Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:11]([O:13][C:14]([CH:16]([CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:31][CH:30]=1)[CH2:17][CH2:18][P:19](=[O:26])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])=[O:15])[CH3:12].I[CH3:44]>O1CCCC1.C(OCC)(=O)C>[CH2:11]([O:13][C:14]([C:16]([CH3:44])([CH2:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:33][CH:34]=1)[CH2:17][CH2:18][P:19](=[O:26])([O:20][CH2:21][CH3:22])[O:23][CH2:24][CH3:25])=[O:15])[CH3:12]
Reactant: CI
Reactant: CCCCCCCCc1ccc(CCC(CCP(=O)(OCC)OCC)C(=O)OCC)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCCc1ccc(CCC(C)(CCP(=O)(OCC)OCC)C(=O)OCC)cc1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 82 %

Procedure:
To a solution potassium bis(trimethylsilyl)amide (0.213 g, 1.068 mmol) in tetrahydrofuran (1 ml) at −78° C. was added (±)-diethyl 3-ethoxycarbonyl-5-(4-(octyl)phenyl)pentylphosphonate (0.250 g, 0.533 mmol) as a solution in 1 ml of tetrahydrofuran. After stirring for 40 minutes at −78° C., iodomethane (0.083 ml, 1.33 mmol) was added. The reaction was stirred for 1 h at −78° C. then allowed to warm to room temperature. The solution was diluted with ethyl acetate (25 ml) and washed with 2N HCl (10 ml) 5% aqueous sodium thiosulfate (10 ml), saturated aqueous sodium chloride (10 ml), dried over magnesium sulfate and concentrated to give a colorless oil (0.211 g): MS m/e 483.4 (M+).
Reaction SMILES: C1(N=C=S)C=CC=CC=1.CC1C=CC(S([O-])(=O)=O)=CC=1.C[N+:22]1([CH2:28][CH2:29][N:30]=[C:31]=[N:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[CH2:27]COCC1.CNC1[C:42](N)=[CH:43][C:44]([N+:47]([O-:49])=[O:48])=[CH:45]C=1>N1C=CC=CC=1>[CH3:27][N:22]1[C:28]2[CH:42]=[CH:43][C:44]([N+:47]([O-:49])=[O:48])=[CH:45][C:29]=2[N:30]=[C:31]1[NH:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CNc1ccc([N+](=O)[O-])cc1N
Reactant: C[N+]1(CCN=C=NC2CCCCC2)CCOCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: c1ccncc1
Solvent: S=C=Nc1ccccc1
Product: Cn1c(Nc2ccccc2)nc2cc([N+](=O)[O-])ccc21
Reaction time: 2 h
Yield: 62 %

Procedure:
A solution of phenyl isothiocyanate (1.58 ml, 13.2 mmol) and 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate (6.6 g, 15.6 mmol) was stirred in pyridine (20 ml) at 90° C. After 2 hours, N1-methyl-4-nitro-benzene-1,2-diamine was added and the reaction was heated overnight. The reaction was cooled and concentrated to a red solid. This was dissolved in EtOAc and washed with water. The organic layer was dried over MgSO4 and concentrated to a red solid. This was stirred in MeOH, filtered, and dried to give the title compound as an orange solid (1.97 g, 62%). 1H NMR (300 MHz, d6-DMSO) δ 8.23 (s, 1H), 8.17 (d, J=1.8 Hz, 1H), 8.02 (dd, J=8.7 and 2.1 Hz, 1H), 7.89 (d, J=8.1 Hz, 2H), 7.50 (d, J=8.7 Hz, 1H), 7.36 (m, 2H), 7.02 (m, 1H), 3.79 (s, 1H) ppm. MS (ESI) m/z=269 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([O:27][CH3:28])[C:3](=[O:26])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH:7]=[CH:6][C:5]=1[NH:15]C(OCC1C=CC=CC=1)=O>C(OCC)(=O)C.CO.[C].[Pd]>[CH3:1][N:2]([O:27][CH3:28])[C:3](=[O:26])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH:7]=[CH:6][C:5]=1[NH2:15]
Reactant: CON(C)C(=O)c1cc(OCC(C)C)ccc1NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1cc(OCC(C)C)ccc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-Methyl-N-methyloxy-2-benzyloxycarbonylamino-5-isobutyloxybenzamide (1.0 g) was dissolved in a mixture of ethyl acetate (10 ml) and methanol (10 ml). To the solution was added 10% palladium-carbon (0.2 g). The mixture was stirred for two hours at room temperature under hydrogen atmosphere. The reaction mixture was subjected to filtration. From the filtrate, the solvent was distilled off to leave N-methyl-N-methyloxy-2-amino-5-isobutyloxybenzamide as a yellow oily product (0.6 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@H:4]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[NH:5][C:6]([C:8]1([NH:13]C(OC(C)(C)C)=O)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[ClH:30]>ClCCl.C(OCC)(=O)C>[ClH:30].[CH3:1][O:2][C:3](=[O:29])[C@H:4]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=1)[NH:5][C:6]([C:8]1([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)C1(NC(=O)OC(C)(C)C)CCCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)C1(N)CCCC1

