Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2[CH2:17][CH2:18][NH:19][CH2:20][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[O:30])[CH:25]=[CH:26][CH:27]=1>O1CCOCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2[CH2:17][CH2:18][N:19]([C:29](=[O:30])[NH:28][C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([CH3:21])[CH:23]=3)[CH2:20][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: c1ccc(Cn2c3c(c4ccccc42)CCNC3)cc1
Solvent: C1COCCO1
Product: Cc1cccc(NC(=O)N2CCc3c(n(Cc4ccccc4)c4ccccc34)C2)c1

Procedure:
A solution of 9-benzyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole(2.66 g, 10.1 mmol) and 3-methylphenylisocyanate (1.42 ml, 11.0 mmol) was stirred in dioxan (40 ml) at room temperature for 4 hours. Evaporation of the solvent and chromatography on silica gel with ethyl acetate-hexane (2:3) as eluant gave the product. (3.04 g, 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([C:10]([OH:12])=O)[CH:3]=1.[F:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH2:18][CH2:17]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([C:10]([N:19]2[C:20]3[C:16](=[CH:15][C:14]([F:13])=[CH:22][CH:21]=3)[CH2:17][CH2:18]2)=[O:12])[CH:3]=1
Reactant: Fc1ccc2c(c1)CCN2
Reactant: COc1cc(Cl)cc(C(=O)O)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(Cl)cc(C(=O)N2CCc3cc(F)ccc32)n1

Procedure:
0.55 g (2.9 mmol) 4-chloro-6-methoxy-pyridine-2-carboxylic acid, 0.41 g (3.0 mmol) 5-fluoroindoline, 1.1 g (3.3 mmol) TBTU and 0.93 mL (6.6 mmol) triethylamine in 5.0 mL DMF were stirred for 3 h at RT. The reaction mixture was purified by HPLC. The product-containing fractions were combined and evaporated down using the rotary evaporator.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][C:27]1([CH3:33])[CH3:32]>>[OH:14][C:13]1[N:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([N:29]3[CH2:30][CH2:31][N:26]([CH3:25])[C:27]([CH3:33])([CH3:32])[CH2:28]3)=[O:20])=[CH:17][N:16]=2)[N:11]=[CH:10][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[CH3:24]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CN1CCNCC1(C)C
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CCN(C)C(C)(C)C3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1,2,2-trimethylpiperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.95 (br. s., 6 H) 2.20 (s, 3 H) 2.35 (s, 3 H) 2.60 (t, J=5.05 Hz, 2 H) 2.97-3.72 (m, 4 H) 7.53 (dd, J=8.08, 1.52 Hz, 1 H) 7.59 (d, J=1.01 Hz, 1 H) 7.85 (d, J=8.08 Hz, 1 H) 7.93 (d, J=7.33 Hz, 1 H) 7.98 (s, 1 H) 8.36 (d, J=8.59 Hz, 1 H) 8.43 (br. s., 1 H); ESI-MS m/z [M+H]+ 431.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[C:14]2[C:9]=1[CH2:10][N:11]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)[C:12](=[O:30])[N:13]2[C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29].[CH3:40][N:41]([CH3:50])[CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([S:18]([N:47]2[CH2:48][CH2:49][N:44]([CH2:43][CH2:42][N:41]([CH3:50])[CH3:40])[CH2:45][CH2:46]2)(=[O:20])=[O:19])[CH:15]=[C:14]2[C:9]=1[CH2:10][N:11]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)[C:12](=[O:30])[N:13]2[C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29]
Reactant: CN(C)CCN1CCNCC1
Reactant: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(S(=O)(=O)Cl)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Product: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(S(=O)(=O)N4CCN(CCN(C)C)CC4)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1

