Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.C([N:15](CC)CC)C.[O:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>CCOCC>[O:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.[N-:15]=[C:5]=[O:11].[CH3:22][CH2:21][O:20][CH2:24][CH3:23]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCN(CC)CC
Solvent: CCOCC
Solvent: C1CCOC1
Product: [N-]=C=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In reaction 1 of Scheme 1, the compounds of formula A-1 or A-2 are converted to the corresponding compounds of Formula II, wherein f is 1 to 8, or III, respectively, by adding triphosgene to a suspension of C-1 or C-2 and triethylamine in a aprotic solvent, such as tetrahydrofuran. The reaction is stirred at room temperature for a time period between about 5 minutes to about 20 minutes, preferably about 15 minutes, and a small amount of ether was added. The triethylammonium salt generated is filtered off. Separately, sodium hydride is added to a suspension of A-1 or A-2, wherein X is OH or NH, in an aprotic solvent, such as tetrahydrofuran, at 0° C. or room temperature. The reaction is stirred at room temperature for a time period between about 5 minutes to about 20 minutes, preferably about 15 minutes, and the isocyanate tetrahydrofuran/ether solution so formed above is added dropwise. Alternatively, the compounds of Formula II and III may be formed by reacting the compounds of D3 or D4 with A-1 and A-2 in presence of a base such triethylamine and diphenylphosphoryl azide in aprotic solvent such toluene as described in procedure discussed above in reaction 4 of Preparation D.
Reaction SMILES: [CH:1]([OH:3])=[O:2].[F:4][CH:5]([F:36])[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]1[N:18]2[CH:19]=[C:20]([C:24]3[CH:25]=[N:26][C:27]([C:30]4([OH:34])[CH2:33][NH:32][CH2:31]4)=[N:28][CH:29]=3)[C:21]([F:23])=[CH:22][C:17]2=[N:16][C:15]=1[CH3:35].C=O.[C:39](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(O)C.C(O)(=O)C>[CH:1]([OH:3])=[O:2].[F:36][CH:5]([F:4])[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]1[N:18]2[CH:19]=[C:20]([C:24]3[CH:25]=[N:26][C:27]([C:30]4([OH:34])[CH2:33][N:32]([CH3:39])[CH2:31]4)=[N:28][CH:29]=3)[C:21]([F:23])=[CH:22][C:17]2=[N:16][C:15]=1[CH3:35]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1nc2cc(F)c(-c3cnc(C4(O)CNC4)nc3)cn2c1Cc1ccccc1OC(F)F
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1nc2cc(F)c(-c3cnc(C4(O)CN(C)C4)nc3)cn2c1Cc1ccccc1OC(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 17.5 %

