Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[C:24]([O:28][C:29]([N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([CH:41]([CH3:48])[CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH:39]=2)[NH:34][CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>O1CCCC1>[C:24]([O:28][C:29]([N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([CH:41]([CH3:48])[CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH:39]=2)[N:34]([C:21](=[O:23])[CH2:20][C:5]2[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Reactant: CCOC(=O)CC(C)c1ccc2c(c1)N(C(=O)OC(C)(C)C)CCN2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(C)c1ccc2c(c1)N(C(=O)OC(C)(C)C)CCN2C(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(OC)c1
Reaction time: 18 h
Yield: 51.7 %

Procedure:
A mixture of [3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetic acid (0.536 g) and 7-(2-ethoxycarbonyl-1-methyl-ethyl)-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester (396 mg, Reference Example 19) in tetrahydrofuran (10 ml) containing 4 Angström molecular sieves (0.5 g) was treated with triethyl amine (638 μl), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (518 mg) and 4-dimethyl-aminopyridin (14 mg). After stirring for 5 hours further aliquots of [3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetic acid (0.178 g) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (172 mg) were added and stirring was continued for a further 18 hours. The reaction mixture was filtered through a celite and the filter pad was washed with ethyl acetate (50 ml). The combined filtrate and washings were washed three times with aqueous saturated ammonium chloride (20 ml), then dried over magnesium sulfate and then evaporated (40° C., 40 mbar). The residue (1.2 g) was submitted to chromatography (36 g silica, 0.040-0.063 mm particle size) eluting with a mixture of cyclohexane and ethyl acetate (70:30, v/v) to afford the title compound as a white powder (379 mg). TLC: RF=15/65 (cyclohexane:ethyl acetate, 1:1). 1H NMR (400 HMz, (CD3)2SO, at room temperature, we observe a mixture of rotamers): δ1.14 (t, J=7 Hz, 31); 1.24 (d, J=7 Hz, 3H); 1.48 (s, 9 H); 2.26 (s, 3H); 2.58 (d, J=7.5 Hz, 2H); 3.17 (m, 1H); 3.64 (m, 2H); from 3.75 to 3.90 (m, 7H); 4.04 (q, J=7 Hz, 2H); from 6.55 to 6.85 (very broad band, 2H); 6.96 (t, J=7.5 Hz, 1H); 7.00 (broad d, J=8 Hz, 1H); from 7.10 to 7.20 (m, 2H); 7.46 (broad band, 1H); 7.64 (broad s, 1H); 7.78 (d, J=8 Hz, 1H); 8.01 (d, J=8 Hz, 1H); 8.48 (s, 1H); 8.54 (broad s, 1H). MS (EI): 644 (M+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:32])=[C:19]([NH:23][S:24]([C:27]3[CH:31]=[CH:30][O:29][CH:28]=3)(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.C([O-])=O.[NH4+]>>[CH3:16][C:13]([C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[CH:2][N:7]=2)=[C:9]([C:17]2[C:18]([F:32])=[C:19]([NH:23][S:24]([C:27]3[CH:31]=[CH:30][O:29][CH:28]=3)(=[O:25])=[O:26])[CH:20]=[CH:21][CH:22]=2)[N:10]=1)([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccoc3)c2F)c(-c2ccnc(Cl)n2)s1
Agent: O=C[O-]
Agent: [NH4+]
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccoc3)c2F)c(-c2ccncn2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 26 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide (77 mg, 0.156 mmol) and ammonium formate (98 mg, 1.562 mmol), the title compound was obtained as a yellow solid (23 mg, 30% yield). MS (ESI): 459 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[C@@H:3]([NH:5][C:6](=[O:11])[CH2:7][C:8](=[O:10])[CH3:9])[CH3:4].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>CN(C)C=O>[CH3:15][N:16]([CH:18]=[C:7]([C:8](=[O:10])[CH3:9])[C:6]([NH:5][C@H:3]([CH:2]([CH3:12])[CH3:1])[CH3:4])=[O:11])[CH3:17]
Reactant: CC(=O)CC(=O)N[C@@H](C)C(C)C
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CC(=O)C(=CN(C)C)C(=O)N[C@@H](C)C(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of N-((2S)-3-methylbutan-2-yl)-3-oxobutanamide obtained in Step A (56.6 g) in N,N-dimethylformamide (220 mL) was added dropwise 1,1-dimethoxy-N,N-dimethylmethanamine (88 mL) over 15 min under ice bath, and the mixture was stirred at room temperature for 20 hr. The solvent was evaporated under reduced pressure to give the title compound (62.7 g).
Reaction SMILES: [ClH:1].Cl.Cl.[NH:4]1[CH:8]=[C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[CH:18][C:19]([C:21]4[CH:22]=N[CH:24]=[CH:25][CH:26]=4)=[CH:20][C:15]=3[CH2:14][N:13]([C:27](=[O:32])[C:28](F)(F)F)[CH:12]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:11]2)[N:6]=[CH:5]1.N1C=C(C=O)N=[CH:41]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(O)(=O)C>[ClH:1].[C:27]([N:13]1[CH2:14][C:15]2[CH:20]=[C:19]([C:21]3[CH:22]=[CH:41][CH:24]=[CH:25][CH:26]=3)[CH:18]=[CH:17][C:16]=2[N:10]([CH2:9][C:7]2[N:6]=[CH:5][NH:4][CH:8]=2)[CH2:11][C@H:12]1[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)(=[O:32])[CH3:28]
Reactant: O=C(N1Cc2cc(-c3cccnc3)ccc2N(Cc2c[nH]cn2)CC1Cc1ccccc1)C(F)(F)F
Reactant: O=Cc1c[nH]cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(=O)N1Cc2cc(-c3ccccc3)ccc2N(Cc2c[nH]cn2)C[C@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.9 %

