Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[N:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1>O.O.O.O.O.O.[Ni](Cl)Cl.CO>[NH:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: CCOC(=O)c1ccc2ncccc2c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)CCCN2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
257 mg (1.1 mmol) of nickel chloride hexahydrate and then 770 mg (20.3 mmol) of sodium borohydride were added to a mixture of 1.00 g (5.0 mmol) of ethyl quinoline-6-carboxylate and 15 ml of methanol under cooling with ice, and they were stirred at room temperature for 20 minutes. Methanol was evaporated, and the residue was purified by the silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:26])[CH:9]2[CH2:25][CH2:24][C:12]3([CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13]3)[CH2:11][CH2:10]2)[C:5]([Cl:27])=[CH:4][N:3]=1.Cl.[CH3:29][N:30]1[CH:34]=[C:33]([NH2:35])[CH:32]=[N:31]1.CCN(C(C)C)C(C)C>CCCCO>[Cl:27][C:5]1[C:6]([N:8]([CH3:26])[CH:9]2[CH2:10][CH2:11][C:12]3([CH2:16][N:15]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:14][CH2:13]3)[CH2:24][CH2:25]2)=[N:7][C:2]([NH:35][C:33]2[CH:32]=[N:31][N:30]([CH3:29])[CH:34]=2)=[N:3][CH:4]=1
Reactant: Cn1cc(N)cn1
Reactant: CN(c1nc(Cl)ncc1Cl)C1CCC2(CC1)CCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CN(c1nc(Nc2cnn(C)c2)ncc1Cl)C1CCC2(CC1)CCN(C(=O)OC(C)(C)C)C2
Temperature: 150 °C
Yield: 93 %

Procedure:
To a suspension of tert-butyl 8-((2,5-dichloropyrimidin-4-yl)(methyl)amino)-2-azaspiro[4.5]decane-2-carboxylate (3.8 A: 0.14 g, 0.34 mmol) in n-BuOH (2.0 mL) was added 1-methyl-1H-pyrazol-4-amine hydrochloride (89 mg, 0.67 mmol) and DIPEA (0.17 g, 1.35 mmol). The mixture was stirred in a sealed tube and heated to 150° C. for 12 h and then concentrated in vacuo. The residue was purified by silica gel column chromatography (EA/PE (v/v)=4/1) to afford 3.9A as a light yellow solid (0.15 g, 93%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:21][CH3:22])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Cl)=[C:8]([NH2:23])[N:7]=1)[CH2:2][CH2:3][CH3:4].[NH:24]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:21][CH3:22])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:24]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:8]([NH2:23])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCCl)c2n1
Reactant: C1CCCNCCC1
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCCN3CCCCCCC3)c2n1

