Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[C@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]([C:17]([OH:19])=O)[CH2:11]2)[CH:3]=1.CCN(C(C)C)C(C)C.[CH:29]1([NH2:35])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[C@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]([C:17]([NH:35][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:19])[CH2:11]2)[CH:3]=1
Reactant: CNc1nc(Cl)cc(N2C[C@@H](C(=O)O)CC[C@H]2C)n1
Reactant: NC1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nc(Cl)cc(N2C[C@@H](C(=O)NC3CCCCC3)CC[C@H]2C)n1
Temperature: 0 °C
Yield: 108.7 %

Procedure:
To a suspension of (3S,6R)-1-[6-chloro-2-(methylamino)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (3.05 g, 10.71 mmol) in CH2Cl2 (50 mL) at room temperature was added Hunig's base (2.70 mL, 15.43 mmol, 1.3 equiv) and cyclohexylamine (1.60 mL, 14.2 mmol, 1.2 equiv), and the resulting mixture was chilled in an ice bath. To this stirred solution was added HATU (4.96 g, 13.1 mmol, 1.1 equiv) in one portion, and the resulting suspension was stirred in the ice bath for 30 minutes. LCMS showed conversion complete. The mixture was diluted with CH2Cl2 (50 mL) and filtered through celite. The filtrate was washed water (2×25 mL) and then brine. The organic was dried over Na2SO4, filtered, and concentrated in vacuo. Silica gel column chromatography using gradient elution of 1% EtOAc in CHCl3 to 50% EtOAc in CHCl3 afforded the title compound (4.26 g) as a foam. LC-MS (ES) m/z=366 [M+H]+.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[C:12]([CH:26]=[O:27])=[C:11]([I:28])[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:29]([C:32]1[CH:37]=[CH:36][C:35]([Mg]Br)=[CH:34][CH:33]=1)([CH3:31])[CH3:30]>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)[C:12]([CH:26]([C:35]3[CH:36]=[CH:37][C:32]([CH:29]([CH3:31])[CH3:30])=[CH:33][CH:34]=3)[OH:27])=[C:11]([I:28])[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC1(C)Cc2nc(C3CCCC3)c(C=O)c(I)c2[C@@H](O[Si](C)(C)C(C)(C)C)C1
Reactant: CC(C)c1ccc([Mg]Br)cc1
Product: CC(C)c1ccc(C(O)c2c(C3CCCC3)nc3c(c2I)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C3)cc1

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-2-cyclopentyl-4-iodo-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 4-iso-propylphenylmagnesium bromide. The product is obtained as a diastereomic mixture, which is used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].S(=O)(=O)(O)[OH:14]>>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]([NH2:5])=[O:14]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N
Reactant: O=S(=O)(O)O
Product: NC(=O)c1cc([N+](=O)[O-])ccc1N
Temperature: 130 °C
Reaction time: 0.67 h

Procedure:
A mixture of 2-amino-5-nitrobenzonitrile (25.4 g) and sulfuric acid (70 mL) was stirred at 130° C. for 40 min. The reaction mixture was added slowly to ice water, and the precipitate was collected by filtration, washed with water, ethanol and diethyl ether to give 2-amino-5-nitrobenzamide (24.6 g).
Reaction SMILES: [C:1]([O:5][OH:6])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[C:9]1([CH3:24])[CH:14]=[CH:13][C:12]([O:15][C:16]([CH2:18][CH2:19][CH2:20][C:21](Cl)=[O:22])=[O:17])=[CH:11][CH:10]=1.O=O>C(OCC)C>[C:21]([O:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:22])[CH2:20][CH2:19][CH2:18][C:16]([O:15][C:12]1[CH:11]=[CH:10][C:9]([CH3:24])=[CH:14][CH:13]=1)=[O:17]
Reactant: Cc1ccc(OC(=O)CCCC(=O)Cl)cc1
Reactant: CC(C)(C)OO
Agent: O=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: Cc1ccc(OC(=O)CCCC(=O)OOC(C)(C)C)cc1
Reaction time: 3.5 h
Yield: 76.7 %

