Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)=O.[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][CH:14]([NH:29]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:15][NH:16][C:17](=[O:28])[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])=[CH:5]1>C(Cl)Cl>[NH2:29][CH:14]([CH2:13][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][CH:5]=1)[CH2:15][NH:16][C:17](=[O:28])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27]
Reactant: COc1ccccc1CCC(=O)NCC(Cc1c[nH]c2ccccc12)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: O=CO
Product: COc1ccccc1CCC(=O)NCC(N)Cc1c[nH]c2ccccc12
Reaction time: 4 h
Yield: 90 %

Procedure:
Formic acid 9.0 ml, 238.540 mmoles) was added to a stirring solution of 3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]-2-(N-triphenylmethylamino)propane (14.11 g, 23.763 mmoles) in anhydrous methylene chloride under a nitrogen atmosphere at 0° C. After 4 hours, the reaction mixture was concentrated to an oil on a rotary evaporator and redissolved in diethyl ether and 1.0N hydrochloric acid. The aqueous layer was washed twice with diethyl ether and basified with sodium hydroxide to a pH greater than 12. The product was extracted out with methylene chloride (4×). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated on a rotary evaporator to a white foam. The compound 2-amino-3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]propane (7.52 g, 21.397 mmols) was isolated giving a 90% yield. No further purification was necessary.
Reaction SMILES: [C:1]1([CH:7]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([CH:25]=[C:26]([C:28]([CH3:33])([CH3:32])[C:29]([OH:31])=[O:30])[N:27]=4)[N:24]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:41]>CO.CC(O)C>[C:34]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([CH:25]=[C:26]([C:28]([CH3:33])([CH3:32])[C:29]([O-:31])=[O:30])[N:27]=4)[N:24]=3)[CH2:13][CH2:14]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[Na+:41]
Reactant: CC(C)(C(=O)O)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)O
Product: CC(C)(C(=O)[O-])c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]imidazo[1,2-b]pyridazin-2-yl]-2-methylpropionic acid (528 mg) in methanol (2 ml), a 2N aqueous solution of sodium hydroxide (0.47 ml) was added, followed by stirring at room temperature for 5 minutes. This solution was diluted with 2-propanol and concentrated under reduced pressure. The residue was dissolved in 2-propanol and again concentrated under reduced pressure. To this residue, 2-propanol and ethyl ether were added; the resulting powder was collected by filtration to yield the title compound (474 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][NH:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:7].[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>C(O)C>[N:15]1([CH2:2][CH2:3][CH2:4][NH:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:7])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1
Reactant: C1CNCCN1
Reactant: CCCCCCNC(=O)NCCCCl
Solvent: CCO
Product: CCCCCCNC(=O)NCCCN1CCNCC1
Yield: 39 %

Procedure:
A mixture of 1-(3-chloropropyl)-3-n-hexylurea (11.0 g; 50 mmole), piperazine (43.0 g; 500 mmole) and reagent ethanol (250 ml) was refluxed for 2 hours. The solvent was removed in vacuo, and the solid residue was dissolved in water. The resulting solution was extracted with methylene chloride, concentrated in vacuo, and the residue was chromatographed on silica gel to give 1-(3-piperazinylpropyl)-3-n-hexylurea as a light yellow oil (6.7 g; 39% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2[S:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:5]=2[CH:4]=1.C1C2C3C=CC=CC=3[O:21][C:20]=2[CH:19]=CC=1>>[C:20]([C:15]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[S:7][C:6]=2[CH:14]=1)(=[O:21])[CH3:19]
Reactant: c1ccc2c(c1)oc1ccccc12
Reactant: COc1ccc2sc3ccccc3c2c1
Product: COc1cc2c(cc1C(C)=O)sc1ccccc12
Yield: 55 %

