Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.[Cl:11][C:12]1[CH:17]=[N:16][CH:15]=[C:14](Cl)[N:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.ClCCl.CO>[Cl:11][C:12]1[N:13]=[C:14]([N:3]2[C:4]3[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=3[N:1]=[CH:2]2)[CH:15]=[N:16][CH:17]=1
Reactant: Clc1cncc(Cl)n1
Reactant: Nc1ccc2[nH]cnc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Nc1ccc2ncn(-c3cncc(Cl)n3)c2c1
Temperature: 25 °C
Yield: 27 %

Procedure:
A mixture of 1H-benzimidazol-5-amine (0.8 g, 6 mmol), 2,6-dichloropyrazine (0.9 g, 6.0 mmol) and cesium carbonate (2.73 g, 8.4 mmol) in DMF (6 mL) was heated under N2 for 6 h. Upon cooling to RT the mixture was diluted with dichloromethane-methanol (6:1, 30 mL) and filtered and the filtrate concentrated in vacuo. The residue was chromatographed using CH2Cl2-MeOH (98:2-94:6) to give from the less polar fractions 1-(6-chloropyrazin-2-yl)-1H-benzimidazol-6-amine (398 mg):
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:14](Cl)(Cl)([O:16]C)=O.N1C=CC=C[CH:21]=1>>[CH2:1]([O:8][CH:9]1[CH2:10][O:11][P:14](=[O:16])([CH3:21])[O:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccncc1
Reactant: OCC(CO)OCc1ccccc1
Reactant: COP(=O)(Cl)Cl
Product: CP1(=O)OCC(OCc2ccccc2)CO1
Temperature: 20 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
A solution 0.5 g (2.75 mmol) of 2-benzyloxy-1,3-propanediol in 3.0 mL of pyridine was stirred at 0° C. under N2 as 0.37 g (2.5 mmol) of methyl dichlorophosphate was added dropwise over 15 mins to keep the solution under 10° C. The cold bath was removed and the reaction mixture was stirred overnight at 20° C.(~14 h). The mixture was filtered, and washed with benzene (10 mL), and the filtrate was evaporated. The residue was dissolved in benzene: CH2Cl2 (1:1, 20 mL), washed with H2O (10 mL), saturated NaHCO3 (10 mL), saturated NaCl (10 mL) and dried over magnesium sulfate. Evaporation afforded 0.26 g (40%) of 5-benzyloxy-2-methyl-1,3,2-dioxaphosphorinane-2-oxide.
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[CH:19][C:4]=1[O:5][CH:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[CH2:7][CH2:8][C:9]([OH:11])=[O:10])#[N:2].[CH:31]1([NH:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>C(OCC)C>[C:1]([C:3]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[CH:19][C:4]=1[O:5][CH:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[CH2:7][CH2:8][C:9]([O-:11])=[O:10])#[N:2].[CH:38]1([NH2+:37][CH:31]2[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]2)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]1
Reactant: C1CCC(NC2CCCCC2)CC1
Reactant: Cc1ccccc1C(CCC(=O)O)Oc1cc(OCc2cccnc2)ccc1C#N
Solvent: CCOCC
Product: C1CCC([NH2+]C2CCCCC2)CC1
Product: Cc1ccccc1C(CCC(=O)[O-])Oc1cc(OCc2cccnc2)ccc1C#N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4-[2-cyano-5-(3-pyridylmethoxy)-phenoxy]-4-(2-methylphenyl)butanoic acid, thought to be the (R)-enantiomer, (50 mg), dicyclohexylamine (0.5 mL) and diethyl ether (10 mL) is stirred at ambient temperature for 18 hours. The resulting precipitate is collected and washed with diethyl ether, to give dicyclohexylammonium 4-[2-cyano-5-(3-pyridylmethoxy)phenoxy]-4-(2-methylphenyl)butanoate, thought to be the (R)-enantiomer, (30 mg) in the form of a white solid, m.p. 92-93° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:22])[CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[OH:10].[N+:23]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=[O:30])([O-:25])=[O:24].C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[Cl:21][C:6]1[CH:5]=[N+:4]([O-:22])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@H:9]([O:10][C:29](=[O:30])[C:28]1[CH:32]=[CH:33][CH:34]=[C:26]([N+:23]([O-:25])=[O:24])[CH:27]=1)[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1
Reactant: COc1ccc([C@@H](O)Cc2c(Cl)c[n+]([O-])cc2Cl)cc1OC
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2cccc([N+](=O)[O-])c2)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.8 %

