Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([O:21][CH3:22])=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([OH:23])[CH:3]=1.Br[CH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:22][O:21][C:19]([C:16]1[S:15][C:11]2[N:12]=[CH:13][N:14]=[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[O:23][CH2:25][CH:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[C:10]=2[C:17]=1[CH3:18])=[O:20]
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O)c2c1C
Reactant: BrCC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OCC3CCOCC3)c2c1C
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Methyl 4-(4-fluoro-2-hydroxyphenylamino)-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylate (100 mg) was dissolved in DMF (2 ml), 4-bromomethyltetrahydropyran (107 mg) and potassium carbonate (83 mg) were added. The reaction was stirred at 60° C. overnight. Then the reaction mixture was diluted with EtOAc and washed with water and brine. The solvent was removed in vacuo and the residue triturated with Et2O.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11]C)=[CH:4][C:5]([O:9][CH3:10])=[C:6]([CH:8]=1)[NH2:7].C[O:14][C:15]1[CH:23]=[CH:22][C:18](C(Cl)=O)=[CH:17][CH:16]=1>>[Cl:1][C:2]1[C:3]([OH:11])=[CH:4][C:5]2[O:9][C:10]([C:18]3[CH:22]=[CH:23][C:15]([OH:14])=[CH:16][CH:17]=3)=[N:7][C:6]=2[CH:8]=1
Reactant: COc1cc(OC)c(Cl)cc1N
Reactant: COc1ccc(C(=O)Cl)cc1
Product: Oc1ccc(-c2nc3cc(Cl)c(O)cc3o2)cc1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 16, from 5-chloro-2,4-dimethoxyaniline, and 4-methoxybenzoyl chloride and was obtained as an off-white solid, m.p. 254-256° C.; MS m/e 262 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=3)[O:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13]2)[CH2:8][CH2:7]1)[CH3:5].[CH3:29][C:30]1[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[C:31]=1[C:32](O)=[O:33]>>[C:25]([C:24]1[CH:23]=[CH:22][C:21]([C:12]2([CH:9]3[CH2:10][CH2:11][N:6]([CH:4]([CH3:5])[CH2:3][CH2:2][NH:1][C:32](=[O:33])[C:31]4[C:35]([CH3:39])=[CH:36][CH:37]=[CH:38][C:30]=4[CH3:29])[CH2:7][CH2:8]3)[O:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13]2)=[CH:28][CH:27]=1)#[N:26]
Reactant: CC(CCN)N1CCC(C2(c3ccc(C#N)cc3)Oc3ccccc3O2)CC1
Reactant: Cc1cccc(C)c1C(=O)O
Product: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(C2(c3ccc(C#N)cc3)Oc3ccccc3O2)CC1
Yield: 75 %

Procedure:
Using general procedure E, 4-{2-[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-benzo[1,3]dioxol-2-yl}-benzonitrile (see EXAMPLE 277) (64 mg, 0.17 mmol) and 2,6-dimethylbenzoic acid (28 mg, 0.19 mmol) afforded COMPOUND 279 as a white foam (65 mg, 75%). 1H NMR (CDCl3) δ0.93 (d, 3H, J=6.6 Hz), 0.94-1.23 (m, 2H), 1.42-1.58 (m, 3H), 1.65-1.78 (m, 1H), 1.86-1.98 (m, 2H), 2.28-2.36 (m, 1H), 2.31 (s, 6H), 2.68-2.79 (m, 3H), 3.26-3.36 (m, 1H), 3.71-3.82 (m, 1H), 6.76-6.80 (m, 4H), 7.03 (d, 2H, J=7.8 Hz), 7.15-7.20 (m, 1H), 7.43 (br s, 1H), 7.51-7.53 (m, 2H), 7.61-7.64 (m, 2H). ES-MS m/z 510 (M+H).
Reaction SMILES: [ClH:1].Cl.C([N:10]1[CH2:14][CH2:13][C:12]([OH:18])([CH2:15][NH:16][CH3:17])[CH2:11]1)C1C=CC=CC=1>CO.[Pd]>[ClH:1].[ClH:1].[OH:18][C:12]1([CH2:15][NH:16][CH3:17])[CH2:13][CH2:14][NH:10][CH2:11]1
Reactant: CNCC1(O)CCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CNCC1(O)CCNC1