Procedure:
To a suspension of Example 325 (81%, 195 mg, 0.3 mmol) in ethanol (4 mL) was added 37% aqueous formaldehyde solution (0.1 mL, 1.33 mmol) and the resulting solution was stirred at room temperature for 20 minutes. Sodium triacetoxyborohydride (160 mg, 0.76 mmol) was added in one portion, followed by acetic acid (0.1 mL), and the whole mixture was stirred at room temperature under nitrogen for 2 h. The reaction mixture was diluted and neutralised with saturated sodium bicarbonate solution (15 mL). The crude material was then extracted into dichloromethane (2×20 mL). The combined organic extracts were dried over sodium sulphate, filtered and concentrated under vacuum. The resulting brown oil (140 mg) was purified by preparative HPLC (Method A) to afford the title compound (27 mg, 17%) as a colourless solid. δH (500 MHz, CD3OD) 9.05 (d, J 1.4 Hz, 2H), 8.38-8.35 (m, 2H), 7.41 (d, J 10.9 Hz, 1H), 7.33-7.27 (m, 1H), 7.18 (d, J 7.9 Hz, 1H), 7.14 (td, J 7.6, 0.9 Hz, 1H), 7.10 (dd, J 7.6, 1.7 Hz, 1H), 6.91 (t, J 74.0 Hz, 1H), 4.72 (d, J 11.3 Hz, 2H), 4.42 (s, 2H), 4.35 (d, J 11.4 Hz, 2H), 3.08 (s, 3H), 2.42 (s, 3H). Method D HPLC-MS: MH+ m/z 470, RT 1.09 minutes.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:8]=[CH:9][C:2]1=2.C([Li])CCC.[C:25](=[O:27])=[O:26].Cl>O1CCCC1.CCCCCC.O>[CH2:18]([N:15]([CH2:16][CH3:17])[CH2:14][CH2:13][O:12][CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:2]2[S:1][C:5]([C:25]([OH:27])=[O:26])=[CH:4][C:3]=2[CH:6]=1)[CH3:19]
Reactant: O=C=O
Reactant: CCN(CC)CCOCCc1ccc2sccc2c1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCN(CC)CCOCCc1ccc2sc(C(=O)O)cc2c1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
In 30 mL of tetrahydrofuran is dissolved 6.00 g of N-[2-(2-benzo[b]thiophen-5-ylethoxy)ethyl]-N,N-diethylamine. The solution is cooled to −60° C., and 10.6 mL of 1.57 mol/L solution of n-butyllithium in hexane is dropwise added. The resulting mixture is stirred at the same temperature as above for one hour, an excessive amount of dry carbon dioxide gas is introduced, after which the temperature is elevated to ambient temperature and the mixture is stirred for 30 minutes. Water is added to the mixture, pH is adjusted to 7 with 2 mol/L hydrochloric acid, and the solvent is distilled off under reduced pressure. The residue is purified by reversed phase column chromatography (eluent:water:methanol=7:3) and filtered together with ethyl acetate. Thus, 3.66 g of 5-{2-[2-(diethylamino)ethoxy]ethyl}-benzo[b]thiophene-2-carboxylic acid is obtained as a crystalline product.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:18])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.C(N(CC)CC)C.[C:26](Cl)([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:29]([O:28][C:26]([NH:1][CH2:2][C@H:3]([OH:18])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH2:7][CH2:6]1)=[O:27])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(C[C@@H](O)CN)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C[C@@H](O)CNC(=O)OCc2ccccc2)CC1
Reaction time: 2 h
Yield: 76.8 %

Procedure:
Tert-butyl 4-[(2S)-3-amino-2-hydroxy-propyl]piperazine-1-carboxylate 7c (1.24 g, 4.80 mmol) was dissolved in 60 mL of dichloromethane followed by the addition of triethylamine (970 mg, 9.60 mmol) and carbobenzoxy chloride (0.90 g, 5.28 mmol). The reaction solution was stirred for 2 hours. The resulting solution was added with 50 mL of saturated sodium bicarbonate solution and extracted with dichloromethane (50 mL×3). The combined organic phase was washed with saturated sodium chloride solution (50 mL×3), then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound tert-butyl 4-[(2S)-3-benzyloxycarbonylamino-2-hydroxy-propyl]piperazine-1-carboxylate 21a (1.45 g, yield: 76.0%) as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[Br:9][C:10]1[S:14][C:13]([S:15](Cl)(=[O:17])=[O:16])=[CH:12][CH:11]=1.C(N(CC)CC)C>C1COCC1>[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][NH:1][S:15]([C:13]2[S:14][C:10]([Br:9])=[CH:11][CH:12]=2)(=[O:17])=[O:16])[CH:4]=1
Reactant: NCc1cccnc1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(NCc1cccnc1)c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.6 %

Procedure:
To a stirred solution of 3-aminomethyl-pyridine (1.24 g, 11.5 mmol) in THF (8 ml) was added at 0° C. (ice water bath) commercially available 5-bromo-thiophene-2-sulfonyl chloride (1.0 g, 3.82 mmol) dissolved in THF (8 ml) and triethylamine (0.59 ml, 4.21 mmol). The reaction mixture was stirred at room temperature for 16 h and evaporated. The crude product was further purified by flash chromatography (dichloromethane/methanol) and crystallization from dichloromethane/hexane to yield the title compound (1.23 g, 97%) as a white solid. MS (ISN) 331.0 [(M−H)−], mp 125° C.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.[CH3:15][C:16](=O)[CH2:17][C:18](=[O:20])[CH3:19].[NH2:22]/[C:23](/[CH3:42])=[CH:24]/[C:25]([O:27][C@H:28]1[CH2:32][C:31](=[O:33])[N:30]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]1=[O:41])=[O:26]>CC(O)C>[C:18]([C:17]1[C@@H:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:24]([C:25]([O:27][C@H:28]2[CH2:32][C:31](=[O:33])[N:30]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]2=[O:41])=[O:26])=[C:23]([CH3:42])[NH:22][C:16]=1[CH3:15])(=[O:20])[CH3:19]
Reactant: C/C(N)=C\C(=O)O[C@H]1CC(=O)N(Cc2ccccc2)C1=O
Reactant: CC(=O)CC(C)=O
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Solvent: CC(C)O
Product: CC(=O)C1=C(C)NC(C)=C(C(=O)O[C@H]2CC(=O)N(Cc3ccccc3)C2=O)[C@@H]1c1cccc2c(=O)cc(C)oc12

