Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]([OH:19])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[CH3:2].Cl[CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:3]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:8][CH:9]=1)([OH:19])[CH2:1][CH3:2]
Reactant: ClCCCN1CCCCC1
Reactant: CCC(O)(c1ccc(O)cc1)c1ccccc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: CCOC(C)=O
Product: CCC(O)(c1ccc(OCCCN2CCCCC2)cc1)c1ccccc1OC

Procedure:
7.7 g. of α-ethyl-α-(2-methoxyphenyl)-4-hydroxy-benzylalcohol and 6.6 g. of N-(3-chloropropyl)-piperidine in 70 ml. of ethyl acetate, in the presence of 14 g. of anhydrous potassium carbonate and 0.5 g. of tetrabutyl ammonium hydrogensulfate are boiled under reflux for 8 hours. Thereafter the solvent is distilled off under reduced pressure, to the residue water is added, and it is extracted with ether. The ethereal phases are combined, washed with water, a 5% aqueous sodium hydroxide solution and again with water till neutral. The organic phase is dried over anhydrous potassium carbonate, and the solvent is distilled off under reduced pressure. Crystallization of the residue from ethyl acetate yields 9.5 g. of the named compound, melting at 110° to 111° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[CH:6]([N:17]1[CH2:22][C@@H:21]([CH3:23])[NH:20][CH2:19][C@@H:18]1[CH3:24])[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)C=[CH:9][CH:8]=1.COC1C=C(C=CC=1)C(Cl)C1C2C(=CC=CC=2)[N:37]=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[CH:6]([N:17]1[CH2:22][C@@H:21]([CH3:23])[NH:20][CH2:19][C@@H:18]1[CH3:24])[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:37]=[CH:9][CH:8]=1
Reactant: COc1cccc(C(c2cccc3ccccc23)N2C[C@@H](C)NC[C@@H]2C)c1
Reactant: COc1cccc(C(Cl)c2ccnc3ccccc23)c1
Product: COc1cccc(C(c2ccnc3ccccc23)N2C[C@@H](C)NC[C@@H]2C)c1

Procedure:
The compound of this Example was prepared by following the synthesis procedure as described for compound 3, but substituting compound 2 for compound 27.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:29])[C@H:11]([CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:12][N:13]([O:16]C2CCCCO2)[CH:14]=[O:15])[C:5]([F:30])=[C:4]([NH:31][CH2:32][C:33]2[S:34][CH:35]=[CH:36][N:37]=2)[N:3]=1>C(O)(=O)C.O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:29])[C@H:11]([CH2:23][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28]2)[CH2:12][N:13]([OH:16])[CH:14]=[O:15])[C:5]([F:30])=[C:4]([NH:31][CH2:32][C:33]2[S:34][CH:35]=[CH:36][N:37]=2)[N:3]=1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)NNc1nc(Cl)nc(NCc2nccs2)c1F)OC1CCCCO1
Solvent: CC(=O)O
Solvent: O
Product: O=CN(O)C[C@@H](CC1CCCC1)C(=O)NNc1nc(Cl)nc(NCc2nccs2)c1F
Reaction time: 8 h
Yield: 57.6 %

Procedure:
[(2R)-3-(2-{2-Chloro-5-fluoro-6-[(1,3-thiazol-2-ylmethyl)amino]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (0.3031 g, 0.5461 mmol) was dissolved in acetic acid (8 mL) and water (2 mL). This reaction mixture was stirred overnight. The volatiles were evaporated and reaction mixture was purified by RP-HPLC to provide [(2R)-3-(2-{2-chloro-5-fluoro-6-[(1,3-thiazol-2-ylmethyl)amino]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl]hydroxyformamide as a white solid (0.1484 g, 58%). LCMS: (M+H)+=472.0.
Reaction SMILES: [CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][C:17](Br)=[CH:18][C:13]=2[CH:12]=[C:11]([C:20]([O:22][CH3:23])=[O:21])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B([O-])([O-])O[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][CH3:38])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>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.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][CH3:38])=[CH:28][CH:27]=3)=[CH:18][C:13]=2[CH:12]=[C:11]([C:20]([O:22][CH3:23])=[O:21])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(Cc2ccccc2)CC1
Reactant: CCCOCCOc1ccc(OB([O-])[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
A mixture of methyl 1-benzyl-7-bromo-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.3 g), 4-(2-propoxyethoxy)phenyl borate (0.24 g), 1M potassium carbonate solution (2.5 ml), ethanol (2.5 ml) and toluene (25 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.04 g), and the mixture was refluxed under argon atmosphere overnight. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 1-benzyl-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.27 g) as yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[CH3:24]O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][C:16]([O:18][CH3:24])=[O:17])=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2oncc2CCC(=O)O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1cnoc1-c1ccc(OC)cc1
Yield: 95 %