Procedure:
The 2-methoxydibenzothiophene was subjected to a Friedel-Crafts acetylation as described for the corresponding dibenzofuran (as in Routier et al., supra) to give 55% of 3-acetyl-2-methoxy-dibenzothiophene, m.p. 163.4°-164.9° after recrystallization from a mixture of heptane and toluene. The PMR spectrum, 200 MHz, supported the structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([NH:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:24][O:25][C:26](=[O:37])[C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]([N:34]=[C:35]=[O:36])[CH:28]=1.CCN(CC)CC>ClCCCl>[CH3:24][O:25][C:26](=[O:37])[C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]([NH:34][C:35]([N:17]([C:16]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[C:10]3[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]3)[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:36])[CH:28]=1
Reactant: COC(=O)c1ccc(C)c(N=C=O)c1
Reactant: Clc1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C)c(NC(=O)N(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c1

Procedure:
In analogy to the procedure described in example 1.2, [2-(4-chloro-phenyl)-2H-indazol-3-yl]-cyclohexyl-amine (example 9.1) was reacted with 3-isocyanato-4-methyl-benzoic acid methyl ester in 1,2-dichloroethane in the presence of Et3N (2.2 eq.) for 3 days under reflux conditions to give the title compound as yellow oil. MS: m/e=517.2 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][C:21]([N+:27]([O-:29])=[O:28])=[CH:22][CH:23]=4)[NH:18][C:17]3=S)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[OH-:33].[K+].O.OO>C(O)C.C(O)(=O)C>[F:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][C:21]([N+:27]([O-:29])=[O:28])=[CH:22][CH:23]=4)[NH:18][C:17]3=[O:33])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCn2c(=S)[nH]c3cc([N+](=O)[O-])ccc3c2=O)CC1
Agent: OO
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: O=C(c1ccc(F)cc1)C1CCN(CCn2c(=O)[nH]c3cc([N+](=O)[O-])ccc3c2=O)CC1
Reaction time: 2.5 h

Procedure:
To a stirred mixture of 7 parts of 3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,3-dihydro-7-nitro-2-thioxo-4(1H)-quinazolinone, 120 parts of a solution of potassium hydroxide in ethanol 5% and 10 parts of water were added dropwise 100 parts of a hydrogen peroxide solution 3% during a 10 minutes period. Upon completion, stirring was continued for 2.50 hours at room temperature. Then there were added 100 parts of water and the whole was neutralized with acetic acid. The precipitated product was filtered off and crystallized from a mixture of N,N-dimethylacetamide and water, yielding 4.8 parts of 3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-7-nitro-2,4(1H,3H)-quinazolinedione; mp. 238.1°-240.1° C. (23).
Reaction SMILES: CC([NH:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([F:12])[CH:6]=1)=O.[N+:13]([O-])([O-:15])=[O:14].[K+]>S(=O)(=O)(O)O>[N+:13]([C:10]1[CH:9]=[C:8]([F:11])[C:7]([F:12])=[CH:6][C:5]=1[NH2:4])([O-:15])=[O:14]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(=O)Nc1ccc(F)c(F)c1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 1 h
Yield: 62.1 %

