Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:10]=[C:11]3[NH:19][C@H:18]([C:20]([F:23])([F:22])[F:21])[CH2:17][CH2:16][N:12]3[C:13](=[O:15])[CH:14]=1)[CH2:2]2.[H-].[Na+].Cl[CH2:27][C@H:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[OH:29]>CN(C=O)C>[OH:29][C@@H:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:27][N:19]1[C:11]2=[N:10][C:9]([N:3]3[CH2:4][CH:5]4[O:8][CH:1]([CH2:7][CH2:6]4)[CH2:2]3)=[CH:14][C:13](=[O:15])[N:12]2[CH2:16][CH2:17][C@H:18]1[C:20]([F:22])([F:21])[F:23]
Reactant: O=c1cc(N2CC3CCC(C2)O3)nc2n1CC[C@@H](C(F)(F)F)N2
Reactant: O[C@H](CCl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1cc(N2CC3CCC(C2)O3)nc2n1CC[C@@H](C(F)(F)F)N2C[C@@H](O)c1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 12 %

Procedure:
200 mg (0.61 mmol) of (8S)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one in 5 mL of DMF are added to a suspension of 60 mg (1.51 mmol) of sodium hydride in 5 mL of DMF. The reaction mixture is heated at 50° C. for 10 minutes. After addition of 142 mg (0.91 mmol) of (S)-2-chloro-1-phenylethanol, the reaction is continued at 90° C. overnight. The reaction medium is evaporated to dryness. The residue is purified by chromatography on a column of silica (eluent: 90/10 DCM/MeOH). The isolated fraction is recrystallized from acetonitrile to give 33 mg of (8S)-9-((S)-2-hydroxy-2-phenylethyl)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, the characteristics of which are as follows:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22]2)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][N:37]([C:40](=[O:42])[CH3:41])[CH2:36][CH2:35]2)=[CH:30][CH:29]=1.C[Si](Cl)(C)C>CCCCO>[OH:26][C@H:23]1[CH2:24][CH2:25][N:21]([C:4]2[C:5]3[CH:10]=[CH:9][N:8]([S:11]([C:14]4[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=4)(=[O:13])=[O:12])[C:6]=3[N:7]=[C:2]([NH:27][C:28]3[CH:29]=[CH:30][C:31]([N:34]4[CH2:35][CH2:36][N:37]([C:40](=[O:42])[CH3:41])[CH2:38][CH2:39]4)=[CH:32][CH:33]=3)[N:3]=2)[CH2:22]1
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N4CC[C@H](O)C4)nc(Cl)nc32)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC(=O)N1CCN(c2ccc(Nc3nc(N4CC[C@H](O)C4)c4ccn(S(=O)(=O)c5ccc(C)cc5)c4n3)cc2)CC1
Yield: 27.1 %

Procedure:
A mixture of (S)-1-(2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-ol (201 mg, 0.512 mmol), 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (160 mg, 0.730 mmol) and trimethylsilyl chloride (0.200 mL, 1.58 mmol) in n-BuOH (5 mL) was stirred at 120° C. for 40 h. n-BuOH was removed in vacuo. The residue was purified by HPLC to give (S)-1-(4-(4-(4-(3-hydroxypyrrolidin-1-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone (80 mg). MS 576.5 (M+H)
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].Cl[S:27]([C:30]1[CH:39]=[CH:38][CH:37]=[CH:36][C:31]=1[C:32]([O:34][CH3:35])=[O:33])(=[O:29])=[O:28]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:27]([C:30]4[CH:39]=[CH:38][CH:37]=[CH:36][C:31]=4[C:32]([O:34][CH3:35])=[O:33])(=[O:29])=[O:28])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Agent: Cl
Product: COC(=O)c1ccccc1S(=O)(=O)N1CCC(N2N=C(c3ccc(OC)c(OC)c3)C(C)(C)C2=O)CC1

