Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:5]([O:7]C)=[O:6])(=[O:3])[CH3:2].[OH-].[K+]>ClCCl>[C:1]([CH:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:5]([OH:7])=[O:6])(=[O:3])[CH3:2]
Reactant: CCCCCCC(C(C)=O)C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCCCCC(C(C)=O)C(=O)O

Procedure:
Analogously to Example 15A, 3.16 g (15.8 mmol) of methyl 2-acetyloctanoate (Example 18A) are reacted with 7 ml of a 3.5 M potassium hydroxide solution to give 2-acetyloctanoic acid in dichloromethane.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[F:25]>>[F:18][C:19]1[CH:20]=[C:21]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([F:17])[CH:3]=2)[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(F)c(F)c4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, light grey solid (71 mg, 86%), MS (ISP) m/z=331.4 [(M+H)+], mp 229.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 3,4-difluoro-phenylboronic acid (51.3 mg, 0.325 mmol).
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:15]2[CH:19]=[C:18]([B:20]3[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]3)[CH:17]=[N:16]2)[CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)#[N:2].C(N(CC)CC)C>C(Cl)Cl.Cl.O1CCOCC1>[CH3:27][C:22]1([CH3:28])[C:23]([CH3:25])([CH3:26])[O:24][B:20]([C:18]2[CH:17]=[N:16][N:15]([C:4]3([CH2:3][C:1]#[N:2])[CH2:5][NH:6][CH2:7]3)[CH:19]=2)[O:21]1
Reactant: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC1(C)OB(c2cnn(C3(CC#N)CNC3)c2)OC1(C)C
Temperature: 25 °C
Yield: 84.5 %

Procedure:
A mixture of tert-butyl 3-(cyanomethyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate (1.5 g, 3.9 mmol) (Example 40, Step 1) in methylene chloride (15 mL) and 4.0 M hydrogen chloride in dioxane (3.9 mL) was stirred at room temperature over weekend. The mixture was treated with triethylamine (1 mL), and the volatiles were removed under reduced pressure. The residue was purified by flash chromatography on a silica gel column with methanol in methylene chloride (0-5%) to afford the desired product (0.95 g, 85%). LCMS (M+H)+: m/z=289.2.
Reaction SMILES: [Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7](=[O:12])[C:6]=2[CH:5]=[N:4][CH:3]=1.[CH3:13][C:14]([CH3:19])([CH2:17]O)[CH2:15][OH:16]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7]3([O:16][CH2:15][C:14]([CH3:19])([CH3:17])[CH2:13][O:12]3)[C:6]=2[CH:5]=[N:4][CH:3]=1
Reactant: O=C1CCCc2c(Br)cncc21
Reactant: CC(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(C)COC2(CCCc3c(Br)cncc32)OC1
Temperature: 135 °C
Yield: 88.8 %

Procedure:
A reaction mixture of 4-bromo-6,7-dihydro-5H-isoquinolin-8-one (intermediate B-11 [C], 5.0 g, 22 mmol), 2,2-dimethyl-propane-1,3-diol (2.8 g, 26.5 mmol) and toluene-4-sulfonic acid (85 mg, 0.44 mmol) in toluene (100 mL) was heated at 135° C. for 12 hours. After cooling to room temperature, it was concentrated under reduced pressure to give a residue which was extracted between EtOAc and water. The organic layer was washed with brine, dried over anhy. Na2SO4, filtered, and concentrated in vacuo to give a crude product (6.1 g, 88.9%) as a light yellow solid. MS: 312.2 & 314.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([N:8]([CH2:20][O:21][CH3:22])[S:9]([C:12]2[CH:16]=[CH:15][S:14][C:13]=2[C:17](Cl)=[O:18])(=[O:11])=[O:10])[O:4][N:3]=1.[C:23]([CH2:25][C:26]1[C:27]([CH3:35])=[C:28]([C:30]([CH3:34])=[CH:31][C:32]=1[CH3:33])[NH2:29])#[N:24].C(N(CC)CC)C.O>ClCCl.CN(C)C1C=CN=CC=1>[C:23]([CH2:25][C:26]1[C:27]([CH3:35])=[C:28]([NH:29][C:17]([C:13]2[S:14][CH:15]=[CH:16][C:12]=2[S:9]([N:8]([C:5]2[O:4][N:3]=[C:2]([CH3:1])[C:6]=2[CH3:7])[CH2:20][O:21][CH3:22])(=[O:11])=[O:10])=[O:18])[C:30]([CH3:34])=[CH:31][C:32]=1[CH3:33])#[N:24]
Reactant: COCN(c1onc(C)c1C)S(=O)(=O)c1ccsc1C(=O)Cl
Reactant: Cc1cc(C)c(CC#N)c(C)c1N
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COCN(c1onc(C)c1C)S(=O)(=O)c1ccsc1C(=O)Nc1c(C)cc(C)c(CC#N)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.6 %