Procedure:
To a solution of N-[[1-[[(1,1-dimethylethoxy)carbonyl]amino]-1-cyclopentyl]-carbonyl]-L-tyrosine methyl ester (3.50 g, 8.6 mmol) in dichloromethane (60 mL) and ethyl acetate (10 mL) is bubbled dry HCl gas for 15 minutes. The solvent is then removed under reduced pressure to give, as a foam, [[1-amino(1-cyclopentyl)]carbonyl]-L-tyrosine methyl ester hydrochloride.
Reaction SMILES: [C:1]([C:3](=[CH:12]OCC)[C:4]([NH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])#[N:2].[F:16][C:17]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:18]=1[NH2:19]>C(O)C>[C:1]([C:3](=[CH:12][NH:19][C:18]1[C:17]([F:16])=[CH:23][CH:22]=[CH:21][C:20]=1[F:24])[C:4]([NH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])#[N:2]
Reactant: Nc1c(F)cccc1F
Reactant: CCOC=C(C#N)C(=O)NC(=O)OCC
Solvent: CCO
Product: CCOC(=O)NC(=O)C(C#N)=CNc1c(F)cccc1F

Procedure:
To 10.0 g of α-cyano-β-ethoxy-N-ethoxycarbonylacrylamide dissolved in about 40 ml of hot ethanol is added 6.45 g of 2,6-difluoroaniline in 15 ml of ethanol. The reaction mixture is stirred at reflux for about 6 hours, cooled and filtered to yield α-cyano-β-(2,6-difluoroanilino)-N-ethoxycarbonylacrylamide, white solid (12.61 g), which is added to 60 ml of tetralin and heated at reflux for 5 hours. The mixture is allowed to cool, filtered and washed with ether to yield 10.21 g of 5-cyano-1-(2,6-difluorophenyl)uracil, white solid.
Reaction SMILES: Cl.[NH2:2][OH:3].[Br:4][C:5]1[CH:6]=[C:7]([CH:13]=O)[S:8][C:9]=1[N+:10]([O-:12])=[O:11].N1C=CC=CC=1>CCO>[Br:4][C:5]1[CH:6]=[C:7]([CH:13]=[N:2][OH:3])[S:8][C:9]=1[N+:10]([O-:12])=[O:11]
Reactant: NO
Reactant: O=Cc1cc(Br)c([N+](=O)[O-])s1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: O=[N+]([O-])c1sc(C=NO)cc1Br
Temperature: 25 °C
Yield: 88 %

Procedure:
Hydroxylamine hydrochloride (85 g, 1.2 mol) was added to a solution of 4-bromo-5-nitro-thiophene-2-carbaldehyde (234 mg, 0.529 mmol, Example 286: step a) in EtOH (7.5 mL, 200 proof—anhydrous):pyridine (100 mL, anhydrous) at rt over 5 min. The reaction mixture was heated to reflux overnight, then cooled to rt. The solvents were removed in vacuo resulting in a solid residue that was washed with water and filtered. The solid was dried overnight under high vacuum to afford the title compound as a yellow solid (225 g, 88%). The solid was used for the next step without further characterization.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:9]=[N:10]/[CH3:11].[Cl:12][C:13]1[CH:18]=[CH:17][C:16](/[C:19](=[CH:22]/[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])/[C:20]#[N:21])=[C:15]([F:28])[CH:14]=1.[OH-].[K+]>CS(C)=O>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([C:20]#[N:21])[CH:22]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH2:11][NH:10][CH:9]2[C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])=[C:15]([F:28])[CH:14]=1
Reactant: C/N=C/c1cccc(Cl)c1Cl
Reactant: CC(C)(C)C/C=C(\C#N)c1ccc(Cl)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)CC1CNC(c2cccc(Cl)c2Cl)C1(C#N)c1ccc(Cl)cc1F
Yield: 17.7 %