Procedure:
1 g (5.32 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde is introduced into 25 ml of 2-propanol and heated under reflux with 0.93 g (9.3 mmol) of 2,4-pentanedione and 1.53 g (5.32 mmol) of (3S)-1-benzyl-2,5-dioxopyrrolidin-3-yl (2E)-3-aminobut-2-enoate [preparation analogous to D. Alker et al., Eur. J. Med. Chem. 26 (9), 907-913 (1991), starting from (3S)-1-benzyl-3-hydroxypyrrolidine-2,5-dione] overnight. The solvent is removed in vacuo, and the residue is purified by preparative HPLC. 950 mg (33% of theory) of the desired product are obtained as 4R/4S diastereomer mixture.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C@@H:4]([CH:5]=[C:6]2[CH2:9][CH2:8][CH2:7]2)[C@H:3]1[C:10](Cl)=[O:11].C1C=CC=CC=1.[CH:20]([OH:23])([CH3:22])[CH3:21].N1C=CC=CC=1>O>[CH3:1][C:2]1([CH3:13])[C@@H:4]([CH:5]=[C:6]2[CH2:9][CH2:8][CH2:7]2)[C@H:3]1[C:10]([O:23][CH:20]([CH3:22])[CH3:21])=[O:11]
Reactant: CC1(C)[C@H](C(=O)Cl)[C@@H]1C=C1CCC1
Reactant: CC(C)O
Solvent: O
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC(C)OC(=O)[C@@H]1[C@H](C=C2CCC2)C1(C)C
Reaction time: 8 h
Yield: 55.9 %

Procedure:
8 g of (1R,cis) 2,2-dimethyl-3-cyclobutylidenemethyl-cyclopropane-1-carboxylic acid chloride and 10 ml of benzene were added at 10° C. to a solution of 50 ml of benzene, 4 g of isopropanol and 4 g of pyridine and the reaction mixture was stirred for 8 hours. The mixture was poured into iced water and the decanted organic phase was washed with water, with aqueous sodium bicarbonate solution, with water, with N hydrochloric acid and finally with water. The solution was dried and evaporated to dryness under reduced pressure at 45° C. The residue was chromatographed over silica gel and was eluted with an 8-2 petroleum ether (b.p.=60°-80° C.)-isopropyl ether mixture to obtain the fraction with an Rf=0.55. The solution was evaporated to dryness under reduced pressure at 45° C. to obtain 5 g of isopropyl (1R,cis) 2,2-dimethyl-3-cyclobutylidenemethyl-cyclopropane-1-carboxylate with a boiling point of 66°~68° C. at 0.1 mm Hg and a specific rotation of [α]D 20 =+74.5° (c=1% in chloroform).
Reaction SMILES: [NH2:1][C:2](=[N:48][N+]([O-])=O)[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35]([N:37]([CH2:43][C:44]([O:46][CH3:47])=[O:45])[CH2:38][C:39]([O:41][CH3:42])=[O:40])=[O:36])=[CH:30][CH:29]=1)=[O:25])[NH:8][C:9](=[O:23])[CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:52]([OH:55])(=[O:54])[CH3:53]>[Pd]>[CH3:42][O:41][C:39]([CH2:38][N:37]([CH2:43][C:44]([O:46][CH3:47])=[O:45])[C:35]([CH2:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][NH:26][C:24](=[O:25])[C@@H:7]([CH2:6][CH2:5][CH2:4][NH:3][C:2](=[NH:1])[NH2:48])[NH:8][C:9](=[O:23])[CH:10]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:33][CH:32]=1)=[O:36])=[O:40].[CH3:10][C:9]([CH2:53][C:52]([OH:55])=[O:54])=[O:23]
Reactant: CC(=O)O
Reactant: COC(=O)CN(CC(=O)OC)C(=O)Cc1ccc(CNC(=O)[C@@H](CCCNC(N)=N[N+](=O)[O-])NC(=O)C(c2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Product: CC(=O)CC(=O)O
Product: COC(=O)CN(CC(=O)OC)C(=O)Cc1ccc(CNC(=O)[C@@H](CCCNC(=N)N)NC(=O)C(c2ccccc2)c2ccccc2)cc1
Yield: 63 %

