Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:11]C)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+:14]>O>[C:1]([O-:11])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[Na+:14]
Reactant: COC(=O)C=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])C=Cc1ccccc1

Procedure:
A 300 ml separable flask was charged with 16.2 grams (0.10 mol) of methyl cinnamate, and a solution of 4.3 grams of 97 wt. % sodium hydroxide in 140 grams of water. The mixture was reacted at 80° C. for 15 minutes with vigorous stirring. The aqueous alkaline solution of sodium cinnamate thus obtained was poured into a hot funnel which was previously kept at 80° C. The solution was added dropwise with stirring to a beaker having 20 ml of aqueous sulfuric acid solution containing 0.053 mol of sulfuric acid. The resultant suspension was cooled to room temperature and filtered with suction. The crystals were washed with 50 ml of water by stirring in a beaker, filtered and dried under reduced pressure. Cinnamic acid obtained was 14.7 grams (99.9% yield). The purity was above 99.9% according to analysis.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][OH:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1
Reactant: OCCBr
Reactant: Nc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCNc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 53.8 %

Procedure:
A mixture of 4-fluoroaniline (1.0 g, 8.99 mmol), 2-bromoethanol (2.25 g, 17.99 mmol), potassium carbonate (2.49 g, 17.99 mmol), and anhydrous N,N-dimethylformamide (4 mL) was added to a 50 mL RBF with a magnetic stirring bar. The mixture was allowed to stir at 80° C. for 18 hours. Progress of the reaction was monitored by TLC using ethyl acetate:hexanes (1:1) (Rf product=0.4). The reaction was partitioned using ethyl acetate (80 mL) and water (30 mL). The organic layer was washed with saturated aqueous NaCl (3×30 mL), dried (Na2SO4), filtered, and concentrated. The crude material was purified by silica gel column chromatography using a gradient elution of 30-100% ethyl acetate in hexanes to afford the title compound as an oil (0.75 g, 54% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([O:15]C)=O)=[C:10](/[N:17]=[CH:18]/[N:19]([CH3:21])C)[CH:9]=2)=[CH:4][CH:3]=1.NC1[CH:43]=[CH:42][C:26]([O:27][CH2:28][C@@H:29]2[CH2:33][C@@H:32]([OH:34])[CH2:31][N:30]2[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[C:25]([O:44][CH3:45])[CH:24]=1>C1(O)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]3[C:13](=[O:15])[N:19]([C:21]4[CH:43]=[CH:42][C:26]([O:27][CH2:28][C@@H:29]5[CH2:33][C@@H:32]([OH:34])[CH2:31][N:30]5[C:35]([O:37][C:38]([CH3:41])([CH3:39])[CH3:40])=[O:36])=[C:25]([O:44][CH3:45])[CH:24]=4)[CH:18]=[N:17][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1/N=C/N(C)C
Reactant: COc1cc(N)ccc1OC[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Solvent: Oc1ccccc1
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OC[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Yield: 41.8 %

Procedure:
Methyl 5-(4-chlorophenyl)-3-{[(E)-(dimethylamino)methylidene]amino}-2-thiophenecarboxylate (857 mg, 2.66 mmol) was mixed with tert-butyl (2S,4R)-2-[(4-amino-2-methoxyphenoxy)methyl]4-hydroxypyrrolidine-1-carboxylate (900 mg) in phenol (1.0 g) at 120° C. for 15 min. Workup and purification of the reaction mixture provided 650 mg of tert-butyl (2S,4R)-2-({4-[6-(4-chlorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl]-2-methoxyphenoxy}methyl)-4-hydroxypyrrolidine-1-carboxylate. A portion of this material (105 mg, 0.179 mmol) was dissolved in a 1:1 mixture of dichloromethane and trifluoroacetic acid. The mixture was stirred at room temperature for 10 min and was then concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with a saturated solution of NaHCO3, brine, dried (Na2SO4) and concentrated to provide the title compound.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=2)[NH:11][CH:10]=1.[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:21]1([S:27]([N:11]2[C:12]3[C:17](=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=3)[C:9]([Br:8])=[CH:10]2)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=[N+]([O-])c1ccc2c(Br)c[nH]c2c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2c(Br)cn(S(=O)(=O)c3ccccc3)c2c1
Reaction time: 8 h

