Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][CH2:15][CH2:16][NH:17][CH2:18][C:19]([CH3:27])=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([O:41][CH3:42])[C:38]=1[O:39][CH3:40])[C:33](O)=[O:34].S(Cl)(Cl)=O>C(N(CC)CC)C>[CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][CH2:15][CH2:16][N:17]([CH2:18][C:19]([CH3:27])=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:33](=[O:34])[C:32]2[CH:31]=[C:30]([O:29][CH3:28])[C:38]([O:39][CH3:40])=[C:37]([O:41][CH3:42])[CH:36]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=Cc1ccccc1)CNCCCN1CCN[C@@H](Cc2ccccc2)C1
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N(CCCN2CCN[C@@H](Cc3ccccc3)C2)CC(C)=Cc2ccccc2)cc(OC)c1OC
Yield: 7 %

Procedure:
Experimental condition similar to Example 18 were used with [3-(S)-(3-benzyl-piperazin-1-yl)-propyl]-(2-methyl-3-phenyl-allyl)-amine (prepared from (S)-2-benzyl piperazine described on scheme 11) 0.08 g (0.24 mmol), 3,4,5-trimethoxy benzoic acid 0.05 g (0.24 mmol), thionyl chloride 0.02 ml (0.46 mmol) and triethylamine. The free amine after purification was transformed to HCl salt, yielding 45 mg of a brown, semi-solid salt. Yield: 7%.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1)=[O:4].[CH3:12][C:13]1[N:14]=[CH:15][NH:16][CH:17]=1>C(#N)C>[I:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][N:16]2[CH:17]=[C:13]([CH3:12])[N:14]=[CH:15]2)=[CH:6][CH:7]=1
Reactant: Cc1c[nH]cn1
Reactant: O=C(CBr)c1ccc(I)cc1
Solvent: CC#N
Product: Cc1cn(CC(=O)c2ccc(I)cc2)cn1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 2.50 g (7.69 mmol) 2-bromo-1-(4-iodo-phenyl)-ethanone in 30 mL ACN are added 1.90 g (23.1 mmol) 4-methylimidazole and the mixture is stirred at rt for 48 h. After that time, the solvent is evaporated and the residue is taken up in EtOAc. The mixture is washed with water and brine (2×) and the organic layer is dried over magnesium sulphate. The solvent is evaporated and the residue is recrystallized from diethyl ether to yield the desired product.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)([OH:3])=[O:2].[NH2:20][CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][N:23]1[CH2:27]C>>[C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1)([OH:3])=[O:2].[CH3:27][N:23]1[CH2:24][CH2:25][CH2:26][CH:22]1[CH2:21][NH:20][C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:3]
Reactant: CCN1CCCC1CN
Agent: O=C(O)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Product: CN1CCCC1CNC(=O)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1

Procedure:
Entry 64: 4-(3-Carboxyphenoxy)-1-nitrobenzene was synthesized according to Method A13, Step 2. 4-(3-Carboxyphenoxy)-1-nitrobenzene was coupled with 2-aminomethyl-1-ethylpyrrolidine according to Method A13, Step 3 to give 4-(3-(N-((1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)-1-nitrobenzene. According to Method A13 Step 4,4-(3-(N-((1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)-1-nitrobenzene was reduced to 4-(3-(N-((1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)aniline. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(N-((1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)aniline to afford the urea.
Reaction SMILES: [NH3:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]=[C:11]2[NH:19][CH:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]=[C:29]=[S:30])[CH2:22][CH2:21]2)=[CH:5][CH:4]=1>CO>[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]=[C:11]2[NH:19][CH:20]2[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][NH:28][C:29]([NH2:1])=[S:30])[CH2:24][CH2:25]2)=[CH:5][CH:4]=1
Reactant: N
Reactant: Fc1ccc(Cn2c(NC3CCN(CCN=C=S)CC3)nc3ccccc32)cc1
Solvent: CO
Product: NC(=S)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
A mixture of 120 parts of methanol saturated with ammonia and 4.1 parts of 1-(4-fluorophenylmethyl)-N-[1-(2-isothiocyanatoethyl)-4-piperidinyl]-1H-benzimidazol-2-amine was stirred overnight at room temperature. The reaction mixture was evaporated and the residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume), saturated with ammonia, as eluent. The pure fractions were collected and the eluent was evaporated. The residue was suspended in 1,1'-oxybisethane. The product was filtered off and crystallized from acetonitrile, yielding 1.1 parts (26%) of N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]thiourea; mp. 186.1° C. (intermediate 149).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])[C:5]=1[C:6]#[N:7])([O-])=O>C(O)C(F)(F)F.FC(F)(F)C(O)C(F)(F)F>[NH2:1][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])[C:5]=1[C:6]#[N:7]
Reactant: N#Cc1c(OCCN2CCCC2=O)cccc1[N+](=O)[O-]
Solvent: OC(C(F)(F)F)C(F)(F)F
Solvent: OCC(F)(F)F
Product: N#Cc1c(N)cccc1OCCN1CCCC1=O
Yield: 100 %