Procedure:
To a solution of 3-[N-(3,4-dimethylisoxazol-5-yl)-N-methoxymethylaminosulfonyl]-2-thiophenecarbonyl chloride (0.49 g, 1.34 mmol) in dichloromethane (4 mL) was added 3-cyanomethyl-2,4,6-trimethylaniline (0.24 g, 1.34 mmol) at 0° C. Triethylamine (0.21 mL, 1.47 mmol) and 4-dimethylaminopyridine (16 mg, 0.13 mmol) were added. The mixture was stirred at room temperature for 2 hours, then mixed with water (10 mL). The organic material was separated, and the aqueous layer was extracted with dichloromethane (2×5 mL). The extracts were combined and washed with water (10 mL) and saturated sodium chloride (10 mL), dried (MgSO4), then concentrated. The residue was purified by flash chromatography (SiO2, hexane:ethyl acetate/3:1, then 1:1) to give N2-(3-cyanomethyl-2,4,6-trimethylphenyl)-3-[N-(3,4-dimethylisoxazol-5-yl)-N-methoxymethylaminosulfonyl]-2-thiophenecarboxamide (0.28 g, 41%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:11])[C:7]=1[C:8](O)=[O:9].[N:12]1[CH:17]=CC=NN=1>CCO.N1CCCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:7]=1[C:8](=[O:9])[NH:12][CH:17]=[N:11]2
Reactant: c1cnnnc1
Reactant: Nc1cccc(Cl)c1C(=O)O
Solvent: C1CCNCC1
Solvent: CCO
Product: O=c1[nH]cnc2cccc(Cl)c12
Reaction time: 8 h
Yield: 69.8 %

Procedure:
A solution of 6-chloro anthranilic acid (2.12 g, 12.3 mmol) and triazine (1.0 g, 12.3 mmol) in EtOH (40 mL) containing piperidine (3 drops) was heated under reflux with stirring for 8 h. On cooling crystals formed, which were filtered to yield 5-chloroquinazolin-4-one (1.55 g, 70%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[C:6]#[N:7].[Br-:13].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[Br:13][C:4]1[C:5]([C:6]#[N:7])=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:3]=1[O:2][CH3:1]
Reactant: [Br-]
Reactant: COc1cc(C#N)cc(OC)c1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COc1cc(C#N)c(Br)c(OC)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.2 %

Procedure:
To a solution of 3,5-dimethoxybenzonitrile (2 g) in CH2Cl2 (100 mL) was added pyridinium tribromide (4 g). The mixture was stirred for 24 h at room temperature then washed successively with aqueous NaHCO3, water and brine, dried (MgSO4) filtered and evaporated. The residue was crystallized from CH2Cl2 and hexane to yield the title compound (1.8 g).
Reaction SMILES: O=[CH:2][C:3](=[CH2:5])[CH3:4].[Br-].[N+:7]([C:10]1[CH:35]=[CH:34][CH:33]=[CH:32][C:11]=1[CH2:12][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O-:9])=[O:8].[OH-].[Na+]>C1C=CC=CC=1>[CH3:4][C:3](=[CH2:5])[CH:2]=[CH:12][C:11]1[CH:32]=[CH:33][CH:34]=[CH:35][C:10]=1[N+:7]([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=C(C)C=O
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: C=C(C)C=Cc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h