Procedure:
To a stirred solution of (1S)-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethanol (0.500 g, 1.45 mmol) and 3-nitrobenzoic acid (0.242 g, 1.45 mmol) in dichloromethane (15.0 mL) was added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.560 g, 2.91 mmol) and N,N-dimethylpyridin-4-amine (0.089 g, 0.73 mmol). The reaction was stirred at room temperature for 16 hours. The reaction was quenched by addition of saturated aqueous sodium bicarbonate solution (25.0 mL) and extracted with dichloromethane (×2). The combined organic extracts were dried on magnesium sulphate, filtered and the solvent removed in vacuo to afford a yellow oil. The crude material was purified by silica gel chromatography eluting sequentially with iso-hexane, ethyl acetate and 10% methanol in ethyl acetate to afford the title compound as a yellow solid (0.642 g, 90% yield).
Reaction SMILES: [OH:1][C:2]1[N:6]([CH:7](O)[CH3:8])[N:5]=[C:4]([CH3:10])[CH:3]=1.[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH:16]=O.CC([OH:22])CC>>[OH:22][CH2:8][CH2:7][N:6]1[C:2](=[O:1])[C:3](=[CH:16][C:12]2[S:11][CH:15]=[CH:14][CH:13]=2)[C:4]([CH3:10])=[N:5]1
Reactant: CCC(C)O
Reactant: O=Cc1cccs1
Reactant: Cc1cc(O)n(C(C)O)n1
Product: CC1=NN(CCO)C(=O)C1=Cc1cccs1

Procedure:
2.85 g of 5-hydroxy-1-hydroxyethyl-3-methyl-1H-pyrazole and 2.25 g of thiophene-2-carboxaldehyde in 30 mL of 2-butanol were allowed to reflux for 7 hours. Upon cooling, a vivid orange-colored dye crystallized.
Reaction SMILES: COC(=O)[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](OC)=[O:13])Br.COC(=O)C(C1C=CC(Cl)=CC=1C(OC)=O)Br.[F:34][C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[C:37]([SH:43])[CH:36]=1.OC1C=CC=CC=1C#N>>[OH:13][C:12]1[C:7]2[C:6](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]2[S:43][C:37]3[CH:36]=[C:35]([F:34])[CH:42]=[CH:41][C:38]=3[C:39]=2[N:40]=1
Reactant: N#Cc1ccc(F)cc1S
Reactant: COC(=O)c1ccccc1C(Br)C(=O)OC
Agent: COC(=O)c1cc(Cl)ccc1C(Br)C(=O)OC
Agent: N#Cc1ccccc1O
Product: Oc1nc2c3ccc(F)cc3sc2c2ccccc12

Procedure:
The procedure was similar to step S19B, while the starting material was 29A in stead of 19A, and used 4-fluoro-2-mercapto-benzonitrile in stead of 2-hydroxy-benzonitrile.
Reaction SMILES: CO[C:3]([CH:5]1[C:10]2[S:11][CH:12]=[CH:13][C:9]=2[S:8](=[O:15])(=[O:14])[N:7]([CH3:16])[C:6]1=[O:17])=[O:4].[NH2:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1>C1(C)C(C)=CC=CC=1>[CH3:16][N:7]1[C:6](=[O:17])[CH:5]([C:3](=[O:4])[NH:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)[C:10]2[S:11][CH:12]=[CH:13][C:9]=2[S:8]1(=[O:14])=[O:15]
Reactant: Nc1nccs1
Reactant: COC(=O)C1C(=O)N(C)S(=O)(=O)c2ccsc21
Solvent: Cc1ccccc1C
Product: CN1C(=O)C(C(=O)Nc2nccs2)c2sccc2S1(=O)=O

Procedure:
0.15 G. of 3,4-dihydro-4-methoxycarbonyl-2-methyl-3-oxo-2H-thieno[2,3-e]1,2-thiazine 1,1-dioxide and 0.071 g. of 2-aminothiazole are dissolved in 30 ml. of absolute xylene and the solution is heated for half an hour under the reflux. After cooling, the crystals are removed by filtration, recrystallized from glacial acetic acid, and 3,4-dihydro-2-methyl-3-oxo-4-(2-thiazolyl-carbamoyl)-2H-thieno[2,3-e]1,2-thiazine 1,1-dioxide, melting point 236° C. to 238° C. (decomposition), is obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[S:7][C:8]([CH:11]=[O:12])=[CH:9][N:10]=1.[CH3:13][C@H:14]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:15](O)=[O:16].ON1C2N=CC=CC=2N=N1.CN1CCOCC1.C(Cl)CCl>C(Cl)Cl>[CH:11]([C:8]1[S:7][C:6]([NH:5][CH2:4][CH2:3][CH2:2][NH:1][C:15](=[O:16])[C@@H:14]([NH:18][C:19](=[O:20])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH3:13])=[N:10][CH:9]=1)=[O:12]
Reactant: NCCCNc1ncc(C=O)s1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCCCNc1ncc(C=O)s1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 76.2 %