Procedure:
A mixture of 3-[5-(4-methoxyphenyl)-4-isoxazolyl]propionic acid (2.75 g), conc. sulfuric acid (0.1 ml) and methanol (100 ml) was refluxed for 4 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[5-(4-methoxyphenyl)-4-isoxazolyl]propionate (2.76 g, yield 95%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). NMR (CDCl3) δ: 2.58–2.70 (2H, m), 2.92–3.04 (2H, m), 3.68 (3H, s), 3.87 (3H, s), 6.96–7.06 (2H, m), 7.59–7.69 (2H, m), 8.18 (1H, s).
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:22])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21].Cl.C(OCC)(=O)C>C1COCC1.O.[Cl-].[Na+].O>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[O:13][CH2:12][C:11]([NH:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([OH:23])=[O:2])=[O:22]
Reactant: COC(=O)c1ccccc1NC(=O)COc1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(COc1ccc(Cl)cc1Cl)Nc1ccccc1C(=O)O
Yield: 89 %

Procedure:
2-[2-(2,4-dichloro-phenoxy)-acetylamino]-benzoic acid methyl ester (94.6 mg, 0.27 mmol) in THF/H2O (3:1, 25 mL) was treated with LiOHH2O (22.7 mg, 0.54 mmol) at room temperature. The reaction mixture was then acidified with 10% HCl to PH 2, and added ethyl acetate and brine. The organic phase was washed with water, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=6:1) to give 2-[2-(2,4-dichloro-phenoxy)-acetylamino]-benzoic acid as a white solid (81.7 mg, 88.9% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)=[C:4]([CH3:24])[C:3]=1[F:25].C(O)C.C(=O)(O)[O-].[Na+]>[Pd]>[F:25][C:3]1[C:4]([CH3:24])=[C:5]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([CH:21]4[CH2:22][CH2:23]4)=[O:20])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:6]=[N:7][CH:2]=1
Reactant: Cc1c(-c2ccc3cc(NC(=O)C4CC4)ncc3c2)cnc(Cl)c1F
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1c(F)cncc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 40 °C
Reaction time: 12 h
Yield: 47.5 %

Procedure:
To a solution of N-(7-(6-chloro-5-fluoro-4-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide (180.0 mg, 0.5059 mmol) in ethanol (10 mL, 200 mmol) was added sodium bicarbonate (95.2 mg, 1.13 mmol) and palladium (60.1 mg, 0.0565 mmol) (10 wt % on carbon). The reaction vessel was purged first with nitrogen and then hydrogen, and then stirred under a hydrogen balloon at 40° C. for 12 hours. The reaction mixture was then filtered through celite and evaporated in vacuo. The crude product was purified via reverse phase HPLC and lyophilized to yield 77.3 mg (48%) of N-(7-(5-fluoro-4-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide. LCMS (ESI): RT (Min)=4.130, M+H=322.1, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.20 (s, 1H), 8.55 (s, 1H), 8.52 (s, 1H), 8.42 (s, 1H), 8.12 (s, 1H), 7.98 (d, J=8.5 Hz, 1H), 7.76 (dd, J=8.5, 1.4 Hz, 1H), 2.26 (d, J=1.8 Hz, 3H), 2.15-2.03 (m, 1H), 0.94-0.75 (m, 4H).
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.C(N(CC)CC)C.Cl[C:18]([O:20][CH2:21][CH2:22][N:23]1[C:27](=[O:28])[CH:26]=[CH:25][C:24]1=[O:29])=[O:19]>O1CCCC1>[C:24]1(=[O:29])[N:23]([CH2:22][CH2:21][O:20][C:18]([N:6]2[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]2=[O:8])=[O:19])[C:27](=[O:28])[CH:26]=[CH:25]1
Reactant: O=C(Cl)OCCN1C(=O)C=CC1=O
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1C=CC(=O)N1CCOC(=O)n1cc(F)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 61 %

