Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([N:14]([CH2:18][C:19]1[C:24](Cl)=[N:23][C:22]([N:26]2[CH2:30][CH2:29][CH2:28][CH:27]2[CH3:31])=[CH:21][N:20]=1)[CH2:15][CH2:16][OH:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>CN(C=O)C>[CH2:7]([N:14]1[CH2:18][C:19]2[N:20]=[CH:21][C:22]([N:26]3[CH2:30][CH2:29][CH2:28][CH:27]3[CH3:31])=[N:23][C:24]=2[O:17][CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC1CCCN1c1cnc(CN(CCO)Cc2ccccc2)c(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CCCN1c1cnc2c(n1)OCCN(Cc1ccccc1)C2
Reaction time: 1.5 h
Yield: 84.3 %

Procedure:
To a solution of potassium tert-butoxide (0.68 g) in DMF (5 mL) was added dropwise a solution of 2-(benzyl{[3-chloro-5-(2-methylpyrrolidin-1-yl)pyrazin-2-yl]methyl}amino)ethanol (1.82 g) in DMF (5 mL) at 0° C., and the mixture was stirred for 1.5 hr. Water (10 ml) was added, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 10→33% ethyl acetate/hexane) to give the title compound (1.38 g, 85%) as a pale-yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[C:31]([N+:32]([O-:34])=[O:33])=[CH:30][CH:29]=[CH:28][N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[C:31]([N+:32]([O-:34])=[O:33])=[CH:30][CH:29]=[CH:28][N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4ncccc4[N+](=O)[O-])cc3CC[C@@H]12
Yield: 65.2 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-3-nitropyridine (73 mg, 0.46 mmol) and 1.5 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (90% ethyl acetate/hexanes eluent) to give 95 mg (65%) of the title compound as an amorphous foam. mp 80°-84°. FDMS: m/e=383. α[D]589 =+73.78 (c=0.49, chloroform).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([CH2:14][N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[C:21]1([CH:27]([N:34]=[C:35]=[O:36])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[CH:27]([NH:34][C:35]([N:18]1[CH2:19][CH2:20][N:15]([CH2:14][C:5]2([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH2:16][CH2:17]1)=[O:36])([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CN1CCC(CN2CCNCC2)(c2ccccc2)CC1
Reactant: O=C=NC(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CN1CCC(CN2CCN(C(=O)NC(c3ccccc3)c3ccccc3)CC2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
To a solution of 1-((methyl-4-phenylpiperidin-4-yl)methyl)piperazine (0.135 g, 0.5 mmol) dissolved in methylene chloride (5 ml) was added diphenylmethyl isocyanate (0.115 g, 0.55 mmol) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated. The residue was applied to flash column chromatography using methylene chloride and methanol (100:10) as eluents to give 0.13 g of desired product.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH:18][CH2:19][CH2:20][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Reactant: OCCN1CCCC1
Product: N=C(OCCN1CCCC1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and N-(2-hydroxyethyl)pyrrolidine, there is obtained 2-pyrrolidino-ethyl 5,7-dihydro-6H-dibenz[c,e]-azepine-6-carboximidate as a resin, mass spectrum m/e: M+ 335 (1), 238 (6), 194 (12), 179 (22), 165 (22), 97 (100), 84 (39), 69 (56);
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].S(Cl)(Cl)=O.[CH3:18]O>>[NH2:1][CH:2]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([Br:13])=[CH:11][CH:12]=1)[C:3]([O:5][CH3:18])=[O:4]
Reactant: NC(Cc1ccc(Br)cc1)C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C(N)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-amino-3-(4-bromophenyl)propanoic acid (2.0 g, 8.2 mmol, Chem-Impex, Cat. No. 06163) in methanol (10 mL) was added thionyl chloride (1.2 mL, 16 mmol) dropwise. The mixture was stirred at r.t. overnight and then concentrated under reduced pressure. The residue was washed with ether and dried under vacuum to afford the desired compound which was directly used in the next step reaction without further purification. LCMS (M+H)+: m/z=258.2.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[C:20]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])=[O:11])[S:7][CH:8]=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29].N1C=CC=CC=1>C(Cl)Cl>[CH:22]1([C:20]([C:14]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=2[NH:12][C:10](=[O:11])[NH:9][C:6]2[S:7][CH:8]=[C:4]([CH2:3][CH2:2][NH:1][S:28]([CH3:27])(=[O:30])=[O:29])[N:5]=2)=[O:21])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(NC(=O)Nc2nc(CCN)cs2)c(C(=O)C2CCCC2)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)Nc2nc(CCNS(C)(=O)=O)cs2)c(C(=O)C2CCCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To 1-[4-(amino-ethyl)-thiazol-2-yl]-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (0.05 g, 0.13 mmol) in 10 mL DCM at 0° C. was added methanesulfonyl chloride (0.02 g, 0.13 mmol) followed by pyridine (0.02 g, 0.21 mmol). The reaction was stirred at ambient temperature overnight, concentrated and purified by flash chromatography on silica gel with 20-50% EtOAc/hexane to obtain the product as white solid in 75% yield.
Reaction SMILES: [C:1]1([NH:11][C:12](=[S:15])[NH:13][NH2:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:16]OC(OC)N(C)C>O1CCOCC1>[C:1]1([N:11]2[CH:16]=[N:14][NH:13][C:12]2=[S:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NNC(=S)Nc1cccc2ccccc12
Reactant: COC(OC)N(C)C
Solvent: C1COCCO1
Product: S=c1[nH]ncn1-c1cccc2ccccc12
Yield: 100.2 %

