Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:15])=[CH:6][C:7]([CH3:14])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=[S:3])[NH2:2].C(=O)(O)[O-].[Na+].Br[CH:22]1[C:27](=O)[CH2:26][CH2:25][O:24][CH2:23]1>C(O)C>[N:2]1[C:27]2[CH2:26][CH2:25][O:24][CH2:23][C:22]=2[S:3][C:1]=1[C:4]1[C:5]([CH3:15])=[CH:6][C:7]([CH3:14])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: O=C1CCOCC1Br
Reactant: COC(=O)c1cc(C(N)=S)c(C)cc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1cc(-c2nc3c(s2)COCC3)c(C)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 126.8 %

Procedure:
To a solution of methyl 5-carbamothioyl-2,4-dimethylbenzoate (compound 130.1, 500 mg, 2.24 mmol, 1.00 equiv) in ethanol (5 mL) was added sodium bicarbonate (396 mg, 4.71 mmol, 1.00 equiv) and 3-bromodihydro-2H-pyran-4(3H)-one (compound 1.10.1, 186 mg, 1.04 mmol, 1.00 equiv). The resulting solution was stiffed overnight at 80° C. under nitrogen. After cooling to room temperature the mixture was concentrated under reduced pressure. The residue was taken up 10 mL of water and ethyl acetate. The aqueous phase was extracted with 2×20 mL of ethyl acetate and the combined organic layers were dried (MgSO4), and concentrated under reduced pressure to yield 400 mg (56%) of the title compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[N:15]=1>ClCCl.N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[N:15]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12]
Reactant: O=S(=O)(Cl)c1ccc(Br)c(F)c1
Reactant: Nc1cccc(Br)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1cccc(Br)n1)c1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-bromo-3-fluorobenzenesulfonyl chloride (684 mg, 370 μl, 2.5 mmol) in dichloromethane (2 ml) was added slowly at room temperature to a solution of 2-amino-6-bromopyridine (346 mg, 2.0 mmol) in pyridine (2 ml). The reaction mixture was stirred at room temperature for 1 h. The solvent was evaporated and the residue partitioned between ethyl acetate (50 ml) and water (50 ml). The organic phase washed with water (×2), separated, dried and evaporated. Purification by column chromatography eluting with 20-60% ethyl acetate in hexanes afforded the title compound (D1), MS (ES+) m/e 409, 411, 413 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([NH:8][C:9]2[C:18]3[C:17]([S:19]([OH:22])(=[O:21])=[O:20])=[CH:16][C:15]([S:23]([OH:26])(=[O:25])=[O:24])=[CH:14][C:13]=3[C:12]([S:27]([OH:30])(=[O:29])=[O:28])=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[N+:33]([O-])=O>CO.[Pd]>[NH2:33][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:2]=1[CH3:1])[C:6]([NH:8][C:9]1[C:18]2[C:17]([S:19]([OH:22])(=[O:21])=[O:20])=[CH:16][C:15]([S:23]([OH:26])(=[O:24])=[O:25])=[CH:14][C:13]=2[C:12]([S:27]([OH:30])(=[O:29])=[O:28])=[CH:11][CH:10]=1)=[O:7]
Reactant: Cc1ccc(C(=O)Nc2ccc(S(=O)(=O)O)c3cc(S(=O)(=O)O)cc(S(=O)(=O)O)c23)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(C(=O)Nc2ccc(S(=O)(=O)O)c3cc(S(=O)(=O)O)cc(S(=O)(=O)O)c23)cc1N

