Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][N:12]2[C:17](=[O:18])[C:16]([CH2:19][CH:20](C(OC(C)(C)C)=O)[C:21]([O:23]C(C)(C)C)=[O:22])=[CH:15][C:14]([C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([F:43])[CH:36]=3)=[N:13]2)[CH2:10][CH2:9]1>>[C:21]([CH2:20][CH2:19][C:16]1[C:17](=[O:18])[N:12]([CH2:11][CH:8]2[CH2:9][CH2:10]2)[N:13]=[C:14]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([F:43])[CH:36]=2)[CH:15]=1)([OH:23])=[O:22]
Reactant: COc1ccc(-c2cc(CC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(=O)n(CC3CC3)n2)cc1F
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2cc(CCC(=O)O)c(=O)n(CC3CC3)n2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
Trifluoroacetic acid (21 mL) was added to 2-cyclopropylmethyl-4-[2,2-di(tert-butoxycarbonyl)ethyl]-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one (1.39 g, 2.77 mmol), and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and toluene was added further, followed by azeotropic boiling. The residue was heated at 190 to 200° C. for 30 minutes under a nitrogen atmosphere to yield the title compound as a pale brown powder (yield: 907 mg, 94.7%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:27])[CH:23]=3)[CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)(OC(C)(C)C)=O.Cl>O1CCOCC1>[Cl:27][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]([S:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)(=[O:15])=[O:16])[CH:26]=[CH:25]2
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring suspension of 1-Boc-4-(6-chloro-naphthalen-2-ylsulfonyl)piperazine (2.8g, 6.8 mmol) in dioxane (50 mL) was added 4 M HCl in dioxane (5 mL, 40 mmol). After stirring overnight at room temperature, the solvent was evaporated in vacuo, and the residue was dissolved in water. The aqueous phase was and made basic with 5 N NaOH and extracted twice with ethyl acetate. The combined extracts were washed with water and brine, then dried over sodium sulfate and evaporated to 2.1 g (100%) solid.
Reaction SMILES: [CH:1]1([C:6]2[NH:14][C:13]3[C:12]([NH:15][C@@H:16]([CH2:19][C:20]4[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=4)[CH2:17]O)=[N:11][C:10](=[O:26])[N:9]([CH2:27][CH2:28][CH3:29])[C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)(Cl)=O>>[CH:1]1([C:6]2[NH:14][C:13]3[C:12]4=[N:15][C@@H:16]([CH2:19][C:20]5[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=5)[CH2:17][N:11]4[C:10](=[O:26])[N:9]([CH2:27][CH2:28][CH3:29])[C:8]=3[N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCCn1c(=O)nc(N[C@H](CO)Cc2ccncc2)c2[nH]c(C3CCCC3)nc21
Solvent: O=S(Cl)Cl
Product: CCCN1C(=O)N2C[C@H](Cc3ccncc3)N=C2c2[nH]c(C3CCCC3)nc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 56.1 %

Procedure:
To Compound 1a (578 mg, 1.46 mmol) was added thionyl chloride (5.0 mL, 68.5 mmol, 47 equivalents) and the mixture was stirred at 60° C. for 2 hours. Excess thionyl chloride was evaporated, to the resulting residue were added chloroform (10 mL) and saturated aqueous sodium hydrogen carbonate (10 mL), and the mixture was stirred at room temperature for 12 hours. The reaction mixture was extracted with chloroform, the organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=98:2), and chloroform and methanol were added to the residue. The deposited crystals were collected by filtration to obtain the title compound (310 mg, 56%) as a white solid.
Reaction SMILES: [CH2:1]([C:3]([CH2:10][OH:11])([CH2:6][CH2:7][CH2:8][CH3:9])[CH:4]=[O:5])[CH3:2].C(C(CCCC)C=O)C.C=O>>[CH2:6]([C:3]([CH2:1][CH3:2])([CH2:4][OH:5])[CH2:10][OH:11])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCC(C=O)(CC)CO
Agent: C=O
Agent: CCCCC(C=O)CC
Product: CCCCC(CC)(CO)CO

