Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]1.[CH2:18]([C:22]1[N:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:25]=[C:24]([CH:33]=O)[CH:23]=1)[CH:19]([CH3:21])[CH3:20]>>[CH2:18]([C:22]1[N:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:25]=[C:24]([CH2:33][NH:17][CH2:16][CH2:15][N:12]2[CH2:13][CH2:14][N:9]([C:3]3[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[CH3:1])[CH2:10][CH2:11]2)[CH:23]=1)[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)Cc1cc(C=O)nn1-c1ccccc1
Reactant: Cc1ccc(N2CCN(CCN)CC2)c(C)c1
Product: Cc1ccc(N2CCN(CCNCc3cc(CC(C)C)n(-c4ccccc4)n3)CC2)c(C)c1
Yield: 69.2 %

Procedure:
Compound 29 was prepared using the same method as that of Example 1 except that 4-(2,4-dimethylphenyl)piperazin-1-ylethylamine and 5-iso-butyl-1-phenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([Cl:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1>>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C:4]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]4[C:18]([Cl:23])=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:12]=3)[CH:10]=2)=[O:5])=[CH:27][CH:28]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3cccnc3Cl)c2)cn1
Reactant: Fc1ccc(Br)cc1
Product: O=C(c1ccc(F)cc1)c1cn(-c2cccc(-c3cccnc3Cl)c2)cn1

Procedure:
This compound is prepared by method C using compound 12l and 1-bromo-4-fluorobenzene
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[CH2:18][CH3:19])[C:5]1=[O:23])(=O)C.[CH3:24][N:25]([CH3:37])[CH2:26][CH2:27][N:28]([CH3:36])[C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1>>[CH3:24][N:25]([CH3:37])[CH2:26][CH2:27][N:28]([C:29]1[CH:30]=[CH:31][C:32]([NH:35]/[C:17](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[CH2:18][CH3:19])=[CH:33][CH:34]=1)[CH3:36]
Reactant: CCOC(CC)=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21
Reactant: CN(C)CCN(C)c1ccc(N)cc1
Product: CC/C(Nc1ccc(N(C)CCN(C)C)cc1)=C1/C(=O)Nc2cc(OC)c(OC)cc21

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone and N-(2-dimethylaminoethyl)-N-methyl-p-phenylenediamine
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:6][CH:7]=1.[C-:14]#[N:15].[K+].C(OCC)(=O)C>C(#N)C.C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1>[C:14]([CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:6][CH:7]=1)#[N:15]
Reactant: ClCc1csc(-c2ccccc2)n1
Reactant: [C-]#N
Agent: [K+]
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#CCc1csc(-c2ccccc2)n1
Temperature: 25 °C
Yield: 73.8 %

Procedure:
1.39 g of 4-chloromethyl-2-phenylthiazole was dissolved in 10 ml of acetonitrile, and 0.65 g of potassium cyanide and 0.05 g of dibenzo-18-crown-6-ether were added thereto at room temperature, and then heated under reflux for 10 hours. After the temperature was returned to room temperature, ethyl acetate was added the resulting mixture, and the insoluble solid was removed through filtration. The resulting ethyl acetate solution was washed with saturated saline and water, and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residual product was purified through silica gel column chromatography to obtain 0.98 g of 4-cyanomethyl-2-phenylthiazole from the fraction eluted with chloroform.
Reaction SMILES: [CH:1]([N:5]1[CH2:8][CH:7]([OH:9])[CH2:6]1)([CH2:3][CH3:4])[CH3:2].[C:10]1([OH:20])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.[OH-].[Na+]>>[C:10]1([O:20][CH2:6][CH:7]([OH:9])[CH2:8][NH:5][CH:1]([CH2:3][CH3:4])[CH3:2])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Oc1cccc2ccccc12
Reactant: CCC(C)N1CC(O)C1
Agent: [Na+]
Agent: [OH-]
Product: CCC(C)NCC(O)COc1cccc2ccccc12
Temperature: 160 °C
Yield: 57 %

