=2C=CC=1)=O.BrC#N>CO>[NH2:23][C:22]1[NH:11][C:10]2[C:9]([O:12][CH3:13])=[CH:8][CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]=2[N:1]=1
Reactant: COC(=O)c1cccc2[nH]c(N)nc12
Reactant: COc1ccc(C(=O)O)c(N)c1N
Agent: N#CBr
Solvent: CO
Product: COc1ccc(C(=O)O)c2nc(N)[nH]c12

Procedure:
0.9 g (4.9 mmol) of 2,3-diamino-4-methoxy-benzoic acid was subjected to a similar cyclization condition as illustrated in intermediate A by using 2.6 g (24.5 mmol) of BrCN in methanol to produce 2-amino-7-methoxy-1H-benzoimidazole-4-carboxylic acid. LCMS: 208 (M+1)+.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Cl:23])[CH:17]=2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=CC(F)=C(Cl)C=2)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[Cl:23][C:18]1[CH:17]=[C:16]([N:15]([CH2:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:30])=[O:3])=[CH:8][N:9]=2)[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2ccc(F)c(Cl)c2)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Agent: Fc1ccc(NCC2CCCC2)cc1Cl
Product: O=C(O)CSc1cnc(NC(=O)N(CC2CCCC2)c2ccc(F)c(Cl)c2)s1

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3-chloro-4-fluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(3-chloro-4-fluoro-phenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [CH:1]1[C:2]([I:10])=[CH:3][C:4]([I:9])=[C:5]([OH:8])[C:6]=1[I:7].[H-].[Na+].CS(O[CH2:18][CH2:19][CH:20]([O:22]S(C)(=O)=O)[CH3:21])(=O)=O.O>CN(C=O)C.C(OCC)(=O)C>[I:7][C:6]1[CH:1]=[C:2]([I:10])[CH:3]=[C:4]([I:9])[C:5]=1[O:8][CH2:18][CH2:19][CH:20]([O:22][C:1]1[C:6]([I:7])=[CH:5][C:4]([I:9])=[CH:3][C:2]=1[I:10])[CH3:21]
Reactant: CC(CCOS(C)(=O)=O)OS(C)(=O)=O
Reactant: Oc1c(I)cc(I)cc1I
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(CCOc1c(I)cc(I)cc1I)Oc1c(I)cc(I)cc1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
A mixture of triiodophenol (5.78 g, 12.3 mmol) and sodium hydride (0.49 g, 60% dispersion, 12.3 mmol) in DMF (15 ml) was stirred at room temperature for 1 hour and then a solution of 1,3-bis-(methanesulfonyloxy) butane (1.37 g, 5.58 mmol) in DMF (5 ml) was added. The mixture was heated to 90° C. for 6 hours and then poured into water after cooling. Ethyl acetate was added and the mixture was allowed to stand overnight. The precipitated solid was collected and dried to give 3.0 g (54%) of the desired product, Mp 173°-175° C.
Reaction SMILES: CC(C)([O-])C.[K+].C1(C)C(S([CH2:16][N+:17]#[C-])(=O)=O)=CC=CC=1.[CH3:20][C:21]1[S:25][C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:23][C:22]=1[CH2:32][O:33][C:34]1[CH:38]=[C:37]([CH2:39][O:40][C:41]2[N:48]=[CH:47][CH:46]=[CH:45][C:42]=2[CH:43]=O)[O:36][N:35]=1.CO>C(COC)OC.O>[CH3:20][C:21]1[S:25][C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:23][C:22]=1[CH2:32][O:33][C:34]1[CH:38]=[C:37]([CH2:39][O:40][C:41]2[C:42]([CH2:43][C:16]#[N:17])=[CH:45][CH:46]=[CH:47][N:48]=2)[O:36][N:35]=1
Reactant: Cc1sc(-c2ccccc2)nc1COc1cc(COc2ncccc2C=O)on1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccccc1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Solvent: CO
Product: Cc1sc(-c2ccccc2)nc1COc1cc(COc2ncccc2CC#N)on1
Temperature: -78 °C
Reaction time: 1 h
Yield: 62.6 %

Procedure:
To a mixture of potassium t-butoxide (0.40 g) and dimethoxyethane (10 mL) was added a solution (10 mL) of toluenesulfonylmethylisocyanide (0.37 g) in dimethoxyethane at −78° C. Further, a solution (10 mL) of 2-[[3-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]-5-isoxazolyl]methoxy]nicotinaldehyde (0.70 g) in dimethoxyethane was added to the reaction mixture. The reaction mixture was stirred at −78° C. for 1 hr. Methanol (10 mL) was added to the reaction mixture at room temperature and the mixture was heated under reflux for 30 min. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (0.45 g, 63%) of 2-[2-[[3-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]-5-isoxazolyl]methoxy]-3-pyridyl]acetonitrile from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 103-104° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:19])[NH:7][N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)[CH:10]=1)=[O:4].Cl[CH2:21][CH:22]1[CH2:24][CH2:23]1>>[CH:22]1([CH2:21][N:7]2[C:6](=[O:19])[C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=3)=[N:8]2)[CH2:24][CH2:23]1
Reactant: COC(=O)c1cc(-c2ccc(SC)cc2)n[nH]c1=O
Reactant: ClCC1CC1
Product: COC(=O)c1cc(-c2ccc(SC)cc2)nn(CC2CC2)c1=O
Yield: 61.5 %