Procedure:
Add triethyl amine (Et3N) (6.7 mL, 48 mmol, 4 eq) and DMAP (240 mg, 2.0 mmol, 0.1 eq) to a slurry of 3-bromo-6-nitro indole, 2 (4.82 g, 20 mmol) in 100 mL of CH2Cl2. Let the solution stir until the 3-bromo-6-nitro indole dissolves and then add benzenesulfonyl chloride (3.1 mL, 24 mmol, 1.2 eq). Let the solution stir overnight. Filter off the precipitate, which forms, wash the precipitate with CH2Cl2, and collect the filtrates to give 6.83 g of the title compound. Sequentially wash the combined filtrates with 1 M HCl, saturated sodium bicarbonate, and brine. Dry the organic layer over Na2SO4, filter, and then concentrate the filtrate. Boil the resulting solid in ˜30 mL of CH2Cl2 and a little MeOH, add 30 mL hexanes, let cool, and then filter off the precipitate to give another 1.3 g of the title compound. 1H NMR (DMSO-d6) δ 8.74 (d, 1H, J=2.2 Hz), 8.58 (s, 1H), 8.19 (dd, 1H, J=2.2, 8.8 Hz), 8.08-8.05 (m, 2H), 7.75-7.68 (m, 2H), 7.63-7.59 (m, 2H)—.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH2:16][C@@:15]4([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=5[C:19](=[O:26])[O:18]4)[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[C:4]([F:27])[CH:3]=1.O1CCCC1.C(P)(C)(C)C.C([Sn](CCCC)(CCCC)[C:43]1[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=1)CCC>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:27][C:4]1[CH:3]=[C:2]([C:43]2[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=2)[CH:7]=[CH:6][C:5]=1[C:8]1([C:11]([N:13]2[CH2:17][CH2:16][C@@:15]3([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[C:19](=[O:26])[O:18]3)[CH2:14]2)=[O:12])[CH2:10][CH2:9]1
Reactant: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(Br)cc4F)CC3)C2)c2ccccc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Agent: [Pd]
Agent: CC(C)(C)P
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(-c5ccncc5)cc4F)CC3)C2)c2ccccc21
Temperature: 120 °C

Procedure:
To a solution of (1R)-1′-{[1-(4-bromo-2-fluorophenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (30 mg, 0.00007 mol, this compound was prepared by using a method that was analogous to that used for the synthesis of 238) in tetrahydrofuran (0.2 mL, 0.002 mol) were added tris(dibenzylideneacetone)dipalladium(0) (3 mg, 0.000003 mol), ti-tert-butylphosphine (1.7 mg, 0.0000083 mol), 4-(tributylstannyl)pyridine (30.7 mg, 0.0000835 mol), and the mixture was heated to 120° C. under microwave for 30 minutes. The reaction mixture was then filtered and the filtrate was diluted with methanol, and the product was isolated and purified by prep-HPLC. LC/MS (M+H+) 429.2.
Reaction SMILES: C([S:4][CH:5]([CH3:12])[CH:6]([CH3:11])[C:7]([O:9][CH3:10])=[O:8])(=O)C>CO>[SH:4][CH:5]([CH3:12])[CH:6]([CH3:11])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)C(C)C(C)SC(C)=O
Solvent: CO
Product: COC(=O)C(C)C(C)S
Yield: 44 %

