Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[OH:8][C:9]1[CH:24]=[CH:23][C:12]([C:13]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]C)=[O:20])=[O:14])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:2]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[O:14])=[CH:23][CH:24]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCBr
Reactant: COC(=O)CCCCC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCOc1ccc(C(=O)CCCCC(=O)O)cc1
Yield: 0.1 %

Procedure:
The title compound is prepared from the methyl ester as follows. 1-Bromohexane (1.65 g, 10 moles) is heated under reflux for four hours with methyl 5-(4-hydroxybenzoyl)pentanoate (2 g, 8.5 moles) in a mixture of acetone (50 ml) and anhydrous potassium carbonate (2.35 g). The reaction mixture is filtered and evaporated under reduced pressure. The residue (3.3 g) is heated under reflux in 2N sodium hydroxide (26 ml) for four hours. The reaction mixture is partitioned between water (200 ml) and ether (300 ml). The ether phase is discarded and the aqueous phase is acidified to pH 1 with concentrated hydrochloric acid and extracted with ether (2×250 ml). The ether extract is dried over magnesium sulfate and evaporated under reduced pressure to a tan crystalline solid. Recrystallization from aqueous ethanol gives 5-(4-n-hexyloxybenzoyl)pentanoic acid (2.3 g) as colorless crystals, m.p. 95°-96° C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([NH:9][N:10]=[C:11]([C:15](=[O:17])[CH3:16])[C:12](=[O:14])[CH3:13])[CH:6]=[CH:7][CH:8]=1.[CH3:20]OC(OC)N(C)C>CN(C=O)C.Cl>[C:15]([C:11]1[C:12](=[O:14])[CH:13]=[CH:20][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:18])([F:19])[F:1])[CH:4]=2)[N:10]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)C(=NNc1cccc(C(F)(F)F)c1)C(C)=O
Reactant: COC(OC)N(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Temperature: 80 °C
Yield: 65.1 %

Procedure:
A mixture of 3-{[3-(trifluoromethyl)phenyl]hydrazono}pentane-2,4-dione (5.00 g, 18.4 mmol) and N,N-dimethylformamide dimethyl acetal (2.44 mL, 18.4 mmol) in DMF (100 mL) was heated to 80° C. for 4 h. The mixture was diluted with 1 M HCl aqueous solution, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, concentrated in vacuo, purified by column chromatography on silica gel (hexane/EtOAc=50/50 to 0/100 and EtOAc/MeOH=100/0 to 80/20) and triturated with EtOAc/hexane to yield the title compound (3.38 g, 65% yield) as a pale yellow solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 2.55 (3H, s), 6.75 (1H, d, J=8.0 Hz), 7.78-7.88 (2H, m), 8.06-8.16 (2H, m), 8.96 (1H, d, J=8.2 Hz).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][NH:9][CH2:8][CH2:7]2.Cl[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][N:9]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:17]=1)[CH2:8][CH2:7]2
Reactant: COc1ccc2c(c1)CCNC2
Reactant: ClCc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(Cc1ccc(-c3ccccc3)cc1)C2

