Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14](Cl)[CH:15]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>O1CCOCC1>[C:23]([O:22][C:20]([N:27]1[CH:31]=[C:30]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]=[C:9]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:18]=[N:17]3)[CH:29]=[N:28]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Clc1ccc2nc(NCc3ccccc3)cnc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)n1cc(-c2ccc3nc(NCc4ccccc4)cnc3c2)cn1
Temperature: 100 °C

Procedure:
A mixture of benzyl-(6-chloro-quinoxalin-2-yl)-amine (0.250 g, 0.92 mmol, 1 eq), N-Boc-4-pyrazole boronic acid pinacol ester (0.328 g, 1.1 mmol, 1.2 eq), caesium carbonate (1.2 g, 3.71 mmol, 4.03 eq), potassium iodide (0.015 g, 0.09 mmol, 0.1 eq) in 1,4-dioxane (12 mL) was degassed at RT under vacuum and placed under an atmosphere of nitrogen. The process was repeated twice and Fu's catalyst (bis(tri-tert-butylphosphine)-palladium(0)) (0.023 g, 0.046 mmol) was added at RT. The reaction mixture was heated to 100° C. by microwave irradiation for 180 min. The organic mixture was diluted with ethyl acetate (150) and washed with water (20 mL×2) and brine (20 mL). The organic solvent was evaporated under vacuum to give crude product.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[N:11][N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([OH:22])=[C:14]([C:23]2[NH:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[S:25](=[O:34])(=[O:33])[N:24]=2)[C:13]1=[O:35].CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:34]=[S:25]1(=[O:33])[C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[NH:28][C:23]([C:14]2[C:13](=[O:35])[N:12]([NH:11][CH:2]3[CH2:3][CH2:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH2:1]3)[C:21]3[C:16]([C:15]=2[OH:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[N:24]1
Reactant: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc2n1N=C1CCc2ccccc2C1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc2n1NC1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 247A (0.070 g, 0.14 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.010 mL, 0.25 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.110 mL, 0.22 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1 M hydrochloric acid to a pH of approximately 2-4, diluted with water, and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with dichloromethane to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.73 (s, 2 H) 3.27 (d, J=12.50 Hz, 4 H) 5.93 (d, J=3.68 Hz, 1 H) 7.07 (m, 6 H) 7.28 (t, J=7.54 Hz, 3 H) 7.55 (m, 2 H) 7.66 (d, J=7.72 Hz, 1 H) 8.07 (dd, J=7.72, 1.47 Hz, 1 H) 16.28 (s, 1 H). MS (ESI−) m/z 485 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([CH3:25])[CH:13]=[C:14]([O:17]CC3C=CC=CC=3)[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:26])[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([CH3:25])[CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(OCc2ccccc2)cc2c1ccn2CC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(O)cc2c1ccn2CC(=O)OC(C)(C)C
Yield: 95 %

Procedure:
A solution of (6-benzyloxy-4-methyl-indol-1-yl)-acetic acid tert-butyl ester (140 mg, 0.4 mmol) in ethanol (14 ml) was hydrogenated over 10% palladium on charcoal (14 mg) at ambient temperature for 3 h. The catalyst was filtered off, the solvent evaporated under reduced pressure to give 100 mg (0.38 mmol, 96%) of the title compound as brown oil which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:10].[C:19]([C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:31]=1[OH:32])[C:26](O)=[O:27])([CH3:22])([CH3:21])[CH3:20].Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH2:12]([NH:11][C:9](=[O:10])[NH:8][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[NH:1][C:26](=[O:27])[C:25]1[CH:29]=[C:30]([C:33]([CH3:34])([CH3:35])[CH3:36])[C:31]([OH:32])=[C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:24]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Reactant: CCCCCCCNC(=O)Nc1cnccc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCCCCCCNC(=O)Nc1cnccc1NC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 15.6 %

