Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([C:11]3[CH:22]=[CH:21][C:14]([O:15][CH:16]=[CH:17][C:18](O)=[O:19])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:23][O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH2:32])[CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:23][O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:18](=[O:19])/[CH:17]=[CH:16]/[O:15][C:14]2[CH:13]=[CH:12][C:11]([C:1]34[CH2:10][CH:5]5[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]5)[CH2:2]3)[CH2:8]4)=[CH:22][CH:21]=2)[CH:27]=1
Reactant: COC(=O)c1cccc(N)c1
Reactant: O=C(O)C=COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc(NC(=O)/C=C/Oc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 10 %

Procedure:
3-(4-Adamantan-1-yl-phenoxy)-acrylic acid (110.6 mg, 0.5 mmol), 3-aminobenzoic acid methyl ester (151.2 mg, 1.0 mmol) and HATU (143.8 mg, 0.75 mmol) were mixed in 5 ml of DMF, to which DIPEA (0.13 ml, 0.75 mmol) was added, followed by stirring for 12 hours at room temperature. The reaction mixture was extracted with ethylacetate and 10% HCl, thereafter the organic layer was washed with NaCl solution and water, dried over anhydrous MgSO4, and concentrated. The residue was purified by silcagel column chromatography (n-Hexane:EtOAc=10:1) to give the target compound as a white solid (21.5 mg, yield: 10.6%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][C:16](C)([CH3:19])[CH2:17][OH:18]>>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:15][CH:16]([CH3:19])[CH2:17][OH:18])=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: CC(C)(N)CO
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Product: CC(CO)Nc1c([N+](=O)[O-])cnc2ccccc12

Procedure:
Using the method of Example 1, 4-chloro-3-nitroquinoline was reacted with 2-amino-2-methyl-1-propanol to afford 2-[(3-nitro-4-quinolinyl)amino]-1-propanol, m.p. 207°-211° C. Analysis: Calculated for C12H13N3O3 : %C, 58.3; %H, 5.3; %N, 17; Found: %C, 58.6; %H, 5.3; %N, 17.2.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([C:12]2[C:13](=[O:27])[C:14]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:15]([C:18]([F:21])([F:20])[F:19])[NH:16][CH:17]=2)=[C:4]([F:28])[CH:3]=1.[H-].[Na+].[CH3:31]I.O>CN(C=O)C>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:10])[CH3:11])=[CH:6][C:5]([C:12]2[C:13](=[O:27])[C:14]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:15]([C:18]([F:21])([F:19])[F:20])[N:16]([CH3:31])[CH:17]=2)=[C:4]([F:28])[CH:3]=1
Reactant: CCOC(=O)c1c(C(F)(F)F)[nH]cc(-c2cc(OC(C)C)c(Cl)cc2F)c1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(F)(F)F)n(C)cc(-c2cc(OC(C)C)c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 13.9 %

