Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[CH2:10](Cl)[CH:11]=[CH2:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:12]([N:4]1[C:3](=[O:8])[C:2]([CH3:9])([CH3:1])[NH:6][C:5]1=[O:7])[CH:11]=[CH2:10]
Reactant: CC1(C)NC(=O)NC1=O
Reactant: C=CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCN1C(=O)NC(C)(C)C1=O

Procedure:
640.6 g (5 mols) of 5,5-dimethylhydantoin, 420.9 g (5 mols+10% excess) of allyl chloride, 380.1 g (2.5 mols+10% excess) of potassium carbonate and 1,000 ml of dimethylformamide are reacted, and worked up, analogously to Example 1. 820 g (97.5% of theory) of a brownish waxy crude product are obtained and are purified by distillation. 713.7 g (84.9% of theory) of a distillate are obtained; this boils at 114° C./13.3 Pas and melts at 66.2°-68.7° C.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[NH2:19][C@@H:20]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:21]([N:23]([CH3:25])[CH3:24])=[O:22]>>[CH3:25][N:23]([CH3:24])[C:21]([C@@H:20]([NH:19][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[CH2:26][CH:27]([CH3:28])[CH3:29])=[O:22]
Reactant: CC(C)C[C@H](N)C(=O)N(C)C
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Agent: Cl
Product: CC(C)C[C@H](NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1)C(=O)N(C)C

Procedure:
The title compound was synthesized in analogy to Example 6, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g) and (2S)-2-amino-N,N,4-trimethyl-pentanamide hydrochloride (1:1) (CAN 207595-81-1) as starting materials, and isolated (68 mg, 85%) as yellow solid; LC-MS (UV peak area, ESI) 100%, 375.2387 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[CH:21]1(B(O)O)[CH2:23][CH2:22]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>Cl[Pd]Cl.O1CCOCC1.O>[CH:21]1([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=3)[N:3]=2)[CH2:23][CH2:22]1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: OB(O)C1CC1
Agent: Cl[Pd]Cl
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc2c(C3CC3)nc(Nc3cc(C)[nH]n3)cc2c1
Temperature: 130 °C
Reaction time: 8 h
Yield: 0.8 %

Procedure:
To a mixture of (1-Chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine (0.2887 g 1 mmol), cyclopropyl boronic acid (0.1718 g, 2 mmol), PdCl2 (0.0177 g, 10% mmol), and K3PO4 (0.5307 g, 2.5 mmol) under Argon was added Dioxane/H2O=10:1(1 ml) and P(tBu)3 (20% mmol). The mixture was heated to 130° C. and stirred overnight. The product was purified by preparative HPLC to give 2.5 mg of solid. LC-MS: m/e 295 (MH+).
Reaction SMILES: CS[C:3]1[N:8]2[CH:9]=[N:10][CH:11]=[C:7]2[CH:6]=[N:5][N:4]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>C1(C)C=CC=CC=1>[N:12]1([C:3]2[N:8]3[CH:9]=[N:10][CH:11]=[C:7]3[CH:6]=[N:5][N:4]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: CSc1nncc2cncn12
Reactant: C1CNCCN1
Solvent: Cc1ccccc1
Product: c1ncn2c(N3CCNCC3)nncc12

