Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:6][C:5]2[CH:7]=[C:8]([CH:11]3[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]3)[CH:9]=[CH:10][C:4]=2[O:3]1.[C:19]([NH:21][C:22]([NH2:24])=[NH:23])#[N:20]>C(OCCOCCO)C>[NH2:24][C:22]1[N:21]=[C:19]([NH2:20])[C:15]2[CH2:16][CH:11]([C:8]3[CH:9]=[CH:10][C:4]4[O:3][C:2]([CH3:18])([CH3:1])[CH2:6][C:5]=4[CH:7]=3)[CH2:12][CH2:13][C:14]=2[N:23]=1
Reactant: CC1(C)Cc2cc(C3CCC(=O)CC3)ccc2O1
Reactant: N#CNC(=N)N
Solvent: CCOCCOCCO
Product: CC1(C)Cc2cc(C3CCc4nc(N)nc(N)c4C3)ccc2O1

Procedure:
This compound is prepared in a manner analogous to that of Example 1, using 3.2 grams (0.013 mole) of 4-(2,3-dihydro-2,2-dimethylbenzofuran-5-yl)-1-cyclohexanone and 1.2 grams (0.014 mole) of cyanoguanidine in 2-(2-ethoxyethoxy)ethanol, yielding 2,4-diamino-6-(2,3-dihydro-2,2-dimethylbenzofuran-5-yl)-5,6,7,8-tetrahydroquinazoline.
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][C:3]=1[C:11]([OH:13])=O.CN(C(ON1N=[N:29][C:24]2[CH:25]=[CH:26][CH:27]=[N:28][C:23]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:38](N(CC)C(C)C)(C)[CH3:39]>CN(C=O)C>[ClH:1].[N:28]12[CH2:27][CH2:26][CH:25]([CH2:38][CH2:39]1)[C@H:24]([NH:29][C:11]([C:3]1[S:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:2]=1[Cl:1])=[O:13])[CH2:23]2
Reactant: O=C(O)c1sc2ccccc2c1Cl
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cl
Product: O=C(N[C@@H]1CN2CCC1CC2)c1sc2ccccc2c1Cl

Procedure:
254.2 mg (1.20 mmol) of 3-chloro-1-benzothiophene-2-carboxylic acid, 238 mg (1.20 mmol) of S-3-aminoquinuclidine dihydrochloride, 545.4 mg (1.43 mmol) of HATU, 556.1 mg (4.30 mmol) of N,N-diisopropylethylamine and 2.0 ml of DMF are reacted according to the general procedure (variant B). The reaction mixture is purified by preparative HPLC. The product is dissolved in 4M HCl in dioxane and then reconcentrated. 213 mg (49.9% of theory) of the title compound are obtained. The analytical data correspond to those of the racemate (example 14).
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].[CH3:5][C:6]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:7][CH:8]=[O:9]>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[C:1]([S:3][C:6]([CH3:5])([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH:8]=[O:9])(=[O:4])[CH3:2]
Reactant: CC(O)=S
Reactant: CCCCCC(C)=CC=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: CCCCCC(C)(CC=O)SC(C)=O
Yield: 41.3 %

Procedure:
Freshly distilled thioacetic acid (64 g) was added with stirring and occasional cooling to a mixture of 98 g 3-methyloct-2-enal and 25 mg of benzoyl peroxide. After 5 hours of reflux the mixture was distilled in vacuo through a 20 cm vigreux column yielding 62.5 g (41.3%) of 3-acetylthio-3-methyloctanal, b.p. 100°-112°C/0.5 mm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH3:17])([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[N:20]([CH:24]([CH3:26])C)[CH:21]([CH3:23])C.N1CCCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH3:17])([C:14]([N:20]2[CH2:21][CH2:23][CH2:26][CH2:24]2)=[O:16])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)O)CC1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N1CCC(C)(C(=O)N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.1 %

