Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([NH:13][CH3:14])=[O:12].C(=O)([O-])[O-].[K+].[K+].[Cl:21][CH2:22][CH2:23][C:24](Cl)=[O:25].CCCCCCC>C1COCC1>[Cl:21][CH2:22][CH2:23][C:24]([NH:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([NH:13][CH3:14])=[O:12])=[O:25]
Reactant: CNC(=O)c1c(N)sc2c1CCCC2
Reactant: O=C(Cl)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CNC(=O)c1c(NC(=O)CCCl)sc2c1CCCC2
Reaction time: 0.08 h
Yield: 43.8 %

Procedure:
2-Amino-N-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (2.82 g, 13.41 mmol) was completely dissolved in THF (90 mL). Potassium carbonate (2.22 g, 16.09 mmol) was then added and the reaction stirred for 5 min. 3-chloropropanoyl chloride (2.04 g, 1.536 mL, 16.09 mmol) was added and the reaction mixture stirred at RT for 30 min. THF was removed in vacuo. Water was added and the reaction mixture extracted into EtOAc (×3). The combined EtOAc layers were washed with brine, dried over MgSO4, filtered and the solvent removed in vacuo. Purification by flash column chromatography-silica gel and elution with 0-60% EtOAc:heptane gave the desired product (1.76 g, 5.87 mmol, 44%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[Cl:9].[OH-:10].[Na+].BrC1C(Cl)=C(Cl)C=CC=1.Cl>[Cu].O.CO>[Cl:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[OH:10]
Reactant: Clc1ccc(Cl)c(Br)c1
Reactant: [OH-]
Agent: [Cu]
Agent: Cl
Agent: Clc1cccc(Br)c1Cl
Solvent: O
Solvent: CO
Product: Oc1cc(Cl)ccc1Cl
Temperature: 25 °C

Procedure:
1-Bromo-2,5-dichlorobenzene (100.0 grams) and sodium hydroxide dissolved in most of the methanol and the desired amount of water were charged into a one-liter stainless steel Magnedrive autoclave reactor equipped with a constant speed stirrer. The reaction mixture was then stirred, and a solution of the copper salt in the remainder of the methanol was added. In Runs 1 and 2 the copper salt was added to the reactor as a solid. Other additives, if used, were then added last of all. The bromodichlorobenzene used in all runs assayed from 98.5 to 99.7 percent by weight. The reactor was then sealed and pressurized to 180 pounds per square inch with nitrogen gas to prevent refluxing into the connecting lines. The reaction mixture was then heated to the desired temperature with stirring for a period of from 1 to 3 hours. After this time the reaction mixture was cooled to room temperature and was added to an equal amount of water. A small amount of caustic was then added to the mixture to prevent the loss of phenols during the first extraction. The reaction mixture was then extracted successively with pentane to remove unreacted starting material and undesired side reaction products. The remaining aqueous phase was then acidified to low pH with hydrochloric acid. The free phenol was then extracted successively with methylene chloride, and the combined extracts were dried over anhydrous sodium sulfate. The dried extracts were then stripped of solvent under reduced pressure (20 mm Hg) to yield the desired 2,5-dichlorophenol.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]([OH:14])=O)=[C:7]([CH3:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:46]1[CH2:51][CH2:50][C:49]2([C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[CH2:53][O:52]2)[CH2:48][CH2:47]1>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]([N:46]3[CH2:51][CH2:50][C:49]4([C:59]5[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=5[CH2:53][O:52]4)[CH2:48][CH2:47]3)=[O:14])=[C:7]([CH3:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: c1ccc2c(c1)COC21CCNCC1
Reactant: Cc1[nH]c2cc(Cl)ccc2c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1[nH]c2cc(Cl)ccc2c1C(=O)N1CCC2(CC1)OCc1ccccc12
Reaction time: 1 h
Yield: 49.7 %

