Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C:15]3[C:24]4[C:19](=[CH:20][C:21]([O:25][CH2:26][CH:27]5[CH2:29][O:28]5)=[CH:22][CH:23]=4)[N:18]=[CH:17][CH:16]=3)=[CH:13][C:8]=2[O:7][C:6]=1[CH3:30])=[O:4].[CH3:31][NH2:32]>C(Cl)Cl.C1COCC1.CO>[OH:28][CH:27]([CH2:29][NH:32][CH3:31])[CH2:26][O:25][C:21]1[CH:20]=[C:19]2[C:24]([C:15]([O:14][C:12]3[CH:11]=[CH:10][C:9]4[C:5]([C:3]([NH:2][CH3:1])=[O:4])=[C:6]([CH3:30])[O:7][C:8]=4[CH:13]=3)=[CH:16][CH:17]=[N:18]2)=[CH:23][CH:22]=1
Reactant: CN
Reactant: CNC(=O)c1c(C)oc2cc(Oc3ccnc4cc(OCC5CO5)ccc34)ccc12
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: CNCC(O)COc1ccc2c(Oc3ccc4c(C(=O)NC)c(C)oc4c3)ccnc2c1
Temperature: 65 °C

Procedure:
A solution of 6-[(7-hydroxyquinolin-4-yl)oxy]-N,2-dimethyl-1-benzofuran-3-carboxamide 123-A (1 g, 2.9 mmol), 2-(bromomethyl)oxirane (467 mg, 3.4 mmol) and Cs2CO3 (1.4 g, 4.2 mmol) in CH3CN (25 ml) was heated to 65° C. for 3 hours. The solution was extracted with EtOAc. N,2-dimethyl-6-{[7-(oxiran-2-ylmethoxy)quinolin-4-yl]oxy}-1-benzofuran-3-carboxamide 123-B (1.1 g) was isolated by a silica gel column using 1-5% MeOH in CH2Cl2. To a solution of 123-B (150 mg, 0.35 mmol) in THF (5 ml) was added a solution of methylamine in MeOH (1N, 1 ml). The solution was heated to 65° C. for 2 hours. The crude product was purified by HPLC (10-40% CH3CN/H2O over 30 min.) to give 6-({7-[2-hydroxy-3-(methylamino)propoxy]quinolin-4-yl}oxy)-N,2-dimethyl-1-benzofuran-3-carboxamide 123.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:22])=[CH:4][C:5]([Cl:21])=[C:6]([CH:20]=1)[O:7][C:8]1[CH:19]=[CH:18][CH:17]=[CH:16][C:9]=1[O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13].Cl[C:24]([O:26][CH3:27])=[O:25].O1CCCC1.Cl>N1C=CC=CC=1>[Cl:21][C:5]1[CH:4]=[C:3]([F:22])[C:2]([NH:1][C:24]([O:26][CH3:27])=[O:25])=[CH:20][C:6]=1[O:7][C:8]1[CH:19]=[CH:18][CH:17]=[CH:16][C:9]=1[O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)Cl
Reactant: COC(=O)COc1ccccc1Oc1cc(N)c(F)cc1Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)COc1ccccc1Oc1cc(NC(=O)OC)c(F)cc1Cl
Temperature: 25 °C

Procedure:
Into a mixture of methyl [2-(5-amino-2-chloro-4-fluorophenoxy)phenoxy]acetate [Intermediate compound A3-22], methyl chloroformate and tetrahydrofuran is added dropwise pyridine, and the mixture is stirred at room temperature. Dilute hydrochloric acid is added to the reaction solution, and this is extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated to obtain methyl [2-(2-chloro-4-fluoro-5-methoxycarbonylaminophenoxy)phenoxy]acetate [Intermediate compound A9-22].
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:27]([CH3:31])[CH2:28][CH2:29][CH3:30])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23]O)=[N:21][CH:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1.S(Cl)(Cl)=O.[Cl-].[CH:37]1([NH2:40])[CH2:39][CH2:38]1>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]([N:27]([CH3:31])[CH2:28][CH2:29][CH3:30])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23][NH:40][CH:37]5[CH2:39][CH2:38]5)=[N:21][CH:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1
Reactant: NC1CC1
Reactant: CCCN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3ncnc3CO)c1)=N2
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3ncnc3CNC3CC3)c1)=N2

