Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1([CH2:10][CH2:11][OH:12])[O:9][CH2:8][CH2:7][CH2:6][O:5]1)CC.[C:13](OCC)(=O)[CH2:14]C(C)=O>>[CH3:1][C:4]1([CH2:10][CH2:11][OH:12])[O:5][CH2:6][C:7]2([CH2:14][CH2:13]2)[CH2:8][O:9]1
Reactant: CCCC1(CCO)OCCCO1
Reactant: CCOC(=O)CC(C)=O
Product: CC1(CCO)OCC2(CC2)CO1
Yield: 36 %

Procedure:
The same procedure as in the steps (8a) and (8b) of Example 8, was repeated using ethyl acetoacetate and 1,1-bis(hydroxymethylcyclopropane) to obtain the title compound (2.9 g, total yield: 36%) as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14](=[O:20])[C:15]([O:17]CC)=[O:16])[CH:5]=[CH:4][C:3]1=2.C(O)C.[OH-].[Na+]>O>[CH3:1][C:2]1([CH3:21])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14](=[O:20])[C:15]([OH:17])=[O:16])[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)C(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(C(=O)C(=O)O)ccc21

Procedure:
16 g (55.6 mmol) of the ester obtained above in (a) and 50 ml of ethyl alcohol are introduced into a round-bottomed flask. A solution of 2.5 g (58.5 mmol) of sodium hydroxide in 50 ml of water is added and the mixture is heated to reflux for one hour. The reaction medium is evaporated to dryness, the residue is taken up with water, the mixture is extracted with ethyl ether, the aqueous phase is separated after settling has taken place, acidified to pH 1 with concentrated hydrochloric acid and extracted with ethyl ether, and the organic phase is separated after settling has taken place, dried over magnesium sulphate and evaporated. 14 g (97%) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylglyoxylic acid are collected in the form of a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[C:14](#[N:19])[C:15]([CH3:18])([CH3:17])[CH3:16].[Cl-].[Al+3].[Cl-].[Cl-]>>[O:11]1[CH2:12][CH2:13][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:14](=[NH:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:9][CH2:10]1
Reactant: CC(C)(C)C#N
Reactant: Nc1ccccc1N1CCOCC1
Agent: [Al+3]
Agent: [Cl-]
Product: CC(C)(C)C(=N)Nc1ccccc1N1CCOCC1

Procedure:
A mixture of 4-(2-aminophenyl)morpholine (3.56 g), pivalonitrile (5 g) and anhydrous aluminium chloride (8 g) was heated at 160°-170° C. for six hours to yield N-(2-morpholinophenyl)pivalamidine (m.p. 126° C.) which was recrystallised from hexane and converted into its monofumarate salt (m.p. 211° C.) which was recrystallised from methanol.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[F:6][C@@H:7]([CH3:11])[C:8](O)=O.O=P(Cl)(Cl)Cl>O1CCOCC1>[F:6][C@H:7]([C:11]1[S:4][C:3]([NH2:5])=[N:2][N:1]=1)[CH3:8]
Reactant: NNC(N)=S
Reactant: C[C@H](F)C(=O)O
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: C[C@H](F)c1nnc(N)s1
Temperature: 0 °C
Yield: 70.4 %

