Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([CH2:7][C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH3:32])[N:23]=4)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].FC(F)(F)C(O)=O.C(N)CN.O>ClCCl.C(OCC)(=O)C>[C:1]([CH:3]1[CH2:6][N:5]([CH2:7][C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH3:32])[N:23]=4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: C[C@H](CN1CC(C#N)C1)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](CN1CC(C#N)C1)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 64.6 %

Procedure:
2-(6-Chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-ethyl]-amide (58 mg, 0.10 mmol) was dissolved in dichloromethane (1.4 ml) and cooled in ice bath. Trifluoroacetic acid (0.6 ml) was slowly added and the reaction was stirred at room temperature for 5 h. The reaction was evaporated and the residue was dissolved in dichloromethane (1 ml). Ethylenediamine (0.40 ml, 6.0 mmol) was added and the mixture was stirred for 18 h. Water and then ethyl acetate were added to the mixture. The layers were separated and the aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed with sodium chloride solution and dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography (methanol/dichloromethane) to afford 29 mg (64%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-ethyl]-amide. MS: (M+H)+=449; mp=235-238° C. 1H NMR (300 MHz, DMSO-d6) δ: 9.10 (s, 1H), 8.44 (d, J=8.7 Hz, 1H), 8.43 (s, 1H), 8.01 (d, J=1.5 Hz, 1H), 8.02 (d, J=8.3 Hz, 1H), 7.34 (dd, J=8.7, 1.5 Hz, 1H), 4.18 (s, 3H), 4.04-4.16 (m, 1H), 3.36-3.53 (m, 4H), 3.28 (d, J=7.9 Hz, 1H), 2.60-2.68 (m, 2H), 1.28 (d, J=6.8 Hz, 3H).
Reaction SMILES: [N-:1]([C:4]#[N:5])[C:2]#[N:3].[Na+].[Cl:7][C:8]1[CH:9]=[C:10]([CH:12]=[C:13]([Cl:15])[CH:14]=1)[NH2:11]>Cl.O>[C:2]([NH:1][C:4]([NH:11][C:10]1[CH:9]=[C:8]([Cl:7])[CH:14]=[C:13]([Cl:15])[CH:12]=1)=[NH:5])#[N:3]
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: N#C[N-]C#N
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N#CNC(=N)Nc1cc(Cl)cc(Cl)c1
Yield: 76.4 %

Procedure:
To a solution of 4.45 g (0.05 mol) of sodium dicyanamide in 50 ml of 1N HCl is added 8.1 g (0.05 mol) of 3,5-dichloroaniline in 50 ml of H2O. The mixture is heated to about 80° C. to 100° C. for two hours. The mixture is then cooled, and the precipitated solids are recovered by filtration, washed and dried to give 8.75 g of the desired product having a melting point of 196° C. -198° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10]([OH:17])[C:11]([NH2:16])([CH2:14]O)[CH2:12][OH:13]>C1(C)C=CC=CC=1>[CH2:14]1[O:7][C@H:6]([C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[N:16]2[C:11]1([CH2:12][OH:13])[CH2:10][O:17][C@H:6]2[C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: NC(CO)(CO)CO
Reactant: O=Cc1ccc(F)cc1
Solvent: Cc1ccccc1
Product: OCC12CO[C@H](c3ccc(F)cc3)N1[C@H](c1ccc(F)cc1)OC2
Temperature: 25 °C

Procedure:
As an example, para-fluorinated compounds were prepared. More specifically, a suspension of 4-fluorobenzaldehyde (27 g, 0.22 mol) and tris(hydroxymethyl)aminomethane (13 g, 0.11 mol) in toluene (350 ml) was heated at reflux temperature with azeotropic removal of water for 12 hours. The reaction mixture was concentrated, stirred at room temperature, and the precipitated, unreacted 4-fluorobenzaldehyde was filtered off. The residue obtained after removal of solvent was subjected to flash chromatography on silica gel using hexane:ethylacetate (4:1 and 1:1). Crystallization of the respective fractions afforded pure compounds TH-237A, TH-236B, and TH-OPEN in yields 66%, 5%, and 21% respectively based on an equimolar product distribution ratio. The structures of the products were assigned by spectral data and the relative stereochemistry of TH-237A was assigned from single crystal X-ray diffraction data. The ellipsoid drawing of the molecular structure TH-237A from X-ray diffraction study is shown in FIG. 1.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[C:6](Cl)(=[O:10])[C:7]([CH3:9])=[CH2:8]>C1COCC1>[CH2:1]([NH:5][C:6](=[O:10])[C:7]([CH3:9])=[CH2:8])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN
Reactant: C=C(C)C(=O)Cl
Solvent: C1CCOC1
Product: C=C(C)C(=O)NCCCC
Temperature: 5 °C

