Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:20])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([O:18]C)([CH3:17])[CH2:9][CH2:8]2)(=[O:3])[CH3:2].Cl>CC(C)=O>[C:1]([O:4][C:5]1[C:6]([CH3:20])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([OH:18])([CH3:17])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: COC1(C)CCc2c(C)c(OC(C)=O)c(C)c(C)c2O1
Agent: Cl
Solvent: CC(C)=O
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(O)O2
Reaction time: 3.5 h

Procedure:
To a solution of (±)-6-acetoxy-2-methoxy-2,5,7,8-tetramethylchroman in 2500 ml. of acetone was added 2000 ml. of H 2 O followed by 16.6 ml. of concentrated aqueous HCl. Solvent was distilled from the stirred mixture until the head temperature reached 90° centigrade. The suspension was cooled in an H 2 O bath to 50° centigrade. At 70° centigrade, 2000 ml. of acetone was added, giving a clear solution. The solution was seeded occasionally until crystallization began. After 3.5 hours, 1500 ml. of H 2 O was added and the suspension was cooled in an ice bath. The solid was removed by filtration, washed with H 2 O and dried at 50° centigrade/0.1mmHg. to give (±)-6-acetoxy-2-hydroxy-2,5,7,8-tetramethylchroman as a granular yellow-tan solid, sintering from 114 degrees centigrade, m.p. 127°-132° centigrade.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:14])[C:5]([C:8](N(OC)C)=[O:9])=[N:6][CH:7]=1.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([F:14])[C:5]([CH:8]=[O:9])=[N:6][CH:7]=1
Reactant: CON(C)C(=O)c1ncc(Br)cc1F
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: O=Cc1ncc(Br)cc1F
Temperature: 16 °C
Reaction time: 2 h

Procedure:
5-Bromo-3-fluoro-N-methoxy-N-methylpicolinamide (0.63 g, 2.4 mmol) was stirred in THF (12 mL) at 60° C. Diisobutylaluminium hydride (1 M in THF, 2.8 mL, 2.8 mmol) was added dropwise and the reaction mixture stirred below 50° C. for 2 h. Further diisobutylaluminium hydride (1 M in THF, 0.85 mL, 0.85 mmol) was added and the reaction mixture allowed to warm to 16° C. over 2 h. Rochelles salt solution (sat. aq.) was added and the aqueous phase extracted with EtOAc. The combined organics were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography using silica gel and eluting with 10-70% EtOAc in isohexanes to afford 5-bromo-3-fluoropicolinaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:33]2[CH2:32][CH2:31][N:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[F:23])[CH2:35][CH2:34]2)=[O:22])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: COc1nc2ccccc2cc1NC(=O)Oc1ccccc1
Product: COc1nc2ccccc2cc1NC(=O)N1CCN(c2ccccc2F)CC1
Yield: 81 %

Procedure:
Phenyl N-(2-methoxyquinolin-3-yl)carbamate and 1-(2-fluorophenyl)piperazine were reacted by the same way with the example 81 to obtain the titled compound.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][N:4]=[C:5]([NH2:19])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][C:17]#[N:18])[N:8]=1.[OH:22]S(O)(=O)=O.[OH-].[Na+]>O>[F:21][C:2]([F:1])([F:20])[CH2:3][N:4]=[C:5]([NH2:19])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][C:17]([NH2:18])=[O:22])[N:8]=1
Reactant: O=S(=O)(O)O
Reactant: N#CCCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)CCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Reaction time: 3 h

