Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([CH3:31])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH3:30])[N:9]=3)[CH2:2]1.Br[CH2:33][C:34]1[O:38][N:37]=[CH:36][CH:35]=1>>[O:38]1[C:34]([CH2:33][N:1]2[CH2:2][CH:3]([CH2:5][C:6]3[N:7]([CH3:31])[C:8]4[C:13]([N:14]=3)=[C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[N:11]=[C:10]([N:21]3[C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=5[N:23]=[C:22]3[CH3:30])[N:9]=4)[CH2:4]2)=[CH:35][CH:36]=[N:37]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Reactant: BrCc1ccno1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(Cc4ccno4)C3)n(C)c2n1

Procedure:
Following General Procedure C, 4-(8-(azetidin-3-ylmethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine and 5-(bromomethyl)isoxazole were reacted to give 571. LCMS m/z: 250.7 (2M+H+)
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:9])([F:8])[CH2:5][CH2:6][OH:7].F[C:11]1[C:20]([CH3:21])=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][N:12]=1>C1COCC1.O>[CH3:21][C:20]1[C:11]([O:7][CH2:6][CH2:5][C:4]([F:9])([F:8])[F:3])=[N:12][CH:13]=[C:14]([CH:19]=1)[C:15]([OH:17])=[O:16]
Reactant: OCCC(F)(F)F
Reactant: COC(=O)c1cnc(F)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)O)cnc1OCCC(F)(F)F
Reaction time: 0.08 h
Yield: 100.3 %

Procedure:
To a solution of sodium hydride (0.844 g, 21.1 mmol) in THF (10 mL), 3,3,3-trifluoropropan-1-ol (1.61 g, 14.1 mmol) in THF (10 mL) is added at 0° C., and stirred for 5 minutes. Then methyl 6-fluoro-5-methylnicotinate (1.19 g, 7.04 mmol, Step-1) in THF (10 mL) is added dropwise to the reaction mixture and stirred at rt for 2 hours. The reaction mixture is diluted with water (30 mL) and stirred overnight. After removal of THF, the mixture is acidified with 2 M hydrochloric acid (11 mL). The resulting white precipitate is collected by filtration and dried to give 1.76 g (>99% yield) of the title compound as white solid. This material is used for the next reaction (Step-3) without further purification.
Reaction SMILES: C[Al](C)C.[F:5][C:6]([F:13])([C:9]([F:12])([F:11])[F:10])[CH2:7][NH2:8].C[O:15][C:16](=O)[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[C:26]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)=[N:27][O:28][C:29]=2[CH2:30][OH:31])=[N:19][CH:18]=1>O1CCOCC1>[F:38][C:35]1[CH:36]=[CH:37][C:32]([C:26]2[C:25]([CH2:24][O:23][C:20]3[CH:21]=[CH:22][C:17]([C:16]([NH:8][CH2:7][C:6]([F:13])([F:5])[C:9]([F:12])([F:11])[F:10])=[O:15])=[CH:18][N:19]=3)=[C:29]([CH2:30][OH:31])[O:28][N:27]=2)=[CH:33][CH:34]=1
Reactant: NCC(F)(F)C(F)(F)F
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)nc1
Agent: C[Al](C)C
Solvent: C1COCCO1
Product: O=C(NCC(F)(F)C(F)(F)F)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)nc1
Reaction time: 8 h
Yield: 77.4 %

Procedure:
Trimethylaluminium solution (2 M in toluene, 0.84 mL, 1.67 mmol) was added to a solution of 2,2,3,3,3-pentafluoropropylamine (121 μL, 1.12 mmol) in dioxane (4 mL). After stirring for 45 min at 50° C. a solution of 6-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (100 mg, 0.28 mmol) in dioxane (4 mL) was added and stirring was continued overnight at 85° C. The dioxane was removed by distillation. The remaining material was purified by chromatography (silica, ethyl acetate:heptane 1:1) to yield the title compound (103 mg, 77%) as a white solid. MS: m/e=474.2 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([NH2:15])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[C:16](OCC)(=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]3=[N:10][CH:11]=[CH:12][CH:13]=[C:14]3[N:15]=[C:16]2[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: Nc1cccnc1Nc1ccc(Cl)cc1
Product: CCOC(=O)c1nc2cccnc2n1-c1ccc(Cl)cc1
Temperature: 140 °C
Reaction time: 18 h

