Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[O:9][CH:10]=[C:11]([CH3:13])[N:12]=1)=[O:6]>C1C=CC=CC=1>[CH3:13][C:11]1[N:12]=[C:8]([N:7]2[CH2:2][CH2:3][CH2:4][C:5]2=[O:6])[O:9][CH:10]=1
Reactant: Cc1coc(NC(=O)CCCCl)n1
Solvent: c1ccccc1
Product: Cc1coc(N2CCCC2=O)n1
Reaction time: 0.17 h
Yield: 41.57 %

Procedure:
2-(4-Chlorobutyramido)-4-methyloxazole (2.20 g., 0.0108 mol) prepared as described in Example 36 was dissolved with stirring under nitrogen in dry benzene (350 mls.) and 1:5-diazobicyclo[4,3,0]non-5-ene (1.47 g., 0.0118 mol) in dry benzene (50 mls.) was added with stirring over 10 minutes. The mixture was stirred at room temperature, wrapped in foil overnight. The organic layer was washed with water (3 × 100 mls.) dried over magnesium sulphate and evaporated under vacuum. The product was recrystallised from ethyl acetate/hexane. Wt. = 0.75 g. m.p. 116° C (Yield = 41.57%).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=1.[F:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[C:25]([F:27])[CH:26]=1>>[F:20][C:21]1[CH:22]=[C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[C:7]([CH3:17])[C:6]=3[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=2)[CH:24]=[C:25]([F:27])[CH:26]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCCNC2=O
Product: Cc1c2n(c3c(-c4cc(F)cc(F)c4)cc(C#N)cc13)CCCNC2=O

Procedure:
The title compound, grey solid (45 mg, 51%), MS (ISP) m/z=352.6 [(M+H)+], mp 265° C., was prepared in accordance with the general method of example 1 from 7-bromo-11-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 17) (79.5 mg, 0.25 mmol) and commercially available 3,5-difluoro-phenylboronic acid (51.3 mg, 0.325 mmol).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:22][C:17]=3[N:16]=[CH:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)(=O)C>CO.[Pd]>[CH3:26][S:23]([C:21]1[CH:20]=[CH:19][C:18]2[N:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:15]=[N:16][C:17]=2[CH:22]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)c1ccc2c(c1)ncn2C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CS(=O)(=O)c1ccc2c(c1)ncn2C1CCNCC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 793.6 %

Procedure:
The crude material from step 3 (10 g) was dissolved in 1 litre of methanol in a pressure vessel, 20 g of moist 10% Pd/C catalyst and 100 mL acetic acid were added and stirred under an atmosphere of hydrogen at 5 bar and 50° C. for 8 hours. The reaction was cooled, filtered and evaporated. The residue was dissolved in water and basified with sodium hydroxide solution, extracted into dichloromethane, dried and evaporated. The brown solid was triturated with isopropanol, filtered, and washed with ether to give the title compound (60 g) as a pale grey solid; NMR: 2.00(m, 4H), 2.75(m, 2H), 3.15(m, 2H), 3.20(s, 3H), 4.60(m, 1H), 7.78 (dd, 1H), 7.85(d, 1H), 8.20(d, 1H), 8.56(s, 1H).
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7]([NH2:9])[NH:6][N:5]=2)[CH2:3][CH2:2]1.C(=O)([O-])O.[Na+].[C:15]1([N:21]=[C:22]=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>C(O)C>[NH2:9][C:7]1[N:6]([C:22]([NH:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:23])[N:5]=[C:4]([CH:1]2[CH2:3][CH2:2]2)[CH:8]=1
Reactant: Nc1cc(C2CC2)n[nH]1
Reactant: O=C=Nc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cc(C2CC2)nn1C(=O)Nc1ccccc1

