Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]([S:32]([C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=1)(=[O:34])=[O:33])[C@H:6]([C:29]([OH:31])=[O:30])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[CH:2]([CH3:4])[CH3:3].[CH3:42][C:43]1[CH:48]=[CH:47][C:46]([S:49]([NH:52][C@H:53]([C:59]([OH:61])=O)[CH2:54][CH2:55][C:56]([OH:58])=[O:57])(=[O:51])=[O:50])=[CH:45][CH:44]=1>>[CH3:42][C:43]1[CH:44]=[CH:45][C:46]([S:49]([NH:52][C@H:53]([C:59]([NH:11][CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]([N:5]([S:32]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[CH2:1][CH:2]([CH3:4])[CH3:3])[C:29]([OH:31])=[O:30])=[O:61])[CH2:54][CH2:55][C:56]([OH:58])=[O:57])(=[O:50])=[O:51])=[CH:47][CH:48]=1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Product: Cc1ccc(S(=O)(=O)N[C@@H](CCC(=O)O)C(=O)NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
The title compound was prepared from solid phase bound Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-(9-fluorenylmethoxycarbonyl)-L-lysine as described in general procedure Bb using Nα-(4-methylbenzenesulfonyl)-L-glutamic acid (360 mg, 1.2 mmol) prepared in step A of this example. The final product was purified by preparative HPLC to yield 20 mg (25%) of the desired material.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1B(O)O)([O-:3])=[O:2].Br[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[C:15]=1[CH3:23]>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>[N+:1]([C:4]1[CH:9]=[C:8]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[C:15]=2[CH3:23])[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1B(O)O
Reactant: Cc1c(Br)cccc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: Cc1c(-c2cccc([N+](=O)[O-])c2)cccc1[N+](=O)[O-]
Yield: 139.2 %

Procedure:
The procedure of Example 12 was used except that the starting material was 1.3 g of 2-nitrophenylboronic acid which was reacted with 3 g of 2-bromo-6-nitrotoluene and 0.480 g of tetrakis(triphenylphosphine)palladium(0). In this way, 2.8 g (79% yield) of yellowish crystals were obtained.
Reaction SMILES: [C:1]([O:4][CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13](/[CH:17]=[CH:18]/[CH:19]=[CH:20]/[CH:21]([O:30][C:31](=[O:33])[CH3:32])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:12]=1)[CH2:6][CH2:7][CH2:8][CH2:9][OH:10])(=[O:3])[CH3:2].CCCCCC.C(OCC)(=O)C>C(Cl)Cl>[C:1]([O:4][CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13](/[CH:17]=[CH:18]/[CH:19]=[CH:20]/[CH:21]([O:30][C:31](=[O:33])[CH3:32])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:12]=1)[CH2:6][CH2:7][CH2:8][CH:9]=[O:10])(=[O:3])[CH3:2]
Reactant: CCCCCCCCC(/C=C/C=C/c1cccc(C(CCCCO)OC(C)=O)c1)OC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCCCCCC(/C=C/C=C/c1cccc(C(CCCC=O)OC(C)=O)c1)OC(C)=O
Yield: 78.1 %