Procedure:
To a mixture of 14.2 parts of 1-(sec.-butyl)-3-azetidinol and 14.4 parts of α-naphthol 0.2 part of sodium hydroxide was added and the mixture was heated under nitrogen gas at 160° C. for 22 hours. The reaction mixture was cooled and then extracted with ether. The extract was washed with 2 N-NaOH aqueous solution and then with water. The liquid was dried over anhydrous sodium sulfate and the solvent was distilled off. Recrystallization of the residue gave 15.5 parts of 1-(α-naphthoxy)-3-(sec.-butylamino)-2-propanol melting at 57°-59° C. The yield was 57%.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[NH2:6][C@H:7]([C:12]([OH:14])=[O:13])[CH2:8][C:9](O)=[O:10].[NH3:15]>CO>[OH2:2].[NH2:6][C@H:7]([C:12]([OH:14])=[O:13])[CH2:8][C:9](=[O:10])[NH2:15]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: N
Reactant: O=S(=O)(O)O
Solvent: CO
Product: NC(=O)C[C@H](N)C(=O)O
Product: O
Temperature: 24 °C
Reaction time: 3.5 h

Procedure:
A solution of 31.5 ml. sulfuric acid in 295 ml. methanol was treated with 66.5 g. L-aspartic acid, and heated at 40-45° C. for 4 hours. The solution was cooled to 24° C., and treated with 28% aqueous ammonia to a pH of 2.5. The mixture was concentrated under vacuum to a thick slurry. The slurry was treated with 750 ml. of 28% aqueous ammonia and 20 ml. water, and stirred at 24° C. for 3.5 hours. The mixture was concentrated under vacuum nearly to dryness, redissolved in 75 ml. water at 55° C., adjusted to pH of 5.4 with excess ammonia, and then cooled to 24° C. The solid was collected by filtration, washed and dried, and finally recrystallized from another 75 ml. water to yield 31.0 g asparagine monohydrate.
Reaction SMILES: CCN(C(C)C)C(C)C.[O:10]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH2:49]([O:51][C:52](=[O:55])[CH2:53][NH2:54])[CH3:50]>CN(C=O)C.O>[CH2:49]([O:51][C:52](=[O:55])[CH2:53][NH:54][C:21](=[O:23])[C:20]1[CH:19]=[CH:18][C:17]([O:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:25][CH:24]=1)[CH3:50]
Reactant: CCOC(=O)CN
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)CNC(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 102.2 %

Procedure:
DIPEA (12.1 g, 16.2 mL, 93.6 mmol) was added to a stirred solution of 4-phenoxy benzoic acid (4.011 g, 18.73 mmol) in DMF (40 mL). HOBT (2.78 g, 20.57 mmol) and EDCI.HCl (9 g, 47 mmol) were then added. After 2 minutes, glycine ethyl ester hydrochloride (3.14 g, 22.5 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with cold water and the product extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over sodium sulphate and concentrated under reduced pressure to afford 5.73 g of (4-phenoxy-benzoylamino)-acetic acid ethyl ester as a white powder. 1H NMR (DMSO): δ 8.85 (t, 1H), 7.85 (d, 2H), 7.4 (t, 2H), 7.2 (t, 1H), 7.0 (m, 4H), 4.1 (q, 2H), 3.9 (d, 2H), 1.2 (t, 3H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([N:12]1[CH2:28][CH2:27][C:15]2([N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][NH:17][C:16]2=[O:26])[CH2:14][CH2:13]1)=O.[BH4-].[Na+].C(OCC)(=O)C.C(OCC)(=O)C.CCCCCC>N1C=CC=CC=1>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:1]=[C:2]1[CH2:10][N:12]1[CH2:28][CH2:27][C:15]2([N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][NH:17][C:16]2=[O:26])[CH2:14][CH2:13]1
Reactant: O=C(C1=Cc2ccccc2C1)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: c1ccncc1
Product: O=C1NCN(c2ccccc2)C12CCN(CC1=Cc3ccccc3C1)CC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 11.8 %

