Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:4]=O)[CH2:3][CH2:2]1.N1CCCCC1.[NH2:12][C:13]1[N:18]=[CH:17][N:16]=[C:15]2[N:19]([CH2:37][C@H:38]3[CH2:42][CH2:41][CH2:40][N:39]3[C:43](=[O:47])[CH2:44][C:45]#[N:46])[N:20]=[C:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]4[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=4)=[CH:24][CH:23]=3)[C:14]=12>CO>[NH2:12][C:13]1[N:18]=[CH:17][N:16]=[C:15]2[N:19]([CH2:37][C@H:38]3[CH2:42][CH2:41][CH2:40][N:39]3[C:43]([C:44](=[CH:4][CH:1]3[CH2:2][CH2:3]3)[C:45]#[N:46])=[O:47])[N:20]=[C:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]4[CH:30]=[C:31]([F:36])[CH:32]=[C:33]([F:35])[CH:34]=4)=[CH:24][CH:23]=3)[C:14]=12
Reactant: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cc(F)cc(F)c3)cc2)c2c(N)ncnc21
Reactant: O=CC1CC1
Solvent: C1CCNCC1
Solvent: CO
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cc(F)cc(F)c3)cc2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 49 %

Procedure:
Into a 10-mL round-bottom flask, was placed cyclopropanecarbaldehyde (28.7 mg, 0.41 mmol, 2.00 equiv), piperidine (17.4 mg, 0.20 mmol, 1.00 equiv), 3-[(2R)-2-([4-amino-3-[4-(3,5-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidin-1-yl]-3-oxopropanenitrile (100 mg, 0.20 mmol, 1.00 equiv), and methanol (5 mL). The resulting solution was stirred for 12 h at 25° C. and then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (50/1) to give 53.12 mg (45%) of the title compound as an off-white solid. LC-MS: (ES, m/z): MS (ESI, pos. ion) m/z: 541 (M+1). 1H-NMR: (CDCl3, ppm): 1HNMR (300 MHz, CD3OD, ppm), 8.283 (1H, s), 7.777˜7.806 (2H, t), 7.269˜7.298 (2H, t), 6.703˜6.754 (3H, t), 6.455˜6.600 (1H, d), 4.400˜4.878 (3H, m), 3.338˜3.618 (2H, m), 1.700˜2.188 (4H, m), 1.280˜1.305 (4H, m), 0.710˜0.912 (2H, m).
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][NH:20]C(=O)C)=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[OH-].[Na+]>>[C:1]1([C:7]2[S:8][CH:9]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][NH2:20])=[CH:16][CH:17]=3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)NCCc1ccc(-c2csc(-c3ccccc3)n2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NCCc1ccc(-c2csc(-c3ccccc3)n2)cc1
Temperature: 120 °C
Yield: 84.6 %

Procedure:
In a round-bottomed flask, N-{2-[4-(2-phenyl-thiazol-4-yl)-phenyl]-ethyl}-acetamide (838 mg, 2.60 mmol) was added to 5.0 ml of concentrated HCl and the resulting solution was heated to about 120° C. for about sixteen hours. The solution was then cooled to about 0° C., brought to pH 12 with 5M sodium hydroxide, and extracted with four portions of methylene chloride. The combined organic extracts were then washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The crude material was purified by column chromatography (silica gel; methylene chloride to 20% methanol/methylene chloride) to afford the product (617 mg, 85% yield). LRMS ([M+H]+)=281.2.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6].[CH3:20][NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:22]([N:21]([CH2:2][CH2:3][CH:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])[CH3:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CNCc1ccccc1
Reactant: O=C(C(CCCl)c1ccccc1)N1CCCCCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCC(C(=O)N1CCCCCC1)c1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
A solution of 2,3,4,5,6,7-hexahydro-1-[4-chloro-2-phenylbutanoyl]-1H-azepine (10.0 g, 35.7 mmol) in acetonitrile (100 ml) was added to a solution of N-methylbenzylamine (4.03 g, 33.3 mmol) and diisopropylethylamine (4.62 g, 35.7 mmol) in acetonitrile (40 ml) and the reaction mixture stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue dissolved in water (100 ml). The aqueous phase was washed with ethyl acetate (3×50 ml) and the combined organic phases washed with brine (50 ml), water (50 ml), dried (MgSO4) and concentrated under reduced pressure. The crude oil obtained was chromatographed on alumina, eluting with hexane:ethyl acetate (2:1) to afford the title compound as an oil (6.93 g, 53%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[C:4]([Cl:12])[N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1>>[Cl:12][C:4]1[N:3]=[C:2]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]=1[CH3:11]
Reactant: Nc1ccc(CCO)cc1
Reactant: Cc1cc([N+](=O)[O-])c(Cl)nc1Cl
Product: Cc1cc([N+](=O)[O-])c(Nc2ccc(CCO)cc2)nc1Cl