Procedure:
6.9 g (23.5 mmol) of 1-benzyl-3-hydroxy-3-methylaminomethylpyrrolidine dihydrochloride in 100 ml of methanol are hydrogenated on 2 g of palladium/active carbon (10%) at 80° C. and 100 bar. The catalyst is filtered off with suction, the solution is concentrated and the residue is triturated with butanol. The crystalline salt is filtered off with suction, washed with acetone and dried.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([C:11]#[N:12])[C:6](=[CH:9][CH:10]=1)[C:7]#[N:8].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:33]>C1COCC1>[Br:33][CH2:2][C:3]1[CH:4]=[C:5]([C:11]#[N:12])[C:6](=[CH:9][CH:10]=1)[C:7]#[N:8]
Reactant: BrC(Br)(Br)Br
Reactant: N#Cc1ccc(CO)cc1C#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(CBr)cc1C#N
Reaction time: 21 h

Procedure:
4-Hydroxymethyl-phthalonitrile from step 2 (1.3 g, 8.2 mmol) was dissolved in THF (41 ml) and treated with Ph3P (3.2 g, 12.3 mmol) followed by CBr4 (4 g, 12.3 mmol). The reaction mixture was stirred at room temp. for 21 hours. The solvent was removed in vacuo and the residue purified by flash chromatography (15% EtOAc/Hexane) to yield the desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[C:6]([N+:11]([O-])=O)[CH:5]=1.[C:15]1([NH:21][C:22](=O)[CH3:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>FC(F)(F)C([O-])=O.[Pd+2].FC(F)(F)C([O-])=O.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:22]([CH3:23])=[N:11][C:6]=2[CH:5]=1)=[O:14]
Reactant: CC(=O)Nc1ccccc1
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Pd+2]
Agent: O=C([O-])C(F)(F)F
Agent: O=C([O-])[O-]
Product: COC(=O)c1ccc2c(c1)nc(C)n2-c1ccccc1
Yield: 78 %

Procedure:
The title compound was prepared following Method A at larger scale, from 4-chloro-3-nitrobenzoic acid methyl ester (5.39 g, 25 mmol), N-phenylacetamide (3.38 g, 25 mmol), palladium trifluoroacetate (416 mg, 1.25 mmol), BINAP (778 mg, 1.25 mmol) and Cs2CO3 11.4 g, 35 mmol) and refluxing just for 5 hours, giving rise to the title compound as colorless crystals (5.19 g, 78%). mp 108° C. to 110° C. 1H NMR (DMSO) δ 2.55 (s, 3H), 3.78 (s, 3H), 7.30 (d, J=8.2Hz, 1H), 7.52-7.71 (m, 5H), 7.92 (d, J=8.2Hz, 1H), 8.30 (br s, 1H); 13C NMR δ 13.6, 52.1, 110.8, 118.5, 124.7, 124.8, 127.0, 129.7, 130.1, 134.0, 137.9, 153.7, 157.8, 166.2. HRMS (FAB): cal. for C16H15N2O2 [M+H+]: 267.1134; found: 267.1128.
Reaction SMILES: C(=[N:8][C:9]1[N:10]=[CH:11][NH:12][C:13]=1[C:14]([NH2:16])=[O:15])C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])[CH2:28]Cl>>[NH2:8][C:9]1[N:10]=[CH:11][N:12]([CH2:28][C:27]2[CH:26]=[C:25]([O:24][CH3:23])[C:32]([O:33][CH3:34])=[C:31]([O:35][CH3:36])[CH:30]=2)[C:13]=1[C:14]([NH2:16])=[O:15]
Reactant: NC(=O)c1[nH]cnc1N=Cc1ccccc1
Reactant: COc1cc(CCl)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(Cn2cnc(N)c2C(N)=O)cc(OC)c1OC
Yield: 72.1 %

