Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ON1C2C=CC=CC=2N=N1.C1CCC(N=[C:18]=[N:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22]C2)CC1.C(NCCCCCC(O)=O)(OC[CH:30]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]2[C:31]1=[CH:32][CH:33]=[CH:34][CH:35]=2)=O.C(OC(=O)C)(=O)C.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[CH:35]1[C:36]2[CH:37]([CH2:18][N:19]3[CH2:20][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:38]3[C:30](=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:31]=2[CH:32]=[CH:33][CH:34]=1
Reactant: O=C(O)CCCCCNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: *CC(*)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Product: c1ccc2c(c1)-c1ccccc1C2CN1CCCCC1

Procedure:
In a 10 mL-syringe equipped with a polypropylene disk are introduced 1.5 g of aminomethylpolystyrene (Sigma, 0.81 mmol NH2 /g of resin), 44.6 mg (0.24 equiv.) of 1-hydroxybenzotriazole in 0.8 mL of DMF, 63.2 mg (0.24 equiv.) of DCC in 2 mL of DCM and 103 mg (0.24 equiv.) of N-Fmoc-6-aminohexanoic acid in 5 mL of DCM and 0.4 mL of DMF and left to react, with occasional stirring, for two hours. The resin is washed with DMF (3×1 min), DCM (3×1 min) and MeOH (3×1 min), dried and the functionalization is determined on an aliquot. The remaining amine groups are acetylated with acetic anhydride (100 equiv.) in DMF for 10 min, after which time DIEA (10 equiv.) is added and left to react for 10 min more, and the resin is washed again. The absence of free amine groups is confirmed by the ninhydrin test. In order to eliminate the Fmoc group, and at the same time determine the degree of substitution, the resin is treated with a solution of 50% piperidine in DMF (3×2 min) and washed with DCM (3×1 min), DMF and MeOH. The filtrates from the treatment with piperidine and DCM washes are pooled and the amount of N-(9-fluorenylmethyl)piperidine formed in the deprotection determined spectrophotometrically (lambda=300 nm, epsilon=7800). Resins with a substitution degree between 0.05 and 0.1 mmol NH2 /g resin are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[C:24]([F:26])[CH:25]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:22]3[CH:21]=[C:20]([F:19])[CH:25]=[C:24]([F:26])[CH:23]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCCNC(=O)c1nnc2c(-c3cc(F)cc(F)c3)cccc2c1N
Yield: 89.9 %

Procedure:
Using method B, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (200 mg, 0.65 mmol), 3,5-difluorophenyl boronic acid (300 mg, 1.90 mmol) and bis(triphenylphosphine)palladium(II) dichloride (24 mg, 0.034 mmol) were reacted to afford the title compound (200 mg, 89.7% yield) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 8.55 (br, 1H), 7.92 (dd, J=8.1, Hz, J′=1.4 Hz, 1H), 7.67-7.82 (m, 2H), 7.22 (m, 2H), 6.88 (m, 1H), 3.47 (q, J=6.7 Hz, 2H), 1.68 (m, J=7.2 Hz, 2H), 1.01 (t, J=7.4 Hz, 3H). MS APCI, m/z=343 (M+H). HPLC 2.14 min.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[C:17]([OH:19])=[O:18].[CH3:20]O>>[CH3:20][O:18][C:17]([C:9]1[CH:10]=[C:11]([C:12]([OH:14])=[O:13])[CH:15]=[CH:16][C:8]=1[O:7][CH3:6])=[O:19]
Reactant: COc1ccc(C(=O)O)cc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(C(=O)O)ccc1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-Methoxy-1,3-benzenedicarboxylic acid 3-monomethyl ester (formula 7) was prepared by adding at 20° C. under stirring 12 ml of concentrated sulphuric acid, d 1.84, to a suspension of 50 g of 4-methoxyisophthalic acid in 400 ml of methanol; stirring was then continued for 1 hour and then the mixture was poured into ice-water (400 ml). The precipitate was collected and stirred with a saturated solution of sodium hydrogen carbonate; the insoluble residue (15 g) was constituted by 4-methoxy-1,3-benzenedicarboxylic acid dimethyl ester. The filtered solution was adjusted to pH 4.8 by adding 6N hydrochloric acid, thus precipitating the desired monoester, which was collected and washed with water, yielding 28.1 g (52.5%) of white solid. By further acidification of the mother liquor unreacted 4-methoxy-1,3-benzenedicarboxylic acid (9 g) was precipitated and collected. In this way a total recovery of 44.2% was obtained by summing together the recovery of the acid and the dimethyl ester, thus allowing a useful yield of 96.7%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[CH:5][N:4]=1)#[N:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:2][CH2:1][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[CH:5][N:4]=1
Reactant: N#Cc1cc(-c2ccccn2)ccn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1cc(-c2ccccn2)ccn1
Temperature: 0 °C
Reaction time: 3 h
Yield: 98.9 %

