Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][C:14]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH3:26])[CH:21]=[C:20]3[C:27]2[N:35]([S:36]([C:39]3[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=3)(=[O:38])=[O:37])[C:30]3=[N:31][CH:32]=[CH:33][CH:34]=[C:29]3[CH:28]=2)=[CH:13][CH2:12]1)=O)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[N:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH3:26])[CH:21]=[C:20]3[C:27]2[N:35]([S:36]([C:39]3[CH:40]=[CH:41][C:42]([CH3:45])=[CH:43][CH:44]=3)(=[O:37])=[O:38])[C:30]3=[N:31][CH:32]=[CH:33][CH:34]=[C:29]3[CH:28]=2)=[CH:13][CH:12]=1
Reactant: [H][H]
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cn(C)c4ccc(C5=CCN(C(=O)OCc6ccccc6)CC5)cc34)cc3cccnc32)cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2c(-c3cn(C)c4ccc(-c5ccncc5)cc34)cc3cccnc32)cc1
Reaction time: 8 h

Procedure:
A mixture of 2-[5-(1-benzyloxycarbonyl-1,2,5,6-tetrahydropyridin-4-yl)-1-methyl-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (1.7 g, Reference Example 61) ethanol (53 mL) and palladium on carbon (0.35 g) was stirred in the presence of hydrogen for 4 hours, then left standing at room temperature overnight. After a further day a further quantity of palladium on carbon (0.18 g, 10%) was added and stirring was continued in the presence of hydrogen for a further 8 hours. After standing at room temperature for 4 days the reaction mixture was filtered through Hyflo and the filter pad was washed well with ethanol. The combined filtrate and washings was treated with palladium on carbon (0.35 g) and the mixture was stirred in the presence of hydrogen. The mixture was filtered through Hyflo and the filter pad was washed well with ethanol. The combined filtrate and washings was evaporated and the residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and pentane (4:1, v/v) to give the title compound as a light brown solid, m.p. 82-85° C.
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC([N:15]1[CH2:20][CH2:19][C:18]([NH:32]C(OC(C)(C)C)=O)([CH2:21][NH:22][C:23](=[O:31])[C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>CO>[ClH:30].[ClH:1].[NH2:32][C:18]1([CH2:21][NH:22][C:23](=[O:31])[C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)NC1(CNC(=O)c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NC1(CNC(=O)c2ccc(Cl)cc2)CCNCC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A 4M solution of HCl in dioxane (0.3 ml, 1.2 mmol) was added dropwise to a solution of 4-tert-butoxycarbonylamino-4-[(4-chloro-benzoylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (5.8 mg, 0.012 mmol) in methanol (0.5 mL). The solution was stirred at room temperature for 17 hours. The solvents were concentrated to give N-(4-amino-piperidin-4-ylmethyl)-4-chloro-benzamide dihydrochloride (6.1 mg, quantitative) that was used in the next step without further purification. 1H NMR (CD3OD) δ 2.23-2.30 (4H, m), 3.46-3.61 (4H, m), 3.89 (2H, s), 7.58 (2H, d, J=7 Hz), 8.03 (2H, d, J=7 Hz).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[CH:8]([N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21])[CH2:9][CH3:10].C(N(CC)CC)C.[H][H]>O1CCCC1.[C].[Pd]>[N:4]1[CH:5]=[CH:6][C:7]([CH:8]([N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH2:9][CH3:10])=[CH:2][N:3]=1
Reactant: CCC(c1cc(Cl)nnc1Cl)N1C(=O)c2ccccc2C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(c1ccnnc1)N1C(=O)c2ccccc2C1=O
Yield: 28 %

Procedure:
2-[1-(3,6-Dichloropyridazin-4-yl)propyl]isoindoline-1,3-dione, triethylamine (1.11 mL, 8 mmol) and 10% palladium-carbon (50 wt %, 100 mg) were stirred in tetrahydrofuran in a hydrogen atmosphere (1 atm) at room temperature for 4 days. The reaction solution was filtered through celite and concentrated under reduced pressure, and the resulting residue was dissolved in chloroform, and the resulting organic layer was washed with water and saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/3) to give the desired product (294 mg, 28% yield, two steps).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[NH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][OH:24])[CH2:19][CH2:18]1>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:15])[CH3:14])=[C:2]2[NH:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][OH:24])[CH2:19][CH2:18]1
Reactant: N[C@H]1CC[C@H](CO)CC1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Product: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](CO)CC1