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and methyl 2-(chlorosulfonyl)benzoate as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C@@H:4]([C:5]#[C:6][C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11].[CH:30]1([CH2:33]O)[CH2:32][CH2:31]1>>[CH3:1][C:2]1([CH3:29])[C@@H:4]([C:5]#[C:6][C:7]([O:9][CH2:33][CH:30]2[CH2:32][CH2:31]2)=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11]
Reactant: OCC1CC1
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1C#CC(=O)O
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1C#CC(=O)OCC1CC1

Procedure:
Using the procedure of Step A of Example 7, 1.4 g of (S)α-cyano-3-phenoxy-benzyl(1R,cis)2,2-dimethyl-3-(2-carboxyethynyl)-cyclopropane-carboxylate and 0.3 ml of cyclopropylcarbinol were reacted and the product was chromatographed over silica gel. Elution with an 8-2 cyclohexane-ethyl acetate mixture yielded 1.5 g of (S)α-cyano-3-phenoxybenzyl(1R,cis)2,2-dimethyl-3-(cyclopropylmethoxycarbonylethynyl)-cyclopropane-carboxylate melting at 72° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:17][CH2:18][CH:19]3[CH2:23][O:22][C:21]([CH3:25])([CH3:24])[O:20]3)=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[CH:5]=[C:4]([NH:26][C:27]2[CH:31]=[C:30]([CH3:32])[NH:29][N:28]=2)[N:3]=1>CC(O)C>[CH3:24][C:21]1([CH3:25])[O:20][CH:19]([CH2:18][O:17][C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][C:9]=2[O:12][CH2:13][CH2:14][O:15][CH3:16])[C:2]([O:12][CH:9]([CH3:10])[CH3:8])=[N:3][C:4]([NH:26][C:27]2[CH:31]=[C:30]([CH3:32])[NH:29][N:28]=2)=[CH:5]3)[CH2:23][O:22]1
Reactant: COCCOc1cc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2cc1OCC1COC(C)(C)O1
Solvent: CC(C)O
Product: COCCOc1cc2c(OC(C)C)nc(Nc3cc(C)[nH]n3)cc2cc1OCC1COC(C)(C)O1

Procedure:
Similar procedure as described in example 10 was used, starting from [1-Chloro-6-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-7-(2-methoxy-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine and 2-propanol to give [6-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-1-isopropoxy-7-(2-methoxy-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 501(MH+).
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[CH2:6][NH:7][C:8](=[O:38])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28](=[O:37])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35]Br)[CH:30]=2)[CH:10]=1.[N-:44]=[N+:45]=[N-:46].[Na+]>CN(C)C=O.O>[F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[CH2:6][NH:7][C:8](=[O:38])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28](=[O:37])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][N:44]=[N+:45]=[N-:46])[CH:30]=2)[CH:10]=1
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CBr)c2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 49.8 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-(3-(bromomethyl)benzamido)-5-(piperidin-1-yl)phenyl)isonicotinamide (200 mg, 0.18 mmol, 1.00 equiv, 60%) in N,N-dimethylformamide (5 mL), and NaN3 (70 mg, 1.08 mmol, 5.00 equiv). The resulting solution was stirred for 2 h at 80° C. in an oil bath. The resulting solution was diluted with 25 mL of water. The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1×50 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:2). The product was obtained as 55 mg (49%) a yellow solid.
Reaction SMILES: [CH3:1][Mg+].[Br-].[Cl:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH2:11][C:10](=[O:15])[CH2:9][CH2:8]2>C(Cl)Cl.O.Cl[Ti](Cl)(Cl)Cl>[Cl:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH2:11][C:10]([CH3:1])([OH:15])[CH2:9][CH2:8]2
Reactant: C[Mg+]
Reactant: O=C1CCc2cc(Cl)ccc2C1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Br-]
Solvent: O
Solvent: ClCCl
Product: CC1(O)CCc2cc(Cl)ccc2C1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of TiCl4 (95 mL, 1M in toluene) at −45° C. is added a solution of CH3MgBr (4.2 mL 3M in THF). The solution is stirred for 20 minutes. After this time, 6-chloro-3,4-dihydro-1H-naphthalene-2-one (11.3 g, 63 mmol) in 80 mL of CH2Cl2 is added dropwise over 15 minutes. The reaction is stirred for an additional 15 min at −45° C. The solution is warmed to 0° C. After 2 h, the solution is diluted with H2O and CH2Cl2. The organic layer is dried over MgSO4, filtered and concentrated. The title compound is obtained as an oil (11.3 g, 57.5 mmol). 1H NMR (CDCl3, 300 MHz) δ7.10 (m, 2H), 6.97 (m, 1H), 3.02 (m, 2H), 2.80 (s, 3H), 1.85 (m, 2H), 1.80 (m, 2H).
Reaction SMILES: F[B-](F)(F)F.[F:6][S:7]([F:19])([F:18])([F:17])([F:16])[C:8]1[CH:13]=[CH:12][C:11]([N+:14]#[N:15])=[CH:10][CH:9]=1.[C:20]1([OH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])(=O)C.[Na+]>C(#N)C>[OH:26][C:20]1[CH:25]=[CH:24][C:23](/[N:15]=[N:14]/[C:11]2[CH:12]=[CH:13][C:8]([S:7]([F:16])([F:17])([F:18])([F:19])[F:6])=[CH:9][CH:10]=2)=[CH:22][CH:21]=1
Reactant: Oc1ccccc1
Reactant: N#[N+]c1ccc(S(F)(F)(F)(F)F)cc1
Agent: CC(=O)[O-]
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CC#N
Product: Oc1ccc(/N=N/c2ccc(S(F)(F)(F)(F)F)cc2)cc1
Yield: 61.7 %

