Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([O:17][CH3:18])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15]Br)[CH:7]=1.C[O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[C:3]([CH:4]([O:17][CH3:18])[CH2:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[O:12][CH2:13][CH2:14][CH2:15][O:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[C:22]([OH:30])=[O:21])([OH:2])=[O:19]
Reactant: COC(=O)C(Cc1cccc(OCCCBr)c1)OC
Reactant: COC(=O)c1cccc(O)c1
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: COC(Cc1cccc(OCCCOc2cccc(C(=O)O)c2)c1)C(=O)O

Procedure:
The title compound was prepared from 3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl ester (Example 323, Step 1) and 3-hydroxybenzoic acid methyl ester via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) for C20H22O7 [M+Na]+: 397.4.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:23]=[C:24]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][C@@H:35]4[CH3:40])[C:25]4[CH2:31][CH2:30][N:29]([CH2:32][CH3:33])[CH2:28][C:26]=4[N:27]=3)=[CH:18][CH:17]=2)[N:10]=1)C1C=CC=CC=1.CO.C(O)(=O)C.O1CCCC1>[OH-].[OH-].[Pd+2]>[CH2:32]([N:29]1[CH2:30][CH2:31][C:25]2[C:24]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][C@@H:35]3[CH3:40])=[N:23][C:22]([C:19]3[CH:18]=[CH:17][C:16]([NH:15][C:11]4[NH:10][C:9](=[O:8])[CH:14]=[CH:13][N:12]=4)=[CH:21][CH:20]=3)=[N:27][C:26]=2[CH2:28]1)[CH3:33]
Reactant: CCN1CCc2c(nc(-c3ccc(Nc4nccc(OCc5ccccc5)n4)cc3)nc2N2CCOC[C@@H]2C)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CCN1CCc2c(nc(-c3ccc(Nc4nccc(=O)[nH]4)cc3)nc2N2CCOC[C@@H]2C)C1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
Step 3—Synthesis of compound xb: (S)-4-(benzyloxy)-N-(4-(7-ethyl-4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)pyrimidin-2-amine (0.066 g, 0.12 mmol) was purged under nitrogen then added 20% Palladium hydroxide on carbon (2:8, Palladium hydroxide:carbon black, 0.101 g) followed by dry Methanol (3.6 mL, 89 mmol), Acetic acid (0.18 mL, 3.2 mmol) and dry Tetrahydrofuran (3.6 mL, 44 mmol) purged with hydrogen, heated at 40° C. and stirred overnight under an atmosphere of hydrogen. The reaction mixture was purged with nitrogen, added celite, filtered through celite, concentrated. chromatographed through silica gel (12 g, 0-10% MeOH in dichloromethane), and purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.23 (d, J=8.7, 2H), 7.77 (t, J=9.4, 3H), 5.85 (d, J=5.9, 1H), 4.15 (d, J=6.5, 1H), 3.87 (d, J=10.8, 1H), 3.75-3.68 (m, 1H), 3.62 (dd, J=16.9, 7.9, 4H), 3.55-3.35 (m, 2H), 2.68 (s, 3H), 2.58-2.52 (m, 3H), 1.25 (d, J=6.6, 3H), 1.11 (t, J=7.1, 3H). LC/MS-m/z+448.2 (M+H)+.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[CH3:14][N:15]1[CH:20]2[CH2:21][CH2:22][CH:16]1[CH2:17][C:18](=[O:23])[CH2:19]2.Cl>CCCCCC.CCOCC>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:18]2([OH:23])[CH2:19][CH:20]3[N:15]([CH3:14])[CH:16]([CH2:22][CH2:21]3)[CH2:17]2)=[CH:8][CH:9]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CN1C2CCC1CC(=O)C2
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CN1C2CCC1CC(O)(c1ccc(F)cc1)C2
Temperature: -45 °C
Reaction time: 1 h
Yield: 66.8 %

