Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9].[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][N:34]([C:37]2([C:40](O)=[O:41])[CH2:39][CH2:38]2)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:40]([C:37]2([N:34]3[CH2:35][CH2:36][N:31]([C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[CH2:32][CH2:33]3)[CH2:39][CH2:38]2)=[O:41])[C@H:13]([C:16](=[O:17])[NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)[CH2:12]1)(=[O:10])=[O:9]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Reactant: CC(C)(C)OC(=O)N1CCN(C2(C(=O)O)CC2)CC1
Product: CC(C)(C)OC(=O)N1CCN(C2(C(=O)N3C[C@H](S(=O)(=O)c4ccccc4Cl)C[C@H]3C(=O)NC3(C#N)CC3)CC2)CC1
Yield: 91 %

Procedure:
The reaction of (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 7H with 1-(4-(tert-butoxycarbonyl)piperazin-1-yl)cyclopropanecarboxylic acid 16E carried out according to the general procedure L yielded tert-butyl 4-(1-((2S,4R)-4-(2-chlorophenylsulfonyl)-2-(1-cyanocyclopropylcarbamoyl)pyrrolidine-1-carbonyl)cyclopropyl)piperazine-1-carboxylate as a white solid (91%). MS ISN (m/e): 604.4/606.3 (41/15) [(M−H)]−, 664.3/666.4 (100/54) [(M+OAc)]−.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:12][C:13]1[C:14]([S:22][CH3:23])=[N:15][C:16]([CH3:21])=[CH:17][C:18]=1[S:19][CH3:20])=[O:11].[CH3:24][O:25][C:26]([C:28]1[C:36]2[O:35][C:34]([SH:37])=[N:33][C:32]=2[CH:31]=[CH:30][CH:29]=1)=[O:27].C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+]>O.CN(C=O)C>[CH3:24][O:25][C:26]([C:28]1[C:36]2[O:35][C:34]([S:37][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:12][C:13]3[C:14]([S:22][CH3:23])=[N:15][C:16]([CH3:21])=[CH:17][C:18]=3[S:19][CH3:20])=[O:11])=[N:33][C:32]=2[CH:31]=[CH:30][CH:29]=1)=[O:27]
Reactant: COC(=O)c1cccc2nc(S)oc12
Reactant: CSc1cc(C)nc(SC)c1NC(=O)CCCCCCCCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2nc(SCCCCCCCCC(=O)Nc3c(SC)cc(C)nc3SC)oc12
Temperature: 80 °C
Reaction time: 4 h
Yield: 69.7 %

Procedure:
To a DMF (4 ml) solution of 9-bromo-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]nonanamide (90 mg, 0.22 mmol) and 7-methoxycarbonyl-2-mercaptobenzoxazole (45 mg, 0.22 mmol) were added 18-crown-6 (6 mg, 0.02 mmol) and potassium carbonate (36 mg, 0.26 mmol), and the mixture was stirred at 80° C. for 4 hours. The rdaction mixture was diluted with water, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was recrystallized from a mixture of ethyl acetate and hexane to obtain 84 mg (yield 72%) of the desired compound as a colorless powdery crystal.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[C:4]([CH:6]1[O:11][CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]1)=[O:5])[CH3:2].[ClH:21]>C(OCC)(=O)C>[ClH:21].[CH2:19]([N:3]([CH2:1][CH3:2])[C:4]([CH:6]1[O:11][CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:20]
Reactant: CCN(CC)C(=O)C1CN(C(=O)OC(C)(C)C)CCO1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)C1CNCCO1

Procedure:
t-Butyl 2-[(diethylamino)carbonyl]morpholine-4-carboxylate was treated with a 4M ethyl acetate solution of hydrochloric acid in ethyl acetate to obtain N,N-diethylmorpholine-2-carboxamide hydrochloride.
Reaction SMILES: [C:1]1([NH:15][C:16](=[O:22])[C:17]([O:19]CC)=[O:18])[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:14])[C:9]([O:11]CC)=[O:10])[CH:2]=1.Cl>[OH-].[Na+].O>[C:1]1([NH:15][C:16](=[O:22])[C:17]([OH:19])=[O:18])[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:14])[C:9]([OH:11])=[O:10])[CH:2]=1
Reactant: CCOC(=O)C(=O)Nc1cccc(NC(=O)C(=O)OCC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C(=O)Nc1cccc(NC(=O)C(=O)O)c1

