Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].F[C:19]1[CH:20]=[CH:21][C:22]([N+:28]([O-:30])=[O:29])=[C:23]([CH:27]=1)[C:24]([OH:26])=[O:25].Cl>CS(C)=O.C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([O:10][C:19]3[CH:20]=[CH:21][C:22]([N+:28]([O-:30])=[O:29])=[C:23]([CH:27]=3)[C:24]([OH:26])=[O:25])=[N:7][C:6]=2[CH:11]=1
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: O=c1[nH]c2cc(Cl)ccc2o1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1cc(Oc2nc3cc(Cl)ccc3o2)ccc1[N+](=O)[O-]
Reaction time: 18 h

Procedure:
A reactor is charged with 1.69 grams (0.01 mole) of 5-chlorobenzoxazol-2-one (Formula II Compound), 10 milliliters of dimethylsulfoxide, and 2.76 grams (0.02 mole) of anhydrous potassium carbonate. To this mixture is added 1.85 grams (0.01 mole) of 5-fluoro-2-nitrobenzoic acid (Formula III Compound) in 4 milliliters of dimethylsulfoxide. After stirring at about 75° C. to 80° C. for about 18 hours, the reaction mixture is stripped of solvent and the residue is dissolved in a mixture of methylene chloride and water. The mixture is acidified to pH 2 to 3 with 5 normal hydrochloric acid and the aqueous phase is extracted with methylene chloride. The combined organic phases are washed with water and saturated sodium chloride solution. Filtration and removal of solvent affords 5-(5-chloro-2-benzoxazolyloxy)-2nitrobenzoic acid. (Formula IV Compound);
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10](Br)[CH:9]=1)(=[O:3])[CH3:2].[N:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([C:30]2[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=2)[CH:9]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1ccncc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccnc(Br)c1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccnc(-c2ccncc2)c1

Procedure:
By carrying out the operation analogously to example 1, starting from 2-bromo-4-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation VII, and 4-pyridineboronic acid, the desired product is obtained in the form of a white solid (yield=53%).
Reaction SMILES: C([O:3][C:4]([CH2:6][O:7][C:8]1[CH:31]=[CH:30][C:11](/[CH:12]=[CH:13]/[C:14]2[N:22]([CH3:23])[C:21]3[C:20](=[O:24])[N:19]([CH2:25][CH3:26])[C:18](=[O:27])[N:17]([CH2:28][CH3:29])[C:16]=3[N:15]=2)=[CH:10][CH:9]=1)=[O:5])C.O.[OH-].[Li+].Cl>O1CCCC1.C(O)C.O>[C:4]([CH2:6][O:7][C:8]1[CH:31]=[CH:30][C:11](/[CH:12]=[CH:13]/[C:14]2[N:22]([CH3:23])[C:21]3[C:20](=[O:24])[N:19]([CH2:25][CH3:26])[C:18](=[O:27])[N:17]([CH2:28][CH3:29])[C:16]=3[N:15]=2)=[CH:10][CH:9]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)COc1ccc(/C=C/c2nc3c(c(=O)n(CC)c(=O)n3CC)n2C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CCn1c(=O)c2c(nc(/C=C/c3ccc(OCC(=O)O)cc3)n2C)n(CC)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.4 %

Procedure:
Compound 180 (200 mg, 0.47 mmol) obtained in Reference Example 119 was dissolved in a mixed solvent of 4 ml of tetrahydrofuran, 4 ml of ethanol, and 2 ml of water. To the solution was added 98 mg (2.34 mmol) of lithium hydroxide monohydrate, and the mixture was stirred at room temperature for one hour. To the reaction solution was added 2N hydrochloric acid, and the mixture was extracted with chloroform and dried over anhydrous sodium sulfate, followed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent:chloroform/methanol/acetic acid) to give 40 mg (yield 21%) of Compound 181 as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[S-:14][C:15]#[N:16].[NH4+]>ClC1C=CC=CC=1C>[C:3]1([CH3:8])[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:15]([NH2:16])=[S:14].[C:3]1([CH3:8])[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8])[C:15]([NH2:16])=[S:14]
Reactant: N#C[S-]
Reactant: Cc1ccccc1N
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: Cc1ccccc1Cl
Product: Cc1ccccc1N(C(N)=S)c1ccccc1C
Product: Cc1ccccc1NC(N)=S
Yield: 4 %