Procedure:
In a manner similar to the method described in Example 3a, [1-(2,3-dichloro-phenyl)-meth-(E)-ylidene]-methyl-amine (3.76 g, 20.00 mmol) reacted with (Z)-2-(4-chloro-2-fluoro-phenyl)-5,5-dimethyl-hex-2-enenitrile (5.03 g, 20.00 mmol) in DMSO (30 mL) in the presence of KOH powder (5.72 g, 56.11 mmol) to give rac-(2S,3S,4S)-3-(4-chloro-2-fluoro-phenyl)-2-(2,3-dichloro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (1.56 g 17.7%). HRMS (ES+) m/z Calcd for C22H22Cl3FN2+H [(M+H)+]: 439.0906, found: 439.0905.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11][O:12][CH2:13][C:14](OC)=[O:15]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][C:14](=[O:15])[CH2:13][O:12][CH3:11])[CH3:9])=[CH:4][CH:3]=1
Reactant: COCC(=O)OC
Reactant: CC(N)c1ccc(Cl)cc1
Product: COCC(=O)NC(C)c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
At room temperature, a solution of 20.06 g (0.129 mol) of racemic 1-(4-chloro-phenyl)-ethylamine in 20 g (0.19 mol) of methyl methoxyacetate is mixed with stirring with 1 g of Novozym 435® (=immobilized lipase from Candida antarctica; 7300 U/g). Stirring is continued at room temperature for one hour and the reaction is then terminated by filtering off the enzyme. The conversion is 43.9%. In the filtrate that remains, the (S)-enantiomer of 1-(4-chloro-phenyl)-ethylamine has an ee value of 61%, while the (R)-enantiomer of N-[l-(4-chlorophenyl)-ethyl]-methoxyacetamide obtained has an ee value of 98.4%.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH2:55]([N:62]=[C:63]=[O:64])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[CH2:55]([NH:62][C:63]([N:50]1[CH2:51][CH2:52][CH:47]([CH2:46][C:45]([NH:44][C:36]2[CH:37]=[CH:38][C:39]3[NH:40][C:41]4[N:42]=[C:26]([NH:27][C:28]5[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=5)[CH2:33][CH2:34][C:35]=2[CH:43]=3)[N:25]=[CH:24][C:23]=4[Cl:22])=[O:53])[CH2:48][CH2:49]1)=[O:64])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1
Reactant: O=C=NCc1ccccc1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)NCc2ccccc2)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 35 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and benzyl isocyanate as starting materials in 35% yield. LCMS for C32H34ClN8O2 (M+H)+: m/z=597.2.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7](O)=[O:8])=[CH:5][N:4]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[N:16]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=[CH:18][C:11]=23)[N:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.C1COCC1.[NH:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1>>[CH3:1][C:2]1[C:6]([C:7]([N:44]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]2)=[O:8])=[CH:5][N:4]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[N:16]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:24])([CH3:25])[CH3:26])[CH:17]=[CH:18][C:11]=23)[N:3]=1
Reactant: Cc1nn(-c2ccnc3c2ccn3COCC[Si](C)(C)C)cc1C(=O)O
Reactant: C1CCNCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1nn(-c2ccnc3c2ccn3COCC[Si](C)(C)C)cc1C(=O)N1CCCCC1
Reaction time: 2 h
Yield: 101.3 %