Procedure:
A mixture of dry ether (600 ml) and 15% BuLi in hexane (500 ml) was cooled to -45° C. A solution of 4-bromo-1-fluorobenzene (145 g) in dry ether (350 ml) was added dropwise at -45° C. followed by stirring for 1 h. A solution of 8-methyl-8-azabicyclo[3,2,1]octan-3-one (85 g) in dry ether (400 ml) was added dropwise at -50° C. followed by stirring for 30 min, the temperature raising to -20° C. The reaction mixture was poured into 2 M hydrochloric acid and the phases separated. The ether phase was extracted with 2 M hydrochloric acid and the combined aqeous phases made alkaline with aqeous NaOH. Extraction with ethyl acetate, drying of the organic phase over magnesium sulfate and removal of solvent in vacuo, gave 3-(4-fluorophenyl)-3-hydroxy-8-methyl-8-azabicyclo(3,2,1]octane (96 g) as a solid, mp: 169° C.
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)=[CH:4][C:3]=1[CH2:16][NH:17][C:18]1[C:19]([CH3:26])=[C:20]([OH:25])[CH:21]=[CH:22][C:23]=1[CH3:24].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36].O>CN(C=O)C>[F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)=[CH:4][C:3]=1[CH2:16][NH:17][C:18]1[C:19]([CH3:26])=[C:20]([CH:21]=[CH:22][C:23]=1[CH3:24])[O:25][CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36]
Reactant: Cc1cc(-c2cccc(F)c2)cc(CNc2c(C)ccc(O)c2C)c1F
Reactant: CC(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-c2cccc(F)c2)cc(CNc2c(C)ccc(OCC(=O)OC(C)C)c2C)c1F
Reaction time: 0.5 h
Yield: 145.9 %

Procedure:
To a solution of 3-[[2-fluoro-5-(3-fluorophenyl)-3-methyl-phenyl]methylamino]-2,4-dimethyl-phenol (106 mg, 0.30 mmol, 1.0 eq) in DMF (6 mL) was added Cs2CO3 (147 mg, 0.45 mmol, 1.5 eq) at room temperature. The reaction mixture was stirred for 30 min, then isopropyl bromoacetate (65 mg, 0.136 mmol, 1.2 eq) was added. The reaction mixture was stirred at room temperature for 1 h. Water was added and the aqueous layer extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (petroleum ether:EtOAc, 50:1 to 40:1) to give the title compound as a colorless oil (90 mg, 66%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N:8]=O.[S:10](=[O:14])(=[O:13])([OH:12])[OH:11]>[Pd]>[S:10]([OH:14])([OH:13])(=[O:12])=[O:11].[NH2:8][C:3]1[CH:4]=[N:5][N:6]([CH3:7])[C:2]=1[NH2:1]
Reactant: Cn1ncc(N=O)c1N
Agent: [Pd]
Agent: O=S(=O)(O)O
Product: Cn1ncc(N)c1N
Reaction time: 10 h
Yield: 81 %

Procedure:
To a suspension of 5-amino-1-methyl-4-nitrosopyrazole (117 g) were added sulfuric acid (91 g) and 10% palladium on carbon (58 g). The mixture was hydrogenated under balloon pressure for 10 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. To the concentrate was added isopropyl alcohol (2.3 L) and the mixture was stirred for 1 hour. The precipitated solid was collected by filtration and dried to give 4,5-diamino-1-methylpyrazole sulfate (158 g).
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][CH:21]([CH2:34][CH3:35])[C@@H:22]([CH2:32][CH3:33])[CH2:23][NH:24]C(=O)OC(C)(C)C)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][CH:21]([CH2:34][CH3:35])[C@@H:22]([CH2:32][CH3:33])[CH2:23][NH2:24])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CCC(Oc1cccc2ccc(-c3nnc4ccccn34)nc12)[C@@H](CC)CNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(Oc1cccc2ccc(-c3nnc4ccccn34)nc12)[C@@H](CC)CN
Temperature: 0 °C
Yield: 29 %

