Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([SiH2:10][CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH:20]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(OCC)C>[CH:20]1([NH:26][Si:10]([NH:26][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)([CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12]2)[CH:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NC1CCCCC1
Reactant: C1=CC([SiH2]C2C=Cc3ccccc32)c2ccccc21
Solvent: CCOCC
Product: C1=CC([Si](NC2CCCCC2)(NC2CCCCC2)C2C=Cc3ccccc32)c2ccccc21
Temperature: 0 °C

Procedure:
Dichloro, diindenyl silane (6.45 g) was slurried in 20 mL hexanes and 10 mL diethyl ether. The mixture was cooled to 0° C. and 9.2 mL of cyclohexylamine in 10 mL hexanes was added slowly. The mixture was heated to reflux for 1 h, cooled and filtered. The solvent was removed to give di(cyclohexylamino)diindenyl silane as a tan solid (7.60 g).
Reaction SMILES: C([O:3][C:4]([C@@:6]1([NH:11][C:12]([C@@H:14]2[CH2:18][C@@H:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:21]=3)[CH2:16][C@H:15]2[C:38](=[O:53])[NH:39][C@H:40]([C:45](=[O:52])[NH:46][CH:47]2[CH2:51][CH2:50][CH2:49][CH2:48]2)[C:41]([CH3:44])([CH3:43])[CH3:42])=[O:13])[CH2:8][C@H:7]1[CH:9]=[CH2:10])=[O:5])C.[Li+].[OH-]>O1CCOCC1.O>[CH:47]1([NH:46][C:45]([C@@H:40]([NH:39][C:38]([C@@H:15]2[CH2:16][C@H:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:21]=3)[CH2:18][C@H:14]2[C:12]([NH:11][C@:6]2([C:4]([OH:5])=[O:3])[CH2:8][C@H:7]2[CH:9]=[CH2:10])=[O:13])=[O:53])[C:41]([CH3:44])([CH3:42])[CH3:43])=[O:52])[CH2:51][CH2:50][CH2:49][CH2:48]1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C[C@H]1C(=O)N[C@H](C(=O)NC1CCCC1)C(C)(C)C)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C[C@H]1C(=O)N[C@H](C(=O)NC1CCCC1)C(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.4 %

Procedure:
To a solution of 52 (14 mg, 0.019 mmol) in dioxane/H2O 1:1: (4 mL) was added 1 M LiOH (115 μL, 0.115 mmol). The solution was stirred for 24 h at room temperature. Thereafter an additional portion of LiOH (75 μL, 0.075 mmol) was added and the solution was stirred for another 24 h. After acidification to approximately pH 3 with 1 M HCl and co-evaporation with toluene the residue was purified by HPLC (MeOH/H2O 70:30 with 0.2% TFA) yielding 53 (8 mg, 60%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([S:7]([NH2:10])(=[O:9])=[O:8])[S:5][CH:6]=1.C[Al](C)C.[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[N:20]=[C:19]([NH:25][C:26](=O)[O:27]C)[N:18]=1.Cl>C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:24][O:23][C:21]1[CH:22]=[C:17]([O:16][CH3:15])[N:18]=[C:19]([NH:25][C:26]([NH:10][S:7]([C:4]2[S:5][CH:6]=[C:2]([Cl:1])[N:3]=2)(=[O:9])=[O:8])=[O:27])[N:20]=1
Reactant: NS(=O)(=O)c1nc(Cl)cs1
Reactant: COC(=O)Nc1nc(OC)cc(OC)n1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2nc(Cl)cs2)n1
Reaction time: 0.17 h
Yield: 40.9 %