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (200 mg, 0.83 mmol) was reacted with (trans-4-aminocyclohexyl)methanol (130 mg, 1.0 mmol) to afford the desired product (180 mg, 65%) as an orange-yellow solid: 1H NMR (500 MHz, CDCl3) δ 10.90 (s, 1H), 8.94 (s, 1H), 8.08 (d, J=8.7 Hz, 1H), 7.52 (d, J=8.7 Hz, 1H), 5.10-4.92 (m, 1H), 3.58-3.47 (m, 2H), 2.68 (s, 3H), 2.37-2.23 (m, 2H), 2.01-1.89 (m, 2H), 1.65-1.51 (m, 1H), 1.42-1.30 (m, 2H), 1.29-1.18 (m, 2H); ESI MS m/z 334 [M+H]+
Reaction SMILES: [O:1]=[C:2]1[CH:11]([NH:12][C:13](=[O:15])[CH3:14])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C(N)(=O)C.C([O-])(=O)C.[Na+].[Br:25]Br>C(O)(=O)C.O>[Br:25][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2](=[O:1])[CH:11]([NH:12][C:13](=[O:15])[CH3:14])[CH2:10]2
Reactant: CC(=O)NC1Cc2ccccc2NC1=O
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: CC(N)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)NC1Cc2cc(Br)ccc2NC1=O

Procedure:
Acetic acid (3,240 mL) was added to N-(2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetamide (405.8 g), and the acetamide was dissolved in acetic acid at an inside temperature of 51° C. The reactor was cooled to an inside temperature of 25° C., and sodium acetate was added thereto. To the mixture maintained at an inside temperature of 25° C., bromine was dropwise added over 30 minutes under stirring. The reaction mixture was added to water (35 L), and the reactor was washed with water (3.24 L). The thus-obtained mixture was stirred at 24° C. for one hour.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[NH:13][C:12](=O)[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:9][O:10][CH2:11][CH2:12][NH:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1COCC(c2cccc(F)c2)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Fc1cccc(C2COCCN2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In step 2-4, a solution of 5-(3-fluorophenyl)morpholin-3-one (4.56 g, 23.4 mmol) in THF at 0° C. was treated with lithium aluminum hydride (4.3 g, 107 mmol) in a single portion. The suspension was warmed to room temperature and stirred overnight. The reaction mixture was quenched with Na2SO4 10 H2O and stirred for 4 hours. The heterogeneous solution was filtered through a celite pad, and the filtrate was concentrated and purified with flash chromatography (5-10% methanol/EtOAc) to obtain 3-(3-fluorophenyl)morpholine (2-4) as a clear oil. 1H NMR CDCl3 (δ) ppm 7.28 (m, 1H), 7.13 (m, 2H), 6.97 (m, 1H), 3.93 (dd, 1H), 3.89 (m, 1H), 3.81 (dd, 1H), 3.64 (td, 1H), 3.35 (m, 1H), 3.12 (td, 1H), 3.02 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]([S:19]([C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)(=[O:21])=[O:20])[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][C:13]([C:16]([NH2:18])=O)=[CH:12]2)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1>O1CCCC1>[CH2:1]([O:3][CH2:4][CH2:5][N:6]([S:19]([C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)(=[O:21])=[O:20])[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][C:13]([C:16](=[S:36])[NH2:18])=[CH:12]2)[CH3:2]
Reactant: CCOCCN(c1cccc2cc(C(N)=O)[nH]c12)S(=O)(=O)c1cccs1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CCOCCN(c1cccc2cc(C(N)=S)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 70 °C
Reaction time: 3 h
Yield: 96.5 %

