Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([C:15]3[O:19][N:18]=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:16]=3[C:26]([F:29])([F:28])[F:27])[O:12][N:11]=2)=[CH:6][CH:5]=1.[NH:30]1[CH2:35][CH2:34][CH2:33][CH:32]([CH2:36][OH:37])[CH2:31]1.CS(C)=O>CC(O)C>[OH:37][CH2:36][CH:32]1[CH2:33][CH2:34][CH2:35][N:30]([CH2:3][CH:2]([C:4]2[CH:9]=[CH:8][C:7]([C:10]3[N:14]=[C:13]([C:15]4[O:19][N:18]=[C:17]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:16]=4[C:26]([F:28])([F:27])[F:29])[O:12][N:11]=3)=[CH:6][CH:5]=2)[OH:1])[CH2:31]1
Reactant: OCC1CCCNC1
Reactant: FC(F)(F)c1c(-c2ccccc2)noc1-c1nc(-c2ccc(C3CO3)cc2)no1
Solvent: CC(C)O
Solvent: CS(C)=O
Product: OCC1CCCN(CC(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)C1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-(4-(oxiran-2-yl)phenyl)-5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazole, Preparation 28C (30 mg, 0.075 mmol) in 2-propanol (2 mL) was added piperidin-3-yl-methanol (17.31 mg, 0.150 mmol). The reaction mixture was heated to 80° C. DMSO (1 mL) was added to help solubilize. The reaction mixture was stirred overnight. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 MeOH:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 MeOH:water with 10-mM ammonium acetate; Gradient: 45-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the Example 30 was 16.0 mg, and its purity was 100%. 1H NMR (400 MHz, MeOD) δ ppm 8.18 (2H, d, J=8.28 Hz), 7.49-7.75 (7H, m), 5.05 (1H, d, J=9.03 Hz), 3.36-3.56 (4H, m), 2.83 (2H, br. s.), 2.11-2.53 (2H, m), 1.62-2.02 (4H, m), 1.03-1.20 (1H, m). MS (m+1)=515.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(N(CC)CC)C.[CH:14]#[C:15][CH2:16][CH2:17][CH2:18][CH3:19].[Na+].[Cl-]>[Cu]I.CCOCC.O.C(#N)C>[C:14]([C:2]1[S:3][CH:4]=[CH:5][N:6]=1)#[C:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: C#CCCCC
Reactant: Brc1nccs1
Agent: [Cu]I
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCC#Cc1nccs1
Yield: 35.8 %

Procedure:
2-Bromothiazole (6.09 mmol, 1.0 g) was added to 40 mL of acetonitrile. CuI (1.52 mmol, 0.29 g), triethylamine (7.31 mmol, 1.01 mL) and bistriphenylphosphine palladium chloride (0.3 mmol, 0.21 g) were added and the solution degassed. Hexyne (6.09 mmol, 0.7 mL) was added and the mixture heated at refluxed overnight. Water was added followed by NaCl and ether. The layers were separated and the aqueous layer extracted with ether (4x). The organic layers were combined, dried (MgSO4), filtered and concentrated. The residue was subjected to flash chromatography (10% ethyl acetate/hexane) to afford 0.36 g (36%) of 2-(1-hexynyl)thiazole.
Reaction SMILES: C([C:10]1[CH:15]=[C:14]([C:16]([CH3:23])([CH3:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:13]=[C:12]([N:24]2[N:28]=[C:27]3[CH:29]=[CH:30][C:31]([C:33]([F:36])([F:35])[F:34])=[CH:32][C:26]3=[N:25]2)[C:11]=1[OH:37])(C1C=CC=CC=1)(C)C.[Cl:38][O-].[Na+].C(O)C.CCCCCCC.O>>[Cl:38][C:10]1[CH:15]=[C:14]([C:16]([CH3:23])([CH3:22])[CH2:17][C:18]([CH3:19])([CH3:21])[CH3:20])[CH:13]=[C:12]([N:24]2[N:28]=[C:27]3[CH:29]=[CH:30][C:31]([C:33]([F:36])([F:34])[F:35])=[CH:32][C:26]3=[N:25]2)[C:11]=1[OH:37]
Reactant: CC(C)(C)CC(C)(C)c1cc(-n2nc3ccc(C(F)(F)F)cc3n2)c(O)c(C(C)(C)c2ccccc2)c1
Reactant: [O-]Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCCCCCC
Solvent: O
Product: CC(C)(C)CC(C)(C)c1cc(Cl)c(O)c(-n2nc3ccc(C(F)(F)F)cc3n2)c1
Temperature: 45 °C

