Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][O:8][C:9](=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C1COCC1>[CH3:7][O:8][C:9](=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:19](=[O:21])[CH3:20])=[CH:13][CH:12]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(OC(C)=O)cc1
Temperature: 44 °C
Reaction time: 1 h

Procedure:
41.5 g of K2CO3 are added to a solution of 40 g of methyl(4-hydroxyphenyl)acetate in 800 mL of anhydrous THF in a 2 L flask equipped with a magnetic stirrer, under nitrogen. 27 mL of acetic anhydride are then added at 9° C. After 1 hour of stirring at 44° C., the insoluble matter is filtered. It is washed with THF and the filtrate is concentrated to yield 53 g of expected product (white solid). The crude product is used directly for preparing the corresponding intermediate VII.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.C(N(CC)CC)C.[CH2:28]([O:30][CH2:31][C:32](Cl)=O)[CH3:29].CCOCC>C(Cl)Cl.CCO>[CH2:28]([O:30][CH2:31][C:32]1[N:12]([NH:13][C:14](=[O:15])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH3:29]
Reactant: CCOCC(=O)Cl
Reactant: CC(C)(C)OC(=O)NNc1c(N)cnc2ccccc12
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCc1nc2cnc3ccccc3c2n1NC(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 94.3 %

Procedure:
A solution of tert-butyl N′-(3-aminoquinolin-4-yl)hydrazinecarboxylate (12.15 g, 44.3 mmol) in 200 mL of anhydrous CH2Cl2 was cooled to 0° C. and treated with triethylamine (7.72 mL, 55.4 mmol) and 2-ethoxyacetyl chloride (5.70 g, 46.5 mmol) under an atmosphere of N2. After 3 h, an additional 1 mL of 2-ethoxyacetyl chloride was added. After stirring for 2 h, the reaction mixture was concentrated under reduced pressure to give a brown solid. This was dissolved in 150 mL of EtOH and treated with 18.5 mL of triethylamine, and the mixture was refluxed overnight. The reaction mixture was concentrated under reduced pressure to give a dark-red oil. The red oil was dissolved in 200 mL of CH2Cl2 and washed with H2O (2×75 mL) and brine (75 mL). The organic portion was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a red solid. The solid was treated with a minimum amount of hot Et2O and filtered to remove insoluble material. The filtrate was concentrated to give tert-butyl N-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)carbamate (14.3 g) as a tan solid.
Reaction SMILES: C([Si]1(OC(C)=C)O[C@@H:7]([C:9]([O:12]C)([CH3:11])[CH3:10])[C@H:6]([C:14](C)(OC)C)O1)C=C.[CH:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl.C(OCC)(=O)C>C1C=CC=CC=1>[CH3:10][C@:9]([OH:12])([CH2:7][CH:6]=[CH2:14])[CH2:11][C@@H:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[OH:30]
Reactant: O=Cc1ccccc1
Reactant: C=CC[Si]1(OC(=C)C)O[C@@H](C(C)(C)OC)[C@H](C(C)(C)OC)O1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: C=CC[C@](C)(O)C[C@H](O)c1ccccc1
Temperature: 40 °C
Reaction time: 48 h
Yield: 70 %

Procedure:
Asymmetric tandem aldol-allylation reaction of benzaldehyde to give (1S,3S)-3-methyl-1-phenyl-hex-5-ene-1,3-diol: To a solution of (4R,5R)-2-allyl-2-isopropenyloxy-4,5-bis-(1-methoxy-1-methyl-ethyl)-[1,3,2]dioxasilolane (0.75 mmol) in benzene (0.3 mL) was added benzaldehyde (0.50 mmol). The mixture was heated to 40° C. (oil bath) and stirred at that temperature for 48 hours. The solution was cooled and 1 M HCl (10 mL) was added followed by ethyl acetate (10 mL). The mixture was stirred for 20 min. The layers were separated and the aqueous layer was extracted with ethyl acetate (10 mL). The combined organic layers were washed with saturated aqueous NaHC03 (10 mL) and brine (10 mL), dried (Na2SO4), filtered, and concentrated. Analysis of the residue by HPLC and 1H NMR revealed a 5.5:1 mixture of diastereomers and an enantiomeric excess for the major product of 68%. The residue was purified by chromatography on silica gel to give (1S,3S)-3-methyl-1-phenyl-hex-5-ene-1,3-diol in 70% yield and in 68% ee.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:14])[O:12][CH3:13])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:18])(=O)=O>C(Cl)Cl>[C:1]([C:5]1[C:9]([Cl:18])=[C:8]([NH:10][C:11](=[O:14])[O:12][CH3:13])[O:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Nc1cc(C(C)(C)C)no1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)Nc1onc(C(C)(C)C)c1Cl
Yield: 102.5 %

