Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[NH2:9].II.S(=O)(=O)(O)O.O[CH2:24][CH:25]([CH2:27]O)O>>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:10]([CH:24]=[CH:25][CH:27]=[N:9]2)=[CH:11][C:12]=1[O:13][CH3:14]
Reactant: OCC(O)CO
Reactant: COc1ccc(N)cc1OCCN(C)C
Agent: II
Agent: O=S(=O)(O)O
Product: COc1cc2cccnc2cc1OCCN(C)C
Temperature: 180 °C
Yield: 8.1 %

Procedure:
3-(2-Dimethylaminoethoxy)-4-methoxyaniline (D14, 200 mg) was treated with glycerol (133 mg) and iodine (5 mg) and to this stirring mixture was added dropwise, concentrated sulphuric acid (267 mg). After the initial exothermic reaction had subsided, the mixture was heated at 180° C. for 1.5 hr. The reaction mixture was cooled and partitioned between 40% aqueous sodium hydroxide and ethyl acetate, the organic phase was dried (Na2SO4) and the solvent evaporated under reduced pressure to leave the title compound as a brown oil (19 mg, 51%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=3C)=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:4]=2[N:3]=1.[CH3:29][N:30]([CH3:35])[CH2:31][CH2:32][NH:33][CH3:34]>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([N:33]([CH2:32][CH2:31][N:30]([CH3:35])[CH3:29])[CH3:34])=[O:19])=[CH:21][CH:22]=3)=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:4]=2[N:3]=1
Reactant: CNCCN(C)C
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(=O)Cl)cc3C)cc12
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(=O)N(C)CCN(C)C)cc3)cc12

Procedure:
4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-N-(2-(dimethylamino)ethyl)-N-methylbenzamide was prepared from 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylbenzoyl chloride (Example 116/Step 2) and N1,N1,N2-trimethylethane-1,2-diamine following the procedures described for Example 117. 1H NMR (CDCl3): δ 8.64 (s, 1H), 8.36 (s, 1H), 8.05 (d, 1H), 7.60 (s, 1H), 7.41 (d, 2H), 7.31 (d, 1H), 7.21 (d, 2H), 3.91 (t, 2H), 3.44 (t, 2H), 3.25 (t, 2H), 3.12 (t, 2H), 3.03 (s, 3H), 3.01 (s, 6H), 2.53 (s, 3H). LRMS [M+H]=442.3
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH:5](Br)[CH3:6])[CH3:2].[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH2:1]([O:3][C:4](=[O:8])[CH:5]([NH:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)Br
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(C)NCc1ccccc1
Temperature: 20 °C
Yield: 97 %

Procedure:
To a solution of 2-bromo-propionic acid ethyl ester (17.90 mL, 1 eq.) in 250 mL of MeCN were added benzylamine (13.45 mL, 0.9 eq.) and potassium carbonate (28.60 g, 1.5 eq.). The reaction was refluxed for 2 h then cooled to 20° C. The crude was filtered, washed with EtOAc. The filtrate was concentrated under reduced pressure, then purified by chromatography on silica gel (elution with heptane/EtOAc: 9/1 to 7/3) to afford 2-benzylamino-propionic acid ethyl ester (24.74 g, yield=97%).
Reaction SMILES: [C:1]1([S:7]([CH3:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Mg]Br)C.[Cl:15][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18].Cl.[Cl-].[NH4+]>C1COCC1.CCOCC>[Cl:15][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([OH:18])[CH2:10][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8]
Reactant: CS(=O)(=O)c1ccccc1
Reactant: O=C(CCl)c1ccccc1
Agent: CC[Mg]Br
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=S(=O)(CC(O)(CCl)c1ccccc1)c1ccccc1
Temperature: -50 °C
Reaction time: 1 h
Yield: 26.1 %

