Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[C:28](Cl)=[O:29]>>[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[C:28]([NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1)=[O:29]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4ccc5ccccc5c4)cc3c2C1
Yield: 71.4 %

Procedure:
Beginning with 10.4 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 10.2 μL (0.051 mMol) 2-naphthoyl chloride, 12.6 mg (72%) of the title compound were recovered as a dark brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][NH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[C:19]([CH:28]([F:30])[F:29])=[N:20][N:21]([CH2:24][C:25](O)=[O:26])[C:22]=1[CH3:23].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:17][C:18]1[C:19]([CH:28]([F:30])[F:29])=[N:20][N:21]([CH2:24][C:25]([N:12]2[CH2:13][CH2:14][CH2:15][C:16]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[N:9]=[CH:10][C:11]2=3)=[O:26])[C:22]=1[CH3:23]
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Reactant: Cc1c(Cl)c(C(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(Cl)c(C(F)F)nn1CC(=O)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
To a mixture of 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine (0.023 g, 0.10 mmol), 2-(4-chloro-3-difluoromethyl-5-methyl-pyrazol-1-yl)acetic acid (0.023 g, 0.10 mmol) and NEt3 (0.065 mL, 0.46 mmol) in DMF (0.6 mL) was added HATU (0.060 g, 0.15 mmol). The mixture was stirred at rt for 30 min. It was then quenched with water and partitioned between EtOAc (50 mL) and sat. NaHCO3 (30 mL). The organic layer was separated, dried over Na2SO4, concentrated in vacuo and purified by reverse phase HPLC to afford the desired product (0.032 g, 75%). 1H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 7.44 (m, 2H), 7.16 (dd, J=8.8, 8.4 Hz, 2H), 6.67 (d, J=54 Hz, 1H), 5.11 (s, 2H), 3.83 (m, 2H), 2.85 (t, J=6.2 Hz, 2H), 2.30 (s, 3H), 2.10 (m, 2H); MS: (ES) m/z calculated for C19H17ClF3N5O [M+H]+ 424.1, found 424.1.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:14]=[N:13][C:12]([C:15]([NH2:17])=[O:16])=[N:11]2)[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@H:2]1[OH:3].C(O[C:22](=[O:24])[CH3:23])(=O)C>N1C=CC=CC=1>[C:2]([O:3][C@@H:2]1[C@H:4]([O:5][C:4](=[O:5])[CH3:6])[C@@H:6]([CH2:8][O:9][C:22](=[O:24])[CH3:23])[O:7][C@H:1]1[N:10]1[CH:14]=[N:13][C:12]([C:15]([NH2:17])=[O:16])=[N:11]1)(=[O:3])[CH3:1]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(N)=O)n2)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.6 %