Procedure:
Prepared as in example 235b from 2-nitro-6-(2-(2-oxopyrrolidin-1-yl)ethoxy)benzonitrile (Example 219c) using trifluoroethanol/hexafluoroisopropanol (1:1) as solvent in 100% yield MS 246 (MH+).
Reaction SMILES: [N:1]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][NH:4][CH:3]([C:7]([O:9][CH3:10])=[O:8])[CH2:2]1.C(N(CC)C(C)C)(C)C.F[C:28]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:29]=1[C:30]#[N:31]>O1CCCC1>[C:30]([C:29]1[CH:32]=[C:33]([N+:36]([O-:38])=[O:37])[CH:34]=[CH:35][C:28]=1[N:4]1[CH2:5][CH2:6][N:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:2][CH:3]1[C:7]([O:9][CH3:10])=[O:8])#[N:31]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1c1ccc([N+](=O)[O-])cc1C#N

Procedure:
To a solution of 1-tert-butyl 3-methyl piperazine-1,3-dicarboxylate (80 g, 328 mmol) and N,N-diisopropylethylamine (192 mL, 741 mmol) in 300 mL of dry tetrahydrofuran was added 2-fluoro-5-nitrobenzonitrile (36 g, 219 mmol) at room temperature. The reaction mixture was heated to reflux for 36 hours. The reaction was concentrated and the resulting residue was purified by silica gel chromatography (30% ethyl acetate in hexane) to give the title compound: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.41 (s, 9H), 3.01-3.15 (m, 1H), 3.29-3.36 (m, 1H), 3.34-3.36 (m, 1H), 3.48-3.55 (m, 1H), 3.66 (s, 3H), 3.72-3.76 (m, 1H), 4.43-7.48 (m, 1H), 4.96-4.98 (m, 1H), 7.30 (d, J=9.1 Hz, 1H), 8.32 (dd, J=9.5, 2.8 Hz, 1H), 8.55 (d, J=2.8 Hz, 1H); MS (DCI/NH3) m/z 391 (M+H)+.
Reaction SMILES: [CH2-:1][C:2]([CH3:4])=O.[O:5]=[CH:6][C@H:7]([CH2:9][OH:10])[OH:8].[CH2-]C(C)=O.COC1C=C(OC)C=CC=1CN=C(C)[CH2-].[O:30]=[CH:31][C@H:32]([CH2:34][OH:35])[OH:33]>>[CH3:1][C:2]1([CH3:4])[O:8][CH:7]([CH:9]2[O:10][C:31](=[O:30])[C:32]([OH:33])=[C:34]2[OH:35])[CH2:6][O:5]1
Reactant: O=C[C@@H](O)CO
Reactant: [CH2-]C(C)=O
Agent: [CH2-]C(C)=NCc1ccc(OC)cc1OC
Product: CC1(C)OCC(C2OC(=O)C(O)=C2O)O1