Procedure:
8-(4-Methyl-3-nitro-benzoylamino)-naphthalene-1,3,5-trisulfonic acid (1 eq) and 10% Pd on carbon (10 mol %) are placed in CH3OH. The solution is degassed and an atmosphere of H2 is generated within the reaction vessel. The reaction is allowed to proceed until the uptake of H2 ceases and TLC indicates the disappearance of starting material (12 hrs). The palladium precipitate is removed by filtration through a bed of celite and the filtrate is evaporated to dryness giving the reduced compound 8-(3-Amino-4-methyl-benzoylamino)-naphthalene-1,3,5-trisulfonic acid.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[Cl:19])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: OB(O)c1ccccc1Cl
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccccc4Cl)cc3CC[C@@H]12
Yield: 84.2 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 2-chlorophenylboronic acid (122 mg, 0.78 mmol) ,0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 186 mg (84 %) of the title compound as an amorphous foam. mp 111°-120°. FDMS: m/e=339. α[D]589 =56.86 (c=0.64, chloroform).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[CH:14][N:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[S:10][C:9]1=S)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(OC)(=O)=O)=CC=1.[NH2:36][C:37]1[CH:38]=[C:39]([C:46](=[O:48])[CH3:47])[CH:40]=[CH:41][C:42]=1[NH:43][CH2:44][CH3:45]>CN(C=O)C.CC#N>[C:46]([C:39]1[CH:40]=[CH:41][C:42]([NH:43][CH2:44][CH3:45])=[C:37]([N:36]=[C:9]2[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:12](=[O:13])[C:11](=[CH:14][N:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])[S:10]2)[CH:38]=1)(=[O:48])[CH3:47]
Reactant: CN(C=C1SC(=S)N(Cc2ccccc2)C1=O)c1ccccc1
Reactant: CCNc1ccc(C(C)=O)cc1N
Agent: COS(=O)(=O)c1ccc(C)cc1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCNc1ccc(C(C)=O)cc1N=C1SC(=CN(C)c2ccccc2)C(=O)N1Cc1ccccc1
Temperature: 125 °C
Reaction time: 2 h
Yield: 9.6 %

Procedure:
A mixture of 3-benzyl-5-[(N-methyl-phenylamino)-methylene]-2-thioxo-thiazolidin-4-one (0.40 g, 1.2 mmol) and methyl p-toluenesulfonate (0.26 g, 1.4 mmol) in DMF (2 mL, anhyd) was heated at 125° C. After 2 h, the reaction mixture was cooled and an aliquot (0.4 mL) of the intermediate was transferred to an oven-dried vial. The intermediate was diluted with MeCN (2 mL, anhyd) and charged with 3′-amino-4′-ethylamino-acetophenone (53 mg, 0.30 mmol). The reaction mixture was warmed to 50° C., charged with TEA (100 μL), sealed and heated at 65° C. After 16 h, the reaction mixture was cooled, concentrated and chromatographed (silica gel, 0:100 to 50:50 EtOAc-Hex) to give the title product (14 mg) as a yellow solid. 1H-NMR (CDCl3): δ 7.92 (1H, s), 7.65 (1H, dd), 7.50 (1H, d), 7.27-7.42 (7H, m), 7.14-7.23 (3H, m), 6.48 (1H, d), 5.12 (2H, s), 4.27 (1H, br s), 3.51 (3H, s), 3.02 (2H, q), 2.45 (3H, s), 1.01 (3H, t); MS (ESI): 485 (MH+).
Reaction SMILES: [NH2:1][C@H:2]([CH2:22][C:23]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=1[F:31])[CH2:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]2[C:12]([C:18]([F:21])([F:20])[F:19])=[N:13][C:14]([C:15]([OH:17])=[O:16])=[C:8]2[CH2:7]1)=[O:5].[OH-].[K+:33]>CO>[NH2:1][C@H:2]([CH2:22][C:23]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=1[F:31])[CH2:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]2[C:12]([C:18]([F:21])([F:19])[F:20])=[N:13][C:14]([C:15]([O-:17])=[O:16])=[C:8]2[CH2:7]1)=[O:5].[K+:33]
Reactant: N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)[O-])c2C1)Cc1cc(F)c(F)cc1F
Reaction time: 0.25 h
Yield: 100.5 %

