Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11].[C:15](#[N:17])[CH3:16]>>[OH:11][CH:10]([C:9]1[CH:12]=[CH:13][CH:14]=[C:7]([O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[CH:8]=1)[CH2:16][C:15]#[N:17]
Reactant: CC#N
Reactant: COCCCOc1cccc(C=O)c1
Product: COCCCOc1cccc(C(O)CC#N)c1

Procedure:
Addition of acetonitrile to 3-(3-methoxypropoxy)benzaldehyde gave 3-hydroxy-3-(3-(3-methoxypropoxy)phenyl)propanenitrile as a yellow oil. Yield (0.86 g, 52%): 1H NMR (400 MHz, CDCl3) δ 7.26-7.32 (m, 1H), 6.86-6.97 (m, 3H), 5.02-5.03 (m, 1H), 4.06 (t, J=6.2 Hz, 2H), 3.55 (t, J=6.0 Hz, 2H), 3.35 (s, 3H), 2.75 (d, J=6.2 Hz, 2H), 2.03-2.09 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].[CH2:17]([O:19][CH:20]([C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1)[C:21](N(OC)C)=[O:22])[CH3:18]>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][C:12]([C:21](=[O:22])[CH:20]([O:19][CH2:17][CH3:18])[C:27]3[CH:28]=[CH:29][C:30]([N:33]4[CH2:34][CH2:35][O:36][CH2:37][CH2:38]4)=[CH:31][CH:32]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COc1cc(-c2ccco2)cc(OC)c1Cl
Reactant: CCOC(C(=O)N(C)OC)c1ccc(N2CCOCC2)cc1
Product: CCOC(C(=O)c1ccc(-c2cc(OC)c(Cl)c(OC)c2)o1)c1ccc(N2CCOCC2)cc1