Procedure:
A mixture of N2-(4-chlorophenyl)pyridine-2,3-diamine (C9) (1.8 g, 8.2 mmol) and diethyl ethanedioate (18 g, 123 mmol) was stirred at 140° C. for 18 hours. Purification using silica gel chromatography (Gradient: 16% to 50% ethyl acetate in petroleum ether) provided the product as a brown solid, containing approximately 30% of a contaminant by 1H NMR analysis. Yield: 250 mg, 0.83 mmol, 10%. 1H NMR (400 MHz, CD3OD), product peaks only: δ 8.49 (dd, J=4.8, 1.5 Hz, 1H), 8.31 (dd, J=8.2, 1.4 Hz, 1H), 7.61 (br d, J=8.9 Hz, 2H), 7.52 (dd, J=8.2, 4.6 Hz, 1H), 7.49 (br d, J=8.9 Hz, 2H), 4.34 (q, J=7.2 Hz, 2H), 1.25 (t, J=7.2 Hz, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)(C(F)(F)F)=O>CCN(CC)CC>[CH2:11]([O:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[NH:8][CH:9]=[CH:10][C:3]=23)=[CH:23][CH:24]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Clc1ccnc2[nH]ccc12
Reactant: Oc1ccc(OCc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(COc2ccc(Oc3ccnc4[nH]ccc34)cc2)cc1

Procedure:
A mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine (1 g, 6.5 mmol), 4-benzyloxyphenol (1.5 g, 7.5 mmol) and Et3N:TFA (1.2 mL) was heated to 150° C. for 96 h. Formation of the compound was monitored by HPLC-mass spec. The crude was directly purified on silica gel without work-up using a Hexanes/EtOAc gradient (100/0 to 0/100) to afford 4-(4-benzyloxy-phenoxy)-1H-pyrrolo[2,3-b]pyridine.
Reaction SMILES: [C:1]([CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(=[O:4])[CH2:2][CH3:3].[F:16][C:17]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:18]=1[CH:19]=O>C1C=CC=CC=1.C([O-])(=O)C.[NH2+]1CCCCC1>[F:16][C:17]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:18]=1[CH:19]=[C:5]([C:1](=[O:4])[CH2:2][CH3:3])[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: O=Cc1ccc(F)cc1F
Reactant: CCC(=O)CC(=O)OCc1ccccc1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Product: CCC(=O)C(=Cc1ccc(F)cc1F)C(=O)OCc1ccccc1
Yield: 100.3 %

Procedure:
A solution of benzyl propionylacetate (157 g, 0.758 mol), 2,4-difluorobenzaldehyde (107.65 g, 0.758 mol), and piperidinium acetate (5.49 g, 38 mmol) in benzene (1 L) were stirred at room temperature for 96 h. The mixture was washed with water (2×100 mL), dried (magnesium sulfate) and the solvent evaporated under reduced pressure to yield the product as a pale yellow syrup (251.2 g) which was used in the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:16][C:17]([F:20])([F:19])[F:18])[CH2:10][CH:11]([CH3:15])[C:12]([OH:14])=O)=[CH:5][C:4]=1[C:21]([F:24])([F:23])[F:22])#[N:2].C(Cl)(=O)C(Cl)=O.C[N:32](C=O)C.[NH4+].[OH-]>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:16][C:17]([F:20])([F:19])[F:18])[CH2:10][CH:11]([CH3:15])[C:12]([NH2:32])=[O:14])=[CH:5][C:4]=1[C:21]([F:23])([F:24])[F:22])#[N:2]
Reactant: CN(C)C=O
Reactant: CC(CN(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(CN(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1)C(N)=O
Temperature: 42 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To an ice-cold solution of 3-[[4-cyano-3-(trifluoromethyl)phenyl](2,2,2-trifluoroethyl)amino]-2-methylpropanoic acid (0.050 g, 0.14 mmol) in CH2Cl2 (3 mL), under nitrogen was added oxalyl chloride (0.023 g, 0.18 mmol) and DMF (cat) and the mixture was heated at 42° C. for 30 min. Upon cooling, additional oxalyl chloride (0.014 g, 0.11 mmol) and DMF (cat.) were added and heated for 30 min. Upon cooling, NH4OH (30% aqueous solution, 5 mL) was added and the mixture stirred at rt. After 1 h, the mixture was partitioned between CH2Cl2 and water. The organic phase was washed with 0.1N HCl and brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (1-5% MeOH—CH2Cl2 gradient) to give the title compound (0.044 g, 88% yield): 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J=8.6 Hz, 1H), 7.01 (d, J=2.6 Hz, 1H), 6.89 (dd, J=8.6, 2.6 Hz, 1H), 5.70 (bs, NH), 5.54 (bs, NH), 4.22-4.08 (m, 2H), 3.85 (dd, J=15.4, 10.3 Hz, 1H), 3.54 (dd, J=15.4, 3.7 Hz, 1H), 2.80-2.70 (m, 1H), 1.23 (d, J=7.0 Hz, 3H).
Reaction SMILES: [CH2:1]([O:9][N:10]=[C:11]([C:17](=O)[CH2:18]Cl)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[NH2:21][C:22]([NH2:24])=[S:23].O.O.O.C([O-])(=O)C.[Na+].O>C(O)C>[NH2:24][C:22]1[S:23][CH:18]=[C:17]([C:11](=[N:10][O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:21]=1
Reactant: CCCCCCCCON=C(C(=O)CCl)C(=O)OCC
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCCCCCON=C(C(=O)OCC)c1csc(N)n1
Yield: 35.8 %