Procedure:
To a solution of methyl 3-t-butyl-5-isoxazolylcarbamate (2.56 g) in methylene chloride (13 ml), sulfuryl chloride (1.81 g) is added dropwise, and the resultant mixture is refluxed for 2 hours. The reaction mixture is evaporated to remove the solvent, whereby methyl 3-t-butyl-4-chloro-5-isoxazolylcarbamate (3.08 g) is obtained as an oil. IR: 1748, 1642 cm-1 (CC14).
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[C:9]([CH3:10])=[N:8][CH:7]=[CH:6][N:5]=1.N1C=CC=CC=1.O>C(Cl)(Cl)Cl>[NH2:3][C:4]1[C:9]([CH3:10])=[N:8][C:7]([Br:1])=[CH:6][N:5]=1
Reactant: Cc1nccnc1N
Reactant: BrBr
Solvent: c1ccncc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1nc(Br)cnc1N
Reaction time: 1 h
Yield: 28 %

Procedure:
A solution of bromine (0.26 ml) in chloroform (40 ml) was added dropwise to a stirred solution of 2-amino-3-methylpyrazine (0.453 g) and pyridine (0.4 ml) in chloroform (100 ml) with shielding from sunlight, over a period of 1 hour. The reaction mixture was stirred for a further 30 minutes and then water (25 ml) was added. The organic layer was separated, dried (MgSO4) and evaporated to afford a brown oil. The oil was purified by chromatography on silica gel, eluting with dichloromethane, to give 2-amino-5-bromo-3-methylpyrazine as a white solid (0.312 g, 28%), m.p. 51°-52° C.; mass spectrum (+ve CI): 188 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH2:11])=[O:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.[CH3:12]C(OC(C)=O)=O>C(OC(OCC)OCC)C>[Br:8][C:5]1[N:4]=[C:3]2[C:2](=[N:7][CH:6]=1)[N:1]=[CH:12][NH:11][C:9]2=[O:10]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)c1nc(Br)cnc1N
Solvent: CCOC(OCC)OCC
Product: O=c1[nH]cnc2ncc(Br)nc12
Temperature: 90 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
To a solution of 3-amino-6-bromopyrazine-2-carboxamide (200 mg, 0.92 mmol) in triethoxymethane (10 mL) was added Ac2O (2 mL). The mixture was stirred at 130° C. for 1 h and 90° C. for 3 h. After being cooled to RT and extracted with EtOAc, the combined organic phases were basified to pH=8 with a.q. NaHCO3, washed with brine, dried over Na2SO4, filtered and evaporated. The crude product was purified by prep-TLC (DCM:MeOH=50:1) to give the product of 6-bromopteridin-4(3H)-one (100 mg, yield: 48%). 1H-NMR (DMSO-d6, 400 MHz) δ 8.59 (s, 1H), 7.89 (s, 1H). MS (M+H)+: 227/229.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[C:15]([O:19][C:20](=[O:31])[NH:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([CH2:28][CH:29]=O)[CH2:24][CH2:23]1)([CH3:18])([CH3:17])[CH3:16].CO.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:15]([O:19][C:20](=[O:31])[NH:21][C@H:22]1[CH2:23][CH2:24][C@H:25]([CH2:28][CH2:29][N:10]2[CH2:9][CH2:8][CH:7]([O:6][C:5]3[CH:13]=[CH:14][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:12][CH2:11]2)[CH2:26][CH2:27]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: Fc1ccc(OC2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCC(Oc3ccc(F)cc3)CC2)CC1
Reaction time: 12 h