Procedure:
5.0 ml of methacrolein was dissolved in 100 ml of benzene. Thereto were added 31.5 g of 2-nitro-benzyltriphenylphosphonium bromide and 100 ml of a 5 N aqueous sodium hydroxide solution. The mixture was stirred at room temperature for 5 hours. The organic layer was separated and washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: toluene) to obtain 2.7 g of 1-(3-methyl-1,3-butadienyl)-2-nitrobenzene (containing about 2.2 g of o-nitrotoluene) as a light yellow oily material.
Reaction SMILES: [ClH:1].Cl.[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:28](=[CH:29][C:30]=1[O:31][CH3:32])[CH:27]=[N:26][C:9]1([CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=3)[CH2:11][CH2:10]1)[CH2:8]2.[BH4-].[Na+]>CO>[ClH:1].[ClH:1].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:28](=[CH:29][C:30]=1[O:31][CH3:32])[CH2:27][NH:26][C:9]1([CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=3)[CH2:11][CH2:10]1)[CH2:8]2
Reactant: COc1cc2c(cc1OC)CC1(CCN(CCc3ccc([N+](=O)[O-])cc3)CC1)N=C2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc2c(cc1OC)CC1(CCN(CCc3ccc([N+](=O)[O-])cc3)CC1)NC2
Reaction time: 0.25 h
Yield: 163.3 %

Procedure:
To a solution of 6,7-dimethoxy-1'-[2-(4-nitrophenyl)ethyl]-spiro[3,4-dihydroisoquinoline-3,4'-piperidine]dihydrochloride (100 mg) in methanol (6 ml) at 0° C. was added NaBH4 (23.8 mg). The reaction was stirred for 15 min. The aqueous solution was extracted with methylene chloride (2×50 ml). The methylene chloride layers were dried over Na2SO4, concentrated to an oil and redissolved in ethanol. Addition of HCL/diethyl ether gave a solid which was filtered, and dried to yield 0.082 g of the title compound. MP 247°-250° C. (Dec).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][NH:7][CH2:8][C:9]1[S:13][C:12](B(O)O)=[CH:11][CH:10]=1)[CH3:2].Br[C:18]1[CH:19]=[C:20]2[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=1)[NH:23][CH:22]=[C:21]2[CH:30]1[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:38])=[O:37])[CH2:32][CH2:31]1.C([O-])([O-])=O.[K+].[K+]>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>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][NH:7][CH2:8][C:9]1[S:13][C:12]([C:18]2[CH:19]=[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=2)[NH:23][CH:22]=[C:21]3[CH:30]2[CH2:31][CH2:32][N:33]([S:36]([CH2:39][CH3:40])(=[O:37])=[O:38])[CH2:34][CH2:35]2)=[CH:11][CH:10]=1)[CH3:2]
Reactant: CCOCCCNCc1ccc(B(O)O)s1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOCCCNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Yield: 10 %

Procedure:
Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), [3-(ethyloxy)propyl]amine (34 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 30 mg of crude [5-({[3-(ethyloxy)propyl]amino}methyl)-2-thienyl]boronic acid. The crude [5-({[3-(ethyloxy)propyl]amino}methyl)-2-thienyl]boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079 mmol) to give 8.1 mg of the title compound (10%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[OH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:3]=1
Reactant: OCc1ccccn1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(OCc2ccccn2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, 2-(hydroxymethyl)pyridine and DBU in DME. ES-MS m/e (%): 294 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:6]([C:5]1[CH:4]=[N:3][C:2]([Cl:1])=[CH:10][CH:9]=1)(=[O:7])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccccc1)c1ccc(Cl)nc1