Procedure:
Disclosed is a continuous process for the manufacture of 2-ethyl-2-(hydroxymethyl)hexanal wherein 2-ethylhexanal, formaldehyde and a tertiary amine are continuously fed to a reaction zone and crude product comprising an aqueous phase and an organic phase containing 2-ethyl-2-(hydroxymethyl)hexanal and 2-ethylhexanal is continuously removed from the reaction zone. Also disclosed are processes for (1) the azeotropic distillation of the organic phase of the crude product whereby unreacted 2-ethylhexanal is recovered and (2) the catalytic hydrogenation of the refined, organic phase of the crude product to produce 2-butyl-2-ethyl-1,3-propanediol.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18](=O)[CH:19]([CH3:21])[CH3:20])[CH2:13][CH2:12]1.C1(C[NH2:30])C=CC=CC=1>CO.[Pd]>[NH2:30][CH:18]([CH:19]([CH3:21])[CH3:20])[CH2:17][N:14]1[CH2:15][CH2:16][CH:11]([NH:10][C:2]2[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[CH2:12][CH2:13]1
Reactant: CC(C)C(=O)CN1CCC(Nc2nc3ccccc3[nH]2)CC1
Reactant: NCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)C(N)CN1CCC(Nc2nc3ccccc3[nH]2)CC1
Reaction time: 24 h
Yield: 4.4 %

Procedure:
A mixture of 1-[4-(1H-benzimidazol-2-ylamino)-1-piperidinyl]-3-methyl-2-butanone (0.03 mol) and benzenemethanamine (0.09 mol) in methanol (200 ml) was hydrogenated at 40° C. under a 3 bar pressure for 48 hours with palladium on activated carbon (1.3 g) as a catalyst. After uptake of hydrogen, the catalyst was filtered through celite, washed with CH3OH and the filtrate was evaporated. Hydrogenation was continued for 24 hours. After uptake of hydrogen, the catalyst was filtered through celite, washed with CH3OH and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 85/14/1; 20–45 μm). The desired fractions were collected and the solvent was evaporated. The residue was crystallized from diethyl ether. The precipitate was filtered off and dried, yielding 0.4 g of (±)-N-[1 (2-amino-3-methylbutyl)-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 138° C. (interm. 37).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[CH:7]=[O:8].[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[Li]>>[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH:7]([C:6]1[O:5][CH:4]=[N:3][C:2]=1[CH3:1])[OH:8]
Reactant: [Li]c1ccco1
Reactant: Cc1ncoc1C=O
Product: Cc1ncoc1C(O)c1ccco1

Procedure:
The title compound was prepared from 4-methyl-5-oxazolecarbaldehyde and 2-furyllithium using the method of Example 28. M.p. 52°-54° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:6]([OH:17])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CN(C)C=O>[CH2:24]([O:17][C:6]1[CH:5]=[C:4]([CH2:3][CH2:2][Br:1])[CH:16]=[CH:15][C:7]=1[O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)COc1ccc(CCBr)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(CCBr)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 13.5 h

Procedure:
To a solution of ethyl 2-[4-(2-bromoethyl)-2-hydroxyphenoxy]acetate (400 mg) in N,N-dimethylformamide (4 ml) were added potassium carbonate (200 mg) and benzyl bromide (0.17 ml) and the mixture was stirred for 13.5 hours at room temperature. The reaction mixture was poured into water and extracted with a mixed solution of diethyl ether and ethyl acetate (3/1). The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, purification of the residue by flash column chromatography on silica gel (eluent: hexane/ethyl acetate=17/3) gave ethyl 2-[2-benzyloxy-4-(2-bromoethyl)phenoxy]acetate (252 mg).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25](=[S:27])[NH2:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:29][C:30]([C:32]1[CH:33]=[N:34][C:35]([Cl:38])=[CH:36][CH:37]=1)=O>>[Cl:38][C:35]1[N:34]=[CH:33][C:32]([C:30]2[N:26]=[C:25]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])[CH2:10]3)[S:27][CH:29]=2)=[CH:37][CH:36]=1
Reactant: O=C(CBr)c1ccc(Cl)nc1
Reactant: NC(=S)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3ccc(Cl)nc3)cs2)C1