Procedure:
A solution of 4-(1-naphthalenyl)-3-thiosemicarbazide (4.01 g, 18.4 mmol) and N,N,-dimethylformamide dimethyl acetal (2.50 mL, 18.8 mmol) in 1,4-dioxane (40 mL) was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure. The residue was taken in hexane and Et2O and the solution was stirred until a suspension was obtained. The suspension was filtered and the solid was triturated with hexane:Et2O (4:1), then was dried under reduced pressure to give the title compound (4.19 g, 90% yield) as a beige solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6].[OH-].[Li+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>O>[CH2:24]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:20])(=[O:21])[NH2:19])[C:10]=1[S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1Sc1ccccc1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: NS(=O)(=O)c1cc(C(=O)O)cc(NCc2ccccc2)c1Sc1ccccc1

Procedure:
A suspension of 3-amino-4-phenylthio-5-sulphamyl-benzoic acid (4.05 g) in water (100 ml) was adjusted to pH 7.5 by addition of 1N lithium hydroxide. Benzyl bromide (2.2 g) was added and, under stirring, the pH was kept at 7.5 by automatic titration with lithium hydroxide. After the base comsumption had become negligible, the pH was adjusted to 2.5 by addition of dilute hydrochloric acid. The precipitated 3-benzylamino-4-phenylthio-5-sulphamyl-benzoic acid was collected and recrystallized from ethanol, whereafter the compound was obtained with a melting point of 224°-225°C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[S:8])=[CH:5][CH:4]=1.Cl[CH:15]([C:20]([CH3:22])=O)[C:16]([O:18][CH3:19])=[O:17].[OH-].[Na+]>O1CCCC1>[CH3:22][C:20]1[N:9]=[C:7]([C:6]2[CH:10]=[CH:11][C:3]([C:2]([F:1])([F:12])[F:13])=[CH:4][CH:5]=2)[S:8][C:15]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C(Cl)C(C)=O
Reactant: NC(=S)c1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Temperature: 77.5 °C
Yield: 95.6 %

Procedure:
4-(Trifluoromethyl)thiobenzamide (20.5 g, 0.1 mol) was dissolved in tetrahydrofuran (300 ml) at room temperature, and then methyl 2-chloroacetoacetate (12.2 ml, 0.1 mol, 1.0 eq.) was added slowly for about 20 minutes therein while stirring. After completion of addition, the mixture was stirred again at room temperature for 30 minutes, and then the mixture was heated and refluxed at 75 to 80° C. for 12 hours. After completion of the reaction, the reaction mixture was cooled to room temperature. Subsequently, 50% aqueous solution of sodium hydroxide (150 ml) was added and stirred for 20 minutes. The resultant organic layer was separated by extraction with brine and ethyl acetate, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to thereby yield 28.8 g of the title compound (yield: 95.6%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH3:13])=[N:10][C:9]2[C:4](=[CH:5][C:6]([CH3:15])=[C:7]([CH3:14])[CH:8]=2)[N:3]=1.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18].N1C=CC=CC=1>ClCCl>[CH3:13][O:12][C:11]1[C:2]([NH:1][C:17](=[O:18])[O:19][CH2:20][CH3:21])=[N:3][C:4]2[C:9](=[CH:8][C:7]([CH3:14])=[C:6]([CH3:15])[CH:5]=2)[N:10]=1
Reactant: COc1nc2cc(C)c(C)cc2nc1N
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1nc2cc(C)c(C)cc2nc1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.7 %

