Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[OH:6][C:7]1[C:16]([OH:17])=[N:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]3[N:20]([CH3:21])[N:19]=[N:18][C:13]3=2)[N:8]=1>S(=O)(=O)(O)O>[OH:6][C:7]1[C:16]([OH:17])=[N:15][C:14]2[C:9](=[CH:10][C:11]([N+:1]([O-:4])=[O:2])=[C:12]3[N:20]([CH3:21])[N:19]=[N:18][C:13]3=2)[N:8]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Cn1nnc2c3nc(O)c(O)nc3ccc21
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cn1nnc2c3nc(O)c(O)nc3cc([N+](=O)[O-])c21
Temperature: 25 °C
Yield: 82.9 %

Procedure:
Finely powdered potassium nitrate (0.47 g, 4.6 mmol) was added portionwise to a stirred solution of 7,8-dihydroxy-3-methyl-3H-1,2,3-triazolo[4,5-f]quinoxaline (1.0 g, 4.6 mmol) in 20 ml of conc. sulfuric acid at 0° C. After 1 h the ice bath was removed and the mixture was stirred over night at room temperature. Then an additional amount of potassium nitrate (0.47 g) was added and stirring was continued over night at room temperature. The solution was poured into ice/water and the precipitated solid was collected, washed with water, and dried to give 1.0 g (83%) of the pure nitro compound; m.p. >300° C.; IR (KBr): 1710 cm-1 ; 1H-NMR (DMSO-d6): 4.50 (s, 3H, CH3), 8.18 (s, 1H, ArH), 12.13 (broad s, 1H, OH), 13.17 (broad s, 1H, OH).
Reaction SMILES: [CH2:1]([N:3]([CH2:6]C)[CH2:4]C)C.Cl.[F:9][C:10]([F:27])([S:23]([O-:26])(=[O:25])=[O:24])[CH:11]([O:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[C:12]([F:15])([F:14])[F:13].[Na+].ClCCl>O>[F:27][C:10]([F:9])([S:23]([O-:26])(=[O:24])=[O:25])[CH:11]([O:16][C:17](=[O:22])[C:18]([CH3:20])([CH3:21])[CH3:19])[C:12]([F:13])([F:15])[F:14].[CH3:1][NH+:3]([CH3:6])[CH3:4]
Reactant: CCN(CC)CC
Agent: CC(C)(C)C(=O)OC(C(F)(F)F)C(F)(F)S(=O)(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C[NH+](C)C

Procedure:
Triethylamine was dissolved in cold water. To the solution, hydrochloric acid was added, and sodium 1,1,3,3,3-pentafluoro-2-(pivaloyloxy)propanesulfonate prepared in Synthesis Example 27 and dichloromethane were added, whereupon the mixture was stirred. The organic layer was separated and washed with water. From the organic layer as washed, the dichloromethane was distilled off in vacuum. Diethyl ether was added to the residue for recrystallization. The crystals were filtered and dried, obtaining the target compound in a yield of 75%.
Reaction SMILES: [CH:1]1([C:7]([Cl:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:29]>>[Cl:29][C:1]1([C:7]([Cl:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ClC(Cl)(Cl)Cl
Reactant: O=C(Cl)C1CCCCC1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: O=C(Cl)C1(Cl)CCCCC1

Procedure:
80 g (0.547 mol) of cyclohexanecarboxylic acid chloride, 30 ml of carbon tetrachloride, 63 ml (0.778 mol) of SO2Cl2 and 1.5 g of benzoyl peroxide are heated for 10 hours. The chlorinated acid chloride is then distilled from the reaction mixture.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1Br)=[O:4].C([O-])([O-])=O.[K+].[K+].[CH:23]1([CH:29]2[NH:34][C:33](=[O:35])[C@:32]([CH2:37][CH2:38][CH2:39][OH:40])([CH3:36])[O:31][CH2:30]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>[Cu]I.O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1[N:34]1[C@H:29]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:30][O:31][C@@:32]([CH2:37][CH2:38][CH2:39][OH:40])([CH3:36])[C:33]1=[O:35])=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1Br
Reactant: C[C@]1(CCCO)OCC(C2CCCCC2)NC1=O
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)[C@@](C)(CCCO)OC[C@H]1C1CCCCC1
Temperature: 120 °C
Reaction time: 18 h
Yield: 26.3 %