Procedure:
1-(5-(4-Chloro-3,5-dimethoxyphenyl)furan-2-yl)-2-ethoxy-2-(4-morpholinophenyl)ethanone was prepared from 2-(4-chloro-3,5-dimethoxyphenyl)furan and 2-ethoxy-N-methoxy-N-methyl-2-(4-morpholinophenyl)acetamide according to the procedure used in Example 30. Purification by chromatography (60% EtOAc-hexanes) gave the product as a pale yellow solid (0.127 g, 26% yield). MS: m/z 486.5 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([OH:25])[C@@H:14]([CH2:26][O:27][S:28]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[O:13][C@@H:10]1[O:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:45](Cl)(=[O:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.Cl>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:45]([O:25][C@@H:15]1[C@@H:14]([CH2:26][O:27][S:28]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[O:13][C@H:10]([O:11][CH3:12])[C@H:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@H:16]1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CO[C@H]1O[C@H](COS(=O)(=O)c2ccc(C)cc2)[C@@H](O)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CO[C@H]1O[C@H](COS(=O)(=O)c2ccc(C)cc2)[C@@H](OC(=O)c2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
Methyl 2,3-di-O-benzyl-6-O-p-toluenesulfonyl-α-D-glucopyranoside (J. Org. Chem., 2001, 66, 5965-5975) (163.9 g, 310 mmol) was dissolved in methylene chloride (1.5 L) and 4-dimethylaminopyridine (43.5 g, 352 mmol) and triethylamine (49.0 mL, 352 mmol) were added thereto. Benzoyl chloride (43.2 mL, 372 mmol) was dropwise thereto and the mixture was stirred at 0° C. for 1 hour. After diluted hydrochloric acid (2N, 500 mL) was added to the reaction mixture and the mixture was extracted with methylene chloride (1 L), the organic layer was washed with saturated aqueous sodium hydrogencarbonate (1 L) and saturated brine (1 L) and dried with anhydrous sodium sulfate, followed by distilling off of the solvent under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane:ethyl acetate, 1:1, V/V) to obtain the desired title compound (196 g, yield 99%) as a colorless solid.
Reaction SMILES: [C:1](=[O:22])([O:3][C@H:4]([CH:8]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)[C:5]([NH2:7])=O)[NH2:2].C(=O)([O-])O.[Na+].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:29]>C(COC)OC>[C:1](=[O:22])([O:3][C@H:4]([CH:8]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)[C:5]([NH2:7])=[S:29])[NH2:2]
Reactant: CC(C)(C)C(c1c[nH]c2ccccc12)[C@@H](OC(N)=O)C(N)=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)C(c1c[nH]c2ccccc12)[C@@H](OC(N)=O)C(N)=S
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (R)-tert-butyl-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl carbamate (6.80 g, 22.4 mmol) in anhydrous dimethoxyethane (100 mL) was mixed in portions with sodium hydrogencarbonate (7.14 g, 85.1 mmol) and diphosphorus pentasulphide (10.2 g, 44.8 mmol) and stirred overnight at room temperature. The reaction mixture was concentrated to low volume in a vacuum, the residue taken up in ethyl acetate (100 mL) and washed with water and saturated sodium hydrogencarbonate solution (3×50 mL each). The organic phase was dried with sodium sulphate and concentrated to low volume in a vacuum. The raw product was taken up in diethyl ether/cyclohexane (50 mL each) and concentrated to low volume again. During this, the product separated out as a white solid, which was filtered off.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:9][C:10]1[CH:24]=[CH:23][C:13]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[O:15])=[CH:12][CH:11]=1.Cl>C(OC)(C)(C)C>[F:9][C:10]1[CH:24]=[CH:23][C:13]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[OH:15])=[CH:12][CH:11]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: Br[Mg]c1ccccc1
Agent: Cl
Solvent: COC(C)(C)C
Product: OC(c1ccccc1)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
Phenylmagnesium bromide (100 mL, 0.1 mol) was added dropwise to a stirring solution of 4,4′-difluorobenzophenone (20 g, 0.092 mol) in t-butylmethyl ether (150 mL) at rt. After the addition was complete the reaction was heated at reflux for 3 h. The solution was cooled to rt and was poured in to ice cold aqueous 1.0 M HCl (100 mL). The organics were extracted with EtOAc (2×50 mL) and dried (Na2SO4). Concentration under reduced pressure gave bis(4-fluorophenyl)phenylmethanol as a pale brown oil. After drying in vacuo for 2 h the crude material was used in the next reaction without any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])[C:10]([CH3:18])=[C:11]([C:13]([O:15]CC)=O)[N:12]=2)=[CH:4][CH:3]=1.[Li+].[OH-].O=S(Cl)[Cl:31]>O.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])[C:10]([CH3:18])=[C:11]([C:13]([Cl:31])=[O:15])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2)n(-c2ccc(Cl)cc2Cl)c1C
Reactant: O=S(Cl)Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(=O)Cl)nc(-c2ccc(Cl)cc2)n1-c1ccc(Cl)cc1Cl
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Part B: Ethyl 2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-5-methyl-1H-imidazole-4-carboxylate (0.250 gram, 0.61 mmol) and LiOH (0.052 gram, 2.17 mmol) are dissolved in H2O/THF (1:1 (v/v); 50 mL) and stirred at 50° C. for one hour. The mixture is concentrated to give crude 2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-5-methyl-1H-imidazole-4-carboxylic acid. To this mixture is added SOCl2 (50 mL) and the resulting mixture is heated at reflux temperature for 1 hour. The mixture is concentrated to give 2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-5-methyl-1H-imidazole-4-carbonyl chloride.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:24])=[N:5]1)([CH3:3])[CH3:2].Cl.[F:26][C:27]1([F:35])[CH2:31][NH:30][C@H:29]([C:32]([NH2:34])=[O:33])[CH2:28]1.CO>C(Cl)Cl>[F:26][C:27]1([F:35])[CH2:31][N:30]([C:21]2[N:20]=[CH:19][C:16]3[C:17]4[N:11]([CH:10]=[C:9]([C:8]5[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=[C:6]([CH3:24])[N:7]=5)[N:18]=4)[CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)[C@H:29]([C:32]([NH2:34])=[O:33])[CH2:28]1
Reactant: NC(=O)[C@@H]1CC(F)(F)CN1
Reactant: Cc1nc(-c2cn3c(n2)-c2cnc(O)cc2OCC3)n(C(C)C)n1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: Cc1nc(-c2cn3c(n2)-c2cnc(N4CC(F)(F)C[C@H]4C(N)=O)cc2OCC3)n(C(C)C)n1
Yield: 17 %

