Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]3)=[O:13])[C:6]=2[CH:21]=1.[CH3:22][N:23]=[C:24]=[O:25]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:15][CH2:16][CH:17]([O:20][C:24](=[O:25])[NH:23][CH3:22])[CH2:18][CH2:19]3)=[O:13])[C:6]=2[CH:21]=1
Reactant: CN=C=O
Reactant: O=C(Cn1c(=O)sc2ccc(Cl)cc21)N1CCC(O)CC1
Solvent: c1ccncc1
Product: CNC(=O)OC1CCN(C(=O)Cn2c(=O)sc3ccc(Cl)cc32)CC1
Temperature: 30 °C
Reaction time: 15 h
Yield: 71.8 %

Procedure:
5-Chloro-3-(4-hydroxypiperidinocarbonylmethyl)benzothiazolin-2-one (3.2 g) was dissolved in dry pyridine (15 ml) and the solution was cooled. After methyl isocyanate (0.9 g) was dropwise added to the solution, the resultant was stirred for 15 hours at 30° C. Pyridine was evaporated off under vacuum from the reaction mixture and the residue was recrystallized from methanol to yield the title compound as colorless crystals (2.7 g). mp 202°-203° C.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[N:9][N:10]([C@H:11]([CH2:16][O:17][CH3:18])[CH2:12][CH2:13][O:14][CH3:15])[C:6]=2[CH:5]=[C:4]([CH3:19])[N:3]=1.[Br:20][C:21]1[CH:22]=[C:23]2[C:27](=[C:28]([Br:30])[CH:29]=1)[NH:26][CH2:25][CH2:24]2.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].O>C1COCC1>[Br:20][C:21]1[CH:22]=[C:23]2[C:27](=[C:28]([Br:30])[CH:29]=1)[N:26]([C:2]1[C:7]3[N:8]=[N:9][N:10]([C@H:11]([CH2:16][O:17][CH3:18])[CH2:12][CH2:13][O:14][CH3:15])[C:6]=3[CH:5]=[C:4]([CH3:19])[N:3]=1)[CH2:25][CH2:24]2
Reactant: Brc1cc(Br)c2c(c1)CCN2
Reactant: COCC[C@@H](COC)n1nnc2c(Cl)nc(C)cc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCC[C@@H](COC)n1nnc2c(N3CCc4cc(Br)cc(Br)c43)nc(C)cc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85.5 %

Procedure:
(S)-4-chloro-1-(1-methoxymethyl-3-methoxypropyl)-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine (0.72 g, 2.54 mmol) and 5,7-dibromoindoline (0.72 g, 2.60 mmol) were dissolved in anhydrous THF (6 mL) and cooled in an ice bath. To that a 1 M solution of NaHMDS in THF (3.0 mL, 3.0 mmol) was added and the reaction was stirred for 20 min, allowed to warm to 25° C. and stirred for 3 h. Then water (30 mL) was added and the mixture was extracted twice with EtOAc (80 and 40 mL). The combined organic extracts was washed with brine (30 mL) dried (MgSO4) and stripped in vacuo. The residue was chromatographed on silica gel using 40% EtOAc/hexanes as eluent to give the product (1.14 g, 85% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)[CH:7]=1.O.O.O.O.O.O.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=[O:24].[Mg+2]>CC(O)C>[Br:1][C:2]1[CH:3]=[N+:4]([O-:24])[CH:5]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)[CH:7]=1
Reactant: Cn1cc(-c2cncc(Br)c2)cn1
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: [Mg+2]
Solvent: CC(C)O
Solvent: O
Product: Cn1cc(-c2cc(Br)c[n+]([O-])c2)cn1