Procedure:
A solution of 115 mg (0.29 mmol) of Compound B in 2.5 mL of dichloroethane and 2.5 mL of glacial acetic acid was treated with 69 mg (0.71 mmol) of 4-imidazole-carboxaldehyde, 3A sieves and stirred at rt for 18 hrs. The mixture was treated with 122 mg (0.58 mmol) of sodium triacetoxyborohydride in one portion and stirred at rt for 30 min and filtered. The filtrate was partitioned between 100 mL of ethyl acetate and 100 mL of 1 N sodium hydroxide. The organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo. The oil was purified by reverse phase preparative HPLC (gradient of aq methanol with 0.1% TFA). The yellow foam was evaporated 3× from methanolic hydrogen chloride. The foam was dissolved in water and lyophilyzed to afford 30 mg (22%) of Compound C as a yellow lyophilate. MS: (M+H)+ =480.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH:7]([O:18][Si](C)(C)C)[CH2:8][P:9]([CH2:14][CH2:15][CH2:16][CH3:17])(=[O:13])[O:10]CC)C(=O)C2=CC=CC=C12.[ClH:29]>>[ClH:29].[NH2:5][CH2:6][CH:7]([OH:18])[CH2:8][P:9]([CH2:14][CH2:15][CH2:16][CH3:17])(=[O:10])[OH:13]
Reactant: CCCCP(=O)(CC(CN1C(=O)c2ccccc2C1=O)O[Si](C)(C)C)OCC
Agent: Cl
Product: CCCCP(=O)(O)CC(O)CN
Temperature: 25 °C

Procedure:
The solution of 2.4 g of ethyl 3-phthalimido-2-trimethylsiloxy-propyl(n-butyl)phosphinate in 50 ml of concentrated aqueous hydrochloric acid is heated to reflux for 20 hours. After this time the suspension is cooled to room temperature and filtered. The filtrate is evaporated to dryness and the resulting semi-solid is co-evaporated with water (5×50 ml) and absolute ethanol (5×100 ml) and the white solid dried in high vacuum overnight. Crystallisation from absolute ethanol affords 3-amino-2-hydroxy-propyl(n-butyl)phosphinic acid hydrochloride, m.p. 158°-160°.
Reaction SMILES: C([O:5][C:6](=[O:34])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13](=[O:33])[C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([C@H:21]([NH:24]C(OC(C)(C)C)=O)[CH2:22][CH3:23])[C:15]=2[F:32])[CH:8]=1)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[NH2:24][C@@H:21]([C:16]1[C:15]([F:32])=[C:14]([C:19]([Cl:20])=[CH:18][CH:17]=1)[C:13]([C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[C:6]([OH:34])=[O:5])=[O:33])[CH2:22][CH3:23]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)c(C(=O)c2cccc(C(=O)OC(C)(C)C)c2)c1F
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC[C@@H](N)c1ccc(Cl)c(C(=O)c2cccc(C(=O)O)c2)c1F
Reaction time: 18 h
Yield: 91.1 %

