Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C1C=CC2N(O)N=NC=2C=1.O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:55]1[CH:60]=[CH:59][C:58]([C:61](O)=[O:62])=[CH:57][CH:56]=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[N:55]1[CH:60]=[CH:59][C:58]([C:61]([N:15]2[CH2:16][CH2:17][N:12]([S:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:18])[F:19])=[CH:8][CH:7]=3)(=[O:10])=[O:11])[CH2:13][CH2:14]2)=[O:62])=[CH:57][CH:56]=1
Reactant: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCNCC1
Reactant: O=C(O)c1ccncc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccncc1)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
To a solution of 1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (Description 1) (100 mg, 0.340 mmol) in DMF (5 ml) was added HOBT.H2O (52.0 mg, 0.340 mmol), HBTU (129 mg, 0.340 mmol), 4-pyridinecarboxylic acid (41.8 mg, 0.340 mmol) and DIPEA (0.178 ml, 1.019 mmol. The reaction mixture was stirred for 2 hours at room temperature. Reaction mixture was transferred to a 100 ml round bottom flask and was reduced to dryness in vacuo. The residue was dissolved in DCM (50 ml) and was transferred to a separating funnel then washed with saturated NaHCO3 solution (5 ml), twice. The organic layer was collected and dried with magnesium sulphate. The solid was removed by filtration and the filtrate collected in a 250 ml round bottom flask and reduced to dryness in vacuo. The residue was then dissolved in 1.8 ml 1:1 MeCN/DMSO and purified by MDAP in 2 batches. The fractions containing desired product were combined in a 250 ml round bottom flask and reduced in vacuo to yield the title compound (107 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:19]([CH:20]=[O:21])[C:18]=1[OH:25].O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:25][C:18]1[C:17]([F:16])=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=[O:21]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=Cc1cccc(F)c1O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1
Product: COc1cc2nccc(Oc3c(F)cccc3C=O)c2cc1OC
Temperature: 130 °C
Reaction time: 8 h

Procedure:
4-Chloro-6,7-dimethoxyquinoline (111 mg), 3-fluorosalicylaldehyde (280 mg), and 4-dimethylaminopyridine (244 mg) were suspended in monochlorobenzene (2 ml), and the suspension was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel using ethyl acetate-hexane for development to give 2-[(6,7-dimethoxy-4-quinolyl)oxy]-3-fluorobenzaldehyde.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[C:27]([NH:29][C:30]4[CH:35]=[CH:34][C:33]([CH:36]5[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]5)=[CH:32][N:31]=4)[C:26](=[O:42])[N:25]([CH3:43])[N:24]=3)[C:18]=1[CH2:44][OH:45])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:58][C:59]([F:62])([F:61])[F:60])(=O)=O.CCOC(C)=O>CN(C=O)C.O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[C:27]([NH:29][C:30]4[N:31]=[CH:32][C:33]([CH:36]5[CH2:41][CH2:40][N:39]([CH2:58][C:59]([F:62])([F:61])[F:60])[CH2:38][CH2:37]5)=[CH:34][CH:35]=4)[C:26](=[O:42])[N:25]([CH3:43])[N:24]=3)[C:18]=1[CH2:44][OH:45])[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1nc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccc(C3CCNCC3)cn2)c1=O
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1nc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccc(C3CCN(CC(F)(F)F)CC3)cn2)c1=O
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To a solution of 6-tert-butyl-8-fluoro-2-(2-(hydroxymethyl)-3-(1-methyl-6-oxo-5-(5-(piperidin-4-yl)pyridin-2-ylamino)-1,6-dihydropyridazin-3-yl)phenyl)phthalazin-1(2H)-one (10 mg, 16.4 μmol) in DMF (1 ml) was added potassium carbonate (6.8 mg, 49.2 μmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (3.81 mg, 2.36 μl, 16.4 μmol) at room temperature. The mixture was stirred for 8 h. at the same temperature. EtOAc was added into the reaction mixture (10 mL) and the mixture was poured into water (10 mL). Organic layer was separated, washed with water (4×5 mL), dried (Na2SO4), and evaporated under vacuum. Crude product was purified by preparative tlc (CH2Cl2:MeOH:NH4OH, 90:9.5:0.5) to give 8 mg of pure product (70% yield): m/z 692[M+H]+.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)=[N:10][OH:11].CC(C)([O-])C.[K+].C(OCC)(=O)C.O>O1CCCC1>[F:8][C:6]1[CH:5]=[CH:4][C:3]2[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)=[N:10][O:11][C:2]=2[CH:7]=1
Reactant: COc1cccc(C(=NO)c2ccc(F)cc2F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cccc(-c2noc3cc(F)ccc23)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Cool (2,4-difluoro-phenyl)-(3-methoxy-phenyl)-methanone oxime (52.66 g, 217 mmol) in tetrahydrofuran (500 mL) to 0° C. Add 1.0 M solution of potassium tert-butoxide in tetrahydrofuran (260 mL, 0.26 mol) and stir at room temperature for 1.5 hours. Reflux reaction mixture for an additional 1.5 hours. Cool to room temperature overnight. Dilute reaction mixture with ethyl acetate and water and separate. Dry the organic layer and concentrate to give the title compound as an oil. Purify by column chromatography (dichloromethane) and triturate with pentane to give the title compound as a white solid (30.2 g, 62% Yield). NMR and M/S are consistent with the final, desired compound. mp=68-69° C.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][C:16]1[CH:17]=[C:18]([CH:24]2[CH2:28][NH:27][C:26](=[O:29])[CH2:25]2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23].[CH2:30](O)[CH:31]=[CH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:30]([O:15][C:16]1[CH:17]=[C:18]([CH:24]2[CH2:28][NH:27][C:26](=[O:29])[CH2:25]2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH:31]=[CH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COc1ccc(C2CNC(=O)C2)cc1O
Reactant: OCC=Cc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C2CNC(=O)C2)cc1OCC=Cc1ccccc1
Temperature: 70 °C
Reaction time: 12 h
Yield: 72.2 %