Procedure:
A slurry of 266 mg (1.12 mmol) 3-bromo-5-(1-methyl-1H-pyrazol-4-yl)-pyridine and 1.30 g (2.23 mmol) magnesium monoperoxyphthalate hexahydrate (85%) in 5 ml 2-propanol was stirred for 18 hours at room temperature. The reaction mixture was evaporated and the residue partitioned between saturated sodium bicarbonate solution and dichloromethane. The organic phase was dried over sodium sulfate and evaporated yielding 3-bromo-5-(1-methyl-1H-pyrazol-4-yl)-pyridine 1-oxide as slightly yellow solid; HPLC-MS: 1.34 min, [M+H] 254/256.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3([CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:44])[C@H:19]([NH:30][C:31](=[O:43])[C:32]([NH:35]C(=O)OC(C)(C)C)([CH3:34])[CH3:33])[CH2:20][C:21]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[NH:23][CH:22]=4)[CH2:13]3)[C:11](=[O:45])[N:10]([CH3:46])[CH2:9]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.CO>C(Cl)Cl>[NH2:35][C:32]([CH3:34])([CH3:33])[C:31]([NH:30][C@H:19]([CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1)[C:18]([N:14]1[CH2:15][CH2:16][CH2:17][C:12]2([C:11](=[O:45])[N:10]([CH3:46])[CH2:9][CH:8]2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:13]1)=[O:44])=[O:43]
Reactant: CN1CC(c2ccc(F)cc2)C2(CCCN(C(=O)[C@@H](Cc3c[nH]c4ccccc34)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CN1CC(c2ccc(F)cc2)C2(CCCN(C(=O)[C@@H](Cc3c[nH]c4ccccc34)NC(=O)C(C)(C)N)C2)C1=O

Procedure:
A mixture comprising tert-butyl 1-((2R)-1-(4-(4-fluorophenyl)-2-methyl-1-oxo-2,7-diazaspiro[4.5]decan-7-yl)-3-(1H-indol-3-yl)-1-oxopropan-2-ylamino)-2-methyl-1-oxopropan-2-ylcarbamate (312.3 mg, 0.493 mmol) (step 1) and TFA (0.380 ml, 4.93 mmol) in DCM (3 ml) was stirred at room temperature for 17 hours. TFA (1 mL, 13 mmol) was added to the reaction mixture. After 3 h 45 min the solvent was removed in vacuo to afford a colourless oil. The oil was dissolved with methanol (3 ml) and passed through a 10 g SCX-2 cartridge eluting with 2M NH3 in methanol (70 ml). The solvent was removed in vacuo to yield the title compound as diastereomeric mixture.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10])=[O:5])[CH3:2].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19]>>[NH2:10][C:9]1[C:8]2[C:7](=[CH:14][C:13]([F:15])=[CH:12][CH:11]=2)[N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:17]=1[C:18](=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: CCOC(=O)Nc1cc(F)ccc1C#N
Product: CCOC(=O)n1c(C(=O)c2ccccc2)c(N)c2ccc(F)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 2-[(ethoxycarbonyl)amino]-4fluorobenzonitrile (step 1) and 2-bromoacetophenone.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.[CH2:11]([N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][N:26]=2)[C:21](Cl)=[CH:20][C:19]1=[O:29])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C=O)C>[CH2:11]([N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][N:26]=2)[C:21]([S:10][C:7]2[CH:8]=[CH:9][C:4]([Br:3])=[CH:5][CH:6]=2)=[CH:20][C:19]1=[O:29])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=c1cc(Cl)c2cccnc2n1Cc1ccccc1
Reactant: Sc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1cc(Sc2ccc(Br)cc2)c2cccnc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.2 %