Procedure:
Step 2 To a solution of 3-[3-((R)-1-tert-Butoxycarbonylamino-propyl)-6-chloro-2-fluoro-benzoyl]-benzoic acid tert-butyl ester (219 mg, 0.45 mmol) in DCM (5 mL) was added 4M HCl in dioxane (0.445 mL, 1.78 mmol, 4 eq) and the reaction stirred for 18 h. Complete conversion. Mixture was concentrated and then triturated with diethyl ether (˜1 mL) and the solid filtered off to give 3-[3-((R)-1-amino-propyl)-6-chloro-2-fluoro-benzoyl]-benzoic acid (154 mg, 0.41 mmol, 92%). [M+H]+ 336
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].CCN(CC)CC.Cl[C:17]1[C:26]2[C:21](=[N:22][CH:23]=[CH:24][N:25]=2)[CH:20]=[C:19]([Cl:27])[N:18]=1>C1COCC1>[Cl:27][C:19]1[N:18]=[C:17]([NH:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6])[C:26]2[C:21](=[N:22][CH:23]=[CH:24][N:25]=2)[CH:20]=1
Reactant: Clc1cc2nccnc2c(Cl)n1
Reactant: COC(=O)CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CCNc1nc(Cl)cc2nccnc12

Procedure:
A solution of methyl 3-aminopropanoate hydrochloride (4.88 mmol), Et3N (6.50 mmol) and 5,7-dichloropyrido[4,3-b]pyrazine (3.25 mmol) in THF (10 mL) was stirred at room temperature overnight. Volatiles were removed under reduced pressure, and the residue was treated with water and extracted with EtOAc. The combined extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography to afford the title compound. MS (m/z): 267 (M+H)+.
Reaction SMILES: [O:1]=[C:2]([CH3:6])[C:3]([OH:5])=[O:4].C([O-])(O)=O.[Na+].O.[C:13](=[O:20])([S:17][CH2:18][CH3:19])[O:14][CH2:15]I>C(Cl)Cl>[C:13](=[O:20])([S:17][CH2:18][CH3:19])[O:14][CH2:15][O:4][C:3](=[O:5])[C:2](=[O:1])[CH3:6]
Reactant: CC(=O)C(=O)O
Reactant: CCSC(=O)OCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCSC(=O)OCOC(=O)C(C)=O

Procedure:
Redistilled 2-oxopropanoic acid (12.6 ml, 0.18 mol) is added to a vigorously stirred mixture of NaHCO3 (30.6 g, 0.36 mol), TBA HSO4 (61.2 g, 0.18 mol), H2O (360 mL), and CH2Cl2 (360 mL) in an open Erlenmeyer flask. Following stirring for 10 min 5b (44.0 g, 0.18 mol) in CH2Cl2 (400 mL) is added during 3 h at 25° C. together with CH2Cl2 (500 mL) in portions to compensate for the evaporation. In this way the formation of sulfurous by-products is minimized. The mixture is extracted with CH2Cl2 (300-200 mL). The combined organic phases are washed with H2O (2×200 mL); dried (MgSO4) and evaporated. The residue is triturated with Et2O (600 mL). After filtration the filtrate is treated with charcoal, evaporated, and the residue crystallized from pentane at -70° C. to yield 6ob, melting below room temperature.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:22](O)(=[O:24])=[O:23])=[C:6]1[CH3:26].[Cl:28]CCl.P(Cl)(Cl)(Cl)(Cl)Cl>CN(C)C=O>[CH3:1][O:2][C:3](=[O:27])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:22]([Cl:28])(=[O:24])=[O:23])=[C:6]1[CH3:26]
Reactant: COC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)O)c2cc(F)ccc21
Reactant: ClCCl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)Cl)c2cc(F)ccc21
Temperature: 25 °C