Procedure:
To a solution of 3,4-difluoroacetanilide (85.5 g) in sulfuric acid (850 ml) is added gradually with stirring potassium nitrate (55.5 g) at room temperature during which the temperature raises to 60° C. The mixture is stirred at 60° C. for one hour. The reaction mixture is poured into ice water, and the precipitated crystals are taken by filtration. The precipitates are dissolved in dichloromethane and washed with aqueous sodium hydrogen carbonate, water and aqueous saturated sodium chloride in this order and dried. The solvent is removed by concentration and washed with n-hexane. The resulting crystals are taken by filtration and dried to give 2-nitro-4,5-difluoroaniline (54 g).
Reaction SMILES: S(Cl)(Cl)=O.C(O)(=O)CCCCCCCCCCC.C(Cl)(=O)CCCCCCCCCCC.[C:33]([N:46]=[C:47]=[S:48])(=[O:45])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44].[CH3:49][O:50][C:51]1[CH:52]=[C:53]2[C:58](=[CH:59][C:60]=1[O:61][CH3:62])[N:57]=[CH:56][CH:55]=[C:54]2[O:63][C:64]1[CH:70]=[CH:69][C:67]([NH2:68])=[CH:66][CH:65]=1>C(O)C.C1(C)C=CC=CC=1>[CH3:49][O:50][C:51]1[CH:52]=[C:53]2[C:58](=[CH:59][C:60]=1[O:61][CH3:62])[N:57]=[CH:56][CH:55]=[C:54]2[O:63][C:64]1[CH:65]=[CH:66][C:67]([NH:68][C:47]([NH:46][C:33](=[O:45])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[S:48])=[CH:69][CH:70]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CCCCCCCCCCCC(=O)N=C=S
Agent: CCCCCCCCCCCC(=O)Cl
Agent: CCCCCCCCCCCC(=O)O
Solvent: O=S(Cl)Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCC(=O)NC(=S)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available dodecanoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and dodecanoyl isothiocyanate was prepared using the resultant dodecanoyl chloride as a starting compound according to the description of the literature. Dodecanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (58 mg, yield 60%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])=[CH:12][CH:11]=2)[C:5]([C:27]#[N:28])=[C:4]([S:29][CH2:30][C:31]2[N:32]=[C:33]([C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=3)[S:34][CH:35]=2)[N:3]=1.[H-].[Na+].Br[CH2:46][C:47]([O:49][CH3:50])=[O:48].[OH2:51]>CN(C=O)C>[NH2:9][C:8]1[C:7]2[C:2](=[N:3][C:4]([S:29][CH2:30][C:31]3[N:32]=[C:33]([C:36]4[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][CH:41]=4)[S:34][CH:35]=3)=[C:5]([C:27]#[N:28])[C:6]=2[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:24])[CH3:25])([CH3:22])[CH3:21])=[CH:12][CH:11]=2)[N:1]([CH2:46][C:47]([O:49][CH3:50])=[O:48])[C:12]=1[C:13]([O:16][CH3:17])=[O:51]
Reactant: O
Reactant: COC(=O)CBr
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(-c2c(C#N)c(N)nc(SCc3csc(-c4ccc(Cl)cc4)n3)c2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(C(=O)OC)c(N)c2c(-c3ccc(OCCO[Si](C)(C)C(C)(C)C)cc3)c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon, 230 mg (0.363 mmol) of the compound from Example 32A were initially charged in 4 ml of DMF, 17 mg (60% pure, 0.435 mmol) of sodium hydride were added a little at a time and the mixture was then stirred at RT for 30 min. A solution of 41 μl (0.435 mmol) of methyl bromoacetate in 1 ml of DMF was then added dropwise, and the resulting solution was stirred at RT overnight. Water was added, and the reaction mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated. The residue was purified by preparative HPLC (Chromasil, water/acetonitrile).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C1(C)C=CC=CC=1.[CH3:19][O:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1O.C(=O)([O-])[O-:30].[Cs+].[Cs+]>O.CCOC(C)=O>[Br:11][C:8]1[CH:9]=[CH:10][C:2]([O:30][C:24]2[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:26][C:25]=2[F:27])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(Br)ccc1Br
Reactant: O=C([O-])[O-]
Reactant: COc1cc(F)ccc1O
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(Oc2ccc(Br)cc2C(=O)O)c(F)c1
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 78.2 %