Procedure:
To a suspension of NaH (24 mg, 1 mmol) in DMF (4 mL) was added 4-bromobenzenethiol (189 mg, 1 mmol) at 0° C. After being stirred at rt for 10 min, a solution of 1-benzyl-4-chloro-1H-[1,8]naphthyridin-2-one (135 mg, 0.5 mmol) in DMF (1 mL) was introduced at rt. The reaction was quenched by adding water followed by extracting with EtOAc. The organic layer was washed with brine and dried over Na2SO4. Column chromatography of the concentrated residue gave 210 mg of product (yield: 100%): 1H NMR (500 MHz, CDCl3) δ 8.63 (d, J=5.0 Hz, 1H), 8.21 (d, J=8.0 Hz, 1H), 7.62 (d, J=8.5 Hz, 2H), 7.46 (d, J=7.5 Hz, 2H), 7.43 (d, J=8.5 Hz, 2H), 7.25 (t, J=7.5 Hz, 2H), 7.21 (dd, J=8.0, 5.0 Hz, 1H), 7.20 (t, J=8.0 Hz, 1H), 6.10 (s, 1H), 5.70 (s, 2H); 13C NMR (125 MHz, CDCl3) 161.65, 150.77, 149.42, 148.87, 137.85, 137.46, 133.78, 132.97, 128.82, 128.47, 127.38, 126.81, 125.50, 118.09, 117.66, 114.65, 44.20; LCMS (EI) m/z 422.8 (M+), 424.8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:9]([CH2:18][NH2:19])[O:8][C:7]=2[CH:20]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22].Cl>N1C=CC=CC=1.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:9]([CH2:18][NH:19][C:21](=[O:23])[CH3:22])[O:8][C:7]=2[CH:20]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2c(c1)OC(CN)=C(c1ccccc1)O2
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc2c(c1)OC(CNC(C)=O)=C(c1ccccc1)O2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.2 g (0.74 mmol) of the amine obtained in Step C is dissolved in 3 ml of anhydrous pyridine; the solution is then cooled to 0° C. After addition of 0.085 ml (0.89 mmol) of acetic anhydride, the reaction medium is stirred for 1 hour at 0° C. The solution is then diluted with dichloromethane and then acidified with a hydrochloric acid solution (1N). The aqueous phase is extracted with dichloromethane; the organic phase is then dried over magnesium sulphate. After evaporation of the solvent in vacuo, the residue obtained is purified on a silica column (eluant:AcOEt/PE:60/40) to yield the title amide in the form of a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]([C:14]1[N:15]=[CH:16][N:17]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:18]=1)[CH2:6][C:7]1[CH:8]=[N:9][C:10]([NH2:13])=[CH:11][CH:12]=1)[CH3:2].C(OC(=O)[C@H](C1N=CN(C2CCCCC2)C=1)CC1C=NC(N)=CC=1)C>C(O)C>[CH2:1]([O:3][C:4](=[O:25])[C@@H:5]([C:14]1[N:15]=[CH:16][N:17]([CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[CH:18]=1)[CH2:6][C:7]1[CH:8]=[N:9][C:10]([NH2:13])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(N)nc1)c1cn(C2CCCCC2)cn1
Agent: CCOC(=O)[C@@H](Cc1ccc(N)nc1)c1cn(C2CCCCC2)cn1
Solvent: CCO
Product: CCOC(=O)[C@H](Cc1ccc(N)nc1)c1cn(C2CCCCC2)cn1

Procedure:
Batches containing 540 g of 3-(6-Amino-pyridin-3-yl)-2-(1-cyclohexyl-1H-imidazol-4-yl)-propionic acid ethyl ester were filled into a column containing 20 kg of Chiralpack AD 20 μm (Ciral Technologies Europe, France) as a chiral stationary phase. Ethanol was pumped through the column until no more (S)-3-(6-Amino-pyridin-3-yl)-2-(1-cyclohexyl-1H-imidazol-4-yl)-propionic acid ethyl ester was eluted. Then a mixture containing ethanol with 0.4% of trifluoroacetic acid were pumped through the column and fractions containing (R)-3-(6-Amino-pyridin-3-yl)-2-(1-cyclohexyl-1H-imidazol-4-yl)-propionic acid ethyl ester were collected. The received title compound showed a purity of 91.7% and an ee of 99.2%. The purity was determined by the chromatography described in Example 8.