Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.Cl[CH:10]([CH:16]=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(O)C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][N:8]=2)[CH:7]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CCOC(=O)C(Cl)C=O
Solvent: CCO
Product: CCOC(=O)c1cnc2ccc(Br)cn12
Temperature: 75 °C
Reaction time: 48 h
Yield: 29.5 %

Procedure:
A mixture of 5-bromopyridin-2-amine (5.22 g, 30.2 mmol) and ethyl 2-chloro-3-oxopropanoate (5.00 g, 33.2 mmol) (Toronto Research Chemicals; 5% solution on benzene) was stirred in ethanol (151 mL, 30.2 mmol) under nitrogen. The mixture was heated to 75° C. for 4 hours and then at ambient temperature for 2 days. The solvent was removed under vacuum to give a solid residue which was purified by silica gel chromatography, eluting with hexane/ethyl acetate (6:4 to 4:6) to give the desired product as a solid (2.40 g; 30%).
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][C:3]1=[O:18].[N:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C(O)(=O)C.[Na]>C(O)C.CO>[CH2:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][N:2]([NH:1][CH:28]2[CH2:27][CH2:26][N:25]([C:22]3[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=3)[CH2:30][CH2:29]2)[C:3](=[O:18])[CH2:4]1)=[O:9])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: NN1CCN(C(=O)OCc2ccccc2)CC1=O
Reactant: O=C1CCN(c2ccncc2)CC1
Agent: [Na]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCO
Product: O=C(OCc1ccccc1)N1CCN(NC2CCN(c3ccncc3)CC2)C(=O)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 70.2 %

Procedure:
A solution of 1-amino-4-benzyloxycarbonyl-2-piperazinone (21.92 g) and 1-(4-pyridyl)-4-piperidone (15.51 g) in ethanol (500 ml) was dehydrated using a Soxlet extractor packed with molecular sieves 4A while refluxing for 24 hours. The reaction mixture was concentrated to obtain a residue, which was dissolved in methanol (300 ml) and combined with acetic acid (18.26 g) with cooling on ice followed by sodium cycanoborohydride (7.16 g) and then stirred at 0° C. for 3 hours. The reaction mixture was concentrated, and the residue was combined with a 1N aqueous solution of sodium hydroxide, and extracted with methylene chloride. The extract was washed with water and brine, dried and concentrated to obtain 4-benzyloxycarbonyl-1-[1-(4-pyridyl)-4-piperidinylamino]-2-piperazinone (25.29 g) as a pale yellow amorphous material.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.[F-].[Cs+]>COCCOC>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=2[CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)=[CH:25][CH:24]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2Br)CC1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2-c2ccc(Cl)cc2)CC1

Procedure:
A solution of EXAMPLE 22A (5.82 g, 16.394 mmol) in DME (80 mL) was treated with 4-chlorophenylboronic acid (3.089 g, 19.673 mmol), CsF (7.476 g, 49.182 mmol) and (Ph3P)2Pd(OAc)2 (1.228 g, 1.639 mmol), heated to reflux for 4 hours, and filtered. The filtrate was partitioned between aqueous NaHCO3 and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined extracts were dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel column chromatography with 15% ethyl acetate/hexane to provide the desired product. MS (ESI) m/e 386, 388 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[NH:4][CH:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12]2[N:13]=[CH:14][C:15]3[C:21]([NH2:22])=[CH:20][C:19](=[O:23])[N:18]([CH2:24][CH2:25][CH2:26][O:27][Si](C(C)(C)C)(C)C)[C:16]=3[N:17]=2)[CH2:7][CH2:6]1>C(O)(=O)C.C1COCC1.O>[CH3:1][O:2][C:3](=[O:35])[NH:4][CH:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12]2[N:13]=[CH:14][C:15]3[C:21]([NH2:22])=[CH:20][C:19](=[O:23])[N:18]([CH2:24][CH2:25][CH2:26][OH:27])[C:16]=3[N:17]=2)[CH2:7][CH2:6]1
Reactant: COC(=O)NC1CCC(Nc2ncc3c(N)cc(=O)n(CCCO[Si](C)(C)C(C)(C)C)c3n2)CC1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)NC1CCC(Nc2ncc3c(N)cc(=O)n(CCCO)c3n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.1 %