Procedure:
A flask containing 2-cumyl-4-(1,1,3,3-tetramethyl-butyl)-6-(5-trifluromethyl-benzotriazol-2-yl)phenol (7.5 g, 0.014 mol), 7% aqueous sodium hypochlorite (125 g, 0.12 mol), ethanol (85 g, 1.83 mol), and heptane (85 g, 0.84 mol) is heated to 45° C. with agitation. After a one hour hold, water (150 g, 8.33 mol) and heptane (150 g, 1.49 mol) are added to the reaction mass to dissolve all solids. The aqueous layer is removed and heptane is distilled off yielding a white residue. The white residue is crystallized from methanol yielding the title compound as a white solid (5.4 g, 91%) melting at 72-81° C.
Reaction SMILES: C([O:4][CH2:5]/[C:6](/[CH3:26])=[CH:7]/[CH2:8][C:9]1[C:14]([CH3:15])=[C:13]([O:16][C:17](=[O:19])[CH3:18])[C:12]([CH3:20])=[C:11]([CH3:21])[C:10]=1[O:22][C:23](=[O:25])[CH3:24])(=O)C.B(F)(F)F.CCOCC.C(=O)(O)[O-].[Na+]>CO>[C:23]([O:22][C:10]1[C:11]([CH3:21])=[C:12]([CH3:20])[C:13]([O:16][C:17](=[O:19])[CH3:18])=[C:14]([CH3:15])[C:9]=1[CH2:8]/[CH:7]=[C:6](\[CH3:26])/[CH2:5][OH:4])(=[O:25])[CH3:24]
Reactant: CC(=O)OC/C(C)=C/Cc1c(C)c(OC(C)=O)c(C)c(C)c1OC(C)=O
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CC(=O)Oc1c(C)c(C)c(OC(C)=O)c(C/C=C(\C)CO)c1C
Temperature: 25 °C
Yield: 90.5 %

Procedure:
5.0 g of (E)-4-(2',5'-diacetoxy-3',4',6'-trimethylphenyl)-2-methyl-2-butenyl acetate are dissolved in 50 ml of methanol and treated with 0.2 g of boron trifluoride etherate. The mixture is boiled at reflux for 4 hours, then cooled to room temperature and poured into aqueous sodium bicarbonate solution. The aqueous solution is extracted with diethyl ether, and the ether phase is washed in sequence with sodium bicarbonate solution and sodium chloride solution, dried over anhydrous sodium sulphate and evaporated to dryness. From the residue (4.6 g) there are obtained by column chromatography (silica gel, diethyl ether/n-hexane/methanol) 4.0 g of (E)-4-(2',5'-diacetoxy-3',4',6'-trimethylphenyl)-2-methyl-2-butenol in the form of white crystals, m.p. 118°-120° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[N:15][N:16]([C:18]([C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=3)([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH:17]=2)=[CH:9][CH:8]=1)[C:4]([O-])=[O:5].[K+].C(N(C(C)C)CC)(C)C.COCCN(S(F)(F)F)CCOC.Cl.[CH3:67][NH:68][O:69][CH3:70]>CN(C=O)C.O>[CH3:70][O:69][N:68]([CH3:67])[C:4](=[O:5])[CH:3]([O:2][CH3:1])[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:14]=[N:15][N:16]([C:18]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)([C:27]3[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=3)[C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=3)[CH:17]=2)=[CH:11][CH:12]=1
Reactant: CNOC
Reactant: COc1ccc(C(c2ccc(OC)cc2)(c2ccc(OC)cc2)n2cc(-c3ccc(C(OC)C(=O)[O-])cc3)cn2)cc1
Agent: COCCN(CCOC)S(F)(F)F
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(c2ccc(OC)cc2)(c2ccc(OC)cc2)n2cc(-c3ccc(C(OC)C(=O)N(C)OC)cc3)cn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.5 %