Procedure:
20 g (47 mol) of 5-(4-chloro-2-fluoro-5- isopropoxyphenyl)-3-ethoxycarbonyl-2-trifluoromethyl-4(1H)-pyridone was dissolved in 150 ml of DMF, and 2.1 g (53 mmol) of 60% sodium hydride was added thereto under cooling with ice, followed by stirring at room temperature for 15 minutes. Then, 14 g (99 mmol) of methyl iodide was added thereto. After stirring at room temperature for 8 hours, the reaction solution was poured into water and extracted with ethyl acetate. After washing with water, the organic layer was dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and then, the obtained residue was purified by silica gel column chromatography to obtain 6 g (yield: 28%) of the desired product. Melting point: 170-172° C. 1H-NMR (400 MHz, CDCl3) δ value: 1.40(9H,m), 3.85(3H,s), 4.40(2H,q), 4.51(1H,m), 7.17(1H,d), 7.40(1H,d), 7.63(1H,s)ppm.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]([Cl:25])=[C:5]([Cl:24])[C:6]=1[C:7](=[O:23])[C:8]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=1.[H-].[Na+].[CH3:28]I.O>CN(C=O)C>[CH3:28][N:3]1[C:4]([Cl:25])=[C:5]([Cl:24])[C:6]([C:7](=[O:23])[C:8]2[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=2)=[C:2]1[Cl:1]
Reactant: CI
Reactant: CC(C)(C)c1cc(C(=O)c2c(Cl)[nH]c(Cl)c2Cl)cc(C(C)(C)C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(Cl)c(Cl)c(C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,4,5-Trichloro-3-(3,5-di-t-butyl-4-hydroxybenzoyl)pyrrole (3.3 g) dissolved in DMF (35 ml) was treated with sodium hydride (50%, 0.432 g) in 4 portions, under nitrogen with stirring at room temperature. After 1 hour at room temperature, 0.56 ml of methyl iodide was added, dropwise, via microsyringe. After stirring 5 minutes more, the reaction mixture was poured into water (300 ml). The organic layer was separated, dried and evaporated to dryness. The residue was purified on silica gel, eluting with hexane:ethyl acetate (80:20). The pure product was recrystallized from ether-pentane to give 2.73 g of the title compound (mp 155°-156° C.).
Reaction SMILES: O[C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:7][C:8]1[N:13]([CH3:14])[C:12](=[O:15])[CH:11]=[CH:10][N:9]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[CH3:14][N:13]1[C:12](=[O:15])[CH:11]=[CH:10][N:9]2[C:8]1=[N:7][C@@H:3]1[CH2:4][CH2:5][CH2:6][C@@H:2]12
Reactant: Cn1c(N[C@@H]2CCC[C@H]2O)nccc1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CN1C(=O)C=CN2C1=N[C@@H]1CCC[C@@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
To a solution of 2-((1R,2R)-2-hydroxycyclopentylamino)-3-methylpyrimidin-4(3H)-one (130 mg, 0.62 mmol) in anhydrous THF (2 mL) is added triphenylphosphine (163 mg, 0.62 mmol). Five minutes later, diethyl azodicarboxylate (DEAD, 0.45 mL, 0.93 mmol) in toluene is added dropwise. The mixture is stirred at room temperature for 2 hours. Solvent is removed under vacuum, the residue is treated with 0.02 N HCl (40 mL). The precipitate is filtered off, and the filtrate is washed with CH2Cl2. The aqueous phase is evaporated to dryness under high vacuum to give product as solids (108 mg, yield 92%), which is used for the next reaction without further purification. MS (ESI) m/z 192.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9]CC)=O)[N:6]=1.O.[NH3:13]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH2:13])=[O:9])[N:6]=1
Reactant: CCOC(=O)c1csc(N)n1
Reactant: N
Solvent: O
Product: NC(=O)c1csc(N)n1
Yield: 76 %

Procedure:
3.0 g Ethyl 2-aminothiazol-4-carboxylate was added to 100 ml ammonia water, reacted for 2 hr, concentrated, and placed aside to precipitate a needle crystal, which was filtered, washed with water, and dried to obtain 1.9 g 2-aminothiazol-4-carboxamide (yield 76%) with mp 208-211° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[OH-].[K+].[I-].[K+].[CH:16]1(Br)[CH2:20][CH2:19][CH2:18][CH2:17]1>C(O)C>[CH:16]1([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[O:10][CH3:11])[CH:5]=[O:6])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: BrC1CCCC1
Reactant: COc1ccc(C=O)cc1O
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C=O)cc1OC1CCCC1
Temperature: 25 °C