Procedure:
(4-{5-Amino-8-[3-(tert-butyl-dimethyl-silanyloxy)-propyl]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino}-cyclohexyl)-carbamic acid methyl ester (prepared as described in Example 2) (0.280 mmol) was dissolved in a mixture of glacial acetic acid, THF and water (3/1/1, 25 mL) and the resulting mixture was stirred at RT overnight. The reaction mixture was concentrated under reduced pressure and the crude residue was purified by preparative TLC (MeOH/DCM, 15/85) to give 11 mg of {4-[5-amino-8-(3-hydroxy-propyl)-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-cyclohexyl}-carbamic acid methyl ester as a yellow powder. MS=391 [M+H]+; MP=190.0-191.0° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[O:14][C:15]([C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:16]([CH3:17])[C:11]2=[CH:10][C:9]=1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1.BrN1C(=[O:37])CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.C[N+]1([O-])CCOCC1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[O:14][C:15]([C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:16]([CH:17]=[O:37])[C:11]2=[CH:10][C:9]=1[C:24]1[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=1
Reactant: Cc1c(C(=O)C(C)(C)C)oc2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)cc12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: C[N+]1([O-])CCOCC1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)C(=O)c1oc2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)cc2c1C=O
Temperature: 25 °C

Procedure:
A 10 mL rb flask equipped with a magnetic stir bar was charged with 0.227 g (0.52 mmol) of the product of Example 89, 0.101 g (0.57 mmol) of N-bromosuccinimide, 3 mL CCl4 and ca. 5 mg of 2,2′-azobisisobutyronitrile (AIBN). The reaction mixture was heated to reflux under a nitrogen atmosphere for 2 h then cooled to room temperature and filtered. The filtrate was evaporated in vacuo, and the residue was then redissolved in 2 mL of DMSO. The solution containing the crude bromination product was transferred to a 10 mL reaction tube of a CEM Corporation Discover 300 Watt microwave reactor and 73 mg (0.62 mmol) of N-methylmorpholine-N-oxide was added. The reaction vessel was sealed, placed in the microwave reactor and heated at 150° C. for 2–3 min. After the reaction mixture had cooled to room temperature, it was partitioned between EtOAc and 10% aq. NaHSO4 and extracted. The organic layer was washed with 10% aq. NaHSO4, water, brine, dried (MgSO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 0–10% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded the title compound. HPLC/MS: 452.1 (M+1), 454.0 (M+3); Rt=4.63 min.
Reaction SMILES: [OH:1][CH:2]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]([C:10]2[S:11][CH2:12][C:13](=[O:16])[NH:14][N:15]=2)=[CH:6][CH2:5]1.S(=O)(=O)(O)O.[OH-].[Na+].[CH3:32]O>>[CH3:32][O:1][CH:2]([C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]([C:10]2[S:11][CH2:12][C:13](=[O:16])[NH:14][N:15]=2)=[CH:6][CH2:5]1
Reactant: COc1ccc(C(O)CN2CC=C(C3=NNC(=O)CS3)CC2)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(C(CN2CC=C(C3=NNC(=O)CS3)CC2)OC)cc1
Temperature: 0 °C

