Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[C:12]([O:19][CH3:20])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:21])[N:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([O:19][CH3:20])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(CN(C)C(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1cc(CN(C)C(=O)OC(C)(C)C)ccc1N

Procedure:
In a 250 mL Parr apparatus, 0.98 g (3.5 mmol) of (3-methoxy-4-nitro-benzyl)-methyl-carbamic acid tert-butyl ester in 40 mL of ethanol was hydrogenated at 2 atm over 300 mg of 10% Pd on carbon for 15 minutes. The catalyst was removed by filtration through a glass fiber filter and the filtrate was concentrated to give a crude product as light yellow oil. 1H NMR (400 MHz, CDCl3): δ6.69 (m, 3H), 3.95 (s, 2H), 3.84 (s, 3H), 2.8 (m, 2H), 2.75 (s, 3H), 1.51 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:19])[CH:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)[OH:10])=[CH:4][CH:3]=1.[Bi]=O>C(O)(=O)C>[CH3:18][S:17][C:14]1[CH:15]=[CH:16][C:11]([C:9](=[O:10])[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[O:19])=[CH:12][CH:13]=1
Reactant: CSc1ccc(C(O)C(=O)c2ccc(F)cc2)cc1
Agent: O=[Bi]
Solvent: CC(=O)O
Product: CSc1ccc(C(=O)C(=O)c2ccc(F)cc2)cc1
Temperature: 80 °C

Procedure:
A mixture of ketone from step 2 (1.25 g, 4.5 mmol) and bismuth oxide (Bi2O3) (2.7 g, 1.2 equiv.) in acetic acid (20 ml) was warmed to 80° C. for 30 minutes. After cooling, the mixture was filtered through Celite® filter agent and the filtrate was concentrated. The residue was dissolved in hot methanol and filtered. The solvent was concentrated under a nitrogen stream, placed in the refrigerator and the precipitate formed was filtered to give 1 g (83%) of titled dione: m.p. 96-970° C. Anal. Calc'd. for C15H11FO2S (M.W. 274.31): C, 65.68; H, 4.04; S, 11.69. Found: C, 65.42; H, 3.85; S, 11.42.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:15][C:16](=[O:37])[CH2:17][C@@H:18]([NH2:36])[C:19]([NH:21][C@H:22]([C:27](=[O:35])[NH:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1)[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CO[CH:40]1[CH:44]([C:45]2[CH:50]=[CH:49][C:48]([C:51]3[CH:56]=[CH:55][C:54]([C:57]#[N:58])=[CH:53][CH:52]=3)=[CH:47][CH:46]=2)[CH2:43][CH:42](OC)O1>>[CH2:8]([O:15][C:16](=[O:37])[CH2:17][C@@H:18]([N:36]1[CH:42]=[CH:43][C:44]([C:45]2[CH:50]=[CH:49][C:48]([C:51]3[CH:52]=[CH:53][C:54]([C:57]#[N:58])=[CH:55][CH:56]=3)=[CH:47][CH:46]=2)=[CH:40]1)[C:19]([NH:21][C@H:22]([C:27](=[O:35])[NH:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1)[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:20])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COC1CC(c2ccc(-c3ccc(C#N)cc3)cc2)C(OC)O1
Reactant: CC(C)(C)[C@H](NC(=O)[C@H](N)CC(=O)OCc1ccccc1)C(=O)Nc1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[C@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccc(C#N)cc3)cc2)c1)C(=O)Nc1ccncc1
Yield: 42 %

