Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:32]=[CH:31][C:21]3[NH:22][C:23]([CH2:25][C:26]([O:28]CC)=O)=[N:24][C:20]=3[CH:19]=2)[CH2:14][CH2:13]1.[NH2:33][C:34]1[C:35]([C:40]#[N:41])=[N:36][CH:37]=[CH:38][CH:39]=1>C1COCC1>[NH2:41][C:40]1[C:35]2[C:34](=[CH:39][CH:38]=[CH:37][N:36]=2)[NH:33][C:26](=[O:28])[C:25]=1[C:23]1[NH:22][C:21]2[CH:31]=[CH:32][C:18]([N:15]3[CH2:14][CH2:13][N:12]([CH3:11])[CH2:17][CH2:16]3)=[CH:19][C:20]=2[N:24]=1
Reactant: CCOC(=O)Cc1nc2cc(N3CCN(C)CC3)ccc2[nH]1
Reactant: N#Cc1ncccc1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCN(c2ccc3[nH]c(-c4c(N)c5ncccc5[nH]c4=O)nc3c2)CC1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
LiHMDS (3.6 eq) was added to ethyl [5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]acetate (1.0 eq) and 3-aminopyridine-2-carbonitrile (1.0 eq) in THF at 0° C. The reaction was stirred overnight and then heated at 40° C. for 3 hours. The resulting mixture was quenched with an aqueous saturated NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo to yield a green solid. The crude material was washed successively with CH2Cl2 and MeOH, and then was purified by reverse phase HPLC to provide the desired product. LC/MS m/z 376.1 (MH+), Rt 1.50 minutes.
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][N:15]=3)[S:13][C:6]=12.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:21]=[CH:20][C:17]([CH2:18][N:33]4[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]4)=[CH:16][N:15]=3)[S:13][C:6]=12
Reactant: O=Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc([N+](=O)[O-])cc5F)c4s3)nc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.3 %

Procedure:
A mixture of 400 (451 mg, 1.14 mmol) and 1-methylpiperazine (152 μL, 137 mg, 1.37 mmol) in DCM (7 mL) was stirred at room temperature for 10 min. It was then treated with NaBH(OAc)3 (340 mg, 1.60 mmol) and stirred at room temperature overnight. The reaction mixture was diluted with DCM (20 mL) and washed with saturated NaHCO3 solution (20 mL). The organic phase was collected, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography using the gradient 30-50% MeOH (with 2% Et3N) in EtOAc to afford 401 (308 mg, 52% yield). MS (m/z): (M+1) 480.0 (100%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16](OCC)=[O:17])[CH2:12][CH2:11]1)[CH2:8][CH3:9].C(OCC)(=O)C.Cl>CCOCC.O>[CH2:7]([C@H:10]1[CH2:15][CH2:14][C@H:13]([CH2:16][OH:17])[CH2:12][CH2:11]1)[CH2:8][CH3:9]
Reactant: CCC[C@H]1CC[C@H](C(=O)OCC)CC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: CCC[C@H]1CC[C@H](CO)CC1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
0.73 g (19.1 mmol) of lithium aluminum hydride was added to 30 ml of dry ether, heat-refluxed for 1 hour and cooled to 10° C. on an iced water bath, and a solution of 5 g (25.5 mmol) of ethyl trans-4-n-propylcyclohexylcarboxylate in 30 ml of dry ether was gradually added dropwise thereto. After the addition, the mixture was stirred for 1 hour and further heat-refluxed for 1 hour, followed by treatment with ethyl acetate and with 6N-hydrochloric acid and pouring into 200 ml of iced water. The resultant mixture was extracted with isopropyl ether and the organic layer was successively washed with water, sodium hydroxide aqueous solution and water, followed by drying with magnesium sulfate, distilling-off of the solvent and purification by silica gel column chromatography to obtain 3.5 g of trans-4-n-propylcyclohexylmethanol.
Reaction SMILES: [C:1]([CH2:6][N:7]1[C:11]2=[CH:12][C:13]3[N:14]=[C:15]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=4)[CH:16]=[N:17][C:18]=3[CH:19]=[C:10]2[CH:9]=[N:8]1)([O:3]CC)=[O:2].[OH-].[K+]>CO>[C:1]([CH2:6][N:7]1[C:11]2=[CH:12][C:13]3[N:14]=[C:15]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=4)[CH:16]=[N:17][C:18]=3[CH:19]=[C:10]2[CH:9]=[N:8]1)([OH:3])=[O:2]
Reactant: CCOC(=O)Cn1ncc2cc3ncc(-c4ccc(OC)c(F)c4)nc3cc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(-c2cnc3cc4cnn(CC(=O)O)c4cc3n2)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-carboethoxymethyl-7-(3-fluoro-4-methoxyphenyl)-1H-pyrazolo[3,4-g]quinoxaline (0.3 g) is added to a solution of KOH (0.22 g) in 15 ml of methanol. The mixture is stirred at room temperature for 11/2 hours then heated at 60° C. for 2 hours. The mixture is concentrated in vacuo and the residue is stirred in 20 ml of 0.5N aqueous HCI for 1/2 hour then the solid is filtered, washed with water and ether and air dried to obtain 1-carboxymethyl-7-(3-fluoro-4-methoxyphenyl)-1H-pyrazolo[3,4-g]quinoxaline (m.p. >260° C.).
Reaction SMILES: C1(S(O[C@H:11]2[CH2:15][C@@H:14]([C:16](=[O:23])[NH:17][C:18]3([C:21]#[N:22])[CH2:20][CH2:19]3)[N:13]([C:24]([C:26]3([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)[CH2:28][CH2:27]3)=[O:25])[CH2:12]2)(=O)=O)C=CC=CC=1.[C:36]1([CH2:42][SH:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:42]([S:43][C@H:11]1[CH2:12][N:13]([C:24]([C:26]2([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[CH2:27][CH2:28]2)=[O:25])[C@H:14]([C:16]([NH:17][C:18]2([C:21]#[N:22])[CH2:19][CH2:20]2)=[O:23])[CH2:15]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: SCc1ccccc1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@H](OS(=O)(=O)c3ccccc3)CN2C(=O)C2(c3ccc(Cl)cc3)CC2)CC1
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](SCc3ccccc3)CN2C(=O)C2(c3ccc(Cl)cc3)CC2)CC1

