Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[C:7]([O:13][S:14](=[O:35])(=[O:34])[NH:15][C:16](=[O:33])[CH2:17][C:18]2[C:23]([CH:24]([CH3:26])[CH3:25])=[CH:22][C:21]([CH:27]([CH3:29])[CH3:28])=[CH:20][C:19]=2[CH:30]([CH3:32])[CH3:31])=[C:6]([CH:36]([CH3:38])[CH3:37])[CH:5]=1.C(N(CC)CC)C.Cl.[CH3:47][N:48]([CH3:53])[CH2:49][CH2:50][CH2:51]Cl>CN(C)C=O.O1CCCC1.C(OCC)C>[CH3:47][N:48]([CH3:53])[CH2:49][CH2:50][CH2:51][O:3][C:4]1[CH:5]=[C:6]([CH:36]([CH3:38])[CH3:37])[C:7]([O:13][S:14](=[O:35])(=[O:34])[NH:15][C:16](=[O:33])[CH2:17][C:18]2[C:19]([CH:30]([CH3:32])[CH3:31])=[CH:20][C:21]([CH:27]([CH3:28])[CH3:29])=[CH:22][C:23]=2[CH:24]([CH3:25])[CH3:26])=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1
Reactant: CN(C)CCCCl
Reactant: CC(C)c1cc(C(C)C)c(CC(=O)NS(=O)(=O)Oc2c(C(C)C)cc(O)cc2C(C)C)c(C(C)C)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)c1cc(C(C)C)c(CC(=O)NS(=O)(=O)Oc2c(C(C)C)cc(OCCCN(C)C)cc2C(C)C)c(C(C)C)c1
Reaction time: 16 h
Yield: 31.4 %

Procedure:
Solid sodium hydride (0.16 g, 4 mmol) was added to a solution of [(2,4,6-triisopropyl-phenyl)-acetyl]-sulfamic acid 4-hydroxy-2,6-diisopropyl-phenyl ester (1.0 g, 1.9 mmol) in 50 mL of N,N-dimethylformamide. The resulting mixture was stirred for 1 hour before a mixture of triethylamine (1.08 mL, 7.8 mmol) and 3-dimethylaminopropylchloride hydrochloride (1.22 g, 3.9 mmol) in 75 mL tetrahydrofuran was added dropwise. The resulting mixture was stirred for 16 hours and then concentrated in vacuo. The residue was partitioned between saturated citric acid and dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give an oily solid. Trituration with a small amount of diethyl ether gave 0.36 g of [(2,4,6-Triisopropyl-phenyl)-acetyl]-sulfamic acid 4-(3-dimethylamino-propoxy)-2,6-diisopropyl-phenyl ester as a white foam.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C(O[C:11](=O)[C:12]1[C:17]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:16][C:15]([Cl:22])=[N:14][C:13]=1[CH3:23])(C)C.O=S(Cl)Cl.C([O-])([O-])=O.[Cs+].[Cs+].[CH:35]1[C:42]([CH:43]([CH3:45])[CH3:44])=[CH:41][CH:40]=[C:38]([CH3:39])[C:36]=1[OH:37]>C1COCC1.C(Cl)Cl.O>[Cl:22][C:15]1[N:14]=[C:13]([CH3:23])[C:12]([CH2:11][O:37][C:36]2[CH:35]=[C:42]([CH:43]([CH3:45])[CH3:44])[CH:41]=[CH:40][C:38]=2[CH3:39])=[C:17]([O:18][CH:19]([CH3:21])[CH3:20])[CH:16]=1
Reactant: Cc1ccc(C(C)C)cc1O
Reactant: Cc1nc(Cl)cc(OC(C)C)c1C(=O)OC(C)C
Agent: O=C([O-])[O-]
Agent: [Al+3]
Agent: [Cs+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(C)C)cc1OCc1c(OC(C)C)cc(Cl)nc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
LiAlH4 (14 mL of 1 M solution in THF, 14 mmol) is added to a solution of 6-chloro-4-isopropoxy-2-methyl-nicotinic acid isopropyl ester (2.0 g, 7.4 mmol) in THF (10 mL) at 0° C. The mixture is stirred for 3 hours at ambient temperature. After quenching with water, the mixture is extracted with EtOAc. The combined extracts are washed with saturated brine, dried (Na2SO4), and concentrated to give the crude alcohol as a colorless oil which is dissolved in CH2Cl2 (10 mL) and treated with SOCl2 (2.7 mL, 37 mmol). The mixture is stirred for 1 hour at room temperature and concentrated in vacuo. The residue is dissolved in DMF (15 mL). To this is added Cs2CO3 (7.2 g, 11 mmol) and carvacrol (1.6 g, 11 mmol). The mixture is stirred for 16 hours at room temperature, poured into water, and extracted with Et2O. The combined extracts are washed with saturated brine, dried (Na2SO4), and concentrated in vacuo. The residue is purified by flash chromatography (elution with Hex/EtOAc 6:1) to yield 6-chloro-4-isopropoxy-3-(5-isopropyl-2-methyl-phenoxymethyl)-2-methyl-pyridine. 1H NMR (CDCl3) 7.05 (d, 1H), 6.82 (s, 1H), 6.79 (d, 1H), 6.724 (s, 1H), 5.02 (s, 2H), 4.60 (m, 1H), 2.88 (m, 1H), 2.59 (s, 3H), 2.12 (s, 3H), 1.37 (d, 6H), 1.24 (d, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[C:12]([O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[CH:28]=[C:29]2[CH2:41][CH2:40][C@@H:39]([CH2:42][C:43](O)=[O:44])[N:31]3[C:32](=[O:38])[C:33](=[O:37])[NH:34][C:35]([CH:36]=1)=[C:30]23.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[Cl:26][C:27]1[CH:28]=[C:29]2[CH2:41][CH2:40][C@@H:39]([CH2:42][C:43](=[O:44])[NH:14][C:13]3[CH:15]=[CH:16][C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:11][C:12]=3[O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[N:31]3[C:32](=[O:38])[C:33](=[O:37])[NH:34][C:35]([CH:36]=1)=[C:30]23
Reactant: CC(C)(C)OC(=O)COc1cc(CNC(=O)OC(C)(C)C)ccc1N
Reactant: O=C(O)C[C@@H]1CCc2cc(Cl)cc3[nH]c(=O)c(=O)n1c23
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)COc1cc(CNC(=O)OC(C)(C)C)ccc1NC(=O)C[C@@H]1CCc2cc(Cl)cc3[nH]c(=O)c(=O)n1c23
Temperature: 25 °C
Reaction time: 96 h
Yield: 63.3 %

