Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([N:14]1[CH2:18][CH2:17]N=[CH:15]1)=[O:13])[CH2:8]2.[CH3:19][O:20][C:21](=[O:33])[C:22]1[CH:27]=[CH:26][C:25]([O:28]CCNC)=[CH:24][CH:23]=1.O>C(Cl)Cl>[CH3:19][O:20][C:21](=[O:33])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:17][CH2:18][N:14]([CH3:15])[C:12]([NH:11][CH:2]2[CH:1]3[CH2:8][CH:7]4[CH2:6][CH:5]([CH2:4][CH:3]2[CH2:9]4)[CH2:10]3)=[O:13])=[CH:24][CH:23]=1
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)N1C=NCC1
Reactant: CNCCOc1ccc(C(=O)OC)cc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(OCCN(C)C(=O)NC2C3CC4CC(C3)CC2C4)cc1

Procedure:
A solution of 4H-Imidazole-1-carboxylic acid adamantan-2-ylamide 0.5 g (2.04 mmol) and 4-(2-Methylamino-ethoxy)-benzoic acid methyl ester 426.8 mg (2.04 mmol) in methylene chloride 10 ml was stirred at room temperature for 2 days. Water was added, the organic phase extracted, dried and concentrated to dryness. The residue was purified by flash chromatography on silica gel (eluant DCM/MeOH: 100/0 to 95/05) yielding 596 mg as white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([C:8]([N:10]2[CH2:16][CH2:15][C:14]3[CH:17]=[N:18][NH:19][C:13]=3[C:12]3[S:20][CH:21]=[CH:22][C:11]2=3)=[O:9])=[CH:6][CH:5]=1)([O-])=O.NN>C(O)C.[Pd]>[NH2:1][C:4]1[CH:24]=[CH:23][C:7]([C:8]([N:10]2[CH2:16][CH2:15][C:14]3[CH:17]=[N:18][NH:19][C:13]=3[C:12]3[S:20][CH:21]=[CH:22][C:11]2=3)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1CCc2cn[nH]c2-c2sccc21
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: Nc1ccc(C(=O)N2CCc3cn[nH]c3-c3sccc32)cc1
Temperature: 60 °C
Yield: 76.8 %

Procedure:
A mixture of 2.0 g of 6-(4-nitrobenzoyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]thieno[3,2-b]azepine in 40 ml of absolute ethanol is stirred under argon while 1.6 ml of hydrazine is added. The reaction mixture is heated at 60° C. for 1.5 hours. The reaction mixture is cooled to room temperature and 400 mg of 10% Pd/C added and the reaction mixture heated at 100° C. for 1.5 hours. The reaction mixture is filtered through diatomaceous earth and the cake washed with methylene chloride. The filtrate is concentrated in vacuo to a residue which is crystallized from ethyl acetate:hexane to give 1.4 g of the desired product as yellow crystals, 242°-260° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]([CH:22]3[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]3)[N:15]3[C:20]=2[C:19]([NH2:21])=[N:18][CH:17]=[N:16]3)=[CH:8][C:7]=1[O:32][CH3:33].[Cl:37]N1C(C)(C)C(=O)N(Cl)C1=O>CN(C=O)C>[Cl:37][C:13]1[C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][C:4]3[CH:34]=[CH:35][CH:36]=[C:2]([Cl:1])[CH:3]=3)=[C:7]([O:32][CH3:33])[CH:8]=2)=[C:20]2[N:15]([C:14]=1[CH:22]1[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:29])=[O:30])[CH2:24][CH2:23]1)[N:16]=[CH:17][N:18]=[C:19]2[NH2:21]
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Reactant: COc1cc(-c2cc(C3CCN(S(C)(=O)=O)CC3)n3ncnc(N)c23)ccc1Oc1cccc(Cl)c1
Solvent: CN(C)C=O
Product: COc1cc(-c2c(Cl)c(C3CCN(S(C)(=O)=O)CC3)n3ncnc(N)c23)ccc1Oc1cccc(Cl)c1
Temperature: 65 °C
Yield: 151.7 %