Procedure:
A mixture of 6.5 gm. of 4-(methylthio)-imidazo[1,5-d]-as-triazine, 17.2 gm. of anhydrous piperazine and 120 ml. of toluene is reacted as described in Example 40 giving the desired product, m.p. 160°-165° C.
Reaction SMILES: F[B-](F)(F)F.C[N+:7](C)=C(N(C)C)ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[C:32]([C:34]1[CH:39]=[CH:38][C:37]([CH:40]2[C:49]3[C:48](=[O:50])[CH2:47][CH:46]([C:51]([OH:53])=O)[CH2:45][C:44]=3[N:43]([C:54]3[CH:59]=[CH:58][CH:57]=[C:56]([C:60]([F:63])([F:62])[F:61])[CH:55]=3)[C:42](=[O:64])[NH:41]2)=[CH:36][CH:35]=1)#[N:33].N>CN(C)C=O.O>[C:32]([C:34]1[CH:35]=[CH:36][C:37]([CH:40]2[C:49]3[C:48](=[O:50])[CH2:47][CH:46]([C:51]([NH2:7])=[O:53])[CH2:45][C:44]=3[N:43]([C:54]3[CH:59]=[CH:58][CH:57]=[C:56]([C:60]([F:63])([F:62])[F:61])[CH:55]=3)[C:42](=[O:64])[NH:41]2)=[CH:38][CH:39]=1)#[N:33]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CC(C(=O)O)C3)cc1
Agent: F[B-](F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CC(C(N)=O)C3)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N,N,N′,N′-Tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate (50 mg, 0.16 mmol) and N,N-diisopropylethylamine (60 μL, 0.34 mmol) are added to a solution of 4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4,5,6,7,8-octahydroquina zoline-7-carboxylic acid (example 10, 70 mg, 0.154 mmol) in N,N-dimethylformamide (1.0 mL). After 10 min aqueous ammonia (35%, 0.5 mL) is added and the mixture is stirred at room temperature for 1 h. Water is added and the mixture is extracted with diethyl ether. The organic layer is concentrated under reduced pressure, and the residue is purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of methanol in water, 0.1% TFA). Yield: 15 mg; ESI mass spectrum [M+H]+=455; Retention time HPLC: 1.02 min (V001—006).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:27])[C@@H:6]([OH:26])[C@@H:7]([N:11](CC2C=CC=CC=2)CC2C=CC=CC=2)[CH2:8][CH2:9][CH3:10])[CH2:3][CH2:2]1>CO.[OH-].[OH-].[Pd+2]>[NH2:11][C@@H:7]([CH2:8][CH2:9][CH3:10])[C@H:6]([OH:26])[C:5]([NH:4][CH:1]1[CH2:2][CH2:3]1)=[O:27]
Reactant: CCC[C@@H]([C@H](O)C(=O)NC1CC1)N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCC[C@H](N)[C@H](O)C(=O)NC1CC1
Reaction time: 2 h
Yield: 92.2 %

