Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:14][C:13]([NH2:15])=[N:12][C:11]2[C:7]=1[N:8]=[CH:9][N:10]=2.C([O-])([O-])=O.[K+].[K+].[C:22]([O:26][CH3:27])(=[O:25])[CH:23]=[CH2:24]>CN(C=O)C.CCOC(C)=O>[NH2:15][C:13]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[CH2:24][CH2:23][C:22]([O:26][CH3:27])=[O:25])=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[N:14]=1
Reactant: Nc1nc2ncnc-2c(-c2ccco2)[nH]1
Reactant: C=CC(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CCn1cnc2c(-c3ccco3)nc(N)nc21
Reaction time: 40 h
Yield: 11.4 %

Procedure:
A solution of 6-(2-furyl)-1H-purine-2-amine (0.70 g, 3.48 mmol) and K2CO3 (0.48 g, 3.48 mmol) in DMF (20 mL) was treated with methyl acrylate (3.3 g, 38.3 mmol), stirred for 40 h, diluted with EtOAc, filtered to remove polymeric acrylate, washed with water, dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2: EtOAc-heptane, (4:1)] to give the title compound (114 mg, 11%) as a white solid.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[NH2:12])(=[O:5])=[O:4].[C:13](N1C=CN=C1)(N1C=CN=C1)=[S:14]>O1CCOCC1.CN(C=O)C>[CH3:1][N:2]1[C:13](=[S:14])[NH:12][C:11]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[S:3]1(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1cnccc1N
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CN1C(=S)Nc2ccncc2S1(=O)=O
Reaction time: 0.5 h

Procedure:
A solution of N-methyl-4-aminopyridine-3-sulfonamide (de Tullio et al., Tetrahedron 1995, 3221-3234) (5.0 g) and thiocarbonyidiimidazole (7.5 g) in dioxane (30 mL) and DMF (15 mL) was heated at 90° C. for 2 h. The solvents were removed by distillation under reduced pressure. The residue was dispersed in 0.6N NaOH (20 mL) and stirred for 30 min. The alkaline solution was treated with charcoal, filtered, and the filtrate was adjusted to pH 4-5. The precipitate was collected by filtration, washed with water and dried (yield: 4 g); m.p. 195°-198° C. (Compound IV).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[F:30])=[C:6]([C:8]2[NH:9][C:10]([CH3:21])=[C:11]3[C:16]=2[CH:15]=[C:14]([C:17]([OH:19])=O)[NH:13][C:12]3=[O:20])[CH:7]=1.C[N:32](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.N>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[F:30])=[C:6]([C:8]2[NH:9][C:10]([CH3:21])=[C:11]3[C:16]=2[CH:15]=[C:14]([C:17]([NH2:32])=[O:19])[NH:13][C:12]3=[O:20])[CH:7]=1
Reactant: Cc1[nH]c(-c2cc(Cl)ccc2Oc2ccc(F)cc2F)c2cc(C(=O)O)[nH]c(=O)c12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1[nH]c(-c2cc(Cl)ccc2Oc2ccc(F)cc2F)c2cc(C(N)=O)[nH]c(=O)c12
Yield: 0 %

Procedure:
A mixture of Example 32a (0.07 g, 0.162 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.074 g, 0.195 mmol), N-ethyl-N-isopropylpropan-2-amine (0.142 mL, 0.812 mmol) and 0.5 M ammonia (1.625 mL, 0.812 mmol) in dimethylformamide (1 mL) was stirred at ambient temperature for two hours. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered and concentrated. Purification by reverse phase chromatography (C18, CH3CN/10 mM ammonium acetate in water, 10-100% gradient) afforded the title compound (0.022 mg, 31%). 1H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 8.95 (s, 1H), 8.07 (s, 1H), 7.56 (d, J=2.44 Hz, 1H), 7.40-7.52 (m, 2H), 7.26-7.39 (m, 3H), 7.06-7.15 (m, 1H), 6.87 (d, J=8.85 Hz, 1H), 2.63 (s, 3H). MS (APCI+) m/z 430 [M+H]+.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:14]=[C:13]2[C:6]([NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH2:12])=[C:5](Br)[CH:4]=1.Cl.[F:17]C1C=C(NN)C=CC=1C>>[ClH:1].[F:17][C:14]1[C:3]([CH3:2])=[CH:4][CH:5]=[C:6]2[C:13]=1[C:9]([CH2:10][CH2:11][NH2:12])=[CH:8][NH:7]2
Reactant: Cc1ccc(NN)cc1F
Reactant: Cc1cc(Br)c2[nH]cc(CCN)c2c1
Agent: Cl
Product: Cc1ccc2[nH]cc(CCN)c2c1F

