Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=[O:27])/[C:5](/[F:26])=[C:6](\[C:8]1[C:17]([O:18][CH2:19][CH2:20][CH3:21])=[CH:16][C:15]2[C:14]([CH3:23])([CH3:22])[CH2:13][CH2:12][C:11]([CH3:25])([CH3:24])[C:10]=2[CH:9]=1)/[CH3:7])C.[CH3:28]C(C[AlH]CC(C)C)C>C1COCC1>[F:26]/[C:5](=[C:6](/[C:8]1[C:17]([O:18][CH2:19][CH2:20][CH3:21])=[CH:16][C:15]2[C:14]([CH3:23])([CH3:22])[CH2:13][CH2:12][C:11]([CH3:25])([CH3:24])[C:10]=2[CH:9]=1)\[CH2:7][CH3:28])/[CH2:4][OH:27]
Reactant: CCCOc1cc2c(cc1/C(C)=C(/F)C(=O)OCC)C(C)(C)CCC2(C)C
Reactant: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: CCCOc1cc2c(cc1/C(CC)=C(/F)CO)C(C)(C)CCC2(C)C
Temperature: -78 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
To a solution of(E)-2-fluoro-3-(5,5,8,8-tetramethyl-3-propoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-but-2-enoic acid ethyl ester (Intermediate 6, 2.2 g, 5.85 mmol) in THF (50 mL) at −78° C. was added DIBAL-H (23.4 mL, 1.0 M in CH2Cl2, 23.4 mmol) over 10 min. After stirring at −78° C. for 3 h, the reaction was quenched with aqueous NH4Cl followed by 1M HCl and was extracted with Et2O (×3). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (10% EtOAc-hexane) to give the title compound (1.02 g, 45% over 2 steps).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:12][CH2:13]Cl)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[C:15](#[N:25])[CH2:16][C:17]1[C:18](=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:19]#[N:20].C(=O)([O-])[O-].[Cs+].[Cs+]>CCOC(C)=O>[C:15]([C:16]1([C:17]2[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=2[C:19]#[N:20])[CH2:13][CH2:12][N:4]([C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:3][CH2:2]1)#[N:25]
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Reactant: N#CCc1ccccc1C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccccc2C#N)CC1
Temperature: 25 °C

Procedure:
A solution of bis(2-chloroethyl)-N-(1,1-dimethylethoxy)carbonyl amine (19 g, 78 mmol) and homophthalonitrile (8.6 g, 60 mmol) and cesium carbonate (79 g, 241 mmol) was stirred at 60° C. for 12 hours. The solution cooled to room temperature and diluted with 500 ml EtOAc and washed with saturated aqueous NaHSO4 and saturated aqueous NaCl. The solution was dried over Na2SO4, concentrated in vacuo, and purified by PCTLC (30% EtOAc in Hexane) to afforded 4-cyano-N-(1,1-dimethylethoxy)carbonyl-4-(2-cyanophenyl) piperidine as a yellow/orange oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][C:9]=1[NH2:19])(C)(C)C.CC1(C)O[C:26]([C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=2)[C:31]#[N:32])=[CH:25][C:24](=[O:36])O1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:36]=[C:24]1[CH2:25][C:26]([C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=2)[C:31]#[N:32])=[N:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)=[CH:10][C:9]=2[NH:19]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc(C2=Nc3ccc(-c4cccs4)cc3NC(=O)C2)c1

Procedure:
Prepared from (2-amino-4-thiophen-2-yl-phenyl)-carbamic acid tert.-butyl ester (Example G18) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (108 mg).
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][NH:5][C:6](=[O:20])[C@@H:7]([CH2:16][CH2:17][S:18][CH3:19])[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[OH-].[K+]>CO>[C:12]([O:11][C:9]([NH:8][C@@H:7]([C:6]([NH:5][CH2:4][C:3]([OH:21])=[O:2])=[O:20])[CH2:16][CH2:17][S:18][CH3:19])=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)CNC(=O)[C@@H](CCSC)NC(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)O