Procedure:
Methyl phenyl sulphone (12.5 g, 0.08 mole) dissolved in THF (150 cc) is added at ambient temperature to a molar solution (100 cc) of ethylmagnesium bromide. The mixture is stirred for 1 h and then cooled to -50° C. 2-Chloroacetophenone (12.5 g, 0.08 mole) dissolved in THF (150 cc) is run in and stirred for 2 h at -20° C. The mixture is poured into normal hydrochloric acid (200 cc) and ammonium chloride (6 g). It is reextracted with ether (3×50 cc), washed until neutral and dried over MgSO4. The crude is precipitated with heptane and recrystallized from isopropyl ether to give flocculent white crystals of 1-chloro-2-phenyl-3-phenylsulphonyl-2-propanol (6.5 g, 26%). Mp=110° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:31])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][C:23]2[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Cl:29][C:27]1[CH:28]=[C:23]([CH:24]=[C:25]([Cl:30])[CH:26]=1)[O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[NH:15][C:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:31]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccccc2Oc2cc(Cl)cc(Cl)c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccccc1Oc1cc(Cl)cc(Cl)c1)C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-[2-(3,5-Dichloro-phenoxy)-phenylcarbamoyl]-piperidine-1-carboxylic acid tert-butyl ester (036 g, 0.77 mmol) was dissolved in DCM (9 ml), and to this was added TFA (4 ml). The reaction was stirred at room temperature for 2 h. This was then poured onto solid K2CO3, and extracted using DCM and water, to afford the desired product as a yellow solid. 0.21 g, (75%), m.p. 138-139° C., Rf. 0.3 (10% Methanol-DCM), 1HNMR (CDCl3, 270 MHz) δ 1.65 (3H, m, CH2 and NH), 1.86 (2H, m, CH2), 2.36 (1H, m, CH), 2.65 (2H, td, J=2.7, 9.6, NCH2), 3.16 (2H, m, NCH2), 6.89 (2H, d, J=1.7, HE, HG), 6.90 (1H, m, HD), 7.06 (1H, td, J=1.5, 7.4, HB), 7.12 (1H, t, J=1.7, HF), 7.18 (1H, td, J=8.2, 1.46, HC), 7.55 (1H, s, NH), 8.43 (1H, dd, J=8.2, HA).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1(C(O)=O)C2C(=CC=CC=2)C=CC=1>C(OCC)(=O)C.C1(C)C=CC=CC=1>[O:16]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Oc1ccccc1
Reactant: N#Cc1ccc(Br)cc1
Agent: O=C(O)c1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
4-Bromobenzonitrile (2.5 mmol), phenol (3.5 or 5.0 mmol), Cs2CO3 (3.5 or 5.0 mmol), (CuOTf)2 PhH (0.0625 mmol, 5.0 mol % Cu), ethyl acetate (0.125 mmol, 5.0 mol %), 1-naphthoic acid (3.5 mmol), molecular sieves (625 mg) and toluene (1.5 mL) were added to an oven-dried test tube which was then sealed with a septum, purged with argon, and heated to 110 C under argon until the aryl halide was consumed as determined by GC analysis. Upon cooling at room temperature, dichloromethane was added and the solvent was removed by filtration. The remaining molecular sieves were stirred with another portion of dichloromethane for 1 h at room temperature, and the solvent was removed by filtration. The combined organic phases were washed with 5% aqueous NaOH. The aqueous layer was then extracted three times with dichloromethane and the combined organic layers were washed with brine. The organic layer was dried over Mg2SO4 and concentrated under vacuum to give the crude product. Purification by flash column chromatography (3% EtOAc/hexane) gave the analytically pure product as a clear oil (405 mg, 86% yield). 1H NMR (300 MHz, CDCl3) δ 7.57 (d, J=8.7 Hz, 2H), 7.40 (t, J=7.9Hz, 2H), 7.22 (t, J=7.6Hz, 1H), 7.05 (d, J=7.9Hz, 2H), 6.98 (d, J=8.8 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 154.6, 133.9, 130.0, 124.9, 120.2, 118.6, 117.7, 105.6; IR (neat): 3068, 2226, 1586, 1483, 1245, 1165 cm−1.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[N:9]([C:10]2[C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][O:13][CH:14]=2)[C:8](=[O:19])[N:7]([CH3:20])[N:6]=1.[NH4+].[Cl-]>CO.C(COC)OC>[CH3:1][O:2][C:5]1[N:9]([C:10]2[C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][O:13][CH:14]=2)[C:8](=[O:19])[N:7]([CH3:20])[N:6]=1
Reactant: C[O-]
Reactant: COC(=O)c1cocc1-n1c(Cl)nn(C)c1=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: COCCOC
Product: COC(=O)c1cocc1-n1c(OC)nn(C)c1=O
Temperature: 40 °C

