Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Br[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>C(Cl)Cl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[C:12]([O:11][C:9]([CH2:8][N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[Cl:1])=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: Clc1ncc[nH]1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Cn1ccnc1Cl

Procedure:
The starting material was prepared by reaction of 2-chloroimidazole with t-butyl bromoacetate in CH2Cl2 /aqueous sodium hydroxide in presence of tetra-n-butyl ammonium hydrogen sulphate to give 1-t-butoxycarbonylmethyl-2-chloroimidazole. Reaction of this compound with trimlethyloxonium tetrafluoroborate in CH2Cl2 gave 1-t-butoxycarbonylmethyl-2-chloro-3-methylimidazolium tetrafluoroborate; n.m.r. in d6DMSO:-1.5(s, 9H); 3.9(s, 3H); 5.17(s, 2H); 7.81(d, 1H): 7.85(d, 1H).
Reaction SMILES: [CH:1]1([C:4]2[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:5]=2[CH:6]=O)[CH2:3][CH2:2]1.[C:13](Br)(Br)([Br:15])[Br:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH:1]1([C:4]2[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:5]=2[CH:6]=[C:13]([Br:15])[Br:14])[CH2:3][CH2:2]1
Reactant: BrC(Br)(Br)Br
Reactant: Cc1cccc(C2CC2)c1C=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cccc(C2CC2)c1C=C(Br)Br

Procedure:
1-Cyclopropyl-2-(2,2-dibromo-vinyl)-3-methyl-benzene was prepared from 2-cyclopropyl-6-methyl-benzaldehyde, carbon tetrabromide and triphenylphosphine in analogy to Example 1d): colourless oil; 1H-NMR (CDCl3): 0.69 (2H, m, CH2), 0.94 (2H, m, CH2), 1.87 (1H, m, CH), 2.26 (3H, s, CH3), 6.77 (1H, d, ArH), 7.03 (1H, d, ArH), 7.17 (1H, t, ArH), 7.52 (1H, s, CH═CBr2).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([CH3:31])[C:21]=1[N:22]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[N:23]1)[O:5][C@H:6]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)[CH2:7][CH2:8][CH3:9].Cl.[NH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([CH3:31])[C:21]=1[N:22]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[N:23]1)[O:5][C@H:6]([C:10]1[CH:11]=[CH:12][C:13]([C:14]([NH:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:16])=[CH:17][CH:18]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCC[C@H](Oc1cc(C)c(-n2cc(C(F)(F)F)cn2)c(C)c1)c1ccc(C(=O)O)cc1
Reactant: CCOC(=O)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC[C@H](Oc1cc(C)c(-n2cc(C(F)(F)F)cn2)c(C)c1)c1ccc(C(=O)NCCC(=O)OCC)cc1
Reaction time: 1 h
Yield: 94.3 %

Procedure:
N,N-dimethylformamide (17.6 mL) was added to a vial containing (S)-4-(1-(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl)benzoic acid (6.1 g, 14.1 mmol), ethyl 3-aminopropanoate hydrochloride (4.33 g, 28.2 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (10.7 g, 28.2 mmol). Diisopropylethylamine (12.3 mL, 70.5 mmol) was then added. The reaction was stirred for 1 h, and was then concentrated. Purification by column chromatography (0-30% ethyl acetate in heptane) afforded (S)-ethyl 3-(4-(1-(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl)benzamido)propanoate (7.07 g, 94% yield) as a colorless gum. 1H NMR (400 MHz, CDCl3, δ): 7.87 (s, 1H), 7.73 (d, J=8.0 Hz, 2H), 7.65 (s, 1H), 7.39 (d, J=8.2 Hz, 2H), 6.84 (d, J=5.9 Hz, 1H), 6.57 (s, 2H), 5.15 (dd, J=7.8, 5.1 Hz, 1H), 4.17 (q, J=7.1 Hz, 2H), 3.71 (q, J=6.0 Hz, 2H), 2.63 (t, J=5.7 Hz, 2H), 2.04-1.91 (m, 1H), 1.88 (s, 6H), 1.86-1.71 (m, 1H), 1.58-1.33 (m, 2H), 1.26 (t, J=7.0 Hz, 3H), 0.96 (t, J=7.4 Hz, 3H). MS (M+1): 532.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:14]([Li])CCC.S(OC)(OC)(=O)=O.[Cl-].[NH4+]>C1COCC1>[CH3:14][C:4]1[C:5]2[O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[C:9]=2[CH:1]=[CH:2][CH:3]=1
Reactant: [Li]CCCC
Reactant: c1ccc2c(c1)oc1ccccc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: COS(=O)(=O)OC
Solvent: C1CCOC1
Product: Cc1cccc2c1oc1ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.2 %

