Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][C:14]1[N:19]2[N:20]=[C:21]([CH3:23])[CH:22]=[C:18]2[N:17]=[C:16]([NH2:24])[CH:15]=1>N1C=CC=CC=1>[Cl:13][C:14]1[N:19]2[N:20]=[C:21]([CH3:23])[CH:22]=[C:18]2[N:17]=[C:16]([NH:24][C:10]([CH:8]2[CH2:9][CH:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:11])[CH:15]=1
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Reactant: Cc1cc2nc(N)cc(Cl)n2n1
Solvent: c1ccncc1
Product: Cc1cc2nc(NC(=O)C3CC3c3ccccc3)cc(Cl)n2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
In a 250 ml round-bottomed flask was added (+/−)-trans-2-phenylcyclopropanecarbonyl chloride (1.9 g, 10 mmol) in pyridine (94 ml) to give a yellow suspension. 7-Chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-amine (1J, 1.7 g, 9.4 mmol) was added portionwise at 0° C. The temperature was slowly raised to room temperature. After 30 min, reaction was complete and was quenched with saturated sodium bicarbonate solution. The layers were extracted with ethyl acetate (3×100 mL), and the organic layers were washed with saturated sodium bicarbonate solution and concentrated in vacuo. The residue was suspended in methanol and filtered. The filtrate was concentrated to obtain the product N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-2-phenylcyclopropanecarboxamide (8C, 1.9 g, 62%) as an orange solid. 1H NMR (DMSO-d6) δ: 11.39 (s, 1H), 7.99 (s, 1H), 7.27-7.34 (m, 2H), 7.15-7.25 (m, 3H), 6.39 (s, 1H), 2.46 (td, 1H), 2.41 (s, 3H), 2.30-2.37 (m, 1H), 1.50-1.58 (m, 1H), 1.46 (ddd, J=8.2, 6.6, 4.2 Hz, 1H). ESI-MS: m/z 327.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][CH2:11][C@H:12]([NH2:18])[C@@H:13]([OH:17])[C:14]#[C:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20](N(CC)C(C)C)(C)C.[CH2:29]([NH:31][C:32](=[O:51])[NH:33][C:34]1[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][C:35]=1[C:36]([NH:38][CH2:39][C:40]([OH:42])=O)=[O:37])[CH3:30].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[OH:17][C@@H:13]([C:14]#[C:15][CH3:16])[C@@H:12]([NH:18][C:40](=[O:42])[CH2:39][NH:38][C:36](=[O:37])[C:35]1[CH:43]=[C:44]([C:47]([F:50])([F:49])[F:48])[CH:45]=[CH:46][C:34]=1[NH:33][C:32]([NH:31][CH:29]([CH3:30])[CH3:20])=[O:51])[CH2:11][NH:10][C:9](=[O:19])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCNC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)O
Reactant: CC#C[C@H](O)[C@@H](N)CNC(=O)OCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CC#C[C@H](O)[C@H](CNC(=O)OCc1ccccc1)NC(=O)CNC(=O)c1cc(C(F)(F)F)ccc1NC(=O)NC(C)C
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of (2S,3S)-[2-(tert-butoxycarbonylamino)-3-hydroxy-hex-4-ynyl]-carbamic acid benzyl ester (0.25 g, prepared as in WO PCT 0250019) in methylene chloride (9 mL) was cooled to 0° C. and charged with trifluoroacetic acid (3 mL). The mixture was allowed to warm to RT and stirred for 45 min before being concentrated in vacuo. The residue was dissolved in methylene chloride and the resultant solution concentrated; this was repeated twice more to afford the TFA salt of (2S,3S)-2-amino-3-hydroxy-hex-4-ynyl-carbamic acid benzyl ester, MS found: (M+H)+=263.3. A solution of this amine in CH2Cl2 (12 mL) was charged successively with N,N-diisopropylethylamine (1.2 mL), 2-(2-(3-ethylureido)-5-(trifluoromethyl)benzamido)acetic acid (240 mg, see WO-02/50019), and BOP (382 mg). The reaction was stirred for 14 h at RT before being partitioned between EtOAc and water. The organic phase was washed with sat. NH4Cl, water, and brine before being dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford benzyl (2S,3S)-3-hydroxy-2-(2-(2-(3-isopropylureido)-5-(trifluoromethyl)benzamido)acetamido)hex-4-ynylcarbamate (289 mg). MS found: (M+H)+=592.35.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH:12]=[O:13].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-:23].[K+].[K+]>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:2]2[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=2[C:12]([OH:13])=[O:23])=[CH:17][CH:16]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=C([O-])[O-]
Reactant: Cn1nc(C(F)(F)F)c(C=O)c1Cl
Agent: [K+]
Product: Cn1nc(C(F)(F)F)c(C(=O)O)c1Oc1ccc(Cl)cc1