Procedure:
2-(2-Cyanopyridin-4-yl)pyridine (Method 99; 563 mg, 3.11 mmol) was dissolved in anhydrous THF (10 ml) under a nitrogen atmosphere and was cooled to 0° C. LiAlH4 (2.3 ml of a 1M solution in THF, 2.3 mmol) was added dropwise and the reaction was stirred at 0° C. for 3 hours. The reaction was quenched with water (0.1 ml) followed by 15% sodium hydroxide solution (0.1 ml) then water (0.3 ml). The mixture was filtered and the filter pad was washed with methanol. The volatiles were removed from the filtrate by evaporation to give the title compound (570 mg, 99%) as a gum. m/z 186 (MH)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N+:3]=1[O-:10].[NH:11]1[CH2:15][CH2:14][C@H:13]2[CH2:16][N:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:18][C@@H:12]12.C([O-])([O-])=O.[K+].[K+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:11]2[CH2:15][CH2:14][C@H:13]3[CH2:16][N:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:18][C@@H:12]23)=[CH:4][N+:3]=1[O-:10]
Reactant: CCOC(=O)N1C[C@@H]2CCN[C@@H]2C1
Reactant: [O-][n+]1cc(CCl)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)N1C[C@@H]2CCN(Cc3ccc(Cl)[n+]([O-])c3)[C@@H]2C1

Procedure:
The titled compound was prepared in analogy to examples 2.2 and 2.3 using 2-chloro-5-(chloromethyl)pyridine 1-oxide (712 mg, 4 mmol), (3aS,6aS)-ethyl hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (1.1 g, 5.97 mmol), and K2CO3 (553 mg, 4 mmol). The obtained crude product was used without further purification in the next reaction step.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]3[CH:23]=[CH:22][C:17]([C:18](OC)=[O:19])=[C:16]([O:24][CH2:25][O:26][CH3:27])[CH:15]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][C:14]3[CH:23]=[CH:22][C:17]([CH2:18][OH:19])=[C:16]([O:24][CH2:25][O:26][CH3:27])[CH:15]=3)=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: COCOc1cc(CCc2ccc(OCC3CC3)cc2)ccc1C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1cc(CCc2ccc(OCC3CC3)cc2)ccc1CO
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.3 %

Procedure:
A solution of methyl 2-(methoxymethoxy)-4-[(4-benzyloxyphenyl)ethynyl]benzoate (7.37 g, 18.3 mmol) obtained in Reference Example 277 and 10% palladium carbon (50% water-containing product, 11.0 g) in ethanol (50 mL)-THF (10 mL) was stirred under a hydrogen atmosphere (normal pressure) for 2 hr. After filtration of the reaction mixture, the filtrate was concentrated under reduced pressure. To a solution of the obtained residue in DMF (50 mL) were added potassium carbonate (7.63 g, 55.2 mmol) and bromomethylcyclopropane (3.60 mL, 36.7 mmol) and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed three times with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by basic silica gel column chromatography (hexane:ethyl acetate=9:1 to 1:1) to give methyl 4-{2-[4-(cyclopropylmethoxy)phenyl]ethyl}-2-(methoxymethoxy)benzoate (4.69 g, yield 69%). A solution of methyl 4-{2-[4-(cyclopropylmethoxy)phenyl]ethyl}-2-(methoxymethoxy)benzoate (4.69 g, 12.7 mmol) in THF (10 mL) was added to a suspension of lithium aluminum hydride (481 mg, 12.7 mmol) in THF (30 mL), and the mixture was stirred at room temperature for 15 min. To the reaction mixture were successively added water (0.48 mL), 15% aqueous sodium hydroxide solution (0.48 mL) and water (1.5 mL), and the mixture was stirred at room temperature for 30 min. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3 to 0:1) to give the title compound (4.23 g, yield 97%) as an oil.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6](O)=[O:7])(=[O:3])[CH3:2].ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.[NH:32]1[CH2:38][CH2:37][CH2:36][C@H:33]1[CH2:34][OH:35]>C1COCC1>[C:1]([NH:4][CH2:5][C:6]([N:32]1[CH2:38][CH2:37][CH2:36][C@H:33]1[CH:34]=[O:35])=[O:7])(=[O:3])[CH3:2]
Reactant: OC[C@@H]1CCCN1
Reactant: CC(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Product: CC(=O)NCC(=O)N1CCC[C@H]1C=O
Temperature: 4 °C
Reaction time: 21 h