Procedure:
Diisopropylazodicarboxylate (61 mg, 0.6 mmol) was added to a solution of 4-(3-hydroxy-4-methoxyphenyl)-2-pyrrolidone (63 mg, 0.3 mmol), cinnamyl alcohol (43 mg, 0.3 mmol) and triphenyl phosphine (157 mg, 0.6 mmol) in 3 mL of tetrahydrofuran and the reaction mixture was stirred at 70° C. After 12 hours, the same work-up procedure as described in Example 1 gave 70 mg (70%) of 4-(3-cinnamyloxy-4-methoxyphenyl)-2-pyrrolidone: 1H NMR (300 MHz, CDCl3) δ 7.40 (d, J=6.8 Hz, 2H), 7.31 (t, J=6.8 Hz, 2H), 7.25 (d, J=7.2 Hz, 1H), 6.86-6.81 (m, 2H), 6.71 (d, J=15.6 Hz, 1H), 6.42 (m, 1H), 5.92 (b, 1H), 4.76 (dd, J=6.0, 1.2 Hz, 2H), 3.87 (s, 3H), 3.71 (t, J=8.8 Hz, 1H), 3.64-3.56 (m, 1H), 3.35 (t, J=8.8 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:24])[C:10]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([O:22][CH3:23])[CH:16]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:25](Br)[C:26]#[CH:27].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:24])[C:10]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:27][C:26]#[CH:25])=[C:17]([O:22][CH3:23])[CH:16]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(CCNC(=O)C(O)c2ccc(Cl)c(Cl)c2)ccc1O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C#CCOc1ccc(CCNC(=O)C(O)c2ccc(Cl)c(Cl)c2)cc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-(3,4-dichloro-phenyl)-2-hydroxy-N-[2-(4-hydroxy-3-methoxy-phenyl)-ethyl]-acetamide, propargyl bromide (0.5 ml) and potassium carbonate (1.5 g) in dimethyl sulfoxide is stirred at +80° C. for 3 hours. The mixture is cooled to room temperature and water (150 ml) is added. The mixture is extracted with ethyl acetate (2×200 ml) and washed with brine (100 ml). The organic layers are collected, dried with MgSO4 and evaporated. 2-(3,4-Dichloro-phenyl)-2-hydroxy-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-acetamide is obtained which is purified by flash column chromatography on silica gel (ethyl acetate/hexane 2:1); the product is an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:19])[O:10][CH:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)[CH:5]=[CH:6][CH:7]=1.[CH2:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O)[CH3:21]>>[CH2:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9](=[O:19])[O:10][CH:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)[CH:3]=1)[CH3:21]
Reactant: O=C(Nc1cccc(Br)c1)OC1CN2CCC1CC2
Reactant: CCc1ccccc1B(O)O
Product: CCc1ccccc1-c1cccc(NC(=O)OC2CN3CCC2CC3)c1
Yield: 78 %