Procedure:
500 mg (3.84 mmol) 5-fluorouracil were dissolved in 100 ml of tetrahydrofuran and diluted with 505 mg (696 μl; 4.99 mmol) of triethylamine. To this solution, 1016 mg (4.99 mmol) of 2-maleinimidoethyl chloroformate, dissolved in 100 ml of tetrahydrofuran, were added drop-wise and the set-up was stirred for 15 h at room temperature. Then, the solvent was removed under the water jet vacuum and the residue purified using column chromatography (LOBAR®-column; running medium: acetic acid/hexane 1.5/1; yield: 61%); melting point: 132° C., Rf-value: 0.64 (diol; acetic acid/hexane 2/1); calculated: C: 44.29% H: 2.68% N: 14.09%, (C11H8N3O6F); found: C: 44.29% H: 2.68% N: 13.58%.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:4][CH2:3]1.[CH2:12]([O:14][CH2:15][CH3:16])[CH3:13]>O>[CH2:12]([O:14][CH:15]([O:1][CH2:2][CH2:3][CH2:4][C:2]1([OH:1])[CH2:11][CH2:10][C:5]2([O:6][CH2:7][CH2:8][O:9]2)[CH2:4][CH2:3]1)[CH3:16])[CH3:13]
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CCOCC
Solvent: O
Product: CCOC(C)OCCCC1(O)CCC2(CC1)OCCO2
Temperature: 25 °C

Procedure:
To the above lithiated intermediate there was added dropwise a solution of 85.8 g (0.55 mol) of 8-oxo-1,4-dioxaspiro[4.5]decane in one liter of dry diethyl ether (fresh cans, as above) over a period of about 2.5 hr. The resulting reaction mixture was allowed to warm slowly to room temperature and then poured into two liters of ice cold half saturated ammonium chloride in water solution. The phases were separated and the aqueous phase was extracted with one liter of diethyl ether. The ether layers were combined and washed with brine solution, dried over sodium sulfate, and then the ether solvent was removed under reduced pressure to leave, after drying to 45° C. (0.25 mm.Hg) for 14 hours, 142.15 g of a light yellow oil, the above named decan-8-ol acetal intermediate, which was of sufficient purity to use in the next step. A small sample of the named oil was distilled at reduced pressure to obtain a purer material bp 135°-140° C. (0.01 mmHg). The nuclear magnetic resonance spectrum (using CDCl3 solvent), was consistent with the above named decan-8-ol acetal compound.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].Cl.[F:22][C:23]([F:37])([F:36])[CH2:24][C:25]1[S:29][C:28]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[N:27][CH:26]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([C:10]([N:33]2[CH2:34][CH2:35][N:30]([C:28]3[S:29][C:25]([CH2:24][C:23]([F:37])([F:22])[F:36])=[CH:26][N:27]=3)[CH2:31][CH2:32]2)=[O:12])[CH:13]=1)(=[O:3])=[O:4]
Reactant: CC(Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Reactant: FC(F)(F)Cc1cnc(N2CCNCC2)s1
Agent: Cl
Product: CC(Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(CC(F)(F)F)s2)CC1)C(F)(F)F
Yield: 32 %

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (Example A2) and 1-[5-(2,2,2-trifluoro-ethyl)-thiazol-2-yl]-piperazine hydrochloride. The crude material was purified by chromatography (SiO2, methanol/dichloromethane) to yield the title compound as a white crystalline solid (yield 32%). MS (m/e): 546.3 (M+H+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1.[CH3:25][O:26][C:27](=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34]Br)[CH:29]=1>>[CH3:25][O:26][C:27](=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][O:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:7]3[C:6]4[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=4)[N:10]=[N:9][C:8]=3[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:19]=2)[CH:29]=1
Reactant: Oc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Reactant: COC(=O)c1cccc(CBr)c1
Product: COC(=O)c1cccc(COc2cccc(-c3c(-c4ccccc4)nnc4c(Cl)cccc34)c2)c1

Procedure:
3-[3-(8-Chloro-3-phenyl-cinnolin-4-yl)-phenoxymethyl]-benzoic acid methyl ester was prepared from 3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenol and 3-bromomethyl-benzoic acid methyl ester according to the procedure of Example 14. MS (ES) m/z 480.8;
Reaction SMILES: O.Cl.[CH3:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:9][NH:10]2)=[CH:6][C:5]=1[N+:19]([O-])=O.[OH-].[NH4+]>C(O)C.[Fe]>[NH2:19][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:4]=1[CH3:3])[NH:10][N:9]=[C:8]2[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1cc2[nH]nc(-c3ccccc3)c2cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1cc2[nH]nc(-c3ccccc3)c2cc1N
Temperature: 20 °C
Yield: 85.6 %