Procedure:
Crude 8-(1H-inden-2-ylcarbonyl)-1-phenyl-1,3,8-triazaspiro-[4.5]decan-4-one (11.4g) is dissolved in dry pyridine (250 ml), treated with sodium borohydride (6.0g), and the resulting mixture is refluxed for 16 hours under a nitrogen atmosphere. The pyridine solution is cooled, poured into 2 liters of ice water, stirred for 1 hour and the precipitates filtered off. The crude product is dissolved in chloroform and washed with water and saturated sodium bicarbonate solution. Concentration of the dried chloroform solution gives a crude solid which is a mixture of compounds. Column chromatography through silica gel using ethyl acetate followed by high pressure liquid chromatography with 4:1 ethyl acetate/hexane gives 1.3g of the title compound, melting point 184°14 186° C.
Reaction SMILES: C([O:3][P:4]([CH2:9][NH:10][C:11](=[O:38])[CH2:12][CH2:13][C:14]([CH3:37])=[CH:15][CH2:16][C:17]1[C:18]([O:30]CC[Si](C)(C)C)=[C:19]2[C:23](=[C:24]([CH3:28])[C:25]=1[O:26][CH3:27])[CH2:22][O:21][C:20]2=[O:29])(=[O:8])[O:5]CC)C.C[Si](Br)(C)C.N1C(C)=CC=CC=1C>C(#N)C>[OH:30][C:18]1[C:17]([CH2:16][CH:15]=[C:14]([CH3:37])[CH2:13][CH2:12][C:11]([NH:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5])=[O:38])=[C:25]([O:26][CH3:27])[C:24]([CH3:28])=[C:23]2[C:19]=1[C:20](=[O:29])[O:21][CH2:22]2
Reactant: CCOP(=O)(CNC(=O)CCC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)OCC
Agent: C[Si](C)(C)Br
Solvent: Cc1cccc(C)n1
Solvent: CC#N
Product: COc1c(C)c2c(c(O)c1CC=C(C)CCC(=O)NCP(=O)(O)O)C(=O)OC2
Reaction time: 8 h
Yield: 9 %

Procedure:
To a solution of ({6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoylamino}-methyl)-phosphonic acid diethyl ester (40 mg, 0.07 mmol) in acetonitrile (1 mL) was added TMSBr (91 μL, 0.7 mmol) followed by 2,6-lutidine (81.5 μL, 0.7 mmol). The reaction was allowed to proceed overnight when it was completed as judged by LCMS. The reaction mixture was quenched with MeOH and concentrated to dryness. The residue was purified by preparative reverse-phase HPLC to afford 2.6 mg (9%) of desired product as a white solid. 1H NMR (300 MHz, CD3OD) δ 1.67 (s, 3H), 2.17 (m, 5H), 2.30-2.46 (m, 2H), 2.80-2.86 (m, 2H), 3.55 (m, 2H), 3.82 (s, 3H), 5.26 (s, 3H) ppm; 31p (121.4 MHz, CD3OD) δ 10.27 ppm; MS (m/z) 412 [M−H]−, 414 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[O:26][CH2:27][CH2:28][CH2:29]Cl>CS(C)=O.O>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:29][CH2:28][CH2:27][O:26][C:17]2[CH:18]=[CH:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=2)=[CH:11][CH:10]=1
Reactant: COc1ccc(N)cc1
Reactant: ClCCCOc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(NCCCOc2ccc3ccccc3c2)cc1
Temperature: 135 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and p-anisidine (0.42 gm, 0.003 mole) was taken in dry DMSO (40 ml). Now 3-(2-naphthyloxy)-1-chloropropane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 135° C. for 7 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(4-methoxyphenyl)-[3-(naphthalen-2-yloxy)propyl]amine yellow solid, m.p. 110° C., (yield 0.66 gm, 95.6%).
Reaction SMILES: C([O:8][C:9]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][N:37]([CH2:40][CH3:41])[CH2:38][CH3:39])=[CH:30][C:10]=1[C:11]([NH:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])=[O:12])C1C=CC=CC=1>CO.C(OCC)(=O)C.[C].[Pd]>[CH2:40]([N:37]([CH2:38][CH3:39])[CH2:36][CH2:35][O:34][C:31]1[CH:32]=[CH:33][C:9]([OH:8])=[C:10]([CH:30]=1)[C:11]([NH:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])=[O:12])[CH3:41]
Reactant: CCN(CC)CCOc1ccc(OCc2ccccc2)c(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)OC)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCN(CC)CCOc1ccc(O)c(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.3 %