Procedure:
Using general procedure E, quinuclidin-3-yl 3-bromophenylcarbamate, 2-ethylphenylboronic acid and [PdCl2(pddf)]CH2Cl2 gave the title v compound as a white solid (110 mg, 78%). 1H NMR (400 MHz, CDCl3) δ 7.42-7.28 (m, 5H), 7.25-7.16 (m, 2H), 7.03-7.00 (m, 1H), 6.88 (br s, 1H), 4.83 (m, 1H), 3.27 (m, 1H), 2.98-2.70 (m, 5H), 2.61 (q, J=7.6 Hz, 2H), 2.08 (m, 1H), 1.92-1.80 (m, 1H), 1.75-1.65 (m, 1H), 1.63-1.55 (m, 1H), 1.46-1.37 (m, 1H), 1.10 (t, J=7.6 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 152.1, 141.7, 140.4, 139.9, 136.4, 128.6, 127.5, 127.4, 126.4, 124.3, 123.2, 118.4, 115.9, 71.0, 54.3, 46.2, 45.3, 25.0, 24.2, 23.4, 18.3, 14.5 ppm. Purity: 100% LCMS (214 nm & 254 nm); retention time 1.61 min; (M+1) 351.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:17]([CH2:20][C:21]1([CH3:32])[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][CH:23]([N:29]=[C:30]=[O:31])[CH2:22]1)=[C:18]=[O:19]>>[CH2:10]([N:8]([O:9][C:30]([NH:29][CH:23]1[CH2:24][C:25]([CH3:27])([CH3:28])[CH2:26][C:21]([CH2:20][NH:17][C:18]([O:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:19])([CH3:32])[CH2:22]1)=[O:31])[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Reactant: ON(Cc1ccccc1)Cc1ccccc1
Product: CC1(C)CC(NC(=O)ON(Cc2ccccc2)Cc2ccccc2)CC(C)(CNC(=O)ON(Cc2ccccc2)Cc2ccccc2)C1

Procedure:
The procedure of Example 1 is repeated using 10.66 g (50 mmol) of N,N-dibenzylhydroxylamine and 5.56 g (25 mmole) of 3-isocyanatomethyl-3,5,5-trimethylcyclohexylisocyanate. The residue is recrystallized from a 1:1 heptane: toluene solvent mixture to give 11.0 g (68%) of a white soldi, m.p. 139°-146° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=2)=[N:6][CH:7]=1.FC(F)OC1C=CC(B2OC(C)(C)C(C)(C)O2)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH3:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:5]2[N:6]=[CH:7][CH:2]=[CH:3][N:4]=2)=[CH:10][C:11]=1[N+:16]([O-:18])=[O:17]
Reactant: Cc1ccc(Nc2ncc(Br)cn2)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)OB(c2ccc(OC(F)F)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccc(Nc2ncccn2)cc1[N+](=O)[O-]
Temperature: 150 °C