Procedure:
To a solution of (2S,3S)—N-cyclopropyl-3-(dibenzylamino)-2-hydroxyhexanamide (35.0 g) in methanol (350 mL) was carefully added palladium hydroxide on carbon (20% Pd(OH)2/C, 7.0 g), and the mixture was stirred under hydrogen at 50 psi for 2 hours. The mixture was filtered through Celite, and washed with methanol (150 mL). The solvent was evaporated under reduced pressure, to provide a light yellow solid, which was further washed with hexanes (2×75 mL), to give (2S,3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide (16.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:11]([CH2:20][NH:21][CH:22]([CH3:24])[CH3:23])[C:10]([C:25]([OH:27])=O)=[N:9]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]2[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[N:9]=[C:10]3[C:25](=[O:27])[N:21]([CH:22]([CH3:23])[CH3:24])[CH2:20][C:11]=23)=[CH:18][CH:17]=1
Reactant: CC(C)NCc1c(C(=O)O)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)N1Cc2c(nn(-c3ccccc3Cl)c2-c2ccc(Cl)cc2)C1=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 1-(2-chloro-phenyl)-5-(4-chloro-phenyl)-4-(isopropylamino-methyl)-1H-pyrazole-3-carboxylic acid I-4d (40 mg, 0.074 mmol), EDC (28 mg, 0.148 mmol), HOAt (20 mg, 0.148 mmol), and triethylamine (0.02 ml, 0.148 mmol) in CH2Cl2 (10 ml) was stirred at room temperature for 17 hours. The reaction mixture was washed with sat'd aq NaHCO3, sat'd aq NaCl, dried and concentrated in vacuo. The crude residue was diluted with cyclohexane and stirred for 17 hours. A solid precipitated out of solution and was collected by filtration to give 3A-1 (11 mg, 38%): +APCl MS (M+1) 386.1; 1H NMR (CDCl3) δ 7.50-7.38 (m, 4H), 7.26 (d, 2H, J=9.6 Hz), 7.06 (d, 2H), 4.69 (m, 1H), 1.3 (d, 6H, J=6.65 Hz).
Reaction SMILES: [OH:1][CH:2]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[CH3:26])[C:3]1[CH:8]=[C:7]([N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH:6]=[CH:5][C:4]=1[CH3:14].[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:37][C@@H:38]([CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:39](Cl)=[O:40])(=[O:36])=[O:35])=[CH:30][CH:29]=1>ClC(Cl)C.N1C=CC=CC=1>[N:9]1([C:7]2[CH:6]=[CH:5][C:4]([CH3:14])=[C:3]([CH:8]=2)[CH:2]([C:15]2[C:16]([CH3:26])=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][C:24]=2[CH3:25])[O:1][C:39](=[O:40])[C@@H:38]([NH:37][S:34]([C:31]2[CH:30]=[CH:29][C:28]([CH3:27])=[CH:33][CH:32]=2)(=[O:36])=[O:35])[CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](Cc2ccccc2)C(=O)Cl)cc1
Reactant: COC(=O)c1cc(C)c(C(O)c2cc(-n3ccnc3)ccc2C)c(C)c1
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1cc(C)c(C(OC(=O)[C@H](Cc2ccccc2)NS(=O)(=O)c2ccc(C)cc2)c2cc(-n3ccnc3)ccc2C)c(C)c1
Yield: 100.5 %

Procedure:
Methyl (±)-4-[α-hydroxy-5-(1-imidazolyl)-2-methylbenzyl]-3,5-dimethylbenzoate (46 g) was suspended in dichloroethane (550 ml) and pyridine (15.8 ml), and a solution of (S)-2-(4-methylbenzenesulfonylamino)-3-phenylpropionyl chloride (53.2 g) in dichloroethane (125 ml) was added dropwise to the suspension over 10 minutes with stirring under ice-cooling. The mixture was stirred at room temperature for 4 hours, and the reaction mixture was washed successively with water, 5% citric acid, 5% potassium carbonate and water. The organic layer was separated and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 86 g of methyl (±)-4-[5-(1-imidazolyl)-2-methyl-α-{(S)-2-(4-methylbenzenesulfonylamino)-3-phenylpropionyloxy}-benzyl]-3,5-dimethylbenzoate as a pale-yellow oil. This was crystallized from ethyl acetate (150 ml) and isopropyl ether (600 ml) and the obtained crystals were recrystallized from ethyl acetate (75 ml) and isopropyl ether (150 ml) to give 29.8 g of methyl (S)-4-[5-(1-imidazolyl)-2-methyl-α-{(S)-2-(4-methylbenzenesulfonylamino)-3-phenylpropionyloxy}benzyl]-3,5-dimethylbenzoate as white crystals, melting point 111-112° C.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:16][CH2:15][C@@H:14]([NH2:17])[CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([CH3:18])=[CH:7][CH:8]=2)[N:3]=1.CCN(CC)CC.Cl[C:27]([O:29][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:28]>C1COCC1>[Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:16][CH2:15][C@@H:14]([NH:17][C:27](=[O:28])[O:29][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([CH3:18])=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC(C)(C)COC(=O)Cl
Reactant: Cc1ccc2c(N3CC[C@@H](N)C3)nc(Cl)nc2c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CC[C@@H](NC(=O)OCC(C)(C)C)C3)nc(Cl)nc2c1
Reaction time: 0.08 h
Yield: 69.8 %