Procedure:
Diazonium salt 1 (11.6 mg, 0.0365 mmol), phenol (9.5 mg, 0.10 mmol), and sodium acetate (10.2 mg, 0.124 mmol) were dissolved in 0.21 g of acetonitrile. After 1 month, the solution was filtered through Celite 545. Evaporation of the solvent gave a red oil, which was purified by SiO2 column chromatography (9:1 hexane/ethyl acetate) and following preparative TLC (SiO2, CH2Cl2) afforded 27d as yellow-orange crystals (7.3 mg, 62%); m.p. 110.0-111.0° C. IR (ATR): {tilde over (v)}=3261, 1593, 1505, 1467, 1436, 1402, 1271, 1235, 1142, 1094, 829 cm−1. MS (GC, EI): m/z=324 [M+], 305 [M+-F], 197, 121, 93, 65. 1H NMR (500 MHz, CDCl3): δ=7.92-7.88 (m, 6H), 6.97 (d, J=8.8 Hz, 2H), 5.50 (br. s, 1H) ppm. 13C NMR (125 MHz, CDCl3): δ=159.1 (C), 154.4 (C), 153.7 (C), 147.0 (C), 127.0 (2CH), 125.6 (2CH), 122.5 (2CH), 116.0 (2CH) ppm. 19F NMR (470 MHz, CDCl3): δ=84.1 (quint, J=150 Hz, 1 F), 63.2 (d, J=150 Hz, 4 F) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][CH2:30]CS([O-])(=O)=O)[CH2:13][C:12](=[O:14])[N:11]([CH2:15][C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:37]1([C:43]2([C:49]([NH2:51])=[O:50])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][CH2:30][N:46]3[CH2:45][CH2:44][C:43]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)([C:49]([NH2:51])=[O:50])[CH2:48][CH2:47]3)[CH2:13][C:12](=[O:14])[N:11]([CH2:15][C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: COc1cc(CN2CC(CCCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)CC2=O)cc(OC)c1OC
Agent: Cl
Product: COc1cc(CN2CC(CCCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)CC2=O)cc(OC)c1OC