Procedure:
A solution of 1-(β -D-ribofuranosyl)-1,2,4-triazole-3-carboxamide (488 mg., 2.00 mmol) in pyridine (10.0 ml.) containing acetic anhydride (1.0 ml.) was added and the solution was stirred at room temperature for 2 hrs. The solvent was removed and water was added to the residue. The mixture was extracted with methylene chloride (three 20-ml. portions) and the organic layer was extracted with aqueous sodium hydrogen carbonate and water. The organic phase was dried over magnesium sulfate, filtered, and evaporated to a syrup which was applied to a silica gel column. Elution with chloroform-methanol (19:1) provided the pure product as an amorphous solid (560 mg., 75.6%).
Reaction SMILES: [CH3:1][Li].[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2([CH3:31])[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15](OP(OCC)(OCC)=O)[CH2:14][CH:13]([CH3:30])[CH2:12]2)[CH:7]=[CH:8][C:9]=1[Cl:10].[Cl-].[NH4+]>C(OCC)C.[Cu]I>[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2([CH3:31])[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([CH3:1])[CH2:14][CH:13]([CH3:30])[CH2:12]2)[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: CCOP(=O)(OCC)OC1=C(C(=O)OC)C(C)(c2ccc(Cl)c(Cl)c2)CC(C)C1
Reactant: [Li]C
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: COC(=O)C1=C(C)CC(C)CC1(C)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A stirred suspension of copper (I) iodide (213 mg) in diethyl ether (10 mL) at 0° C. was treated with methyllithium (1.6 M, 1 equivalent), forming a cloudy yellow mixture. Additional methyllithium (1.6 M, 1 equivalent) was added, forming a cloudy grey mixture. This cloudy grey mixture was stirred at 0° C. for 15 min, and then treated with a solution of methyl (4RS,6SR)-6-(3,4-dichlorophenyl)-2-(diethoxyphosphoryloxy)-4,6-dimethylcyclohexen-1-carboxylate (130 mg) in diethyl ether (5 mL). A deep red color formed over 30 min. Stirring was continued while warming to rt for 2 h more. At the conclusion of this period, the resulting mixture was treated with 3:1 saturated aqueous ammonium chloride/concentrated ammonium hydroxide, and stirred for 10 min. The mixture was then extracted three times with diethyl ether, and the combined organic layers were washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under vacuum. The resulting residue was purified by column chromatography on silica gel, eluting with 15% ethyl acetate/hexanes, to provide methyl (4RS,6RS)-6-(3,4-dichlorophenyl)-2,4,6-trimethylcyclohex-1-enecarboxylate (57 mg). Mass spectrum m/z 349.17 (M+Na+).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.C(O)(C(F)(F)F)=O.[CH3:20][O:21][C:22](=[O:45])[CH2:23][CH2:24][C:25]([NH:27][C:28]1[CH:44]=[CH:43][C:31]([C:32]([NH:34][NH:35]C(OC(C)(C)C)=O)=[O:33])=[CH:30][CH:29]=1)=[O:26]>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:35][NH:34][C:32]([C:31]1[CH:30]=[CH:29][C:28]([NH:27][C:25](=[O:26])[CH2:24][CH2:23][C:22]([O:21][CH3:20])=[O:45])=[CH:44][CH:43]=1)=[O:33]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: COC(=O)CCC(=O)Nc1ccc(C(=O)NNC(=O)OC(C)(C)C)cc1
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCC(=O)Nc1ccc(C(=O)NN=C2C(=O)Nc3ccc(I)cc32)cc1
Temperature: 100 °C
Yield: 92 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid in the presence of 5% TFA was added tert-butyl 2-{4-[(4-methoxy-4-oxobutanoyl)amino]benzoyl}hydrazinecarboxylate. After stirring at 100° C., the reaction mixture was cooled to rt and an orange solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. for 60 min gave 89 mg of the title compound (92%) as an orange solid in 98.8% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:20]#[N:21])=[C:18]([OH:19])[C:13]=3[C:12]3[CH:22]=[C:23]([Br:26])[CH:24]=[N:25][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][CH:36](O)[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>CN(C=O)C.C(OCC)(=O)C>[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][CH:36]([O:19][C:18]2[C:13]3[C:12]4[CH:22]=[C:23]([Br:26])[CH:24]=[N:25][C:11]=4[N:10]([S:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)(=[O:8])=[O:9])[C:14]=3[CH:15]=[N:16][C:17]=2[C:20]#[N:21])[CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: N#Cc1ncc2c(c1O)c1cc(Br)cnc1n2S(=O)(=O)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2c(C#N)ncc3c2c2cc(Br)cnc2n3S(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.1 %