Procedure:
Conditions are the same as for Example 2, but with the product of Example 3 as the starting component and methanol as solvent; 44% yield. Odor: at 0.1 ppm in DPG—onions, green vegetable, peach, tropical fruit, metallic. GC/MS (EI): m/z (%) 148(46), 115(25), 88(100), 61(64), 59(100). 1H NMR (CDCl3): δ 3.69 (s mix of isomers, 3H), 3.13-3.30 (m, 1H), 2.48-2.58 (m, 1H), 1.66 & 1.51 (2d, J=7.34 Hz, 1H mix of diastereomers), 1.31-1.34 (2d mix of isomers, J=6.87 Hz, 3H), 1.18-1.27 (2d mix of isomers, J=6.87 Hz, 3H). 13C NMR (CDCl3) for mix of diastereomers: δ 175.0, 51.9, 51.6, 48.7, 47.6, 37.7, 37.1, 23.5, 21.9, 14.3, 13.5.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.Br[CH2:25][C:26]([NH2:28])=[O:27]>>[C:19]([C:12]1[CH:11]=[C:10]2[C:15]([C:16]3[C:17](=[O:18])[C:5]4[CH:4]=[CH:3][C:2]([O:1][CH2:25][C:26]([NH2:28])=[O:27])=[CH:23][C:6]=4[C:7]([CH3:21])([CH3:22])[C:8]=3[NH:9]2)=[CH:14][CH:13]=1)#[N:20]
Reactant: NC(=O)CBr
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: CC1(C)c2cc(OCC(N)=O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound A7-17, the title compound was prepared from Compound A6 and 2-bromo-acetamide.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=C(C(C)C)C=C(C(C)C)[C:5]=1S(N/N=C(/C(C)C)\C)(=O)=O)(C)[CH3:2].C([Li])CCC.[Si:31]([O:38][CH2:39][C@@H:40]([N:43]([CH2:51][C:52](N(OC)C)=[O:53])[C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH:41]=[CH2:42])([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>CCCCCC.CN(CCN(C)C)C>[Si:31]([O:38][CH2:39][C@@H:40]([N:43]([CH2:51][C:52](=[O:53])[C:1](=[CH2:2])[CH:4]([CH3:9])[CH3:5])[C:44](=[O:50])[O:45][C:46]([CH3:48])([CH3:49])[CH3:47])[CH:41]=[CH2:42])([C:34]([CH3:35])([CH3:36])[CH3:37])([CH3:32])[CH3:33]
Reactant: C/C(=N\NS(=O)(=O)c1c(C(C)C)cc(C(C)C)cc1C(C)C)C(C)C
Reactant: C=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(CC(=O)N(C)OC)C(=O)OC(C)(C)C
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Product: C=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(CC(=O)C(=C)C(C)C)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a suspension of (E)-2,4,6-triisopropyl-N′-(3-methylbutan-2-ylidene)benzenesulfonohydrazide (Intermediate 33, 8 g, 21.82 mmol) in hexane (65 mL) and TMEDA (6.50 mL) at −78° C. was added dropwise n-butyllithium (1.6M in hexanes) (34.1 mL, 54.56 mmol). The reaction mixture turned orange and was stirred for 30 minutes at −78° C., then was warmed to 0° C. and bubbling started immediately. The suspension became a yellow solution. After ˜15 minutes the bubbling stopped and (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)but-3-en-2-yl(2-(methoxy(methyl)-amino)-2-oxoethyl)carbamate (Intermediate 5, 4.39 g, 10.91 mmol) was added as a solution in hexane (2 mL). After ˜15 minutes LC/MS shows desired product and no remaining Weinreb amide starting material. The reaction mixture was quenched with saturated sodium bicarbonate and extracted with ether twice. The ether extracts were dried over magnesium sulfate, filtered and concentrated to afford a yellow oil. Silica gel chromatography (0%-10% ethyl acetate/hexanes) afforded the desired product (2.219 g, 49.4%) as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:14])=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][NH:10][CH2:9]2)[CH:5]=C[CH:7]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=1)[C:19]([NH:21][CH2:22][C:23](O)=[O:24])=[O:20].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[Cl:15][C:16]1[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=1)[C:19]([NH:21][CH2:22][C:23]([N:10]1[CH2:11][C:12](=[O:13])[N:8]([C:4](=[CH2:5])[C:3]([CH3:14])=[C:2]([Cl:1])[CH3:7])[CH2:9]1)=[O:24])=[O:20]
Reactant: Cc1c(Cl)cccc1N1CNCC1=O
Reactant: O=C(O)CNC(=O)c1cccc(Cl)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: C=C(C(C)=C(C)Cl)N1CN(C(=O)CNC(=O)c2cccc(Cl)c2)CC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(3-Chloro-2-methyl-phenyl)-imidazolidin-4-one (360 mg, 1.7 mmol, 1 eq), (3-Chloro-benzoylamino)-acetic acid (365 mg, 1.7 mmol, 1 eq), BOP (909 mg, 2.05 mmol, 1.2 eq), and TEA (0.88 ml) in DMF (5 ml) was stirred at room temperature overnight. It was purified with HPLC to give the desired product. LCMS observed for (M+H)+: 406.1
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[Cl:20][C:21]1[CH:31]=[CH:30][C:24]2[NH:25][C:26](=[O:29])[CH2:27][O:28][C:23]=2[CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[Cl:20][C:21]1[CH:31]=[CH:30][C:24]2[N:25]([CH2:2][C:3]([N:5]3[CH2:10][CH2:9][N:8]([C:11]4[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=4)[CH2:7][CH2:6]3)=[O:4])[C:26](=[O:29])[CH2:27][O:28][C:23]=2[CH:22]=1
Reactant: O=C1COc2cc(Cl)ccc2N1
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(N2CCN(C(=O)CN3C(=O)COc4cc(Cl)ccc43)CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (1) (331 mg, 1.1 mmol, 1 equiv) in 5 ml of DMF, 4H-Benzo[1,4]oxazin-3-one (28) (200 mg, 1.1 mmol, 1.0 equiv) and cesium carbonate (710 mg, 2.2 mmol, 2 equiv) was stirred at RT overnight. The reaction solution was diluted with EtOAc, and the organic solution was washed with water. Purification of the crude reaction mixture using flash chromatography provided 7-chloro-4-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-4H-benzo[1,4]oxazin-3-one (29): LCMS Retention time, 2.58 min.; LCMS observed (M+H)+: 450.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][C:15]([OH:17])=[O:16])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C[O-].[Li+].[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]#[C:29][C:30]1[C:31]([O:40][CH3:41])=[CH:32][C:33]([O:38][CH3:39])=[C:34]([CH:37]=1)[CH:35]=O>CN(C=O)C.CO>[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]#[C:29][C:30]1[C:31]([O:40][CH3:41])=[CH:32][C:33]([O:38][CH3:39])=[C:34](/[CH:35]=[CH:2]/[C:1]([C:4]2[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][C:15]([OH:17])=[O:16])(=[O:12])=[O:11])=[CH:6][CH:5]=2)=[O:3])[CH:37]=1
Reactant: CC(=O)c1ccc(S(=O)(=O)NCC(=O)O)cc1
Reactant: COc1cc(OC)c(C=O)cc1C#Cc1ccccc1N
Agent: C[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc(OC)c(/C=C/C(=O)c2ccc(S(=O)(=O)NCC(=O)O)cc2)cc1C#Cc1ccccc1N
Temperature: 25 °C
Reaction time: 23 h
Yield: 35.8 %