Procedure:
To a solution of 54.9 g (0.36 mol) of 3-hydroxy-4-methoxybenzaldehyde in 400 mL of absolute ethanol was added 40.4 g (0.72 mol) of potassium hydroxide, 1.0 g (0.01 mol) of potassium iodide, and 77.0 mL (0.72 mol) of cyclopentyl bromide. The mixture was warmed to reflux for 48 hours at the end of which time the completed reaction was cooled to room temperature and concentrated to a syrup. The resulting residue was dissolved in 500 ml of ethyl acetate, washed with one, 100-mL portion of water, with one, 50-mL portion of dilute hydrochloric acid, with one, 100-mL portion of saturated sodium bicarbonate, and with one, 50-mL portion of saturated sodium chloride. The organic fraction was dried over sodium sulfate and concentrated to dryness. The amber syrup was liquid chromatographed over 500 g of silica gel using 20% ethyl ether in hexane as an eluent to provide the analytically pure oil upon drying in vacuo.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br.BrC[CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.CN(C=O)C.[C:23]1([C:29]2[S:34][C:33]3[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=3[O:31][C:30]=2[C:39]2[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(OCC)(=O)C>[C:23]1([C:29]2[S:34][C:33]3[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=3[O:31][C:30]=2[C:39]2[CH:40]=[CH:41][C:42]([O:45][CH2:15][CH2:16][CH2:17][N:12]3[CH2:11][CH2:10][CH2:14][CH2:13]3)=[CH:43][CH:44]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Oc1ccc(C2=C(c3ccccc3)Sc3ccccc3O2)cc1
Reactant: BrCCCN1CCCCC1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: c1ccc(C2=C(c3ccc(OCCCN4CCCC4)cc3)Oc3ccccc3S2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
Potassium carbonate (83 mg) and 1-(3-bromopropyl)piperidine hydrobromide (54.6 mg) were added to a DMF (3 mL) solution of 4-(3-phenyl-1,4-benzoxathiin-2-yl)phenol (63.7 mg, 0.2 mmol) obtained in Reference Example 1-1, and stirred at 80° C. for 8 hours. The reaction liquid was restored to room temperature, diluted with ethyl acetate, and extracted with distilled water. The organic layer was dried with magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by preparative thin-layer silica gel column chromatography (chloroform:methanol=9:1) to obtain the entitled compound (43.7 mg, 51%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH2:10](O)[CH2:11][OH:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:12][CH2:11][CH2:10][O:6]2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Brc1cccc(C2OCCO2)c1
Yield: 100.6 %

Procedure:
To a stirred solution of 3-bromobenzaldehyde (5.00 g, 27.0 mmol) in toluene (35 ml) was added ethylene glycol (4.52 ml, 81.1 mmol) and p-toluenesulphonic acid (0.5 g). The mixture was heated to reflux for 2 hours, cooled, and washed with water and saturated sodium hydrogen carbonate solution. The organic layer was dried over MgSO4. The solvent was removed under reduced pressure to give the desired product as a colourless oil (6.22 g, 100%). δH (CDCl3) 4.09 (4H, m), 5.79 (1H, s), 7.2-7.7 (4H) ppm.
Reaction SMILES: [N+:1]([C:4]1[O:5][C:6]2[C:18]([CH:19]=O)=[CH:17][CH:16]=[CH:15][C:7]=2[C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O-:3])=[O:2].Cl.[NH2:22][NH:23][C:24]([NH2:26])=[O:25].C([O-])(=O)C.[Na+]>C(O)C>[N+:1]([C:4]1[O:5][C:6]2[C:18]([CH:19]=[N:22][NH:23][C:24]([NH2:26])=[O:25])=[CH:17][CH:16]=[CH:15][C:7]=2[C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O-:3])=[O:2]
Reactant: NNC(N)=O
Reactant: O=Cc1cccc2c(-c3ccccc3)c([N+](=O)[O-])oc12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: NC(=O)NN=Cc1cccc2c(-c3ccccc3)c([N+](=O)[O-])oc12

Procedure:
To a mixture of 2.1 g. (0.0079 mole) of 2-nitro-3-phenylbenzofuran-7-carboxaldehyde in 70 ml. of ethanol is added 1.34 g. (0.012 mole) of semicarbazide hydrochloride and 1.07 g. (0.013 mole) of sodium acetate. The mixture is heated to its reflux temperature and maintained at reflux for 3 hours. The precipitated product is separated by filtration, washed with water and diethyl ether. The solid is washed with hot dichloroethane, separated by filtration, then dissolved in a mixture of 650 ml. of chloroform and 100 ml. of acetone by heating. This solution is washed twice with water, once with sodium bicarbonate solution, again with water, once with dilute hydrochloric acid, and twice with water. The solution is dried and the dry solution is evaporated to provide solid 2-nitro-3-phenylbenzofuran-7-carboxaldehyde semicarbazone, m.p. 249° C. (dec.).
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:15][CH2:14][CH:13]([NH2:16])[CH2:12][CH2:11]2)=[N:3][CH:2]=1.[N:17]1[CH:22]=[C:21]([C:23](O)=[O:24])[CH:20]=[N:19][CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:1]1[C:6]2=[N:7][CH:8]=[CH:9][C:5]2=[C:4]([N:10]2[CH2:11][CH2:12][CH:13]([NH:16][C:23]([C:21]3[CH:22]=[N:17][CH:18]=[N:19][CH:20]=3)=[O:24])[CH2:14][CH2:15]2)[N:3]=[CH:2]1
Reactant: O=C(O)c1cncnc1
Reactant: NC1CCN(c2ncnc3[nH]ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CCN(c2nc[nH]c3nccc2-3)CC1)c1cncnc1
Temperature: 25 °C