Procedure:
A mixture of [5-fluoro-2-methyl-3-(2-sulfobenzyl)indol-1-yl]acetic acid methyl ester (0.30 g) and dichloromethane (1.5 mL) was treated portion wise with phosphorus pentachloride (0.15 g), followed by N,N-dimethylformamide (0.070 mL), and the resulting mixture was heated at reflux overnight. The mixture was cooled to room temperature, concentrated under reduced pressure and diluted with dichloromethane. The mixture was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with dichloromethane to afford the title compound as a yellow solid (1.3 g).
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[C:14]2[CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10][C:9]=2[N:8]=[C:7]2[CH:22]=[CH:23][CH:24]=[CH:25][C:6]=12)=[O:3].[ClH:26].O1CCOCC1>O1CCOCC1.CO>[ClH:26].[ClH:26].[C:2]([NH:4][C:5]1[C:14]2[CH2:13][NH:12][CH2:11][CH2:10][C:9]=2[N:8]=[C:7]2[CH:22]=[CH:23][CH:24]=[CH:25][C:6]=12)(=[O:3])[CH3:1]
Reactant: CC(=O)Nc1c2c(nc3ccccc13)CCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(=O)Nc1c2c(nc3ccccc13)CCNC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
10-Methylcarbonylamino-2-t-butoxycarbonyl-1,2,3,4-tetrahydro-benzo[b][1,6]-naphthyridine (0.5 g, 1.47 mmol) was suspended in a mixture of dioxane (4.5 ml) and methanol (1 ml), followed by adding thereto 4N-hydrogen chloride/dioxane (7.35 ml) under ice-cooling, and the resulting mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated to obtain the desired compound (0.369 g, quant.).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:19]1(=[O:25])[O:24][C:22](=[O:23])[CH:21]=[CH:20]1>>[CH:1]([CH:20]1[CH2:21][C:22](=[O:23])[O:24][C:19]1=[O:25])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: C=CCCCCCCCCCCCCCCCC
Reactant: O=C1C=CC(=O)O1
Product: CCCCCCCCCCCCCCCCC=CC1CC(=O)OC1=O
Temperature: 200 °C
Yield: 53.5 %

Procedure:
One thousand and eight grams (4.0 moles) of 1-octadecene and 490 grams (5.0 moles) of maleic anhydride were placed in a 2 liter stirred autoclave equipped with a thermocouple. The reaction was carried out by heating the mixture at 200° C. for 4 hours, and the cooled product was transferred to a 2 liter round bottom flask equipped with a magnetic stir bar, a thermometer, and a distilling head mounted on a Vigreux Column. Unreacted starting materials were removed at 200° C. and 10 torr, leaving the product ODSA (750 grams) in the pot. It was typically a tan solid (m.p. 40°-55° C.) with strong adsorption in its IR spectrum at 1860 and 1785 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:15]([C:16]#[N:17])[CH:14]=1)=[O:9]
Reactant: N#Cc1cccc(N)c1
Reactant: O=C(O)c1cc(Cl)ccc1O
Product: N#Cc1cccc(NC(=O)c2cc(Cl)ccc2O)c1

Procedure:
This material was prepared according to the method of Example 1 using 5-chlorosalicylic acid and 3-aminobenzonitrile, with reagents and solvents employed in similar molar ratios. 1HNMR (500 MHz, DMSO-d6): δ 3.72 (s, 3H), 6.74 (m, 1H), 7.05 (m, 1H), 7.45 (m, 1H), 7.58 (br m, 2H), 7.83 (m, 1H), 7.88 (m, 1H), 8.19 (br s, 1H), 10.59 (s, 1H).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][CH2:6][CH2:7][S:8][CH2:9][C:10]([OH:12])=[O:11].[CH3:13]O>>[Cl:5][CH2:6][CH2:7][S:8][CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: O=C(O)CSCCCl
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CSCCCl
Temperature: 5 °C
Reaction time: 2.5 h