Procedure:
To 0.4 g (3.2 mmol) of 3-cyclopropyl-5-amino-1H-pyrazole in 10 ml of 95% ethanol containing 0.3 g of sodium hydrogencarbonate 0.35 ml (3 mmol) of phenylisocyanate were added dropwise over several minutes. After 30 min water was added, and the solid was filtered, washed with 10% HCl and then with water. The filtrate was concentrated in vacua. The crude was recrystallized from methanol/water to give white peddles of 5-amino-3-cyclopropyl-N-phenyl-1H-pyrazole-l-carboxamide,
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[N:14]=[C:13]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=2)=[CH:8][CH:7]=1.[CH2:34]([C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)[CH2:35][CH3:36]>>[CH3:1][O:2][C:3](=[O:33])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[N:14]=[C:13]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:40]3[CH:41]=[CH:42][C:37]([CH2:34][CH2:35][CH3:36])=[CH:38][CH:39]=3)=[CH:28][CH:27]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)CNc1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)cc1
Reactant: CCCc1ccc(B(O)O)cc1
Product: CCCc1ccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(NCC(=O)OC)cc3)cc2)cc1

Procedure:
{4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenylamino}-acetic acid methyl ester (1.8 g, 3.3 mmol) was coupled with 4-n-propyl-phenyl boronic acid (659 m g, 4.0 mmol) according to general procedure G to give {4-[4-(2,4-dichloro-phenyl)-2-(4′-propyl-biphenyl-4-ylmethyl)-imidazol-1-yl]-phenylamino}-acetic acid methyl ester.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH3:13][S:14][C:15]1[CH:16]=[C:17]([CH:28]=[CH:29][CH:30]=1)[O:18][C:19]1[N:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([OH:23])=O.[NH2:31][C@H:32]1[CH2:37][CH2:36][CH2:35][CH2:34][C@H:33]1[OH:38].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[OH:38][C@@H:33]1[CH2:34][CH2:35][CH2:36][CH2:37][C@@H:32]1[NH:31][C:21](=[O:23])[C:20]1[CH:24]=[CH:25][CH:26]=[N:27][C:19]=1[O:18][C:17]1[CH:28]=[CH:29][CH:30]=[C:15]([S:14][CH3:13])[CH:16]=1
Reactant: CSc1cccc(Oc2ncccc2C(=O)O)c1
Reactant: N[C@H]1CCCC[C@H]1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1cccc(Oc2ncccc2C(=O)N[C@H]2CCCC[C@H]2O)c1
Reaction time: 18 h
Yield: 48.5 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (293 mg, 1.53 mmol) was added to a solution of 2-(3-methylsulfanyl-phenoxy)-nicotinic acid (200 mg, 0.765 mmol), (1R,2S)-2-aminocyclohexanol hydroformate [8151/195/2] (123 mg, 0.765 mmol), 1-hydroxybenzotriazole (114 mg, 0.842 mmol) and triethylamine (430□l, 3.10 mmol) in dimethylformamide (5 ml) under nitrogen at room temperature. The reaction was stirred for 18 h and partitioned between diethyl ether (25 ml) and water (25 ml). The organic phase was washed with brine (30 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography using ethyl acetate:cyclohexane (50:50 as eluant) to give N-[(1 S,2R)-2-hydroxycyclohexyl]-2-[3-(methylsulfanyl)phenoxy]nicotinamide (133 mg) as a gum.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl[CH2:10][C:11]1[N:15]([CH3:16])[N:14]=[N:13][N:12]=1>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:10][C:11]2[N:15]([CH3:16])[N:14]=[N:13][N:12]=2)=[CH:4][CH:3]=1
Reactant: Cn1nnnc1CCl
Reactant: Nc1ccc(Cl)cc1
Product: Cn1nnnc1CNc1ccc(Cl)cc1
Yield: 36.3 %