Procedure:
The title compound was prepared in analogy to example 457d) using (3S,5S)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-5-(1-cyanocyclopropylcarbamoyl)pyrrolidin-3-yl benzenesulfonate (example 457, step 3; 200 mg) and phenylmethanethiol (57 mg) to yield 109 mg (53%) of a white solid. MS (ESI): m/z=480.15 [M−H]+.
Reaction SMILES: O.[NH2:2][NH2:3].[Br:4][C:5]1[C:12]([F:13])=[C:11]([F:14])[C:8]([C:9]#[N:10])=[C:7](F)[C:6]=1[F:16].O>C(O)C>[Br:4][C:5]1[C:6]([F:16])=[C:7]2[C:8]([C:9]([NH2:10])=[N:2][NH:3]2)=[C:11]([F:14])[C:12]=1[F:13]
Reactant: NN
Reactant: N#Cc1c(F)c(F)c(Br)c(F)c1F
Solvent: O
Solvent: CCO
Product: Nc1n[nH]c2c(F)c(Br)c(F)c(F)c12

Procedure:
1.14 cm3 of hydrazine monohydrate are added to 2.0 g of 4-bromo-2,3,5,6-tetrafluorobenzonitrile in 40 cm3 of absolute ethanol. The mixture is refluxed for 18 hours, 30 cm3 of distilled water are then added and the reaction medium is concentrated under reduced pressure (2 kPa; 50° C.). The residue is taken up in 100 cm3 of ethyl acetate and 10 cm3 of water, and the organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 50° C.); after drying (90 Pa; 40° C.), 2.1 g of 6-bromo-4,5,7-trifluoro-1H-indazole-3-amine are obtained in the form of a beige-coloured solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[S:10][CH:9]=[C:8]([C:11]([OH:13])=O)[CH:7]=2)[CH:3]=[N:2]1.[C:14]([O:18][C:19]([N:21]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:14]([O:18][C:19]([N:21]1[CH2:27][CH2:26][CH2:25][N:24]([C:11]([C:8]2[CH:7]=[C:6]([C:4]3[CH:5]=[N:1][NH:2][CH:3]=3)[S:10][CH:9]=2)=[O:13])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: O=C(O)c1csc(-c2cn[nH]c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCN(C(=O)c2csc(-c3cn[nH]c3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
5-(1H-Pyrazol-4-yl)-thiophene-3-carboxylic acid (0.194 g, 1.0 mmol) and [1,4]diazepane-1-carboxylic acid tert-butyl ester (0.25 g, 1.25 mmol) were dissolved in DMF (5 mL) then DIPEA (0.387 g, 3.0 mmol) and HATU (0.46 g, 1.2 mmol) were added and the reaction mixture stirred at room temperature overnight. The solvent was removed by evaporation then the residue was dissolved in DCM and washed with water. The organic phase was washed with 0.5 M HCl then aqueous sodium hydrogen carbonate solution then the organics were evaporated. The crude material was purified by flash chromatography on a 10 g silica II cartridge, eluting with 2% methanol in DCM. The fractions containing the desired product were concentrated under vacuum to give 4-[5-(1H-pyrazol-4-yl)-thiophene-3-carbonyl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester (0.29 g) as a white solid. LCMS m/z 377.32 [M+H]+ R.T.=3.00 min (Analytical Method 6).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][C:20]1=[O:25].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[CH:9]=[C:4]([CH:3]=[C:2]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][C:20]3=[O:25])[CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[N:13][CH:14]=1
Reactant: O=C1COCCN1
Reactant: COC(=O)c1cc(Br)cc(-c2ccc(C)cn2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccc(C)cn2)cc(N2CCOCC2=O)c1