Procedure:
A mixture of 4-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylthio]butyronitrile (0.14 g.) and concentrated H2SO4 was left at room temperature for 3 hours and then diluted with crushed ice and water. The solution was basified with 10N aqueous NaOH and the mixture extracted three time with EtOAc. The combined extracts were dried and evaporated to dryness to give 4-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylthio]butyramide (0.13 g.) which was characterised as the hydrogen maleate, m.p. 202°-203° on recrystallisation from aqueous EtOH.
Reaction SMILES: O=C(Cl)[O:3][C:4](Cl)(Cl)[Cl:5].[CH:9]1[C:21]2[CH:20]([CH2:22][O:23][C:24]([N:26]3[CH2:31][CH2:30][CH:29]([C:32]4[O:36][N:35]=[C:34]([C@@H:37]5[CH2:42][CH2:41][C@@H:40]([NH:43][O:44][CH2:45][C:46]6[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=6)[CH2:39][N:38]5[C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[N:33]=4)[CH2:28][CH2:27]3)=[O:25])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[CH:18]1[C:19]2[CH:20]([CH2:22][O:23][C:24]([N:26]3[CH2:27][CH2:28][CH:29]([C:32]4[O:36][N:35]=[C:34]([C@@H:37]5[CH2:42][CH2:41][C@@H:40]([N:43]([O:44][CH2:45][C:46]6[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=6)[C:4]([Cl:5])=[O:3])[CH2:39][N:38]5[C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[N:33]=4)[CH2:30][CH2:31]3)=[O:25])[C:21]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](NOCc2ccccc2)CC[C@H]1c1noc(C2CCN(C(=O)OCC3c4ccccc4-c4ccccc43)CC2)n1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](N(OCc2ccccc2)C(=O)Cl)CC[C@H]1c1noc(C2CCN(C(=O)OCC3c4ccccc4-c4ccccc43)CC2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
Diphosgene (144 mg, 0.727 mmol) was added to a solution of (2S,5R)-tert-butyl 2-(5-(1-(((9H-fluoren-9-yl)methoxy) carbonyl)piperidin-4-yl)-1,2,4-oxadiazol-3-yl)-5-(benzyloxyamino)piperidine-1-carboxylate (380 mg, 0.559 mmol) and TEA (113 mg, 1.118 mmol) in DCM (5.0 mL). The mixture was stirred at 0° C. for 1 h, then, DCM (20 mL) was added and the mixture was washed with saturated sodium chloride (2×), dried over Na2SO4, and concentrated to give (2S,5R)-tert-butyl 2-(5-(1-(((9H-fluoren-9-yl)methoxy)carbonyl)piperidin-4-yl)-1,2,4-oxadiazol-3-yl)-5-(benzyloxy(chlorocarbonyl)amino)piperidine-1-carboxylate (400 mg), which was directly used in the next step. ESI-MS (EI+, m/z): 742 [M+H]+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C@H:27]1[N:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][C@@H:30]([CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[NH:48][C:49](=[O:69])[C@H:50]([CH:56]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[NH:51][C:52]([O:54][CH3:55])=[O:53])[O:29][CH2:28]1.[C:70](O)(=[O:77])[C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1.N1C(C)=CC=CC=1C>CN(C=O)C.CCOC(C)=O>[CH3:55][O:54][C:52]([NH:51][C@H:50]([C:49]([NH:48][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=1[CH2:41][CH2:40][C@H:30]1[O:29][CH2:28][C@@H:27]([CH2:26][NH:25][C:70]([C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)=[O:77])[N:32]([C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])[CH2:31]1)=[O:69])[CH:56]([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)=[O:53]
Reactant: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CN)CO1)C(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CNC(=O)c2ccccc2)CO1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
HATU (1.4 eq) was added to a stirred mixture a solution of tert-butyl (2R,5R)-5-(aminomethyl)-2-[2-(2-{[N-(methoxycarbonyl)-β-phenyl-L-phenylalanyl]amino}phenyl)ethyl]morpholine-4-carboxylate (1 eq), benzoic acid (1.2 eq) and 2,6-lutidine (2 eq) in DMF (0.05 M) and the mixture was stirred at room temperature for 16 hrs. The mixture was diluted in EtOAc, The organic layer was washed with aqueous saturated NH4Cl and brine. The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by automated silica gel flash chromatography system eluted with a gradient 10% to 100% of EtOAc/Hex to afford title compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([NH2:7])[N:4]([C:8]([NH:10][CH3:11])=[S:9])[N:3]=1.[C:12]([O:15][CH:16](OCC)OCC)(=O)[CH3:13]>>[NH2:7][C:5]1[N:4]([C:8]([NH:10][CH3:11])=[S:9])[N:3]=[C:2]([N:1]=[CH:16][O:15][CH2:12][CH3:13])[N:6]=1
Reactant: CCOC(OCC)OC(C)=O
Reactant: CNC(=S)n1nc(N)nc1N
Product: CCOC=Nc1nc(N)n(C(=S)NC)n1
Reaction time: 1 h
Yield: 73 %