Procedure:
The title compound was prepared from 8-chloro-7-(methyl-propyl-amino)-4-[3-(5-hydroxymethyl-[1,2,4]triazol-1-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 162) (220 mg, 0.50 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with cyclopropylamine in DMF according to the method described in Example 45. Obtained as a light yellow solid (95 mg, 40%).
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:20]([C:22]1[N:23]([CH2:35][C:36]#[CH:37])[C:24]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N:27]=[CH:26][C:25]=2[N:34]=1)[CH3:21]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].[Cu]I>[CH2:20]([C:22]1[N:23]([CH2:35][C:36]#[C:37][C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)[C:24]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N:27]=[CH:26][C:25]=2[N:34]=1)[CH3:21]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#CCn1c(CC)nc2cnc3ccccc3c21
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(C#CCn2c(CC)nc3cnc4ccccc4c32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (65.9 mg, 0.03 eq.), ethyl 4-iodobenzoate (388 μL, 1.1 eq.), triethylamine (887 μL, 3.0 eq.), and copper (I) iodide (24.2 mg, 0.06 eq.) were added sequentially to a solution of 2-ethyl-1-(2-propynyl)-1H-imidazo[4,5-c]quinoline (499 mg, 2.12 mmol, 1.0 eq.) in DMF (10.6 mL). The reaction mixture was stirred at ambient temperature for 1 hour and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel eluting with 5/95 methanol/chloroform) to provide 0.70 g of ethyl 4-[3-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1-propynyl]benzoate as a light tan solid.
Reaction SMILES: [CH3:1][C:2]1C=NNC=1.C(=O)CC.[CH:11]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])OCC.[N+]([O-])([O-])=O.[NH4+]>C(O)C>[CH2:19]([O:18][CH:11]([O:15][CH2:16][CH3:17])[CH2:1][CH3:2])[CH3:20]
Reactant: CCOC(OCC)OCC
Reactant: Cc1cn[nH]c1
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCC=O
Product: CCOC(CC)OCC

Procedure:
In the first step of the present synthesis of 4-MP, propionaldehyde is reacted with triethyl orthoformate in the presence of ethanol and ammonium nitrate to produce 1,1-diethoxypropane. In the second step, the 1,1-diethoxypropane produced in the first step is reacted neat (without a solvent) with a catalyst, which comprises an acid and an amine, to produce 1-ethoxy-1-propene (ethyl-1-propenyl ether). In the third step, this material is purified by washing and drying, without distillation. In the fourth step, the 1-ethoxy-1-propene from the third step is reacted with triethyl orthoformate in the presence of boron trifluoride-diethyl etherate to produce 1,1,3,3-tetraethoxy-2-methyl propane (“TEMP”). In the fifth step, the TEMP from the third step is reacted with hydrazine or a hydrazonium salt or hydrazine hydrate at elevated temperatures to produce 4-methylpyrazole.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Br:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([OH:18])[N:12]=[CH:11]2.C(O)(C)(C)C.C1(C)C=CC=CC=1.CC(=O)CC.[C:36]([CH:40]1[CH2:45][CH2:44][CH:43](OS(C)(=O)=O)[CH2:42][CH2:41]1)([CH3:39])([CH3:38])[CH3:37]>>[Br:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([O:18][CH:43]1[CH2:44][CH2:45][CH:40]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:41][CH2:42]1)[N:12]=[CH:11]2
Reactant: CC(C)(C)C1CCC(OS(C)(=O)=O)CC1
Reactant: Oc1ncc2cc(Br)ccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)(C)O
Solvent: CCC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)C1CCC(Oc2ncc3cc(Br)ccc3n2)CC1
Temperature: 110 °C
Yield: 20 %