Procedure:
To a solution of 0.040 g (0.19 mmol) 6-chloro-2-methyl-1H-indole-3-carboxylic acid, 0.069 ml (0.40 mmol) N,N-diisopropylethylamine and 0.061 g (0.19 mmol) 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate in 1 ml dry N,N-dimethylformamide were added 0.036 g (0.19 mmol) spiro[isobenzofuran-1(3H),4′-piperidine] at room temperature. After stirring for 1 h the reaction mixture was quenched with 0.5 M aqueous sodium hydroxide solution (20 ml) and extracted with ethyl acetate (2×30 ml). The combined organic layers were washed with water (2×30 ml) and brine (1×30 ml), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (n-heptane/ethyl acetate) to give the title compound (0.036 g, 49%) as a white solid.
Reaction SMILES: I[C:2]1[C:10]2[O:9][CH2:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH:23]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:13][O:12][C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:11])[CH2:8][O:9][C:10]=2[C:2]=1[C:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COc1ccc2c(c1I)OCC2=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc2c(c1C1=CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 47.2 %

Procedure:
A solution of 7-iodo-6-methoxybenzofuran-3(2H)-one (0.100 g, 0.345 mmol) synthesized in Example B46, Step 2 in 1,4-dioxane (6 mL) was added with tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.107 g, 0.345 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.0252 g, 0.0345 mmol) and 2 M aqueous sodium carbonate (0.515 mL, 1.03 mmol), and the mixture was stirred at 150° C. for 30 minutes under irradiation of microwaves. The reaction mixture was poured into water, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated, and the resulting residue was subjected to silica gel column chromatography (hexane/ethyl acetate). The resulting crude product was purified again by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl 4-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.0562 g, 47%).
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[N:15]=2)[CH:10]=[CH:9][C:8]1=[O:19].FC(F)(F)C(O)=O>O>[CH3:18][O:17][C:14]1[N:15]=[C:16]2[C:11]([CH:10]=[CH:9][C:8](=[O:19])[N:7]2[CH2:6][CH:2]=[O:1])=[CH:12][CH:13]=1
Reactant: COc1ccc2ccc(=O)n(CC3OCCO3)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1ccc2ccc(=O)n(CC=O)c2n1
Temperature: 66 °C
Reaction time: 0.33 h
Yield: 77.3 %

Procedure:
To 2.8 g of 1-(1,3-dioxolan-2-ylmethyl)-7-methoxy-1,8-naphthyridin-2(1H)-one, 20 mL of an 80% aqueous trifluoroacetic acid solution was added, and the mixture was stirred at 60 to 72° C. for 3 hours 20 minutes, and at 80 to 85° C. for 2 hours 20 minutes, 4 mL of water was then added thereto and the mixture was further stirred for 4 hours. The reaction mixture was cooled to room temperature and then left overnight, and the solvent was distilled off under reduced pressure. To the resultant residue, a saturated aqueous sodium hydrogen carbonate solution and chloroform were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.8 g of (7-methoxy-2-oxo-1,8-naphthyridin-1(2H)-yl)acetaldehyde as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:33]=[CH:32][CH:31]=[CH:30][C:3]=1[CH2:4][N:5]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29])[CH2:6][CH2:7][N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=1)[CH2:9][CH2:10][NH2:11].C>C(O)C.[Pd]>[OH:1][C:2]1[CH:33]=[CH:32][CH:31]=[CH:30][C:3]=1[CH2:4][N:5]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29])[CH2:6][CH2:7][N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1)[CH2:9][CH2:10][NH2:11]
Reactant: NCCN(CCN(Cc1ccccc1O)Cc1ccccc1O)Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: NCCN(CCN(Cc1ccccc1O)Cc1ccccc1O)Cc1ccc(N)cc1
Reaction time: 24 h

