Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH:9]=[C:10]([CH2:11][CH3:12])[C:3]=12.[Li]C(CC)C.CN([CH:31]=[O:32])C.Cl.C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[C:7]([CH:31]=[O:32])=[CH:6][N:5]=[C:4]2[N:8]([Si:13]([CH:14]([CH3:15])[CH3:16])([CH:20]([CH3:21])[CH3:22])[CH:17]([CH3:19])[CH3:18])[CH:9]=[C:10]([CH2:11][CH3:12])[C:3]=12
Reactant: CN(C)C=O
Reactant: CCc1cn([Si](C(C)C)(C(C)C)C(C)C)c2nccc(Cl)c12
Agent: Cl
Agent: O=C([O-])O
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1cn([Si](C(C)C)(C(C)C)C(C)C)c2ncc(C=O)c(Cl)c12
Temperature: -70 °C
Reaction time: 1.25 h
Yield: 91.1 %

Procedure:
4-Chloro-3-ethyl-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (1.5 g, 4.45 mmol) in THF (25 mL) was cooled to about −70° C. then the sec-BuLi (1.4 M in cyclohexane, 6.36 mL, 8.90 mmol) was added over about 10 min. The mixture was stirred for about 1.25 h at about −70° C. then DMF (1.00 mL, 13.4 mmol) was added over about 5 min. The mixture was stirred for about 30 min then HCl (4.0 M in 1,4-dioxane, 1.11 mL, 4.45 mmol) was added. The mixture was allowed to warm to rt then saturated aqueous NaHCO3 (50 mL) and EtOAc (50 mL) were added. The layers were separated then the aqueous layer was extracted with EtOAc (25 mL) then the combined organics were extracted with saturated aqueous NaCl (25 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The material was purified on a 80 g silica gel column with 9:1 heptane/EtOAc as an eluent to give 4-chloro-3-ethyl-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (1.48 g, 91%): LC/MS (Table 2, Method g) Rt=2.44 min; MS m/z 365 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([OH:6])[CH3:5].[Cl:7][C:8]1[N:9]=[C:10](Cl)[C:11]2[C:16]([I:17])=[CH:15][N:14]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:12]=2[N:13]=1>C1COCC1>[Cl:7][C:8]1[N:9]=[C:10]([O:6][CH:4]([CH3:5])[CH3:3])[C:11]2[C:16]([I:17])=[CH:15][N:14]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:12]=2[N:13]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)nc(Cl)nc21
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)Oc1nc(Cl)nc2c1c(I)cn2COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a suspension of sodium hydride (1 equiv, 60% in mineral oil) in dry THF (0.9 M) under nitrogen atmosphere was added propan-2-ol (0.52 equiv). The reaction mixture was stirred at room temperature for 30 min before a solution of 2,4-dichloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (0.5 equiv) in dry THF (0.45 M) was added. The mixture was stirred at room temperature for 1 h. The reaction was monitored by thin layer chromatography. Upon completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel flash column chromatography (0-10% ethyl acetate in petroleum ether) to afford the title compound as a yellow oil (81% yield). MS (ESI) m/z 468.2 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]#[N:18])=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:19][N:20]([CH3:25])[S:21](Cl)(=[O:23])=[O:22]>>[CH3:19][N:20]([CH3:25])[S:21](=[O:23])(=[O:22])[O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2[C:17]#[N:18])=[CH:6][CH:7]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: N#Cc1cc([N+](=O)[O-])ccc1-c1ccc(O)cc1
Product: CN(C)S(=O)(=O)Oc1ccc(-c2ccc([N+](=O)[O-])cc2C#N)cc1