Procedure:
To a solution of 5-bromo-N-(4-methyl-3-nitrophenyl)pyrimidin-2-amine 27 (0.5 mmol) in 1,4-dioxane (2.0 mL) is added 2-(4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 7 (0.5 mmol), Na2CO3 (1.5 mmol of a 3.0 M aq. solution) and Pd(PPh3)4 (0.025 mmol). The reaction is evacuated and backfilled with nitrogen twice then heated in the microwave oven at 150° C. for 10 min. The reaction mixture is diluted with water (10 mL) and extracted with DCM (2×50 mL). The organic layer is separated, dried over Na2SO4 and concentrated. Purification by preparative HPLC (ACN gradient 10-70%) affords 4-(difluoromethoxy)phenyl)-N-(4-methyl-3-nitrophenyl)pyrimidin-2-amine 28a. 1H NMR (400 MHz, d6-DMSO) δ 10.23 (s, 1H), 8.92 (s, 2H), 8.66 (d, J=2.4 Hz, 1H), 7.93 (dd, J=2.4, 8.4 Hz, 1H), 7.82 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.4 Hz, 1H), 7.31 (t, J=74.0 Hz, 1H), 7.29 (d, J=8.4 Hz, 2H), 2.47 (s, 3H). MS (m/z) (M+1)+: 373.1.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]([CH2:40][CH3:41])[CH:32]=1)=[O:30]>>[ClH:20].[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]([CH2:40][CH3:41])[CH:32]=3)=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: CCn1cc(C(=O)CCCCCBr)c2ccccc21
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: CCn1cc(C(=O)CCCCCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC2)c2ccccc21
Yield: 33.9 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.56 g) as starting compound and 6-bromo-1-(1-ethyl-1 H-indol-3-yl)-1-hexanone (1.50 g) were reacted and treated in the same manner as in Example 199 to give 0.41 g of 4-amino-5-chloro-2-methoxy-N-((1-(6-(1-ethyl-1 H-indol-3-yl)-6-oxohexyl)piperidin-4-yl)methyl)-benzamide hydrochloride.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]=[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=O)[CH3:21])[N:15]=1)[CH3:13])([CH3:4])([CH3:3])[CH3:2].[CH3:23][C:24]1[CH:25]=[C:26]([CH:28]=[C:29]([CH3:31])[CH:30]=1)[NH2:27]>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]=[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[N:27][C:26]2[CH:28]=[C:29]([CH3:31])[CH:30]=[C:24]([CH3:23])[CH:25]=2)[CH3:21])[N:15]=1)[CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)c1cccc(C(C)=Nc2ccccc2C(C)(C)C)n1
Reactant: Cc1cc(C)cc(N)c1
Solvent: Cc1ccccc1
Product: CC(=Nc1cc(C)cc(C)c1)c1cccc(C(C)=Nc2ccccc2C(C)(C)C)n1
Reaction time: 60 h

Procedure:
Monoimine (9,1.13 g, 3.87 mmol) and 3,5-dimethylaniline (0.5 g, 4.13 mmol) were dissolved in 25 ml of toluene. To this solution, molecular sieves (4 Å) were added. After standing for 60 hours the mixture was filtered. The solvent was removed in vacuo. The residue was recrystallised from ethanol. Yield 0.79 g (52%) of mixed diimine (12). 1H-NMR (CDCl3) δ 8.37 (d, 1H, Py-Hm), 8.32 (d, 1H, Py-Hm), 7.87 (t, 1H, Py-Hp), 7.42 (d, 1H, ArH), 7.18 (t, 1H, ArH), 7.07 (t, 1H, ArH), 6.76 (s, 1H, ArH), 6.54 (d, 1H, ArH), 6.46 (s, 2H, ArH), 2.40 (s, 3H, Me), 2.39 (s, 3H, Me), 2.33 (s, 3H, Me), 1.36 (s, 9H, But).
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[C:14]([F:16])[C:13]([O:17][CH2:18][CH:19]3[CH2:21][CH2:20]3)=[CH:12][C:11]=2[F:22])=[CH:6][N:5]=[C:4]([O:24][CH2:25][C@@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH3:27])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.[Cu]I>[CH:19]1([CH2:18][O:17][C:13]2[C:14]([F:16])=[CH:15][C:10]([C:9]3[O:23][C:2]4[CH:3]=[C:4]([O:24][CH2:25][C@@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH3:27])[N:5]=[CH:6][C:7]=4[N:8]=3)=[C:11]([F:22])[CH:12]=2)[CH2:21][CH2:20]1
Reactant: C[C@@H](COc1cc(Cl)c(NC(=O)c2cc(F)c(OCC3CC3)cc2F)cn1)NC(=O)OC(C)(C)C
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](COc1cc2oc(-c3cc(F)c(OCC4CC4)cc3F)nc2cn1)NC(=O)OC(C)(C)C
Temperature: 160 °C
Reaction time: 4 h
Yield: 32.8 %