Procedure:
In accordance with the process of Example 1 except using 107.2 g of o-toluidine, 250 ml of o-chlorotoluene, 51.6 g of conc. sulfuric acid and 87.5 g of ammonium thiocyanate and reacting them at 90° to 100° C. for 10 hours to obtain o-tolylthiourea having a purity of 95.8% (4.0% of N,N-di-o-tolylthiourea) in an yield of 70.6% as a pure product. The separation of ditolylthiourea was not satisfactory and the yield was low.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)[N:6]2[N:5]=1)=O.[CH3:21][N:22]1[C:26]2[CH:27]=[C:28]([NH2:31])[CH:29]=[CH:30][C:25]=2[N:24]=[CH:23]1>>[CH3:20][O:19][C:16]1[N:15]=[CH:14][C:13]([C:12]2[N:6]3[C:7]([CH:8]=[N:9][C:4]([NH:31][C:28]4[CH:29]=[CH:30][C:25]5[N:24]=[CH:23][N:22]([CH3:21])[C:26]=5[CH:27]=4)=[N:5]3)=[CH:10][CH:11]=2)=[CH:18][CH:17]=1
Reactant: COc1ccc(-c2ccc3cnc(S(C)=O)nn23)cn1
Reactant: Cn1cnc2ccc(N)cc21
Product: COc1ccc(-c2ccc3cnc(Nc4ccc5ncn(C)c5c4)nn23)cn1

Procedure:
Following the synthetic and purification procedures described in Example 1293d, 2-methanesulfinyl-7-(6-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazine (60 mg, 0.2 mmol) was coupled to 3-methyl-3H-benzimidazol-5-ylamine (53 mg, 0.36 mmol) at 105° C. for 86 h to afford the title compound. Yield of TFA salt: 33 mg (34%) of brown powder. LC/MS: 372 (M+H); HPLC: 95% pure, RT=2.29 min; 1H NMR: (DMSO, δ) 10.04 (s, 1H), 9.34 (s, 1H), 9.22 (d, J=2.0, 1H), 9.06 (s, 1H), 8.51 (s, 1H), 8.35 (dd, J=8.9, 2.4, 1H), 7.79 (d, J=9.0, 1H), 7.64 (dd, J=9.0, 1.4, 1H), 7.24 (d, J=4.9, 1H), 7.05 (s, 1H), 7.03 (d, J=4.9, 1H), 4.06 (s, 3H), 3.95 (s, 3H).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([OH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:17][CH2:18][CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1)[CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH2:25][C:24]2[CH:23]=[CH:22][C:21]([O:20][CH2:19][CH2:18][O:17][CH2:14][CH2:15][CH3:16])=[CH:28][CH:27]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1ncc(O)c(Cl)c1=O
Reactant: CCCOCCOc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOCCOc1ccc(COc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Reaction time: 3 h
Yield: 35.9 %

Procedure:
In 30 ml of N,N-dimethylformamide were dissolved 2.0 g of 2-t-butyl-4-chloro-5-hydroxy-3(2H)-pyridazinone and 3.0 g of 4-(2-propoxyethoxy)-benzyl bromide, and then 2.0 g of anhydrous potassium carbonate was added thereto. The mixture was heated under stirring on an oil bath at 80° to 90° C. for 3 hours. Then, procedures similar to those in Preparation Example 2 were carried out to obtain 1.4 g of the aimed product as an oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][C:6]=2[CH:7]=1.Cl.[NH2:15][OH:16].C(N(CC)C(C)C)(C)C>C(O)C>[OH:16][NH:15][C:12]([C:9]1[CH:10]=[CH:11][C:5]2[O:4][C:3]([CH2:2][OH:1])=[CH:7][C:6]=2[CH:8]=1)=[NH:13]
Reactant: NO
Reactant: N#Cc1ccc2oc(CO)cc2c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: N=C(NO)c1ccc2oc(CO)cc2c1
Temperature: 71 °C
Reaction time: 3 h
Yield: 76.4 %

