Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.N1C(C)=CC(C)=CC=1C.F[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N+:27]([O-:29])=[O:28].ClCCl>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N+:27]([O-:29])=[O:28])[CH2:6][CH2:5]2
Reactant: Brc1ccc2c(c1)CCN2
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])c1ccccc1N1CCc2cc(Br)ccc21
Temperature: 25 °C
Yield: 54.8 %

Procedure:
5-Bromoindoline (4.0 g, 0.02 mole), collidine (3.6 g, 0.03 mole), and o-fluoronitrobenzene (2.8 g, 0.02 mole) in xylene (25 ml) were heated at 185° C. (oil bath temperature) for 24 hours. The mixture was cooled to room temperature and poured into dichloromethane. The dichloromethane solution was washed with 1N hydrochloric acid (3 times, 150 ml), brine (200 ml), dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated. Crystallization of the residue was induced by stirring in ether (15 ml) followed by hexane (200 ml), then chilling in the refrigerator overnight. The solid was filtered and washed with hexane and dried to yield 3.5 g (55%) of product. Recrystallization from 2-propanol yielded the analytical sample, mp 12°-114° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([S:11][CH3:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N:19]=[C:20]=[O:21])[CH:14]=1>>[Cl:1][C:2]1[C:10]([S:11][CH3:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:20](=[O:21])[NH:19][C:15]1[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=1
Reactant: O=C=Nc1cccnc1
Reactant: CSc1ccc2c(c1Cl)CCN2
Product: CSc1ccc2c(c1Cl)CCN2C(=O)Nc1cccnc1
Yield: 84 %

Procedure:
4-Chloro-5-methylthioindoline (D49) (0.9 g, 4.51 mmol) was treated with 3-pyridylisocyanate as in the procedure described in Example 1. The crude product was filtered-off and recrystallised from ethanol to give the title compound (1.22 g, 84%) as a white crystalline solid m.p. 237°-241° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][C:17]([O:19]C)=[O:18])=[N:12][C:11]=2[CH:21]([CH3:23])[CH3:22])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][C:17]([OH:19])=[O:18])=[N:12][C:11]=2[CH:21]([CH3:23])[CH3:22])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(=O)Cc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)c1nc(CC(=O)O)n(C)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.4 %

Procedure:
A mixture of methanol (1 ml), 0.10 g of methyl [5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-1H-imidazol-2-yl]acetate (33)and 1N-sodium hydroxide (0.32 ml)was stirred at room temperature for 1.5 hours. To the reaction mixture was added 0.32 ml of 1N-hydrochloric acid to yield crystals, which were filtered, washed with water and then with chilled methanol to obtain 87 mg of the target compound (Compound I-80)(yield 90%). mp 118° C. (degradation).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH:10]([CH3:15])[C:11]2=O)=[C:7]([C:16]2[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:19]=[C:18]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:17]=2)[C:6]=1[O:30][CH3:31])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].CO.CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1.C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:13]=[C:12]2[C:8](=[C:7]([C:16]3[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:19]=[C:18]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:17]=3)[C:6]=1[O:30][CH3:31])[CH2:9][C:10]([CH3:15])=[CH:11]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1c(C(C)(C)C)cc2c(c1-c1cc(C(C)(C)C)cc(C(C)(C)C)c1)CC(C)C2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1c(C(C)(C)C)cc2c(c1-c1cc(C(C)(C)C)cc(C(C)(C)C)c1)CC(C)=C2
Temperature: 5 °C
Reaction time: 7 h
Yield: 100 %