Procedure:
In 40 mL of absolute ethanol was dissolved 400 mg of bis(2-hydroxybenzyl)-4-(p-nitrobenzyl)-diethylenetriamine (prepared in Example 1) and 100 mg of palladium or activated charcoal (10% Pd). The mixture was hydrogenated at 40 psi (275.8 kPa) for 24 hours. The catalyst was removed by filtration. The ethanolic solution was evaporated to provide bis(2-hydroxybenzyl)-4-(p-aminobenzyl)diethylenetriamine, and was characterized by:
Reaction SMILES: C(C1C=[C:5](C=CC=1O)[C:6](NNC(C1OC=C(C2C=CC=CC=2)C=1C1C=CC=CC=1)=O)=[O:7])#N.[OH:33][C:34]1[CH:62]=[CH:61][C:37]([C:38]([NH:40][NH:41][C:42]([C:44]2[O:45][CH:46]=[C:47]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[C:48]=2[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[O:43])=[O:39])=[CH:36][C:35]=1[N+:63]([O-:65])=[O:64]>>[C:6]([O:33][C:34]1[CH:62]=[CH:61][C:37]([C:38]([NH:40][NH:41][C:42]([C:44]2[O:45][CH:46]=[C:47]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[C:48]=2[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[O:43])=[O:39])=[CH:36][C:35]=1[N+:63]([O-:65])=[O:64])(=[O:7])[CH3:5]
Reactant: N#Cc1cc(C(=O)NNC(=O)c2occ(-c3ccccc3)c2-c2ccccc2)ccc1O
Reactant: O=C(NNC(=O)c1occ(-c2ccccc2)c1-c1ccccc1)c1ccc(O)c([N+](=O)[O-])c1
Product: CC(=O)Oc1ccc(C(=O)NNC(=O)c2occ(-c3ccccc3)c2-c2ccccc2)cc1[N+](=O)[O-]

Procedure:
A reaction and treatment was carried out in the same manner as in Example 94 except that the compound of Example 18 used in Example 94 was replaced with the compound of Example 19, thereby giving the desired compound. HPLC retention time: 15.15 minutes.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[CH:12]=[C:13]([CH2:17][NH2:18])[CH:14]=[N:15][CH:16]=1.[CH:19]([S:22](Cl)(=[O:24])=[O:23])([CH3:21])[CH3:20]>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[CH:12]=[C:13]([CH2:17][NH:18][S:22]([CH:19]([CH3:21])[CH3:20])(=[O:24])=[O:23])[CH:14]=[N:15][CH:16]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: Cn1c(-c2cncc(CN)c2)cc2ccccc21
Product: CC(C)S(=O)(=O)NCc1cncc(-c2cc3ccccc3n2C)c1

Procedure:
C-[5-(1-Methyl-1H-indol-2-yl)-pyridin-3-yl]-methylamine (Example 200b) and isopropylsulfonyl chloride are processed according to the method described in Example 186f to give N-[5-(1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-isopropylsulfonamide. 1H NMR (400 MHz, MeOD) δ ppm 1.40 (d, J=6.82 Hz, 6H), 3.23-3.32 (m, 1H), 3.83 (s, 3H), 4.45 (s, 2H), 6.70 (s, 1H), 7.09-7.17 (m, 1H), 7.27 (ddd, J=7.6, 1.14 Hz, 1H), 7.48 (d, J=8.3 Hz, 1H), 7.63 (d, J=8.1 Hz, 1H), 8.11 (t, J=2.1 Hz, 1H), 8.61 (d, J=2.0 Hz, 1H), 8.71 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z 344.1431 [(M+H)+ Calcd for C18H22N3O2S: 344.1433].
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]N)=[CH:11][C:10]=1[N+:17]([O-:19])=O)([C:3]([O:5]CC)=O)=[O:2].[CH3:20][N:21](C)C=O>>[C:20]([CH2:13][C:12]1[CH:11]=[C:10]2[C:9]([NH:8][C:1](=[O:2])[C:3](=[O:5])[N:17]2[OH:19])=[CH:16][CH:15]=1)#[N:21]
Reactant: CN(C)C=O
Reactant: CCOC(=O)C(=O)Nc1ccc(CN)cc1[N+](=O)[O-]
Product: N#CCc1ccc2[nH]c(=O)c(=O)n(O)c2c1
Yield: 82 %

Procedure:
A solution of 1.0 g (3.6 mmol) 4-ethoxalylamino-3-nitrobenzylamine in 30 ml dimethylformamide was hydrogenated at atm. pressure by using 100 mg 5% Pt-c as a catalyst. The reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was stirred with water and the precipitate was filtered off. The product was washed with water and 5 ml ethanol to give 0.64 g (82%) of 7-cyanomethyl-1-hydroxyquinoxaline-2,3(1H,4H)-dione. M.p. decomp. 1H-NMR (DMSO-d6): 12,3 (1H, broad s), 7.6-7.3 (3H, m), 4.2 (2H, s). IR (KBr): 2250 cm-1.
Reaction SMILES: [Cl-].[CH2:2]([NH+:9]1[CH2:13][CH:12](S(C2C=CC=CC=2)=O)[C:11]([C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=2)([C:22]([F:25])([F:24])[F:23])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1>[CH2:2]([N:9]1[CH:13]=[CH:12][C:11]([C:26]2[CH:27]=[C:28]([Cl:33])[CH:29]=[C:30]([Cl:32])[CH:31]=2)([C:22]([F:25])([F:24])[F:23])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=S(c1ccccc1)C1C[NH+](Cc2ccccc2)CC1(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)C=CN(Cc2ccccc2)C1
Yield: 34.8 %