Procedure:
The compound (15.40 mg, 0.029 mmol) prepared in Example 26 and 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (2.87 mg, 0.015 mmol) were taken up in 2 mL of DMF and heated to 65° C. for 16 hours. The reaction was cooled to room temperature and the DMF removed under vacuum and the reaction mixture submitted for prep-HPLC purification to obtain the title compound (12.8 mg) having the following physical data.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].Cl.[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[C:19]([C:21]3[CH:30]=[C:29]4[C:24]([CH2:25][CH2:26][N:27]([C:31](=[O:39])[CH2:32][CH:33]5[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]5)[CH2:28]4)=[CH:23][CH:22]=3)[N:18]=[C:17]([NH2:40])[N:16]=2)[CH2:11][CH2:10]1>>[CH2:1]([S:3]([N:36]1[CH2:35][CH2:34][CH:33]([CH2:32][C:31]([N:27]2[CH2:26][CH2:25][C:24]3[C:29](=[CH:30][C:21]([C:19]4[CH:20]=[C:15]([N:12]5[CH2:13][CH2:14][N:9]([CH3:8])[CH2:10][CH2:11]5)[N:16]=[C:17]([NH2:40])[N:18]=4)=[CH:22][CH:23]=3)[CH2:28]2)=[O:39])[CH2:38][CH2:37]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)CC3CCNCC3)CC4)nc(N)n2)CC1
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Product: CCS(=O)(=O)N1CCC(CC(=O)N2CCc3ccc(-c4cc(N5CCN(C)CC5)nc(N)n4)cc3C2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 71, Step 4 starting from ethanesulfonyl chloride and 4-(4-methylpiperazin-1-yl)-6-[2-(piperidin-4-ylacetyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=542.3.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH2:14])[CH:5]=[CH:4][C:3]1=2.C(N(CC)CC)C.[C:23](Cl)(=[O:29])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>ClCCl>[CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH:14][C:23](=[O:29])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:5]=[CH:4][C:3]1=2
Reactant: CCCCCC(=O)Cl
Reactant: CC1(C)CCC(C)(C)c2cc(N)ccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCC(=O)Nc1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamine (1) (0.5 g, 2.46 mmole) in 20 mL of dichloromethane was treated successively with 0.51 mL of triethylamine (1.5 eq.) and 0.35 mL of hexanoyl chloride (1 eq.). The reaction mixture was stirred at room temperature for two hours, diluted with an additional 20 mL of dichloromethane and washed with two 50 mL portions of water and one 50 mL portion of saturated aqueous sodium chloride solution. The organic phase was dried over MgSO4, filtered and concentrated in vacuo, giving 740 mg (100%) of hexanoic acid (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-amide (15) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[H-].[Na+].[Cl:14][C:15]1[N:20]=[C:19](Cl)[CH:18]=[CH:17][N:16]=1.O>CN(C=O)C>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][C:17]1[CH:18]=[CH:19][N:20]=[C:15]([Cl:14])[N:16]=1
Reactant: Nc1ccccc1C(F)(F)F
Reactant: Clc1ccnc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccccc1Nc1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-(trifluoromethyl)aniline (0.570 g, 3.54 mmol) in anhydrous DMF (4 mL), NaH (60% dispersion in mineral oil, 0.384 g, 9.6 mmol) was added portion wise at 0° C. under Argon, followed by the addition of 2,4-dichloropyrimidine (0.528 g, 3.54 mmol). The reaction mixture was slowly warmed to room temperature and stirred for a further 24 h. The solvent was removed under reduced pressure to provide a red/orange solid. The residue was slurried with water (30 mL) and solid was filtered and washed with water (10 mL×2). The dried solid was suspended in diethyl ether (5 mL) and sonicated, then filtered and washed with diethyl ether (5 mL), hexane (10 mL) to afford the title compound as a yellow solid. The solid was re-dissolved in ethyl acetate, activated charcoal was added and the mixture was stirred for 20 min at room temperature. The activated charcoal was removed by filtration through a celite/silica bed. The filtrate was collected, the solvent removed under reduced pressure to provide 5f (0.261 g, 28%) as an off-white solid. m.p. 139° C. (dec.). 1H NMR (400 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.11 (d, J=5.9 Hz, 1H), 7.81 (d, J=8.2 Hz, 1H), 7.74 (t, J=7.7 Hz, 1H), 7.57-7.51 (m, 2H), 6.57 (d, J=5.9 Hz, 1H); LC-MS (ESI+) m/z 274.04 (M+H)+; HRMS (ESI+) m/z calculated for C11H8F3ClN3 (M+H)+ 274.0353. found 274.0354.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2[CH:12]=[N:13][C:14]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:16]=2[C:17]#[N:18])=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([O:23][CH3:24])[CH:3]=1.C(N(CC)CC)C.[CH3:32][C:33]1[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[C:34]=1[NH2:35]>C(Cl)Cl>[Cl:1][C:2]1[C:10]([C:11]2[CH:12]=[N:13][C:14]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:16]=2[C:17]#[N:18])=[CH:9][C:5]([C:6]([NH:35][C:34]2[C:36]([CH3:40])=[CH:37][CH:38]=[CH:39][C:33]=2[CH3:32])=[O:7])=[C:4]([O:23][CH3:24])[CH:3]=1
Reactant: COc1cc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)cc1C(=O)Cl
Reactant: Cc1cccc(C)c1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)cc1C(=O)Nc1c(C)cccc1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 62.9 %