Procedure:
1.65 g (7.7 mmol) of 4-benzylideneamino-5-imidazole carboxamide, 4.26 g (30.8 mmol) of potassium carbonate, and 3.84 g (23 mmol) of 3,4,5-trimethoxybenzyl chloride were reacted in the same manner as in Reference Example 2 to obtain 1.7 g of 4-amino-1-(3,4,5-trimethoxybenzyl)-5-imidazole carboxamide (yield 73%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[S:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.[CH:24](N1CCCCC1)=[O:25]>O1CCCC1>[CH2:1]([O:8][CH2:9][C:10]1[S:11][C:12]([CH:24]=[O:25])=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CN1CCCCC1
Reactant: Brc1csc(COCc2ccccc2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1sc(COCc2ccccc2)cc1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 2-benzyloxymethyl-4-bromo-thiophene (29.2 g, 103 mmol, Intermediate (86)] in tetrahydrofuran (100 mL) was added dropwise a 1.8M solution of LDA in tetrahydrofuran (63 mL, 113 mmol) at 0° C. under nitrogen atmosphere. The solution was stirred at 0° C. for 30 minutes. Then N-formyl piperidine (13.75 mL, 127 mmol) was added and the reaction was stirred at 0° C. for 45 minutes, at room temperature for 15 minutes, and was quenched with saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residual oil was chromatographed through silica gel (n-heptane/ethyl acetate, 90/10 as eluant) to afford 5-benzyloxymethyl-3-bromo-thiophene-2-carbaldehyde [23.3 g, Intermediate (87)] as an orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH2:15]([S:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH:16]=[CH2:17]>>[CH2:15]([S:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)[CH:4]=2)=[O:26])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH:16]=[CH2:17]
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: C=CCS(=O)(=O)c1ccc(C(=O)O)cc1
Product: C=CCS(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
7.3 g of 4-(3-hydroxypropylthio)benzonitrile was reacted via Procedure R to yield 4-(3-hydroxypropylsulfonyl)benzonitrile. 1.9 g of NBS was added to a solution of 2 g of 4-(3-hydroxypropylsulfonyl)benzonitrile and 2.8 g of triphenylphosphine in 10 mL of dichloromethane at 0° C. The reaction mixture was stirred at 0˜5° C. for 1 h. The mixture was diluted with dichloromethane, washed with H2O, dried (MgSO4) and evaporated. Purified by silica gel chromatography (10-70% ethyl acetate/hexane) to afford 4-(3-bromopropylsulfonyl)benzonitrile. 300 mg of 4-(3-bromopropylsulfonyl)benzonitrile was reacted via Procedure T to give 4-(allylsulfonyl)benzoic acid. 40 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(allylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 4-(allylsulfonyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. MS (Q1) 413.2 (M)+.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH:3]([CH3:6])[CH:4]=O.S(=O)(=O)(O)O.Cl.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][C@H:32]([O:36][CH2:37][CH3:38])[C:33]([OH:35])=[O:34])=[CH:27][CH:26]=2)=[CH:18][CH:17]=1.[BH4-].[Na+]>O1CCCC1.ClCCl.CO>[CH2:37]([O:36][C@@H:32]([CH2:31][C:28]1[CH:29]=[CH:30][C:25]([O:24][CH2:23][CH2:22][C:19]2[CH:20]=[CH:21][C:16]([NH:15][CH2:4][CH:3]([CH3:6])[C:2]([F:8])([F:7])[F:1])=[CH:17][CH:18]=2)=[CH:26][CH:27]=1)[C:33]([OH:35])=[O:34])[CH3:38]
Reactant: CC(C=O)C(F)(F)F
Reactant: CCO[C@@H](Cc1ccc(OCCc2ccc(N)cc2)cc1)C(=O)O
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: CCO[C@@H](Cc1ccc(OCCc2ccc(NCC(C)C(F)(F)F)cc2)cc1)C(=O)O
Temperature: 0 °C
Yield: 54.1 %

Procedure:
2-(Trifluoromethyl)propionaldehyde (0.0724 g; 0.574 mmole) was dissolved in tetrahydrofurane (3 ml) and sulfuric acid (4 M; 0.041 ml; 0.164 mmole) was added under stirring, followed by addition of 3-{4-[2-(4-aminophenyl)ethoxy]phenyl}-(S)-2-ethoxypropanoic acid hydro chloride (described in Example 56a) (0.2 g; 0.547 mmole) dissolved in tetrahydrofurane (2 ml). The reaction mixture was stirred for 10 minutes, then cooled to 0° C in an ice-bath and sodium borohydride (0.042 g; 1.10 mmole) was added. After addition, the cooling bath was removed. The mixture was stirred overnight and then evaporated to remove tetrahydrofurane. Ethyl acetate and water were added into the residue and the organic phase was separated, washed with brine, dried with magnesium sulfate. The solvent was then evaporated. Chromatography on silica gel(Isolute, SI ) using dichloromethane and then 1% methanol in dichloromethane as eluant gave 0.13 g (40% yield) of (S)-2-ethoxy-3-(4-{2-[4-(3,3,3-trifluoro-2-methyl-(R/S)-propylamino)phenyl]ethoxy}phenyl)propanoic acid.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=3)=[CH:13][CH:12]=[N:11]2)=[CH:6][CH:5]=1>ClCCl>[Br:1][C:13]1[CH:12]=[N:11][N:10]([C:7]2[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=2)[C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=1
Reactant: CSc1ccc(-c2ccnn2-c2ccc(F)cc2)cc1
Reactant: BrBr
Solvent: ClCCl
Product: CSc1ccc(-c2c(Br)cnn2-c2ccc(F)cc2)cc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 63.6 %