Procedure:
The same procedure as step 2 of example 1 was accomplished except for using p-chloroaniline (5.8 g, 45.3 mmol) and 5-chloromethyl-1-methyl-1H-tetrazol (6 g, 45.3 mmol). The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=2:1), to give desired compound (3.68 g, yield: 36%).
Reaction SMILES: [C:1]([C:5]1[C:14]([N+:15]([O-])=O)=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[N+:18]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[NH2:15][C:14]1[CH:13]=[C:8]([CH:7]=[C:6]([NH2:18])[C:5]=1[C:1]([CH3:3])([CH3:2])[CH3:4])[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(C(C)(C)C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(N)c(C(C)(C)C)c(N)c1

Procedure:
28.2 G. of methyl 4-tert. butyl-3,5-dinitrobenzoate dissolved in 200 ml. of methanol were hydrogenated under normal pressure and at room temperature in the presence of 2 g. of palladium/carbon (5%). After the uptake of the theoretical amount of hydrogen, the solution was filtered from the catalyst and evaporated. The residue was dissolved in benzene and purified over aluminum oxide, there being obtained methyl 3,5-diamino-4-tert. butylbenzoate having a melting point of 71°-73° C. after recrystallization from benzene/petroleum ether.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:10]([N+:12]([O-:14])=[O:13])=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1c(Cl)cccc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2,6-Dichloro-benzoic acid (10 g, 52 mmol) was treated with a previously stirred mixture of nitric acid (15 mL) and sulfuric acid (30 mL) at 55° C. for 30 minutes followed by stirring at room temperature for 30 minutes. The reaction mixture was poured in ice cold water (1 L) and the solid obtained was filtered and dried to afford the product (9 gm). The filtrate was extracted with ethyl acetate (2×200 mL). The combined organic layer was dried over anhydrous sodium sulphate and concentrated to dryness to yield more product (2 gm). (11 g, 88%).
Reaction SMILES: [CH2:1]([C:5]1[O:9][C:8]([NH:10][C@H:11]([C:15]([O:17]C)=[O:16])[CH:12]([CH3:14])[CH3:13])=[N:7][N:6]=1)[CH2:2][CH:3]=[CH2:4].[Li+].[OH-].Cl>O.C1COCC1>[CH2:1]([C:5]1[O:9][C:8]([NH:10][C@H:11]([C:15]([OH:17])=[O:16])[CH:12]([CH3:14])[CH3:13])=[N:7][N:6]=1)[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCc1nnc(N[C@H](C(=O)OC)C(C)C)o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=CCCc1nnc(N[C@H](C(=O)O)C(C)C)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 0.18 M solution of methyl N-(5-but-3-en-1-yl-1,3,4-oxadiazol-2-yl)-L-valinate (from Step 4) in H2O/THF (1/1 v/v), LiOH (2 eq.) was added at RT. The resulting reaction mixture was stirred for 1 h at RT and then treated with HCl 1N until pH=2 was reached. The aqueous phase was extracted with EtOAc and the organic layer dried over Na2SO4 to obtain a pale yellow solid. MS (ES+) C11H17N3O3 requires: 239 found: 240 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][N:12]=[C:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([OH:23])[CH2:21][CH3:22]>>[C:1]([O:5][C:6]([NH:8][C:9]1[S:13][N:12]=[C:11]([CH:14]([CH:20]([OH:23])[CH2:21][CH3:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)Cc1nsc(NC(=O)OC(C)(C)C)n1
Reactant: CCCO
Product: CCOC(=O)C(c1nsc(NC(=O)OC(C)(C)C)n1)C(O)CC