Procedure:
Following the procedure as described in Example 24, except using the material from Example 68 (254 mg, 0.984 mmol), N-alpha-t-BOC-L-Alanine (201 mg, 1.06 mmol), 1-hydroxy-7-azabenzotriazole (70.0 mg, 0.514 mmol), CH2Cl2 (15 mL), N-methylmorpholine (224 μlit, 2.04 mmol), and EDC (229 mg, 1.21 mmol), and stirring at room temp for 45 min., 267.3 mg (76%) of the title compound is obtained as a yellow solid. Purification is done by BIOTAGE® Silica gel chromatography on a 25 g Thompson Single Step silica cartridge using a linear gradient from 100% CH2Cl2 to 100% EtOAc, over 8.5 column volumes, with a hold at 100% EtOAc for 15 column volumes. LC/MS (Condition A): ret. T=2.54 min, (M+H)+ 357.20.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[CH:12][N:11]=[C:10]([S:21][CH3:22])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:24]N(C)C=O.CI.O>[Cl-].[Na+].O.C(Cl)Cl>[C:1]([O:5][C:6](=[O:23])[N:7]([C:8]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[CH:12][N:11]=[C:10]([S:21][CH3:22])[N:9]=1)[CH3:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1ncc(-c2ccccc2Cl)c(NC(=O)OC(C)(C)C)n1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CI
Product: CSc1ncc(-c2ccccc2Cl)c(N(C)C(=O)OC(C)(C)C)n1
Reaction time: 1 h
Yield: 96.2 %

Procedure:
To a solution of 2.0 g (5.68 mmol) [5-(2-chloro-phenyl)-2-methylsulfanyl-pyrimidin-4-yl]-carbamic acid tert.-butyl ester in 30 ml N,N-dimethylformamide 0.34 g (8.53 mmol) sodiumhydride (60% dispersion in mineraloil) was added and the reaction mixture stirred for 1 hr. After the addition of 0.56 ml (9.09 mmol) methyl iodide at 0°, the reaction mixture was stirred for 3 hrs. The reaction mixture was distributed between 75 ml H2O, 75 ml brine and 75 ml CH2Cl2. The phases were separated, the aqueous layer washed twice with 75 ml CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/ethyl acetate 19:1) to give 2.0 g (96%) [5-(2-chloro-phenyl)-2-methylsulfanyl-pyrimidin-4-yl]-methyl-carbamic acid tert.-butyl ester as a pale yellow oil, MS (EI): 365 (M+).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12].C(Cl)Cl.[C:17](OC(=O)C)(=[O:19])[CH3:18].C(O)(=O)C1C=CC=CC=1>C(N(CC)CC)C.O1CCCC1>[C:17]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12])(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)c1cc(C(=O)O)ccc1O
Agent: O=C(O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)Oc1ccc(C(=O)O)cc1C(C)=O

Procedure:
To a suspension of 2.3 g. of 4-hydroxy-3-acetylbenzoic acid in 100 ml. of methylene chloride and 100 ml. of tetrahydrofuran, a mixture of 1.5 g. of triethylamine, 1.6 g. of 4-N-dimethylaminopyridine and 1.5 g. of acetic anhydride is added. The reaction mixture is heated at 50° for one hour. The solution is extracted with ethyl acetate, the organic layer washed with water and dilute hydrochloric acid and evaporated to dryness to yield 2.1 g. of the benzoic acid product. NMR in CDCl3
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[C:12]([Cl:17])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([N:20]1[CH2:25][CH2:24][CH2:23][C:22](=[O:26])[CH2:21]1)[CH3:19]>>[CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[C:12]([Cl:17])[C:11]=2[N:10]=[C:9]1[C:22]1([OH:26])[CH2:23][CH2:24][CH2:25][N:20]([CH2:18][CH3:19])[CH2:21]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1nccc2c1ncn2Cc1ccccc1
Reactant: CCN1CCCC(=O)C1
Product: CCN1CCCC(O)(c2nc3c(Cl)nccc3n2Cc2ccccc2)C1