Procedure:
According to the procedure described in Example 1(c) for the preparation N-(1,7-diaza-4-oxa-8-oxo-tricyclo-[9.6.1.012,17]-octadeca-11(18),12,14,16-tetraen-9S-yl)-3-(R)-3-phenyl-1H-pyrrol-1-yl)sucinnamic acid benzyl ester, crude 3(R)-amino-N-[2,2-dimethyl-1(S)-(pyridin-4-ylcarbamoyl)propyl]succinamic acid benzyl ester trifluoroacetate salt and 4′-(2,5-dimethoxy-tetrahydrofuran-3-yl)-biphenyl-4-carbonitrile were condensed to give 75 mg(42%) of 3(R)-[3-(4′-cyanobiphenyl-4yl)-1H-pyrrol-1yl]-N-[2,2-dimethyl-1(S)-(pyridin-4-ylcarbamoyl)propyl]succinamic acid benzyl ester as an off-white powder, mp 115-6° C. 1H NMR: δ 8.42 (d, 2H, J=5.6 Hz), 7.72 (s, 2H), 7.58 (s, 2H), 7.50 (d, 2H, J=5.0 Hz), 7.31 (s, 2H), 7.26 (s, 7H), 7.12 (m, 1H), 6.85 (dd, 1H, J=2.5, 2.5 Hz), 6.64 (dd, 1H, J=1.6, 2.8 Hz), 6.25 (m, 1H), 5.20-5.10 (m, 3H), 4.15 (d, 1H, J=8.1 Hz), 3.39 (dd, 1H, J=5.5, 17.3 Hz), 3.25 (dd, 1H, J=7.9, 17.3 Hz), 0.94 (s, 9H). IR (KBr): 3331, 2959, 2225, 1735, 1687, 1655, 1602, 1559, 1511, 1288, 1203, 825 cm−1. HRFABMS: Calculated for C35H37N4O4 (M+H+): 640.2924. Found: 640.2908. Anal. Calculated for C39H37N5O4.1.1EtOAc C, 70.76; H, 6.27; N, 9.51. Found: C, 70.73; H, 6.19; N, 9.16.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])(CC)C.[N:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[CH:47]=[O:48]>C1COCC1>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[C:22]([CH:47]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][N:41]=2)[OH:48])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2Cl)C[C@H](C)O1
Reactant: O=Cc1ccccn1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(O)c3ccccn3)c(F)c2Cl)C[C@H](C)O1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (2R,6S)-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-chloro-3-fluorophenyl]-2,6-dimethylmorpholine (Intermediate 42, 2.0 g, 3.9 mmol) in anhydrous THF (10 mL), sec-Butyl lithium (1.4 M in cyclohexane, 2.1 eq) was added and the solution was stirred for ½ h at −78° C. Pyridine-2-carbaldehyde (0.74 mL, 7.8 mmol) in THF (5 mL) was added dropwise and the solution was stirred for additional 1 h. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulphate. The solvent was removed under vacuum and the residue was purified over silica gel chromatography column using ethyl acetate-pet. ether gradient to obtain product. Yield: 900 mg, (37%)
Reaction SMILES: Cl[O-].[Na+].[N:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]=[N:11][OH:12].[C:13]([O:17][C:18]([NH:20][CH2:21][C:22]#[CH:23])=[O:19])([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl>[C:13]([O:17][C:18]([NH:20][CH2:21][C:22]1[O:12][N:11]=[C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]=2)[CH:23]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: ON=Cc1ccccn1
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1cc(-c2ccccn2)no1
Temperature: 25 °C
Yield: 42.7 %

Procedure:
Sodium hypochlorite (16 ml of a 14% w/v aqueous solution, 29.5 mmol) was added dropwise to a solution of 2-pyridinealdoxime (2 g, 16.4 mmol) and N-tert-butoxycarbonyl-propargylamine (5.6 g, 36.1 mmol) in DCM (30 ml) cooled in an ice bath. The mixture was stirred vigorously and allowed to warm to ambient temperature and stirred for 18 hours. The aqueous layer was separated and extracted with DCM. The combined organic extracts were combined, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography on silica gel eluting with diethyl ether/isohexane (1:1) to give the title compound (1.93 g, 43%). NMR (CDCl3) 1.45 (s, 9H), 4.5 (m, 2H), 5.03 (bs, 1H), 6.8 (s, 1H), 7.35 (m, 1H), 7.8 (m, 1H), 8.05 (d, 1H), 8.67 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:21]=O.[Br:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][C:27](=[O:33])[NH:28]2>>[Br:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1/[C:26](=[CH:21]/[C:3]1[NH:4][C:5]3[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]4[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]4)[C:7](=[O:20])[C:6]=3[C:2]=1[CH3:1])/[C:27](=[O:33])[NH:28]2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Reactant: O=C1Cc2c(Br)cccc2N1
Product: Cc1c(/C=C2\C(=O)Nc3cccc(Br)c32)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Yield: 91.2 %

