Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1.O[C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[C:26](=[O:30])[CH2:25][CH2:24][CH2:23]2>>[CH3:18][O:17][C@@H:13]([CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][O:1][C:20]2[CH:29]=[CH:28][C:27]3[C:26](=[O:30])[CH2:25][CH2:24][CH2:23][C:22]=3[CH:21]=2)=[CH:7][CH:8]=1)[C:14]([OH:16])=[O:15]
Reactant: CO[C@@H](Cc1ccc(OCCCO)cc1)C(=O)O
Reactant: O=C1CCCc2cc(O)ccc21
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc3c(c2)CCCC3=O)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling with 6-hydroxy-1,2,3,4-tetrahydronaphtalenone and cleavage from the resin (Standard Procedure G) gave an oily solid.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[Cl:32][C:33]1[S:37][C:36]([S:38](Cl)(=[O:40])=[O:39])=[CH:35][CH:34]=1.N1C=CC=CC=1>ClCCl>[Cl:32][C:33]1[S:37][C:36]([S:38]([NH:8][C:7]2[CH:6]=[CH:5][C:4]([F:9])=[C:3]([NH:10][C:11]3[C:16]([C:17]4[N:25]=[CH:24][N:23]=[C:22]5[C:18]=4[N:19]=[CH:20][N:21]5[CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][O:27]4)=[CH:15][CH:14]=[CH:13][N:12]=3)[C:2]=2[F:1])(=[O:40])=[O:39])=[CH:35][CH:34]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1ccc(Cl)s1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 5-chlorothiophene-2-sulfonyl chloride (15 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: [C:1]1([CH3:48])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH2:13][CH:12]([NH:32][C:33]([NH:35][C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([O:44]CC)=[O:43])[CH:37]=3)=[O:34])[C:11]2=[O:47])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.O.[OH-].[Li+].O1CCCC1>CO>[C:1]1([CH3:48])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH2:13][CH:12]([NH:32][C:33](=[O:34])[NH:35][C:36]3[CH:37]=[C:38]([CH:39]=[CH:40][CH:41]=3)[C:42]([OH:44])=[O:43])[C:11]2=[O:47])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cccc(NC(=O)NC2CN(C(=O)OCc3ccccc3)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(NC(=O)Nc1cccc(C(=O)O)c1)CN2C(=O)OCc1ccccc1
Yield: 72.3 %

Procedure:
1-[1-(2-Toluoylmethyl)-2-oxo-5-benzyloxycarbonyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea (435 mg) was dissolved in methanol (20 ml), aqueous lithium hydroxide monohydrate (141 mg) solution (10 ml) and tetrahydrofuran (10 ml) were added, the mixture was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water (150 ml), washed with diethyl ether (100 ml), acidified with 1N hydrochloric acid, and extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, n-hexane was added to the residue for trituration, and collected by filtration, to thereby obtain 301 mg of the titled compound (Yield: 72.5%).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:15][CH2:16][CH3:17])=[C:4](OC)[C:5]([O:10][CH2:11][CH3:12])=[C:6]([OH:9])[C:7]=1[CH3:8].[H-].[Na+].[CH3:20][O:21][CH2:22]Cl>CN(C=O)C>[Br:1][C:2]1[C:3]([O:15][CH2:16][CH3:17])=[CH:4][C:5]([O:10][CH2:11][CH3:12])=[C:6]([O:9][CH2:20][O:21][CH3:22])[C:7]=1[CH3:8]
Reactant: COCCl
Reactant: CCOc1c(O)c(C)c(Br)c(OCC)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc(OCC)c(OCOC)c(C)c1Br
Temperature: 0 °C