Procedure:
The title compound was prepared using 5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde and 4-chlorophenol in the manner similar to the method in Production Example 1 above except potassium carbonate was used instead of potassium hydroxide.
Reaction SMILES: [N+]([C:4]1[NH:5][CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[N:8]=1)([O-])=O.[CH3:12][C:13]1([CH2:16][NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][O:14]1.C([O-])(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)C.C(Cl)Cl>[CH3:15][C:13]1([CH2:16][NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:14][C:4]2=[N:8][C:7]([N+:9]([O-:11])=[O:10])=[CH:6][N:5]2[CH2:12]1
Reactant: O=[N+]([O-])c1c[nH]c([N+](=O)[O-])n1
Reactant: CC1(CNC(=O)OCc2ccccc2)CO1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CC1(CNC(=O)OCc2ccccc2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 70 °C
Reaction time: 8 h
Yield: 4.7 %

Procedure:
2,4-Dinitro-1H-imidazole (3 g, 19 mmol) and benzyl (2-methyloxiran-2-ylmethyl)carbamate (4.31 g, 19 mmol) were dissolved in ethanol (20 ml). To the solution, sodium acetate (1.56 g, 19.0 mmol) was added followed by stirring at 70° C. overnight. To the reaction mixture, a saturated sodium hydrogencarbonate solution and methylene chloride were added, and the solution was extracted with methylene chloride. The organic phase was dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1, methylene chloride/methanol=50/1) and recrystallized from ethyl acetate-methylene chloride to afford benzyl (2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)carbamate (0.298 g, yield 4.7%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:22]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:37].[CH3:38][N:39]([CH3:43])[CH2:40][CH2:41][NH2:42].C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:42][CH2:41][CH2:40][N:39]([CH3:43])[CH3:38])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:22]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:37]
Reactant: Cc1ccc(C(=O)Nc2nccs2)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Reactant: CN(C)CCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)Nc2nccs2)cc1-c1nc(NCCN(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.4 %

Procedure:
To the solution of 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-1,3-thiazol-2-ylbenzamide (30 mg, 0.055 mmol) in dichloromethane (3.0 mL) were added N,N-dimethyl-1,2-ethanediamine (12.2 μL, 0.11 mmol) and triethylamine (15.6 μL, 0.11 mmol). The reaction mixture was stirred at room temperature for 16 hours then was concentrated, redissolved in DMSO (0.5 mL), filtered and applied to the reverse phase HPLC to afford the titled compound 16.9 mg (54%). LC-MS m/z 565 (M+H)+; 1H-NMR (MeOD) 2.20 (s, 3H), 2.33 (m, 7H), 2.81 (s, 2H), 3.26 (m, 1H), 4.13 (m, 1H), 4.43 (s, 1H), 7.17 (m, 3H), 7.50 (m, 3H), 8.01 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3](I)=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]#[CH:29])=[CH:23][CH:22]=1>>[F:14][C:13]1([F:15])[CH2:12][O:11][C:10]([NH2:16])=[N:9][C@@:8]1([C:6]1[CH:7]=[C:2]2[C:3]([CH2:29][C:28]([CH2:27][C:24]3[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][CH:23]=3)=[N:1]2)=[CH:4][C:5]=1[F:18])[CH3:17]
Reactant: C#CCc1ccc(C)cc1
Reactant: C[C@]1(c2cc(N)c(I)cc2F)N=C(N)OCC1(F)F
Product: Cc1ccc(CC2=Nc3cc([C@@]4(C)N=C(N)OCC4(F)F)c(F)cc3C2)cc1
Yield: 73 %

