Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[C:20](=O)[CH2:19][CH2:18]4)=[CH:13][N:14]=2)[N:11]=1)[CH2:2][CH2:3][CH3:4].C([O-])(=O)C.[NH4+].C([BH3-])#[N:31].[Na+]>CO>[NH2:31][CH:20]1[C:21]2[C:17](=[CH:16][C:15]([C:12]3[N:10]4[N:11]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH:7]=[CH:8][C:9]4=[N:14][CH:13]=3)=[CH:23][CH:22]=2)[CH2:18][CH2:19]1
Reactant: CCCCNc1ccc2ncc(-c3ccc4c(c3)CCC4=O)n2n1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCCCNc1ccc2ncc(-c3ccc4c(c3)CCC4N)n2n1
Temperature: 25 °C
Yield: 50.6 %

Procedure:
A mixture of 5-(6-butylamino-imidazo[1,2-b]pyridazin-3-yl)-indan-1-one (50 mg, 0.16 mmol), ammonium acetate (500 mg), and methanol (5 mL) was maintained at RT for 5 min, then treated with sodium cyanoborohydride (500 mg). The resulting mixture was heated to 50° C. and maintained 16 h, then cooled to RT and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were washed with brine, then dried (MgSO4), filtered and concentrated to afford a residue that was purified by reverse phase HPLC to afford [3-(1-amino-indan-5-yl)-imidazo[1,2-b]pyridazin-6-yl]-butyl-amine (26 mg, 52%) as a white solid: 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.22 (s, 1H), 8.12 (d, J=8.1 Hz, 1H), 7.78 (s, 1H), 7.54-7.66 (m, 2H), 6.72 (d, J=9.6 Hz, 1H), 4.77-4.83 (m, 1H), 3.38 (t, J=7.2 Hz, 2H), 3.18-3.30 (m, 1H), 3.01-3.13 (m, 1H), 2.59-2.73 (m, 1H), 2.06-2.22 (m, 1H), 1.72 (quin, J=7.4 Hz, 2H), 1.43-1.57 (m, 2H), 1.02 (t, J=7.3 Hz, 3H); LCMS (ESI) m/e 322.3 [(M+H)+, calcd for C19H24N5 322.2].
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[CH:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[C:18]([F:20])[C:17]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[C:16]([C:26]#[CH:27])[CH:15]=2)=[O:11])=[CH:6][CH:5]=[C:4]([C:28]([F:31])([F:30])[F:29])[N:3]=1.[CH3:32][O:33][CH2:34][CH2:35][NH2:36].Cl>O>[C:26]([C:16]1[CH:15]=[C:14]([CH:19]=[C:18]([F:20])[C:17]=1[NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:13][NH:12][C:10](=[O:11])[CH:9]=[CH:8][C:7]1[C:2]([NH:36][CH2:35][CH2:34][O:33][CH3:32])=[N:3][C:4]([C:28]([F:31])([F:30])[F:29])=[CH:5][CH:6]=1)#[CH:27]
Reactant: COCCN
Reactant: C#Cc1cc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2Cl)cc(F)c1NS(C)(=O)=O
Agent: Cl
Solvent: O
Product: C#Cc1cc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2NCCOC)cc(F)c1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 12 %

Procedure:
A mixture of 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl)-acrylamide (30 mg, 0.28 mmol) and 2-methoxyethylamine (100 μl) was stirred at ambient temperature for 48 hrs. The reaction mixture was diluted with water and then acidified with 2N HCl solution. The aqueous phase was extracted with EtOAc and the combined organic phase was washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Hex/EtOAc=2/3) to give the title compound (4.0 mg, 12%).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH:5](=[N:12][NH:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:27][N:28]([CH3:39])[CH2:29][CH2:30][O:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1>C1(C)C=CC=CC=1>[CH:5](=[N:12][N:13]([C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)[C:1]([NH:36][C:35]1[CH:37]=[CH:38][C:32]([O:31][CH2:30][CH2:29][N:28]([CH3:39])[CH3:27])=[CH:33][CH:34]=1)=[O:2])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(Cl)Cl
Reactant: C(=NNc1ccc(Oc2ccccc2)cc1)c1ccccc1
Reactant: CN(C)CCOc1ccc(N)cc1
Solvent: Cc1ccccc1
Product: CN(C)CCOc1ccc(NC(=O)N(N=Cc2ccccc2)c2ccc(Oc3ccccc3)cc2)cc1
Reaction time: 24 h

