Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([NH:7][CH2:8][CH2:9][CH2:10][C:11]#[N:12])=[CH:3][CH:2]=1.[C:14]([O:21]CC)(=O)[C:15]([O:17]CC)=O.[O-]CC.[Na+]>C(O)C>[O:21]=[C:14]1[C:15](=[O:17])[CH:10]([C:11]#[N:12])[CH2:9][CH2:8][N:7]1[C:4]1[CH:3]=[CH:2][C:1]([CH3:13])=[CH:6][CH:5]=1
Reactant: Cc1ccc(NCCCC#N)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(N2CCC(C#N)C(=O)C2=O)cc1
Temperature: 25 °C
Yield: 51.6 %

Procedure:
4-(p-Tolylamino)butanenitrile (13.23 g, 75.929 mmol) was dissolved in ethanol (189.8 mL). After adding diethyl oxalate (10.3 mL, 75.929 mmol) and then adding sodium ethoxide (34.0 mL, 91.115 mmol) to the resultant reaction mixture, reaction was carried out under reflux for 2 days. The reaction solution was cooled to room temperature and the concentrated solution was filtered. A target compound (8.94 g, 39.167 mmol, 51.6%) was yielded as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=2)[N:7]=1.Cl[C:13]([O:15][CH2:16][C:17]([Cl:20])([Cl:19])[Cl:18])=[O:14].O>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:13](=[O:14])[O:15][CH2:16][C:17]([Cl:20])([Cl:19])[Cl:18])[N:10]=2)[N:7]=1
Reactant: Nc1cn2nc(Cl)ccc2n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(Nc1cn2nc(Cl)ccc2n1)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
To a solution of 6-chloroimidazo[1,2-b]pyridazine-2-amine (561 g, 3.3 mmol) in dimethylacetamide (11 ml) was added 2,2,2-trichloroethyl chloroformate (0.506 ml, 3.66 mmol) with ice-cooling, and the mixture was stirred at room temperature for 1 hour. Water was poured into the reaction solution, and a solid was separated by filtration, which was washed with water to give 724 mg (63.3%) of the desired product as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][CH:11]=2)[OH:9])=[CH:4][C:3]=1[S:22]([NH2:25])(=[O:24])=[O:23].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:9])[C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:14][CH:15]=2)=[CH:4][C:3]=1[S:22]([NH2:25])(=[O:24])=[O:23]
Reactant: CCCCCOc1ccc(C(O)c2ccc(Cl)c(S(N)(=O)=O)c2)cc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: CCCCCOc1ccc(C(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)cc1
Reaction time: 0.5 h

Procedure:
2-Chloro-5-[(4-pentyloxy-phenyl)-hydroxy-methyl]-benzenesulfonamide is dissolved in acetone (10 mL), and treated with a solution of Jones reagent (3 M in water, 0.91 mmol). The reaction is allowed to stir for 30 minutes. The reaction is diluted with water and extracted with dichloromethane. The organic phase is separated and concentrated in vacuo. The residue is purified by silica gel chromatography (gradient of ethyl acetate in hexanes 25-75%) followed by recrystallization from ether affording 15 mg of the title compound. 1H NMR (DMSO) 0.90 (t, 3H, J=6.79 Hz), 1.31-1.46 (m, 4H), 1.70-1.79 (m, 2H), 4.09 (t, 2H, J=6.49 Hz), 7.10 (d, 2H, J=9.04 Hz), 7.75-7.90 (m, 4H), 8.24 (d, 1H, J=1.89). MS (m/z): 382 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.Br[C:24]1[CH:25]=[C:26]([CH2:30][NH:31][S:32]([CH2:35][CH3:36])(=[O:34])=[O:33])[CH:27]=[N:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1[C:24]1[CH:25]=[C:26]([CH2:30][NH:31][S:32]([CH2:35][CH3:36])(=[O:33])=[O:34])[CH:27]=[N:28][CH:29]=1
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)c(Cl)cc21
Reactant: CCS(=O)(=O)NCc1cncc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)NCc1cncc(-c2cc3c(cc2Cl)N(C)C(=O)CC3)c1
Temperature: 120 °C
Yield: 30 %