Procedure:
A solution of sodium methoxide (11.4 mL, 30% in methanol) was added to a solution of the title compound of Step D (5.34 g) in methanol/dimethoxyethane (26 mL/26 mL) while stirring under nitrogen. The yellow solution was heated to 40° C. for 5 h, cooled to room temperature and left to stir overnight under nitrogen. The reaction mixture was poured into saturated aqueous NH4Cl (50 mL) and the resulting mixture was extracted three times with ethyl acetate. The combined organic extracts were dried (MgSO4), filtered and concentrated to a yellow solid. The yellow solid was dried under vacuum to afford 4.7 g of the title compound of Step E melting at 131-133° C. 1H NMR (CDCl3): δ 8.04 (d,1H), 7.68 (d,1H), 3.94 (s,3H), 3.78 (s,3H), 3.43 (s,3H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][NH:3]1.Cl[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][N:11]=1.C(N(CC)CC)C>CN1CCCC1=O>[CH3:1][C@@H:2]1[CH2:7][NH:6][C@@H:5]([CH3:8])[CH2:4][N:3]1[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][N:11]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: C[C@@H]1CN[C@@H](C)CN1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: C[C@@H]1CN[C@@H](C)CN1c1ccc(C#N)cn1
Yield: 9 %

Procedure:
Combine (2S,5R)-2,5-dimethyl-piperazine (200 mg, 1.75 mmol), 6-chloro-nicotinonitrile (1.75 mmol) and triethylamine (5.25 mmol) in a 0.875 M solution of 1-methyl-2-pyrrolidinone. Microwave reaction mixture for 30 min at 150° C. Partition between ethyl acetate and water, collecting organic phase. Wash aqueous layer again with ethyl acetate and combine organics. Dry with sodium sulfate, filter and concentrate. Purify on preparative HPLC to give the title compound. (9% yield)
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[C:19]([C:21]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[CH:24]=[C:23]([CH3:34])[N:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:25]2[CH:24]=[C:23]([CH3:34])[N:22]=[C:21]([C:19]3[CH:18]=[CH:17][N:16]=[C:15]([C:11]4[CH:10]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:14]=[CH:13][CH:12]=4)[CH:20]=3)[N:26]=2)=[CH:32][CH:31]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(-c2ccnc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-c2ccnc(-c3cccc(S(N)(=O)=O)c3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 46 %