Procedure:
Following the procedure of Example 13 and using 1-benzyl-4-chloro-1H-imidazo[4,5-c]pyridine (0.60 g, 2.5 mmol) and (0.36g, 2.8 mmol) of N-ethyl-3-piperidone gave the free base of the title compound which was purified by flash chromatography on silica gel eluting with EtOAc to give, after preparation of the salt, the dihydrochloride, 0.59 hydrate as an amorphous solid, 0.30 g (26%):
Reaction SMILES: [N:1]1([C:7]([C:9]2[C:10]([C:27]([F:30])([F:29])[F:28])=[N:11][C:12]([NH:15][C:16]34[CH2:25][CH:20]5[CH2:21][CH:22]([CH2:24][C:18](O)([CH2:19]5)[CH2:17]3)[CH2:23]4)=[N:13][CH:14]=2)=[O:8])[CH2:6][CH2:5]OC[CH2:2]1.C(N(S(F)(F)[F:37])CC)C.[C:40](=[O:43])([O-])O.[Na+]>ClCCl>[F:37][C:18]12[CH2:19][CH:20]3[CH2:21][CH:22]([CH2:23][C:16]([NH:15][C:12]4[N:11]=[C:10]([C:27]([F:30])([F:29])[F:28])[C:9]([C:7]([N:1]5[CH2:2][CH2:40][O:43][CH2:5][CH2:6]5)=[O:8])=[CH:14][N:13]=4)([CH2:25]3)[CH2:17]1)[CH2:24]2
Reactant: O=C(c1cnc(NC23CC4CC(CC(O)(C4)C2)C3)nc1C(F)(F)F)N1CCOCC1
Reactant: O=C([O-])O
Reactant: CCN(CC)S(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1cnc(NC23CC4CC(CC(F)(C4)C2)C3)nc1C(F)(F)F)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 3-{[5-(morpholin-4-ylcarbonyl)-4-(trifluoromethyl)pyrimidin-2-yl]amino}adamantan-1-ol (150 mg) and dichloromethane (3 mL) was added diethylaminosulfur trifluoride (70 μL) under ice-cooling, followed by stirring at room temperature for 30 minutes. The reaction mixture was alkalified by adding a saturated aqueous sodium hydrogen carbonate solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain N-(3-fluoroadamantan-1-yl)-5-(morpholin-4-ylcarbonyl)-4-(trifluoromethyl)pyrimidin-2-amine (115 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([CH2:12][C:13]([OH:15])=[O:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl[Si](C)(C)[CH3:18]>CO>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([CH2:12][C:13]([O:15][CH3:18])=[O:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1ccc2cccc(CC(=O)O)c2n1
Reactant: C[Si](C)(C)Cl
Solvent: CO
Product: COC(=O)Cc1cccc2ccc(C)nc12
Temperature: 25 °C
Yield: 87 %

Procedure:
To a solution of 2-(2-methylquinolin-8-yl)acetic acid (1.45 g, 7.21 mmol) in dry MeOH (100 mL) was added chlorotrimethylsilane (1.82 mL, 14.4 mmol) dropwise at 0° C. After addition, the reaction mixture was stirred at reflux for 2 hours. After cooling to ambient temperature, the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate (50 mL) and saturated sodium bicarbonate (20 mL). The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (5:1 hexane/ethyl acetate) to give methyl 2-(2-methylquinolin-8-yl)acetate (1.35 g, 87.0%) as an oil.
Reaction SMILES: C[O:2][C:3](=[O:18])[C@@H:4]1[CH2:8][C@H:7]([F:9])[CH2:6][N:5]1[C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Li+]>O1CCCC1.O.O>[C:10]([N:5]1[CH2:6][C@@H:7]([F:9])[CH2:8][C@H:4]1[C:3]([OH:18])=[O:2])(=[O:17])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)[C@@H]1C[C@H](F)CN1C(=O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1C[C@H](F)CN1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Part A (cis)-1-benzoyl-4-fluoro-L-proline methyl ester (3.7 g, 14.74 mmole) in tetrahydrofuran-water (37 ml-7 ml) was added 31 ml of a 1N solution of lithium hydroxide in water. The reaction was stirred at room temperature for 2 hours. The tetrahydrofuran was evaporated, the pH of the residual aqueous solution was adjusted to 8 and extracted with ethyl acetate. The organic extracts were discarded. The aqueous phase was acidified to pH 2 with concentrated HCl and extracted with dichloromethane. The organic extracts were washed with brine and dried (sodium sulfate). The organic solution was filtered and concentrated to 2.9 g of solid.
Reaction SMILES: Cl[CH2:2][CH2:3][C@H:4]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[Cl:13].[I-:19].[Na+]>CC(C)=O>[Cl:13][C:7]1[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:6]=1[O:5][C@@H:4]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)[CH2:3][CH2:2][I:19]
Reactant: ClCC[C@@H](Oc1cc(Cl)ccc1Cl)c1cccs1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Clc1ccc(Cl)c(O[C@H](CCI)c2cccs2)c1
Yield: 73.3 %