Procedure:
Phosgene (20% in toluene; 0.091 mL) was added dropwise to a solution of N-benzylidene-N′-(4-phenoxyphenyl)hydrazine (50 mg) in toluene (1 mL) at 0° C. After 24 hours at room temperature, 4-(2-dimethylaminoethoxy)aniline (31 mg) was added. After two hours, the crystals which had separated out were filtered off with suction. The product with the molecular weight of 494.60 (C30H30N4O3); MS (ESI): 495 ([M+H]+), was obtained in this way.
Reaction SMILES: [C:1]([O-:7])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[NH2:8]/[C:9](/[CH3:18])=[CH:10]\[C:11]([O:13][CH2:14][CH2:15][C:16]#[N:17])=[O:12].[N+:19]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O)([O-:21])=[O:20].CCCCCC>C(O)C.CC(C)=O>[C:16]([CH2:15][CH2:14][O:13][C:11]([C:10]1[CH:25]([C:24]2[CH:27]=[CH:28][CH:29]=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=2)[C:2]([C:1]([OH:7])=[O:6])=[C:3]([CH3:5])[NH:8][C:9]=1[CH3:18])=[O:12])#[N:17]
Reactant: CC(=O)CC(=O)[O-]
Reactant: C/C(N)=C/C(=O)OCCC#N
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CC(C)=O
Solvent: CCO
Solvent: CCCCCC
Product: CC1=C(C(=O)O)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCCC#N)=C(C)N1
Yield: 78.2 %

Procedure:
9.7 g of 2-nitratoethyl acetoacetate, 7.7 g of 2-cyanoethyl 3-aminocrotonate and 7.6 g of 3-nitrobenzaldehyde in 76 ml of ethanol were heated at reflux for 7 hours. The mixture was treated in a manner similar to that of Referential Example 1, and the crystals thus obtained were applied to a silica gel column chromatography [eluent: a mixture of hexane and acetone (5:3)] and recrystallized from isopropyl alcohol to give 14.5 g of 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(2-cyanoethyl) ester 5-(2-nitratoethyl) ester.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH:3]=[CH2:4].[N+:7]([CH2:10][CH3:11])([O-])=[O:8].C1(N=C=O)C=CC=CC=1>C(OCC)C>[CH3:11][C:10]1[CH2:4][CH:3]([C:2]([F:6])([F:5])[F:1])[O:8][N:7]=1
Reactant: C=CC(F)(F)F
Reactant: CC[N+](=O)[O-]
Solvent: CCOCC
Solvent: O=C=Nc1ccccc1
Product: CC1=NOC(C(F)(F)F)C1
Temperature: 22 °C
Reaction time: 60 h
Yield: 40 %

Procedure:
To a solution of 3,3,3-trifluoroprop-1-ene (ca. 18 g) in diethyl ether (120 ml) was added subsequently at −78° C. nitroethane (5.74 g, 76.5 mmol), TEA (76 mg, 0.75 mmol) and phenyl isocyanate (18.2 g, 153 mmol), the solution was warmed to 22° C. and stirring was continued for 60 h. The suspension was filtered and the filtrate distilled from bulb to bulb at 75° C./1.0 mbar to give 3-methyl-5-(trifluoromethyl)-4,5-dihydroisoxazole (4.69 g) as a pale yellow liquid. MS: m/z=153 [M]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][CH:3]=1.[Cl:11][CH2:12][C:13]([CH2:15]Cl)=O.O.[OH-].[Na+]>C(O)(C)C>[Cl:11][CH2:12][C:13]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[S:7][CH:15]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=S)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: ClCc1csc(-c2ccc(Cl)cc2)n1
Temperature: 20 °C
Reaction time: 10 h