Procedure:
Dibenzofuran (26.94 g, 160 mmol) was dissolved in dry THF (500 ml) and cooled to -78° C. n-Butyl lithium (1.6M in hexane, 200 ml, 320 mmol) was added in portions over 30 mins. and the solution was allowed to warm to room temperature over 2.5 hours. The solution was recooled to -70° C. and a mixture of dimethyl sulphate (32 ml, 340 mmol) in dry THF (100 ml) was added dropwise. Once the addition was complete, the reaction was allowed to warm to room temperature, stirred for 18 hours and poured onto saturated ammonium chloride solution (400 ml). The phases were separated and the aqueous extracted twice with ether. The combined organic phases were dried (MgSO4) and evaporated in vacuo. Chromatography on silica (eluting with 40-60 petrol) gave the pure product as a clear oil (29.2 g, 100%) δH [2H6 ]-DMSO 8.1 (1H, d), 7.9 (1H, d), 7.7 (1H, d),7.5 (1H, t), 7.4 (1H, t), 7.25 (2H, m), 2.55 (3H, s).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1.[F:13][C:14]([F:22])([F:21])[CH:15]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]1>>[CH2:9]([O:8][C:6]1[CH:7]=[C:2]([N:17]2[CH2:18][CH2:19][CH2:20][CH:15]([C:14]([F:22])([F:21])[F:13])[CH2:16]2)[N:3]=[CH:4][N:5]=1)[C:10]#[C:11][CH3:12]
Reactant: FC(F)(F)C1CCCNC1
Reactant: CC#CCOc1cc(Cl)ncn1
Product: CC#CCOc1cc(N2CCCC(C(F)(F)F)C2)ncn1
Reaction time: 10 h
Yield: 61.4 %

Procedure:
0.3 g of 4-chloro-6-(2-butynyloxy)pyrimidine and 0.25 g of 3-trifluoromethylpiperidine were mixed and left for 10 hours at room temperature. The reaction mixture was subjected to silica gel column chromatography to obtain 0.30 g of 4-(2-butynyloxy)-6-(3-trifluoromethylpiperidino)pyrimidine (hereinafter, referred to as Compound (24)).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.[NH4+:11].[OH-]>N.CO>[NH2:11][CH2:10][C@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[OH:9]
Reactant: Brc1cccc([C@H]2CO2)c1
Reactant: [NH4+]
Agent: N
Agent: [OH-]
Solvent: CO
Product: NC[C@@H](O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(S)-2-(3-Bromophenyl)oxirane was dissolved in 7N NH3/MeOH solution (5 mL) and aqueous NH4OH (25%, 5 mL) was added to the reaction mixture which was stirred at room temperature for 18 hrs. The reaction mixture was concentrated under reduced pressure to give (S)-2-amino-1-(3-bromophenyl)ethanol (0.801 g) which was used in the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH2:20][CH:19]([CH3:22])[CH2:18][C:17](=[O:23])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:24]([O:26][CH3:27])=[O:25])[CH:5]=[CH:6][CH:7]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[C:19]([CH3:22])[CH:18]=[C:17]([OH:23])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:24]([O:26][CH3:27])=[O:25])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc2c1c1c(n2Cc2cccc(F)c2)CC(C)CC1=O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc2c1c1c(O)cc(C)cc1n2Cc1cccc(F)c1
Yield: 24.2 %

Procedure:
A solution of the 9-[(3-fluorophenyl)methyl]-5-carbomethoxy-2-methyl-1,2-dihydrocarbazol-4(3H)-one (1.37 g, 3.75 mM) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.94 g, 4.13 mM) in 38 mL of toluene was stirred between 80-90° C. for 3 hours. The mixture was purified by column chromatography on silica gel (elution with methylene chloride) to afford 0.33 g (24%) of 9-[(3-fluorophenyl)methyl]-2-methyl-4-hydroxy-5-carbomethoxy carbazole. 1H NMR (CDCl3) δ 10.45 (s, 1H), 8.0 (d, J=8 Hz, 1H), 7.55 (d, J=8 Hz, 1H), 7.4 (dd, J=8 and 8 Hz, 1H), 7.3 (m, 2H), 6.95 (m, 1H), 6.85 (d, J=8 Hz, 1H), 6.75 (m, 1H), 6.65 (s, 1H), 5.5 (s, 2H), 4.1 (s, 3H), 2.45 (s, 3H). MS (ES) m/e 332, 364.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[NH2:11][OH:12].[OH-].[Na+].Cl>C(O)C.O>[Cl:1][C:2]1[C:7]([CH:8]=[N:11][OH:12])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1cccnc1Cl
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: ON=Cc1cccnc1Cl
Temperature: 0 °C
Yield: 91.1 %