Procedure:
The title compound was prepared under the same conditions as described in step 5 of Example 32 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 32d obtained from step 4 of Example 32 and 4-bromo-1,3-dihydro-indol-2-one as starting materials to obtain (Z)-2-(4-bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-piperidin-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 57 (68 mg, yield 91.2%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:11])[S:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1.[CH2:14]([NH2:17])[CH2:15][CH3:16]>C(OCC)(=O)C>[Cl:11][C:9]1[S:10][C:5]2[S:4](=[O:13])(=[O:12])[N:3]=[C:2]([NH:17][CH2:14][CH2:15][CH3:16])[NH:7][C:6]=2[CH:8]=1
Reactant: O=S1(=O)N=C(Cl)Nc2cc(Cl)sc21
Reactant: CCCN
Solvent: CCOC(C)=O
Product: CCCNC1=NS(=O)(=O)c2sc(Cl)cc2N1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
The title compound was prepared from 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide and n-propylamine by a procedure analogous to the procedure described in example 1Bb, except that the mixture was stirred for 16 h at 60° C.; mp 258°-261° C. (ethyl acetate); 1H-NMR (DMSO-d6): δ 0.89 (t, 3H), 1.52 (sext, 2H), 3.15 (q, 2H), 7.05 (s, 1H), 7.29 (br. s, 1H), 10.95 (br. s, 1H).
Reaction SMILES: [C:1](#[N:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20]1([O:26]P(OC2C=CC=CC=2)OC2C=CC=CC=2)C=CC=CC=1>[Rh]>[CH:20]([CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:1]#[N:19])=[O:26]
Reactant: CCCCCCCC/C=C\CCCCCCCC#N
Reactant: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Agent: [Rh]
Product: CCCCCCCCCCCCCCCCC(C#N)C=O
Temperature: 130 °C

Procedure:
Into a 1 liter, 316 SS autoclave equipped with stirrer and heat exchange coil is placed 617 grams of olenitrile, 3.0 grams of 5 percent rhodium on aluminum (Englehardt Industries) and 3.2 grams of triphenylphosphite. The autoclave is flushed with nitrogen then pressurized with carbon monoxidehydrogen (1:1) to 1080 psig. The temperature is increased to 127-133 degrees C. and maintained from 3.3 hours with a CO--H2 pressure of 970-1080 psig. At this point a GC analysis indicated complete reaction of oleonitrile with the formation of FON. The reaction was cooled, the pressure vented and the product filtered. The yield of FON is 681. Rhodium is removed from the product by vacuum distillation.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:25]([OH:27])=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>>[F:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]([C:25]([OH:27])=[O:26])[NH:18][C:16]([O:15][CH2:14][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[O:17])(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Product: O=C(N[C@@H](CCCCNS(=O)(=O)c1ccc(F)cc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Yield: 51 %

Procedure:
Nα-(9-fluorenylmethoxycarbonyl)-L-lysine was reacted with 4-fluorobenzenesulfonyl chloride under the conditions used in example 2 giving 51% of the title compound.
Reaction SMILES: [ClH:1].[CH2:2]([N:4]1[C:8]2=[N:9][CH:10]=[C:11]([C:20]3[O:24][N:23]=[C:22]([CH2:25][CH:26]4[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]4)[N:21]=3)[C:12]([NH:13][CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[C:7]2[CH:6]=[N:5]1)[CH3:3]>O1CCOCC1>[ClH:1].[CH2:2]([N:4]1[C:8]2[N:9]=[CH:10][C:11]([C:20]3[O:24][N:23]=[C:22]([CH2:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:21]=3)=[C:12]([NH:13][CH:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[C:7]=2[CH:6]=[N:5]1)[CH3:3]
Reactant: CCn1ncc2c(NC3CCOCC3)c(-c3nc(CC4CCN(C(=O)OC(C)(C)C)CC4)no3)cnc21
Agent: Cl
Solvent: C1COCCO1
Product: CCn1ncc2c(NC3CCOCC3)c(-c3nc(CC4CCNCC4)no3)cnc21
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A solution of hydrogen chloride in dioxane (1 ml) was added to Intermediate 124 (0.052 g, 0.1 mmol) and the reaction mixture stirred at 20° C. for 2 hours. The solution was evaporated in vacuo to afford Intermediate 125 as a yellow solid (0.047 g). LCMS showed MH+=412; TRET=2.21 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]([F:40])([F:39])[C:12]([F:38])([F:37])[O:13][C:14]([F:36])([F:35])[C:15]([F:34])([F:33])[O:16][C:17]([F:32])([F:31])[C:18]([F:30])([F:29])[C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([N+:26]([O-])=O)[CH:20]=2)[CH:7]=[CH:8][C:9]=1[OH:10])([O-])=O.Cl.[H][H]>C(O)C.[Pd]>[NH2:26][C:21]1[CH:20]=[C:19]([C:18]([F:29])([F:30])[C:17]([F:31])([F:32])[O:16][C:15]([F:33])([F:34])[C:14]([F:35])([F:36])[O:13][C:12]([F:37])([F:38])[C:11]([F:40])([F:39])[C:6]2[CH:7]=[CH:8][C:9]([OH:10])=[C:4]([NH2:1])[CH:5]=2)[CH:24]=[CH:23][C:22]=1[OH:25]
Reactant: O=[N+]([O-])c1cc(C(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)c2ccc(O)c([N+](=O)[O-])c2)ccc1O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1cc(C(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)c2ccc(O)c(N)c2)ccc1O
Reaction time: 8 h
Yield: 53 %