Procedure:
The procedure of Example 88 was repeated, except that 120 mg of 4′-hydroxy-4-nitro-2-biphenylcarbonitrile was used in place of N-(4′-hydroxybiphenyl-4-yl)methanesulfonamide, and 0.430 ml of N,N-dimethylsulfamoyl chloride was used in place of sulfamoyl chloride. The resulting crude product was purified by TLC (using a 16:1 mixture of chloroform and acetone as the developing solvent) to obtain 97 mg of 2′-cyano-4′-nitrobiphenyl-4-yl N,N-dimethylsulfamate.
Reaction SMILES: C(N1CCN(C2N=C(Br)C=C3C=CSC=23)CC1)C.[CH2:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:28]=[C:29]([C:36]3[CH:41]=[CH:40][C:39]([O:42][CH2:43][CH2:44][CH2:45][O:46]C4CCCCO4)=[CH:38][CH:37]=3)[CH:30]=[C:31]3[CH:35]=[CH:34][S:33][C:32]=23)[CH2:23][CH2:22]1)[CH3:20].[ClH:53]>C(OCC)(=O)C>[ClH:53].[ClH:53].[CH2:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:28]=[C:29]([C:36]3[CH:41]=[CH:40][C:39]([O:42][CH2:43][CH2:44][CH2:45][OH:46])=[CH:38][CH:37]=3)[CH:30]=[C:31]3[CH:35]=[CH:34][S:33][C:32]=23)[CH2:23][CH2:22]1)[CH3:20]
Reactant: CCN1CCN(c2nc(-c3ccc(OCCCOC4CCCCO4)cc3)cc3ccsc23)CC1
Agent: CCN1CCN(c2nc(Br)cc3ccsc23)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCN1CCN(c2nc(-c3ccc(OCCCO)cc3)cc3ccsc23)CC1

Procedure:
The resulting compound and 7-(1-ethylpiperazin-4-yl)-5-bromothieno[2,3-c]pyridine (0.29 g) were reacted in the same manner as in Example 300-4, to give a reaction solution containing 7-(4-ethylpiperazin-1-yl)-5-[4-[3-(tetrahydropyran-2-yl)oxypropoxy]phenyl]thieno[2,3-c]pyridine. Ethyl acetate and 2N hydrochloric acid were added to the reaction solution, and the resulting insoluble matters were filtered off. The aqueous layer was separated, while the organic layer was extracted with 2N hydrochloric acid. The aqueous layers were combined and washed with ethyl acetate thrice. The pH of the resulting solution was adjusted to pH 10 by adding a 8N aqueous soluton of sodium hydroxide thereto, and the resulting solution was extracted with ethyl acetate thrice. The extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by NH silica gel column chromatography (ethyl acetate/n-hexane system), to give 0.26 g of the free compound of the title compound as a colorless amorphous.
Reaction SMILES: C([O:5][NH:6][C:7](=[N:60]S(C1C(C)=C(C)C2OC(C)(C)CC=2C=1C)(=O)=O)[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:42][C:43](=[O:59])OCC1C2C=CC=CC=2C2C1=CC=CC=2)[C:14](=[O:41])[NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:29]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)=[CH:28][C:27]([C:37]([F:40])([F:39])[F:38])=[N:26]2)=[CH:21][CH:20]=1)(=[O:18])=[O:17])(C)(C)C.[C:78](OC(=O)CC)(=O)[CH2:79]C>>[OH:5][N:6]=[C:7]([NH2:60])[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:42][C:43](=[O:59])[CH2:78][CH3:79])[C:14]([NH:15][S:16]([C:19]1[CH:20]=[CH:21][C:22]([N:25]2[C:29]([C:30]3[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=3)=[CH:28][C:27]([C:37]([F:40])([F:38])[F:39])=[N:26]2)=[CH:23][CH:24]=1)(=[O:17])=[O:18])=[O:41]
Reactant: CCC(=O)OC(=O)CC
Reactant: Cc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(S(=O)(=O)NC(=O)[C@H](CCCCNC(=NS(=O)(=O)c3c(C)c(C)c4c(c3C)CC(C)(C)O4)NOC(C)(C)C)NC(=O)OCC3c4ccccc4-c4ccccc43)cc2)cc1
Product: CCC(=O)N[C@@H](CCCCNC(N)=NO)C(=O)NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(C)cc2)cc1