Procedure:
Prepare according to the method of example 3.3 using 3--[3-(3,4-dichloro-phenyl)-1(3,4,5-trimethoxy-benzyl)-5-oxo -pyrrolidin-3-yl]-propyl-methanesulfonate (5 mmol) and 4-phenyl -piperidine-4-carboxylic acid amide hydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [OH:1][CH:2]([PH:4](=[O:6])[OH:5])[CH3:3].[CH2:7](O)[CH2:8][CH2:9][CH3:10].O>C1C=CC=CC=1>[OH:1][CH:2]([PH:4](=[O:5])[O:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:3]
Reactant: CC(O)[PH](=O)O
Reactant: CCCCO
Solvent: c1ccccc1
Solvent: O
Product: CCCCO[PH](=O)C(C)O
Yield: 81.6 %

Procedure:
A solution of α-hydroxyethylphosphinic acid (2.2 g) and 1-butanol (5.0 g) in benzene (30 ml) was heated for 3 hours with removal of water through a Dean-Stark apparatus. After cooling, the reaction mixture was washed with water, dried over magnesium sulfate and concentrated in vacuo to give 2.71 g (81.6%) of n-butyl α-hydroxyethylphosphinate (Compound No. 5).
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:38]=[CH:37][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30]CCCCCC)=[O:29])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.F[C:40]1[CH:50]=[CH:49][C:43]([O:44][CH2:45][C@@H:46]2[CH2:48][O:47]2)=[CH:42][CH:41]=1>>[CH2:7]([C:49]1[CH:50]=[CH:40][CH:41]=[CH:42][C:43]=1[O:44][CH2:45][C@@H:46]([OH:47])[CH2:48][NH:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([N:27]([CH2:25][CH2:26][CH2:21][CH2:22][CH2:23][CH3:24])[C:28]([NH2:30])=[O:29])=[CH:25][CH:26]=3)(=[O:20])=[O:19])[CH2:14][CH2:13]2)=[CH:37][CH:38]=1)[CH:6]=[CH2:5]
Reactant: Fc1ccc(OC[C@@H]2CO2)cc1
Reactant: CCCCCCNC(=O)Nc1ccc(S(=O)(=O)N2CCC(Nc3ccc(CCN)cc3)CC2)cc1
Solvent: O=CO
Product: C=CCc1ccccc1OC[C@@H](O)CNCCc1ccc(NC2CCN(S(=O)(=O)c3ccc(N(CCCCCC)C(N)=O)cc3)CC2)cc1
Yield: 36.9 %

Procedure:
N-[4-({4-[4-(2-Aminoethyl)anilino]-1-piperidinyl}sulfonyl)phenyl]-N′-hexylurea formate (0.172 g 0.314 mmol) was reacted (2S)-2-[(4-fluorophenoxy)methyl]oxirane (0.06 g, 0.315 mmol) according to Procedure G to give the title compound (0.04 g, 0.058 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.[CH3:14][CH:15](O)[CH:16]=[CH2:17].COC(OC)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:14]([CH:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]1=[O:13])[CH:15]=[CH:16][CH3:17]
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: COC(C)(C)OC
Product: CC=CCC1CCc2cc(OC)ccc2C1=O
Reaction time: 50 h
Yield: 57 %

Procedure:
3,4-dihydro-6-methoxy-1(2H)-naphthalenone (198 g) was dissolved in 2000 ml of toluene under argon and treated in succession with 193 ml of 3-buten-2-ol, 206 ml of 2,2-dimethoxypropane and 1.9 g of p-toluenesulphonic acid. The reaction mixture was boiled at reflux for 20 hours, treated with a further 175 ml of 3-buten-2-ol and 180 ml of 2,2-dimethoxypropane and boiled for a further 50 hours. After cooling the solution was washed with 500 ml of saturated sodium hydrogen carbonate solution, the aqueous phase was extracted once with 600 ml of ethyl acetate, the organic phases were combined, dried with MgSO4 and freed from solvent. The residue, 269 g of brown oil, was chromatographed on 3000 g of silica gel with hexane/diethyl ether (5:1) as the eluent. There were obtained 147 g (57%) of 2-(2-butenyl)-3,4-dihydro-6-methoxy-1(2H)-naphthalenone which was processed without further purification.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[NH2:11][C:12]1[S:13][C:14]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[C:15]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1>>[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:15]1[N:16]=[C:12]([NH:11][C:2]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)=[O:9])[S:13][C:14]=1[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: Nc1nc(-c2ccco2)c(N2CCOCC2)s1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Product: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)c1cccnc1
Yield: 60.6 %