Procedure:
To a solution of 16.3 g (38.8 mmol) of 6-tert-butyl-4-(3,5-di-tert-butylphenyl)-5-methoxy-2-methylindan-1-one in 200 ml of THF cooled to 5° C. 1.47 g (38.9 mmol) of NaBH4 was added. Further on, 80 ml of methanol was added dropwise to this mixture by vigorous stirring for ca. 7 h at 5° C. The resulting mixture was evaporated to dryness, and the residue was treated by 300 ml of dichloromethane and 300 ml of 2 M HCl. The organic layer was separated, the aqueous layer was additionally extracted with 100 ml of dichloromethane. The combined organic extract was evaporated to dryness to give a colorless oil. To a solution of this oil in 250 ml of toluene 0.1 g of TsOH was added, this mixture was refluxed with Dean-Stark head for 15 min and then cooled to room temperature using water bath. The resulting solution was washed by 10% aqueous Na2CO3. The organic layer was separated, the aqueous layer was extracted with 2×50 ml of dichloromethane. The combined organic extract was dried over K2CO3 and then passed through a short layer of silica gel 60 (40-63 um). The silica gel layer was additionally washed by 100 ml of dichloromethane. The combined organic elute was evaporated to dryness to give 15.7 g (99%) of a white crystalline product which was further used without an additional purification.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:5]2[C:14]3[CH:13]=[CH:12][C:11]([OH:15])=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:16]=1)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][C:29]([N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)=[O:30].CO>CN(C=O)C.O.C(OCC)C>[CH2:1]([C:3]1[N:4]([CH2:17][CH:18]([CH3:19])[CH3:20])[C:5]2[C:14]3[CH:13]=[CH:12][C:11]([O:15][CH2:28][C:29]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[O:30])=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:16]=1)[CH3:2]
Reactant: O=C(CBr)N1CCOCC1
Reactant: CCc1nc2cnc3cc(O)ccc3c2n1CC(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCc1nc2cnc3cc(OCC(=O)N4CCOCC4)ccc3c2n1CC(C)C
Temperature: 85 °C
Yield: 94.9 %

Procedure:
Under a nitrogen atmosphere, a mixture of 2-ethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-ol (1.97 g, 7.31 mmol), solid cesium carbonate (4.77 g, 14.6 mmol), and DMF (105 mL) was heated at 85° C. for 30 minutes. The heat was removed, and a solution of 4-(2-bromoacetyl)morpholine (1.83 g, 8.77 mmol) in DMF (20 mL) was added over a period of 12 minutes. The reaction was heated at 85° C. for 3.5 hours, and methanol (1 mL) was then added. The reaction mixture was filtered to remove solids, and the filtrate was concentrated under reduced pressure to provide an orange oil. The oil was triturated with ethyl acetate and water to provide a fluffy, white solid that was isolated by filtration. The filtrate was concentrated under reduced pressure to provide a solid that was stirred with diethyl ether and water and isolated by filtration. The two solids were combined and dried in a vacuum oven at 60° C. to provide 2.75 g of 2-ethyl-1-(2-methylpropyl)-7-(2-morpholin-4-yl-2-oxoethoxy)-1H-imidazo[4,5-c]quinoline as a yellow semi-solid.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[N:13]=[C:14]([NH:17][C:18]([NH2:20])=[NH:19])[S:15][CH:16]=1)SC)#[N:2].[CH:21]1[CH:26]=[C:25]([OH:27])[CH:24]=[C:23]([CH:28]([OH:31])[CH2:29][NH2:30])[CH:22]=1>[N+]([O-])([O-])=O.[Ag+].C(O)C>[C:1]([NH:3][C:4]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[N:13]=[C:14]([NH:17][C:18]([NH2:20])=[NH:19])[S:15][CH:16]=1)=[N:30][CH2:29][CH:28]([OH:31])[C:23]1[CH:22]=[CH:21][CH:26]=[C:25]([OH:27])[CH:24]=1)#[N:2]
Reactant: CSC(=NCCSCc1csc(NC(=N)N)n1)NC#N
Reactant: NCC(O)c1cccc(O)c1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CCO
Product: N#CNC(=NCC(O)c1cccc(O)c1)NCCSCc1csc(NC(=N)N)n1
Yield: 63.2 %

