Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:20]([N+:21]([O-])=O)=[C:19]([CH2:24][C:25]#[N:26])[CH:18]=[CH:17][N:16]=2)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)C.[Fe]>[CH2:2]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:20]([NH2:21])=[C:19]([CH2:24][C:25]#[N:26])[CH:18]=[CH:17][N:16]=2)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N#CCc1ccnc(N2CCN(Cc3ccccc3)CC2)c1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: N#CCc1ccnc(N2CCN(Cc3ccccc3)CC2)c1N
Reaction time: 0.5 h

Procedure:
43 ml of hydrochloric acid and 35 g of iron powder are added to a suspension, that has been heated at 80° C. for 1 hour, of 59 mmol of the product obtained in Step A in 1.5 l of absolute ethanol. After 2 hours 30 minutes at 80° C., filtration while hot, and concentration of the reaction mixture under reduced pressure, the residue is taken up in water, rendered basic with a 20% sodium hydroxide solution and extracted with ethyl acetate. The organic phase is subsequently dried, filtered and evaporated, and chromatography of the residue on silica gel (dichloromethane/ethanol: 90/10) enables the expected product to be isolated.
Reaction SMILES: [ClH:1].CC1(C)[O:7][C@@H:6]2[CH2:8][CH2:9][C@@H:10]([N:11]3[C:19]4[C:18]([F:20])=[CH:17][N:16]=[C:15]([NH2:21])[C:14]=4[N:13]=[CH:12]3)[C@@H:5]2[O:4]1>CO>[NH2:21][C:15]1[C:14]2[N:13]=[CH:12][N:11]([C@@H:10]3[CH2:9][CH2:8][C@@H:6]([OH:7])[C@H:5]3[OH:4])[C:19]=2[C:18]([F:20])=[CH:17][N:16]=1.[ClH:1]
Reactant: CC1(C)O[C@H]2[C@H](n3cnc4c(N)ncc(F)c43)CC[C@H]2O1
Agent: Cl
Solvent: CO
Product: Nc1ncc(F)c2c1ncn2[C@@H]1CC[C@@H](O)[C@H]1O

Procedure:
Concentrated HCl (5 mL) was added to 1-((3aS,4R,6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-7-fluoro-1H-imidazo[4,5-c]pyridin-4-amine (1-7) (2.3 g, 7.9 mmol, 1 equiv) in methanol (60 mL). After disappearance of the starting material as monitored by LC-MS analysis, the mixture was concentrated to afford (1R,2S,3R)-3-(4-amino-7-fluoro-1H-imidazo[4,5-c]pyridin-1-yl)cyclopentane-1,2-diol (1-9) as a tan solid of the bis-HCl salt. 1H NMR (1-9) (500 MHz, DMSO): δ 8.76 (s, 1H); 8.55 (s, 2H); 8.03 (d, J=5.5 Hz, 1H); 4.88 (q, J=9.3 Hz, 1H); 4.19 (dd, J=9.4, 4.0 Hz, 1H); 4.00 (t, J=4.5 Hz, 1H); 2.41-2.31 (m, 1H); 2.15-2.06 (m, 1H); 1.92-1.83 (m, 1H); 1.66 (ddd, J=14.0, 9.7, 4.9 Hz, 1H). HRMS m/z (M+H) 253.1093 found, 253.1095 required. 1H NMR (1-10) (500 MHz, DMSO): δ 8.95 (s, 1H); 8.14 (s, 2H); 8.06 (d, J=4.5 Hz, 1H); 4.96 (q, J=8.4 Hz, 1H); 4.10 (dd, J=8.7, 4.8 Hz, 1H); 4.02 (d, J=4.4 Hz, 1H); 2.38-2.29 (m, 1H); 2.20-2.11 (m, 2H); 1.72-1.65 (m, 1H). HRMS m/z (M+H) 253.1095 found, 253.1095 required.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:32]([N:35](CC2C=CC(OC)=CC=2OC)[C:36]2[S:40][N:39]=[CH:38][N:37]=2)(=[O:34])=[O:33])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])=[CH:12][C:11]=1[C:26]1[CH:31]=[CH:30][N:29]=[N:28][CH:27]=1)#[N:2]>Cl.O1CCOCC1>[C:1]([C:3]1[CH:4]=[C:5]([S:32]([NH:35][C:36]2[S:40][N:39]=[CH:38][N:37]=2)(=[O:33])=[O:34])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:23])[F:24])=[CH:12][C:11]=1[C:26]1[CH:31]=[CH:30][N:29]=[N:28][CH:27]=1)#[N:2]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Oc3ccc(-c4ccccc4C(F)(F)F)cc3-c3ccnnc3)c(C#N)c2)c(OC)c1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1Oc1ccc(-c2ccccc2C(F)(F)F)cc1-c1ccnnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.9 %

