Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([N:35]([CH2:44][C:45]2[CH:54]=[CH:53][C:48]([C:49]([NH:51]O)=[NH:50])=[CH:47][CH:46]=2)[CH:36]2[CH2:42][CH2:41][CH2:40][CH2:39][NH:38][C:37]2=[O:43])(=[O:34])=[O:33])=[CH:28][CH:27]=1.O>CN(C)C=O>[CH2:1]([O:8][CH2:9][C:10]1[O:12][N:50]=[C:49]([C:48]2[CH:53]=[CH:54][C:45]([CH2:44][N:35]([CH:36]3[CH2:42][CH2:41][CH2:40][CH2:39][NH:38][C:37]3=[O:43])[S:32]([C:29]3[CH:28]=[CH:27][C:26]([Cl:25])=[CH:31][CH:30]=3)(=[O:34])=[O:33])=[CH:46][CH:47]=2)[N:51]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N=C(NO)c1ccc(CN(C2CCCCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Reactant: O=C(O)COCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NCCCCC1N(Cc1ccc(-c2noc(COCc3ccccc3)n2)cc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.8 %

Procedure:
To a solution of benzyloxyacetic acid (162 μl, 1.10 mmol) in 5 ml dimethylformamide were added 1,1′-carbonyl-diimidazole (0.18 g, 1.10 mmol). The mixture was stirred at room temperature for 10 minutes, heated to 40° C. for a few minutes and cooled to room temperature. 4-{[(4-Chloro-benzenesulfonyl)-(2-oxo-azepan-3-yl)-amino]-methyl}-N-hydroxy-benzamidine (0.45 g, 1.00 mmol) was added and the mixture was stirred at 100° C. for 5 hours and then poured into water. Filtration and chromatography on silicagel with ethylacetate/heptane (1/1 to 4/1) yielded 0.51 g (87%) N-[4-(5-benzyloxymethyl-[1,2,4]oxadiazol-3-yl)-benzyl]-4-chloro-N-(2-oxo-azepan-3-yl)-benzenesulfonamide as white solid, MS: m/e (%)=581.1 (MH+, 100).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:22]=[CH:21][C:12]([O:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16](Cl)[CH:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=O.C[CH2:28][N:29](C(C)C)C(C)C.CN>C1COCC1>[CH2:1]([O:8][C:9]1[CH:22]=[CH:21][C:12]([O:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:29][CH3:28])[CH:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Clc1cc(Oc2ccc(OCc3ccccc3)cc2)ccn1
Agent: CN
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CNc1cc(Oc2ccc(OCc3ccccc3)cc2)ccn1
Temperature: 100 °C

Procedure:
In a 350 mL sealed tube fitted with stirring bar were combined at 0° C. 4-(4-benzyloxy-phenoxy)-2-chloro-pyridine (Step a, 2.11 g, 6.79 mmol), DMSO (10 mL), DIEA (1.3 mL, 7.47 mmol), and CH3NH2 (4.1 mL of a 2 N solution in THF, 8.15 mmol). The reaction was heated to 100° C. for 7 days. During that period, an additional amount of CH3NH2 solution was added on four separate days (for a total of 70 mL). The reaction was cooled to RT and diluted into 1N NaOH and Et2O after evaporating off THF. After separation of the layers, the organic layer was washed 3× with 1 N NaOH then with brine. The crude residue was eluted on a silica gel column with a hexanes/EtOAc gradient to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:31][CH3:32])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[C:24]4[N:23]=[CH:22][N:21]=[CH:20][C:19]=4[NH:18][N:17]=3)=[O:15])=[CH:11][N:10]([C:25]([CH3:30])([CH3:29])[C:26](O)=[O:27])[N:9]=2)[CH:7]=1.[NH:33]1[CH2:36][CH2:35][CH2:34]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[N:33]1([C:26](=[O:27])[C:25]([N:10]2[CH:11]=[C:12]([NH:13][C:14]([C:16]3[C:24]4[N:23]=[CH:22][N:21]=[CH:20][C:19]=4[NH:18][N:17]=3)=[O:15])[C:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:31][CH3:32])=[N:9]2)([CH3:30])[CH3:29])[CH2:36][CH2:35][CH2:34]1
Reactant: COc1ccc(Cl)cc1-c1nn(C(C)(C)C(=O)O)cc1NC(=O)c1n[nH]c2cncnc12
Reactant: C1CNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1-c1nn(C(C)(C)C(=O)N2CCC2)cc1NC(=O)c1n[nH]c2cncnc12
Reaction time: 6 h
Yield: 58.8 %