Procedure:
Following the procedures of Example 339, 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol and 4,4-difluoro-L-prolinamide hydrochloride with added TEA (2.5 eq.) were reacted and the crude product subjected to flash chromatography (SiO2, gradient 0 to 5% methanol in DCM) to give 383 as a white solid (29 mg, 17%). LCMS: RT=3.14 min, [M+H]+=459. 1H NMR 400 MHz (DMSO-d6) δ: 9.09 (1 H, s), 7.85 (1 H, d, J=0.64 Hz), 7.55 (1 H, br), 7.15 (1 H, br), 6.05 (1 H, s), 5.93-5.81 (1 H, m), 4.61 (1 H, dd, J=9.53, 4.24 Hz), 4.58-4.49 (4 H, m), 4.00-3.98 (2 H, m), 2.91-2.90 (1 H, m), 2.45 (1 H, dd, J=13.51, 4.18 Hz), 2.25 (3 H, s), 1.49 (6 H, dd, J=6.59, 3.35 Hz)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]4[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[C:17]([CH3:23])[N:16]=4)[N:14]=[C:7]3[C:6]=2[CH:24]=1.[F:25][C:26]1[N:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[F:25][C:26]1[N:31]=[CH:30][C:29]([C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][N:8]4[CH:12]=[C:13]([C:15]5[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[C:17]([CH3:23])[N:16]=5)[N:14]=[C:7]4[C:6]=3[CH:24]=2)=[CH:28][CH:27]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(Br)ccc2OCC3)n(C(C)C)n1
Product: Cc1nc(-c2cn3c(n2)-c2cc(-c4ccc(F)nc4)ccc2OCC3)n(C(C)C)n1
Yield: 39 %

Procedure:
10-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine was reacted with 6-fluoropyridin-3-ylboronic acid to give 10-(6-fluoropyridin-3-yl)-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (0.121 g, 39%). 1H NMR (500 MHz, DMSO) δ 8.67 (d, J=2.4, 1H), 8.52 (d, J=2.6, 1H), 8.25 (td, J=8.2, 2.7, 1H), 7.92 (s, 1H), 7.68 (dd, J=8.5, 2.5, 1H), 7.31 (dd, J=8.4, 2.8, 1H), 7.19 (d, J=8.5, 1H), 5.69 (dt, J=13.3, 6.6, 1H), 4.56 (s, 4H), 2.26 (s, 3H), 1.47 (d, J=6.6, 6H). MS (ESI(+)): m/z 405.2 (M+H)
Reaction SMILES: [OH:1]O.O.S(=O)(=O)(O)O.[CH3:9][C:10]([OH:16])([CH3:15])[C:11]([CH3:14])([CH3:13])[CH3:12]>ClCCl>[CH3:9][C:10]([O:16][OH:1])([CH3:15])[C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: OO
Reactant: CC(C)(C)C(C)(C)O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)C(C)(C)OO
Reaction time: 2 h
Yield: 91.7 %

Procedure:
A 300-ml four-necked flask equipped with a stirrer, thermometer and dropping funnel was charged with 73.7 g of a 50% hydrogen peroxide aqueous solution. Stirring was started, the flask was kept at a temperature below 20° C. by water cooling, and 51.7 g of 98% conc. sulfuric acid was added dropwise to form a mixed acid. While the flask was cooled at a temperature of 0° to 5° C. with an ice bath, with stirring, 40 ml of a dichloromethane solution containing 42.9 g of 1,1,2,2-tetramethylpropyl alcohol which was previously synthesized according to Journal of the American Chemical Society/89:7/Mar. 29, 1967, was slowly added dropwise. At the end of addition, stirring was continued for a further 2 hours. The reaction solution was washed with pure water until the organic layer became neutral. The organic layer was dried over anhydrous sodium sulfate and distilled of the solvent, yielding 47.4 g of 1,1,2,2-tetramethylpropylhydroperoxide having structural formula (2).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=1>[Cu].ClC1C=CC=CC=1Cl>[C:5]1([CH3:6])[CH:15]=[CH:16][CH:2]=[CH:3][C:4]=1[NH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH3:17])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(=O)c2ccc(N)cc2)cc1
Reactant: Cc1ccc(I)cc1
Agent: [Cu]
Solvent: Clc1ccccc1Cl
Product: Cc1ccccc1Nc1ccc(C(=O)c2ccc(Nc3ccccc3C)cc2)cc1
Temperature: 180 °C
Yield: 277.8 %