Procedure:
In a manner analogous to that described in Example 39, the coupling and cyclisation reaction of (R)-4-(5-amino-2-fluoro-4-iodo-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate B6.1) with 1-methyl-4-prop-2-ynyl-benzene yielded the title compound (73% yield) as a light green foam. MS (ISP): m/z=388.3 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]12[CH2:12][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH2:11]1)[CH2:9]2)(C)(C)C.[ClH:18]>CCOC(C)=O>[Cl-:18].[C:13]([C:10]12[CH2:12][C:8]([NH2:7])([CH2:11]1)[CH2:9]2)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)NC12CC(C(C)(C)C)(C1)C2
Reactant: Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)C12CC(N)(C1)C2
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
A solution of tert-butyl(3-(tert-butyl)bicyclo[1.1.1]pentan-1-yl)carbamate (0.983 g, 4.11 mmol) in EtOAc (10.3 mL) was treated with HCl (4.0M in dioxane, 41.1 mmol, 10.3 mL) and allowed to stir at r.t. overnight. The solution was concentrated under reduced pressure to afford the crude product as an off-white solid. The solid was triturated with Et2O (3×10 mL) to afford compound 15 as a white solid (0.6911 g). MS: m/z 140.2 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12](C)[CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:16].[CH2:17]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20].[C:27]([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:17]([CH:21]1[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][CH2:4][N:5]2[C:14]3[C:9](=[C:10]([CH3:27])[CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7][C:6]2=[O:16])[CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]
Reactant: Cc1ccc2c(c1)N(CCCCl)C(=O)CC2
Reactant: O=C([O-])[O-]
Reactant: CCCCC1CCNCC1
Agent: [K+]
Solvent: CC#N
Product: CCCCC1CCN(CCCN2C(=O)CCc3c(C)cccc32)CC1
Yield: 35.7 %

Procedure:
A 4 mL vial was charged with 1-(3-chloropropyl)-7-methyl-3,4-dihydro-1H-quinolin-2-one (107LH27-13,1) (0.117 g, 0.49 mmol), 4-butylpiperidine (0.071 g, 0.50 mmol), KI (0.166 g, 1.00 mmol), and K2CO3 (0.138 g, 1.00 mmol) in MeCN and shaken at 50°. The reaction mixture was quenched with water, and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The product was purified by flash CC (SiO2; EtOAc, MeOH/EtOAc 1:4) to give the title compound (107LH28) (0.060 g, 74%). 1H NMR δ 7.06 (d, J=7.4 Hz, 1H), 6.97 (s, 1H), 6.84 (d. J=7.6 Hz, 1H), 3.97 (t, J=7.4 Hz, CH2), 2.91 (d, J=11.2 Hz, 2H), 2.82 (t, J=6.8 Hz, CH2), 2.57-2.54 (m, 2H), 2.41-2.37 (m, 2H), 2.33 (s, CH3), 1.98-1.92 (m, 2H), 1.87-1.79 (m, 2H), 1.68 (d, J=9.6 Hz, 2H), 1.30-1.17 (m, 9H), 0.89 (t, J=6.8 Hz, CH3); 13C NMR (CD3OD) δ 172.7, 140.1, 138.5, 128.9, 125.1, 124.9, 117.0, 57.0, 55.0, 41.3, 37.3, 36.8, 33.1, 30.1, 25.8, 25.6, 23.9, 21.6, 14.4; HPLC-MS (ammonium acetate) [M+H]+=343.37.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Cl[CH2:10][C:11]1[N:15]=[CH:14][O:13][N:12]=1.C(N(CC)CC)C.O>C1COCC1>[O:13]1[CH:14]=[N:15][C:11]([CH2:10][S:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)=[N:12]1
Reactant: ClCc1ncon1
Reactant: Nc1ccc(S)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(SCc2ncon2)cc1
Yield: 82.2 %