Procedure:
Cesium carbonate (3.1308 g, 9.6089 mmol) was added to a mixture of 6-bromoquinazolin-2-ol (1.0812 g, 4.8044 mmol) in tert-butyl alcohol (15 mL, 160 mmol), toluene (25 mL, 230 mmol) and 2-butanone (10 mL, 100 mmol). The mixture was heated at 110° C. for 1 hour in a sealed tube then cooled to room temperature and methanesulfonic acid 4-tert-butyl-cyclohexyl ester (2.2519 g, 9.6089 mmol) was added. The reaction was then heated at 110° C. overnight. The reaction mixture was cooled to room temperature then filtered through a pad of celite. The filtrate was concentrated under reduced pressure, adsorbed onto silica gel and purified by flash chromatography (80 g SiO2 column; 0-40% EtOAc in heptane eluent) to give the title compound in 20% yield. ESI-MS (M+H+): 365.1
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20]#[C:21][C:22]3[CH:23]=[CH:24][C:25]([N:28]4[CH2:32][CH2:31][C@@H:30]([OH:33])[CH2:29]4)=[N:26][CH:27]=3)=[N:18][CH:19]=2)=[CH:10][CH:9]=1.C([O-])(O)=O.[Na+].C(OC)(C)(C)C>C(Cl)Cl>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20]#[C:21][C:22]3[CH:23]=[CH:24][C:25]([N:28]4[CH2:32][CH2:31][C:30](=[O:33])[CH2:29]4)=[N:26][CH:27]=3)=[N:18][CH:19]=2)=[CH:10][CH:9]=1
Reactant: O[C@@H]1CCN(c2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cn2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1CCN(c2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cn2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.43 mL (5.32 mmol) pyridine and 2.26 g (0.80 mmol, 15 percent by weight) Dess-Martin-periodinane in DCM are added to a solution of 200 mg (0.53 mmol) (R)-1-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-pyrrolidin-3-ol in 10 mL DCM. The reaction mixture is stirred for 3 h at RT and added to a solution of semisaturated NaHCO3 solution and tert-butylmethylether. The aqueous phase is extracted twice with EtOAc. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac. The product is further reacted without purification.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][C:15]=2[C:16]([F:19])([F:18])[F:17])[NH:12][C:11](=[O:20])[C:10](=[O:21])[NH:9]3)[CH:5]=[CH:4][CH:3]=[CH:2]1.Br[CH2:23][C:24]([O:26][CH3:27])=[O:25]>C(Cl)Cl.C(OCC)(=O)C>[CH3:27][O:26][C:24]([CH2:23][N:9]1[C:8]2[C:13](=[CH:14][C:15]([C:16]([F:17])([F:18])[F:19])=[C:6]([N:1]3[CH:5]=[CH:4][CH:3]=[CH:2]3)[CH:7]=2)[NH:12][C:11](=[O:20])[C:10]1=[O:21])=[O:25]
Reactant: O=c1[nH]c2cc(-n3cccc3)c(C(F)(F)F)cc2[nH]c1=O
Reactant: COC(=O)CBr
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)Cn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(-n3cccc3)cc21
Yield: 39.7 %

Procedure:
35 g (118.6 mmol) of 6-(1-pyrrolyl)-7-trifluoromethyl-2,3(1H,4H)-quinoxalinedione (Example 2) were reacted with 23.8 g (155.5 mmol) of methyl bromoacetate as in Example 23. The mobile phase used for the chromatography was methylene chloride/ethyl acetate=3/2. 17.3 g (40%) of the product were obtained.
Reaction SMILES: [OH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.[CH2:12]=[O:13].C(#N)C.Cl[CH:18]([F:20])[F:19]>[OH-].[K+]>[F:19][CH:18]([F:20])[O:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH2:12][OH:13]
Reactant: C=O
Reactant: Cn1nc(C(F)(F)F)cc1O
Reactant: FC(F)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: Cn1nc(C(F)(F)F)c(CO)c1OC(F)F
Temperature: 25 °C
Yield: 88.2 %

Procedure:
16.6 g (0.10 mole) of the 5-hydroxy-1-methyl-3-trifluoromethylpyrazole synthesized in Reference Example 1 was dissolved in 35.0 g (0.15 mole) of a 24% aqueous potassium hydroxide solution. To the solution being stirred at room temperature was dropwise added 9.7 g (0.12 mole) of a 37% formalin solution, followed by stirring at the same temperature for 1 hour. Then, there were added 70.0 g (0.3 mole) of a 24% aqueous potassium hydroxide solution and 100 ml of acetonitrile. Therein was blown 17.3 g (0.20 mole) of chlorodifluoromethane at room temperature in 2 hours, followed by stirring at room temperature for 2 hours to give rise to a reaction. After the reaction, the organic layer which appeared by phase separation, was concentrated under reduced pressure to obtain 26.5 g (purity: 82.0%, yield: 88.2%) of a crude solution of title compound. The crude solution was subjected to vacuum distillation to obtain a title compound as a colorless transparent solution.
Reaction SMILES: [Cu]([C:4]#[N:5])C#N.C(#N)C.[Cl:9][C:10]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13]>C1(C)C=CC=CC=1>[Cl:19][C:18]1[C:10]([Cl:9])=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([C:4]#[N:5])=[O:13]
Reactant: O=C(Cl)c1cccc(Cl)c1Cl
Reactant: N#C[Cu]C#N
Solvent: CC#N
Solvent: Cc1ccccc1
Product: N#CC(=O)c1cccc(Cl)c1Cl