Procedure:
To a 10 mL vial was added trans-cyclohexane diamine (13.4 mg, 0.12 mmol, 1.0 equiv), 3-bromo-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (70.8 mg, 0.24 mmol, 2.0 equiv), K2CO3 (32.5 mg, 0.24 mmol, 2.0 equiv), CuI (22 mg, 0.12 mmol, 1.0 equiv), (R)-5-cyclohexyl-2-(3-hydroxy-propyl)-2-methyl-morpholin-3-one (30 mg, 0.12 mmol, 1.0 equiv) and 1,4-dioxane (0.4 mL). The mixture was flushed with N2 and stirred at 120° C. for 18 hours. The mixture was filtered through celite and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, EtOAc/heptane 80% to give product 15 mg (yield 26%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH2:11](O)[CH3:12]>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:11][CH3:12])=[O:7])=[CH:4][N:3]=1
Reactant: CCO
Reactant: Nc1ccc(C(=O)O)cn1
Product: CCOC(=O)c1ccc(N)nc1

Procedure:
To a suspension of 1.3 g(9.4 mmol) 6-aminonicotinic acid in 100 mL of ethanol, was bubbled in dry hydrochloric acid at 0 C, then the solution was refluxed until all the solids dissolved. The solvents were removed under reduced pressure, the residue dissolved in ethyl acetate, washed with saturated sodium bicarbonate, brine and concentrated to afford 1.37 g of a white solid, m/e=166(M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:14](=[N:15][CH:16]=2)[NH:13][CH2:12][CH2:11][CH2:10]3)[CH:2]=1.[C:17]([N:25]=C=O)(=[O:24])C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:14](=[N:15][CH:16]=2)[N:13]([C:17]([NH2:25])=[O:24])[CH2:12][CH2:11][CH2:10]3)[CH:2]=1
Reactant: c1cncc(-c2cnc3c(c2)CCCN3)c1
Reactant: O=C=NC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NC(=O)N1CCCc2cc(-c3cccnc3)cnc21
Temperature: 50 °C
Yield: 55.7 %

Procedure:
6-Pyridin-3-yl-1,2,3,4-tetrahydro-[1,8]naphthyridine (50 mg, 0.24 mmol) and benzoyl isocyanate (58 mg, 0.36 mmol) are dissolved in 1.5 mL of DCM. The mixture is heated at 50° C. for 5 hrs. Then the solvent is removed in vacuum and the residue is dissolved in 1.5 mL of EtOH. K2CO3 (56 mg, 0.40 mmol) is added and the mixture is heated at 80° C. for 55 min. Then the solvent is removed and the residue is partitioned between water (35 mL) and EtOAc (55 mL). The aqueous layer is separated and extracted with EtOAc (2×30 mL). The organic layers are combined and concentrated to give the crude product. To the crude product is added EtOAc (1 mL) and the white solid formed is filtered, rinsed with EtOAc/heptane (1:1) mixture and dried to give 34 mg of the titled product.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=O.O.[NH2:18][NH2:19]>C(O)CO>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=[N:18][NH2:19]
Reactant: COc1ccc(C(=O)c2sccc2Br)cc1
Reactant: NN
Solvent: OCCO
Solvent: O
Product: COc1ccc(C(=NN)c2sccc2Br)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture prepared form 18 g of (3-bromothien-2-yl) (4-methoxyphenyl)methanone, 12 ml of hydrazine hydrate (99%) and 120 ml of ethylene glycol was stirred at 120° for 2 hours. Thereafter, the mixture was cooled and diluted with 1000 g of ice water and quickly extracted with ether (3×500 ml). The combined ether solution was washed four times with water to remove unreacted hydrazine and dried over anhydrous magnesium PG,54 sulfate overnight.
Reaction SMILES: [ClH:1].Cl.Cl.[CH3:4][N:5]1[CH2:10][CH2:9][NH:8][CH:7]([CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:6]1.[CH3:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[CH:23]([C:27]([Cl:29])=[O:28])[CH2:22][C:21]2=[O:30]>C(N(CC)CC)C>[ClH:29].[ClH:1].[CH3:4][N:5]1[CH2:10][CH2:9][N:8]([C:27]([CH:23]2[C:24]3[C:20](=[CH:19][C:18]([CH3:17])=[CH:26][CH:25]=3)[C:21](=[O:30])[CH2:22]2)=[O:28])[CH:7]([CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:6]1
Reactant: CN1CCNC(CN2CCCC2)C1
Reactant: Cc1ccc2c(c1)C(=O)CC2C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)C(=O)CC2C(=O)N1CCN(C)CC1CN1CCCC1
Yield: 57.4 %