Procedure:
Prepared similarly to Intermediate 38 from 2-(butyloxy)-9-(5-chloropentyl)-8-(methyloxy)-9H-purin-6-amine and octahydroazocine.
Reaction SMILES: OC1C=CC=CN=1.[C:8]([O:12][C:13](=[O:41])[NH:14][C@H:15]([C@@H:34]1[CH2:38][C@@H:37]([CH3:39])[C:36](=[O:40])[O:35]1)[CH2:16][N:17]1[CH2:22][C:21](=[O:23])[N:20]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])[CH2:19][C:18]1([CH3:33])[CH3:32])([CH3:11])([CH3:10])[CH3:9].O.[CH:43]1([NH2:49])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1>>[C:8]([O:12][C:13](=[O:41])[NH:14][C@@H:15]([CH2:16][N:17]1[CH2:22][C:21](=[O:23])[N:20]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])[CH2:19][C:18]1([CH3:33])[CH3:32])[C@@H:34]([OH:35])[CH2:38][C@H:37]([C:36](=[O:40])[NH:49][CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)[CH3:39])([CH3:11])([CH3:9])[CH3:10]
Reactant: C[C@@H]1C[C@@H]([C@H](CN2CC(=O)N(c3c(F)cccc3F)CC2(C)C)NC(=O)OC(C)(C)C)OC1=O
Reactant: NC1CCCCC1
Agent: Oc1ccccn1
Solvent: O
Product: C[C@H](C[C@H](O)[C@H](CN1CC(=O)N(c2c(F)cccc2F)CC1(C)C)NC(=O)OC(C)(C)C)C(=O)NC1CCCCC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
7.9 mg of 2-hydroxypyridine (0.08 mmol) was added to a solution of 200 mg of {(S)-2-[4-(2,6-difluorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-1-[(2S,4R)-4-methyl-5-oxotetrahydrofuran-2-yl]ethyl}carbamic acid t-butyl ester obtained in Example (93b) (0.41 mmol) in cyclohexylamine (1.0 ml), and the mixture was stirred at 80° C. for three hours. The reaction mixture was cooled and then water was added, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=20/1) to obtain 218 mg of the title compound (yield: 88%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2C2CCCCO2)=[C:4]([NH:17][CH:18]([C:20]2[N:21]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:22](=[O:31])[C:23]3[C:28]([CH:29]=2)=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:30])[CH3:19])[N:3]=1.C([O-])(O)=O.[Na+]>Cl.CCO>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:17][C@H:18]([C:20]2[N:21]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:22](=[O:31])[C:23]3[C:28]([CH:29]=2)=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:30])[CH3:19])[N:3]=1.[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:17][CH:18]([C:20]2[N:21]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:22](=[O:31])[C:23]3[C:28]([CH:29]=2)=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:30])[CH3:19])[N:3]=1
Reactant: Cc1cccc2cc(C(C)Nc3nc(Cl)nc4c3ncn4C3CCCCO3)n(-c3ccccc3)c(=O)c12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc2cc(C(C)Nc3nc(Cl)nc4[nH]cnc34)n(-c3ccccc3)c(=O)c12
Product: Cc1cccc2cc([C@H](C)Nc3nc(Cl)nc4[nH]cnc34)n(-c3ccccc3)c(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 180 %

Procedure:
3-(1-(2-Chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-ylamino)ethyl)-8-methyl-2-phenylisoquinolin-1(2H)-one (compound 5303) (172 mg, 0.33 mmol) was dissolved in HCl/EtOH (3 M, 5 mL) and the resulting mixture was stirred at room temperature for 1 h. The mixture was neutralized with saturated NaHCO3 aqueous solution to pH=7-8, and then extracted with CH2Cl2 (50 mL×3). The combined organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and recrystallized from ethyl acetate and hexanes. The solid was collected by filtration and dried in vacuo to afford the desired product, 3-(1-(2-chloro-9H-purin-6-ylamino)ethyl)-8-methyl-2-phenylisoquinolin-1(2H)-one (5304, compound 244 in Table 4) (128 mg, 90% yield) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([OH:13])[CH:10]([CH2:14]S(C)(=O)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:19]=[N+:20]=[N-:21].[Na+]>CO.O>[CH2:1]([N:8]1[CH2:12][CH:11]([OH:13])[CH:10]([CH2:14][N:19]=[N+:20]=[N-:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)CC1CN(Cc2ccccc2)CC1O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: [N-]=[N+]=NCC1CN(Cc2ccccc2)CC1O
Yield: 85.7 %

Procedure:
1-Benzyl-4-hydroxy-3-methanesulfonylmethylpyrrolidine (80.8 g) is added to methanol-water (3:2) (1 liter), and thereto is added dropwise sodium azide (24.5 g), and the mixture is refluxed for 24 hours. After the reaction, the mixture is concentrated and extracted with dichloromethane. The dichloromethane solution is washed with water and saturated saline, dried and concentrated to give 1-benzyl-4-hydroxy-3-azidomethylpyrrolidine (59.7 g) as an oil.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([F:26])[CH:19]=3)=[N:6]2)[CH2:3][CH2:2]1.[CH3:27][NH2:28].C(O)C>>[CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][NH:28][CH3:27])=[CH:8][C:7]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([F:26])[CH:19]=3)=[N:6]2)[CH2:3][CH2:2]1
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC3CC3)n2)cc1F
Reactant: CN
Solvent: CCO
Product: CNCc1cc(-c2ccc(OC)c(F)c2)nn(CC2CC2)c1=O