Procedure:
In a mixture of 128 gm. of copper cyanide, 120 ml. of acetonitrile and 200 ml. of toluene, the solution of 200 gm. of 2,3-dichlorobenzoylchloride (II) in 250 ml of toluene was added. The reaction mixture was refluxed for 16 hour. After filtration, the solvent was removed under reduced pressure to give 200 ml of oily 2,3-dichlorobenzoyl cyanide (III).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[I-].[C:8]1([CH2:14][C:15]([NH:17][CH:18]2[C:61](=[O:62])[N:20]3[C:21]([C:45]([O:47][CH:48]([C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=4)[C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)=[O:46])=[C:22]([CH2:25][P+:26]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:23][S:24][C@H:19]23)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O.C(Cl)Cl>[C:8]1([CH2:14][C:15]([NH:17][CH:18]2[C:61](=[O:62])[N:20]3[C:21]([C:45]([O:47][CH:48]([C:55]4[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=4)[C:49]4[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=4)=[O:46])=[C:22]([CH:25]=[P:26]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH2:23][S:24][C@H:19]23)=[O:16])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=P(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
14.0 g (0.132 mol) of Na2CO3, dissolved in 150 ml of water, are added to a suspension of 78.0 g (0.088 mol) of benzhydryl 7-phenylacetamido-3-(triphenylphosphonio)methyl-3-cephem-4-carboxylate iodide (Example 7) in 400 ml of methylene chloride and the mixture is stirred vigorously at room temperature for 15 minutes. The CH2Cl2 layer is separated off, the aqueous phase is extracted again with 200 ml of CH2Cl2 and the combined organic phases are dried over sodium sulphate. The methylene chloride phase is concentrated to dryness and the residue is stirred in about 600 ml of acetone for 1 hour. The product is filtered off with suction and rinsed thoroughly with acetone.
Reaction SMILES: [F:1][C:2]1([F:17])[CH2:4][C@@H:3]1[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=1.C1COCC1.[OH-].[Na+].Cl>CO>[F:1][C:2]1([F:17])[CH2:4][C@@H:3]1[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(OC[C@H]2CC2(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OC[C@H]2CC2(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.1 %

Procedure:
A mixture of methyl 4-(((1R)-2,2-difluorocyclopropyl)methoxy)benzoate (637 mg), THF (10 mL), methanol (10 mL) and 1M aqueous sodium hydroxide solution (10 mL) was stirred at room temperature overnight. The reaction mixture was neutralized with 1M hydrochloric acid at 0° C., and the mixture was extracted with ethyl acetate. The combined organic layer were washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (559 mg).
Reaction SMILES: [C:1]1([CH:7]([CH3:10])[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:11]Br>CCCCCC.Br.C(OCC)(=O)C>[Br:11][C:4]1[CH:5]=[CH:6][C:1]([CH:7]([CH3:10])[CH2:8][NH2:9])=[CH:2][CH:3]=1
Reactant: CC(CN)c1ccccc1
Reactant: BrBr
Agent: Br
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(CN)c1ccc(Br)cc1
Yield: 23 %