Procedure:
To an ice-cold solution of potassium 2-methoxy-2-(4-(1-(tris(4-methoxyphenyl)methyl)-1H-pyrazol-4-yl)phenyl)acetate (1.25 g, 2.1 mmol) in anhydrous DMF (10 mL) under argon was added diisopropylethylamine (0.54 mL, 3.1 mmol) and bis(2-methoxyethyl)aminosulfur trifluoride (0.46 mL, 2.5 mmol) dropwise. The reaction was stirred for 30 min then N,O-dimethylhydroxylamine hydrochloride (0.303 g, 3.1 mmol) was added. After stirring for a further 15 min over an ice bath, the mixture was allowed to warm to room temperature and stirred for 3.5 hrs. H2O was added and the mixture was extracted with EtOAc. The combined organics were washed with H2O, saturated aqueous NH4Cl, saturated aqueous NaHCO3, and brine then dried over Na2SO4 and concentrated in vacuo. Purification by chromatography (45-90% EtOAc-hexanes; EtOAc containing 1% Et3N) to give N,2-dimethoxy-N-methyl-2-(4-(1-(tris(4-methoxyphenyl)methyl)-1H-pyrazol-4-yl)phenyl)acetamide (0.478 g from two reactions, 32% yield overall).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[N:12]1([C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:29])([F:28])[F:27])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[NH2:8][C:6]1[CH:7]=[C:2]([N:15]2[CH2:14][CH2:13][N:12]([C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:28])([F:27])[F:29])=[O:19])[CH2:17][CH2:16]2)[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Nc1cc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 79 %

Procedure:
A mixture of 5-chloro-2-nitrophenylamine (3.000 g, 17.38 mmol), piperazin-1-yl-(2-trifluoromethylphenyl)methanone (5.360 g, 20.80 mmol) and cesium carbonate (11.32 g, 34.76 mmol) was heated at 140° C. in anhydrous DMSO (15 mL) for 12 h. The mixture was cooled and poured over ice water. The solid product obtained was extracted with ethyl acetate. The organic extracts were combined, dried over anhydrous sodium sulphate, concentrated in vacuo. The residue was purified by column chromatography to obtain the product, [4-(3-amino-4-nitrophenyl)piperazin-1-yl]-(2-trifluoromethylphenyl)methanone, in 79% yield (6.800 g). 1H NMR (300 MHz, CDCl3) δ 8.01 (d, 1H, J=9.6 Hz), 7.72 (d, 1H, J=7.9 Hz), 7.62 (t, 1H, J=7.1 Hz), 7.54 (t, 1H, J=7.4 Hz), 7.34 (d, 1H, J=7.3 Hz), 6.22 (dd, 1H, J=2.6,9.7 Hz), 6.15 (br. s, 2H), 5.94 (d, 1H, J=2.6 Hz), 4.05-3.93 (m, 1H), 3.90-3.80 (m, 1H), 3.50-3.40 (m, 2H), 3.35-3.20 (m, 4H). MS (ES+) m/z 395.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:10]([CH2:20][C:21]([N:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[C:33](Cl)[N:32]=[CH:31][N:30]=4)[CH2:25][CH2:24]3)=[O:22])[N:9]=2)=[CH:4][CH:3]=1.[CH3:36][NH:37][CH3:38]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:10]([CH2:20][C:21]([N:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[C:33]([N:37]([CH3:38])[CH3:36])[N:32]=[CH:31][N:30]=4)[CH2:25][CH2:24]3)=[O:22])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=C(Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1)N1CCN(c2cc(Cl)ncn2)CC1
Solvent: C1CCOC1
Product: CN(C)c1cc(N2CCN(C(=O)Cn3nc(-c4ccc(F)cc4)nc3-c3ccc(F)cc3)CC2)ncn1

Procedure:
40 mg 2-(3,5-Bis-(4-fluoro-phenyl)-(1,2,4)triazol-1-yl)-1-(4-(6-chloro-pyrimidin-4-yl)-piperazin-1-yl)-ethanone and 2 mL 2 M dimethylamine solution in THF were stirred 30 min at 170° C. under microwave condition. The mixture was purified by HPLC to give 19.1 mg of the desired product. Rt: 1.88 min (method I), (M+H)+: 505
Reaction SMILES: [SH:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[NH2:7][CH2:8][CH2:9][CH2:10]O.[BrH:12]>>[BrH:12].[BrH:12].[NH2:7][CH2:8][CH2:9][CH2:10][S:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1
Reactant: NCCCO
Reactant: Sc1nc[nH]n1
Agent: Br
Product: NCCCSc1nc[nH]n1