Procedure:
2-Amino-3-methoxy-6,7-dimethylquinoxaline (2.34 g, 11.5 mmol) and ethyl chloroformate (2.50 g, 23.0 mmol) were dissolved in dichloromethane (50 ml) at room temperature and thereto pyridine (1.82 g, 23.0 mmol) was added. The mixture was stirred at room temperature for 12 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (3:1) mixture and concentration gave 2.65 g of the titled compound (yield, 84%).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[Cl:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43][NH2:44])=[CH:41][CH:40]=1>>[Cl:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43][NH:44][C:3]([C:5]2[N:14]3[C:8]([CH2:9][N:10]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=4)=[O:20])[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[CH2:13]3)=[CH:7][CH:6]=2)=[O:4])=[CH:41][CH:40]=1
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Reactant: NCc1ccc(Cl)cc1
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)NCc4ccc(Cl)cc4)n3Cc3ccccc32)ccc1-c1ccccc1C
Yield: 86 %

Procedure:
The title compound was prepared in 86% yield in the manner of Example 36 from 2,2,2-trichloro-1-{10-[(2-methoxy-2′-methyl-1,1′-biphenyl4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 35 and 4-chlorobenzylamine, m.p. 218-219° C. MS (+)ESI, m/z]: 576 [M+H]+ Anal. Calcd for C35H30CIN3O3: C, 72.97; H, 5.25; N, 7.29. Found: C, 72.67; H, 5.34; N, 7.11.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])=[C:13]([CH:17]=1)[C:14](O)=[O:15].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])=[C:13]([CH:17]=1)[C:14]([NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:15]
Reactant: Nc1cccnc1
Reactant: COc1ccccc1COc1ccc(Br)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1ccccc1COc1ccc(Br)cc1C(=O)Nc1cccnc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Solid pyridin-3-amine (156 mg, 1.66 mmol) was added in one charge to a stirred solution of 5-bromo-2-({[2-(methyloxy)phenyl]methyl}oxy)benzoic acid (may be prepared as described in Description 32; 280 mg, 0.83 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (191 mg, 1.00 mmol) and 1-Hydroxybenzotriazole (135 mg, 1.00 mmol) in DMF (20 ml) under nitrogen at 20° C. The reaction mixture was stirred at 20° C. for 16 h. The organic phase was washed with water (25 ml), extracted with ethyl acetate (3×30 ml), dried over sodium sulphate, evaporated in vacuo and purified by column chromatography (petroleum ether:ethyl acetate=2:1) to yield the title compound as a white solid. 270 mg.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[C:23]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([OH:30])[CH2:25]2)=[C:22]2[C:17]([CH:18]=[CH:19][CH:20]=[N:21]2)=[C:16]([Cl:31])[CH:15]=1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)C>[Cl:31][C:16]1[CH:15]=[C:14]([CH:12]([NH:11][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:13])[C:23]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([OH:30])[CH2:25]2)=[C:22]2[C:17]=1[CH:18]=[CH:19][CH:20]=[N:21]2
Reactant: CC(N)c1cc(Cl)c2cccnc2c1N1CCC[C@H](O)C1
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(Nc1ncnc2[nH]cnc12)c1cc(Cl)c2cccnc2c1N1CCC[C@H](O)C1