Procedure:
A mixture of 4-(4-fluorophenoxy)piperidine (0.150 g, 0.485 mmol), trans-[4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (0.117 g, 0.48 mmol), in 1, 2 dichloroethane (3 mL) and methanol (0.500 mL) was stirred for 4 hours at room temperature. Sodium triacetoxyborohydride (0.175 g, 0.829 mmol) was added and the resulting solution was stirred for 12 hours until the TLC indicated completion of the reaction. The mixture was filtrated and concentrated to dryness and purified with column chromatography on silica gel using CH2Cl2-CH2Cl2/CH3OH (1-9:1). The product fractions were concentrated to give 0.176 g (0.45 mmol, 92.5% yield) of a light yellow solid. MS (m/e): 393.4 (M+H+).
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]([C:23]([NH:25][C@H:26]([CH2:36][OH:37])[CH2:27][NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:24])[CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])C1C=CC=CC=1>[Pd].C(O)C>[C:19]([O:18][C:16]([NH:15][CH2:14][CH2:13][CH2:12][C@@H:11]([C:23]([NH:25][C@H:26]([CH2:36][OH:37])[CH2:27][NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:24])[NH2:10])=[O:17])([CH3:20])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](CO)CNC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCC[C@H](N)C(=O)N[C@H](CO)CNC(=O)OC(C)(C)C
Reaction time: 12 h

Procedure:
40 mg of palladium on activated carbon (10%) are added to a mixture of 0.216 g (0.40 mmol) of the compound from Example 252A in 10 ml of ethanol, and the mixture is then hydrogenated under atmospheric pressure for 12 h. The reaction mixture is filtered through kieselguhr, and the filtrate is concentrated in vacuo and dried under high vacuum. The crude product is reacted without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=3)=[CH:11][C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:31][O:32][CH2:33][CH2:34]Br>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:34][CH2:33][O:32][CH3:31])[CH:14]=3)=[CH:11][C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cccc(O)c2)n(-c2cccc(Cl)c2)n1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc(-c2cccc(OCCOC)c2)n(-c2cccc(Cl)c2)n1

Procedure:
100 mg (0.292 mmol) of the compound of Example 44A are provided in 2 ml of dry acetone, 44.4 mg (0.321 mmol) of potassium carbonate and 40.6 mg (0.292 mmol) of 2-bromoethyl methyl ether are added, and the mixture is heated under reflux overnight. The reaction mixture is subsequently purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with the addition of 0.1% formic acid) and 48 mg (41% of theory) of the title compound are obtained.
Reaction SMILES: CC1(C)[O:6][CH:5](/[CH:7]=[CH:8]/[C:9]2[CH:10]=[C:11]3[C:23](=[CH:24][CH:25]=2)[C:22](=[O:26])[C:14]2[C:15]4[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=4[O:17][C:13]=2[C:12]3([CH3:28])[CH3:27])[CH2:4][O:3]1>[Pd].CO>[OH:6][CH:5]([CH2:4][OH:3])[CH2:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:23](=[CH:24][CH:25]=1)[C:22](=[O:26])[C:14]1[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[O:17][C:13]=1[C:12]2([CH3:28])[CH3:27]
Reactant: CC1(C)OCC(/C=C/c2ccc3c(c2)C(C)(C)c2oc4ccccc4c2C3=O)O1
Agent: [Pd]
Solvent: CO
Product: CC1(C)c2cc(CCC(O)CO)ccc2C(=O)c2c1oc1ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
To the MeOH solution (5 ml) of 8-[(E)-2-(2,2-dimethyl-[1,3]dioxolan-4-yl)-vinyl]-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11-one (125 mg), 10% Pd—C(25 mg) was added and the mixture was stirred overnight at room temperature under hydrogen atmosphere. The catalyst was removed by filtration. The residues obtained after concentration under reduced pressure were purified by HPLC to obtain the title compound (35 mg, 31%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:20]([C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)([CH3:22])[CH3:21].[Cl:30][C:31]1[C:36]([CH2:37]O)=[CH:35][CH:34]=[CH:33][N:32]=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Cl:30][C:31]1[C:36]([CH2:37][O:29][C:26]2[CH:27]=[CH:28][C:23]([CH:20]([CH3:22])[CH3:21])=[CH:24][CH:25]=2)=[CH:35][CH:34]=[CH:33][N:32]=1
Reactant: CC(C)c1ccc(O)cc1
Reactant: OCc1cccnc1Cl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)c1ccc(OCc2cccnc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a mixture of triphenylphosphine (2740 mg), 4-isopropylphenol (1138 mg), (2-chloropyridin-3-yl)methanol (1000 mg) and dehydrated THF (20 ml) was added DEAD (40% toluene solution, 4549 mg) at room temperature over 30 min. The reaction mixture was stirred at room temperature for 2 hr, DEAD (40% toluene solution, 919 mg) was added at room temperature, and the mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1623 mg) as an orange oil.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:15]3[C:10](=[CH:11][C:12]([NH:16]C(=O)OC(C)(C)C)=[CH:13][CH:14]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].C1(SC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[C:5]1[S:4][C:3]([C:1]#[N:2])=[N:7][C:6]=1[CH:8]=[CH:9]2
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(ccc3nc(C#N)sc32)c1
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1nc2ccc3cc(N)ccc3c2s1
Reaction time: 1 h
Yield: 94.8 %