Procedure:
(R)-7-[3-Amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 3 (100 mg, 0.22 mmol) was dissolved in 5 mL of methanol followed by addition of aqueous potassium hydroxide (0.44 mL, 0.22 mmol). The reaction was stirred for 15 minutes. The reaction mixture was concentrated under reduced pressure to obtain the title compound potassium (R)-7-[3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylate 6 (108 mg, 100%) as a white solid. HPLC: 92.78%. MS m/z (ESI): 451.2 [M+1]. 1H NMR (400 MHz, CD3OD, ppm): δ 7.31-7.38 (m, 1H), 7.14-7.23 (m, 1H), 5.07-5.27 (m, 2H), 4.26-4.36 (m, 2H), 4.01-4.15 (m, 2H), 3.52-3.60 (m, 1H), 2.80-2.92 (m, 2H), 2.59-2.74 (m, 2H).
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([NH:16][C:17](=[O:25])[CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[H-].[Na+].CI.[CH3:30]N(C=O)C>C1COCC1.CCOC(C)=O>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([N:16]([CH3:30])[C:17](=[O:25])[CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: CN(C)C=O
Reactant: CCn1c2ccccc2c2cc(NC(=O)Cc3cccnc3)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CCOC(C)=O
Product: CCn1c2ccccc2c2cc(N(C)C(=O)Cc3cccnc3)ccc21
Reaction time: 8 h
Yield: 2.2 %

Procedure:
To a suspension of N-(9-Ethyl-9H-carbazol-3-yl)-2-pyridin-3-yl-acetamide (329 mg, 0.899 mmol) in THF at 0° C. was added NaH (60% oil dispersion, 86 mg, 2.158 mmol), then the cooling bath removed. After stirring an additional 25 minutes methyl iodide (67 μl, 1.08 mmol) was added, and the reaction mixture stirred overnight. A portion of DMF (4 ml) was then added and stirring continued for several hours. The reaction mixture was then diluted with EtOAc and the organic layer washed with saturated aq. NaHCO3, H2O, and brine, dried (Na2SO4), and concentrated to afford the crude product as a brown oil. Chromatographic purification (silica, 10% MeOH/CH2Cl2) afforded the desired product (7 mg, 2.2% yield). MS m/z @ 344 (m+1).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C@H:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)=[CH:16][CH:17]=3)[C@@H:12]3[CH2:29][CH2:30][CH2:31][N:11]3[CH2:10]2)[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br>C(Cl)Cl>[N:23]1([CH2:22][CH2:21][CH2:20][O:19][C:15]2[CH:14]=[C:13]3[C:18]([C@H:9]([C:5]4[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=4)[CH2:10][N:11]4[CH2:31][CH2:30][CH2:29][C@H:12]43)=[CH:17][CH:16]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COc1cccc([C@@H]2CN3CCC[C@H]3c3cc(OCCCN4CCCCC4)ccc32)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cccc([C@@H]2CN3CCC[C@H]3c3cc(OCCCN4CCCCC4)ccc32)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.6 %

Procedure:
To a solution of cis-6-(3-methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline (27.0 mg, 0.042 mmol) in CH2Cl2 (0.2 mL) was added BBr3 (1 M in CH2Cl2, 0.21 mL) and the reaction mixture was stirred at rt for 15 min. The reaction was quenched with water and the mixture was concentrated under a stream of N2. The crude material was purified by reverse-phase HPLC to give 14.1 mg (53%) of the desired product as a TFA salt. MS: exact mass calcd for C26H34N2O2, 406.3; m/z found, 407.5 [M+H]+. 1H NMR (acetone-d6): 7.20 (m, 1H), 6.92 (m, 1H), 6.78 (m, 5H), 4.83 (m, 1H), 4.46 (m, 1H), 4.11 (t, J=7.2, 2H), 3.87 (m, 1H), 3.59 (m, 2H), 3.38 (m, 2H), 3.28 (m, 2H), 2.89 (m, 3H), 2.87 (m, 2H), 2.29 (m, 5H), 1.88 (m, 4H), 1.57 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][N:33]([CH3:43])[C:34](=[O:42])[CH2:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:39]5[CH2:38][CH2:37][N:36]([CH2:35][C:34]([N:33]([CH3:43])[CH3:32])=[O:42])[CH2:41][CH2:40]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CN(C)C(=O)CN1CCNCC1
Product: CN(C)C(=O)CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1