Procedure:
To a vigorously stirred solution of 4.9 g. (0.045 mole) of 82.0% t-butyl hydroperoxide and 18.0 g. (0.045 mole) of aqueous 10% sodium hydroxide at 10°-14° C was slowly added 8.2 g. (0.034 mole) of 4-(p-tolyloxycarbonyl)butyryl chloride (prepared from p-tolyl 4-carboxybutyrate and thionyl chloride) in 25 ml. of diethyl ether. The reaction mixture was then stirred for 3.5 hours at 8°-10° C. After a work-up simular to that in Example I 8.2 g. (theory, 10.0 g.) of white solid, m.p. 50°-55° C, was obtained. The assay according to "active oxygen" content was 93.6% and the corrected yield was 76.7%.
Reaction SMILES: [F:1][C:2]([F:52])([F:51])[C:3]1[CH:4]=[C:5]([C:13]([CH3:50])([CH3:49])[C:14]([N:16]([CH3:48])[C:17]2[C:18]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:41]=3[CH3:47])=[CH:19][C:20]([C@@H:23]3[N:27](C(OC(C)(C)C)=O)[C@:26]([CH3:39])([C:35]([O:37][CH3:38])=[O:36])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(O)(C(F)(F)F)=O>ClCCl>[F:52][C:2]([F:1])([F:51])[C:3]1[CH:4]=[C:5]([C:13]([CH3:49])([CH3:50])[C:14]([N:16]([CH3:48])[C:17]2[C:18]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:41]=3[CH3:47])=[CH:19][C:20]([C@@H:23]3[NH:27][C@:26]([CH3:39])([C:35]([O:37][CH3:38])=[O:36])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: COC(=O)[C@]1(C)CC[C@H](c2cc(-c3ccc(F)cc3C)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)N1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@]1(C)CC[C@H](c2cc(-c3ccc(F)cc3C)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
To a solution of 1-(1,1-dimethylethyl) 2-methyl (2S,5R)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-1,2-pyrrolidinedicarboxylate (Intermediate 8, 50 mg, 0.068 mmol) in dry Dichloromethane (3 ml) was added TFA (1 ml, 12.98 mmol) and the reaction mixture was stirred for 2 hours at r.t. The solvent and the excess of TFA were evaporated and the residue was purified by SPE-SCX cartridge affording the title compound (42 mg, 0.066 mmol, 97% yield) as a white solid. HPLC: Rt 5.79 min. MS: m/z 640 [M+H]+ and 662 [M+Na]+.
Reaction SMILES: Cl[CH:2]=[CH:3][C:4](=[O:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[I-:11].[Na+]>CC(C)=O>[I:11][CH:2]=[CH:3][C:4](=[O:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCC(=O)C=CCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCCC(=O)C=CI
Reaction time: 18 h
Yield: 64.5 %

Procedure:
A mixture of 25 g (0.16 moles) of 1-chloro-1-octen-3-one (Example 187) and 35 g (0.23 moles) of sodium iodide in 200 ml of reagent acetone is stirred at the reflux temprature for 18 hours. The cooled mixture is filtered and the mother liquor taken to dryness. The residual oil is dissolved in benzene and the solution is washed with 5% sodium thiosulfate solution, saturated sodium chloride solution, dried and taken to dryness. The residual oil is crystallized from hexane to give 26 g of a white solid, mp 35°-37° C.; λ max 1670, 950 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[N:12]2[CH:20]=[N:21][N:22]=[C:11]2[CH2:10][O:9]1.[Br:23]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:23][C:20]1[N:12]2[C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[O:9][CH2:10][C:11]2=[N:22][N:21]=1
Reactant: Clc1ccc2c(c1)C(c1ccccc1Cl)OCc1nncn1-2
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc2c(c1)C(c1ccccc1Cl)OCc1nnc(Br)n1-2
Yield: 36.4 %

Procedure:
A suspension of Compound 9 prepared in Example 4-(1) (1.2 g), N-bromosuccinimide (0.675 g), and α,α'-azobis-isobutyronitrile (10 mg) in carbon tetrachloride (70 ml) is refluxed under heating for 1 hour. The insoluble materials are removed by filtration and the solvent is evaporated. The residue is treated on column chromatography (silica gel/ethyl acetate) to give the title compound (0.54 g), which is recrystallized from ethyl acetate. Yield 36.4%
Reaction SMILES: C[O-].[Na+].[C:4]1([C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][O:6]1)=[O:5].[CH:14]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20])=O.C(OCC)(=O)CC>CO>[O:5]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:6])[CH:14]1[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20]
Reactant: N#Cc1cccc(C=O)c1
Reactant: O=C1OCc2ccccc21
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(=O)CC
Solvent: CO
Product: N#Cc1cccc(C2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 67.3 %