Procedure:
54 g of 5-bromo-2,4-diethoxy-3-methoxy-6-methylphenol prepared in Referential Example 7 was dissolved in 250 ml of DMF, and 8.5 g of sodium hydride (55% oil suspension) was added thereto and cooled by ice while stirring. The mixture was stirred at room temperature for 30 min and cooled again with ice, and 17.1 g of methoxymethyl chloride was dropwise added thereto. After the completion of the dropwise addition, the mixture was further stirred at room temperature for 30 min. Ice water was added thereto, and the mixture was extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate, concentrated and purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=95:5) to prepare 43.6 g of the product compound as a colorless oleaginous substance.
Reaction SMILES: [N-]1C=CN=C1.[CH:6]1([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:33])=[C:16]([N:20]4[CH2:24][CH2:23][CH:22]([NH:25]C(OC(C)(C)C)=O)[CH2:21]4)[C:17]=3[Cl:19])[C:12](=[O:34])[C:11]([C:35]([OH:37])=O)=[CH:10]2)[CH2:8][CH2:7]1.C(=O)([O-])[O-].[K+].[K+].[C:44]([CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])#[N:45]>C(#N)C>[ClH:19].[CH:6]1([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:33])=[C:16]([N:20]4[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21]4)[C:17]=3[Cl:19])[C:12](=[O:34])[C:11]([C:35](=[O:37])[CH:46]([C:44]#[N:45])[C:47]([O:49][CH2:50][CH3:51])=[O:48])=[CH:10]2)[CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2Cl)C1
Reactant: CCOC(=O)CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1c[n-]cn1
Solvent: CC#N
Product: CCOC(=O)C(C#N)C(=O)c1cn(C2CC2)c2c(Cl)c(N3CCC(N)C3)c(F)cc2c1=O
Product: Cl
Reaction time: 0.5 h
Yield: 140.1 %

Procedure:
5.2 g of 1-cyclopropyl-6-fluoro-8-chloro-7-(3-t-butoxycarbonylaminopyrrolidin-1-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid imidazolide and 6.9 g of potassium carbonate were put into 200 ml of acetonitrile, and 5.66 g of ethyl cyanoacetate was added thereto, and then refluxed under heating for 5 hours. Acetonitrile was distilled off under reduced pressure, and then water and ethyl acetate were added thereto. The pH of the reaction mixture was adjusted to about 3 with 1N-HCl, and then the organic layer was separated. The organic layer was dehydrated with anhydrous MgSO4, and the solvent was distilled off under reduced pressure. The residue was purified on a silica gel column chromatography, and 50 ml of 10% HCl-ethyl acetate was added to the purified compound. The reaction mixture was stirred for 30 minutes, and the resulting solid was filtered, and then dried to obtain 3.4 g of the object compound
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[Br:19][C:20]1[C:21]([NH2:31])=[N:22][NH:23][C:24]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[Br:19][C:20]1[C:21]([NH:31][CH:8]=[C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])=[N:22][NH:23][C:24]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C1Nc2ccccc2/C1=C/O
Reactant: Nc1n[nH]c(-c2ccccc2)c1Br
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C1=CNc1n[nH]c(-c2ccccc2)c1Br

Procedure:
The named compound is prepared by substituting 4-bromo-5-phenyl-1H-pyrazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.1489 gms.) is reacted with 0.4557 gms. of 4-bromo-5-phenyl-1H-pyrazol-3-ylamine by refluxing in tetrahydrofuran (3.0 mL).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([NH2:7])=[O:6].[CH3:12][O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21].O.[C:26]([OH:30])(=[O:29])[CH:27]=O>C(#N)C.CN(C=O)C>[C:5]([C:4]1[CH:3]=[C:2]([NH:1][CH:27]([C:16]2[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:14]([O:13][CH3:12])[CH:15]=2)[C:26]([OH:30])=[O:29])[CH:10]=[C:9]([CH3:11])[CH:8]=1)(=[O:6])[NH2:7]
Reactant: Cc1cc(N)cc(C(N)=O)c1
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: O=CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1ccc(C(Nc2cc(C)cc(C(N)=O)c2)C(=O)O)cc1OC
Temperature: 100 °C
Yield: 44.1 %

Procedure:
A mixture of 89C (75 mg, 0.5 mmol), 3,4-dimethoxyphenylboronic acid (91 mg, 0.5 mmol) and glyoxylic acid monohydrate (46 mg, 0.5 mmol) in acetonitrile (1.0 mL) and DMF (0.1 mL) was heated at in a microwave reactor at 100° C. for 10 min. The precipitate formed was collected by filtration. The filtrate was concentrated and the residue was triturated with ethyl acetate and ether. This solid was combined with the original precipitate to give 89D (76 mg, 44%) as an orange solid. 1H NMR (400 MHz, CD3OD) δ ppm 2.26 (s, 3H) 3.81 (s, 3H) 3.82 (s, 3H) 5.09 (s, 1H) 6.70 (s, 1H) 6.92 (d, J=8.4 Hz, 1H) 7.00 (s, 1H) 7.02 (s, 1H) 7.07 (dd, J=8.4, 2.2 Hz, 1H) 7.11 (d, J=1.8 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[O:12][N:11]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.O1CCCC1.[OH-].[Na+].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Cl>CN(C)C=O>[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:10]2[CH:9]=[C:8]([C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=3)[O:12][N:11]=2)=[CH:15][CH:16]=1
Reactant: COc1cccc(CCl)c1
Reactant: Nc1ncccc1-c1cc(Cc2ccc(O)cc2)no1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cccc(COc2ccc(Cc3cc(-c4cccnc4N)on3)cc2)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 82.4 %