Procedure:
In 150 ml of THF was dissolved 11.7 g of acetyl-glycin. To this solution were added 11.5 g of HOSu and 20.6 g of DCC, and the mixture was stirred for 21 hours at 4° C. The reaction liquid was filtered and the filtrate was evaporated under reduced pressure whereby a semi-solid substance was obtained. This substance was recrystallized from chloroform to obtain a white solid substance which was then dissolved in 350 ml of THF. To this solution was added 4.2 g of L-prolinol, and the mixture was stirred for 72 hours at room temperature. After removal of THF by distillation, the residue was dissolved in 200 ml of ethyl acetate and the solution was washed with 100 ml of 1-M Na2CO3, dehydrated with anhydrous Na2SO4 and evaporated until dryness. To the resultant oily substance were added 18.6 g of WSCD.HCl and 75 ml of redistilled DMSO, and the mixture was stirred for 10 minutes. Subsequently, 3.2 ml of a DMSO solution of 2-M anhydrous H3PO4 was added and the mixture was stirred for further 2 hours. The reaction was stopped with 160 ml of a buffer solution of 1-M potassium phosphate of pH 7.5. The reaction mixture was extracted with 150 ml of ethyl acetate, and the extract was dried over anhydrous Na2SO4. The ethyl acetate was distilled off and the residue was dissolved in 100 ml of ethanol. To this solution was added 50 g of NaHOS3 in 90 ml of water, and the mixture was stirred vigorously for 10 minutes. After concentration of the ethanol up to about 90 ml, unreacted materials were eliminated twice with 60 ml of ether, and solid Na2CO3 was added until the pH value of the liquid became 9. After 5 minutes, the reaction liquid was extracted twice with 60 ml of ether, and the ether was then distilled off to leave an oily substance. Yield 0.3 g (1.5%).
Reaction SMILES: [Cl:1][C:2]1[O:6][C:5]([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18](O)=[O:19])[O:9][N:8]=2)=[CH:4][CH:3]=1.N#N.[OH-].[Na+].OO>C1COCC1.O>[Cl:1][C:2]1[O:6][C:5]([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([CH2:18][OH:19])[O:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1onc(-c2ccc(Cl)o2)c1-c1ccccc1
Agent: N#N
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1onc(-c2ccc(Cl)o2)c1-c1ccccc1
Yield: 52 %