Procedure:
Using 4-methoxycarbonyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one and (chloromethyl)cyclopropane as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 61.5%.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11](O)[CH3:12])[CH:8]=[CH:9][CH:10]=1.C1(P([N:33]=[N+:34]=[N-:35])(C2C=CC=CC=2)=O)C=CC=CC=1.O>C1(C)C=CC=CC=1>[N:33]([CH:11]([C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[O:4][C:3]1[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:2]=1[NH2:1])[CH3:12])=[N+:34]=[N-:35]
Reactant: CC(O)c1cccc(Oc2ccc(Cl)cc2N)c1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(N=[N+]=[N-])c1cccc(Oc2ccc(Cl)cc2N)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To the product from Example 170c in toluene (25 mL) was added diphenylphosphoryl azide (1.72 g, 6.23 mmol), followed by 1,8-diazabicyclo[4.3.0]undec-7-ene (0.95 g, 6.2 mmol). The mixture was stirred at 25° C. for 18 h. The reaction was poured into water and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered and concentrated under vacuum giving the title compound. The crude product was purified on silica gel, eluting with hexanes/ethyl acetate/methanol (85:17:3) to provide the title compound (700 mg, 50%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][C:8]2[N:12]3[C:13](=[O:25])[C:14]4[NH:15][CH:16]=[N:17][C:18]=4[N:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:11]3=[N:10][N:9]=2)=[CH:5][CH:4]=1.[Br:28]N1C(=O)CCC1=O>C1COCC1>[Br:28][C:16]1[NH:15][C:14]2[C:13](=[O:25])[N:12]3[C:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:27][CH:26]=4)=[N:9][N:10]=[C:11]3[N:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:18]=2[N:17]=1
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(Cc3ccc(OC)cc3)nnc12
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(Cc3ccc(OC)cc3)nnc12
Temperature: 70 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
To the solution of 3-(4-methoxybenzyl)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one (0.40 g, 1.1 mmol) in THF was added N-Bromosuccinimide (0.29 g, 1.6 mmol). The mixture was stirred at 70° C. for 1 hour. The mixture was concentrated and purified by preparative LCMS to yield the desired product (290 mg, 60%). 1HNMR (300 MHz, d6-DMSO): δ 7.16 (d, J=8.3 Hz, 2H), 6.81 (d, J=8.3 Hz, 2H), 4.46 (s, 3H), 4.20 (t, J=7.2 Hz, 2H), 3.67 (s, 2H), 1.79 (m, 2H), 1.28 (m, 4H), 0.83 (m, 3H). LCMS calculated for C19H21BrN6O2 (M+H): 445.1. found: 445.0, 447.0.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][CH:10]=[N:9]2)[CH:3]=O.[F:16][C:17]1[CH:18]=[C:19]([N:24]2[CH2:29][CH2:28][N:27]([CH:30]=[O:31])[CH2:26][CH2:25]2)[CH:20]=[CH:21][C:22]=1[F:23].[BH-](O[C:42]([CH3:44])=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[F:16][C:17]1[CH:18]=[C:19]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([C@H:7]3[C@@H:42]4[C@@H:44]([CH2:1][CH2:2][CH2:5][CH2:6]4)[CH2:10][N:9]([CH2:3][C@@H:2]([CH3:1])[CH2:5][C:6]4[CH:7]=[C:8]5[C:13](=[CH:14][CH:15]=4)[N:12]=[CH:11][CH:10]=[N:9]5)[CH2:8]3)=[O:31])[CH2:26][CH2:25]2)[CH:20]=[CH:21][C:22]=1[F:23]
Reactant: C[C@H](C=O)Cc1ccc2nccnc2c1
Reactant: O=CN1CCN(c2ccc(F)c(F)c2)CC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: C[C@@H](Cc1ccc2nccnc2c1)CN1C[C@@H]2CCCC[C@@H]2[C@H](C(=O)N2CCN(c3ccc(F)c(F)c3)CC2)C1
Reaction time: 0.08 h

Procedure:
To a solution of (S)-2-methyl-3-quinoxalin-6-yl-propionaldehyde (2.7 g, 13.48 mmol) in dichloroethane (100 ml) is added (4S,4aS,8aR)-decahydro-isoquinolin-4-yl)-[4-(3,4-difluoro-phenyl)-piperazin-1-yl]-methanone (5.36 g, 11.22 mmol) and stirred for 5 minutes. NaBH(OAc)3 (3.56 g, 16.8 mmol) is added and the mixture stirred for 1 h. A 1 M solution of NaHCO3 (100 ml) is added and intensively stirred for 15 minutes. The phases are separated, the organic phase dried over Na2SO4 and evaporated to afford 7.2 g of the crude product. MPLC purification (silicagel, EtOAc, then EtOAc/MeOH 5:1) yield pure [4-(3,4-Difluoro-phenyl)-piperazin-1-yl]-[(4S,4aS,8aR)-2-(2(S)-methyl-3-quinoxalin-6-yl-propyl)-decahydro-isoquinolin-4-yl]-methanone. This base is dissolved in 60 ml warm MeOH and treated with maleic acid (1.3 g, 11.22 mmol) in 20 ml MeOH. The solution is diluted with Et2O (450 ml), and the slightly cloudy solution filtered through Hyflo. Crystallisation first at room temperature and then at 5° afford the maleic acid salt, m.p. 1200-1230. Recrystallization from 50 ml MeOH and 100 ml Et2O yield the pure maleic acid salt, m.p. 129°-131°.