Procedure:
To a cooled and stirred solution of 3-{4-[4-(4-chloro-phenyl)-6-methyl-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonic acid tert-butylamide (0.47 g) in dichloromethane (6 mL) was added TFA (6 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried to yield the title compound as a white solid (0.2, 46%). MS (ISP) 437.1 [(M+H)+]; mp 224° C.
Reaction SMILES: N1CCCC(COC2C=C([O:16][S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])(=[O:19])=[O:18])C=C(C)C=2)C1.C(N(CC)C(C)C)(C)C.NN=CS(O)(=O)=O>CN(C=O)C>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[S:17]([OH:19])(=[O:18])=[O:16]
Reactant: Cc1cc(OCC2CCCNC2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Agent: NN=CS(=O)(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=S(=O)(O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
A solution of 2-chlorobenzenesulfonic acid 3-[(piperidin-3-yl)methoxy]-5-methylphenyl ester (396 mg, 1.0 mmol), as prepared in the preceding step, in DMF (10 mL) containing N,N-diisopropylethylamine (0.5 mL) and aminoiminomethanesulfonic acid (248 mg, 2.0 mmol) was stirred at room temperature overnight. The DMF was removed in vacuo and the residue was purified by flash column chromatography (90:10 methylene chloride:methanol saturated with NH3) to give the title compound as a white foam (159 mg, 36%). 1H-NMR (300 MHz, CDCl3) δ 1.45-1.92 (m, 4H), 2.11 (m, 1H), 2.23 (s, 3H), 3.07 (m, 2H), 3.81 (d, 2H), 3.92 (m, 2H), 6.50 (s, 2H), 6.61 (s, 1H), 7.24 (bs, 3H), 7.40 (m, 1H), 7.63 (m, 2H), 7.95 (dd, 1H). Mass spectrum (MALDI-TOF, sinapinic acid matrix) calcd. for C20H24N3 O4SCl: 438.1 (M+H), 460.1 (M+Na), Found: 438.5, 460.5.
Reaction SMILES: Cl.N[C@H:3]([C:11]([OH:13])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.S(=O)(=O)(O)[OH:15].N([O-])=O.[Na+].O>C(OCC)C>[OH:15][C@@H:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:11]([OH:13])=[O:12]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=S(=O)(O)O
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: O=C(O)[C@@H](O)Cc1ccccc1
Yield: 41.8 %

Procedure:
L-Phenylalanine hydrochloride (12.2 g, 60.5 mmol) was added to 183 ml of 5% sulfuric acid (sulfuric acid: 96.0 mmol) and the solution was treated with a mixture of 8.35 g (121 mmol) of sodium nitrite and 44.5 g of water at 0° C. for 3 hours. Thereafter, 100 ml of diethyl ether was added to the reaction mixture and, after stirring, the organic phase was separated (extract 1). Further, 50 ml of diethyl ether was added to the aqueous phase and, after stirring, the organic phase was separated (extract 2). The extracts 1 and 2 were combined. The combined extract (95.0 g) contained 4.2 g of (2S)-2-hydroxy-3-phenylpropionic acid (yield 42%, optical purity 92.6% ee). The proton concentration (normality) in the reaction of this comparative example was 1.4 mol/kg, the amount of the protonic acid was 4.0 equivalents (relative to L-phenylalanine), and the reaction temperature was 0° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[CH3:13][C:14]1[CH:41]=[CH:40][CH:39]=[CH:38][C:15]=1[CH2:16][N:17]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH3:37])[C@@H:18]([CH2:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=1)[CH:19]=[O:20]>C1COCC1>[CH3:13][C:14]1[CH:41]=[CH:40][CH:39]=[CH:38][C:15]=1[CH2:16][N:17]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH3:37])[C@@H:18]([CH2:21][C:22]1[CH:23]=[C:24]([F:29])[CH:25]=[C:26]([F:28])[CH:27]=1)[C@@H:19]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[OH:20]
Reactant: Brc1ccccn1
Reactant: Cc1ccccc1CN(Cc1ccccc1C)[C@H](C=O)Cc1cc(F)cc(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccccc1CN(Cc1ccccc1C)[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)c1ccccn1
Temperature: -78 °C
Yield: 40.8 %