Procedure:
A 2M solution of the borane-dimethylsulphide complex in THF (1.72 ml, 3.44 mmoles) is added drop wise to the [3-(5-chlorofuran-2-yl)-4-phenylisoxazol-5-yl]carboxylic acid (500 mg, 1.73 mmoles) solubilised in anhydrous THF (6 ml) and kept stirring at 0° C. in an atmosphere of N2. The reaction mixture is brought to ambient temperature and kept stirring. After 15 hours more BMS is added (1.72 ml), and after 9 more hours the reaction is blocked by adding H2O (10 ml), NaOH 3N (10 ml) and H2O2 (30% w/w, 10 ml). The mixture is kept stirring for 30 minutes. The two phases are separated and the aqueous phase is extracted three times with ethyl acetate. The combined organic extracts are dried over Na2SO4 and the solvent distilled in a vacuum. The residue (470 mg) subjected to column chromatography (silica gel, petroleum ether/ethyl acetate=9:1 until 1:1, modified with the elution of the products) gives the product which is crystallised cold from ethyl acetate/hexane (1:1) with a final yield of 52%, the equivalent of 248 mg. M.p. 102-103° C. FT-IR (KBr): 3600-3210, 3144, 3128, 3054, 2927, 1594, 1511, 1447, 1405, 1356, 1289, 1216, 1129, 1019, 1010, 942, 925, 902, 802, 769, 702 cm−1. 1H NMR (400 MHz, CDCl3, δ): 7.45-7.41 (m, 3H, aromatic protons); 7.35-7.30 (m, 2H, aromatic protons); 6.28 (d, J=3.4 Hz, 1H, furyl proton); 6.12 (d, J=3.4 Hz, 1H, furyl proton); 4.65 (s, 2H, CH2OH); 2.30-2.05 (bs, 1H, OH: exchange with D2O). 13C NMR (100 MHz, CDCl3, δ): 167.6, 152.5, 143.2, 138.9, 130.2, 129.1, 129.0, 128.5, 116.6, 114.3, 108.2, 54.8. GC-MS (70 eV) m/z (rel.int.): 277 [M(37Cl)+, 33], 275 [M(35Cl)+, 100], 246 (12), 244 (32), 238 (14), 218 (14), 217 (16), 216 (32), 212 (29), 211 (31), 190 (21), 188 (58), 183 (10), 182 (11), 180 (10), 154 (42), 153 (38), 152 (35), 129 (18), 128 (14), 127 (25), 91 (14), 89 (42), 77 (13), 63 (11). Anal. Calc. for C14H10ClNO3: C, 60.99; H. 3.66; N, 5.08. Found: C, 61.00; H, 3.62; N, 5.06.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1)=[O:5].[F:19][C:20]([F:32])([F:31])[C:21]1[CH:22]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1>>[CH3:14][N:10]1[CH:11]=[CH:12][N:13]=[C:9]1[CH2:8][CH2:7][NH:6][C:4](=[O:5])[C:3]1[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=1[NH:1][S:27]([C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:19])([F:31])[F:32])[CH:22]=1)(=[O:29])=[O:28]
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: Cn1ccnc1CCNC(=O)c1ccccc1N
Product: Cn1ccnc1CCNC(=O)c1ccccc1NS(=O)(=O)c1cccc(C(F)(F)F)c1
Yield: 87.1 %

Procedure:
The titled compound was prepared substantially in accordance with the method set forth in Example 1C using 4.84 g (0.0198 mol) of 2-amino-N-[2-(1-methyl-1H-imidazol-2-yl)ethyl]benzamide (prepared in a similar manner as the compound in Example 6A) and 5.25 g (0.0215 mol) of m-trifluoromethylbenzenesulfonyl chloride. After reducing the organic layer to dryness, the resulting yellow solid was recrystallized from an ethyl acetate/diethyl ether solution to provide 7.8 g of the desired titled compound (m.p. 127°-129° C.)
Reaction SMILES: [N:1]1[C:10]2[C:5](=[C:6]([C:11]([C:13]3[N:14]=[CH:15][N:16](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:17]=3)=[O:12])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)(=O)C.O>[NH:16]1[CH:17]=[C:13]([C:11]([C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[CH:4]=[CH:3][CH:2]=[N:1]3)=[O:12])[N:14]=[CH:15]1
Reactant: O=C(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1cccc2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=C(c1c[nH]cn1)c1cccc2ncccc12

Procedure:
Quinolin-5-yl-(1-trityl-1H-imidazol-4-yl)-methanone (Intermediate G1) in acetic acid:water (˜2:1) was heated to 100° C. for 1 h. The mixture was basified with 1 M NaOH and extracted (6×) with CHCl3:iPrOH (3:1). The organic solution was dried over MgSO4, filtered, and concentrated onto silica gel. The material was eluted from a column of silica with 5% NH3-MeOH:CH2Cl2 to give (1H-imidazol-4-yl)-quinolin-5-yl-methanone (Intermediate G2).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[Br:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([Br:29])[CH:28]=1)[CH2:24]Br>>[Br:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([Br:29])[CH:28]=1)[CH2:24][N:7]1[C:8]([O:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18]
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: BrCc1cc(Br)cc(Br)c1
Product: CCc1c(Oc2cc(C)cc(C)c2)n(Cc2cc(Br)cc(Br)c2)c(=O)[nH]c1=O
Yield: 73.9 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 3,5-dibromobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (375 mg, yield: 73.9%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=1.[CH3:18][C:19]([SH:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:19]([S:22][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=1)([CH3:21])([CH3:20])[CH3:18]
Reactant: CC(C)(C)C(=O)Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)Sc1ccc([N+](=O)[O-])c(NC(=O)C(C)(C)C)c1
Temperature: 100 °C
Reaction time: 17 h
Yield: 88.1 %