Procedure:
4.0 g of 6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride, 4.1 g of 4-chloromethylbiphenyl and 6.0 g of finely powdered potassium carbonate in 50 ml of dimethylformamide are stirred at 80° for 5 hours. The solvent is removed in vacuo, the residue is taken up in water/methylene chloride, the organic phase is shaken twice with water, and the organic phase is dried with magnesium sulfate and evaporated in a rotary evaporator. The crude product, which is only slightly impure, can be reacted further without further purification. A sample recrystallized from ethyl acetate has a melting point of 120°.
Reaction SMILES: I[C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N+:13]([O-:15])=[O:14])=[CH:5][CH:6]=1.[CH3:16][C:17]([CH3:21])([CH3:20])[C:18]#[CH:19].O>N1CCCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:16][C:17]([CH3:21])([CH3:20])[C:18]#[C:19][C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N+:13]([O-:15])=[O:14])=[CH:5][CH:6]=1
Reactant: C#CC(C)(C)C
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(I)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: C1CCNCC1
Product: CC(C)(C)C#Cc1ccc(-c2ccccc2[N+](=O)[O-])s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-iodo-5-(2-nitro-phenyl)-thiophene (28 g, 84 mmol) in piperidine (235 ml) were added successively copper(I) iodide (0.8 g, 4.2 mmol), bis(triphenylphosphine)palladium(II) chloride (2.9 g, 4.2 mmol) and 3,3-dimethyl-1-butyne (14 g, 0.17 mol). This mixture was stirred for 16 hours at room temperature. Subsequently, it was poured into 1 litre of water, stirred for 15 minutes and extracted with tert-butyl methyl ether. The combined organic layer was washed with brine, dried over magnesium sulfate and evaporated. The remaining oil was purified by silica gel chromatography using ethyl acetate and hexane as eluents, giving Compound No. 6.030.i (22 g).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:28])[C@@H:15]([NH:16][C:17](=[O:27])[CH2:18][C:19]3[CH:24]=[CH:23][NH:22][C:21](=[N:25][OH:26])[CH:20]=3)[C@H:12]2[S:11][CH2:10][C:9]=1[CH2:29][O:30][C:31](=[O:33])[CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+](=[CH:36][CH3:37])=[N-]>O1CCCC1.CCOCC>[C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:28])[C@@H:15]([NH:16][C:17](=[O:27])[CH2:18][C:19]3[CH:24]=[CH:23][NH:22][C:21](=[N:25][O:26][CH2:36][CH3:37])[CH:20]=3)[C@H:12]2[S:11][CH2:10][C:9]=1[CH2:29][O:30][C:31](=[O:33])[CH3:32])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)Cc3cc[nH]c(=NO)c3)[C@H]2SC1
Reactant: CC=[N+]=[N-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCON=c1cc(CC(=O)N[C@@H]2C(=O)N3C(C(=O)OC(C)(C)C)=C(COC(C)=O)CS[C@H]23)cc[nH]1

Procedure:
A solution of t-butyl-3-acetoxymethyl-7β-(2-hydroxyiminopyrid-4-ylacetamido)-ceph-3-em-4-carboxylate (syn-isomer) (1.15g) in tetrahydrofuran (20 ml) was treated with an excess of diazoethane at 20° for 40 minutes. The mixture was diluted with ether, washed with water and extracted with 2N-hydrochloric acid. The aqueous extract was neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate. Evaporation of the dried organic extract offered the title ester as a foam (0.84 g, 69%), [Ε]D + 47° (c 0.84, DMSO), λmax. (EtOH) 259 nm (ε 15,450), νmax. (Nujol) 3300 (NH), 1788 (β-lactam), 1740 (OAc), 1724 (CO2R), 1678 and 1540 cm.-1 (CONH), τ (d6 -DMSO) values include 0.12 (d, J 8Hz; NH), 1.26 and 2.42 (multiplets; aromatic protons), 5.69 (q, J 7Hz, OCH2CH3 ), 7.93 (s; OCOCH3), 8.50 (s; (CH3)3) and 8.69 (t, J 7Hz; OCH2CH3).
Reaction SMILES: [CH2:1]1[CH2:13][CH2:12][CH:11]2[CH2:14][CH2:15][CH2:16][N:9]3[C:10]2=[C:2]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=13.ClC1C(=O)C(C#N)=C(C#N)C(=[O:25])C=1Cl>O1CCCC1.O>[C:1]1(=[O:25])[CH2:13][CH2:12][CH:11]2[CH2:14][CH2:15][CH2:16][N:9]3[C:10]2=[C:2]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=13
Reactant: c1ccc2c(c1)c1c3n2CCCC3CCC1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: C1CCOC1
Product: O=C1CCC2CCCn3c2c1c1ccccc13
Temperature: 0 °C