Procedure:
3-Cyano-N-(2,4-dimethoxybenzyl)-4-{[3-pyridazin-4-yl-2′-(trifluoromethyl)biphenyl-4-yl]oxy}-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 21, 400 mg, 0.55 mmol) was dissolved in a 4M solution of HCl in 1,4-dioxane (9 mL). The mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was purified by silica gel column chromatography (0%-15% methanol in dichloromethane gradient elution), followed by trituration in tert-butylmethyl ether. The residue was purified further by a silica plug column (0%-20% methanol in dichloromethane) to afford the title compound (73 mg, 23%) as a white solid.
Reaction SMILES: Cl.N[C@H]1CCCC[C@H]1CNC.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[CH2:20][NH:21][C:22]([C:24]1[C:25](=[O:52])[C:26]([O:44]CC2C=CC=CC=2)=[C:27]2[C:41](=[O:42])[N:31]3[CH:32]4[CH:37]([CH2:38][N:39]([CH3:40])[CH:30]3[CH2:29][N:28]2[CH:43]=1)[CH2:36][CH2:35][CH2:34][CH2:33]4)=[O:23]>[Pd]>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[CH2:20][NH:21][C:22]([C:24]1[C:25](=[O:52])[C:26]([OH:44])=[C:27]2[C:41](=[O:42])[N:31]3[CH:32]4[CH:37]([CH2:38][N:39]([CH3:40])[CH:30]3[CH2:29][N:28]2[CH:43]=1)[CH2:36][CH2:35][CH2:34][CH2:33]4)=[O:23]
Reactant: CN1CC2CCCCC2N2C(=O)c3c(OCc4ccccc4)c(=O)c(C(=O)NCc4ccc(F)cc4F)cn3CC12
Agent: [Pd]
Agent: CNC[C@@H]1CCCC[C@@H]1N
Agent: Cl
Product: CN1CC2CCCCC2N2C(=O)c3c(O)c(=O)c(C(=O)NCc4ccc(F)cc4F)cn3CC12
Yield: 63 %