Procedure:
A 350 mL sealable pressure vessel was charged with thiosemicarbazide (11.17 g, 122.5 mmol) and dry dioxane (100 mL), and the mixture was cooled at 0° C. under an N2 atmosphere. To this rapidly stirring mixture was slowly added a solution of (S)-2-fluoropropanoic acid (9.40 g, 102.1 mmol, from Fritz-Langhals, E., Tetrahedron Asymmetry, 981 (1994)) in dioxane (10 mL). To the resulting mixture was added POCl3 (11.22 mL, 122.5 mmol) dropwise, then the cooling bath was removed and the thick white slurry was stirred at room temperature for 1 h. The vessel was then sealed and the mixture was heated at 90-95° C. (oil bath temperature) for 5 h. The cooled mixture was stirred at room temperature for 14 h (Note: this was for convenience only and is optional) and then the supernatant (two-phase mixture) was decanted and concentrated under reduced pressure. The lower phase was slowly poured into ice water (250 mL) and then the concentrate was also added. This mixture was rapidly stirred until it was essentially a homogeneous (turbid) solution, and then it was basified to pH 9-9.5 using 40% aqueous NaOH. The resulting slurry was filtered and the filter-cake was washed with water (Note: LC of this beige solid showed that it contained only a trace of the desired product, so it was not further investigated). The combined filtrate was then extracted with EtOAc (×3) and the organic phase was dried (Na2SO4) and evaporated to give a cream solid (10.58 g, 70%) which was the essentially pure product according to LC and LCMS. This material was used as such without further purification. An analytical sample was purified by flash chromatography [Isco/0-20% (MeOH—NH4OH, 9:1)-DCM] to give a white solid. LC (Method B): 0.608 min. MS (ESI) calcd. for C4H6FN3S m/z: 147.03. found: 148.05 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 7.38 (s, 2H), 5.82 (dq, J=6.4, 48.0 Hz, 1H), 1.65 (dd, J=6.4, 24.0 Hz, 3H). Chiral LC: S:R=95:5.
Reaction SMILES: [C:1]([O:14][CH2:15][CH:16]=[CH2:17])(=[O:13])[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH2:8][CH2:9][C:10](Cl)=[O:11])=[O:5].[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C@@:26]([OH:55])([CH2:49][N:50]1[CH:54]=[N:53][CH:52]=[N:51]1)[C@H:27]([S:29][C@@H:30]1[CH2:35][O:34][C@@H:33](/[CH:36]=[CH:37]/[CH:38]=[CH:39]/[C:40]2[CH:47]=[CH:46][C:43]([C:44]#[N:45])=[CH:42][C:41]=2[F:48])[O:32][CH2:31]1)[CH3:28].[H-].[Na+]>>[C:1]([O:14][CH2:15][CH:16]=[CH2:17])(=[O:13])[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH2:8][CH2:9][C:10]([O:55][C@:26]([C:20]1[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=1[F:18])([CH2:49][N:50]1[CH:54]=[N:53][CH:52]=[N:51]1)[C@H:27]([S:29][C@@H:30]1[CH2:31][O:32][C@@H:33](/[CH:36]=[CH:37]/[CH:38]=[CH:39]/[C:40]2[CH:47]=[CH:46][C:43]([C:44]#[N:45])=[CH:42][C:41]=2[F:48])[O:34][CH2:35]1)[CH3:28])=[O:11])=[O:5]
Reactant: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: C=CCOC(=O)CCC(=O)OCCCC(=O)Cl
Agent: [H-]
Agent: [Na+]
Product: C=CCOC(=O)CCC(=O)OCCCC(=O)O[C@@](Cn1cncn1)(c1ccc(F)cc1F)[C@@H](C)S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1
Yield: 40 %

Procedure:
The crude allyl 4-chloro-4-oxobutyl succinate was treated with 4-[(1E,3E)-4-[trans-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-1,3-butadienyl]-3-fluorobenzonitrile (814 mg, 1.50 mmol) described in Reference example 1 and sodium hydride (55% dispersion in mineral oil; 70 mg, 1.6 mmol) according to a similar procedure to that described in Example 13-(2). The obtained crude title compound was purified by recycle preparative HPLC [LC-908; Japan Analytical Industry Co., Ltd.; GPC column JAIGEL-1H (20 mm i.d.×600 mm) and JAIGEL-2H (20 mm i.d.×600 mm) connected in series for use; solvent, chloroform] to afford the title compound (459 mg, 40% yield) as a colorless viscous material.
Reaction SMILES: [CH3:1][N:2]([C:14]1[CH:25]=[CH:24][C:17]([O:18][CH:19]([CH3:23])[C:20](O)=[O:21])=[CH:16][CH:15]=1)[C:3]1[CH:12]=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:13])[CH:9]=2)[N:4]=1.S(Cl)([Cl:28])=O>>[CH3:1][N:2]([C:14]1[CH:25]=[CH:24][C:17]([O:18][CH:19]([CH3:23])[C:20]([Cl:28])=[O:21])=[CH:16][CH:15]=1)[C:3]1[CH:12]=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:13])[CH:9]=2)[N:4]=1
Reactant: CC(Oc1ccc(N(C)c2cnc3cc(Cl)ccc3n2)cc1)C(=O)O
Reactant: O=S(Cl)Cl
Product: CC(Oc1ccc(N(C)c2cnc3cc(Cl)ccc3n2)cc1)C(=O)Cl