Procedure:
A mixture of the product of Step B (0.22 g; 1.27 mmol) and HCl×NH2OH (0.18 g; 2.59 mmol) and N,N-diisopropylethylamine (DIPEA) (0.67 ml; 3.82 mmol) in ethanol (EtOH) (2 ml) was stirred for 3 h at ˜71° C. The solvents were removed in vacuo and the residue was treated with H2O (3 ml) and the product was taken up by EtOAc (3×15 ml). The combined organic phase was washed with brine, dried over anhydrous MgSO4, filtered and filtrate evaporated to dryness to give the title compound (0.2 g; 76%), as colourless solid, which was used in the next step without further purification.
Reaction SMILES: C1C[C@H](C(O)=O)CC[C@H]1CN.[CH3:12][CH:13]([CH3:33])[C:14]([O:16][C@H:17]([CH3:32])[O:18][C:19]([NH:21][CH2:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([C:29]([OH:31])=[O:30])[CH2:25][CH2:24]1)=[O:20])=[O:15].C(=O)(O)[O-].[Na+:38].C(#N)C>O>[CH3:12][CH:13]([CH3:33])[C:14]([O:16][C@@H:17]([O:18][C:19]([NH:21][CH2:22][C@H:23]1[CH2:24][CH2:25][C@H:26]([C:29]([O-:31])=[O:30])[CH2:27][CH2:28]1)=[O:20])[CH3:32])=[O:15].[Na+:38]
Reactant: CC(C)C(=O)O[C@H](C)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)C(=O)O[C@H](C)OC(=O)NC[C@H]1CC[C@H](C(=O)[O-])CC1

Procedure:
Following the general procedure for the formation of the corresponding sodium carboxylates of acyloxyalkyl carbamates of tranexamic acid, 90.0 mg (0.2854 mmol) of (+)-trans-4-({[(15)-1-(2-methylpropanoyloxy)ethoxy]carbonylamino}methyl)-cyclohexanecarboxylic acid 15 was reacted with 24.0 mg (0.2854 mmol) of sodium bicarbonate (NaHCO3) in 4 mL of a mixture of acetonitrile and water (1:1) to yield 96.3 mg (quant.) of the title compound 16 as a colorless powder. The enantiomeric excesses were determined with an analytical Waters 2690/ZQ LC/MS apparatus using a ChiralPak AD-RH column, an isocratic eluent consisting of 30% acetonitrile/70% water/0.05% formic acid, and a flowrate of 60 μL/min (Rf=12.1 min; e.e.=98.5%). 1H NMR (400 MHz, DMSO-d6): δ=0.72-0.84 (br. m, 2H), 1.057 (d, J=6.4 Hz, 3H), 1.059 (d, J=6.8 Hz, 3H), 1.20-1.32 (br. m, 3H), 1.38 (d, J=5.2 Hz, 3H), 1.59-1.73 (br. m, 3H), 1.75-1.83 (m, 2H), 2.43-2.53 (m, 1H), 2.72-2.84 (br. m, 2H), 6.62 (q, J=5.6 Hz, 1H), 7.42 (t, J=5.6 Hz, 1H). MS (ESI) m/z 338.16 (M+Na)+; 314.12 (M−H)−.
Reaction SMILES: Br[CH2:2][C:3](Br)=[O:4].[CH2:6]([NH:13][CH2:14][CH3:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:16][O:17][C:18]1[N:23]=[CH:22][C:21]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])(=[O:27])=[O:26])=[CH:20][CH:19]=1>>[CH2:6]([N:13]([CH2:14][CH3:15])[C:3](=[O:4])[CH2:2][N:24]([C:21]1[CH:22]=[N:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1)[S:25]([C:28]1[C:29]([CH3:34])=[CH:30][CH:31]=[CH:32][CH:33]=1)(=[O:26])=[O:27])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCNCc1ccccc1
Reactant: O=C(Br)CBr
Reactant: COc1ccc(NS(=O)(=O)c2ccccc2C)cn1
Product: CCN(Cc1ccccc1)C(=O)CN(c1ccc(OC)nc1)S(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of 2-bromoacetyl bromide with N-benzyl-N-ethylamine and N-(6-methoxy-pyridin-3-yl)-2-methyl-benzenesulfonamide
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1.[CH:32]([NH2:35])([CH3:34])[CH3:33]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH2:28][NH:35][CH:32]([CH3:34])[CH3:33])=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1
Reactant: CC(C)N
Reactant: O=Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1
Product: CC(C)NCc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1