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[F:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.[Na].[CH3:22][CH:23]1[O:28][CH2:27][CH2:26][N:25]([C:29]2[N:30]=[C:31]([CH2:36][C:37](O)=[O:38])[NH:32][C:33](=[O:35])[CH:34]=2)[CH2:24]1>CN(C)C=O.N1C=CC=CC=1>[F:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:37](=[O:38])[CH2:36][C:31]2[NH:32][C:33](=[O:35])[CH:34]=[C:29]([N:25]3[CH2:26][CH2:27][O:28][CH:23]([CH3:22])[CH2:24]3)[N:30]=2)=[CH:16][CH:15]=1
Reactant: CC1CN(c2cc(=O)[nH]c(CC(=O)O)n2)CCO1
Reactant: Nc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC1CN(c2cc(=O)[nH]c(CC(=O)Nc3ccc(F)cc3)n2)CCO1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.46 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride, 6.7 ml of pyridine and 0.7 ml of 4-fluoroaniline are added to a solution of 700 mg of sodium salt of [4-(2-methylmorpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetic acid in 6.7 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 24 hours and then concentrated under reduced pressure. Water and ethyl acetate are added and the resulting mixture is stirred for 30 minutes. The precipitate formed is filtered off and washed with dichloromethane and with ethyl ether, so as to give 300 mg of N-(4-fluorophenyl)-2-[4-(2-methylmorpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [Br:1]Br.C([O-])(=O)C.[K+].[C:8]([C:10]1[CH:11]=[C:12]([C:17]2[N:18]=[C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[S:20][CH:21]=2)[CH:13]=[C:14]([F:16])[CH:15]=1)#[N:9].S([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[Br:1][C:21]1[S:20][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:18][C:17]=1[C:12]1[CH:13]=[C:14]([F:16])[CH:15]=[C:10]([C:8]#[N:9])[CH:11]=1
Reactant: CCOC(=O)c1nc(-c2cc(F)cc(C#N)c2)cs1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=S([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CCOC(=O)c1nc(-c2cc(F)cc(C#N)c2)c(Br)s1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
At room temperature, 12.8 g (79.8 mmol) of bromine and 7.83 g (79.8 mmol) of potassium acetate are added to 2.21 g (7.98 mmol) of the compound from Example 24A in 75 ml of conc. acetic acid. The mixture is stirred at 100° C. for 12 h, whereby after 6 and 9 h the same amounts of bromine (in each case 12.8 g, 79.8 mmol) and potassium acetate (in each case 7.83 g, 79.8 mmol) are again added. A 1M aqueous sodium sulfite solution is subsequently added, and the reaction solution is extracted with dichloromethane. The combined organic phases are dried over MgSO4, filtered and concentrated under reduced pressure. The crude product is purified by flash chromatography (mobile phase: cyclohexane/ethyl acetate 20:1→10:1). 2.31 g (78% of theory) of the title compound are obtained.
Reaction SMILES: [N:1]1([CH:7]([C:11]2[CH:15]=[CH:14][S:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[N:41]12[CH2:48][CH2:47][CH:44]([CH2:45][CH2:46]1)[C@@H:43](O)[CH2:42]2>C1COCC1.CN(C=O)C>[N:1]1([CH:7]([C:11]2[CH:15]=[CH:14][S:13][CH:12]=2)[C:8]([O:10][C@@H:43]2[CH:44]3[CH2:47][CH2:48][N:41]([CH2:46][CH2:45]3)[CH2:42]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(O)C(c1ccsc1)N1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(O[C@H]1CN2CCC1CC2)C(c1ccsc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 58.4 %