Procedure:
171.65 g (1.0 mol) of 4-chlorothiobenzamide are dissolved in 550 ml of isopropyl alcohol and 133.3 g (1.05 mol) of 1,3-dichloroacetone are added at a temperature of a maximum of 30° C. over a period of 3hours. The mixture is subsequently stirred at 40° C. for 5.5 hours and at 20° C. for 10 hours. In order to complete the reaction the mixture is then heated to 55° C. for 7.5 hours. The product is isolated by cooling to 10° C. and adding 950 ml of water. The pH value is adjusted to 4 to 5 using sodium hydroxide solution and the product is filtered off with suction.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13](Cl)=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:20][C:21]1[C:29]([Cl:30])=[N:28][C:27]([Cl:31])=[CH:26][C:22]=1[C:23](O)=[O:24].C(N(CC)CC)C.CS(Cl)(=O)=O>C(#N)C>[Cl:31][C:27]1[N:28]=[C:29]([Cl:30])[C:21]2[N:20]=[C:13]([C:12]3[N:8]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=4)[N:9]=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=3)[O:14][C:23](=[O:24])[C:22]=2[CH:26]=1
Reactant: Nc1c(C(=O)O)cc(Cl)nc1Cl
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Agent: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2c(Cl)nc(Cl)cc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96.9 %

Procedure:
5-Trifluoromethyl-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid chloride (example 2, step 3) (242 mg) was added to a mixture of 3-amino-2,6-dichloroisonicotinic acid (example 1, step 8) (190 mg) in acetonitrile (3 mL). The mixture was stirred for 5 minutes at room temperature and triethylamine (220 μL) was added and stirred for 20 minutes, before a second portion of triethylamine (220 μL) was added. After the mixture was stirred for further 20 minutes at room temperature, methanesulfonyl chloride (70 μL) was added. After stirring for 2 hours at room temperature, the formed precipitate was filtered off, washed carefully with water and MTB-ether and dried in vacuum to afford 350 mg of the title compound of the formula
Reaction SMILES: C[Al](C)C.[CH3:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])[CH2:8][CH2:7]1.C[O:25][C:26]([C:28]1[C:37]2[C:32](=[CH:33][C:34]([CH2:38][C:39]3[CH:44]=[C:43]([NH:45][C:46](=[O:48])[CH3:47])[N:42]=[CH:41][N:40]=3)=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)=O.[Cl-].[NH4+]>C1(C)C=CC=CC=1.C1COCC1.CCOC(C)=O>[CH3:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:26]([C:28]3[C:37]4[C:32](=[CH:33][C:34]([CH2:38][C:39]5[CH:44]=[C:43]([NH:45][C:46](=[O:48])[CH3:47])[N:42]=[CH:41][N:40]=5)=[CH:35][CH:36]=4)[CH:31]=[CH:30][CH:29]=3)=[O:25])=[CH:15][C:14]=2[C:20]([F:23])([F:21])[F:22])[CH2:8][CH2:7]1
Reactant: COC(=O)c1cccc2cc(Cc3cc(NC(C)=O)ncn3)ccc12
Reactant: CN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cc(Cc2ccc3c(C(=O)Nc4ccc(CN5CCN(C)CC5)c(C(F)(F)F)c4)cccc3c2)ncn1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A solution of 2 ml trimethylaluminium (2 M in toluene, 4 mMol) is added to a stirred solution of 355 mg (1.3 mMol) 4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine in 20 ml toluene at 10° C. under an argon atmosphere. After 1 h at r t, a solution of 436 mg (1.3 mMol) 6-(6-acetylaminopyrimidin-4-ylmethyl)-naphthalene-1-carboxylic acid methyl ester (Step 9.2) in 5 ml THF is added and the reaction mixture is heated at 90° C. for 45 min. After cooling to 5° C., a solution of sat. aqueous ammonium chloride (50 ml) is added dropwise. The mixture is poured into EtOAc and filtered over hyflo. The separated aq. phase is extracted with EtOAc. The combined organic phases are washed with water and brine, dried (Na2SO4) and concentrated. The crude product is purified by chromatography (SiO2, CH2Cl2/EtOH/NH3 90:9:1) and is recrystallised from hot EtOAc and hexane to afford the title compound as a colourless solid: m.p.: 202-204° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([CH3:13])([CH3:12])[CH2:7][CH2:6][C:5]([CH3:15])([CH3:14])[C:4]=2[CH:3]=1.ClCCl.[Cl-].[Al+3].[Cl-].[Cl-].[C:23](Cl)(=[O:26])[CH2:24][CH3:25]>O>[CH2:24]([C:23]([C:11]1[C:2]([OH:1])=[CH:3][C:4]2[C:5]([CH3:15])([CH3:14])[CH2:6][CH2:7][C:8]([CH3:13])([CH3:12])[C:9]=2[CH:10]=1)=[O:26])[CH3:25]
Reactant: CCC(=O)Cl
Reactant: CC1(C)CCC(C)(C)c2cc(O)ccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCC(=O)c1cc2c(cc1O)C(C)(C)CCC2(C)C
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To 5,6,7,8-tetrahydro-2-hydroxy-5,5,8,8-tetramethylnaphthalene (204 mg, 1.00 mmol) were added anhydrous dichloromethane (1 mL), aluminum chloride (148 mg, 1.12 mmol), and propionyl chloride (101.7 mg, 1.10 mmol) followed by stirring at 60° C. for 16 hours. The reaction solution was poured into cold water and extracted by ethyl acetate. The organic layer was washed by water, a saturated sodium hydrogen carbonate aq. solution, and a saturated saline solution, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using hexane/ethyl acetate (20/1) as an elution solvent. The yield was 117 mg (45%).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:13]([C:20]#[N:21])[CH2:14][C:15]([O:17]CC)=O)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[BH4-].[Na+]>CO.O.O.O.O.O.O.Cl[Co]Cl>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[C:5]([CH:13]2[CH2:20][NH:21][C:15](=[O:17])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: CCOC(=O)CC(C#N)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C1CC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CN1
Temperature: 20 °C
Reaction time: 18 h
Yield: 47.6 %