Procedure:
To a mixture of 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinamine D2 (65.2 mg), 5-pyrimidinecarboxylic acid (37.2 mg, 0.300 mmol), HATU (137 mg, 0.360 mmol) and HOAt (24.50 mg, 0.180 mmol) in DMF (1.5 mL) was added DIPEA (252 μL, 1.440 mmol). The reaction mixture was stirred at room temperature until reaction was complete then solvent was removed in vacuo. The crude mixture was purified by MDAP using a high pH method to afford E14 (21 mg), 1H NMR (d6-DMSO) δ 11.70 (1H, brs), 9.30 (1H, s), 9.15 (2H, s), 8.65 (1H, d), 8.17 (1H, s), 7.17 (1H, d), 6.60 (1H, d), 4.65 (2H, dt), 4.15 (1H, m), 3.25 (2H, dt), 1.90 (2H, m), 1.55 (2H, m), MS(ES+) 324 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]([CH3:17])=[C:15]2[C:10]([CH:11]=[C:12]([C:18]3[CH:19]=[C:20]([CH:28]4[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]4)[N:21]4[C:26]=3[C:25]([NH2:27])=[N:24][CH:23]=[N:22]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][N:35]([CH3:40])[CH2:36][C:37](O)=[O:38].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:1]([N:8]1[C:16]([CH3:17])=[C:15]2[C:10]([CH:11]=[C:12]([C:18]3[CH:19]=[C:20]([CH:28]4[CH2:33][CH2:32][CH2:31][N:30]([C:37](=[O:38])[CH2:36][N:35]([CH3:40])[CH3:34])[CH2:29]4)[N:21]4[C:26]=3[C:25]([NH2:27])=[N:24][CH:23]=[N:22]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CC(=O)O
Reactant: Cc1c2ccc(-c3cc(C4CCCNC4)n4ncnc(N)c34)cc2nn1Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c2ccc(-c3cc(C4CCCN(C(=O)CN(C)C)C4)n4ncnc(N)c34)cc2nn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 15.8 %

Procedure:
A mixture of 5-(2-benzyl-3-methyl-2H-indazol-6-yl)-7-piperidin-3-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.23 mmol), N,N-dimethylglycine (28 mg, 0.27 mmol), EDCl (48 mg, 0.25 mmol), HOBt (34 mg, 0.25 mmol), and N,N-diisopropylethylamine (119 μL, 0.69 mmol) in DMF (1.5 mL) was stirred at rt for 16 h. The crude mixture was purified by preparative HPLC using a gradient elution from 15% to 45% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 19 mg (16%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 7.92 (d, 1 H), 7.76 (d, 1 H), 7.53 (s, 1 H), 7.25-7.38 (m, 3 H), 7.21 (d, 2 H), 7.08 (d, 1 H), 6.63-6.68 (m, 1 H), 5.63 (s, 2 H), 3.96-4.95 (m, 2 H), 2.83-3.34 (m, 5 H), 2.57-2.77 (m, 4 H), 2.06-2.23 (m, 6 H), 1.69-1.92 (m, 2 H), 1.39-1.64 (m, 1 H); ES-MS m/z 523.41 [M+H]+, HPLC RT (min) 2.20.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:13][C:14]([F:28])([F:27])[C:15]1[CH:26]=[CH:25][C:18]([O:19][CH:20]2[CH2:24][CH2:23][NH:22][CH2:21]2)=[CH:17][CH:16]=1>>[Cl:12][C:9]1[CH:10]=[N:11][C:2]([N:22]2[CH2:23][CH2:24][CH:20]([O:19][C:18]3[CH:17]=[CH:16][C:15]([C:14]([F:13])([F:28])[F:27])=[CH:26][CH:25]=3)[CH2:21]2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: FC(F)(F)c1ccc(OC2CCNC2)cc1
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Product: COC(=O)c1cc(Cl)cnc1N1CCC(Oc2ccc(C(F)(F)F)cc2)C1
Yield: 66 %