Procedure:
A solution of (R)-1-(2-chloro-7-methylquinazolin-4-yl)pyrrolidin-3-amine (100 mg, 0.38 mmol) in 2 mL of THF was cooled to −30° C. To it was added Et3N followed by the addition of neopentyl chloroformate (53 μL, 0.38 mmol) dropwise. The reaction was complete after 5 minutes. The reaction was quenched with water, the layers separated, and the aqueous layer was twice extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification via silica gel chromatography using 0%-10% EtOAc in DCM gave (R)-neopentyl 1-(2-chloro-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate (100 mg, 70% yield). LC/MS: m/z 377.5 (M+H)+ at 2.90 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[OH:26][C:27]1([CH2:33][C:34](O)=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:34](=[O:35])[CH2:33][C:27]5([OH:26])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]5)[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)CC1(O)CCCCC1
Agent: Cl
Product: O=C(CC1(O)CCCCC1)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, light yellow solid (21.3 mg, 64.7%), MS (ISP) m/z=471.5[(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (25.7 mg, 0.07 mmol) and 2-(1-hydroxycyclohexyl)acetic acid
Reaction SMILES: ClCCl.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16].[CH2:18]([NH2:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].ClC(Cl)C>C(N(CC)CC)C>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:34][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(=[O:13])=[O:12])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16]
Reactant: CCCCCCCCCCCCCCCCN
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Solvent: CC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCNS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 89 %

Procedure:
To one liter of dichloromethane was added 800 g of 4-chloro-3-nitrobenzenesulfonyl chloride prepared in the above step and the mixture was cooled to 0° C. Then, a mixture of 600 g of hexadecylamine, 251 ml of triethylamine, and 780 ml of dichloroethane was added dropwise to the mixture at 20° C. to 30° C. After performing the reaction for 2 hours at room temperature, the dichloromethane was distilled off from the reaction mixture under reduced pressure and the residue was dissolved in 3 liters of methanol under heating. After gradually cooling the solution to room temperature to form crystals, 3 liters of methanol was added to the solution and the mixture was ice-cooled to deposit crystals which were then recovered by filtration and dried to provide 1020 g of the above-described compound with a yield of 88%. The melting point thereof was 91° C. to 93° C.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].O.[S-2:13].[Na+].[Na+].O>C(O)C>[Cl:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[SH:13]
Reactant: [S-2]
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cccc(Cl)c1S
Temperature: 25 °C
Reaction time: 48 h
Yield: 59.7 %

Procedure:
Twenty grams of 2,3-dichloronitrobenzene was dissolved in 200 ml of absolute ethanol and the resulting solution added dropwise over three hours to a mixture of 40.0 g of sodium sulfide hydrate in 225 ml of absolute ethanol. The reaction temperature did not exceed 30° C. during the addition. The reaction was allowed to stir for 48 hours at room temperature. Since some of the 2,3-dichloronitrobenzene was still present, as indicated by GLC, an additional 9.0 g of the sodium sulfide hydrate was added at once and the reaction was allowed to stir overnight at room temperature. The ethanol was removed and the concentrate was partitioned between 300 ml of water and 250 ml of ether, the ether extract was discarded, and the aqueous phase made acidic by the dropwise addition of 50 ml of concentrated hydrochloric acid with the evolved gas being scrubbed through a bleach trap. A large amount of solid formed. Water, 100 ml, was added and the aqueous phase extracted with 350 ml of methylene chloride. The organic phase was dried with magnesium sulfate, filtered and concentrated to yield 11.8 g of a tan solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:13][CH:14]=[C:15]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]4)[N:16]=2)=[CH:8][CH:7]=1)=[O:5])C.[OH-].[K+]>C(O)C>[C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[S:13][CH:14]=[C:15]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]4)[N:16]=2)=[CH:10][CH:11]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccc(-c2nc(-c3ccc4c(c3)CCC(=O)N4)cs2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1CCc2cc(-c3csc(-c4ccc(C(=O)O)cc4)n3)ccc2N1
Yield: 36.9 %