Procedure:
A mixture of 2-(piperidin-1-yl)-2-(thiophen-3-yl)acetic acid 21c (250 mg, 1.11 mmol), DCC (458 mg, 2.22 mmol), HOBT (340 mg, 2.22 mmol) and (R)-quinuclidin-3-ol (282 mg, 2.22 mmol) in dry THF (11.1 ml) and dry DMF (5.5 ml) was stirred at room temperature under nitrogen for 48 hours. The solvent was evaporated and the crude was purified by flash chromatography (DCM/MeOH=97/3+0.3% NH4OH). The product was triturated with THF (10 ml) to obtain the title compound (217 mg, 58.5% yield) as a colorless oil.
Reaction SMILES: [OH:1][CH:2]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([C:20](OC(C)C)=[O:21])[CH:14]=[CH:13]2)[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[CH3:9].[Li]>O1CCCC1>[OH:21][CH2:20][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([CH:2]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[CH3:9])[OH:1])[CH:19]=[CH:18]2
Reactant: Cc1ccncc1C(O)c1ccc2cc(C(=O)OC(C)C)ccc2c1
Agent: [Li]
Solvent: C1CCOC1
Product: Cc1ccncc1C(O)c1ccc2cc(CO)ccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.6 %

Procedure:
0.3 g (0.9 mmol) of isopropyl 6-[1-hydroxy-1-(4-methyl-3-pyridyl)methyl]-2-napthoate in 5 ml of absolute tetrahydrofuran is added, at 0° C., to 38 mg (1 mmol) of lithium alanate in 1 ml of absolute tetrahydrofuran, and the mixture is then stirred at room temperature (24 h). After addition of a further 40 mg (1 mmol) of lithium alanate the mixture is stirred at room temperature for 24 h. Excess lithium alanate is destroyed with 2 N HCl, and the solution is neutralized with sodium bicarbonate solution. It is extracted with ethyl acetate, and this is evaporated, and the residue is chromatographed on silica gel using ethyl acetate/methanol 4:1. 0.16 g (65%) of 1-(6-hydroxymethyl-2-naphthyl)-1-(4-methyl-3-pyridyl)methanol is obtained. Melting point 151°-3° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.Cl.[NH:26]1[CH2:31][CH2:30][S:29](=[O:33])(=[O:32])[CH2:28][CH2:27]1.C(N(CC)CC)C.O>C1COCC1.CN(C1C=CN=CC=1)C>[OH2:10].[O:32]=[S:29]1(=[O:33])[CH2:30][CH2:31][N:26]([C:19]([C:18]2[CH:17]=[N:16][C:15]([O:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:9][O:10][C:11]=3[CH3:24])=[CH:23][CH:22]=2)=[O:21])[CH2:27][CH2:28]1
Reactant: O=S1(=O)CCNCC1
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)N2CCS(=O)(=O)CC2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-[3-(4-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (23.0 g, 70.1 mmol) and 1,1-carbonyldiimidazole (15.3 g, 94.6 mol, 1.35 eq.) were dissolved in THF (120 mL) and the resulting solution was stirred for one hour at room temperature. This solution was then added to a suspension of thiomorpholine-1,1-dioxide HCl (16.9 g, 98.5 mmol), DMAP (400 mg, 3.27 mmol) and triethylamine (9.78 g, 96.7 mmol) in THF (120 mL). The resulting mixture was heated to reflux temperature and subsequently stirred at this temperature for 50 hours. The mixture was cooled to room temperature and then treated within one hour with water (300 mL). From the resulting suspension THF was distilled off under reduced pressure and with a jacket temperature of 60° C. and continuously replaced by ethanol (426 g) at constant volume. The suspension was cooled to room temperature and stirred for 2 hours. The crystals were filtered off, washed with a mixture of ethanol (100 mL) and water (100 mL) and subsequently dried at 55° C./<25 mbar until constant weight to afford 28.9 g (92%) of Form B as a colorless solid with purity of 99.7% (area) as measured by HPLC.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][CH:11]([F:41])[C:12]1[N:16]([C:17]2[N:22]=[C:21]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:20]=[C:19]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:18]=2)[C:15]2[CH:35]=[CH:36][CH:37]=[C:38]([O:39][CH3:40])[C:14]=2[N:13]=1.[Cl-].Cl[S:44]([CH2:47][CH2:48][C:49]1[CH:54]=[CH:53][NH+:52]=[CH:51][CH:50]=1)(=[O:46])=[O:45].O>C(Cl)Cl>[F:41][CH:11]([F:10])[C:12]1[N:16]([C:17]2[N:22]=[C:21]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[N:20]=[C:19]([N:29]3[CH2:34][CH2:33][N:32]([S:44]([CH2:47][CH2:48][C:49]4[CH:50]=[CH:51][N:52]=[CH:53][CH:54]=4)(=[O:45])=[O:46])[CH2:31][CH2:30]3)[N:18]=2)[C:15]2[CH:35]=[CH:36][CH:37]=[C:38]([O:39][CH3:40])[C:14]=2[N:13]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCNCC2)nc(N2CCOCC2)n1
Reactant: O=S(=O)(Cl)CCc1cc[nH+]cc1
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(=O)(=O)CCc3ccncc3)CC2)n1
Reaction time: 3 h
Yield: 64.8 %

Procedure:
DIPEA (0.29 mL, 1.66 mmol) was added to a suspension of 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (Example 2) (150 mg, 0.336 mmol) and 4-[2-(chlorosulfonyl)ethyl]pyridinium chloride (122 mg, 0.504 mmol) in CH2Cl2 (10 mL) at room temperature under nitrogen, and the mixture was stirred for 3 hrs. Additional 4-[2-(chlorosulfonyl)ethyl]pyridinium chloride (41 mg, 0.169 mmol) was added and the mixture stirred for another 21 hrs. Water was added and the phases were separated. The aqueous phase was extracted with CH2Cl2 (1×), the combined organic extracts were dried (Na2SO4), and the solvent was removed under vacuum. Chromatography on silica eluting with CH2Cl2/MeOH (100:0 to 98:2) followed by recrystallization from CH2Cl2/MeOH gave 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[2-(4-pyridinyl)ethyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (134 mg, 65%).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH2:10][O:11][CH:12]2[CH2:15][CH2:14][CH2:13]2)=[CH:4][C:3]=1[O:16][CH3:17].C([Li])CCC.[B:23](OC)([O:26]C)[O:24]C.[Cl-].[NH4+]>C(OCC)(=O)C.C1COCC1>[CH:12]1([O:11][CH2:10][C:5]2[CH:6]=[C:7]([O:8][CH3:9])[C:2]([B:23]([OH:26])[OH:24])=[C:3]([O:16][CH3:17])[CH:4]=2)[CH2:15][CH2:14][CH2:13]1
Reactant: COB(OC)OC
Reactant: COc1cc(COC2CCC2)cc(OC)c1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(COC2CCC2)cc(OC)c1B(O)O
Reaction time: 1 h
Yield: 42.8 %