Procedure:
A microwave vial was charged with methyl 3-bromo-5-(5-methylpyridin-2-yl)benzoate (100 mg, 0.33 mmol), morpholin-3-one (42 mg, 0.41 mmol), palladium acetate (4 mg), cesium carbonate (169 mg, 0.52 mmol), xantphos (3 mg), and 1,4-dioxane (1 mL). The reaction mixture was subjected to microwave irradiation at 110° C. for 15 min. The reaction mixture was filtered and the filterate was concentrated under reduced pressure. The resultant residue was purified by preparative HPLC to get the product as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:43])[CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([NH:10][C:11]2[N:12]=[C:13]([O:28][C:29]3[CH:30]=[C:31]([NH:35]C(=O)OC(C)(C)C)[CH:32]=[CH:33][CH:34]=3)[C:14]3[CH:19]=[CH:18][N:17]([CH2:20][O:21]CC[Si](C)(C)C)[C:15]=3[N:16]=2)[CH:7]=[N:6]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:35][C:31]1[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=1)[O:28][C:13]1[C:14]2[CH:19]=[CH:18][N:17]([CH2:20][OH:21])[C:15]=2[N:16]=[C:11]([NH:10][C:8]2[CH:7]=[N:6][N:5]([CH2:4][CH2:3][N:2]([CH3:43])[CH3:1])[CH:9]=2)[N:12]=1
Reactant: CN(C)CCn1cc(Nc2nc(Oc3cccc(NC(=O)OC(C)(C)C)c3)c3ccn(COCC[Si](C)(C)C)c3n2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)CCn1cc(Nc2nc(Oc3cccc(N)c3)c3ccn(CO)c3n2)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl (3-{[2-({1-[2-(dimethylamino)ethyl]-1H-pyrazol-4-yl}amino)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy}phenyl)carbamate in DCM (5 mL) was added TFA (3 mL) and stirred at rt for 4 hrs. This was concentrated down to give the title compound as a dark oil that was taken on to the next step with no purification. m/z (ESI+) for O20H24N8O2 409.1 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[F:11][C:12]1([F:56])[CH2:17][CH2:16][CH:15]([C:18]2[C:27]3[CH:26]([OH:28])[CH2:25][C:24]([CH3:30])([CH3:29])[CH2:23][C:22]=3[N:21]=[C:20]([CH:31]3[CH2:36][CH2:35][N:34]([C:37]4[N:42]=[CH:41][C:40]([OH:43])=[CH:39][N:38]=4)[CH2:33][CH2:32]3)[C:19]=2[CH:44]([F:55])[C:45]2[CH:50]=[CH:49][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:47][CH:46]=2)[CH2:14][CH2:13]1>>[CH2:9]([O:8][C:6]([CH2:5][CH2:4][CH2:3][CH2:2][O:43][C:40]1[CH:39]=[N:38][C:37]([N:34]2[CH2:33][CH2:32][CH:31]([C:20]3[C:19]([CH:44]([F:55])[C:45]4[CH:50]=[CH:49][C:48]([C:51]([F:52])([F:53])[F:54])=[CH:47][CH:46]=4)=[C:18]([CH:15]4[CH2:16][CH2:17][C:12]([F:11])([F:56])[CH2:13][CH2:14]4)[C:27]4[CH:26]([OH:28])[CH2:25][C:24]([CH3:30])([CH3:29])[CH2:23][C:22]=4[N:21]=3)[CH2:36][CH2:35]2)=[N:42][CH:41]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)CCCCBr
Reactant: CC1(C)Cc2nc(C3CCN(c4ncc(O)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1
Product: CCOC(=O)CCCCOc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(O)CC(C)(C)C4)CC2)nc1