Procedure:
A solution of 9-benzenesulfonyl-3-bromo-5-hydroxy-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (200 mg, 0.46 mmol), 3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (670 mg, 3.56 mmol) and triphenylphosphine (724 mg, 2.76 mmol) in anhydrous DMF (2 mL) was treated dropwise with diethyl azodicarboxylate (0.53 mL, 3.40 mmol) and the mixture stirred at ambient temperature for 3 h then left to stand overnight. The mixture was diluted with ethyl acetate (20 mL) and washed with brine (3×15 mL), dried over magnesium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography (silica, 20 g column, Si-SPE, 0-20% methanol in DCM). Collecting appropriate fractions afforded the title compound (160 mg, 57%). 1H NMR (CDCl3, 400 MHz): 9.57 (s, 1H), 8.76 (d, J=2.3 Hz, 1H), 8.46 (d, J=2.3 Hz, 1H), 8.24-8.23 (m, 1H), 8.23-8.21 (m, 1H), 7.71-7.61 (m, 1H), 7.58-7.45 (m, 2H), 5.88-5.83 (m, 1H), 4.36-4.11 (m, 1H), 3.87-3.36 (m, 2H), 2.48-2.26 (m, 2H), 2.13-2.05 (m, 1H), 1.46 (s, 9H). LCMS (Method B): RT=4.51 min, M+H+=598/600.
Reaction SMILES: C([O:4][CH2:5][C@:6]1([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:10][C@@H:9]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[C@H:8]([O:20]C(=O)C)[C@@H:7]1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=O)C.C[O-].[Na+].Cl>CO>[CH2:25]([O:24][C@@H:7]1[C@@:6]([CH2:5][OH:4])([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:10][C@@H:9]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[C@@H:8]1[OH:20])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(=O)OC[C@]1(COCc2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OCc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1cn([C@@H]2O[C@](CO)(COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H]2O)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of nucleoside 34 (553 mg, 1.05 mmol) in methanol (5.5 cm3) was added sodium methoxide (287 mg, 5.25 mmol). The reaction mixture was stirred at room temperature for 10 min, then neutralised with dilute hydrochloric acid. The solvent was partly evaporated and extraction was performed with dichloromethane (2×20 cm3). The combined organic phase was washed with saturated aqueous sodium hydrogencarbonate (3×20 cm3) and was dried (Na2SO4). The solvent was removed under reduced pressure to give 35 as a white solid material (476 mg, 97%). δH (CDCl3) 7.47 (1H, d, J 1.0 6-H), 7.36-7.22 (10H, m, Bn), 6.07 (1H, d, J 3.8, 1′-H), 4.87 (1H, d, J 11.7, Bn), 4.55 (1H, d, J 11.7, Bn), 4.50-4.32 (4H, m, Bn, 2′-H, 3′-H), 3.84-3.53 (4H, m, 5′-Ha, 1″-Ha, 1″-Hb), 1.50 (3H, d, J 1.1, CH3). δC (CDCl3) 164.3 (C-4), 151.3 (C-2), 137.6 (C-6) 136.4, 136.3, 128.8, 128.6, 128.4, 128.3, 127.9 (Bn), 111.1 (C-5), 91.1, 91.0, 88.1 (C-1′, C-3′, C-4′), 77.4 (C-2′), 74.8, 73.8, 71.4, 63.2 (Bn, C-5′, C-1″), 12.0 (CH3). FAB-MS m/z 491 [M+Na]+. Found. C, 63.4; H, 6.0; N, 5.5; C25H28N2O7,¼H2O requires C, 63.5; H, 6.1; N, 5.9%.
Reaction SMILES: C1COCC1.[NH:6]1[CH2:20][CH2:19][CH2:18][C@H:7]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].Cl.C1C=CC2N(O)N=NC=2C=1.[NH:32]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C@H:33]([C:35](O)=[O:36])[CH3:34]>CN(C=O)C>[NH:32]([C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[C@H:33]([C:35]([N:6]1[CH2:20][CH2:19][CH2:18][C@H:7]1[C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9])=[O:36])[CH3:34]
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 100.5 %