Procedure:
A solution of the compound (500 mg) obtained in Example 31 and diethoxymethyl acetate (7 ml) was stirred at room temperature. After stirring for 1 hour, the resulting crystals were collected by filtration to give 480 mg of a white powdery solid (yield 73%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([OH:10])[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][C:18](=O)[O:19]C1C=CC=CN=1.[NH4+].[Cl-]>C1COCC1.CCOCC>[C:18](=[O:19])([O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=1)[O:10][C:4]1([CH3:3])[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: CC1(O)CCOCC1
Reactant: O=C(Oc1ccccn1)Oc1ccccn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(OC(=O)Oc2ccccn2)CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride, 60% in mineral oil (207 mg, 5.17 mmol) in THF (20 mL) was added 4-methyltetrahydro-2H-pyran-4-ol (500 mg, 4.30 mmol) at 0° C. After stirring 30 min, the solution was transferred to a solution of di(pyridin-2-yl)carbonate (931 mg, 4.30 mmol) in THF (20 mL) through a cannula. The formed slurry was stirred at 0° C. for 30 min. The slurry was warmed to rt and stirred for 2 h. At room temperature, to the reaction mixture was added sat. aq. NH4Cl (1 mL) upon which brief and significant effervescence was observed. The mixture was transferred to a 250 mL separatory funnel and was diluted with Et2O (50 mL). The solution was washed with water:brine (25 mL: 25 mL). The aq. phase was extracted with EtOAc (100 mL). The combined organics were dried over MgSO4; filtered; then concentrated in vacuo. The resulting residue was dissolved in acetone and then concentrated onto Celite in vacuo. The resulting powder was subjected to SiO2 purification on the Biotage system [90 g SiO2 column, hexanes:EtOAc 90:10 to 60:40 over 8 CV] to get the product as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.48-8.39 (m, 1H), 7.87-7.76 (m, 1H), 7.30-7.24 (m, 2H), 7.16-7.09 (m, 1H), 3.83-3.69 (m, 4H), 2.29-2.16 (m, 2H), 1.80 (ddd, J=14.3, 8.9, 5.9 Hz, 2H), 1.66 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:12])[C:9]=1[O:10][CH3:11])[CH:5]=O.C1C(/C=N/O)=CC=[N+:17](C[N+]2C=CC(/C=N/O)=CC=2)C=1.[Br-].[Br-].B>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:12])[C:9]=1[O:10][CH3:11])[CH2:5][NH2:17]
Reactant: COc1c(F)cc(C=O)cc1F
Reactant: O/N=C/c1cc[n+](C[n+]2ccc(/C=N/O)cc2)cc1
Agent: B
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1c(F)cc(CN)cc1F
Yield: 50 %

Procedure:
The reaction of 3,5-difluoro-4-methoxybenzaldehyde methoxime, (7 g, 35 mmole) and 0.98M borane in tetrahydrofuran (46 ml) substantially as described in 1B above produced 3 g, (50%) of the title compound as a clear oil.
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.B([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][C:19]=1[F:27])(O)O>>[Cl:12][C:11]1[C:2]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][C:19]=2[F:27])=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([O:13][CH3:14])=[CH:6][CH:5]=2
Reactant: O=C(O)c1ccc(B(O)O)c(F)c1
Reactant: COc1ccc2nc(Cl)c(Cl)cc2c1
Product: COc1ccc2nc(-c3ccc(C(=O)O)cc3F)c(Cl)cc2c1

Procedure:
Scheme 3: starting from 2,3-dichloro-6-methoxyquinoline (Intermediate 4) and 4-borono-3-fluorobenzoic acid. An aqueous/EtOAc workup was performed followed by purification by silica gel column (PE/EtOAc=1/1) to give the desired product.
Reaction SMILES: C(OC(=O)NC1SC2C=CC=CC=2N=1)C.C(OC(=O)[NH:20][C:21]1[S:22][C:23]2[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:24]=2[N:25]=1)C>O>[NH2:20][C:21]1[S:22][C:23]2[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:24]=2[N:25]=1
Reactant: CCOC(=O)Nc1nc2ccc([N+](=O)[O-])cc2s1
Agent: CCOC(=O)Nc1nc2ccccc2s1
Solvent: O
Product: Nc1nc2ccc([N+](=O)[O-])cc2s1

