Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][CH2:26][CH2:27][C:28](OC)=[O:29])[CH:20]=1.[Li+].CC([N-]C(C)C)C>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:27]([CH2:26][CH2:25][C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)[C:28]2=[O:29])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=Cc1cccnc1Nc1cccc([N+](=O)[O-])c1
Reactant: COC(=O)CCCc1cccnc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=c1c(CCc2cccnc2)cc2cccnc2n1-c1cccc([N+](=O)[O-])c1

Procedure:
The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), methyl 4-(pyridin-3-yl)butanoate (1.3 eq., prepared in Synthetic Example 7) and LDA (1.3 eq.) to obtain 1-(3-nitrophenyl)-3-[2-(pyridin-3-yl)ethyl]-1,8-naphthyridin-2(1H)-one, mp 221 to 223° C./DMF, wherein the product was purified through silica gel column chromatography and recrystallization.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH2:22])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)=[O:24].[C:38](O)(=[O:41])[CH2:39][CH3:40]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH:22][C:38]([CH2:39][CH3:40])=[O:41])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[CH2:27][CH2:26]1)=[O:24]
Reactant: Cc1ccc(Cl)c(Nc2c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc3c(S(N)(=O)=O)cnn23)c1
Reactant: CCC(=O)O
Product: CCC(=O)NS(=O)(=O)c1cnn2c(Nc3cc(C)ccc3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 92 %

Procedure:
Using 7-(2-chloro-5-methylphenylamino)-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-sulfonamide (0.08 g, 0.147 mmol) obtained in Example 12 step 5 and propionic acid (0.055 mL, 0.737 mmol) instead of cyclopropanecarboxylic acid, and in the same manner as in Example 1 step 6, the title compound (0.081 g, 92%) was obtained.
Reaction SMILES: [CH3:1][C:2]([C:4]([O:6]CCN(C)C)=[O:5])=[CH2:3].C1C=[C:16](C2N=CC=CC=2)[N:15]=[CH:14]C=1>O.Cl[Cu]>[C:4]([O:6][N:15]([CH3:16])[CH3:14])(=[O:5])[C:2]([CH3:1])=[CH2:3]
Reactant: c1ccc(-c2ccccn2)nc1
Reactant: C=C(C)C(=O)OCCN(C)C
Agent: Cl[Cu]
Solvent: O
Product: C=C(C)C(=O)ON(C)C
Temperature: 55 °C
Reaction time: 0.17 h

Procedure:
7 ml DMAEMA (6.531 g; 41.5 mmol), 0.0206 g CuCl (0.208 mmol) and 0.0658 g BiPy (0.421 mmol) were mixed and stirred for 10 minutes. A clear brown solution was formed. To this solution, a solution of 0.1355 g (0.205 mmol) azo-initiator 2 in 7 ml water was added. The temperature of the experiment was maintained at 55° C. The progress of the polymerization is shown in Table 7.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([OH:9])=[C:4]([Cl:10])[N:3]=1.[C:11]([Si:15]([CH3:24])([CH3:23])[O:16][CH:17]([CH:20]1[CH2:22][CH2:21]1)[CH2:18]O)([CH3:14])([CH3:13])[CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:11]([Si:15]([CH3:24])([CH3:23])[O:16][CH:17]([CH:20]1[CH2:22][CH2:21]1)[CH2:18][O:9][C:5]1[C:4]([Cl:10])=[N:3][C:2]([Cl:1])=[N:7][C:6]=1[Cl:8])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)OC(CO)C1CC1
Reactant: Oc1c(Cl)nc(Cl)nc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC(COc1c(Cl)nc(Cl)nc1Cl)C1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.7 %