Procedure:
tert-Butyl (2S)-3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2-ethylpentylcarbamate was dissolved in 5 mL DCM and cooled to 0° C. TFA (5 mL) was added and the mixture was allowed to warm to ambient temperature over 1 hour. The reaction mixture was evaporated to dryness, and the residue was dissolved in 30 mL DCM and washed with 1N NaOH. The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography followed by preparative TLC to give the desired product (42.5 mg, 29%).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:20]([F:23])([F:22])[F:21])=[C:15]([CH2:33]O)[CH:14]=1.ClC1C=C(C=CC=1)CO.C1C=CC(P([N:58]=[N+:59]=[N-:60])(C2C=CC=CC=2)=O)=CC=1>C1COCC1>[N:58]([CH2:33][C:15]1[CH:14]=[C:13]([Cl:12])[CH:18]=[CH:17][C:16]=1[CH:19]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[C:20]([F:23])([F:22])[F:21])=[N+:59]=[N-:60]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(NC(c2ccc(Cl)cc2CO)C(F)(F)F)cc1
Agent: OCc1cccc(Cl)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1ccc(NC(c2ccc(Cl)cc2CN=[N+]=[N-])C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
DBU (0.483 mL, 3.23 mmol) was added to a stirred solution of N-{1-[4-chloro-2-(hydroxymethyl)phenyl]-2,2,2-trifluoroethyl}-N-(4-methoxyphenyl)amine (0.46 g of a 1:1.7 mixture with 3-chlorobenzyl alcohol) and DPPA (0.696 mL, 3.23 mmol) in THF (4 mL) at 0° C. The mixture was warmed to ambient temperature and after 3 h was partitioned between ether and water. The organic layer was washed with 1 M sodium hydroxide solution and brine, dried (Na2SO4) and evaporated to an oil which was purified by flash column chromatography on silica (eluting with 5% methylene chloride, 0-15% ethyl acetate/hexanes) to give N-{1-[2-(azidomethyl)-4-chlorophenyl]-2,2,2-trifluoroethyl}-N-(4-methoxyphenyl)amine (0.199 g) as an oil: 1H NMR (CDCl3, 400 MHz) δ 3.72 (s, 3H), 3.97 (d, J=7.3 Hz, 1H), 4.37 (d, J=14.1 Hz, 1H), 4.48 (d, J=14.1 Hz, 1H), 5.20 (pentet, J=7.1 Hz, 1H), 6.63 (d, J=9.0 Hz, 2H), 6.75 (d, J=9.0 Hz, 2H), 7.37 (m, 2H), 7.55 (d, J=8.2 Hz, 1H).
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22]C(C#N)=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH:4]=[CH2:5].C(O)CO[CH2:29][CH2:30][OH:31].[OH-:33].[K+].Cl>O>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:29]([C:30]([OH:31])=[O:33])=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: C=CCCC[C@H]1CC[C@H](c2ccc(-c3ccc(C#N)cc3)cc2)CC1
Reactant: [OH-]
Reactant: OCCOCCO
Agent: Cl
Agent: [K+]
Solvent: O
Product: C=CCCC[C@H]1CC[C@H](c2ccc(-c3ccc(C(=O)O)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 9.88 g of 4'-[trans-4-(4-pentenyl)cyclohexyl]-4-biphenylcarbonitrile, 735 ml of diethylene glycol and 79.9 g of potassium hydroxide was heated to 150°-160° C. while stirring and gassing with nitrogen and held at this temperature for 1 hour. Subsequently, the reaction mixture was cooled to room temperature and treated with 230 ml of semi-concentrated hydrochloric acid while cooling with an ice-bath. Thereafter, the reaction mixture was poured into 1.5 l of water, stirred at room temperature for 10 minutes and then suction filtered. The residue was washed neutral with water and dried in vacuo at 60° C., whereby 10.3 g (98.5%) of 4'-[trans-4-(4-pentenyl)cyclohexyl]-4-biphenylcarboxylic acid were obtained as colourless crystals.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18]>>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:13]2[CH:14]=[C:15]([O:19][CH3:20])[C:16]([O:17][CH3:18])=[C:11]([O:10][CH3:9])[CH:12]=2)[N:7]=1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: Cc1ccnc(Br)n1
Product: COc1cc(-c2nccc(C)n2)cc(OC)c1OC

Procedure:
2-Bromo−4-methylpyrimidine (1.5 g) and 3,4,5-trimethoxyphenylboronic acid (1.83 g) were reacted in the same manner as in Preparation Example 1 to obtain the title compound.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][N:16]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:15]=1.C(N(C(C)C)CC)(C)C.[NH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1COCC1.O>[C:41]1([NH:40][C:5]([NH:13][C:14]2[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][N:16]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:15]=2)=[O:11])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1N
Reactant: Nc1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1NC(=O)Nc1ccccc1
Temperature: 40 °C
Reaction time: 5 h
Yield: 71 %