Procedure:
A solution of 193 mg of the above-produced alcohol in 5 ml of methylene chloride is instilled in a mixture of 1.25 g of Collins reagent (chromic acid-pyridine complex) in 20 ml of methylene chloride at 0° C. with stirring, and it is stirred for 1 hour at 0° C. Then, enough Celite is added until a thick paste results, the latter is suspended with hexane/ethyl acetate (1:1), filtered off, washed well with hexane/ethyl acetate (1:1) and the filtrate is concentrated by evaporation in a vacuum. 150 mg of (5RS)-5-acetoxy-5-{3-[(1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl]-phenyl)-pentanal is obtained as colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[N:6][N:7]([C:9]2[CH:14]=[C:13]([C:15]#[N:16])[CH:12]=[CH:11][N:10]=2)[CH:8]=1.CCN(CC)CC.[CH3:24][S:25](Cl)(=[O:27])=[O:26].O>C(Cl)Cl>[CH3:24][S:25]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[N:6][N:7]([C:9]2[CH:14]=[C:13]([C:15]#[N:16])[CH:12]=[CH:11][N:10]=2)[CH:8]=1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccnc(-n2cc(CCO)cn2)c1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1cnn(-c2cc(C#N)ccn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To a mixture of 2-[4-(2-hydroxyethyl)pyrazol-1-yl]pyridine-4-carbonitrile (700 mg, 3.3 mmol), Et3N (670 mg, 6.6 mmol) in DCM (15 mL) was added MeSO2Cl (410 mg, 3.6 mmoL) at 0° C., the mixture was then stirred for 2 hours at room temperature, water was added and extracted with DCM and concentrated give the title compound (830 mg, 87%). [M+H] Calc'd for C12H12N4O3S, 293; Found, 293.
Reaction SMILES: [CH3:1][N:2]([C:16](F)=[O:17])[S:3][N:4]=[C:5]([S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:6]([CH3:8])[CH3:7].[CH3:19][C:20]1([CH3:30])[CH2:24][C:23]2[CH:25]=[CH:26][CH:27]=[C:28]([OH:29])[C:22]=2[O:21]1.C(OC(=O)C)C>[Cl-].C([N+](CC1C=CC=CC=1)(C)C)CCCCCCCCCCCCCCC.C(Cl)Cl.[OH-].[Na+].CCCCCC>[CH3:1][N:2]([C:16]([O:29][C:28]1[C:22]2[O:21][C:20]([CH3:30])([CH3:19])[CH2:24][C:23]=2[CH:25]=[CH:26][CH:27]=1)=[O:17])[S:3][N:4]=[C:5]([S:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)C(=NSN(C)C(=O)F)Sc1ccccc1
Reactant: CC1(C)Cc2cccc(O)c2O1
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)C(=NSN(C)C(=O)Oc1cccc2c1OC(C)(C)C2)Sc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of phenyl N-[[methyl[fluorocarbonyl]amino]thio]-2-methylpropiothioimidate (7.8 g, 27 mmoles) as prepared in Preparation 1 and cetylbenzyldimethylammonium chloride (0.9 g) in methylene chloride (150 ml) is added a solution of 2,3-dihydro-2,2-dimethyl-7-benzofuranol (4.5 g, 27 mmoles) in 0.18N sodium hydroxide (150 ml). The two-phase reaction mixture is stirred vigorously at ambient temperature for 90 minutes. The layers are separated and the organic phase dried over anhydrous sodium sulfate. Removal of the solvent gives a clear brown oil. This material is transferred to a column of silica gel and the chromatogram developed with a solvent mixture consisting of 8% ethylacetate in Skellysolve B. From the appropriate fraction there is obtained a white solid which is recrystallized from hexane to give the product phenyl N-[[methyl[[[2,3-dihydro-2,2-dimethyl-7-benzofuranyl]oxy]carbonyl]amino]thio]-2-methyl-propiothioimidate as a white crystalline solid, mp 104°-106°.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([N:5]1[CH:9]=[CH:8][C:7]([C:10]2[CH:17]=[C:16]([F:18])[C:13]([C:14]#[N:15])=[C:12]([F:19])[CH:11]=2)=[N:6]1)[CH3:4].[C:20]([CH2:22][C:23]1[S:24][CH:25]=[C:26]([C:28](O)=[O:29])[N:27]=1)#[N:21]>>[C:14]([C:13]1[C:16]([F:18])=[CH:17][C:10]([C:7]2[CH:8]=[CH:9][N:5]([C@H:3]([CH3:4])[CH2:2][NH:1][C:28]([C:26]3[N:27]=[C:23]([CH2:22][C:20]#[N:21])[S:24][CH:25]=3)=[O:29])[N:6]=2)=[CH:11][C:12]=1[F:19])#[N:15]
Reactant: C[C@H](CN)n1ccc(-c2cc(F)c(C#N)c(F)c2)n1
Reactant: N#CCc1nc(C(=O)O)cs1
Product: C[C@H](CNC(=O)c1csc(CC#N)n1)n1ccc(-c2cc(F)c(C#N)c(F)c2)n1