Procedure:
A solution of 2-(3-(5-chloro-2-methoxyphenyl)-4-(pyrazolo pyrimidine-3-carboxamido)-1H-pyrazol-1-yl)-2-methylpropanoic acid (0.050 g, 0.11 mmol, 1 equiv), azetidine (18.5 μL, 0.275 mmol, 2.50 equiv), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl)uranium hexafluorophosphate (84 mg, 0.20 mmol, 2.00 equiv), and N,N-diisopropylethylamine (380 μL, 2.2 mmol, 20 equiv) in N,N-dimethylformamide (1 mL) was heated at 50° C. After 6 h, the reaction mixture was concentrated, and the resulting residue was partitioned between saturated aqueous sodium bicarbonate (5 mL) and ethyl acetate (5 mL). The aqueous was extracted with ethyl acetate (2×5 mL). The combined organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by preparative HPLC afforded product (32 mg, 60% yield). 1H NMR (400 MHz, DMSO-d6), δ: 9.70 (s, 1H), 9.34 (m, 1H), 8.77 (dd, J=4.2, 1.5 Hz, 1H), 8.64 (s, 1H), 8.36 (s, 1H), 7.52 (dd, J=8.9, 2.7 Hz, 1H), 7.41 (d, J=2.6 Hz, 1H), 7.28-7.32 (m, 2H), 3.88 (s, 2H), 3.86 (s, 3H), 3.41 (m, 2H), 2.04 (m, 2H), 1.72 (s, 6H). LCMS (ESI): M+H=494.1.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]#[CH:15])=[CH:11][CH:12]=2)[C@H:7]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=2)[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2].CN(C)C=O.C[Si]([N:34]=[N+:35]=[N-:36])(C)C>[Cu]I.CO>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[N:34]=[N:35][NH:36][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=2)[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2]
Reactant: C#Cc1ccc2c(c1)[C@H](Nc1ccc(C)cn1)C[C@H](C)N2C(C)=O
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: [Cu]I
Solvent: CO
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3c[nH]nn3)cc2[C@H](Nc2ccc(C)cn2)C[C@@H]1C
Temperature: 100 °C
Reaction time: 2 h
Yield: 0.93 %