Procedure:
Ex-51A: A solution (4-acetylbenzenesulfonylamino)acetic acid (Ex-26A, 238 mg, 1.01 mmol) in DMF (4.4 mL) and MeOH (1.9 mL) was treated with lithium methoxide (153 mg, 4.04 mmol), followed by the addition of 5-(2-amino-phenylethynyl)-2,4-dimethoxybenzaldehyde (Ex-35C, 300 mg, 1.07 mmol). The reaction mixture was stirred at room temperature for 23 h under nitrogen. It was quenched with water (10 mL) and extracted with ethyl acetate (25 mL). The aqueous phase was acidified with 6N HCl to pH3 and was extracted with (3:1) ethyl acetate/THF (5×25 mL). The organic phase was brined, dried over sodium sulfate, and concentrated to a yellow oil. The crude material was purified by column chromatography (0–7.5% MeOH in dichloromethane) to give (4-{3E-[5-(2-amino-phenylethynyl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonylamino)acetic acid (188 mg, 36%) as an orange solid. 1H-NMR (300 MHz, DMSO-d6) 8.23 (d, 2H, J=8.7), 8.19 (s, 1H), 7.99 (d, 1H, J=15.9 Hz), 7.92 (d, 2H, J=7.80 Hz), 7.82 (d, 1H, J=16.5 Hz), 7.16 (d, 1H, J=6.6 Hz), 7.05 (t, 1H, J=8.1 Hz), 6.76 (s, 1H), 6.71 (d, 1H, J=7.8 Hz), 6.52 (t, 1H, J=7.2 Hz), 5.72 (s, 1H), 5.45 (br s, 1H), 3.96 (s, 3H), 3.95 (s, 3H), 3.41 (m, 2H).
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[C:21]([N:37]2[CH2:42][C@H:41]([CH3:43])[O:40][C@H:39]([CH3:44])[CH2:38]2)=[C:22]([F:36])[C:23]2[O:27][N:26]=[C:25]([C:28]3[CH:33]=[N:32][CH:31]=[C:30]([Cl:34])[N:29]=3)[C:24]=2[CH:35]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.Cl>C(O)C.CCOC(C)=O>[Cl:34][C:30]1[N:29]=[C:28]([C:25]2[C:24]3[CH:35]=[C:20]([CH2:19][OH:18])[C:21]([N:37]4[CH2:42][C@H:41]([CH3:43])[O:40][C@H:39]([CH3:44])[CH2:38]4)=[C:22]([F:36])[C:23]=3[O:27][N:26]=2)[CH:33]=[N:32][CH:31]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc3c(-c4cncc(Cl)n4)noc3c2F)C[C@H](C)O1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: C[C@@H]1CN(c2c(CO)cc3c(-c4cncc(Cl)n4)noc3c2F)C[C@H](C)O1
Temperature: 70 °C