Procedure:
The title compound was prepared following the procedure described for Example 94, but starting from 4-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde, obtained as described in Example 113, Step 1, (200 mg; 0.48 mmol) and iso-propylamine (57.3 mg; 0.97 mmol) to give Example 165 as a yellow solid. 1H NMR: (CDCl3, 400 MHz) δ 8.72 (2H, dd, J=4.6, 1.6 Hz), 8.05 (2H, d, J=8.1 Hz), 7.64-7.53 (2H, m), 7.46 (2H, d, J=8.0 Hz), 7.39-7.34 (3H, m), 7.22-7.16 (1H, m), 3.86 (2H, s), 2.92-2.85 (1H, m), 1.12 (6H, d, J=6.3 Hz). LC/MS (Method C): 456 (M+H)+. HPLC (Method I) Rt 11.31 min (Purity: 91.3%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([CH:25]=[O:26])=[CH:11][C:12]3[N:16]([CH2:17][CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:15]=[N:14][C:13]=3[C:23]=2[F:24])=[C:4]([Cl:27])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].S([CH2:44][N+:45]#[C-:46])(C1C=CC(C)=CC=1)(=O)=O>CO>[F:24][C:23]1[C:13]2[N:14]=[CH:15][NH:16][C:12]=2[CH:11]=[C:10]([C:25]2[O:26][CH:46]=[N:45][CH:44]=2)[C:9]=1[NH2:8].[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:25]3[O:26][CH:46]=[N:45][CH:44]=3)=[CH:11][C:12]3[N:16]([CH2:17][CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:15]=[N:14][C:13]=3[C:23]=2[F:24])=[C:4]([Cl:27])[CH:3]=1
Reactant: CS(=O)(=O)CCn1cnc2c(F)c(Nc3ccc(Br)cc3Cl)c(C=O)cc21
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CS(=O)(=O)CCn1cnc2c(F)c(Nc3ccc(Br)cc3Cl)c(-c3cnco3)cc21
Product: Nc1c(-c2cnco2)cc2[nH]cnc2c1F
Temperature: 25 °C
Yield: 18 %
Yield: 4 %

Procedure:
6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(2-methanesulfonyl-ethyl)-3H-benzoimidazole-5-carbaldehyde 10z (0.025 g, 0.053 mmol) is suspended in MeOH (2 mL) and K2CO3 (0.015 g, 0.105 mmol) is added following by tosylmethyl isocyanide (0.011 g 0.058 mmol). The reaction mixture is heated to reflux under N2 for 16 hours. After cooling additional tosylmethyl isocyanide (0.011 g, 0.058 mmol) is added and the reaction mixture heated to reflux under N2 for 16 hours. The reaction mixture is cooled to room temperature, concentrated under reduced pressure and dissolved in ethyl acetate. The organic solution is washed with water and brine. The combined aqueous washes are extracted with ethyl acetate. The combined organic extracts are dried (Na2SO4) and concentrated under reduced pressure. Purification by flash column chromatography eluted with 20:1 methylene chloride:MeOH gives 4 mg (18%) desired product 10x and 1 mg (4%) (4-bromo-2-chloro-phenyl)-[4-fluoro-1-(2-methanesulfonyl-ethyl)-6-oxazol-5-yl-1H-benzoimidazol-5-yl]-amine.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[CH3:10].[C:11](=[O:13])=[O:12]>O1CCCC1.BrC(Br)C.BrC1C=CC(F)=CC=1C>[CH3:10][C:4]1[CH:5]=[C:6]([F:9])[CH:7]=[CH:8][C:3]=1[C:11]([OH:13])=[O:12]
Reactant: O=C=O
Reactant: Cc1cc(F)ccc1Br
Agent: CC(Br)Br
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1C(=O)O
Temperature: 55 °C