Procedure:
1-Benzyl-3-(3,5-dichlorophenyl)-4-(phenylsulfinyl)-3-(trifluoromethyl)pyrrolidinium chloride (1.00 g, 82% purity, 1.53 mmol) is suspended in toluene (3 mL) under a nitrogen atmosphere. Sodium carbonate (810 mg, 7.65 mmol) was added and the mixture was heated to reflux for 2.5 hours. After cooling water was added, the phases were separated and the aqueous phase was extracted twice with toluene. The combined organic phases were dried over sodium sulphate, filtered and the solvent evaporated. The residue was repeatedly crystallized from n-heptane to yield 1-benzyl-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-2,3-dihydro-1H-pyrrole (198 mg, 89% purity, 31% yield).
Reaction SMILES: [BrH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2(O)[CH2:13][S:12][C:11](=[N:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:10]2[CH3:21])=[CH:5][C:4]=1[S:23](=[O:28])(=[O:27])[N:24]([CH3:26])[CH3:25]>C(O)(=O)C>[BrH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH3:21])[C:11](=[N:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[S:12][CH:13]=2)=[CH:5][C:4]=1[S:23](=[O:28])(=[O:27])[N:24]([CH3:25])[CH3:26]
Reactant: CN1C(=Nc2ccccc2)SCC1(O)c1ccc(Cl)c(S(=O)(=O)N(C)C)c1
Agent: Br
Solvent: CC(=O)O
Product: CN(C)S(=O)(=O)c1cc(-c2csc(=Nc3ccccc3)n2C)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10.1 g (0.02 mole) of 4-(4-chloro-3-dimethylsulfamoylphenyl)-3-methyl-2-phenyliminothiazolidin-4-ol hydrobromide in 80 ml of glacial acetic acid are heated to the boil over a period of 20 minutes. After cooling, crystallization is brought to completion by adding about 150 ml of diisopropyl ether, the mixture is stirred for a further one hour at room temperature and the product is filtered off. Colorless crystals; melting point 258°-260° C. (with decomposition).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:18]=[CH:17][C:16]3[C:11](=[C:12]([O:20][CH2:21][C:22]([O:24]C)=[O:23])[C:13]([CH3:19])=[CH:14][CH:15]=3)[N:10]=2)[CH2:4][CH2:3]1.[OH-].[Na+].CCOC(C)=O>CO>[OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:18]=[CH:17][C:16]3[C:11](=[C:12]([O:20][CH2:21][C:22]([OH:24])=[O:23])[C:13]([CH3:19])=[CH:14][CH:15]=3)[N:10]=2)[CH2:4][CH2:3]1
Reactant: COC(=O)COc1c(C)ccc2cnc(N[C@H]3CC[C@H](O)CC3)nc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc2cnc(N[C@H]3CC[C@H](O)CC3)nc2c1OCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl ({2-[(trans-4-hydroxycyclohexyl)amino]-7-methylquinazolin-8-yl}oxy)acetate (11 g, 0.032 mol) in MeOH (210 mL) was added 2 N aq. NaOH (81.4 mL, 0.163 mol) in one portion. The reaction mixture was stirred at room temperature overnight. TLC (EtOAc) indicated the reaction was complete. The solvent was removed in vacuo. The residue was adjusted to pH 6 with 1 N aq. HCl. The precipitate was filtered, washed with ether (30 mL×2) and dried in vacuo to give the title compound (9.8 g, 92.4%) as an off-white solid. m/e 332.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[C:6]([O:15][CH3:16])[C:7]=1[CH2:8][N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.N1C=CC=CC=1.[F:24][C:25]([F:31])([F:30])[S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([O:17][S:26]([C:25]([F:31])([F:30])[F:24])(=[O:28])=[O:27])[CH:5]=[C:6]([O:15][CH3:16])[C:7]=1[CH2:8][N:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: COc1cc(O)cc(Cl)c1CN1CCCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(OS(=O)(=O)C(F)(F)F)cc(Cl)c1CN1CCCCC1
Temperature: 25 °C
Yield: 101.1 %