Procedure:
A solution of 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one (160 mg, 0.42 mmol) in 30% methylamine/ethanol (5 mL) was stirred at 80° C. for 4 hours in a sealed tube. The solvent was distilled off under reduced pressure, and the residue was purified by preparative thin-layer chromatography on silica gel [developing solvent: chloroform/methanol (10/1)] to yield title compound as a slightly yellow oil (87 mg, 65.5%).
Reaction SMILES: [Br:1][C:2]1[O:3][C:4]2[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.C[O:25][C:26](=[O:36])[CH:27]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)O>>[Br:1][C:2]1[O:3][C:4]2[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=2[C:6]=1[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH:27]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:26]([OH:36])=[O:25])=[CH:15][CH:14]=2)=[CH:11][CH:12]=1
Reactant: Oc1ccc(-c2ccc(-c3c(Br)oc4ccccc34)cc2)cc1
Reactant: COC(=O)C(O)Cc1ccccc1
Product: O=C(O)C(Cc1ccccc1)Oc1ccc(-c2ccc(-c3c(Br)oc4ccccc34)cc2)cc1

Procedure:
The title compound was prepared from 4′-(2-bromo-benzofuran-3-yl)-biphenyl-4-ol and 3-phenyllactic acid methyl ester, in substantially the same manner, as described in Example 1, steps g-h, and was obtained as a white solid, mp 148-149° C.; MS m/e 512 (M+);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[N:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccc1
Reactant: COc1cccc(C=O)c1
Solvent: CCOCC
Product: COc1cccc(C=Nc2ccccc2)c1

Procedure:
A solution of 85.4 gm. of 3-methoxybenzaldehyde, 58.7 gm. of aniline, and 185 gm. of 3A molecular sieves in 700 ml. of anhydrous ether was refluxed for 16 hours. The ether was dried (Na2SO4), filtered, and concentrated in vacuo to an oil which upon distillation provided 93.2 gm of oil. b.p. 141°-143°/0.5 Torr.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\[NH2:17])/[CH2:4][CH2:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][NH:10][C:9]=2[N:8]=1.[CH2:18]1[CH2:22][C:21]2([CH2:29][C:27](=O)[O:26][C:24](=[O:25])[CH2:23]2)[CH2:20][CH2:19]1>O1CCOCC1>[N:8]1[C:9]2[NH:10][CH2:11][CH2:12][CH2:13][C:14]=2[CH:15]=[CH:16][C:7]=1[CH2:6][CH2:5][CH2:4][C:3]1[N:17]=[C:27]([CH2:29][C:21]2([CH2:23][C:24]([OH:26])=[O:25])[CH2:22][CH2:18][CH2:19][CH2:20]2)[O:1][N:2]=1
Reactant: N/C(CCCc1ccc2c(n1)NCCC2)=N\O
Reactant: O=C1CC2(CCCC2)CC(=O)O1
Solvent: C1COCCO1
Product: O=C(O)CC1(Cc2nc(CCCc3ccc4c(n3)NCCC4)no2)CCCC1
Temperature: 100 °C

Procedure:
A stirred mixture of (1Z)-N′-hydroxy-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butanimidamide (100 mg, WO 99/30709), 3,3-tetramethyleneglutaric anhydride (80 mg, Aldrich) and 1,4-dioxane (2 mL, Aldrich) was heated to 100° C. for 16 hrs. The resulting mixture was purified by HPLC to provide the title compound as a gum. 1H (CD3OD) δ 1.68 (8H, m); 1.95 (2H, p); 2.13 (2H, p); 2.45 (2H, s); 2.80 (6H, m); 3.15 (2H, s); 3.50 (2H, t); 6.63 (1H, d);
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C@H:16]([NH:18]C(=O)OC(C)(C)C)[CH3:17])[C:3]=1[C:26]([NH:28][C:29]1[S:30][CH:31]=[CH:32][N:33]=1)=[O:27].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:18][C@@H:16]([C:4]1[C:3]([C:26]([NH:28][C:29]2[S:30][CH:31]=[CH:32][N:33]=2)=[O:27])=[C:2]([OH:1])[C:11]2[C:6](=[C:7]([C:12]([F:13])([F:15])[F:14])[CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:17]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](N)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1