Procedure:
The title compound of Example 8 (32.0 g, 0.1 mole) was dissolved in 200 ml of methanol to which was added 200 ml of 2M potassium hydroxide. After ca. 5 min. at room temperature the solution was concentrated to about half volume and diluted with ethyl acetate. The solution was neutralized by washing with two portions of 0.5M potassium bisulfate, and then dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was recrystallized to give the title compound, which was used in subsequent reactions without further purification.
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][CH:7]([C:12]([O:14][CH3:15])=[O:13])[C:8]([O:10][CH3:11])=[O:9])(=[O:5])[CH3:4].Br[CH:17]1[CH2:23][CH2:22][CH2:21][C:20]2[CH:24]=[C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:26]=[CH:27][C:19]=2[C:18]1=[O:36]>CN(C=O)C>[CH3:11][O:10][C:8](=[O:9])[C:7]([NH:6][C:3](=[O:5])[CH3:4])([CH:17]1[CH2:23][CH2:22][CH2:21][C:20]2[CH:24]=[C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:26]=[CH:27][C:19]=2[C:18]1=[O:36])[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)C(NC(C)=O)C(=O)OC
Reactant: CCCCCCCCc1ccc2c(c1)CCCC(Br)C2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCc1ccc2c(c1)CCCC(C(NC(C)=O)(C(=O)OC)C(=O)OC)C2=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 15.2 %

Procedure:
Sodium hydride (720 mg, 18.0 mmol) 60% in mineral oil was suspended in dry DMF (10 mL) and a solution of dimethyl acetamidomalonate (3.00 g, 15 mmol) in dry DMF (10 mL) was added. The solution was stirred at 0° C. for 3 h until the anion had formed. A solution of 4 (2.12 g, 6.0 mmol) in dry DMF (10 mL) was added and the solution warmed to room temperature and stirred overnight. The mixture was poured into distilled water (50 mL), acidified to pH 3 with 1M hydrochloric acid in an ice-bath and extracted into ethyl acetate (3×50 mL). The organic phases were washed with brine (2×30 mL) and dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography (Silica gel, 40% EtOAc in hexanes) to give 0.420 g compound 5 (15%). 1H NMR (300 MHz, CDCl3) δ 0.85 (t, 3H, J=6.22 Hz), 1.24 (m, 10H), 1.58 (p, 2H, J=6.95 Hz), 1.97 (s, 3H), 2.45-2.60 (m, 4H), 2.83-3.21 (m, 4H), 3.88 (dd, 1H, J=14.00 Hz, 3.68 Hz), 4.05 (s, 6H), 6.86 (s, 1H), 7.03 (s, 1H), 7.07 (d, 1H, J=8.69 Hz), 7.84 (d, 1H, J=8.36 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:40])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[CH:39]=[CH:38][N:37]=[N:36]2)[CH:30]=1)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:26](=[O:25])[CH2:27][C:28](=[O:40])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[CH:39]=[CH:38][N:37]=[N:36]2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Yield: 74.1 %

Procedure:
Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G37) (152 mg, 0.5 mmol) and 3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionic acid ethyl ester (Example H2) (200 mg, 0.77 mmol) according to the general procedure K. Obtained as a yellow oil (191 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:19](=[O:20])[N:18]([CH3:21])[C:11]3[N:12]=[C:13](SC)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[NH:22][C:23]([NH:25][C:26]1[CH:31]=[C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:29]=[CH:28][N:27]=1)=[O:24].[CH3:38][NH2:39].C1COCC1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:19](=[O:20])[N:18]([CH3:21])[C:11]3[N:12]=[C:13]([NH:39][CH3:38])[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[NH:22][C:23]([NH:25][C:26]1[CH:31]=[C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:29]=[CH:28][N:27]=1)=[O:24]
Reactant: CN
Reactant: CSc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cc(-c5ccccc5)ncn4)c3)c(=O)n(C)c2n1
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cc(-c5ccccc5)ncn4)c3)c(=O)n(C)c2n1
Yield: 54 %