Procedure:
To a solution mixture of the obtained methyl 2-(2-(benzyloxy)-5-(2-(diethylamino)ethoxy)benzamido)-4-phenylbenzoate (0.15 g) in methanol (3.0 mL) and ethyl acetate (3.0 mL), 10% palladium-carbon (0.030 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 3 hours. The insoluble substance was removed by filtration, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-96% chloroform/methanol] to obtain 0.087 g of methyl 2-(5-(2-(diethylamino)ethoxy)-2-hydroxybenzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: [Cl:1][CH:2]([C:7]([CH3:9])=O)[C:3]([O:5][CH3:6])=[O:4].C([O-])(=O)C.[NH4+:14]>CO>[NH2:14][C:7]([CH3:9])=[C:2]([Cl:1])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(Cl)C(C)=O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CO
Product: COC(=O)C(Cl)=C(C)N
Yield: 63.9 %

Procedure:
50 g (0.33 mol) of methyl 2-chloroacetoacetate are reacted with 64 g (0.83 mol) of ammonium acetate in 100 ml of methanol and worked up in analogy to Example 2. Yield: 63.9% [GC]
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7]2.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([S:14]([CH3:13])(=[O:16])=[O:15])[CH2:8][CH2:7]2
Reactant: CS(=O)(=O)Cl
Reactant: Brc1ccc2c(c1)CCN2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To DMF (5.0 ml) was added sodium hydride (53 mg, 1.3 mmol) and the solution stirred at room temperature for 30 min. 5-Bromoindoline (240 mg, 1.2 mmol) was added and the solution was stirred at room temperature for 30 min. Methanesulfonyl chloride (94 ul, 1.2 mmol) was added and the solution stirred at room temperature overnight, then concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 2% CH3OH/CHCl3 to give the title compound (202 mg, 60%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:8]=2)[N:5]=[C:4]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:3]=1.[Cl:26][C:27]1[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][C:28]=1[C:29](O)=[O:30]>>[CH2:14]([O:13][C:9]1[CH:8]=[C:7]([N:6]2[C:2]([NH:1][C:29](=[O:30])[C:28]3[CH:32]=[C:33]([Br:36])[CH:34]=[CH:35][C:27]=3[Cl:26])=[CH:3][C:4]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:5]2)[CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)c1cc(Br)ccc1Cl
Reactant: CCOC(=O)c1cc(N)n(-c2cccc(OCc3ccccc3)c2)n1
Product: CCOC(=O)c1cc(NC(=O)c2cc(Br)ccc2Cl)n(-c2cccc(OCc3ccccc3)c2)n1

Procedure:
The title compound was prepared according to the method described for Preparation 16 using ethyl 5-amino-1-(3-(benzyloxy)phenyl)-1H-pyrazole-3-carboxylate (Preparation 54) and 2-chloro-5-bromobenzoic acid. The residue was purified using silica gel column chromatography eluting with 30-40% EtOAc in heptanes.
Reaction SMILES: [CH2:1]([O:8][C:9]([C@@H:11]1[CH2:15][CH2:14][C:13]([CH2:17]C(O)=O)([OH:16])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:23]([CH2:26]C)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:35])C=CC=CC=1>C1(C)C=CC=CC=1.O1CCCC1>[O:35]=[C:26]1[NH:23][CH2:17][C:13]2([CH2:14][CH2:15][C@@H:11]([C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[CH2:12]2)[O:16]1
Reactant: CCN(CC)CC
Reactant: O=C(O)CC1(O)CC[C@@H](C(=O)OCc2ccccc2)C1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C1NCC2(CC[C@@H](C(=O)OCc3ccccc3)C2)O1
Temperature: 80 °C
Yield: 15.5 %