Procedure:
Combine 2-chloropyridine-3-carboxaldehyde (2.75 g, 0.0195 mol) with hydroxylamine hydrochloride (1.38 g, 0.021 mol) and ice (40 g) in an ethanol/water (15 mL/15 mL) mixture. Add aqueous sodium hydroxide (1.95 g, 0.049 mol, in 5 mL of water) dropwise and stir for 2.5 h near ambient temperature. Adjust the mixture to approx. pH 7.0 with aqueous hydrochloric acid, allowing for product precipitation. Extract with diethyl ether and wash with water and dry over sodium sulfate. Concentrate to obtain the desired crude oxime (2.78 g, 91%) as a white solid. MS(EI): (M)+ 156.3, 158.3 m/z.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:20][C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:28])[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.[OH-].[K+]>C1COCC1>[O:21]=[C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])[CH:17]=2)[N:12]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]2)[NH:20]1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(-c4ccccc4C)cc3c(=O)[nH]2)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccccc1-c1ccc2nc(-n3cc(C(=O)O)cn3)[nH]c(=O)c2c1
Reaction time: 16 h
Yield: 8.1 %

Procedure:
A mixture of 1-(4-oxo-6-o-tolyl-3,4-dihydro-quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (40.0 mg, 1.07 mmol), 1M aq. KOH (0.5 mL) and THF (1 mL) was stirred for 16 h. The reaction mixture was concentrated under reduced pressure to remove the THF and the aqueous residue was acidified to pH 2 with 1 M aq. HCl. The resulting precipitate was collected by filtration to provide the titled compound (30.0 mg, 81%). MS (ESI): mass calcd. for C19H14N4O3, 346.1; m/z found 347.0 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 13.04 (s, 1H), 12.93 (s, 1H), 8.99 (s, 1H), 8.28 (s, 1H), 8.02 (s, 1H), 7.86 (d, J=7.5 Hz, 1H), 7.76 (d, J=7.8 Hz, 1H), 7.37-7.29 (m, 4H), 2.28 (s, 3H).
Reaction SMILES: [C:1]([CH:4]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=2[N:9]=[C:8]1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)(O)=[O:2].[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[N:33]1([C:1]([CH:4]([CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:5][CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=3[N:9]=[C:8]2[CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[O:2])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: C1CCNCC1
Reactant: Cc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCC(Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCC(Cc1ccccc1)C(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 64 h
Yield: 162.1 %

Procedure:
To a stirring solution of 1-[3-carboxy-4-phenylbutyl]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole (1.0 g, 2.2 mmol) in N,N-dimethylformamide (75 ml) were added sequentially piperidine (206 mg, 1.1 eq), 1-hydroxy-benzotriazole (327 mg, 1.1 eq), and dicyclohexylcarbodiimide (500 mg, 1.1 eq). The resulting mixture was then stirred under a nitrogen atmosphere at room temperature for 64 hours. The reaction mixture was then filtered and the resulting filtrate was concntrated under reduced pressure. This residue was taken into ethyl acetate (200 ml) and washed once with water (200 ml), dried over potassium carbonate. The solvents were removed in vacuo to yield 1.84 grams of a tan foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:20])=[O:19])=[CH:14][CH:13]=1)/[C:6]([CH3:21])=[C:5]2[CH2:22][CH2:23][O:24][NH2:25].[CH3:26][O:27][CH2:28][CH2:29][CH:30]=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:20])=[O:19])=[CH:14][CH:13]=1)/[C:6]([CH3:21])=[C:5]2[CH2:22][CH2:23][O:24][N:25]=[CH:30][CH2:29][CH2:28][O:27][CH3:26]
Reactant: CC1=C(CCON)c2cc(F)ccc2/C1=C\c1ccc(S(C)=O)cc1
Reactant: COCCC=O
Product: COCCC=NOCCC1=C(C)/C(=C/c2ccc(S(C)=O)cc2)c2ccc(F)cc21