Procedure:
To a stirred solution of tert-butyl (2-cyanonaphtho[2,1-d]thiazol-7-yl)carbamate (72 mg, 0.22 mmol) and thioanisole (0.5 mL) in 2 mL of DCM in an ice bath, 2 mL of trifluoroacetic acid was added. After 1 h, the reaction was concentrated under reduced pressure, and the product (47 mg, 94%) was isolated by silica gel chromatography eluting with 0→75% EtOAc in heptanes. 1H NMR (CD2Cl2) d 8.01 (d, 1H); 7.90 (dt, 1H); 7.76 (d, 1H); 7.09-7.16 (m, 2H).
Reaction SMILES: B([O-])=O.[Na+].[CH:5]1([CH:11]=[C:12]([N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)[C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.O>O1CCCC1>[CH:5]1(/[CH:11]=[C:12](/[N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)\[CH:13]([OH:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)C(=O)C(=CC1CCCCC1)n1cncn1
Agent: O=B[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C(O)/C(=C\C1CCCCC1)n1cncn1
Reaction time: 2 h

Procedure:
0.68 g (0.018 mol) of sodium boranate is added to a suspension of 5.2 g (0.018 mol) of S-2-(dibenzyl-hydroxymethyl)-pyrrolidine hydrochloride in 75 ml of absolute tetrahydrofuran at -30° C., with stirring. The temperature is allowed to rise gradually to 20° C. and stirring is continued at 20° C. for a further 2 hours. Thereafter, 3.15 g (0.012 mol) of the (E)-isomer of 1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pent-1-en-3-one are added dropwise and the mixture is stirred at 40° C. for 20 hours. The reaction mixture is then poured into water. The resulting mixture is extracted with ethyl acetate and the combined organic phases are concentrated under reduced pressure. The residue which remains is chromatographed with a mixture of chloroform/ethyl acetate=4:1 on silica gel. 2.1 g (67% of theory) of the (-)-antipode of (E)-1-cyclohexyl-4,4-dimethyl-3-hydroxy-2-(1,2,4-triazol-1-yl)-pent-1-ene are obtained in this manner in the form of a crystalline product.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]([F:20])([O:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14](O)=[O:15])[CH:7]([F:9])[F:8]>N1C=CC=CC=1.ClCCCl>[F:5][C:6]([F:20])([O:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([Cl:3])=[O:15])[CH:7]([F:9])[F:8]
Reactant: O=C(O)c1cccc(OC(F)(F)C(F)F)c1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCCl
Product: O=C(Cl)c1cccc(OC(F)(F)C(F)F)c1
Reaction time: 4 h
Yield: 95 %

Procedure:
203 parts by weight of thionyl chloride and 1 drop of pyridine are added to a mixture of 352 part by weight of 3-(1',1',2',2'-tetrafluoroethoxy)-benzoic acid in 900 parts by volume of 1,2-dichloroethane. After stirring the mixture for 4 hours under reflux and concentrating it under reduced pressure, 359 parts by weight (yield: 95% of theory) of 3-(1',1',2',2'-tetrafluoroethoxy)-benzoyl chloride, of nD 25 =1.4660, are obtained. The IR spectrum shows C=O bands at 1770 and 1748 cm-1, and fluoroalkoxy bands at 1225, 1190 and 1125 cm-1.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][OH:10])=[CH:6][CH:5]=1.[Na].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1.O.CCCCCC>[CH2:14]([O:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][OH:10])=[CH:6][CH:5]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OCCc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: OCCc1ccc(OCc2ccccc2)cc1
Reaction time: 0.33 h