Procedure:
The title compound was prepared from (R)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2,6-difluorobenzonitrile (380 mg, 1.45 mmol) and 2-(cyanomethyl)-thiazole-4-carboxylic acid (244 mg, 1.45 mmol) using the method of Example 34(d). Yield 70 mg. 1H NMR (400 MHz; d6-DMSO): δ 1.47 (d, 3H), 3.29 (s, 2H), 3.67 (m, 2H), 4.74 (m, 1H), 6.99 (d, 1H), 7.77 (m, 2H), 7.92 (d, 1H), 8.25 (d, 1H), 8.44 (m, 1H).
Reaction SMILES: CSC.[Cl:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1.[C:13]1([CH:19]=[N+]=[N-])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[Cl:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]2[CH:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:10]2)=[CH:7][CH:6]=1
Reactant: [N-]=[N+]=Cc1ccccc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: CSC
Solvent: ClCCl
Product: Clc1ccc(C2OC2c2ccccc2)cc1
Yield: 76 %

Procedure:
To a stirred solution of dimethyl sulphide (0.20 mmol), rhodium (II) acetate (0.01 mmol) and p-chlorobenzaldehyde (1 mmol) in dichloromethane (4 ml) was added a solution of phenyldiazomethane (1 mmol in 6 ml of tert-butylmethyl ether) at room temperature over a period of 24 hours. After addition was completed the solvent was removed in vacuo and the residue was chromatographed over silica to provide the title oxirane in 76% yield.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:3]1.[C:15](Cl)(=[O:17])[CH3:16].[Cl-].[Al+3].[Cl-].[Cl-]>[N+](C)([O-])=O>[CH3:1][C:2]1([CH3:14])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:15](=[O:17])[CH3:16])[CH:8]=2)[O:3]1
Reactant: CC1(C)CC(C)(C)c2ccccc2O1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: CC(=O)c1ccc2c(c1)C(C)(C)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To an ice bath cooled solution of 2 g (10.53 mmol) of 2,2,4,4-tetramethylchroman (Compound 40) in 25 ml of nitromethane was added, under nitrogen, 941 mg (11.99 mmol) of acetyl chloride followed by 1.59 g (11.92) mmol) of aluminum chloride. The cooling bath was then removed and the mixture stirred at room temperature for 16 h. The mixture was then cooled again in an ice bath and treated with 25 ml of conc. HCl. The mixture was then filtered and the residue washed with methylene chloride. The filtrate was concentrated in vacuo and the resultant residue was purified by flash chromatography (silica; 10% ethyl acetate in hexanes) to give the title compound as a yellow oil. PMR (CDCl3): & 1.38 (6H, s), 1.39 (6H, s), 1.87 (2H, s), 2.56 (3H, s), 6.83 (1H, d, J~8.7 Hz), 7.71 (1H, dd, J~8.7 Hz, 2.1 Hz), 7.98 (1H, d, J~2.1 Hz) MS exact mass, m/e 232.1468 (calcd. for C13H20O2, 232.1464).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]3[O:18][C:17](=[O:19])[C:16]([CH3:21])([CH3:20])[O:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)=O.[BH4-].[Na+].[OH-].[Na+]>[Pd].C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][O:15][C:16]([CH3:21])([CH3:20])[C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC1(C)OC(c2ccc(-c3ccc(Cl)cc3)cc2)OC1=O
Agent: [Pd]
Agent: O=C=O
Agent: [BH4-]
Solvent: O
Solvent: CCO
Product: CC(C)(OCc1ccc(-c2ccc(Cl)cc2)cc1)C(=O)O
Yield: 42 %