Procedure:
2-[1-[2-Hydroxy-2-(4-methoxyphenyl)ethyl]-1,2,5,6-tetrahydropyrid-4-y1]-4H,6H-1,3,4-thiadiazin-5-one (150 mg, 0.43 mmol) was dissolved in methanol (5 ml), added with concentrated sulfuric acid (0.8 ml, 15 mmol) and refluxed with heating for four hours. The solution was poured into ice water and neutralized with 2N aqueous sodium hydroxide.
Reaction SMILES: O.O.[Sn](Cl)Cl.[N:6]([CH2:9][C:10]1[S:14][C:13]([C:15]2[N:20]=[N:19][C:18]([N:21]([CH2:29][C:30]3([C:34]4[C:39]([F:40])=[CH:38][CH:37]=[CH:36][N:35]=4)[CH2:33][CH2:32][CH2:31]3)[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:17][CH:16]=2)=[N:12][CH:11]=1)=[N+]=[N-].C(OCC)(=O)C>CO>[NH2:6][CH2:9][C:10]1[S:14][C:13]([C:15]2[N:20]=[N:19][C:18]([N:21]([CH2:29][C:30]3([C:34]4[C:39]([F:40])=[CH:38][CH:37]=[CH:36][N:35]=4)[CH2:33][CH2:32][CH2:31]3)[C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[CH:17][CH:16]=2)=[N:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(-c2ncc(CN=[N+]=[N-])s2)nn1
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(-c2ncc(CN)s2)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 185.9 %

Procedure:
Tin(II) chloride dihydrate (15.5 g, 80 mmol) was added to a solution of t-butyl 6-(5-(azidomethyl)thiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (20 g, 40 mmol) in methanol (400 mL) and the reaction was stirred at rt for 30 min. The reaction was poured into ethyl acetate (1000 mL), washed with water (3×200 mL), and the combined organic layers were separated, dried over Na2SO4, filtered, concentrated, and purified using silica gel column chromatography (9% MeOH/90% EtOAc/1% TEA) to give 35 g of t-butyl 6-(5-(aminomethyl)thiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[Cl:17].[NH2:18][C@H:19]([C:25]([OH:27])=O)[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24].N[C@H](C(O)=O)C>>[ClH:17].[ClH:17].[NH2:18][C@H:19]([C:25]([NH-:1])=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24].[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[Cl:17]
Reactant: NCCCC[C@H](N)C(=O)O
Agent: C[C@H](N)C(=O)O
Agent: Nc1ccc(-c2nc3ccccc3s2)cc1Cl
Product: Cl
Product: [NH-]C(=O)[C@@H](N)CCCCN

Procedure:
The title compound was prepared using the method of Example 22 but with 2-(4′-amino-3′-chlorophenyl)benzothiazole instead of 2-(4′-aminophenyl)-benzothiazole and BOC protected lysine instead of BOC protected alanine.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][C:8]=1[OH:9])#[N:2].[Br:20]N1C(=O)CCC1=O>C(#N)C>[Br:20][C:7]1[CH:6]=[C:5]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:4]=[C:3]([C:1]#[N:2])[C:8]=1[OH:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccnc(-c2ccc(O)c(C#N)c2)c1
Solvent: CC#N
Product: COC(=O)c1ccnc(-c2cc(Br)c(O)c(C#N)c2)c1

Procedure:
Methyl 2-(3-cyano-4-hydroxyphenyl)isonicotinate and N-bromosuccinimide were stirred at room temperature in acetonitrile to obtain methyl 2-(3-bromo-5-cyano-4-hydroxyphenyl)isonicotinate. FN: 333.
Reaction SMILES: [CH:1]1([C:4]([CH3:6])=[O:5])[CH2:3][CH2:2]1.[CH3:7][Si:8](C#N)([CH3:10])[CH3:9].[C-:13]#[N:14].[K+]>C1OCCOCCOCCOCCOCCOC1>[CH:1]1([C:4]([O:5][Si:8]([CH3:10])([CH3:9])[CH3:7])([CH3:6])[C:13]#[N:14])[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)C#N
Reactant: CC(=O)C1CC1
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Product: CC(C#N)(O[Si](C)(C)C)C1CC1
Temperature: 145 °C
Reaction time: 1 h
Yield: 685.1 %