Procedure:
A mixture of 7-[(2-ethoxyethyl)(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (4.70 g), Lawesson's reagent (3.06 g) and tetrahydrofuran (30 ml) was stirred at 70° C. for 3 hr. The reaction mixture was concentrated, and toluene was added to the residue. The obtained solid was washed with toluene to give the title compound (2.99 g, yield 58%) as crystals. melting point 182° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:20]([S:28][CH2:29][CH2:30][C:31]([O:33]C)=[O:32])[S:21][CH2:22][CH2:23][C:24]([O:26]C)=[O:25])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Li+].O>COCCOC>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:20]([S:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])[S:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)CCSC(SCCC(=O)OC)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: O=C(O)CCSC(SCCC(=O)O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of dimethyl ester (Step 2) (1.7 g) in 1,2-dimethoxyethane (60 ml) was added lithium hydroxide (10 ml of 2N). The reaction mixture was stirred overnight at room temperature. H2O (100 ml) was added and the 1,2-dimethoxyethane was removed under vacuo. The solution was extracted with ethylacetate (300 ml). The aqueous phase was acidified to pH 3, extracted with ethylacetate (200 ml), dried and evaporated. Flash chromatography of the residue using 5% EtOH in CH2Cl2 with 1% of acetic acid afforded the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:14][C:13]2[CH:12]=[CH:11][C:10]3[NH:9][C:8](=[O:15])[C:7](=[O:16])[NH:6][C:5]=3[C:4]=2[CH2:3]1.[Cl:17][S:18](O)(=[O:20])=[O:19]>>[Cl:17][S:18]([C:12]1[C:13]2[CH2:14][N:2]([CH3:1])[CH2:3][C:4]=2[C:5]2[NH:6][C:7](=[O:16])[C:8](=[O:15])[NH:9][C:10]=2[CH:11]=1)(=[O:20])=[O:19]
Reactant: CN1Cc2ccc3[nH]c(=O)c(=O)[nH]c3c2C1
Reactant: O=S(=O)(O)Cl
Product: CN1Cc2c(S(=O)(=O)Cl)cc3[nH]c(=O)c(=O)[nH]c3c2C1

Procedure:
A solution of 1,7,8,9-tetrahydro-8-methyl-2H-pyrrolo[3,4-f]quinoxaline-2,3(4H)-dione in chlorosulfonic acid was stirred at 120° C. for 3 hours, whereafter it was cooled and poured on ice. This afforded a crystalline precipitate of the product, which was filtered off and washed with water, mp>300° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.CO>Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]([CH2:14][CH3:15])[C:11](=[O:12])[NH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCNC(=O)NCC(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: CO
Product: CCn1c(-c2ccc(Cl)cc2)c[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
990 mg (4.113 mmol) of N-[2-(4-chlorophenyl)-2-oxoethyl]-N′-ethylurea from Example 115A are suspended in 16 ml concentrated hydrochloric acid, treated with 16 ml of methanol and stirred for one hour at room temperature. The reaction mixture is evaporated to dryness, the residue extracted with dichloromethane, and the organic phase dried over sodium sulphate and again concentrated. The crude product is purified by flash chromatography on silica gel (eluent: dichloromethane/methanol 100:1, then 50:1) and 701 mg (77% of theory) of the target compound are thus obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].[CH3:12]O>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C(=O)O)ccc1N
Reactant: CO
Product: COC(=O)c1ccc(N)c(C)c1

Procedure:
In a 300 mL three-necked, round-bottomed flask were dissolved 5.2 g (34.4 mmole) of 4-amino-3-methylbenzoic acid in 75 ml of anhydrous methanol. Anhydrous hydrogen chloride was bubbled into the flask for 3 to 5 minutes and the resulting solution was refluxed for 2 hours. The solvent was removed using a rotary evaporator, the resulting residue was introduced into a mixture of 200 ml of water and 100 ml of methylene chloride and the mixture was then separated into two phases. The aqueous layer was made basic with 10% aqueous sodium hydroxide and extracted with methylene chloride (3×100 ml). The combined organic layers were dried over anhydrous magnesium sulfate and the solvent removed using a rotary evaporator yielding 5.68 g methyl 4-amino-3-methylbenzoate.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]1[C:12]2[CH2:13][NH:14][CH2:15][C:11]=2[CH2:10][N:9]1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:27])([F:26])[F:25])=[O:17].Cl[C:29]1[N:30]=[N:31][C:32]([O:35][CH2:36][CH:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)=[CH:33][CH:34]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[O:40]1[CH2:41][CH2:42][CH:37]([CH2:36][O:35][C:32]2[N:31]=[N:30][C:29]([N:14]3[CH2:13][C:12]4[CH2:8][N:9]([C:16]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=5[C:24]([F:27])([F:25])[F:26])=[O:17])[CH2:10][C:11]=4[CH2:15]3)=[CH:34][CH:33]=2)[CH2:38][CH2:39]1
Reactant: Clc1ccc(OCC2CCOCC2)nn1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CC2=C(CNC2)C1
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccccc1C(F)(F)F)N1CC2=C(C1)CN(c1ccc(OCC3CCOCC3)nn1)C2