Procedure:
To a solution of 4-methylpiperidine-1,4-dicarboxylic acid mono-tert-butyl ester (229 mg, 0.94 mmol) in DMF (10 mL) were added DIPEA (0.493 mL, 2.83 mmol), pyrrolidine (0.118 mL, 1.41 mmol) and HATU (537 mg, 1.41 mmol). The reaction mixture was stirred at room temperature for 18 hours and then partitioned between water and EtOAc. The organic layer was separated and washed with a 0.1N aqueous HCl solution and brine, dried over Na2SO4, filtered and concentrated to give 4-Methyl-4-(pyrrolidine-1-carbonyl)piperidine-1-carboxylic acid tert-butyl ester as a white solid (279 mg, 100%). LCMS (Method H): RT 4.00 min; [M+Na]+ 319
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[O:13][CH2:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.[F:14][C:15]([F:23])([F:22])[C:16](=[O:21])[CH:17]=[C:18]([CH3:20])[CH3:19]>[Cu]I>[O:9]1[CH2:10][CH2:11][CH2:12][O:13][CH:8]1[C:4]1[CH:3]=[C:2]([C:18]([CH3:20])([CH3:19])[CH2:17][C:16](=[O:21])[C:15]([F:23])([F:22])[F:14])[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(C2OCCCO2)c1
Reactant: CC(C)=CC(=O)C(F)(F)F
Agent: [Cu]I
Product: CC(C)(CC(=O)C(F)(F)F)c1cccc(C2OCCCO2)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of the Grignard reagent derived from 2-(3-bromophenyl)-[1,3]dioxane (52.6 mL of 0.25M in THF, 13.1 mmol) at 0° C. was added copper (I) iodide (25 g, 13.1 mmol). After 45 minutes, 1,1,1-trifluoro-4-methylpent-3-en-2-one (2 g, 13.1 mmol) was added and the reaction mixture slowly warmed to room temperature and stirred overnight. The mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried with sodium sulfate, and concentrated in vacuo. The residue was triturated with hexanes and filtered. The filtrate was concentrated in vacuo to give 4-(3-[1,3]dioxan-2-ylphenyl)-1,1,1-trifluoro-4-methylpentan-2-one.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][C:6]1[CH:14]=[CH:13][C:9]2[S:10][CH:11]=[CH:12][C:8]=2[CH:7]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C=O)C>[CH2:15]([O:3][CH2:4][CH2:5][C:6]1[CH:14]=[CH:13][C:9]2[S:10][CH:11]=[CH:12][C:8]=2[CH:7]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCCc1ccc2sccc2c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(COCCc2ccc3sccc3c2)cc1
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
To a solution of NaH (60% oil dispersion, 2.4 g, 0.06 mol) in DMF (50 ml) heated at 60° C. with stirring under N2 was added dropwise a solution of 5-(2-hydroxyethyl)benzo[b]thiophene (8.9 g, 0.05 mol) in DMF (50 ml). After 1/2 hour, a solution of benzyl bromide (10.3 g, 7.2 ml, d=1.438, 0.06 mol) in DMF (50 ml) was added dropwise. After 15 hours, the solution was poured into H2O and the aqueous phase extracted with ethyl acetate (3X). The organic layers were backwashed with H2O, saturated NaCl, dried, filtered and concentrated to dryness. The residue was chromatographed on silica gel and the product was eluted with 10% (V/V) ethyl acetatehexane to yield 9.7 g (72%) of product. The material was used directly in the next step without further purification.
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].[CH2:13](O)[CH3:14]>>[ClH:3].[NH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCO
Reactant: NCCCCC(=O)O
Reactant: O=S(Cl)Cl
Product: CCOC(=O)CCCCN
Product: Cl

Procedure:
To 100 ml of absolute ethanol, stirred under a dry nitrogen atmosphere and cooled in an ice bath, was added 12.0 ml (167 mmole) of thionyl chloride, followed by 10.0 gm (85.3 mmole) of 5-aminopentanoic acid. The mixture was heated at reflux for 18 hours, cooled and concentrated in vacuo to a sticky solid. The crude ester was triturated with 150 ml of diethyl ether, and the resultant fluffy white solid was collected, washed thoroughly with diethyl ether, and dried in vacuo over potassium hydroxide to give 14.3 gm (78.7 mmole) of ethyl 5-aminopentanoate hydrochloride. The ester was sufficiently pure according to nmr spectroscopy (in (CD3)2SO) for subsequent use without further purification.
Reaction SMILES: [C:1](=[O:12])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.Cl.[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24])[CH2:17][CH2:16]1.[C@H:27]1([NH:36][C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[CH:40][CH:41]=[C:42]([NH2:47])[CH:43]=3)[N:38]=2)[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH2:28]1>>[C@H:27]1([NH:36][C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[CH:40][CH:41]=[C:42]([NH:47][C:1]([NH:14][CH:15]4[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]([F:26])([F:24])[F:25])[CH2:17][CH2:16]4)=[O:12])[CH:43]=3)[N:38]=2)[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH2:28]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: NC1CCN(CCC(F)(F)F)CC1
Agent: Cl
Product: O=C(Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)NC1CCN(CCC(F)(F)F)CC1