Procedure:
In a 1 liter 3-necked flask were combined 400 ml dry THF and 40 ml distilled n-butylamine (0.405 mol). After cooling to 5° C. in an ice bath, 20 ml (0.205 mol) methacryloyl chloride was added slowly so as to keep the temperature below 10° C. The precipitate was removed by filtration, and the filtrate concentrated on a rotary evaporator. 1 g DNPD was added and the oil distilled at 76°-78° C. and 20 m torr. Yield 24.3 g (84%).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]2[S:24][C:23]([SH:25])=[N:22][C:21]=2[CH:26]=1>>[N:5]1([C:3](=[O:4])[CH2:2][S:25][C:23]2[S:24][C:20]3[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:26][C:21]=3[N:22]=2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: O=C(CCl)N1CCCc2ccccc21
Reactant: COc1ccc2sc(S)nc2c1
Product: COc1ccc2sc(SCC(=O)N3CCCc4ccccc43)nc2c1
Yield: 83 %

Procedure:
The title compound was synthesized according to General Procedure A using compound 4 as the electrophile and 5-methoxybenzo[d]thiazole-2-thiol as the nucleophile to yield 18 as a pale yellow solid (83%): MS m/z: 371 (M+H)+. Anal. Calcd. For, C19H18N2O2S2: C, 61.60; H, 4.90; N, 7.56; S, 17.31. Found: C, 61.40; H, 4.90; N, 7.48; S, 17.26.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:46])([CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:35]=[CH:34][C:33]([NH:36][C:37](OC4C=CC=CC=4)=[O:38])=[CH:32][CH:31]=3)[CH2:26][CH2:25]2)=[CH:20][CH:19]=1)[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.Cl.C([O:50][C:51](=O)[CH2:52][NH:53][CH3:54])C.C(=O)(O)[O-].[Na+]>CN(C1C=CN=CC=1)C.O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:46])([CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)[CH2:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:25][CH2:26][N:27]([C:30]3[CH:31]=[CH:32][C:33]([N:36]4[C:51](=[O:50])[CH2:52][N:53]([CH3:54])[C:37]4=[O:38])=[CH:34][CH:35]=3)[CH2:28][CH2:29]2)=[CH:22][CH:23]=1
Reactant: O=C(Nc1ccc(N2CCN(c3ccc(OCC(O)(Cn4cncn4)c4ccc(Cl)cc4Cl)cc3)CC2)cc1)Oc1ccccc1
Reactant: CCOC(=O)CNC
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: C1COCCO1
Product: CN1CC(=O)N(c2ccc(N3CCN(c4ccc(OCC(O)(Cn5cncn5)c5ccc(Cl)cc5Cl)cc4)CC3)cc2)C1=O
Yield: 90.8 %

Procedure:
A mixture of 2-(2,4-dichlorophenyl)-3-(4-[4-(4-phenoxycarbonylaminophenyl)piperazin-1-yl]phenoxy)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol (see Preparation 2) (0.3 g, 0.45 mmole), sarcosine ethyl ester hydrochloride (0.09 g, 0.58 mmole), 4-(N,N-dimethylamino)pyridine (0.03 g, 0.24 mmole) and sodium bicarbonate (0.09 g, 1 mmole) in 1,4-dioxane (30 ml) was heated under reflux for 18 hours. After cooling, the mixture was diluted with water, extracted with ethyl acetate and the organic phase washed with brine. After drying over magnesium sulphate, the organic phase was concentrated under reduced pressure to yield a gum, which on trituration with ether gave a pale yellow solid (0.260 g). Purification of this solid material by flash chromatography on silica gel eluting with methylene chloride (90):isopropanol (10):acetic acid (0.2) yielded, after collection and evaporation of appropriate fractions, the desired product as a colourless solid, m.p. 213°-215° (0.13 g, 45%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:16]([O:17][CH3:18])=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[O:19][CH3:20].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:31][C:32]#[N:33])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]>>[CH3:21][O:22][C:23]1[CH:24]=[C:25](/[C:31](=[CH:13]/[C:12]2[CH:15]=[C:16]([O:17][CH3:18])[C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])=[C:10]([O:19][CH3:20])[CH:11]=2)/[C:32]#[N:33])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: COc1cc(C=O)cc(OC)c1OCCCCCCO
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1ccc(/C(C#N)=C/c2cc(OC)c(OCCCCCCO)c(OC)c2)cc1OC
Yield: 97 %