Procedure:
To a solution of 2,4,6-trichloro-pyrimidin-5-ol (250 mg, 1.25 mmol), 2-(tert-butyl-dimethyl-silanyloxy)-2-cyclopropyl-ethanol (407 mg, 1.88 mmol) and triphenylphosphine (493 mg, 1.88 mmol) in THF (12 mL) was added DIAD (370 μL, 1.88 mmol). The reaction mixture was stirred at RT for 18 hours before being concentrated in vacuo. The resultant residue was purified by column chromatography (SiO2, gradient 0-30% ethyl acetate in cyclohexane) to give 5-[2-(tert-Butyl-dimethyl-silanyloxy)-2-cyclopropyl-ethoxy]-2,4,6-trichloro-pyrimidine as a viscous yellow oil (411 mg, 83%). 1H NMR (400 MHz, CDCl3): δ 4.14 (1H, dd, J=8.83, 6.02 Hz), 3.99 (1H, dd, J=8.82, 4.21 Hz), 3.60-3.53 (1H, m), 1.13-1.03 (1H, m), 0.89 (9H, s), 0.56-0.50 (2H, m), 0.46-0.28 (2H, m), 0.10 (3H, s), 0.07 (3H, s).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[NH:9]1[CH:13]=[CH:12][N:11]=[CH:10]1>O1CCCC1>[Cl:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[N:7]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: c1c[nH]cn1
Solvent: C1CCOC1
Product: Clc1ccnc(-n2ccnc2)n1
Yield: 22.2 %

Procedure:
In anhydrous tetrahydrofuran, 1500 mg of 2,4-dichloropyrimidine was substituted with 680 mg of imidazole. The reaction mixture was treated according to the procedure of Example 5 to yield 401 mg of 4-chloro-2-(1-imidazolyl)pyrimidine recrystallized from a mixture of n-hexane and ethyl acetate, having a melting point of 138°-139° C.
Reaction SMILES: [F:1][CH:2]1[CH2:8][N:7]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-])=O)[CH2:6][CH2:5][CH:4]([NH:18]C(=O)OC(C)(C)C)[CH2:3]1.C(OC([NH:33][C:34]1[S:38][C:37]([C:39]2[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47](O)=[O:48])=O)(C)(C)C.CO.C(Cl)Cl.N>CO>[NH2:33][C:34]1[S:38][C:37]([C:39]2[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47]([NH:15][C:10]1[CH:11]=[N:12][N:13]([CH3:14])[C:9]=1[N:7]1[CH2:6][CH2:5][CH:4]([NH2:18])[CH2:3][CH:2]([F:1])[CH2:8]1)=[O:48]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCC(NC(=O)OC(C)(C)C)CC(F)C1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CCC(N)CC(F)C1

Procedure:
Following the procedure for Example 101, Intermediate 20, tert-butyl 6-fluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ylcarbamate and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid from Example 25 gave, after silica gel column chromatography (0-10% MeOH/DCM, 1% 7 N ammonia in MeOH), a white solid (273 mg, 19% over three steps). Compound 154 was obtained as a single enantiomer from SFC chiral separation of the racemic mixture. 1H NMR (400 MHz, DMSO) δ 8.77 (s, 1H), 7.61-7.41 (m, 4H), 7.27 (dd, J=14.5, 5.8 Hz, 2H), 4.84-4.56 (m, 1H), 3.67 (d, J=7.4 Hz, 3H), 3.44-3.34 (m, 2H), 3.21-2.86 (m, 3H), 2.22-2.07 (m, 1H), 1.87 (ddt, J=34.3, 21.1, 7.4 Hz, 3H), 1.70-1.53 (m, 1H). MS (ESI) m/z: 466.1 [M+H+].
Reaction SMILES: [C:1]([OH:14])(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16].Cl.C(OCC)(=O)C>N1C=CC=CC=1>[C:15]([O:10][C:9]1[CH:11]=[CH:12][C:4](/[CH:3]=[CH:2]/[C:1]([OH:14])=[O:13])=[CH:5][C:6]=1[O:7][CH3:8])(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1cc(/C=C/C(=O)O)ccc1OC(C)=O
Reaction time: 24 h
Yield: 84.7 %

Procedure:
To a solution of ferulic acid (5 g, 25.75 mmoles) in pyridine (75 ml) cooled to 0° C. and sheltered from light, acetic anhydride (13.14 g, 128.7 mmoles) is added in small aliquots. When the addition is ended the temperature is let reach the room value maintaining the solution under magnetic stirring for 24 hours. HCl 18.5% (160 ml) is added up to pH 2, one extracts with ethyl acetate and the organic phase is anhydrified and the solvent is evaporated at a reduced pressure. 5.15 g of trans-3-[4-acetyloxy-3-methoxyphenyl]-2-propenoic acid are obtained as a white solid. M.p. 199-205° C. Yield 85%.
Reaction SMILES: [O-]CC.[Na+].[Na].[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][C:13]#[N:14])[CH:7]=1.[N:15](OCCCC)=[O:16]>C(O)C>[OH:16][N:15]=[C:12]([C:8]1[CH:7]=[N:6][CH:11]=[CH:10][CH:9]=1)[C:13]#[N:14]
Reactant: CCCCON=O
Reactant: N#CCc1cccnc1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: N#CC(=NO)c1cccnc1