Procedure:
2.05 g of 2-(4-ethoxycarbonylphenyl)-4-(3,4-dihydrocarbostyril-6-yl)thiazole was suspended in 20 ml of a 10% aqueous potassium hydroxide solution and 50 ml of ethanol. The suspension was refluxed for 5 hours. Ethanol was removed by distillation. After cooling, the residue was mixed with hydrochloric acid to make it acidic (pH 1). The resulting crystals were collected by filtration and recrystallized from dimethylformamide to obtain 0.70 g of 2-(4-carboxyphenyl)-4-(3,4-dihydrocarbostyril-6-yl)thiazole as a light yellow powder.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=2)[CH:6]=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(Cl)(Cl)Cl>N1C=CC=CC=1>[C:19]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=2)[CH:6]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cccc(-c2cc(OCCO)cc(C)n2)n1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1cccc(-c2cc(OCCOC(=O)c3ccccc3)cc(C)n2)n1

Procedure:
4-(2-Hydroxyethoxy)-6,6'-dimethyl-2,2'-bipyridine (24) (1.0 g, 4.1 mmoles) was dissolved in dry pyridine (20 ml), and benzoyl chloride (0.63 g, 4.5 mmoles) was added. After 30 minutes chloroform (50 ml) was added and the solution was extracted with saturated sodium bicarbonate. The chloroform phase was dried and the solvent was evaporated and coevaporated with dry toluene. The product was purified by means of flash chromatography (silica, 0-50% methanol/dichloromethane).
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>O>[N:11]1([C:2]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[O:4][N:3]=2)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: Clc1noc2ccccc12
Reactant: C1CNCCN1
Solvent: O
Product: c1ccc2c(N3CCNCC3)noc2c1
Yield: 82 %

Procedure:
A mixture of 3-chloro-1,2-benzisoxazole (19.6 g., 0.128 mole) and piperazine (110 g., 1.28 mole) is heated for a period of 20 hr. at 120° C. in a closed reactor. The reaction mixture is diluted with water and the aqueous mixture repeatedly extracted with methylene chloride. Extracts are combined, dried over magnesium sulfate and concentrated in vacuo to afford 21.2 g. (82% yield) of 3-(1-piperazinyl)-1,2-benzisoxazole free base.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:15])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8](I)[CH:7]=2)[CH2:3][CH2:2]1.[H-].[Na+].C([Li])CCC.[B:23](OC(C)C)([O:28]C(C)C)[O:24]C(C)C>O1CCCC1.O>[CH:1]1([NH:4][C:5]([C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([B:23]([OH:28])[OH:24])[CH:7]=2)=[O:15])[CH2:3][CH2:2]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1I
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1B(O)O
Temperature: -75 °C
Reaction time: 4 h

Procedure:
N-Cyclopropyl-5-fluoro-3-iodo-4-methylbenzamide (Intermediate 63) (5 g) in tetrahydrofuran (75 ml) was cooled to 0° C. then treated with sodium hydride (60% oil dispersion, 1.23 g) portionwise over 10 minutes. Once effervescence had ceased the reaction was cooled to −75° C. and n-butyl lithium (1.6M in hexanes, 20 ml) was added over 25 min maintaining a temperature of <−70° C. Triisopropyl borate (8 ml) was added over 10 min and the mixture was stirred at −70° C. for 4 h. Water (20 ml) was added and the mixture was allowed to warm to 5° C. The solvent was removed under vacuum and the residue was partitioned between saturated aqueous ammonium chloride and ethyl acetate. The organic phase was washed with saturated aqueous ammonium chloride and brine, dried (Na2SO4) and concentrated under vacuum. The residue was dissolved in dichloromethane/ethyl acetate and purified by column chromatography on silica eluting with dichloromethane:ethyl acetate (95:5 to 0:100) then methanol to give the title compound.
Reaction SMILES: CC1C=CC(S(O[C@@H:12]([CH2:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:13][CH:14]([C:21]#[N:22])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=O)=O)=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>CN(C=O)C.CCOC(C)=O>[C:15]1([C@:14]2([C:21]#[N:22])[CH2:13][C@H:12]2[CH2:23][O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H](COCc2ccccc2)CC(C#N)c2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#C[C@@]1(c2ccccc2)C[C@H]1COCc1ccccc1
Temperature: -42 °C
Yield: 94.7 %