Procedure:
A solution of 1,8-bis(3-nitro-4-hydroxyphenyl)perfluoro-3,6-dioxaoctane (6.10 g, 0.010 mole) in 185 ml of ethanol was deoxygenated by passing nitrogen through the boiling solution for 14 minutes. Concentrated hydrochloric acid (37 ml, 0.44 mole) and 10% Pd/C(0.75 g) were added to the cooled solution and the catalytic reduction was run overnight at room temperature and 50 psi of hydrogen. The catalyst was filtered off and the water white solution reduced to dryness under water aspirator pressure. The light tan residue (6.1 g) was slurried in a water-ether mixture. After careful neutralization with solid sodium bicarbonate, the product dissolved in the ether layer, which was washed several times with water, dried over magnesium sulfate and evaporated to dryness. The soluble portion of the filtrate was taken up in 6 liters of boiling heptane, the solution treated with charcoal and reduced in volume to 3 liters to give upon cooling 2.9 g (53% yield) of slightly off-white product, mp 150°-152° C.
Reaction SMILES: C([Li])CCC.CN(C[N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)C.[I:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=[O:19].Cl>O1CCCC1>[NH:10]1[CH:14]=[CH:13][N:12]=[C:11]1[CH:18]([C:17]1[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=1[I:15])[OH:19]
Reactant: CN(C)Cn1ccnc1
Reactant: O=Cc1ccccc1I
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1ncc[nH]1)c1ccccc1I
Reaction time: 8 h
Yield: 38 %

Procedure:
n-Butyl lithium solution (2.5M in hexanes, 0.84 mL, 2.10 mmol) was added to 1-(dimethylaminomethyl)imidazole (prepared by the method detailed in JOC 1988, 53, 5685-5689; 0.25 g, 2.0 mmol) in tetrahydrofuran (8 mL) at ≦−65° C. with stirring under nitrogen. After 1 hour at this temperature a solution of 2-iodobenzaldehyde (0.50 g, 2.09 mmol) in tetrahydrofuran (1 mL) was added and the mixture allowed to return to ambient temperature overnight. Dilute hydrochloric acid (2N, 10 mL) was then added and organic solvent removed in vacuo before neutralising with sodium bicarbonate. Dichloromethane (3×30 mL) extracts were washed with saturated brine then dried (MgSO4), filtered and concentrated in vacuo to give a yellow oil. Purification by flash column chromatography eluting with 50% ethyl acetate/isohexane gave a white solid of 1H-imidazol-2-yl(2-iodophenyl)methanol (0.22 g, 38%). 1H NMR (500 MHz, d6-DMSO) δ 11.94 (1H, s), 7.80 (1H, dd, J=1.0, 7.8 Hz), 7.53 (1H, dd, J=1.7, 7.8 Hz), 7.41-7.37 (1H, m), 7.04-7.00 (2H, m), 6.74 (1H, s), 6.20 (1H, d, J=4.7 Hz), 5.83 (1H, d, J=4.7 Hz); m/z (ES+) 301 [MH+].
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[CH:20]=[CH:19][C:13]([C:14]([O:16]CC)=O)=[CH:12][CH:11]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[NH2:21][C:22]1[N:26](C(OC(C)(C)C)=O)[N:25]=[C:24]([CH2:34][CH2:35][C:36]2[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[C:38]([O:44][CH3:45])[CH:37]=2)[CH:23]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH:1]1([N:4]2[CH2:5][CH2:6][N:7]([C:10]3[CH:11]=[CH:12][C:13]([C:14]([NH:21][C:22]4[CH:23]=[C:24]([CH2:34][CH2:35][C:36]5[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[C:38]([O:44][CH3:45])[CH:37]=5)[NH:25][N:26]=4)=[O:16])=[CH:19][CH:20]=3)[CH2:8][CH2:9]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1ccc(N2CCN(C3CC3)CC2)cc1
Reactant: COc1cc(CCc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CCN(C5CC5)CC4)cc3)n[nH]2)cc(OC)c1
Yield: 12 %