Procedure:
A dry 100 L glass jacketed reactor equipped with an addition funnel, reflux condenser, solids addition system and temperature probe was charged with 2,5-dibromobenzoic acid (2685 g, 9.6 mol) and copper (I) triflate toluene complex (2:1, 50.0 g, 0.2 mol). Toluene (30 L) and EtOAc (20 mL) were then charged, followed by 2-methoxy-4-fluorophenol (1500 g, 10.6 mol). With vigorous stirring cesium carbonate (6258 g, 19.2 mol) was added in portions. The mixture was heated to 90° C. for 4 hours. The mixture was cooled to 35° C. and water (15 L) was added. After 15 minutes of stirring the phases were separated and the aqueous phase was washed with toluene (7.5 L). With stirring, EtOAc (15.0 L) was added to the aqueous phase, followed by 6 M HCl (5.6 L) keeping the internal temperature below 30° C. The layers were separated and the organics were dried over magnesium sulfate. Filtration through a pad of celite and concentration provided a solid that was reslurried in 915 mL of EtAOc and 9.2 L of heptanes. Stirring was continued for 1 hour before the solids were filtered and washed with heptanes. Drying provided 2560 g of 5-bromo-2-(2-fluoro-4-methoxyphenoxy)benzoic acid as a cream colored solid. Step 2: A dry 100 L glass jacketed reactor equipped with an addition funnel, reflux condenser and temperature probe was charged with 5-bromo-2-(2-fluoro-4-methoxyphenoxy)benzoic acid (2340 g, 6.9 mol). TFA (11.7 L) was carefully added followed by TFAA (1144 mL). Boron trifluoride diethyl etherate (85 mL, 0.68 mol) was then carefully added. Stirring was continued to 4 hours at which point the reaction was transferred to another 100 L glass reactor containing 35.1 L of water cooled to 0° C. The resulting slurry was allowed to warm to RT and stir for 1 hour. The solids were filtered and washed with water (4.7 L) and 3 N NaOH (2×3.5 L) and water (7 L). The solids were transferred into a 22 L reactor and acetone (4.7 L) was added. The solids were slurried for 1.5 hour and the filtered, washing well with acetone (4.7 L). An additional slurry with acetone (6.4 L@45° C.) provided 1310 g of 7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-one as an off white solid.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH3:5].CC([OH:12])CCC.[Cl-].C(N(CC)CC)C.[CH3:21][C:22]1[CH:35]=[C:34]2[C:25]([S:26][C:27]3[CH:28]=[C:29]([C:37](Cl)=[O:38])[CH:30]=[CH:31][C:32]=3[C:33]2=[O:36])=[CH:24][CH:23]=1>O.C(Cl)Cl>[CH3:21][C:22]1[CH:35]=[C:34]2[C:25]([S:26][C:27]3[CH:28]=[C:29]([C:37]([O:38][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[O:12])[CH:30]=[CH:31][C:32]=3[C:33]2=[O:36])=[CH:24][CH:23]=1
Reactant: CCCCCO
Reactant: Cc1ccc2sc3cc(C(=O)Cl)ccc3c(=O)c2c1
Reactant: CCCC(C)O
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCOC(=O)c1ccc2c(=O)c3cc(C)ccc3sc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
1.0 g (11.36 mmoles) of pentan-1-ol (containing also -pentan-2-ol) and 1.0 g (9.90 mmoles) of triethyl amine chloride are added to the CH2Cl2 solution containing 2.26 g (7.41 mmoles) of 7-methyl-9-oxo-thioxanthene-3-carbonyl chloride. After approximately 1 hour at room temperature under stirring, the mixture is poured in water, the organic phase is separated and washed again with water. The organic phase is then separated, dehydrated and after purification on a flash column (SiO2— eluent: CH2Cl2:AcOEt 8:2) it is dried, obtaining 1.74 g (71.6%) of a yellow solid with the following spectral properties:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([CH3:9])=[C:6]([CH3:8])[N:7]=1.[CH3:10][O:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([N:23]=[C:24]=[O:25])(=[O:22])=[O:21])=[O:13]>C(#N)C>[CH3:8][C:6]1[N:7]=[C:2]([NH:1][C:24]([NH:23][S:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:12]([O:11][CH3:10])=[O:13])(=[O:22])=[O:21])=[O:25])[N:3]=[N:4][C:5]=1[CH3:9]
Reactant: Cc1nnc(N)nc1C
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: CC#N
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nnc(C)c(C)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.8 %