Procedure:
The 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-({4-[2-(dimethylamino)ethyl]piperazin-1yl}sulfonyl)-3-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one was prepared from 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-2-oxo-1,2,3,4-tetrahydroquinazoline-7-sulfonyl chloride (COMPOUND CCC8) and N,N-dimethyl-2-piperazin-1-ylethanamine by a procedure analogous to that described in EXAMPLE CCC25, STEP B. Mass spectrum (ESI) 742 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([OH:10])=O.[NH2:11][C:12]([CH3:16])([CH3:15])[CH2:13]O>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:13][C:12]1([CH3:16])[CH2:15][O:10][CH:8]([C:4]2[S:5][CH:6]=[CH:7][C:3]=2[O:2][CH3:1])[NH:11]1
Reactant: CC(C)(N)CO
Reactant: COc1ccsc1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccsc1C1NC(C)(C)CO1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
50.2 g (0.32 moles) of 3-methoxy-2-thiophene carboxylic acid are refluxed in 300 ml of thionyl chloride for 2 hours, the reaction solution is evaporated in vacuo, the crystalline residue (56 g) is dissolved in 250 ml of methylene chloride and added dropwise with stirring to a solution of 57 g (0.64 moles) of 2-amino-2-methyl-1-propanol in 200 ml of methylene chloride at 0° C. within 1/2 hour. After 12 hours of stirring at room temperature, the solution is concentrated under vacuum, cooled, the precipitate is aspirated, washed well with water, dried, 135 ml of thionyl chloride are added slowly with cooling, and the solution is stirred at room temperature for 12 hours. Then it is evaporated in vacuo, the residue is dissolved in water, extracted with ether, the aqueous phase is made alkaline with aqueous 2N sodium hydroxide and extracted several times with methylene chloride. The combined methylene chloride phases are dried with sodium sulfate and evaporated in vacuo. Yield: 57.0 g (84%), m.p. (petroleum ether) 97°-98° C.
Reaction SMILES: [CH2:1]([C:19]1([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]/[CH:38]=[CH:39]\[CH2:40]/[CH:41]=[CH:42]\[CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[O:24][CH2:23][CH:22]([CH2:25]S(C)(=O)=O)[CH2:21][O:20]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:48][NH:49][CH3:50]>C1COCC1.CO.C(Cl)(Cl)Cl>[CH2:1]([C:19]1([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]/[CH:38]=[CH:39]\[CH2:40]/[CH:41]=[CH:42]\[CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[O:24][CH2:23][CH:22]([CH2:25][N:49]([CH3:50])[CH3:48])[CH2:21][O:20]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CNC
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCC1(CCCCCCCC/C=C\C/C=C\CCCCC)OCC(CS(C)(=O)=O)CO1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CO
Product: CCCCC/C=C\C/C=C\CCCCCCCCC1(CCCCCCCC/C=C\C/C=C\CCCCC)OCC(CN(C)C)CO1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
To the above crude material (VII, 1.0 g) under nitrogen was added 20 mL of dimethylamine in THF (2.0 M). The resulting mixture was stirred at room temperature for 7 days. An oily residual was obtained upon evaporation of the solvent. Column chromatography on silica gel (230-400 mesh, 100 mL) with 0-3% methanol gradient in chloroform as eluent resulted in 150 mg of the product DLin-K6S-C1-DMA as pale oil. 1H NMR (400 MHz, CDCl3) δ: 5.24-5.51 (8, m, 4×CH═CH), 4.04 (2H, dd, 2×OCH)), 3.75 (2H, dd OCH), 2.7-2.9 (2H, br, NCH2), 2.78 (4H, t, 2×C═C—CH2—C═C), 2.57 (6H, s, 2×NCH3), 1.95-2.17 (9H, q, 4× allylic CH2 and CH), 1.67-1.95 (2H, m, CH2), 1.54-1.65 (4H, m, 2×CH2), 1.22-1.45 (32H, m), 0.90 (6H, t, 2×CH3) ppm.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:19][N:18]=1.[Si:28]([O:35][C:36]1([CH2:41]/[CH:42]=[N:43]/[S:44]([C:46]([CH3:49])([CH3:48])[CH3:47])=[O:45])[CH2:39][CH:38]([CH3:40])[CH2:37]1)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].[NH4+].[Cl-]>C1COCC1>[Si:28]([O:35][C:36]1([CH2:41][C@H:42]([NH:43][S:44]([C:46]([CH3:47])([CH3:49])[CH3:48])=[O:45])[C:22]2[C:17]([F:16])=[N:18][CH:19]=[C:20]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:21]=2)[CH2:39][CH:38]([CH3:40])[CH2:37]1)([C:31]([CH3:34])([CH3:32])[CH3:33])([CH3:30])[CH3:29]
Reactant: CC(C)(C)Cc1ccc(F)nc1
Reactant: CC1CC(C/C=N/S(=O)C(C)(C)C)(O[Si](C)(C)C(C)(C)C)C1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1CC(C[C@H](NS(=O)C(C)(C)C)c2cc(CC(C)(C)C)cnc2F)(O[Si](C)(C)C(C)(C)C)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 61.3 %