Procedure:
7 g of the product of Example 3 were suspended in 140 ml of methylene chloride and 70 ml of trifluoroacetic acid were slowly added with the temperature falling to 15° C. Contact was maintained for 4 hours and then, after concentrating to dryness under reduced pressure, the residue was taken up in 100 ml of ether. The crystals were separated by filtration and the product was slowly added to 50 ml of a 10% aqueous solution of sodium bicarbonate. After stirring, filtration, and washing with water, the crude product was treated at reflux with 300 ml of methanol without complete solution and after cooling and concentrating to 50 ml, 2.3 g of 2-[(R) 1-aminoethyl]-4-hydroxy-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline-carboxamide melting at 265° C. and with a specific rotation of [α]D =-72°±2.5° (c=0.5% in CH3COOH) were obtained.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:20][CH:19]4[CH:15]([CH2:16][NH:17][CH2:18]4)[CH2:14]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:21][C:22]1[CH:23]=[CH:24][C:25]([C:31]2[N:36]=[CH:35][CH:34]=[CH:33][N:32]=2)=[C:26]([CH:30]=1)[C:27](O)=[O:28]>>[F:21][C:22]1[CH:23]=[CH:24][C:25]([C:31]2[N:32]=[CH:33][CH:34]=[CH:35][N:36]=2)=[C:26]([C:27]([N:17]2[CH2:16][CH:15]3[CH:19]([CH2:20][N:13]([C:9]4[N:8]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH:12]=[CH:11][N:10]=4)[CH2:14]3)[CH2:18]2)=[O:28])[CH:30]=1
Reactant: c1ccc(-c2ccnc(N3CC4CNCC4C3)n2)cc1
Reactant: O=C(O)c1cc(F)ccc1-c1ncccn1
Product: O=C(c1cc(F)ccc1-c1ncccn1)N1CC2CN(c3nccc(-c4ccccc4)n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 26 and Intermediate 13. MS (ESI): mass calculated for C27H23FN6O, 466.52; m/z found 467.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.72-8.66 (m, 2H), 8.44-8.29 (m, 2H), 8.16-8.02 (m, 2H), 7.53-7.45 (m, 3H), 7.21-7.14 (m, 1H), 7.10-7.06 (m, 1H), 7.01-6.98 (m, 1H), 6.87 (br s, 1H), 4.05-3.50 (m, 7H), 3.31-2.98 (m, 3H).
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][CH2:22][C@@H:23]([C:25]4[CH:34]=[CH:33][C:32]([O:35]CC5C=CC=CC=5)=[C:31]5[C:26]=4[CH:27]=[CH:28][C:29](=[O:43])[NH:30]5)[OH:24])=[CH:15][CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>[Pd]>[C:1]12([CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][CH2:22][C@@H:23]([C:25]4[CH:34]=[CH:33][C:32]([OH:35])=[C:31]5[C:26]=4[CH:27]=[CH:28][C:29](=[O:43])[NH:30]5)[OH:24])=[CH:15][CH:14]=3)[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: O=c1ccc2c([C@@H](O)CNCCc3ccc(OCC45CC6CC(CC(C6)C4)C5)cc3)ccc(OCc3ccccc3)c2[nH]1
Agent: [Pd]
Product: O=c1ccc2c([C@@H](O)CNCCc3ccc(OCC45CC6CC(CC(C6)C4)C5)cc3)ccc(O)c2[nH]1
Yield: 65.2 %

Procedure:
Obtained from Intermediate 38 (0.17 g, 0.32 mmol) and palladium on charcoal (10%, 0.034 g) by the same procedure described in Example 1 (reaction time: 2 days). The crude obtained was triturated with ether and filtrated to obtain the title compound as a yellow solid (0.102 g, 69%).
Reaction SMILES: N1(CCN2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)CCCCCC1.Cl.Cl.NC1C=C[C:39]([C@H:42]([N:44]([CH3:51])[CH:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)[CH3:43])=CC=1>>[CH3:51][N:44]([CH:45]1[CH2:46][CH2:47][O:48][CH2:49][CH2:50]1)[C@@H:42]([C:43]1[CH:11]=[CH:12][C:13]([NH:16][C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[C:25]([O:28][CH2:29][CH:30]([CH3:31])[CH3:32])[CH:24]=[CH:23][CH:22]=3)=[O:18])=[CH:14][CH:15]=1)[CH3:39]
Reactant: C[C@H](c1ccc(N)cc1)N(C)C1CCOCC1
Reactant: CC(C)COc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCCCCC4)CC3)cc12
Agent: Cl
Product: CC(C)COc1cccc2[nH]c(C(=O)Nc3ccc([C@@H](C)N(C)C4CCOCC4)cc3)cc12