Procedure:
Using a procedure analogous to Example A1, 1-(2-fluoro-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(6-phenylpyrimidin-4-yl)urea (265 mg, 0.516 mmol) and 2.00 N methylamine in THF (3.87 mL, 7.73 mmol) were combined to afford 1-(2-fluoro-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(6-phenylpyrimidin-4-yl)urea (139 mg, 54% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.89 (m, 3H), 3.54-3.62 (m, 3H), 7.29-7.35 (m, 2H), 7.53-7.55 (m, 3H), 7.70-7.82 (m, 1H), 7.91 (s, 1H), 8.03-8.06 (m, 2H), 8.13 (s, 1H), 8.44-8.46 (s, 1H), 8.60-8.75 (m, 1H), 8.98 (s, 1H), 10.1 (br. s, 1H), 10.2 (s, 1H); MS (ESI) m/z: 497.2 (M+H+).
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[CH3:13][N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1>CO.O>[NH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:17]1[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH:16]=1
Reactant: CN1CCC(=O)CC1
Reactant: Nc1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN1CC=C(c2c[nH]c3ccc(N)cc23)CC1
Yield: 48.8 %

Procedure:
To a solution of 1.29 gm (20 mMol) potassium hydroxide in 10 mL methanol were added 1.32 gm (10 mMol) 5-amino-1H-indole followed by 2.46 mL (20 mMol) 1-methyl-4-piperidone. The reaction mixture was then heated to reflux for 18 hours. The reaction mixture was cooled to ambient, diluted with 20 ml water and the precipitate collected by filtration. The solid was recrystallized from ethyl acetate:methanol to give 1.11 gm (48.9%) 5-amino-3-(1-methyl-1,2,3,6-tetrahydropyr-idin-4-yl)-1H-indole as a tan solid (m.p.=200°-203° C.). The tan solid was subjected to flash chromatography, eluting with 100:20:0.5 dichloromethane:methanol:ammonium hydroxide, to give 0.99 gm 5-amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole as a cream colored solid (m.p.=212°-215° C. (ethyl acetate:methanol)).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([NH:9][NH2:10])=[C:4]([F:11])[CH:3]=1.[C:12]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C:16]1=O)(=O)[CH3:13].C(O)(=O)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:12]([CH3:13])=[C:15]3[C:16]([CH2:17][CH2:18][CH2:19][CH2:20]3)=[N:10]2)=[C:4]([F:11])[CH:3]=1
Reactant: NNc1cc(O)c(Cl)cc1F
Reactant: CC(=O)C1CCCCC1=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1C
Product: Cc1c2c(nn1-c1cc(O)c(Cl)cc1F)CCCC2
Yield: 88.1 %

Procedure:
4-Chloro-2-fluoro-5-hydroxyphenylhydrazine (0.5 g), 2-acetylcyclohexanone (0.4 g) and a catalytic amount of acetic acid were admixed with xylene (15 ml), and the resultant mixture was heated under reflux for 5 hours while removing water. After cooling, the mixture was concentrated, and the residue was purified by silica gel column chromatography to obtain 0.7 g of 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-3-methyl-4,5,6,7-tetrahydro-2H-indazole. m.p., 188.5°-190° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].Cl.Cl[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[CH:18][C:17]=1[N+:26]([O-:28])=[O:27]>>[N+:26]([C:17]1[CH:18]=[N:19][C:20]2[C:25]([C:16]=1[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])=[CH:24][CH:23]=[CH:22][CH:21]=2)([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CC(C)(C)OC(=O)NCCCCN
Agent: Cl
Product: CC(C)(C)OC(=O)NCCCCNc1c([N+](=O)[O-])cnc2ccccc12
Yield: 99886.9 %