Procedure:
4-Fluoro-5-methyltryptamine hydrochloride was prepared (2.20 g) as described for 5-methyl-7-bromotryptamine hydrochloride in Example 4, except using 3-fluoro-4-methylphenylhydrazine hydrochloride (6.00 g) as starting material.
Reaction SMILES: [C:1]([NH:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([C:16]2[CH:21]=[C:20]([C:22]3[NH:26][N:25]=[N:24][N:23]=3)[CH:19]=[CH:18][C:17]=2[OH:27])[CH:13]=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(Cl)Cl.[OH-].[Na+].Cl.[C:35](OCC)(=[O:37])C>>[C:1]([NH:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([C:16]2[CH:21]=[C:20]([C:22]3[NH:26][N:25]=[N:24][N:23]=3)[CH:19]=[C:18]([CH:35]=[O:37])[C:17]=2[OH:27])[CH:13]=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)NC(=O)NCc1cccc(-c2cc(-c3nnn[nH]3)ccc2O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)NC(=O)NCc1cccc(-c2cc(-c3nnn[nH]3)cc(C=O)c2O)c1

Procedure:
1-tert-Butyl-3-[2′-hydroxy-5′-(1H-tetrazol-5-yl)-biphenyl-3-ylmethyl]-urea (0.56 g, 1.5 mmol) was dissolved in a mixture of chloroform (0.2 mL, 3 mmol) and sodium hydroxide (10% aqueous, 5 mL, 12 mmol) and the mixture was refluxed for 5 days. The mixture was worked up with 1N hydrochloric acid and ethyl acetate. Some solids precipitated out of solution and were filtered and dried. The organic layer from the extraction was dried and combined with the solids above gives 1-tert-butyl-3-[3′-formyl-2′-hydroxy-5′-(1H-tetrazol-5-yl)-biphenyl-3-ylmethyl]-urea as a 3:1 mixture of starting material to product.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[CH:7]=1.CC1(C)C(C)(C)OB([C:27]2[N:31]([C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=3)[N:30]=[CH:29][CH:28]=2)O1>>[F:41][C:38]([F:39])([F:40])[C:35]1[CH:34]=[CH:33][C:32]([N:31]2[C:27]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([C:11]5[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=5)=[CH:9][N:10]=4)[CH:7]=3)=[CH:28][CH:29]=[N:30]2)=[CH:37][CH:36]=1
Reactant: CC1(C)OB(c2ccnn2-c2ccc(C(F)(F)F)cc2)OC1(C)C
Reactant: N#Cc1ccc(-c2cnc3ccc(Br)cn23)cc1
Product: N#Cc1ccc(-c2cnc3ccc(-c4ccnn4-c4ccc(C(F)(F)F)cc4)cn23)cc1

Procedure:
The title compound, off-white solid (59 mg, 41%), MS (ISP) m/z=430.6 [(M+H)+], mp 201° C., was prepared in accordance with the general method of example 1 from 4-(6-bromo-imidazo[1,2-a]pyridin-3-yl)-benzonitrile (intermediate N) (0.1 g, 0.335 mmol) and 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(4-trifluoromethyl-phenyl)-1H-pyrazole (intermediate P) (0.15 g, 0.44 mmol).
Reaction SMILES: [Si:1]([O:18][C@@H:19]1[C@@H:23]([CH2:24][O:25][N:26]2C(=O)C3=CC=CC=C3C2=O)[O:22][C@@H:21]([N:37]2[CH:45]=[C:43]([CH3:44])[C:41](=[O:42])[NH:40][C:38]2=[O:39])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CNN>C(Cl)Cl>[NH2:26][O:25][CH2:24][C@H:23]1[O:22][C@@H:21]([N:37]2[CH:45]=[C:43]([CH3:44])[C:41](=[O:42])[NH:40][C:38]2=[O:39])[CH2:20][C@@H:19]1[O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cn([C@H]2C[C@H](O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@@H](CON3C(=O)c4ccccc4C3=O)O2)c(=O)[nH]c1=O
Agent: CNN
Solvent: ClCCl
Product: Cc1cn([C@H]2C[C@H](O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@@H](CON)O2)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 12 h
Yield: 88.6 %