Procedure:
This compound is synthesized analogously to Example 1 from 4-Isobutoxy-1H-indole-2-carboxylic acid 80 (preparation see Example 8) and amine 72.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[F:32])[CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CO.C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[F:32])[CH:12]2[CH2:17][CH2:16][N:15]([S:43]([CH3:42])(=[O:45])=[O:44])[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)CC1
Solvent: CO
Solvent: O=CO
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCC(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 40 h
Yield: 53.2 %

Procedure:
The product of Step (b) (72 mg, 0.15 mmol) in 96% formic acid (2 ml) was stirred at room temperature under nitrogen for 17 hours. Methanol was added and the mixture was evaporated in vacuo. The residue was dissolved in a small volume of water (10 ml), basified with saturated potassium carbonate solution and extracted with dichloromethane (10 ml). The combined organic extracts were dried (MgSO4) and evaporated in vacuo. This residue was dissolved in dichloromethane (2 ml) under nitrogen and triethylamine (0.029 ml, 0.21 mmol) and methanesulfonyl chloride (0.016 ml, 0.21 mmol) were added sequentially. The resulting mixture was stirred at room temperature for 40 hours and then partitioned between dichloromethane (10 ml) and water (10 ml). The aqueous layer was separated and re-extracted with dichloromethane and the combined organic extracts were dried (MgSO4) and evaporated in vacuo. The residue was purified by flash chromatography, eluting with 40% ethyl acetate in iso hexane to give the title compound as a white solid (37 mg, 58%).
Reaction SMILES: [CH:1]1([C:5]2[N:13]3[C:8]([C:9]([NH2:14])=[N:10][CH:11]=[N:12]3)=[C:7](I)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[C:16]1([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][C:26](B4OC(C)(C)C(C)(C)O4)=[CH:27][CH:28]=3)[N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[CH:1]1([C:5]2[N:13]3[C:8]([C:9]([NH2:14])=[N:10][CH:11]=[N:12]3)=[C:7]([C:26]3[CH:25]=[C:24]4[C:29]([CH:30]=[CH:31][C:22]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)=[N:23]4)=[CH:28][CH:27]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OB(c2ccc3ccc(-c4ccccc4)nc3c2)OC1(C)C
Reactant: Nc1ncnn2c(C3CCC3)nc(I)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Nc1ncnn2c(C3CCC3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Temperature: 75 °C

Procedure:
A flask was charged with 7-cyclobutyl-5-iodo-imidazo[5,1-f][1,2,4]triazin-4-ylamine (30 mg, 0.095 mmol), 2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline (38 mg, 0.110 mmol), and sodium carbonate (Na2CO3) (30 mg, 0.286 mmol) was evacuated and charged with nitrogen (N2) (3×). To this mixture was quickly added tetrakis(triphenylphosphine)palladium(0) and evacuated and charged with N2 (2×). This mixture was charged with a previously degassed solvent DME/H2O (5:1) (2 mL) and heated overnight at 75° C. The reaction mixture was filtered through an autovial (0.45 μM frit) and washed with MeOH (3×). The filtrate was concentrated in vacuo and purified by mass directed purification (MDP) resulting in the title compound as a pale yellow solid; 1H NMR (CDCl3, 400 MHz) δ 1.96-2.10 (m, 1H), 2.10-2.25 (m, 1H); 2.40-2.56 (m, 2H); 2.60-2.78 (m, 2H); 4.12-4.29 (m, 1H); 5.99 (brs, 2H); 7.42-7.58 (m, 3H); 7.84-8.05 (m, 4H); 8.18 (d, J=7.2 Hz, 2H); 8.28 (d, J=8.4 Hz, 1H); 8.39 (s, 1H); MS (ES+): m/z 393.14 (100) [MH+], HPLC: tR=3.51 min (MicromassZQ, polar—5 min).
Reaction SMILES: [CH3:1][C:2]([CH:9]([CH3:11])[CH3:10])=[CH:3][C:4](OCC)=[O:5].S(Cl)([Cl:14])=O.Cl>C1C=CC=CC=1>[CH3:1][C:2]([CH:9]([CH3:11])[CH3:10])=[CH:3][C:4]([Cl:14])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)C=C(C)C(C)C
Agent: Cl
Solvent: c1ccccc1
Product: CC(=CC(=O)Cl)C(C)C