Procedure:
Ethyl 2-n-octyloxyimino-4-chloro-3-oxobutyrate (syn isomer, 169.6 g.), thiourea (42.3 g.), sodium acetate trihydrate (75.5 g.), water (420 ml.) and ethanol (1020 ml.) were treated in a similar manner to that of Example F-(3) to give ethyl 2-(2-aminothiazol-4-yl)-2-n-octyloxyiminoacetate (syn isomer, 65 g.), mp. 77° to 78° C.
Reaction SMILES: [N+:1]([C:4]1[CH:40]=[CH:39][C:7]([C:8](O[C@H]2CC3C(=CC=CC=3)[C@@H]2NC2C(CC)=NC(C3C=CC(Cl)=CC=3Cl)=C(CC)N=2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:41]([C:43]1[C:44]([NH:60][C@@H:61]2[CH2:65][O:64][CH2:63][C@H:62]2[OH:66])=[N:45][C:46]([CH2:58][CH3:59])=[C:47]([C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][C:50]=2[CH3:57])[N:48]=1)[CH3:42]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:66][C@H:62]2[C@@H:61]([NH:60][C:44]3[C:43]([CH2:41][CH3:42])=[N:48][C:47]([C:49]4[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][C:50]=4[CH3:57])=[C:46]([CH2:58][CH3:59])[N:45]=3)[CH2:65][O:64][CH2:63]2)=[O:9])=[CH:39][CH:40]=1)([O-:3])=[O:2]
Reactant: CCc1nc(-c2ccc(OC)cc2C)c(CC)nc1N[C@@H]1COC[C@H]1O
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@H]1c2ccccc2C[C@@H]1OC(=O)c1ccc([N+](=O)[O-])cc1
Product: CCc1nc(-c2ccc(OC)cc2C)c(CC)nc1N[C@H]1COC[C@H]1OC(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
Following the procedure for the preparation of (1S,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-yl 4-nitrobenzoate but substituting trans-(+/−)-4-{[3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-yl]amino}tetrahydrofuran-3-ol and making non-critical variations provided the title compound as a light yellow semi-solid. MS (ESI+) for m/z 507.1 (M+H)+.
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:17])=O>>[C:1]1([CH2:11][C:12]([Cl:17])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1cccc2ccccc12
Product: O=C(Cl)Cc1cccc2ccccc12
Reaction time: 2 h

Procedure:
15 g of 1-naphthyl acetic acid and 90 ml of thionyl chloride were heated with stirring for 2 hours and the solution was concentrated under reduced pressure. The residue was taken up in toluene and concentrated to dryness under reduced pressure to obtain 16.3 g of the expected product which used as is for the next step.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:3]=1.Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([Cl:1])=[N:3][C:4]=2[N:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: Clc1nc(N2CCOCC2)c2nc[nH]c2n1
Product: Clc1nc(N2CCOCC2)c2ncn(Cc3ccccc3)c2n1