Procedure:
To a flask fit with a reflux condenser and addition funnel was added magnesium (2.6 g, 106 mmol) and tetrahydrofuran (10 mL). A solution of 2-bromo-5-fluorotoluene (1.0 g, 5.3 mmol) in tetrahydrofuran (2 mL) and dibromoethane (0.04 mL) was added. The solution was warmed gently in a 55° C. oil bath until a vigorous reflux began. A solution of 2-bromo-5-fluorotoluene (9.0 g, 48 mmol) in tetrahydrofuran (18 mL) was added dropwise to maintain a gentle reflux. After addition was complete, the reaction mixture was heated in a 55° C. oil bath for 1 h. The reaction mixture was allowed to cool to room temperature and poured onto crushed dry ice (50 mL). The excess dry ice was allowed to sublime. The solution was partitioned between ethyl acetate (100 mL) and 3% HCl (50 mL). The organic layer was washed with brine, dried over magnesium sulfate, and the solvent was removed in vacuo. to afford the title compound (8.3 g) in quantitative yield. Rf=0.34 (silica gel, 5% isopropanol/dichloromethane).
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C)C=O>[OH:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: OCCCCCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCCCCCCCCOCc1ccccc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
16 g (100 mmol) of nonane-1,9-diol was dissolved in 150 ml of dimethylformamide and instilled in a suspension of 2.88 g (1.20 mmol) of sodium hydride in 100 ml of DMF. It is stirred for 2 hours at 50° C. It is cooled in an ice bath to 0° C. and 17.1 g (100 mmol) of benzyl bromide is instilled within 3 hours. Then, it is stirred for 5 hours at 60° C. The solution is cooled to room temperature, 1 l of water is added and it is extracted 3 times with 150 ml of ether. The combined organic phases are dried on magnesium sulfate and concentrated by evaporation in a vacuum. The remaining oil is chromatographed on silica gel (mobile solvent: hexane/acetone=15:1).
Reaction SMILES: COP([CH2:7][C:8](=[O:29])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[N:14]=1)(=O)OC.[N:30]1[CH:35]=[C:34](C=O)[CH:33]=[N:32][CH:31]=1.[C:38]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][NH:19][C:15]2[N:14]=[C:13]([CH2:12][CH2:11][CH2:10][CH2:9][C:8](=[O:29])[CH:7]=[CH:38][C:35]3[CH:34]=[CH:33][N:32]=[CH:31][N:30]=3)[CH:18]=[CH:17][CH:16]=2)=[CH:26][CH:25]=1
Reactant: O=Cc1cncnc1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(CNc2cccc(CCCCC(=O)CP(=O)(OC)OC)n2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CNc2cccc(CCCCC(=O)C=Cc3ccncn3)n2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.6 %

Procedure:
To a solution of 6-7 (1.87 g, 4.44 mmol), pyrimidine-5-carbaldehyde (0.480 g, 4.44 mmol) in 15 mL DMF was added K2CO3 (0.922 g, 6.67 mmol). The mixture was stirred at ambient temperature for 15 hr, and concentrated to a paste. The residue was diluted with water, extracted with ethyl acetate, and dried over sodium sulfate. Following concentration, the residue was chromatographed on silica gel (5% MeOH/CH2Cl2) to give 1.44 g of 6-8 as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([I:12])[CH:11]=1)[C:5](OC)=[O:6].O.[NH2:14][NH2:15].O>C(O)C>[I:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([I:12])[CH:11]=1)[C:5]([NH:14][NH2:15])=[O:6]
Reactant: NN
Reactant: COC(=O)c1cc(I)cc(I)c1
Solvent: CCO
Solvent: O
Product: NNC(=O)c1cc(I)cc(I)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To Methyl 3,5-diiodobenzoate (5.0 g, 12.89 mmol) in ethanol (70.0 ml) was added hydrazine hydrate (20.0 ml) under stirring. During heating, white solid was appeared. The reaction was kept 50° C. for 1 h. Heating was stopped and then water (100.0 ml) was added. After cooling down to room temperature, the white product solid was collected by filtration. The product was washed with water and dried under vacuum. Final white product was obtained in 4.6 g (92.0%). 1H NMR (400 MHz, DMSO-d6, δ): 9.92 (s, 1H, NH), 8.22 (t, J=1.6 Hz, 1H), 8.12 (d, J=1.6 Hz, 2H), 4.53 (s, 2H, NH2).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[C:10]([C:15]2[O:19][C:18](/[CH:20]=[CH:21]/[NH2:22])=[CH:17][CH:16]=2)[CH:11]=[CH:12][C:13]=1[Cl:14].CO.O>C1COCC1>[Cl:7][C:8]1[CH:9]=[C:10]([C:15]2[O:19][C:18]([CH2:20][CH2:21][NH2:22])=[CH:17][CH:16]=2)[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: N/C=C/c1ccc(-c2ccc(Cl)c(Cl)c2)o1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 11 %