Procedure:
4.4 g of 4,4'-diaminobenzophenon, 30.9 g of P-iodotoluene, 19.5 g of potassium carbonate anhydride and 10 g of copper powder were added to 70 ml of o-dichlorobenzene, and the mixture thus obtained was refluxed with stirring for twenty-four hours at 180° C. After the reaction, the mixture was filtered and washed with ethyl acetate. Then, the mixture was separated by silica gel column chromatography using chloroform, thereby obtaining 11.3 g of 4,4'-ditolylaminobenzophenon.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:2]=1[Cl:1]
Reactant: O=C(O)c1ccc(O)cc1Cl
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(O)cc1Cl
Reaction time: 24 h

Procedure:
A solution of 2-chloro-4-hydroxy-benzoic acid (3.70 g, 21.4 mmol)) in methanol (50 ml) was treated with thionyl chloride (2.4 ml, 32 mmol) dropwise and stirred for 24 hours and the solvents were removed in vacuo. The residue was dissolved in ethyl acetate and washed with sat. sodium hydrogen carbonate, dried and solvents were removed in vacuo. The residue was purified by column chromatography on silica gel (eluant with 30% EtOAc:70% cyclohexane) to yield the desired product as a yellow solid, 3.68 g, 92%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][CH:6]=1.[Cl:14][C:15]1[C:20]([O:21][CH2:22][CH:23]2[O:25][CH2:24]2)=[N:19][CH:18]=[CH:17][N:16]=1>C(O)(C)C>[C:9]([C:8]1[CH:12]=[CH:13][C:5]([O:4][CH2:3][CH2:2][NH:1][CH2:24][CH:23]([OH:25])[CH2:22][O:21][C:20]2[C:15]([Cl:14])=[N:16][CH:17]=[CH:18][N:19]=2)=[CH:6][CH:7]=1)(=[O:10])[NH2:11]
Reactant: Clc1nccnc1OCC1CO1
Reactant: NCCOc1ccc(C(N)=O)cc1
Solvent: CC(C)O
Product: NC(=O)c1ccc(OCCNCC(O)COc2nccnc2Cl)cc1

Procedure:
A solution of 9.0 g of 4-(2-aminoethoxy)-benzamide in 120 ml of isopropanol is heated to the reflux temperature and a solution of 9.3 g of 2-chloro-3-(2,3-epoxy-propoxy)-pyrazine in 120 ml of isopropanol is added dropwise; duration of the addition: 5 hours. Thereafter the reaction mixture is heated to the reflux temperature for a further 7 hours. After completion of the reaction, the mixture is evaporated under a waterpump vacuum. The residue crystallises from ethyl acetate and gives 1-[2-(4-carbamoylphenyl-oxy)-ethyl-amino]-3-(2-chloro-3-pyrazinyloxy)-2-propanol, melting point 134°-135° C. after recrystallisation from isopropanol. The hydrochloride prepared therefrom using the calculated amount of methanolic hydrochloric acid melts at 223°-225° C. after crystallisation from a mixture of methanol and acetone.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH2:22][CH:23]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:24][OH:25]>>[OH:25][CH2:24][CH:23]([NH:22][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21])[CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: CCCCC(N)CO
Product: CCCCC(CO)Nc1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1[N+](=O)[O-]
Yield: 61 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with 2-amino-hexan-1-ol according to the GPA affording 24 mg (61%) of a purple powder. Rt=4.5 min.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]([C:28]1[S:29][CH:30]=[C:31]([C:33]([N:35]2[CH2:40][C:39]3([CH2:45][CH2:44][N:43]([CH2:46][CH2:47][C:48]4[CH:61]=[CH:60][C:51]([CH2:52][CH2:53][O:54][CH2:55][CH2:56][C:57](O)=[O:58])=[CH:50][CH:49]=4)[CH2:42][CH2:41]3)[O:38][CH2:37][CH2:36]2)=[O:34])[N:32]=1)([CH3:27])[CH3:26].[CH3:62][O:63][CH:64]([O:73][CH3:74])[CH2:65][NH:66][CH:67]1[CH2:72][CH2:71][CH2:70][CH2:69][CH2:68]1.C(N(CC)CC)C>CN(C=O)C>[CH:67]1([N:66]([CH2:65][CH:64]([O:73][CH3:74])[O:63][CH3:62])[C:57](=[O:58])[CH2:56][CH2:55][O:54][CH2:53][CH2:52][C:51]2[CH:60]=[CH:61][C:48]([CH2:47][CH2:46][N:43]3[CH2:42][CH2:41][C:39]4([O:38][CH2:37][CH2:36][N:35]([C:33]([C:31]5[N:32]=[C:28]([CH:25]([CH3:26])[CH3:27])[S:29][CH:30]=5)=[O:34])[CH2:40]4)[CH2:45][CH2:44]3)=[CH:49][CH:50]=2)[CH2:72][CH2:71][CH2:70][CH2:69][CH2:68]1
Reactant: COC(CNC1CCCCC1)OC
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCc4ccc(CCOCCC(=O)O)cc4)CC3)C2)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(CN(C(=O)CCOCCc1ccc(CCN2CCC3(CC2)CN(C(=O)c2csc(C(C)C)n2)CCO3)cc1)C1CCCCC1)OC
Temperature: 20 °C
Reaction time: 1 h