Procedure:
To 4-chloro-2-methoxy-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl chloride (70 mg, 0.19 mmol) in DCM (0.5 mL) were added triethylamine (39 μL, 0.28 mmol) and 2,6-dimethylaniline (28 μL, 0.22 mmol). The mixture was stirred at rt for 12 hrs and was purified via a prep TLC plate eluting with ethyl acetate in hexane (30%) to give 4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-(2,6-dimethyl-phenyl)-2-methoxy-benzamide (55.0 mg). MS [M+H]+460.2; tR=2.85 min (method 1)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[S:18][C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[C:11]=1[C:19]([O:21]CC)=O.[NH3:24].C(Cl)Cl>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[S:18][C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[C:11]=1[C:19]([NH2:24])=[O:21]
Reactant: CCOC(=O)c1c(Nc2ccc(I)cc2F)sc2ncccc12
Reactant: N
Solvent: CCO
Solvent: ClCCl
Product: NC(=O)c1c(Nc2ccc(I)cc2F)sc2ncccc12
Temperature: 95 °C

Procedure:
A solution of Example 1 (250 mg, 0.56 mmol) in ethanol (5 mL) was added to liquid ammonia (15 mL) and the mixture heated in a Parr apparatus to 95° C. at 800 psi for 18 hours. The volatiles were removed in vacuo to give an oily brown residue. Repeated trituration with ethanol and DCM afforded the title compound as a white solid (18 mg). δH (DMSO-d6) 11.20 (1H, bs), 8.34 (1H, d, J 3.4 Hz), 8.20 (1H, dd, J 8.2, 1.3 Hz), 7.76 (1H, dd, J 10.4, 1.8 Hz), 7.62 (1H, d, J 8.2 Hz), 7.57 (2H, br s), 7.49-7.39 (2H, m). LCMS (ES+) RT 3.11 minutes, 412 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][C:9]([OH:10])=[C:7]([OH:8])[CH:6]=1.[CH:13]1([C:16](Cl)=[O:17])[CH2:15][CH2:14]1>N1C=CC=CC=1>[OH:8][C:7]1[CH:6]=[C:5]([CH2:4][CH2:3][NH:2][C:16]([CH:13]2[CH2:15][CH2:14]2)=[O:17])[CH:12]=[CH:11][C:9]=1[OH:10]
Reactant: O=C(Cl)C1CC1
Reactant: NCCc1ccc(O)c(O)c1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(NCCc1ccc(O)c(O)c1)C1CC1
Reaction time: 5 h