Procedure:
4-(2-Chloro-9H-purin-6-yl)morpholine (75 mg) was reacted with (bromomethyl)benzene via General Procedure C to give 4-(9-benzyl-2-chloro-9H-purin-6-yl)morpholine which was reacted with 150 mg tert-butyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl carbonate via General Procedure A and purified via reverse phase HPLC to give 92.2 mg of 143 as a white solid. MS (Q1) 388.2 (M)+
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:49]2[CH2:51][CH2:50]2)=[N:4][N:5]([CH3:48])[C:6]=1[N:7]1[CH2:47][CH2:46][C:10]2[N:11]=[C:12]([C:25]3[C:33]([CH3:34])=[CH:32][CH:31]=[C:30]4[C:26]=3[C:27]([CH3:45])=[N:28][N:29]4S(C3C=CC(C)=CC=3)(=O)=O)[N:13]=[C:14]([N:15]3[CH2:20][CH2:19][C@@H:18]([O:21][CH3:22])[C:17]([CH3:24])([CH3:23])[CH2:16]3)[C:9]=2[CH2:8]1.C([O-])([O-])=O.[K+].[K+]>CO.CCOC(C)=O>[Cl:1][C:2]1[C:3]([CH:49]2[CH2:50][CH2:51]2)=[N:4][N:5]([CH3:48])[C:6]=1[N:7]1[CH2:47][CH2:46][C:10]2[N:11]=[C:12]([C:25]3[C:33]([CH3:34])=[CH:32][CH:31]=[C:30]4[C:26]=3[C:27]([CH3:45])=[N:28][NH:29]4)[N:13]=[C:14]([N:15]3[CH2:20][CH2:19][C@@H:18]([O:21][CH3:22])[C:17]([CH3:24])([CH3:23])[CH2:16]3)[C:9]=2[CH2:8]1
Reactant: CO[C@@H]1CCN(c2nc(-c3c(C)ccc4c3c(C)nn4S(=O)(=O)c3ccc(C)cc3)nc3c2CN(c2c(Cl)c(C4CC4)nn2C)CC3)CC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CO[C@@H]1CCN(c2nc(-c3c(C)ccc4[nH]nc(C)c34)nc3c2CN(c2c(Cl)c(C4CC4)nn2C)CC3)CC1(C)C
Reaction time: 2 h