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate, 1-(4-amino-piperidin-1-yl)-3,3,3-trifluoro-propan hydrochloride and (R)—N2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=498.6 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][CH:15]3[CH2:17][CH2:16]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[N:28]1[CH:32]=[N:31][N:30]=[N:29]1)[C:22](O)=[O:23]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]([CH:15]3[CH2:17][CH2:16]3)[C:22](=[O:23])[C:21]3[CH:25]=[CH:26][C:27]([N:28]4[CH:32]=[N:31][N:30]=[N:29]4)=[C:19]([F:18])[CH:20]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(-n2cnnn2)c(F)c1
Reactant: Clc1cnc(N2CCC(NC3CC3)CC2)nc1
Product: O=C(c1ccc(-n2cnnn2)c(F)c1)N(C1CC1)C1CCN(c2ncc(Cl)cn2)CC1

Procedure:
The title compound is prepared from [1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yl]-cyclopropyl-amine and 3-fluoro-4-tetrazol-1-yl-benzoic acid following a procedure analogous to that described in Example 107. LC (method 19): tR=4.18 min; Mass spectrum (ESI+): m/z=443 [M+H]+.
Reaction SMILES: [CH2:1]([C:4]1[C:16]([Cl:17])=[C:15]([Cl:18])[CH:14]=[CH:13][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]Br)[CH2:2][CH3:3].[C-]#[N:20].[Na+]>CN(C)C=O>[CH2:1]([C:4]1[C:16]([Cl:17])=[C:15]([Cl:18])[CH:14]=[CH:13][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[N:20])[CH2:2][CH3:3]
Reactant: CCCc1c(OCCCCCBr)ccc(Cl)c1Cl
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCCC#N)ccc(Cl)c1Cl

Procedure:
A solution of 1.6 g. of 5-(2-propyl-3,4dichlorophenoxy)pentyl bromide and 0.22 g. of sodium cyanide were heated overnight at 75°-85° C. in 50 ml. of dimethylformamide. The solution was evaporated in vacuo and ethyl acetate and water were added to the residue. The layers were separated and the organic layer was washed several times with a saturated sodium chloride solution. The organic solution was filtered through sodium sulfate and evaporated to dryness to give 1.38 g. of the desired sub-title intermediate. NMR.
Reaction SMILES: [NH:1]([C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[C@@H:2]([C:4]([NH:6][CH2:7][C:8]([NH:10][C@H:11]([C:19]([O:21]CC)=O)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:9])=[O:5])[CH3:3].O.[NH2:35][NH2:36].C(OCC)C>CO>[NH:1]([C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[C@@H:2]([C:4]([NH:6][CH2:7][C:8]([NH:10][C@H:11]([C:19]([NH:35][NH2:36])=[O:21])[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:9])=[O:5])[CH3:3]
Reactant: NN
Reactant: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](C)NC(=O)OCc1ccccc1
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: C[C@@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NN
Reaction time: 48 h

Procedure:
In 50 ml of MeOH is dissolved 3.3 g of Z-(D)-Ala-Gly-Phe-OEt and after 1 mlof hydrazine hydrate is added, the solution is allowed to stand at room temperature for 2 days. It is then treated with diethyl ether, collected by filtration and recrystallized from ethanol. 3.0 g (94%); m.p. 196°-197° C; Rf1 =0.34; [α]D27 +2.4°(c=0.37, DMF).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:10])[CH2:4][CH2:5][CH2:6][C:7](O)=[O:8].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:44]1[CH2:49][CH2:48][O:47][CH2:46][CH:45]1[C:50]1[C:58]2[S:57][C:56]([NH2:59])=[N:55][C:54]=2[C:53]([O:60][CH3:61])=[CH:52][CH:51]=1>C1COCC1.C(Cl)(Cl)Cl>[CH3:2][N:3]([CH3:10])[CH2:4][CH2:5][CH2:6][C:7]([NH:59][C:56]1[S:57][C:58]2[C:50]([CH:45]3[CH2:46][O:47][CH2:48][CH2:49][O:44]3)=[CH:51][CH:52]=[C:53]([O:60][CH3:61])[C:54]=2[N:55]=1)=[O:8]
Reactant: CN(C)CCCC(=O)O
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)CCCN(C)C)nc12