Procedure:
A solution of bromine (0.9 g) in dichloromethane (2 ml) was added dropwise to an ice-cooled solution of 1-(4-fluorophenyl)-5-[4-(methylthio)phenyl]pyrazole (1.6 g) in dichloromethane (10 ml). The mixture was stirred at 5° C. for 1 hour, washed with a solution of sodium bisulfite and water, dried, and concentrated in vacuo. The residue (1.9 g) was recrystallized from ethanol to give crystals of 4-bromo-1-(4-fluorophenyl)-5-[4-(methylthio)phenyl]pyrazole (1.3 g).
Reaction SMILES: Cl.C([O:5][C@H:6]([CH3:33])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:16](=[O:17])[C:15]2[C:18](=[O:30])[CH:19]=[C:20]([CH3:29])[N:21]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:14]=2[N:13]([CH3:31])[C:12]1=[O:32])(=O)C>CO>[CH2:22]([N:21]1[C:14]2[N:13]([CH3:31])[C:12](=[O:32])[N:11]([CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]([OH:5])[CH3:33])[C:16](=[O:17])[C:15]=2[C:18](=[O:30])[CH:19]=[C:20]1[CH3:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(=O)cc(C)n(Cc3ccccc3)c2n(C)c1=O
Agent: Cl
Solvent: CO
Product: Cc1cc(=O)c2c(=O)n(CCCC[C@@H](C)O)c(=O)n(C)c2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
37% Aqueous hydrochloric acid (5 ml) was added to a solution of the crude (R)-3-(5-acetoxyhexyl)-8-benzyl-1,7-dimethylpyrido[2,3-d]pyrimidine-2,4,5(1H,3H,8H)-trione in methanol (20 ml). After stirring at room temperature for 18 hours, the solution was concentrated under reduced pressure. The residue was treated with water (20 ml) and extracted with ethyl acetate (2×20 ml). The combined extracts were concentrated under reduced pressure to provide an oil which solidified on standing. The solid was recrystallized (ethyl acetate-hexanes) to afford (R)-8-Benzyl-1,7-dimethyl-3-(5-hydroxyhexyl)pyrido[2,3-d]pyrimidine-2,4,5(1H,3H,8H)-trione (1.26 g, 60% yield for 2 steps) as a white powder. 1H NMR (300 MHz, CDCl3) δ 1.19 (d, 3H), 1.35-1.52 (m, 4H), 1.54-1.70 (m, 2H), 2.47 (s,3H), 3.63 (s, 3H), 3.78 (m, 1H), 4.05 (t, 2H), 5.29 (s, 2H), 6.54 (s, 1H), 7.25-7.55 (m, 5H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[C@@H:15]([CH2:16][CH3:17])[CH2:14][O:13][C:12]3=[O:18])=[N:7][C:6]=12.CC1(C)C(C)(C)OB([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[N:37]=[CH:36][N:35]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[N:34]=3)=[CH:29][CH:28]=2)O1.C([O-])([O-])=O.[Na+].[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:16]([C@H:15]1[CH2:14][O:13][C:12](=[O:18])[N:11]1[C:8]1[CH:9]=[CH:10][N:5]2[N:4]=[CH:3][C:2]([C:27]3[CH:28]=[CH:29][C:30]([C:33]4[N:37]=[CH:36][N:35]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[N:34]=4)=[CH:31][CH:32]=3)=[C:6]2[N:7]=1)[CH3:17]
Reactant: CC1(C)OB(c2ccc(-c3ncn(COCC[Si](C)(C)C)n3)cc2)OC1(C)C
Reactant: CC[C@H]1COC(=O)N1c1ccn2ncc(Br)c2n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(COCC[Si](C)(C)C)n4)cc3)c2n1
Temperature: 90 °C
Yield: 46.8 %