Procedure:
7.2 g (0.034 mol) of 2,3,3a,4,5,6-hexahydro-1H-pyrido[3,2,1-jk]carbazole prepared according to A. S. Baily et al. J. C. S. Perkin I (1980) 97, were dissolved in 300 ml of tetrahydrofuran. The mixture was diluted with 30 ml of water and cooled to 0° C. A solution of 17.0 g (0.075 mol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in 150 ml of tetrahydrofuran was added dropwise in 10 minutes while stirring thoroughly at a reaction temperature between 0° and 5° C. The reaction mixture was stirred for 1 hour and evaporated in vacuum. The residue was extracted with methylene chloride. The methylene chloride solution was washed with 200 ml of 0.5N sodium hydroxide solution and evaporated in vacuum. The residue was chromatographed over 500 g of silicagel using ethyl acetate as an eluent. After evaporating the good fraction, the desired ketone was obtained in a yield of 4.6 g (60%) having a melting-point of 172°-173° C.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1.C([O:38][C@@H:39]([CH3:43])[C:40](Cl)=[O:41])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:40](=[O:41])[C@@H:39]([OH:38])[CH3:43])[CH2:33][CH2:34]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1
Reactant: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)cc1F
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)NC4CCN(C(=O)[C@H](C)O)CC4)c(C)[nH]c23)cc1F

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-2-methyl-N-piperidin-4-yl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f26) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([C:5]1[CH:20]=[CH:19][C:8]([O:9][CH2:10][C:11]2[O:12][CH:13]=[C:14]([OH:18])[C:15](=[O:17])[CH:16]=2)=[CH:7][CH:6]=1)[C:2]([CH3:4])=O.C(=O)(O)O.[Cl:25][C:26]1[CH:27]=[C:28]([CH:32]([OH:35])[CH2:33][NH2:34])[CH:29]=[CH:30][CH:31]=1>C1C=CC=CC=1>[Cl:25][C:26]1[CH:27]=[C:28]([CH:29]=[CH:30][CH:31]=1)[CH:32]([OH:35])[CH2:33][NH:34][CH:2]([CH3:4])[CH2:1][C:5]1[CH:20]=[CH:19][C:8]([O:9][CH2:10][C:11]2[O:12][CH:13]=[C:14]([OH:18])[C:15](=[O:17])[CH:16]=2)=[CH:7][CH:6]=1
Reactant: CC(=O)Cc1ccc(OCc2cc(=O)c(O)co2)cc1
Reactant: NCC(O)c1cccc(Cl)c1
Agent: O=C(O)O
Solvent: c1ccccc1
Product: CC(Cc1ccc(OCc2cc(=O)c(O)co2)cc1)NCC(O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 10.5 %