Procedure:
Diethyl N,N'-(m-phenylene)dioxamate (1.0 gram) is stirred in 1.0N aqueous sodium hydroxide for 0.5 hour. The solution is diluted with water (100 ml.) and the pH adjusted to pH 3 with concentrated hydrochloric acid. The resulting precipitate is collected and recrystallized from ethanol (0.46 grams, M. P. 240° C.).
Reaction SMILES: C(OC([N:8]1[CH2:26][CH2:25][N:11]2[C:12](=[O:24])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([Br:19])=[CH:15][C:14]=3[C:20]([F:23])([F:22])[F:21])=O)(C)(C)C.[ClH:27]>C(OCC)C>[ClH:27].[Br:19][C:16]1[CH:17]=[C:18]2[C:13]([C:12](=[O:24])[N:11]3[CH2:25][CH2:26][NH:8][CH2:9][C@H:10]32)=[C:14]([C:20]([F:23])([F:22])[F:21])[CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(cc(Br)cc3C(F)(F)F)[C@@H]2C1
Agent: Cl
Solvent: CCOCC
Product: O=C1c2c(cc(Br)cc2C(F)(F)F)[C@@H]2CNCCN12
Reaction time: 0.25 h
Yield: 37 %

Procedure:
To N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-bromo-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one from Step A (105 mg, 0.24 mmol) was added diethyl ether (2 mL) and saturated aqueous hydrochloric acid (1 mL). After 15 min of stirring, the reaction was concentrated and treated with saturated aqueous ammonium hydroxide (2 mL). The solution was concentrated to dryness and the resulting residue was purified by radial chromatography (2% ammonium hydroxide in 4% methanol in dichloromethane) to give a clear residue. The residue was treated with 1N aqueous hydrogen chloride and lyophilized to afford the desired product (33 mg, 37%) as an off-white solid. MS (ESI) 335.2, 337.2 (M−Cl).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl.Cl.N1CCCNCC1.[I-].[Na+].[CH3:19][S:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1)(=[O:22])=[O:21]>C(O)C>[CH3:19][S:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:1]2[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[CH:25][CH:24]=1)(=[O:21])=[O:22]
Reactant: C1CNCCNC1
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(CN2CCCNCC2)cc1
Temperature: 70 °C
Reaction time: 14 h
Yield: 65.4 %

Procedure:
A mixture of 120 mg of homopiperazine, 216 mg of homopiperazine dihydrochloride salt, 3 mL of ethanol was heated to 70° C. into a solution. To this solution were added sequentially 383 mg of sodium iodide and 250 mg of 4-(methylsulfonyl)benzyl bromide, followed by stirring at 70° C. for 14 hours. After the solution was cooled to room temperature, ethanol was removed under reduced pressure and 20 mL of aqueous 2N sodium hydroxide was added and the mixture was extracted with 20 mL×2 of ethyl acetate. The organic layers were combined, washed with 20 mL of aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated to give 176 mg of 1-[4-(methylsulfonyl)benzyl]homopiperazine.
Reaction SMILES: [NH2:1][CH:2]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:15][C:14]3=[CH:16][N:17]=[C:18]([CH3:19])[N:13]3[C:12]2=[O:20])[CH2:7][CH2:6]1)=[O:4].[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:1][CH:2]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:3]([N:5]2[CH2:10][CH2:9][CH:8]([N:11]3[CH2:15][C:14]4=[CH:16][N:17]=[C:18]([CH3:19])[N:13]4[C:12]3=[O:20])[CH2:7][CH2:6]2)=[O:4])=[O:36])=[CH:30][CH:29]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: Cc1ncc2n1C(=O)N(C1CCN(C(=O)C(N)c3ccccc3)CC1)C2
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ncc2n1C(=O)N(C1CCN(C(=O)C(NC(=O)Nc3ccc(Cl)cc3)c3ccccc3)CC1)C2
Yield: 62.7 %