Procedure:
Compound (20a) is treated according to the methods of Example 16, with substitution of propionic anhydride as the acylating agent, to afford the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2([CH2:26][C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([N:17]=CC3C=CC=CC=3)[C:9]2=[O:25])=[CH:3][CH:2]=1.O.NN>C(O)C>[NH2:17][N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([CH2:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)([CH2:26][C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)[C:9]1=[O:25]
Reactant: O=C1N(N=Cc2ccccc2)c2ccccc2C1(Cc1ccncc1)Cc1ccncc1
Agent: NN
Solvent: CCO
Solvent: O
Product: NN1C(=O)C(Cc2ccncc2)(Cc2ccncc2)c2ccccc21
Temperature: 0 °C
Yield: 40.4 %

Procedure:
To a solution consisting of 3,3-bis-(4-pyridinylmethyl)-1,3-dihydro-1-[(phenylmethylene)amino]-2H-indol-2-one (7.84 g) and absolute ethanol (68 ml) was added hydrazine hydrate (6.4 ml). The resulting mixture was heated at reflux for 5.75 hours, followed by cooling to 0° C. The product crystallized upon cooling. Filtration and washing with ether-pentane afforded 2.50 g of 1-amino-3,3-bis(4-pyridinylmethyl)-1,3-dihydro-2H-indol-2-one.
Reaction SMILES: [CH2:1]=[C:2]([CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([OH:5])=[O:4].[C:15]([OH:18])(=[S:17])[CH3:16]>>[C:15]([S:17][CH2:1][CH:2]([CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]([OH:5])=[O:4])(=[O:18])[CH3:16]
Reactant: C=C(CCCc1ccccc1)C(=O)O
Reactant: CC(O)=S
Product: CC(=O)SCC(CCCc1ccccc1)C(=O)O
Temperature: 100 °C
Yield: 100 %

Procedure:
3-Phenylpropylialonic acid (6.14 g) was converted to 2-methylene-5-phenylpentanoic acid (2.1 g, 40%) by the method described in Example 32a). δH (CDCl3) 1.88 (2 H, m, CH2), 2.37 (2 H, t, J 7.6 Hz, CH2), 2.67 (2 H, t, J 7.6 Hz, CH2), 5.68 and 6.33 (2 H, 2×s, ##STR9## 7.26 (5 H, m, Ph). The solid was dissolved in thioacetic acid (5 ml) and heated at 100° C. for 2 hours. Evaporated to give the title compound (2.9 g, 100%); δH (CDCl3) 1.71 (4 H, m, 2×CH2), 2.33 (3 H, s, COCH3), 2.64 (3 H, m, CH, CH2), 3.08 (2 H, m, CH2), 7.27 (5 H, m, Ph).
Reaction SMILES: [OH:1][CH:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[C:5](=[O:19])[N:4]([C:20]2[CH2:21][O:22][C:23](=[O:26])[C:24]=2[CH3:25])[CH2:3]1.C(=O)(O)[O-].[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH3:25][C:24]1[C:23](=[O:26])[O:22][CH2:21][C:20]=1[N:4]1[CH2:3][C:2](=[O:1])[C:6]2([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]2)[C:5]1=[O:19]
Reactant: CC1=C(N2CC(O)C3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)COC1=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1=C(N2CC(=O)C3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)COC1=O
Reaction time: 1.5 h

Procedure:
To tert-butyl 4-hydroxy-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (I-37, Step C) (200 mg, 0.546 mmol) in DCM (2.8 mL) was added sodium bicarbonate (68.8 mg, 0.819 mmol) and Dess-Martin periodinane (347 mg, 0.819 mmol). The reaction mixture was vigorously stirred for 1.5 h, then quenched with 10% Na2S2O3, NaHCO3, and stirred for 20 min. The aqueous layer was extracted with DCM, and the organic layers were washed with brine, dried, and concentrated to give the title compound. LC/MS: [(M+1)]+=365;
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]#[N:18])=[C:12]([O:19][CH3:20])[CH:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:32][CH2:33][CH2:34][CH2:35]Br>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([C:16]2([C:17]#[N:18])[CH2:35][CH2:34][CH2:33][CH2:32]2)=[C:12]([O:19][CH3:20])[CH:11]=1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1CC#N
Reactant: BrCCCCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(-c2nc3ccccc3o2)ccc1C1(C#N)CCCC1
Temperature: 25 °C