Procedure:
THF (200 ml), H-Pro-OBzl.HCl (48.3 g, 0.2 M) and HOBT (27.0 g, 0.2 M) were added to BOC-Ala-OH (37.8 g, 0.2 M); DMF (100 ml) was added, and WSCI (36.6 ml, 0.2 M) was added dropwise at 0° C. After stirring at 0° C. for one hour and at room temperature overnight, the solvent was distilled off in vacuo. The residue was dissolved in ethyl acetate (500 ml), washed three times with 5% sodium bicarbonate solution, three times with 1 N HCl and three times with water, in that order, dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was dissolved in a small amount of benzene and charged on a column of silica gel (250 g) packed with benzene. Elution was carried out with benzene (1 l.), benzene-ethyl acetate (10:1) (1 l.) and benzene-ethyl acetate (1:1) (1 l.), and the corresponding fractions were collected and checked by TLC and concentrated in vacuo to obtain the oily substance [24] (75.55 g, yield: 100%).
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2](OCC)=O.[F:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[C:17]([C:23]([NH2:25])=[O:24])[C:18]([NH2:22])=[N:19]2)=[CH:14][CH:13]=1>CCCCCC>[F:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[C:17]3[C:23](=[O:24])[NH:25][C:2]([C:1]([O:8][CH2:9][CH3:10])=[O:7])=[N:22][C:18]3=[N:19]2)=[CH:14][CH:13]=1
Reactant: NC(=O)c1cc2ccc(F)cc2nc1N
Reactant: CCOC(=O)C(=O)OCC
Solvent: CCCCCC
Product: CCOC(=O)c1nc2nc3cc(F)ccc3cc2c(=O)[nH]1
Temperature: 160 °C

Procedure:
Diethyl oxalate (47.5 g., 0.326 mole) and 7-fluoro-2-aminoquinoline-3-carboxamide (3.7 g., 0.015 mole) are mixed together and heated at 160° C. for 7 hours. The reaction mixture is cooled to room temperature, hexane (300 ml.) added, and the brown solid which precipitates filtered off, and washed with hexane (60 ml.). It is then slurried in hot chloroform (250 ml.) and the insoluble material removed by filtration. The hot filtrate is decolorized with charcoal, filtered and dried (Na2SO4). The light brown solid which precipitates upon cooling is filtered off and recrystallized from isopropyl alcohol. Yield = 1.04 g. (29.2%) of the title ethyl ester. M.P. 248°-251° C.
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[C:10](=[CH:11][C:12]([F:18])=[C:13](F)[C:14]=3[F:16])[C:9](=[O:19])[C:8]([C:20]([OH:22])=[O:21])=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:23]([NH:25][CH2:26][CH:27]1[CH2:31][CH2:30][NH:29][CH2:28]1)[CH3:24]>C(#N)C>[CH:1]1([N:6]2[C:15]3[C:10](=[CH:11][C:12]([F:18])=[C:13]([N:29]4[CH2:30][CH2:31][CH:27]([CH2:26][NH:25][CH2:23][CH3:24])[CH2:28]4)[C:14]=3[F:16])[C:9](=[O:19])[C:8]([C:20]([OH:22])=[O:21])=[CH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCNCC1CCNC1
Reactant: O=C(O)c1cn(C2CCCC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CC#N
Product: CCNCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CCCC4)c3c2F)C1
Yield: 74.2 %

Procedure:
To 0.86 g (2.7 mmol) of the 1-cyclopentyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 10 ml of acetonitrile was added 0.40 g (2.7 mmol) of 1,8-diazobicyclo[5.4.0]undec-7-ene and 0.36 g (2.7 mmol) of 3-[(ethylamino)methyl]pyrrolidine. The mixture was refluxed for seven hours, cooled, filtered, and the solids washed with ether to give 0.84 g of 1-cyclopentyl-7-[3-[(ethylamino)methyl]-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, mp 214°-217° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.CC1C(C(O)=O)=C(C)N(C2C=CC(C(F)(F)F)=CN=2)[N:24]=1>>[Si:15]([O:14][C@H:11]1[CH2:12][CH2:13][C@H:8]([C:5]2[N:6]=[CH:7][C:2]([NH2:24])=[CH:3][CH:4]=2)[CH2:9][CH2:10]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: Cc1nn(-c2ccc(C(F)(F)F)cn2)c(C)c1C(=O)O
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](c2ccc(Br)cn2)CC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](c2ccc(N)cn2)CC1

Procedure:
trans-5-Bromo-2-[4-(tert-butyldimethylsilyloxy)cyclohex-1-yl]pyridine (1.54 g) described in Reference Example 103 (3) was used in place of 1-(5-bromopyridin-2-yl)-c-4-(tert-butyldimethylsilanyloxy)-r-1-cyclohexanecarbonitrile in Reference Example 144 (2) and (3), and reacted and treated in a similar manner to give the titled compound (1.11 g) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>CN1CCCC1=O>[N:9]1([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: Nc1cc(Cl)ccn1
Reactant: C1COCCN1
Solvent: CN1CCCC1=O
Product: Nc1cc(N2CCOCC2)ccn1