Procedure:
A flask was charged with (2S,4R)-1-acetyl-6-ethynyl-2-methyl-N-(5-methyl-2-pyridinyl)-1,2,3,4-tetrahydro-4-quinolinamine (for a preparation see Intermediate 110) (57 mg, 0.178 mmol) and copper(I) iodide (3.40 mg, 0.018 mmol) then filled with N,N-dimethylformamide (DMF) (1.8 mL) and methanol (0.2 mL) and the resulting mixture was treated with trimethylsilyl azide (0.095 mL, 0.714 mmol). The flask was flushed with nitrogen then the mixture was stirred at 100° C. for 2 h under microwave irradiation then cooled to room temperature. Most of the methanol was removed in vacuo and the residue partitioned between AcOEt and water. The layers were separated and the aqueous layer was extracted with AcOEt. The combined organic phases were washed with water, dried over MgSO4 and concentrated in vacuo. Purification of the residue by MDAP (modifier: ammonium bicarbonate) gave (2S,4R)-1-acetyl-2-methyl-N-(5-methyl-2-pyridinyl)-6-(1H-1,2,3-triazol-4-yl)-1,2,3,4-tetrahydro-4-quinolinamine (0.6 mg, 1.655 μmol, 0.928% yield) as a colourless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[N:7]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[N:6]=[C:5]2[CH3:22].N1C=CC=CC=1.[C:29](Cl)(Cl)=[O:30]>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N:11]=[C:29]=[O:30])[N:7]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[N:6]=[C:5]2[CH3:22]
Reactant: Cc1ccc(S(=O)(=O)n2nc(C)c3cc(Br)c(N)cc32)cc1
Reactant: O=C(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2nc(C)c3cc(Br)c(N=C=O)cc32)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-Bromo-3-methyl-1-(toluene-4-sulfonyl)-1H-indazol-6-ylamine (138 mg, 0.36 mmol) was dissolved in 5 ml of toluene at room temperature. DMAP (1 eq, 44 mg), pyridine (1.3 eq, 0.04 ml) were added followed by phosgene (1.33 eq, 0.24 ml of a 20% solution in toluene). The mixture was allowed to stir at room temperature for 2 hours, forming a fine white precipitate. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was diluted with dichloromethane and concentrated in vacuo again to give 5-bromo-6-isocyanato-3-methyl-1-(toluene-4-sulfonyl)-1H-indazole (150 mg, quantitative) as a white crystalline solid.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][NH:6][C:7](=[O:31])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:21][C:22]2[CH:27]=[C:26]([CH3:28])[C:25](Br)=[C:24]([CH3:30])[CH:23]=2)[CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:10][CH:9]=1.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1>>[CH3:28][C:26]1[CH:27]=[C:22]([O:21][CH:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:32])=[O:31])=[CH:9][CH:10]=2)[CH2:15][CH2:16][C:17]([F:18])([F:19])[F:20])[CH:23]=[C:24]([CH3:30])[C:25]=1[C:38]1[CH:39]=[CH:40][C:35]([C:34]([F:45])([F:44])[F:33])=[CH:36][CH:37]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCC(F)(F)F)Oc2cc(C)c(Br)c(C)c2)cc1
Product: Cc1cc(OC(CCC(F)(F)F)c2ccc(C(=O)NCCC(=O)O)cc2)cc(C)c1-c1ccc(C(F)(F)F)cc1

Procedure:
The title compound is prepared in a manner substantially similar to Example 128 starting from 3-{4-[1-(4-bromo-3,5-dimethyl-phenoxy)-4,4,4-trifluoro-butyl]-benzoylamino}-propionic acid methyl ester and 4-trifluoromethyl phenyl boronic acid. MS: 566.2 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17](N)=[C:16]([S:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]1[Cl:24].C(ON=O)(C)(C)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16]([S:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]1[Cl:24]
Reactant: Nc1c(SC(F)(F)F)nc(Cl)n1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Product: FC(F)(F)Sc1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(Cl)n1
Yield: 83 %