Procedure:
In a manner similar to that described in example Z-35, from racemic-{[(1S,2S)-2-aminocyclohexyl]methyl}methylamine hydrochloride (46 mg, 0.215 mmol) and 16a (35 mg, 0.0744 mmol) was prepared racemic-(4aS,6aS,14aS)-N-[(2,4-difluorophenyl)methyl]-6-methyl-11,13-dioxo-12-[(phenylmethyl)oxy]-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide (17 mg, 41%) as a white solid. This material was deprotected in s second step similar to the procedure described in example Z-37. Thus, from racemic-(4aS,6aS,14aS)-N-[(2,4-difluorophenyl)methyl]-6-methyl-11,13-dioxo-12-[(phenylmethyl)oxy]-1,2,8,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide (17 mg, 0.0302 mmol) and 10% Pd/C (1 mg) was prepared the title compound as a white solid (9 mg, 64%). 1H NMR (CDCl3) 10.44 (m, 1H), 8.29 (s, 1H), 7.34 (m, 1H), 6.79 (m, 2H), 4.78 (m, 1H), 4.62 (br s, 2H), 4.20 (br s, 2H), 3.41 (s, 1H), 2.92 (m, 1H), 2.66 (m, 1H), 2.35-2.25 (m, 4H), 1.90-1.74 (m, 2H), 1.67-1.24 (m, 6H); ES+MS: 473 (M+1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(=O)([O-])N.CC([N:15]([C@H:19]([CH2:24][N:25]=[N+]=[N-])[CH2:20][CH:21]([CH3:23])[CH3:22])[C:16](=[O:18])[O-:17])(C)C.OS([O-])(=O)=O.[Na+]>C1COCC1.O.CCOC(C)=O>[NH2:25][CH2:24][C@@H:19]([NH:15][C:16](=[O:18])[O:17][C:21]([CH3:23])([CH3:22])[CH3:20])[CH2:20][CH:21]([CH3:22])[CH3:23]
Reactant: CC(C)C[C@@H](CN=[N+]=[N-])N(C(=O)[O-])C(C)(C)C
Agent: NC(=O)[O-]
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)C[C@@H](CN)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Lithium aluminum hydride (0.24 g; 6.4 mmole) was slurried in THF (20 mL) and cooled to 0° C. The suspension was treated with a solution of the carbamate from (c) above (1.1 g; 4.6 mmole) in THF (10 mL) and stirred for 2 hours at 0° C. The mixture was further cooled to -30° C. and a solution of NaHSO4 (0.6 g; 4.3 mmole) in H2O (5 mL) was cautiously added and then diluted with EtOAc (50 mL), and filtered through celite. The filtrate was dried over MgSo4, filtered, and concentrated in vacuo leaving a colorless liquid. Yield: 1.0 g (100%)
Reaction SMILES: [Cl-].[NH4+].O.C(O)C.[CH2:7]([O:14][C:15]1[CH:16]=[CH:17][C:18]([N+:28]([O-])=O)=[C:19]([CH2:21][C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[CH:20]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(OCC)C.[Fe]>[CH2:7]([O:14][C:15]1[CH:16]=[CH:17][C:18]([NH2:28])=[C:19]([CH2:21][C:22]([O:24][CH:25]([CH3:26])[CH3:27])=[O:23])[CH:20]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)OC(=O)Cc1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: CC(C)OC(=O)Cc1cc(OCc2ccccc2)ccc1N
Reaction time: 3 h

Procedure:
A mixture of ammonium chloride (5.63 g), a water/ethanol mixed solvent (1:1 v/v, 240 ml ) and powdery iron (29.3 g) was heated under reflux for one hour and a Soxhlet extractor containing isopropyl 5-benzyloxy-2-nitrophenylacetate was set and refluxing was continued for a further 3 hours and then allowed to stand at room temperature overnight. Insolubles were filtered off with Celite and the solvent was distilled off under reduced pressure. The residue thus obtained was dissolved in ethyl ether, and the solution was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The oily substance thus obtained (18.9 g) was purified by a silica gel column chromatography (hexane:ethyl acetate=4:1) to give the title compound (10.8 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[NH:11][N:10]=2)=[CH:4][C:3]=1[N:20]1[C:24](=[O:25])[C:23]([CH3:27])([CH3:26])[N:22]([CH2:28][C:29]([OH:31])=[O:30])[C:21]1=[O:32].S(=O)(=O)(O)O.[CH3:38]O>>[CH3:38][O:30][C:29](=[O:31])[CH2:28][N:22]1[C:23]([CH3:26])([CH3:27])[C:24](=[O:25])[N:20]([C:3]2[CH:4]=[C:5]([CH2:8][C:9]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12](=[O:19])[NH:11][N:10]=3)[CH:6]=[CH:7][C:2]=2[F:1])[C:21]1=[O:32]
Reactant: CO
Reactant: CC1(C)C(=O)N(c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)C(=O)N1CC(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)CN1C(=O)N(c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)C(=O)C1(C)C
Temperature: 70 °C