Procedure:
With 15 ml of ethanol were mixed 3.0 g of N-cyano-N'-{2-[(2-guanidino-4-thiazolyl)methylthio]ethyl}-S-methylisothiourea, 4.9 g of DL-[2-hydroxy-2-(3-hydroxyphenyl)ethyl]amine and 1.97 g of silver nitrate, and the resulting mixture was subjected to reaction under reflux for 1.5 hours. After completion of the reaction, the insolubles were removed by filtration, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by a column chromatography (Wako Silica Gel C-200, eluent; chloroform:methanol=5:1 by volume) and crystallized from methanol to obtain 2.5 g (yield 68%) of N-cyano-N'-{2-[(2-guanidino-4-thiazolyl)methylthio]ethyl}-N"-[2-hydroxy-2-(3-hydroxyphenyl)ethyl]guanidine having a melting point of 162°-164° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([N+:15]([O-])=O)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].O1CCCC1>C(O)C.[C].[Pd]>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([NH2:15])[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(NC(=O)OC(C)(C)C)cc1N
Temperature: 25 °C
Reaction time: 22 h
Yield: 99.7 %

Procedure:
To a solution of tert-butyl(4-methyl-3-nitrophenyl)carbamate (10.1 g, 39.8 mmol) in ethanol (60 mL)/tetrahydrofuran (20 mL) was added 10% palladium-carbon (2.12 g), and the mixture was stirred at room temperature under a hydrogen atmosphere (3 atm) for 22 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (8.82 g, 99%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)[CH2:15][NH2:16])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[N:29]#[C:30]Br>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:14]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[CH:18]=4)[CH2:15][NH:16][C:30]3=[NH:29])=[CH:9][CH:8]=2)=[CH:27][CH:28]=1
Reactant: NCC(Nc1ccc(Oc2ccc(Cl)cc2)cc1)c1cccc(C(F)(F)F)c1
Reactant: N#CBr
Solvent: CCO
Product: N=C1NCC(c2cccc(C(F)(F)F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 80 °C

Procedure:
To a solution of N1-(4-(4-chlorophenoxy)phenyl)-1-(3-(trifluoromethyl)phenyl)ethane-1,2-diamine (20.0 mg, 0.0492 mmol) in EtOH (0.5 mL) are added cyanogen bromide (6.2 mg, 0.0590 mmol) and TEA (8.22 μL, 0.0590 mmol). The reaction mixture is heated at 80° C. for 2 h before removal of the solvent. The residue is purified by preparatory LC/MS to provide the title compound; 1H NMR (CDCl3, 400 MHz) δ 7.65-7.50 (m, 4H), 7.33 (d, 2H), 7.01 (d, 2H), 6.94 (m, 4H), 5.24 (dd, 1H), 4.30 (t, 1H), 3.79 (dd, 1H); HPLC-MS calculated for C22H17ClF3N3O (M+H+) 432.1, found 432.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH2:7][CH2:6][CH2:5]2.[B:12]([O-])([O-:14])[O-:13].Cl.O>CCCCCC.C1COCC1>[CH2:8]1[C:9]2[C:4](=[CH:3][C:2]([B:12]([OH:14])[OH:13])=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH2:7]1
Reactant: [O-]B([O-])[O-]
Reactant: Brc1ccc2c(c1)CCCC2
Agent: Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: OB(O)c1ccc2c(c1)CCCC2
Temperature: -69 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
In a 5 liter three-necked flask, 67.55 g of 6-bromo-1,2,3,4-tetrahydronaphthalene and 1480 ml of dry tetrahydrofurah (THF) were placed and cooled to −70 to −68° C. on a dry ice-acetone bath in a dry nitrogen gas atmosphere. At that temperature, to the mixture, 200 ml of 1.6 M-butyllithium solution in hexane was added dropwise, followed by stirring for 2 hours at −67° C. or below. To borate in 435 ml of dry THF was added dropwise at −70 to −68° C., followed by stirring for 2 hours at −67° C. or below. The reaction mixture was gradually warmed to room temperature and left standing overnight. The resultant reaction mixture was gradually added dropwise to a mixture of 108 ml of HCl and 438 ml of water kept at 10° C. or below, followed by stirring for 1 hour at that temperature. Thereafter, the mixture was subjected to extraction with toluene. The organic layer was washed with water, followed by distilling-off of the solvent under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=2/1) and recrystallized from hexane to obtain 30.4 g of 1,2,3,4-tetrahydronaphthalene-6-boronic acid (Yield: 54.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH:19]([CH2:22][O:23][CH3:24])[CH2:20][CH3:21])[C:13]=1[N+:25]([O-])=O.[O-]S(S([O-])=O)=O.[Na+].[Na+]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH:19]([CH2:22][O:23][CH3:24])[CH2:20][CH3:21])[C:13]=1[NH2:25]
Reactant: CCC(COC)Nc1nccc(-c2ccc(C(F)(F)F)cc2Cl)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: CCC(COC)Nc1nccc(-c2ccc(C(F)(F)F)cc2Cl)c1N
Yield: 77.6 %