Procedure:
A stirred suspension of 2-[4-(4-chlorophenyl)phenyl]-5,5-dimethyl-1,3-dioxolan-4-one (100.0 g.), 5% w/w palladium on carbon (10 g.) in a mixture of ethanol (500 ml.) and water (1000 ml.) was cooled to 10° to 15° C. and treated with carbon dioxide gas. The temperature and gas flow were maintained during the addition of a solution of sodium borohydride (63.0 g.) in water (250 ml.) during 1 hour. After 5 hours at 15° to 20° C. the pH of the reaction mixture was adjusted to pH 12 with 47% w/w sodium hydroxide solution and diluted with ethanol (1000 ml.). The residue was separated by filtration and washed successively with ethanol (2×250 ml.) and water (2×250 ml.). The combined filtrate and washings were evaporated to about half volume and the pH adjusted to 3 with 34% w/w hydrochloric acid. The solid which formed was recrystallised twice from toluene to give 2-[4-(4-chlorophenyl)benzyloxy]-2-methylpropionic acid, (m.p. 154°-155° C.) in 42% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9](=O)[CH3:10].[NH2:12][C:13]([NH2:15])=[S:14]>>[NH2:15][C:13]1[S:14][CH:10]=[C:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[N:12]=1
Reactant: NC(N)=S
Reactant: CC(=O)c1cc(F)ccc1F
Product: Nc1nc(-c2cc(F)ccc2F)cs1
Yield: 77.8 %

Procedure:
Using 2′,5′-difluoroacetophenone and thiourea as the raw materials, the same operation as the Example 395(1) gave the title compound.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10](I)[CH:9]=1.[Cl:17][C:18]1[CH:23]=[C:22](B(O)O)[CH:21]=[CH:20][N:19]=1>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[Cl:17][C:18]1[CH:23]=[C:22]([C:10]2[CH:9]=[C:8]([Cl:7])[CH:13]=[CH:12][C:11]=2[O:14][CH3:15])[CH:21]=[CH:20][N:19]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: COc1ccc(Cl)cc1I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(Cl)cc1-c1ccnc(Cl)c1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To a nitrogen purged aqueous solution of sodium carbonate (2M, 14 mL) and ethylene glycol dimethyl ether (25 mL) was added 4-chloro-2-iodoanisole (2.50 g, 0.00931 mol), 2-chloropyridine-4-boronic acid (1.61 g, 0.0102 mol) and bis(triphenylphosphine)palladium (II) dichloride (327 mg, 0.00047 mol). The reaction mixture was warmed to 50° C. and stirred for 5 hours. Following LCMS analysis the reaction was warmed to 75° C. and stirred for 5 hours before cooling to room temperature. The reaction was partitioned between ethyl acetate (100 mL) and a 10% w/v aqueous solution of citric acid (50 mL). The organic layer was washed with water (50 mL), dried over anhydrous magnesium sulphate, filtered and the solvents removed in vacuo to give the crude product as an orange oil (2.95 g). The material was purified using an ISCO™ companion (120 g column, eluting with 100% heptane to 7:3 heptane/ethyl acetate). Fractions containing product were combined and concentrated in vacuo to obtain the title compound as an off white solid (1.10 g).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[CH3:18][C:19]1[CH:20]=[N:21][N:22]([CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][O:38]2)[C:23]=1[Sn](CCCC)(CCCC)CCCC.CN(C)C=O.[F-].[Cs+]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.[Cu]I>[CH3:18][C:19]1[CH:20]=[N:21][N:22]([CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][O:38]2)[C:23]=1[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(C)cnn1C1CCCCO1
Reactant: O=C(Nc1cc2ccc(Br)cc2cn1)C1CC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cu]I
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cnn(C2CCCCO2)c1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 67.6 %

Procedure:
To a mixture of N-(7-bromoisoquinolin-3-yl)cyclopropanecarboxamide (50.4 mg, 0.173 mmol) and 4-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(tributylstannyl)-1H-pyrazole (76.9 mg, 0.169 mmol) was added N,N-dimethylformamide (1.5 mL, 19 mmol). Nitrogen gas was bubbled through the reaction mixture for 5 minutes, and then bis(tri-t-butylphosphine)palladium (11.5 mg, 0.0225 mmol), copper(I) iodide (6.1 mg, 0.032 mmol), and cesium fluoride (53.4 mg, 0.352 mmol) was added. The reaction mixture was stirred in a sealed vial at 50° C. for 2 hours, and then at 80° C. for 16 hours. The mixture was then partitioned between ethyl acetate and water, and the organic layer was washed with water and brine, dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 20-100% ethyl acetate in heptanes) to yield 43.0 mg (67%) of N-(7-(4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)isoquinolin-3-yl)cyclopropanecarboxamide. LCMS (ESI): M+H=377.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:11][C:12]#[CH:13].C(N(C(C)C)C(C)C)C.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:13][C:12]#[CH:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: C#CCBr
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C#CCNc1ccc(Cl)c(Cl)c1