Procedure:
To a suspension of 1.6 g of 4-chloro-2-thiazolesulfonamide in 100 ml methylene chloride under a nitrogen atmosphere, 4.4 ml of a 2.0M solution of trimethylaluminum in toluene was added slowly via a syringe. The reaction mixture was stirred 10 minutes; 1.9 g of methyl N-(4,6-dimethoxypyrimidin-2-yl)carbamate was added, and the reaction mixture refluxed for 18 hours. The reaction mixture was cooled to 0°, and 55 ml of 5% hydrochloric acid was added dropwise giving a flocculant solid. The reaction mixture was extracted with 100 ml of ethyl acetate. The organic solution was washed wtih brine, dried over magnesium sulfate, filtered and the solvent evaporated. The resulting tan solid was slurried in 1-chlorobutane, collected, washed with hexane and dried giving 1.25 g of the title compound as a white solid, m.p. 182°-183°(d). IR: 2.98 and 3.25μ (NH), 5.80μ (C=O).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[C:14](F)[CH:13]=[C:12]([F:17])[C:11]=1[N+:18]([O-:20])=[O:19].[CH3:21][O-:22].[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[C:14]([O:22][CH3:21])[CH:13]=[C:12]([F:17])[C:11]=1[N+:18]([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1Nc1ccc(I)cc1F
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(F)c([N+](=O)[O-])c(Nc2ccc(I)cc2F)c1
Reaction time: 1 h
Yield: 53.3 %

Procedure:
To a solution of 2-fluoro-N-(3,5-difluoro-2-nitrophenyl)-4-iodobenzenamine (Intermediate 14, 1.05 g, 2.7 mmol) in THF (25 mL) was added NaOMe solution (prepared by dissolving Na metal (61 mg, 2.7 mmol) in 6 mL of methanol)-78° C. The reaction mixture was brought to rt and stirred for 1 h at same temperature. The progress of reaction was monitored by TLC. After completion, the reaction mixture was quenched with water and extracted with ether. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography to yield 2-fluoro-N-(3-fluoro-5-methoxy-2-nitrophenyl)-4-iodobenzenamine as yellow solid (584 mg). 1H-NMR (400 MHz, CDCl3): δ 3.91 (3H, s), 6.23 (1H, d, J=10.4), 6.35 (1H, d, J=10.8), 7.04-7.08 (1H, m), 7.45-7.52 (2H, m), 7.83 (1H, s).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[I:25][C:26]1[NH:30][C:29]([C@@H:31]2[CH2:36][C@@H:35]3[C@@H:33]([CH2:34]3)[NH:32]2)=[N:28][CH:27]=1.[CH3:37][O:38][C:39]([NH:41][C@@H:42]([CH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1)[C:43](O)=[O:44])=[O:40].CCN(C(C)C)C(C)C>CN(C=O)C.CO.O.CO.C(Cl)Cl>[I:25][C:26]1[NH:30][C:29]([C@@H:31]2[CH2:36][C@@H:35]3[C@@H:33]([CH2:34]3)[N:32]2[C:43](=[O:44])[C@@H:42]([NH:41][C:39](=[O:40])[O:38][CH3:37])[CH:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)=[N:28][CH:27]=1
Reactant: Ic1cnc([C@@H]2C[C@H]3C[C@H]3N2)[nH]1
Reactant: COC(=O)N[C@H](C(=O)O)C1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)N[C@H](C(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(I)[nH]1)C1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.2 %

Procedure:
HATU (846 mg, 2.23 mmol) was added to a solution of (1R,3S,5R)-3-(5-iodo-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane (510 mg, 1.85 mmol), (S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid (483 mg, 2.23 mmol) and DIEA (3.24 mL, 18.5 mmol) in DMF (5 mL) and the reaction was stirred 2 h at room temperature. The reaction mixture was diluted with MeOH (5 mL) and water (5 mL). The volatiles were removed under vacuum and the residue was purified with flash chromatography (sample was dry loaded on silica gel and eluted with 0-100% ethyl acetate/hexanes then 10% MeOH/DCM) to afford the methyl(S)-2-((1R,3S,5R)-3-(5-iodo-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate (370 mg, 0.780 mmol, 42.1% yield) as white foam. Impure material was further purified on reverse phase HPLC (water/methanol, 0.1% TFA) to afford the TFA salt of methyl(S)-2-((1R,3S,5R)-3-(5-iodo-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate, (387 mg) as colorless oil. LC-MS retention time 0.690 min; m/z 474.95 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire C18 4.6×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where Solvent A was 10% methanol/90% water/0.1% TFA and Solvent B was 10% water/90% methanol/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (TFA salt, 500 MHz, MeOD) δ ppm 7.58 (s, 1H), 5.04 (dd, J=9.2, 6.7 Hz, 1H), 4.56 (d, J=7.8 Hz, 1H), 3.96 (td, J=11.7, 3.1 Hz, 2H), 3.74-3.81 (m, 1H), 3.65-3.73 (m, 3H), 3.35-3.44 (m, 2H), 2.61 (dd, J=13.6, 9.3 Hz, 1H), 2.37 (ddd, J=13.6, 6.7, 6.5 Hz, 1H), 1.96-2.09 (m, 2H), 1.37-1.62 (m, 4H), 1.06 (dt, J=8.8, 5.9 Hz, 1H), 0.84 (td, J=5.6, 2.4 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C([O-])([O-])=O.[K+].[K+].[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41])[CH2:35]Br>C1COCC1.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[CH2:13][N:12]([CH2:35][C:34]3[CH:37]=[C:38]([O:42][CH3:43])[C:39]([O:40][CH3:41])=[C:32]([O:31][CH3:30])[CH:33]=3)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(C2(CCCOC3CCCCO3)CCNC2)cc1Cl
Reactant: COc1cc(CBr)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(CN2CCC(CCCOC3CCCCO3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reaction time: 16 h