Procedure:
To a solution of 2.0 g (4.64 mmole) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-5-amino-2-chloro-4-trifluoromethylsulfenylimidazole in 40 ml of tetrahydrofuran was added 2.76 ml (23.2 mmole) of t-butylnitrite. The resulting mixture was heated to reflux under a nitrogen atmosphere for 2 h. The mixture was evaporated to dryness and the residue was purified by column chromatography using 10% ethyl acetate in hexane to give 1.6 g (83.0% yield) of the desired product, mp 112° C.
Reaction SMILES: [CH2:1]([N+:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]=1[CH3:12])[CH3:2].CC1C=CC(S(O)(=O)=O)=CC=1.[Cl:24][C:25]([Cl:46])([Cl:45])[C:26]1[N:31]=[C:30]([C:32]([Cl:35])([Cl:34])[Cl:33])[N:29]=[C:28]([C:36]2[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=2)[C:39](Cl)=[O:40])[N:27]=1.C1(C)C=CC=CC=1>C(N(CC)CC)C>[Cl:35][C:32]([Cl:33])([Cl:34])[C:30]1[N:31]=[C:26]([C:25]([Cl:46])([Cl:24])[Cl:45])[N:27]=[C:28]([C:36]2[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=2)[C:39]([CH:12]=[C:4]2[N:3]([CH2:1][CH3:2])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[S:5]2)=[O:40])[N:29]=1
Reactant: O=C(Cl)c1cccc(-c2nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n2)c1
Reactant: CC[n+]1c(C)sc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCN1C(=CC(=O)c2cccc(-c3nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n3)c2)Sc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-Ethyl-2-methyl-benzothiazolium-p-toluenesulfonate (5.0 pbw) and 3-(4,6-bis-trichloromethyl-s-triazin-2-yl) benzoylchloride (7.4 pbw) are successively suspended or dissolved, respectively, in 50 pbw of toluene. The mixture is cooled to 15° C. and, at this temperature, 6.0 pbw of triethylamine are added dropwise with the exclusion of moisture. The mixture discolors towards dark brown and is stirred for 3 hours at room temperature. The precipitate that forms is removed by filtration with suction and washed with cold toluene. The residue is digested in 200 pbw of methanol and stirred for about 60 minutes, filtered again and dried. The product is recrystallized from 2-methoxy-ethanol, giving orange-colored crystals.
Reaction SMILES: [CH:1]([C:4]1[C:5]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:6]([CH3:9])[NH:7][CH:8]=1)([CH3:3])[CH3:2].[I:15]N1C(=O)CCC1=O>ClCCl>[I:15][C:8]1[NH:7][C:6]([CH3:9])=[C:5]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: CCOC(=O)c1c(C(C)C)c[nH]c1C
Solvent: ClCCl
Product: CCOC(=O)c1c(C)[nH]c(I)c1C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
A solution of 1.03 g of ethyl 4-isopropyl-2-methyl-1H-pyrrole-3-carboxylate in 27 ml of anhydrous dichloromethane was treated with 2.06 g of N-iodosuccinimide and stirred at room temperature for 2 h. The mixture was diluted with a further 50 ml of dichloromethane and washed with 50 ml of saturated sodium thiosulphate solution and 50 ml of saturated sodium hydrogen carbonate solution. The dichloromethane extract was dried over anhydrous sodium sulphate then filtered and evaporated. The residue was triturated with 50 ml of petroleum ether (bp 40-60° C.). The orange solid product was filtered off and dried to give 1.32 g of ethyl 5-iodo-4-isopropyl-2-methyl-1H-pyrrole-3-carboxylate; mass spectrum (ESI) m/z 322 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:18][NH2:19]>>[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:18][NH:19][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: Cc1cc(Cl)c2cccc(C)c2n1
Product: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(C)c2n1

Procedure:
Preparation was made using a similar procedure as described in example 1, method 1.3. Starting materials were 4-chloro-2-methyl-8-methylquinoline and 3,4-dichlorobenzylamine.
Reaction SMILES: Br[CH:2]([CH3:14])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[C:7]=1[OH:13])=[O:4].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:12][C:8]1[C:7]2[O:13][CH:2]([CH3:14])[C:3](=[O:4])[NH:5][C:6]=2[CH:11]=[CH:10][CH:9]=1
Reactant: CC(Br)C(=O)Nc1cccc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1Oc2c(Br)cccc2NC1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 60 %

Procedure:
A mixture of 2-bromo-N-(3-bromo-2-hydroxyphenyl)propionamide (4.70 g, 14.6 mmol) and potassium carbonate (2.01 g, 14.6 mmol) in N,N-dimethylformamide (100 ml) was stirred at room temperature for 15 h. The mixture was poured into water and extracted with ether. The extract was washed with brine, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography eluting with 20% ethyl acetate/n-hexane to afford 2.12 g (60%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:26][C:27](=[O:29])[CH3:28])[S:13][C:14]=2[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.C([N:38]=[C:39]=[S:40])(=O)C1C=CC=CC=1.O>CC(C)=O>[NH2:38][C:39]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:26][C:27](=[O:29])[CH3:28])[S:13][C:14]=2[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:6][CH:7]=1)=[S:40]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CC(=O)Nc1nc(CCc2ccc(N)cc2)c(Cc2ccc(S(C)(=O)=O)cc2)s1
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)Nc1nc(CCc2ccc(NC(N)=S)cc2)c(Cc2ccc(S(C)(=O)=O)cc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.2 %