Procedure:
Dissolve 15.0 g. of dopamine hydrochloride in 200 ml. of pyridine. Add with stirring 24.96 g. of cyclopropane-carboxylic acid chloride portionwise over a 2-hour period at room temperature. Stir at room temperature overnight. Add methanol (200 ml.), water (75 ml.) and concentrate ammonium hydroxide solution (50 ml.) to the reaction mixture and allow the clear solution to stand for 5 hours at room temperature. Pour the solution into 2 liters of of 2N hydrochloric acid and ice with vigorous agitation. Extract the oily precipitate with ethyl acetate. Wash the extract with saturated aqueous sodium bicarbonate solution, dry over sodium sulfate and evaporate to a residue. Dissolve the residue from ethyl acetate-ethyl ether and crystallize to obtain the title compound, m.p. 174.5°-176° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]([NH:17][CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[C@H:27]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:26][CH2:25]4)[C:14]([C:37]([F:40])([F:39])[F:38])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH3:4].[CH3:41]N(C=O)C>>[CH2:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:16]=[C:15]([N:17]([CH3:41])[CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[C@H:27]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:26][CH2:25]4)[C:14]([C:37]([F:40])([F:38])[F:39])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)[CH3:4]
Reactant: CN(C)C=O
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCNc3nc(-c4ccc(CC)cc4)ccc3C(F)(F)F)ccc21
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCN(C)c3nc(-c4ccc(CC)cc4)ccc3C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8 %

Procedure:
Sodium hydride (0.02 g, 0.86 mmol) was added to a solution of ethyl [(1 S)-5-(3-{[6-(4-ethylphenyl)-3-(trifluoromethyl)-2-pyridinyl]amino}propoxy)-2,3-dihydro-1H-inden-1-yl]acetate (Example 318) (0.21 g, 0.39 mmol) in DMF (2 mL). After stirring at rt for 30 min, Mel (0.05 mL, 6.32 mmol) was added. The mixture was stirred at rt for 18 h, quenched with water (5 mL), and extracted with ether (3×). The combined ether extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The product (0.017 g, 8%) was isolated after silica gel flash chromatography (2:1 hexanes/EtOAc). 1H NMR (400 MHz, CD2Cl2) δ 7.99 (d, 2H), 7.85 (d, 1H), 7.35-7.25 (m, 3H), 7.01 (d, 1H), 6.72 (d, 1H), 6.65 (dd, 1H), 4.15 (q, 2H), 4.00 (t, 2H), 3.73 (t, 2H), 3.47 (qt, 1H), 3.08 (s, 3H), 2.90-2.68 (m, 5H), 2.42-2.30 (m, 2H), 2.15 (qt, 2H), 1.78-1.68 (m, 1H), 1.32-1.26 (m, 6H).
Reaction SMILES: [N:1](=[C:3]1[N:7]=[C:6]([CH2:8][CH3:9])[C:5]([CH2:11][CH3:12])([CH3:10])[S:4]1)[OH:2].[CH3:13][N:14]=[C:15]=[O:16]>>[CH3:13][NH:14][C:15]([O:2][N:1]=[C:3]1[N:7]=[C:6]([CH2:8][CH3:9])[C:5]([CH2:11][CH3:12])([CH3:10])[S:4]1)=[O:16]
Reactant: CCC1=NC(=NO)SC1(C)CC
Reactant: CN=C=O
Product: CCC1=NC(=NOC(=O)NC)SC1(C)CC

Procedure:
2-oxo-4,5-diethyl-5-methyl-3-thiazoline-oxime was reacted with methyl isocyanate as described in Example 4 to yield 2-oxo-4,5-diethyl-5-methyl-3-thiazoline-O-(methylcarbamoyl)-oxime, m.p. 88°-90° C. The 2-oxo-4,5-diethyl-5-methyl-3-thiazoline-oxime starting material melts at 125°-128° C.
Reaction SMILES: C(O)(=O)C.OO.[NH:7]1[CH:11]=[N:10][C:9]([SH:12])=[N:8]1.[OH-].[Na+]>O>[NH:7]1[CH:11]=[N:10][C:9]([S:12][S:12][C:9]2[N:10]=[CH:11][NH:7][N:8]=2)=[N:8]1
Reactant: Sc1nc[nH]n1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: c1nc(SSc2nc[nH]n2)n[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Glacial acetic acid (7.89 g) was added to 18.7 g of a 15% aqueous hydrogen peroxide solution. The resulting solution was added slowly to a solution prepared from 16.5 g 1,2,4-triazole-3-thiol, 160 g of water and 16.3 g 40% NaOH. The reaction temperature was moderated with the use of an ice bath during the addition. After stirring overnight at room temperature, the product was filtered, washed with water and then dried under vacuum at 70 C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2.[OH-].[K+].C1C(=O)N([Br:27])C(=O)C1>CN(C=O)C.O>[Br:27][C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[CH:10]=2)[NH:14][CH:13]=1
Reactant: Fc1cccc(F)c1-c1ccc2[nH]ccc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cccc(F)c1-c1ccc2[nH]cc(Br)c2c1
Reaction time: 1 h