Procedure:
A mixture of N-(5-chloro-2-nitropheny)-2,2-dimethylpropanamide (Step A, 1.54 g, 6.0 mmol), 2-methyl-2-propanethiol (675 μL, 6.0 mmol) and potassium carbonate (993 mg, 7.2 mmol) in N,N-dimethylformamide (25 mL) was stirred in a sealed tube at 100° C. for 17 h. Water (20 mL) was added and precipitate was collected by filtration and dried in vacuo at 50° C. to afford the title compound (1.64 g, 88%) as an orange solid.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][C:4]2[O:8][C:9]3[C:15](=[N+:16]([O-])[C:3]=2[CH:2]=1)[CH:14]=[CH:13][C:11](=[O:12])[CH:10]=3>O.[NH4+].[OH-].[Zn]>[OH:7][C:6]1[CH:5]=[C:4]2[C:3](=[CH:2][CH:1]=1)[N:16]=[C:15]1[C:9](=[CH:10][C:11](=[O:12])[C:13]([CH2:4][CH2:5][CH2:6][OH:7])=[CH:14]1)[O:8]2
Reactant: O=c1ccc2[n+]([O-])c3ccc(O)cc3oc-2c1
Agent: [NH4+]
Agent: [OH-]
Agent: [Zn]
Solvent: O
Product: O=c1cc2oc3cc(O)ccc3nc-2cc1CCCO
Reaction time: 0.33 h

Procedure:
The crude resazurin compound was suspended in a mixture of 200 mL of water and 50 mL of conc. NH4OH. Zinc dust (2.0 g) was added and the suspension was stirred for 20 min. The resultant purple mixture was filtered, the filtrate was vigorously stirred on air to oxidize the leuco resorufin, the product of partial over reduction. The reaction was acidified with acetic acid, the brown solid formed was collected by filtration washed with water and dried. The yield was 2.1 g. The material contained ˜50% of 2,3,4-trihydro-2H-pyrano[3,2-b]phenoxazin-9-one, product of intramolecular cyclization which had been carried over from the first step. The rest of the material was the desired title compound 35.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[NH:11][C:10]2[C:12]([CH:27]3[CH2:31][CH2:30][CH2:29][O:28]3)=[C:13]([F:26])[C:14]([C:16]3[CH:17]=[N:18][C:19]([C:22]([OH:25])([CH3:24])[CH3:23])=[N:20][CH:21]=3)=[CH:15][C:9]=2[N:8]=1)=[O:5])[CH3:2]>CCO.CCOCC>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[NH:11][C:10]2[C:12]([C@H:27]3[CH2:31][CH2:30][CH2:29][O:28]3)=[C:13]([F:26])[C:14]([C:16]3[CH:17]=[N:18][C:19]([C:22]([OH:25])([CH3:24])[CH3:23])=[N:20][CH:21]=3)=[CH:15][C:9]=2[N:8]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(C(C)(C)O)nc3)c(F)c(C3CCCO3)c2[nH]1
Solvent: CCOCC
Solvent: CCO
Product: CCNC(=O)Nc1nc2cc(-c3cnc(C(C)(C)O)nc3)c(F)c([C@H]3CCCO3)c2[nH]1
Reaction time: 0.17 h
Yield: 45.4 %