Procedure:
A mixture of 27% sodium methoxide solution in methanol (400 g, 2 mol) and methanol (150 ml) was added dropwise between ambient temperature and 30° C. over 15 minutes to a stirred mixture of phthalide (67 g, 0.5 mol), 3-formylbenzonitrile (65.5 g, 0.5 mol) and ethyl propionate (250 ml), the mixture was stirred at ambient temperature for 40 minutes and at reflux temperature for 1 hour, then it was allowed to cool to ambient temperature. The resulting red solid was collected by filtration, washed with ethyl acetate (2×50 ml) and dissolved in water (1800 ml). The solution was acidified by the addition of acetic acid (60 ml) and the resulting red solid was collected by filtration, washed with water (2×200 ml) and dried in vacuo to give 3-(1,3-dioxoindan-2-yl)benzonitrile (83.2 g) as a dark red solid, m.pt. 179-182° C., m/z (M+H)+. 248, which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:9])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[F:10][C:11]([F:15])([F:14])[CH2:12][OH:13]>>[Br:1][C:2]1[C:3]([F:9])=[N:4][C:5]([CH2:8][O:13][CH2:12][C:11]([F:15])([F:14])[F:10])=[CH:6][CH:7]=1
Reactant: OCC(F)(F)F
Reactant: Cc1ccc(Br)c(F)n1
Product: Fc1nc(COCC(F)(F)F)ccc1Br

Procedure:
The title compound was prepared in an analogous manner to that described in Example 198 (Step 1) using 3-bromo-2-fluoro-6-methylpyridine (1.44 g, 7.58 mmol) (Waterstone Technology) and 2,2,2-trifluoroethanol. 1H NMR (400 MHz, d6-DMSO) δ 8.34 (1H, t, J=8.5 Hz); 7.34 (1H, d, J=7.9 Hz); 4.69 (2 H, s); 4.22 (2 H, q, J=9.5 Hz). m/z (ESI, +ve ion) 288/290 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:13]([O-:15])=[O:14])[NH:4][CH:3]=1.CC1C(=O)C2C(=CC([N+]([O-])=O)=CC=2)NC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>C1(C)C=CC=CC=1>[CH2:42]([O:41][C:39](=[O:40])[CH2:38][N:4]1[C:5]2[C:10](=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=[CH:7][CH:6]=2)[C:11](=[O:12])[C:2]([CH3:1])=[CH:3]1)[CH3:43]
Reactant: Cc1c[nH]c2cccc([N+](=O)[O-])c2c1=O
Reactant: CCOC(=O)CBr
Agent: Cc1c[nH]c2cc([N+](=O)[O-])ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: CCOC(=O)Cn1cc(C)c(=O)c2c([N+](=O)[O-])cccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A suspension of 3-methyl-5-nitroquinolin-4(1H)-one and 3-methyl-7-nitroquinolin-4(1H)-one (Eur. J. Med. Chem. 1997, 32, 547, 500 mg, 2.45 mmol,) and cesium carbonate (800 mg (2.45 mmol) in toluene (50 mL) was treated with ethyl bromoacetate (0.3 mL, 2.45 mmol) and stirred at RT for 3 days. The solid (Cesium salt of starting materials) was filtered and washed with dichloromethane. The filtrate was concentrated to give 400 mg of the crude material which was purified using flash column chromatography (DCM:MeOH, 99:1) to isolate the desired region-isomer: 100 mg 1H NMR (CDCl3, 300 MHz): δ 1.3 (m, 3H, J=7.2 Hz), 2.08 (s, 3H), 4.25 (q, 2H, J=7.2 Hz), 4.8 (s, 2H), 7.3 (m, 2H), 7.4 (s, 1H), 7.65 (t, J=8 Hz, 1H). The other isomer was also recovered: 70 mg.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[CH2:17]([OH:25])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Cl:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[O:25][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Cl
Reactant: OCCc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: Nc1nc(OCCc2ccccc2)c(Cl)c(-c2ccco2)n1

Procedure:
From 5-chloro-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, phenethyl alcohol and DBU in dioxane. ES-MS m/e (%): 318 (M{37Cl}+H+, 33), 316 (M{35Cl}+H+, 100).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH2:11].Cl.[Cl:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18]Cl>C(OCCOCCO)C.CO>[ClH:13].[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: Nc1ccc2ccccc2c1
Reactant: ClCCNCCCl
Agent: Cl
Solvent: CCOCCOCCO
Solvent: CO
Product: c1ccc2cc(N3CCNCC3)ccc2c1
Yield: 57.4 %