Procedure:
A mixture of 2-{4-[N-methyl-N-(6-chloroquinoxalin-2-yl)amino]phenoxy}propionic acid (2.0 g; compound no 27, Example 9) and thionyl chloride (25 ml) was heated under reflux for a period of 2 hours. The excess thionyl chloride was removed by distillation under reduced pressure to give 2-{4-[N-methyl-N-(6-chloroquinoxalin-2-yl)amino]phenoxy}propionyl chloride. A mixture of n-propanol (10 ml) and triethylamine (10 ml) was added and the mixture was stirred at room temperature for a period of 1 hour. The mixture was poured into water (200 ml) and the aqueous mixture was extracted with dichloromethane. The organic extract was washed several times with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure and the residue was chromatographed over alumina (eluent dichloromethane) to give n-propyl 2-{4-[N-methyl-N-(6-chloroquinoxalin-2-yl)amino]phenoxy}propionate as an oil.
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][S:9][C:10]#[N:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:13]S(O)(=O)=O.O>CC(O)=O>[C:1]1([C:7]2[NH:11][C:10](=[O:13])[S:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CSCC(=O)c1ccccc1
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c(-c2ccccc2)cs1

Procedure:
To a solution of 1-phenyl-2-thiocyanato-ethanone (20 g, 113 mmol) in HOAc (100 mL) was added 50% aqueous H2SO4 (20 mL). The mixture was refluxed for 10 min. The mixture was poured into water. The solid formed was collected by filtration to give crude 4-phenyl-3H-thiazol-2-one (20 g) which was used for the next step without further purification.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH:20]1[O:24][CH2:23][CH2:22][CH2:21]1)[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N+:25]([O-])([N+]([O-])=O)=[O:26]>>[Cl:1][CH2:2][CH2:3][N:4]([N:25]=[O:26])[C:5]([N:7]([CH2:19][CH:20]1[O:24][CH2:23][CH2:22][CH2:21]1)[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: O=C(NCCCl)N(CC1CCCO1)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Product: O=NN(CCCl)C(=O)N(CC1CCCO1)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 72.7 %

Procedure:
3.7 g of 1-(2-chloroethyl)-3-tetrahydrofurfuryl-3-(D-galactopyranosyl)urea and 6 g of nitrogen tetroxide gas are treated in the same manner as described in Example 23-(2). 2.9 g of 1-(2-chloroethyl)-1-nitroso-3-tetrahydrofurfuryl-3-(D-galactopyranosyl)urea are thereby obtained as yellow caramel.
Reaction SMILES: [C:1]1([C:7]2[CH2:11][CH:10]([CH2:12][CH2:13][CH:14]=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][N:27]([CH2:14][CH2:13][CH2:12][CH:10]2[O:9][N:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:11]2)[CH2:26][CH2:25]1
Reactant: Clc1ccccc1N1CCNCC1
Reactant: O=CCCC1CC(c2ccccc2)=NO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Clc1ccccc1N1CCN(CCCC2CC(c3ccccc3)=NO2)CC1
Yield: 78.1 %

Procedure:
3-(3-Phenyl-4,5-dihydroisoxazol-5-yl)propanal (20.7 mg, 0.094 mmol), 1-(2-chlorophenyl)piperazine hydrochloride (20.0 mg, 0.086 mmol), molecular sieve (5 beads), NaBH(OAc)3 (54.5 mg, 0.257 mmol) and diisopropylethylamine (26.9 L, 0.085 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 25.8 mg (87.2%) of the target compound was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=[O:18])[CH2:8]1.N1C=CC=CC=1.S(Cl)([Cl:28])(=O)=O.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[Cl:28][C:5]1[S:4][C:3]([CH:7]2[CH2:16][C:15]3[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=3[C:9](=[O:18])[CH2:8]2)=[C:2]([CH3:1])[CH:6]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1ccsc1C1CC(=O)c2c(C)ccnc2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1cc(Cl)sc1C1CC(=O)c2c(C)ccnc2C1
Reaction time: 4 h
Yield: 74.3 %