Procedure:
To 4-(5-(2-amino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (30 mg, 0.11 mmol) described in Manufacturing Example 5-1-1 were tetrahydrofuran (3 mL) and a 5N sodium hydroxide aqueous solution (22.4 μL, 0.11 mmol), which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction solution was then concentrated under a reduced pressure, which gave a white solid. To a suspension of this solid in N,N-dimethylformamide (1 mL) was added an N,N-dimethylformamide (1 mL) solution of 3-methoxybenzyl chloride (21.0 mg, 0.13 mmol), which was stirred for 12 hours at 60° C. This mixture was cooled to room temperature and partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and this residue was purified by NH silica gel column chromatography (heptane: ethyl acetate=1:1) to obtain the title compound (35.1 mg, 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=[O:14])[C:11]([C:15]([OH:17])=[O:16])=[CH:10][C:9]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH3:24]O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:13][C:12](=[O:14])[C:11]([C:15]([O:17][CH3:24])=[O:16])=[CH:10][C:9]=2[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)c1cc(-c2ccccc2)c(-c2ccc(Cl)cc2)[nH]c1=O
Product: COC(=O)c1cc(-c2ccccc2)c(-c2ccc(Cl)cc2)[nH]c1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Into a suspension of 6-(4-chlorophenyl)-5-(phenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (5.0 g, 15.3 mmol) from Step C in methanol (400 mL) was bubbled HCl gas until the resulting solution was saturated. The mixture was stirred at rt for 20 h, then heated at 60° C. for 8 h, and again at rt for 16 h. The reaction was concentrated in vacuo, made basic with saturated sodium carbonate solution, and extracted twice with methylene chloride. The organic layers were washed with a portion of brine and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product. The crude product was purified by flash column chromatography on silica gel eluted with 100% methylene chloride, then a gradient of 1 to 4% methanol in methylene chloride to afford the desired title compound. HPLC/MS: 340 (M+1); Rt=3.0 min;
Reaction SMILES: [O-2:1].[U+6:2].[O-2:3].[O-2].[N+:5]([O-:8])([OH:7])=[O:6]>>[N+:5]([O-:8])([O-:7])=[O:6].[U+2:2](=[O:3])=[O:1].[N+:5]([O-:8])([O-:7])=[O:6]
Reactant: [U+6]
Reactant: [O-2]
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])[O-]
Product: O=[U+2]=O

Procedure:
reacting the insoluble uranium oxide material with nitric acid to form uranyl nitrate; and,
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[S:9][CH:10]=1)[CH3:2].[OH:19]C1C=CC=C(O)C=1C(=S)N.ClCC(=O)CC(OCC)=O.[Li+].[Br-]>C1COCC1>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[N:7]=[C:8]([C:11]2[C:16]([OH:19])=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[S:9][CH:10]=1)[CH3:2]
Reactant: NC(=S)c1c(O)cccc1O
Reactant: CCOC(=O)Cc1csc(-c2ccccc2O)n1
Agent: CCOC(=O)CC(=O)CCl
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1csc(-c2c(O)cccc2O)n1
Yield: 69 %