Procedure:
2,2,6,6-Tetramethylpiperidine (2.47 ml, 14.7 mmol) was dissolved in 100 ml THF and cooled to −78° C. 1-Butyllithium (5.23 ml, 13.1 mmol, 2.5M) was added and the reaction was allowed to warm up to 0° C. for 5 min before it was cooled back to −78° C. again. At this point, a solution of 2-fluoro-5-neopentylpyridine (1.75000 g, 10.5 mmol) was added dropwise and the reaction was stirred for 1 h. Next, a solution of (E)-N-(2-(1-(tert-butyldimethylsilyloxy)-3-methylcyclobutyl)ethylidene)-2-methylpropane-2-sulfinamide (3.98 g, 11.5 mmol) in THF was added dropwise and stirring was continued for 1 h. The mixture was hydrolyzed with NH4Cl in the cold, warmed up to RT extracted with EtOAc (3×150 ml), dried over MgSO4 and evaporated. N-((S)-2-(1-(tert-Butyldimethylsilyloxy)-3-methylcyclobutyl)-1-(2-fluoro-5-neopentylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (3.30 g, 61.5% yield) was obtained after glass col. Chrom. (20-70% EtOAc in Hex.). Low yield due to the formation of a minor diastereomer at the NH center (approx 30%). Mixture of cis/trans at the cyclobutylring (4:1).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].[CH2:17](OC(OCC)(OCC)C)[CH3:18]>O>[CH3:17][C:18]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4](=[O:5])[C:3]2[C:2](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:1]=1
Reactant: Nc1ccccc1C(=O)Nc1ccccc1
Reactant: CCOC(C)(OCC)OCC
Solvent: O
Product: Cc1nc2ccccc2c(=O)n1-c1ccccc1
Yield: 75.2 %

Procedure:
A mixture of 2-amino-N-phenyl-benzamide 26 (2 g, 0.009 mol) and 1,1,1-triethoxy-ethane (5.2 mL, 0.028 mol) were heated for 5 hours. The reaction mixture was poured into water, filtered off, washed with water yielding 2-methyl-3-phenyl-3H-quinazolin-4-one 27 (1.6 g, 82%). After recrystallization it was used in next step without further purification.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:4](C(OC(C)CC)=O)[C:5]2[C:6]([N:22]=1)=[N:7][CH:8]=[C:9]([C:11]1[CH:12]=[CH:13][C:14]3[O:20][CH2:19][CH2:18][NH:17][CH2:16][C:15]=3[CH:21]=1)[CH:10]=2.Cl[C:31]1[C:36]([CH3:37])=[C:35]([Cl:38])[N:34]=[CH:33][N:32]=1.C(N(C(C)C)CC)(C)C>CN1CCCC1=O.C(OCC)(=O)C>[Cl:38][C:35]1[N:34]=[CH:33][N:32]=[C:31]([N:17]2[CH2:16][C:15]3[CH:21]=[C:11]([C:9]4[CH:10]=[C:5]5[NH:4][C:3]([CH3:2])=[N:22][C:6]5=[N:7][CH:8]=4)[CH:12]=[CH:13][C:14]=3[O:20][CH2:19][CH2:18]2)[C:36]=1[CH3:37]
Reactant: Cc1c(Cl)ncnc1Cl
Reactant: CCC(C)OC(=O)n1c(C)nc2ncc(-c3ccc4c(c3)CNCCO4)cc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1nc2ncc(-c3ccc4c(c3)CN(c3ncnc(Cl)c3C)CCO4)cc2[nH]1
Yield: 28.8 %