Procedure:
To a ice-cold solution of N-{4-[2-(4-aminophenyl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide (247.6 mg) in acetone (4.8 ml) was added benzoyl isothiocyanate (94.1 mg), and the mixture was stirred at r.t. for 1 hour. Water was added to the mixture, and the mixture was extracted with AcOEt. The organic layer was washed with water and brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residual amorphous substance was dissolved in EtOH (5 ml), and 6N—NaOH (0.288 ml) was added to the solution at 0° C. The reaction mixture was stirred at r.t. for 2 hours, and neutralized with 1N—HCl at 0° C. The mixture was extracted with AcOEt. The organic layer was washed with water and brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was solidified with ethyl ether to give N-{4-(2-{4-[(aminocarbonothioyl)amino]phenyl}ethyl)-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide (290.7 mg) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[C:24]([O:25][CH2:26][CH3:27])=[CH:23][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][N:15]=3)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:28][CH2:29][CH3:30].[NH2:31][CH2:32][CH2:33][OH:34].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[C:24]([O:25][CH2:26][CH3:27])=[CH:23][C:5]([CH2:6][N:7]2[CH2:8][CH2:9][CH:10]([NH:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:31][CH2:32][CH2:33][OH:34])=[O:20])=[CH:16][N:15]=3)[CH2:11][CH2:12]2)=[CH:4][C:3]=1[O:28][CH2:29][CH3:30]
Reactant: CCOc1cc(CN2CCC(Nc3ccc(C(=O)O)cn3)CC2)cc(OCC)c1Cl
Reactant: NCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1cc(CN2CCC(Nc3ccc(C(=O)NCCO)cn3)CC2)cc(OCC)c1Cl
Temperature: 60 °C
Yield: 42 %

Procedure:
To a mixture of 6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-nicotinic acid (65.09 mg, 0.15 mmol, 1.0 equiv; example 70) and 2-amino-ethanol (46.4 mg, 0.25 mmol, 1.67 equiv; commercially available) in dry DMF (2.0 mL) and N-ethyl diisopropylamine (0.3 mL) was added HATU (68.44 mg, 0.18 mmol, 1.2 quiv; commercially available) and the reaction stirred at 60° C. over night. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 30.1 mg (42%) of the title compound. MS (ISP): 477.3 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.[C:9]([C:11]1[CH:16]=[CH:15][N:14]2[N:17]=[CH:18][C:19]([C:20]3[N:25]=[C:24](N[C@@H]4CCCN(C(OC(C)(C)C)=O)C4)[CH:23]=[CH:22][N:21]=3)=[C:13]2[CH:12]=1)#[N:10]>CN(C=O)C>[OH:8][C@H:5]1[CH2:6][CH2:7][C@H:2]([NH:1][C:22]2[CH:23]=[CH:24][N:25]=[C:20]([C:19]3[CH:18]=[N:17][N:14]4[CH:15]=[CH:16][C:11]([C:9]#[N:10])=[CH:12][C:13]=34)[N:21]=2)[CH2:3][CH2:4]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ccnc(-c3cnn4ccc(C#N)cc34)n2)C1
Solvent: CN(C)C=O
Product: N#Cc1ccn2ncc(-c3nccc(N[C@H]4CC[C@H](O)CC4)n3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trans-4-aminocyclohexanol (85 mg, 0.74 mmol) was added to a solution of 3-(4-(1H-benzo[d][1,2,3]triazol-1-yloxy)pyrimidin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile (byproduct of Preparation 7a, 105 mg, 0.30 mmol) in N,N′-dimethylformamide (3 mL) and the mixture was stirred at ambient temperature overnight. The solvent was then evaporated and the residue was partitioned between water and ethyl acetate. The organic layer was separated, washed with water and brine, dried (MgSO4) and the solvent evaporated. The crude product was purified by flash chromatography (dichloromethane to 9:1 dichloromethane/methanol) to give the title compound (66 mg, 67%) as a yellow solid.
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH3:8])[NH:5][C:6]=1[CH3:7].[Cl:9][C:10]1[CH:15]=[C:14](F)[CH:13]=[CH:12][N:11]=1>>[Cl:9][C:10]1[CH:15]=[C:14]([N:5]2[C:6]([CH3:7])=[C:2]([I:1])[N:3]=[C:4]2[CH3:8])[CH:13]=[CH:12][N:11]=1
Reactant: Cc1nc(I)c(C)[nH]1
Reactant: Fc1ccnc(Cl)c1
Product: Cc1nc(I)c(C)n1-c1ccnc(Cl)c1