Procedure:
To a suspension of lithium aluminium hydride (0.939 g, 24.8 mmol) in THF (20 ml) under nitrogen atmosphere at 0° C. was added slowly a solution of (E)-2-(5-(3,4-dichlorophenyl)furan-2-yl)ethenamine in THF (20 ml). Reaction mixture was stirred at RT for 1 h. Some methanol was added slowly to the mixture followed by addition of water. The mixture was evaporated, and the solid residue was extracted with EtOAc (3×). Combined EtOAc fractions were washed with 2M NaOH and brine. Organic phase was dried over Na2SO4, evaporated and purified by chromatography (CombiFlash, silica column, eluent: 10-20% MeOH/DCM) to give 227 mg (11%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 2.74 (t, 2H), 2.85 (t, 2H), 6.29 (d, 1H), 7.03 (d, 1H), 7.62 (dd, 1H), 7.63 (d, 1H), 7.88 (d, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH3:15])([CH3:14])[C:12](=[O:16])[N:11]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=3)[C:10]2=[S:29])=[CH:5][C:4]=1[F:30].[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.C(O)(C(F)(F)F)=O.C(#N)C>C1(C)C=CC=CC=1>[F:30][C:4]1[CH:5]=[C:6]([N:9]2[C:13]([CH3:14])([CH3:15])[C:12](=[O:16])[N:11]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:27])([F:28])[F:26])[CH:18]=3)[C:10]2=[S:29])[CH:7]=[CH:8][C:3]=1[CH2:2][N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1c1ccc(CCl)c(F)c1
Reactant: C1CCNC1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1c1ccc(CN2CCCC2)c(F)c1
Reaction time: 0.17 h

Procedure:
Compound 6 was prepared according to General Method 2. A solution of 4-(3-(4-(chloromethyl)-3-fluorophenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (100 mg, 0.21 mmol) and pyrrolidine (78 mg, 1.05 mmol) in toluene (10 mL) was refluxed for 12 h. The solvent was removed and residue was purified by silica gel chromatography (eluant: 60% ethyl acetate in hexane) to obtain 13 mg of 4-(3-(3-fluoro-4-((pyrrolidin-1-yl)methyl)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-trifluoromethyl)benzonitrile, HPLC, Column: SUNFIRE C18, 4.6×250 mm, 5 μm, Mobile Phase A: 0.05% TFA, Mobile Phase B: ACN, Gradient: 10% to 90% B in 10 min, hold for 10 min. 90% to 10% B in 1 min, Flow Rate: 1 mL/min, Retention time: 7.491 min, M+1, 491.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][N:13]2[C:17](=[O:18])[CH2:16][CH2:15][CH:14]2[CH2:19][CH2:20][CH:21]([OH:30])[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:6][CH:5]=1.[OH-].[Na+]>CO>[F:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][CH:21]([OH:30])[CH2:20][CH2:19][CH:14]2[CH2:15][CH2:16][C:17](=[O:18])[N:13]2[CH2:12][CH2:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:31])=[O:2])=[CH:5][CH:6]=2)=[CH:28][CH:27]=1
Reactant: COC(=O)c1ccc(CCCN2C(=O)CCC2CCC(O)Cc2ccc(F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(CCCN2C(=O)CCC2CCC(O)Cc2ccc(F)cc2)cc1
Yield: 76.1 %

Procedure:
Analogous to the procedure described for Example 1A, Step F, 4-(3-{2-[4-(4-fluoro-phenyl)-3-hydroxy-butyl]-5-oxo-pyrrolidin-1-yl}-propyl)-benzoic acid methyl ester (61.1 mg, 0.143 mmol) was hydrolyzed with 6N NaOH (1 mL) in MeOH (5 mL) at room temperature over 24 h. Purification by medium pressure chromatography eluting with a solvent gradient (CH2Cl2 to 2% MeOH in CH2Cl2 to 4% MeOH in CH2Cl2 to 6% MeOH in CH2Cl2 to 10% MeOH in CH2Cl2) provided the title compound (45 mg). 1H NMR (CDCl3) δ7.97 (d, 2H), 7.25 (m, 2H), 7.14 (m, 2H), 6.99 (m, 2H), 3.75–3.58 (m, 3H), 2.97 (m, 1H), 2.69 (m, 4H), 2.40 (m, 2H), 2.15–1.35 (m, 9H); MS 413.8 (M+).