Procedure:
A solution of 3-methyl-1-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazole-4-carboxylic acid (0.040 g, 0.00011 mol) (1:1 of AcOH) and N,N-carbonyldiimidazole (0.035 g, 0.00021 mol) in THF (1 mL, 0.01 mol) was stirred for 1.2 h, after which time piperidine (32 μL, 0.00032 mol) was added. After another 2 h, another portion of piperidine (15 μL) was added and the resulting mixture was stirred overnight. The reaction mixture was then partitioned between ethyl acetate and water, and washed sequentially with sat. NaHCO3 and brine. The organic phase was dried and evaporated to give 49 mg of the crude product as an orange oil/glass. The crude product was chromatographed with 75-100% ethyl acetate/hexanes, sample in DCM. Collected 25 mg of the purified product as a colorless glass/oil (50% yield).
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(O)[CH2:6]2.C(O)(=O)C.Cl.[C:22]([OH:28])(=[O:27])[CH2:23][C:24]([OH:26])=[O:25]>C(O)C>[C:22]([OH:28])(=[O:27])[CH2:23][C:24]([OH:26])=[O:25].[CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH:4]=[C:5]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:6]2
Reactant: CN1C2CCC1CC(O)(c1ccccc1)C2
Agent: Cl
Agent: O=C(O)CC(=O)O
Solvent: CC(=O)O
Solvent: CCO
Product: CN1C2C=C(c3ccccc3)CC1CC2
Reaction time: 2 h
Yield: 100 %

Procedure:
The title compound was prepared from 8-methyl-3-phenyl-8-azabicyclo[3.2.1]octan-3-ol (8 g, 37 mmol), glacial acetic acid (25 mL) and concentrated hydrochloric acid (8 mL). The free base of the title compound (7.4 g, 37 mmol) was dissolved in absolute ethanol (20 mL) and added malonic acid (3.9 g, 37.5 mmol), the solution was heated at reflux for a couple of minutes, some impurities was removed by filtration while the solution was still hot, the solution was cooled and kept at 5° C. for at while, then seeded with a crystal and precipitation of the title compound began, after 2 hours at 5° C., the title compound was isolated by filtration, the crystals was washed with cold absolute ethanol (10 mL). Yield 5.9 g (53%), m.p. 131-131.8° C.
Reaction SMILES: [OH:1][CH:2]([CH2:16][S:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:15])[NH:10]2.[OH:24]O>>[OH:1][CH:2]([CH2:16][S:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:24])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:15])[NH:10]2
Reactant: O=C1CCc2c(cccc2OCC(O)CSc2ccccc2)N1
Reactant: OO
Product: O=C1CCc2c(cccc2OCC(O)CS(=O)c2ccccc2)N1

Procedure:
Prepared analogous to Example 2 from 5-(2-hydroxy-3-phenylmercapto-propoxy)-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].Cl[CH:21]1[CH2:25][CH2:24][CH2:23][C:22]1=[O:26]>CN(C=O)C>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[O:1][CH:21]1[CH2:25][CH2:24][CH2:23][C:22]1=[O:26]
Reactant: COC(=O)c1ccc(OC)c(O)c1
Reactant: O=C1CCCC1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)c(OC2CCCC2=O)c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
23.8 g of methyl 3-hydroxy-4-methoxybenzoate are dissolved in 200 ml of anhydrous DMF and the solution is treated with 35 g of potassium carbonate (ground) and 13 ml of 2-chlorocyclopentanone. The mixture is stirred at 60° C. for 3 h, then the solid is filtered off with suction and the filtrate is concentrated in vacuo. The residue is chromatographed on a silica gel column using ethyl acetate/petroleum ether (4:6). The chromatographically pure fractions are combined, concentrated and dried in a high vacuum. 24.3 g of the title compound are obtained as a pale yellow oil.
Reaction SMILES: [N:1]1[C:2]2[C:14](=[O:15])[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:3]=2[NH:4][C:5](=[O:7])[CH:6]=1.[OH:16]O>C(O)(=O)C.C(OC(=O)C)(=O)C>[NH:1]1[C:6](=[O:16])[C:5](=[O:7])[NH:4][C:3]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14](=[O:15])[C:2]1=2
Reactant: O=C1c2ccccc2-c2[nH]c(=O)cnc21
Reactant: OO
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1c2ccccc2-c2[nH]c(=O)c(=O)[nH]c21
Yield: 79.6 %