Procedure:
HATU (0.23 g) was added in one portion to an ice cold solution of 3-(4-(2-(4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethyl)phenethoxy)propanoic acid [Example 1, step e] (0.3 g) and N-(2,2-dimethoxyethyl)cyclohexanamine [WO 2008075025] (0.087 g) and triethylamine (0.26 mL) in DMF (10 mL). The mixture was stirred at 20° C. for 1 hour before being partitioned between ethyl acetate and brine. The organic layer was washed with brine (×2), dried, filtered and the solvent evaporated under reduced pressure to afford the subtitled compound. Yield 0.32 g.
Reaction SMILES: [H-].[Na+].C1(S)C=CC=CC=1.C[O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[N:18]=[CH:17][N:16]=[C:15]2[N:24]1[CH2:29][CH2:28][CH:27]([N:30]2[C:39](=[O:40])[C:38]3[C:33](=[CH:34][CH:35]=[C:36]([CH3:41])[CH:37]=3)[N:32]([CH3:42])[C:31]2=[O:43])[CH2:26][CH2:25]1.O>CN(C=O)C>[OH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[N:18]=[CH:17][N:16]=[C:15]2[N:24]1[CH2:29][CH2:28][CH:27]([N:30]2[C:39](=[O:40])[C:38]3[C:33](=[CH:34][CH:35]=[C:36]([CH3:41])[CH:37]=3)[N:32]([CH3:42])[C:31]2=[O:43])[CH2:26][CH2:25]1
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)c2cc1OC
Agent: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2ncnc(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)c2cc1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 22.6 %

Procedure:
In 5 ml of DMF was suspended 360 mg (9.0 mmol) of 60% sodium hydride, and a solution of 0.92 ml (9.0 mmol) of thiophenol in 10 ml of DMF was added dropwise to the suspension under ice cooling. After stirring for 10 minutes, a solution of 1.38 g (3.0 mmol) of Compound 50 obtained in Example 41 in 10 ml of DMF was added thereto under ice cooling, followed by stirring at 100° C. for 10 hours. After the reaction mixture was cooled to room temperature, water was added thereto, and the mixture was extracted with chloroform. The aqueous layer was adjusted to pH 5 by addition of 4N hydrochloric acid and extracted with chloroform. The combined organic layer was washed with an aqueous solution of sodium chloride and dried. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol=50/1). The compound eluted as a component with low polarity was recrystallized from ether to give 302.8 mg (yield: 23%) of Compound 90 as white crystals. The substance eluted as a component with high polarity was recrystallized from ether/ethanol to give 787.9 mg (yield: 59%) of Compound 89 as white crystals.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[CH3:22][C:23]([CH3:37])([CH2:26][O:27][CH2:28][CH:29]=[CH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:24][OH:25].C(OCC)C>C(Cl)Cl>[CH3:22][C:23]([CH3:37])([CH2:26][O:27][CH2:28][CH:29]=[CH:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH:24]=[O:25]
Reactant: CC(C)(CO)COCC=Cc1ccccc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C=O)COCC=Cc1ccccc1