Procedure:
A solution of 16.20 g (0.1 mol) of 3,4-dichlorobenzenamine, 16.36 g (0.11 mol) of an 80% solution of 3-bromo-1-propyne in toluene, and 17.4 ml (0.11 mol) of N-ethyl-N-(1-methylethyl)-2-propanamine in 350 ml of toluene is heated at 90° for six hours. Ethyl acetate is added to the reaction suspension, and the suspension is washed three times with water. The organic layer is separated, dried (magnesium sulfate), and concentrated to give 19.85 g of a dark brown liquid. This is applied to a column of 1 kg of flash silica gel packed in hexane/dichloromethane (5:1). Elution with the same solvent gives 1.48 g (11.3%) of 3,4-dichloro-N,N-di-2-propynylbenzenamine as a yellow oil which crystallizes on standing; mp 48°-50° C. Further elution gives 15.80 g (79%) of the desired product as a gold liquid. NMR (200 MHz, DMSO) δ=3.13 (t, J<3 Hz, 1, C≡CH), 3.92 (d, J<3 Hz, 2, CH2), 6.48 (br s, 1, NH, disappears on D2O addition), 6.64 (dd, J=8.9 Hz, 2.8 Hz, 1, 6H), 6.84 (d, J<3 Hz, 1, 2H), 7.32 (d, J=8.9 Hz, 1, 5H); MS (DEI): m/e=199 (M+); IR (LF): =3297, 1601, 1494 cm-1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:17][C@H:18]([CH3:23])[C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.[OH:24]OS([O-])=O.[K+]>CC(C)=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([OH:24])[CH:5]=[N:4][C:3]=1[O:17][C@H:18]([CH3:23])[C:19]([F:22])([F:21])[F:20]
Reactant: C[C@@H](Oc1ncc(B2OC(C)(C)C(C)(C)O2)cc1Cl)C(F)(F)F
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C[C@@H](Oc1ncc(O)cc1Cl)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 54 %

Procedure:
To a solution of 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methylethoxy]pyridine (Preparation 236, 560 mg, 1.59 mmol) in acetone (5 mL) was added an aqueous solution of Oxone® (5 mL, 1.24 g, 1.91 mmol) dropwise with stirring at 0° C. for 15 minutes. The reaction mixture was diluted with water and extracted with EtOAc (3×15 mL), the combined organic phases were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a crude product as a brown oil. The crude product was purified by silica gel column chromatography eluting with 0-40% EtOAc in heptane to give the title compound (361 mg, 54%) as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH:34]([NH2:36])[CH3:35]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:14])([F:15])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:36][CH:34]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[F:27])[CH3:35]
Reactant: CC(N)c1ccccc1F
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC(Nc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2)c1ccccc1F
Yield: 34.6 %

Procedure:
Use a method similar to the General Procedure 5-1 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (250 mg, 0.6 mmol) with (±)-1-(2-fluorophenyl)-ethylamine (206 mg, 1.5 mmol) in toluene (5 mL). Purify the residue by chromatography on silica gel eluting with hexane/EtOAc (9:1 to 1:1) followed by SCX chromatography [pre-wash column with methanol followed by DCM, load material dissolved in DCM, then elute with DCM/2M ammonia in methanol (1:1) and concentrate in vacuo] to obtain (±)-7-chloro-6-[1-(2-fluorophenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (86 mg, 35%). GC-MS m/z: 414 (M30 ).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([OH:9])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=N[C:35]2[CH:36]=[CH:37][CH:38]=[N:39][C:34]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1CCCCC1>CN(C=O)C>[Br:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([N:39]1[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1)=[O:9]
Reactant: O=C(O)c1cc(-c2ccccc2)sc1Br
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(-c2ccccc2)sc1Br)N1CCCCC1
Temperature: 25 °C
Yield: 7.7 %