Procedure:
A solution of naphthalen-2-amine (2 g, 14 mmol) and bis(2-chloroethyl)amine hydrochloride (2.51 g, 14.1 mmol, 1 eq) in diethylene glycol monoethyl ether (3 mL) was stirred overnight at 149° C. (oil bath). The resulting solution was diluted with methanol (2 ml). The crude product was re-crystallized from diethyl ether to afford 1-(naphthalen-2-yl)piperazine hydrochloride as a yellow solid (2 g, 58%). (ES, m/z): [M+H]+ 213.0
Reaction SMILES: [OH:1][CH:2]([CH:6]([CH3:8])[CH3:7])[C:3](O)=[O:4].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:42][N:43]1[C:52]2[C:47](=[CH:48][N:49]=[C:50]([CH3:53])[CH:51]=2)[CH:46]=[C:45]([C:54]2[CH:55]=[C:56]([NH:61]/[C:62](/[NH2:65])=[N:63]/O)[CH:57]=[CH:58][C:59]=2[CH3:60])[C:44]1=[O:66]>CN(C=O)C>[OH:1][CH:2]([C:3]1[O:4][N:63]=[C:62]([NH:61][C:56]2[CH:57]=[CH:58][C:59]([CH3:60])=[C:54]([C:45]3[C:44](=[O:66])[N:43]([CH3:42])[C:52]4[C:47]([CH:46]=3)=[CH:48][N:49]=[C:50]([CH3:53])[CH:51]=4)[CH:55]=2)[N:65]=1)[CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)C(O)C(=O)O
Reactant: Cc1cc2c(cn1)cc(-c1cc(N/C(N)=N/O)ccc1C)c(=O)n2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc2c(cn1)cc(-c1cc(Nc3noc(C(O)C(C)C)n3)ccc1C)c(=O)n2C
Temperature: 100 °C

Procedure:
To a solution of 2-hydroxy-3-methylbutanoic acid (70 mg, 0.6 mmol) in DMF (6 mL) were added DIPEA (0.125 mL, 0.7 mmol) and HATU (0.23 g, 0.6 mmol). After stirring at rt for 15 min 17 (0.2 g, 0.6 mmol) was added as a solution in DMF (2 mL). The reaction was stirred at rt until complete consumption of 17 was determined by LC/MS and then was heated at 100° C. for 1 h. The reaction was cooled to rt, purified by preparative LCMS to afford crude material, which was further purified by flash column chromatography on silica with DCM/2% MeOH as eluant to give 3-(5-(5-(1-hydroxy-2-methylpropyl)-1,2,4-oxadiazol-3-ylamino)-2-methylphenyl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (A64) as an off white solid. 1H NMR (400 MHz, CD4OD) δ 8.76 (s, 1H), 7.93 (s, 1H), 7.47 (s, 1H), 7.39 (dd, J=8, 2 Hz, 1H), 7.36 (d, J=2 Hz, 1H), 7.22 (d, J=8 Hz, 1H), 4.51 (d, J=6 Hz, 1H), 3.76 (s, 3H), 2.69 (s, 3H), 2.16 (m, 1H), 2.14 (s, 3H), 1.02 (d, J=6 Hz, 3H), 0.94 (d, J=6 Hz, 3H). MS m/z 420.4 (M+1).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:17])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:16])(=[O:15])[NH:11][CH2:12][CH2:13]O)=[CH:6][CH:5]=1.C(C1C=CC(S(Cl)(=O)=O)=CC=1)#N.[C:30]([O:34][C:35](=[O:40])[NH:36]CCN)([CH3:33])([CH3:32])[CH3:31]>>[C:30]([O:34][C:35](=[O:40])[NH:36][CH2:13][CH2:12][NH:11][S:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3](=[NH:17])[NH:2][OH:1])=[CH:5][CH:6]=1)(=[O:16])=[O:15])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: N=C(NO)c1ccc(S(=O)(=O)NCCO)cc1
Agent: N#Cc1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1ccc(C(=N)NO)cc1