Procedure:
A solution of the product from step (a) (788 mg) and sodium iodide (4.5 g) in acetone (30 ml) was heated under reflux for 18 h. The solvent was removed in vacuo, water added and the mixture was extracted twice with ether. The organic layers were dried (magnesium sulphate), evaporated and purified by chromatography on silica eluting with petrol—diethyl ether (19:1) to give the title compound as a pale yellow oil (742 mg).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]([NH:9][CH2:10][CH2:11][NH:12]C(=O)OC(C)(C)C)=[O:8])[C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.FC(F)(F)C(O)=O.C(Cl)[Cl:34]>>[ClH:34].[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]([NH:9][CH2:10][CH2:11][NH2:12])=[O:8])[C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1noc(N)c1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: NCCNC(=O)c1noc(N)c1-c1ccccc1
Yield: 73.5 %

Procedure:
1.5 g (4.33 mmol) of t-butyl [2-(5-amino-4-phenyl-3-isoxazolecarboxamido)ethyl]carbamate in 5 ml of methylene chloride were stirred at room temperature for 16 hours with 1.7 ml of trifluoroacetic acid. Thereafter, the reaction mixture was evaporated under reduced pressure: the residue was dissolved in ethanol, whereupon the solution was treated with 2 ml of ethanolic hydrochloric acid (17.5% w/v) and again evaporated. Recrystallization of the residue from methanol/ether yielded 0.9 g (73.5%) of 5-amino-N-(2-aminoethyl)-4-phenyl-3-isoxazolecarboxamide hydrochloride as white crystals, melting point 187°-189°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]3[N:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:15][CH2:14]2)[CH:8]=1)([O-])=O.[BH4-].[Na+].O>C(O)C.O.O.O.O.O.O.[Ni](Cl)Cl>[NH2:1][C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][N:16]([C:19]3[N:20]=[CH:21][CH:22]=[CH:23][N:24]=3)[CH2:17][CH2:18]2)[CH:8]=1
Reactant: O=[N+]([O-])c1cnn(CCCCN2CCN(c3ncccn3)CC2)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1cnn(CCCCN2CCN(c3ncccn3)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
10.2 g (43.2 mmol) of nickel(II) chloride hexahydrate are added to a solution of 7.2 g (21 mmol) of 4-nitro-1-{4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl}-1H-pyrazole, Example no. 7, in 60 ml of ethanol with vigorous stirring. The mixture is cooled in an ice bath and 10.2 g (81 mmol) of sodium borohydride are added slowly. The mixture is left stirring for 1 hour and, after 1 hour at room temperature, water is added, the mixture is evaporated under vacuum, the residue is acidified with concentrated hydrochloric acid and the resulting mixture is filtered, alkalinised with ammonia solution and extracted with ethyl ether. 4.4 g of 4-amino-1-{4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl}-1H-pyrazole are thereby obtained in liquid form.
Reaction SMILES: [CH:1]1([C:5]2[C:13]3[C:8](=[N:9][CH:10]=[C:11]([NH:14][C:15](=[O:31])[C:16]4[C:21]([F:22])=[CH:20][CH:19]=[C:18]([NH:23][S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])[C:17]=4[F:30])[CH:12]=3)[N:7](S(C3C=CC=CC=3)(=O)=O)[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+]>CO.CCOC(C)=O>[CH:1]1([C:5]2[C:13]3[C:8](=[N:9][CH:10]=[C:11]([NH:14][C:15](=[O:31])[C:16]4[C:21]([F:22])=[CH:20][CH:19]=[C:18]([NH:23][S:24]([CH2:27][CH2:28][CH3:29])(=[O:25])=[O:26])[C:17]=4[F:30])[CH:12]=3)[NH:7][CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3c(c2)c(C2CCC2)cn3S(=O)(=O)c2ccccc2)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(C4CCC4)c3c2)c1F
Temperature: 60 °C
Yield: 15 %