Procedure:
Ethyl 3-(3,5-bis(trifluoromethyl)phenyl)-3-cyanopropanoate (1.2 g, 1.0 eq.) was dissolved in MeOH (48 mL). Dichlorocobalt hexahydrate (1.68 g, 2.0 eq.) was added and the reaction mixture was cooled to 20° C. NaBH4 (1.98 g, 15 eq.) was added portion wise by maintaining temperature below 30° C. After completion of addition, this reaction mixture was stirred for 18 h at 25° C. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (25 mL) and water (25 mL). The reaction mixture was filtered through Celite™ and the organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 0.65 g of crude product, which after trituration with petroleum ether gave 0.5 g of 4-(3,5-bis(trifluoromethyl)phenyl)pyrrolidin-2-one (Yield 47.61%).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][C:13]([CH:25]=[O:26])=[C:14]2Cl)[CH2:6]1)(=[O:3])[CH3:2].[NH:27]1[CH:31]=[CH:30][N:29]=[N:28]1.C([O-])([O-])=O.[K+].[K+]>>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][C:13]([CH:25]=[O:26])=[C:14]2[N:28]2[N:29]=[CH:30][CH:31]=[N:27]2)[CH2:6]1)(=[O:3])[CH3:2].[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][C:13]([CH:25]=[O:26])=[C:14]2[N:27]2[CH:31]=[CH:30][N:29]=[N:28]2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(Cl)=C(C=O)C[C@@H]32)C1
Reactant: c1c[nH]nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(n4ccnn4)=C(C=O)C[C@@H]32)C1
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(n4nccn4)=C(C=O)C[C@@H]32)C1

Procedure:
This Example describes the reaction of 3β-acetoxy-17-chloro-16-formylandrosta-5,16-diene (Compound 3) with 1H-1,2,3-Triazole and K2CO3 to give 3β-acetoxy-17-(2H-1,2,3-triazol-2-yl)-16-formylandrosta-5,16-diene (Compound 15) and 3β-acetoxy-17-(1-H-1,2,3-triazol-1-yl)-16-formylandrosta-5,16-diene (Compound 16), respectively.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[C:7]([N+:9]([O-])=O)[CH:8]=1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=1
Reactant: COc1cc(-c2ccccc2)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: COc1cc(N)cc(-c2ccccc2)c1
Yield: 90.6 %