Procedure:
The title compound is prepared in analogy to N-hydroxy-4-(2-hydroxy-ethylsulfamoyl)-benzamidine starting from 4-cyano-benzenesulfonyl chloride and (2-amino-ethyl)-carbamic acid tert-butyl ester; LC-MS: tR=0.40 min; [M+1]+=359.09; 1H NMR (D6-DMSO): δ1.35 (s, 9H), 2.73-2.81 (m, 2H), 2.92-3.00 (m, 2H), 5.96 (s, 2H), 6.78 (t br, J=5.5 Hz, 1H), 7.69 (t br, J=6.0 Hz, 1H), 7.75-7.79 (m, 2H), 7.86-7.90 (m, 2H), 9.92 (s, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[CH2:8]([NH2:12])[CH2:9][C:10]#[CH:11].[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][S:22](Cl)(=[O:24])=[O:23])[CH:17]=[CH:18][C:19]=1[Cl:20]>O.C1COCC1>[CH2:8]([NH:12][S:22]([CH2:21][C:16]1[CH:17]=[CH:18][C:19]([Cl:20])=[C:14]([Cl:13])[CH:15]=1)(=[O:24])=[O:23])[CH2:9][C:10]#[CH:11]
Reactant: O=S(=O)(Cl)Cc1ccc(Cl)c(Cl)c1
Reactant: C#CCCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C#CCCNS(=O)(=O)Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of potassium carbonate (40.2 g, 296 mmol) in water (50 mL) and THF (50 mL) at 15-20° C. was added but-3-ynylamine hydrogen chloride (10.4 g, 98.5 mmol). Then, (3,4-dichlorophenyl)methanesulfonyl chloride (5, 30.7 g, 118 mmol) was added in portions during of a period of 30 ml. The mixture was stirred for 4 h at rt. THF is evaporated. The mixture is extracted with EtOAc (2×200 mL). The combined organic extracts were dried over Na4SO4. The solvent is evaporated to give a white solid (20.5 g, 71%%). 1H NMR (CDCl3): δ7.53 (d, 1H, J=2.0 Hz), 7.47 (d, 1H, J=4.2 Hz), 7.27 (m, 1H), 4.52 (t, 1H, J=6.2 Hz), 4.22 (s, 2H), 3.17 (dd, 2H, J=6.2 Hz, 12.5 Hz), 2.41 (m, 2H), 2.07 (m, 1H)
Reaction SMILES: [CH2:1]([O:13][C:14]1[C:15]2[S:42][CH:41]=[CH:40][C:16]=2[C:17]2[CH:18]=[C:19]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:20]3[S:26][CH:25]=[CH:24][C:21]=3[C:22]=2[CH:23]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C1COCC1.[Li+].CCC[CH2-].[CH3:53][Sn:54](Cl)([CH3:56])[CH3:55]>CCCCCC>[CH2:28]([O:27][C:19]1[C:20]2[S:26][C:25]([Sn:54]([CH3:56])([CH3:55])[CH3:53])=[CH:24][C:21]=2[C:22]2[CH:23]=[C:14]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:15]3[S:42][C:41]([Sn:54]([CH3:56])([CH3:55])[CH3:53])=[CH:40][C:16]=3[C:17]=2[CH:18]=1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: C[Sn](C)(C)Cl
Reactant: CCCCCCCCCCCCOc1cc2c3ccsc3c(OCCCCCCCCCCCC)cc2c2ccsc12
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCCCCCCOc1cc2c3cc([Sn](C)(C)C)sc3c(OCCCCCCCCCCCC)cc2c2cc([Sn](C)(C)C)sc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
5,10-Bis-dodecyloxy-1,6-dithia-dicyclopenta[a,f]naphthalene (BB-3, 0.366 g, 0.6 mmol) was added into a 50 mL flask. The system was vacuumed and backfilled with argon 3 times before 17 mL of anhydrous THF was injected. N-Butyllithium (0.6 mL, 2.5 M in hexane, 1.5 mmol) was added after the mixture was cooled to −78° C. A white precipitate was observed after the mixture was stirred at −78° C. for 30 minutes. Stirring was continued at room temperature for one more hour before the mixture was cooled down to −78° C. again. Trimethyltin chloride (0.5 g, 2.5 mmol) was added in portions and stirring was continued overnight at room temperature. Hexane (100 mL) was added and the organic layer was washed with 150 mL of water. The aqueous layer was extracted with 50 mL of hexane twice. The combined organic layer was dried over anhydrous Na2SO4. Removal of the solvent under vacuum yielded a white solid. The colorless crystalline product (0.48 g, ˜85.7% yield) was obtained after recrystallization from a hexane/iso-propanol mixture. 1H NMR (CDCl3, 500 MHz): δ 7.80 (s, 2H), δ 7.51 (s, 2H), δ 4.37 (t, 4H, J=6.5 Hz), δ 2.00 (m, 4H), δ 1.63 (m, 4H), δ 1.46 (m, 4H), δ 1.30 (m, 28H), δ 0.90 (t, 6H, J=7.0 Hz), δ 0.51 (m, 18H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]([CH3:18])=[CH:6]2.[C:19]([O-:22])(=[O:21])[CH3:20].[Na+].O>CN(C)C=O>[C:19]([O:22][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]([CH3:18])=[CH:6]2)(=[O:21])[CH3:20]
Reactant: CCOC(=O)c1nc2ccc(CBr)cc2cc1C
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1nc2ccc(COC(C)=O)cc2cc1C
Reaction time: 24 h
Yield: 69.3 %