Procedure:
From 4-(dimethylamino)butyric acid hydrochloride, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+24.2° (c=0.53, CHCl3), ES-MS m/e (%): 380 (M+H+, 100).
Reaction SMILES: CC1(C)[C:10]2[C:5](=[CH:6][C:7]([CH3:11])=[CH:8]C=2)[CH:4]([CH2:12][C:13]2C=C[C:16](C)=[CH:15][CH:14]=2)[CH:3]1C.[Cl-].[Cl-].[Cl-].[Al+3].[C:26](Cl)(=[O:28])[CH3:27]>ClCCCl>[C:26]([C:6]1[C:7]([CH3:8])([CH3:11])[C:12]2[C:4]([C:5]=1[CH3:10])=[CH:3][C:15]([CH3:16])=[CH:14][CH:13]=2)(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(CC2c3cc(C)ccc3C(C)(C)C2C)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)C1=C(C)c2cc(C)ccc2C1(C)C
Temperature: 29 °C
Yield: 34.9 %

Procedure:
To a mixture of 50.8 g 90.8% pure 1,1,2,5-tetramethyl-3-(4-methyl-benzyl)indane and 52.5 g 1,2-dichloroethane was added with stirring at 28-30° C. a mixture of 26.7 g aluminum trichloride, 14.8 g acetyl chloride and 75 g 1,2-dichloroethane in the course of one hour and twenty minutes. After an additional stirring period of 30 minutes at 20° C. the mixture was poured on ice and stirred for another hour. The organic layer was washed with subsequently 5%-sodium carbonate solution, saturated sodium chloride solution and concentrated by means of a rotatory evaporator yielding 34.9% 2-acetyl-1,1,3,5-tetramethylindene in 45.6 g residue. Recrystallization from methanol gave 99.4% pure 2-acetyl-1,1,3,5-tetramethylindene.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([N:6]([CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[O:8])=[C:4]([CH:19]=O)[CH:3]=1.CC(C)([O-])C.[K+].O.Cl>C(O)(C)(C)C>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([CH:7]=[O:8])[CH2:9][CH2:10][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:19][C:4]=2[CH:3]=1.[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([CH:7]=[O:8])[CH2:9][CH2:10][C:11]([C:12]([OH:14])=[O:13])=[CH:19][C:4]=2[CH:3]=1
Reactant: CCOC(=O)CCCN(C=O)c1ccc(Br)cc1C=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: CCOC(=O)C1=Cc2cc(Br)ccc2N(C=O)CC1
Product: O=CN1CCC(C(=O)O)=Cc2cc(Br)ccc21
Yield: 10 %
Yield: 22 %

Procedure:
In t-butanol (500 ml) were dissolved ethyl 4-(4-bromo-2,N-diformylanilino)butyrate (15.32 g) and potassium t-butoxide (5.53 g), and the mixture was refluxed for 30 minutes. To the mixture were added water (500 ml) and 1N hydrochloric acid (50 ml), and the mixture was extracted with ethyl acetate (1000 ml). The organic layer was washed with saturated brine (200 ml) and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (300 g, hexane:ethyl acetate=4:1→1:1) to give ethyl 7-bromo-1-formyl-2,3-dihydro-1-benzazepine-4-carboxylate (3.13 g, 22%) and 7-bromo-1-formyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (1.39 g, 10%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1.[CH2:14]([Br:23])[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16]>CC(O)C>[BrH:23].[BrH:23].[OH:1][CH2:2][CH2:3][NH:4][C:5]1[N:6]([CH2:14][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1
Reactant: OCCNc1nc2ccccc2[nH]1
Reactant: O=C(CBr)c1ccccc1
Solvent: CC(C)O
Product: Br
Product: O=C(Cn1c(NCCO)nc2ccccc21)c1ccccc1
Yield: 89 %