Procedure:
A mixture of 7-chloro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (20 mg, 0.06 mmol), ethanesulfonic acid (5-bromo-pyridin-3-ylmethyl)-amide (intermediate A-11, 26 mg, 0.09 mmol), bis(triphenylphosphine)-palladium(II) chloride (4.2 mg, 0.006 mmol) and sodium carbonate (2 N aq., 0.06 mL) in DMF (1 mL) was heated in a microwave at 120° C. for 30 minutes. The mixture was diluted with EtOAc, washed with water, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by prep-HPLC to afford the title product (7.1 mg, 30%) as a white solid. MS, 394.2 (M+H+)+.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([C:7](=[O:10])[CH2:8]Br)=[CH:3][CH:2]=1.CCO.[N-:20]=[N+]=[N-].[Na+].[BH4-].[Na+]>CO>[NH2:20][CH2:8][CH:7]([C:4]1[CH:5]=[CH:6][C:1]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:2][CH:3]=1)[OH:10]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CBr)c1ccc(-c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: NCC(O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution consisting of 1-biphenyl-4-yl-2-bromo-ethanone (412 mg. 1.5 mmol) and EtOH (6 mL) was added NaN3 (107 mg, 1.6 mmol) at rt. The mixture was stirred at rt for 2 h and then cooled to 0° C. NaBH4 (61 mg, 1.6 mmol) was added and the mixture stirred for 45 min. A mixture (black slurry) of CuSO4.5H2O (37 mg)/NaBH4 (28 mg) in MeOH 2 mL) was prepared by adding the NaBH4 to CuSO4.5H2O in MeOH at 0° C. This slurry was poured into the reaction mixture. The reaction vessel was allowed to gradually warm to rt. An additional amount of NaBH4 (28 mg) was added 30 min after the addition of the slurry. The reaction was stirred at rt for 2 h. The mixture was filtered through a pad of celite, adhered to silica gel (7-8 g) and purified (FCC) to give the title compound (256 mg, 80%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH:24]([O:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH:20]2[CH2:44][O:45][CH3:46])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]2[CH:24]([O:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)[CH2:23][NH:22][CH2:21][CH:20]2[CH2:44][O:45][CH3:46])=[CH:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCC1CN(C(=O)OC(C)(C)C)CC(OCc2ccc3ccccc3c2)C1c1ccc(OCCCOCc2ccccc2)cc1
Agent: Cl
Solvent: CO
Product: COCC1CNCC(OCc2ccc3ccccc3c2)C1c1ccc(OCCCOCc2ccccc2)cc1

Procedure:
In an analogous manner to that described in Example 22(l), from tert-butyl (3SR,4RS,5RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-methoxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate by cleavage of the BOC group by means of hydrogen chloride in methanol there was obtained (3SR,4RS,5RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-methoxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine as an amorphous, colourless solid; MS: 526 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:11]=2[Cl:19])=[CH:4][C:3]=1[N:20]1[C:24](=[O:25])[N:23]([CH:26]([F:28])[F:27])[C:22]([CH3:29])=[N:21]1>C(O)(=O)C.O.[Fe]>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C:5]2[C:6]([Cl:8])=[CH:7][C:2]([Cl:1])=[C:3]([N:20]3[C:24](=[O:25])[N:23]([CH:26]([F:27])[F:28])[C:22]([CH3:29])=[N:21]3)[CH:4]=2)=[C:11]([Cl:19])[CH:12]=1
Reactant: Cc1nn(-c2cc(Oc3ccc([N+](=O)[O-])cc3Cl)c(Cl)cc2Cl)c(=O)n1C(F)F
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Cc1nn(-c2cc(Oc3ccc(N)cc3Cl)c(Cl)cc2Cl)c(=O)n1C(F)F
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 92.9 %

Procedure:
To a stirred mixture of 10.0 g (0.021 mole) of 1-[2,4-dichloro-5-(2-chloro-4-nitrophenoxy) phenyl]-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one in 100 ml of glacial acetic acid and 5 ml of water was added slowly 10.0 g (0.179 mole) of iron powder. The reaction mixture was heated at 50° C. and then was allowed to cool to room temperature at which it was stirred for 1.5 hours. The mixture was poured into ice-water, and the aqueous mixture was extracted with diethyl ether. The extract was evaporated under reduced pressure leaving a residue. This residue was purified by column chromatography to yield 8.5 g of 1-[5-(4-amino-2-chlorophenoxy)-2,4-dichlorophenyl]-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one as a solid, m.p. 161°-162° C., compound 180 of Table 1.
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].S(Cl)(Cl)=O.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([F:23])[CH:17]=1>O1CCCC1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:1](=[O:10])[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[OH:4])=[C:18]([F:23])[CH:17]=1
Reactant: O=C(O)c1ccccc1O
Reactant: Nc1ccc(Cl)cc1F
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)cc1F)c1ccccc1O