Procedure:
To a stirred solution of sodium ethoxide in anhydrous ethanol, prepared from 5 g of sodium and 50 ml of anhydrous ethanol, 24 g of 3-pyridineacetonitrile was added, followed by dropwise addition of 21 g freshly distilled n-butyl nitrite. The reaction mixture was stirred for another hour and the precipitated sodium salt of the oxime was filtered and washed with ether. The free oxime was obtained by acidification of an aqueous solution of the salt and recrystallization from water, yielding 17 g (58%) of the title compound. M.p. 234°-238° C. under decomposition. Usually, the salt was directly used in succeeding reactions.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8](Br)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cu](C#N)[C:13]#[N:14].Cl>CN1CCCC1=O.O>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([C:13]#[N:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1ccc(Br)cc1C(=O)O
Reactant: N#C[Cu]C#N
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(N)c(C(=O)O)c1
Temperature: 190 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
A solution of 2-amino-5-bromobenzoic acid (6.9 g, 31.9 mmol) in N-methyl-2-pyrrolidinone (100 mL) was treated with copper cyanide (4.14 g, 46 mmol) and the mixture was heated at 190° C. for 4.5 hours before being cooled to room temperature and allowed to stand overnight. The mixture was diluted with water (500 mL), acidified with 6N aqueous HCl (100 mL) and extracted with ethyl acetate (6×40 mL). The organic extracts were dried (MgSO4) and concentrated under reduced pressure to yield the crude nitrile (4.35 g, 84%).
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17](=O)/[CH:18]=[CH:19]/[N:20](C)C)=[N:11]2)[CH:7]=[CH:8][CH:9]=1.[F:25][C:26]1[CH:27]=[C:28]([NH:32]N)[CH:29]=[CH:30][CH:31]=1.N([O-])=O.[Na+].[Sn](Cl)Cl>>[F:1][CH:2]([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17]3[N:32]([C:28]4[CH:29]=[CH:30][CH:31]=[C:26]([F:25])[CH:27]=4)[N:20]=[CH:19][CH:18]=3)=[N:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)F)c2)ccc1=O
Reactant: NNc1cccc(F)c1
Agent: Cl[Sn]Cl
Agent: O=N[O-]
Agent: [Na+]
Product: O=c1ccn(-c2cccc(OC(F)F)c2)nc1-c1ccnn1-c1cccc(F)c1
Yield: 37 %

Procedure:
The product was obtained starting from 1-(3-Difluoromethoxy-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-10) and (3-fluoro-phenyl)-hydrazine (prepared from the corresponding amino derivative using sodium nitrite and tin(II) chloride as described in J. Med. Chem. 2003, 46, 4676-4686) according to the method described for Example 91 in 37% yield. MS: M=399.1 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10](I)=[N:9]2)=[CH:5][CH:4]=1.[CH3:29][N:30]([CH3:36])[C@H:31]1[CH2:35][CH2:34][NH:33][CH2:32]1.C([O-])([O-])=O.[K+].[K+].N1CCC[C@H]1C(O)=O>CS(C)=O.ClCCl>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][C:16]2[CH:15]=[CH:14][N:13]=[C:12]3[N:8]([CH2:7][C:6]4[CH:27]=[CH:28][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:9]=[C:10]([N:33]4[CH2:34][CH2:35][C@H:31]([N:30]([CH3:36])[CH3:29])[CH2:32]4)[C:11]=23)=[C:19]([F:25])[CH:20]=1
Reactant: CN(C)[C@H]1CCNC1
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1ccc(Cn2nc(N3CC[C@H](N(C)C)C3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Temperature: 90 °C
Yield: 19.9 %