Procedure:
(2Z)-2-(3,4-dimethoxyphenyl)-3-{4-[(6-hydroxyhexyl)oxy]-3,5-dimethoxyphenyl}prop-2-enenitrile is prepared starting from 4-[(6-hydroxyhexyl)oxy]-3,5-dimethoxybenzaldehyde and (3,4-dimethoxyphenyl)acetonitrile according the same procedure following for example 10 in 97% yield. This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([S:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[CH3:21])=O.[NH2:22][C:23]([NH2:25])=[S:24]>CCO>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([S:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]([C:3]3[N:22]=[C:23]([NH2:25])[S:24][CH:2]=3)=[C:6]([CH3:21])[CH:7]=2)=[CH:14][CH:15]=1
Reactant: NC(N)=S
Reactant: COc1ccc(Sc2cc(C)c(C(=O)CBr)c(C)c2)cc1
Solvent: CCO
Product: COc1ccc(Sc2cc(C)c(-c3csc(N)n3)c(C)c2)cc1
Yield: 89.7 %

Procedure:
A reaction mixture containing 2-bromo-1-(4-(4-methoxyphenylthio)-2,6-dimethylphenyl)ethanone (1.06 g, 2.9 mmol, 1.0 equiv) and thiourea (221.5 mg, 2.9 mmol, 1.0 equiv) in EtOH (20.0 mL) was heated at reflux for 16 h. The solution was concentrated under reduced pressure, and the residue was re-dissolved in EtOAc (50 mL). The solution was washed with saturated aqueous NaHCO3 (30 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (5.0% EtOAc in hexanes as eluant) to provide 4-(4-(4-methoxyphenylthio)-2,6-dimethylphenyl)thiazol-2-amine (890.9 mg, 2.6 mmol) as yellow solids in 90% yield: 1H NMR (DMSO-d6, 500 MHz) δ 7.40 (d, J=8.7 Hz, 2 H), 7.00 (d, J=8.7 Hz, 2 H), 6.86-6.87 (m, 4 H), 6.33 (s, 1 H), 3.78 (s, 3 H), 2.03 (s, 6 H); ESI-MS m/z 343.9 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]#[C:12][Si](C)(C)C)[C:7]([NH2:10])=[N:8][CH:9]=1)([O-:3])=[O:2].[OH-].[Na+]>C(O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[CH:11]=[CH:12][NH:10][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C[Si](C)(C)C#Cc1cc([N+](=O)[O-])cnc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=[N+]([O-])c1cnc2[nH]ccc2c1
Temperature: 140 °C
Reaction time: 0.5 h

Procedure:
To a solution of 500 mg 5-Nitro-3-trimethylsilanylethynyl-pyridin-2-ylamine in 4 ml ethanol were added 93.5 mg sodium hydroxide, and the mixture was stirred under irradiation in a microwave-oven for 30 minutes (min) at 140° C. 20 equal batches of this kind were combined and evaporated. The residue was dissolved in 100 ml conc. hydrochloric acid and stirred for 30 min at RT. It was again evaporated and the residue was refluxed with THF for 30 min. Insoluble parts were removed by filtration, the filtrate was evaporated and the residue was chromatographed on silica in ethyl acetate/heptane mixtures.
Reaction SMILES: C[O:2][C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=O>O>[C:3]1(=[O:2])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][NH:5]1
Reactant: COC(=O)NCCc1ccccc1
Solvent: O
Product: O=C1NCCc2ccccc21
Yield: 76.3 %