Procedure:
In a dry three-neck flask equipped with a mechanical stirrer and an addition funnel was placed 128 g of pyridinium dichromate and 320 ml of dry CH2Cl2. The mixture was vigorously stirred and a solution of 32.37 g (0.147 mole) of 2,2-dimethyl-3-(3-phenyl-2-propenoxy)propanol, the product of Example 10a, in 50 ml of CH2Cl2 was added in one portion. The reaction mixture was stirred at room temperature for three days and then was poured into 400 ml of ethyl ether. The resulting mixture was filtered through a column packed with dry silica gel to obtain a yellow filtrate. The filtrate was concentrated to obtain a yellow residue. Kugelrohr distillation of the residue gave the title compound, bp 90°/0.05 mm Hg.
Reaction SMILES: [C:1]([O-:4])(O)=[O:2].[Na+].[NH2:6][C@H:7]([CH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[C:15]([NH2:22])=[C:14]([Cl:23])[CH:13]=1)[C:8]([OH:10])=[O:9]>O.C1COCC1>[NH2:22][C:15]1[C:16]([C:18]([F:20])([F:21])[F:19])=[CH:17][C:12]([CH2:11][C@@H:7]([NH:6][C:1]([O:4][C:12]([CH3:17])([CH3:13])[CH3:11])=[O:2])[C:8]([OH:10])=[O:9])=[CH:13][C:14]=1[Cl:23]
Reactant: Nc1c(Cl)cc(C[C@@H](N)C(=O)O)cc1C(F)(F)F
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](Cc1cc(Cl)c(N)c(C(F)(F)F)c1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3.71 g (35.0 mmol) of NaHCO3 in 100 mL water was added to a solution of 6.5 g (23.0 mmol) of (R)-2-amino-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-propionic acid in 140 mL of THF. 15.28 g (70.0 mmol) of Boc-anhydride was added and the mixture was stirred for 3 h at RT. THF was evaporated off i. vac., the aqueous phase was washed with EtOAc and acidified with 10% citric acid solution. The aqueous phase was exhaustively extracted with EtOAc, the combined org. extracts were dried over Na2SO4 and evaporated down i. vac. The crude product was used in the next reaction step without any further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:20]=[CH:19][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=O)[C:11]=2[F:18])=[O:8])=[CH:5][CH:4]=1.[N+:22]([CH3:25])([O-:24])=[O:23].C([O-])(=O)C.[NH4+].C(O)(=O)C>>[CH3:1][N:2]([CH3:21])[C:3]1[CH:20]=[CH:19][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12](/[CH:16]=[CH:25]/[N+:22]([O-:24])=[O:23])[C:11]=2[F:18])=[O:8])=[CH:5][CH:4]=1
Reactant: C[N+](=O)[O-]
Reactant: CN(C)c1ccc(C(=O)Nc2cccc(C=O)c2F)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: CN(C)c1ccc(C(=O)Nc2cccc(/C=C/[N+](=O)[O-])c2F)cc1
Yield: 31 %

Procedure:
A mixture of 4-(dimethylamino)-N-(2-fluoro-3-formylphenyl)benzamide (1.83 g, the crude product from previous step), nitromethane (0.859 mL, 15.98 mmol), and ammonium acetate (1.232 g, 15.98 mmol) in acetic acid (25 mL, 52.4 mmol) was heated at 100° C. for 2 hr. Acetic acid was removed under vacuum. To the residue was added CH2Cl2 (60 mL) and water (60 mL) and the mixture was basified with solid Na2CO3 to pH 9. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (3×50 mL). The combined organic phase was washed with saturated NaHCO3 solution (40 mL) and brine (40 mL), and dried over anhydrous MgSO4. The desired product (0.786 g, 31% over 2 steps) was isolated by ISCO (120 g silica gel, 0-5% ethyl acetate/CH2Cl2) as a red solid.