Procedure:
Thionyl chloride (10 ml) was added to a solution of the title compound of Example 9 (9.7 g, 0.06 mole) in methyl alcohol (100 ml) cooled to 5° C. via an ice bath. The ice bath was removed and the reaction stirred for 2.5 hours at room temperature. The methyl alcohol and excess thionyl chloride were removed using a rotary evaporator to give 9.8 g, of an oil which was identified by NMR as the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:28][O:29][C:30]1[N:35]=[C:34]([O:36][CH3:37])[C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][N:31]=1>>[CH3:28][O:29][C:30]1[N:35]=[C:34]([O:36][CH3:37])[C:33]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:32][N:31]=1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)c(OC)n1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: COc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(S(C)(=O)=O)CC4)cc3n2)c(OC)n1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared via General Procedure B-3, was reacted with 2,4-dimethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine in General Procedure A. Purification on silica yielded 225. NMR (400 MHz CDCl3): 2.68 (4H, m, CH2), 2.81 (3H, s, CH3), 3.30 (4H, m, CH2), 3.85-3.88 (6H, m, CH2), 4.00-4.03 (4H, m, CH2), 4.06 (3H, s, CH3), 4.09 (3H, s, CH3), 7.33 (1H, s, ar), 8.93 (1H, s, ar). MH+=536.30
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14]C)[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>>[CH3:1][O:2][C:3]([CH:5]1[C:13]2[C:8](=[CH:9][C:10]([C:21](=[O:22])[C:20]3[CH:24]=[CH:25][C:17]([Cl:16])=[CH:18][CH:19]=3)=[C:11]([OH:14])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1CCc2ccc(OC)cc21
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: COC(=O)C1CCc2cc(C(=O)c3ccc(Cl)cc3)c(O)cc21

Procedure:
Analogously to the process described in Example 5, 19 g of 6-methoxy-indane-1-carboxylic acid methyl ester and 48 g of p-chlorobenzoyl chloride give 5-(p-chlorobenzoyl)-6-hydroxy-indane-1-carboxylic acid methyl ester of melting point 96°-98° C. (from ether-petroleum ether).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Li]CCCC.[C:12](OCC)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCOC(C)=O>C1COCC1>[C:13]1([C:12](=[O:19])[CH2:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1nccs1
Reactant: CCOC(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Cc1nccs1)c1ccccc1
Reaction time: 1 h
Yield: 16.4 %

Procedure:
To a solution of 2-methylthiazole (500 mg, 5.1 mmol) in anhydrous THF (10 mL) at −78° C. under nitrogen was added dropwise n-BuLi (2.5 mol/L, 2.0 mL), after being stirred at this temperature for 1 hour, a solution of ethyl benzoate (1.1 g, 7.3 mmol) in anhydrous THF (5 mL) was added, and the reaction mixture was stirred at room temperature overnight. When TLC (PE:EtOAc=7:1) indicated that the starting materials were consumed, water was added to quench the reaction, and the aqueous layer extracted with EtOAc (10 mL×3). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, concentrated, and purified by column chromatography (PE:EtOAc=15:1) to afford Intermediate 3 as a yellow oil (170 mg, yield: 17.0%).
Reaction SMILES: [CH3:1][C@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:3][CH2:4][C:5]([OH:7])=O.C(N(CC)CC)C.CC(C)(C)C(Cl)=O.[Li+].[Cl-].[CH3:29][C@@H:30]1[CH:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:33][C:32](=[O:41])[NH:31]1>C1COCC1>[CH3:29][C@@H:30]1[C@H:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:33][C:32](=[O:41])[N:31]1[C:5](=[O:7])[CH2:4][CH2:3][C@H:2]([CH3:1])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: C[C@H]1NC(=O)OC1c1ccccc1
Reactant: CCCCC[C@@H](C)CCC(=O)O
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCC[C@@H](C)CCC(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 87.7 %