Procedure:
To 40 ml of a solution of 5.28 g of 6-chloronicotinoyl chloride in benzene, 16 g of aluminum chloride was added under ice-cooling and the resulting mixture was heated under reflux for six hours. After cooling, the reaction mixture was poured into a solution of ice/hydrochloric acid and extracted with ether. The organic phase was washed with water and dried over anhydrous sodium sulfate. After filtering off the sodium sulfate and distilling off the solvent, 4.6 g of 3-benzoyl-6-chloropyridine was obtained. m.p.: 39°-40° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[CH:23][CH:22]=[C:21]2[N:26]1[C:30]([NH2:31])=[CH:29][C:28]([CH3:32])=[N:27]1.ClCCl>N1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:31][C:30]2[N:26]([C:21]3[C:20]4[C:25](=[C:16]([F:15])[CH:17]=[CH:18][CH:19]=4)[N:24]=[CH:23][CH:22]=3)[N:27]=[C:28]([CH3:32])[CH:29]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc(N)n(-c2ccnc3c(F)cccc23)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n(-c2ccnc3c(F)cccc23)n1
Temperature: 80 °C
Yield: 2 %

Procedure:
A mixture of 4-t-butylbenzenesulfonyl chloride (0.13 g, 0.55 mmol) and crude 1-(8-fluoroquinolin-4-yl)-3-methyl-1H-pyrazol-5-amine (0.14 g, 0.55 mmol) in pyridine (1 mL) was heated at 80° C. for 15 h with stirring. After cooling to room temperature, dichloromethane was added to the reaction mixture and washed with 1 M aqueous sodium hydrogen sulfate (1 mL). The aqueous layer was further extracted with dichloromethane (2×5 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by reverse phase HPLC(C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.005 g, 0.011 mmol, 2%). 1H NMR (400 MHz, CDCl3) δ 8.80 (d, J=4.8 Hz, 1H), 7.61 (d, J=1.6 Hz, 1H), 7.59 (d, J=2.0 Hz, 1H), 7.47-7.41 (m, 5H), 7.13 (d, J=4.8 Hz, 1H), 6.20 (s, 1H), 2.35 (s, 3H), 1.35 (s, 9H); MS: (ES) m/z calculated for C23H24FN4O2S [M+H]+ 439.5. found 439.3.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][OH:7])[CH2:2]1.C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C1COCC1>[CH3:15][S:16]([O:7][CH2:6][CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1)(=[O:18])=[O:17]
Reactant: OCC1CCOC1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CCOC1

Procedure:
The tetrahydro-3-furanmethanol (Aldrich, 0.13 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:15]I.O>CN(C=O)C>[CH3:15][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([CH3:1])[CH:10]=2)[C:6]([CH:11]=[O:12])=[CH:7]1
Reactant: CI
Reactant: Cc1ccc2c(C=O)c[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(C=O)cn(C)c2c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
A solution of the known 6-methyl-1H-indole-3-carboxaldehyde (5 g, 31 mm) in DMF (100 mL) was cooled to 0° C. and treated with NaH (38 mm), and stirred at 0° C. for 3 hours. After treatment with CH3I (2.35 mL, 38 mm), the mixture was allowed to warm to room temperature overnight. The mixture was poured into H2O(500 mL) and extracted with ethylacetate (EtOAc) (200 mL×3). The combined organic layers were dried over MgSO4, filtered and evaporated. Purification by flash column chromatography afforded 1,6-dimethyl-1H-indole-3-carboxaldehyde (5.2 g, 97%).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH:8]([N:14]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:15][CH2:16][CH3:17])[CH2:9]2.C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)Cl>[C:35]([NH:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH:8]([N:14]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:15][CH2:16][CH3:17])[CH2:9]2)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: CCCN(CCCCc1ccccc1)C1CCc2c(N)cccc2C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN(CCCCc1ccccc1)C1CCc2c(cccc2NC(C)=O)C1
Reaction time: 3 h