Procedure:
A mixture of 4-tert-butoxycarbonylaminomethyl-2-tert-butoxycarbonylmethoxyaniline (930 mg, 2.61 mmol), (S)-9-chloro-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (807 mg, 2.74 mmol), Bop-Cl (770 mg, 2.99 mmol), and triethylamine (2 mL) in dichloromethane (20 mL) was stirred for 4 days at room temperature. The mixture was diluted with ethyl acetate (500 mL) and washed with 5% aqueous potassium hydrogen sulfate, water, phosphate buffer (pH 7.5), water, and brine, successively, dried over magnesium sulfate, and concentrated. The residual solid was recrystallized from acetone-ethyl acetate to give 1.04 g of the title compound. The mother liquid was concentrated and the residue was purified by silica gel column chromatography with 0.3% acetic acid/ethyl acetate to give additionally 360 mg of the title compound. A total amount of 1.40 g of the title compound was obtained (85%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Li]CCCC.[Br:23]Br>C1COCC1.CC(OC)(C)C>[Br:23][C:15]1[S:14][C:13]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[C:2]([F:1])[CH:3]=2)=[CH:17][CH:16]=1
Reactant: BrBr
Reactant: CCCCCc1ccc(-c2cccs2)cc1F
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CCCCCc1ccc(-c2ccc(Br)s2)cc1F
Temperature: -70 °C
Reaction time: 1 h