Procedure:
[4-(2-Chloro-4-trifluoromethyl-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl)-amine (0.40 g, 1.0 mmol) and Na2S2O4 (1.39 g, 8.0 mmol) were treated substantially as described in Part E of Example 9 to yield 0.29 g (78%) of 4-(2-chloro-4-trifluoromethyl-phenyl)-N2-(1-methoxymethyl-propyl)-pyridine-2,3-diamine: MS (AP) m/z 373.8 [(M+H)+, 100].
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[CH2:7][O:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12]O)([CH3:4])([CH3:3])[CH3:2].N1C(C)=CC(C)=CC=1C.[Cl-].[Li+].CS([Cl:30])(=O)=O>CN(C)C=O>[C:1]([O:5][C:6](=[O:14])[CH2:7][O:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][Cl:30])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)COC/C=C\CO
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1cc(C)nc(C)c1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COC/C=C\CCl

Procedure:
To a solution of 420 mg of 2-[4-hydroxy-(Z)-2-buten-1-yloxy]acetic acid tert-butyl ester in 10 ml of N,N-dimethylformamide, 1.00 g of 2,4,6-collidine and 350 mg of lithium chloride were added. While stirring under ice cooling, 0.64 ml of methanesulfonyl chloride was added dropwise, followed by stirring at room temperature for 2 hours. The reaction solution was extracted with ethyl acetate after adding iced water, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 350 mg of the desired compound as a colorless oily substance.
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[N:6]([CH:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH3:16])[C:5]1=[O:24])=[N+]=[N-]>C(O)C.[Pd]>[NH2:1][CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[N:6]([CH:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH3:16])[C:5]1=[O:24]
Reactant: CC(C(=O)OC(C)(C)C)N1C(=O)C(N=[N+]=[N-])CCc2ccccc21
Agent: [Pd]
Solvent: CCO
Product: CC(C(=O)OC(C)(C)C)N1C(=O)C(N)CCc2ccccc21