Procedure:
To a solution of ethyl 6-bromomethyl-3-methylquinoline-2-carboxylate (700 mg) in dimethylformamide (7 ml) was added sodium acetate (373 mg) at ambient temperature, and the mixture was stirred for 24 hours at the same temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, sodium bicarbonate solution and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative thin-layer chromatography (n-hexane:ethyl acetate=1:2, V/V) to give ethyl 6-acetoxymethyl-3-methylquinoline-2-carboxylate (452 mg) as an oil.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([N:10]2[C:22](=[O:23])[C:14]3=[CH:15][N:16]4[C:21]([CH2:20][CH2:19][CH2:18][CH2:17]4)=[C:13]3[CH:12]=[N:11]2)[N:5]=[CH:4][CH:3]=1.[CH3:24][N:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH:53]4[CH2:56][O:55][CH2:54]4)[CH2:49][CH2:48]3)=[CH:43][N:42]=2)[C:26]1=[O:57].C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>O>[CH3:24][N:25]1[C:26](=[O:57])[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH:53]4[CH2:54][O:55][CH2:56]4)[CH2:49][CH2:48]3)=[CH:43][N:42]=2)=[CH:28][C:29]([C:2]2[C:7]([CH:8]=[O:9])=[C:6]([N:10]3[C:22](=[O:23])[C:14]4=[CH:15][N:16]5[C:21]([CH2:20][CH2:19][CH2:18][CH2:17]5)=[C:13]4[CH:12]=[N:11]3)[N:5]=[CH:4][CH:3]=2)=[CH:30]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Reactant: O=Cc1c(Cl)ccnc1-n1ncc2c3n(cc2c1=O)CCCC3
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccnc(-n3ncc4c5n(cc4c3=O)CCCC5)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 50 °C
Yield: 40.8 %

Procedure:
A 50-mL round bottomed flask equipped with a reflux condenser was charged with 4-chloro-2-(4-oxo-7,8,9,10-tetrahydropyridazino[4,5-a]indolizin-3(4H)-yl)nicotinaldehyde 192c (118 mg, 0.36 mmol), 1-methyl-3-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl-amino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 101l (171 mg, 0.36 mmol), Na2CO3 (78 mg, 0.72 mmol), Pd (dppf)Cl2 (30 mg, 0.036 mmol), DMF (10 mL), and water (1 mL). After bubbling nitrogen through the mixture for 30 minutes, it was heated at 50° C. for 10 hours under N2 protection. It was then cooled to room temperature and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 20:1 dichloromethane/methanol to afford 198a (93 mg, 40%) as a brown solid. MS-ESI: [M+H]+ 634.3.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5].Cl.[CH3:19][O:20][C:21]1[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=1[O:23][CH2:24][CH2:25][NH2:26].C(=O)([O-])O.[Na+].CS(C)=O>O>[CH3:19][O:20][C:21]1[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=1[O:23][CH2:24][CH2:25][NH:26][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5]
Reactant: COc1ccccc1OCCN
Reactant: Cc1cc(Nc2cc(C)c(C#N)c(Cl)n2)n[nH]1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccccc1OCCNc1nc(Nc2cc(C)[nH]n2)cc(C)c1C#N
Temperature: 100 °C
Reaction time: 27 h
Yield: 14.4 %

Procedure:
Compound A (400 mg, 1.63 mmol), 2-(2-methoxyphenoxy)ethylamine hydrochloride (1.10 g) and sodium hydrogencarbonate (1.37 g) were added to DMSO (12 ml), and the mixture was stirred at 100° C. for 27 hr. After stirring, the reaction mixture was added to cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and concentrated, and the residue was washed by suspending in ethyl acetate to give the object compound of 2-(2-(2-methoxyphenoxy)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-4-methylnicotinonitrile (89 mg).