Procedure:
20.0 g (80.5 mmol) of 2-(3-fluoro-4-pentylphenyl)thiophene are initially introduced in 200 ml of THF, and 50.0 ml of n-BuLi (79.6 mmol, 15% solution in hexane) are added dropwise to the solution at a temperature in the range 0-5° C. After 1 h at 0° C., the batch is cooled to −70° C., and 4.1 ml (80.0 mmol) of bromine are metered in. When the addition is complete, the mixture is stirred at 0° C. for 1 h. The batch is diluted with MTBE and washed successively with 2 N HCl, 10% sodium hydrogensulfite solution, sat. sodium hydrogencarbonate solution and sat. sodium chloride solution. The solution is dried using sodium sulfate and evaporated to dryness. The crude product is purified by column chromatography (SiO2, n-heptane). 2-Bromo-5-(3-fluoro-4-pentylphenyl)thiophene is obtained as a yellowish liquid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([C:11]2[C:16]([CH:17]([CH3:19])[CH3:18])=[C:15]([O:20][CH3:21])[N:14]=[C:13]([O:22][CH3:23])[N:12]=2)=[O:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C([O-])(=O)C.[Na+].[C:29](#[N:32])[CH:30]=[CH2:31].CCOCC>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[CH:17]([C:16]1[C:11]([C:9]([C:4]2[CH:3]=[C:2]([CH:31]=[CH:30][C:29]#[N:32])[CH:7]=[C:6]([CH3:8])[CH:5]=2)=[O:10])=[N:12][C:13]([O:22][CH3:23])=[N:14][C:15]=1[O:20][CH3:21])([CH3:19])[CH3:18]
Reactant: COc1nc(OC)c(C(C)C)c(C(=O)c2cc(C)cc(Br)c2)n1
Reactant: C=CC#N
Agent: [Pd+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1nc(OC)c(C(C)C)c(C(=O)c2cc(C)cc(C=CC#N)c2)n1
Temperature: 111 °C
Reaction time: 23 h
Yield: 17 %

Procedure:
To a stirred solution of (3-bromo-5-methyl-phenyl)-(5-isopropyl-2,6-dimethoxy-pyrimidin-4-yl)-methanone (3.79 g, 10 mmol) in anhydrous DMF (10 mL), was added sodium acetate (902 mg, 11 mmol), palladium acetate (224 mg, 1 mmol), tetrakis(triphenylphosphine)palladium(0) (1.049 g, 4 mmol), and acrylonitrile in this order. The mixture was then stirred at 90-132° C. (oil bath) for about 23 hr. After cooling to room temperature, ether and ethyl acetate (2:1) was added to the reaction mixture. The mixture was then washed with aqueous saturated sodium bicarbonate solution, washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexanes (1:4)) to afford 595 mg (17%) of a white solid. Z-isomer (275 mg, 8%) was also obtained as a white solid. m.p. 144-145° C.; 1H NMR (300 MHz, CDCl3) δ 1.19 (6H, d, J=6.9 Hz), 2.42 (3H, s), 2.83 (1H, m), 3.94 (3H, s), 4.08 (3H, s), 5.92 (1H, d, J=16.8 Hz), 7.39 (1H, d, J=16.8 Hz), 7.49 (1H, s), 7.69 (1H, s), 7.75 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2(C#N)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: N#CC1(c2ccc(Br)cn2)CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Brc1ccc(C2CCOCC2)nc1
Temperature: 100 °C
Reaction time: 72 h
Yield: 57.9 %

Procedure:
4-(5-Bromopyridin-2-yl)tetrahydro-2H-pyran-4-carbonitrile (2 g) described in Reference Example 87 in concentrated hydrochloric acid (10 ml) was stirred at 100° C. for 3 days. After completion of the reaction, a saturated aqueous solution of potassium carbonate was added to alkalify the mixture, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated to give the titled compound (1.05 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([N:22]2[C:30]3[CH:29]=[C:28]4[C:31]5([CH2:37][O:38][C:27]4=[CH:26][C:25]=3[CH2:24][CH2:23]2)[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]5)=[O:21])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:46][CH2:47][OH:48]>CC(=O)CC>[OH:48][CH2:47][CH2:46][N:34]1[CH2:33][CH2:32][C:31]2([C:28]3[C:27](=[CH:26][C:25]4[CH2:24][CH2:23][N:22]([C:20]([C:17]5[CH:16]=[CH:15][C:14]([C:3]6[CH:4]=[CH:5][C:6]([C:8]7[N:12]=[C:11]([CH3:13])[O:10][N:9]=7)=[CH:7][C:2]=6[CH3:1])=[CH:19][CH:18]=5)=[O:21])[C:30]=4[CH:29]=3)[O:38][CH2:37]2)[CH2:36][CH2:35]1
Reactant: OCCCl
Reactant: Cc1nc(-c2ccc(-c3ccc(C(=O)N4CCc5cc6c(cc54)C4(CCNCC4)CO6)cc3)c(C)c2)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1nc(-c2ccc(-c3ccc(C(=O)N4CCc5cc6c(cc54)C4(CCN(CCO)CC4)CO6)cc3)c(C)c2)no1
Reaction time: 30 h
Yield: 37.6 %