Procedure:
A mixture of 6-bromo-9H-purine (0.0234 g, 0.118 mmol), (3S)-1-[7-(1-aminoethyl)-5-chloroquinolin-8-yl]piperidin-3-ol (0.018 g, 0.059 mmol), and N,N-diisopropylethylamine (0.0205 mL, 0.118 mmol) in ethanol (0.2 mL) was heated at reflux under nitrogen overnight. The mixture was evaporated and the resulting residue was purified on a RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at a flow rate of 30 mL/min) to give the products. First peak retention time 1.482 minutes, LCMS calculated for C21H23ClN7O (M+H)+: m/z=424.2; Found: 424.0. Second peak retention time 1.583 minutes, LCMS calculated for C21H23ClN7O (M+H)+: m/z=424.2; Found: 424.0.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:8])[CH2:4][C:5](O)=[O:6].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[O:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]1[N:34]1[C:42]2[C:37](=[CH:38][C:39]([C:43]3[N:47]=[CH:46][N:45]([C:48]([C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=4)([C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=4)[C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[N:44]=3)=[CH:40][CH:41]=2)[C:36]([C:67]2[CH:68]=[C:69]([NH2:73])[CH:70]=[CH:71][CH:72]=2)=[N:35]1>ClCCl>[CH3:2][N:3]([CH3:8])[CH2:4][C:5]([NH:73][C:69]1[CH:70]=[CH:71][CH:72]=[C:67]([C:36]2[C:37]3[C:42](=[CH:41][CH:40]=[C:39]([C:43]4[N:47]=[CH:46][N:45]([C:48]([C:49]5[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=5)([C:55]5[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=5)[C:61]5[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=5)[N:44]=4)[CH:38]=3)[N:34]([CH:29]3[CH2:30][CH2:31][CH2:32][CH2:33][O:28]3)[N:35]=2)[CH:68]=1)=[O:6]
Reactant: CN(C)CC(=O)O
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CC(=O)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(dimethylamino)acetic acid hydrochloride (0.077 g, 0.55 mmol) in 5 mL of dichloromethane was added 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDCI) (0.105 g, 0.55 mmol) and triethyl amine (0.077 mL, 0.55 mmol). The reaction was stirred at room temperature for 10 min before 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.300 g, 0.498 mmol), dissolved in 1 mL of dichloromethane was added to the solution. The reaction was stirred at room temperature overnight. Further conversion was promoted by reacting an additional equivalent of reagents and stirring at room temperature for 12 hours. The reaction mixture was then partitioned between water and dichloromethane. The crude material that was obtained from evaporation of the extracts was not purified further. (Yield not calculated) ES-MS (m/z) 688 [M+H]+.
Reaction SMILES: Cl[CH:2]1[NH:7][N:6]=[CH:5][C:4]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([NH:13][CH3:14])=[O:12])=[CH:3]1.[NH3:18]>CCO>[NH2:18][CH:2]1[NH:7][N:6]=[CH:5][C:4]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([NH:13][CH3:14])=[O:12])=[CH:3]1
Reactant: N
Reactant: CNC(=O)c1cccc(C2=CC(Cl)NN=C2)c1
Solvent: CCO
Product: CNC(=O)c1cccc(C2=CC(N)NN=C2)c1
Temperature: 160 °C