Procedure:
To a solution of 2-((3R)-3-(benzyloxycarbonyl)-1-hydroxycyclopentyl)acetic acid (from step B, 130 mg, 0.467 mmol) in a mixture of toluene (2 mL) and tetrahydrofuran (1.0 mL) was added triethylamine (0.098 mL, 0.701 mmol) and diphenylphosphoryl azide (154 mg, 0.561 mmol) at room temperature. The resulting mixture was heated to 80° C. for 45 min. The reaction mixture was concentrated and the residue was subjected to preparative HPLC (Shimadzu VP-ODS 20×100 mm, 8 min. gradient, Solvent A: 10% MeOH, 90% H2O, 0.1% TFA; Solvent B: 90% MeOH, 10% H2O, 0.1% TFA). The fractions corresponding to the individual diasteromers were collected, concentrated, freeze dried and taken forward individually. Isomer 1: 20 mg, 0.073 mmol, 15.5% yield, MS (ESI+) m/z 276 (M+H)+; Isomer 2: 20 mg, 0.073 mmol, 15.5% yield, MS (ESI+) m/z 276 (M+H)+
Reaction SMILES: [Br:1]P(Br)Br.[Cl:5][C:6]1[CH:7]=[C:8]([CH2:13]O)[CH:9]=[N:10][C:11]=1[Cl:12].O>ClCCl>[Br:1][CH2:13][C:8]1[CH:7]=[C:6]([Cl:5])[C:11]([Cl:12])=[N:10][CH:9]=1
Reactant: BrP(Br)Br
Reactant: OCc1cnc(Cl)c(Cl)c1
Solvent: O
Solvent: ClCCl
Product: Clc1cc(CBr)cnc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
3.0 mL of tribromophosphine was added to 3.0 g of (5,6-dichloropyridin-3-yl)methanol (16.9 mmol) dissolved in 60 mL of dichloromethane, and stirred at room temperature for 2 hours. 30 mL of water was added dropwise thereto, and the organic layer was separated. The organic layer was washed with saturated sodium bicarbonate, and dried over magnesium sulfate. Then, the organic layer was concentrated under reduced pressure to obtain 3.66 g of 5-(bromomethyl)-2,3-dichloropyridine (yield 90%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:30])[CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.[H-].[Na+].[CH:33]([C:35]1[C:36]([NH:41][C:42](=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44])=[N:37][CH:38]=[CH:39][CH:40]=1)=[O:34]>O1CCCC1>[OH:34][CH:33]([C:35]1[C:36]([NH:41][C:42](=[O:47])[C:43]([CH3:45])([CH3:44])[CH3:46])=[N:37][CH:38]=[CH:39][CH:40]=1)[CH:16]([CH:17]1[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:21][CH2:22]1)[C:15]([O:14][CH3:13])=[O:30]
Reactant: CC(C)(C)C(=O)Nc1ncccc1C=O
Reactant: COC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C(C1CCN(C(=O)OC(C)(C)C)CC1)C(O)c1cccnc1NC(=O)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 93 %