Procedure:
To (1R)-3-cyano-3-phenyl-1-{[(phenylmethyl)oxy]methyl}propyl 4-methylbenzenesulfonate (7.4 g, 17.0 mmol), accessed via the method of preparation 2, in 70 mL DMF at −42° C. was added 1M lithium bis(trimethylsilyl)amide in hexanes (25.5 mL, 25.5 mmol, 1.5 eq) dropwise and stirred with continued cooling at −42° C. for 1 h. The reaction mixture was diluted with EtOAc, washed successively with water (4×) and brine, dried over MgSO4, filtered and concentrated to give the title compound (4.25 g, 16.1 mmol, 95%) as a yellow oil which was shown to be a 94:6 mix of the title compound to the product of Preparation 3B. 1H NMR (300 MHz, CDCl3) δ 7.42-7.29 (m, 10H), 4.64 (m, 2H), 3.91-3.86 (m, 1H), 3.74-3.68 (m,1H), 2.00-1.90 (m, 1H), 1.68-1.56 (m, 2H).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)=[O:10].Cl[C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][N:24]=1>>[CH3:29][C:27]1[CH:26]=[CH:25][N:24]=[C:23]([N:7]2[CH2:8][CH:4]3[CH:5]([CH2:1][N:2]([C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:17]4[S:18][CH:19]=[CH:20][CH:21]=4)=[O:10])[CH2:3]3)[CH2:6]2)[CH:28]=1
Reactant: O=C(c1ccccc1-c1cccs1)N1CC2CNCC2C1
Reactant: Cc1ccnc(Cl)c1
Product: Cc1ccnc(N2CC3CN(C(=O)c4ccccc4-c4cccs4)CC3C2)c1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 37 and 2-chloro-4-methyl-pyridine. MS (ESI): mass calculated for C23H23N3OS, 389.52; m/z found 390.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.00 (d, J=5.2, 1H), 7.56-7.47 (m, 1H), 7.45-7.31 (m, 3H), 7.25-7.11 (m, 2H), 7.09-6.90 (m, 1H), 6.42 (d, J=5.2, 1H), 6.06 (br s, 1H), 3.98-2.59 (m, 10H), 2.27 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].C1(C)C=CC=CC=1.[Si]([CH:21]=[N+:22]=[N-:23])(C)(C)C.C(O)(C(F)(F)F)=O>O1CCCC1>[NH:23]1[CH:2]([C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH2:3][CH:21]=[N:22]1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C1CC=NN1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.4 %

Procedure:
1,1-Dimethylethyl 2-propenoate (10.25 ml, 70 mmol) was added to a round-bottom flask equipped with a stirring bar and charged with toluene (100 ml) and tetrahydrofuran (THF) (100 ml) under nitrogen, and then TMS-Diazomethane (42.0 ml, 84 mmol) was added. After 4 h, the reaction solvents and excess TMS-Diazomethane were removed in vacuo. The residue was dissolved in dichloromethane (150 mL). TFA (6.26 ml, 84 mmol) was added at 0° C. and the resulting mixture was stirred at room temperature overnight. After this time, the reaction was quenched with sat. Na2CO3 and extracted with dichloromethane. The organic layer was dried over Na2SO4. The solvent was removed under reduced pressure to give the crude product as yellow oil, which was purified by silica gel chromatography (Combiflash, 120 g column, hexane/ethyl acetate 0-30% 60 min) to yield the desired product 1,1-dimethylethyl 4,5-dihydro-1H-pyrazole-5-carboxylate (9.7 g, 81% yield) as yellow oil.