Procedure:
To a well stirred mixture of cyclopropylmethylketone (27.8 mL, 0.3 mol), trimethylsilylcyanide (55.8 mL, 0.45 mol) and 18-crown-6 (4.87 g, 18.5 mmol) was added potassium cyanide (2.44 g, 37.5 mmol). The temperature rose to ˜100° C. and stirring was continued for 1 h with heating to 145° C. After cooling the mixture was purified by silica gel chromatography (500 g silica, heptane/ethylacetate 6:1) to yield 47.1 g of the title compound as light brown oil, 1H NMR (CDCl3): 0.23 (s, 9H), 0.56 (m, 4H), 1.17 (m, 1H), 1.63 (s, 3H, CH3).
Reaction SMILES: [Cl:1][C:2]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3F)[O:8][C:4]=2[CH:3]=1.[C:22](=O)([O-])[O-:23].[K+].[K+].CO>O>[Cl:1][C:2]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[O:23][CH3:22])[O:8][C:4]=2[CH:3]=1
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)c(Cl)cc2o1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1cnccc1-c1nc2cc(C(F)(F)F)c(Cl)cc2o1
Temperature: 60 °C
Yield: 44.7 %

Procedure:
A mixture of 0.28 g of 6-chloro-2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.24 g of potassium carbonate and 3 ml of methanol was stirred while heating at 60° C. for two hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.13 g of 6-chloro-2-(3-methoxypyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 91”).
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH2:4][CH2:5][C:6]1[N:10]=[CH:9][NH:8][CH:7]=1.[OH-].[Na+].[CH:13](=O)[CH:14]([CH3:16])[CH3:15].Cl>O.CO>[ClH:1].[CH:14]([CH:16]1[C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH2:5][CH2:4][NH:3]1)([CH3:15])[CH3:13]
Reactant: CC(C)C=O
Reactant: NCCc1c[nH]cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)C1NCCc2[nH]cnc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 48.7 %