Procedure:
Compound 154 (6.504 g, 37.76 mmol) was dissolved in THF (95 mL) and cooled to 0° C. Triethylamine (19.74 mL, 141.6 mmol) was added dropwise, followed by dropwise addition of trimethylacetyl chloride (6.98 mL, 56.64 mmol). The thick white suspension was stirred at 0° C. for 90 minutes. LiCl (1.86 g, 41.54 mmol), (4R)-4-methyl-5-phenyl-1,3-oxazolidin-2-one (6.824 g, 38.51 mmol), and THF (70 mL) were added, and the reaction warmed to room temperature overnight. The solvent was evaporated. The solids were taken up in EtOAc, filtered off, and washed generously with EtOAc. The filtrate was washed with water (2×50 mL), and brine. The organics were dried over MgSO4, filtered, and rotovapped. The crude material was chromatographed on silica eluting with 10% EtOAc/hexanes to give 155 as an oil (10.974 g, 88%). 1H NMR (400 MHz, CDCl3) δ 7.44–7.35 (m, 3H), 7.31–7.26 (m, 2H), 5.66 (d, J=7.33 Hz, 1H), 4.76 (quint, J=7.03 Hz, 1H), 3.04–2.96 (m, 1H), 2.93–2.86 (m, 1H), 1.74–1.66 (m, 1H), 1.52–1.47 (m, 1H), 1.46–1.36 (m, 2H), 1.27–1.16 (m, 2H), 0.92–0.87 (m, 8H); [α]D=+34.1 (c1 in CHCl3).
Reaction SMILES: [Cl:1][C:2]1[C:6]([N:7]([CH2:15][CH3:16])[C:8](=[O:14])[CH:9]([CH3:13])[CH2:10][CH:11]=[O:12])=[CH:5][N:4]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1.[CH3:23][Mg]Br.C([O-])(O)=O.[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C1COCC1>[Cl:1][C:2]1[C:6]([N:7]([CH2:15][CH3:16])[C:8](=[O:14])[CH:9]([CH3:13])[CH2:10][C:11](=[O:12])[CH3:23])=[CH:5][N:4]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1
Reactant: C[Mg]Br
Reactant: CCN(C(=O)C(C)CC=O)c1cn(-c2cccnc2)nc1Cl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(C(=O)C(C)CC(C)=O)c1cn(-c2cccnc2)nc1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-2-methyl-4-oxobutanamide (0.390 g, 1.22 mmol) was dissolved in THF (12 mL) at −78° C. To this stirring solution was added dropwise methylmagnesium bromide (0.446 mL, 1.34 mmol). The reaction mixture was stirred at −78° C. for 30 minutes and was warmed to 0° C., at which point the reaction was quenched with a saturated aqueous NH4Cl solution. The reaction product was extracted with diethyl ether, and the combined organics were washed with brine, then dried over Na2SO4 and concentrated under vacuum to provide a yellow oil. The oil was loaded onto CELITE® and purified by flash column chromatography using 0-50% acetone/hexanes as eluent. The secondary alcohol recovered as an impure oil was used immediately. The residual oil was taken up in CH2Cl2 (10 mL) and buffered with NaHCO3 (0.153 g, 1.82 mmol). The resulting mixture was cooled to 0° C. and Dess-Martin periodinane (0.516 g, 1.22 mmol) was added in a single portion. The reaction mixture was stirred at 0° C. for 1 hour, then was warmed to room temperature. The reaction was quenched by slow addition of a saturated aqueous sodium bisulfite solution, and extracted with CH2Cl2. The organic layer was washed with brine, dried over Na2SO4 and concentrated to an oil that was loaded directly onto CELITE®. Purification by flash column chromatography using 0-40% acetone/hexanes as eluent provided the title compound as a clear, colorless oil. (0.0900 g, 20% over two steps).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:20])=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([Cl:20])[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: OC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Solvent: ClCCl
Product: Clc1ccc(C(Cl)c2ccc(Cl)cc2)cc1
Reaction time: 4 h

Procedure:
To a solution of bis(4-chlorophenyl)methanol (2.0 g) in dichloromethane (20 ml) was added oxalylchloride (1 ml). The mixture was stirred for 4 hours and the solvent was removed in vacuo. The residue was dissolved in n-hexane (20 ml) and filtered off. The solvent was removed in vacuo to give colorless oil of bis(4-chlorophenyl)methyl chloride (2.15 g).