Procedure:
5-Amino-6-methyl-3-phenyl-1H-indazole can be obtained in the following way: 0.5 ml of water and 0.18 ml of an aqueous 12N hydrochloric acid solution are added to a solution of 0.53 g of 6-methyl-5-nitro-3-phenyl-1H-indazole in 30 ml of ethanol. The reaction mixture is then heated at the reflux of the solvent and 0.36 g of powdered iron are added in 2 steps. The reaction mixture is then stirred at the reflux of the solvent for 4.5 hours and is then cooled to a temperature in the region of 20° C. and treated with 50 ml of ice-cold water. The mixture is then basified with an aqueous 32% ammonium hydroxide solution, to a pH in the region of 11. After settling out, the aqueous phase is extracted with one times 50 ml then 2 times 25 ml of ethyl acetate. The organic extracts are pooled, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue thus obtained is purified by chromatography on a silica column (particle size 63-200 μm), eluting with a cyclohexane/ethyl acetate (75/25 by volume) mixture. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 0.4 g of 5-amino-6-methyl-3-phenyl-1H-indazole is thus obtained in the form of a beige crystalline solid melting at 133° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([NH:40][C:41]2[CH:49]=[C:48](B3OC(C)(C)C(C)(C)O3)[CH:47]=[C:46]3[C:42]=2[CH:43]=[CH:44][N:45]3[CH2:59][O:60][CH2:61][CH2:62][Si:63]([CH3:66])([CH3:65])[CH3:64])(=[O:39])=[O:38])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:48]2[CH:47]=[C:46]3[C:42]([CH:43]=[CH:44][N:45]3[CH2:59][O:60][CH2:61][CH2:62][Si:63]([CH3:66])([CH3:65])[CH3:64])=[C:41]([NH:40][S:37]([C:34]3[CH:33]=[CH:32][C:31]([O:30][CH3:29])=[CH:36][CH:35]=3)(=[O:39])=[O:38])[CH:49]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: COc1ccc(S(=O)(=O)Nc2cc(B3OC(C)(C)C(C)(C)O3)cc3c2ccn3COCC[Si](C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(S(=O)(=O)Nc2cc(-c3c(N)ncnc3N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)cc3c2ccn3COCC[Si](C)(C)C)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 63.1 %

Procedure:
A solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.23 mmol) were added 4-methoxy-N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-4-yl)benzenesulfonamide (194 mg, 0.30 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (18 mg, 0.02 mmol) and 227 μl of a 2M aqueous solution of cesium carbonate in dioxane (2 ml). The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude was purified using SP1® Purification System (0% to 75%, hexane-ethyl acetate) to obtain 115 mg (60% yield) of the title compound as a white solid. Purity 95%.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.C(N(CC)CC)C.[C:30]([Si:36]([CH2:42][CH:43]([CH3:45])[CH3:44])([CH2:38][CH:39]([CH3:41])[CH3:40])Cl)([CH:33]([CH3:35])[CH3:34])([CH3:32])[CH3:31]>C1(C)C=CC=CC=1>[C:1]([O:6][Si:36]([C:30]([CH:33]([CH3:35])[CH3:34])([CH3:31])[CH3:32])([CH2:38][CH:39]([CH3:40])[CH3:41])[CH2:42][CH:43]([CH3:45])[CH3:44])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CC(C)C[Si](Cl)(CC(C)C)C(C)(C)C(C)C
Reactant: C=C(C)C(=O)O
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)O[Si](CC(C)C)(CC(C)C)C(C)(C)C(C)C
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A flask equipped with a stirrer, reflux condenser, dropping funnel and thermometer was charged with 17.2 g (0.2 mol) of methacrylic acid, 120 ml of toluene, and 0.06 g of 2,6-di-tert-butyl-4-methylphenol. At room temperature, 22.3 g (0.22 mol) of triethylamine was added dropwise over one hour. At the end of dropwise addition, the flask was heated at 80° C. After the internal temperature became constant, 52.6 g (0.20 mol) of thexyldiisobutylchlorosilane was added dropwise over two hours. After the completion of dropwise addition, the reaction solution was stirred for 5 hours at 80° C. The reaction solution was then cooled to room temperature, and the resulting hydrochloric acid salt removed by filtration. The filtrate was distilled, collecting 46.3 g of a fraction having a boiling point of 104-110° C./0.13 kPa.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].Cl[C:12]1[CH:13]=[C:14]2[N:21]([CH:22]3[CH2:24][CH2:23]3)[CH2:20][CH2:19][N:15]2[C:16](=[O:18])[N:17]=1>>[CH:22]1([N:21]2[C:14]3[N:15]([C:16](=[O:18])[N:17]=[C:12]([O:1][CH2:2][C:3]4[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=4)[C:6]#[N:7])[CH:13]=3)[CH2:19][CH2:20]2)[CH2:24][CH2:23]1
Reactant: O=c1nc(Cl)cc2n1CCN2C1CC1
Reactant: N#Cc1cccc(CO)c1
Product: N#Cc1cccc(COc2cc3n(c(=O)n2)CCN3C2CC2)c1