Procedure:
A solution of 4-aminothiophenol (1.0 g), 3-chloromethyl-1,2,4-oxadiazole (1.0 g) and triethylamine (1.1 ml) in THF (10 ml) was stirred at room temperature for 18 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:3→1:2), to give 4-(1,2,4-oxadiazol-3-ylmethylthio)aniline (1.36 g) as pale yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.CCN(CC)CC.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([O:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)(=[O:25])=[O:24]
Reactant: CC(C)OC(=O)N1CCC(CO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.7 %

Procedure:
A solution of 1-methylethyl 4-(hydroxymethyl)-1-piperidinecarboxylate (prepared as in Example 9, Step 1, 0.5 g, 2.36 mmol) in CH2Cl2 (5 mL) was cooled to 0° C. Et3N (0.5 mL, 3.54 mmol) was added, followed by dropwise addition of methanesulfonyl chloride (0.2 mL, 2.60 mmol). The reaction mixture was allowed to warm up to ambient temperature and stirred for 1 h and diluted with CH2Cl2. The mixture was washed with water, saturated aqueous NaHCO3, brine and dried over Na2SO4, filtered, and the filtrate was concentrated to give 0.71 g of the crude 1-methylethyl 4-{[(methylsulfonyl)oxy]methyl}-1-piperidinecarboxylate as a light brown solid, which was used without further purification. 1H NMR (400 MHz, CDCl3): δ 4.90 (septet, 1H, J=6.2 Hz), 4.25-4.15 (m, 2H), 4.06 (d, 2H, J=6.6 Hz), 3.01 (s, 3H), 2.80-2.65 (m, 2H), 2.00-1.85 (m, 1H), 1.80-1.65 (m, 2H), 1.30-1.15 (m, 8H).
Reaction SMILES: S(O)(O)(=O)=O.[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][NH:13][C:14]([NH2:16])=[NH:15].[CH3:17][O-:18].[Na+].[CH3:20]O>C(O)C>[C:17]([NH:15][C:14]([NH:13][CH2:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][N:6]=1)=[NH:16])(=[O:18])[CH3:20]
Reactant: C[O-]
Reactant: N=C(N)NCc1ccccn1
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: CC(=O)NC(=N)NCc1ccccn1
Reaction time: 2 h

Procedure:
19.92 g of 1-(2-pyridylmethyl) guanidine sulfate and 5.94 g of sodium methoxide are added to 100 ml of methanol. The mixture is stirred for 21/2 hrs. at RT and filtered. The resulting solid is washed with methanol, and the solvent evaporated in vacuo, yielding a red solid. Absolute ethanol is added to the red solid in two stages and the resulting mixture is filtered. The filtered solid is washed with absolute ethanol and the solvent evaporated in vacuo yielding the guanidine as a solid. The guanidine is dissolved in 150 ml of boiling ethyl acetate and the solution separated from any residue and concentrated under N2. The concentrated solution is heated in a sealed stainless steel bomb at 100° C. for one day. The reaction mixture is cooled, diluted with ethyl acetate containing a trace of methanol, heated, concentrated and cooled, resulting in the formation of a precipitate. The precipitate is washed with ethyl acetate and dried in vacuo yielding the desired acetyl guanidine as a white powder, M.P. 148°-150° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C(Cl)Cl.CCOC(C)=O>[C:24]([O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CC(c2ccccc2)c2ccc(O)cc21
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccc2c(c1)C(=O)CC2c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
2,3-Dihydro-6-hydroxy-3-phenylinden-1-one (22.5 g, 100 mmol) obtained in Step 2 was placed into a flask and dissolved in CH2Cl2 (300 mL). To the solution at 0° C., pyridine (40 mL, 5.0 eq) and acetic anhydride (47 mL, 5.0 eq) were added dropwise. The mixture was stirred for 8 h at room temperature. The reaction mixture was diluted with EtOAc and washed with H2O. The organic layer was dried over MgSO4 and concentrated in vacuo to give the desired product (20.0 g, 77%).
Reaction SMILES: O=[C:2]1[CH:7]=[CH:6][NH:5][C:4]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[N:3]1.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1ccc(Nc2nc(=O)cc[nH]2)cc1
Product: N#Cc1ccc(Nc2nccc(Cl)n2)cc1
Temperature: 25 °C