Procedure:
(3,4,5,6-Tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl)(2-trifluoromethylphenyl)methanone trifluoroacetate (example 1b) (500 mg, 1.26 mmol) was reacted analogously to example 4b with 3-chloro-6-(tetrahydropyran-4-ylmethoxy)pyridazine (288.6 mg, 1.26 mmol). Yield: 129 mg (17%), M+H+: 475.18.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH:3]=1.[Cl:29]N1C(C)(C)C(=O)N(Cl)C1=O.O>C(#N)C>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20])[C:3]=1[Cl:29]
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Reactant: COc1c(Cl)ccc(-c2nc(C(=O)OCc3ccccc3)cc(N)c2F)c1F
Solvent: O
Solvent: CC#N
Product: COc1c(Cl)ccc(-c2nc(C(=O)OCc3ccccc3)c(Cl)c(N)c2F)c1F
Temperature: 25 °C
Yield: 228.3 %

Procedure:
Benzyl 4-amino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropicolinate (2.07 g, 5.12 mmol) was slurried in acetonitrile (20 mL) in a scintillation vial. 1,3-Dichloro-5,5-dimethylhydantoin (554 mg, 2.181 mmol) was added as a solid, and the reaction mixture was stirred at reflux for 1 h. After cooling to room temperature, water (40 mL) was added to precipitate the product. The solid was collected on a Buchner funnel and washed with water. Drying under vacuum at 55° C. gave a white solid (2.187 g, 97%): 1H NMR (400 MHz, CDCl3) δ 7.50-7.41 (m, 2H, aromatic), 7.41-7.20 (m, 5H, aromatic), 5.42 (s, 2H, CH2Ph), 4.92 (br s, 2H, NH2), 3.97 (d, J=1.2 Hz, 3H, OMe); 19F{1H} NMR (CDCl3) δ −128.19 (d, J=33.9 Hz, F2′), −137.79 (d, J=33.8 Hz, F5).
Reaction SMILES: [C:1]1([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][N:19](COCC[Si](C)(C)C)[C:20]3[N:24](COCC[Si](C)(C)C)[C:23]4[CH:33]=[CH:34][C:35]([CH:37]([OH:40])[CH2:38][CH3:39])=[CH:36][C:22]=4[N:21]=3)[CH2:14][CH2:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(OCC)(=O)C.O>CN(C)C=O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]1([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH:19][C:20]3[NH:24][C:23]4[CH:33]=[CH:34][C:35]([CH:37]([OH:40])[CH2:38][CH3:39])=[CH:36][C:22]=4[N:21]=3)[CH2:14][CH2:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCC(O)c1ccc2c(c1)nc(N(COCC[Si](C)(C)C)CC1CCN(Cc3cccc4ccccc34)CC1)n2COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCC(O)c1ccc2[nH]c(NCC3CCN(Cc4cccc5ccccc45)CC3)nc2c1
Temperature: 100 °C
Reaction time: 13 h