Procedure:
A solution of 3-mercapto-1,2,4-triazole and 3-aminopropanol in hydrobromic acid is heated under reflux for 24 hours. The reaction mixture is evaporated to dryness and the residue recrystallised from ethanol/ether to give 3-(3-aminopropylthio)-1,2,4-triazole dihydrobromide.
Reaction SMILES: [N+:1]([C:4]1[C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[C:13](O)=[O:14])([O-:3])=[O:2].B.CO>O1CCCC1>[N+:1]([C:4]1[C:9]([CH2:10][OH:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:13][OH:14])([O-:3])=[O:2]
Reactant: O=C(O)c1cccc(C(=O)O)c1[N+](=O)[O-]
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: O=[N+]([O-])c1c(CO)cccc1CO
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A solution of 2-nitro-1,3-benzenedicarboxylic acid (12.7 g, 0.06 mole) in tetrahydrofuran (60 ml) is cooled to 0° C. and 1N borane:tetrahydrofuran (300 ml, 0.3 mole) is added dropwise over one hour. The mixture is allowed to warm slowly to 25° C. and is stirred for 36 hours. Methanol (50 ml) is added slowly, the mixture is filtered and evaporated. The residue is dissolved in ethyl acetate (100 ml) and washed with water (25 ml), dried (MgSO4), filtered, and evaporated to yield a yellow solid. This is further purified by flash chromatography over silica (elution with 1:1 hexane:ethyl acetate) to afford after concentration pure 2-nitro-1,3-benzenedimethanol, mp 100-101° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:22]([NH:24][NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10]>C(O)(=O)C.[Pt]=O>[CH:15]1([CH2:14][CH2:13][CH2:12][C@@H:11]([C@@H:21]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:22]([NH:24][NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])[C:9](=[O:10])[NH:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CC(C)CNNC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CC(C)CNNC(=O)[C@H](CC(C)C)[C@H](CCCC1CCCCC1)C(=O)NOC1CCCCO1
Yield: 92.4 %