Procedure:
To a stirred solution of 3'-O-(t-butyldiphenylsilyl)-5'-O-phthalimidothymidine (10 g, 16 mmol) in dry CH2Cl2 (100 ml) was added methylhydrazine (1.3 ml, 24 mmol) under argon at room temperature and solution stirred for 12 h. The solution was cooled (0° C.) and filtered. The white residue was washed with CH2Cl2 (2×25 ml) and combined filtrates were evaporated to furnish gummy residue. The residue on purification by silica gel column chromatography (elution with CH2Cl2 :MeOH, 98:2, v/v) furnished 7.03 g (89%) of 5'-O-amino-3'-O-(t-butyldiphenylsilyl)thymidine that crystallized from CH2Cl2 /MeOH mp 141-143° C. 1H NMR (DMSO-d6) δ 11.29 (s, 1, NH), 7.42-7.62 (m, 11, TBDPhH, C6H), 6.25 (dd, 1, H1', J1',2' =8.4 Hz, J1',2" =6.3 Hz), 6.02 (s, 2, NH2), 4.35 (m, 1, H4'), 4.04 (m, 1, H3+), 3.34-3.51 (m, 2, H5',5"), 2.04 (m, 2, H2',2"), 1.73 (s, 3, CH3), 1.03 (s, 9, C(CH3)3). Anal. Calcd. for C26H33O5N3Si: C, 63.00; H, 6.71; N, 8.48. Found: C, 62.85; H, 6.67; N, 8.32
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.[F:49]C1C=C(C=CC=1)N>C(O)(=O)C>[F:49][C:3]1[CH:2]=[C:1]([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: Nc1cccc(F)c1
Agent: COC(=O)c1scc(-c2ccccc2)c1N
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: O=c1c2scc(-c3ccccc3)c2ncn1-c1cccc(F)c1
Yield: 12 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (50 mg, 0.21 mmol), triethyl orthoformate (0.47 ml), 3-fluoroaniline (44.3 mg, 0.4 mmol), and acetic acid (0.06 ml) were used to give 8.1 mg (0.025 mmol, 12% yield) of the title compound.
Reaction SMILES: [CH:1]([N:4]1[C:8]([SH:9])=[N:7][C:6]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[N:5]1)([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:18]=[C:19]([NH:23][C:24](=[O:27])[CH2:25]Cl)[CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>ClCCl>[Cl:16][C:17]1[CH:18]=[C:19]([NH:23][C:24](=[O:27])[CH2:25][S:9][C:8]2[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[C:6]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)[N:7]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: O=C(CCl)Nc1cccc(Cl)c1
Reactant: CC(C)n1nc(-c2ccncc2)nc1S
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)n1nc(-c2ccncc2)nc1SCC(=O)Nc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of the thiol TFA salt from Step A (100 mg, 0.30 mmol), N-(3-Chlorophenyl)-2-chloroacetamide (61 mg, 0.30 mmol), and triethylamine (0.145 mL 1.040 mmol) in dichloromethane (2.0 mL) was stirred at room temperature for 6 h. The solvent was removed by evaporation, and the crude product was purified by HPLC to afford the title compound as a colorless solid, 127 mg (85%). MS (ES): 388 (M+H)+
Reaction SMILES: [CH2:1]([C:5]1[N:13]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Sn](CCCC)(CCCC)CCCC)=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4].I[C:38]1[CH:47]=[CH:46][CH:45]=[CH:44][C:39]=1[C:40]([O:42][CH3:43])=[O:41].O>CN(C=O)C>[CH3:43][O:42][C:40](=[O:41])[C:39]1[CH:44]=[CH:45][CH:46]=[CH:47][C:38]=1[C:20]1[CH:21]=[CH:22][C:23]2[C:18](=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]2[C:8]3=[N:9][CH:10]=[CH:11][CH:12]=[C:7]3[N:6]=[C:5]2[CH2:1][CH2:2][CH2:3][CH3:4])[CH:19]=1
Reactant: COC(=O)c1ccccc1I
Reactant: CCCCc1nc2cccnc2n1-c1cccc2cc([Sn](CCCC)(CCCC)CCCC)ccc12
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1nc2cccnc2n1-c1cccc2cc(-c3ccccc3C(=O)OC)ccc12
Temperature: 105 °C
Yield: 41.7 %