Procedure:
To a solution of {3-[2-fluoro-5-(4-oxo-3,4-dihydro-phthalazin-1-ylmethyl)-phenyl]-5,5-dimethyl-2,4-dioxo-imidazolidin-1-yl}-acetic acid (36B)(0.044 g, 0.10 mmol) in methanol (2 ml) was added concentrated sulfuric acid (0.25 ml) and heated at 70° C. for 90 minutes before being cooled to rt. The reaction mixture was then concentrated in vacuo, diluted with water (5 ml) an extracted with ethyl acetate (2×10 ml). The organic layer was then dried over magnesium sulfate and concentrated in vacuo to afford a colourless oil. Single peak in LC-MS, (42 mg, 91% purity) and required no further purification; m/z (LC-MS, ESP), RT=3.31 mins (M+H) 453;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].[CH2:12]([O:19][C:20](=[O:25])[CH2:21][C:22](O)=[O:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:6][C:22](=[O:23])[CH2:21][C:20]([O:19][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:25])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=C(O)CC(=O)OCc1ccccc1
Reactant: COc1ccc(N)cc1OC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)CC(=O)OCc2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.4 %

Procedure:
3,4-dimethoxyaniline (500 mg, 3.26 mmol), 3-(benzyloxy)-3-oxopropanoic acid (1268 mg, 6.53 mmol), DMAP (798 mg, 6.53 mmol), and EDC (1877 mg, 9.79 mmol) were dissolved in DMF (7 ml). The reaction was stirred at RT for 4 hours to achieve completion. The reaction mixture was diluted with water, and the precipitate was washed with water, dissolved in EtOAc and extracted with HCl 1N, Na2CO3 sat. sol. and brine. The organic phase was dried over Na2SO4 and concentrated under vacuum to give benzyl 3-(3,4-dimethoxyphenylamino)-3-oxopropanoate (530 mg, 49.3% yield).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:25])=[C:11]([N:15]4[CH2:20][CH2:19][O:18][CH:17]([CH2:21][N:22]([CH3:24])[CH3:23])[CH2:16]4)[C:12]=3[F:14])[C:7](=[O:26])[C:6]([C:27]([O:29]CC)=[O:28])=[CH:5]2)[CH2:3][CH2:2]1.[ClH:32]>O.C(O)C>[ClH:32].[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:25])=[C:11]([N:15]4[CH2:20][CH2:19][O:18][CH:17]([CH2:21][N:22]([CH3:24])[CH3:23])[CH2:16]4)[C:12]=3[F:14])[C:7](=[O:26])[C:6]([C:27]([OH:29])=[O:28])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CCOC(CN(C)C)C3)c(F)cc2c1=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: CN(C)CC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CCO1
Yield: 80 %

Procedure:
A solution of 2.21 g of ethyl 1-cyclopropyl-6,8-difluoro-7-[2-(dimethylaminomethyl)morpholino]-1,4-dihydro-4-oxoquinoline-3-carboxylate and 5 ml of concentrated hydrochloric acid in 10 ml of water and 10 ml of ethanol is refluxed, for 2.5 hours. The resultant mixture is concentrated under reduced pressure and to the obtained crystals is added ethanol. The crystals are filtered off with suction, washed with ethanol and then dried to give 1.82 g of 1-cyclopropyl-6,8-difluoro-7-[2-(dimethylaminomethyl)morpholino]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.hydrochloride in 80% yield, melting at 267°-268° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([C@H:9]1[C@H:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:12][NH:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:30]([C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1)#[N:31]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:22])[N:7]([C@H:9]1[C@H:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:12][N:11]([C:36](=[O:37])[C:35]2[CH:39]=[CH:40][C:32]([C:30]#[N:31])=[CH:33][CH:34]=2)[CH2:10]1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CNC[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CN(C(=O)c2ccc(C#N)cc2)C[C@H]1c1ccc(Cl)c(Cl)c1
Yield: 97.8 %