Procedure:
2-(4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazin-1-yl)-N,N-dimethyl-acetamide one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and N,N-dimethyl-2-piperazin-1-yl-acetamide following General Procedure C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[C:21]3[C:16](=[C:17]([CH2:22][S:23][CH3:24])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH2:9][CH2:10][C:11]#[N:12])=[CH:4][CH:3]=1.CS(CC1C=CC=C2C=1NC=C2C(C1C=CC(C(F)(F)F)=CC=1)CCC#N)=[O:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:13]2[C:21]3[C:16](=[C:17]([CH2:22][S:23]([CH3:24])=[O:27])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH2:9][CH2:10][C:11]#[N:12])=[CH:6][CH:7]=1
Reactant: CS(=O)Cc1cccc2c(C(CCC#N)c3ccc(C(F)(F)F)cc3)c[nH]c12
Reactant: CSCc1cccc2c(C(CCC#N)c3ccc(Cl)cc3)c[nH]c12
Product: CS(=O)Cc1cccc2c(C(CCC#N)c3ccc(Cl)cc3)c[nH]c12

Procedure:
The title compound was prepared starting from 85.0 mg (0.24 mmol) of the compound from Example 36 in analogy to the synthesis of the compound from Example 77. Purification by preparative HPLC (RP18 column; mobile phase: acetonitrile-water gradient with addition of 0.1% formic acid) resulted in 86 mg (97% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:25]([O-])=O)=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C@H:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1)[CH:6]=[CH:5]2.C(O)C.[Cl-].[NH4+].O>[Fe]>[NH2:25][C:3]1[C:2]([CH3:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]([C@H:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1)[C:8]2=[O:12]
Reactant: Cc1ccc2c(=O)n([C@H]3CCN(C(=O)OC(C)(C)C)C3)ccc2c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1ccc2c(=O)n([C@H]3CCN(C(=O)OC(C)(C)C)C3)ccc2c1N
Reaction time: 0.5 h

Procedure:
A round bottom flask was charged with (S)-tert-butyl 3-(6-methyl-5-nitro-1-oxoisoquinolin-2(1H)-yl)pyrrolidine-1-carboxylate (500.0 mg, 0.001339 mol), ethanol (5 mL, 0.08 mol) and ammonium chloride (716.3 mg, 0.01339 mol) in water (3 mL, 0.2 mol) was added at 85° C. Iron (299 mg, 0.00536 mol) was added in portions and was stirred at that temperature for 30 minutes, poured onto methylene chloride (50 mL) and extracted. The solvent was removed under reduced pressure to afford the pure product as light yellow solid.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Li]CCCC.[CH3:34][CH:35]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH:36]=O>>[CH3:36][CH:35]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH:34]=[CH:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCCCCCCC(C)C=O
Agent: [Br-]
Agent: [Li]CCCC
Product: CCCCCCCCCC(C)C=CCc1ccccc1
Yield: 60.6 %

Procedure:
Starting from phenethyltriphenylphosphonium bromide (3.60 g, 8.05 mmol, 1.0 equiv.), n-BuLi (1.6 M in hexanes, 5.0 mL, 8.05 mmol, 1.0 equiv.) and 2-methylundecanal (2.25 g, 12.1 mmol, 1.5 equiv.), 1.33 g (61%) of the title compound as a colorless oil was obtained after purification by flash chromatography on SiO2 (hexanes).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH2:17][CH2:18][C:19]([NH:21][NH2:22])=[O:20])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].C(=O)(O)[O-].[Na+].[N:28]#[C:29]Br>O1CCOCC1.O.C(OCC)(=O)C>[NH2:28][C:29]1[O:20][C:19]([CH2:18][CH2:17][S:16][C:7]2[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]([OH:11])=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[CH:6]=2)=[N:21][N:22]=1
Reactant: CC(C)(C)c1cc(SCCC(=O)NN)cc(C(C)(C)C)c1O
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(SCCc2nnc(N)o2)cc(C(C)(C)C)c1O
Reaction time: 5 h
Yield: 78 %