Procedure:
To a solution of 7-(3-methyl-2-thienyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.38 g) in ethyl acetate (10 ml) were added pyridine (0.023 g) and sulfuryl chloride (0.3 g) at room temperature, and the mixture was stirred at the same temperature for 4 hours. To the reaction solution was added sodium hydrogen carbonate solution, and the organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (EtOAc/hexane) to give 7-(5-chloro-3-methyl-2-thienyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.32 g), which was dissolved in ethanol (20 ml). To the solution were added aminoguanidine hydrochloride (0.15 g), concentrated hydrochloric acid (0.27 ml) and water (0.27 ml), and the mixture was refluxed for 7 hours. Under reduced pressure, the solvent was evaporated. To the residue was added water, and the mixture was washed with ethyl acetate. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol to give 7-(5-chloro-3-methyl-2-thienyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 122) (0.32 g) as colorless crystals.
Reaction SMILES: [N:1]([C@H:4]1[C:7](=[O:8])[N:6]([Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[C@@H:5]1[C:16]([OH:18])=[O:17])=[N+:2]=[N-:3].CO.[CH2:21]1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N:1]([C@H:4]1[C:7](=[O:8])[N:6]([Si:9]([C:12]([CH3:14])([CH3:15])[CH3:13])([CH3:11])[CH3:10])[C@@H:5]1[C:16]([O:18][CH3:21])=[O:17])=[N+:2]=[N-:3]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)[C@H](N=[N+]=[N-])[C@H]1C(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@@H]1[C@@H](N=[N+]=[N-])C(=O)N1[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of crude 131 (1.58 g) in CH2Cl2 (25 mL) was added methanol (0.26 mL, 6.43 mmol). DCC (1.45 g, 7.02 mmol) and catalytic DMAP. The solution was stirred at room temperature overnight. The solution was then filtered through Celite and concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting with 20% EtOAc in hexanes, to yield pure 132.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[O:16][CH3:17])O.[I-:18].[Na+]>CC(=O)CC>[CH3:17][O:16][C:10]1[CH:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=1[CH:7]=[CH:6][CH2:5][CH2:4][CH2:3][CH2:2][I:18]
Reactant: [I-]
Reactant: COc1cc(Cl)ccc1C(O)CCCCCBr
Agent: [Na+]
Solvent: CCC(C)=O
Product: COc1cc(Cl)ccc1C=CCCCCI

Procedure:
A mixture of 74 g. of 5-bromopentyl 2-methoxy-4-chlorophenyl carbinol, 50 g. of sodium iodide and 500 ml. of 2-butanone was heated under reflux for 2.5 days. The reaction mixture was concentrated, water added and the mixture extracted with ether. The ether extracts were dried over anhydrous magnesium sulfate and concentrated to give 84 g. of oil used directly in the next reaction without further purification.
Reaction SMILES: N[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]1[CH:25]=[CH:24][O:23][CH:22]=1.N(OC(C)(C)C)=O>O1CCCC1>[C:19]([C:4]1[C:3]([C:21]2[CH:25]=[CH:24][O:23][CH:22]=2)=[CH:2][N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:17])([F:15])[F:16])=[CH:11][C:12]=2[Cl:13])[N:5]=1)#[N:20]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1ccoc1
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1-c1ccoc1
Temperature: 65 °C