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 34 from 2,6-dichloro-5-methyl-3-nitropyridine (Horn, U.; Mutterer, F.; Weis, C. D. Helv. Chim. Acta., 1976, 59, 190.) and 4-aminophenylethyl alcohol.
Reaction SMILES: [NH2:1][C:2]1[N:22]=[C:5]2[C:6]([C:10]3[CH:11]=[C:12]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])[CH:13]=[CH:14][CH:15]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.Br[C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[CH:26][CH:25]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:21][N:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:1][C:24]4[CH:25]=[CH:26][C:27]([N:30]5[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]5)=[CH:28][CH:29]=4)[N:22]=3)[CH:9]=[CH:8][CH:7]=2)[CH:11]=1)[S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: CN(c1cccc(-c2cccn3nc(N)nc23)c1)S(C)(=O)=O
Reactant: CN1CCN(c2ccc(Br)cc2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4c(-c5cccc(N(C)S(C)(=O)=O)c5)cccn4n3)cc2)CC1

Procedure:
N-Methyl-N-(3-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl}-phenyl)-methanesulfonamide was prepared from N-[3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-phenyl]-N-methyl-methanesulfonamide (75.0 mg, 0.236 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (67.0 mg, 0.262 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow foam (0.033 g, 28%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.41 (d, J=6.6, 1H), 8.13 (s, 3H), 7.93 (d, J=7.9 Hz, 1H), 7.59 (d, J=7.4 Hz, 1H), 7.56-7.45 (m, 3H), 7.44 (dd, J=8.2, 1.2 Hz, 1H), 6.98-6.92 (m, 3H), 6.64 (s, 1H), 3.42 (s, 3H), 3.19-3.14 (m, 4H), 2.89 (s, 3H), 2.63-2.57 (m, 4H), 2.36 (s, 3H). MS=492 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[CH:26]=[N:25][C:24]2[C:19](=[CH:20][C:21]([F:28])=[C:22]([F:27])[CH:23]=2)[N:18]=1>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][NH:15][C:26]1[CH:17]=[N:18][C:19]2[C:24](=[CH:23][C:22]([F:27])=[C:21]([F:28])[CH:20]=2)[N:25]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1cc2ncc(Cl)nc2cc1F
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1CN
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1CNc1cnc2cc(F)c(F)cc2n1
Temperature: 90 °C

Procedure:
(S)-2-Aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (0.607 g), and 2-chloro-6,7-difluoroquinoxaline McQuaid et al. J. Med Chem. (1992), 35(18), 3319-24 (0.569 g) were dissolved in dimethylformamide (1 ml) and heated to 90 ° C. for 5 days under an atmosphere of argon. After cooling, the reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with water, saturated brine, dried and evaporated. The residue was chromatographed over silica gel, eluting with a gradient of 10 to 50% ethyl acetate in hexane. The title compound was obtained as a pale yellow solid (0.460 g), MH+ 379.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[O:10])=[CH:4][CH:3]=1.Br[CH:20]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][N:15]([CH:20]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:14]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(NCC1CNCCO1)Nc1ccc(Cl)cc1
Reactant: CCOC(=O)C(Br)c1ccccc1
Product: CCOC(=O)C(c1ccccc1)N1CCOC(CNC(=O)Nc2ccc(Cl)cc2)C1
Yield: 232.3 %