Procedure:
A mixture of 2-butyl-3-(6-tributylstannanyl-naphthalen-1-yl)-3H-imidazo[4,5-b]-pyridine (120 mg, 0.22 mmol), methyl 2-iodobenzoate (79 mg, 0.3 mmol) and PdCl2 (PPh3)2 (15 mg, 0.02 mmol) in 1.0 mL DMF was heated at 105° C. for 20 hours. The cooled reaction mixture was poured into H2O (20 mL). The aqueous solution was extracted with EtOAc (3×50 mL). The combined extracts were washed with saturated aqueous NaHCO3 (25 mL), dried MgSO4) and concentrated in vacuo. The residue was chromatographed on SiO2 -gel using a gradient of 20% ethyl acetate/hexanes to 100% ethyl acetate to give 40 mg of product. 1H NMR (250 MHz, CDCl3): d 8.27 (dd, 1H, J=1.15, 4.85 Hz), 8.14 (dd, 1H, J=1.21, 7.96 Hz), 8.08 (d, 1H, J=8.2 Hz), 7.94 (d, 1H, J=1.4 Hz), 7.89 (d, 1H, J=7.9 Hz), 7.69 (t, 1 H), 7.58 (m), 7.48 (m), 7.26 (m), 7.14 (d, 1H, J=8.5 Hz), 3.57 (s, 3 H), 2.72 (t, 2 H), 1.78 (m, 2 H), 1.27 (m, 2 H), 0.83 (t, 3 H).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:10])=[C:4]([C:7]([OH:9])=O)[S:5][CH:6]=1.[F:11][C:12]([F:25])([F:24])[C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1)[NH2:16]>>[Br:1][C:2]1[C:3]([OH:10])=[C:4]([C:7]([NH:16][C:15]2[CH:17]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:19]=[C:13]([C:12]([F:11])([F:24])[F:25])[CH:14]=2)=[O:9])[S:5][CH:6]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(O)c1scc(Br)c1O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1scc(Br)c1O
Yield: 82.4 %

Procedure:
Using 4-bromo-3-hydroxythiophene-2-carboxylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.ClCCl>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:2]([Cl:1])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1c(C)cccc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(Cl)cccc1CBr
Temperature: 25 °C
Yield: 95.1 %

Procedure:
A mixture of methyl 2-chloro-6-methylbenzoate (3.0 g, 16.2 mmol), N-bromosuccinimide (3.0 g, 17.0 mmol), and benzoyl peroxide (catalytic) in anhydrous carbon tetrachloride (50 mL) was stirred at reflux overnight. Dichloromethane (50 mL) was added after cooling to room temperature. The mixture was extracted with 1 N NaOH (2×100 mL). The organic layer was recovered, dried over MgSO4, filtered, and evaporated, and the residue was dried in vacuo, affording methyl 2-(bromomethyl)-6-chlorobenzoate (4.06 g, 95% yield), which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:18]([F:21])([F:20])[F:19])=[CH:11][C:12]=2[S:13][C:14]([F:17])([F:16])[F:15])=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:27]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:18]([F:21])([F:19])[F:20])=[CH:11][C:12]=2[S:13]([C:14]([F:16])([F:17])[F:15])=[O:27])=[CH:4][CH:3]=1
Reactant: FC(F)(F)Sc1cc(C(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=S(c1cc(C(F)(F)F)[nH]c1-c1ccc(Cl)cc1)C(F)(F)F

Procedure:
A solution of 2-(p-chlorophenyl)-5-(trifluoromethyl)-3-[(trifluoromethyl)thio]pyrrole (5.5 g, 15.9 mmol) in chloroform is cooled to 0° C., treated with 3-chloroperoxybenzoic acid (5.49 g, 60%, 19.1 mmol), stirred for several hours and filtered to remove solids. The solids are dissolved into ether and the organic solution is washed with water and saturated sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a solid. Recrystallization of the solid from ether gives the title product as a white solid (mp 198°-200° C.) which is identified by 1HNMR, 19FNMR and 13CNMR spectral analyses.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][CH:19]([CH3:35])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:24]=1)=[O:21]>>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[CH:17]=[CH:16][C:13]([CH2:14][N:32]3[CH2:33][CH2:34][CH:29]([C:25]4[CH:24]=[C:23]([NH:22][C:20](=[O:21])[CH:19]([CH3:18])[CH3:35])[CH:28]=[CH:27][CH:26]=4)[CH2:30][CH2:31]3)=[CH:12][CH:11]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: CC(C)(C)c1csc(-c2ccc(C=O)cc2)n1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(-c4nc(C(C)(C)C)cs4)cc3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 4-(4-tert-butyl-1,3-thiazol-2-yl)benzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide.
Reaction SMILES: [C:1](=O)([O-])O.[Na+].Cl.[CH3:7][O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@H:14](CN)[CH2:13][CH2:12]1)=[O:10].C1C2C(COC(N=C=S)=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>C(Cl)(Cl)Cl>[CH3:7][O:8][C:9]([C:11]1([CH3:1])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)=[O:10]
Reactant: COC(=O)[C@H]1CC[C@H](CN)CC1
Reactant: O=C([O-])O
Agent: Cl
Agent: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Agent: [Na+]
Solvent: C1CCNCC1
Solvent: ClC(Cl)Cl
Product: COC(=O)C1(C)CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.2 %