Procedure:
To a solution of (R)-6-(4-chloro-3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-2-(3,5-dimethyl-1-tosyl-1H-indazol-4-yl)-4-(4-methoxy-3,3-dimethylpiperidin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (0.050 g, 0.068 mmol) in MeOH (3 mL) was added K2CO3 (0.057 g, 0.410 mmol). The mixture was heated at 55C. under a nitrogen atmosphere for 2 h. At that point the mixture was diluted with EtOAc and washed with sat aq NH4Cl and then brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by FCC (0-10% MeOH/DCM) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.59 (s, 1 H), 7.39 (d, J=8.3 Hz, 1 H), 7.21 (d, J=8.8 Hz, 1 H), 4.39 (d, J=14.9 Hz, 1 H), 4.25 (d, J=14.7 Hz, 1 H), 3.62-3.78 (m, 1 H), 3.56 (s, 3 H), 3.46-3.55 (m, 2 H), 3.30 (d, J=3.5 Hz, 1 H), 3.26 (s, 3 H), 2.99-3.08 (m, 1 H), 2.97 (dd, J=9.1, 4.0 Hz, 1 H), 2.92 (app. t, J=5.9 Hz, 2 H), 2.85 (d, J=12.9 Hz, 1 H), 2.18 (s, 3 H), 1.85-1.96 (m, 4 H), 1.74-1.82 (m, 1 H), 1.49-1.60 (m, 1 H), 0.92 (s, 3 H), (overlapped m, 2 H), 0.81 (s, 3H), 0.72-0.77 (m, 2 H); MS (ESI+) m/z 575.5 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C:25]3[CH2:26][CH2:27][O:28][CH2:29][CH:30]=3)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11].I[CH3:32]>CN(C=O)C.O>[O:28]1[CH2:27][CH:26]=[C:25]([C:24]2[C:19]([O:18][C:15]3[CH:14]=[CH:13][C:12]([C:10]([C:2]4[N:3]([CH3:32])[C:4]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=5[N:1]=4)=[O:11])=[CH:17][CH:16]=3)=[N:20][CH:21]=[CH:22][CH:23]=2)[CH2:30][CH2:29]1
Reactant: O=C(c1ccc(Oc2ncccc2C2=CCOCC2)cc1)c1nc2ccccc2[nH]1
Reactant: CI
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(C(=O)c2ccc(Oc3ncccc3C3=CCOCC3)cc2)nc2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of (1H-benzo[d]imidazol-2-yl)(4-(3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)methanone (0.350 g, 0.881 mmol) in DMF (5 mL) was treated with iodomethane (0.083 mL, 1.321 mmol). The mixture was stirred at RT and after 4 hours, it was diluted with water and extracted (2×) with DCM. The organic portions were combined and washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate, reduced and purified by column chromatography on silica gel using a gradient of 30 to 80% EtOAc in hexanes to afford (4-(3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)(1-methyl-1H-benzo[d]imidazol-2-yl)methanone as white solid. MS (ESI, pos. ion) m/z: 411.9 (M+1). IC50 (uM) +++++.
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[N:7]=1)[CH3:2].[CH:22]1([C:28](Cl)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:1]([C:3]1[S:4][C:5]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:28]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:29])[CH:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[N:7]=1)[CH3:2]
Reactant: O=C(Cl)C1CCCCC1
Reactant: CCc1nc(-c2cccc(C)c2)c(-c2ccnc(N)c2)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCc1nc(-c2cccc(C)c2)c(-c2ccnc(NC(=O)C3CCCCC3)c2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
To a solution of 4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine (0.80 g, 2.7 mmol) in tetrahydrofuran (10 mL) were added cyclohexanecarbonyl chloride (0.40 mL, 3.0 mmol) and triethylamine (0.39 mL, 2.8 mmol) sequentially, and the mixture was stirred for 1 hour at room temperature. To the reaction mixture was added an aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extracts were washed with an aqueous sodium hydrogen carbonate solution, then, dried and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=20:1 to 4:1) to obtain a crystal. This crystal was washed with hexane to obtain a title compound (0.83 g, yield 75%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2/[CH:14]=[N:15]/[S:16]([CH3:19])(=[O:18])=[O:17])=[CH:4][CH:3]=1.[C:20]1([CH2:26][CH2:27][CH2:28][Mg]Br)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH2:28][CH2:27][CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][CH:3]=1
Reactant: Br[Mg]CCCc1ccccc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1/C=N/S(C)(=O)=O
Product: Cc1noc(-c2ccc(Br)cc2)c1C(CCCc1ccccc1)NS(C)(=O)=O

Procedure:
Prepared according to the procedure described in Example 114, Step 3, using N-[1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-meth-(E)-ylidene]-methanesulfonamide and 3-(phenyl)propylmagnesium bromide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH2:25])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:33][O:34][CH2:35][CH2:36]N>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH:25][CH2:36][CH2:35][O:34][CH3:33])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(N)=O)C1
Reactant: COCCN
Product: COCCNC(=O)Nc1cn(-c2cccc(F)c2)cc1C(=O)N[C@H]1CCCN(C(=O)OC(C)(C)C)C1

Procedure:
Following general method 6, employing (S)-3-{[1-(3-fluorophenyl)-4-ureido-1H-pyrrole-3-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester and 2-methoxyethylamine, afforded the crude title compound as an orange foam (109 mg); LCMS (method B): RT=3.69 min, M+H+=504. This crude material was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[N:3]([C:13]2[N:14]=[CH:15][N:16]=[C:17]([NH2:20])[C:18]=2[N:19]=1)[C@@H:4]1[O:12][C@H:9]([CH2:10][OH:11])[C@@H:7]([OH:8])[C@H:5]1[OH:6].[CH2:21]([O:28][C:29]1[CH:30]=[C:31]([C:35]2[CH:40]=[CH:39][C:38]([CH2:41][NH2:42])=[CH:37][CH:36]=2)[CH:32]=[CH:33][CH:34]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)C(C)C)(C)C>C(O)CC>[CH2:21]([O:28][C:29]1[CH:30]=[C:31]([C:35]2[CH:36]=[CH:37][C:38]([CH2:41][NH:42][C:2]3[N:3]([C:13]4[N:14]=[CH:15][N:16]=[C:17]([NH2:20])[C:18]=4[N:19]=3)[C@@H:4]3[O:12][C@H:9]([CH2:10][OH:11])[C@@H:7]([OH:8])[C@H:5]3[OH:6])=[CH:39][CH:40]=2)[CH:32]=[CH:33][CH:34]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Nc1ncnc2c1nc(Br)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: NCc1ccc(-c2cccc(OCc3ccccc3)c2)cc1
Solvent: CCCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncnc2c1nc(NCc1ccc(-c3cccc(OCc4ccccc4)c3)cc1)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Yield: 57.6 %