Procedure:
To a stirred solution of 4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (49 mg, 0.1 mmol) (prepared in Example 7, step B) in 300 μL DMSO at ambient temperature in a capped reaction vial was added (S)—N,N-dimethylpyrrolidin-3-amine (19 uL, 0.15 mmol) followed by K2CO3 (27 mg, 0.2 mmol), Cu(I)I (19 mg, 0.01 mmol) and L-proline (2.3 mg, 0.02 mmol). The mixture was heated 90° C. overnight, then the mixture was cooled to room temperature, diluted to 30 mL with dichloromethane and washed with H2O. The organic layer was dried (MgSO4), filtered and concentrated. The crude product was loaded onto a Biotage 12S column with dichloromethane and eluted with 5/95 MeOH/dichloromethane to provide the product as a tan oil (9.5 mg, 20% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([OH:16])(=[O:15])[C:9]([CH2:11][C:12](O)=[O:13])=[CH2:10]>Cl>[O:13]=[C:12]1[N:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:10][CH:9]([C:8]([OH:16])=[O:15])[CH2:11]1
Reactant: Nc1ccccc1
Reactant: C=C(CC(=O)O)C(=O)O
Agent: Cl
Product: O=C(O)C1CC(=O)N(c2ccccc2)C1
Temperature: 0 °C

Procedure:
In accordance with the method of “Journal of the American Chemical Society”, vol. 72, 1950, p. 1415, aniline was added to an itaconic acid aqueous solution and heated under reflux for 12Hours. After completion of the reaction, this was ice-cooled and mixed with 70 ml of 1 M hydrochloric acid, and the thus precipitated crystals were collected by filtration to obtain 5-oxo-1-phenylpyrrolidine-3-carboxylic acid. EP: 206.
Reaction SMILES: [Cl:1][C:2]1[C:20]([C:21](=[O:36])[NH:22][CH2:23][CH2:24][N:25]2[C:29](=[O:30])[C:28]3=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]3[C:26]2=[O:35])=[CH:19][CH:18]=[C:17]([Cl:37])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2.[H-].[Na+].[CH3:40]I.O>CN(C)C=O>[Cl:1][C:2]1[C:20]([C:21](=[O:36])[N:22]([CH3:40])[CH2:23][CH2:24][N:25]2[C:26](=[O:35])[C:27]3=[CH:34][CH:33]=[CH:32][CH:31]=[C:28]3[C:29]2=[O:30])=[CH:19][CH:18]=[C:17]([Cl:37])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2
Reactant: CI
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(C(=O)NCCN4C(=O)c5ccccc5C4=O)c3Cl)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(C(=O)N(C)CCN4C(=O)c5ccccc5C4=O)c3Cl)c2n1
Reaction time: 0.25 h
Yield: 89.9 %

Procedure:
To a solution of 8-[2,6-dichloro-3-[N-(2-phthalimidoethyl)carbamoyl]benzyloxy]-2-methylquinoline (390 mg) in N,N-dimethylformamide (4 ml) was added sodium hydride (32.1 mg) under ice-cooling, and the mixture was stirred for 15 minutes at the same temperature. Methyl iodide (114 mg) was added thereto under ice-cooling, and the mixture was stirred for 15 minutes at the same temperature and for 2 hours at ambient temperature. To the mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash chromatography (chloroform:ethyl acetate=3:1, V/V) to give 8-(2,6-dichloro-3-[N-methyl-N-(2-phthalimidoethyl)carbamoyl]benzyloxy]-2-methylquinoline (360 mg) as colorless amorphous.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[F:15][C:16]1[CH:17]=[C:18]([CH:24]=[C:25]([F:27])[CH:26]=1)[CH:19]=[CH:20][C:21](O)=O>>[F:15][C:16]1[CH:17]=[C:18]([CH:24]=[C:25]([F:27])[CH:26]=1)/[CH:19]=[CH:20]/[C:21]1[NH:1][C:2]2[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=2[N:8]=1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: O=C(O)C=Cc1cc(F)cc(F)c1
Product: CCn1c(=O)c2[nH]c(/C=C/c3cc(F)cc(F)c3)nc2n(CC)c1=O
Yield: 63.1 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 3.00 g (15.1 mmol) of 5,6-diamino-1,3-diethyluracil and 3.06 g (16.6 mmol) of 3,5-difluorocinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 3.30 g (yield 63%) of Compound 150 as pale yellow plates.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13](O)=[O:14])=[CH:4][CH:3]=1.Cl.[F:24][C:25]([F:34])([F:33])[C:26]1[O:30][N:29]=[C:28]([CH2:31][NH2:32])[N:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:32][CH2:31][C:28]2[N:27]=[C:26]([C:25]([F:34])([F:33])[F:24])[O:30][N:29]=2)=[O:14])=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: NCc1noc(C(F)(F)F)n1
Agent: Cl
Product: O=C(NCc1noc(C(F)(F)F)n1)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (CAS Registry No. 1018782-82-5) and C-(5-trifluoromethyl-[1,2,4]oxadiazol-3-yl)-methylamine hydrochloride (example AI), LC-MS (UV peak area/ESI) 93%, 479.035 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10]C)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].B(Br)(Br)[Br:13]>C(Cl)Cl>[Br:13][C:7]1[C:8]([OH:10])=[CH:9][C:2]([F:1])=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: BrB(Br)Br
Reactant: COc1ccc(C=O)c(F)c1
Solvent: ClCCl
Product: O=Cc1cc(Br)c(O)cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51.5 %