Procedure:
In 400 ml of pure water was suspended 43.2 g of 5,6-O-isopropylidene-L-ascorbic acid, and 40 g of calcium carbonate was added. The mixture was cooled and 80 ml of 30% aqueous hydrogen peroxide was added dropwise while maintaining the temperature at 10° C. or below. Thereafter, the temperature was raised to 20° C. over a period of an hour, followed by stirring at the same temperature for 2 hours and at 30° to 35° C. for 30 minutes. To the reaction mixture were portionwise added 8 g of activated carbon and 1 g of 10 w/w % palladium-on-carbon (50 w/w % hydrous) to treat the unreacted hydrogen peroxide therewith and the mixture was cooled, followed by removal of the insoluble substance with the aid of Hyflo Super-Cel to give 650 ml of an aqueous solution containing CIT. Thereafter, according to the procedure of Example 2 there was synthesized (S)-glyceraldehyde acetonide and the acetonide was then converted to (S)-glyceraldehyde acetonide 2,4-dimethoxybenzylimine. The yield of the imine was 39.3 g (70% overall yield from 5,6-O-isopropylidene-L-ascorbic acid).
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:8]3[N:9]([N:14]=[C:15]([NH2:17])[N:16]=3)[CH:10]=[C:11]([CH3:13])[CH:12]=2)[CH2:3][CH2:2]1.[CH3:18][C:19]1[N:24]=[CH:23][N:22]=[C:21]([N:25]2[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]2)[CH:20]=1.C(Cl)Cl>C(Cl)Cl.CO>[O:1]1[CH2:2][CH:3]=[C:4]([C:7]2[C:8]3[N:9]([N:14]=[C:15]([NH:17][CH:28]4[CH2:29][CH2:30][N:25]([C:21]5[CH:20]=[C:19]([CH3:18])[N:24]=[CH:23][N:22]=5)[CH2:26][CH2:27]4)[N:16]=3)[CH:10]=[C:11]([CH3:13])[CH:12]=2)[CH2:5][CH2:6]1
Reactant: Cc1cc(C2=CCOCC2)c2nc(N)nn2c1
Reactant: Cc1cc(N2CCC(=O)CC2)ncn1
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(C2=CCOCC2)c2nc(NC3CCN(c4cc(C)ncn4)CC3)nn2c1

Procedure:
Prepared in analogy to example 1h, starting from 8-(3,6-dihydro-2H-pyran-4-yl)-6-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine and 1-(6-methylpyrimidin-4-yl)piperidin-4-one (see example 93b). The title compound was obtained as a yellow oil (yield: 5%) after column chromatography on silica gel using a gradient from methylene chloride to methylene chloride/methanol 19:1 (v/v) as eluent. MS ISP (m/e): 406.5 (100) [(M+H)+].
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[C:12]([CH3:15])[C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([N:29]=[C:30]=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:22]([NH:29][C:30]([N:19]1[CH2:18][CH2:17][N:16]([C:11]2[N:10]=[N:9][C:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:13]([CH3:14])[C:12]=2[CH3:15])[CH2:21][CH2:20]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C=NCc1ccccc1
Reactant: Cc1c(Cc2ccccc2)nnc(N2CCNCC2)c1C
Solvent: ClCCl
Product: Cc1c(Cc2ccccc2)nnc(N2CCN(C(=O)NCc3ccccc3)CC2)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.7 %