Procedure:
To a solution of salicylic acid (1.38 g, 10 mmole) in tetrahydrofuran (40 mL) was added thionyl chloride (2.5 mL, 35 mmole) and refluxed 3 hr. The mixture was steamed (110° C.) by Dean-Stark. The residue was directly reacted with 4-chloro-2-fluorobenzenamine (1.1 mL, 10 mmole) in THF (40 mL) for 14 hr. The reaction mixture was concentrated and extracted with ethyl acetate, dried over anhydrous magnesium sulfate. Recrystallization of desired products from hot dichloromethane afforded the compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([S:16](Cl)(=[O:18])=[O:17])[N:5]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[Cl:7].[CH3:20][NH:21][CH3:22]>CC(C)=O.C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([S:16]([N:21]([CH3:22])[CH3:20])(=[O:18])=[O:17])[N:5]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[Cl:7]
Reactant: C[Si](C)(C)CCOCn1c(S(=O)(=O)Cl)nc(Cl)c1Cl
Reactant: CNC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1nc(Cl)c(Cl)n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
A solution of 4,5-dichloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-2-sulfonyl chloride (0.826 mmol) in acetone (2.5 mL) and THF (1.5 mL) was added to dimethylamine (2.0 mL of a 2M solution in THF, 4.0 mmol). The reaction mixture was stirred at RT for 1 h and then evaporated to dryness. The residue was taken up in EtOAc and washed with brine. The organic layer was dried (Na2SO4), filtered, evaporated and purified by silica gel chromatography (0-30% EtOAc/hexanes) to provide the title compound (0.18 g, 57%) as a light yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 5.62 (s, 2H), 3.61-3.75 (m, 2H), 3.06 (s, 6H), 0.84-1.00 (m, 3H), 0.00 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH2:10][C:11](O)([C:13]([F:16])([F:15])[F:14])[N:12]=2)[N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH:10]=[C:11]([C:13]([F:15])([F:16])[F:14])[N:12]=2)[N:3]=1
Reactant: Cc1cccc(C2=NC(O)(C(F)(F)F)CN2c2ccc(S(C)(=O)=O)cc2)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc(-c2nc(C(F)(F)F)cn2-c2ccc(S(C)(=O)=O)cc2)n1
Yield: 38.6 %

Procedure:
A mixture of the 4,5-dihydro-imidazole of step 2 (1.3 g, 3.26 mmol) and p-toluenesulfonic acid monohydrate (0.26 g, 1.36 mmol) in toluene (200 ml) was heated to reflux for 24 hours. The reaction mixture was cooled and the solvent removed under reduced pressure. The crude mixture (1.56 g) was chromatographed on silica gel using ethyl acetate/acetone (98/2) to give pure 2-methyl-6-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine (0.48 g, 38%) as a white solid: mp (DSC) 205° C. Anal. Calc'd. for C17H14N3SO2F3 0.25H2O: C, 52.91, H, 3.79, N, 10.89, S, 8.31. Found: C, 52.67, H, 3.55, N, 10.64, S, 8.68.
Reaction SMILES: [I:1]I.[Cl:3][C:4]([Cl:13])([Cl:12])[C:5]([C:7]1[NH:8][CH:9]=[CH:10][CH:11]=1)=[O:6].O>ClCCl.FC(F)(F)C([O-])=O.[Ag+]>[Cl:13][C:4]([Cl:3])([Cl:12])[C:5]([C:7]1[NH:8][CH:9]=[C:10]([I:1])[CH:11]=1)=[O:6]
Reactant: II
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: O=C(c1cc(I)c[nH]1)C(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 5 h
Yield: 93.7 %