Procedure:
A solution of 2-(4-acetonylphenoxymethyl)-5-hydroxy-4H-pyran-4-one (0.7 g) and 2-(3-chlorophenyl)-2-hydroxyethylamine carbonate 0.52 g in benzene was heated under reflux for 2.5 h using a Dean and Stark head. The reaction mixture was allowed to cool and the solvent removed in vacuo. The residue was taken up in methanol, treated with sodium cyanoborohydride (0.2 g) and stirred at ambient temperature for 18 h. The solvent was evaporated under reduced pressure, the residue dissolved in ethyl acetate, washed with water (2×50 ml), brine(1×50 ml) and dried (magnesium sulphate). After filtration and evaporation of solvent the residue was purified by column chromatography on silica using methanol:chloroform (3:97) as eluent, followed by crystallisation from acetone to give 2-[4-[2-[(3-chloro-β-hydroxyphenethyl)amino]propyl]phenoxymethyl]-5-hydroxy-4H-pyran-4-one, (0.1 g), as a (35:65) mixture of diastereoisomers.
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5].[C:14]([O-])(O)=O.[Na+]>CO>[CH3:14][O:5][C:4](=[O:6])[CH:3]([OH:2])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)C(O)Cc1ccccc1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
Hydrogen chloride was bubbled for 15 minutes into a solution of 2-hydroxy-3-phenyl-propionic acid (10.0 g, 60 mmol) in 100 mL of methanol at room temperature. The vessel was sealed and then stirred overnight at room temperature. The reaction was made basic by the addition of 5% NaHCO3 and then concentrated under reduced pressure to remove the methanol. The residue was diluted with water and extracted with ethyl acetate. The organic layer was extracted with saturated NaCl, dried (MgSO4), filtered and the solvent removed under reduced pressure to give 2-hydroxy-3-phenyl-propionic acid methyl ester (9.7 g, 90%) as a yellow oil, MS m/z 180 [M]+. Elemental Analysis for C10H12O3 Calc'd: C, 66.65; H, 6.71; N, 0.00. Found: C, 66.52; H, 6.86; N, 0.29
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[O:9][C:10]([CH3:13])=[CH:11][N:12]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.[CH3:23][N:24]1[CH2:29][CH2:28][C:27]2([C:40]3[C:32](=[CH:33][C:34]4[CH2:35][CH2:36][NH:37][C:38]=4[CH:39]=3)[O:31][CH2:30]2)[CH2:26][CH2:25]1>>[CH3:23][N:24]1[CH2:25][CH2:26][C:27]2([C:40]3[C:32](=[CH:33][C:34]4[CH2:35][CH2:36][N:37]([C:20]([C:17]5[CH:18]=[CH:19][C:14]([C:3]6[CH:4]=[CH:5][C:6]([C:8]7[O:9][C:10]([CH3:13])=[CH:11][N:12]=7)=[CH:7][C:2]=6[CH3:1])=[CH:15][CH:16]=5)=[O:22])[C:38]=4[CH:39]=3)[O:31][CH2:30]2)[CH2:28][CH2:29]1
Reactant: Cc1cnc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)o1
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCC3
Product: Cc1cnc(-c2ccc(-c3ccc(C(=O)N4CCc5cc6c(cc54)C4(CCN(C)CC4)CO6)cc3)c(C)c2)o1

Procedure:
The title compound was prepared from 2'-methyl-4'-(5-methyloxazol-2-yl)biphenyl-4-carboxylic acid (D76) and 2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (D8) following the procedure of Example 1 (58%). This was converted to its oxalate salt and crystallised from acetone/methanol as a white solid m.p. 230-233° C.
Reaction SMILES: Cl.[N:2]1[N:3]([CH2:7][C:8]([OH:10])=O)[N:4]=[CH:5][CH:6]=1.[Cl:11][C:12]1[S:16][C:15]([CH2:17][C@H:18]2[CH2:22][NH:21][C@H:20]([C:23]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]4[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=4)=[CH:28][CH:27]=3)=[O:24])[CH2:19]2)=[CH:14][CH:13]=1>>[N:4]1[N:3]([CH2:7][C:8]([N:21]2[CH2:22][C@H:18]([CH2:17][C:15]3[S:16][C:12]([Cl:11])=[CH:13][CH:14]=3)[CH2:19][C@H:20]2[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)=[CH:28][CH:27]=2)=[O:24])=[O:10])[N:2]=[CH:6][CH:5]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(Cl)s2)CN1
Reactant: O=C(O)Cn1nccn1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(Cl)s2)CN1C(=O)Cn1nccn1
Yield: 58 %

Procedure:
Proceeding as in Example 1, but substituting 2-(2H-1,2,3-triazol-2-yl)acetic acid hydrochloride and (2S,4S)-4-((5-chlorothien-2-yl)methyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 66, (2S,4S)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-4-((5-chlorothien-2-yl)methyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (58.3 mg, 58%). 1H-NMR (400 MHz, CDCl3): σ 9.14 (s, 1H), 7.72 (s, 2H), 7.42 (d, 2H), 7.00 (t, 2H), 6.95-6.90 (m, 4H), 6.75 (d, 1H), 6.61 (d, 1H), 5.39 (s, 2H), 4.86 (d, 1H), 3.62 (dd, 1H), 3.19 (t, 1H), 3.03-2.85 (m, 2H), 2.83-2.77 (m, 1H), 2.72 (dd, 1H), 1.72-1.64 (m, 1H). MS (EI) for C26H23ClFN5O3S. found 540.1 (MH+).
Reaction SMILES: [CH:1]1([SiH2:10][CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH:20]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(OCC)C>[CH:20]1([NH:26][Si:10]([NH:26][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)([CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12]2)[CH:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C1=CC([SiH2]C2C=Cc3ccccc32)c2ccccc21
Reactant: NC1CCCCC1
Solvent: CCOCC
Product: C1=CC([Si](NC2CCCCC2)(NC2CCCCC2)C2C=Cc3ccccc32)c2ccccc21
Temperature: 0 °C