Procedure:
A solution of 3-azido-1-(1-t-butyloxycarbonylethyl)-2,3,4,5-tetrahydro-1H-[1]-benzazepin-2-one (7 g) in ethanol (70 ml) was hydrogenated on a Parr shaker at 3 atmospheres pressure for 3 hours using 10% Pd-C (0.5 g) as catalyst. The catalyst was removed by filtration and the ethanol removed under reduced pressure to give 3-amino-1-(1-t-butyloxycarbonylethyl)-2,3,4,5-tetrahydro-1H-[1]-benzazepin-2-one as an oil. High pressure liquid chromatography (HPLC) indicated that the product was an approximately 1:1 mixture of diastereomers. This material was used without further purification.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:34]([C:37]1[CH:38]=[N:39][C:40]2[C:45]([C:46]=1[NH:47][C:48]1[CH:53]=[CH:52][CH:51]=[C:50]([O:54][CH3:55])[CH:49]=1)=[CH:44][C:43]([S:56]([C:59]1[CH:60]=[C:61]([CH:65]=[CH:66][CH:67]=1)[C:62](O)=[O:63])(=[O:58])=[O:57])=[CH:42][C:41]=2[CH3:68])(=[O:36])[NH2:35].[NH2:69][C:70]1[CH:75]=[CH:74][C:73]([C:76]2([CH2:81][CH2:82][CH2:83][CH2:84][N:85]([CH2:93][C@H:94]([O:107][Si:108]([C:111]([CH3:114])([CH3:113])[CH3:112])([CH3:110])[CH3:109])[C:95]3[CH:104]=[CH:103][C:102]([OH:105])=[C:101]4[C:96]=3[CH:97]=[CH:98][C:99](=[O:106])[NH:100]4)[C:86](=[O:92])[O:87][C:88]([CH3:91])([CH3:90])[CH3:89])[S:80][CH2:79][CH2:78][S:77]2)=[CH:72][CH:71]=1>CN(C1C=CN=CC=1)C.CN1C(=O)CCC1>[Si:108]([O:107][C@H:94]([C:95]1[CH:104]=[CH:103][C:102]([OH:105])=[C:101]2[C:96]=1[CH:97]=[CH:98][C:99](=[O:106])[NH:100]2)[CH2:93][N:85]([CH2:84][CH2:83][CH2:82][CH2:81][C:76]1([C:73]2[CH:74]=[CH:75][C:70]([NH:69][C:62](=[O:63])[C:61]3[CH:65]=[CH:66][CH:67]=[C:59]([S:56]([C:43]4[CH:44]=[C:45]5[C:40](=[C:41]([CH3:68])[CH:42]=4)[N:39]=[CH:38][C:37]([C:34](=[O:36])[NH2:35])=[C:46]5[NH:47][C:48]4[CH:53]=[CH:52][CH:51]=[C:50]([O:54][CH3:55])[CH:49]=4)(=[O:57])=[O:58])[CH:60]=3)=[CH:71][CH:72]=2)[S:80][CH2:79][CH2:78][S:77]1)[C:86](=[O:92])[O:87][C:88]([CH3:91])([CH3:90])[CH3:89])([C:111]([CH3:114])([CH3:113])[CH3:112])([CH3:110])[CH3:109]
Reactant: CC(C)(C)OC(=O)N(CCCCC1(c2ccc(N)cc2)SCCS1)C[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c2[nH]c(=O)ccc12
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)O)c4)cc23)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(C6(CCCCN(C[C@H](O[Si](C)(C)C(C)(C)C)c7ccc(O)c8[nH]c(=O)ccc78)C(=O)OC(C)(C)C)SCCS6)cc5)c4)cc23)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
DMAP (20 mg), HATU (110 mg, 0.29 mmol) and DIEA (0.15 mL, 0.87 mmol) were added to a stirring mixture of 3-[[3-carbamoyl-4-[(3-methoxyphenyl)amino]-8-methylquinolin-6-yl]sulfonyl]benzoic acid (144 mg, 0.29 mmol) and Intermediate 105 (0.18 g, 0.35 mmol) in NMP (3 mL). The reaction mixture was stirred overnight in an 80° C. oil bath and then purified by reverse-phase high performance liquid chromatography (RP-HPLC, acetonitrile/water/0.1% TFA) to provide, after concentration, the title compound as a dark yellow solid (90 mg, 27%). ES/MS calcd. for C60H71N6O10S3Si+ 1159.4. Found m/z=1159.6 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])/[C:4](/[NH:11]C(OCC1C=CC=CC=1)=O)=[CH:5]/[C@H:6]1[CH2:9][C@@H:8]([CH3:10])[CH2:7]1.[H][H]>[Pd].CO>[CH3:1][O:2][C:3](=[O:22])[CH:4]([NH2:11])[CH2:5][C@H:6]1[CH2:7][C@H:8]([CH3:10])[CH2:9]1
Reactant: COC(=O)/C(=C/[C@H]1C[C@@H](C)C1)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(N)C[C@H]1C[C@H](C)C1
Reaction time: 1 h
Yield: 86 %

Procedure:
A mixture of (Z)-2-benzyloxycarbonylamino-3-(cis-3-methyl-cyclobutyl)-acrylic acid methyl ester (prepared in Example 214, 275 mg, 0.91 mmol), methanol (10 mL) and 10% palladium on activated carbon (50 mg) was placed in a Parr shaker bottle. It was then placed on the Parr hydrogenator apparatus and charged with hydrogen to 40 psi and shaken for 1 h. After such time, the catalyst was filtered through a plug of celite and the filterate was concentrated in vacuo to afford 2-amino-3-(trans-3-methyl-cyclobutyl)-propionic acid methyl ester (134 mg, 86%) as a pale yellow oil.
Reaction SMILES: ClCCCl.[CH:5]([C:7]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([C:15]([F:18])([F:17])[F:16])=[CH:9][C:8]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:20]=1)=O.[Cl:29][C:30]1[CH:35]=[C:34]([NH2:36])[CH:33]=[CH:32][C:31]=1[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1>C(Cl)Cl>[Cl:29][C:30]1[CH:35]=[C:34]([NH:36][CH2:5][C:7]2[C:12]([O:13][CH3:14])=[CH:11][C:10]([C:15]([F:16])([F:17])[F:18])=[CH:9][C:8]=2[C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:20]=2)[CH:33]=[CH:32][C:31]=1[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1
Reactant: COC(=O)c1ccc(-c2cc(C(F)(F)F)cc(OC)c2C=O)cc1
Reactant: Nc1ccc(-c2ccc(Cl)cc2)c(Cl)c1
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)c1ccc(-c2cc(C(F)(F)F)cc(OC)c2CNc2ccc(-c3ccc(Cl)cc3)c(Cl)c2)cc1
Temperature: 25 °C