Procedure:
0.90 g (0.0022 mol) of 5-amino-2-[N-(4-phenylbutyl)-N-n-propyl-amino]-tetraline-dihydrochloride (Example 4.5.4) and 1.00 g (0.0099 mol) of triethylamine are mixed with 15 ml of absolute methylene chloride with stirring and cooling with ice and 0.20 g (2.55 mmol) of acetylchloride in 5 ml of absolute methylene chloride are added. After 3 hours at ambient temperature or 30 minutes refluxing, the mixture is extracted three times with 5 ml of water, dried with sodium sulphate and concentrated by rotary evaporation, finally at 80° C. under a complete water-jet vacuum. The residue is crystallised from diethylether/petroleum ether.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH2:26]([NH2:30])[CH2:27][CH2:28][NH2:29]>>[NH2:29][CH2:28][CH2:27][CH2:26][NH:30][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1
Reactant: O=S1(=O)CCN(c2cc(Cl)c3cc(O)ccc3n2)Cc2ccccc21
Reactant: NCCCN
Product: NCCCNc1cc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccc(O)cc12
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 27 %

Procedure:
A mixture of 4-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-quinolin-6-ol (400 mg, 1.067 mmol) and propane-1,3-diamine (158 mg, 2.134 mmol) was heated with stirring for 1.5 hours at 150° C. under microwave irradiation. The reacting mixture was purified by preparative HPLC and SPE to give 118.8 mg of the desired product (yield was 27%). MS obsd. (ESI+)[(M+H)+] 413, 1H NMR (400 MHz, CD3OD) δ ppm 8.10-8.05 (d, J=7.6 Hz, 1 H), 7.85-7.80 (d, J=8 Hz, 1 H), 7.71-7.62 (m, 2 H), 7.60-7.52 (t, J=7.2 Hz, 1 H), 7.40-7.35 (m, 1 H), 7.26-7.20 (dd, J=2.8 Hz, 12.8 Hz, 1 H), 5.91 (s, 1 H), 5.27 (s, 2 H), 4.52-4.42 (m, 2 H), 3.72-3.68 (t, J=2.8 Hz, 2 H), 3.60-3.52 (t, J=6.8 Hz, 2 H), 3.10-3.02 (t, J=7.2 Hz, 2 H), 2.10-2.00 (m, 2 H);
Reaction SMILES: [C:1]1(=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=O)=[C:12]([F:25])[CH:11]=1.O.C([O-])([O-])=O.[K+].[K+]>O1CCCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[C:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[C:12]([F:25])[CH:11]=1
Reactant: O=C1CCCCCC1
Reactant: O=C(c1ccc(O)cc1)c1ccc(Br)cc1F
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Oc1ccc(C(=C2CCCCCC2)c2ccc(Br)cc2F)cc1
Temperature: 25 °C
Yield: 88 %

Procedure:
To a slurry of Zn powder (3.4 g, 51.5 mmol) in dry tetrahydrofuran (50 mL) was slowly added TiCl4 (2.7 mL, 25.1 mmol) at RT under a nitrogen atmosphere. The reaction mixture was heated at reflux for 2.5 h. To the reaction mixture was added a solution of cycloheptanone (2.4 mL, 20.3 mmol) and (4-bromo-2-fluoro-phenyl)-(4-hydroxy-phenyl)-methanone (76) (2 g, 6.78 mmol) in dry tetrahydrofuran (50 mL). The reaction mixture was heated at reflux for 2 h. The reaction mixture was cooled to room temperature, then water (40 mL) was added followed by 10% K2CO3 (40 mL). The reaction mixture was filtered through a pad of Celite and the pad was washed with EtOAc. The filtrate was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The crude material was loaded onto silica gel and purified by flash chromatography with a hexanes:EtOAc gradient (100:0 to 90:10) to give 2.24 g (88%) of compound 175. 1H NMR indicates that the product contains ˜3% cycloheptanone. 1H NMR (400 MHz, DMSO-d6): δ 1.43-1.50 (m, 8H), 2.05-2.08 (m, 2H), 2.23-2.24 (m, 2H), 6.65 (d, J=8.4 Hz, 2H), 6.91 (d, J=8.4 Hz, 2H), 7.14, (t, J=8.1 Hz, 1H), 7.32-7.35 (m, 1H), 7.44-7.47 (m, 1H), 9.33 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[CH2:7][C@@H:8]([CH2:14]OS(C1C=CC(C)=CC=1)(=O)=O)[C@@H:9]([CH3:13])[CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].[N-:27]=[N+:28]=[N-:29].[Na+].O>CS(C)=O>[C:1]([O:5][C:6](=[O:26])[CH2:7][C@@H:8]([CH2:14][N:27]=[N+:28]=[N-:29])[C@@H:9]([CH3:13])[CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](CC(=O)OC(C)(C)C)[C@@H](C)C(C)C)cc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)[C@H](C)[C@H](CN=[N+]=[N-])CC(=O)OC(C)(C)C
Yield: 79.3 %