Procedure:
The title compound is prepared by reaction of O-2-[Z-5-fluoro-2-methyl-1-(4-methylsulfinylphenyl)methylene-1H-inden-3-yl]ethyl hydroxylamine with 3-methoxypropanal by the method of Example 1.
Reaction SMILES: [NH3:1].Cl.CO[N:5]=[CH:6][C:7]1[CH:15]=[C:11]([C:12]([OH:14])=[O:13])[C:10]([OH:16])=[CH:9][CH:8]=1>CO>[C:6]([C:7]1[CH:15]=[C:11]([C:12]([OH:14])=[O:13])[C:10]([OH:16])=[CH:9][CH:8]=1)(=[NH:5])[NH2:1]
Reactant: N
Reactant: CON=Cc1ccc(O)c(C(=O)O)c1
Agent: Cl
Solvent: CO
Product: N=C(N)c1ccc(O)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 40 ml of methanol and 20 ml of liquid ammonia, was added 4.0 g of 5-methoxyiminomethylsalicylic acid hydrochloride. The mixture was stirred overnight at room temperature. A colorless gelatinous substance precipitated from the reaction mixture was washed with methanol, and washed with a water-acetone (20 ml-80 ml) mixture to obtain 2.6 g of 5-amidinosalicylic acid.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=CC=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:26][O:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:29]=1[C:38]1[C:47]2[C:42](=[CH:43][C:44]([S:48](Cl)(=[O:50])=[O:49])=[N:45][CH:46]=2)[N:41]=[CH:40][CH:39]=1>C1COCC1>[CH3:26][O:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:29]=1[C:38]1[C:47]2[C:42](=[CH:43][C:44]([S:48]([NH:8][C:9]3[S:10][CH:11]=[CH:12][N:13]=3)(=[O:50])=[O:49])=[N:45][CH:46]=2)[N:41]=[CH:40][CH:39]=1
Reactant: COc1cc(C(F)(F)F)ccc1-c1ccnc2cc(S(=O)(=O)Cl)ncc12
Reactant: COc1ccc(CNc2nccs2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(C(F)(F)F)ccc1-c1ccnc2cc(S(=O)(=O)Nc3nccs3)ncc12
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 19.4 %

Procedure:
A round-bottom flask was charged with N-(4-methoxybenzyl)thiazol-2-amine (0.048 g, 0.218 mmol) and THF (1.00 mL), and the vessel was cooled to −78° C. for 15 minutes. LHMDS (1.0 M in THF) (0.238 ml, 0.238 mmol) was then added drop wise over 1 minute. The reaction was stirred for 10 minutes, and then a solution of 4-(2-methoxy-4-(trifluoromethyl)phenyl)-1,6-naphthyridine-7-sulfonyl chloride (0.080 g, 0.199 mmol) in THF (1.00 mL) was added drop wise. The bath was removed, and the resulting mixture was stirred for 45 minutes. The reaction was diluted with saturated ammonium chloride (aq.) solution (30 mL), and was washed with ethyl acetate (20 mL×3). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated. The resulting material was purified via silica gel MPLC chromatography (40 g), eluting with 0 to 100% ethyl acetate in heptanes. The fractions were concentrated under reduced pressure and the resulting material was taken up in DCM (10 mL) and TFA (1 mL) was added. The reaction was stirred for 2 hours and then the solvent was removed under reduced pressure. The resulting material was taken up in DCM (30 mL) and washed with aqueous sodium bicarbonate (sat. solution). The organic layer was dried over magnesium sulfate, filtered and concentrated. The resulting solid was triturated with diethyl ether (20 mL) and filtered. The solid was dried under reduced pressure to provide 0.018 g of 4-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)-1,6-naphthyridine-7-sulfonamide as an off white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.86 (s, 3H) 6.94 (d, J=4.60 Hz, 1H) 7.34 (d, J=4.60 Hz, 1H) 7.56-7.62 (m, 2H) 7.69 (d, J=7.73 Hz, 1H) 7.81 (d, J=4.50 Hz, 1H) 8.47-8.51 (m, 1H) 8.98-9.02 (m, 1H) 9.36 (d, J=4.50 Hz, 1H) 12.99 (br. s., 1H). m/z (ESI) 467.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=[O:6])[CH3:2].[Cl:8][C:9]1[C:18]([NH2:19])=[C:17]([NH:20][CH2:21][CH2:22][CH2:23][C:24]#[CH:25])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.C(N(CC)CC)C>ClCCl>[Cl:8][C:9]1[C:18]([NH:19][C:5](=[O:6])[CH2:4][O:3][CH2:1][CH3:2])=[C:17]([NH:20][CH2:21][CH2:22][CH2:23][C:24]#[CH:25])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: CCOCC(=O)Cl
Reactant: C#CCCCNc1c(N)c(Cl)nc2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCCCNc1c(NC(=O)COCC)c(Cl)nc2ccccc12
Yield: 94.8 %