Procedure:
To a solution of triphosgene (35.7 mg) in THF (2 ml), was slowly added a solution of 3-amino-1-benzyl-4-ethoxycarbonylpyrazole (30 mg) and diisopropylethylamine (0.0936 ml) in THF (1 ml) over 15 min, and the resulted mixture was stirred at 40° C. for 5 h. To this, was added a solution of aniline (0.0111 ml) and diisopropylethylamine (0.0936 ml) in THF (1 ml), and the resulted mixture was further stirred to react. After completion of the reaction, water was added followed by evaporation under reduced pressure. Ether was added to the residue to crystallize the title compound (32 mg, yield 71%). The product gave the similar 1H-NMR spectrum to an authentic sample prepared by a reported method [Chem. Pharm. Bull., 20, 391-397 (1972)].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:38])=[C:6]([N:8]2[C:15](=[O:16])[C:14]3[CH:13]=[C:12]([C:17]4[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=4[O:26][CH3:27])[C:20]([OH:22])=O)[N:11]([CH:28]([CH3:30])[CH3:29])[C:10]=3[CH:9]2[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH:7]=1.[CH3:39][S:40]([CH2:43][CH2:44][NH2:45])(=[O:42])=[O:41].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:38])=[C:6]([N:8]2[C:15](=[O:16])[C:14]3[CH:13]=[C:12]([C:17]4[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=4[O:26][CH3:27])[C:20]([NH:45][CH2:44][CH2:43][S:40]([CH3:39])(=[O:42])=[O:41])=[O:22])[N:11]([CH:28]([CH3:30])[CH3:29])[C:10]=3[CH:9]2[C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)[CH:7]=1
Reactant: COc1ccc(C(=O)O)cc1-c1cc2c(n1C(C)C)C(c1ccc(Cl)cc1)N(c1cc(Cl)ccc1C)C2=O
Reactant: CS(=O)(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)NCCS(C)(=O)=O)cc1-c1cc2c(n1C(C)C)C(c1ccc(Cl)cc1)N(c1cc(Cl)ccc1C)C2=O

Procedure:
To a solution of 3-[5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-b]pyrrol-2-yl]-4-methoxy-benzoic acid (Example 35) (0.147 mmol) in DMF (1 mL), were added 2-methanesulfonyl-ethylamine [49773-20-8] (0.183 mmol), EDC.HCl (0.183 mmol), HOBT.H2O (0.109 mmol) and Et3N (0.513 mmol) and the mixture was stirred at rt for 30 h. The mixture was diluted with H2O and extracted with CH2Cl2 (3×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified using a RediSep® silica gel column to afford the title compound as a white solid. tR: 4.84 min (HPLC 1); ESI-MS: tR=1.19 min, [M+H]+ 654/656/658 (LC-MS 1); TLC: Rf=0.22 (95:5 CH2Cl2/MeOH); 1H-NMR (d6-DMSO, 600 MHz): 8.69 (m, 1H), 7.96 (m, 1H), 7.82 (s, 1H), 7.79 (s, 1H), 7.38 (m, 2H), 7.25 (m, 2H), 7.22 (d, 1H), 7.15 (m, 1H), 7.10 (m, 1H), 6.52 (s, 1H), 6.26 (s, 1H), 3.92 (m, 1H), 3.82 (s, 3H), 3.64 (m, 2H), 3.36 (m, 2H), 3.02 (s, 3H), 1.93 (s, 3H), 1.31 (m, 3H), 0.45 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.Br[CH2:23][CH2:24][C:25]([F:29])=[C:26]([F:28])[F:27].O>C(#N)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:23][CH2:24][C:25]([F:29])=[C:26]([F:28])[F:27])=[O:7])=[CH:4][CH:3]=1
Reactant: FC(F)=C(F)CCBr
Reactant: O=C(O)c1ccc(Cl)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: O
Product: O=C(OCCC(F)=C(F)F)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 45.3 %