Procedure:
Sodium hydrogen carbonate (1.68 g, 20.0 mmol) was added to a solution of trans-4-aminomethyl cyclohexanecarboxylic acid methyl ester hydrochloride (2.07 g, 10.0 mmol) obtained in Step 1, 9-fluorenylmethoxycarbonyl isothiocyanate (2.81 g, 10.0 mmol) in chloroform (40 ml) while ice-cooled. The reaction solution was stirred at room temperature for 16 hours, piperidine (5 ml, 50 mmol) was added, and the mixture was stirred at room temperature for further 6 hours. Trans-4-thiouredide methylcyclohexane carboxylic acid methyl ester (1.55 g, 67%) was obtained by concentrating the reaction solution in vacuo and purifying the obtained solid by silica gel column chromatography (ethyl acetate).
Reaction SMILES: CN(C1C=CC=CN=1)C.Cl.CN(CCCN=C=NCC)C.[CH2:22]([N:24]1[CH:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:27](=[O:35])[N:26]([C:36]([CH3:41])([CH3:40])[C:37]([OH:39])=O)[CH2:25]1)[CH3:23].[Cl:42][C:43]1[C:49]([Cl:50])=[CH:48][CH:47]=[CH:46][C:44]=1[NH2:45]>ClCCl.O>[Cl:42][C:43]1[C:49]([Cl:50])=[CH:48][CH:47]=[CH:46][C:44]=1[NH:45][C:37](=[O:39])[C:36]([N:26]1[C:27](=[O:35])[CH:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:24]([CH2:22][CH3:23])[CH2:25]1)([CH3:41])[CH3:40]
Reactant: CCN1CN(C(C)(C)C(=O)O)C(=O)C1c1ccccc1
Reactant: Nc1cccc(Cl)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CCN1CN(C(C)(C)C(=O)Nc2cccc(Cl)c2Cl)C(=O)C1c1ccccc1
Reaction time: 0.25 h
Yield: 21.9 %

Procedure:
Dimethylaminopyridine (50 mg) and dimethylaminopropylethylcarbodiimide hydrochloride (0.5 g) were added to a solution of 2-(1-ethyl-5-phenylimidazolidin-4-on-3-yl)isobutyric acid (0.6 g) prepared according to Example 8 in dichloromethane (15 mL) at 0° C. After stirring for 15 minutes at 0° C. to room temperature, 2,3-dichloroaniline (0.4 g) was added and the mixture was stirred overnight at room temperature. The reaction solution was poured into water whose pH was 2, and the mixture was extracted with chloroform. The organic layer was washed with water and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the resulting crude product was purified by thin-layer chromatography (silica gel, ethyl acetate/n-hexane=2/3) to give 0.2 g of the title compound.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][C:7](=[O:8])[CH:3]([CH2:4]2)[CH2:2]1.[C:9]1([Mg]Br)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl-].[NH4+].Cl>C1COCC1.CCOCC>[C:9]1([C:7]2([OH:8])[CH2:6][CH:5]3[CH2:4][CH:3]2[CH2:2][CH2:1]3)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CC2CCC1C2
Reactant: Br[Mg]c1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC1(c2ccccc2)CC2CCC1C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of norcamphor (60.0 g, 0.54 mole) in THF (1 L) at −65° C. was added phenyl magnesium bromide (200 mL of a 3 M solution in ether, 0.60 mole). The temperature was kept between −65° C. and −20° C. during the addition. After completion of addition, the mixture was slowly warmed to room temperature and stirred overnight. The mixture was cooled to 0° C. and saturated aqueous ammonium chloride (200 mL) was added carefully. A solution of 1 N hydrochloric acid was added until the residual salts were dissolved. The mixture was then extracted twice with ether and the combined organic phases were washed successively with water and brine. The organic layer was dried (MgSO4) and concentrated. Flash chromatography of the residue (silica gel; hexane/EtOAc 9:1) provided I-2a as a white solid (95.0 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[CH:5]2.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:10][CH:9]=3)=[CH:12][CH:13]=1
Reactant: Clc1ccc(-c2cc3cc(Br)ccc3[nH]2)cc1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: Clc1ccc(-c2cc3cc(-c4ccccc4)ccc3[nH]2)cc1
Temperature: 160 °C
Yield: 10.6 %