Procedure:
The title compound (D91) (230 mg) was prepared according to the experimental procedure described in Description 62 starting methyl 2,5-dichloronicotinate (180 mg, 0.87 mmol) and 3-(4-(trifluoromethyl)phenoxy)pyrrolidine (D57) (242 mg, 1.05 mmol).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[H-].[Na+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[CH2:17]([N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)OB(c2cnn(Cc3ccccc3)c2)OC1(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
Into a 100-mL three neck round-bottom flask, was placed a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.60 g, 18.6 mmol) in THF (50 mL). Sodium hydride (742 mg, 18.6 mmol, 60% dispersion in mineral oil) was carefully added in portions at 0° C. The resulting mixture was stirred for 30 min at 0° C., then benzyl bromide (2.21 mL, 18.6 mmol) was added. The resulting mixture was stirred overnight at room temperature, then carefully quenched with water (10 mL). The pH of the mixture was adjusted to 9-10 with aqueous HCl (2 M) and the aqueous phase was extracted with EtOAc (300 mL). The combined organic layers were washed with brine (2×150 mL), dried (Na2SO4), filtered and concentrated under vacuum. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1/2) as eluent to yield the title compound as a yellow oil (3.47 g, 66%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1)[CH3:2].FC(F)(F)S(O)(=O)=O.[Br:20]N1C(C)(C)C(=O)N(Br)C1=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>ClCCl>[Br:20][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1ccc([N+](=O)[O-])cc1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=S(=O)(O)C(F)(F)F
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCc1ccc([N+](=O)[O-])cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 132.3 %

Procedure:
25 g (165 mmol) of 4-ethylnitrobenzene are placed in 200 ml of dichloromethane in a round-bottomed flask and under a stream of nitrogen. 20 ml (230 mmol) of trifluoromethanesulfonic acid and 33 g (115 mmol) of 1,3-dibromo-5,5-dimethylhydantoin are added and the reaction medium is stirred for 2 hours at room temperature. Saturated aqueous sodium hydrosulfite solution is then added. The phases are separated and the organic phase is neutralized with aqueous 2M sodium carbonate solution and then washed with water. It is then dried over magnesium sulfate, filtered and evaporated. 35 g (92%) of the expected product are obtained in the form of a yellow oil.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([OH:12])=O.[CH2:13]([CH2:15][NH2:16])[OH:14]>>[OH:14][CH2:13][CH2:15][NH:16][C:10]([C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1)=[O:12]
Reactant: O=C(O)c1cc2ccccc2s1
Reactant: NCCO
Product: O=C(NCCO)c1cc2ccccc2s1
Yield: 73 %

Procedure:
2-Benzothiophenecarboxylic acid (3.0 g, 16.8 mmol) and ethanolamine (1.21 ml, 20 mmol) were coupled according to the procedure of Example 17 to 2.7 g (73% yield) of an off-white solid. 1H NMR (DMSO-d6): δ 3.3 (m, CH2), 3.5 (q, CH2), 4.79 (t, NH), 7.1-7.4 (m, 2 Ar H), 7.90 (m, 1 Ar H), 7.95 (m, 1 Ar H), 8.09 (s, 1 Ar H), 8.89 (t, NH) Electrospray Mass Spec: m/z 222.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@@H:22]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23]1)[C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19]CC)=[O:18])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.[ClH:34]>O1CCOCC1>[ClH:34].[ClH:34].[C:1]([O:5][C:6]([N:8]([C@@H:22]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23]1)[C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCCN1CC[C@@H](N(C(=O)OC(C)(C)C)c2ccc(/C=C/C(=O)OCC)cn2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCCN1CC[C@@H](N(C(=O)OC(C)(C)C)c2ccc(/C=C/C(=O)O)cn2)C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-butyl-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (308 mg) in dioxane (7.4 mL) was added 1N sodium hydroxide (2.21 mL). After stirring at 60° C. for 2 hours, the reaction mixture was added H2O (37 mL) and acidified with 1N hydrochloric acid (to pH 1). A resulting mixture was extracted with CHCl3, and the organic layer was dried over MgSO4, filtered, and evaporated in vacuo to give (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-butyl-3-pyrrolidinyl]amino}-3-pyridinyl)acrylic acid dihydrochloride (214 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:21]([C:12]1[CH:13]=[C:14]([C:17]([F:18])([F:19])[F:20])[CH:15]=[CH:16][C:11]=1[O:9][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([Cl:8])=[CH:6][CH:5]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Oc1ccc(Cl)c(Cl)c1
Temperature: 120 °C
Reaction time: 24 h