Procedure:
3,4-Dimethyl-2-pentenoic acid (XI, 4.1 g) was heated to a gentle boil with thionyl chloride (50 g) in benzene (50 mL) until the generation of hydrochloric acid gas ceased. Removal of the excess thionyl chloride and benzene by evaporation in vacuo followed by a distillation of the reaction product gave pure 3,4-dimethyl-2-pentenoylchloride (IX, 64° C. (9.5 mm)).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([C:11]([N:13]2[C:22]3[C:17](=[C:18]([O:41][C:42]4[CH:47]=[C:46]([CH3:48])[N:45]=[C:44]([CH3:49])[CH:43]=4)[C:19]([C:23]4[CH:24]=[N:25][N:26]([CH:28]5[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]5)[CH:27]=4)=[CH:20][CH:21]=3)[CH2:16][CH2:15][C@@H:14]2[CH3:50])=[O:12])[CH2:10][CH2:9]1>ClCCl>[CH:8]1([C:11]([N:13]2[C:22]3[C:17](=[C:18]([O:41][C:42]4[CH:43]=[C:44]([CH3:49])[N:45]=[C:46]([CH3:48])[CH:47]=4)[C:19]([C:23]4[CH:24]=[N:25][N:26]([CH:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)[CH:27]=4)=[CH:20][CH:21]=3)[CH2:16][CH2:15][C@@H:14]2[CH3:50])=[O:12])[CH2:9][CH2:10]1
Reactant: Cc1cc(Oc2c(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)ccc3c2CC[C@H](C)N3C(=O)C2CC2)cc(C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Oc2c(-c3cnn(C4CCNCC4)c3)ccc3c2CC[C@H](C)N3C(=O)C2CC2)cc(C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (1 mL) was added to a solution of (S)-tert-butyl 4-(4-(1-(cyclopropanecarbonyl)-5-(2,6-dimethylpyridin-4-yloxy)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.030 g, 0.05 mmol) in dichloromethane (3 mL), and the resulting solution stirred for 1 h at room temperature. The reaction mixture was concentrated under vacuum, and the residue was purified via column chromatography on silica gel (eluting with 1:2, ethyl acetate/petroleum ether). The crude product was further purified by preparative-HPLC with the following conditions (Waters I): Column, SunFire Prep C18, 5 um, 19×100 mm; mobile phase, water (0.05% ammonium bicarbonate) and acetonitrile (65% to 85% acetonitrile in 7 min, flow rate: 20 mL/min); Detector, UV 220254 nm. This afforded (S)-cyclopropyl(5-(2,6-dimethylpyridin-4-yloxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone (0.003 g, 12%) as a white powder. 1H NMR (400 MHz, CD3OD) δ ppm 0.73-0.84 (m, 1H), 0.92-1.03 (m, 2H), 1.12-1.21 (m, 4H), 1.42-1.51 (m, 1H), 1.99-2.20 (m, 5H), 2.20-2.29 (m, 2H), 2.29-2.41 (m, 6H), 2.63-2.72 (m, 1H), 2.95-3.04 (m, 2H), 3.31-3.41 (m, 2H), 4.35-4.45 (m, 1H), 4.79-4.90 (m, 1H), 6.53 (s, 2H), 7.45 (d, J=8.40 Hz, 1H), 7.63 (d, J=8.80 Hz, 1H), 7.79 (s, 1H), 7.96 (s, 1H). MS (ESI, pos. ion) m/z 486 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[N:10]([CH2:31][CH3:32])[CH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34]([O:36][C:37](=[O:54])[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[C:41](Br)[CH:40]=1)[CH3:35]>>[CH2:34]([O:36][C:37](=[O:54])[CH2:38][C:39]1[CH:40]=[C:41]([C:13]2[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:19])[F:20])=[CH:17][C:12]=2[CH2:11][N:10]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:33])[CH2:31][CH3:32])[C:42]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[CH:43][CH:44]=1)[CH3:35]
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)OCc1ccccc1
Reactant: CCOC(=O)Cc1ccc(OCc2ccccc2)c(Br)c1
Product: CCOC(=O)Cc1ccc(OCc2ccccc2)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)OCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: ethyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-carbamic acid benzyl ester and (4-benzyloxy-3-bromo-phenyl)-acetic acid ethyl ester.