Procedure:
To a stirred solution of 3-chloro-5-methoxy-4-piperidin-1-ylmethylphenol (223 mg, 0.87 mmol) and pyridine (0.28 mL, 3.5 mmol) in DCM (10 mL) at −20° C. was added trifluoromethanesulfonyl chloride (0.29 mL, 1.7 mmol). After the addition was complete the reaction mixture was allowed to warm to ambient temperature then diluted with DCM (20 mL) then washed with water (10 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford an oil that was purified by flash chromatography (silica, 12 g column, ISCO, 0-100% ethyl acetate in cyclohexane) to afford the title compound as a red oil (341 mg, 73%). 1H NMR (CDCl3, 300 MHz): 7.06 (d, J=2.3 Hz, 1H), 6.85 (d, J=2.3 Hz, 1H), 4.40 (s, 2H), 4.05 (s, 3H), 3.72-3.42 (m, 1H), 3.06-2.72 (m, 1H), 2.23-1.75 (m, 4H), 1.73-1.36 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9](Cl)[N:8]=1.[C:18]([O:22][C:23](=[O:29])[NH:24][C@@H:25]([CH3:28])[CH2:26][NH2:27])([CH3:21])([CH3:20])[CH3:19].C(N(C(C)C)CC)(C)C>C(#N)C.CCOC(C)=O>[Br:1][C:2]1[N:3]=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:27][CH2:26][C@@H:25]([NH:24][C:23](=[O:29])[O:22][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:28])[N:8]=1
Reactant: CC(C)(C)c1nc(Br)c(-c2ccnc(Cl)n2)[nH]1
Reactant: C[C@@H](CN)NC(=O)OC(C)(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](CNc1nccc(-c2[nH]c(C(C)(C)C)nc2Br)n1)NC(=O)OC(C)(C)C
Temperature: 85 °C
Yield: 127.4 %

Procedure:
A mixture of 4-(4-bromo-2-tert-butyl-1H-imidazol-5-yl)-2-chloropyrimidine (2.0 g, 4.5 mmol; Example 6, Step 4), (S)-tert-butyl-1-aminopropan-2-ylcarbamate (1.0 g, 5.8 mmol; Example 23, Step 2), and diisopropylethyl amine (2.4 mL, 13.5 mmol) in dry acetonitrile was heated at 85° C. for 16 h. An additional charge of (S)-tert-butyl-1-aminopropan-2-ylcarbamate (145 mg, 0.8 mmol) was added and the reaction was maintained at 85° C. for 5 h. After allowing to cool to rt, the reaction was diluted with EtOAc (40 mL), washed with water (2×15 mL), dried (Na2SO4), and concentrated to provide 2.6 g of (S)-tert-butyl 1-(4-(4-bromo-2-tert-butyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate which was carried forward without further purification: LCMS (m/z): 585.0 (MH+), tR=1.07 min.
Reaction SMILES: [O:1]=[C:2]1[CH:11]2[CH2:12][CH2:13]O[C:10]2=[C:9]2[C:4]([C:5]([CH3:15])=[CH:6][CH:7]=[CH:8]2)=[N:3]1.[NH2:16][C:17]1[C:18]([CH3:24])=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=1.O>C(O)COCCO>[CH3:24][C:18]1[CH:19]=[C:20]([OH:23])[CH:21]=[CH:22][C:17]=1[N:16]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([CH3:15])[C:4]=3[NH:3][C:2](=[O:1])[C:11]=2[CH2:12][CH2:13]1
Reactant: Cc1cccc2c1=NC(=O)C1CCOC=21
Reactant: Cc1cc(O)ccc1N
Solvent: O
Solvent: OCCOCCO
Product: Cc1cc(O)ccc1N1CCc2c1c1cccc(C)c1[nH]c2=O
Temperature: 250 °C
Yield: 68.5 %