Procedure:
A solution of diisopropylamine (6.0 mL, 43 mmol) in tetrahydrofuran (200 mL) was cooled to −78° C. A 2.5M solution of n-butyllithium in hexanes (17.0 mL, 43 mmol) was added to the mixture drop-wise. Mixture was held at −78° C. with stirring for 20 minutes. A solution of tert-butyl 4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (9.3 g, 36 mmol) in tetrahydrofuran (35 mL) was added to the mixture drop-wise. Mixture was held at −78° C. for 1.5 hours. In a separate flask, 60% sodium hydride in mineral oil (1.57 g, 39 mmol) was washed in hexanes and then suspended in tetrahydrofuran (70 mL). Mixture was cooled to 0° C. A solution of N-(3-formylpyridin-2-yl)pivalamide (6.74 g, 33 mmol) in tetrahydrofuran (20 mL) was added to the mixture drop-wise. Reaction was held at 0° C. with stirring for 2 hours. Mixture was warmed to room temperature and then added to the butyllithium containing solution drop-wise. Reaction mixture was held at −78° C. with stirring for 2 hours. Mixture was allowed to slowly warm to room temperature. Mixture stirred at room temperature for 14 hours. Reaction was quenched with aqueous ammonium chloride. The mixture was extracted with ethyl acetate (2×100 mL). Organic extracts were combined, dried (magnesium sulfate), filtered and concentrated in vacuo. Silica gel chromatography afforded the title compound as white foam in 93% yield. (M+H)+=464.2.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[NH:11][CH:10]=[N:9][C:8]2=O)(=[O:3])[CH3:2].C(N(CC)C(C)C)(C)C.P(Cl)(Cl)(Cl)=O.[Cl:32][C:33]1[C:34]([F:40])=[C:35]([CH:37]=[CH:38][CH:39]=1)[NH2:36]>C1(C)C=CC=CC=1>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[NH:36][C:35]1[CH:37]=[CH:38][CH:39]=[C:33]([Cl:32])[C:34]=1[F:40])(=[O:3])[CH3:2]
Reactant: COc1cc2[nH]cnc(=O)c2cc1OC(C)=O
Reactant: Nc1cccc(Cl)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-Acetoxy-7-methoxy-4(1H)-quinazolinone (150 g; prepared as described in WO96/15118, Example 39 thereof), N,N-diisopropylethylamine (123 ml) and toluene (1275 ml) were stirred at 70° C., under nitrogen. Phosphorus oxychloride (150 ml) was added over 15 minutes to the slurry at 70° C. The mixture was held at 70° C. for 2 hours to complete the chlorination. A dark brown solution formed after 30 minutes following addition of the phosphorus oxychloride. Toluene (680 ml) was added to the reaction mixture, followed by addition of 3-chloro-2-fluoroaniline (78 ml) over 10 minutes at 70° C. On completion of the addition, a solid precipitated resulting in a beige slurry. The slurry was held at 70° C. for 1 hour and then cooled to ambient temperature. The reaction mixture was filtered and washed with toluene (2×300 ml), aqueous IMS (2×450 ml and IMS (2×450 ml). The solid was left to pull dry on the filter overnight to give 6-acetoxy-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline.HCl salt; NMR Spectrum: (DMSO d6) 2.39 (s, 3H); 4.02 (s, 3H); 7.36 (t, 1H); 7.58 (s, 1H); 7.64 (t, 1H); 8.79 (s, 1H) 8.91 (s, 1H); 11.93 (bs 1H); Mass Spectrum: M+H362.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[C:12]1[N:13]=[N:14][C:15]([N:18]([CH3:29])[CH:19]2[CH2:24][C:23]([CH3:26])([CH3:25])[NH:22][C:21]([CH3:28])([CH3:27])[CH2:20]2)=[CH:16][CH:17]=1)[C:6](O)=[O:7].[CH2:30]([NH2:33])[CH:31]=[CH2:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[CH2:30]([NH:33][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:11]([C:12]2[N:13]=[N:14][C:15]([N:18]([CH3:29])[CH:19]3[CH2:20][C:21]([CH3:27])([CH3:28])[NH:22][C:23]([CH3:26])([CH3:25])[CH2:24]3)=[CH:16][CH:17]=2)=[C:3]([O:2][CH3:1])[CH:4]=1)[CH:31]=[CH2:32]
Reactant: C=CCN
Reactant: COc1cc(C(=O)O)ccc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CCNC(=O)c1ccc(-c2ccc(N(C)C3CC(C)(C)NC(C)(C)C3)nn2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.3 %

Procedure:
To a solution of crude 3-methoxy-4-(6-(methyl(2,2,6,6 tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)benzoic acid (0.354 mmol) in DMF (4 mL) and CH2Cl2 (4 mL) was added TEA (0.40 mL, 2.83 mmol), allyl amine (0.053 mL, 0.71 mmol), and HATU (202 mg, 0.53 mmol). The crude reaction was allowed to stir at RT overnight. The crude mixture was quenched with sat aq NaHCO3 and diluted with CH2Cl2. The organic layer is washed with water (6×), brine, dried over MgSO4, filtered, and concentrated. The crude product was purified via HPLC to give N-allyl-3-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)benzamide (8.2 mg). LCMS Rt=1.08 min (condition B); MS (M+1)=438.1