Procedure:
The procedure described in Example 24 was repeated, but using 1.0 g of 1-methyl-3-(pyrrolidin-1-ylmethyl)piperazine trihydrochloride, 2.1 ml of triethylamine and 0.75 g of 5-methyl-3-oxoindan-1-carbonyl chloride, to afford 0.84 g of the title compound, melting at 220°-223° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=[O:12].I[CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:14]([N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[F:1])[C:7](=[O:12])[C:8]1=[O:11])[CH3:15]
Reactant: CCI
Reactant: O=C1Nc2c(F)cccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1C(=O)C(=O)c2cccc(F)c21

Procedure:
7-Fluoro-1H-indole-2,3-dione (prepared according to the method of Gassman as described in U.S. Pat. No. 4,188,325 (4.00 g, 24.2 mmol), iodoethane (3.87 ml, 48.5 mmol) and potassium carbonate (6.61 g, 48.5 mmol) in DMF (20 ml) are stirred at room temperature for 20 hours. The reaction mixture is diluted with cold water and the resulting precipitate filtered and dried to give the title compound as an orange solid. HPLC r.t. 4.48 min; MS for C10H8FNO2 m/z 193.9 (M+H)+.
Reaction SMILES: [OH-].[Na+].[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1/[C:8](=[N:16]/[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[N:28]=[C:29]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:30][C:31]=2[CH3:32])=[CH:21][CH:20]=1)/[CH2:9][CH2:10][C:11]([O:13]CC)=[O:12].CO.Cl>O1CCCC1>[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1/[C:8](=[N:16]/[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[N:28]=[C:29]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[O:30][C:31]=2[CH3:32])=[CH:21][CH:20]=1)/[CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)CC/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccco1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CCC(=O)O)c2ccco2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added to a solution of ethyl E-4-(2-furyl)-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]butyrate (190 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at room temperature for 1 hour. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4-(2-furyl)-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]butyric acid (140 mg, yield 78%) as colorless crystals. m.p. 124-125° C.
Reaction SMILES: [CH:1]1([CH:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([OH:17])[CH:10]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1.S(Cl)(Cl)=O.O.[CH3:23]O>>[CH:1]1([CH:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([OH:17])[CH:10]=2)[CH2:5][C:6]([O:8][CH3:23])=[O:7])[CH2:3][CH2:2]1
Reactant: CO
Reactant: COc1ccc(C(CC(=O)O)C2CC2)cc1O
Solvent: O=S(Cl)Cl
Solvent: O
Product: COC(=O)CC(c1ccc(OC)c(O)c1)C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-cyclopropyl-3-(3-hydroxy-4-methoxyphenyl)propanoic acid (1.40 g) in methanol (50 mL) was added dropwise thionyl chloride (2.0 mL) at room temperature, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (4.30 g) as a colorless oil. Ethyl acetate (250 mL) was added to the reaction mixture, and the insoluble material was filtered off. The filtrate was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.00 g) as a yellow oil.
Reaction SMILES: CS(Cl)(=O)=O.O[C@@H:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@H:8]1[N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.[CH2:22]([N:24](CC)CC)C>C(Cl)Cl>[CH3:22][NH:24][C@@H:9]1[C:14]2[C:15](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:16][CH2:7][C@H:8]1[N:17]1[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CCN(CC)CC
Reactant: O[C@@H]1CCc2ccccc2[C@H]1N1CCCC1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CN[C@@H]1c2ccccc2CC[C@H]1N1CCCC1
Yield: 56.8 %