Procedure:
2-Bromo-5-phenyl-thiophene-3-carboxylic acid (0.99 g, 3.5 mmol) was dissolved in DMF (20 mL). DIPEA (7.0 mmol), HATU (3.5 mmol) and piperidine (3.5 mmol) were added and the solution stirred at room temperature. The reaction mixture was partitioned between ethyl acetate and 1 N hydrochloric acid. The organic solution was dried over magnesium sulfate, filtered and the solvent evaporated. The residue was purified by flash chromatography on silica, eluting with 0%-50% ethyl acetate in cyclohexane. The fractions containing the desired product were concentrated under vacuum to give a solid which was further purified by HPLC, eluting with 50%-90% acetonitrile in water (0.1% formic acid) over 30 minutes. The fractions containing the desired product were concentrated under vacuum then freeze-dried to give the title compound (95 mg). LCMS m/z 350.07 [M+H]+ R.T.=12.57 min (Analytical Method 1). 1H NMR (400 MHz, CHCl3-d): δ 7.50 (d, 1H), 7.40 (t, 2H), 7.3 (m, 1H), 7.1 (s, 1H), 3.7 (m, 2H), 3.4 (t, 2H), 1.7 (m, 4 H), 1.6 (m, 2H).
Reaction SMILES: C[C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[O-][Mn](=O)(=O)=O.[K+].[C:23]([O-:26])([O-])=[O:24].[Na+].[Na+].OS(O)(=O)=O>O>[C:23]([C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8])([OH:26])=[O:24]
Reactant: O=C([O-])[O-]
Reactant: CCOP(=O)(Cc1ccccc1C)OCC
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: CCOP(=O)(Cc1ccccc1C(=O)O)OCC

Procedure:
4 g of diethyl 2-methylbenzylphosphonate were added to a solution of 12 g of KMnO4 and 4 g of Na2CO3 in 300 ml of water and the mixture was boiled under reflux for 24 hours. It was acidified with 15 ml of concentrated H2SO4 and extracted five times with 300 ml of ether each time. The organic phase was dried over MgSO4, the solvent was evaporated off on a rotary evaporator and the residue was chromatographed over silica gel (CH2Cl2 /methanol/triethylamine 9/1/0.1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[N:7]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][CH2:14][C:15]1[C:20]([CH3:21])=[CH:19][C:18]([Cl:22])=[CH:17][N:16]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([C:34]2[C:35]([CH:40]=O)=[N:36][CH:37]=[CH:38][CH:39]=2)([CH3:33])[CH3:32])=[CH:27][CH:26]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([O:5][C:6](=[O:23])[N:7]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]([CH2:14][C:15]1[C:20]([CH3:21])=[CH:19][C:18]([Cl:22])=[CH:17][N:16]=1)[CH2:40][C:35]1[C:34]([C:31]([C:28]2[CH:27]=[CH:26][C:25]([F:24])=[CH:30][CH:29]=2)([CH3:33])[CH3:32])=[CH:39][CH:38]=[CH:37][N:36]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(Cl)cnc1CNCCCCN(C)C(=O)OC(C)(C)C
Reactant: CC(C)(c1ccc(F)cc1)c1cccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Cc1cc(Cl)cnc1CN(CCCCN(C)C(=O)OC(C)(C)C)Cc1ncccc1C(C)(C)c1ccc(F)cc1

Procedure:
Using General Procedure B: Reaction of {4-[(5-chloro-3-methyl-pyridin-2-ylmethyl)-amino]-butyl}-methyl-carbamic acid tert-butyl ester, 3-[1-(4-fluoro-phenyl)-1-methyl-ethyl]-pyridine-2-carbaldehyde and NaBH(OAc)3 gave [4-((5-chloro-3-methyl-pyridin-2-ylmethyl)-{3-[1-(4-fluoro-phenyl)-1-methyl-ethyl]-pyridin-2-ylmethyl}-amino]-butyl]-methyl-carbamic acid tert-butyl ester as a light brown solid. Deprotection with TFA using General Procedure F gave N-(5-Chloro-3-methyl-pyridin-2-ylmethyl)-N-{3-[1-(4-fluoro-phenyl)-1-methyl-ethyl]-pyridin-2-ylmethyl}-N1-methyl-butane-1,4-diamine (326 mg, excess) which was used immediately in the next reaction.