Procedure:
Combine 4-(3,4-dichloro-phenyl)-4-[3-(tetrahydro-pyran-2-yloxy)-propyl]-pyrrolidine (10 mmol), K2CO3 (30 mmol), and 3,4,5-trimethoxy-benzyl bromide (10 mmol) in THF/H2O (4/1, 200 mL). Heat to reflux and stir for 16 h. Concentrate in vacuo to obtain a residue. Dilute the residue with ethyl acetate and extract with H2O. Separate the layers, dry the organic layer over MgSO4, filter, and concentrate in vacuo. Chromatograph on silica gel to give the title compound.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:8]([OH:10])=[O:9])[CH2:6][SH:7])(=[O:3])[CH3:2].[C:11]([NH:16][C@H:17]([C:20]([OH:22])=[O:21])[CH2:18][SH:19])(=[O:15])[CH:12]([CH3:14])[CH3:13].OO>CO>[C:1]([NH:4][C@@H:5]([CH2:6][S:7][S:19][CH2:18][C@H:17]([NH:16][C:11](=[O:15])[CH:12]([CH3:13])[CH3:14])[C:20]([OH:22])=[O:21])[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H](CS)C(=O)O
Reactant: CC(C)C(=O)N[C@@H](CS)C(=O)O
Agent: OO
Solvent: CO
Product: CC(=O)N[C@@H](CSSC[C@H](NC(=O)C(C)C)C(=O)O)C(=O)O
Reaction time: 3 h
Yield: 31 %

Procedure:
A mixture of N-acetyl-L-cysteine (0.652 g, 4 mmol) and N-isobutyryl-L-cysteine (0.764 g, 4 mmol) in 10 mL of MeOH was stirred while hydrogen peroxide (30%, 0.60 mL, 5 mmol) was added dropwise. The stirring was continued for 3 hours at room temperature, after which the solvent was removed on the rotary evaporator. Addition of 25 mL of acetone and repeated evaporation afforded 1.5 g of crude material as an oil which solidified on standing. The desired title compound was isolated from this mixture by preparative HPLC as described in Example 17.
Reaction SMILES: C([O:4][C:5]1[CH:12]=[C:11]([CH3:13])[C:8]([CH:9]=[O:10])=[C:7]([CH3:14])[CH:6]=1)C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)=O>C(OCC)(=O)C.CC(O)=O.CC(O)=O.[Pd]>[CH3:13][C:11]1[CH:12]=[C:5]([OH:4])[CH:6]=[C:7]([CH3:14])[C:8]=1[CH:9]=[O:10]
Reactant: C=CCOc1cc(C)c(C=O)c(C)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O=CO
Solvent: CC(=O)O
Product: Cc1cc(O)cc(C)c1C=O
Reaction time: 0 h
Yield: 51 %