Procedure:
To a solution of 3-benzyl-4,5-dimethyl-6-piperazin-1-yl-pyridazine (60 mg, 0.21 mmol)) in CH2Cl2 (5 mL) at 25° C. is added benzyl isocyanate (37 mg, 0.28 mmol). After being stirred at 25° C. for 2 h, the reaction mixture is concentrated and purified by HPLC (CH3CN/H2O: 22%˜45% with 0.1% TFA) to give 4-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-piperazine-1-carboxylic acid benzylamide (46 mg, 60%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[C:15]3[CH2:23][N:22]([C:24]4[CH:25]=[N:26][C:27]([O:34][CH3:35])=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=4)[CH2:21][CH2:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:9]1)=[O:7])(C)(C)C.[C:36](O)([C:38](F)(F)F)=O.C([O-])(O)=O.[Na+].C(Cl)(=O)CC>C(Cl)Cl.CCOC(C)=O>[CH3:35][O:34][C:27]1[N:26]=[CH:25][C:24]([N:22]2[CH2:21][CH2:20][C:16]3[N:17]=[CH:18][N:19]=[C:14]([NH:13][C@H:10]4[CH2:11][CH2:12][N:8]([C:6](=[O:7])[CH2:36][CH3:38])[CH2:9]4)[C:15]=3[CH2:23]2)=[CH:29][C:28]=1[C:30]([F:33])([F:31])[F:32]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ncc(N2CCc3ncnc(N[C@H]4CCN(C(=O)OC(C)(C)C)C4)c3C2)cc1C(F)(F)F
Agent: CCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCC(=O)N1CC[C@H](Nc2ncnc3c2CN(c2cnc(OC)c(C(F)(F)F)c2)CC3)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of (S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 24) (13.4 g, 27.1 mmol) in CH2Cl2 (100 mL), was added TFA (41.8 mL) and the mixture stirred at rt for 1 h. Concentrated in vacuo and partitioned between 2M NaOH(aq) (300 mL) and CH2Cl2 (200 mL). The organic phase was separated and the aqueous phase extracted with CH2Cl2 (2×200 mL). The organic phases were combined, dried (MgSO4) and evaporated in vacuo to give a brown foam. The foam was dissolved in CH2Cl2 (50 mL) and was added simultaneously portionwise with sat.NaHCO3(aq) (50 mL) to a vigourously stirring solution of propionyl chloride (2.63 g, 28.5 mmol) in CH2Cl2 (50 mL) at rt. The resulting biphasic mixture was stirred at rt for 1 h. Further propionyl chloride (0.566 g, 6.12 mmol) was added and continued stirring vigorously for 20 min. The organic layer was separated and the aqueous layer extracted with CH2Cl2 (100 mL). The organic layers were combined, dried (MgSO4) and concentrated in vacuo to give a brown gum. The gum was stirred in EtOAc (100 mL) and the resulting solid filtered (9.4 g). The mother liquors were concentrated in vacuo and purified by column chromatography through a Biotage® amino silica gel eluting with EtOAc/MeOH, 100/0 to 90/10 to give a yellow foam which was then stirred in EtOAc (20 mL) and the resulting solid filtered (870 mg). Both batches of solids were combined and stirred in refluxing EtOAc (50 mL) for 1 h. Filtered to give 1-{(S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin-1-yl}-propan-1-one as a colourless solid (9.42 g, 76% yield). 1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 0.95-1.05 (m, 3H) 1.87-2.32 (m, 4H) 2.77-2.86 (m, 2H) 3.25-3.88 (m, 6H) 3.93 (s, 3H) 3.98 (s, 2H) 4.55-4.80 (m, 1H) 6.70-6.80 (m, 1H, N—H) 7.86-7.92 (m, 1H) 8.27-8.33 (m, 1H) 8.33-8.37 (m, 1H) LCMS: [M+H]+=451.0, Rt(6)=1.49 min.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28]([CH3:33])=[C:27]2[CH3:34].Cl>C(O)(C)C>[ClH:1].[CH3:33][C:28]1[NH:29][C:30]2[C:26]([C:27]=1[CH3:34])=[CH:25][C:24]([NH:23][C:2]1[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=1)=[CH:32][CH:31]=2
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Reactant: Cc1[nH]c2ccc(N)cc2c1C
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2c(Nc3ccc4[nH]c(C)c(C)c4c3)ncnc2cc1OCC1CCN(C)CC1
Temperature: 70 °C
Yield: 79 %

Procedure:
A suspension of 4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (100 mg, 0.31 mmol), (prepared as described for the starting material in Example 10), and 5-amino-2,3-dimethylindole (55 mg, 0.34 mmol) in isopropanol (6 ml) containing 5.5M hydrogen chloride in isopropanol (60 μL) was heated for 30 minutes at 70° C. After cooling, the solid was collected by filtration, washed with isopropanol, followed by ether and dried under vacuum to give 4-(2,3-dimethylindol-5-ylamino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline hydrochloride (118 mg, 74%).
Reaction SMILES: [C:1]1(C2C3C(=C4C(=CC=3)C(C3C=CC=CC=3)=CC=N4)N=CC=2)C=CC=C[CH:2]=1.C(OCCCC)=C.[CH2:34]([O:36][C:37]([C:39]1[C:40]([CH3:52])=[N:41][N:42]([C:44]2[C:49]([CH2:50][OH:51])=[CH:48][CH:47]=[CH:46][N:45]=2)[CH:43]=1)=[O:38])[CH3:35]>C(N(CC)CC)C.FC(F)(F)C([O-])=O.[Pd+2].FC(F)(F)C([O-])=O>[CH3:52][C:40]1[C:39]([C:37]([O:36][CH2:34][CH3:35])=[O:38])=[CH:43][N:42]([C:44]2[C:49]([CH2:50][O:51][CH:1]=[CH2:2])=[CH:48][CH:47]=[CH:46][N:45]=2)[N:41]=1
Reactant: c1ccc(-c2ccnc3c2ccc2c(-c4ccccc4)ccnc23)cc1
Reactant: CCOC(=O)c1cn(-c2ncccc2CO)nc1C
Agent: [Pd+2]
Agent: C=COCCCC
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(CC)CC
Product: C=COCc1cccnc1-n1cc(C(=O)OCC)c(C)n1
Temperature: 75 °C
Reaction time: 24 h
Yield: 67.9 %