Procedure:
4-Oxo-6-methyl-2,3-dihydrofuro[3,2-c]quinoline (201 mg, 1.0 mmol) was dissolved in 10 ml of diethylene glycol in a pressure tube and 4-amino-m-cresol (308 mg, 2.5 mmol) was added under nitrogen. The reaction mixture was heated at 250° C. for 15 hours. The reaction mixture was diluted in 20 ml of salt water and the aqueous layer was extracted by methylene chloride (15 ml×3). After washing with water (15 ml×3), the organic layer was dried by anhydrous magnesium sulfate and filtered, and concentrated under reduced pressure. The residue was purified with ethyl acetate as eluent by silica gel chromatography to obtain 210 mg of desired compound as solid in 81% of yield.
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:20][CH2:19][C:18]4[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=4[NH:16][C:15]3=[O:25])[CH2:10][CH2:9]2)C=CC=CC=1.[H][H]>CO.[Pd]>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:20][CH2:19][C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=3[NH:16][C:15]2=[O:25])[CH2:12][CH2:13]1
Reactant: [H][H]
Reactant: O=C1Nc2ccccc2CCN1C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: O=C1Nc2ccccc2CCN1C1CCNCC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
10.00 kg (29.81 mol, 1.0 eq) 3-[1-(phenylmethyl)-4-piperidinyl]-2,3,4,5-tetrahydro-1,3-benzodiazepin-2(1H)-one from Example 3 are dissolved in 100 L methanol, combined with 1.00 kg 10% Pd/C and hydrogenated in the pressurised reactor at 70° C. and 3 bar. After the uptake of hydrogen has ended the catalyst is filtered off and washed with 30 L methanol. The filtrate is concentrated in vacuo and the residue is suspended in 100 L acetone. Then it is refluxed, the suspension is stirred for 15 minutes at reflux temperature and half the acetone is distilled off under normal pressure. After distillation has ended the mixture is cooled to 0° C. and stirred for a further hour. The product is suction filtered, washed with 20 L acetone and dried at 50° C.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[S:8][C:7]=1[C:17]([NH2:19])=[O:18])[CH2:2][CH2:3][CH3:4].[CH3:20][C:21]([CH3:23])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH2:1]([N:5]1[C:6]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[S:8][C:7]=2[C:17](=[O:18])[NH:19][C:21]1([CH3:23])[CH3:20])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)=O
Reactant: CCCCNc1cc(-c2ccncc2)sc1C(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCCN1c2cc(-c3ccncc3)sc2C(=O)NC1(C)C
Temperature: 70 °C
Reaction time: 72 h
Yield: 70 %

Procedure:
A mixture of 3-(butylamino)-5-(pyridin-4-yl)thiophene-2-carboxamide (0.100 g, 0.400 mmol), acetone (3.0 mL), p-toluenesulfonic acid monohydrate (0.0095 g, 0.050 mmol) and acetic acid (2.0 mL) was stirred for 3 days at 70° C. in a sealed tube. The mixture was poured into sat. aqueous sodium hydrogen carbonate (100 mL). Extraction with ethyl acetate-tetrahydrofuran (2:1, 100 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure gave an oil. The oil was purified by column chromatography (Combiflash, 12 g silica gel, hexane to ethyl acetate) to afford the title compound (0.0879 g, 70%) as a yellow solid:
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])[C:22]3=[O:25])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C:35]1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1.CC1C=CC(C(Cl)=O)=CC=1.FC1C=C(F)C=CC=1C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)=O>>[CH3:32][CH:31]([CH3:33])[C@H:26]([N:21]1[CH2:20][C:19]2[C:23](=[CH:24][C:16]([C:13]3[CH:12]=[CH:11][C:10]([NH:9][C:1](=[O:8])[C:2]4[CH:3]=[CH:4][C:5]([CH3:35])=[CH:6][CH:7]=4)=[CH:15][CH:14]=3)=[CH:17][CH:18]=2)[C:22]1=[O:25])[C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(F)cc4F)cc3)cc2C1=O
Agent: Cc1ccc(C(=O)Cl)cc1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C)cc4)cc3)cc2C1=O

Procedure:
The compound of example 111 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 4-methylbenzoyl chloride. The compound of example 111 was used directly without isolation for the preparation of compound of example 110.