Procedure:
A mixture of 4-[(1,4-dihydro-4-oxo-2-pyrimidinyl)amino]benzonitrile (0.12 mol) in POCl3 (90 ml) was stirred and refluxed under Argon for 20 minutes. The reaction mixture was slowly poured onto 750 ml ice/water, and the solid was separated by filtration. The solid was suspended in 500 ml water, and the pH of the suspension was adjusted to neutral by adding a 20% NaOH solution. The solid was again separated by filtration, suspended in 200 ml 2-propanone, and 1000 ml CH2Cl2 was added. The mixture was heated until all solid had dissolved. After cooling to room temperature, the aqueous layer was separated, and the organic layer was dried. During removal of the drying agent by filtration, a white solid formed in the filtrate. Further cooling of the filtrate in the freezer, followed by filtration, yielded 21.38 g (77.2%) of [4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile (interm. 5).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH2:7][C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][C:9]=2[C:17]([O:19][CH3:20])=[O:18])=[CH:4][CH:3]=1.O1CCCC1.B>CO>[F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH2:7][C:8]2[CH:16]=[CH:15][C:11]([CH2:12][OH:13])=[CH:10][C:9]=2[C:17]([O:19][CH3:20])=[O:18])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(C(=O)O)ccc1CCc1ccc(F)cc1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(CO)ccc1CCc1ccc(F)cc1
Temperature: 25 °C
Yield: 82.8 %

Procedure:
A mixture of 4-(4-fluorophenethyl)-3-methoxycarbonylbenzoic acid (16.5 g, 54.88 mmol), tetrahydrofuran (500 ml) and borane in tetrahydrofuran (1 M. complex, 218 ml, 218 mmol) was stirred under an inert atmosphere at reflux for 6 hours. The reaction was cooled to ambient temperature and methanol (1 L) was added. It was then evaporated to dryness to give a dark oil which was purified by flash chromatography using iso-hexane/ethyl acetate (1:1) as eluant to give as a clear gum methyl 2-(4-fluorophenethyl)-5-hydroxymethylbenzoate (13.10 g).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:8]1[CH2:12][CH2:11][C@H:10]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)=[O:14])[CH2:9]1.N1CC(C(NC2C=CC(OC3CCN(C(OC(C)(C)C)=O)CC3)=CC=2)=O)[CH2:36]1>>[CH3:36][C:3]1[C:2]([N:8]2[CH2:12][CH2:11][C@H:10]([C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([CH:22]4[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:27]4)=[CH:20][CH:21]=3)=[O:14])[CH2:9]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Brc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC(=O)C3CNC3)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)[C@H]3CCNC3)cc2)CC1
Product: Cc1ncccc1N1CC[C@H](C(=O)Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)C1