Procedure:
Iodine (1.2 g, 4.7 mmol) was added portion wise to a solution of 2,2,2-trichloro-1-(1H-pyrrol-2-yl)ethanone (1 g, 4.7 mmol) and silver trifluoroacetate (1.1 g, 5 mmol) in dry dichloromethane (24 mL), cooled to 0° C. The reaction mixture was allowed to warm up slowly to 18° C. (water bath) and stirred at the same temperature for 5 h. The solid was filtered, the organic phase washed with Na2S2O5 (5% aq. solution) until decoloration occurs and finally washed with H2O (1×20 mL). The organic phase was dried over Na2SO4 and filtered through a plough of SiO2 (hexane-EtOAc 4:1), to obtain compound 2,2,2-trichloro-1-(4-iodo-1H-pyrrol-2-yl)ethanone (IX) as an off-white solid (1.49 g, 94% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.[Br:16][C:17]1[S:21][C:20]([C:22]2[O:23][CH:24]=[C:25]([CH2:27]Cl)[N:26]=2)=[CH:19][C:18]=1[CH3:29]>>[Br:16][C:17]1[S:21][C:20]([C:22]2[O:23][CH:24]=[C:25]([CH2:27][O:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]4[CH:15]=[CH:14][N:13]=[CH:12]4)=[CH:4][CH:3]=3)[N:26]=2)=[CH:19][C:18]=1[CH3:29]
Reactant: Cc1cc(-c2nc(CCl)co2)sc1Br
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: Cc1cc(-c2nc(COc3ccc(CCCn4ccnc4)cc3)co2)sc1Br
Yield: 77 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 2-(5-bromo-4-methyl-2-thienyl)-4-chloromethyloxazole to give 2-(5-bromo-4-methyl-2-thienyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole. The yield was 77%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 92-93° C.
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[C:7]([NH:9][CH:10]2[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]2)[C:6]([F:20])=[CH:5][N:4]=1.[CH:21]1([C:24]2[C:29]([N:30]3[C:34]([CH:35]4[CH2:37][CH2:36]4)=[N:33][N:32]=[N:31]3)=[CH:28][C:27]([NH2:38])=[C:26]([F:39])[CH:25]=2)[CH2:23][CH2:22]1>CC(O)C>[CH:21]1([C:24]2[C:29]([N:30]3[C:34]([CH:35]4[CH2:37][CH2:36]4)=[N:33][N:32]=[N:31]3)=[CH:28][C:27]([NH:38][C:3]3[N:8]=[C:7]([NH:9][CH:10]4[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]4)[C:6]([F:20])=[CH:5][N:4]=3)=[C:26]([F:39])[CH:25]=2)[CH2:23][CH2:22]1
Reactant: CC1(C)CC(Nc2nc(Cl)ncc2F)CC(C)(C)N1
Reactant: Nc1cc(-n2nnnc2C2CC2)c(C2CC2)cc1F
Agent: Cl
Solvent: CC(C)O
Product: CC1(C)CC(Nc2nc(Nc3cc(-n4nnnc4C4CC4)c(C4CC4)cc3F)ncc2F)CC(C)(C)N1
Temperature: 70 °C
Yield: 68.5 %

Procedure:
A mixture of 2-chloro-5-fluoro-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidin-4-amine hydrochloride (256 mg, 0.791 mmol, 1 equiv), 4-cyclopropyl-5-(5-cyclopropyl-1H-tetrazol-1-yl)-2-fluorobenzenamine (205 mg, 0.791 mmol, 1 equiv), and PTSA monohydrate (120 mg, 0.633 mmol, 0.8 equiv) in IPA (8 mL) were heated to 70° C. for 8 days. After cooling to ambient temperature, the crude mixture was concentrated to dryness and taken in water, EtOAc, and 1N NaOH. The layers were separated. The organic layer was washed with 1N NaOH 2×, dried over Na2SO4, filtered, and concentrated to dryness. The crude product was purified by trituration from EtOAc:hexane to give compound N2-(4-cyclopropyl-5-(5-cyclopropyl-1H-tetrazol-1-yl)-2-fluorophenyl)-5-fluoro-N4-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidine-2,4-diamine (276 mg, 68%) as a solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]2[O:15][CH2:14][CH2:13][C:12]([C:16]([OH:18])=O)=[CH:11][C:10]=2[CH:19]=1.[CH3:20][N:21]([CH2:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)[CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>CN(C)C=O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]2[O:15][CH2:14][CH2:13][C:12]([C:16]([NH:33][C:32]3[CH:34]=[CH:35][C:29]([CH2:28][N:21]([CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH3:20])=[CH:30][CH:31]=3)=[O:18])=[CH:11][C:10]=2[CH:19]=1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Reactant: O=C(O)C1=Cc2cc(-c3ccco3)ccc2OCC1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccco4)ccc3OCC2)cc1)C1CCOCC1
Temperature: 25 °C
Yield: 37.3 %