Procedure:
A suspension of tert-butyl ((2S)-1-((4-chloro-5-((4-(cyclopropylmethoxy)-2,5-difluorobenzoyl)amino)pyridin-2-yl)oxy)propan-2-yl)carbamate (5.39 g), potassium carbonate (2.91 g) and copper(I) iodide (201 mg) in DMF (30 mL) was stirred at 160° C. for 4 hr under microwave irradiation. To the reaction mixture was added water, and the obtained mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and subjected to silica gel column chromatography (NH, ethyl acetate). The solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.64 g).
Reaction SMILES: C([O:9][C@H:10]1[C@:14]([F:16])([CH3:15])[C@H:13]([N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][C:20]([NH2:27])=[N:21][C:22]=3Cl)[O:12][C@@H:11]1[CH2:28][O:29]C(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH2:38]([OH:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.[H-].[Na+]>CN(C=O)C>[NH2:27][C:20]1[N:19]=[C:18]2[C:23]([N:24]=[CH:25][N:17]2[C@@H:13]2[O:12][C@H:11]([CH2:28][OH:29])[C@@H:10]([OH:9])[C@:14]2([F:16])[CH3:15])=[C:22]([O:45][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:21]=1
Reactant: C[C@@]1(F)[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@H]1n1cnc2c(Cl)nc(N)nc21
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(OCc3ccccc3)nc(N)nc21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a 500 mL of dry round-bottomed flask were added (2R,3R,4R,5R)-5-(2-amino-6-chloro-9H-purin-9-yl)-2-(benzoyloxymethyl)-4-fluoro-4-methyltetrahydrofuran-3-yl benzoate (6a, 8.0 g, 15.2 mmol) and anhydrous benzyl alcohol (128 mL). To another 250 mL of dry round-bottomed flask were charged NaH (60% in mineral oil, 2.44 g, 60.8 mmol) and anhydrous DMF (40 mL). The suspension was stirred at 0° C. in an ice-water bath. Benzyl alcohol (27 mL) was added drop-wise via a syringe. A solution was slowly formed and it was transferred to the nucleoside suspension quickly under a nitrogen atmosphere at room temperature. The mixture was heated to 50° C. and stirred. The reaction was complete after 3 h and cooled to ambient temperature. It was neutralized by the addition of 4 NHCl to ca. pH=7 (12 mL). The solution was concentrated under reduced pressure (4 mbar, 90° C. bath). The cloudy residue was diluted with dichloromethane (100 mL) and washed with water (3×30 mL), brine (30 mL) and dried over Na2SO4. The suspension was filtered and the filtrate was concentrated under reduced pressure to an oily residue. This was purified by column chromatography (Analogix, 0 to 8% gradient of MeOH in DCM). The product eluted at 4% MeOH in DCM. The product containing fractions were combined, concentrated under reduced pressure and dried (50° C., 0.2 mmHg, 17 h) to a white foam solid (4.57 g, 11.7 mmol, 77.2%).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29].[CH3:30][N:31]([CH3:41])[C:32]1[N:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[CH3:30][N:31]([CH3:41])[C:32]1[N:37]=[CH:36][C:35]([C:2]2[C:10]3[O:9][CH2:8][CH:7]([C:11]4[CH:16]=[CH:15][C:14]([CH:17]([CH3:18])[CH3:19])=[CH:13][CH:12]=4)[C:6]=3[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=2[CH3:29])=[CH:34][CH:33]=1
Reactant: CN(C)c1ccc(B(O)O)cn1
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1-c1ccc(N(C)C)nc1)OCC2c1ccc(C(C)C)cc1
Yield: 26 %

Procedure:
Using N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 35 and (6-(dimethylamino)pyridin-3-yl)boronic acid, the title compound was obtained in the same manner as in Example 107. Yield: 26%. Melting point: 217-220° C. (ethyl acetate-hexane).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:7][CH2:6][N:5](CC2C=CC=CC=2)[CH2:4]1.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32].CCN(C(C)C)C(C)C.C(C(O)=O)(F)(F)F>[Pd].C(Cl)Cl.CCO.CO>[CH3:1][NH:2][CH:3]1[CH2:7][CH2:6][N:5]([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:4]1
Reactant: CNC1CCN(Cc2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Agent: [Pd]
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CO
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CNC1CCN(S(C)(=O)=O)C1