Procedure:
The title compound was prepared as described in Example 1C, substituting 3-bromo-2-methylpyridine for 3-bromopyridine and (S)-tert-butyl 4-(4-(pyrrolidine-3-carboxamido)phenyl)piperidine-1-carboxylate for tert-butyl 4-(4-(azetidine-3-carboxamido)phenoxy)piperidine-1-carboxylate.
Reaction SMILES: [Br:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([O:6][C:7]2[N:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=O)=[C:4]([Cl:19])[CH:3]=1.C(N(C(C)C)C(C)C)C.[I-].ClC1C=CC=C[N+]=1C.[NH:38]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:41][CH2:40][CH2:39]1>ClCCl>[Br:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([O:6][C:7]2[C:8]([C:9]([N:38]3[C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[CH2:41][CH2:40][CH2:39]3)=[O:11])=[CH:12][CH:13]=[CH:14][N:15]=2)=[C:4]([Cl:19])[CH:3]=1
Reactant: c1ccc2c(c1)CCCN2
Reactant: O=C(O)c1cccnc1Oc1cc(Cl)c(Br)cc1Cl
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1cccnc1Oc1cc(Cl)c(Br)cc1Cl)N1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
To a solution of 2-(4-bromo-2,5-dichloro-phenoxy)-nicotinic acid (50 mg, 0.14 mmol, 1.0 equiv; Example 163, Step 1) in anhydrous dichloromethane (1.5 mL) was added N-ethyldiisopropylamine (152 mg, 200 μL, 1.18 mmol, 8.4 equiv; [CAS RN 7087-68-5]) and 2-chloro-1-methylpyridinium iodide (42 mg, 0.17 mmol, 1.2 equiv; [CAS RN 14338-32-0]) and the reaction mixture stirred at rt. After 1 h, 1,2,3,4-tetrahydro-quinoline (22 mg, 21 μL, 0.17 mmol, 1.2 equiv; [CAS RN 635-46-1]) was added and stirring at rt continued over night. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 41 mg (61%) of the title compound as a white powder. MS (ISP): 476.9 [M+H]+.
Reaction SMILES: [CH:1]12[NH:9][CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH:3]([NH:10][C:11]([C:13]1[N:17]3[CH:18]=[CH:19][CH:20]=[C:21]([O:22][CH2:23][C:24]4[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=4[F:31])[C:16]3=[N:15][C:14]=1[CH3:32])=[O:12])[CH2:2]2.[CH2:33]1COC[CH2:34]1.[H-].[Na+].ICC>C(OCC)(=O)C>[F:30][C:29]1[CH:28]=[CH:27][CH:26]=[C:25]([F:31])[C:24]=1[CH2:23][O:22][C:21]1[C:16]2[N:17]([C:13]([C:11]([NH:10][CH:3]3[CH2:2][CH:1]4[N:9]([CH2:33][CH3:34])[CH:5]([CH2:6][CH2:7][CH2:8]4)[CH2:4]3)=[O:12])=[C:14]([CH3:32])[N:15]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC1CC2CCCC(C1)N2
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CCI
Solvent: CCOC(C)=O
Product: CCN1C2CCCC1CC(NC(=O)c1c(C)nc3c(OCc4c(F)cccc4F)cccn13)C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
60 mg of N-(9-azabicyclo[3.3.1]non-3-yl)-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]-pyridine-3-carboxamide (Example 27, 0.14 mmol) were initially charged in 1.4 ml of abs. THF, 4.2 mg of sodium hydride (purity 95%, 0.16 mmol) were added and the mixture was stirred at RT for 15 min. 0.011 ml of iodoethane (0.14 mmol) were then added dropwise, and the mixture was stirred at RT overnight. The reaction mixture was diluted with ethyl acetate and washed twice with water. The organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and filtered. The filtrate was concentrated and dried. The crude product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product-containing fractions were concentrated and the residue taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulphate and filtered and the filtrate was concentrated and lyophilized. This gave 35 mg of the title compound (55% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([C:18]2[C:22]([Br:23])=[CH:21][N:20]([CH3:24])[N:19]=2)[CH:15]=[CH:16][CH:17]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:23][C:22]1[C:18]([C:14]2[CH:13]=[C:12]([NH:11][C:6]([C:5]3[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:7])[CH:17]=[CH:16][CH:15]=2)=[N:19][N:20]([CH3:24])[CH:21]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Cn1cc(Br)c(-c2cccc(N)c2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(Br)c(-c2cccc(NC(=O)c3ccc(Cl)cc3)c2)n1
Reaction time: 16 h
Yield: 73.6 %

Procedure:
To 4-chlorobenzoyl chloride (15 mg, 0.08 mmol) in CH2Cl2 (1 mL) was added dropwise a solution of 3-(3-aminophenyl)4-bromo-1-methylpyrazole (21 mg, 0.08 mmol) and triethylamine (12 μL, 0.08 mmol) in CH2Cl2 (0.5 mL). The mixture was stirred for 16 h and concentrated. Chromatography on flash silica (50% EtOAc/hexane) gave the title compound as a colourless solid (23 mg, 72%), m.p. 184.4-184.8° C. (EtOAc/hexane).