Procedure:
To a solution of 7-(2-furyl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (0.15 g), 4-(N-methyl-N-(tetrahydropyran-4-yl)aminomethyl)aniline (0.15 g) and triethylamine (0.25 ml) in dimethylformamide (10 ml) was added diethyl cyanophosphate (0.13 ml) under ice-cooling, and the mixture was stirred under nitrogen atmosphere at room temperature over night. The solvent was evaporated, and the residue was purified with silica gel column (methanol/ethyl acetate/triethylamine) to give crude crystals, which were recrystallized from ethyl acetatehexane to give 7-(2-furyl)-N-(4-((N-tetrahydropyran-4-yl-N-methylamino)methyl)phenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 148) (0.1 g) as brown crystals.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:11]1([CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)([CH3:22])[CH3:21])[CH:15]=[CH:14][N:13]=[CH:12]1.C(N(CC)CC)C>ClCCl>[C:1]1([S:7]([O:29][C:26]2[CH:27]=[CH:28][C:23]([C:20]([NH:19][CH2:18][CH2:17][CH2:16][N:11]3[CH:15]=[CH:14][N:13]=[CH:12]3)([CH3:22])[CH3:21])=[CH:24][CH:25]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(NCCCn1ccnc1)c1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(NCCCn1ccnc1)c1ccc(OS(=O)(=O)c2ccccc2)cc1

Procedure:
A solution of benzenesulphonyl chloride (0.51 g) in dichloromethane (5 ml) was added in portions over 5 minutes to a solution of 4-{1-[3-(imidazol-1-yl)propylamino]-1-methylethyl}phenol (0.75 g) and triethylamine (0.29 g) in dichloromethane (5 ml) at 0° C. with stirring. The mixture was stirred at ambient temperature for 3 hours then diluted with dichloromethane and washed with water. The organic layer was separated, dried and evaporated. The residue was purified by flash column chromatography on silica using methanol as the mobile phase to give 4-{1-[3-(imidazol-1-yl)propylamino]-1-methylethyl}phenyl benzenesulphonate as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[CH2:11][C:12](=[O:16])C(O)=O)([O-:3])=[O:2].[OH-:17].[Na+].OO.Cl>O>[Cl:10][C:8]1[CH:7]=[CH:6][C:5]([CH2:11][C:12]([OH:16])=[O:17])=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=1
Reactant: [OH-]
Reactant: O=C(O)C(=O)Cc1ccc(Cl)cc1[N+](=O)[O-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Product: O=C(O)Cc1ccc(Cl)cc1[N+](=O)[O-]