Procedure:
To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(furan-3-yl)pyrazole (0.204 g) in tetrahydrofuran (3 ml) was added t-butyl nitrite (187.8 μl). The mixture was heated to 65° C. for 1 hour, then cooled and evaporated The residue was purified by column chromatography on silica gel (5 g) eluted with hexane containing increasing amounts of dichloromethane (up to 100%). Combination and evaporation of appropriate fraction gave the title compound as a white solid, m.p. 139° C.
Reaction SMILES: [P:1]([O:18]CC1C=CC=CC=1)([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[I:26]I>C(Cl)Cl>[P:1]([I:26])(=[O:18])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: c1ccc(COP(OCc2ccccc2)OCc2ccccc2)cc1
Reactant: II
Solvent: ClCCl
Product: O=P(I)(OCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of tribenzyl phosphite (0.708 g, 2.01 mmol) in CH2Cl2 (5 mL) at 0° C. was added I2 (0.49 g, 1.93 mmol). The mixture was stirred at 0° C. for 10 min or until the solution became clear and colorless. The solution was then stirred at room temperature for 10 min and used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:6]=[C:7]([CH3:9])[CH:8]=1)[NH2:5].[Br-:11].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)(Cl)Cl>[Br:11][C:8]1[C:7]([CH3:9])=[CH:6][C:4]([NH2:5])=[C:3]([CH3:10])[C:2]=1[Cl:1]
Reactant: [Br-]
Reactant: Cc1cc(N)c(C)c(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClC(Cl)Cl
Product: Cc1cc(N)c(C)c(Cl)c1Br
Temperature: 2.5 °C
Reaction time: 0.08 h
Yield: 35.5 %

Procedure:
To a solution of compound 21B (1.56 g, 10 mmol) in CHCl3 (30 mL) cooled to 0-5° C. was added portionwise tetrabutylammonium tribromide (434 mg, 9.0 mmol). After addition, the reaction was stirred at 0-5° C. for 5 min, then quenched with saturated aqueous NaHCO3 (30 mL) and 5% aqueous Na2S2O3 (30 mL). The mixture was stirred at rt for 10 min, then extracted with CH2Cl2 (3×). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was chromatographed (silica gel), eluting with 20-60% EtOAc/hexane to give the title compound (0.75 g, 32% yield).
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][C:9]1[C:20]([NH:21][C:22](=[O:24])[CH3:23])=[CH:19][C:12]2[CH2:13][CH2:14][CH2:15][C:16](=[O:18])[CH2:17][C:11]=2[CH:10]=1.S(O)(C1C=CC(C)=CC=1)(=O)=O.[CH2:36](O)[CH2:37][OH:38]>CCOC(C)=O>[CH3:8][C:9]1[C:20]([NH:21][C:22](=[O:24])[CH3:23])=[CH:19][C:12]2[CH2:13][CH2:14][CH2:15][C:16]3([CH2:17][C:11]=2[CH:10]=1)[O:38][CH2:37][CH2:36][O:18]3
Reactant: CC(=O)Nc1cc2c(cc1C)CC(=O)CCC2
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cc2c(cc1C)CC1(CCC2)OCCO1
Temperature: 25 °C
Yield: 72.6 %

Procedure:
In a 50 L mechanically stirred vessel with Dean-Stark trap, toluene (22 L) was added to N-(3-methyl-6-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)acetamide (77) (1.04 kg, 4.50 mol). TosOH (84.0 g, 442 mmol) and ethylene glycol (750 mL, 13.4 mol) were added. The resulting mixture was heated to reflux overnight, cooled to rt, diluted with EtOAc (12 L) and washed with sat. aq. NaHCO3 (12 L) and sat. aq.s NaCl (12 L). The combined aq. washes were extracted with DCM (2×8 L). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel. The product containing fractions were combined and concentrated under reduced pressure to afford N-(3-methyl-5,7,8,9-tetrahydrospiro[benzo[7]annulene-6,2′-[1,3]dioxolan]-2-yl)acetamide (78) (900 g, 73% yield). 1H NMR (300 MHz, CDCl3): δ 7.45 (s, 1H), 7.03 (s, 1H), 6.92 (s, 1H), 3.96 (m, 4H), 3.02 (s, 2H), 2.76 (m, 2H), 2.20 (s, 3H), 2.18 (s, 3H), 1.98 (m, 2H), 1.74 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=O)[S:5][C:6]=1[C:7]1[N:11]([CH3:12])[N:10]=[CH:9][C:8]=1[Cl:13].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:40])[F:39])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:14]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]([F:41])([F:39])[F:40])[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:16])[S:5][C:6]=1[C:7]1[N:11]([CH3:12])[N:10]=[CH:9][C:8]=1[Cl:13]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1ncc(Cl)c1-c1sc(C(=O)O)cc1Cl
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc(Cl)c1-c1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1Cl
Reaction time: 1 h
Yield: 81.3 %