Procedure:
NaH (1.42 g of 60% in oil, 0.036 mol) was washed 2×5 ml hexane and then suspended in tetrahydrofuran (20 ml). 4-Hydroxyphenethyl alcohol (5.0 g, 0.036 mol) was added portionwise and the mixture stirred for 20 minutes to assure complete conversion to the sodium salt. Benzyl bromide (4.2 ml, 1 equivalent) was added and the resulting mixture refluxed for 4 hours, then poured into 50 ml H2O and extracted 3×50 ml ether. The organic layers were combined, extracted 2×20 ml 1N NaOH and then 2×20 ml H2O, dried (MgSO4), stripped, and the solid residue recrystallized from ethyl acetate and cyclohexane to yield title product 4.4 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12](O)=[O:13])=[N:10][CH:11]=1.B>C1COCC1>[NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][OH:13])=[N:10][CH:11]=1
Reactant: Nc1cc(Oc2ccc(C(=O)O)nc2)ccc1F
Agent: B
Solvent: C1CCOC1
Product: Nc1cc(Oc2ccc(CO)nc2)ccc1F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 99.1 %

Procedure:
5-(3-amino-4-fluorophenoxy)picolinic acid (0.14 g, 0.56 mmol) was dissolved in THF (3 mL) and stirred at 0° C. for 5 min. 1M Borane (3.4 mL) solution was added dropwise to the reaction mixture at 0° C. over a period of 30 min. The ice bath was removed and stirring continued at RT for 7 hours. The reaction mixture was cooled in an ice bath and treated with 3M HCl (5 mL). The solution was heated for 1 h at 50° C. The solution was washed with EtOAc (2×) and the aqueous layer was cooled in an ice bath and neutralized with 3M NaOH. The solution was extracted with EtOAc (3×), the combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo to obtain (5-(3-amino-4-fluorophenoxy)pyridin-2-yl)methanol (0.13 g, 98% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.24 (d, J=2.8 Hz, 1H), 7.46 (d, J=8.8 Hz, 1H), 7.40 (dd, J=2.8, 8.4 Hz, 1H), 6.99 (dd, J=8.8, 11.2 Hz, 1H), 6.40 (dd, J=2.8, 7.6 Hz, 1H), 6.15 (dt, J=3.2, 8.8 Hz, 1H), 5.40 (t, J=5.6 Hz, 1H), 5.33 (s, 2H), 4.54 (d, J=6.0 Hz, 2H); MS (ESI) m/z: 235.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]([CH3:37])[CH:29]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([N+:15]([O-])=O)[C:12]([N:18]3[CH2:22][CH2:21][C@@H:20]([N:23]([CH3:25])[CH3:24])[CH2:19]3)=[CH:11][C:10]=2[O:26][CH3:27])=[N:6][CH:7]=1.[NH4+].[Cl-].C(Cl)Cl.CO>C(O)C.O.[Fe]>[Cl:1][C:2]1[C:3]([C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]([CH3:37])[CH:29]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([O:26][CH3:27])=[CH:11][C:12]([N:18]3[CH2:22][CH2:21][C@@H:20]([N:23]([CH3:25])[CH3:24])[CH2:19]3)=[C:13]([NH2:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: COc1cc(N2CC[C@@H](N(C)C)C2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: COc1cc(N2CC[C@@H](N(C)C)C2)c(N)cc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Reaction time: 0.25 h
Yield: 32.7 %