Procedure:
A solution of methanesulfonyl chloride (10.3 g) in methylene chloride (50 ml) was added rapidly in drops to a stirred and cooled (0.5° C.) solution of trans-1,2,3,4-tetrahydro-2-hydroxy-1-(pyrrolidin-1-yl)naphthalene (10.3 g) and triethylamine (10 g) in methylene chloride (100 ml). After the addition was complete, the mixture was stirred at room temperature for 3 hours and then evaporated under reduced pressure. The residue was treated carefully with a 33% solution of methylamine in ethanol (125 ml) and the mixture was stirred at reflux for 2 hours followed by evaporation of the solvent under reduced pressure. The residue was treated with water and extracted twice with ether. The combined ether extracts were washed with 2N sodium hydroxide and then with water, dried over magnesium sulfate and evaporated under reduced pressure. The residual viscous liquid was distilled under vacuum to yield trans-1,2,3,4-tetrahydro-1-methylamino-2-(pyrrolidin-1-yl)naphthalene (6.2 g), b.p. 126°-134°/0.25 torr.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[C-:19]#[N:20].[Na+]>O>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][C:19]#[N:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1cccc(Oc2ccccc2)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CCc1cccc(Oc2ccccc2)c1
Yield: 91 %

Procedure:
To a solution of 218 g. m-phenoxy-benzyl chloride in 850 ml. of 96% ethyl alcohol a solution of 57.8 g. of sodium cyanide in 100 ml. of water is added at once. The reaction mixture is boiled under stirring until the starting material cannot be detected anymore by thin layer chromatography. When the reaction is completed the reaction mixture is poured into 1 liter of water and the separating oil is extracted with 3×500 ml. of benzene. The combined benzene solutions are washed with 1 liter of water and dried above sodium sulphate. Sodium sulphate is filtered off and benzene is distilled off. 190 g. (91%) of m-phenoxy-benzyl cyanide are obtained (purity more than 90%, determined by gas chromatography). Boiling point 138° C./0.2 mmHg.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9](Br)([F:11])[F:10])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[Br:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1I.O>CN(C)C(=O)C.[Zn].[Cu]Br>[CH2:1]([O:3][P:4]([C:9]([C:15]1[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=1[Br:13])([F:11])[F:10])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(OCC)C(F)(F)Br
Reactant: Cc1ccc(I)c(Br)c1
Agent: [Cu]Br
Agent: [Zn]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOP(=O)(OCC)C(F)(F)c1ccc(C)cc1Br
Reaction time: 3 h
Yield: 82.3 %