Procedure:
Solid NaBH(Oac)3 (113 mg, 0.54 mmol) was added to a DCE solution (4 mL) of methyl 2′-formyl-3′-methoxy-5′-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylate (121 mg, 0.36 mmol) and 2,4′-dichloro-[1,1′-biphenyl]-4-amine (93 mg, 0.39 mmol), and the resulting mixture was stirred at room temperature. After 16 h the resulting mixture was diluted with DCM, washed with saturated aqueous NaHCO3 and water, dried (Na2SO4), concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: [N:1]([CH:4]([C:17]1[CH:21]=[CH:20][O:19][C:18]=1[Si:22]([CH2:27][CH3:28])([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[N+]=[N-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:35][S:36](Cl)(=[O:38])=[O:37]>>[CH3:35][S:36]([NH:1][CH:4]([C:17]1[CH:21]=[CH:20][O:19][C:18]=1[Si:22]([CH2:27][CH3:28])([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:38])=[O:37]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCCCCCCCC(N=[N+]=[N-])c1ccoc1[Si](CC)(CC)CC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCCCCCCCCCCCC(NS(C)(=O)=O)c1ccoc1[Si](CC)(CC)CC

Procedure:
Reducing 3-(1-azidotridecyl)-2-triethylsilylfuran (Compound 24 with lithium aluminum hydride, as in Example 8, followed by reacting the intermediate with methanesulfonyl chloride, gives 3-(1-methanesulfonamidotridecyl)-2-triethylsilylfuran (Compound 26). Oxidizing this sulfonamide, under conditions as in Example 1, followed by reduction with sodium borohydride gives 3-(1-methanesulfonamidotridecyl)-2(5H)-furanone (Compound 11).
Reaction SMILES: [N:1]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:6][CH2:5][C:4]2([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[CH2:8][S:7]2)[CH2:3][CH2:2]1.[OH:22]OS([O-])=O.[K+].O.S([O-])([O-])(=O)=S.[Na+].[Na+]>O.C(Cl)Cl.CC(C)=O>[N:1]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:2][CH2:3][C:4]2([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[CH2:8][S:7]2=[O:22])[CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)SCc1ccccc12
Reactant: O=S([O-])OO
Agent: O=S([O-])([O-])=S
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)c1ccccc1CS2=O
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 133.9 %

Procedure:
10.0 g of the crude tert-butyl spiro[benzo[c]thiophene-1(3H),4′-piperidine]-1′-carboxylate, obtained in Example 1, were added to 50 ml of methylene chloride and 150 ml of acetone followed by cooling to 0 to 5° C. A solution of 15.0 g (24.4 mmol) of Oxone™ in 75 ml of water was dropped in at 5° C. or lower followed by stirring for 3 hours at 0 to 5° C. A solution of 1.72 g (9.8 mmol) of sodium thiosulfate-hydrate in 50 ml of water was added followed by stirring for 30 minutes at 20 to 25° C. 100 ml of methylene chloride and 100 ml of water were then added followed by separation of the aqueous layer. After washing the organic layer with 100 ml of water, it was dried with anhydrous magnesium sulfate followed by distilling off the solvent to obtain 10.5 g of tert-butyl spiro[benzo[c]thiophene-1-(3H),4′-piperidine]-1′-carboxylate 2-oxide as a white foamy substance (crude yield: 100%).