Procedure:
4-Allyloxy-2,6-dimethyl-benzaldehyde, 9.67 g (50.9 mmole), 1.14 g (5.09 mmole) of palladium II acetate, and 8.00 g (30.5 mmole)of triphenylphosphine was mixed in a flask. Formic acid, 2.11 ml (56 mmole), was added and the mixture was swirled in a 80° oil bath. Within 15 seconds the reaction exothermed and turned very dark. The gum was dissolved in ethyl acetate, washed once in sodium bicarbonate, once in water, and once in brine then chromatographed on 350 ml silica, using 20%, then 40% ethyl acetate/hexane. Fractions were bulked and crystallize from methylene chloride/hexane to give 3.90 g (51%) of subtitled product which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:12][CH2:11][CH:10]([NH:13]C(=O)OC(C)(C)C)[CH2:9]2)[CH:3]=1.[H-].[Na+].Cl[C:24]1[S:25][C:26]([C:29]#[N:30])=[CH:27][N:28]=1>>[NH2:13][CH:10]1[CH2:11][CH2:12][N:8]([C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:1][C:24]3[S:25][C:26]([C:29]#[N:30])=[CH:27][N:28]=3)[CH:3]=2)[CH2:9]1
Reactant: N#Cc1cnc(Cl)s1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cc(N)ncn2)C1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1cnc(Nc2cc(N3CCC(N)C3)ncn2)s1

Procedure:
Tert-butyl 1-(6-aminopyrimidin-4-yl)pyrrolidin-3-ylcarbamate 14-2 (0.483 g, 1.73 mmol), sodium hydride (0.277 g, 6.92 mmol) and 2-chloro-1,3-thiazole-5-carbonitrile 2-2 (0.25 g, 1.73 mmol) were treated as in Scheme 4 above. The product was purified on a C18 preparative column after treating the crude product with trifluoroacetic acid and then isolated via lyophilization. Hi-Res MS: calc: 288.1026 found: 288.1046. 1NMR (CD3OD): 8.43 ppm (s, 1H); 8.0 ppm (s, 1H); 6.02 ppm (s, 1H); 4.05 ppm (m, 1H); 3.87 ppm (m, 1H); 3.69 ppm (m, 3H); 2.51 ppm (m, 1H); 2.22 ppm (m, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1)=[O:2].FC(F)(F)C([O-])=O.[Tl+3].FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.[I-:35].[Na+]>FC(F)(F)C(O)=O.O>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[C:7]([I:35])[CH:8]=1)=[O:2]
Reactant: CC(=O)Nc1ccc(C=O)cc1
Reactant: [I-]
Agent: O=C([O-])C(F)(F)F
Agent: [Na+]
Agent: [Tl+3]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(=O)Nc1ccc(C=O)cc1I
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-(4-formyl-phenyl)-acetamide (1.25 g, 7.67 mmol) in trifluoroacetic acid (70 mL) was slowly added thallium(III)trifluoroacetate (5.00 g, 9.20 mmol). The reaction mixture was stirred at room temperature for 30 minutes. Then, a solution of sodium iodide (1.19 g, 7.95 mmol) in water (10 mL) was added slowly. The color changed to dark purple and a lot of solid was formed. Stirring continued at room temperature for 16 hours. Solvent was evaporated to half of the volume, and water (50 mL) was added. The pH was adjusted to approximately 13 with 4 N NaOH solution. The mixture was extracted with ethyl acetate (2×100 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated on a rotary evaporator. The solid obtained was washed with ethyl acetate (2×5 mL), ether (2×10 mL), and dried under vacuum to give N-(4-formyl-2-iodo-phenyl)-acetamide as an off-white solid. Yield: 0.760 g (34%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].Br[CH:16]([CH3:18])[CH3:17]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)Br
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccccc1Br
Temperature: 60 °C
Reaction time: 5 h
Yield: 91.4 %

Procedure:
A mixture of 2-bromophenol (23.2 mL, 0.20 mol), potassium carbonate (33.2 g, 0.24 mol) and 2-bromopropane (28.0 mL, 0.30 mol) in dimethylformamide (200 mL) was stirred in a preheated oil bath (60° C.) for 5 h. The cooled reaction mixture was then partitioned between ether and water. The layers were separated and the aqueous phase was extracted with ether. The combined organic solution was washed with copious amounts of water, 3N aqueous NaOH, dried (MgSO4), filtered and concentrated in vacuo to furnish 39.3 g (91%) of XIV as a pale yellow oil which was carried on without further purification. The structure was supported by GC/MS and 90 MHz 1H NMR.
Reaction SMILES: [CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][C:4]([OH:6])=O.[NH:23]1[CH:27]=[CH:26][N:25]=[CH:24]1>>[CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][C:4]([N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)=[O:6]
Reactant: c1c[nH]cn1
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC(=O)O
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC(=O)n1ccnc1
Yield: 91.5 %