Procedure:
Histamine dihydrochloride (61.9 g, 336 mmol) was dissolved in a solution of NaOH (33.6 g, 841 mmol) in water (125 mL) and MeOH (500 mL), and isobutyraldehyde (61.4 mL, 672 mmol) was added. The reaction mixture was heated under reflux at 80° C. for 24 h, cooled to room temperature, the pH was adjusted to 7 with 1 M aq HCl solution (250 mL) and the solvents were removed in vacuo. The residue was dissolved in warm MeOH (300 mL), allowed to stand for 1 h, filtered and the solvents were removed in vacuo. The residue was stirred in MeOH (50 mL) and acetone (400 mL) for 2 h and was cooled to 4° C. for 2 h. The resulting precipitate was filtered and washed with acetone (100 mL) to give 4-isopropyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine hydrochloride (33.0 g, 48.7%) as a white solid.
Reaction SMILES: [CH:1](=[C:8]1[CH2:12][N:11]([C:13]([O:15]C(C)(C)C)=O)[C@H:10]([C:20]([OH:22])=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][N:24]([CH3:31])[CH2:25][CH2:26][CH2:27]C(Cl)=O.[N:32]1[C:41]2[C:36](=[CH:37][C:38]([NH2:42])=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1>>[CH:1](=[C:8]1[CH2:12][N:11]([C:13](=[O:15])[CH2:27][CH2:26][CH2:25][N:24]([CH3:31])[CH3:23])[C@H:10]([C:20]([NH:42][C:38]2[CH:37]=[C:36]3[C:41](=[CH:40][CH:39]=2)[N:32]=[CH:33][CH:34]=[CH:35]3)=[O:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CCCC(=O)Cl
Reactant: Nc1ccc2ncccc2c1
Reactant: CC(C)(C)OC(=O)N1CC(=Cc2ccccc2)C[C@H]1C(=O)O
Product: CN(C)CCCC(=O)N1CC(=Cc2ccccc2)C[C@H]1C(=O)Nc1ccc2ncccc2c1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-benzylidene-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, 4-(dimethylamino)butanoyl chloride, and 6-quinolinamine the title compound was obtained in 71% purity by LC/MS. MS(ESI+): m/z=443.6.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[CH2:12]Cl.[CH3:14][S:15]([O-:17])=[O:16].[Na+]>CN(C)C=O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[CH2:12][S:15]([CH3:14])(=[O:17])=[O:16]
Reactant: ClCc1cnc2ccccc2c1Cl
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Cc1cnc2ccccc2c1Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
4-Chloro-3-chloromethylquinoline (14.2 g.) was added to a stirred suspension of sodium methanesulphinate (7.3 g.) in dimethylformamide (150 ml.) at room temperature. The mixture was stirred for 14 hours at room temperature, then for 0.5 hour at 95°-100°. The solvent was evaporated to half volume and water added to the residue. The resulting solid product was collected and dissolved in dichloromethane. The solution was dried, filtered from charcoal, and evaporated. The resulting solid was triturated with petroleum ether to give the novel compound 4-chloro-3-methylsulphonylmethylquinoline, m.p. 202°-204°.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[NH:13][C:14]([C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[C:20]([Cl:25])[CH:19]=2)=[O:15])=[O:6])#[N:2].[H-].[Na+].[CH3:28]I>CN(C=O)C>[C:1]([CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[NH:13][C:14]([C:16]1[N:17]([CH3:28])[C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[C:20]([Cl:25])[CH:19]=2)=[O:15])=[O:6])#[N:2]
Reactant: N#CCNC(=O)C1CCCCC1NC(=O)c1cc2ccc(Cl)cc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(C(=O)NC2CCCCC2C(=O)NCC#N)cc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
To a solution of 6-Chloro-1H-indole-2-carboxylic acid [2-(cyanomethyl-carbamoyl)-cyclohexyl]-amide (6.17 g, 17.19 mmol) in DMF (35 ml) were added NaH as a 60% wt suspension in mineral oil (0.687 g, 17.19 mmol) at 0° C. The slurry was stirred for one hour at room temperature and methyl iodide (1.07 ml, 17.19 mmol) was added. The solution was stirred for four hours and partitioned between ethyl acetate (200 ml) and 1 N HCl (300 ml). The organic layer was washed with water, brine, dried over magnesium sulfate and concentrated. Recrystallizing from ethyl acetate: hexane (1:10) yielded 6-Chloro-1-methyl-1H-indole-2-carboxylic acid [2-(cyanomethyl-carbamoyl)-cyclohexyl]-amide (4.76 g, 74%). [M+H=373].
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH:13]=[C:14]([CH2:18][NH:19][C:20]([CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH:27]([O:30][C:31](=[O:45])[NH:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH2:26][CH2:25]3)=[O:21])[CH:15]=[CH:16][CH:17]=2)=[O:11])=[CH:5][CH:4]=1)=O.C(O)(=O)C.[NH2:50][CH2:51][C@@H:52]([C:61]1[CH:70]=[CH:69][C:68]([OH:71])=[C:67]2[C:62]=1[CH:63]=[CH:64][C:65](=[O:72])[NH:66]2)[O:53][Si:54]([C:57]([CH3:60])([CH3:59])[CH3:58])([CH3:56])[CH3:55].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.CO>[Si:54]([O:53][C@H:52]([C:61]1[CH:70]=[CH:69][C:68]([OH:71])=[C:67]2[C:62]=1[CH:63]=[CH:64][C:65](=[O:72])[NH:66]2)[CH2:51][NH:50][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([C:12]2[CH:13]=[C:14]([CH2:18][NH:19][C:20]([CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH:27]([O:30][C:31](=[O:45])[NH:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH2:26][CH2:25]3)=[O:21])[CH:15]=[CH:16][CH:17]=2)=[O:11])=[CH:7][CH:8]=1)([C:57]([CH3:60])([CH3:59])[CH3:58])([CH3:56])[CH3:55]
Reactant: O=Cc1ccc(NC(=O)c2cccc(CNC(=O)CCN3CCC(OC(=O)Nc4ccccc4-c4ccccc4)CC3)c2)cc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c2[nH]c(=O)ccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNCc1ccc(NC(=O)c2cccc(CNC(=O)CCN3CCC(OC(=O)Nc4ccccc4-c4ccccc4)CC3)c2)cc1)c1ccc(O)c2[nH]c(=O)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of biphenyl-2-ylcarbamic acid 1-(2-{[3-(4-formylphenylcarbamoyl)-phenyl]methylcarbamoyl}ethyl)piperidin-4-yl ester (151 mg, 0.250 mmol) and 5-[(R)-2-amino-1-(tert-butyldimethylsilanyloxy)ethyl]-8-hydroxy-1H-quinolin-2-one acetic acid salt (98.6 mg, 0.250 mmol) in 1:1 MeOH:DCM (2.0 mL) was stirred at room temperature for 3 h. Sodium triacetoxyborohydride (159 mg, 0.750 mmol) was added and the reaction mixture was stirred at room temperature for 3 h. LC-MS (Method 10-90) showed product was present (Rt 3.32 min; m/z 923.6 [M+H]+. Saturated aqueous sodium bicarbonate solution was added and the layers were separated. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound, which was used in the next reaction without further purification.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[NH:27])[NH:25][OH:26])[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[C:28](Cl)(=O)[CH2:29][CH3:30]>>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[N:27]=[C:28]([CH2:29][CH3:30])[O:26][N:25]=3)[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1
Reactant: CCC(=O)Cl
Reactant: N=C(NO)N1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Product: CCc1nc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)no1