Procedure:
2-(1-(2-Amino-2-phenylacetyl)-4-piperidinyl)-5-methyl-1,2-dihydro-3H-imidazo[1,5-c]imidazol-3-one (0.10 g) obtained in Example 50b) was dissolved in DMF (3.0 ml), 4-chlorophenyl isocyanate (0.05 g) was added thereto, and mixed at room temperature for 1 hour. The reaction mixture was dissolved in ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with basic silica gel column (ethyl acetate to methanol/ethyl acetate=1/10). The product was crystallized from ethyl acetate-diethyl ether to obtain the title compound as colorless powder (0.09 g, 59%).
Reaction SMILES: C(O)(=O)C.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:7]=1[O:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C.[Zn]>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[O:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=[N+]([O-])c1ccc(Br)c(OCCOc2ccccc2)c1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1ccc(Br)c(OCCOc2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
Acetic acid (1.068 mL, 18 mmol) was added to the mixture of 25b (600 mg, 1.8 mmol) and zinc dust (1.157 g, 18.0 mmol) in ethanol (10 mL) at 0° C. The reaction mixture was warmed to room temperature and stirred for 4 hrs. The mixture was filtered, the solvent distilled off under reduced pressure and the crude was purified by flash column chromatography to obtain the aniline 25c in 84% yield.
Reaction SMILES: [CH:1]1[S:5][CH:4]=[CH:3][C:2]=1[C:6]([OH:8])=[O:7].[N+](=[CH2:11])=[N-]>CCOCC>[CH3:11][O:7][C:6](=[O:8])[C:2]1[CH:3]=[CH:4][S:5][CH:1]=1
Reactant: O=C(O)c1ccsc1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)c1ccsc1

Procedure:
A suspension of 3-thenoic acid (prepared as described by S. Gronowitz in Arkiv. Kemi., 7, 361-369, 1954) (4.7 g, 0.037 mole) in anhydrous ether was treated with an ethereal solution of diazomethane (from 7-8 g N-nitroso-methylurea and 40% aqueous potassium hydroxide (30 ml) and ether (100 ml)). Evaporation in vacuo gave methyl-3-thenoate (4.9 g). Lithium aluminium hydride (1.3 g) reduction in ether gave 3-hydroxymethylthiophene (3.4 g, 93%) as a colourless oil.
Reaction SMILES: C[O:2][C:3]1(OC)[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]([C:10](=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4]1=O.Cl.[NH2:21]O>CCO>[O:2]=[C:3]1[C:4]2=[N:21][O:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: NO
Reactant: CCOC(=O)C(=O)C1CCCCC(OC)(OC)C1=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1onc2c1CCCCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
To a solution of ethyl (3,3-dimethoxy-2-oxocycloheptyl)(oxo)acetate (0.850 g, 3.12 mmol) in 15 mL of EtOH, hydroxylamine hydrochloride (0.225 g, 3.24 mmol) was added. The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the crude solid was purified by flash chromatography on silica gel (eluant: AcOEt/hexane:1/9) to afford 0.245 g (35% yield) of:
Reaction SMILES: [CH:1]([NH:3][C:4]1[N:8]([CH3:9])[N:7]=[CH:6][CH:5]=1)=[O:2].[H-].[Na+].CI.[C:14](OCC)(=O)C>CN(C)C=O.O>[CH:1]([N:3]([C:4]1[N:8]([CH3:9])[N:7]=[CH:6][CH:5]=1)[CH3:14])=[O:2]
Reactant: Cn1nccc1NC=O
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CN(C=O)c1ccnn1C
Reaction time: 1 h

Procedure:
To a solution of 5-formamido-1-methylpyrazole in N,N-dimethylformamide (50 ml) was sodium hydride (1.6 g) under ice-cooling. Then, to the mixture was added methyl iodide (2.5 ml) at the same condition. The mixture was stirred for 1 hour under ice-cooling. To the reaction mixture was added a mixture of ethyl acetate (500 ml) and water (100 ml). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (50 ml×2). The organic solution was dried over magnesium sulfate. The solvent was distilled off and the residue was subjected to a column chromatography on silica gel using a mixture of ethyl acetate and diisopropyl ether (3:1) as an eluent. Fractions containing the object compound were collected and evaporated in vacuo to give 5-(N-formyl-N-methylamino)-1-methylpyrazole (2.5 g).
Reaction SMILES: [C:1]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:12]3[CH:13]=[C:14]([F:19])[C:15](I)=[C:16]([F:17])[C:11]=3[N:10]=[C:9]2[O:20][CH:21]2[CH2:24][CH:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:22]2)=[CH:3][CH:2]=1.B(O)(O)[C:37]1[CH:38]=[CH:39][C:40]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[CH:41][CH:42]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:40]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:41]=[CH:42][C:37]([C:15]2[C:14]([F:19])=[CH:13][C:12]3[N:8]([CH2:7][C:4]4[CH:5]=[CH:6][C:1]([C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=5)=[CH:2][CH:3]=4)[C:9]([O:20][CH:21]4[CH2:22][CH:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:24]4)=[N:10][C:11]=3[C:16]=2[F:17])=[CH:38][CH:39]=1
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)C1CC(Oc2nc3c(F)c(I)c(F)cc3n2Cc2ccc(-c3ccccc3)cc2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C1CC(Oc2nc3c(F)c(-c4ccc(-c5ccccc5)cc4)c(F)cc3n2Cc2ccc(-c3ccccc3)cc2)C1
Temperature: 120 °C