Procedure:
9H-Indeno[1,2-b]pyrazine-3,9(4H)-dione (20 g, 100.9 mmol), recrystallized from acetic acid, was suspended in a mixture of 135 ml acetic acid and 135 ml acetic anhydride and hydrogen peroxide (9.8 ml, 35%) was added. After stirring overnight another portion (9.8 ml, 35%) of hydrogen peroxide was added. This was repeated five times over a week. The red precipitate was filtered off, washed with acetic acid and water and dried to give 18.5 g (79.6%) of the title compound, which could be further purified by dissolving in aqueous sodium hydroxide and precipitation by hydrochloric acid. M.p. >300° C. 1H-NMR (DMSO-d6, δ): 7.15-7.45 (m, 4H), 12 (s, 1H), 12.8 (s,1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:9][CH:8]=[CH:7][CH:6]=2.C(O[C:29](OCC)(OCC)[CH2:30][CH2:31][CH2:32][CH3:33])C.Cl.[NH+]1C=CC=CC=1.C>C1(C)C=CC=CC=1.CO>[CH2:30]([C:29]1[N:12]([CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCCC(OCC)(OCC)OCC
Reactant: CC(C)(C)OC(=O)NCCOCCNc1c(N)cnc2ccccc12
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: Cc1ccccc1
Product: CCCCc1nc2cnc3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 99.9 %

Procedure:
A solution of tert-butyl 2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethylcarbamate (3.46 g, 10.0 mmol) in 50 mL of toluene was treated with triethylorthovalerate (2.5 mL, 14.5 mmol) and the reaction mixture was heated to reflux. A 25 mg portion of pyridinium hydrochloride was then added and refluxing was continued for 4 h. The reaction was then concentrated to dryness under reduced pressure. The residue was dissolved in 50 mL of CH2Cl2 and washed with saturated NaHCO3, H2O and brine. The organic portion was dried over Na2SO4 and concentrated to give a green oil. The green oil was dissolved in 50 mL of hot MeOH and treated with activated charcoal. The hot solution was filtered and concentrated to give 4.12 g of tert-butyl 2-[2-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as a yellow oil.
Reaction SMILES: [C:1]([NH:9][C:10]([NH:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-])=O)[CH:21]=2)[CH2:15][CH2:14]1)=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd]>[C:1]([NH:9][C:10]([NH:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[CH:21]=2)[CH2:15][CH2:14]1)=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=C(NC(=O)c1ccccc1)NC1CCN(Cc2cccc([N+](=O)[O-])c2)CC1
Agent: [Pd]
Product: Nc1cccc(CN2CCC(NC(=O)NC(=O)c3ccccc3)CC2)c1
Yield: 46.1 %

Procedure:
1-Benzoyl-3-[1-(3-nitrobenzyl)piperid-4-yl]urea 4.47 g (from Example 13) was hydrogenated with 5% Pd/C (0.5 g) at atmospheric pressure and room temperature until no more hydrogen was taken up. The catalyst was filtered and the filtrate evaporated. The residue was dissolved in water and basified with .880 ammonia. The precipitated solid was filtered, washed well with water, dried, treated with charcoal, and evaporated to give the title compound, (1.9 gms). This was recrystallised from ethanolic HCl to give the dihydrochloride salt, monohydrate, m.p. 194°-195° C.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=O)[NH:8][C:7]=1[CH3:14])([OH:3])=[O:2].[Cl:15][C:16]1[C:17]([CH3:26])=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH2:19]2>N1CCCCC1.C(O)C>[Cl:15][C:16]1[C:17]([CH3:26])=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[CH:12][C:9]1[NH:8][C:7]([CH3:14])=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:10]=1[CH3:11]
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Reactant: Cc1c(Cl)ccc2c1CC(=O)N2
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(Cl)c(C)c32)c(C)c1CCC(=O)O
Yield: 55.6 %

Procedure:
3-(2-Carboxyethyl)-2,4-dimethyl-5-formylpyrrole (98 mg), 91 mg 5-chloro-4-methyl-2-oxindole and 2 drops piperidine in 2 mL of ethanol were heated at 90° C. for 4 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 100 mg of the title compound.
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([OH:24])=O)=O)(C)(C)C.[NH2:25][C:26]1[C:27]([N:35]2[CH2:40][C@H:39]([CH3:41])[C@:38]([OH:43])([CH3:42])[C@H:37]([NH:44]C(=O)OC(C)(C)C)[CH2:36]2)=[C:28]2[CH2:34][CH2:33][O:32][C:29]2=[N:30][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:8][C:9]1[S:13][C:12]([C:14]2[C:15]([F:21])=[CH:16][CH:17]=[CH:18][C:19]=2[F:20])=[N:11][C:10]=1[C:22]([NH:25][C:26]1[C:27]([N:35]2[CH2:40][C@H:39]([CH3:41])[C@:38]([OH:43])([CH3:42])[C@H:37]([NH2:44])[CH2:36]2)=[C:28]2[CH2:34][CH2:33][O:32][C:29]2=[N:30][CH:31]=1)=[O:24]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: C[C@H]1CN(c2c(N)cnc3c2CCO3)C[C@@H](NC(=O)OC(C)(C)C)[C@]1(C)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3N)cnc3c2CCO3)C[C@@H](N)[C@]1(C)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.3 %