Procedure:
A stirred solution of 5-(2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl4-carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (E3 in WO 96/19477, 0.44 g, 0.87 mmole) in 2-butanone (30 ml) was treated with potassium carbonate (0.36 g, 2.6 mmole) and 2-chloroethanol (0.18 ml, 2.6 mmole) and heated under reflux for 56 hours, then additional potassium carbonate (0.36 g, 2.6 mmole) and 2-chloroethanol (0.18 ml, 2.6 mmole) added. Reflux was continued for a further 30 hours, then the mixture was concentrated in vacuo and the residue treated with 10% Na2CO3 solution and extracted with ethyl acetate. The extract was dried, concentrated in vacuo and the residue chromatographed on silica gel eluting with 0-10% methanol/chloroforn to afford the title compound as a pale yellow oil (0.18 g, 38%). This was converted to its hydrochloride salt and crystallised from acetone mp. >230° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[F:28][C:29]([F:42])([F:41])[C:30]1[CH:31]=[C:32]([CH2:36][CH2:37][C:38](=O)[CH3:39])[CH:33]=[CH:34][CH:35]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][CH:38]([CH3:39])[CH2:37][CH2:36][C:32]4[CH:33]=[CH:34][CH:35]=[C:30]([C:29]([F:28])([F:41])[F:42])[CH:31]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: CC(=O)CCc1cccc(C(F)(F)F)c1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCc4cccc(C(F)(F)F)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 4-(3-trifluoromethyl-phenyl)-butan-2-one.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([OH:9])=O)=[CH:2]1.[CH2:10]([O:14][C:15](=[O:26])[C@H:16]([CH3:25])[NH:17]C(=O)CC(C)CC)[CH:11]([CH3:13])[CH3:12]>>[CH2:10]([O:14][C:15](=[O:26])[C@H:16]([CH3:25])[NH:17][C:7](=[O:9])[CH2:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)[CH:11]([CH3:13])[CH3:12]
Reactant: O=C(O)Cc1ccsc1
Reactant: CCC(C)CC(=O)N[C@@H](C)C(=O)OCC(C)C
Product: CC(C)COC(=O)[C@H](C)NC(=O)Cc1ccsc1

Procedure:
Following General Procedure I above, and using 3-thiopheneacetic acid (Aldrich) and alanine iso-butyl ester (prepared following General Procedure 3 above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:27][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[O:21][CH:22]([C:24]([OH:26])=O)[CH3:23])[C:7]=2[C:6]=1[CH3:28])=[O:4].[NH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36]>>[CH3:1][O:2][C:3]([C:5]1[S:27][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[O:21][CH:22]([C:24](=[O:26])[NH:29][CH2:30][CH2:31][NH:32][C:33]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:39])[CH3:23])[C:7]=2[C:6]=1[CH3:28])=[O:4]
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC(C)C(=O)O)c2c1C
Reactant: CC(C)(C)OC(=O)NCCN
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC(C)C(=O)NCCNC(=O)OC(C)(C)C)c2c1C

Procedure:
Prepared analogously to example 56.1 using the product from 55 (170 mg) and tert-butyl N-(2-aminoethyl)carbamate (90 μl).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:12]([O:24][CH3:25])[CH:11]=2)=[O:8])=[C:4]([N+:26]([O-])=O)[CH:3]=1.O.[Sn](Cl)(Cl)(Cl)Cl.[CH2:35](O)C>>[Br:1][C:2]1[S:6][C:5]2[C:7](=[O:8])[N:9]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[C:12]([O:24][CH3:25])[CH:11]=3)[CH:35]=[N:26][C:4]=2[CH:3]=1
Reactant: COc1cc(NC(=O)c2sc(Br)cc2[N+](=O)[O-])ccc1OCCN1CCCC1
Reactant: CCO
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Product: COc1cc(-n2cnc3cc(Br)sc3c2=O)ccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
5-Bromo-N-[3-methoxy-4-(pyrrolidin-1ylethoxy)phenyl]-3-nitrothiophene-carboxamide (0.2926 g, 0.6239 mmol) was dissolved in ethanol (10 mL). Tin chloride monohydrate (0.7038 g, 3.1195 mmol) was added and the reaction was heated to reflux. Stirred for 30 min, cooled to RT and concentrated. Ethyl acetate (20 mL) and a saturated solution of Rochelle's salts (20 mL) were added and the mixture was stirred for 2 h. Organics were removed and dried over MgSO4, filtered and concentrated. The residue was taken up in formic acid (5 mL), stirred at reflux for 1 h, and then concentrated to give 0.1182 g (0.2633 mmol, 42%) of the product. 1H NMR (CDCl3) δ 8.03 (s, 1H), 7.38 (s, 1H), 7.01 d, 1H J=8.4 Hz), 6.92-6.88 (m, 2H)), 4.41 (t, 2H, J=5.0 Hz), 3.85 (s, 3H), 3.44 (t, 2H, J=5.0 Hz), 3.28-3.2 (bs, 4H), 2.01-1.9 (bs, 4H).
Reaction SMILES: C(=O)(O)[O-:2].[Na+].Cl.NO.[F:9][C:10]([F:22])([F:21])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]#[N:20])[CH:14]=1>C(O)C>[F:22][C:10]([F:9])([F:21])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]([NH2:20])=[O:2])[CH:14]=1
Reactant: N#Cc1cc(OCC(F)(F)F)ccn1
Reactant: O=C([O-])O
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1cc(OCC(F)(F)F)ccn1
Reaction time: 10 h
Yield: 98.9 %