Procedure:
A solution of 1-methylpropyl 2-methyl-6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-imidazo[4,5-b]pyridine-1-carboxylate hydrochloride (0.213 g, 0.512 mmol, example 6, step 2), 4,6-dichloro-5-methylpyrimidine (0.100 g, 0.613 mmol), and diisopropylethylamine (0.330 g, 2.56 mmol) in N-methylpyrrolidinone (2 mL) was stirred at room temperature for 17 h. The reaction mixture was diluted with ethyl acetate (100 mL), washed with saturated sodium bicarbonate (50 mL) and brine (25 mL), and dried over sodium sulfate. Filtration, concentration and purification by column chromatography on silica (97:3 dichloromethane/methanol) provided 4-(6-chloro-5-methylpyrimidin-4-yl)-7-(2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (0.06 g, 31% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.50 (s, 1H), 8.22 (s, 1H), 8.04 (s, 1H), 7.60 (s, 1H), 7.50 (d, 1H), 7.08 (d, 1H), 4.81 (s, 2H), 4.39-4.32 (m, 2H), 4.03-3.97 (m, 2H), 2.64 (s, 3H), 2.37 (s, 3H); MS (EI) for C21H19ClN6O: 407 (MH+).
Reaction SMILES: C([O:8][C:9]1[C:14]([Br:15])=[CH:13][N:12]=[C:11]([NH:16][C:17]2[S:18][CH:19]=[C:20]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:21]=2)[CH:10]=1)C1C=CC=CC=1.[ClH:30]>O1CCOCC1>[ClH:30].[Br:15][C:14]1[C:9]([OH:8])=[CH:10][C:11]([NH:16][C:17]2[S:18][CH:19]=[C:20]([CH2:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:21]=2)=[N:12][CH:13]=1
Reactant: Brc1cnc(Nc2nc(CCc3ccccc3)cs2)cc1OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: Oc1cc(Nc2nc(CCc3ccccc3)cs2)ncc1Br
Temperature: 95 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
A flask was charged with 4-(benzyloxy)-5-bromo-N-(4-phenethylthiazol-2-yl)pyridin-2-amine (1.0 g, 2.1 mmol), dioxane (20 mL), concentrated HCl (70 mL) and 6N HCl (10 mL). The reaction was stirred at 95° C. overnight. The reaction was filtered and the collected solids were washed with water and under high vacuum overnight to give the desired product (0.80 g, 89% yield) as light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]([N+:13]([O-])=O)=[CH:5][N:4]=1.CO.[H][H]>[OH-].[OH-].[Pd+2].C(Cl)Cl.CO>[CH3:1][O:2][C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]([NH2:13])=[CH:5][N:4]=1
Reactant: [H][H]
Reactant: COC(=O)c1cc([N+](=O)[O-])cnc1OC
Agent: [Pd+2]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc(N)cnc1OC
Reaction time: 2 h
Yield: 93.3 %

Procedure:
2-Methoxy-3-carbomethoxy-5-nitropyridine (850 mg, 4 mmol) was added to a medium pressure Parr shaker bottle (250 mL) containing 100 mg of 20% Pearlman's catalyst (palladium hydroxide/carbon) and 50 mL of methanol. The bottle was pressurized to 50 psi of hydrogen and shaken for 2 hours. By TLC, no starting material was observed (98/2 CH2Cl2 /MeOH). The catalyst was filtered off, the methanol was removed under reduced pressure and the product used in the next step without further purification. Recovered 680 mg of product (95% yield).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[NH2:17][C:18]1[CH:19]=[C:20]([OH:26])[C:21]([Cl:25])=[CH:22][C:23]=1[F:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:17][C:18]1[C:23]([F:24])=[CH:22][C:21]([Cl:25])=[C:20]([CH:19]=1)[O:26][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Reactant: Nc1cc(O)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c(Cl)cc1F
Yield: 56.2 %

Procedure:
To a solution of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (600 mg, 1.83 mmol) in N,N-dimethylformamide (12 mL) were added 3-amino-6-chloro-4-fluorophenol (443 mg, 2.74 mmol) and potassium carbonate (505 mg, 3.66 mmol). In the same manner as in Example 232, the title compound (372 mg, 56%) was obtained as a brown powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([F:9])[CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[C:21]1[N:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:22]=1[C:23]([OH:25])=[O:24]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:21]2[N:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:22]=2[C:23]([OH:25])=[O:24])=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Cl)nc1Nc1ccc(Br)cc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
To a solution of 4-bromo-2-fluorophenylamine (10.4 g, 54.7 mmol) in THF (25 mL) at −78° C. under N2 was added lithium bis(trimethylsilyl)amide (83.3 mL, 83.3 mmol, 1 M solution in hexanes) dropwise over 15 minutes. The reaction mixture was stirred for one hour at −78° C. 2,6-Dichloro-nicotinic acid (5.00 g, 26.0 mmol) was then added dropwise as a solution in THF (15 mL) and the reaction mixture was allowed to warm from −78° C. to room temperature and stir for 16 hours. The reaction mixture was quenched by the addition of H2O and the pH was adjusted to 0-2 with 6 N HCl and then diluted with EtOAc. The organic layer was separated and washed with H2O, saturated NaCl, dried (Na2SO4), and concentrated under reduced pressure. The crude product was triturated several times with ethyl acetate and the resulting solid was collected, washed with dichloromethane and dried under vacuum to yield 7.50 g (83%) pure desired product as a dark pink solid.
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([NH:12][C:13](=[O:18])[CH2:14][C:15]([OH:17])=O)=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[Cl:51][C:52]1[CH:64]=[CH:63][CH:62]=[CH:61][C:53]=1[O:54][CH:55]1[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]1>CN(C=O)C.O>[Cl:51][C:52]1[CH:64]=[CH:63][CH:62]=[CH:61][C:53]=1[O:54][CH:55]1[CH2:60][CH2:59][N:58]([C:15](=[O:17])[CH2:14][C:13]([NH:12][C:10]2[S:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][N:9]=2)=[O:18])[CH2:57][CH2:56]1
Reactant: O=C(O)CC(=O)Nc1ncc(-c2ccccc2)s1
Reactant: Clc1ccccc1OC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CC(=O)N1CCC(Oc2ccccc2Cl)CC1)Nc1ncc(-c2ccccc2)s1
Reaction time: 8 h
Yield: 24.3 %