Procedure:
A racemic sample of 1-ethyl-3-[6-fluoro-5-[2-(1-hydroxy-1-methyl-ethyl)pyrimidin-5-yl]-7-tetrahydrofuran-2-yl-1H-benzimidazol-2-yl]urea (133.60 g) was resolved on a CHIRALPAK® IC® column (by Chiral Technologies) eluting with DCM/MeOH/TEA (60/40/0.1) at 25° C. giving the desired enantiomer as an off-white solid (66.8 g, 99.8% HPLC purity, 99+% ee). Analytical chiral HPLC retention time was 7.7 min (CHIRALPAK® IC® 4.6×250 mm column, 1 mL/min flow rate, 30° C.). The solid was suspended in 2:1 EtOH/Et2O (5 volumes), stirred for 10 minutes, collected by filtration, washed with 2:1 EtOH/Et2O, and dried under reduced pressure giving a white solid (60.6 g). 1H NMR (300 MHz, MeOD) δ 8.95 (d, J=1.6 Hz, 2H), 7.45 (d, J=6.5 Hz, 1H), 5.38 (br.s, 1H), 4.27 (dd, J=14.9, 7.1 Hz, 1H), 4.01 (dd, J=15.1, 7.0 Hz, 1H), 3.37-3.29 (m, 2H), 2.55 (br.s, 1H), 2.19-2.07 (m, 2H), 2.02-1.82 (br.s, 1H), 1.63 (s, 6H), 1.21 (t, J=7.2 Hz, 3H) ppm.
Reaction SMILES: C([O:3][C:4](=[O:22])[C:5]([OH:21])([C:17]([F:20])([F:19])[F:18])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)([CH3:9])[CH3:8])C.[CH3:23][N:24](C)C=O>[C-]#N.[Zn+2].[C-]#N>[C:23]([C:13]1[CH:14]=[CH:15][C:10]([C:7]([CH3:8])([CH3:9])[CH2:6][C:5]([OH:21])([C:17]([F:18])([F:19])[F:20])[C:4]([OH:3])=[O:22])=[CH:11][CH:12]=1)#[N:24]
Reactant: CN(C)C=O
Reactant: CCOC(=O)C(O)(CC(C)(C)c1ccc(Br)cc1)C(F)(F)F
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(CC(O)(C(=O)O)C(F)(F)F)c1ccc(C#N)cc1

Procedure:
From 4-(4-bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid ethyl ester, zinc cyanide and tetrakis-triphenylphosphine-palladium in dimethylformamide at 140° C. After saponification, the title acid is obtained as a foam.
Reaction SMILES: [OH:1][C:2]1[C:10]([N+:11]([O-])=O)=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:14][C@@H:15]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:16])=[CH:4][CH:3]=1.C(O)(=O)C>[Fe].O>[NH2:11][C:10]1[C:2]([OH:1])=[CH:3][CH:4]=[C:5]2[C:9]=1[N:8]([CH2:14][C@@H:15]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH3:16])[N:7]=[CH:6]2
Reactant: C[C@@H](Cn1ncc2ccc(O)c([N+](=O)[O-])c21)NC(=O)OCc1ccccc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: C[C@@H](Cn1ncc2ccc(O)c(N)c21)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product from Step C (0.20 g, 0.54 mmol) was combined with acetic acid (5 mL), water (5 mL), and iron powder (0.30 g mmol) and stirred at room temperature for 1 h. The reaction mixture was filtered and evaporated to a dark oil (0.47 g) which was was used in the next reaction: LC/MS m/z 341.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9])(=[O:3])[CH3:2].C(N(CC)CC)C.C[Si](C)(C)Cl.[C:22](Cl)([Cl:24])=[O:23]>C1C=CC=CC=1>[C:1]([N:4]1[CH2:8][CH2:7][N:6]([C:22]([Cl:24])=[O:23])[C:5]1=[O:9])(=[O:3])[CH3:2]
Reactant: O=C(Cl)Cl
Reactant: CC(=O)N1CCNC1=O
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(=O)N1CCN(C(=O)Cl)C1=O
Reaction time: 18 h

Procedure:
20 parts by weight of N-acetyl-imidazolid-2-one mixed with 25 parts by weight of triethylamine and 150 parts by volume of dry benzene were first taken and 27 parts by weight of trimethylchlorosilane in 40 parts by volume of benzene were added dropwise at room temperature over the course of 30 minutes, with stirring. The mixture was subsequently boiled for 18 hours under reflux, moisture being excluded, and the triethylamine hydrochloride which precipitated (22 parts by weight = 100%) was filtered off after cooling and carefully rinsed with dry benzene. The benzene solution thus obtained was treated with a solution of 17 parts by weight of phosgene in 50 parts by volume of benzene at 5° C and left to stand overnight at 5° C. Thereafter the solvent was stripped off in vacuo and the residue was dried under an oil pump. It was recrystallized from acetone/pentane mixture.