Procedure:
In a manner similar to that in Example 1, by using nicotinoyl chloride hydrochloride (356 mg, 2.00 mmol) in place of isonicotinoyl chloride hydrochloride and using 2-amino-4-(2-furyl)-5-morpholinothiazole (251 mg, 1.00 mmol) obtained in Step 1 of Example 29 in place of Compound a obtained in Reference Example 1, the entitled Compound 31 (216 mg, 61%) was obtained.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[CH:5][C:6]([F:28])=[C:7]([N:9]2[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])=[C:11]([Br:26])[C:10]2=[O:27])[CH:8]=1.C(N(CC)CC)C.[C:36]([O:39][CH2:40][C:41](Cl)=[O:42])(=[O:38])[CH3:37].[Cl-].[NH4+]>O1CCCC1>[C:36]([O:39][CH2:40][C:41]([NH:2][C:3]1[CH:4]=[CH:5][C:6]([F:28])=[C:7]([N:9]2[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])=[C:11]([Br:26])[C:10]2=[O:27])[CH:8]=1)=[O:42])(=[O:38])[CH3:37]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1cc(N)ccc1F
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OCC(=O)Nc1ccc(F)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of the compound of Example 722 (0.5 g, 1.05 mmol) in tetrahydrofuran (20 mL) was treated with triethyl amine (0.3 mL, 2.1 mmol) and acetoxy acetylchloride (0.12 mL, 1.15 mmol). After stirring at room temperature for 2 h, the reaction was complete. The reaction mixture was poured into saturated aqueous ammonium chloride. The solids were filtered off and were washed with water and diethyl ether. Title product was isolated as a white solid (0.32 g, 58%). 1H NMR (400 MHz, CD3OD) δ 7.65 (m, 3H), 7.32 (t, J=8.4 Hz, 1H), 7.04 (t, J=8.4 Hz, 2H), 6.64 (s, 1H), 5.35 (s, 2H), 4.68 (s, 2H), 2.15 (s, 3H), 2.10 (s, 3H) ppm. 19F NMR (400 MHz, CD3OD) δ −111.56 (1F), −115.99 (1F), −129.48 (1F) ppm. LC/MS, tr=5.35 minutes (5 to 95% acetonitrile/water over 8 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 540 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].[Na+].[CH3:15][Si:16]([CH2:19][CH2:20][O:21][CH2:22]Cl)([CH3:18])[CH3:17]>>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([CH2:22][O:21][CH2:20][CH2:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[C:6]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1nc[nH]c1-c1ccccc1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Product: Cc1ncn(COCC[Si](C)(C)C)c1-c1ccccc1
Yield: 44.3 %