Procedure:
To a stirred solution of N-(5-phenyl-thiazol-2-yl)-malonamic acid (0.075 g, 0.00028 mole) in DMF (2 mL) was added DIPEA (0.11 g, 0.00085 mole), HOBt (0.038 g, 0.00028 mole) and EDCI.HCl (0.065 g, 0.00034 mole). After 2 minutes 4-(2-chloro-phenoxy)-piperidine hydrochloride (0.078 g, 0.00031 mole) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure to afford 0.031 g (24%) of 3-[4-(2-chloro-phenoxy)-piperidin-1-yl]-3-oxo-N-(5-phenyl-thiazol-2-yl)-propionamide. LC-MS purity: 456.11 (M+1)+, 93.27%, 1H NMR (CDCl3): δ 11.6 (s, 1H), 7.9 (d, 2H), 7.44 (t, 3H), 7.3 (d, 1H), 7.22 (d, 1H), 7.14 (s, 1H), 6.92 (d, 2H), 4.7 (s, 1H), 4.1 (m, 1H), 3.8 (m, 1H), 3.7-3.5 (m, 4H), 2.0 (d, 4H).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][O:9][S:10](=[O:13])(=[O:12])[NH2:11])[CH2:4][C@H:3]1[NH:14][C:15]1[N:20]2[N:21]=[C:22]([C:24]3[CH:33]=[CH:32][CH:31]=[C:30]4[C:25]=3[CH:26]=[CH:27][C:28]([C:34]([O:36]C)=[O:35])=[CH:29]4)[CH:23]=[C:19]2[N:18]=[CH:17][CH:16]=1.CN(C=O)C.[OH-].[Na+]>>[OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][O:9][S:10](=[O:13])(=[O:12])[NH2:11])[CH2:4][C@H:3]1[NH:14][C:15]1[N:20]2[N:21]=[C:22]([C:24]3[CH:33]=[CH:32][CH:31]=[C:30]4[C:25]=3[CH:26]=[CH:27][C:28]([C:34]([OH:36])=[O:35])=[CH:29]4)[CH:23]=[C:19]2[N:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc2c(-c3cc4nccc(N[C@@H]5C[C@H](COS(N)(=O)=O)[C@@H](O)[C@H]5O)n4n3)cccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: NS(=O)(=O)OC[C@H]1C[C@@H](Nc2ccnc3cc(-c4cccc5cc(C(=O)O)ccc45)nn23)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 8.6 %

Procedure:
To a solution of (rac)-methyl rel-5-[7-({(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoyloxy)methyl]cyclopentyl}amino)pyrazolo[1,5-a]pyrimidin-2-yl]-2-naphthoate (0.048 g, 0.091 mmol) in DMF (2.0 mL, 26 mmol) is added 1.0 M NaOH (1.0 mL, 1.0 mmol). The mixture is stirred at room temperature for 1.5 hr and then concentrated in vacuo as an azeotropic mixture with toluene. The crude material is purified by preparative HPLC to provide (rac)-rel-5-[7-({(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoyloxy)methyl]cyclopentyl}amino)pyrazolo[1,5-a]pyrimidin-2-yl]-2-naphthoic acid (4.0 mg, yield 8.5%). LCMS: (AA) M+1 514; 1H NMR (400 MHz, DMSO) δ 8.71-8.63 (m, 1H), 8.55 (d, J=8.9 Hz, 1H), 8.25-8.16 (m, 2H), 8.09-7.98 (m, 1H), 7.98-7.90 (m, 1H), 7.89-7.79 (m, 1H), 7.75-7.63 (m, 1H), 7.55-7.25 (m, 1H), 6.79 (s, 1H), 6.33 (d, J=5.4 Hz, 1H), 5.2-4.6 (m, 2H), 4.18-4.05 (m, 1H), 4.06-3.90 (m, 3H), 3.80-3.68 (m, 1H), 2.40-2.15 (m, 2H), 1.56-1.36 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1)#[N:2].Cl.[CH3:18][O:19][C:20](=[O:26])[C@H:21]([CH:23]([CH3:25])[CH3:24])[NH2:22].C([BH3-])#N.[Na+]>>[CH3:18][O:19][C:20](=[O:26])[C@H:21]([CH:23]([CH3:25])[CH3:24])[NH:22][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])=[CH:14][CH:13]=1
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: N#Cc1ccccc1-c1ccc(C=O)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: COC(=O)[C@@H](NCc1ccc(-c2ccccc2C#N)cc1)C(C)C