Procedure:
The procedure used for the preparation of 4a was repeated with 2,6-dihydroxybenzenecarbothioamide 3b (1.02 g, 6.04 mmol), ethyl 4-chloroacetoacetate (1.99 g, 12.1 mmol), and LiBr (525 mg, 6.04 mmol) in dry THF (15 mL) to give 4b (1.16 g, 69%) as a white solid after chromatographic purification on silica gel (gradient EtOAc/CH2Cl2 : 0-12%) and recrystallization from EtOAc/hexane. mp 152.5°-154.0° C.; IR (KBr) 3256 (br), 1742, 1460, 1157 cm-1 ; 1H NMR (DMSO-d6) δ 1.17 (3H, t, J=7.2 Hz, CH3), 3.88 (2H, s, CH2), 4.08 (2H, q, J=7.2 Hz, CH2), 6.44 (2H, d, J=8.2 Hz, Ar), 7.09 (1H, t, J=8.2 Hz, Ar), 7.51 (1H, s), 12.19 (2H, s, OH); FDMS m/z 279 (M+); Anal. Calcd for C13H13NO4S: C, 55.90; H, 4.69; N, 5.01. Found: C, 56.19; H, 4.85; N, 4.86.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=O)[C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:46]([C:50]1[CH:70]=[CH:69][C:53]([CH2:54][NH:55][CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][C:61]([F:64])=[C:60]([C:65]([F:68])([F:67])[F:66])[CH:59]=2)=[CH:52][CH:51]=1)([CH3:49])([CH3:48])[CH3:47]>CN(C=O)C.O>[C:46]([C:50]1[CH:70]=[CH:69][C:53]([CH2:54][N:55]([CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][C:61]([F:64])=[C:60]([C:65]([F:67])([F:68])[F:66])[CH:59]=2)[C:12]([C:9]2[C:10]([F:11])=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:14])=[CH:52][CH:51]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(F)c(C(F)(F)F)c2)cc1
Reactant: O=C(O)c1c(F)c(Cl)cc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)c1ccc(CN(CCc2ccc(F)c(C(F)(F)F)c2)C(=O)c2c(F)c(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 44.9 %

Procedure:
To a solution of 60 mg (0.28 mmol) of 5-chloro-6-fluoro-1H-indole-7-carboxylic acid and 90 mg of TBTU (0.3 mmol) in 3 ml DMF, were added 0.24 ml (1.4 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 99 mg (0.28 mmol) of (4-tert-butyl-benzyl)-[2-(4-fluoro-3-trifluoromethyl-phenyl)-ethyl]-amine in 2 ml DMF were added. After stirring for 15 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:19 then 1:9) followed by a second column chromatography (8 g silica gel; gradient DCM/heptane from 70% to 90% DCM) to give 69 mg white solid (44%). MS (ISP) 549.3 (M+H)+.
Reaction SMILES: Cl[CH2:2][Si:3]([CH3:6])([Cl:5])[Cl:4].[Cl:7][SiH:8]([Cl:10])[Cl:9]>[Cl-].C([P+](CCCC)(CCCC)CCCC)CCC>[Cl:7][Si:8]([Cl:10])([Cl:9])[CH2:2][Si:3]([Cl:5])([Cl:4])[CH3:6]
Reactant: Cl[SiH](Cl)Cl
Reactant: C[Si](Cl)(Cl)CCl
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Product: C[Si](Cl)(Cl)C[Si](Cl)(Cl)Cl
Yield: 59.8 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.18 g (0.61 mmol) of tetrabutylphosphonium chloride, 1.00 g (6.12 mmol) of (chloromethyl)methyldichlorosilane, and 2.52 g (18.6 mmol) of trichlorosilane were reacted at 150° C. for 2 hrs. The resulting mixture was distilled to give 0.96 g of 1,1,1,3,3-pentachloro-1,3-disilabutane (yield; 60%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][CH2:17][N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:15]=3)[S:10][C:3]=12.[F:27][C:28]1[CH:48]=[C:47]([N+:49]([O-:51])=[O:50])[CH:46]=[CH:45][C:29]=1[O:30]C1C=CN=C2C=C(C3SC=CN=3)SC=12>>[F:27][C:28]1[CH:48]=[C:47]([N+:49]([O-:51])=[O:50])[CH:46]=[CH:45][C:29]=1[O:30][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][CH2:17][N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:15]=3)[S:10][C:3]=12
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4nccs4)sc23)c(F)c1
Reactant: CN(CCn1cc(-c2cc3nccc(Cl)c3s2)cn1)C(=O)OC(C)(C)C
Product: CN(CCn1cc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)cn1)C(=O)OC(C)(C)C
Yield: 37 %