Procedure:
A solution of 4-chloro-pyridin-2-ylamine (800 mg, 6.22 mmol) and morpholine (8.1 mL, 93.34 mmol) in N-methyl-2-pyrrolidone (NMP) (2 mL) was heated in a microwave (Emry's Optimizer) at 200° C. for 10 minutes. The resulting solution was directly purified by flash chromatography (SiO2, 95:5:0.5/DCM:MeOH:NH4OH) to give 4-morpholin-4-yl-pyridin-2-ylamine (Int-1). MS found for C9H13N3O as (M+H)+ 180.39. A solution of Int-1 (418 mg, 2.34 mmol) and 3-chloro-pentane-2,4-dione (0.3 mL, 2.45 mmol) in NMP (2.5 mL) was added and heated in a microwave (Emry's Optimizer) at 150° C. for 30 minutes. The resulting solution was directly purified by flash chromatography (SiO2, 96:4:/DCM:MeOH) to give 1-(2-methyl-7-morpholin-4-yl-imidazo[1,2-a]pyridin-3-yl)-ethanone (Int-2). MS found for C14H17N3O2 as (M+H)+ 260.39. A mixture of Int-2 (293 mg, 1.13 mmol) and DMF.DMA (2.3 mL) was heated at 150° C. for 10 hours. The mixture was concentrated and used further without purification. MS found for C17H22N4O2 as (M+H)+ 315.23. A solution of 1-(2-methyl-7-morpholin-4-yl-imidazo[1,2-a]pyridin-3-yl)-ethanone (263 mg, 0.84 mmol), 4-guanidinobenzoic acid hydrochloride (180 mg, 0.841) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.25 mL, 1.67 mmol) in DMF (3 mL) was heated in a microwave (Emry's Optimizer) at 150° C. for 30 minutes. The reaction mixture was then diluted with water and acetonitrile and purified by preparative HPLC affording 4-[4-(2-methyl-7-morpholin-4-yl-imidazo[1,2-a]pyridin-3-yl)-pyrimidin-2-ylamino]-benzoic acid after lyophilization. MS found for C23H22N6O3 as (M+H)+ 431.46. To the above carboxylic acid (10 mg, 0.023 mmol) in DMF (1 mL), was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (13 mg, 0.034 mmol), 1,2-phenylenediamine (5 mg, 0.046 mmol), DIPEA (0.01 mL, 0.068 mmol), and stirred at room temperature for 16 hours. The reaction mixture was diluted with water and acetonitrile and directly purified by preparative HPLC affording the title compound after lyophilization. MS found for C29H28N8O2 as (M+H)+ 521.28. 1H NMR (400 MHz, dmso-d6): δ 9.54 (d, J=8.0 Hz, 1H); 8.41 (d, J=5.6 Hz, 1H); 7.90 (d, J=8.4 Hz, 2H); 7.79 (d, J=8.4 Hz, 2H); 7.11 (d, J=7.6 Hz, 1H); 7.02-6.97 (m, 2H); 6.83 (d, J=7.6 Hz, 2H); 6.71-6.67 (m, 2H); 3.76 (m, 4H); 3.29 (m, 4H); 2.58 (s, 3H).
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][S:7]([CH2:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=[O:15])(=[O:9])=[O:8].C([Li])CCC.[CH3:31][C:32]([CH3:34])=[O:33].FC(F)(F)C(O)=O>C1COCC1>[OH:33][C:32]([CH3:34])([CH3:31])[CH:10]([C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=[O:15])[S:7](=[O:8])(=[O:9])[NH2:6]
Reactant: CC(C)=O
Reactant: COc1ccc(CNS(=O)(=O)Cc2cccc(C(=O)O)c2)c(OC)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O)C(c1cccc(C(=O)O)c1)S(N)(=O)=O
Reaction time: 0.17 h