Procedure:
The starting material can be obtained, for example, analogously to Example 1b): Reaction of 0.5 g of 2'-cyanobiphenyl-4-carbaldehyde, 2.5 g of molecular sieve 5 A, 0.815 g of (L)-valine methyl ester hydrochloride and 180 mg of sodium cyanoborohydride yields N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester after flash chromatography (N3). (TLC: N3) Rf : 0.5.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH:12][C:13](=[O:17])[C:14]([OH:16])=[O:15])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([S:20][CH:21](O)[CH3:22])[CH3:19]>>[C:1]1([C:7]2[N:8]=[C:9]([NH:12][C:13](=[O:17])[C:14]([O:16][CH2:19][CH2:18][S:20][CH2:21][CH3:22])=[O:15])[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCSC(C)O
Reactant: O=C(O)C(=O)Nc1nc(-c2ccccc2)cs1
Product: CCSCCOC(=O)C(=O)Nc1nc(-c2ccccc2)cs1

Procedure:
Using a method similar to Example 12, 6.2 g of N-(4-phenyl-thiazol-2-yl)-oxamic acid and 6.6 g of ethylthioethanol give, after crystallization of the product from ethanol, 3.4 g of the compound of the formula I, with R1 =C6H5 and R2 =CH2CH2SC2H5, of melting point 148°-149° C.
Reaction SMILES: [CH3:1][NH2:2].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12](Cl)(=[O:14])=[O:13])=[CH:7][CH:6]=1)#[N:4]>O1CCCC1>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12]([NH:2][CH3:1])(=[O:14])=[O:13])=[CH:7][CH:6]=1)#[N:4]
Reactant: N#Cc1ccc(CS(=O)(=O)Cl)cc1
Reactant: CN
Solvent: C1CCOC1
Product: CNS(=O)(=O)Cc1ccc(C#N)cc1
Temperature: 25 °C

Procedure:
Gaseous methylamine was introduced into a solution of 0.8 g (3.71 mMol) of 4-cyanobenzenemethanesulphonic acid chloride in 20 ml of tetrahydrofuran until a distinctly alkaline reaction was obtained. The mixture was stirred for a further hour at ambient temperature, the excess methylamine together with the solvent was distilled off in vacuo and the residue was triturated with diethylether. The crystals formed were suction filtered and dried. 420 mg (54% of theory) of colourless crystals were obtained, Mp. 151-152° C.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[S:9][C:8]([NH2:10])=[N:7][N:6]=1.[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3([C:27](O)=[O:28])[CH2:26][CH2:25]3)=[CH:23][C:18]=2[O:17][CH2:16]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(#N)C>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[S:9][C:8]([NH:10][C:27]([C:24]2([C:22]3[CH:21]=[CH:20][C:19]4[O:15][CH2:16][O:17][C:18]=4[CH:23]=3)[CH2:26][CH2:25]2)=[O:28])=[N:7][N:6]=1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Reactant: Nc1nnc(Cc2ccccc2Cl)s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(Nc1nnc(Cc2ccccc2Cl)s1)C1(c2ccc3c(c2)OCO3)CC1
Reaction time: 16 h
Yield: 14 %

Procedure:
5-(2-Chloro-benzyl)-[1,3,4]thiadiazol-2-ylamine (23 mg, 0.10 mmol) and 1-benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid (21 mg, 0.10 mmol) were dissolved in acetonitrile (1.5 mL) containing triethylamine (42 L, 0.30 mmol). Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP, 49 mg, 0.11 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography to yield the pure product (5.7 mg, 0.014 mmol, 14%). ESI-MS m/z calc. 413.1. found; 414.3 (M+1)+ Retention time 3.38 minutes.