Procedure:
To a solution of rac-[(3S,4R)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester (810 mg, 2.35 mmol, described herein above) in CH2Cl2 (20 ml) was added triethyl-amine (0.42 ml, 3.05 mmol) and 4-cyano-benzoyl chloride (466 mg, 2.81 mmol). Stirring was continued over night at RT, concentrated under vacuo and purification by flash chromatography (SiO2, EtOAc/Hx 2:1) afforded 1.09 g (98%) of the title compound as a white foam. ES-MS m/e: 474.4 (M+H+).
Reaction SMILES: [N+](C1C=CC(C(O)=O)=CC=1)([O-])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.O[Li].O.[C@H:49]1([OH:57])[CH2:56][CH2:55][CH2:54][O:53][CH2:52][O:51][CH2:50]1>C1COCC1.CO.O.C(Cl)(Cl)Cl>[C@@H:49]1([OH:57])[CH2:56][CH2:55][CH2:54][O:53][CH2:52][O:51][CH2:50]1
Reactant: O[C@H]1CCCOCOC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: [Li]O
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: C1CCOC1
Product: O[C@@H]1CCCOCOC1
Temperature: 23 °C
Reaction time: 8 h

Procedure:
To a mixture of (S)-8a (46 mg, 0.35 mmol), p-nitrobenzoic acid (86 mg, 0.52 mmol), and triphenylphosphine (181 mg, 0.69 mmol), diisopropylazodicarboxylate (135 μL, 0.69 mmol) was added dropwise and the resulting mixture was stirred at 23° C. overnight. The solvent was removed under reduced pressure and the residue was purified by flash-chromatography (1:3 EtOAc/Hex). The resulting ester was dissolved in a 3:2:1 mixture of THF, methanol and water (4 mL) and LiOH.H2O (72 mg, 1.7 mmol) was added. The yellow mixture was stirred at 23° C. overnight and then the solvent was removed in vacuo, the residue was diluted with water and the aqueous phase was extracted with ether. The organic extracts were dried (Na2SO4) and the solvent evaporated. Purification of the residue by flash-chromatography (EtOAc) afforded 20 mg (44%) of (R)-8c as a colourless liquid. [α]D20=+12.1 (c 1.4, CHCl3). 1H and 13C NMR are consistent with those reported for the (S)-enantiomer 8a
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22](O)[CH:21]=2)=[CH:5][CH:4]=1.[Br:27][CH2:28][CH2:29][CH2:30][CH2:31]Br.C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH2:31][CH2:30][CH2:29][CH2:28][Br:27])[CH:21]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2-c2cccc(O)c2)cc1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1ccc(-c2sc3cc(OC)ccc3c2-c2cccc(CCCCBr)c2)cc1