Procedure:
To a solution of 4-chloro-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (136.1 mg, 0.49 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (179 mg, 0.51 mmol) [prepared according to Preparation 6], diisopropylethyl amine (260 uL, 1.5 mmol) in DCM (5 mL) was added PyBrop (341 mg, 0.75 mmol) in one portion. After 1 h, the reaction contents were partitioned between H2O/DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, gradient 0-50% ethyl acetate/hexane) affording the title compound (242 mg, 82%) as a white solid: LCMS (ES) m/z=607 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][N:9]([C:12]([C@:14]34[CH2:21][C@H:20]([N:22]5C(=O)C6C(=CC=CC=6)C5=O)[CH2:19][C@H:15]3[O:16][CH2:17][CH2:18]4)=[O:13])[CH2:8][C:7]=2[CH:33]=1.NN>C(O)C>[NH2:22][C@@H:20]1[CH2:19][C@H:15]2[O:16][CH2:17][CH2:18][C@@:14]2([C:12]([N:9]2[CH2:8][C:7]3[CH:33]=[C:3]([C:2]([F:35])([F:34])[F:1])[CH:4]=[CH:5][C:6]=3[O:11][CH2:10]2)=[O:13])[CH2:21]1
Reactant: O=C1c2ccccc2C(=O)N1[C@@H]1C[C@H]2OCC[C@@]2(C(=O)N2COc3ccc(C(F)(F)F)cc3C2)C1
Agent: NN
Solvent: CCO
Product: N[C@@H]1C[C@H]2OCC[C@@]2(C(=O)N2COc3ccc(C(F)(F)F)cc3C2)C1

Procedure:
A solution of the product of Step D (5.39 g, 11.1 mmol, 1 eq) and hydrazine (7.1 mL, 222 mmol, 20 eq) in ethanol (60 mL) was stirred at rt 18 hours. The white solid was filtered, washed with methanol and DCM, and the filtrates concentrated. Saturated NaHCO3 was added, the aqueous extracted with DCM, the organics combined, dried over MgSO4 and concentrated to afford the product of Step E. Calculated for C17H19F3N2O3: 357.1 (M+1). found: 357.3.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9](=[O:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH:17]=O.[OH-].[Na+].O>C(O)C>[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1/[CH:17]=[CH:10]/[C:9](=[O:11])/[CH:8]=[CH:7]/[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)/C=C/c1ccccc1
Reactant: O=Cc1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(/C=C/c1ccccc1)/C=C/c1cccs1
Temperature: 25 °C
Reaction time: 15 h
Yield: 79.2 %

Procedure:
A mixture of 65.1g (0.45 mol)of E-4-phenyl-3-buten-2-one, 50 g (0.45 mol)of 2-thiophenecarboxaldehyde, 4 mL of aqueous 10% sodium hydroxide, 50 mL of water, and 75 mL of ethanol was stirred at ambient temperature for 15 hours. The solid which separated was collected by filtration and air dried to give 85.6 g (80% yield) of E,E- 1-(2-thienyl)-5-phenyl- 1,4-pentadien-3-one as a yellow solid. 1H NMR, IR, and FDMS analyses were consistent with the expected structure.
Reaction SMILES: [O:1]=[C:2]1[NH:8][CH2:7][CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.Cl[CH2:17][O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:18][CH2:17][N:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][C:2]1=[O:1])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCCNC(=O)C1
Reactant: ClCOCc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCN(COCc2ccccc2)C(=O)C1

Procedure:
The title compound was prepared from tert-butyl hexahydro-3-oxo-1H-1,4-diazepine-1-carboxylate (Example 2, Step B) and benzyl chloromethyl ether essentially following the method described in Example 2, Step C.