Procedure:
Palladium(II)trifluoroacetate (5.1 mg, 15.3 mmoles) and 4,7-diphenyl-phenanthroline (5.1 mg, 15.3 mmoles) are dissolved in n-butyl vinyl ether (6.1 mL, 61.2 mmol) and 1-(3-hydroxymethyl-pyridin-2-yl)-3-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (800 mg, 3.1 mmol) and a few drops of triethylamine are added. The flask is sealed and stirred at 75° C. for 24 hours. Then the mixture is cooled to 24° C. and filtrated through a pad of celite. The solvent is eliminated under reduced pressure and the residue is purified by normal phase Isco chromatography using hexane and ethyl acetate as eluents (5-20% in ethyl acetate) to give 605 mg of ethyl 3-methyl-1-[3-(vinyloxymethyl)-2-pyridyl]pyrazole-4-carboxylate. MS (m/z): 288 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[CH:12]=2)[CH:3]=1.CN.[C:21]([BH3-])#[N:22].[Na+].[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29]>C(O)(=O)C.CO>[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:22][CH3:21])[CH:12]=2)[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1Oc1cccc(C=O)c1
Reactant: [BH3-]C#N
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNCc1cccc(Oc2cc(Cl)ccc2C#N)c1
Yield: 58.4 %

Procedure:
4-Chloro-2-(3-formyl-phenoxy)-benzonitrile (0.52 g, 2.02 mmol), methylamine (2M in methanol, 1.0 ml, 2.0 mmol) and sodium cyanoborohydride (0.14 g, 2.2 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (30 ml) for 18 h. The solvent was removed in vacuo. The residue was treated with 10% aqueous sodium carbonate and extracted with ethyl acetate. The ethyl acetate layer was separated and washed with water, brine and dried over MgSO4. After filtration, fumaric acid (0.23 g, 2.0 mmol) was added to the filtrate and the solvent removed in vacuo. The residue was triturated with ethyl acetate overnight, filtered and dried to give 4-chloro-2-(3-methylaminomethyl-phenoxy)-benzonitrile fumarate (454 mg, 58%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[N:18][C:19]#[N:20])OC2C=CC=CC=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:21]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22]1.C(N(CC)CC)C>C(#N)C>[C:19]([NH:18][C:10]([NH:26][CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)=[N:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1)#[N:20]
Reactant: N#CN=C(Nc1cc(Cl)cc(Cl)c1)Oc1ccccc1
Reactant: NC1CCCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#CNC(=Nc1cc(Cl)cc(Cl)c1)NC1CCCC1
Temperature: 82 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
To a solution of N-(3,5-dichlorophenyl)-N'-cyano-O-phenylisourea (0.8 mmol, 250 mg) in dry acetonitrile (2 ml), cyclopentylamine (0.9 mmol, 0.089 ml) and triethylamine (0.125 ml) were added. The mixture was stirred for 21/2 h at 82° C. under nitrogen. After concentration the residue was purified by flash chromatography (ethyl acetate/heptane 1:2) to give the title compound (160 mg, 66%) as crystals. Mp 147.5-148.5° C.; 1H-NMR (CDCl3): δ 1.45 (m, 2H), 1.65 (m, 4H), 2.05 (m, 2H), 4.11 (sextet, 1H), 5.1 (br, 1H), 7.2 (m, 3H), 8.02 ppm (br, 1H); EI SP/MS: 296 (M+), 298 (M+2), 300 (M+4). MA calc for C13H14Cl2N4 : C, 52.54%; H, 4.75%; N, 18.85%. Found: C, 52.17%; H, 4.71%; N, 18.50%.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[CH2:6][CH2:7][NH2:8])[CH3:3].[CH3:10][O:11][C:12]([C:14]1[C@H:19]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=2)[N:18]([C:28](OC2C=CC([N+]([O-])=O)=CC=2)=[O:29])[C:17](=[O:40])[NH:16][C:15]=1[CH2:41][O:42][CH3:43])=[O:13].C(N(CC)CC)C>ClCCl>[CH3:10][O:11][C:12]([C:14]1[C@H:19]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=2)[N:18]([C:28]([NH:8][CH2:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:9])=[O:29])[C:17](=[O:40])[NH:16][C:15]=1[CH2:41][O:42][CH3:43])=[O:13]
Reactant: CCOC(=O)CCN
Reactant: COCC1=C(C(=O)OC)[C@H](c2ccc(F)c(F)c2)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)N1C(=O)NC(COC)=C(C(=O)OC)[C@@H]1c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
β-Alanine ethyl ester hydrochloride (87 mg, 0.57 mmol), (+)-5-methyoxycarbonyl-4-methoxymethyl-1,2,3,6-tetrahydro-2-oxo-6 (S)-(3,4-difluorophenyl)-1-[(4-nitrophenyloxy)-carbonyl]pyrimidine (as described in Section I.A.(c)) (227 mg, 0.48 mmol), and triethylamine (209 mL, 1.50 mmol) were combined in 5 mL of dichloromethane. The yellow mixture was stirred at ambient temperature for 1 hour, then evaporated to dryness. The resulting oil was purified by “flash” chromatography (5.02, 98:2:0.2 of dichloromethane: methanol:ammonium hydroxide). The product fractions were evaporated to dryness to give the title compound as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C@@H:8]([OH:21])[CH2:9][O:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.N1C=CN=C1.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].C(OCC)(=O)C>CN(C)C=O>[C:30]([Si:27]([CH3:29])([CH3:28])[O:21][C@H:8]([C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:9][O:10][S:11]([C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=1)(=[O:13])=[O:12])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](O)c2ccc(Cl)nc2)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(Cl)nc2)cc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 84.7 %