Procedure:
Prepared analogously to Example 4c) from (R)-N5 -(amino(nitroimino)-methyl]-N-[[4-[[[bis-(methoxycarbonylmethyl)amino]carbonyl]methyl]phenyl]methyl]-N2 -(diphenylacetyl)-ornithinamide by catalytic hydrogenation in the presence of palladium black and 80% aqueous acetic acid in a yield of 63% of theory.
Reaction SMILES: [SH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9]CC)=O)[N:6]=1.[CH3:12][CH2:13][Mg+].[Br-].[CH3:16][CH2:17]OCC>>[SH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])([CH2:12][CH3:13])[CH2:16][CH3:17])[N:6]=1
Reactant: CCOCC
Reactant: CCOC(=O)c1csc(S)n1
Reactant: CC[Mg+]
Agent: [Br-]
Product: CCC(O)(CC)c1csc(S)n1

Procedure:
To a solution of ethyl 2-mercapto-1,3-thiazole-4-carboxylate ((Ref: J. Am. Chem. Soc. 1935, 57, 1127), 0.694 g, 3.67 mmol) in Et2O (40 mL) at 0° C. was added EtMgBr (3 M in Et2O, 2.7 mL, 8.07 mmol). The reaction mixture was heated to reflux for 15 min, quenched with NH4Cl, extracted with 3 portions of Et2O, dried over MgSO4, filtered and concentrated in vacuo. The crude material was treated with more EtMgBr (3 M in Et2O, 6 mL, 18 mmol) at rt for 10 min, quenched, extracted and isolated in the same way. The residue was washed with Et2O and Et2O/hexane to afford the title compound.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:12][NH:13][C:14]([NH:16][NH2:17])=[O:15].C(=O)(O)[O-].[Na+].C(=O)=O>CO>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([NH:12][NH:13][C:14]([NH:16][NH:17][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])=[O:15])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NNC(=O)NN
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NNC(=O)NNS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 65 °C

Procedure:
190.5 g (1.0 mole) p-toluene sulfonyl chloride, 45 g (0.5 mole) carbohydrazide, 84 g (1.0 mole) sodium bicarbonate and 1000 ml methanol were placed in a 2 liter flask. The mixture was stirred and heated to reflux (65° C) for 90 minutes. Carbon dioxide evolution was complete at this point. The solid product and sodium chloride were filtered off. The material was suspended in water to dissolve the sodium chloride and the residual solid product was filtered off, washed well with water, and dried at 60° C. Yield: 139 g -- Dec. temp. 232° C.
Reaction SMILES: Br[C:2]1[C:3]([CH3:12])=[C:4]([N+:9]([O-:11])=[O:10])[C:5](=[O:8])[NH:6][CH:7]=1.[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15].C(OCC)(=O)C>CN(C=O)C.C(N(CC)CC)C>[CH3:13][Si:14]([C:17]#[C:18][C:2]1[C:3]([CH3:12])=[C:4]([N+:9]([O-:11])=[O:10])[C:5](=[O:8])[NH:6][CH:7]=1)([CH3:16])[CH3:15]
Reactant: Cc1c(Br)c[nH]c(=O)c1[N+](=O)[O-]
Reactant: C#C[Si](C)(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(C#C[Si](C)(C)C)c[nH]c(=O)c1[N+](=O)[O-]
Temperature: 90 °C
Yield: 96.4 %