Procedure:
2-Phenyl-propylamine (1 g, 7.4 mmol) was dissolved in n-hexane (30 mL) and HBr/aq (5 drops) together with ZnBr on silica (1.75 mmol/g, 1 g). Br2 (14.8 mmol, 900 μL) was slowly added and the slurry was stirred over night. The slurry was diluted with ethyl acetate (300 mL) and washed with 2M Na2CO3 (300 mL). The organic phase was dried over Na2SO4, filtered and evaporated to dryness. Purification and separation of regioisomers was done on semi prep-HPLC C18-column (H2O:CH3CN, 1% NH4OAc buffer, gradient 10% to 60% CH3CN, 30 min). Yield 23%
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:26])([CH3:25])[C:23]#[N:24])=[C:18]([F:27])[CH:17]=3)[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28][C:29]1[CH:30]=[N:31][C:32]2[N:33]([N:35]=[C:36]([CH:38]=O)[N:37]=2)[CH:34]=1>CO>[CH:1]1([C:6]2([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:26])[C:23]#[N:24])=[C:18]([F:27])[CH:17]=3)[CH2:11][C:10]([OH:12])=[C:9]([CH2:38][C:36]3[N:37]=[C:32]4[N:31]=[CH:30][C:29]([CH3:28])=[CH:34][N:33]4[N:35]=3)[C:8](=[O:13])[O:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1cnc2nc(C=O)nn2c1
Reactant: CC(C)(C#N)c1ccc(OCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F
Solvent: CO
Product: Cc1cnc2nc(CC3=C(O)CC(COc4ccc(C(C)(C)C#N)c(F)c4)(C4CCCC4)OC3=O)nn2c1
Reaction time: 5 h
Yield: 32.4 %

Procedure:
A solution of 2-[4-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-ylmethoxy)-2-fluoro-phenyl]-2-methyl-propionitrile (200 mg, 0.54 mmol) in anhydrous MeOH (4.0 mL) was treated with 6-Methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (140 mg, 0.86 mmol), followed by borane-dimethylamine complex (47 mg, 0.8 mmol) at room temperature. The reaction was stirred for 5 hours before it was quenched by the addition of 0.5N HCl (25 mL). The mixture was extracted with 10% MeOH in CH2Cl2 (3×10 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by crystallization from EtOAc/Hexanes to give the product as a white solid (91 mg, 32% yield). 1H NMR (300 MHz, DMSO-d6) δ: 1.67 (m, 8 H), 1.70 (s, 6 H), 2.38 (s, 3 H), 2.55 (m, 1 H), 2.77 (m, 2 H), 3.77 (m, 2 H), 4.12 (m, 1 H), 4.44 (m, 1 H), 6.97 (m 2 H), 7.35 (m, 1 H), 8.69 (s, 1 H), 9.03 (s, 1 H), 10.98 (brs, 1 H).
Reaction SMILES: O.[C:2]([OH:6])(=[O:5])[CH:3]=O.[NH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.[S:12]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13]1>C(Cl)Cl>[N:7]1([CH:3]([C:14]2[CH:15]=[CH:16][S:12][CH:13]=2)[C:2]([OH:6])=[O:5])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: C1CCNC1
Reactant: OB(O)c1ccsc1
Reactant: O=CC(=O)O
Solvent: O
Solvent: ClCCl
Product: O=C(O)C(c1ccsc1)N1CCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.4 %

Procedure:
A mixture of glyoxylic acid monohydrate (10.79 g, 0.11 mol) and pyrrolidine (9.69 mL, 0.11 mol) in DCM (375 mL) was sonicated for 15 minutes. Thiophene-3-boronic acid (15 g, 0.11 mol) was added and the mixture was stirred at rt for 24 h. The solid was filtered and washed with little DCM to gave 38 g crude product as crop-1. The mother liquor concentrated under reduced pressure to give an additional 4 g as crop-2. The combined crude product purified by Biotgae SNAP 100 g silica column (gradient 0-50% MeOH in DCM) gave the title compound as a cream solid (21.7 g, 70%). 1H NMR (400 MHz, CD3OD) δ ppm 7.66 (dd, J=2.8 Hz, J=1.2 Hz, 1H), 7.53 (dd, J=5.2 Hz, J=2.8 Hz, 1H), 7.28 (dd, J=5.2 Hz, J=1.2 Hz, 1H), 4.65 (s, 1H), 3.06 (br. s, 2H), 2.04-1.95 (br. s, 4H), 2H merged with solvent peak; MS ESI 212 [M+H]+, calcd for [C10H13NO2S+H]+ 212.07.
Reaction SMILES: [N+]([O-])(O)=O.[F:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH2:15])=[NH:14])=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17].CN(C)[CH:21]=[CH:22][C:23]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)=O>>[F:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[N:15]=[C:23]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[CH:22]=[CH:21][N:14]=2)=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17]
Reactant: N=C(N)Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: CN(C)C=CC(=O)c1cccnc1
Solvent: O=[N+]([O-])O
Product: O=[N+]([O-])c1cc(Nc2nccc(-c3cccnc3)n2)ccc1F
Yield: 63 %