Procedure:
After dissolving 1-[2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-(2-trimethylsilanyl-ethoxymethyl)-amino]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazol-5-yl]-propan-1-ol (50 mg, 0.073 mmol) in anhydrous dimethylformamide (2 ml), tetrabutylammonium fluoride (0.5 ml, 1.0 M tetrahydrofuran solution) was added and the mixture was stirred at 100° C. for 13 hours. Ethyl acetate and water were added, after which the aqueous layer was adjusted to pH 11 and extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by thin-layer silica gel chromatography (ethyl acetate/methanol=4/1). The purified product was further purified by preparative HPLC to obtain 1-{2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazol-5-yl}-propan-1-ol.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:22])[CH:7]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1.[CH3:23][CH:24]([CH3:43])[C:25]([NH:27][C:28]1[C:33]([F:34])=[CH:32][C:31]([F:35])=[C:30]([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[C:29]=1[F:42])=[O:26]>>[F:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:6]([NH:5][CH2:4][CH2:3][CH2:2][N:39]2[CH2:40][CH2:41][CH:36]([C:30]3[C:29]([F:42])=[C:28]([NH:27][C:25](=[O:26])[CH:24]([CH3:23])[CH3:43])[C:33]([F:34])=[CH:32][C:31]=3[F:35])[CH2:37][CH2:38]2)=[O:22])=[CH:9][CH:10]=1
Reactant: CC(C)C(=O)Nc1c(F)cc(F)c(C2CCNCC2)c1F
Reactant: O=C(NCCCBr)C(c1ccc(F)cc1)c1ccc(F)cc1
Product: CC(C)C(=O)Nc1c(F)cc(F)c(C2CCN(CCCNC(=O)C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c1F

Procedure:
Example 173 was prepared from N-(3-bromopropyl)-2,2-bis(4-fluoro phenyl)acetamide and 2-methyl-N-[2,4,6-trifluoro-3-(4-piperidinyl)phenyl]propanamide according to the procedures described in Scheme 14; ESMS m/e: 588.3 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([C:16]1[N:21]=[C:20]2[CH2:22][O:23]C(C3C=CC=CC=3)[O:25][C:19]2=[CH:18][CH:17]=1)[CH2:3][N:4]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:5]([CH3:8])([CH3:7])[CH3:6].[ClH:32].Cl.Cl.OCCC1C(O)=CC=C(C(O)CN(CC2C=CC=CC=2)C(C)(C)C)N=1>CO>[ClH:32].[ClH:32].[OH:23][CH2:22][C:20]1[C:19]([OH:25])=[CH:18][CH:17]=[C:16]([CH:2]([OH:1])[CH2:3][N:4]([CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:5]([CH3:8])([CH3:7])[CH3:6])[N:21]=1
Reactant: CC(C)(C)N(Cc1ccccc1)CC(O)c1ccc2c(n1)COC(c1ccccc1)O2
Agent: CC(C)(C)N(Cc1ccccc1)CC(O)c1ccc(O)c(CCO)n1
Agent: Cl
Solvent: CO
Product: CC(C)(C)N(Cc1ccccc1)CC(O)c1ccc(O)c(CO)n1

Procedure:
A solution of 8.40 g. (0.02 mole) 6-[1-hydroxy-2-(N-tert-butylbenzylamino)ethyl]-2-phenyl-4H-1,3-dioxino[5,4-b]pyridine in 75 ml. of methanol containing 10 ml. of concentrated hydrochloric acid was stirred at room temperature for 4 hours, then the solvents were evaporated in vacuo to give a solid. Recrystallization from isopropanol/methanol gave 6.30 g. (74%) of 2-hydroxyethyl-3-hydroxy-6-[1-hydroxy-2-(N-tert-butylbenzylamino)ethyl]pyridine dihydrochloride; m.p. 173°-175° C. (dec.)
Reaction SMILES: F[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[C:4]([F:11])[N:3]=1.Cl.[F:13][C:14]([F:29])([F:28])[C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][O:23][CH2:24][C:25]([NH2:27])=[NH:26])[CH:18]=[CH:19][CH:20]=1>>[F:11][C:4]1[CH:5]=[CH:6][C:7]2[C:8](=[O:10])[NH:27][C:25]([CH2:24][O:23][CH2:22][CH2:21][C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([F:13])([F:28])[F:29])[CH:16]=3)=[N:26][C:2]=2[N:3]=1
Reactant: O=C(O)c1ccc(F)nc1F
Reactant: N=C(N)COCCc1cccc(C(F)(F)F)c1
Agent: Cl
Product: O=c1[nH]c(COCCc2cccc(C(F)(F)F)c2)nc2nc(F)ccc12