Procedure:
[4-(1,3-Benzoxazol-2-yl)-2-methoxyphenyl]acetonitrile (130 mg, 0.49 mmol) in THF (5.0 mL) was cooled to −78° C. under argon atmosphere. Sodium bis(trimethylsilyl)amide (1.8 mL, 1.08 mmol) was added slowly and after fifteen minutes, added 1,4-dibromobutane (0.07 mL, 0.59 mmol) to dark brown reaction mixture. Let mixture warm to rt overnight. After concentrating reaction mixture in vacuo, the resulting pink oil was purified by flash chromatography, using a gradient elution of 1:9 EtOAc:hexanes to 1:4 EtOAc:hexanes. This afforded the desired compound, 1-[4-(1,3-benzoxazol-2-yl)-2-methoxyphenyl]cyclopentanecarbonitrile, as a yellow solid. 1H NMR(CDCl3, 300 MHz) δ 7.86–7.26 (m, 7H), 4.07 (s, 3H), 2.59–1.91 (m, 8H). MS (ESI) 319.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[C:4]([F:25])[CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].O.C(O)(C(F)(F)F)=O.Br[C:58]1[CH:59]=[C:60]([CH:69]=[CH:70][CH:71]=1)[C:61]([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)=[O:62].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH:21]1([C:19]([N:16]2[CH2:17][CH2:18][C@@H:14]([CH2:13][C:12]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([C:67]5[CH:66]=[CH:65][CH:64]=[C:63]([C:61]([C:60]6[CH:69]=[CH:70][CH:71]=[CH:58][CH:59]=6)=[O:62])[CH:68]=5)=[CH:3][C:4]=4[F:25])[C:9](=[O:24])[NH:10][N:11]=3)[CH2:15]2)=[O:20])[CH2:23][CH2:22]1
Reactant: O=C(c1ccccc1)c1cccc(Br)c1
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2F)C1
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: O=C([O-])[O-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: O=C(c1ccccc1)c1cccc(-c2ccc(-n3c(C[C@@H]4CCN(C(=O)C5CC5)C4)n[nH]c3=O)c(F)c2)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
In a sealed microwave vial under nitrogen, a mixture of 4-(4-bromo-2-fluorophenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (124 mg, 0.303 mmol), bis(pinacolato)diboron (81 mg, 0.318 mmol), potassium acetate (89 mg, 0.909 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (12.37 mg, 0.015 mmol) in 1,4-dioxane (2.5 mL) was stirred at 100° C. in an oil bath for 1 h. The reaction was cooled to room temperature. Analysis by LCMS showed complete conversion to the boronic ester intermediate (boronic ester cleavage to acid also observed on LCMS due to water/TFA conditions). 3-Bromobenzophenone (79 mg, 0.303 mmol) and 2M aq potassium carbonate (0.45 mL, 0.909 mmol) were added to the reaction mixture. The resultant reaction mixture was stirred at 100° C. in an oil bath for 1 h. The reaction was cooled to room temperature. The reaction mixture was then transferred to a separatory funnel and the layers were separated. The aqueous layer was adjusted to pH˜5 using 1N aq HCl and then extracted with ethyl acetate (2×50 mL). The organic layers were combined, dried over MgSO4, and concentrated in vacuo. Purification of the residue by silica gel chromatography (0-5% methanol/ethyl acetate) provided the desired product as a white solid, which was dried in a vacuum oven (70° C.) overnight. The solid was further purified by reverse phase HPLC (10-80% acetonitrile/water+0.1% NH4OH). The desired product was dissolved in acetonitrile (2 mL) and water (10 mL), frozen, and lyophilized over the weekend. The solid was further dried in a vacuum oven (70° C.) overnight to give the title compound as a white solid (72 mg, 46%). MS(ES)+ m/e 511.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([C:28]#[N:29])([CH3:27])[CH3:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[CH:6][N:5]2[CH:31]=1.[CH:32]1([C:35](Cl)=[O:36])[CH2:34][CH2:33]1>CN(C)C(=O)C.C(OCC)(=O)C>[C:28]([C:25]([C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[C:18]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([O:10][C:7]2[CH:8]=[CH:9][C:4]3[N:5]([CH:31]=[C:2]([NH:1][C:35]([CH:32]4[CH2:34][CH2:33]4)=[O:36])[N:3]=3)[CH:6]=2)[CH:12]=1)=[O:30])([CH3:27])[CH3:26])#[N:29]
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(N)cn4c3)c2)c1
Reactant: O=C(Cl)C1CC1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.9 %