Procedure:
Dichloro, diindenyl silane (6.45 g) was slurried in 20 mL hexanes and 10 mL diethyl ether. The mixture was cooled to 0° C. and 9.2 mL of cyclohexylamine in 10 mL hexanes was added slowly. The mixture was heated to reflux for 1 h, cooled and filtered. The solvent was removed to give di(cyclohexylamino)diindenyl silane as a tan solid (7.60 g).
Reaction SMILES: [C:1]([C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[O:7][C:8]1[C:13]([NH:14][C:15](=[S:18])[NH:16][NH2:17])=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:23][CH2:24][C:25](Cl)=O>>[C:1]([C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[O:7][C:8]1[C:13]([NH:14][C:15]2[S:18][C:25]([CH2:24][Cl:23])=[N:17][N:16]=2)=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1NC(=S)NN
Reactant: O=C(Cl)CCl
Product: CC(C)(C)c1ccccc1Oc1ncccc1Nc1nnc(CCl)s1

Procedure:
Example 473a was synthesized following the procedure for Example 1 using 4-(2-(2-tert-butylphenoxy)pyridin-3-yl)thiosemicarbazide (Example 1b) with chloroacetyl chloride.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.Cl[CH2:12][C:13](=O)[CH2:14][C:15]([O:17][CH3:18])=[O:16]>C(#N)CC>[CH3:18][O:17][C:15](=[O:16])[CH2:14][C:13]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][CH:4]=2)[O:7][CH:12]=1
Reactant: NC(=O)c1ccc(O)cc1
Reactant: COC(=O)CC(=O)CCl
Solvent: CCC#N
Product: COC(=O)Cc1coc(-c2ccc(O)cc2)n1
Temperature: 98 °C
Yield: 411.2 %

Procedure:
A solution of 4-hydroxybenzamide (10 g, 7.3 mmol, 1 eq) and methyl 4-chloro-3-oxobutanoate (15 g, 11 mmol, 5 eq) in propionitrile (300 ml) is stirred at reflux (98° C.) during 3 days. After concentration under reduced pressure, the residue is purified over silicagel (eluent: dichloromethane/methanol/ammonia 90:9:1) to yield 7 g of methyl[2-(4-hydroxyphenyl)-1,3-oxazol-4-yl]acetate i50.
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)=[N+]=[N-].C(OCC)(=O)C>CO.[Pd]>[NH2:1][CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(N=[N+]=[N-])CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N)CC1
Yield: 97.6 %