Procedure:
Starting from the chloride 180 and following the procedure described above for the synthesis of compound 11 (scheme 2, example 12), title compound 181 was obtained in 37% yield. LRMS (M+1) 514.1 (100%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([O:22][CH3:23])=[O:21]>CN(C=O)C>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:2]2[O:1][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:4][C:3]=2[CH:6]=1
Reactant: COC(=O)CBr
Reactant: COc1ccc(O)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc(OC)ccc2o1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-Hydroxy-5-methoxy-benzaldehyde (10 g, 65.8 mmol) was stirred in DMF (90 mL) with potassium carbonate (23 g, 0.17 mol) under nitrogen, then methyl bromoacetate was added dropwise. The mixture was stirred at room temperature for 4 h. The reaction was then heated to 80° C. for 18 h. The reaction was allowed to cool then poured onto ice water (200 mL) and the resulting brown suspension was allowed to stir for 30 min. After this time the solid was collected by filtration and washed with water. The solid was dried to afford (5.22 g, 39%), which was taken through to the next step with no further purification.
Reaction SMILES: [CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[NH:10][C:9](/[CH:14]=[CH:15]/[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=3)=[N:8][C:7]=2[N:6]([CH2:24][CH3:25])[C:4]1=[O:5])[CH3:2].[C:26](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[N:10]([CH3:26])[C:9](/[CH:14]=[CH:15]/[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=3)=[N:8][C:7]=2[N:6]([CH2:24][CH3:25])[C:4]1=[O:5])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCn1c(=O)c2[nH]c(/C=C/c3cccc(OC)c3)nc2n(CC)c1=O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCn1c(=O)c2c(nc(/C=C/c3cccc(OC)c3)n2C)n(CC)c1=O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
Compound r (1.70 g, 5.0 mmol) obtained in Reference Example 17 was dissolved in 40 ml of dimethylformamide. To the solution were added 1.73 g (12.5 mmol) of potassium carbonate and subsequently 0.62 ml (10.0 mmol) of methyl iodide, and the resulting mixture was stirred at 50° C. for 30 minutes. After cooling, insoluble matters were filtered off, and 100 ml of water was added to the filtrate. The mixture was extracted three times with 50 ml of chloroform. The extract was washed twice with water and once with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, followed by evaporation under reduced pressure. The obtained crude crystals were purified by silica gel column chromatography (eluent: 40% ethyl acetate/hexane), followed by recrystallization from cyclohexane/toluene to give 1.10 g (yield 62%) of Compound s as pale yellow needles.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][C:6]2([CH3:15])[CH3:14])#[CH:2].I[C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1>C(N(CC)CC)C.[Pd](Cl)Cl.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>[CH3:14][C:6]1([CH3:15])[C:5]2[CH:4]=[C:3]([C:1]#[C:2][C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=3)[CH:12]=[CH:11][C:10]=2[C:9](=[O:13])[CH2:8][CH2:7]1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCC2=O
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 8.8 g (47.8 mmol) of 6-ethynyl-1,2,3,4-tetrahydro-4,4-dimethylnaphthalen-1-one (Compound K) flushed for 15 minutes with a stream of argon, and 13.2 g (47.8 mmol) of ethyl 4-iodobenzoate in 200 ml of triethylamine was added 1.1 g (1.6 mmol) of bis(triphenylphosphine) palladium(II) chloride and 0.30 g (1.6 mmol) of cuprous iodide. The solution mixture was flushed with argon for 5 minutes and then stirred at ambient temperature for 18 hours. The reaction mixture was filtered through Celite and the filtrate concentrated in vacuo. Purification by flash chromatography (silica, 10% EtOAc-hexane) yielded the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[NH:4][C@H:5]1[C@@H:10]([CH3:11])[CH2:9][CH2:8][NH:7][CH2:6]1.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[NH:4][C@H:5]1[C@@H:10]([CH3:11])[CH2:9][CH2:8][N:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6]1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)N[C@@H]1CNCC[C@@H]1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)N[C@@H]1CN(Cc2ccccc2)CC[C@@H]1C
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
The reductive amination of cis-(4-methyl-piperidin-3-yl)-carbamic acid methyl ester was carried out by charging 3.9 grams (1 equiv., 22.6 mmol) to 2.07 ml benzaldehyde (0.9 equiv., 20.4 mmol), 9.6 grams sodium triacetoxyborohydride (2 equivs., 45.3 mmol) and 39 ml methylene chloride (10 volumes). The reaction was stirred at 20° C. and was allowed to exotherm to 30°-35° C. The reaction was complete by GCMS within 30 minutes. The reaction was quenched with 78 ml saturated sodium bicarbonate (20 volumes), extracted into 78 ml methylene chloride (20 volumes) and concentrated to a clear oil. (70% yield). 1H NMR: δ7.2-7.3 (5 H, m, aromatic protons), 5.50-5.48 (1 H, d, J=8.8 Hz), 3.77-3.75 (1 H, d, J=8.0 Hz), 3.63 (3 H, s), 3.45-3.38 (2 H, m), 2.77-2.74 (2 H, d, J=11.2 Hz), 2.14-2.01 (1 H, m), 1.94-1.89 (1 H, m), 1.57-1.55 (1 H, brs), 1.37-1.20 (2 H, m), 0.876 (3 H, d, J=9.2 Hz).