Procedure:
To a stirred suspension of 1.2 g of 3-amino-5,6-dimethyl-1,2,4-triazine in 25 ml of anhydrous acetonitrile was added at ambient temperature 2.4 g of 2-methoxycarbonylbenzenesulfonylisocyanate. After stirring for 24 hours at ambient temperature, the resultant precipitate was filtered off to yield 2.5 g of the desired compound melting at 150°-151°. It showed infrared absorption peaks at 1700, 1680 and 1550 cm-1, consistent for N-[(5,6-dimethyl-1,2,4-triazin-3-yl)-aminocarbonyl]-2-methoxycarbonylbenzenesulfonamide.
Reaction SMILES: [K].[CH3:2][O:3][C:4]1[CH:25]=[CH:24][C:7]2[NH:8][C:9]([S:11]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)=[O:12])=[N:10][C:6]=2[CH:5]=1.C(O)(=O)C.CO.O.O.O.O.O.O.[Cl-].[Mg+2:39].[Cl-]>O>[Mg:39].[CH3:2][O:3][C:4]1[CH:25]=[CH:24][C:7]2[NH:8][C:9]([S:11]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)=[O:12])=[N:10][C:6]=2[CH:5]=1
Reactant: [Mg+2]
Agent: COc1ccc2[nH]c(S(=O)Cc3ncc(C)c(OC)c3C)nc2c1
Agent: [Cl-]
Agent: [K]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: [Mg]
Temperature: 25 °C
Reaction time: 0.21 h

Procedure:
5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole potassium salt (100 g) was taken in water (500 ml) and was stirred at room temperature for 10-15 minutes. The pH was adjusted to 10-11 with acetic acid at and the mixture was stirred for half an hour 20-25° C. Methanol (100 ml) was added. Aqueous solution of magnesium chloride hexahydrate (20.3 g dissolved in 100 ml) was then added to the above mixture at room temperature under stirring. The mixture was stirred for 60 minutes at room temperature. The resulting solid was filtered, washed with methanol and water. The wet material was dried under reduced pressure at 40-45° C. for 8-10 hours.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([NH:11][C:12]([C@@H:14]([NH:18][C:19]([C@H:21]([CH2:30][CH:31]=[CH2:32])[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:20])[CH:15]([CH3:17])[CH3:16])=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.I[C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[C:36]([CH3:46])[CH:35]=1>C(#N)C.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][C@@H:4]([NH:11][C:12]([C@@H:14]([NH:18][C:19]([C@H:21]([CH2:30]/[CH:31]=[CH:32]/[C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[C:36]([CH3:46])[CH:35]=1)[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:20])[CH:15]([CH3:17])[CH3:16])=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C=CC[C@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@H](COC)c1ccccc1)C(C)C
Reactant: Cc1cc(I)ccc1-c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC[C@@H](NC(=O)[C@@H](NC(=O)[C@H](C/C=C/c1ccc(-c2ccccc2)c(C)c1)CC(=O)OC(C)(C)C)C(C)C)c1ccccc1
Yield: 66 %