Procedure:
A solution of (bromo-difluoro-methyl)-phosphonic acid diethyl ester (25.00 g, 93.6 mmol) in N,N-dimethylacetamide (50 mL) was added drop wise into a suspension of activated zinc (6.12 g, 93.6 mmol) under Argon. The reaction was initiated by heating and kept under 50° C. After the mixture was stirred for 3 h, copper (I) bromide (13.43 g, 93.6 mmol) was added and stirred for 1 h. A solution of 2-bromo-1-iodo-4-methyl-benzene (11.88 g, 40.0 mmol) in N,N-dimethylacetamide (25 mL) was added slowly to the reaction mixture. The resulting suspension was then stirred at room temp for 18 h. Water (100 mL) was added to the reaction mixture and the solution filtered through celite. The filtrate was diluted with EtOAc (250 mL) and organic layer was washed with H2O (50 mL), NaHCO3 (5%, 50 mL) and H2O (50 mL). The solvent was removed and the residue was purified by column chromatography on silica gel, eluting with hexanes/EtOAc (4:1) to provide a colorless oil (11.75 g, 82%): 1H NMR (300 MHz, CDCl3) δ 7.51 (d, 1H), 7.49 (s, 1H), 7.19 (d, 1H), 4.26 (m, 4H), 2.36 (s, 3H), 1.48 (s, 9H), 137 (m, 6 H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].C(N(CC)CC)C.[Cl:15][CH2:16][CH2:17][CH2:18][S:19](Cl)(=[O:21])=[O:20]>ClCCl>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:5][S:19]([CH2:18][CH2:17][CH2:16][Cl:15])(=[O:21])=[O:20]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: COC(CN)OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(CNS(=O)(=O)CCCCl)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cold (0° C.) solution of aminoacetaldehyde dimethyl acetal (2.22 mL, 20.4 mmol) and triethylamine (3.54 mL, 25.4 mmol) in dichloromethane (60 mL) was added 3-chloropropanesulfonyl chloride (2.06 mL, 16.9 mmol) in dichloromethane (40 mL) dropwise. The reaction mixture was warmed to room temperature and stirred one hour. The reaction mixture was quenched with water. The organic phase was washed with water and brine, then dried over sodium sulfate. Filtration and concentration, followed by trituration with ether provided N-[2,2-bis(methyloxy)ethyl]-3-chloro-1-propanesulfonamide as a white solid. 1H NMR (400 MHz, CDCl3) δ 4.56 (s, 1 H), 4.42 (t, J=5.0 Hz, 1 H), 3.68 (t, J=6.1 Hz, 2 H), 3.42 (s, 6 H), 3.25-3.21 (m, 4 H), 2.28 (m, 2 H).
Reaction SMILES: Cl.Cl.[CH3:3][C@H:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][CH:9]=[N:8][C:7]=2[CH2:6][CH2:5]1.[C:19]([O:23][C:24]([N:26]([CH:39]([CH3:41])[CH3:40])[CH2:27][CH:28]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:29](O)=[O:30])=[O:25])([CH3:22])([CH3:21])[CH3:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.C(N(CC)CC)C>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([CH:28]([C:29]([N:16]2[CH2:17][CH2:18][N:13]([C:11]3[C:12]4[C@H:4]([CH3:3])[CH2:5][CH2:6][C:7]=4[N:8]=[CH:9][N:10]=3)[CH2:14][CH2:15]2)=[O:30])[CH2:27][N:26]([CH:39]([CH3:40])[CH3:41])[C:24](=[O:25])[O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[CH:33][CH:34]=1
Reactant: CC(C)N(CC(C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reactant: C[C@@H]1CCc2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)N(CC(C(=O)N1CCN(c2ncnc3c2[C@H](C)CC3)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.1 %

Procedure:
To a solution of (R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine dihydrochloride (30 mg, 0.1 mmol) in DCM (10 mL) and triethylamine (1 mL) were added 3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (35 mg, 0.1 mmol) and HBTU (39 mg, 0.1 mmol). The mixture was stirred at room temperature for 2 hours. The solvent was removed and the residue was purified by silica gel chromatography, eluting with ethyl acetate to give tert-butyl 2-(4-chlorophenyl)-3-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (25 mg, 44%). 1H NMR (CDCl3, 400 MHz) δ 8.44 (s, 1H), 7.30-7.20 (m, 4H), 3.90-3.18 (m, 9H), 3.18-2.70 (m, 4H), 2.28 (m, 1H), 1.83 (m, 1H), 1.65 (m, 1H), 1.47 (s, 9H), 1.12 (m, 3H), 0.98 (m, 3H), 0.68 (m, 3H). MS (APCI+) [M+H]+542.
Reaction SMILES: [ClH:1].[NH2:2][CH:3]1[C:11]2[C:6](=[C:7]([CH3:13])[CH:8]=[CH:9][C:10]=2[OH:12])[CH2:5][CH2:4]1.Cl.[I:15]Cl>O>[ClH:1].[NH2:2][CH:3]1[C:11]2[C:6](=[C:7]([CH3:13])[CH:8]=[C:9]([I:15])[C:10]=2[OH:12])[CH2:5][CH2:4]1
Reactant: Cc1ccc(O)c2c1CCC2N
Reactant: ClI
Agent: Cl
Solvent: O
Product: Cc1cc(I)c(O)c2c1CCC2N
Reaction time: 2 h