Procedure:
100 mg (0.224 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethyl)phenyl]piperidine-3-carbothioamide (Example 53A) and 85 mg (0.269 mmol) of 2-bromo-1-(6-chloropyridin-3-yl)ethanone were reacted according to the General Method 3. Yield: 17 mg (14% of theory)
Reaction SMILES: Cl.N1C=CC=CC=1.C[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)[N:11]=1>C(#N)C>[OH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)[N:11]=1
Reactant: COc1ccnc(Nc2ccc(C#N)cc2)n1
Agent: Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: N#Cc1ccc(Nc2nccc(O)n2)cc1
Temperature: 155 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
Pyridine hydrochloride (23 gm) was added to 4-(4-methoxypyrimidin-2-ylamino)benzonitrile (15 gm) and then heated to 150 to 160° C. for 3 hours. The mixture was then cooled to room temperature, then transferred into ice water and stirred for 1 hour. The resulting precipitate was filtered and washed with water. The solid thus obtained was slurried in acetonitrile at 0 to 5° C. for 1 hour and filtered. The solid obtained was dried to give 12.3 gm of 4-(4-hydroxypyrimidin-2-ylamino)benzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:41])[C:9]2[C:18]3[C:17](=[O:19])[N:16]([CH2:20][CH2:21][CH2:22][O:23]C4CCCCO4)[C:15](=[O:30])[N:14]([CH3:31])[C:13]=3[N:12]=[CH:11][C:10]=2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH:38]([CH3:40])[CH3:39])=[CH:4][CH:3]=1.Cl.CO>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:41])[C:9]2[C:18]3[C:17](=[O:19])[N:16]([CH2:20][CH2:21][CH2:22][OH:23])[C:15](=[O:30])[N:14]([CH3:31])[C:13]=3[N:12]=[CH:11][C:10]=2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH:38]([CH3:39])[CH3:40])=[CH:4][CH:3]=1
Reactant: CC(C)c1ccccc1-c1cnc2c(c1C(O)c1ccc(Cl)cc1)c(=O)n(CCCOC1CCCCO1)c(=O)n2C
Agent: Cl
Solvent: CO
Product: CC(C)c1ccccc1-c1cnc2c(c1C(O)c1ccc(Cl)cc1)c(=O)n(CCCO)c(=O)n2C
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.9 %

Procedure:
To a solution of 5-((4-chlorophenyl)(hydroxy)methyl)-6-(2-isopropylphenyl)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (50 mg, 0.087 mmol) in MeOH (2 mL) was added saturated HCl/MeOH (2 mL, MeOH was saturated by HCl gas at 0° C.). The reaction was stirred at RT for 18 h, concentrated then diluted with EA (10 mL) and aq. NaHCO3 (3 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 5-((4-chlorophenyl)(hydroxy)methyl)-3-(3-hydroxypropyl)-6-(2-isopropylphenyl)-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (15 mg, 35% yield) as a white solid. 1H NMR (DMSO-d6) δ: 8.61 (s, 1H), 7.48-7.35 (m, 2H), 7.24-7.15 (m, 3H), 7.11-6.96 (m, 3H), 6.74 (m, 0.3H), 6.35 (m, 0.8H), 6.10 (m, 0.3H), 5.66 (m, 0.7H), 3.93 (m, 2H), 3.68 (s, 3H), 3.38 (m, 2H), 2.72 (m, 1H), 1.64 (m, 2H), 1.15 (d, J=6.8 Hz, 2H), 1.08 (m, 3H), 0.81 (d, J=6.7 Hz, 1H). LCMS: [M+ —OH] 476 and TR=2.931 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.N1C(C)=CC=CC=1C.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](Cl)=[O:26]>O1CCCC1>[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1)=[O:26]
Reactant: O=C(Cl)c1ccco1
Reactant: Cc1nc2cc(N)ccc2o1
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Product: Cc1nc2cc(NC(=O)c3ccco3)ccc2o1
Temperature: 3 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
5-Amino-2-methylbenzoxazole (14 8 g, 0.100 mol) and 2,6-lutidine (12.0 g, 0.111 mol) were combined with 100 mL of tetrahydrofuran (THF) and the solution was cooled to 3° C. in an ice-bath under nitrogen. 2-Furoyl chloride (13.7 g, 0.105 mol) in 20 mL of THF was added dropwise so as to keep the temperature below 10° C. After addition the ice-bath was removed and after stirring for 1 hour the mixture was poured into 300 mL of water. The solid was collected and washed with water and dried. This afforded 21.1 g (87% yield) of product; m.p. 156°-158° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[C:6]([CH3:8])[O:5][N:4]=1.[F:9][B-:10]([F:13])([F:12])[F:11].[CH3:14][O+](C)C>C(Cl)Cl>[F:9][B-:10]([F:13])([F:12])[F:11].[CH3:14][N+:4]1[O:5][C:6]([CH3:8])=[CH:7][C:3]=1[O:2][CH3:1]
Reactant: C[O+](C)C
Reactant: COc1cc(C)on1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COc1cc(C)o[n+]1C