Procedure:
3-Methoxy-5-nitro-biphenyl (176 mg, 0.77 mmol) are hydrogenated in ethanol (5 ml) using palladium on carbon (10%, 17 mg) at atmospheric pressure for 2h. The catalyst is filtered off and the solvent removed in vacuo. Flash chromatography (silica, eluent ethyl acetate/cyclohexane 1:1) affords the product (139 mg, 91%) as a bown oil. MS: m/e=199 (M+).
Reaction SMILES: [N:1]([C:4]1[S:5][C:6]([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[C:7]([CH3:9])[N:8]=1)=[N+:2]=[N-:3].C(N(CC)C(C)C)(C)C.[C:29]1([C:35]#[CH:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1.[Cu]I>[CH2:13]([NH:12][C:10]([C:6]1[S:5][C:4]([N:1]2[CH:36]=[C:35]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:3]=[N:2]2)=[N:8][C:7]=1[CH3:9])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C#Cc1ccccc1
Reactant: Cc1nc(N=[N+]=[N-])sc1C(=O)NCc1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-n2cc(-c3ccccc3)nn2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
To a solution of 2-azido-N-benzyl-4-methylthiazole-5-carboxamide (0.65 g, 2.38 mmol) in tetrahydrofuran (10 mL) was added copper(I) iodide (0.45 g, 2.38 mmol), N,N-diisopropylethylamine (1.24 mL, 7.14 mmol) and phenylacetylene (0.37 g, 3.57 mmol). The reaction mixture was stirred at ambient temperature for 18 hours and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate:petroleum ether, 1:1) to afford the title compound as a white solid in 70% yield: mp 175-178° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.60 (s, 1H), 7.90 (d, J=9.0 Hz, 2H), 7.47-7.37 (m, 8H), 6.11 (br s, 1H), 4.64 (d, J=6.0 Hz, 2H), 2.72 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 160.9, 155.4, 153.3, 148.7, 137.4, 129.2, 129.0, 128.9, 128.8, 127.8, 126.0, 124.4, 116.7, 44.3, 17.4; MS (ES+) m/z 376.3 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[C:10]([NH:13][CH2:14][C:15]([OH:17])=[O:16])(=[O:12])[CH3:11].[C:18]([O-])(=O)C.[Na+].O>C(OC(=O)C)(=O)C.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[C:14]([NH:13][C:10](=[O:12])[CH3:11])[C:15]([O:17][CH3:18])=[O:16]
Reactant: CC(=O)[O-]
Reactant: CC(=O)NCC(=O)O
Reactant: O=Cc1cccc(Br)c1
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)C(=Cc1cccc(Br)c1)NC(C)=O
Temperature: 25 °C

Procedure:
3-Bromobenzaldehyde (23.7 g, 128.2 mmol), N-acetyl glycine (10.0 g, 85.5 mmol) and sodium acetate (5.26 g, 64.1 mmol) in acetic anhydride (60 mL) was heated to reflux for 1 h. The reaction was cooled to room temperature and water (100 mL) was added. The resulting suspension was filtered and the solid was washed with water (2×50 mL). The remaining solid was dissolved in methylene chloride (100 mL), dried (MgSO4), filtered and concentrated in vacuo to give a yellow solid. The solid was suspended in dry MeOH (200 mL) and heated to reflux for 9 h. The reaction mixture was concentrated in vacuo to give a yellow solid. Recrystallization from EtOAc and petroleum ether gave methyl m-bromo-α-acetamidocinnamate as a yellow solid. MS (CI) m/z 298 (M++1 (Br=79), 100%), 300 (M++1 (Br=81), 100%) 13C NMR (50 MHz, d6-DMSO): δ 23.3, 52.8, 122.5, 125.0, 128.06, 130.0, 130.2, 132.2, 132.3, 135.9, 165.4 and 168.8.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Cl:27])=[CH:4][N:3]=1.[CH3:28][N:29]([CH3:38])[C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Cl:27][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:19])[CH2:13][CH2:12]2)=[C:7]2[N:8]=[C:34]([C:33]3[CH:36]=[CH:37][C:30]([N:29]([CH3:38])[CH3:28])=[CH:31][CH:32]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: Nc1ncc(Cl)c(N2CCN(CC(=O)Nc3ccccc3)CC2)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1ccc(-c2nc3c(N4CCN(CC(=O)Nc5ccccc5)CC4)c(Cl)cnc3[nH]2)cc1
Temperature: 70 °C