Procedure:
The same procedure as in Example 1 was repeated except that 6.1 g of 3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenoic acid and 1.4 g of imidazole were used as the starting materials. 6.5 g (91%) of the title compound was obtained as a colorless oil.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)=[C:15]3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](NC(C)=O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f16) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](O)=[O:6].C([NH2:20])(=O)C1C=CC=CC=1.C(Cl)(C(Cl)=O)=O.[NH4+].[OH-]>>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH2:20])=[O:6]
Reactant: NC(=O)c1ccccc1
Reactant: Cc1ccc(C(=O)O)cc1I
Agent: O=C(Cl)C(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Product: Cc1ccc(C(N)=O)cc1I
Yield: 93 %

Procedure:
3-Iodo-4-methyl benzoic acid was converted to the corresponding benzamide according to the procedure described for compound la above ((COCl)2, NH4OH), to provide 3-iodo-4-methyl benzamide in 93% yield. Further conversion according to Method B described above provided compound 10 in 48% yield. 1H NMR (CDCl3) δ 8.02 (1 H, d, J=1.6 Hz), 7.95 (1 H, d, J=7.9 Hz), 7.29 (1 H, d, J=7.9 Hz), 6.46 (1 H, d, J=15.9 Hz), 6.10 (1 H, br s), 5.75 (1 H, br s), 4.08 (2 H, q, J=7.1 Hz), 2.48 (3 H, s), 1.42 (3 H, t, J=7.1 Hz) Anal. (C13H12N2O3.0.2 H2O) C, H, N.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][CH2:9][NH:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]=1[N+:21]([O-])=O)([CH3:4])([CH3:3])[CH3:2].CO>O1CCCC1.[Pt]=O>[C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][CH2:9][NH:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]=1[NH2:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCNc1ccc2ccccc2c1[N+](=O)[O-]
Agent: O=[Pt]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCNc1ccc2ccccc2c1N
Temperature: 25 °C
Reaction time: 7 h
Yield: 95.3 %

Procedure:
tert-Butyl[2-[(1-nitro-2-naphthyl)amino]ethyl]carbamate (746 mg, 2.25 mmol) was dissolved in tetrahydrofuran (7.5 mL), and methanol (7.5 mL), the solution was added with platinum oxide (7.5 mg), and the mixture was stirred at room temperature for 7 hours under a hydrogen atmosphere. The catalyst was separated by filtration, then the solvent was evaporated under reduced pressure, and the residue was washed with hexane to give the title compound (646 mg, yield 95%) as brown crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([CH2:11][N:12]3[CH2:16][CH:15]([CH2:17][CH2:18][CH3:19])[CH2:14][C:13]3=[O:20])=[C:4]2[N:3]=1.[CH3:21][O-:22].[Na+]>CO>[CH3:21][O:22][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([CH2:11][N:12]3[CH2:16][CH:15]([CH2:17][CH2:18][CH3:19])[CH2:14][C:13]3=[O:20])=[C:4]2[N:3]=1
Reactant: CCCC1CC(=O)N(Cc2cnn3ccc(Cl)nc23)C1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCC1CC(=O)N(Cc2cnn3ccc(OC)nc23)C1
Temperature: 80 °C
Yield: 53.7 %

Procedure:
To a solution of 1-[(5-chloropyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one 205 (0.575 mmol, 1 eq, 0.22 g) in MeOH (10 ml) is added sodium methoxide (5.75 mmol, 10 eq, 0.4 g). The mixture is heated at 80° C. for 2 hours. The solvent is removed under reduce pressure, water is added and the resulting mixture is extracted with CH2Cl2. The organic phases are combined, and dried over MgSO4. Volatiles are removed under reduced pressure to afford 89 mg of 1-[(5-methoxypyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one 208.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([C:14](=[O:16])[CH3:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[OH:28])[CH:23]=O>>[F:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:15][C:14]([C:12]2[S:13][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:17])([F:1])[F:18])=[CH:8][CH:7]=3)=[CH:10][CH:11]=2)=[O:16])[CH:25]=[CH:26][C:27]=1[OH:28]
Reactant: O=Cc1ccc(O)c(F)c1
Reactant: CC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)s1
Product: O=C(C=Cc1ccc(O)c(F)c1)c1ccc(-c2ccc(C(F)(F)F)cc2)s1