Procedure:
A mixture of 5-bromo-4-methyl-3-nitro-2-pyridone (1.0 g, 2.8 mmol), trimethylsilylacetylene (1.2 mL, 8.5 mmol), bis(triphenylphosphine)Pd(II) chloride (0.100 g) and cuprous iodide (0.025 g) in DMF (4 mL) and triethylamine (2 mL) was heated at 90 ° C. in a sealed tube for 7 hours. Ethyl acetate was added, and the mixture was washed with water, dried, filtered and evaporated. Chromatography of the residue over silica gel (40% ethyl acetate/hexane) gave 5-trimethylsilylethynyl-4-methyl-3-nitro-2-pyridone (1.0 g, 2.7 mmol, 96%)
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)(N1C=CN=C1)=[O:2].[S:13]1[CH:17]=[C:16](C(O)=O)[CH:15]=[C:14]1[C:21]([OH:23])=O.[CH2:24]([NH2:34])[C:25]1[CH:33]=[CH:32][C:31]2[O:30][CH2:29][O:28][C:27]=2[CH:26]=1>>[O:30]1[C:31]2[CH:32]=[CH:33][C:25]([CH2:24][NH:34][C:21]([C:14]3[S:13][CH:17]=[C:16]([C:1]([NH:8][CH2:12][C:11]4[CH:25]=[CH:26][C:27]5[O:28][CH2:29][O:30][C:31]=5[CH:32]=4)=[O:2])[CH:15]=3)=[O:23])=[CH:26][C:27]=2[O:28][CH2:29]1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1csc(C(=O)O)c1
Product: O=C(NCc1ccc2c(c1)OCO2)c1csc(C(=O)NCc2ccc3c(c2)OCO3)c1
Yield: 91.2 %

Procedure:
The title compound was prepared according to the procedure described for Example 2 using carbonyldiimidazole (1.2 g, 7.4 mmol), 2,4-thiophene-dicarboxylic acid (0.5 g, 3.0 mmol), and piperonylamine (1.05 g, 6.7 mmol) to afford 1.2 g of thiophene-2,4-dicarboxylic acid bis-[(1,3-benzodioxol-5-ylmethyl)-amide]. Recrystallization of a sample from ethanol gave product with a mp 174-175° C.
Reaction SMILES: [F:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([C@@H:8]([CH3:18])[CH2:9][C@:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:21][C:22]1[CH:31]=[C:30]([F:32])[C:29]([F:33])=[C:28]2[C:23]=1[CH:24]=[N:25][C:26]([CH3:34])=[N:27]2>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[F:32][C:30]1[C:29]([F:33])=[C:28]2[C:23]([CH:24]=[N:25][C:26]([CH3:34])=[N:27]2)=[C:22]([N:21]=[CH:11][C@:10]([C:13]([F:14])([F:15])[F:16])([OH:17])[CH2:9][C@@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=2[O:19][CH3:20])[CH3:18])[CH:31]=1
Reactant: Cc1ncc2c(N)cc(F)c(F)c2n1
Reactant: COc1c(F)cccc1[C@@H](C)C[C@@](O)(C=O)C(F)(F)F
Agent: [Ti+4]
Agent: CC[O-]
Product: COc1c(F)cccc1[C@@H](C)C[C@@](O)(C=Nc1cc(F)c(F)c2nc(C)ncc12)C(F)(F)F

Procedure:
In the same way as in Example 1, 170 mg (0.58 mmol) of (2R*,4S*)-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanal, 124 mg (0.60 mmol) of 5-amino-7,8-difluoro-2-methylquinazoline and 0.31 ml of titanium tetraethoxide are reacted to give (2R*,4S*)-1-[(7,8-difluoro-2-methylquinazolin-5-yl)imino]-4-(3-fluoro-2-methoxyphenyl)-2-(trifluoromethyl)pentan-2-ol. 85 mg of imine purified by column chromatography (silica gel, hexane/ethyl acetate 0-30%) are cyclized in the same way as in Example 1 at −20° C. using 0.72 ml (0.72 mmol) of 1 M boron tribromide solution to give the desired product. Preparative thin-layer chromatography on silica gel (hexane/ethyl acetate 50%) yields 15 mg of product.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[CH2:34]([N:36]1[C:48]2[CH:47]=[CH:46][C:45]([NH2:49])=[CH:44][C:43]=2[C:42]2[C:37]1=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH3:35]>>[C:28]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:29]=[CH:30][C:31]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:49][C:45]2[CH:46]=[CH:47][C:48]3[N:36]([CH2:34][CH3:35])[C:37]4[C:42]([C:43]=3[CH:44]=2)=[CH:41][CH:40]=[CH:39][CH:38]=4)=[O:18])=[O:7])=[CH:32][CH:33]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CCn1c2ccccc2c2cc(NC(=O)[C@@H]3CC(=NOC)CN3C(=O)c3ccc(-c4ccccc4)cc3)ccc21