Procedure:
5-((tert-Butyldiphenylsilyloxy)methyl)-3-(6-chloropyrazin-2-yl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole (Intermediate 329, 320 mg, 0.51 mmol) was dissolved in ethanol (10 ml) and was treated with 15 ml of 10% aq HCl, the mixture was heated at 70° C. for 1 hour. The reaction was cooled and diluted with EtOAc before being quenched with aqueous sodium bicarbonate solution. The mixture was extracted with EtOAc, which was washed with brine, dried (MgSO4) and concentrated.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:22]=[CH:21][C:12]([O:13][CH2:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[C:11]([C:23]([F:26])([F:25])[F:24])[CH:10]=2)O1.[NH2:28][C:29]1[C:30]([C:38]#[N:39])=[N:31][C:32](Cl)=[CH:33][C:34]=1[NH:35][CH3:36].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:28][C:29]1[C:30]([C:38]#[N:39])=[N:31][C:32]([C:9]2[CH:22]=[CH:21][C:12]([O:13][CH2:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[C:11]([C:23]([F:24])([F:25])[F:26])[CH:10]=2)=[CH:33][C:34]=1[NH:35][CH3:36]
Reactant: CNc1cc(Cl)nc(C#N)c1N
Reactant: CC1(C)OB(c2ccc(OCc3cccnc3)c(C(F)(F)F)c2)OC1(C)C
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CNc1cc(-c2ccc(OCc3cccnc3)c(C(F)(F)F)c2)nc(C#N)c1N
Temperature: 100 °C
Reaction time: 2 h
Yield: 53.3 %

Procedure:
A suspension of 3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenoxy)methyl)pyridine (2.38 g), 3-amino-6-chloro-4-(methylamino)-picolinonitrile (1.15 g), tris(dibenzylideneacetone)dipalladium (0) (296 mg), tricyclohexylphosphine (218 mg) and potassium phosphate (2.78 g) in 1,4-dioxane (20 ml) and water (10 ml) was stirred at 100° C. for 2 h. The reaction mixture was cooled and partitioned between water and ethyl acetate, washed with water, brine, dried over sodium sulfate, filtered and concentrated. Purified by Biotage SNAP cartridge KP-Sil column (50 g, heptane:ethyl acetate=1:0, 1:1 to 0:1 then dichloromethane:methanol=1:0, 20:1) to give 1.335 g brown solid as 3-amino-4-(methylamino)-6-(4-(pyridin-3-ylmethoxy)-3-(trifluoromethyl)phenyl)picolinonitrile (53%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[NH:21][C:22]([C:24]1[C:28]2[N:29]=[CH:30][N:31]=[C:32](S(C)=O)[C:27]=2[S:26][CH:25]=1)=[O:23].CCN(C(C)C)C(C)C.[CH3:45][O:46][C:47]1[CH:52]=[CH:51][C:50]([NH2:53])=[CH:49][CH:48]=1>O1CCOCC1.C(OCC)(=O)C>[CH3:45][O:46][C:47]1[CH:52]=[CH:51][C:50]([NH:53][C:32]2[C:27]3[S:26][CH:25]=[C:24]([C:22]([NH:21][C:3]4[CH:4]=[C:5]([C:8](=[O:20])[NH:9][C:10]5[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[CH:11]=5)[CH:6]=[CH:7][C:2]=4[CH3:1])=[O:23])[C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:49][CH:48]=1
Reactant: COc1ccc(N)cc1
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1NC(=O)c1csc2c(S(C)=O)ncnc12
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(Nc2ncnc3c(C(=O)Nc4cc(C(=O)Nc5cccc(C(F)(F)F)c5)ccc4C)csc23)cc1
Temperature: 120 °C
Reaction time: 18 h
Yield: 80.8 %

Procedure:
N-(2-methyl-5-(3-(trifluoromethyl)phenylcarbamoyl)phenyl)-4-(methylsulfinyl)thieno[3,2-d]pyrimidine-7-carboxamide (30 mg, 0.060 mmol) was dissolved in dioxane (1 mL) and DIPEA (20 μL, 0.119 mmol) and 4-methoxybenzeneamine (37 mg, 0.298 mmol) were added thereto. The reaction mixture was stirred at 120° C. for 18 hours, cooled to room temperature, diluted with ethyl acetate and washed with a brine. The organic layer was dried with MgSO4, filtered and concentrated under reduced pressure. The resulting mixture was purified by silica gel chromatography to obtain the title compound (28 mg, 81% yield).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]#[N:12])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(O)(C)(C)C.CCOCC>[N:13]1([C:2]2[C:3]3[C:10]([C:11]#[N:12])=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C1CCNCC1
Reactant: N#Cc1c[nH]c2ncnc(Cl)c12
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: N#Cc1c[nH]c2ncnc(N3CCCCC3)c12
Temperature: 25 °C
Yield: 42.5 %