Procedure:
3-(6-Chloro-1,6-dihydro-pyridazin-4-yl)-N-methyl-benzamide (1 eq, 2.46 mmol, 610 mg) is dissolved in a solution of NH3 (7N, 20 ml) in EtOH and heated at 160° C. in a sealed tube for 48 h. The solvent is then removed in vacuo. The reaction mixture is purified by flash column chromatography eluting with 8:2:0.5 DCM/MeOH/NH3 to give 3-(6-Amino-1,6-dihydro-pyridazin -4-yl)-N-methyl-benzamide as a brown solid; [M+H]+=229
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:28])[C:15]([C:18]2[CH:27]=[CH:26][C:25]3[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=3[CH:19]=2)=[CH:16][OH:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CN(C)C=O.Br[CH2:35][F:36].[H-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:28])[C:15]([C:18]2[CH:27]=[CH:26][C:25]3[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=3[CH:19]=2)=[CH:16][O:17][CH2:35][F:36])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: FCBr
Reactant: COc1ccc(CCNC(=O)C(=CO)c2ccc3c(c2)CCCC3)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CCNC(=O)C(=COCF)c2ccc3c(c2)CCCC3)cc1OC
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
0.76 g (2.0 mmol) of N-[2-(3,4-dimethoxyphenyl)ethyl]-3-hydroxy-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide and 8ml of anhydrous N,N-dimethylformamide were mixed and 0.5 ml of bromofluoromethane was added thereto at −15° C. 88 mg (2.2 mmol) of 60% sodium hydride was added and stirred at −15° C. for 30 minutes and then stirred at approximately 0° C. for 1.5 hours. Water was added to the reaction mixture, followed by extracted with ethyl acetate, washed with 5% hydrochrolic acid and saturated brine subsequently, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel preparative thin layer chromatography (eluent, hexane:ethyl acetate=1:1) to give 0.68 g of N-[2-(3,4-dimethoxyphenyl)ethyl]-3-fluoromethoxy-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide(the present compound 1103).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:9][C:10]1[N:19]=[C:18](Cl)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:9][C:10]1[N:19]=[C:18]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[F:1])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: Nc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccccc1Nc1nc(Cl)nc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
To a mixture of 2-fluoroaniline (232 mg), 2,4-dichloroquinazoline (400 mg) and N,N-dimethylformamide (4 mL), potassium carbonate (430 mg) was added and stirred at room temperature for 8 hours. The reaction mixture was diluted with water (40 mL), and the precipitated solid was collected by filtration and purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=5:1-3:1) to give 2-chloro-N-(2-fluorophenyl)quinazoline-4-amine (0.22 g) as a light-yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[C:3]=1[CH3:27].[O:28]1[CH2:33][CH2:32][N:31]([C:34]2[C:39]([NH2:40])=[CH:38][C:37]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)=[CH:36][N:35]=2)[CH2:30][CH2:29]1>C1(C)C=CC=CC=1>[O:28]1[CH2:33][CH2:32][N:31]([C:34]2[C:39]([NH:40][C:2]3[C:11]4[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=4[F:12])[N:5]=[C:4]([N:14]4[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]4)[C:3]=3[CH3:27])=[CH:38][C:37]([N:41]3[CH2:42][CH2:43][O:44][CH2:45][CH2:46]3)=[CH:36][N:35]=2)[CH2:30][CH2:29]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2cc(F)cc(F)c2c1Cl
Solvent: Cc1ccccc1
Product: Cc1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
Essentially prepared according to Procedure H using tert-butyl 4-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)piperazine-1-carboxylate (240.0 mg, 0.60 mmol) and 2,5-dimorpholinopyridin-3-amine in toluene to give tert-butyl 4-(4-(2,5-dimorpholinopyridin-3-ylamino)-5,7-difluoro-3-methylquinolin-2-yl)piperazine-1-carboxylate. 1H NMR (CDCl3) δ ppm 7.62 (1H, d, J=2.7 Hz), 7.57 (1H, d, J=11.2 Hz), 7.31 (1H, d, J=7.6 Hz), 6.80 (1H, ddd, J=13.4, 8.8, 2.5 Hz), 6.25 (1H, d, J=2.5 Hz), 3.88-3.94 (4H, m), 3.72-3.83 (4H, m), 3.62 (4H, br. s.), 3.36 (4H, br. s.), 3.15 (4H, br. s.), 2.90-3.04 (4H, m), 2.11 (3H, s), 1.48-1.56 (9H, m). Mass Spectrum (ESI) m/e=626.3 (M+1).
Reaction SMILES: [BH4-].[Na+].C[O:4][C:5](=O)[CH2:6][C:7]1[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:10]=[C:9]([O:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[CH:8]=1.CO>O1CCCC1>[OH:4][CH2:5][CH2:6][C:7]1[N:12]=[C:11]([C:13]([F:15])([F:16])[F:14])[N:10]=[C:9]([O:17][CH:18]2[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:23]2)[CH:8]=1
Reactant: COC(=O)Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)nc(C(F)(F)F)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(CCO)nc(C(F)(F)F)n2)CC1
Reaction time: 2 h

Procedure:
Sodium tetrahydroborate (32 mg, 0.83 mmol) was added to a solution of tert-butyl 4-{[6-(2-methoxy-2-oxoethyl)-2-(trifluoromethyl)pyrimidin-4-yl]oxy}piperidine-1-carboxylate (125 mg, 0.209 mmol, from Step 2) in tetrahydrofuran (2.0 mL). Methanol (0.21 mL) was added in portions. After stirring for 2 hours, the mixture was quenched by the addition of saturated ammonium chloride solution. The reaction was diluted with additional water, and the product was extracted with EtOAc. The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography on a 12 g silica gel column, eluting with a gradient from 0-30% EtOAc in hexanes afforded product (26 mg, 32%). 1H NMR (400 MHz, CDCl3) δ 6.74 (s, 1H), 5.35 (tt, J=7.8, 3.7 Hz, 1H), 4.07-3.96 (m, 2H), 3.81-3.61 (m, 2H), 3.31 (ddd, J=13.5, 8.4, 3.7 Hz, 2H), 2.99 (t, J=5.4 Hz, 2H), 2.03-1.92 (m, 2H), 1.79-1.68 (m, 2H), 1.47 (s, 9H); 19F NMR (376 MHz, CDCl3) δ-71.37 (s); LCMS (M+Na)+: 414.0.