Procedure:
Ethoxyacetyl chloride (96%, 4.40 g, 34.3 mmol) was added to a 6° C. solution of 2-chloro-N4-pent-4-ynylquinoline-3,4-diamine (8.10 g, 31.2 mmol) and triethylamine (6.50 mL, 46.8 mmol) in dichloromethane (100 mL). Additional ethoxyacetyl chloride (3.0 g) was added after 45 minutes until all the starting material had been consumed. The solution was diluted with dichloromethane and washed with saturated aqueous potassium carbonate, water, and brine, dried over potassium carbonate, filtered, and concentrated to afford N-[2-chloro-4-(pent-4-ynylamino)quinolin-3-yl]-2-ethoxyacetamide as a pale yellow solid (10.23 g).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([NH2:14])=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][N:11]=[CH:10]2)=[O:4].[CH:15]([NH2:17])=O>>[NH:12]1[C:13]2=[C:5]3[C:6]([CH:7]=[CH:8][C:9]2=[CH:10][NH:11]1)=[N:14][CH:15]=[N:17][C:3]3=[O:4]
Reactant: NC=O
Reactant: COC(=O)c1c(N)ccc2cn[nH]c12
Product: O=c1ncnc2ccc3c[nH][nH]c3c12

Procedure:
6-Amino-1H-indazole-7-carboxylic acid methyl ester (formula 14, obtained according to Example IV) (1.35 g, 7.0 m-mol) was heated with formamide (4.2 ml) at 140° for a period of 4 hours and again at 180° for a period of 1.5 hours. The product that formed on cooling was collected and washed with a small amount of cold water to yield 555 mg of the formula 2 target compound. Additional amounts of the target compound were obtained by working-up the mother liquor. The cumulative product yield was 965 mg (74%), m.p. 325°-327° (decomp.); ir (KBr): 1570, 1620, 1685 cm-1 (aromatic, C=C, C=N, CO); pmr (DMSO-d6): δ 7.45 and 8.22 (2 d, 2, J=9 Hz, H4 and H5), 8.30 and 8.32 (2s, 2, H3 and H7), 13.44 (broad m, 2, D2O-exchangeable N1 --H and N8 --H); ms (70 eV): m/e 186 (100%, M+), 158 (16%, M+--CO).
Reaction SMILES: N1C=CC=CC=1.Cl.[CH2:8]([C:11]1[N:15]2[CH2:16][CH2:17][CH2:18][N:19]=[C:14]2[S:13][C:12]=1[C:20]([Cl:22])=[O:21])[CH2:9][CH3:10].[CH2:23]([O:25][C:26]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][S:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1)=[O:27])[CH3:24].CN(C1C=CC=CN=1)C>CN(C)C=O>[ClH:22].[CH2:23]([O:25][C:26]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][S:33][C:34]1[CH:40]=[CH:39][C:37]([NH:38][C:20]([C:12]2[S:13][C:14]3=[N:19][CH2:18][CH2:17][CH2:16][N:15]3[C:11]=2[CH2:8][CH2:9][CH3:10])=[O:21])=[CH:36][CH:35]=1)=[O:27])[CH3:24]
Reactant: CCCC1=C(C(=O)Cl)SC2=NCCCN21
Reactant: CCOC(=O)CCCCCSc1ccc(N)cc1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCCC1=C(C(=O)Nc2ccc(SCCCCCC(=O)OCC)cc2)SC2=NCCCN21
Temperature: 70 °C
Reaction time: 16 h
Yield: 36.5 %