Procedure:
A solution of the tosylate 21 (1.19 g, 3.1 mmol) and sodium azide (402 mg, 6.2 mmol) in DMSO (15 mL) was warmed to 60° C. for 2.5 hours. Water (100 mL) was added and the solution extracted with ether. The combined organic phases were dried (MgSO4) and concentrated. Flash chromatography (9:1 hexane/ethyl acetate) gave the azide 22 (628 mg, 80%) as a colorless oil. 1H NMR (CDCl3) δ 3.4 (dd, 1H, J=12.21 and 6.11 Hz), 3.3 (dd, 1H, J=21.11 and 6.59 Hz), 2.30 (dd, 1H, J=15.14 and 3.66 Hz), 2.25 (m, 1H), 2.05 (dd, 1H, J=15.14 and 9.04 Hz), 1.55 (m, 1H), 1.45 (s, 9H), 1.35 (m, 1H), 0.95 (d, 1H, J=6.59 Hz), 0.90 (d, 1H, J=6.83 Hz), 0.80 (d, 1H, J=7.08 Hz). MS (m/z): (relative intensity): 228 [M−N2, 35%], 172 [M−N2-tBu, 100%].
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:30])[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:17]=1)[CH2:10][C:9]2([CH3:32])[CH3:31])=[O:5])C.[OH-].[Na+].Cl>CO.O1CCCC1.O>[CH3:31][C:9]1([CH3:32])[C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:12][CH:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:30])[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10]1
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(C(=O)Nc3ccccc3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC1(C)CC(c2cccc(C(=O)Nc3ccccc3)c2)Nc2ccc(C(=O)O)cc21
Temperature: 60 °C
Reaction time: 16 h
Yield: 934.7 %

Procedure:
To a stirred mixture solution of 4,4-dimethyl-2-(3-phenylcarbamoyl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.8 g, 1.87 mmol) in methanol (10 mL) and tetrahydrofuran (20 mL) was added 30% sodium hydroxide in water (10 mL). The reaction mixture was stirred at 60° C. for 16 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 4,4-dimethyl-2-(3-phenylcarbamoyl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (7 g, 93%) as a light white solid which was used for next step without further purification: MS (ESI) M+1=401.2.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(C)(C)C.C(OC(=O)N[C@@H]1CCN([C:27]2[C:32]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:30]=[CH:29][N:28]=2)C1)(C)(C)C.FC(F)(F)C1C(N2CC[C@@H](N)C2)=NC=CC=1>>[F:34][C:33]([F:36])([F:35])[C:32]1[CH:31]=[CH:30][C:29]([N:11]2[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]2)=[N:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ncccc2C(F)(F)F)C1
Agent: N[C@@H]1CCN(c2ncccc2C(F)(F)F)C1
Product: NC1CCN(c2ccc(C(F)(F)F)cn2)CC1

Procedure:
The title compound was prepared from D7 and 2-chloro-5-ifluoromethylpyridine using the procedure outlined for Descriptions D1 and D2.