Procedure:
To 6 ml of ethanol were added 0.54 g of sodium bicarbonate and 0.45 g of hydroxylamine hydrochloride, and the mixture was heated to reflux for 1 hour. After allowing to cool, 0.65 g of 4-(2,2,2-trifluoroethoxy)pyridine-2-carbonitrile was added at room temperature, and the mixture was stirred for 10 hours, and concentrated. To the residue was added water, the resultant solution was extracted with ethyl acetate three times, and the organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was washed with hexane three times to obtain 0.7 g of 4-(2,2,2-trifluoroethoxy)pyridine-2-carboxamide=oxime.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8](O)=[O:9])[NH:5][C:4]2[C:11](=[O:19])[O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:3]1=2.C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:33][C:34]1[NH:38][N:37]=[N:36][N:35]=1>CN(C)C=O>[O:1]=[C:2]1[CH:7]=[C:6]([C:8]([NH:33][C:34]2[NH:38][N:37]=[N:36][N:35]=2)=[O:9])[NH:5][C:4]2[C:11](=[O:19])[O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:3]1=2
Reactant: O=C(O)c1cc(=O)c2c([nH]1)c(=O)oc1ccccc12
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1nnn[nH]1)c1cc(=O)c2c([nH]1)c(=O)oc1ccccc12
Yield: 46.6 %

Procedure:
A mixture of 1,5-dihydro-1,5-dioxo-4H-1-benzopyrano[3,4-b]pyridine-3-carboxylic acid (2.57 g, 0.01 mole) and 1,1'-carbonyldiimidazole (3.24 g, 0.02 mole) in dimethylformamide (50 ml) is heated at 100 for 60 minutes under nitrogen. The reaction mixture is cooled. 5-aminotetrazole monohydrate (1.03 g, 0.01 mole) is added and the resulting mixture is heated at 100 for 60 minutes, cooled and filtered. The product is recrystallized from dimethylformamide to give white crystals (1.51 g, 39%) mp 265-270. The product crystallizes as a 1:1 salt or complex with 1H-imidazole.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[C:18](O)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1>>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:5]2[C:6]([C:7]([NH2:9])=[O:8])=[C:2]([NH:1][C:18]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[O:25])[N:3]=[CH:4]2)=[CH:12][CH:13]=1
Reactant: Cc1ccc(Cn2cnc(N)c2C(N)=O)cc1
Reactant: O=C(O)c1cccnc1
Product: Cc1ccc(Cn2cnc(NC(=O)c3cccnc3)c2C(N)=O)cc1
Yield: 61 %

Procedure:
An amidation reaction and post-treatment were carried out under the same conditions as in Example 19, using 1.61 g (6.99 mmol) of 4-amino-1-(4-methylbenzyl)-5-imidazole carboxamide which was prepared in the same manner as in Example 87 and nicotinic acid instead of cyclopentylacetic acid to obtain 1.43 g of 1-(4-methylbenzyl)-4-(3-pyridylcarbonylamino)-5-imidazolecarboxamide (yield 61%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16]Br)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.Cl.[F:29][C@H:30]1[CH2:34][CH2:33][NH:32][CH2:31]1>CN(C=O)C.CO.C(OCC)(=O)C.CCCCCC>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:32]2[CH2:33][CH2:34][C@H:30]([F:29])[CH2:31]2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: F[C@H]1CCNC1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(CBr)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)NCCc1ccc(CN2CC[C@H](F)C2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 79 %