Procedure:
To a mixture of 2-(4-(2-amino-5-chloro-3-nitropyridin-4-yl)piperazin-1-yl)-N-phenylacetamide (0.040 g, 0.10 mmol), ethanol (3 ml), and 4-dimethylaminobenzaldehyde (0.019 g, 0.13 mmol) was added a freshly prepared aqueous solution of Na2S2O4 (1M; 0.40 ml, 0.40 mmol). The reaction mixture was heated at 70° C. for 3 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 20% ethyl acetate in dichloromethane and then 1% methanol in ethyl acetate/dichloromethane (v/v; 1:1). The title compound was obtained as a yellow solid after trituration with diethyl ether (0.006 g, 12%); 1H-NMR (500 MHz, DMSO-d6) 2.76 (br s, 4H, piperazine N(CH2)2), 3.00 (s, 6H, N(CH3)2), 3.23 (s, 2H, NCH2CO), 3.75 (br s, 4H, piperazine N(CH2)2), 6.81 (d, J=7.90 Hz, 2H) and 8.01 (d, J=8.49 Hz, 2H) (3,5-C6H4NMe2 and 2,6-C6H4—NMe2), 7.07 (t, J=7.27 Hz, 1H, p-ArH), 7.32 (t, J=8.48 Hz, 2H, m-ArH), 7.67 (d, J=8.48 Hz, 2H, o-ArH), 8.06 (s, 1H, imidazo[4,5-b]pyridine 5-H), 9.77 (s, 1H, CONH), 13.11 (s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([N:15]4[CH2:20][CH2:19][CH:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=5)[CH2:17][CH2:16]4)=[N:13][N:14]=[C:10]3[CH2:9][NH:8][CH2:7][C:6]=2[CH:27]=1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>ClCCl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([N:15]4[CH2:20][CH2:19][CH:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=5)[CH2:17][CH2:16]4)=[N:13][N:14]=[C:10]3[CH2:9][N:8]([S:36]([CH3:35])(=[O:38])=[O:37])[CH2:7][C:6]=2[CH:27]=1
Reactant: Clc1ccc2c(c1)CNCc1nnc(N3CCC(c4ccccn4)CC3)n1-2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2N2CCC(c3ccccn3)CC2)C1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of the compound from example 1 (100 mg, 0.26 mmol) in dichloromethane (3 mL) was added triethylamine (54.4 μL, 0.39 mmol) at room temperature. The solution was cooled to 0° C. and methanesulfonyl chloride (24 μl, 0.31 mmol) was added. The reaction was stirred for a further 45 minutes. The reaction mixture was then diluted with water (5 mL) and stirred vigorously for 5 minutes. The phases were separated and the organic phase concentrated in vacuo to give the crude residue which was azeotroped with ethyl acetate to afford the product as a crystalline solid, 78 mg (65%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:17]([NH:19][CH3:20])=[O:18])=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[CH:5][CH:4]=1.[O:21]1[C:26]2[CH:27]=[CH:28][C:29]([CH2:31][N:32]([CH:40]3[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)[C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:30][C:25]=2[O:24][CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCl>[O:21]1[C:26]2[CH:27]=[CH:28][C:29]([CH2:31][N:32]([CH:40]3[CH2:45][CH2:44][N:43]([CH2:14][CH2:13][N:10]4[C:11]5[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=5)[C:7]([C:17]([NH:19][CH3:20])=[O:18])=[CH:8][C:9]4=[O:16])[CH2:42][CH2:41]3)[C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:36])[CH3:37])=[CH:30][C:25]=2[O:24][CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: CNC(=O)c1cc(=O)n(CC=O)c2cc(OC)ccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CNC(=O)c1cc(=O)n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2cc(OC)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
To 2 mL of dichloromethane suspension containing 77 mg of 7-methoxy-N-methyl-2-oxo-1-(2-oxoethyl)-1,2-dihydroquinoline-4-carboxamide, 2 mL of dichloromethane solution containing 98 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate and 16 μL of acetic acid were added and stirred at room temperature for 2 hours. To the reaction mixture, 89 mg of sodium triacetoxyborohydride was added and stirred at the same temperature for 30 min. Chloroform and aqueous saturated sodium hydrogen carbonate solution were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=10:1] to give 0.16 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-methoxy-4-((methylamino)carbonyl)-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a light brown foam.