Procedure:
To a sealed tube was added (S)-3-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)-4-ethyloxazolidin-2-one (0.100 g, 0.321 mmol), 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole (0.168 g, 0.418 mmol) and 2.0 M Na2CO3 (0.482 mL, 0.964 mmol) in dioxane (1.6 mL). The mixture was degassed by bubbling N2 through the solution. Pd2 dba3 (0.0147 g, 0.0161 mmol), and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.0153 g, 0.0321 mmol) were added and the vessel was sealed under a N2 atmosphere. The mixture was heated at 90° C. for 18 hours. The reaction mixture was cooled to ambient temperature, filtered through glass fiber filter paper, concentrated and purified on silica gel (1-55% EtOAc in DCM) to provide (S)-4-ethyl-3-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)oxazolidin-2-one (0.076 g, 47% yield) as a yellow gum.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:21]=[CH:20][C:19]2[O:18][C:17]3[C:12](=[CH:13][C:14]([C:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26]Cl)=[CH:15][CH:16]=3)[CH2:11][C:10]=2[CH:9]=1)=[O:7].[I-].[K+].[CH2:31]([NH:34][CH2:35][CH:36]=[CH2:37])[CH:32]=[CH2:33]>O1CCCC1>[CH2:31]([N:34]([CH2:35][CH:36]=[CH2:37])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:21]=[CH:20][C:19]2[O:18][C:17]3[C:12](=[CH:13][C:14]([C:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][N:34]([CH2:35][CH:36]=[CH2:37])[CH2:31][CH:32]=[CH2:33])=[CH:15][CH:16]=3)[CH2:11][C:10]=2[CH:9]=1)=[O:7])[CH:32]=[CH2:33]
Reactant: O=C(CCCCCl)c1ccc2c(c1)Cc1cc(C(=O)CCCCCl)ccc1O2
Reactant: C=CCNCC=C
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCN(CC=C)CCCCC(=O)c1ccc2c(c1)Cc1cc(C(=O)CCCCN(CC=C)CC=C)ccc1O2
Temperature: 120 °C
Reaction time: 24 h

Procedure:
A mixture of 41.9 g (0.1 mole) of 2,7-bis(5-chlorovaleryl)-xanthene, 2 g of potassium iodide, 100 ml of diallylamine and 200 ml. of tetrahydrofuran was heated and stirred at 120°C. for 24 hours. After cooling, the reaction mixture was filtered and the filtrate evaporated to dryness. The resulting residue was cooled, dissolved in 10% HCl, extracted with diethyl ether and made alkaline. The product was extracted with methylene chloride, evaporated to dryness, recrystallized six times from heptane and dried in vacuo to give the desired product. M.P. 54°-55°C.
Reaction SMILES: Cl[C:2]1([NH2:20])[N:19]=[CH:18][N:17]=[C:16]2[C:3]1=[N:4][CH2:5][N:6]2[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9].[CH:21]1(N)[CH2:25][CH2:24][CH2:23][CH2:22]1>C(O)C>[CH:21]1([NH:20][C:2]2[C:3]3[N:4]=[CH:5][N:6]([C:16]=3[N:17]=[CH:18][N:19]=2)[C@@H:7]2[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]2[OH:9])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NC1(Cl)N=CN=C2C1=NCN2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: NC1CCCC1
Solvent: CCO
Product: OC[C@H]1O[C@@H](n2cnc3c(NC4CCCC4)ncnc32)[C@H](O)[C@@H]1O
Temperature: 8 °C
Reaction time: 12 h
Yield: 75.2 %