Procedure:
A solution of 3-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]propanoic acid hydrazide (0.50 g, 1.54 mmol) in dioxane (15 mL) is added to a solution of sodium bicarbonate (0.14 g, 1.62 mmol) in water (4 mL). Cyanogen bromide (0.17 g, 1.62 mmol) is added in four equal portions at 1-minute intervals, and stirring is continued for 5 hours. The reaction mixture is diluted with ethyl acetate and sequentially washed with aqueous sodium bicarbonate, water, and brine. Drying the organic phase over magnesium sulfate and evaporation provides a solid which is crystallized from ethyl acetate/hexane to give 0.42 g (78%) of 4-[[2-(5-amino-1,3,4-oxadiazol-2-yl)ethyl]thio]-2,6-bis(1,1-dimethylethyl)phenol, mp 172.0°-174.0° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:28]3[CH2:33][CH2:32][N:31](OCC)[CH2:30][C:29]3=C=O)[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C@H:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:21])[N:14]=2)=[CH:4][CH:3]=1.C[Si](I)(C)C.Cl.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl.C(O)CC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:28]3[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]3)[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C@H:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:21])[N:14]=2)=[CH:6][CH:7]=1
Reactant: CCON1CCN(c2nc(-c3ccc(F)cc3)c(-c3ccnc(N[C@@H](C)c4ccccc4)n3)o2)C(=C=O)C1
Agent: C[Si](C)(C)I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: CCCO
Product: C[C@H](Nc1nccc(-c2oc(N3CCNCC3)nc2-c2ccc(F)cc2)n1)c1ccccc1

Procedure:
4-(4-Fluorophenyl)-5-(2-[1-(S)-phenylethyl]amino-4-pyrimidyl)-2-(4-ethoxy-carbonylpiperazin-1-yl)oxazole (130 mg; 0.251 mmol in CHCl3 (2.6 ml) is treated with trimethylsilyl iodide (0.113 ml; 0.83 mmol) at 60 C. After 3 h a second portion of trimethylsilyl iodide (0.113 ml; 0.83 mmol) is added and the reaction heated at 60 C for 21 h. 6 M HCl in 1-propanol (3 ml) is added to the reaction mixture, stirred until dissolution is complete and then poured on a saturated solution of Na2CO3.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[C:12]([C@@H:14]3[CH2:16][C@H:15]3[C:17]([O:19]CC)=[O:18])[CH:11]=[C:10]([CH3:22])[N:9]=2)[N:3]=1.[Li+].[OH-].Cl>O1CCCC1.CO.O>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[C:12]([C@@H:14]3[CH2:16][C@H:15]3[C:17]([OH:19])=[O:18])[CH:11]=[C:10]([CH3:22])[N:9]=2)[N:3]=1
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1cc(C)nc(-n2nc(C)nc2C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc([C@@H]2C[C@H]2C(=O)O)cc(-n2nc(C)nc2C)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl trans-2-(2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-6-methylpyridin-4-yl)cyclopropanecarboxylate (25-2, 96 mg, 0.320 mmol) in tetrahydrofuran (2 mL) and methanol (2 mL) was added a solution of LiOH (38 mg, 1.60 mmol) in water (2 mL). The mixture was stirred at room temperature for 3 hours, neutralized with 2 M HCl to pH 7, and concentrated. The residue was purified by silica gel column chromatography (0-8% methanol in DCM) to give trans-2-(2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-6-methylpyridin-4-yl)cyclopropanecarboxylic acid (25-3) as a white solid. LRMS m/z (M+H) 273 found, 273 required.
Reaction SMILES: [CH2:1]([C:4]1[C:12]2[O:11][N:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8]=2[CH:7]=[CH:6][C:5]=1[OH:19])[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:28])C=1.O.[OH-].[Na+]>C(Cl)Cl>[C:13]1([C:9]2[C:8]3[CH:7]=[CH:6][C:5]4[O:19][CH:2]([CH2:3][OH:28])[CH2:1][C:4]=4[C:12]=3[O:11][N:10]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCc1c(O)ccc2c(-c3ccccc3)noc12
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: OCC1Cc2c(ccc3c(-c4ccccc4)noc23)O1
Temperature: 0 °C
Yield: 96.7 %