Procedure:
19 g (0.09 mol) of benzothiazol-2-yl-carbamic acid ethyl ester are nitrated as described in Example 1. The resulting water-moist paste of 6-nitro-benzothiazol-2-yl-carbamic acid ethyl ester is saponified at pH 10 to 12 and the mixture is worked up, as described in Example 1. 9.8 g of 2-amino-6-nitrobenzothiazole of melting point 249° to 252° C. are obtained. The content of isomeric nitro compounds is less than 1%.
Reaction SMILES: C(C1C=C(OC2C=CC(NC3N=CC=CC=3C(NC3C=CC([Cl:29])=CC=3)=O)=CC=2F)C=CN=1)(=O)N.[ClH:35].[NH2:36][C:37]1[CH:42]=[C:41]([O:43][C:44]2[CH:49]=[CH:48][C:47]([NH:50][C:51]3[N:67]=[CH:66][CH:65]=[CH:64][C:52]=3[C:53]([NH:55][C:56]3[CH:61]=[CH:60][C:59](F)=[CH:58][C:57]=3F)=[O:54])=[CH:46][C:45]=2[F:68])[CH:40]=[CH:39][N:38]=1>>[ClH:29].[NH2:36][C:37]1[CH:42]=[C:41]([O:43][C:44]2[CH:49]=[CH:48][C:47]([NH:50][C:51]3[N:67]=[CH:66][CH:65]=[CH:64][C:52]=3[C:53]([NH:55][C:56]3[CH:61]=[CH:60][C:59]([Cl:35])=[CH:58][CH:57]=3)=[O:54])=[CH:46][C:45]=2[F:68])[CH:40]=[CH:39][N:38]=1
Reactant: NC(=O)c1cc(Oc2ccc(Nc3ncccc3C(=O)Nc3ccc(Cl)cc3)cc2F)ccn1
Reactant: Nc1cc(Oc2ccc(Nc3ncccc3C(=O)Nc3ccc(F)cc3F)cc2F)ccn1
Agent: Cl
Product: Nc1cc(Oc2ccc(Nc3ncccc3C(=O)Nc3ccc(Cl)cc3)cc2F)ccn1
Yield: 25 %

Procedure:
2-(4-(2-Carbamoylpyridin-4-yloxy)-3-fluorophenylamino)-N-(4-chlorophenyl)nicotinamide (0.088 g, 0.18 mmol) was converted to the title compound (0.022 g, 25%) in a manner similar to the preparation of 2-(4-(2-aminopyridin-4-yloxy)-3-fluorophenylamino)-N-(2,4-difluorophenyl)nicotinamide (Step E of Example 3). 1H NMR (DMSO-d6) δ 10.65 (s, 1H), 10.40 (s, 1H), 8.36 (dd, 1H, J=4.9, 1.6 Hz), 8.25-8.28 (m, 1H), 8.11 (dd, 1H, J=13.6, 2.4 Hz), 7.71-7.92 (m, 5H), 7.29-7.45 (m, 4H), 6.98 (dd, 1H, J=7.7, 4.9 Hz), 6.65 (dd, 1H, J=7.3, 2.5 Hz), 6.13 (d, 1H, J=2.4 Hz);
Reaction SMILES: [C:1]([O:9]C)(=O)/[CH:2]=[CH:3]\[C:4](OC)=[O:5].[CH2:11]([NH2:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17]>C1(C)C=CC=CC=1>[NH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][NH:18][C:1](=[O:9])[CH:2]([NH:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][NH2:18])[CH2:3][C:4]([NH:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][NH2:18])=[O:5]
Reactant: NCCCCCCN
Reactant: COC(=O)/C=C\C(=O)OC
Solvent: Cc1ccccc1
Product: NCCCCCCNC(=O)CC(NCCCCCCN)C(=O)NCCCCCCN

Procedure:
Dimethyl maleate (72 g, 0.5 moles) is added over a 2-3 hour period to a solution of 1,6-hexanediamine (174 g, 1.5 moles) in toluene (360 g) at 75°-80° C. The reaction temperature rises from 80° to 110° C. under reflux conditions. After the addition is completed, methanol is distilled at a reaction temperature of 120°-125° C. Additional toluene (320 g) is added to maintain reaction volume. The reaction may be followed by amine titration or by disappearance of the methyl ester in the 1H NMR spectrum. After the reaction is complete, toluene is removed under vacuum (50°-70° C., 15-20 mm Hg) to give N,N'-bis(6-aminohexyl)-2-[(6-aminohexyl)amino]butanediamide as a viscous liquid which solidifies on standing.
Reaction SMILES: C([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([NH:21][C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:28][CH:27]=1)=[O:23])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=O)C1C=CC=CC=1.[C:40](OC(=O)C)(=O)C>CO.[Pd]>[C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([NH:21][C:22]([NH:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([NH:32][C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])=[CH:30][CH:31]=1)=[O:23])[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:8])[CH3:40]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)NCc1ccc(NC(=O)OC(C)(C)C)cc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)[C@@H](CCCNC(C)=O)NC(=O)NCc1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.8 %