Procedure:
A slurry of 4.04 g (11 mmol) of 2-(4-Methoxyphenyl)-3-(3-hydroxyphenyl)-6-methoxybenzo[b]thiophene, 1,4-dibromobutane 26.3 mL (220 mmol), and 3.5 g (25.3 mmol) of K2CO3 in 200 mL of 2-butanone was preapared. The reaction mixture was heated to reflux for two hours, then filtered, and evaporated to dryness. The resulting oil was chromatographed on a silica gel column eluted with a linear gradient begining with EtOAc-hexane (1:9) (v/v) and ending with EtOAc-hexane (1:4) (v/v). The desired fractions were combined and evaporated to a yellow oil. This yielded 5 g of the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:14][C:13]2[C:12]([NH:15][CH2:16][CH2:17][C:18]3[S:22][C:21]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=4)=[O:25])=[N:20][CH:19]=3)=[N:11][CH:10]=[N:9][C:8]=2[CH:7]=1)=[O:5])C.O[Li].O.Cl>C1COCC1.O>[F:36][C:33]([F:34])([F:35])[C:29]1[CH:28]=[C:27]([NH:26][C:24](=[O:25])[NH:23][C:21]2[S:22][C:18]([CH2:17][CH2:16][NH:15][C:12]3[C:13]4[S:14][C:6]([C:4]([OH:5])=[O:3])=[CH:7][C:8]=4[N:9]=[CH:10][N:11]=3)=[CH:19][N:20]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=O)c1cc2ncnc(NCCc3cnc(NC(=O)Nc4cccc(C(F)(F)F)c4)s3)c2s1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1cccc(C(F)(F)F)c1)Nc1ncc(CCNc2ncnc3cc(C(=O)O)sc23)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of compound 66.1 (2 mmol) and LiOH.H2O (4 mmol) in THF (20 mL) and H2O (5 mL) was stirred at room temperature for 2 hours and then neutralized with 1.0 N HCl (4 mL). The reaction was concentrated to dryness to give 4-(2-{2-[3-(3-trifluoromethyl-phenyl)-ureido]-thiazol-5-yl}-ethylamino)-thieno[3,2-d]pyrimidine-6-carboxylic acid (compound 66.2) which is used without further purification in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][C:11]2[NH:12][C:13]([CH3:30])=[C:14]([C:26]([O:28][CH3:29])=[O:27])[CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[N:16]=2)=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][C:11]2[N:16]([S:38]([CH3:37])(=[O:40])=[O:39])[CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[C:14]([C:26]([O:28][CH3:29])=[O:27])=[C:13]([CH3:30])[N:12]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)C1=C(C)NC(SCc2ccc(OC)cc2)=NC1c1cccc([N+](=O)[O-])c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C1=C(C)N=C(SCc2ccc(OC)cc2)N(S(C)(=O)=O)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1, 4-dihydro-2-[[(4-methoxyphenyl)methyl]thio-]6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, methyl ester (1.14 g, 2.66 mmole) in 15 ml of dichloromethane under argon at 0°-5° C. was treated with pyridine (0.42 ml, 0.42 g, 5.32 mmole) and methanesulfonyl chloride (0.28 ml, 0.41 g, 3.57 mmole). The mixture was then allowed to stir at room temperature overnight.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[C:12](=[O:13])[C:11]3=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]3[C:9]2=[O:18])[N:3]=1.[Br:19]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:19][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[C:9](=[O:18])[C:10]3=[CH:17][CH:16]=[CH:15][CH:14]=[C:11]3[C:12]2=[O:13])[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(N2C(=O)c3ccccc3C2=O)n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1c1cccc(CBr)n1
Yield: 39.8 %

Procedure:
A mixture of N-(2-methylpyridin-6-yl)phthalimide (16.7 g), N-bromosuccinimide (15.0 g) and benzoyl peroxide (300 mg) in chloroform (150 ml) was refluxed for 5 hours with stirring under ultraviolet irradiation, and then additional N-bromosuccinimide (12.5 g) and benzoyl peroxide (300 mg) were added thereto. The mixture was further refluxed for 18 hours with stirring under ultraviolet irradiation. The reaction mixture was evaporated to dryness and the residue was extracted with ethyl acetate. The extract was washed with water, dried and evaporated to dryness. The residue was subjected to column chromatography on silica gel eluting with a mixed solvent (toluene:ethyl acetate=20:1) to give N-(2-bromomethylpyridin-6-yl)phthalimide (8.85 g). mp: 169°-170° C.
Reaction SMILES: [N+]([N:4]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[N:6]=[CH:5]1)([O-])=O.[CH:12]1(N)[CH2:15][CH2:14][CH2:13]1>CO>[CH:12]1([N:4]2[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[N:6]=[CH:5]2)[CH2:15][CH2:14][CH2:13]1
Reactant: NC1CCC1
Reactant: O=[N+]([O-])c1cn([N+](=O)[O-])cn1
Solvent: CO
Product: O=[N+]([O-])c1cn(C2CCC2)cn1
Reaction time: 16 h
Yield: 91.7 %