Procedure:
Dissolve 2-bromopyridine (0.485 mL, 5.07 mmol) in THF (30 mL) and cool to −78° C. Add n-butyllithium (2.0 mL, 2.5 M in hexanes). Slowly add 2-(S)-[bis-(2-methylbenzyl)-amino]-3-(3,5-difluorophenyl)-propionaldehyde (1.37 g, 3.3 mmol) in THF (10 mL) and stir 2 h. Quench reaction with saturated aqueous ammonium chloride. Warm to room temperature. Wash organic layer twice with 5% aqueous citric acid, saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify twice (silica gel chromatography, eluting with hexanes and ethyl acetate, and then dichloromethane and ethyl acetate) to give the title compound as a foam (0.636 g, 40%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(#N)C.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)#[N:11].Br[CH:20]([CH2:26][CH3:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>O>[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH:20]([CH2:26][CH3:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:14][CH:13]=1)#[N:11]
Reactant: CCOC(=O)C(Br)CC
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C(CC)Oc1ccc(C#N)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
Potassium carbonate (14.5 g, 105 mmol) was added to an acetonitrile (80.0 mL) solution of 4-cyanophenol (5.00 g, 42.0 mmol) and ethyl 2-bromobutyrate (9.83 g, 50.4 mmol) at room temperature, and the mixture was stirred for 3 hours at 80° C. After the mixture was cooled to room temperature, water was added to the reaction mixture, and the mixture was subjected to extraction two times with ethyl acetate. The organic layer thus obtained was washed with saturated brine, and then was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→2:1, v/v). Thus, the title compound (9.79 g, yield: 100%) was obtained.
Reaction SMILES: [CH2:1]1[CH2:7][CH:6]([C:8]([NH2:10])=[O:9])[C:4](=O)[CH2:3][CH2:2]1.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C=CC=CC=1>O>[CH2:11]([NH:18][C:4]1[CH2:3][CH2:2][CH2:1][CH2:7][C:6]=1[C:8]([NH2:10])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: NC(=O)C1CCCCC1=O
Solvent: Cc1ccccc1
Solvent: O
Product: NC(=O)C1=C(NCc2ccccc2)CCCC1

Procedure:
A mixture of cyclohexanone-2-carboxamide (U.S. Pat. No. 4,169,952 to du Pont de Nemours, (1979)) (10.0 g), benzylamine (8.4 g), toluene (35 mL) and molecular sieves (Union Carbide 3A, 2 g) was refluxed for 2 h in a Dean-Stark water separator. The reaction mixture was filtered, and the filtrate was evaporated. The residue was crystallized from light petroleum to give the title compound (16 g). Mp 73-74° C.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([CH3:24])[NH:19][C:18]2=[O:25])=[CH:12][C:5]=1[C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7]>C(O)(=O)C>[Cl:3][C:4]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[C:21]([Br:1])=[C:20]([CH3:24])[NH:19][C:18]2=[O:25])=[CH:12][C:5]=1[C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7]
Reactant: Cc1cc(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)[nH]1
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1[nH]c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)c1Br

Procedure:
A solution of 1.7 g of bromine in 20 ml of acetic acid is added dropwise with stirring to a solution of 3.4 g of isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-4-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate in 20 ml of acetic acid at 25° C. during 25 minutes. The reaction mixture is stirred for a further hour and evaporated to dryness under reduced pressure. The residue is dissolved in diethyl ether and washed with aqueous sodium bicarbonate solution, thereafter with water. The organic phase is dried over anhydrous sodium sulphate and evaporated to dryness. The residue is recrystallized from diethyl ether/n-hexane. There is obtained isopropyl 2-chloro-4-fluoro-5-[5-bromo-3,6-dihydro-4-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, m.p. 187°-189° C.
Reaction SMILES: [CH:1]1([C:5]2[C:26]([C:27]3[NH:31][C:30]([CH3:32])=[N:29][N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:16][CH2:15][CH:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[CH2:13][CH2:12]3)=[O:10])=[C:7]([CH3:33])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:34][O:35]CC(NN)=O>>[CH:1]1([C:5]2[C:26]([C:27]3[NH:31][C:30]([CH2:32][O:35][CH3:34])=[N:29][N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:12][CH2:13][CH:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[CH2:15][CH2:16]3)=[O:10])=[C:7]([CH3:33])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COCC(=O)NN
Reactant: Cc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)[nH]1
Product: COCc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)[nH]1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of 4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 152) but using 2-methoxyacetohydrazide (compound 190.6) in place of acetohydrazide. m/z (ES+) 470 (M+H)+. 1H NMR (400 MHz, CDCl3): δ 12.15 (br s, 1H), 7.64-7.57 (m, 2H), 7.43 & 7.33 (2 singlets, amide rotamers, Ar—H, 1H), 7.30 (d, J=8.4 Hz, 2H), 7.20 (s, 1H), 5.04-4.92 (m, 1H), 4.65 (s, 2H), 4.18-4.03 (m, 1H), 3.63 (br d, J=13.2 Hz, 1H), 3.51 (s, 3H), 3.08 (t with fine structure, J=12.8 Hz, 1H), 2.93-2.77 (m, 2H), 2.38 & 2.30 (2 singlets, amide rotamers, ArCH3, 3H), 2.25-1.84 (m, 6H), 1.84-1.43 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.COCCOC.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[Cl:1][C:2]1[CH:7]=[C:6]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH3:9])[N:5]=[CH:4][N:3]=1
Reactant: COc1ccccc1B(O)O
Reactant: Clc1cc(Cl)ncn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1ccccc1-c1cc(Cl)ncn1
Temperature: 85 °C