Procedure:
To a solution of 3-[(2,4-dimethoxybenzylsulfamoyl)methyl]benzoic acid (4.1 g) in THF (50 ml) was added dropwise, at −78° C., butyllithium (1.6 M, 25 ml). The mixture was stirred for 10 min. Subsequently, acetone (4.5 ml) was added and the mixture was stirred at −78° C. for a further 30 min. The reaction mixture was then admixed with trifluoroacetic acid (4 ml) and concentrated. The residue was suspended in dichloromethane and trifluoroacetic acid (10 ml) admixed. After 2 h, water was added and the mixture was filtered. The aqueous phase was removed and freeze-dried. The residue was purified by means of preparative HPLC. This gave the product (1.1 g) with a molecular weight of 273.3 g/mol (C11H15NO5S).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[N:16]=[CH:15][C:14]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4]CC1.C(O)(C(F)(F)F)=O.[OH-].[Na+]>O>[O:4]=[C:5]1[CH2:10][CH2:9][CH:8]([C:11]2[N:16]=[CH:15][C:14]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1
Reactant: O=C(Nc1ccc(C2CCC3(CC2)OCCO3)nc1)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCC(c2ccc(NC(=O)OCc3ccccc3)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice water cooled solution of benzyl [6-(1,4-dioxaspiro[4.5]dec-8-yl)pyridin-3-yl]carbamate, prepared as above, (4.94 g, 13.41 mmol) was added TFA (20 mL) followed by water (1.1 mL). The reaction mixture was allowed to stir at ambient temperature for 2 hours. It was treated with 2M NaOH to adjust the pH to 10 and then the mixture was extracted into EtOAc (3×200 mL), the organic phase was separated, dried (MgSO4) and concentrated to leave a gum, 4.05 g (12.26 mmol, 93%) which was used directly in the next stage; 1H NMR (CDCl3) δ 1.97-2.10 (m, 2H), 2.24-2.29 (m, 2H), 2.49-2.53 (m, 4H), 3.13-3.21 (m, 1H), 5.22 (s, 2H), 6.82 (s, 1H), 7.18 (d, 1H), 7.36-7.40 (m, 5H), 7.96 (s, 1H), 8.41 (s, 1H); MS m/e MH+ 325.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:3]=1.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.CC(O)C>Cl.O>[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]3[S:9][CH:10]=[CH:11][CH:12]=3)[CH:3]=2)[CH2:16][CH2:15]1
Reactant: Clc1ccnc(-c2cccs2)c1
Reactant: CN1CCNCC1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: CN1CCN(c2ccnc(-c3cccs3)c2)CC1
Temperature: 180 °C

Procedure:
To a microwave tube was added 4-chloro-2-thiophen-2-yl-pyridine (98 mg, 0.5 mmol), 1-methylpiperazine (200 mg, 1 mmol), 2-propanol (1.0 mL) and concentrated HCl (1 drop). The resulting mixture was heated at 180° C. for 40 min using a Personal Chemistry Smith Synthesizer. The resulting mixture was poured into water and extracted with CH2Cl2. The organic layer was dried and concentrated to yield a reside. The residue was purified by preparative TLC (CH2Cl2/MeOH) to yield the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([NH2:11])[CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(N)ncc1[N+](=O)[O-]
Product: CC(=O)Nc1cc(C)c([N+](=O)[O-])cn1

Procedure:
4-Methyl-5-nitro-pyridin-2-ylamine (1.0 g) was treated with acetic anhydride according to General Procedure Y to give N-(4-Methyl-5-nitro-pyridin-2-yl)-acetamide (1.1 g). LCMS (m/z): 196. N-(4-Methyl-5-nitro-pyridin-2-yl)acetamide (0.5 g) was reduced under hydrogen atmosphere according to General Procedure Z to give N-(5-Amino-4-methyl-pyridin-2-yl)-acetamide (0.4 g), LCMS (m/z): 166. This was converted to 6-acetylamino-4-methyl-pyridine-3-sulfonyl chloride (0.35 g) according to General Procedure AA. LCMS (m/z): 249.