Procedure:
4-Fluoro-3-nitrophenyl-guanidine nitrate (40 g, 0.153 mol) and 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one (27 g, 0.153 mol) were reacted according to the same procedure as Step 1.3 of Preparation 1 to give N-(4-fluoro-3-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine (30 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7](Cl)=[O:8])([O-:3])=[O:2].[C:16]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:18])[CH3:17].[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[C:16]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:7]([C:6]2[CH:10]=[CH:11][C:12]([N+:13]([O-:15])=[O:14])=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:8])=[CH:22][CH:21]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Nc1ccccc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C(=O)c2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)cc1
Temperature: 40 °C
Yield: 6.6 %

Procedure:
A mixture of 3,4-dinitrobenzoyl chloride (4 mmol), acetoanilide (540 mg, 4 mmol), and AlCl3 (1.6 g) in CH2Cl2 was heated at 40° C. for 24 h. The slurry was washed with HCl (aq) and the product was extracted with ether. It was washed with K2CO3 (aq), dried, and evaporated. Purification by column-chromatography on silica-gel (hexane:AcOEt=1:3) provided 87 mg of the title compound; MS m/e 328 (M−1).
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:12]([OH:14])=O)[CH:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:47][C:48]1[C:49]([CH3:57])=[N:50][N:51]([CH2:54][CH2:55][OH:56])[C:52]=1[CH3:53]>C(Cl)Cl.O>[OH:56][CH2:55][CH2:54][N:51]1[C:52]([CH3:53])=[C:48]([NH:47][C:12]([C:8]2[N:9]=[CH:10][O:11][C:7]=2[C:3]2[CH:2]=[C:1]([CH3:15])[CH:6]=[CH:5][CH:4]=2)=[O:14])[C:49]([CH3:57])=[N:50]1
Reactant: Cc1cccc(-c2ocnc2C(=O)O)c1
Reactant: Cc1nn(CCO)c(C)c1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: Cc1cccc(-c2ocnc2C(=O)Nc2c(C)nn(CCO)c2C)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 5-(m-tolyl)oxazole-4-carboxylic acid (550 mg, 2.71 mmol) in DCM (15 mL), TBTU (1.303 g, 4.06 mmol) and DIPEA (1.39 mL, 8.12 mmol) was added. After stirring for 40 min at rt, 2-(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)ethanol (420 mg, 2.71 mmol) dissolved in DCM (5 mL) was added to the solution and the resulting mixture was stirred at rt for 1 h. The reaction mixture was diluted with DCM and water, the organic layer was separated and the aq. layer was extracted with DCM (2×). The combined org. layers were washed with brine, dried (MgSO4), filtered and the solvent was removed under reduced pressure. Purification by FC (DCM/MeOH 92:8) yielded the title compound as a white solid. LC-MS conditions A: tR=0.70 min, [M+H]+=341.46.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][C:35]([F:38])([F:37])[F:36])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:39][S:40]([CH2:43][CH2:44][CH2:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)(=[O:42])=[O:41]>>[ClH:22].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:49]3[CH2:48][CH2:47][N:46]([CH2:45][CH2:44][CH2:43][S:40]([CH3:39])(=[O:41])=[O:42])[CH2:51][CH2:50]3)=[O:31])[C@H:13]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C@H:14]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[N:15]=2)=[C:7]([O:33][CH2:34][C:35]([F:36])([F:38])[F:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)CCCN1CCNCC1
Reactant: CC(C)(C)c1ccc(C2=N[C@@H](c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)Cl)c(OCC(F)(F)F)c1
Product: CC(C)(C)c1ccc(C2=N[C@@H](c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)N2CCN(CCCS(C)(=O)=O)CC2)c(OCC(F)(F)F)c1
Product: Cl

Procedure:
[(4S,5R)-2-[4-tert-Butyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(3-methanesulfonyl-propyl)-piperazin-1-yl]-methanone hydrochloride was prepared from (4S,5R)-2-[4-tert-butyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12l) and 1-(3-methanesulfonyl-propyl)-piperazine (example 16e) in an analogous manner as described in example 25. LR-MS: 753.4 [(M+H)+]