Procedure:
(R)-ethyl 5-(benzyloxycarbonylamino)-2-(3-(4-(tert-butoxy-carbonylamino)benzyl)ureido)pentanoate (1 equivalent, 115 mg, 0.21 mmol) was dissolved in 50 ml of MeOH. The Pd/C (12 mg) and the acetic anhydride (3 equivalent, 60 μl, 0.63 mmol). The reaction mixture was stirred under hydrogen at room temperature for 4 h. Then the mixture was filtrated on celite and the filter was concentrated. the crude was washed by 30 ml NaHCO3 and extracted by 3×30 ml EtOAc. The organic phase was dried over Na2SO4, filtered and concentrated. The crude was purified by flash chromatography (CH2Cl2/MeOH) to afford the amide (84 mg, 78%) a colourless oil Rf=0.27 (CH2Cl2/MeOH 95/5). 1H NMR (200 MHz, CDCl3): δ 7.30 (d, J=8.6 Hz, 2H), 7.18 (d, J=8.6 Hz, 2H), 6.63 (broad s, 1H), 6.28-6.10 (m, 1H), 5.45 (d, J=7.6 Hz, 1H), 5.34-5.20 (m, 1H), 4.52-4.35 (m, 1H), 4.29 (d, J=5.8 Hz 2H), 4.15 (q, J=7.1 Hz, 2H), 3.32-3.12 (m, 2H), 1.94 (s, 3H), 1.90-1.36 (m, 4H) 1.50 (s, 9H), 1.25 (1, J=7.5 Hz, 3H).
Reaction SMILES: [C:1](=O)([O:32]C1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][C:4](=[C:13]1[CH2:16][N:15]([CH:17]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:14]1)[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[CH:6]=1.[CH:43]([NH2:46])([CH3:45])[CH3:44]>C(Cl)Cl>[CH:43]([NH:46][C:1](=[O:32])[O:2][CH2:3][C:4](=[C:13]1[CH2:16][N:15]([CH:17]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH2:14]1)[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[CH:6]=1)([CH3:45])[CH3:44]
Reactant: CC(C)N
Reactant: O=C(OCC(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: CC(C)NC(=O)OCC(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 45 mg (0.073 mmol) of 2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-2-(3,5-difluorophenyl)ethyl 4-nitrophenyl carbonate in 3 mL of methylene chloride was added 0.3 mL of isopropylamine and stirred for 4 h at rt. The reaction mixture was then concentrated and the residue was purified by silica gel chromatography with hexanes/ethyl acetate=4:1 to afford the title compound as a white solid. 1NMR (CDCl3) δ 1.15 (d, 6H, J=5.7 Hz), 3.90 (br s, 1H), 3.99 (s, 2H), 4.06 (s, 2H), 4.54 (s, 1H), 4.74 (s, 2H), 6.68-6.74 (m, 3H), 7.29-7.39 (m, 8H); Mass Spectrum: m/e=531 (M+1 35Cl, 35Cl) and 533 (M+1 35Cl, 37Cl).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C[O-].[Na+].[C:9]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:14]=[CH:13][C:12]([C:15]([OH:27])([CH2:25]Cl)[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])=[CH:11][CH:10]=1>CO.CN(C)C=O>[C:9]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:10]=[CH:11][C:12]([C:15]([OH:27])([CH2:25][N:4]2[CH:3]=[N:2][N:1]=[CH:5]2)[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])=[CH:13][CH:14]=1
Reactant: OC(CCl)(Cc1ccc(Cl)cc1Cl)c1ccc(-c2ccccc2)cc1
Reactant: c1nc[nH]n1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: OC(Cc1ccc(Cl)cc1Cl)(Cn1cnnc1)c1ccc(-c2ccccc2)cc1
Temperature: 70 °C
Yield: 10.4 %