Procedure:
To a stirred solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (54 mg/0.3 mmol) (prepared by the method of Townsend, et. al., J. Am. Chem. Soc., 1969, 91, 2102) suspended in 3.0 mL tert-Butanol was added piperidine (59 μL/0.60 mmol). The resulting mixture was then heated at reflux for 2.5 h and after cooling to room temperature, was transferred to a separatory funnel and diluted with ether (20 mL). The solution was extracted 2×10 mL with 1N HCl, the combined aqueous layers were adjusted to pH 7 with 2 N potassium hydroxide (KOH) solution forming a precipitate which was collected by filtration, washed with water and dried under reduced pressure to give 29 mg (42%) of the title compound as a colorless solid. Mp 209-211° C.; 1H NMR (400 MHz) (acetone-d6)δ: 1.72-1.74 (m, 6H), 3.72-3.79 (m, 4H), 8.12 (s, 1H), 8.29 (s, 1H). LRMS: 228 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][N:12]=[C:11]([CH3:14])[C:10]=1[C:15](O)=[O:16]>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][N:12]=[C:11]([CH3:14])[C:10]=1[CH2:15][OH:16]
Reactant: Cc1ccc(-c2snc(C)c2C(=O)O)c(F)c1
Solvent: C1CCOC1
Product: Cc1ccc(-c2snc(C)c2CO)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 25-mL round-bottom flask, was placed 5-(2-fluoro-4-methylphenyl)-3-methyl-1,2-thiazole-4-carboxylic acid (180 mg, 0.72 mmol, 1.00 equiv), tetrahydrofuran (10 mL). This was followed by the addition of BH3 (2.1 mL) at 0-5° C. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:3). This resulted in 100 mg (59%) of [5-(2-fluoro-4-methylphenyl)-3-methyl-1,2-thiazol-4-yl]methanol as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][NH:13][C:12]1=[O:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24](I)[CH2:25][CH2:26][CH3:27]>[Ag]=O.CN(C)C=O>[CH2:24]([N:13]1[CH2:14][C@@H:15]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[C:12]1=[O:23])[CH2:25][CH2:26][CH3:27]
Reactant: CCCCI
Reactant: CC(C)(C)OC(=O)[C@@H]1CNC(=O)N1C(=O)OCc1ccccc1
Agent: O=[Ag]
Solvent: CN(C)C=O
Product: CCCCN1C[C@@H](C(=O)OC(C)(C)C)N(C(=O)OCc2ccccc2)C1=O
Yield: 89.1 %

Procedure:
6.4 g of tert.-butyl (4S)-3-benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylate, 8.6 g of silver oxide, 18.4 g of n-butyl iodide and 100 ml of dimethylformamide are treated in the same manner as described in Example 1-(2). 6.7 g of tert.-butyl (4S)-1-n-butyl-3-benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylate are obtained as colorless syrup.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.C(N(CC)CC)C.[Cl-].[CH3:17][O:18][C:19](=[O:26])[CH2:20][CH2:21][CH2:22][C:23](O)=[O:24].O>O1CCCC1.C(OCC)C>[CH3:17][O:18][C:19](=[O:26])[CH2:20][CH2:21][CH2:22][C:23]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1)=[O:24]
Reactant: COC(=O)CCCC(=O)O
Reactant: Nc1cccc(Br)n1
Agent: [Cl-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)CCCC(=O)Nc1cccc(Br)n1

Procedure:
A solution of 1.0 g of 2-amino-6-bromopyridine and 580 mg of triethylamine in 12 ml of tetrahydrofuran is mixed with stirring and ice cooling by instillation with 0.78 ml of glutaric acid methyl ester chloride and the mixture is stirred for 17 hours at room temperature. The reaction mixture is added to water, shaken out with diethyl ether, the organic phase is dried (sodium sulfate) and concentrated by evaporation. The residue is chromatographed on silica gel with dichloromethane/methanol=95/5. 668 mg of 5-(6-bromo-2-pyridylamino)-5-oxo-pentanoic acid methyl ester of melting point 128°-131° C. is obtained.