Procedure:
A solution of 1.0 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbarnoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in 30 ml of glacial acetic acid was hydrogenated in the presence of 0.300 g of platinum(II)oxide for 2 hours. The catalyst was removed by filtration and the solvent was evaporated and trituration with hexane gave 0.94 g of 2(R)-[4-cyclohexyl-1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]butyl]-2′-isobutyl-4-methylvalerohydrazide in the form of a white solid.
Reaction SMILES: [O:1]1[CH:5]=[N:4][C:3]([C:6]2([NH:10]S(C(C)(C)C)=O)[CH2:9][CH2:8][CH2:7]2)=[N:2]1.[ClH:17]>CO>[ClH:17].[O:1]1[CH:5]=[N:4][C:3]([C:6]2([NH2:10])[CH2:9][CH2:8][CH2:7]2)=[N:2]1
Reactant: CC(C)(C)S(=O)NC1(c2ncon2)CCC1
Agent: Cl
Solvent: CO
Product: NC1(c2ncon2)CCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-(1-(1,2,4-oxadiazol-3-yl)cyclobutyl)-2-methylpropane-2-sulfinamide (45 mg, 0.19 mmol) was taken up in 1 mL of MeOH and treated with 1 mL of HCl (2M in Et2O) at rt and allowed to stir for 30 min at rt. The reaction was then concentrated to dryness azeotroping with toluene 3× to give 1-(1,2,4-oxadiazol-3-yl)cyclobutanamine hydrochloride (32 mg, 0.18 mmol). Then 14 mg (0.077 mmol) of this material was combined with 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(3,3,3-trifluoropropyl)furo[2,3-b]pyridin-5-yl)benzoic acid (25 mg, 0.051 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.027 mL, 0.15 mmol) in DMF (1 mL) at rt. To this stirring solution 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (29 mg, 0.077 mmol) was added. The mixture was allowed to stir at rt for 30 min. The crude reaction mixture was purified via preparative LC/MS with the following conditions: Column:Waters XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 20-mM ammonium acetate; Gradient: 40-80% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 20.2 mg, and its estimated purity by LCMS analysis was 100%. Two analytical LC/MS injections were used to determine the final purity. Injection 1 conditions: Column:Waters BEH C18, 2.0×50 mm, 1.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 40° C.; Gradient: 0.5 min hold at 0% B, 0-100% B over 4 minutes, then a 0.5-minute hold at 100% B; Flow: 1 mL/min. retention time: 3.02 min; M+H: 608. Injection 2 conditions: Column:Waters BEH C18, 2.0×50 mm, 1.7-μm particles; Mobile Phase A: 5:95 methanol:water with 10 mM ammonium acetate; MobilePhase B: 95:5 methanol:water with 10 mM ammonium acetate; Temperature: 40° C.; Gradient: 0.5 min hold at 0% B, 0-100% B over 4 minutes, then a 0.5-minute hold at 100% B; Flow: 0.5 mL/min. retention time: 4.06 min; M+H: 608. Proton NMR was acquired in deuterated DMSO. 1H NMR (500 MHz, DMSO-d6) δ 9.48 (s, 1H), 9.33 (s, 1H), 8.55-8.46 (m, 1H), 8.10-8.02 (m, 2H), 7.98 (s, 3H), 7.69-7.59 (m, 2H), 7.46-7.37 (m, 2H), 3.05-2.97 (m, 2H), 2.85-2.71 (m, 5H), 2.67-2.56 (m, 4H), 2.10-1.99 (m, 2H).
Reaction SMILES: [CH:1](=[CH:8]/[C:9](=[O:11])[CH3:10])\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][Al](C)C.O>O1CCOCC1.C1(C)C=CC=CC=1>[C:2]1([CH:1]([CH3:12])[CH2:8][C:9](=[O:11])[CH3:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Al](C)C
Reactant: CC(=O)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)CC(C)c1ccccc1
Temperature: 22 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
143 mg of CuBr is added to 1.46 g (10 mmol) of cis/trans-benzylideneacetone (3-phenyl-but-3-en-2-one) in 20 ml of absolute dioxane. 9.4 ml (11 mmol) of a 10% solution of trimethyl aluminum in toluene is added to the reaction at room temperature under nitrogen atmosphere and, after completion of the addition, stirred for 10 minutes at 22° C. For hydrolysis of the reaction solution, 1 ml of water dissolved in 5 ml of dioxane is carefully added to the reaction. It is stirred for 10 minutes more and the inorganic precipitate filtered off with dioxane is washed again. The dioxane solution is concentrated by evaporation on a rotary evaporator and the residue is chromatographed on silica gel with ethyl acetate/hexane as eluent. After concentration by evaporation of the fractions, 1.21 g of 4-phenyl-pentan-2-one (75% of theory) is obtained a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]([OH:24])=O)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[NH:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:25][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]([N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)=[O:24])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: C1COCCN1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC(=O)O)n2)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC(=O)N3CCOCC3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.7 %

Procedure:
To a solution containing {3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-acetic acid (prepared in example 3, 100 mg, 0.22 mmol) in methylene chloride (2 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (121 μL, 0.24 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (28 μL, 0.24 mmol) was added to the solution. After 1 h, morpholine (21 μL, 0.24 mmol) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with saturated aqueous ammonium chloride solution, the organic phase was concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(2-morpholin-4-yl-2-oxo-ethyl)-1H-pyrazol-3-yl]-propionamide (71 mg, 62%) as a white solid: ESI-LRMS m/e calcd for C24H31ClN4O5S [M+] 522.17, found 523.4 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.05-1.18 (m, 2H, CH2), 1.41-1.95 (m, 8H, 4×CH2), 2.15-2.24 (m, 1H, CH), 3.26 (s, 3H, SO2CH3), 3.46 (m, 2H, NCH2), 3.55 (t, J=7.5 Hz, 1H, CH),), 3.58-3.70 (m, 6H, 2×OCH2 and NCH2), 4.81 (s, 2H, NCH2), 6.71 (m, 1H, Ar), 7.34 (m, 1H, Ar), 7.42 (m, 1H, Ar), 7.56 (m, 1H, Ar), 8.04 (d, Jo=8.1 Hz, 1H, Ar), 8.10 (s, 1H, NH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15](OS(C(F)(F)F)(=O)=O)=[N:16]2)=[CH:11][CH:10]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[CH2:38][CH2:37][N:36]([CH2:39][C:40]([NH2:42])=[O:41])[CH2:35][CH2:34]2)=[C:29]([O:43][CH3:44])[CH:28]=1>>[CH3:44][O:43][C:29]1[CH:28]=[C:27]([NH:26][C:15]2[N:14]=[CH:13][C:12]3=[CH:11][CH:10]=[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])[N:17]3[N:16]=2)[CH:32]=[CH:31][C:30]=1[CH:33]1[CH2:38][CH2:37][N:36]([CH2:39][C:40]([NH2:42])=[O:41])[CH2:35][CH2:34]1
Reactant: COc1ccccc1-c1ccc2cnc(OS(=O)(=O)C(F)(F)F)nn12
Reactant: COc1cc(N)ccc1C1CCN(CC(N)=O)CC1
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc(C4CCN(CC(N)=O)CC4)c(OC)c3)nn12
Yield: 33.7 %