Procedure:
A mixture of a 8-bromoadenosine (0.130 g), 3′-benzyloxy-biphenyl-4-ylmethylamine (0.326 g) and N,N-diisopropyl-ethylamine (0.262 mL) in 1-propanol (3.8 mL) was stirred under reflux for 24 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by column chromatography on amino-propylated silica gel (eluent: dichloromethane/methanol=12/1) to give the title compound (0.120 g).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:4]([C:15]([O:17][CH3:18])=[O:16])[CH2:3]1.[Cl:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:31][CH3:32])=[C:27](O)[CH:28]=2)[N:23]=[CH:22][N:21]=1>>[Cl:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:31][CH3:32])=[C:27]([O:1][C@H:2]3[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[C@@H:4]([C:15]([O:17][CH3:18])=[O:16])[CH2:3]3)[CH:28]=2)[N:23]=[CH:22][N:21]=1
Reactant: COC(=O)[C@H]1C[C@H](O)CCN1C(=O)OC(C)(C)C
Reactant: COc1cc2ncnc(Cl)c2cc1O
Product: COC(=O)[C@H]1C[C@@H](Oc2cc3c(Cl)ncnc3cc2OC)CCN1C(=O)OC(C)(C)C

Procedure:
1-tert-butyl 2-methyl (2R,4R)-4-hydroxypiperidine-1,2-dicarboxylate (16) was coupled to 4-chloro-7-methoxyquinazolin-6-ol analogously as for the equivalent step in Example 7 to give 1-tert-butyl 2-methyl (2R,4S)-4-[(4-chloro-7-methoxyquinazolin-6-yl)oxy]piperidine-1,2-dicarboxylate (17): 1H NMR Spectrum: (DMSO-d6) δ1.39-1.46 (10H, m), 1.73-1.84 (1H, m), 1.92-2.03 (1H, m), 2.10-2.18 (1H, m), 2.60-2.69 (1H, m), 3.15-3.40 (3H, m), 3.74-3.85 (1H, m), 4.01 (3H, s), 4.61-4.73 (1H, m), 5.06 (1H, s), 7.43 (1H, s), 7.47 (1H, s), 8.89 (1H, s), 8.97 (1H, s); Mass Spectrum: (M+H)+ 452.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH:9]=2)[O:4][C:3]=1[C:26](=[O:31])[C:27]([OH:30])([CH3:29])[CH3:28].[C:32]([O:35][CH2:36][C:37](Cl)=[O:38])(=[O:34])[CH3:33].C(#N)C>C(OCC)(=O)C>[C:32]([O:35][CH2:36][C:37]([NH:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=3)[CH:9]=2)[O:4][C:3]=1[C:26](=[O:31])[C:27]([OH:30])([CH3:28])[CH3:29])=[O:38])(=[O:34])[CH3:33]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CC(C)(O)C(=O)c1oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc2c1N
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(=O)OCC(=O)Nc1c(C(=O)C(C)(C)O)oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Temperature: 25 °C

Procedure:
The product of Step B (0.120 g; 0.253 mmol) and acetoxyacetyl chloride (0.11 mL; 1.01 mmol) were added to 2 mL of acetonitrile and stirred at room temperature. After 50 minutes the reaction mixture was diluted with ethyl acetate and washed two times with aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate then concentrated. The residue was triturated in 10 mL of methanol. The solid product was collected and rinsed two times with methanol then dried in vacuo. HPLC/MS 576.8 (M+2); Rt=4.32 min.