Procedure:
1.0 g (3.5 mMol) of product from Example 28 were reacted with 0.76 ml (~10 mMol) of propanol for 5 days in the manner described in Example 29 and the separated into the erythro and threo forms by chromatography on silica gel using toluene/ethyl acetate 4:1.
Reaction SMILES: Br[CH2:2][CH2:3][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[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][CH2:28][CH2:29][CH3:30])=[O:26])=[C:20]([Cl:31])[CH:19]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>CN(C)C=O>[Cl:31][C:20]1[CH:19]=[C:18]([O:17][C:8]2[C:7]3[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([O:4][CH2:3][CH2:2][N:42]4[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]4)[CH:6]=3)[N:11]=[CH:10][N:9]=2)[CH:23]=[CH:22][C:21]=1[NH:24][C:25]([NH:27][CH2:28][CH2:29][CH3:30])=[O:26]
Reactant: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OCCBr)cc23)cc1Cl
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OCCN4CCN(C)CC4)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
N-{2-Chloro-4-[(6-hydroxy-7-methoxy-4-quinazolinyl)oxy]phenyl}-N′-propylurea (500 mg), potassium carbonate (857 mg), and 1,3-dibromopropane (0.5 ml) were dissolved in N,N-dimethylformamide (5 ml), and the solution was stirred at room temperature for 3 hr. The solvent was removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with chloroform/2-propanol (4/1). The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 451 mg (yield 71%) of N-(4-{[6-(2-bromoethoxy)-7-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl}-N′-propylurea. N-(4-{[6-(2-Bromoethoxy)-7-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl]-N′-propylurea 50 mg), potassium carbonate (40 mg), and N-methylpiperazine (50 μl) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/methanol to give 20 mg (yield 44%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3C[C@H](NC(=O)CO)[C@@H:18]([OH:26])[C@H:17]3[OH:27])=[C:9]([NH:28][CH2:29][CH:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:8]=2)[CH:6]=1.ClC1N=C2C(N=CN2[C@@H]2C[C@H:56]([NH:58][C:59]([CH2:61][O:62]C(=O)C)=[O:60])[C@@H:55](O)[C@H]2O)=C(NCC(C2C=CC=CC=2)C2C=CC=CC=2)N=1>>[CH2:56]([NH:58][C:59]([C@@H:61]1[C@@H:18]([OH:26])[C@@H:17]([OH:27])[C@H:16]([N:13]2[CH:12]=[N:11][C:10]3[C:14]2=[N:15][C:7]([N:5]2[CH:6]=[C:2]([NH2:1])[CH:3]=[N:4]2)=[N:8][C:9]=3[NH:28][CH2:29][CH:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:62]1)=[O:60])[CH3:55]
Reactant: CC(=O)OCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: Nc1cnn(-c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)CO)[C@@H](O)[C@H]4O)c3n2)c1
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(-n4cc(N)cn4)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared analogously to N-{(1S,2R,3S,4R)-4-[2-(4-amino-pyrazol-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-hydroxy-acetamide (Intermediate ZP), by substituting (2S,3S,4R,5R)-5-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-3,4-dihydroxy-tetrahydro-furan-2-carboxylic acid ethylamide (Intermediate ZY) for acetic acid {(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentylcarbamoyl}-methyl ester (Intermediate Q1) in step ZP1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:4]([C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.O>CN(C)C=O>[C:10]1([C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:3][C:4]=2[C:17]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:18])=[O:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCc1ccccc1
Reactant: O=C(Nc1ccc(O)cc1C(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(OCc2ccccc2)cc1C(=O)c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 144.6 %