Procedure:
The title compound is prepared from N-cyclopropyl-N-[1-(N-hydroxycarbamimidoyl)-piperidin-4-yl]-4-oxazol-5-yl-benzamide and propionyl chloride following a procedure analogous to that described in Example 47. LC (method 3): tR=1.83 min; Mass spectrum (ESI+): m/z=408 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](/[CH:10]=[CH:11]/[CH2:12][O:13][CH3:14])[C:3]=1[C:4]#[N:5].[NH2:15][S:16](Cl)(=[O:18])=[O:17]>CC(N(C)C)=O.CCOC(C)=O>[S:16]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](/[CH:10]=[CH:11]/[CH2:12][O:13][CH3:14])[C:3]=1[C:4]#[N:5])(=[O:18])(=[O:17])[NH2:15]
Reactant: NS(=O)(=O)Cl
Reactant: COC/C=C/c1cccc(N)c1C#N
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COC/C=C/c1cccc(NS(N)(=O)=O)c1C#N
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of (E)-2-amino-6-(3-methoxyprop-1-enyl)benzonitrile (Example 97b) (188 mg, 1.0 mmol) in DMA was added NH2SO2Cl (347 mg, 3.0 mmol) at 0° C. under nitrogen. The reaction mixture was then stirred at room temperature for 6 hrs, diluted with EtOAc, washed with brine (5×), and dried over Na2SO4. The solvent was evaporated under reduced pressure to give (E)-2-sulfamoylamino-6-(3-methoxyprop-1-enyl)benzonitrile as a pale-yellow solid, which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([OH:12])=O)=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.C(OC(=O)[NH:50][C@H:51]([CH2:59][NH2:60])[CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)(C)(C)C>CN(C=O)C>[NH2:50][C@@H:51]([CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[CH2:59][NH:60][C:10]([C:3]1[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=1)=[O:12]
Reactant: Nc1nc(N)c(C(=O)O)nc1Cl
Reactant: CC(C)(C)OC(=O)N[C@H](CN)Cc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Nc1nc(N)c(C(=O)NC[C@@H](N)Cc2ccccc2)nc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3,5-diamino-6-chloro-pyrazine-2-carboxylic acid (0.225 g, 1.2 mmol) and HATU (0.46 g, 1.2 mmol) in DMF (10 mL) is added N-methylmorpholine (0.53 mL, 4.8 mmol) and ((S)-1-aminomethyl-2-phenyl-ethyl)-carbamic acid tert-butyl ester (0.3 g, 1.2 mmol) and the resulting yellow solution is stirred at RT for 18 h. The solvent is removed in vacuo and the residue is diluted with water (10 mL). The precipitate which forms is collected by filtration and dissolved in DCM (5 mL). TFA (1 mL) is added and the solution stirred at RT for 1 h. The solvent is removed in vacuo, and the residue is purified by reverse phase chromatography (Isolute™ C18, 0-100% acetonitrile in water with 0.1% TFA) to yield the title compound. [M+H]+ 321