Procedure:
To a stirred solution of 1.6 grams (0.01 mole) of 4-chlorobenzoic acid in 35 ml of acetonitrile was added 1.5 ml (0.01 mole) of 1,8-diazabicyclo[5.4.0]-undec-7-ene, followed by 1.9 grams (0.01 mole) of 4-bromo-1,1,2-trifluoro-1-butene. The reaction mixture was heated under reflux for four hours then allowed to cool to ambient temperature. Water, 25 ml, was added to the reaction mixture, and the reaction mixture was extracted with three 20 ml portions of diethyl ether. The combined extracts were washed in succession with one 25 ml portion of water, two 25 ml portions of aqueous 5% sodium hydroxide and, finally, one 25 ml portion of water. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 1.2 grams of (3,4,4-trifluoro-3-butenyl) 4-chlorobenzoate as an oil. The nmr and the ir spectra were consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH2:10][O:9][C:8](=[O:12])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:13]Br>C(O)(=O)C.C(O)(C(F)(F)F)=O>[Br:13][C:3]1[CH:4]=[CH:5][C:6]2[NH:7][C:8](=[O:12])[O:9][CH2:10][C:11]=2[C:2]=1[CH3:1]
Reactant: Cc1cccc2c1COC(=O)N2
Reactant: BrBr
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: Cc1c(Br)ccc2c1COC(=O)N2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 5-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (0.695 g, 4.3 mmol) in acetic acid (5 mL), Br2 (0.805 g=5 mmol) solution in TFA (5 mL)+acetic acid (5 mL) was added at 10° C. Reaction mixture was stirred for 2 hours and poured over ice water. Yellow precipitate was filtered and dried at 120° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([C:10]([OH:12])=O)[CH2:7][C:6]=2[CH:13]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[N:43]1([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>ClCCl.O>[C:52]([O:51][C:49]([N:43]1[CH2:48][CH2:47][N:46]([C:10]([CH:8]2[CH2:7][C:6]3[CH:13]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[O:9]2)=[O:12])[CH2:45][CH2:44]1)=[O:50])([CH3:55])([CH3:53])[CH3:54]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)C1Cc2cc(F)ccc2O1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C2Cc3cc(F)ccc3O2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.9 %

Procedure:
In a 250 ml round-bottomed flask containing a solution of 5-fluoro-2,3-dihydro-benzofuran-2-carboxylic acid (1.8 g, 9.9 mmol) in 100 ml of dichloromethane was added EDAC.HCl (2.85 g, 14.9 mmol, 1.5 eq), HOBt (2.00 g, 14.8 mmol, 1.5 eq), triethylamine (2.00 g, 19.8 mmol, 2.0 eq), and t-butyl piperazine-1-carboxylate (2.20 g, 11.8 mmol, 1.2 eq). The solution was stirred overnight at room temperature before diluting with 50 ml of water. The crude product was then extracted from the mixture using 3×50 ml of dichloromethane. The organic layers were combined, dried over magnesium sulfate, filtered, and then concentrated under vacuum. The crude residue was purified by silica gel chromatography using ethyl acetate/petroleum ether to elute. The product-containing fractions were combined and concentrated under vacuum to afford 1.8 grams of the desired amide as a light yellow solid (52%); 1H NMR (300 MHz, CDCl3): δ 6.92 (dd, J=2.4 Hz, 7.8 Hz, 1H), 6.79 (m, 1H), 6.69 (dd, J=4.2 Hz, 8.7 Hz, 1H), 5.40 (dd, J=7.2 Hz, 9.9 Hz, 1H), 3.78-3.91 (m, 3H), 3.46-3.67 (m, 5H), 3.26-3.39 (m, 2H), 1.49 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][N:10]=[C:9]2[SH:18])=[CH:4][CH:3]=1.[OH-].[Li+]>O1CCOCC1.CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[C:9]2[SH:18])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnc(S)n1-c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cnc(S)n1-c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 1-(4-fluorophenyl)-2-mercapto-1H-imidazole-5-carboxylate (3) (2.62 g, 9.84 mmol) in 1,4-dioxane (21 mL) and methanol (10 mL) was added lithium hydroxide (825 mg, 19.7 mmol) in water (21 mL). The reaction was stirred at 50° C. overnight and the organic solvents were removed in vacuo. The mixture was acidified with 1M HCl until a white solid crashed out of the solution. The solid was collected by vacuum filtration and washed with water to afford 1-(4-fluorophenyl)-2-mercapto-1H-imidazole-5-carboxylic acid (4).
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:33]=[CH:32][C:9]([O:10][CH2:11][CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:20](=[O:31])[C@@H:21]([NH:23]C(=O)OC(C)(C)C)[CH3:22])[CH2:16][CH2:15]3)=[CH:8][CH:7]=2)=[O:5])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.C(O)(=O)[C@@H]([C@H](C(O)=O)O)O>ClCCl>[NH2:23][C@@H:21]([CH3:22])[C:20]([N:17]1[CH2:16][CH2:15][N:14]([CH2:13][CH2:12][CH2:11][O:10][C:9]2[CH:8]=[CH:7][C:6]([C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])=[CH:33][CH:32]=2)[CH2:19][CH2:18]1)=[O:31]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(CCCOc2ccc(C(=O)C3CC3)cc2)CC1
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)C(=O)N1CCN(CCCOc2ccc(C(=O)C3CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 83 %