Procedure:
In the mixture of 50 ml of pyridine and 5 ml of dimethylformamide was suspended 0.95 g of 3-propyl-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine-2-carbonylchloride hydrochloride (described in Example 13). To the suspension was added 1.0 g of 4-(5-ethoxycarbonylpentylthio) aniline prepared in a similar manner as described in Reference Example 7 and added 43.4 mg of dimethylaminopyridine, followed by stirring at 70° C. for 16 hours. The reaction mixture was concentrated and to the concentrate was added saturated sodium hydrogencarbonate aqueous solution. The mixture was extracted with chloroform. The extract was washed with saturated sodium chloride aqueous solution and dried over anhydrous potassium carbonate. The solvent was removed under reduced pressure. The residue was dissolved in ethanol. To the mixture was added saturated hydrogenchloride diethylether solution and stirred at room temperature, following by removing the solvent under reduced pressure. The residue was purified by silica gel column chromatography (silica gel:100 g) using a mixed solvent of chloroform and methanol (10:1 by volume) as an eluent. To the resulting substance was added saturated hydrogenchloride diethylether solution. The solvent was removed under reduced pressure. The residue was recrystallized from methanol-diethylether to obtain 632 mg of the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([OH:12])=O)[CH:7]([CH3:9])[CH3:8])=[O:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[S:27]1[C:31]([C:32]2[CH:37]=[CH:36][C:35]([CH2:38][N:39]([NH2:64])[CH2:40][C@H:41]([OH:63])[C@@H:42]([NH:50][C:51](=[O:62])[C@H:52]([C@H:58]([CH2:60][CH3:61])[CH3:59])[NH:53][C:54]([O:56][CH3:57])=[O:55])[CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[CH:34][CH:33]=2)=[CH:30][N:29]=[CH:28]1>CN(C=O)C>[S:27]1[C:31]([C:32]2[CH:33]=[CH:34][C:35]([CH2:38][N:39]([NH:64][C:10](=[O:12])[C@H:6]([CH:7]([CH3:8])[CH3:9])[NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:40][C@H:41]([OH:63])[C@@H:42]([NH:50][C:51](=[O:62])[C@H:52]([C@H:58]([CH2:60][CH3:61])[CH3:59])[NH:53][C:54]([O:56][CH3:57])=[O:55])[CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[CH:36][CH:37]=2)=[CH:30][N:29]=[CH:28]1
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2cncs2)cc1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2cncs2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)C

Procedure:
Analogously to Example 7, 140 mg (0.80 mmol) of N-methoxycarbonyl-(L)-valine, 288 mg (1.5 mmol) of EDC and 135 mg (1.0 mmol) of HOBT in 2 ml of DMF and 418 μl of TEA are reacted with 0.5 mmol of 1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-amino-5(S)-N-(N-methoxycarbonyl-(L)-iso-leucyl)amino-6-phenyl-2-azahexane in 5 ml of DMF to form the title compound: m.p: 202-204° C.; HPLC20-100 : tRet =14.0; FAB MS (M+H)+ =697.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9]([F:15])=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].Br[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1>>[C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9]([F:15])=[N:10][CH:11]=[C:12]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cc(Br)cnc1F
Reactant: Brc1ccccn1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cc(-c2ccccn2)cnc1F

Procedure:
By carrying out the operation analogously to example 231, starting from 5-bromo-2-fluoro-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation VIII, and 2-bromopyridine, the desired product is obtained and is used directly in the deacetylation stage.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][CH:10]2[CH:5]3[CH2:6][CH:7]4[CH:9]2[CH:8]4[CH:4]13.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[S:21])=[CH:15][CH:14]=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[S:21])[NH:2][CH:3]2[CH2:11][CH:10]3[CH:5]4[CH2:6][CH:7]5[CH:9]3[CH:8]5[CH:4]24)=[CH:15][CH:14]=1
Reactant: NC1CC2C3CC4C2C4C13
Reactant: S=C=Nc1ccc(Cl)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: S=C(Nc1ccc(Cl)cc1)NC1CC2C3CC4C2C4C13

Procedure:
8-Aminotetracyclo[4,3,0,02,4,03,7 ]nonane hydrochloride (0.5 g.) (prepared as described in U.K. Patent Specification No. 1,180,749) was dissolved in a mixture of chloroform (25 ml.) and triethylamine (0.33 g.). To this solution was added p-chlorophenylisothiocyanate (0.5 g.) and the mixture refluxed for 16 hours. The chloroform solution, after cooling, was washed successively with 10 ml. portions of 2N HCl, water and saturated brine, and then dried over anhydrous MgSO4. After filtration, the solvent was evaporated in vacuo and the residue crystallised from toluene/cyclohexane (1:2 v/v) to give 8-[3-(p-chlorophenyl)thioureido]tetracyclo[4,3,0,02,4,03,7 ]-nonane, m.p. 168°-170°.