Procedure:
To a solution of polyphosphoric acid (200 mL) at 140° C. N-methoxycarbonyl-phenethylamine (28 g, 0.16 mol) was added portionwise over a 5 hour period. The reaction solution was poured into cold water (400 mL) and extracted with methylene chloride (5×200 mL). The organic layers were combined, dried with anhydrous magnesium sulfate, filtered and concentrated to give the title compound (17.96 g, 86% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[N:18]=2)=[CH:6][CH:5]=1)([O-])=O.[NH4+].[Cl-].C(OCC)(=O)C.CCN(CC)CC>CO.O.[Fe]>[O:11]1[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N:18]=[C:10]1[C:7]1[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc3cnccc3o2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: Nc1ccc(-c2nc3cnccc3o2)cc1
Yield: 61.9 %

Procedure:
2-(4-Nitrophenyl)oxazolo[4,5-c]pyridine (2.261 g, 9.3 mmol), iron powder (2.814 g, 48.0 mmol) and NH4Cl (4.314 g, 80.1 mmol) were refluxed in CH3OH/H2O (4:1, 469 mL) for 6 h. The mixture was filtered and the filtrate was evaporated in vacuo. The residue was purified by chromatography on silica gel eluted with petroleum ether:ethyl acetate:Et3N=160:40:1 to afford 4-(oxazolo[4,5-c]pyridin-2-yl)benzenamine as a yellow solid (1.215 g, yield: 62%). 1H NMR (400 MHz, DMSO-d6) δ: 6.11 (2H, s), 6.69 (2H, d, J=8.4 Hz), 7.75 (1H, d, J=5.6 Hz), 7.87 (2H, d, J=8.4 Hz), 8.46 (1H, d, J=5.6 Hz), 8.94 (1H, s); MS (ESI) calcd. for C12H9N3O (m/z): 211. found: 212 [M+1]+.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([NH:12][CH2:13][C:14]([CH2:20][NH:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[N:25][N:26]2[C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)([OH:19])[C:15]([F:18])([F:17])[F:16])[CH3:11]>>[CH2:10]([N:12]([CH2:13][C:14]([CH2:20][NH:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[N:25][N:26]2[C:31]1[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=1)([OH:19])[C:15]([F:17])([F:18])[F:16])[C:1](=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:11]
Reactant: CCNCC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Reactant: O=C(O)c1ccccc1
Product: CCN(CC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1ccccc1

Procedure:
Prepared similarly to Example 1 from benzoic acid and 3-(ethylamino)-1,1,1-trifluoro-2-({[1-(4-fluorophenyl)-1H-indazol-4-yl]amino}methyl)-2-propanol.
Reaction SMILES: C([Si](C)(C)[O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:18]3=[N:19][C:20](Cl)=[N:21][CH:22]=[C:17]3[CH2:16][N:15]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=3[F:32])[C:14]2=[O:33])[CH2:9][CH2:8]1)(C)(C)C.[CH3:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[F:32][C:25]1[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:24]=1[N:15]1[CH2:16][C:17]2[C:18](=[N:19][C:20]([NH:44][C:41]3[CH:42]=[CH:43][C:38]([O:37][CH3:36])=[CH:39][CH:40]=3)=[N:21][CH:22]=2)[N:13]([C@H:10]2[CH2:9][CH2:8][C@H:7]([OH:6])[CH2:12][CH2:11]2)[C:14]1=[O:33]
Reactant: COc1ccc(N2Cc3cnc(Cl)nc3N([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)C2=O)c(F)c1
Reactant: COc1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: COc1ccc(Nc2ncc3c(n2)N([C@H]2CC[C@H](O)CC2)C(=O)N(c2ccc(OC)cc2F)C3)cc1
Temperature: 160 °C