Procedure:
One gram of 1-amino-7-hydroxy-4-methylindane hydrochloride was dissolved in 20 ml of water, then 5 ml of 3N-hydrochloric acid solution containing 0.85 g of iodine monochloride was added dropwise at a room temperature under vigorous stirring condition. The reaction mixture was stirred at the same temperature for 2 hours, then ice-cooled. The crystals precipitated were collected by filtration, and changed them to hydrochloride, washed with ether and dried. 0.70 Grams of 1-amino-7-hydroxy-6-iodo-4-methylindane hydrochloride was obtained in the form of yellow needle-like crystals. Melting point: Over 200° C. (decomp.).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=O.[CH2:17]([NH2:19])[CH3:18].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH2:6][NH:19][CH2:17][CH3:18]
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
3,5-Bis-trifluoromethylbenzaldehyde (3.00 g) is dissolved in 1,2-dichloroethane (50 ml), and thereto are added 70% aqueous ethylamine solution (0.80 ml) and acetic acid (2.1 ml), followed by an addition of triacetoxy-sodium borohydride (13.1 μg) at room temperature over 1 hour with stirring. The mixture is stirred at room temperature for additional 30 minutes, and to the reaction mixture is then added a saturated aqueous sodium bicarbonate solution, and the mixture is extracted with ethyl acetate. The organic layer is washed successively with a saturated aqueous sodium bicarbonate solution and a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane ethyl acetate=4:1) to give (3,5-bis-trifluoromethyl-benzyl)-ethyl-amine (1.52 g). MS (m/z): 272 [M+H]+
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[N:8]=[CH:7][C:6]([CH:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])=[CH:5][CH:4]=1.[Li+].CC([N-]C(C)C)C.[C:25](C#N)(=[O:29])[O:26][CH2:27][CH3:28]>>[O:14]=[C:10]1[CH:9]([C:6]2[CH:7]=[N:8][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:4][CH:5]=2)[CH2:13][CH2:12][CH:11]1[C:25]([O:26][CH2:27][CH3:28])=[O:29]
Reactant: O=C1CCCC1c1ccc(C(F)(F)F)nc1
Reactant: CCOC(=O)C#N
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CCOC(=O)C1CCC(c2ccc(C(F)(F)F)nc2)C1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
2-(6-(trifluoromethyl)pyridin-3-yl)cyclopentanone (700 mg, 3.05 mmol) was added to a solution of LDA (2.291 mL, 4.58 mmol) at −78° C. After stirring for 30 min at −78° C., ethyl carbonocyanidate (0.329 mL, 3.36 mmol) was added to the reaction mixture. The resulting solution was warmed to room temperature with stirring over 3 h. The reaction mixture was quenched with 1 mL of water, washed with brine, dried over MgSO4, and purified by Biotage (Hexanes/EtOAc 2:1) to afford ethyl 2-oxo-3-(6-(trifluoromethyl)pyridin-3-yl)cyclopentanecarboxylate (764 mg, 2.54 mmol, 83% yield). LC-MS (M+H)+=302.2.
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:9][C:8]([CH2:10][NH:11][C:12]([C:14]2[C:19](=[O:20])[C:18](Br)=[C:17]([CH3:22])[N:16]([CH:23]([CH3:25])[CH3:24])[CH:15]=2)=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:26][CH:27]([F:37])[C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1>>[CH3:1][S:2]([C:5]1[S:9][C:8]([CH2:10][NH:11][C:12]([C:14]2[C:19](=[O:20])[C:18]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([CH:27]([F:37])[F:26])[CH:33]=3)=[C:17]([CH3:22])[N:16]([CH:23]([CH3:25])[CH3:24])[CH:15]=2)=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: Cc1c(Br)c(=O)c(C(=O)NCc2ccc(S(C)(=O)=O)s2)cn1C(C)C
Reactant: OB(O)c1cccc(C(F)F)c1
Product: Cc1c(-c2cccc(C(F)F)c2)c(=O)c(C(=O)NCc2ccc(S(C)(=O)=O)s2)cn1C(C)C

Procedure:
Example 40 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 39a and replacing 3-(trifluoromethyl)phenylboronic acid with 3-(difluoromethyl)phenylboronic acid. ESI mass spectrum: [M+H]+=495; Retention time HPLC: 0.82 min (Z011_S03).