Procedure:
Trifluoro-methanesulfonic acid 7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (0.100 g, 0.268 mmol) and 2-[4-(4-Amino-2-methoxy-phenyl)-piperidin-1-yl]-acetamide (0.0882 g, 0.335 mmol) were reacted in an analogous manner to Example 908D at 50° C. for 16 h. The reaction mixture was concentrated, taken up in EtOAc, and washed with brine. The EtOAc layer was dried, filtered over MgSO4, and concentrated. The resulting residue was purified by Gilson RP-HPLC and lyophilized. The product was taken up in EtOAc and washed with NaHCO3 to free-base it to afford title compound (44 mg, 32%). LCMS=487.0 (M+H), HPLC rt=2.500, purity=98%. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.29 (s, 1H), 8.94 (s, 1H), 7.70 (d, J=7.3 Hz, 1H), 7.45 (dd, J=7.3, 7.7 Hz, 1H), 7.37 (s, 1H), 7.19 (d, J=8.3 Hz, 2H), 7.08 (d, J=7.4 Hz, 1H), 6.97 (d, J=8.3 Hz, 1H0, 6.91 (d, J=4.3 Hz, 1H), 6.88 (d, J=4.3 Hz, 1H), 3.76 (s, 3H), 3.42 (s, 3H), 3.31 (s, 2H), 2.89-2.82 (m, 3H), 2.80-2.68 (m, 1H), 2.20-2.05 (m, 2H), 1.72-1.58 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([F:29])[CH2:18][CH2:17][CH:16]([CH:19]([C:22]2[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=2)[CH2:20][NH2:21])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([CH:16]1[CH2:17][CH2:18][C:13]([F:29])([F:12])[CH2:14][CH2:15]1)[C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: Cc1ncc(C(CN)C2CCC(F)(F)CC2)cn1
Product: Cc1ncc(C(CNC(=O)c2cccc(Cl)c2Cl)C2CCC(F)(F)CC2)cn1

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2,3-dichlorobenzoic acid and 2-(4,4-difluorocyclohexyl)-2-(2-methylpyrimidin-5-yl)ethanamine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=448.1, tR (minutes, Method F)=2.95. [α]D20=+49.6 (c=4.8 mg/mL,CHCl3)
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[CH3:14])[CH:2]=[CH2:3].[OH-].[Na+].[CH3:17]I>CS(C)=O>[CH2:1]([N:4]([CH3:17])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[CH3:14])[CH:2]=[CH2:3]
Reactant: C=CCNc1ccc([N+](=O)[O-])cc1C
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: C=CCN(C)c1ccc([N+](=O)[O-])cc1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99 %

Procedure:
20 g (104 mmol) of N-allyl-2-methyl-4-nitroaniline were dissolved in 600 ml of dimethyl sulfoxide. 41.6 g (1.04 mol) of sodium hydroxide powder were added to the resultant solution, whereupon the solution became deep red. 44.3 g (19.6 ml, 312 mmol) of methyl iodide were added in one portion, and the solution became red-brown. The red-brown solution was stirred at room temperature for from 1 to 2 hours, poured into 3 l of ice water and then extracted three times with 500 ml of dichloromethane in each case. The combined dichloromethane phases were subsequently washed three times with 500 ml of water in each case, dried over sodium sulfate, filtered and evaporated under reduced pressure, to give a brown oil (21.4 g, corresponding to a yield of 99%), which was purified by chromatography on silica gel (eluent: n-hexane/ethyl acetate 15/1), to give N-allyl-N-methyl-2-methyl-4-nitroaniline (compound I-8 according to the invention) in a yield of 19.5 g, corresponding to 90%.