Procedure:
To a mixture of 2-bromo-5-[(cyclobutyloxy)methyl]-1,3-dimethoxybenzene (2.39 g, 7.94 mmol) and THF (20 mL) was added n-butyllithium (2.73 M solution in n-hexane: 3.49 mL, 9.53 mmol) at −78° C. (internal temperature), and the mixture was stirred for 1 hour. After then adding trimethyl borate (1.07 mL, 9.53 mmol) to the mixture, the temperature was slowly raised to room temperature while stirring. A saturated aqueous solution of ammonium chloride was added to the reaction mixture while cooling on ice, and then ethyl acetate was added. After thoroughly shaking the mixture, the organic layer was separated and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The mixture was filtered, and then the solvent in the filtrate was distilled off under reduced pressure. Heptane (30 mL) was added to the residue, the precipitated solid was collected by filtration and dried under reduced pressure to obtain the title compound (905 mg, 3.40 mmol).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:39])/[C:11](/[CH2:27][O:28][C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=[CH:31][CH:30]=2)=[CH:12]/[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([NH:19][O:20]C2CCCCO2)=[O:18])[CH:5]=[CH:4][N:3]=[CH:2]1.FC(F)(F)C(O)=O.CO.ClCCl>CO>[N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:39])/[C:11](/[CH2:27][O:28][C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=[CH:31][CH:30]=2)=[CH:12]/[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([NH:19][OH:20])=[O:18])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(CCCC/C=C(\COc1cccc2ccccc12)C(=O)NCCCn1ccnc1)NOC1CCCCO1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C(CCCC/C=C(\COc1cccc2ccccc12)C(=O)NCCCn1ccnc1)NO
Temperature: 25 °C
Yield: 36.8 %

Procedure:
(E)-N1-(3-(1H-imidazol-1-yl)propyl)-2-((naphthalen-1-yloxy)-methyl)-N8-(tetrahydro-2H-pyran-2-yloxy)-2-octenediamide (203 mg, 0.38 mM) obtained in Example (2-1-3) was dissolved in methanol (2 ml), and trifluoroacetic acid (146 μl, 1.90 mM) was slowly added thereto at 0° C. Then, the resulting mixture was heated to room temperature and reacted for 18 hrs. After the completion of reaction, the solvent was removed under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography (eluent: methanol/dichloromethane=1/9) to obtain 63 mg of the title compound (yield 37%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15](=O)/[CH:16]=[CH:17]/[N:18](C)C)=[N:9]2)=[CH:4][CH:3]=1.[Cl:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([NH:33]N)=[CH:25][CH:24]=1>>[Cl:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([N:33]2[C:15]([C:10]3[C:11](=[O:14])[CH:12]=[CH:13][N:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[N:9]=3)=[CH:16][CH:17]=[N:18]2)=[CH:25][CH:24]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(Cl)cc2)ccc1=O
Reactant: NNc1ccc(Cl)c2ccccc12
Product: O=c1ccn(-c2ccc(Cl)cc2)nc1-c1ccnn1-c1ccc(Cl)c2ccccc12

Procedure:
The product was obtained starting from 1-(4-Chloro-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-24) and (4-chloro-naphthalen-1-yl)-hydrazine according to the method described for example 1. MS: M=433.1 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[C:21]2[CH2:20][CH2:19][CH2:18][C@@H:17]([NH2:22])[C:16]=2[CH:15]=[N:14][CH:13]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[C:12]1[C:21]2[CH2:20][CH2:19][CH2:18][C@@H:17]([NH:22][S:24]([CH3:23])(=[O:26])=[O:25])[C:16]=2[CH:15]=[N:14][CH:13]=1
Reactant: N[C@@H]1CCCc2c(-c3ccc(C(F)(F)F)cc3F)cncc21
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)N[C@@H]1CCCc2c(-c3ccc(C(F)(F)F)cc3F)cncc21
Yield: 60 %

Procedure:
In analogy to the procedure described for the preparation of example 2, (+)-(R)-4-(2-fluoro-4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroisoquinolin-8-amine (example 74) and methanesulfonyl chloride gave the title compound as white solid in 60% yield. MS: 389.1 (M+H+).