Procedure:
Reactions similar to those of Example 13 were performed except for using ethyl 5-bromovalerate instead of ethyl iodide, and from 85 mg (0.13 mmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-hydroxypyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Example 10, the crude title compound was obtained. The total amount of the obtained compound was used in Example (23-2).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([N:12]1[CH2:17][CH2:16][O:15][C@H:14]([CH3:18])[CH2:13]1)=[CH:8][C:7]2=[O:19].C([Sn](CCCC)(CCCC)[C:29]([O:31]CC)=[CH2:30])CCC>O1CCOCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:29]([C:2]1[CH:3]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([N:12]1[CH2:17][CH2:16][O:15][C@H:14]([CH3:18])[CH2:13]1)=[CH:8][C:7]2=[O:19])(=[O:31])[CH3:30]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1cc(Br)c2oc(N3CCO[C@H](C)C3)cc(=O)c2c1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(C(C)=O)c2oc(N3CCO[C@H](C)C3)cc(=O)c2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
Methyl 8-bromo-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxylate (1.45 g, 3.79 mmol), bis(triphenylphosphine) palladium(II) chloride (0.107 g, 0.15 mmol) and tributyl(1-ethoxyvinyl)stannane (1.346 mL, 3.98 mmol) in 1,4-dioxane (20 mL) were degased, purged with argon and heated to 90° C. for 4 hrs. After cooling to RT, HC12N (1.9 mL, 3.79 mmol) was added and the mixture was left to stir for 1 h. The reaction mixture was concentrated, suspended in water, neutralised with NaHCO3 and extracted with DCM. The combined organic phases were washed with water, brine, dried over magnesium sulfate and concentrated. The crude product was triturated with n-heptane, filtered and retriturated with ether, filtered and dried to give methyl 8-acetyl-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxylate (1.15 g, 88%) as a grey solid. Mass Spectrum: M+H+ 346.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1B(O)O>>[C:18]([N:13]1[C:12]([C:31]2[S:30][CH:34]=[CH:33][CH:32]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)([CH3:19])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C(C)(C)C)c(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: OB(O)c1cccs1
Product: CC(C)(C)n1nc2c(c1-c1cccs1)CCNCC2
Yield: 65.5 %

Procedure:
The title compound (83 mg) was prepared according to Example 215 using 203 mg of 2-(tert-butyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 215, Step A) and 176 mg of 2-thiopheneboronic acid. MS (ESI): exact mass calculated for C15H21N3S, 275.15; found, m/z 276.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.57-7.56 (m, 1H), 7.08-7.06 (m, 1H), 7.01-7.00 (m, 1H), 3.29-3.27 (m, 2H), 3.17-3.14 (m, 2H), 2.51-2.48 (m, 2H), 1.37 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]([CH3:49])=[C:16]([N:33]([CH2:47][CH3:48])[CH:34]2[CH2:39][CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36][CH2:35]2)[CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:22][CH:21]=2)[CH:19]=1)=[O:13].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)=[CH:22][CH:21]=2)[CH:17]=[C:16]([N:33]([CH2:47][CH3:48])[CH:34]2[CH2:35][CH2:36][NH:37][CH2:38][CH2:39]2)[C:15]=1[CH3:49])=[O:13]
Reactant: CCN(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
tert-Butyl 4-((5-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-4-methyl-4′-(morpholinomethyl)-[1,1′-biphenyl]-3-yl)(ethyl)amino)piperidine-1-carboxylate (1.3 g, 0.1.93 mmol) was taken in DCM (20 mL), to it TFA (10 mL) was added at 0° C. and stirred at rt for 2 h. On completion of reaction, solvent was removed under reduced pressure, reaction was quenched with aqueous sodium bicarbonate and extracted with 10% MeOH/DCM. Combined organic layers were dried over sodium sulphate and concentrated under reduced pressure to obtain crude; which then purified by acetonitrile washing to give the title compound (0.9 g, 81.81%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[CH3:26][N:27]([CH3:43])[CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:42])[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[OH:41]>CC(C)=O>[CH3:43][N:27]([CH3:26])[CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:42])[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[O:41][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CN(C)CCCNC(=O)CCc1ccccc1O
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCOc1ccccc1CCC(=O)NCCCN(C)C
Temperature: 60 °C
Reaction time: 24 h
Yield: 41.8 %