Procedure:
To a mixture of 5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (55 mg, 0.15 mmol), tert-butyl [(3R,4R,5S)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-4-hydroxy-4,5-dimethylpiperidin-3-yl]carbamate (44 mg, 0.12 mmol) and HATU (134 mg, 0.353 mmol), DMF (2.0 mL) was added, followed by DIPEA (86 mg, 0.67 mmol). The reaction mixture was stirred at room temperature for 3 h, and then concentrated under reduced pressure. DCM (2.0 mL) was added to the resulting residue followed by TFA (2.0 mL). The mixture was stirred at room temperature for 30 min. and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min.) to afford the title compound as a white solid (20 mg, 34%). LCMS calc. for C24H27F2N6O3s (M+H)+: m/z=517.2. found 517.0. 1H NMR (500 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.61 (s, 1H), 7.59-7.45 (m, 3H), 7.21 (t, J=8.6 Hz, 2H), 4.52-4.42 (m, 2H), 4.06 (s, 1H), 3.37 (t, J=8.5 Hz, 2H), 2.99-2.92 (m, 1H), 2.90-2.79 (m, 2H), 2.77-2.64 (m, 2H), 1.93-1.82 (m, 1H), 1.46 (br, 2H), 0.92 (s, 3H), 0.71 (d, J=6.9 Hz, 3H) ppm.
Reaction SMILES: [O:1]=[C:2]([NH:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])/[C:3](/[CH2:13][S:14][C:15](=[O:17])[CH3:16])=[CH:4]/[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.B(F)(F)F.CCOCC>C(Cl)Cl>[O:1]=[C:2]([NH:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:22])/[C:3](/[CH2:13][S:14][C:15](=[O:17])[CH3:16])=[CH:4]\[C:5]1[CH:6]=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COc1ccc(/C=C(\CSC(C)=O)C(=O)NCCC(=O)OCc2ccccc2)cc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc(/C=C(/CSC(C)=O)C(=O)NCCC(=O)OCc2ccccc2)cc1
Yield: 52 %

Procedure:
4.93 g (11.5 mmol) of the (Z) diester obtained in Example 17 (step D) are dissolved in 100 ml of methylene chloride which has been passed over basic alumina. The solution is irradiated for 2.5 h using a Hanovia TQ 150 lamp after having added dropwise 1.53 ml of boron trifluoride etherate solution (11.5 mmol). The solution is then washed with 1N hydrochloric acid solution (twice 80 ml), with saturated sodiumhydrogen carbonate solution (twice 80 ml) and is dried over magnesium sulphate. After filtration and evaporation, 2.56 g of (E) isomer are recovered after flash chromatography. Yield=52% (after flash chromatography, eluent: ether/petroleum ether 65/35) m.p.<50° C. IR (nujol): 3290, 1740, 1690, 1630 cm -1 1H NMR (CDCl3): 7.35 to 7.05 (m, 7H; 6.75 (AB, 2H, J=8 Hz); 6.70 (s, 1H); 6.10 (t, 1H, J=5 Hz); 4.95 (s, 2H); 3.80 (s, 3H); 3.40 (q app, 2H, J app.=6 Hz); 2.45 (t, 2H, J=6 Hz); 2.25 (s, 3H). 13C NMR (CDCl3): 194.8, 171.6; 168.6; 159.4; 135.4; 132.0; 131.6; 129.8; 128.5; 128.2; 128.0; 127.2; 113.6; 66.2; 55.0; 34.6; 33.6; 33.2; 30.4 Microanalysis: C23H25O5NS Calc. % C=64.61 H=5.89 N=3.27 Found. % C=64.17 H=5.91 N=3.48