Procedure:
To the solution of 2-fluoro-4-methoxybenzaldehyde (3 g, 19.5 mmol, 1 eq., Aldrich, Milwaukee, Wis., USA) in DCM (80 mL) was added dropwise BBr3 (14.5 g, 58.7 mmol, 3 eq.) at 0° C. The mixture was stirred for 15 min, then warmed to room temperature and continued to stir for additional 3 h. The reaction was quenched by careful addition of water (50 mL), the organic layer was separated, and remaining the aqueous layer was extracted with DCM (2×50 mL). The combined organic layers were concentrated in vacuo and purified by silica gel chromatography (DCM:MeOH=25:1 to 10:1) to afford 2.2 g (80.6%) of 2-fluoro-4-hydroxybenzaldehyde (24).
Reaction SMILES: [ClH:1].C([O:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:18][CH2:19][C:20]2[O:24][C:23]([C:25]([O:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[C:33]([C:38](=[NH:40])[NH2:39])[CH:34]=4)[CH:29]=3)=[O:26])=[CH:22][CH:21]=2)=[O:17])=[CH:11][CH:10]=1)=[O:8])(C)(C)C.C(O)(=O)C.Cl>O>[ClH:1].[C:7]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([NH:18][CH2:19][C:20]2[O:24][C:23]([C:25]([O:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[C:33]([C:38](=[NH:39])[NH2:40])[CH:34]=4)[CH:29]=3)=[O:26])=[CH:22][CH:21]=2)=[O:17])=[CH:13][CH:14]=1)([OH:8])=[O:6]
Reactant: CC(C)(C)OC(=O)c1ccc(CC(=O)NCc2ccc(C(=O)Oc3ccc4cc(C(=N)N)ccc4c3)o2)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: N=C(N)c1ccc2cc(OC(=O)c3ccc(CNC(=O)Cc4ccc(C(=O)O)cc4)o3)ccc2c1
Reaction time: 2 h
Yield: 65.8 %

Procedure:
To 5.4 g of 6-amidino-2-naphthyl 5-(4-t-butoxycarbonylphenylacetylaminomethyl)furan-2-carboxylate hydrochloride was added 8 ml of acetic acid, and hydrogen chloride gas was passed into the mixture for 2 hours while stirring and cooling with ice. The mixture was further stirred for 2.5 hours with water-cooling, the precipitate was collected by filtration and washed twice with 20 ml of acetone. The crystals were dissolved in 20 ml of DMF, then 1 g of active carbon was added to the solution and stirred for 30 minutes while cooling with ice. The insolubles were removed by filtration, the filtrate was added to 250 ml of acetone and stirred for 2 hours at room temperature. The precipitate was collected by filtration to obtain 3.2 g of the intended product.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.[CH3:12][C:13]([NH2:17])([CH2:15][CH3:16])[CH3:14].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:11][S:10][C:4]1[N:3]=[C:2]([NH:17][C:13]([CH2:15][CH3:16])([CH3:14])[CH3:12])[C:7]([C:8]#[N:9])=[CH:6][N:5]=1
Reactant: CCC(C)(C)N
Reactant: CSc1ncc(C#N)c(Cl)n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)(C)Nc1nc(SC)ncc1C#N
Temperature: 70 °C