Procedure:
Example 44 was prepared in an analogous manner to Example 19 using a mixture of Intermediate 9 (0.01 g) and ethyl bromo(phenyl)acetate (0.029 g) to give the title compound (0.0372 g). LC-MS (System A): Rt 3.43 mins, Mass Spectrum m/z 432 [MH+].
Reaction SMILES: [CH3:1][Si:2]([CH3:20])([CH3:19])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:15]2[CH:14]=[N:13][C:12]([C:16](=O)[CH3:17])=[N:11][C:10]=2[CH:9]=[CH:8]1.Cl.[CH2:22]([NH2:24])[CH3:23].C([BH3-])#N.[Na+]>CCO>[CH2:22]([NH:24][CH:16]([C:12]1[N:13]=[CH:14][C:15]2[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:20])([CH3:19])[CH3:1])[CH:8]=[CH:9][C:10]=2[N:11]=1)[CH3:17])[CH3:23]
Reactant: CCN
Reactant: CC(=O)c1ncc2c(ccn2COCC[Si](C)(C)C)n1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CCNC(C)c1ncc2c(ccn2COCC[Si](C)(C)C)n1
Temperature: 130 °C
Reaction time: 0.03 h

Procedure:
A microwave vial charged with 1-(5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidin-2-yl)ethanone (1.50 g, 5.15 mmol), ethylamine hydrochloride (3.36 g, 41.2 mol), sodium cyanoborohydride (420.5 mg, 6.69 mmol), and anhydrous EtOH (40 mL) was stirred under microwave irradiation (300 Watts) at 130° C. for 2 min. The solid was filtered and rinsed well with EtOH. Volatile solvent from the filtrate was removed under reduced pressure. The resultant crude was redissolved in EtOAc and washed with 10% aqueous NaOH solution (2×), water, and brine. The organic phase was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude was triturated in DCM, and the insoluble solid was filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure and dried on high-vac to afford N-ethyl-1-(5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidin-2-yl)ethanamine as an oil. 1H NMR (400 MHz, CDCl3) δ 8.92 (s, 1H), 7.50 (d, J=3.2 Hz, 1H), 6.65 (d, J=3.2 Hz, 1H), 5.50 (s, 2H), 4.09 (q, J=6.7 Hz, 1H), 3.46 (t, J=8.1 Hz, 2H), 2.57 (dd, J=11.2, 7.2 Hz, 1H), 2.46 (dd, J=11.2, 7.0 Hz, 1H), 2.08 (br s, 1H), 1.46 (d, J=6.7 Hz, 3H), 1.08 (t, J=7.1 Hz, 3H), 0.88 (t, J=8.1 Hz, 2H), −0.07 (d, J=0.9 Hz, 9H)); MS (ESI) m/z: 321.4 [M+1]+.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]([CH2:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=1)[C@H:10]([OH:22])[CH2:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1.[CH2:32]([N:35]([CH2:49][CH2:50][CH3:51])[C:36]([C:38]1[CH:39]=[C:40](C=C(CC)C=1)[C:41](O)=[O:42])=[O:37])[CH2:33][CH3:34]>>[F:31][C:26]1[CH:25]=[C:24]([CH:29]=[C:28]([F:30])[CH:27]=1)[CH2:23][C@H:9]([NH:8][C:41](=[O:42])[CH2:40][CH2:39][CH2:38][C:36]([N:35]([CH2:32][CH2:33][CH3:34])[CH2:49][CH2:50][CH3:51])=[O:37])[C@H:10]([OH:22])[CH2:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1
Reactant: CCCN(CCC)C(=O)c1cc(CC)cc(C(=O)O)c1
Reactant: COc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Solvent: O=C(O)C(F)(F)F
Product: CCCN(CCC)C(=O)CCCC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNCc1cccc(OC)c1

Procedure:
Following the general procedure of EXAMPLEs 6 and making non-critical variations and using (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-methoxybenzyl)amino]-2-butanol (VIII, EXAMPLE 5) with 5-(dipropylamino)-5-oxopentanoic acid (IX), the title compound is obtained, MH+=534.2.
Reaction SMILES: [CH3:1][O:2][C:3](/[CH:5]=[CH:6]/[C:7]([OH:9])=[O:8])=[O:4].Cl.CN(C)CCCN=C=NCC.[CH2:22]([N:24]([CH2:30][CH3:31])[C:25](=[O:29])[C@@H:26](O)[CH3:27])[CH3:23]>ClCCl.CN(C1C=CN=CC=1)C>[C:7]([O:9][C@H:26]([C:25](=[O:29])[N:24]([CH2:30][CH3:31])[CH2:22][CH3:23])[CH3:27])(=[O:8])/[CH:6]=[CH:5]/[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)/C=C/C(=O)O
Reactant: CCN(CC)C(=O)[C@H](C)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCN(CC)C(=O)[C@H](C)OC(=O)/C=C/C(=O)OC
Yield: 21.5 %