Procedure:
1,4-Dinitroimidazole (237 mg, 1.5 mmol, J. Phys. Chem. 1995, 99, 5009–5015) was added to a solution of cyclobutylamine (107 mg, 1.5 mmol) in methanol (10 mL) at 23° C. The reaction mixture was stirred for 16 h, then the solvent was removed in vacuo and the resulting residue was purified by silica gel chromatography (1:1 hexanes-ethyl acetate) to afford 230 mg (92% yield) of 1-cyclobutyl-4-nitro-1H-imidazole; 1H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 7.45 (s, 1H), 4.64 (m, 1H), 2.6 (m, 2H), 2.4 (m, 2H), 2.0 (m, 2H); MS (AP/CI): 168.2 (M+H)+. Note: 1,4-Dinitroimidazole is a highly energetic, semi-stable substance and should be stored in a freezer at all times it is not in use. Thermodynamic measurements have shown that it can potentially generate enough energy at 35° C. under adiabatic conditions to violently explode. Extreme caution should be exercised at all times using this material.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[I:12]I>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][C:11]=1[I:12]
Reactant: II
Reactant: COC(=O)c1ccc(N)cc1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: COC(=O)c1ccc(N)c(I)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl 4-aminobenzoate (30.23 g, 200 mmol) was added to a mixture of iodine (60.91 g, 240 mmol) and silver sulfate (81.07 g, 260 mmol) in 1 L of ethanol at room temperature. The mixture was stirred at room temperature for 18 hours, filtered over Celite and the filtrate was evaporated to dryness under reduced pressure. The residue was chromatographed on silica gel (230–400 mesh) and eluted with 1% ethyl acetate in hexane to give 35 g (63%).
Reaction SMILES: C([O:4][C:5]1[C:6]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:7][C:8]2[O:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]=2[C:15]=1[CH3:16])(=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:17]([C:6]1[C:5]([OH:4])=[C:15]([CH3:16])[C:9]2[CH2:10][C:11]([CH3:13])([CH3:14])[O:12][C:8]=2[CH:7]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C)CC(C)(C)O2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(O)c(C(C)(C)C)cc2c1CC(C)(C)O2
Temperature: 25 °C
Yield: 45.4 %

Procedure:
Under argon atmosphere, 65 mg of 5-acetoxy-6-t-butyl-2,2,4-trimethyl-2,3-dihydrobenzofuran was dissolved in 1.5 ml of anhydrous tetrahydrofuran, a solution of 22 mg of lithium aluminium hydride in 1 ml of anhydrous tetrahydrofuran was added, and the mixture was stirred at room temperature for a whole day and night. After cooling to 0° C., the reaction was quenched with water and then the reaction solution was combined with 10% hydrochloric acid and extracted with ethyl acetate. The organic layers were washed with a saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated. The concentrate was recrystallized from hexane to give 25 mg of 6-t-butyl-5-hydroxy-2,2,4-trimethyl-2,3-dihydrobenzofuran as a white solid (yield 45%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[CH2:10][CH2:11][OH:12].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:12][CH2:11][CH2:10][C:9]1[CH:13]=[CH:14][CH:15]=[C:7]([O:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:8]=1)(=[O:4])=[O:3]
Reactant: OCCc1cccc(O)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1cccc(OS(C)(=O)=O)c1
Temperature: 25 °C
Yield: 87.3 %

Procedure:
9.09 g (79.6 mmole) methanesulfonyl chloride was slowly added to a solution of 5 g (36.2 mmole) 3-hydroxyphenethyl alcohol and 9.14 g (90.5 mmole) triethylamine in 150 ml dichloromethane at 0° C. After stirring at room temperature over night the salts were filtered off, the organic phase was washed with sodium bicarbonate and brine, dried (magnesium sulfate) and evaporated in vacuo to give 9.3 g (yield 87%) of 3-(methylsulfonyloxy)phenethyl methanesulfonate.