Procedure:
The starting material may be prepared by reaction of 3-methoxy-5-methylisoxazole with trimethyloxonium tetrafluoroborate in CH2Cl2 for 3.5 hours at reflux to give 2,5-dimethyl-3-methoxyisoxazolium tetrafluoroborate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[CH:13][N:12]=[C:11]3[NH:15][N:16]=[C:17]([C:18]4[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=4)[C:10]=23)[CH:5]=[CH:6][CH:7]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[CH:13][N:12]=[C:11]3[NH:15][N:16]=[C:17]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=4)[C:10]=23)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: Oc1ccc(-c2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Temperature: 0 °C

Procedure:
With the exclusion of air and moisture, a mixture of 0.442 g (1.2 mmol) of 4-(3-chloro-phenylamino)-3-(4-methoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidine [see Example 34], 1.16 g (8.7 mmol) of anhydrous aluminum chloride and 20 ml of benzene is heated under reflux for 45 minutes. The reaction mixture is then poured into ice-water, filtered and washed with water and the filter residue is partitioned between a 5% solution of sodium hydrogen carbonate in water and ethyl acetate. The organic phase is washed with brine, dried over sodium sulfate and concentrated in vacuo. A small amount of hexane is added and the desired product precipitates. Washing with hexane and purification of the crude product by flash chromatography on silica gel (230-400 mesh) using an ethyl acetate/hexane mixture (7:3) yield the title compound; m.p. >220° C.; MS: (M)+ =337.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.[Cl-].[Li+].C([Sn](CCCC)(CCCC)[C:37]1[N:42]=[C:41]([Cl:43])[CH:40]=[CH:39][N:38]=1)CCC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:25]([O:24][C@@H:18]([C:9]1[C:8]([CH3:29])=[CH:7][C:5]2[N:6]=[C:2]([C:37]3[N:42]=[C:41]([Cl:43])[CH:40]=[CH:39][N:38]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:28])([CH3:27])[CH3:26]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccc(Cl)n1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3nccc(Cl)n3)sc2c1-c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
(S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (500 mg, 1.01 mmol), tetrakis(triphenylphosphine)palladium(0) (174 mg, 0.15 mmol), lithium chloride (128 mg, 3.02 mmol), and copper(I) iodide (58 mg, 0.3 mmol) were taken in a microwave vial, and the vial was vacuum pumped and flushed with argon three times. To this mixture was added 2-(tributylstannyl)-4-chloropyrimidine (447 mg, 1.11 mmol) in dioxane (12 mL) and the resulting mixture was stirred at 90° C. for 18 h. The reaction mixture was then cooled, filtered through Celite (ethyl acetate eluent), and concentrated. Purification by flash column chromatography on silica gel (hexanes/ethyl acetate eluent) provided the product. LCMS-ESI+ calc'd for C26H26Cl2N3O3S (M+H+): 530.1; Found: 530.0 (M+H+).
Reaction SMILES: N[C:2]1[C:7](F)=CC=C[C:3]=1[OH:9].[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[C:12]=1[NH:18][C:19](=[O:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+].C(C1OC1)Br>O.CO.CN(C=O)C.C(OCC)(=O)C.O>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:7][CH:2]2[CH2:3][O:9]2)[C:12]=1[NH:18][C:19](=[O:21])[CH3:20]
Reactant: Nc1c(O)cccc1F
Reactant: CC(=O)Nc1c(O)cccc1F
Agent: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1c(F)cccc1OCC1CO1
Temperature: 70 °C
Reaction time: 3 h
Yield: 45.8 %