Procedure:
Following general procedure B2, (2E)-3-(methoxycarbonyl)prop-2-enoic acid (methyl hydrogen fumarate, MHF) (0.50 g, 3.84 mmol) was activated with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC) (0.88 g, 4.60 mmol) in 12 mL of dichloromethane (DCM) at ca. 0° C. (2S)—N,N-Diethyl-2-hydroxypropanamide (0.44 g, 3.07 mmol) (0.44 g, 3.07 mmol) and 4-(N,N-dimethyl)aminopyridine (DMAP) (0.40 g, 3.18 mmol) were added to the activated carboxylic acid. After work-up and isolation, and purification by mass-guided preparative HPLC/lyophilization and by silica gel flash column chromatography (Biotage) using ethyl acetate (EtOAc) and hexanes afforded 0.17 g (18% yield) of the title compound (33) as a clear oil. 1H NMR (CDCl3, 400 MHz): δ 6.95-6.87 (m, 2H), 5.43 (q, J=6.8 Hz, 1H) 3.80 (s, 3H), 3.50-3.26 (m, 4H), 1.49 (d, J=6.4 Hz, 3H), 1.26 (t, J=6.8, 3H), 1.12 (t, J=7.6 Hz, 3H). MS (ESI): m/z 258.06 (M+H)+.
Reaction SMILES: [C:1]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.Cl.[C:21](Cl)(Cl)(Cl)[Cl:22].CCCCCC>C(O)(=O)C>[C:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([CH2:21][Cl:22])=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)N1CCc2ccccc21
Reactant: ClC(Cl)(Cl)Cl
Agent: C=O
Agent: Cl
Solvent: CCCCCC
Solvent: CC(=O)O
Product: O=C(c1ccccc1)N1CCc2cc(CCl)ccc21
Yield: 60 %

Procedure:
1-Benzoyl-2,3-dihydro-1H-indole (Beilstein, 20, 257) (5.58 g, 25 mmole) is dissolved in 50 ml of glacial acetic acid, then 56 ml (ca 70 mmoles) of 40% formaldehyde are added, and dry hydrogen chloride passed into the solution which is maintained at 70° for 3 hours. The solution is evaporated, and the residue dissolved in benzene, and again evaporated to dryness to give 6.53 g of crude product. This residue is treated with carbon tetrachloride-hexane to give 4.05 g (60%) of 1-benzoyl-5-chloromethyl-2,3-dihydro-1H-indole, m.p. 107.5 - 110.0°.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[OH:14])[CH:9]=O)[CH2:2][CH2:3][CH3:4].[Cl-].[CH3:16][O:17][CH:18]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:19]([O:21][CH3:22])=[O:20].C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:5][C:6]1[CH:7]=[C:8](/[CH:9]=[C:18](\[O:17][CH3:16])/[C:19]([O:21][CH3:22])=[O:20])[CH:11]=[CH:12][C:13]=1[OH:14])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(C=O)ccc1O
Reactant: COC(=O)C(OC)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCOc1cc(/C=C(\OC)C(=O)OC)ccc1O
Temperature: 40 °C
Reaction time: 16 h
Yield: 91.8 %

Procedure:
4.0 g (20.6 mmol) of 3-butoxy-4-hydroxybenzaldehyde and 13.25 g (30.9 mmol) of (methoxy(methoxycarbonyl)methyl)triphenylphosphonium chloride are suspended in 40 ml of tetrahydrofuran. 6 ml (42 mmol) of triethylamine are added and then the reaction medium is stirred at 40° C. for 16 hours. The reaction medium is filtered and then the solvents are evaporated. 50 ml of diethyl ether are added and the mixture is stirred at ambient temperature for 10 minutes and then filtered. After evaporation of the solvents, the residue is taken up in a heptane/ethyl acetate 8/2 mixture and then filtered through a silica patch (2 cm). 5.3 g of methyl (Z)-3-(3-butoxy-4-hydroxyphenyl)-2-methoxyacrylate are obtained after evaporation of the solvents.
Reaction SMILES: CC(C)([O-])C.[Na+].[F:7][C:8]1[CH:25]=[CH:24][C:11]([CH2:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:23])[NH:15][N:14]=2)=[CH:10][C:9]=1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([OH:34])[CH2:30][CH2:29]1)=[O:27].Cl.Cl[C:37]1[CH:42]=[CH:41][N:40]=[CH:39][N:38]=1>O1CCCC1>[F:7][C:8]1[CH:25]=[CH:24][C:11]([CH2:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:23])[NH:15][N:14]=2)=[CH:10][C:9]=1[C:26]([N:28]1[CH2:29][CH2:30][CH:31]([O:34][C:37]2[CH:42]=[CH:41][N:40]=[CH:39][N:38]=2)[CH2:32][CH2:33]1)=[O:27]
Reactant: Clc1ccncn1
Reactant: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCC(O)CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCC(Oc2ccncn2)CC1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 50.8 %