Procedure:
To a solution of N-[4-hydroxy-2-(phenylcarbonyl)phenyl]benzamide (4.0 g, 12.6 mmol) in dimethyl formamide (DMF) (15 mL) was added potassium carbonate (K2CO3) (large excess) then benzyl bromide (660 μL, 5.5 mmol). The reaction was stirred overnight. It was added to water (100 mL) then extracted with ethyl acetate (3×40 mL). The combined organic layers were dried (Na2SO4) then concentrated under vacuo to give a solid which was recrystallized with ethyl acetate/hexane to give the title compound (3.24 g, 63% yield, analytical).
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]#[CH:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:20](=[N:22][OH:23])[CH3:21].Cl[O-].[Na+]>C(Cl)(Cl)Cl>[C:1]([O:9][CH2:10][C:11]1[O:23][N:22]=[C:20]([CH3:21])[CH:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CCOC(=O)c1ccccc1
Reactant: CC=NO
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cc(COC(=O)c2ccccc2)on1
Temperature: 0 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
A solution of prop-2-yn-1-yl benzoate (26.0 g, 162 mmol) in chloroform (598 mL) was treated with triethylamine (11.3 mL, 81.2 mmol) and acetaldoxime (14.4 g, 244 mmol). The reaction mixture was cooled to 0° C., treated with sodium hypochlorite (551 mL, 487 mmol) (commercial grade ˜5% aqueous), and stirred overnight at room temperature. The layers were separated and the aqueous layer was extracted with dichloromethane (2×200 mL). The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to give the crude product. Purification by flash column chromatography (100% hexanes to 30% ethyl acetate/hexanes) gave the desired product (20.1 g, 57%). LCMS calculated for C12H12NO3 (M+H)+: m/z=218.1. found: 218.1.
Reaction SMILES: Cl.[F:2][C:3]1([C:9]2[S:10][C:11]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)=[CH:12][N:13]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Cl[C:27]1[N:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][N:28]=1.CCN(C(C)C)C(C)C>CC(O)C>[CH2:33]([C:30]1[CH:29]=[N:28][C:27]([N:6]2[CH2:5][CH2:4][C:3]([F:2])([C:9]3[S:10][C:11]([CH2:14][O:15][C:16]4[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=4)=[CH:12][N:13]=3)[CH2:8][CH2:7]2)=[N:32][CH:31]=1)[CH3:34]
Reactant: CS(=O)(=O)c1ccc(OCc2cnc(C3(F)CCNCC3)s2)cc1
Reactant: CCc1cnc(Cl)nc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cnc(N2CCC(F)(c3ncc(COc4ccc(S(C)(=O)=O)cc4)s3)CC2)nc1

Procedure:
A solution of 4-fluoro-4-[5-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine hydrochloride (1.2 g, 2.76 mmol), 2-chloro-5-ethyl-pyrimidine (425 mg, 1.1 eq.) and DIPEA (1.4 g, 4 eq.) in 2-propanol (20 mL) in a sealed pressure vessel was stirred at 160° C. (oil bath temperature) overnight. After cooling, the solvent was removed in vacuo. The residue was partitioned between water and EtOAc. The organic phase was washed with brine and dried over Na2SO4. After removal of the solvent, the crude product was purified on silica gel (EtOAc:hexanes=1:1) to afford the desired product as a white solid. 1H NMR (CDCl3): δ 8.19 (2H, s), 7.90 (2H, d, J=8.8 Hz), 7.73 (1H, d), 7.10 (2H, d, J=8.8 Hz), 5.31 (2H, s), 4.67 (2H, m), 3.44 (2H, m), 3.04 (3H, s), 2.48 (2H, q, J=7.6 Hz), 2.13˜2.38 (4H, m), 1.20 (3H, t, J=7.6 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[OH-].[Na+].[NH2:16][CH:17]([C:22]([OH:24])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20]>O>[CH3:20][CH:19]([CH3:21])[CH2:18][CH:17]([NH:16][S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[C:22]([OH:24])=[O:23]
Reactant: CC(C)CC(N)C(=O)O
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)CC(NS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)O
Temperature: 25 °C
Yield: 42.4 %

Procedure:
A solution of 2-nitrobenzenesulfonylchloride (11 g; 50 mmol) and NaOH (2.1 g; 53 mmol) in H2O (100 ml) was added DL-leucine (6.55 g; 50 mmol) and left over night with stirring at rt. The reaction mixture was added 4 M NaOH (12.5 ml) and filtered. The filtrate was acidified with 1 M HCl (50 ml) and extracted with EtOAc. The combined organic fractions were dried (Na2SO4) and evaporated to dryness to give 6.7 g (42%) product.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([Cl:10])=[N:5][CH:6]=[N:7][C:8]=1Cl.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[N:16][CH:17]=1.C(O)C>O>[CH3:19][O:18][C:15]1[N:16]=[CH:17][C:12]([NH:11][C:8]2[C:3]([NH2:2])=[C:4]([Cl:10])[N:5]=[CH:6][N:7]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(N)cn1
Reactant: Nc1c(Cl)ncnc1Cl
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1ccc(Nc2ncnc(Cl)c2N)cn1
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 53.3 %