Procedure:
To a solution of tert-butyl{2-[4-(bromomethyl)phenyl]ethyl}carbamate (450 mg, 1.43 mmol) in DMF (4 ml) were added N,N-diisopropylethylamine (0.749 ml, 4.30 mmol) and (3S)-3-fluoropyrrolidine hydrochloride (180 mg, 1.43 mmol), and the mixture was stirred at room temperature for 22 hr. Ethyl acetate was added to the reaction mixture, and the mixture was washed with aqueous sodium hydrogen carbonate solution and brine. The solvent was evaporated under reduced pressure, and the residue was purified by NH-silica gel chromatography (developing solvent; ethyl acetate), and then silica gel chromatography (developing solvent; hexane:ethyl acetate=1:1 (volume ratio)→ethyl acetate:methanol=9:1 (volume ratio)) to give the title compound (364 mg, 1.13 mmol) as a colorless liquid.
Reaction SMILES: [CH2:1]([C:8]1[NH:9][C:10]([CH2:13][OH:14])=[CH:11][N:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Cl:15]N1C(=O)CCC1=O>>[Cl:15][C:11]1[N:12]=[C:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[NH:9][C:10]=1[CH2:13][OH:14]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCCCCCc1ncc(CO)[nH]1
Product: CCCCCCCc1nc(Cl)c(CO)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.4 %

Procedure:
To a solution of 2-heptyl-5-(hydroxymethyl)-imidazole (10.0 g, 51 mmol) in EtOH1,4-dioxane (1:1; 600 mL) was added N-chlorosuccinimide (7.9 g, 59 mmol). After being stirred for 1 hour at room temperature the solvents were removed on a rotary evaporator an the solid residue was partitioned between ethyl acetate and water (300 mL each). The organic phase was washed with water (150 mL), dried (MgSO4), filtered and concentrated to afford 12.4 g crude product. Recrystallization (1:1 EtOAc/hexane, 60 mL) gave 5.7 g (45%) of white crystals; m.p. 134°-140°. NMR (200 MHz, CDCl3 /CD3OD) δ 4.50 (s, 2H); 4.00-3.80 (br s, 2H); 2.65 (t 2H, 5Hz); 1.80-1.60 (m, 2H); 1.40-1.20 (m, 8); 0.90-0.80 (m, 3H). Mass Spec. 230.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5]([OH:7])=O.S(Cl)(Cl)=O.[CH3:18][C:19]1[CH:25]=[C:24]([C:26]([F:35])([C:31]([F:34])([F:33])[F:32])[C:27]([F:30])([F:29])[F:28])[CH:23]=[C:22]([CH3:36])[C:20]=1[NH2:21].N1C=CC=CC=1>ClCCl>[NH2:1][C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5]([NH:21][C:20]1[C:22]([CH3:36])=[CH:23][C:24]([C:26]([F:35])([C:27]([F:28])([F:29])[F:30])[C:31]([F:32])([F:33])[F:34])=[CH:25][C:19]=1[CH3:18])=[O:7]
Reactant: Nc1c(F)c(F)cc(C(=O)O)c1F
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1N
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cc(F)c(F)c(N)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
3-Amino-2,4,5-trifluoro-benzoic acid (commerically available) (12.5 g, 65.50 mmol) was heated with thionyl chloride (110 ml) at 90° C. for 2 hours under a nitrogen atmosphere. The excess thionyl chloride was removed in vacuo. To a solution of the residue (13.37 g, 52.30 mmol) in dichloromethane (218 ml) under a nitrogen atmosphere was added a solution of 2,6-dimethyl-4-(heptafluoroprop-2-yl)aniline (prepared according to EP 1,006,102) (15.12 g, 52.30 mmol) in pyridine (4.2 ml, 52.30 mmol). The reaction mixture was stirred at ambient temperature for 2 hours and then extracted with aqueous hydrochloric acid (1M). The aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed with aqueous sodium hydrogen carbonate (1M), dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 7:3) to give 3-amino-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-2,4,5-trifluoro-benzamide (18.4 g, 76% yield). 1H-NMR (400 MHz, CDCl3): 2.35 (6H, s), 4.07 (2H, bs), 7.3-7.35 (1H, m), 7.36 (2H, s), 7.83 (1H, d) ppm.