Procedure:
Using the general method of Example 1 Part A, tert-butyl N-(4-aminobutyl)carbamate (254 g, 1.35 mol) was reacted with 4-chloro-3-nitroquinoline hydrochloride (331 g, 1.35 mmol) to provide 486 g of tert-butyl N-(4-[(3-nitroquinolin-4-yl)amino]butyl)carbamate as yellow solid. Analysis: Calculated for C18H24N4O4: %C, 59.99; %H, 6.71; %N, 15.55; Found: %C, 59.68; %H, 6.59; %N, 15.74.
Reaction SMILES: [NH2:1][C:2]([CH2:7][CH3:8])([CH2:5][CH3:6])[C:3]#[CH:4].[F:9][C:10]1[C:11](I)=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])/[C:13]/2=[CH:20]\[C:21]1[NH:25][CH:24]=[N:23][C:22]=1[CH3:26]>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.CN(C=O)C.CCN(CC)CC>[NH2:1][C:2]([CH2:7][CH3:8])([CH2:5][CH3:6])[C:3]#[C:4][C:11]1[C:10]([F:9])=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:20]/[C:21]1[NH:25][CH:24]=[N:23][C:22]=1[CH3:26])/[C:14](=[O:19])[NH:15]2
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CC(N)(CC)CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(N)(C#Cc1c(F)ccc2c1/C(=C/c1[nH]cnc1C)C(=O)N2)CC

Procedure:
Using Method C above, 3-amino-3-ethyl-1-pentyne (37.6 mg, 0.34 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (Starting Material 3 supra) (50 mg, 0.135 mmol) using (Ph3P)4Pd (16 mg) and Cul (3 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 6 h to give (Z)-4-[3-amino-3-ethyl-1-pentynyl]-1,3-dihydro-5-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one. (Yield 45 mg, 95%).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[C:11](#[N:15])[C:12]([CH3:14])=[CH2:13]>O1CCCC1.CO>[N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH:6][CH2:13][CH:12]([CH3:14])[C:11]#[N:15])([O-:3])=[O:2]
Reactant: C=C(C)C#N
Reactant: Nc1ccccc1[N+](=O)[O-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C#N)CNc1ccccc1[N+](=O)[O-]

Procedure:
69 g (mol/2) of o-nitroaniline in solution in 270 ml of tetrahydrofuran are heated under reflux for 2 hours with 67 g (1 mol) of methacrylonitrile and 16 ml of a 40% solution of "Triton B" in methanol. After evaporation of the volatile substances under vacuum, washing the residue with water and then extraction with ethyl acetate, and after evaporation of the solvent, a yellow solid of melting point 44°-47° C. is obtained in a yield of 51.3 g = 50% (theoretical yield: 102.6 g). After recrystallisation from isopropanol and then from ethanol, there is obtained a yellow product of melting point 75°-76° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][C@H:9]([N:12]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10][OH:11])=[O:4].[CH:38](=O)[CH2:39][CH2:40][CH3:41]>>[NH2:26][C:23]1[CH:22]=[CH:21][C:20]([S:17]([N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[C@H:9]([CH2:10][OH:11])[CH2:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[C@@H:2]([NH:1][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)(=[O:19])=[O:18])=[CH:25][CH:24]=1
Reactant: CCCC=O
Reactant: CC(C)CN([C@H](CO)CCCNC(=O)[C@@H](N)Cc1cccc2ccccc12)S(=O)(=O)c1ccc(N)cc1
Product: CCCCN[C@@H](Cc1cccc2ccccc12)C(=O)NCCC[C@@H](CO)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from (2S,4S)-2-amino-N-{4-[(4-amino-benzenesulfonyl)-isobutyl-amino]-5-hydroxy-pentyl}-3-naphthalen-1-yl-propionamide (product of example 8) as described in general procedure F using butyraldehyde. The final product was obtained in 13% yield.
Reaction SMILES: [CH2:1]([O:17][C:18]1[CH:28]=[CH:27][C:21]([O:22][CH2:23][C:24](O)=[O:25])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(Cl)(=O)C([Cl:32])=O>CN(C)C=O.C(Cl)Cl>[CH2:1]([O:17][C:18]1[CH:28]=[CH:27][C:21]([O:22][CH2:23][C:24]([Cl:32])=[O:25])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCOc1ccc(OCC(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCOc1ccc(OCC(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 97.7 %