Procedure:
A solution of 4.05 g (17.9 mmol) of 4-azido-1-t-butoxycarbonylpiperidine from Step A in 50 mL of methanol was hydrogenated with 350 mg of 10% Pd/C under a hydrogen balloon for 16 h when the reaction was complete by TLC (10% ethyl acetate in hexanes). The catalyst was filtered off and the volatiles removed in vacuo to give 3.5 g of title compound which was used directly in subsequent reactions.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[C:5]([N:11]2[C:15]([CH3:16])=[CH:14][CH:13]=[C:12]2[CH3:17])=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>C1COCC1>[CH3:17][C:12]1[N:11]([C:5]2[C:6]([C:8]([OH:10])=[O:9])=[N:7][C:2]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[C:3]([C:18]([F:21])([F:20])[F:19])[CH:4]=2)[C:15]([CH3:16])=[CH:14][CH:13]=1
Reactant: C1CCNC1
Reactant: Cc1ccc(C)n1-c1cc(C(F)(F)F)c(Br)nc1C(=O)O
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1cc(C(F)(F)F)c(N2CCCC2)nc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of 6-bromo-3-(2,5-dimethyl-1H-pyrrol-1-yl)-5-(trifluoromethyl)picolinic acid (300 mg, 0.826 mmol) in THF (1 ml), pyrrolidine (0.136 ml, 1.652 mmol) was added. The orange solution was stirred at RT overnight. The reaction mixture was partitioned between 0.5M HCl (30 ml) and EtOAc (30 ml) and shaken. The organic portion was separated and washed with brine (30 ml), dried over MgSO4, filtered and concentrated in vacuo to give a red oil. The crude product was purified on silica eluting with 0-40% EtOAc in iso-hexane to afford the title product;
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:38]([CH3:39])=[CH:37][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:36]=[CH:35][C:28]5[N:29]([CH3:34])[C:30](=[O:33])[N:31]([CH3:32])[C:27]=5[CH:26]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:12]1[C:38]([CH3:39])=[CH:37][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:36]=[CH:35][C:28]5[N:29]([CH3:34])[C:30](=[O:33])[N:31]([CH3:32])[C:27]=5[CH:26]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:40]1[CH:41]=[CH:42][C:43]([Cl:46])=[CH:44][CH:45]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5c(c4)n(C)c(=O)n5C)c3)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2nc(-c3ccnc(-c4ccc5c(c4)n(C)c(=O)n5C)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)pyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (7.0 mg, 0.011 mmol) in THF (0.5 mL) and methanol (0.5 mL) was added 1N NaOH solution (0.5 mL, excess). The reaction mixture was stirred at 50° C. for 2 h and then purified by reverse phase HPLC, eluting by 0-100% acetonitrile in H2O with 0.1% TFA to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C34H32ClN4O4S: 627.2; found: 627.3. 1H NMR (400 MHz, CD3OD) δ 8.68 (d, J=6.0 Hz, 1H), 8.47 (s, 1H), 7.98 (dd, J=5.6, 1.6 Hz, 1H), 7.93 (s, 1H), 7.80 (d, J=1.6 Hz, 1H), 7.78 (s, 1H), 7.71-7.68 (m, 1H), 7.62-7.58 (m, 3H), 7.24 (d, J=8.4 Hz, 1H), 5.28 (s, 1H), 3.47 (s, 3H), 3.42 (s, 3H), 2.63 (s, 3H), 0.98 (s, 9H).
Reaction SMILES: [CH:1]([NH:3][CH:4](P(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:6])=[S:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:41][C:42](=O)[CH2:43][O:44][CH3:45]>CC(C)=O>[CH3:45][O:44][CH2:43][C:42]1[CH2:41][S:2][CH:1]=[N:3][C:4]=1[C:5]([O:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=1)=[O:6]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)C(NC=S)P(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: COCC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N=CSC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of p-nitrobenzyl α-thioformamidodiphenylphosphonoacetate (2.43 g), powdered anhydrous potassium carbonate (2.07 g), 1-chloro-3-methoxy-2-propanone (0.67 g), and acetone (25 ml) is stirred under a nitrogen atmosphere at room temperature for 16 hours. The mixture is filtered and the filtrate evaporated under reduced pressure. The residue is dissolved in methylene chloride, washed twice with water and saturated brine, dried over MgSO4, filtered, and evaporated in vacuo to yield crude p-nitrobenzyl 5-methoxymethyl-6H-1,3-thiazine-4-carboxylate.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][C:3]=1[CH:4]=[O:5].C1C(=O)N([I:22])C(=O)C1.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C>[OH:1][C:2]1[C:9]([I:22])=[CH:8][C:7]([O:10][C:11]([F:12])([F:13])[F:14])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1cc(OC(F)(F)F)ccc1O
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cc(OC(F)(F)F)cc(I)c1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 9.3 %

Procedure:
2-hydroxy-5-(trifluoromethoxy)benzaldehyde (2.0 g, 9.7 mmol) was dissolved into DMF (20 mL) and then added with NIS (5.4 g, 24 mmol) in batches. The mixture was stirred for 2 days at room temperature. At the end of reaction, saturated sodium thiosulfate solution was added and extracted with ethyl acetate, and the organic phase was dried and evaporated in vacuum to obtain the product (0.30 g, 78%) by column chromatography.