Procedure:
Sodium tert-butoxide (125 mg, 1.30 mmol) was added in one portion to 4-(4-fluoro-3-(4-hydroxypiperidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (2a) (150 mg, 0.39 mmol) in tetrahydrofuran (2 ml) at 20° C. The resulting suspension was stirred at 20° C. for 10 minutes. 4-chloropyrimidine hydrochloride (49.5 mg, 0.43 mmol) was added in one portion and the resulting mixture was stirred at 50° C. for 2 hours. Sodium tert-butoxide (41 mg, 0.43 mmol) was added in one portion followed by 4-chloropyrimidine hydrochloride (65 mg, 0.43 mmol) and the mixture heated at 50° C. for 2 hours and then stirred at ambient temperature overnight. The crude product was purified by ion exchange chromatography using an SCX column. The desired product was eluted from the column using 2M NH3/MeOH and pure fractions were evaporated to dryness to afford crude product. This was purified by preparative HPLC (Sunfire column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 0.1% TFA) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired compound as a solid (91 mg, 50.4%); 1H NMR (400.132 MHz, DMSO) δ 1.53-1.61 (1H, m), 1.66-1.73 (1H, m), 1.88-1.94 (1H, m), 2.02-2.09 (1H, m), 3.14-3.25 (1H, m), 3.32-3.48 (2H, m), 3.98-4.07 (1H, m), 4.34 (2H, s), 5.33-5.39 (1H, m), 6.95 (1H, d), 7.21-7.25 (1H, m), 7.37-7.44 (2H, m), 7.80-7.84 (1H, m), 7.87-7.90 (1H, m), 7.97 (1H, d), 8.26 (1H, d), 8.54 (1H, d), 8.79 (1H, s), 12.56 (1H, s); m/z (LC-MS, ESI+), RT=1.69 (M+H 460.6).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:15]1([NH:21][C:22]2[CH:31]=[C:30]3[C:25]([C:26](=[O:39])[C:27]([CH:37]=O)=[CH:28][N:29]3[CH:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:24][C:23]=2[F:40])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[NH2:41][C:42]1[CH:47]=[CH:46][C:45]([OH:48])=[CH:44][CH:43]=1.C(=O)([O-])O.[Na+]>C(O)(=O)C.ClCCCl>[CH:15]1([NH:21][C:22]2[CH:31]=[C:30]3[C:25]([C:26](=[O:39])[C:27]([CH2:37][NH:41][C:42]4[CH:47]=[CH:46][C:45]([OH:48])=[CH:44][CH:43]=4)=[CH:28][N:29]3[CH:32]3[CH2:33][CH2:34][CH2:35][CH2:36]3)=[CH:24][C:23]=2[F:40])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: Nc1ccc(O)cc1
Reactant: O=Cc1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: O=c1c(CNc2ccc(O)cc2)cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc12
Reaction time: 24 h

Procedure:
169 mg of sodium triacetoxyborohydride was added to a mixed solution 10 ml of 1,2-dichloroethane and 0.05 ml of acetic acid of 142 mg 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbaldehyde and 66 mg of 4-aminophenol, followed by stirring for 24 hours. Aqueous saturated sodium hydrogen carbonate was added thereto, followed by extraction with chloroform. After drying over anhydrous sodium sulfate and subsequent filtration, concentration under a reduced pressure was carried out. The resulting residue was purified by silica gel column chromatography and then crystallized from ethyl acetate to obtain 46 mg of [7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-3-{[(4-hydroxyphenyl)amino]methyl}quinolin-4(1H)-one.
Reaction SMILES: [F:1][CH:2]1[C:7]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[NH:10][CH:9]=2)=[CH:6][CH2:5][N:4]([CH3:18])[CH2:3]1.I.CS[C:22]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)=[NH:23]>C(O)C>[F:1][CH:2]1[C:7]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:22]([C:24]4[S:25][CH:26]=[CH:27][CH:28]=4)=[NH:23])[CH:15]=3)[NH:10][CH:9]=2)=[CH:6][CH2:5][N:4]([CH3:18])[CH2:3]1
Reactant: CSC(=N)c1cccs1
Reactant: CN1CC=C(c2c[nH]c3ccc(N)cc23)C(F)C1
Agent: I
Solvent: CCO
Product: CN1CC=C(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)C(F)C1
Reaction time: 20 h
Yield: 58.2 %