Procedure:
Reaction of 4-methyl-5-phenyl-1H-imidazole (400 mg, 2.53 mmol), NaH (60%, 98 mg, 2.46 mmol), and SEMCl (474 uL, 2.68 mmol) followed by column chromatography on silica gel (hexane/EtOAC 3:2) gave the title compound (323 mg, 46%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 0.00 (s, 9H), 0.92 (t, 2H, J=7.5 Hz), 2.47 (s, 3H), 3.52 (t, 2H, J=7.5 Hz), 5.26 (s, 2H), 7.26-7.27 (m, 1H), 7.41 (dd, 2H, J=7.5, 7.5 Hz), 7.57 (s, 1H), 7.68 (d, 2H, J=9.0 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[C:16](Cl)[N:15]=[C:14]([NH2:19])[N:13]=2)[CH:5]=[CH:4][N:3]=1.[Cl:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[C:25]([Cl:27])[CH:26]=1>>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[C:16]([C:23]3[CH:22]=[C:21]([Cl:20])[CH:26]=[C:25]([Cl:27])[CH:24]=3)[N:15]=[C:14]([NH2:19])[N:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccc(NCCNc2cc(Cl)nc(N)n2)n1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Product: Nc1nccc(NCCNc2cc(-c3cc(Cl)cc(Cl)c3)nc(N)n2)n1

Procedure:
The product of Example 6A (62 mg, 0.221 mmol) and 3,5-dichlorophenyl boronic acid (46 mg, 0.243 mmol) were treated under the conditions described in Example 6B to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.92 (s, 2H) 7.66 (t, J=2.03 Hz, 1H) 7.61 (d, J=5.76 Hz, 1H) 6.99 (s, 1H) 6.86 (s, 1H) 6.33 (s, 1H) 6.15 (s, 2H) 5.85 (s, 2H) 5.74 (d, J=5.76 Hz, 1H) 3.33-3.51 (m, 4H); MS (ESI+) m/z 390.9 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]2)=[N:22][CH:23]=1.[Cl:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[C:41]([O:54][CH3:55])[C:40]=1[OH:56]>>[NH2:30][C@@H:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:21]2[N:22]=[CH:23][C:18]([NH:17][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:43]5[CH:42]=[C:41]([O:54][CH3:55])[C:40]([OH:56])=[C:39]([Cl:38])[CH:44]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12]([CH:14]3[CH2:15][CH2:16]3)=[O:13])=[CH:19][CH:20]=2)[CH2:25]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(Nc4ccc(N5CCC[C@@H](N)C5)nc4)c3c2)cc(Cl)c1O
Yield: 32.4 %

Procedure:
Following general procedure D, (R)-tert-butyl 1-(5-(6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino)pyridin-2-yl)piperidin-3-ylcarbamate (100 mg, 0.17 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (74 mg, 0.26 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (30 mg, 32% over 2 steps) as an orange-yellow solid: 1H NMR (500 MHz, MeOD+TFA-d) δ 9.40 (br s, 1H), 8.28-8.20 (m, 2H), 8.10 (br s, 1H), 8.00 (d, J=8.8 Hz, 1H), 7.65 (dd, J=9.1, 2.8 Hz, 1H), 7.05 (d, J=9.1 Hz, 1H), 6.99 (s, 1H), 6.83 (br s, 1H), 4.55-4.49 (d, J=11.6 Hz, 1H), 4.04-3.95 (m, 1H), 3.91 (s, 3H), 3.28-3.18 (m, 3H), 2.87 (br s, 1H), 2.22-2.14 (m, 1H), 1.96-1.87 (m, 1H), 1.76-1.62 (m, 2H), 1.28-1.16 (m, 414).; ESI MS m/z 544 [C30H30ClN5O3+H]+; HPLC>99.0% (AUC), tR=10.74 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.[CH2:24]([N:31]1[CH2:37][CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>O1CCCC1>[CH2:24]([N:31]1[CH2:37][CH2:36][CH2:35][N:34]([C:2]2[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[N:3]=2)[CH2:33][CH2:32]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Reactant: c1ccc(CN2CCCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCN(Cc3ccccc3)CC2)nc1-c1ccc(C)cc1
Yield: 59.8 %

Procedure:
This compound was prepared according to the method C from methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (0.095 g; 0.285 mmol), 1-benzyl-1,4-diazepane (0.178 g, 0.937 mmol) and triethyl amine (0.200 mL; 1.43 mmol) in tetrahydrofuran (2 mL). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-30%) in heptane furnished 0.083 g (54%) of the titled compound as a colorless oil.