Procedure:
The filtrate of Step A, above, is adjusted to pH 8-9 with 2 N sodium hydroxide and is heated at 35°-40° C. while adding a 3-6% aqueous hydrogen peroxide solution until samples no longer turn dark on treatment with 2 N sodium hydroxide. The tan precipitate is suspended in 1500 ml. of water, adjusted to pH 8-9 and similarly treated with aqueous hydrogen peroxide. The combined reaction mixtures are then acidified with concentrated hydrochloride acid to obtain a precipitate which are recovered by filtration, washed 3 times with water and dried in vacuo. The crude product (mp 145°-150° C.) is recrystallized from ether to obtain 4-chloro-2-nitro-phenylacetic acid, m.p. 156°-159° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][CH2:13][CH2:14][CH2:15][N:16]2[C:24](=[O:25])[NH:23][C:22]3[C:17]2=[N:18][C:19]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[N:20][C:21]=3[NH2:26])[CH:6]=1.C(N(C(C)C)CC)(C)C.Cl.[CH3:43][N:44]1[CH2:49][CH2:48][CH:47]([C:50](O)=[O:51])[CH2:46][CH2:45]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN1C(=O)CCC1>[CH3:1][O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][N:12]([CH2:13][CH2:14][CH2:15][N:16]2[C:24](=[O:25])[NH:23][C:22]3[C:17]2=[N:18][C:19]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[N:20][C:21]=3[NH2:26])[C:50]([CH:47]2[CH2:48][CH2:49][N:44]([CH3:43])[CH2:45][CH2:46]2)=[O:51])[CH:6]=1
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCNCc3cccc(CC(=O)OC)c3)c2n1
Reactant: CN1CCC(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(Cc3cccc(CC(=O)OC)c3)C(=O)C3CCN(C)CC3)c2n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The product from step (iii) (0.1 g), diisopropyl ethylamine (0.1 ml) and 1-methylpiperidine-4-carboxylic acid hydrochloride (45 mg) were dissolved in NMP (3 ml) then HATU (130 mg) added to the mixture. The mixture was stirred at rt for 5 h then purified by SCX and RPHPLC, which afforded the title compound. Yield 70 mg.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:40])[C@@H:6]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:7][C:8]1[CH:31]=[CH:30][C:11]([O:12][C:13]([NH:15][CH2:16][CH2:17][C@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:19](O)=[O:20])=[O:14])=[CH:10][CH:9]=1)[CH:2]=[CH2:3].[N:41]([CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:49][CH2:50][CH2:51][O:52][CH2:53][CH2:54][NH2:55])=[N+:42]=[N-:43].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:1]([O:4][C:5](=[O:40])[C@H:6]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13](=[O:14])[NH:15][CH2:16][CH2:17][C@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:19](=[O:20])[NH:55][CH2:54][CH2:53][O:52][CH2:51][CH2:50][O:49][CH2:48][CH2:47][O:46][CH2:45][CH2:44][N:41]=[N+:42]=[N-:43])=[CH:30][CH:31]=1)[NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:34])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1)NC(=O)OC(C)(C)C
Reactant: [N-]=[N+]=NCCOCCOCCOCCN
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: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCOCCOCCOCCN=[N+]=[N-])cc1)NC(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
518 mg (0.92 mmol) of the compound from example 2A was dissolved in 15 ml dichloromethane. 200 mg (0.92 mmol) 2-{2-[2-(2-Azidoethoxy)ethoxy]ethoxy}ethanamine, 160 μl (0.92 mmol) N,N-diisopropylethylamine and 348 mg (0.92 mmol) HATU were added. The reaction mixture was heated for 30 min in a sealed tube at 60° C. in a microwave synthesizer. From the reaction mixture the solvent was removed under reduced pressure. The raw product was purified by preparative RP-HPLC on a C18 column with a water methanol gradient from 9/1 to 1/9. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 276 mg (0.34 mmol, 37% of theory) of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[C:4]([CH3:13])[CH:3]=1.C([O-])(=O)C.[Na+].[Br:19]Br.[OH-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Br:19][C:10]1[S:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[CH3:13])=[CH:12][CH:11]=1
Reactant: Cc1cc(Br)ccc1-c1cccs1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1cc(Br)ccc1-c1ccc(Br)s1
Reaction time: 1 h

Procedure:
To a stirred homogeneous solution of 2-(4-bromo-2-methylphenyl)thiophene (5.0 mmol, from Step A) and sodium acetate (10 mmol) in acetic acid (25 mL), bromine (5.0 mmol) was added dropwise via syringe at rt over 20-30 min and the resulting mixture was stirred for 1 h. The reaction mixture was combined with 1 M sodium hydroxide (250 mL) and ethyl acetate (250 mL). Organic layer was separated, washed sequentially with 1M sodium hydroxide (100 mL) and brine (100 mL), and dried over sodium sulfate. Silica gel chromatography using hexanes as the eluant afforded the title compound: 1H NMR (CDCl3) 7.46 (d, J=0.6, 1H), 7.38 (dd, J=3.9, 0.6, 1H), 7.24 (d, J=3.9, 1H), 7.09 (d, J=2.9, 1H), 6.83 (d, J=2.9, 1H), 2.43 (s, 3H); HPLC A 4.41 min, ESI-MS (m/z)=334.