Procedure:
To a stirred solution of 5-(2,6-difluorophenyl)-1H-indole (2.0 g, 8.7 mmol) in DMF (20 mL) was added KOH (0.98 g, 17.5 mmol) and NBS (1.55 g, 8.7 mmol) at RT and stirred for 1 h. The resulting mixture was diluted with water, extracted with DCM (20 mL), dried over Na2SO4, filtered, concentrated to give crude 3-bromo-5-(2,6-difluorophenyl)-1H-indole.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH2:20]/[C:21](/[CH3:28])=[CH:22]\[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(O)CCC>[CH3:28][C:21]1[NH:20][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:22]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)/C=C(/C)N
Reactant: O=C(C=Cc1cccc([N+](=O)[O-])c1)c1ccccc1
Solvent: CCCCO
Product: CCOC(=O)C1=C(C)NC(c2ccccc2)=CC1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 20.8 %

Procedure:
A mixture of 3-(3-nitrophenyl)-1-phenyl-2-propen-1-one (2 g), ethyl 3-aminocrotonate (1.2 g) and n-butanol (20 ml) was refluxed for 6 hours. After allowing to cool at ambient temperature, the reaction mixture was evaporated in vacuo. The residue was subjected to a column chromatography on silica gel (150 ml) eluting with a mixture of benzene and ethyl acetate (30:1 V/V). The fractions containing the object compound were combined and concentrated under reduced pressure to give ethyl 1,4-dihydro-2-methyl-4-(3-nitrophenyl)-6-phenyl-3-pyridinecarboxylate (0.6 g).
Reaction SMILES: BrC1C=CC(S([O:11][C@@H:12]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:14]([C:24]([O:26][CH3:27])=[O:25])[CH2:13]2)(=O)=O)=CC=1.[Br:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[NH:35][C:34]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[CH:33][C:32]2=O.C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>CN1CCCC1.O>[Br:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[C:34]([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[CH:33]=[C:32]2[O:11][C@H:12]1[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C@H:14]([C:24]([O:26][CH3:27])=[O:25])[CH2:13]1
Reactant: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(Br)cc2)CN1C(=O)OC(C)(C)C
Reactant: COc1cc2[nH]c(-c3ccccc3)cc(=O)c2cc1Br
Agent: CN1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)c(Br)cc23)CN1C(=O)OC(C)(C)C
Temperature: 45 °C
Reaction time: 15 h
Yield: 92.1 %

Procedure:
To a solution of the product from Step 4 (19.4 g, 41.7 mmol) and 6-bromo-7-methoxy-2-phenylquinolin-4(1H)-one (Step 3, 13.5 g, 40.9 mmol) in N-methylpyrrolidine (200 mL) was added cesium carbonate (20.0 g, 61.3 mmol). The reaction mixture was then heated at 45° C. with stirring for 15 hours and cooled to RT. The reaction mixture was poured into EtOAc and water, and the white solids removed by filtration. The layers were separated, and the organic phase washed with saturated aqueous NaHCO3, water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified on silica (gradient elution 10% to 50% EtOAc in hexanes) to give the title compound (21.0 g) as a pale yellow solid. LRMS (M+H)+ Calcd.: 557.1; found 557.3.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>CC#N.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>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Brc1cncc(Br)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: [Na+]
Solvent: CC#N
Product: COc1ccc(-c2cncc(Br)c2)cc1

Procedure:
To a solution of 3,5-dibromopyridine (Sigma-Aldrich, St. Louis, USA) (1 eq, 8.4 mmol, 2 g) and 4-methoxy-phenylboronic acid (Sigma-Aldrich, St. Louis, USA) (1 eq, 8.4 mmol, 1.30 g) in MeCN (12 ml), Na2CO3 (2 eq, 16.7 mmol, 1.79 g) and Pd(PPh3)4 (0.04 eq, 0.334 mmol, 398 mg) are added. The mixture is heated using microwave radiation at 140° C. for 10 min. The solvents are evaporated, the residue is taken up in aqueous NaOH solution (1 M) and extracted with DCM. The organic layer is washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification by column chromatography (hexane/EtOAc) yields the title compound; [M+H]+=264/266.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].C(N(CC)CC)C.[F:12][C:13]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[CH:16][C:14]=1[NH2:15]>CCOCC>[F:12][C:13]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[CH:16][C:14]=1[N:15]=[C:1]=[S:2]
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(F)c(F)c1F
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Fc1ccc(N=C=S)c(F)c1F
Temperature: 20 °C
Yield: 77.2 %