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from 3-(hydroxymethyl)benzonitrile and 7-chloro-1-cyclopropyl-2,3-dihydroimidazo-[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8]O)[CH:3]=1.O=S(Cl)[Cl:12].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][Cl:12])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(Br)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: ClCc1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 79 %

Procedure:
To a solution of 4-bromo-2-pyridylmethanol (3.38 g, 0.016 mol) in CH2Cl2 (210 mL) was slowly added SOCl2 (21 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred for 20 h, then satd. NaHCO3 was added. The organic layer was washed with brine, dried (MgSO4), and concentrated to give crude 4-bromo-2-(chloromethyl)pyridine (2.93 g, 79%) as a yellow oil. APCI MS m/z 205.7, 207.7 (M+H). 1H NMR (400 MHz, (CD3)2SO) δ 8.47 (d, J=5.3 Hz, 1H), 7.68 (d, J=1.7 Hz, 1H), 7.42 (dd, J=5.3, 1.75 Hz, 1H), 4.64 (s, 2H).
Reaction SMILES: [C:1]([CH2:5][C:6]([O:8][CH3:9])=[O:7])(=[O:4])[CH2:2][CH3:3].[CH:10](OC)(OC)[O:11][CH3:12].C(OC(=O)C)(=O)C>>[C:1]([C:5](=[CH:10][O:11][CH3:12])[C:6]([O:8][CH3:9])=[O:7])(=[O:4])[CH2:2][CH3:3]
Reactant: COC(OC)OC
Reactant: CCC(=O)CC(=O)OC
Solvent: CC(=O)OC(C)=O
Product: CCC(=O)C(=COC)C(=O)OC

Procedure:
A mixture of methyl propionylacetate (112.2 g, 0.86 mol), trimethyl orthoformate (188 ml, 1.72 mol) and acetic anhydride (81 ml, 0.86 mol) was heated at reflux for 17 hours, then the volatile material removed in vacuo, finally at 70°/0.3mm. The residue was predominantly methyl 2-propanoyl-3-methoxyacrylate, and was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][C:10]([O:19][C:20]3[CH:25]=[C:24]([F:26])[C:23]([F:27])=[C:22]([F:28])[CH:21]=3)(C(OCC)=O)[C:9]2=[O:29])=[CH:5][CH:4]=1.[OH-].[Na+].Cl>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([O:19][C:20]3[CH:21]=[C:22]([F:28])[C:23]([F:27])=[C:24]([F:26])[CH:25]=3)[C:9]2=[O:29])=[CH:30][CH:31]=1
Reactant: CCOC(=O)C1(Oc2cc(F)c(F)c(F)c2)CCCN(Cc2ccc(OC)cc2)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(CN2CCCC(Oc3cc(F)c(F)c(F)c3)C2=O)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.7 %

Procedure:
A mixture of ethyl 1-(4-methoxybenzyl)-2-oxo-3-(3,4,5-trifluorophenoxy)piperidine-3-carboxylate (352 mg) and 1N aqueous sodium hydroxide solution (1.6 mL) in THF (3 mL) was stirred at room temperature for 2 days, and acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate/hexane, the white crystals were separated by filtration, and the filtrate was concentrated. A mixture of the residue and the white crystals in toluene (3 mL) was stirred at 100° C. for 1 hr, and the solvent was evaporated under reduced pressure to give the title compound (252 mg).