Procedure:
A mixture of 5-chloro-N-{4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl}-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 86, 747 mg, 1.43 mmol), iron (479 mg, 8.59 mmol) and NH4Cl (53.6 mg, 1.00 mmol) in ethanol (48 mL) and water (16 mL) was heated at reflux for 3 h. The mixture was then cooled and concentrated in vacuo to give a thick slurry. CH2Cl2 (100 mL) and CH3OH (10 mL) were then added and the mixture was stirred for 0.25 h and then filtered. The filter cake was washed with further CH2Cl2 and MeOH and the combined organics were dried (MgSO4) and concentrated in vacuo. Purification by FCC (split into two batches), eluting with 1-9% methanolic ammonia in CH2Cl2 gave the title compound (230 mg, 33%) as a yellow gum which crystallised on standing, and (2nd batch) more of the title compound (329 mg, 47%) as a yellow gum; 1H NMR: (CDCl3) 1.87 (1H, ddt), 2.13 (1H, dtd), 2.29 (6H, s), 2.86 (1H, dq), 2.98-3.09 (2H, m), 3.20 (2H, dd), 3.66 (2H, s), 3.84 (3H, s), 3.88 (3H, s), 6.70 (1H, s), 7.25-7.35 (2H, m), 7.38 (1H, dd), 7.61 (1H, s), 8.10 (1H, s), 8.19 (1H, d), 8.32 (1H, s), 8.66 (1H, dd); m/z: ES+ MH+ 492.27.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[CH:16]=[C:15]([NH:17][CH:18]([CH3:20])[CH3:19])[C:14]([C:21]4[O:22][C:23]([NH:26][CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[N:24][N:25]=4)=[CH:13][N:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C1C[O:36][CH2:35][CH2:34]1.CCN(C(C)C)C(C)C.C(Cl)(=O)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:12]=[CH:13][C:14]([C:21]4[O:22][C:23]([NH:26][CH:27]5[CH2:32][CH2:31][N:30]([C:35](=[O:36])[CH3:34])[CH2:29][CH2:28]5)=[N:24][N:25]=4)=[C:15]([NH:17][CH:18]([CH3:20])[CH3:19])[CH:16]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1-c1nnc(NC2CCNCC2)o1
Reactant: C1CCOC1
Agent: CN(C)c1ccncc1
Solvent: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCC(Nc2nnc(-c3cnc(Nc4ccc5ncsc5c4)cc3NC(C)C)o2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of N2-(benzo[d]thiazol-6-yl)-N4-isopropyl-5-(5-(piperidin-4-ylamino)-1,3,4-oxadiazol-2-yl)pyridine-2,4-diamine (Example 131) (40 mg, 0.08 mmol) in DCM (5 mL): THF (5 mL), added DIPEA (0.08 mmol, 1.5 equiv.) and DMAP (0.008 mmol, 0.1 equiv.) and stirred for 5 min. Added acetyl chloride (0.8 mmol, 0.8 equiv.) dropwise at 0° C. Stirred the reaction mixture at 0° C. for 1 h, the reaction temperature was raised to room temperature and stirred overnight. The reaction mixture was diluted with DCM. The DCM layer was washed with 10% NaHCO3 solution followed by water. The DCM layer was collected, dried over Na2SO4, filtered and concentrated. The material obtained was purified by prep HPLC to afford the title compound, 1-(4-((5-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)amino)piperidin-1-yl)ethanone. 1H NMR: 400 MHz, CD3OD: δ 1.34 (d, J=6.40 Hz, 6H), 1.57-1.66 (m, 2H), 1.97 (s, 3H), 2.00-2.06 (m, 2H), 3.77-3.82 (m, 1H), 3.93-3.98 (m, 1H), 4.03-4.06 (m, 2H), 6.17 (s, 1H), 7.53-7.56 (m, 1H), 7.98 (d, J=8.80 Hz, 1H), 8.38 (s, 1H), 8.43 (d, J=2.00 Hz, 1H), 9.08 (s, 1H). LC/MS: ZORBAX SB C18, 4.6×50 mm, 5 μm; Solvent A=10% MeOH: 90% H2O: 0.1% TFA; Solvent B=90% MeOH: 10% H2O: 0.1% TFA; gradient 0-100% B over 2 min (3 min run time); retention time: 1.514 min; LCMS (ES-API), m/z 493.2 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H2O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H2O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min; Retention time: 5.396 min; Purity: 99.4%.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9](Cl)[CH:8]=2)[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:3]=1.[O:20]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21]1>>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]([C:22]3[CH:23]=[CH:24][O:20][CH:21]=3)[CH:8]=2)[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:3]=1
Reactant: N#Cc1ccc(-n2c(N)nc3ccccc32)cc1Cl
Reactant: OB(O)c1ccoc1
Product: N#Cc1ccc(-n2c(N)nc3ccccc32)cc1-c1ccoc1

Procedure:
2-Amino-1-[3-(3-furyl)-4-cyanophenyl]benzimidazole was prepared from 2-amino-1-[3-chloro-4-cyanophenyl]benzimidazole and 3-furylboronic acid by method B. mp 140°-144° C.