Procedure:
A solution of Example 1D (3.0 g, 6.5 mmol) in dichloromethane (30 mL) at 0° C. was treated, over a period of 10 minutes, with trifluoroacetic acid (7.5 mL, 97 mmol). The reaction mixture was allowed to warm to room temperature, stirred for 24 hours, and concentrated. The concentrate was dissolved in dichloromethane (300 mL) and the solution was washed sequentially with saturated NaHCO3, water, and brine, dried (MgSO4), filtered, and concentrated. The concentrate was dissolved in methanol (120 mL), treated with L-tartaric acid (1.0 equivalent based on recovered material), stirred for 18 hours at room temperature, and concentrated. The concentrate was dissolved in water (25 mL) and lyophilized to afford the desired product in 83% yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].Br[CH2:11][CH:12]1[CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:11][CH:12]1[CH2:14][CH2:13]1
Reactant: BrCC1CC1
Reactant: Oc1ccc(F)cc1Br
Product: Fc1ccc(OCC2CC2)c(Br)c1

Procedure:
Starting from commercially available 2-bromo-4-fluoro-phenol and commercially available bromomethyl-cyclopropane the title compound is obtained as colorless oil after distillation at 5×10−3 mbar.
Reaction SMILES: [CH2:1](OC1CCCCO1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[C:12][CH2:13][CH3:14].C(Br)(Br)(Br)[Br:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:23][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[C:12][CH2:13][CH3:14]
Reactant: CCC#CCCCCCCCCCCOC1CCCCO1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCC#CCCCCCCCCCCBr
Temperature: 25 °C
Reaction time: 5 h
Yield: 87 %

Procedure:
The alkynyl ether 16 (5.62 g, 0.0191 mol) in dichloromethane (150 ml) at 0° C. was treated successively with carbon tetrabromide (8.23 g, 0.0248 mol) and triphenylphosphine (13 g, 0.050 mol) and stirred for 5 h at r.t. The solution was treated with silica gel, the solvent removed invacuo and the dry residue loaded onto a prepared flash column. Elution with hexanes yielded the pure bromide 17 (87% from 15); δH (270 MHz, CDCl3) 1.10 (3H, t, J 7.4), 1.27-1.54 (14H, m), 1.84 (2H, quin, J 7.3), 2.15 (4H, m) and 3.40 (2H, t, J 6.8). δC (100 MHz, CDCl3) 12.82, 14.79, 27.28, 29.23, 29.26, 29.4, 29.53, 29.80, 29.80, 30.11, 33.04, 79.96 (quartenary) and 82.00 (quartenary).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]2[O:6][CH2:7][C:8](=O)[NH:9][C:4]=2[CH:3]=1.C1COCC1.Cl.[OH-].[Na+]>O.CCO>[O:6]1[CH2:7][CH2:8][NH:9][C:4]2[CH:3]=[C:2]([NH2:1])[CH:12]=[CH:11][C:5]1=2
Reactant: Nc1ccc2c(c1)NC(=O)CO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc2c(c1)NCCO2
Temperature: 80 °C
Reaction time: 8 h
Yield: 50.7 %

Procedure:
6-Amino-2H-benzo[b][1,4]oxazin-3(4H)-one (590 mg, 3.6 mmol) was added to a THF solution of borane tetrahydrofuran complex (9 mL, 1M solution) and the reaction mixture was refluxed for 2.5 h. EtOH (2 mL) was added and stirred at 70° C. for 1 h before 1 mL HCl (conc.) was added. The mixture was stirred at 80° C. overnight then the volatiles were removed under vacuum to leave a crude reside. The residue was dissolved in water, NaOH was added until pH˜10, and the mixture was extracted with CH2Cl2. The organic phase was washed with water and the solvent was removed under vacuum. The residue was purified by column chromatography on silica gel to give the product (274 mg, 51%) as a colorless oil.