Procedure:
To a suspension of 5-bromo-2-(4-chlorophenyl)-1H-indole (200 mg, 0.65 mmol) in dioxane/water 4:1 v/v (5 mL) was added phenylboronic acid (87 mg, 0.72 mmol) and a few milligrams of tetrakis(triphenylphosphine)palladium(0). The resulting suspension was heated in the microwave at 160° C. for 15 min. After cooling, the reaction was poured into water to give a precipitate, which was filtered off and washed with water. The resulting solid was purified by column chromatography eluting using a gradient (hexanes to ethyl acetate/hexanes 30:70 v/v), followed by a recrystallisation from hot ethyl acetate to afford 21 mg (11%) of the title compound (LCMS RT=8.54 min, MH+304.1)
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:20])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[CH:8][CH:7]=[C:6]([OH:19])[CH:5]=2.BrC1C(=O)C2C(C=1C1C=CC=CC=1)=CC=C(O)C=2.[CH3:39][S:40]([N:43]1[CH2:48][CH2:47][N:46]([CH2:49][CH2:50]O)[CH2:45][CH2:44]1)(=[O:42])=[O:41]>>[Br:1][C:2]1[C:3](=[O:20])[C:4]2[C:9]([C:10]=1[C:11]1[CH:12]=[C:13]([F:18])[CH:14]=[C:15]([F:17])[CH:16]=1)=[CH:8][CH:7]=[C:6]([O:19][CH2:50][CH2:49][N:46]1[CH2:47][CH2:48][N:43]([S:40]([CH3:39])(=[O:41])=[O:42])[CH2:44][CH2:45]1)[CH:5]=2
Reactant: O=C1C(Br)=C(c2cc(F)cc(F)c2)c2ccc(O)cc21
Reactant: CS(=O)(=O)N1CCN(CCO)CC1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(O)cc21
Product: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(Br)=C3c2cc(F)cc(F)c2)CC1
Reaction time: 96 h
Yield: 99 %

Procedure:
The procedure of Step 6 of Example 1 was repeated except for using 2-bromo-3-(3,5-difluorophenyl)-6-hydroxy-1H-inden-1-one obtained in Step 5 of Example 36 as a starting material instead of 2-bromo-6-hydroxy-3-phenyl-1H-inden-1-one, 2-(4-(methylsulfonyl)piperazin-1-yl)ethanol instead of 4-(2-hydroxyethyl)morpholine, being stirred for 4 d, and being purified by silica gel column chromatography (CH2Cl2/EtOAc=1:2) to obtain the title compound (99%)
Reaction SMILES: [C:1]([NH:18][C@H:19]([C:26]([OH:28])=O)[CH2:20][O:21][C:22]([CH3:25])([CH3:24])[CH3:23])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:37]>ClCCl>[C:1]([NH:18][C@H:19]([C:26]([F:37])=[O:28])[CH2:20][O:21][C:22]([CH3:25])([CH3:24])[CH3:23])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2]
Reactant: CC(C)(C)OC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: Fc1nc(F)nc(F)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
N-FMOC-O-t-Butyl-L-serine (10 g, 26.07 mmol) (Bachem) was dissolved in dichloromethane (135 mL). Pyridine (2.11 mL, 26.07 mmol) (Aldrich) and cyanuric fluoride (3.52 g, 26.07 mmol) (Aldrich) were successively added at room temperature and the mixture was stirred overnight. Ice cold water (100 mL) was added and the resulting slurry was filtered. The filtrate was poured into a separatory funnel and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford N-FMOC-O-t-butyl-L-serinyl fluoride as a colorless oil which solidified upon standing. (Yield 9.79 g., 97%).