Procedure:
A mixture of 13.2 g of product from Example 86, 6.4 g of oxalyl chloride, 225 ml of methylene chloride and 5 drops of dimethylformamide is stirred at room temperature for 17 hours. The solvent is concentrated in vacuo, the residue is dissolved in ether, filtered through diatomaceous earth and concentrated in vacuo to give 13.5 g of the desired product.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]2([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[O:30][CH2:29]2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37][S:38]([NH2:41])(=[O:40])=[O:39]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:41][S:38]([CH3:37])(=[O:40])=[O:39])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:24][CH2:25][C:26]2([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[O:30][CH2:29]2)[CH2:27][CH2:28]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC4(CC3)COc3ccccc34)cnc12
Reactant: CS(N)(=O)=O
Product: CS(=O)(=O)NC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC4(CC3)COc3ccccc34)cnc12
Yield: 47.7 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-(2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.105 g, 0.217 mmol) obtained in step 2 and methanesulfonamide (0.103 g, 1.09 mmol), the title compound (0.058 g, 47%) was obtained.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH2:8]([N:15]1[CH2:20][CH2:19][N:18]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCO>[CH2:8]([N:15]1[CH2:16][CH2:17][N:18]([CH:21]2[CH2:26][CH2:25][N:24]([CH2:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH2:23][CH2:22]2)[CH2:19][CH2:20]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: C=CC(=O)OCC
Reactant: c1ccc(CN2CCN(C3CCNCC3)CC2)cc1
Solvent: CCO
Product: CCOC(=O)CCN1CCC(N2CCN(Cc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.5 mL (50.8 mmol) ethyl acrylate were added to a solution of 11.7 g (44.9 mmol) 1-benzyl-4-piperidin-4-yl-piperazine in 120 mL dry EtOH and the reaction mixture was refluxed for 1 h and then stirred overnight at RT. The solvent was eliminated i.vac. and the residue was dried for 1 h under an oil pump vacuum. The crude product was reacted further without purification.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:5]=2[CH:12]([C:14]2[N:15]=[CH:16][N:17](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:18]=2)O)[CH2:3][CH2:2]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:5]=2[CH2:12][C:14]2[N:15]=[CH:16][NH:17][CH:18]=2)[CH2:2][CH2:3]1
Reactant: CCc1cccc(C2CC2)c1C(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cccc(C2CC2)c1Cc1c[nH]cn1

Procedure:
Prepared in analogy to Example 57(e) from rac-(2-cyclopropyl-6-ethyl-phenyl)-(1-trityl-1H-imidazol-4-yl)-methanol, triethylsilane and trifluoroacetic acid in dichloromethane. Off-white crystalline solid. MS (ISP): 227.4 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12]O)[CH:3]=1.P(Br)(Br)[Br:15].O>CCOCC>[Br:15][CH2:12][CH2:11][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:1])=[CH:3]1
Reactant: Cc1cn(CCO)c2ccccc12
Reactant: BrP(Br)Br
Solvent: O
Solvent: CCOCC
Product: Cc1cn(CCBr)c2ccccc12
Temperature: 25 °C
Reaction time: 42 h