Procedure:
A solution of ethyl 3-{[1-(biphenyl-4-ylmethyl)-4,6-difluoro-5-iodo-1H-benzimidazol-2-yl]oxy}cyclobutanecarboxylate (0.350 g, 0.595 mmol), biphenylboronic acid (0.130 g, 0.654 mmol), and Pd(PPh3)4 (0.027 g, 0.024 mmol) in 6 mL of DMF was treated with a 1 M solution of K2CO3 (1.20 mL). The resulting yellow solution was heated at 120° C. for 45 min, and then diluted with EtOAc and H2O. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. Purification of the resulting residue by flash chromatography (0-15% then 15-20% then 20% EtOAc/hexanes) provided the desired product as a white solid. LCMS: calculated for C39H32F2N2O3 614.68, observed ink 615.1 (M+H)+ (Rt 2.79/4 min).
Reaction SMILES: [Li].[Br:2][C:3]1[CH:4]=[C:5]([C:14]([O-])=[CH:15][C:16](=O)[C:17]([O:19]CC)=[O:18])[CH:6]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:8]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.[Cl:46][C:47]1[N:52]=[C:51]([NH:53][NH2:54])[CH:50]=[CH:49][CH:48]=1>>[Br:2][C:3]1[CH:4]=[C:5]([C:14]2[N:53]([C:51]3[CH:50]=[CH:49][CH:48]=[C:47]([Cl:46])[N:52]=3)[N:54]=[C:16]([C:17]([OH:19])=[O:18])[CH:15]=2)[CH:6]=[C:7]([O:9][C:10]([F:11])([F:12])[F:13])[CH:8]=1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cc(Br)cc(OC(F)(F)F)c1
Reactant: NNc1cccc(Cl)n1
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: O=C(O)c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2cccc(Cl)n2)n1

Procedure:
1.10 g (2.40 mmol) of the compound of Example 5A is reacted analogously to the synthesis of the compound of Example 20A with 518 mg (3.61 mmol) of 6-chloropyridin-2-yl-hydrazine. After hydrolysis, 737 mg (66% of theory) of the title compound is obtained.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH2:12][O:13][CH3:14])[CH2:3][CH2:2]1.[CH3:18][C:19]([CH3:27])([C:21]1[N:25]=[C:24]([CH3:26])[O:23][N:22]=1)[NH2:20]>>[CH3:18][C:19]([NH:20][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH2:12][O:13][CH3:14])[N:8]=1)=[O:17])([C:21]1[N:25]=[C:24]([CH3:26])[O:23][N:22]=1)[CH3:27]
Reactant: COCCOc1nc(C(=O)O)ccc1C1CC1
Reactant: Cc1nc(C(C)(C)N)no1
Product: COCCOc1nc(C(=O)NC(C)(C)c2noc(C)n2)ccc1C1CC1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(2-methoxyethoxy)-pyridine-2-carboxylic acid (Example 142 d) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials, MS (EI): m/e=361.1 [M+H]+.
Reaction SMILES: [C:1]([Si:5]([CH3:30])([CH3:29])[O:6][CH:7]1[CH2:12][CH2:11][CH:10]([N:13]2[CH:17]=[C:16]([C:18]3[CH:23]=[N:22][C:21]([NH2:24])=[C:20]4[O:25][C:26](Cl)=[CH:27][C:19]=34)[CH:15]=[N:14]2)[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:39]2[CH:47]=[C:46]3[C:42]([CH2:43][NH:44][C:45]3=[O:48])=[CH:41][CH:40]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:24][C:21]1[N:22]=[CH:23][C:18]([C:16]2[CH:15]=[N:14][N:13]([C@H:10]3[CH2:11][CH2:12][C@H:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:30])[CH3:29])[CH2:8][CH2:9]3)[CH:17]=2)=[C:19]2[CH:27]=[C:26]([C:39]3[CH:47]=[C:46]4[C:42]([CH2:43][NH:44][C:45]4=[O:48])=[CH:41][CH:40]=3)[O:25][C:20]=12
Reactant: CC1(C)OB(c2ccc3c(c2)C(=O)NC3)OC1(C)C
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(n2cc(-c3cnc(N)c4oc(Cl)cc34)cn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](n2cc(-c3cnc(N)c4oc(-c5ccc6c(c5)C(=O)NC6)cc34)cn2)CC1
Temperature: 120 °C