Procedure:
To a stirred solution of 2-amino-3-fluorophenol (300 mg, 2.36 mmol) in water-methanol (10 ml) acetic acid anhydride was added until all 2-amino-3-fluorophenol was used. The solution was then concentrated to a residue of N-(2-fluoro-6-tiydroxyphenyl) acetamide. To a mixture of N-(2-fluoro-6-hydroxyphenyl) acetamide (399 mg, 2.36 mmol) and potassium carbonate (652 mg, 4.72 mmol) in DMF (5 ml) was added epibromohydrin (388 mg, 2.8 mmol) and was stirred at 70° C. for 3 hrs. Water and ethyl acetate were added. the organic phase separated, dried and concentrated. The resulting residue was purified by RP-HPLC (10-40% CH3CN ) to give the desired product as a solid (242 mg, 1.08 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[NH:10][CH2:11][C:12]([OH:14])=O)[CH:5]=[CH:6][CH:7]=1.[NH:16]([CH:23]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=1)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.S(Cl)(Cl)=O>>[Cl:38][C:33]1[CH:32]=[C:31]([CH:23]([N:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:12](=[O:14])[CH2:11][NH:10][C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)=[O:15])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:36]=[CH:35][C:34]=1[Cl:37]
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Reactant: CC(C)(C)OC(=O)C(Nc1ccccc1)c1ccc(Cl)c(Cl)c1
Solvent: O=S(Cl)Cl
Product: Cc1cccc(NC(=O)NCC(=O)N(c2ccccc2)C(C(=O)OC(C)(C)C)c2ccc(Cl)c(Cl)c2)c1
Yield: 48 %

Procedure:
The procedure is as in Example 1, but 2.1 g of 2-[3-(3-methylphenyl)ureido]acetic acid, 3.52 g of tert-butyl (RS)-2-anilino-2-(3,4-dichlorophenyl)acetate and 0.72 cm3 of thionyl chloride are used as starting materials. The product obtained is purified by chromatography on 100 g of silica (0.04-0.063 mm) contained in a column 3 cm in diameter [eluent: ethyl acetate/cyclohexane (30/70 by volume)], using an excess pressure of 40 kPa of nitrogen and collecting 10-cm3 fractions. Fractions 13 to 24 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. and the residue obtained is recrystallized from diisopropyl ether. 2.6 g of tert-butyl (RS)-2-(3,4-dichlorophenyl)-2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}acetate melting at 176° C. are then obtained.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[Cl:16][C:17]1[CH:18]=[C:19]([CH:29]([NH2:31])[CH3:30])[CH:20]=[N:21][C:22]=1[O:23][CH2:24][C:25]([F:28])([F:27])[CH3:26]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:31]([CH:29]([C:19]3[CH:20]=[N:21][C:22]([O:23][CH2:24][C:25]([F:27])([F:28])[CH3:26])=[C:17]([Cl:16])[CH:18]=3)[CH3:30])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: CC(N)c1cnc(OCC(C)(F)F)c(Cl)c1
Agent: Cl
Product: CC(c1cnc(OCC(C)(F)F)c(Cl)c1)N1Cc2c(ccnc2Cl)C1=O
Yield: 83 %