Procedure:
To a stirred solution of 7.2 g of 3-methylindole-1-ethanol, described in Example 1, in 500 ml. of dry ether (ice bath) is slowly added 1.2 ml of phosphorus tribromide in 100 ml of dry ether. A dark red oily complex separates. The reaction mixture is stirred 36-48 hours at room temperature, then decomposed with ice and water. The separated ether-layer is quickly washed with a 10% solution of sodium bicarbonate and with water again, dried over calcium chloride for 2 min., decanted, and dried over magnesium sulfate for 30 min. The filtrate is evaporated yielding 1-(2-bromoethyl)-3-methylindole.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH:8]([CH:13]=[N:14][OH:15])[CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].[CH3:17][O:18][C:19](=[O:26])[C:20]([CH3:25])([CH3:24])[CH2:21][C:22]#[CH:23]>>[CH3:17][O:18][C:19](=[O:26])[C:20]([CH3:25])([CH3:24])[CH2:21][C:22]1[O:15][N:14]=[C:13]([CH:8]([NH:7][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:16])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH:23]=1
Reactant: C#CCC(C)(C)C(=O)OC
Reactant: CC(C)CC(C=NO)NC(=O)OC(C)(C)C
Product: COC(=O)C(C)(C)Cc1cc(C(CC(C)C)NC(=O)OC(C)(C)C)no1

Procedure:
Prepared from [1-(hydroxyimino-methyl)-3-methyl-butyl]-carbamic acid tert-butyl ester (7I) and 2,2-dimethyl-pent-4-ynoic acid methyl ester according to the procedure outlined in example 6A. MS (CI) m/z: 313.2 (M-tBu), 269.3 (M−99)
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[OH:17])[CH:12]=O.N1CCCCC1>C(O)(=O)C>[OH:8][C:9]1[CH:10]=[C:11]([CH:12]=[C:5]2[S:1][C:2](=[O:7])[NH:3][C:4]2=[O:6])[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[OH:17]
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: O=C1NC(=O)C(=Cc2cc(O)c(O)c([N+](=O)[O-])c2)S1
Temperature: 80 °C

Procedure:
A solution containing 0.59 g (0.005 mol) of thiazolidine-2,4-dione, 0.92 g (0.005 mol) of 3,4-dihydroxy-5-nitrobenzaldehyde and 0.05 ml of piperidine in 5 ml of acetic acid was heated for 7-8 h at 80° C. The crystals were filtered and washed with ethanol. Yield 1.0 g (72%), mp 295°-298° C.
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1F)([O-:10])=[O:9].[CH3:21][C:22]1[NH:23][CH:24]=[C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:26]=1>C1(C)C=CC=CC=1>[N+:8]([C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[N:23]1[CH:24]=[C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:26]=[C:22]1[CH3:21])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: CCOC(=O)c1c[nH]c(C)n1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(-c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])c(C)n1

Procedure:
16 ml of triethylamine was added to 14.5 g (0.078 mol) of 2,4-dinitrofluorobenzene, 12 g (0.078 mol) of ethyl 2-methylimidazole-4-carboxylate and 500 ml of toluene, and the mixture was refluxed for 18 hours. The solvent was then distilled off under reduced pressure and the residue was chromatographed using pentane/ethyl acetate as mobile phase.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1F.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[OH:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1[O:21][C:15]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[F:13]
Reactant: Oc1ccc(F)cc1F
Reactant: Fc1ccc(C(F)(F)F)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc(Oc2ccc(C(F)(F)F)cc2Br)c(F)c1
Temperature: 80 °C
Yield: 80.5 %

Procedure:
A mixture of 3-bromo-4-fluorobenzotrifluoride (0.5 mL, 3.52 mmol), 2,4-difluorophenol (0.337 mL, 3.52 mmol), and potassium carbonate (0.486 g, 3.52 mmol) in dimethylformamide (7 mL) was heated at 80° C. overnight. The reaction mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organics were washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation. The crude material was purified by flash chromatography (ethyl acetate/hexanes) to provide the title compound (1.0 g, 80% yield).