Procedure:
To a solution of N-{3-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]phenyl}-3-(1-cyano-1-methylethyl)benzamide (200 mg, 0.486 mmol) in N,N-dimethylacetamide (2.0 mL) was added cyclopropanecarbonyl chloride (46 μL, 0.510 mmol), and the mixture was stirred at room temperature for 8 hr. The reaction mixture was diluted with ethyl acetate (100 mL), washed with 5% aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (NH silica gel, hexane/ethyl acetate=50/50→0/100), and fractions containing the desired product were concentrated under reduced pressure. The residue was triturated with ethyl acetate and diisopropyl ether to give the title compound (100 mg, 43%) as a colorless solid.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](Cl)[N:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].Cl.Cl.[CH2:21]([N:23]1[CH2:27][CH2:26][C:25]2([CH2:31][CH2:30][NH:29][CH2:28]2)[CH2:24]1)[CH3:22]>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10]([N:29]3[CH2:30][CH2:31][C:25]4([CH2:26][CH2:27][N:23]([CH2:21][CH3:22])[CH2:24]4)[CH2:28]3)[N:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Reactant: CCN1CCC2(CCNC2)C1
Agent: Cl
Product: CCN1CCC2(CCN(c3nc4c(cc3F)c(=O)c(C(=O)O)cn4CC)C2)C1

Procedure:
The title compound was prepared according to example 24 by reacting 1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid with 2-ethyl-2,7diazaspiro[4.4]nonane dihydrochloride; mp 215°-217° C.(dec).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=[S:26]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1cc(C)c(N2CCCCC2=O)c(Cl)c1
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(N2CCCCC2=S)c(Cl)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 161 %

Procedure:
1-(2-Chloro-4,6-dimethylphenyl)piperidin-2-one (18.8 g) and Lawesson's reagent [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide] (19.2 g) were combined in 150 mL toluene and the mixture was stirred in an 80° C. oil bath for 3 h. The reaction mixture was then cooled to room temperature and filtered. The filtrate was concentrated on the rotary evaporator and the residue was chromatographed on silica gel, eluting with 9:1 hexane/acetone, to provide 19.4 g of 1-(2-chloro-4,6-dimethylphenyl)piperidine-2-thione, mp 146.8–148.0° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][C:12]([CH2:15][C:16]([NH2:18])=[O:17])=[C:11]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:10]=2)=[CH:4][CH:3]=1.[C:27]([N:34]1[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]1)([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C1(C)C=CC=CC=1.O1CCCC1>[CH2:20]([NH:19][C:11]1[CH:10]=[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][CH:37]3[CH2:38][CH2:39][N:34]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:35][CH2:36]3)=[CH:7][CH:6]=2)[N:14]=[CH:13][C:12]=1[CH2:15][C:16]([NH2:18])=[O:17])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: NC(=O)Cc1cnc(Nc2ccc(N)cc2)cc1NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Nc3cc(NCc4ccccc4)c(CC(N)=O)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 61.1 %