Procedure:
A mixture of 3,4-dichlorophenol (25 gram (hereinafter g), 0.153 mol), 4-chloro-3-nitrobenzo-trifluoride (52 g, 0.23 mol) and potassium carbonate (63 g, 0.459 mol) in dimethylformamide (450 mL)was stirred under argon at 120° C. for 24 h. The reaction mixture was filtered and the filtrate evaporated. The residue was dissolved in ethyl acetate, washed with water, brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was flash chromatographed (silica gel, methylene chloride/hexane), to give the title compound as a yellow oil.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:8]([CH2:9][OH:10])=[CH:7][C:6]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[N:5]1.[H-].[Na+].O>CN(C)C=O>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:6]2[CH:7]=[C:8]3[CH2:9][O:10][CH2:2][CH2:3][N:4]3[N:5]=2)=[CH:12][CH:13]=1
Reactant: OCc1cc(-c2ccc(F)cc2)nn1CCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(-c2cc3n(n2)CCOC3)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a 100 ml round-bottom flask, 780 mg (3.00 mmol) of [1-(2-chloroethyl)-3-(4-fluorophenyl)-1H-pyrazol-5-yl]methanol are dissolved in 20 ml of N,N-dimethylformamide. Under argon and at 0° C., 120 mg of sodium hydride (3.00 mmol) are then added as a 60% suspension in oil. The mixture is then stirred at 25° C. for 18 h. The reaction mixture is then carefully poured into water and extracted repeatedly with ethyl acetate. The combined organic phases are then dried over Na2SO4 and concentrated. Purification is carried out by silica gel chromatography (cyclohexane/ethyl acetate). This gives 480 mg (49%) of the desired product; log P(HCOOH): 2.01; 1H-NMR (MeCN-d3): δ=7.81-7.77 (m, 2H), 7.15-7.11 (m, 2H), 6.36 (s, 1H), 4.81 (s, 2H), 4.14-4.12 (m, 2H), 4.10-4.08 (m, 2H).
Reaction SMILES: [Cl:1][C:2]([Cl:13])([Cl:12])[CH2:3][O:4][C:5]([NH:7][CH2:8][C:9](O)=[O:10])=[O:6].C(Cl)(=O)C([Cl:17])=O.CN(C=O)C>C(Cl)Cl>[Cl:1][C:2]([Cl:13])([Cl:12])[CH2:3][O:4][C:5]([NH:7][CH2:8][C:9]([Cl:17])=[O:10])=[O:6]
Reactant: O=C(O)CNC(=O)OCC(Cl)(Cl)Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CNC(=O)OCC(Cl)(Cl)Cl

Procedure:
N-(2,2,2-Trichloroethyloxycarbonyl)-glycine (0.75 g, 3 mMol) is suspended in CH2Cl2 (30 ml) and the mixture is stirred under N2 with ice-bath cooling. Oxalyl chloride (0.28 ml, 3.3 mMol) and DMF (0.023 ml, 0.3 mMol) are added thereto, and the mixture is stirred for 1 hour in the cold. The resulting solution is washed with ice-cold water and ice-cold brine, dried briefly over Na2SO4, and filtered. This solution of N-(2,2,2-trichloroethyloxycarbonyl)glycyl chloride is used immediately in the next step.