Procedure:
4-(4-cyclopropylpiperazin-1-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzamide was prepared as for Example 94, but starting from ethyl 4-(4-cyclopropylpiperazin-1-yl)benzoate (193 mg, 0.7 mmol), tert-butyl 5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate (292 mg, 0.84 mmol) and 1M NaHMDS (1.23 ml, 1.23 mmol) in THF (5 ml). The crude product was purified by reverse phase prep. HPLC (acidic) using a 16-36% gradient of acetonitrile in water containing 0.1% TFA. The clean fractions were neutralised and evaporated to afford the title compound as a white solid (40 mg, 12%); 1H NMR (500.13 MHz, DMSO-d6+d4 Acetic Acid) δ 0.46 (2H, d), 0.50 (2H, d), 1.79-1.84 (1H, m), 2.78 (4H, t), 2.90 (4H, s), 3.24-3.31 (4H, m), 3.75 (6H, s), 6.32 (1H, s), 6.33 (1H, t), 6.42 (2H, d), 6.94-6.96 (2H, m), 7.86-7.88 (2H, m).
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[C:22]3[C:17](=[CH:18][C:19]([O:23]C)=[CH:20][CH:21]=3)[O:16][CH2:15][C@H:14]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl.N1C=CC=CC=1>O.C(O)C.ClCCl>[CH2:1]([C:7]1[CH:8]=[CH:9][C:10]([C@H:13]2[C:22]3[C:17](=[CH:18][C:19]([OH:23])=[CH:20][CH:21]=3)[O:16][CH2:15][C@H:14]2[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc([C@H]2c3ccc(OC)cc3OC[C@H]2c2ccccc2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CCO
Product: CCCCCCc1ccc([C@H]2c3ccc(O)cc3OC[C@H]2c2ccccc2)cc1
Temperature: 152.5 °C

Procedure:
A mixture of (±)-cis-4-(4-hexylphenyl)-7-methoxy-3-phenylchromane (0.46 g, 1.15 mmol) and anhydrous pyridine hydrochloride (6.60 g, 57.4 mmol) was heated to 150-155° C. as a melt for 18 hours. The mixture was cooled to room temperature, and the resulting orange coloured wax dissolved in a mixture of water (100 ml), hot ethanol (10 ml) and dichloromethane (100 ml). The organic layer was separated and the aqueous layer further extracted with dichloromethane (3×50 ml). The combined organic layers were washed with saturated sodium chloride, dried over sodium sulfate and evaporated to a dark coloured oil, which was purified by column chromatography on silica gel 60, with 2% methanol in dichloromethane as eluent; giving the title compound as a red oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C@H:13]([O:14]C(=O)C(C)(C)C)[CH2:12][N:11]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:10][CH:9]=2)=[CH:4][CH:3]=1.O.[OH-].[Li+]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C@H:13]([OH:14])[CH2:12][N:11]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)cc2)[C@H](OC(=O)C(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)cc2)[C@H](O)C1