Procedure:
A mixture of 1-[trans-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-7-chloro-3-(2-fluoro-4-methoxy-phenyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (0.20 g, 0.38 mmol) (from Example 17c supra), p-anisidine (61.5 mg, 0.50 mmol) (Aldrich) and p-toluenesulfonic acid monohydrate (95.1 mg, 0.50 mmol) (Aldrich) in 2-propanol (4 mL) was placed in a microwave reactor (SmithSynthesizer™). The reaction mixture was heated at 160° C. for 15 minutes. After cooling, it was concentrated under reduced pressure and purified by RP-HPLC (C-18, eluted with acetonitrile-water) to give 3-(2-fluoro-4-methoxy-phenyl)-1-(trans-4-hydroxy-cyclohexyl)-7-(4-methoxy-phenylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one. (Yield 0.12 g, 61%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[CH:12]([C:16]([OH:18])=[O:17])[CH:11]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[CH:10]1[CH:5]2[CH2:6][CH2:7][CH2:8][CH2:9]1.[C:26](Cl)(C)=O.CO.C(OCC)(=O)C>O>[CH3:26][O:17][C:16]([CH:12]1[CH:11]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[C:4]2[C:13]1=[CH:14][CH:15]=[C:2]([OH:1])[CH:3]=2)=[O:18]
Reactant: O=C(O)C1c2ccc(O)cc2C2CCCCC2C1c1ccc(O)cc1
Reactant: CC(=O)Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)C1c2ccc(O)cc2C2CCCCC2C1c1ccc(O)cc1
Reaction time: 72 h
Yield: 99 %

Procedure:
Combine 6-hydroxy-10-(4-hydroxy-phenyl)-1,2,3,4,4a,9,10,10a-octahydro-phenanthrene-9-carboxylic acid (0.903 g, 2.67 mmol), AcCl (2 mL), and methanol (20.0 mL), and reflux under nitrogen atmosphere. After 72 hours, concentrate reaction to dryness under vacuum, add ethyl acetate and water. Separate the organic phase and wash with brine. Dry the organic phase with anhydrous sodium sulfate and concentrate to yield the titled compound (0.980 g, 99%) as a brown solid. 1H NMR (d-methanol): 7.15 (d, 2H, J=8.4 Hz), 7.04 (d, 1H, J=8.8 Hz), 6.91 (s, 1H), 6.77 (d, 2H, J=8.4 Hz), 6.64 (m, 1H), 4.32 (d, 1H, J=12.8 Hz), 3.58 (s, 3H), 3.45 (dd, 1H, J=12.6, 2.4 Hz), 3.34 (s, 1H), 2.52 (d, 1H, J=14.1 Hz), 1.97 (m, 1H), 1.68 (m, 2H), 1.44 (m, 2H), 1.11 (m, 3H); MS m/z 351 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]2[CH:7]([CH3:11])[CH2:8][CH2:9][O:10][C:5]=2[CH:4]=1.[C:14](O)(=[O:16])[CH3:15]>C1C=CC=CC=1>[C:14]([C:13]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[O:10][CH2:9][CH2:8][CH:7]([CH3:11])[C:6]=2[CH:12]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)O
Reactant: COc1ccc2c(c1)OCCC2C
Solvent: c1ccccc1
Product: COc1cc2c(cc1C(C)=O)C(C)CCO2
Reaction time: 8 h
Yield: 95 %

Procedure:
The methyl ether of step (c) (58.0 g) was dissolved in dry benzene (1 l) and glacial acetic acid (22.3 ml) was added. Boron trifluoride gas was bubbled through the reaction mixture for 1 hour and then stirring was continued overnight. The reaction mixture was poured into water, the organic layer was separated and the aqueous phase was extracted with more ether. The organic extracts were washed with sodium bicarbonate solution, then water, and dried. Evaporation gave 67.8 g of the desired product (95%). MS and NMR analysis were correct for the required compound.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[S:8][C:7]([NH:9][C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6][C:5]=1/[C:29](=[N:35]/[OH:36])/[C:30]([O:32][CH2:33][CH3:34])=[O:31].[C:37](Cl)([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(OCC)(=O)C>[CH3:3][C:4]1[S:8][C:7]([NH:9][C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[N:6][C:5]=1/[C:29](=[N:35]/[O:36][C:37]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)/[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)/C(=N\O)c1nc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)sc1C
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)/C(=N\OC(c1ccccc1)(c1ccccc1)c1ccccc1)c1nc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)sc1C
Reaction time: 20 h
Yield: 40.1 %