Procedure:
4-Chloro-2-(methylthio)pyrimidine-5-carbonitrile (500 mg, 2.69 mmol) was dissolved in DMF (5 mL), 2-methylbutan-2-amine (0.378 mL, 3.24 mmol) and DIEA (1.411 mL, 8.08 mmol) were added and the reaction was heated at 70° C. overnight. LCMS showed the desired product mass as the dominant peak and no starting material remaining. The reaction was removed from heat and partitioned between ethyl acetate and water. The organic layer was washed once with brine before drying over magnesium sulfate, filtering, and condensing. The crude material was purified by silica gel chromatography (0-80% ethyl acetate in hexane over 1650 mL; 40 mL/min). Product fractions were combined, evaporated, and dried under high vacuum to afford 2-(methylthio)-4-(tert-pentylamino)pyrimidine-5-carbonitrile (359 mg, 1.519 mmol, 56.4% yield) as a white solid; MS (ESI) m/z 236.9 [M+1]+
Reaction SMILES: CO[C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:23][CH2:24][CH:25]([OH:27])[CH3:26]>>[CH2:18]([C:13]1[C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:23][CH2:24][CH:25]([OH:27])[CH3:26])=[O:22])=[CH:5][N:6]=2)=[C:16]([CH3:17])[O:15][N:14]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)OC)cn1
Reactant: CC(O)CN
Product: CCCCc1noc(C)c1COc1ccc(C(=O)NCC(C)O)cn1
Yield: 3 %

Procedure:
As described for example 9, 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (150 mg, 0.49 mmol) was converted, using rac-1-amino-2-propanol instead of rac-2-amino-1-propanol, to the title compound (5 mg, 3%) which was obtained as a yellow oil after purification by chromatography (silica, 0 to 6% methanol in dichloromethane). MS: m/e=348.3 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]2[NH:7][C:8]([SH:10])=[N:9][C:5]=2[CH:4]=1)#[N:2].[CH3:13][O:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22]Br)[CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.CN(C=O)C>[C:1]([C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([S:10][CH2:22][C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([C:15]([O:14][CH3:13])=[O:24])[CH:17]=3)[NH:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: N#Cc1ccc2[nH]c(S)nc2c1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: COC(=O)c1cccc(CSc2nc3ccc(C#N)cc3[nH]2)c1
Yield: 58.8 %

Procedure:
A suspension of 5-cyano-1H-benzoimidazole-2-thiol (35 mg, 0.2 mmol), 3-bromomethyl-benzoic acid methyl ester (46 mg, 0.2 mmol) and K2CO3 (55 mg, 0.4 mmol) in acetone (0.6 ml) and 3 drops of DMF is refluxed for 2 h. It is cooled down and filtered over a short plug of silica gel and rinsed with AcOEt. The solvent is removed under a stream of air. The crude residue is purified by flash chromatography on silica-gel (AcOEt/heptane, 1:2), yielding the title compound (38 mg) in 59% as a yellowish gum: tR=6.14 min (LC-1), ESI-MS (pos.): m/z 324.14 [M+H]+, ESI-MS (neg.): m/z 322.22 [M−H]+; 1H-NMR (CDCl3): δ (ppm) 3.92 (s, 3H, Me), 4.67 (s, 2H, SCH2), 5.29 (s, 1H, NH), 7.36-7.56 (m, 4Harom), 7.65 (d, 1Harom), 7.94 (d, 1Harom), 8.10 (s, 1Harom)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH3:15])[CH2:13]Cl)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.[OH-].[Na+]>CCOCC>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:13][CH:12]([CH3:15])[CH2:11][C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=2)[CH2:19][CH2:18]1
Reactant: CN1CCNCC1
Reactant: CC(CCl)Cc1ccc(C(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(Cc1ccc(C(C)(C)C)cc1)CN1CCN(C)CC1
Yield: 93.6 %

Procedure:
533 g of 3-(4-tert.butylphenyl)-2-methylpropyl chloride and 714 g of 4-methylpiperazine were stirred for 7 hours at 140° C. and then cooled to +10° C. in an ice bath, and 400 ml of 50% strength sodium hyroxide solution were added slowly, followed by the addition of 500 ml of ether. The organic phase was separated off, dried over sodium hydroxide and distilled to give 640 g of 1-methyl-4-[3-(4-tert.-butylphenyl)-2-methylpropyl]-piperazine of boiling point 135°-140° C./0.3 mbar.