Procedure:
N-(3-Cyclobutyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide was dissolved in methanol (1 mL), and aqueous 2M potassium carbonate (1 mL) was added. The mixture was warmed to 60° C. for 1 hour. The mixture was then diluted with EtOAc, washed with 10% aqueous citric acid (1×), water (1×), dried over sodium sulfate and concentrated. Prep TLC (2×0.5 mm plates, 7% MeOH/DCM as the eluant) afforded N-(3-cyclobutyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (15%). 1H NMR (400 MHz, DMSO-d6) δ 11.37 (br s, 1H), 10.82 (br s, 1H), 9.78 (br s, 1H), 8.31-8.38 (m, 2H), 7.49-7.58 (m, 1H), 7.20-7.34 (m, 2H), 3.62-3.71 (m, 1H), 3.07-3.14 (m, 2H), 2.30-2.41 (m, 2H), 2.14-2.22 (m, 2H), 1.97-2.08 (m, 1H), 1.85-1.94 (m, 1H), 1.71-1.81 (m, 2H), 0.96-1.02 (m, 3H); m/z (APCI-pos) M+1=449.1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[OH:10])[C:5]#[N:6].CC1C=CN=C(N)C=1C.[Br:21][C:22]1[C:23]([NH:38][C:39](=[O:46])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[N:24][C:25]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=2)=[N:26][C:27]=1Cl>CN(C)C=O>[Br:21][C:22]1[C:23]([NH:38][C:39](=[O:46])[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[N:24][C:25]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=2)=[N:26][C:27]=1[O:10][C:9]1[C:8]([CH3:11])=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1cc(C#N)cc(C)c1O
Reactant: N#Cc1ccc(Nc2nc(Cl)c(Br)c(NC(=O)c3ccccc3)n2)cc1
Agent: Cc1ccnc(N)c1C
Solvent: CN(C)C=O
Product: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc(NC(=O)c2ccccc2)c1Br
Temperature: 73 °C
Reaction time: 0.5 h

Procedure:
1300 ml of dimethylformamide was added to a RB flask, to this was added 54 g of 3,5-dimethyl-4-hydroxybenzonitrile, 51.38 g of dimethyl amino pyridine, 68.30 g of diazabicyclo undecene and 150 g of N-[5-bromo-6-chloro-2-(4-cyanophenylamino)-pyrimidin-4-yl]-benzamide at 27±3° C. The reaction mixture was heated to 73±2° C. and maintained at the same for 5 hrs. The reaction mixture was cooled to 27±3° C. and filtered. The filtrate was taken into an RB flask to which was added 300 ml of IPA and stirred for 30 mins. 3000 ml of water was taken in another RB flask and the reaction mass added. The reaction mass was heated to 47±3° C., stirred, cooled to 42±3° C. and filtered hot. The solid was washed with water and suck dried at 27±3° C. The solid was further washed with 150 ml of IPA and the wet cake was charged into a clean RB flask. To this was added 1500 ml of dimethyl formamide and heated to 47±3° C. To the reaction mass was slowly added 3000 ml of water with continued stirring, followed by cooling the reaction mass to 27±3° C. The reaction mass was filtered, and the solid was washed with water followed by IPA. The solid was then dried under vacuum to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.Cl[C:10]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11].[CH3:19][Mg]Br>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]([C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[CH:5]([CH3:19])[CH:4]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1ccncc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: COC1=CC(C)N(C(=O)Oc2ccccc2)C=C1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
A 3-L four neck round-bottom flask was purged and maintained with a nitrogen atmosphere and a solution of 4-methoxypyridine (30.0 g, 275 mmol, 1.00 equiv) in tetrahydrofuran (1.2 L) was added. The mixture was cooled to −40° C. and phenyl chloroformate (45.0 g, 287 mmol, 1.05 equiv) was added dropwise. The resulting solution was stirred for 1 h at −40° C., then methylmagnesium bromide (3M, 110 mL, 1.20 equiv) was added to the reaction mixture while maintaining the temperature at −40° C. The resulting solution was warmed slowly to 5-10° C. and stirred for 2 h, then carefully quenched with ice water (100 mL). The resulting mixture was extracted with ethyl acetate (2×1 L) and the combined organics was washed with brine (1×300 mL), dried (Na2SO4), filtered and concentrated in vacuo to yield the title compound as a light brown oil (71.0 g, >theoretical).