Procedure:
To a cooled (50° C.), stirred solution of (R)-toluene-4-sulfonic acid 2-(6-chloro-pyridin-3-yl)-2-hydroxy-ethyl ester (4.9 g) and imidazole (2.0 g) in anhydrous dimethyformamide (14 mL) was added t-butyldimethylsilyl chloride (2.8 g). The reaction mixture was allowed to warm to room temperature and stirring was continued for 18 h. Ethyl acetate was added, followed by washing with water (2×), drying over sodium sulfate and concentration in vacuo to afford an oil. Chromatography (Flash 40M®) utilizing 10% ethyl acetate/hexanes afforded 5.6 g of the title compound (I-2e) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]([C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19](Cl)=[O:20])[CH2:15][CH2:14]1)([CH3:12])([CH3:11])[CH3:10].N1C=CC=CC=1>ClCCl>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:19]([C@H:16]2[CH2:17][CH2:18][C@H:13]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:14][CH2:15]2)=[O:20])=[CH:3][CH:4]=1
Reactant: CC(C)(C)[C@H]1CC[C@H](C(=O)Cl)CC1
Reactant: Nc1ccc(O)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[C@H]1CC[C@H](C(=O)Nc2ccc(O)cc2)CC1
Reaction time: 8 h

Procedure:
To a solution of 4-aminophenol (3.08 g, 28.2 mmol) in dichloromethane (50 ml) were added cis/trans-4-tert-butyl-cyclohexanecarbonyl chloride (11.43 g, 56.4 mmol) and pyridine (4.56 ml, 56.4 mmol), while cooling the reaction mixture in an ice bath. After the addition was completed, the cooling bath was removed and stirring was continued overnight at room temperature. The solvent was removed by evaporation and the residue was dissolved in THF (300 ml). 6N NaOH (aq, 33 ml) was added and the mixture was stirred at room temperature overnight. The organic phase was removed by evaporation. Water (200 ml) was added and the solid material collected by filtration, washed with water, dried and dissolved in methanol (100 ml). A solution of KOH (2.4 g) in methanol (50 ml) was added. After stirring for 2 h at room temperature water (200 ml) was added and the organic solvent was removed by evaporation. The aqueous phase was acidified with 1 N HCl and extracted with ethyl acetate (3×300 ml). The combined organic phases were dried and evaporated, yielding a pink oil, which was dried in vacuo. The solid material was crystallised from ethyl acetate/heptane yielding the title compound (2.03 g, 26%) as pink crystals. From the first aqueous extract a second portion of product was isolated by extraction with ethyl acetate (3×250 ml). The combined organic layers were washed with water (400 ml), saturated sodium bicarbonate (2×400 ml), dried, filtered and evaporated, yielding a pink thick oil. Crystallisation from ethyl acetate/heptane yielded a second amount of the title compound (2.75 g, 35%).