Procedure:
3-(Methylamino)-1-(methanesulfonyl)pyrrolidine was prepared from 3-(methylamino)-1-benzylpyrrolidine after four steps: i) (Boc)2O, MeOH, rt; ii) H2 (1 atm), 10% Pd/C, EtOH; iii) CH3S(O)2Cl, i-Pr2NEt, CH2Cl2; iv) CF3CO2H, CH2Cl2. (m/z): [M+H]+ calcd for C6H14H2O2S: 179.08; found, 179.2. 3R-Methylamino-1-(methanesulfonyl)pyrrolidine was prepared in a similar manner from (3R)-(methylamino)-1-benzylpyrrolidine.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.[B-](F)(F)(F)[F:12].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[F:12][C:3]1[S:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1csc2ccccc12
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: Cc1c(F)sc2ccccc12
Temperature: 70 °C
Yield: 72 %

Procedure:
A stirred solution of 3-methylbenzothiophene (0.51 g, 3.37 mmol) in acetonitrile (5 μL) under nitrogen was treated with SELECTFLUOR™ (1.25 g, 3.35 mmol) and heated to 70° C. overnight. The solvent was removed in vacuo. The residue was taken up in ethyl acetate and washed with sodium hydrogen carbonate solution, water and brine, dried over MgSO4 and evaporated in vacuo. Purification by flash column chromatography on silica, eluting with isohexane, gave 2-fluoro-3-methyl-1-benzothiophene (72% pure, 190 mg, 0.82 mmol) which was treated according to the method of Example 29 Step 2 to give 3-(bromomethyl)-2-fluoro-1-benzothiophene (95 mg, 12%). 1H NMR (500 MHz, CDCl3) δ 7.75 (1H, d, J=8.0 Hz), 7.68 (1H, d, J=8.0 Hz), 7.46 (1H, t, J=7.6 Hz), 7.39–7.35 (1H, m), 4.65 (2H, s).
Reaction SMILES: ClC1C=C(C=CC=1)C(C1C2C=CC=CC=2OC=1C1C=CC(O)=CC=1)=O.C(C1OC1)Br.[Cl:31][C:32]1[CH:33]=[C:34]([CH:57]=[CH:58][CH:59]=1)[C:35]([C:37]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[O:39][C:38]=1[C:46]1[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH:54]2[O:56][CH2:55]2)=[CH:48][CH:47]=1)=[O:36].[CH:60]([NH2:63])([CH3:62])[CH3:61]>>[Cl:31][C:32]1[CH:33]=[C:34]([CH:57]=[CH:58][CH:59]=1)[C:35]([C:37]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[O:39][C:38]=1[C:46]1[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH:54]([OH:56])[CH2:55][NH:63][CH:60]([CH3:62])[CH3:61])=[CH:48][CH:47]=1)=[O:36]
Reactant: CC(C)N
Reactant: O=C(c1cccc(Cl)c1)c1c(-c2ccc(OCC3CO3)cc2)oc2ccccc12
Agent: BrCC1CO1
Agent: O=C(c1cccc(Cl)c1)c1c(-c2ccc(O)cc2)oc2ccccc12
Product: CC(C)NCC(O)COc1ccc(-c2oc3ccccc3c2C(=O)c2cccc(Cl)c2)cc1

Procedure:
Treatment of 3-m-chlorobenzoyl-2-p-hydroxyphenylbenzofuran with epibromohydrin as described in Example 26 followed by reaction of the 3-(3'-chlorobenzoyl)-2-[4'-(2,3-epoxypropoxy)phenyl]benzofuran with isopropylamine as described in Example 25 gave the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH:5]=[CH:6][C:7]([OH:9])=[O:8]>C(O)C.[Pt]=O>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][CH2:6][C:7]([OH:9])=[O:8])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14]
Reactant: COc1ccc(C=CC(=O)O)cc1F
Agent: O=[Pt]
Solvent: CCO
Product: COc1ccc(CCC(=O)O)cc1F
Reaction time: 1.5 h

Procedure:
2.0 g of 3-fluoro-4-methoxy cinnamic acid was dissolved in 100 ml ethyl alcohol. To this was added 100 mg of platinum oxide as a catalyst. The mixture was hydrogenated in a Parr apparatus for 90 minutes. After the hydrogenation was over, the mixture was filtered and concentrated. The solid was crystallized by adding water. Yield=1.63 g. m.p. 107°-112° C.