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 66% purity by LC/MS. MS(ESI+): m/z=531.4.
Reaction SMILES: [C:1](=[O:12])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.[CH3:13][O:14][CH2:15][CH2:16][NH2:17].[C@H:18]1([NH:27][C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[C:33]([NH2:38])[CH:34]=3)[N:29]=2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19]1>>[C@H:18]1([NH:27][C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[C:33]([NH:38][C:1]([NH:17][CH2:16][CH2:15][O:14][CH3:13])=[O:12])[CH:34]=3)[N:29]=2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19]1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COCCN
Product: COCCNC(=O)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate, 2-methoxyethylamine and (R)—N2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=377.5 (M+H+).
Reaction SMILES: [FH:1].[F:2][CH:3]([F:24])[C@H:4]1[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C:20](=[CH:21][CH2:22][C@:5]12[CH3:6])[C@:18]1([CH3:19])[C:13](=[CH:14][C:15](=[O:23])[CH2:16][CH2:17]1)[CH2:12][CH2:11]3.[Cl:25]N1C(=O)CCC1=O.C(=O)([O-])[O-].[K+].[K+]>O.C(Cl)Cl.C1COCC1>[Cl:25][C@:20]12[C@@H:21]([F:1])[CH2:22][C@@:5]3([CH3:6])[C@@H:7]([CH2:8][CH2:9][C@@H:4]3[CH:3]([F:24])[F:2])[C@@H:10]1[CH2:11][CH2:12][C:13]1[C@:18]2([CH3:19])[CH2:17][CH2:16][C:15](=[O:23])[CH:14]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@]2(C)[C@@H](C(F)F)CC[C@@H]12
Reactant: F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: C[C@]12C[C@H](F)[C@@]3(Cl)[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(F)F
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 2.9 ml of liquid hydrogen fluoride and 2.0 ml of THF previously cooled to -78° under nitrogen is added a solution of 17b-difluoroandrosta-4,9(11)-dien-3-one (XI, Example 5, 1.5 g) with 10-15 ml of methylene chloride. After termal equilibrium is obtained, solid N-chlorosuccinimide (0.8 g) is added and the mixture stirred at -78° for approximately 3 hrs. The mixture is warmed to -20° over a 25 min period and then warmed to 0° over the next 30 min and then poured slowly into an ice-cooled solution of potassium carbonate (15 g) and water (50 ml). The phases are separated and the aqueous phase is washed twice with methylene chloride. The organic phases are combined and washed with a solution of sodium sulfite (2.5 g in 30 ml), dried over sodium sulfate and concentrated under reduced pressure to give a solid which is purified by column chromatography to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8]C=1C#N)([O-:3])=[O:2].[C:14]([OH:17])(=[O:16])[CH3:15].S(=O)(=O)(O)O>O>[N+:1]([C:4]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:15]=1[C:14]([OH:17])=[O:16])([O-:3])=[O:2]
Reactant: COc1ccc(C#N)c([N+](=O)[O-])c1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1ccc(C(=O)O)c([N+](=O)[O-])c1
Yield: 91.8 %

Procedure:
A mixture of 2-nitro-4-methoxybenzonitrile (14.0 g, 78.6 mM) in a solution of acetic acid (28 mL), sulfuric acid (28 mL) and water (28 mL) was refluxed for 11 hr, allowed to cool and diluted with water (200 mL). The resulting precipitate which formed was collected, washed with water and dried to give the title benzoic acid (14.2 g, 91.8%) as a yellow crystalline solid; MS(CI): 198 (M+H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]([CH:26]([CH3:28])[CH3:27])[C:23]([NH2:25])=[O:24])[CH:17]=1)[C:10]([CH3:30])([CH3:29])[CH2:9]2)=[O:5])C.Cl>CO.O1CCCC1.[OH-].[Na+].O>[CH:26]([N:22]([C:18]1[CH:17]=[C:16]([CH:11]2[C:10]([CH3:29])([CH3:30])[CH2:9][C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=3)[NH:12]2)[CH:21]=[CH:20][CH:19]=1)[C:23]([NH2:25])=[O:24])([CH3:28])[CH3:27]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N(C(N)=O)C(C)C)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)N(C(N)=O)c1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 8.9 %

Procedure:
A mixture of 2-[3-(1-isopropyl-ureido)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (347 mg, 0.85 mmol) in methanol (5 mL) and tetrahydrofuran (10 mL), 30% sodium hydroxide in water (10 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-[3-(1-isopropyl-ureido)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (29 mg, 8%) as a white solid: LC/MS m/e calcd for C22H27N3O3 (M+H)+: 382.48, observed: 382.1.