Procedure:
To a solution of 4-{1-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-1H-pyrazol-4-yl}-2-chloro-furo[2,3-c]pyridin-7-ylamine (50.0 mg, 0.112 mmol) in DME (0.894 mL) was added 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (43.5 mg, 0.168 mmol), sodium carbonate (2.0 M in water, 0.089 mL, 0.18 mmol), and Pd(PPh3)4 (20 mg, 0.02 mmol) and the reaction mixture was heated at 120° C. for 15 min in a microwave reactor. The reaction mixture was then concentrated. Purification of the residue by ISCO chromatography (0 to 5% 7 N NH3/MeOH:EtOAc) afforded 49 mg (80%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[CH2:4][O:5][C:6](=[O:8])[CH3:7].[N+:14]([O-])([OH:16])=[O:15]>>[F:1][C:2]1[C:12]([N+:14]([O-:16])=[O:15])=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[CH2:4][O:5][C:6](=[O:8])[CH3:7]
Reactant: CC(=O)OCc1c(F)cccc1F
Reactant: O=[N+]([O-])O
Product: CC(=O)OCc1c(F)ccc([N+](=O)[O-])c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
Acetic acid 2,6-difluorobenzyl ester (8 g, 42.9 mmol) was added dropwise to fuming nitric acid (50 mL) at 0° C. and the reaction mixture stirred at 0° C. for 30 min. The reaction mixture was poured onto ice and the product extracted with DCM (3×30 mL). The combined organic fractions were washed with sat, aq, NaHCO3 then brine, dried (MgSO4) and concentrated in vacuo to give the title compound as a yellow oil (8.69 g, 87%). 1H NMR 300 MHz δ (CDCl3): 8.21-8.12 (1H, m), 7.09 (1H, ddd, J=9.6, 7.9, 1.9 Hz), 5.24 (2H, t, J=1.5 Hz), 2.10 (3H, s).
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[C:11](=S)=[S:12].[OH-].[K+]>O.C(O)C>[SH:12][C:11]1[O:8][C:1]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[N:9][N:10]=1
Reactant: NNC(=O)c1cccnc1
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Sc1nnc(-c2cccnc2)o1

Procedure:
13.7 g (0.1 mol) of nicotinic acid hydrazide and 8 g (0.105 mol) of carbon disulfide are added dropwise to a solution of 56 g (0.1 mol) of potassium hydroxide in 20 g of water and 350 ml of 95% ethanol. The reaction mixture is refluxed for 3 hours, then the solvent is evaporated off under vacuum and the residue is dried under a high vacuum. The dry residue is stirred in 75 ml of water, filtered, and the filtrate is neutralised with 1N hydrochloric acid. The precipitated product is isolated by filtration, washed in succession with acetone and hexane and vacuum dried, affording 9.9 g (55% of theory) of the title compound with a melting point of 237° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C(P(CCCC)CCCC)CCC.[CH:26]1([NH:29][C:30]([C:32]2[N:33]=[N:34][N:35]([C:41]3[CH:46]=[CH:45][C:44]([C:47]([NH:49][CH2:50][CH3:51])=[O:48])=[CH:43][CH:42]=3)[C:36]=2[CH2:37][CH2:38][CH2:39]O)=[O:31])[CH2:28][CH2:27]1.N(/C(N1CCCCC1)=O)=N\C(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH:26]1([NH:29][C:30]([C:32]2[N:33]=[N:34][N:35]([C:41]3[CH:42]=[CH:43][C:44]([C:47]([NH:49][CH2:50][CH3:51])=[O:48])=[CH:45][CH:46]=3)[C:36]=2[CH2:37][CH2:38][CH2:39][O:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:9][CH:8]=2)=[O:31])[CH2:27][CH2:28]1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCO)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(/N=N/C(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCOc2ccc(OC(F)(F)F)cc2)cc1
Yield: 64.3 %