Procedure:
A solution of compound 133 (0.062 g, 0.252 mmol) in dry ethanol (5 mL) was treated with thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.144 g, 0.505 mmol) at room temperature and stirred for 20 h. Solvent was evaporated, crude was diluted with sat. NaHCO3 solution (20 mL) and product was extracted into CH2Cl2 (2 20 mL). The combined CH2Cl2 layer was washed with brine (15 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in methanol: CH2Cl2, 0:100 to 1:9) to obtain compound 134 (0.052 g, 58%) as a solid. mp 127-129° C.; 1H NMR (DMSO-d6) δ 2.29 (s, 3H), 2.42-2.57 (m, 1H), 2.72-2.81 (m, 1H), 3.00-3.09 (m, 1H), 3.32-3.42 (m, 1H), 5.41 (d, 1H, J=49.2 Hz), 6.30-6.40 (m, 3H), 6.69 (dd, 1H, J=1.2, 8.4 Hz), 7.10 (t, 1H, J=3.9 Hz), 7.22 (s, 1H), 7.34 (d, 1H, J=8.4 Hz), 7.42 (s, 1H), 7.60 (d, 1H, J=4.8 Hz), 7.73 (d, 1H, J=2.7 Hz), 11.05 (s, 1H); ESI-MS m/z (%): 355 (MH+, 100), 335 (21), 312 (33); ESI-HRMS calculated for C19H20FN4S (MH+), Calculated: 355.1391; Observed: 355.1387.
Reaction SMILES: [N:1]([CH2:4][C@H:5]([NH:19][C:20](=[O:29])[C@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:22])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:8][CH:7]=1)=[N+]=[N-]>C(O)C.[Pd]>[NH2:1][CH2:4][C@H:5]([NH:19][C:20](=[O:29])[C@H:21]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH3:22])[C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][CH:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:10][CH:11]=1
Reactant: CCCC(C)COc1ccc([C@H](CN=[N+]=[N-])NC(=O)[C@@H](C)c2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCCC(C)COc1ccc([C@H](CN)NC(=O)[C@@H](C)c2ccccc2)cc1
Reaction time: 1 h
Yield: 62.5 %

Procedure:
To a solution of (2S)-N-((1R)-2-azido-1-(4-(2-methylpentyloxy)phenyl)ethyl)-2-phenylpropanamide (12.0 g, 30.4 mmol) in ethanol (40 mL) in a Parr shaker bottle was added 10% Pd/C (3.0 g, 2.82 mmol, Degussa type). The reaction mixture was placed under an H2 atmosphere at 40 psi for 1 h. The mixture was then filtered through a pad of diatomaceouse earth (Celite®) and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (10% methanol in dichloromethane) to afford (2S)-N-((1R)-2-amino-1-(4-(2-methylpentyloxy)phenyl)ethyl)-2-phenylpropanamide (7.0 g, 63% yield) as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ 8.22 (d, J=8.1 Hz, 1H), 7.22-7.31 (m, 4H), 7.13-7.22 (m, 1H), 6.99 (d, 2H), 6.74 (d, 2H), 4.56-4.70 (m, 1H), 3.69-3.79 (m, 2H), 3.65 (dd, J=9.3, 6.5 Hz, 1H), 3.34 (br. s., 2H), 2.61-2.75 (m, 2H), 1.83 (dddd, J=12.5, 6.5, 6.4, 6.3 Hz, 1H), 1.33-1.36 (m, 3H), 1.24-1.48 (m, 3H), 1.10-1.20 (m, 1H), 0.93 (d, J=6.8 Hz, 3H), 0.87 (t, J=7.1 Hz, 3H); LRMS (ESI) m/e 369.2 [(M+H)+, calcd for C23H33N2O2 369.3].