Procedure:
Step 1: 1 Liter of ethanol was charged into a reactor and stirred rapidly. 0.3 kg of 6-chloroadenosine and 0.267 kg of cyclopentylamine were added to the ethanol in the reactor. The reactor was heated to reflux for 2 hr, then cooled to 8 degrees C. and kept under these conditions for 12 hours. The crystallized material was filtered from the mother liquid and the solid cake was washed with 0.33 L of ethanol to produced a wet cake. The wet cake was dried to obtain N6-cyclopentyladenosine (0.249 kg).
Reaction SMILES: [N:1]1[C:2]([CH:14]=O)=[N:3][N:4]2[CH:13]=[CH:12][C:11]3[N:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]=12.[Cl-].[CH3:17][C:18]1[N:23]2[N:24]=[C:25]([CH2:27][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:26]=[C:22]2[CH:21]=[CH:20][CH:19]=1.C1CCN2C(=NCCC2)CC1>C1COCC1.C(Cl)Cl>[CH3:17][C:18]1[N:23]2[N:24]=[C:25](/[CH:27]=[CH:14]/[C:2]3[N:1]=[C:5]4[C:6]5[CH:7]=[CH:8][CH:9]=[N:10][C:11]=5[CH:12]=[CH:13][N:4]4[N:3]=3)[N:26]=[C:22]2[CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1nc2c3cccnc3ccn2n1
Reactant: Cc1cccc2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nn12
Agent: [Cl-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cccc2nc(/C=C/c3nc4c5cccnc5ccn4n3)nn12
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.9 %

Procedure:
To a solution of [1,2,4]triazolo[5,1-f][1,6]naphthyridine-2-carbaldehyde (20 mg, 0.1 mmol) in THF (1 mL) was added a solution of ((5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)methyl)triphenylphosphonium chloride (49 mg, 0.11 mmol) in DCM (3 mL), followed by the addition of DBU (45 mg, 0.3 mmol) at 0° C. under N2. The resulting mixture was stirred for 4 h at room temperature and diluted with DCM (15 mL). The mixture was washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a crude residue, which was purified by prep. TLC to afford the title compound (17 mg, yield 52%). ESI MS: m/z 328 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:31])[CH:3]=1.[H][H]>[Pd].CO>[NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([CH:16]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:18][CH2:17]4)[S:15][C:8]=23)=[C:4]([F:31])[CH:3]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Temperature: 25 °C
Yield: 98.3 %

Procedure:
A round-bottomed flask was charged with tert-butyl 4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl) -5,6-dihydropyridine-1(2H)-carboxylate (Example 149, Step A, 146.3 mg, 0.3314 mmol), palladium on carbon (117.7 mg, 0.099 mmol, 10%) and MeOH (10 mL). The air was exchanged with nitrogen three times and then was exchanged with hydrogen another three times. Then the reaction mixture was stirred under hydrogen at room temperature until the starting material had been consumed (2 hours). The mixture was filtered to remove the palladium on carbon and then the solvent was removed under reduced pressure to afford crude product. The crude product was purified by silica gel chromatography (dichloromethane/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (144.5 mg, 98.3%). LRMS (APCI pos): >95% purity, 254 nm, m/e 444 (M+1). 1H NMR (400 MHz, CD3Cl) δ 8.41 (d, 1H), 7.27 (m, 1H), 7.02 (t, 1H), 6.54 (dd, 1H), 6.46 (m, 2H), 4.24 (m, 2H), 3.84 (br s, 2H), 3.07 (m, 1H), 2.88 (m, 2H), 2.09 (m, 2H), 1.74 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: [I:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5](=[O:14])[NH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]O)=[CH:27][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.O>[I:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([O:14][CH2:29][C:28]2[CH:31]=[CH:32][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)=[N:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1
Reactant: COc1ccc(-c2[nH]c(=O)c3cc(OC)ccc3c2I)cc1
Reactant: COc1ccc(CO)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(COc2nc(-c3ccc(OC)cc3)c(I)c3ccc(OC)cc23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 25-mL flask under argon, 4-iodo-7-methoxy-3-(4-methoxyphenyl)isoquinolin 1(2H)-one (500 mg, 1.23 mmol) is dissolved in 15 mL of anhydrous THF. 4-methoxybenzyl alcohol (217 μl, 1.84 mmol), triphenylphosphine (482 mg, 1.84 mmol) and diisopropyl azodicarboxylate (261 μl, 1.84 mmol) are added to the previous solution. After stirring overnight at ambient temperature, the medium is hydrolyzed with 20 mL of water and extracted with 3×20 mL of dichloromethane. The organic phases are washed with 3×10 mL of water, dried over MgSO4 and concentrated under vacuum. Compound 69 is obtained by recrystallization from ether (358 mg, 55%). 1H NMR CDCl3 δ 7.94 (s, 1H), 7.89 (d, 1H), 7.34 (d, 1H), 6.98 (d, 2H), 6.91 (d, 2H), 6.81 (d, 2H), 6.72 (d, 2H), 5.19 (s, 2H), 3.97 (s, 3H), 3.88 (s, 3H), 3.74 (s, 3H);