Procedure:
To a suspension of sodium hydride (1.37 g) in 110 ml of ethyl acetate, ethyl 2-(5-methyl-2-tritylaminothiazol-4-yl)-2-(Z)-(hydroxyimino)acetate (16.15 g) was added at room temperature. The mixture was treated with a solution of trityl chloride (9.55 g) in ethyl acetate (66 ml). After 20 hours, the reaction was quenched by ice-water. The aqueous phase was extracted with ethyl acetate, and the combined extracts were washed with brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel with 5%-17% ethyl acetate/hexane to give 9.8 g of ethyl 2-(5-methyl-2-tritylaminothiazol-4-yl)-2-(Z)-(trityloxyimino)acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[C:8]1=[O:27].[CH2:35]([O:37][CH2:38][CH2:39][N:40]1[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[N:42]=[C:41]1[NH:49][CH:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)[CH3:36].C(N(CC)C(C)C)(C)C.C(N(CC)CC)C>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:53]2[CH2:52][CH2:51][CH:50]([NH:49][C:41]3[N:40]([CH2:39][CH2:38][O:37][CH2:35][CH3:36])[C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=4[N:42]=3)[CH2:55][CH2:54]2)([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[C:8]1=[O:27]
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Reactant: COc1cc(CN2CCC(CCOS(C)(=O)=O)(Cc3ccc(F)cc3)C2=O)cc(OC)c1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOCCn1c(NC2CCN(CCC3(Cc4ccc(F)cc4)CCN(Cc4cc(OC)c(OC)c(OC)c4)C3=O)CC2)nc2ccccc21
Reaction time: 12 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzyl)-3-(4-fluorophenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine (0.42 g, 1.3 mmol) and (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine (1.2 mmol), and N,N-diisopropylethylamine (0.32 g, 2.5 mmol) in acetonitrile (10 mL). Heat to reflux. After 12 hours, cool and partition the reaction mixture between dichloromethane and water. Separate the layers and extract the organic layer with brine. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on a short column of silica gel eluting with 2% triethylamine/10% methanol/ethyl acetate to give a residue. Partition the residue between dichloromethane and brine. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to give the title compound: Rf=0.19 (silica gel, 2% triethylamine/10% methanol/ethyl acetate).
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH3:12])[CH2:5][C@H:6]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]1.C(N(CC)CC)C.[F:20][C:21]([F:37])([F:36])[C:22]1[O:26][N:25]=[C:24]([C:27]2[S:31][C:30]([C:32](Cl)=[O:33])=[CH:29][CH:28]=2)[C:23]=1[CH3:35]>C1COCC1.CN(C=O)C>[CH3:3][N:4]([CH2:5][C@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:32]([C:30]2[S:31][C:27]([C:24]3[C:23]([CH3:35])=[C:22]([C:21]([F:36])([F:37])[F:20])[O:26][N:25]=3)=[CH:28][CH:29]=2)=[O:33])[CH2:7]1)[CH3:12]
Reactant: CN(C)C[C@H]1CCCNC1
Reactant: Cc1c(-c2ccc(C(=O)Cl)s2)noc1C(F)(F)F
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccc(C(=O)N3CCC[C@H](CN(C)C)C3)s2)noc1C(F)(F)F
Reaction time: 16 h
Yield: 30.9 %

Procedure:
A solution of dimethyl-(S)-1-piperidin-3-ylmethyl-amine, dihydrochloride (Preparative Example 29, 108 mg, 0.5 mmol) in THF/DMF (3 mL/500 μL) was treated with triethylamine (95 μL, 1.0 mmol) followed by 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carbonyl chloride (74 mg, 0.25 mmol, as prepared in Example 2 Method B). The reaction mixture was vigorously stirred or 16 h then evaporated and diluted with water (5 mL). The crude reaction mixture was extracted with EtOAc (2×3 mL) which was then washed with a 1 N NaOH solution (2×3 mL), dried over MgSO4, filtered, and evaporated in vacuo to afford product as a colorless solid. The solid was dissolved in a EtOAc/hexanes (1:1) mixture (1 mL), filtered through a PTFE syringe filter, and again evaporated in vacuo to afford product as a colorless solid (31 mg, 31%). LC/MS 5.13 min, [M+1]+ 402.