Procedure:
The title compound is prepared in 83% yield (1200 mg, colorless amorphous solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (1000 mg, 3.6 mmol, Step-1 of Intermediate-1) and 1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (1030 mg, 3.6 mmol, Amine-63, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:15][O:16][C:17](Cl)=[O:18].O>C(Cl)Cl>[CH3:15][O:16][C:17]([N:5]1[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]1)=[O:18]
Reactant: CC1CCNCC1
Reactant: COC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CCC(C)CC1
Reaction time: 8 h

Procedure:
To a three neck round bottom flask was added 360 g of 4-methylpiperdine, 470 mL of triethylamine, and 390 mL of methylene chloride and the mixture was cooled in an ice bath. To this mixture was added methylchloroformate (260 mL) in methylene chloride (215 mL) slowly to maintain a reaction temperature of 20 C or below. The reaction was stirred overnight, then 200 mL of water was added and the layers were separated. The organic layer was washed with dilute HCl, satd. NaHCO3, and brine, and then the organic layer was dried over sodium sulfate and the solvent was removed in vacuo. The product was distilled at 90-93 C at ˜10 mm pressure to provide 338 g of product.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH:27]([CH3:29])[CH3:28])=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.C(OC(N1CCN(C2[C:52]3[C:47](=[CH:48][C:49](F)=[C:50](F)[CH:51]=3)[N:46]=CN=2)CC1)=O)(C)(C)C>>[CH:27]([O:26][C:20]1[CH:19]=[C:18]2[C:23]([C:14]([N:11]3[CH2:10][CH2:9][N:8]([C:6]([NH:46][C:47]4[CH:48]=[CH:49][C:50]([O:24][C:21]5[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=5)=[CH:51][CH:52]=4)=[O:7])[CH2:13][CH2:12]3)=[N:15][CH:16]=[N:17]2)=[CH:22][C:21]=1[O:24][CH3:25])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc3cc(F)c(F)cc23)CC1
Reactant: COc1cc2c(N3CCN(C(=O)OC(C)(C)C)CC3)ncnc2cc1OC(C)C
Product: COc1cc2c(N3CCN(C(=O)Nc4ccc(Oc5ccccc5)cc4)CC3)ncnc2cc1OC(C)C
Yield: 100 %

Procedure:
Substantially the same procedure as in Example 329 was repeated, except that 4-(7-isopropoxy-6-methoxy-4-quinazolinyl)-1-piperazinecarboxylic acid tert-butyl ester obtained in Reference Example 9 was used in place of 4-(6,7-difluoro-4-quinazolinyl)-1-piperazinecarboxylic acid tert-butyl ester, to give the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH:9]([CH3:14])[C:10]([O:12]C)=[O:11])=[CH:7][N:6]=[CH:5][N:4]=1.O.[OH-].[Li+]>O.C(O)C>[CH3:1][O:2][C:3]1[C:8]([CH:9]([CH3:14])[C:10]([OH:12])=[O:11])=[CH:7][N:6]=[CH:5][N:4]=1
Reactant: COC(=O)C(C)c1cncnc1OC
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ncncc1C(C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 0.21 g (1.06 mmol) of methyl 2-(4-methoxypyrimidin-5-yl)propanoate from Step B in 0.5 mL of water and 1.5 mL of ethanol was added 81 mg (1.9 mmol) of lithium hydroxide hydrate. The reaction mixture was stirred at ambient temperature for 2 h then concentrated in vacuo to remove all volatiles. The residue was diluted with 3 mL of 2.0 N aqueous hydrogen chloride and then concentrated in vacuo to remove all volatiles to yield the title compound as an off white solid (70 mg, 36%). 1H-NMR (500 MHz, CD3OD) δ: 8.67 (s 1H), 8.4 (s, 1H), 4.07 (s, 3H), 3.9 (q, J=7 Hz, 2H), 1.58 (d, J=7 Hz, 3H). LC-MS: m/z (E/S) 183 (MH)+.