Procedure:
3-(3-Fluoro-4-hydroxyphenyl)-1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)prop-2-en-1-one is prepared from 1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)ethanone and 3-fluoro-4-hydroxybenzaldehyde according to general procedure B. The residue is crystallized from acetonitrile.
Reaction SMILES: Br.[F:2][C:3]([F:33])([F:32])[C:4]1[CH:5]=[C:6](O)[N:7]=[N:8][C:9]=1[C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[N:13][CH:14]=[CH:15][C:16]=2[NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=2)[N:11]=1.O=P(Cl)(Cl)[Cl:36]>>[Cl:36][C:6]1[N:7]=[N:8][C:9]([C:10]2[N:11]=[C:12]3[C:17]([C:16]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=4)=[CH:15][CH:14]=[N:13]3)=[CH:18][CH:19]=2)=[C:4]([C:3]([F:33])([F:32])[F:2])[CH:5]=1
Reactant: Oc1cc(C(F)(F)F)c(-c2ccc3c(Nc4ccc(C(F)(F)F)cn4)ccnc3n2)nn1
Reactant: O=P(Cl)(Cl)Cl
Agent: Br
Product: FC(F)(F)c1ccc(Nc2ccnc3nc(-c4nnc(Cl)cc4C(F)(F)F)ccc23)nc1

Procedure:
Dissolve 5-(trifluoromethyl)-6-(5-{[5-(trifluoromethyl)pyridin-2-yl]amino}-1,8-naphthyridin-2-yl)pyridazin-3-ol hydrobromide in neat POCl3 (20 mL). Heat the mixture at reflux for 4 hours. Cool and evaporate to dryness. Add toluene (25 mL) and remove the solvent under reduced pressure. Dissolve the residue in CH2Cl2 (30 mL) and sat. NaHCO3 (aq) (30 mL). Extract the aqueous phase with CH2Cl2 (3×30 mL). Combine, dry and evaporate the organic extracts to yield the title compound. LC/MS (MH+) 472.04.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][NH:8][CH2:9][CH2:10][NH2:11].[CH3:12][N:13]=[C:14]=[O:15]>>[CH3:12][NH:13][C:14]([NH:11][CH2:10][CH2:9][NH:8][CH2:7][C:2]1[N:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:15]
Reactant: CN=C=O
Reactant: NCCNCc1ncccn1
Product: CNC(=O)NCCNCc1ncccn1

Procedure:
By the procedure of Example 24, N-(2-pyrimidylmethyl)ethylenediamine is reacted with methyl isocyanate to give, after concentrating and separating the residue by column chromatography, the title compound.
Reaction SMILES: [C:1]([C:4]([CH3:31])([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])=[CH:12][CH:11]=1)[C:5]([O:7]C)=[O:6])(=[O:3])[NH2:2].[OH-].[Na+].Cl.O>CO.O1CCCC1.C(OCC)(=O)C>[C:1]([C:4]([CH3:31])([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])=[CH:14][CH:15]=1)[C:5]([OH:7])=[O:6])(=[O:3])[NH2:2]
Reactant: COC(=O)C(C)(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC(C)(C(N)=O)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
Methyl 2-carbamoyl-2-methyl-3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propionate (1.17 g, 2.77 mmol) obtained in Example 27 was dissolved in methanol-tetrahydrofuran (1:1, 20 ml). 1N Aqueous sodium hydroxide solution (10 ml) was added and the mixture was stirred at room temperature for 1 hr. 1N Hydrochloric acid was added to acidify the reaction mixture, and water (50 ml) and ethyl acetate (150 ml) were added for partition. The organic layer was washed with saturated brine (50 ml), dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (1.02 g, yield 90%) as a white solid.