Procedure:
According to the method of Preparation 15 a), tert-butyl (3R)-3-({[({[(1S)-2-methoxy-1-phenylethyl]amino}carbonyl)-(1S)-2-methyl-1-propyl]amino}carbonyl)hex-5-enoate (from c) above) (1.08 g, 2.42 mmol) was reacted with 4-iodo-2-methyl-1-phenylbenzene (Preparation 29)(1.07 g, 3.63 mmol) under palladium catalysis at reflux in acetonitrile for 18 h. After being cooled, the mixture was diluted with ethyl acetate (200 mL) and washed sequentially with 5% aqueous citric acid (50 mL), saturated aqueous sodium bicarbonate (50 mL), saturated aqueous brine (50 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution with dichloromethane:ethyl acetate=30:1 to 3:1) to give tert-butyl (3R, 5E)-3-({[({[(1S)-2-methoxy-1-phenylethyl]amino}carbonyl)-(1S)-2-methyl-1-propyl]amino}carbonyl)-6-[3-methyl-(4-phenyl)phenyl]hex-5-enoate as a pale brown foam (980 mg, 66%).
Reaction SMILES: [F:1][C:2]([F:7])([CH2:4][CH:5]=[CH2:6])[CH3:3].[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CC(C)([O-:19])C.[K+]>O1CCCC1>[F:1][C:2]([F:7])([CH2:4][CH:5]=[CH2:6])[CH2:3][O:19][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)[O-]
Reactant: BrCc1ccccc1
Reactant: C=CCC(C)(F)F
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCC(F)(F)COCc1ccccc1
Reaction time: 8 h

Procedure:
To a mixture of 2,2-difluoro 4-pentene (9.8 g, 80 mmoles) and benzyl bromide (13.7 g, 80 mmoles) in dry tetrahydrofuran (100 ml), potassium t-butoxide (9.5 g, 85 mmoles) is added in portions over a period of 1 hour. The reaction mixture is kept overnight at room temperature, concentrated under reduced pressure, hydrolyzed with 1N HCl (pH approximately 2) and diluted with water and ether. Usual work-up gives 2,2-difluoro-1-benzyloxy-4-pentene as a colorless oil (16.8 g, , 99%, RF: 0.2, ethyl acetate/petroleum ether: 2/98).
Reaction SMILES: ClC(O[C:6](=[O:12])OC(Cl)(Cl)Cl)(Cl)Cl.Cl.[NH2:14][CH:15]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:16]([C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1)=[O:17].[CH3:30][C:31]1[N:36]=[C:35]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[C:22]([C:21]1[CH:24]=[CH:25][C:18]([C:16](=[O:17])[CH:15]([NH:14][C:6]([N:40]2[CH2:41][CH2:42][N:37]([C:35]3[CH:34]=[CH:33][CH:32]=[C:31]([CH3:30])[N:36]=3)[CH2:38][CH2:39]2)=[O:12])[C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:19][CH:20]=1)#[N:23]
Reactant: Cc1cccc(N2CCNCC2)n1
Reactant: CC(C)(C)C(N)C(=O)c1ccc(C#N)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: Cc1cccc(N2CCN(C(=O)NC(C(=O)c3ccc(C#N)cc3)C(C)(C)C)CC2)n1
Reaction time: 0.33 h
Yield: 90.6 %

Procedure:
Bis(trichloromethyl)carbonate (60.6 mg, 0.20 mmol) was added portion-wise to 4-(2-amino-3,3-dimethylbutanoyl)benzonitrile hydrochloride (Example 3, 129 mg, 0.51 mmol) and TEA (0.285 mL, 2.04 mmol) in DCM (2 mL) under 1 minute at rt. After stirring for 20 min, a solution of 1-(6-methylpyridin-2-yl)piperazine (CAS 55745-89-6, 90 mg, 0.51 mmol) and TEA (0.142 mL, 1.02 mmol) in DCM (2 mL) was added drop-wise and the reaction was stirred for 90 min. The volatiles were removed before the reaction mixture was diluted with MeOH, filtered and purified by preparative HPLC. Fractions were pooled and freeze-dried to give N-(1-(4-cyanophenyl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(6-methylpyridin-2-yl)piperazine-1-carboxamide (76 mg, 36%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=3)[N:3]=2)=[CH:22][CH:21]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: Cc1cc(Nc2cc3ccccc3c(-c3ccc(F)cc3)n2)n[nH]1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-fluoro-phenylboronic acid to give [1-(4-fluoro-phenyl)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 315(MH+).