Procedure:
Heat at reflux for three hours 8.95 g (50 mmol) of 2-(2-hydroxyethylamino)benzimidazole and 10 g of phenacyl bromide in 100 ml of 2-propanol. Allow to cool. Suction-filter the resulting precipitate and wash with acetone. The title compound is obtained.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:10])[CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(#N)C>[NH2:1][C@@H:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:10])[CH2:5]1
Reactant: [N-]=[N+]=N[C@@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: N[C@@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 86.4 %

Procedure:
To a solution of (3R)-3-azido-1-(p-nitrobenzyloxycarbonyl)pyrrolidine (4.48 g, 15.4 mmol) (obtained as described in Reference Example 53(4)) in acetonitrile (134 ml) was added triphenylphosphine (4.22 g, 16.1 mmol), and the mixture was stirred in an oil bath (70° C.) for 1.5 hours. After checking the disappearance of the raw materials, sodium sulfate decahydrate (5.19 g, 16.1 mmol) was added thereto and then the reaction mixture was stirred for 5 hours. After checking the completion of the reaction, the reaction mixture was filtered and partitioned between methylene chloride and 0.1M aqueous hydrogen chloride solution. To the obtained aqueous layer were added methylene chloride and sodium hydrogencarbonate, and the aqueous layer was extracted with methylene chloride. The obtained organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dried under reduced pressure to give (3R)-3-amino-1-(p-nitrobenzyloxycarbonyl)pyrrolidine (3.53 g, yield 86%) as pale yellow crystals.
Reaction SMILES: [C:1]([C:5]1[CH:24]=[CH:23][C:8]([CH2:9][CH:10]([CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[OH:15])C(O)=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([N:27]([CH2:30]C)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:39])C=CC=CC=1>O1CCCC1>[C:1]([C:5]1[CH:24]=[CH:23][C:8]([CH2:9][CH:10]2[CH:14]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[O:15][C:30](=[O:39])[NH:27]2)=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)c1ccc(CC(C(=O)O)C(O)c2ccc(F)cc2)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CC2NC(=O)OC2c2ccc(F)cc2)cc1
Yield: 79.5 %

Procedure:
To a solution of (2RS,3RS)-2-[4-(tert-butyl)benzyl]-3-(4-fluorophenyl)-3-hydroxypropionic acid (5.07 g, 15.3 mmol) in tetrahydrofuran (150 ml) were added triethylamine (3.2 ml, 22.95 mmol) and diphenylphosphoryl azide (3.63 ml, 16.8 mmol) at room temperature, and the mixture was heated under reflux for 5 hrs. The solvent was evaporated, passed through silica gel column, and purified by recrystallization (hexane-ethyl acetate) to give (4RS,5SR)-4-[4-(tert-butyl)benzyl]-5-(4-fluorophenyl)-1,3-oxazolidin-2-one (3.98 g, 79%) as colorless crystals.
Reaction SMILES: B(O)O.Br[C:5]1[N:10]=[C:9]([CH:11]=[O:12])[CH:8]=[CH:7][CH:6]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1>>[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[C:19]([C:5]2[N:10]=[C:9]([CH:11]=[O:12])[CH:8]=[CH:7][CH:6]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: O=Cc1cccc(Br)n1
Agent: OBO
Product: O=Cc1cccc(-c2cccc(C(F)(F)F)c2)n1

Procedure:
6-(3-(trifluoromethyl)phenyl)picolinaldehyde was prepared using the general boronic acid coupling procedure for 6-bromopicolinaldehyde and (3-(trifluoromethyl)phenyl)boronic acid (115 mg, 135.1 mg theoretical, 85.1%). LC-MS m/z 252.2 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]([C@@H:5]1[CH2:8][CH2:7][N:6]1[C:9]1[CH2:13][S:12][C:11](=[O:14])[N:10]=1)=[O:4].[F:16][C:17]([F:38])([F:37])[C:18]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:19]=1[CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([CH:27]=O)[CH2:23][CH2:22]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:38][C:17]([F:16])([F:37])[C:18]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:19]=1[CH2:20][N:21]1[CH2:26][CH2:25][CH:24](/[CH:27]=[C:13]2/[C:9]([N:6]3[CH2:7][CH2:8][C@H:5]3[C:3]([N:2]([CH3:15])[CH3:1])=[O:4])=[N:10][C:11](=[O:14])[S:12]/2)[CH2:23][CH2:22]1
Reactant: CN(C)C(=O)[C@@H]1CCN1C1=NC(=O)SC1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CN(C)C(=O)[C@@H]1CCN1C1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 35.8 %