Procedure:
The title compound was prepared in analogy to example 85 from 2,6-difluoropyridine-3-carboxylic acid and 2-[2-(3-trifluoromethyl-phenyl)-ethoxy]-acetamidine hydrochloride. Brown solid. MS: m/e=368.1 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[S:13][CH:14]=[C:15]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]4)[N:16]=2)[CH:6]=[CH:7][C:8]=1[S:9]([CH3:11])=[O:10].ClC1C=CC=C(C(OO)=[O:36])C=1>C(Cl)(Cl)Cl.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[S:13][CH:14]=[C:15]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]4)[N:16]=2)[CH:6]=[CH:7][C:8]=1[S:9]([CH3:11])(=[O:36])=[O:10]
Reactant: COc1cc(-c2nc(-c3ccc4c(c3)CCC(=O)N4)cs2)ccc1S(C)=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COc1cc(-c2nc(-c3ccc4c(c3)CCC(=O)N4)cs2)ccc1S(C)(=O)=O
Reaction time: 1 h
Yield: 16.6 %

Procedure:
In 100 ml of chloroform-ethanol was suspended 2.9 g of 2-(3-methoxy-4-methylsulfinylphenyl)- 4- (3,4-dihydrocarbostyril-6-yl)thiazole. Under ice-cooling, 1.72 g of m-chloroperbenzoic acid (80%) was added in small portions and the mixture was stiffed for 1 hour. Then, the mixture was returned to room temperature and stirred overnight. The resulting crystals were collected by filtration, washed with ethanol and diethyl ether, and dried. Recrystallization from dimethylformamide-water to obtain 0.50 g of 2-(3-methoxy-4-methylsulfonylphenyl)-4-(3,4- dihydrocarbostyril-6-yl)thiazole as a white powder.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH:12]([CH2:17][C:18]([O:20]C)=O)[C:13](OC)=[O:14])=[C:4](Cl)[N:3]=1.[BH4-].[Li+].[OH2:25]>C(O)(C)(C)C>[OH:20][CH2:18][CH2:17][CH:12]([CH2:13][OH:14])[CH2:11][N:8]1[CH:7]=[N:6][C:5]2[C:4](=[O:25])[NH:3][C:2]([NH2:1])=[N:10][C:9]1=2
Reactant: COC(=O)CC(Cn1cnc2c(Cl)nc(N)nc21)C(=O)OC
Reactant: O
Agent: [BH4-]
Agent: [Li+]
Solvent: CC(C)(C)O
Product: Nc1nc2c(ncn2CC(CO)CCO)c(=O)[nH]1
Reaction time: 1 h

Procedure:
Dimethyl 2-(2-amino-6-chloropurin-9-ylmethyl)succinate (8.00 g, 0.0244 mol) was dissolved in 200 ml of tert. butanol at 50° C., lithium borohydride (2.66 g, 0.122 mol) was added in portions, and the mixture was stirred for 1 h. Then 100 ml of water was added and the stirring was continued over-night, the inorganic salts were filtered off and the solution was evaporated to dryness in vacuum. The residue was found to contain 78 mole-% of 2-amino-6-tert.butoxy-9-[4-hydroxy-2(hydroxymethyl)butyl]purine together with the 6-chloro compound.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8](N)[CH:9]=2)[CH2:4][CH2:3][NH:2]1.S(=O)(=O)(O)[OH:13].N([O-])=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>O.CO>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:13])[CH:9]=2)[CH2:4][CH2:3][NH:2]1
Reactant: Nc1ccc2c(c1)CNCC2
Reactant: O=S(=O)(O)O
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Oc1ccc2c(c1)CNCC2
Temperature: 120 °C

Procedure:
A solution of 1,2,3,4-tetrahydro-isoquinolin-7-amine (4.5 g, 30 mmol) in sulfuric acid (6.5 mL, 120 mmol) and water (20 mL) was cooled to 0° C. To this cold solution was added a solution of sodium nitrite (2.51 g, 36 mmol) in water (20 mL) over 15 min. After the addition, the reaction mixture was heated at 120° C. for 2 h and then allowed to cool to rt. Solid Na2CO3 was added slowly to the reaction mixture until no gas generated. A small amount of water was added to dissolve the remaining Na2CO3 and a sticky brown glue was formed. The residue was dissolved in MeOH and filtered through Celite. The filtrate was concentrated to give 1,2,3,4-tetrahydroisoquinolin-7-ol as a brown solid (3.7 g, 82% crude yield), which was directly used in the next step without further purification. MS: 150.