Procedure:
Reference Example 1 Thiophosgene (1.4 g) was dissolved in 25 ml of ether, 2.0 g of triethylamine was added thereto with ice cooling and stirring (at not higher than 20° C.), then a mixture of 1.4 g of 2,3,4-trifluoroaniline and 3 ml of ether was gradually dropped thereinto at the same temperature, and the mixture was stirred for one hour at the same temperature. Then it was filtered off, the filtrate was concentrated, the residue was extracted with n-hexane, insoluble matters were removed by filtration, the resulting hexane-soluble matters were subjected to a silica gel column chromatography (Wacogel C-200 in the amount of 15 g) and eluted with n-hexane to give 1.39 g of 2,3,4-trifluorophenyl isothiocyanate.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[N:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[C:35]1[N:40]=[C:39]([NH2:41])[N:38]=[C:37]([NH2:42])[CH:36]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CO>[F:23][C:2]([F:22])([F:1])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:35]4[N:40]=[C:39]([NH2:41])[N:38]=[C:37]([NH2:42])[CH:36]=4)=[CH:17][CH:16]=3)=[N:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Oc1ccc(-c2nnc(Nc3cccc(C(F)(F)F)c3)o2)cc1
Reactant: Nc1cc(Cl)nc(N)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1cc(Oc2ccc(-c3nnc(Nc4cccc(C(F)(F)F)c4)o3)cc2)nc(N)n1
Temperature: 80 °C
Yield: 37.7 %

Procedure:
4-(5-{[3-(trifluoromethyl)-phenyl]amino}-1,3,4-oxadiazol-2-yl)phenol (160.6 mg, 0.5 mmol) was dissolved in 3 mL of anhydrous DMF in a 2-5 mL microwave vial (Personal Chemistry). Solid potassium bis(trimethylsilyl)amide (119.7 mg, 0.6 mmol) was added and the reaction mixture was stirred with heating at 80° C. for 10 min, then 6-chloro-2,4-diamino-pyrimidine (86.7 mg, 0.6 mmol) was added, followed by anhydrous K2CO3 (69.1 mg, 0.5 mmol). Then the vial was capped and microwaved at 200° C. for 20 min. Then the reaction mixture was diluted with ca. 1 mL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.01% TFA. Fractions, containing the product, were partitioned between ca. 40 mL of EtOAc and ca. 40 mL of saturated NaHCO3. EtOAc layer was washed with brine, dried over anhydrous Na2SO4 and filtered. Solvent was removed in vacuo to give the title product as a beige solid (81.0 mg). Yield 37.7%.
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[CH:10]=[CH:11][C:12]([CH2:15][P:16](=[O:23])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])=[N:13][CH:14]=1)=O)(C)(C)C.[ClH:31]>CCOC(C)=O>[ClH:31].[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][P:16](=[O:23])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])=[N:13][CH:14]=1
Reactant: CCOP(=O)(Cc1ccc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cn1)OCC
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1ccc(N)cn1)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of diethyl ({5-[bis(tert-butoxycarbonyl)amino]pyridin-2-yl}methyl)phosphonate (Compound 260B, 2.5 g, 5.6 mmol) in dry EtOAc (150 mL) was added HCl in EtOAc solution dropwise. The reaction mixture was stirred at room temperature for 1 h. The solids were collected by filtration, dried to give 2.1 g of the desired product as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ=1.16 (t, J=7.2 Hz, 6 H), 3.64 (d, J=22.0 Hz 2 H), 3.97-4.04 (m, 4H), 7.50 (dd, J=2.0, 8.8 Hz, 1 H), 7.64 (dd, J=2.0, 8.8 Hz, 1 H), 7.95 (d, J=2.4 Hz, 1 H).