Procedure:
40 mL conc. aqueous hydrochloric acid was added dropwise to 40 g of 5-amino-4,6-dichloropyrimidine and 60.5 g of 5-amino-2-methoxypyridine in 800 ml mixture of ethanol and water (1/1) at room temperature. This mixture was stirred at 130° C. for 7 hours and 20 minutes, and 800 mL water was added to the reaction mixture at room temperature. The resulting suspension was filtered to give crude crystals, and then the crude crystals were subjected to re-crystallization from dimethylformamide and water, to give the title compound (32.7 g, 53% y) as greenish brown crystals. (2) 5-(6-Chloro-9H-9-purinyl)-2-pyridyl methyl ether
Reaction SMILES: [OH:1][CH2:2][C:3]([O:14][CH2:15][CH2:16][CH3:17])([CH3:13])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:5].[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(N(CC)CC)C>C(Cl)Cl>[CH3:18][S:19]([O:1][CH2:2][C:3]([O:14][CH2:15][CH2:16][CH3:17])([CH3:13])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:5])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: CCCOC(C)(CO)C(=O)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOC(C)(COS(C)(=O)=O)C(=O)c1ccc(Cl)cc1
Temperature: -40 °C
Yield: 42.1 %

Procedure:
To 11 g (44 mmole) of crude 2-hydroxymethyl-2-propoxy-4'-chloropropiophenone (Example 96d) in 50 ml of methylene chloride was added 4.5 g (39 mmole) of methanesulfonyl chloride. The mixture was cooled to -40° C. and then 6.0 g (60 mmole) of triethylamine was slowly added. The mixture was allowed to warm to room temperature over 1 hour and was then washed with water, dilute aqueous hydrochloric acid, and brine. It was then dried over anhydrous magnesium sulfate, filtered, concentrated in vacuo, and chromatographed over silica gel using diethyl ether and hexanes to yield 5.5 g of the title compound, an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]2.Br[CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)[CH:6]=[CH:5]2
Reactant: O=c1[nH]ccc2cc(Br)ccc12
Reactant: COC(=O)c1ccc(CBr)cc1
Product: COC(=O)c1ccc(Cn2ccc3cc(Br)ccc3c2=O)cc1

Procedure:
The sub-title compound was prepared by the method of intermediate 4, using intermediate 1 and 4-(bromomethyl)benzoic acid, methyl ester.
Reaction SMILES: [CH:1]([Li])([CH2:3][CH3:4])[CH3:2].[CH:6]([O:9][B:10](OC(C)C)[O:11][CH:12]([CH3:14])[CH3:13])([CH3:8])[CH3:7]>>[CH:1]([B:10]([O:11][CH:12]([CH3:14])[CH3:13])[O:9][CH:6]([CH3:8])[CH3:7])([CH2:3][CH3:4])[CH3:2]
Reactant: [Li]C(C)CC
Reactant: CC(C)OB(OC(C)C)OC(C)C
Product: CCC(C)B(OC(C)C)OC(C)C
Temperature: 50 °C

Procedure:
Following the method of Example 1, reaction of sec-butyllithium (208 mL, 250 mmol) and triisopropoxyborane (47.0 mL, 250 mmol), with solvents removed at 0° C. and 15 mm Hg and oil bath temperature maintained at 50° C., yielded sec-butyldiisopropoxyborane, 42.0 g (206 mmol, 90%), bp 138°-140° C. (754 mm Hg); proton NMR (neat) δ4.35 (septet, J=18 Hz, 2H), 1.09 (d, J=18 Hz, 12H), 0.8 (bm, 9H); boron NMR (neat δ+79.5 ppm (s).