Procedure:
To a solution of 4-(trifluoromethoxy)phenol (52 mg) in toluene (0.5 ml) was added a solution of tributylphosphine (51 mg) in toluene (0.5 ml) under stirring, a solution of N-cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-5-(3-hydroxypropyl)-1H-1,2,3-triazole-4-carboxamide (29 mg) in toluene (0.5 ml) and a solution of 1,1′-[(E)-diazene-1,2-diyldicarbonyl]dipiperidine in toluene (0.5 ml) were successively added, and the mixture was stirred at room temperature for 64 hr. The reaction mixture was filtered through a filter tube (Biospin column, Bio-Rad), and washed with 1 ml of ethyl acetate. The filtrates were combined, 1 ml of ethyl acetate and 1 ml of saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was vigorously stirred at room temperature for 30 min. The organic layer was recovered using Presep™ Dehydration (Wako Pure Chemical Industries, Ltd.) and concentrated to dryness. The residue was dissolved in DMSO (0.7 ml) and purified by preparative HPLC (Gilson, Inc., high-throughput purification system, column: YMC CombiPrep ODS-A S-5 μm, 50×20 mm, solvent: solution A; 0.1% formic acid aqueous solution, solution B; 0.1% formic acid acetonitrile solution, gradient cycle: 0 min (solution A/solution B=95/5), 1.00 min (solution A/solution B=95/5), 5.20 min (solution A/solution B=5/95), 6.40 min (solution A/solution B=5/95), 6.50 min (solution A/solution B=95/5), 6.60 min (solution A/solution B=95/5), flow rate: 25 ml/min, detection method: UV 220 nm) to give the title compound (27 mg) (LC/MS purity 100%, ESI+:518 [M+H]+).
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].[C:5]12[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[NH:10]C(=O)[O:8][C:6]2=O>CN(C=O)C.O.C(Cl)Cl>[NH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:5]=1[C:6]([NH:4][CH2:1][C:2]#[CH:3])=[O:8]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: C#CCN
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: C#CCNC(=O)c1ccccc1N
Temperature: 45 °C
Reaction time: 16 h
Yield: 50.2 %

Procedure:
A solution of propargylamine (1.00 mL, 14.6 mmol) in DMF (4.0 mL) was added dropwise to a solution of isatoic anhydride (1.57 g, 9.72 mmol) in DMF (8.0 mL) at 45° C. The solution was stirred at 45° C. for 16 h and diluted with water and CH2Cl2. The aqueous phase was extracted with CH2Cl2 washed with water, brine, dried and concentrated. The crude product was recrystallised from EtOAc/petrol to give 2-amino-N-propargylbenzamide (0.85 g, 51%) as a colourless solid; mp 100-101° C., lit. [29] 98-100° C.; δH (400 MHz, DMSO-d6) 3.08 (t, J=2.4 Hz, 1H, C≡CH), 3.97 (dd, J=5.6, 2.4 Hz, 2H, CH2), 6.45 (s, 2H, NH2), 6.49 (t, J4,5=J5,6=7.8 Hz, 1H, H5), 6.68 (d, J3,4=7.8 Hz, 1H, H3), 7.13 (t, J3,4=J4,5=7.8 Hz, 1H, H4), 7.46 (d, J5,6=7.8 Hz, 1H, H6), 6.61 (t, J=5.6 Hz, 1H, NH).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)[CH:8]=[CH:7]2)([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)[CH:8]=[CH:7]2
Reactant: CC(C)(C)OC(=O)N1CCC(n2ccc3cc([N+](=O)[O-])ccc32)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(n2ccc3cc(N)ccc32)CC1

Procedure:
tert-Butyl 4-(5-nitro-1H-indol-1-yl)piperidine-1-carboxylate (9.04 mmol, 3.123 g) and 10% palladium on carbon (0.452 mmol, 0.481 g) were combined and stirred under a hydrogen atmosphere at 5 bar at room temperature in ethanol (25 mL) for 1 hour. The reaction mixture was filtered and concentrated at reduced pressure to afford the title compound. (2.506 g). MS (ESI) m/z 316.1 [M+H]+