Procedure:
To a 1,4-dioxane (500 μL)-water (100 μL) solution of tert-butyl (S)-4-(4-fluorophenyl)-5-(pivaloyloxy)-5,6-dihydropyridine-1(2H)-carboxylate (50.0 mg, 0.132 mmol) synthesized in Reference Synthesis Example 136, lithium hydroxide monohydrate (17.0 mg, 0.405 mmol) was added and the resultant mixture was stirred at 115° C. for 10 hours. After completion of the reaction, the reaction solution was analyzed with chiral column chromatography to measure optical purity.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]4[CH2:27][CH2:26][CH2:25]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:30])[CH:3]=1.[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[C:46]1([CH2:52][C:53]([N:55]=[C:56]=[S:57])=[O:54])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C(OCC)C>C(O)C.C1(C)C=CC=CC=1.CCCCCC>[F:30][C:4]1[CH:3]=[C:2]([NH:1][C:56]([NH:55][C:53](=[O:54])[CH2:52][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)=[S:57])[CH:29]=[CH:28][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]3[CH2:27][CH2:26][CH2:25]3)[CH2:18][CH2:17]2)=[O:15])[CH:8]=1
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCN(CCN4CCC4)CC3)c2)c(F)c1
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc(NC(=O)N3CCN(CCN4CCC4)CC3)c2)c(F)c1
Reaction time: 0.08 h
Yield: 43.3 %

Procedure:
4-[2-(Azetidin-1-yl)ethyl]piperazine-1-carboxylic acid [4-(4-amino-2-fluorophenoxy)pyridin-2-yl]amide (60 mg) was dissolved in ethanol (1.5 ml) under a nitrogen atmosphere, and then (S)-(+)-10-camphorsulfonic acid (101 mg) was added thereto, followed by stirring for 5 min. A 0.25 M solution of phenylacetyl isothiocyanate in toluene (0.87 ml) was added thereto, followed by stirring for 13 hrs. The reaction mixture was partitioned between ethyl acetate (50 ml) and a saturated aqueous solution of sodium hydrogencarbonate (30 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (30 ml), water (30 ml), brine (30 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; heptane:ethyl acetate=1:8, ethyl acetate, then ethyl acetate:ethanol=95:5). Fractions containing the target compound were concentrated under reduced pressure to give a residue, to which diethyl ether (2 ml) and hexane (2 ml) were then added to suspend. The solid was filtered off, and dried under aeration to provide the titled compound (37.2 mg, 43.3%) as white powder.
Reaction SMILES: [F:1][C:2]1[C:3]([C:23]2[N:27]=[CH:26][N:25](C3CCCCO3)[N:24]=2)=[CH:4][C:5]([CH3:22])=[C:6]([C:8]2[N:13]=[C:12]3[N:14]([CH:19]([CH3:21])[CH3:20])[C:15](=[O:18])[CH2:16][NH:17][C:11]3=[N:10][CH:9]=2)[CH:7]=1.C(N1C2=NC([Sn](C)(C)C)=CN=C2NCC1=O)(C)C.BrC1C(C)=CC(C2N=CN(C3CCCCO3)N=2)=C(F)C=1>CN(C)C=O.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>[F:1][C:2]1[C:3]([C:23]2[N:27]=[CH:26][NH:25][N:24]=2)=[CH:4][C:5]([CH3:22])=[C:6]([C:8]2[N:13]=[C:12]3[N:14]([CH:19]([CH3:21])[CH3:20])[C:15](=[O:18])[CH2:16][NH:17][C:11]3=[N:10][CH:9]=2)[CH:7]=1
Reactant: Cc1cc(-c2ncn(C3CCCCO3)n2)c(F)cc1-c1cnc2c(n1)N(C(C)C)C(=O)CN2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)N1C(=O)CNc2ncc([Sn](C)(C)C)nc21
Agent: Cc1cc(-c2ncn(C3CCCCO3)n2)c(F)cc1Br
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc[nH]n2)c(F)cc1-c1cnc2c(n1)N(C(C)C)C(=O)CN2
Temperature: 140 °C
Yield: 52 %

Procedure:
7-(5-Fluoro-2-methyl-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)phenyl)-1-isopropyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one. 1-Isopropyl-7-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (300 mg, 0.84 mmol), 3-(4-bromo-2-fluoro-5-methylphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazole (428 mg, 1.26 mmol) and bis(triphenylphosphine)palladium(II) dichloride (56 mg, 0.08 mmol) were combined in N,N-dimethylformamide (5 mL). The mixture was degassed and heated at 140° C. under nitrogen for 3 h. After being cooled to room temperature, the reaction mixture was filtered and the filtrate was partitioned between ethyl acetate (15 mL) and water (15 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (10 mL×2). The combined organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure and purified by preparative TLC (15% methanol in dichloromethane) to give the title compound (200 mg, yield 52%) as a solid.