Procedure:
Potassium carbonate (0.55 g) and 1-bromooctadecane (0.67 g) were added to a solution containing N-[3-(dimethylamino)propyl]-3-(2-hydroxyphenyl)propanamide (0.50 g) obtained in Example 1(1) in acetone (5 ml). After being stirred for 24 hours at 60° C., the reaction mixture was concentrated. The residue, with ethyl acetate added thereto, was washed with water and brine successively, dried over sodium sulfate anhydride, and concentrated. The residue was purified by silica gel column chromatography (silica gel 40 g, chloroform: methanol=10:1), thereby yielding the entitled compound (0.42 g) as white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:29])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH3:23][C:19]1[C:18]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[C:17]([CH:22]=[CH:21][CH:20]=1)[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:29]
Reactant: CCCCCc1c(C)cccc1C(=O)NC1(C(=O)OCC)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCc1c(C)cccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.4 %

Procedure:
The mixture of 2-(3-methyl-2-pentyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (126) (68 mg, 0.17 mmol) and KOH (500 mg, 8.9 mmol) is dissolved in EtOH (8 mL) and water (0.5 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more white precipitate came out of the water. The precipitate is filtered to give a pure product (127) as a pale brown solid (63 mg, 100%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][CH:11]([C:14]([O:16]CC)=O)[O:10][C:9]=2[CH:19]=1)(=[O:3])[CH3:2].[CH2:20]([NH2:23])[CH:21]=[CH2:22]>C(O)C>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][CH:11]([C:14]([NH:23][CH2:20][CH:21]=[CH2:22])=[O:16])[O:10][C:9]=2[CH:19]=1)(=[O:3])[CH3:2]
Reactant: C=CCN
Reactant: CCOC(=O)C1COc2ccc(NC(C)=O)cc2O1
Solvent: CCO
Product: C=CCNC(=O)C1COc2ccc(NC(C)=O)cc2O1
Reaction time: 18 h

Procedure:
A mixture of 3.5 g of 4A, 30 ml of 2-propenylamine and 25 ml of ethanol was stirred for 18 hours. The volatile materials were evaporated under reduced pressure and the residue was co-evaporated with ethanol until a solid formed. The solid was dissolved in a minimum amount of hot ethanol. The solution was filtered through charcoal, chilled and the solid product was separated. The solvent was evaporated under reduced pressure. The residue was held in a freezer over a weekend. 20 ml of water was added with stirring and the solid was collected. The solid was stirred with a further 20 ml of water; the solid was collected, washed with ether, and triturated with hexane until a gum precipitated. The solvent phase was separated. The gum was again triturated with hexane and the solvent phase was separated. The two extracts were combined; the solvent was evaporated under reduced pressure, and the residue was washed with ether, then dried to 4, as a solid, mp: 138°-140° C.
Reaction SMILES: [NH2:1][CH:2]([C:7]1([CH2:14][CH3:15])[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1)[CH2:3][CH2:4][O:5][CH3:6].[Cl:16][C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][N:23]=[C:24]2[O:27]C)=[CH:19][C:18]=1F.Cl>>[NH2:1][CH:2]([C:7]1([CH2:14][CH3:15])[CH2:12][CH2:11][CH:10]([O:13][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][C:17]=2[Cl:16])[C:24](=[O:27])[NH:23][CH:22]=[CH:21]3)[CH2:9][CH2:8]1)[CH2:3][CH2:4][O:5][CH3:6]
Reactant: COc1nccc2cc(F)c(Cl)cc12
Reactant: CCC1(C(N)CCOC)CCC(O)CC1
Agent: Cl
Product: CCC1(C(N)CCOC)CCC(Oc2cc3cc[nH]c(=O)c3cc2Cl)CC1
Yield: 43 %

Procedure:
Example 98 was synthesized using the reaction sequence as described for the alternative synthesis of Example 1 (step d and e). 60 mg of 4-(1-Amino-3-methoxy-propyl)-4-ethyl-cyclohexanol (59) and 53.9 mg of 7-chloro-6-fluoro-1-methoxy-isoquinoline (4) were used to give 43 mg of Example 98 as hydrochloride. Stereochemistry was not assigned. Rt=1.78 min (Method N). Detected mass: 393.3 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH:4]=[CH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1.[CH3:20][N:21]([CH2:23][CH2:24]Cl)[CH3:22].Cl>>[CH3:20][N:21]([CH3:22])[CH2:23][CH2:24][O:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH:4]=[CH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: Oc1ccccc1C=Cc1ccc2ccccc2n1
Reactant: CN(C)CCCl
Agent: Cl
Product: CN(C)CCOc1ccccc1C=Cc1ccc2ccccc2n1

Procedure:
2-[o-(β-Dimethylamino-ethoxy)-styryl]-quinoline was prepared from 2-(o-hydroxy-styryl)-quinoline (m.p. 274°-278° C.) and dimethylamino-ethyl chloride, and the free base was converted into its monohydrochloride, yielding 86% of theory of the compound of the formula ##STR8## which had a melting point of 188° C.