Procedure:
The title compound, white crystalline solid, MS: m/e=329.2, 331.1 (M+H+) was prepared in accordance with the general method of example 1b from 4-iodo-2,5-dimethyl-1H-imidazole (CAS: [631897-38-6]) and 2-chloro-4-fluoropyridine.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:18][C:19]#[N:20]>>[CH3:13][O:14][C:15]1[CH:16]=[C:17](/[C:18](=[CH:6]/[C:5]2[CH:8]=[CH:9][C:2]([F:1])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=2)/[C:19]#[N:20])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: O=Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1ccc(/C(C#N)=C/c2ccc(F)c([N+](=O)[O-])c2)cc1OC
Yield: 49.3 %

Procedure:
4-Fluoro-3-nitrobenzaldehyde (507 mg) and 3,4-dimethoxybenzyl cyanide (532 mg) were subjected to condensation in accordance with process B of (production process 2), to thereby produce the target product (485 mg, yield: 30%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[O:11])=[C:4]([CH3:29])[CH:3]=1.[NH2:30][CH2:31][CH2:32][OH:33].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([NH:30][CH2:31][CH2:32][OH:33])=[O:25])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[O:11])=[C:4]([CH3:29])[CH:3]=1
Reactant: NCCO
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NCCO)cc1

Procedure:
In analogy to example 207, step 2, 4-(1-(4-chloro-2-methylphenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)benzoic acid was coupled with 2-aminoethanol using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in tetrahydrofuran to give the title compound as an off-white solid, MS (ESI+): m/z=453.2 [M+H]+.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:24])[CH:20]=3)[N:15]=2)[CH2:10][CH2:9]1)(=O)=O.[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C)C=O>[N:25]([CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:24])[CH:20]=3)[N:15]=2)[CH2:10][CH2:9]1)=[N+:26]=[N-:27]
Reactant: CS(=O)(=O)OCCC1CCN(c2ccc3cc(Cl)ccc3n2)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCC1CCN(c2ccc3cc(Cl)ccc3n2)CC1

Procedure:
A solution of 5 g (13.55 mmol) of 2-[1-(6-chloroquinolin-2-yl)piperidin-4-yl]ethyl methanesulfonate, prepared in step 6.1., and 1.76 g (27.11 mmol) of sodium azide in 30 mL of N,N-dimethylformamide is refluxed for 4 hours, under an inert atmosphere.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[CH:15]=[CH:14][C:10]([CH2:11][C:12]#[N:13])=[CH:9][CH:8]=1.O>CC(N(C)C)=O>[Cl:1][CH2:2][C:3]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([CH2:11][C:12]#[N:13])=[CH:9][CH:8]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: N#CCc1ccc(N)cc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: N#CCc1ccc(NC(=O)CCl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.8 %

Procedure:
2-Chloroacetyl chloride (3.3 ml, 5.0 g, 44 mmol) was added dropwise at 10°-15° C. to a solution of 4-aminobenzylcyanide (5.3 g, 40 mmol) in dimethyl acetamide (20 ml) and the mixture was stirred at room temperature for one hour. After pouring into water the precipitate was collected, washed with water and dried over P2O5 under reduced pressure to give the title compound (7.33 g) as nearly colorless crystals, yield: 87.8%, mp 124°-125° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:8][O:9][C:10]=2[C:11]([F:14])([F:13])[F:12])[N:3]=[CH:2]1.B(O)(O)[C:22]1[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=1>>[C:15]1([C:7]2[C:6]([C:4]3[N:3]=[CH:2][N:1]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)[CH:5]=3)=[C:10]([C:11]([F:14])([F:12])[F:13])[O:9][N:8]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: FC(F)(F)c1onc(-c2ccccc2)c1-c1c[nH]cn1
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)cc1
Yield: 42 %

Procedure:
As described for Example 1j, 4-(1H-imidazol-4-yl)-3-phenyl-5-trifluoromethyl-isoxazole (100 mg, 0.36 mmol) was converted, using p-tolylboronic acid instead of phenylboronic acid, to the title compound (55 mg, 42%) which was obtained as a white solid. MS (ESI): m/e=370.1 [M+H]+.