Procedure:
To a solution of (2S)—N,N-dimethyl-1-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)azetidine-2-carboxamide (682 mg) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1018 mg) is in 2-propanol (10 mL) was added piperidinium acetate (436 mg) at room temperature. The reaction mixture was stirred at 60° C. overnight, and the solvent was evaporated. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (590 mg).
Reaction SMILES: [CH2:1]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:13][C:14]1[N:19]=[CH:18][CH:17]=[CH:16][N:15]=1>>[CH2:1]([C:8]1[S:9][C:10]([C:16]2[CH:17]=[CH:18][N:19]=[C:14]([Cl:13])[N:15]=2)=[CH:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncccn1
Reactant: c1ccc(Cc2cccs2)cc1
Product: Clc1nccc(-c2ccc(Cc3ccccc3)s2)n1

Procedure:
The title compound was prepared from 2-benzylthiophene and 2-chloropyrimidine in a manner analogous to Example 255, Step 1. MS (M+H)+ 287.
Reaction SMILES: [OH:1][CH:2]([CH2:5][NH2:6])[CH2:3][NH2:4].[ClH:7].[NH2:8][C:9](N)=N.CC(O)C>CC#N>[ClH:7].[NH:8]=[C:9]1[NH:6][CH2:5][CH:2]([OH:1])[CH2:3][NH:4]1
Reactant: N=C(N)N
Reactant: NCC(O)CN
Agent: Cl
Solvent: CC#N
Solvent: CC(C)O
Product: N=C1NCC(O)CN1
Temperature: 140 °C

Procedure:
A mixture of 2-hydroxy -1,3-diaminopropane (9.80 g, 108 mmol) and guanidine hydrochloride (10.4 g, 108 mmol) in a 100 mL RBF was heated at 140° C. under nitrogen for 5 h. The reaction mixture, while under vigorous stirring, was let cooled to 100° C. whereby a mixture of iPrOH (5 mL) and CH3CN (5 mL) were added, resulting in the formation of a slurry. After cooled to room temperature, the mixture was filtered and the solid was washed with additional CH3CN (total 30 mL). The solid was further dried under vacuum to yield a white solid. 1H NMR (400 MHz, D2O): 4.21 (m, 1 H), 3.34 (dt, J 15.2, 2.8, 2H), 3.22 (dt, J 15.2, 2.8).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[CH2:9][CH2:8][CH2:7]2.B(F)(F)[F:14].CCOCC.N(OC(C)(C)C)=O>C(Cl)Cl.CCCCC>[F:14][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[CH2:9][CH2:8][CH2:7]2
Reactant: Nc1cccc2c1C(=O)CCC2
Reactant: FB(F)F
Agent: CC(C)(C)ON=O
Solvent: CCCCC
Solvent: ClCCl
Solvent: CCOCC
Product: O=C1CCCc2cccc(F)c21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
The amine (Intermediate J3, 1.83 g, 11.3 mmol) in CH2Cl2 (17 mL) was added to BF3.OEt2 (2.80 mL, 22.1 mmol) at −15° C. More CH2Cl2 (20 mL) was added to the precipitate. Next, t-butyl nitrite (1.8 mL, 12.9 mmol) in CH2Cl2 (20 mL) was added at −15° C. and stirred for 10 min. and at 0° C. for 20 m. The mixture was diluted with pentane (40 mL), filtered and the solids were collected, washed with ether, and dried under vacuum. The solids were placed in a flask and heated to 115° C. for 10-15 min. followed by addition of 2N NaOH and CHCl3. The suspension was filtered and the aqueous phase was extracted with CHCl3. The organic layers were combined, dried over MgSO4, filtered and purified by chromatography on SiO2 with 15% EtOAc:Hx. The product, 8-fluoro-3,4-dihydro-2H-naphthalen-1-one (Intermediate J4) was isolated; 750 mg (40%).