Procedure:
30 mg of 6-[(4-aminophenyl)amino]-4-(benzylamino) pyridine-3-carboxyamide (Example 65) was dissolved in 2 mL of toluene and 2 mL of tetrahydrofuran, to which 54 mg of 1-Boc-4-piperidone and 38 mg of sodium triacetoxyborohydride were added, and stirred at room temperature for 19 hours. To the reaction mixture, water was added, extracted with chloroform, and dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel thin layer chromatography (chloroform:methanol=5:1) to obtain 28 mg (60%) of the title compound as a light brown crystalline powder.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[C:5]([OH:17])[N:4]=1)[CH3:2].Cl.Cl[CH2:20][C:21]1[C:22]([NH:36][CH2:37][CH2:38][NH:39][C:40](=[O:42])[CH3:41])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([O:31][CH2:32][CH:33]1[CH2:35][CH2:34]1)=[CH:26][CH:25]=2.[Li+].[OH-]>C1COCC1>[CH:33]1([CH2:32][O:31][C:27]2[CH:28]=[C:29]3[C:24](=[CH:25][CH:26]=2)[N:23]=[C:22]([NH:36][CH2:37][CH2:38][NH:39][C:40](=[O:42])[CH3:41])[C:21]([CH2:20][C:6]2[C:7]4[C:12](=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=4)[C:3]([CH2:1][CH3:2])=[N:4][C:5]=2[OH:17])=[CH:30]3)[CH2:34][CH2:35]1
Reactant: CC(=O)NCCNc1nc2ccc(OCC3CC3)cc2cc1CCl
Reactant: CCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1nc(O)c(Cc2cc3cc(OCC4CC4)ccc3nc2NCCNC(C)=O)c2cc(OC)c(OC)cc12
Temperature: 160 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 47022 (128 mg, 0.55 mmol) in THF (13 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added N-(2-(3-(chloromethyl)-6-(cyclopropylmethoxy)quinolin-2-ylamino)ethyl)acetamide hydrochloride SLA 47096B (211 mg, 0.55 mmol) and 2 N aq. LiOH solution (0.55 mL, 1.10 mmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to RT, THF was then removed at 40° C. under vacuum and the residue was taken up in CH2Cl2 (50 mL), washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 93:7) followed by a new purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:5) gave 27 mg of N-(2-(6-(cyclopropylmethoxy)-3-((1-ethyl-3-hydroxy-6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-2-ylamino)ethyl)acetamide. This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.149 M HCl solution in MeOH (2.0 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to give N-(2-(6-(cyclopropylmethoxy)-3-((1-ethyl-3-hydroxy-6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-2-ylamino)ethyl)acetamide dihydrochloride 87 as a brown solid (28.9 mg, 8% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8](I)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15].[CH3:17][C:18]1[CH:22]=[C:21]([Sn](CCCC)(CCCC)CCCC)[N:20]([CH2:36][CH2:37][O:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[N:19]=1>O1CCOCC1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:21]2[N:20]([CH2:36][CH2:37][O:38][CH2:39][Si:40]([CH3:41])([CH3:43])[CH3:42])[N:19]=[C:18]([CH3:17])[CH:22]=2)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C)nn1CCOC[Si](C)(C)C
Reactant: COC(=O)c1cc(I)c(C(F)(F)F)cc1N
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2cc(C)nn2CCOC[Si](C)(C)C)c(C(F)(F)F)cc1N
Temperature: 90 °C
Reaction time: 18 h
Yield: 58.7 %

Procedure:
2-Amino-5-iodo-4-trifluoromethyl-benzoic acid methyl ester (583 mg, 1.69 mmol) and 3-methyl-5-tributylstannanyl-1-(2-trimethylsilanylmethoxy-ethyl)-1H-pyrazole (847 mg, 1 equiv) were weighed in air and added to a flame-dried flask. Bistriphenylphosphinedichloropalladium (119 mg, 0.1 equiv) was added. Dioxane (15 mL) was added and the mixture was stirred for 18 h at 90° C. The mixture was evaporated to dryness. The crude product was purified by flash chromatography (hexanes to EtOAc/hexanes (1:4)) to furnish 2-amino-5-[5-methyl-2-(2-trimethylsilanylmethoxy-ethyl)-2H-pyrazol-3-yl]-4-trifluoromethyl-benzoic acid methyl ester (426 mg, 59%) as a yellow paste (ESI-MS: m/z 430.5 [M+H]+, rt 6.54 min).