Procedure:
7.6 g (0.11 mol) of 1,2,4-triazole are added to a solution of 3.5 g (0.065 mol) of a sodium methylate in 18 ml of methyl alcohol; a solution of 19.5 g (0.05 mol) of 2-(4-biphenylyl)-3-chloro-1-(2,4-dichlorophenyl)-propan-2-ol in 38 ml of dimethylformamide is then added dropwise and the mixture is heated to 70° C. for 90 minutes. The solvent is removed in vacuo in a rotary evaporator and the residue is stirred with water. The resulting crystals are washed with diethyl ether and recrystallised from acetonitrile. 2.2 g of 2-(4-biphenylyl)-1-(2,4-dichlorophenyl)-3-(1,3,4-triazol-1-yl)-propan-2-ol of melting point 260° C. are obtained.
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-])=O)[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl-].[NH4+].CO>[Fe].O>[NH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:13][C:11]1[CH:10]=[CH:9][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([F:1])[CH:12]=1
Reactant: CCOC(=O)c1ccc(Nc2ccccc2[N+](=O)[O-])cc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CCOC(=O)c1ccc(Nc2ccccc2N)cc1F
Temperature: 100 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
200 mg ethyl 2-fluoro-4-(2-nitrophenylamino)benzoate (compound in Production Example 331), 180 mg iron powder, 350 mg ammonium chloride and 8 mL solution mixture of methanol and water (5:3) were stirred at 100° C. for 1 hour. Insolubles were filtered off with Celite, and water was added to the filtrate which was then extracted with dichloromethane. The extract was purified by NH silica gel chromatography (ethyl acetate), to give 179 mg of the title compound as pale brown crystals.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:11][C:12]1[C:21]([CH3:22])=[CH:20][C:19](I)=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15])(=[O:10])[CH3:9].[CH2:24]([OH:27])[C:25]#[CH:26]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:8]([O:11][C:12]1[C:21]([CH3:22])=[CH:20][C:19]([C:26]#[C:25][CH2:24][OH:27])=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15])(=[O:10])[CH3:9]
Reactant: COC(=O)c1cc(I)cc(C)c1OC(C)=O
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C#CCO)cc(C)c1OC(C)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Triethylamine (0.943 mL, 6.76 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.092 g, 0.132 mmol) were added to a mixture of methyl 2-(acetyloxy)-5-iodo-3-methylbenzoate (1.0 g, 2.99 mmol) and propargyl alcohol (0.161 mL, 2.69 mmol) in THF (20 mL) at room temperature, and then copper (I) iodide (0.053 g, 0.278 mmol) was added. The resulting mixture was stirred at room temperature for 18 h. The reaction was quenched with water (20 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were washed with water (50 mL), brine (40 mL), dried (MgSO4), and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 0-20% EtOAc in hexanes over 30 min) to afford methyl 2-(acetyloxy)-5-(3-hydroxyprop-1-yn-1-yl)-3-methylbenzoate, as a yellow solid. 1H NMR (500 MHz, CHCl3): δ 7.97 (s, 1 H); 7.53 (s, 1 H); 4.91 (s, 2 H); 3.88 (s, 3 H); 2.22 (s, 3 H); 2.16 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:11][C:10]=2[C:21]2[CH:26]=[CH:25][C:24]([C:27]([CH3:31])([CH3:30])[C:28]#[N:29])=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.Cl.CC[OH:35]>[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:11][C:10]=2[C:21]2[CH:22]=[CH:23][C:24]([C:27]([CH3:31])([CH3:30])[C:28]([NH2:29])=[O:35])=[CH:25][CH:26]=2)=[CH:4][CH:3]=1
Reactant: Cn1c(-c2ccccc2)nc(-c2ccc(C(C)(C)C#N)cc2)c1Sc1ccc(Cl)cc1
Reactant: CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(-c2ccccc2)nc(-c2ccc(C(C)(C)C(N)=O)cc2)c1Sc1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 48 h

Procedure:
A suspension of 2-(4-{5-[(4-chlorophenyl)thio]-1-methyl-2-phenyl-1H-imidazol-4-yl}phenyl)-2-methylpropanenitrile (Example 76, 120 mg, 0.270 mmol) in 3 mL of EtOH and 2 mL of 2 N NaOH was stirred at 90° C. over two days. The mixture was neutralized with 2 N HCl (pH=ca 5) and the product was extracted with EtOAc. The extracts were concentrated to dryness, and the residue was purified by reverse phase HPLC to afford the title compound. 1H NMR (500 MHz, (CD3OD): 7.88 (d, 2H), 7.74 (m, 2H), 7.58 (m, 3H), 7.44 (d, 2H), 7.26 (d, 2H), 7.31 (d, 2H), 3.64 (s, 3H), 1.58 (s, 6H). LCMS: m/z 462 (M+H)+.