Procedure:
To an ice-cooled solution of 7-allyl-6-hydroxy-3-phenyl-1,2-benzisoxazole (17.5 g) in methylene chloride (500 ml), m-chloroperbenzoic acid (20.8 g) was added in small portions under agitation, and the mixture was refluxed for 4 hours. After cooling the mixture, water and an aqueous solution of 2N sodium hydroxide (80 ml) were added and the mixture was subjected to extraction with methylene chloride. The methylene chloride layer was washed with water and dried. By distilling off the solvent, 18 g of 7,8-dihydro-3-phenylfuro[2,3-g]-1,2-benzisoxazole-7-methanol was obtained. m.p. 107°-109° C. This compound exhibited a mass spectrum having a molecular ion peak at m/e 267.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH2:9][CH3:10])[C:5](N)=[C:4]([CH2:11][CH3:12])[CH:3]=1.[I:13]I.C(ON=O)(C)(C)C.[O-]S([O-])=O.[Na+].[Na+]>C(#N)C>[Br:1][C:2]1[CH:8]=[C:7]([CH2:9][CH3:10])[C:5]([I:13])=[C:4]([CH2:11][CH3:12])[CH:3]=1
Reactant: CCc1cc(Br)cc(CC)c1N
Reactant: II
Agent: CC(C)(C)ON=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCc1cc(Br)cc(CC)c1I
Temperature: 25 °C
Reaction time: 4 h
Yield: 12.7 %

Procedure:
A solution of 4-bromo-2,6-diethylaniline (10 g, 44 mmol) in acetonitrile (20 mL) was added dropwise to a solution of I2 (33.4 g, 131.6 mmol), tert-butylnitrite (7.4 mL, 65.8 mmol) in acetonitrile (80 mL), never allowing the internal temperature to exceed 30° C. After stirring 4 h at ambient temperature, Na2SO3 (100 mL, saturated aqueous) was added and stirred for 1 h. The mixture was extracted with hexanes (3×200 mL). The organics were combined, washed with brine, dried over Na2SO4 and concentrated. The crude oil was purified by flash chromatography (100% hexanes) to afford 37A (1.9 g, 13%) as a red oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.20 (t, J=7.45 Hz, 6 H) 2.77 (q, J=7.58 Hz, 4 H) 7.18 (s, 2 H).
Reaction SMILES: Cl.CCOC(C)=O.C(OC([NH:15][NH:16][C:17](=[O:49])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=2)=[CH:20][C:19]=1[C:36]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:41][CH:40]2[CH2:42][CH:37]1[CH2:38][CH2:39]2)=O)(C)(C)C>C(Cl)Cl>[C:43]1([C:36]2([C:19]3[CH:20]=[C:21]([O:24][CH2:25][C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=4)[CH:22]=[CH:23][C:18]=3[C:17]([NH:16][NH2:15])=[O:49])[CH2:41][CH:40]3[CH2:42][CH:37]2[CH2:38][CH2:39]3)[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: CC(C)(C)OC(=O)NNC(=O)c1ccc(OCc2ccc3ccccc3n2)cc1C1(c2ccccc2)CC2CCC1C2
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: NNC(=O)c1ccc(OCc2ccc3ccccc3n2)cc1C1(c2ccccc2)CC2CCC1C2
Reaction time: 1 h

Procedure:
Cold hydrogen chloride/EtOAc (10 mL; saturated solution) was added to a stirred solution of 4c (0.99 g, 1.76 mmol) in methylene chloride (5 mL) at room temperature. After approximately 1 h, the reaction mixture was concentrated in vacuo and the crude residue partitioned between saturated aqueous sodium bicarbonate and methylene chloride. The organic phase was separated, and the aqueous phase was re-extracted twice with methylene chloride. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo to afford 4d as a white powder (m/z (ES) 464 (MH)+) which was used without further purification in the subsequent reaction.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[C:5]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=[O:11])[N:6]=1.[CH3:16]COCC>CO>[CH3:16][O:11][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][CH:15]=[C:7]([C:5]2[N:6]=[C:2]([CH3:1])[O:3][CH:4]=2)[CH:8]=1
Reactant: CCOCC
Reactant: Cc1nc(-c2cccc(C(=O)O)c2)co1
Solvent: CO
Product: COC(=O)c1cccc(-c2coc(C)n2)c1

Procedure:
A solution of 3-(2-methyl-oxazol-4-yl)-benzoic acid (1.42 g) in a mixture of MeOH (30 mL) and 4NHCl/Et2O (6 mL) was heated to 40° C. for 4 h. The solution was evaporated in vacuum and the residual oil was stirred with H2O (30 mL), the pH of the mixture being set to about 6 by the addition of sat. NaHCO3 solution. The precipitate was isolated by filtration to give 3-(2-methyl-oxazol-4-yl)-benzoic acid methyl ester (1.18 g) as light-brown solid,