Procedure:
A mixture of 4,6-dichloropyrimdine (0.98 g), 2-methoxy-benzeneboronic acid (1.0 g), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (11) (0.54 g), 1,2-dimethoxyethane (60 ml), sodium hydrogen carbonate (1.1 g) and water (20 ml) were heated together at 85° C. for 16 hours. The mixture was cooled to room temperature, diluted with ethyl acetate and the organic phase separated, dried over magnesium sulphate, filtered, evaporated, then purified by column chromatography (silica gel, ethyl acetate/petroleum ether), to give 4-Chloro-6-(2-methoxy-phenyl)-pyrimidine, 1.18 g
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([CH2:8]Cl)=[C:4]([N:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[NH:23][CH:24]=[CH:25][N:26]=2)[N:17]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[N:6][C:5]([CH2:8][N:26]2[CH:25]=[CH:24][N:23]=[C:22]2[C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([F:15])[N:17]=2)=[C:4]([N:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[CH:3]=1
Reactant: CCN(CC)c1cc(Cl)nnc1CCl
Reactant: Fc1cccc(-c2ncc[nH]2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)c1cc(Cl)nnc1Cn1ccnc1-c1cccc(F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.5 %

Procedure:
A mixture of (6-chloro-3-chloromethyl-pyridazin-4-yl)-diethyl-amine (crude, 180 mg, 0.77 mmol), 2-fluoro-6-(1H-imidazol-2-yl)-pyridine (78 mg, 0.48 mmol) and K2CO3 (330 mg, 2.4 mmol) in DMF (5 mL) is stirred at room temperature overnight. The reaction is quenched with brine (4 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers are dried and solvent removed. PTLC separation (10% MeOH in DCM) gives 39 mg of {6-chloro-3-[2-(6-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-pyridazin-4-yl}-diethyl-amine as a solid. 1H NMR (CDCl3) 8.12 dd, 1H), 7.90 (dd, 1H), 7.19 (s, 1H), 7.07 (s, 1H), 6.79 (s, 1H), 6.77 (dd, 1H), 6.04 (s, 2H), 3.28 (q, 4H), 1.17 (t, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH2:4][OH:5].[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=O>C(OCC)(=O)C.C(O)(=O)C1C=CC=CC=1>[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]1[O:1][C:2]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=2[CH2:4][O:5]1
Reactant: O=Cc1ccccc1F
Reactant: O=[N+]([O-])c1ccc(O)c(CO)c1
Agent: O=C(O)c1ccccc1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc2c(c1)COC(c1ccccc1F)O2
Temperature: 5 °C
Yield: 71.4 %

Procedure:
An intimate mixture of 2-hydroxy-5-nitrobenzyl alcohol (4.56g), 2-fluorobenzaldehyde (4.02g) and benzoic acid (0.2g) was stirred and heated to 90° C. (±5° C.) under nitrogen for 31/2 hours. The resulting clear reaction mixture was left to cool for two days whereupon it solidified. This material was dissolved in ethyl acetate (250 ml) and the solution was washed with saturated aqueous sodium bicarbonate, 20% aqueous sodium bisulphite and then with water. The organic phase was dried over sodium sulphate and evaporated to yield the crude product as a solid residue which was purified by suspending briefly in hot ethanol and cooling to 0°-5° C. The pure product was thus obtained as a white crystalline powder (5.3g, 71%), mp 137°-138° C.