Procedure:
A mixture of 1-(4-amino-3-pyridyl)-3-heptylurea (0.50 g), 3,5-di-t-butyl-4-hydroxybenzoic acid (0.60 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide monohydrochloride (0.46 g) was stirred in dichloromethane (10 ml) at room temperature overnight. The reaction solution was washed with water, saturated saline and dried over anhydrous MgSO4. The solvent was distilled off and the residue was purified by a silica gel column chromatography (chloroform:methanol=20:1) to give N-[3-(3-heptylureido)-4-pyridyl]-3,5-di-t-butyl-4-hydroxybenzamide (0.15 g, 16%) as crystals.
Reaction SMILES: N(OCCC(C)C)=O.[N:9]1[C:18]2[C:13](=[CH:14][C:15]([CH2:19][N:20]3[C:24]4[N:25]=[C:26](N)[N:27]=[CH:28][C:23]=4[N:22]=[N:21]3)=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.C(I)[I:31]>>[I:31][C:26]1[N:27]=[CH:28][C:23]2[N:22]=[N:21][N:20]([CH2:19][C:15]3[CH:14]=[C:13]4[C:18](=[CH:17][CH:16]=3)[N:9]=[CH:10][CH:11]=[CH:12]4)[C:24]=2[N:25]=1
Reactant: Nc1ncc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: ICI
Agent: CC(C)CCON=O
Product: Ic1ncc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 85 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
Isoamyl nitrite (0.78 mL) was added to a suspension of 3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine (102 mg, 0.370 mmol) in CH2I2 (2.4 mL) under a nitrogen atmosphere. The mixture was stirred at 85° C. for 1 h. The solvent was removed under reduced pressure. Flash chromatography of the resulting residue over silica gel to afford the desired product (57 mg, 40%). 1H NMR (300 MHz, CDCl3) δ 6.03 (s, 2H), 7.44 (m, 1H), 7.79-8.18 (m, 4H), 8.94 (m, 1H), 9.27 (s, 1H); LCMS (APCI) m/z 389.0 (M+H+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:22]3[CH:23]=[C:24]4[C@:29]([CH2:31][OH:32])([CH2:30][C:21]=3[CH:20]=[N:19]2)[CH2:28][N:27]([S:33]([C:36]2[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH2:26][CH2:25]4)=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl.O>[F:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:22]3[CH:23]=[C:24]4[C@:29]([CH:31]=[O:32])([CH2:30][C:21]=3[CH:20]=[N:19]2)[CH2:28][N:27]([S:33]([C:36]2[CH:37]=[CH:38][C:39]([C:42]([F:45])([F:43])[F:44])=[CH:40][CH:41]=2)(=[O:35])=[O:34])[CH2:26][CH2:25]4)=[CH:14][CH:13]=1
Reactant: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(CO)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(C(F)(F)F)cc1)C2
Temperature: -55 °C
Reaction time: 0.25 h
Yield: 95.3 %

Procedure:
A solution of oxalyl chloride (7.35 g, 58.8 mmol) in dry dichloromethane (160 mL) was cooled to −60° C. under nitrogen and treated dropwise with dry dimethyl sulfoxide (9.55 g, 122.5 mmol) such that the temperature did not rise above −50° C. The mixture was stirred at −55° C. for 15 minutes. A solution of (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)methanol (12.40 g, 24.5 mmol) in dry dichloromethane (140 mL) was added such that the temperature did not rise above −50° C. The mixture was stirred for 2 hours allowing the temperature to rise to −15° C. Triethylamine (12.64 g, 125 mmol) was added dropwise such that the temperature did not rise above −5° C. and the resultant mixture was stirred until the temperature reached 0° C. Water (100 mL) was added, the phases were separated, the aqueous phase was extracted with further dichloromethane (×2) and the combined organic phases were dried over sodium sulfate. The solids were removed by filtration, the filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with a mixture of ethyl acetate and dichloromethane (1:1 by volume) followed by ethyl acetate to afford (R)-1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carbaldehyde as a white foam (11.8 g). 1H NMR (400 MHz, CDCl3): δ 9.48 (s, 1 H); 7.93 (d, J=8.2 Hz, 2 H); 7.84 (d, J=8.3 Hz, 2 H); 7.39-7.40 (m, 3 H); 7.15-7.16 (m, 2 H); 6.52 (d, J=2.4 Hz, 1 H); 4.32 (dd, J=12.2, 2.1 Hz, 1 H); 3.90 (dd, J=11.0, 5.6 Hz, 1 H); 3.14 (d, J=16.4 Hz, 1 H); 2.71-2.73 (m, 1 H); 2.60 (d, J=16.4 Hz, 1 H); 2.49-2.51 (m, 3 H).
Reaction SMILES: [CH:1]1[CH:13]=[CH:12][C:11]2[CH2:14][CH2:15][N:9]3[C:10]=2[C:2]=1[C:3]1[C:4](=O)[CH2:5][CH2:6][CH2:7][C:8]=13.Cl.[NH2:18][OH:19].Cl>N1C=CC=CC=1>[CH:1]1[CH:13]=[CH:12][C:11]2[CH2:14][CH2:15][N:9]3[C:10]=2[C:2]=1[C:3]1[C:4](=[N:18][OH:19])[CH2:5][CH2:6][CH2:7][C:8]=13
Reactant: O=C1CCCc2c1c1cccc3c1n2CC3
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: ON=C1CCCc2c1c1cccc3c1n2CC3
Yield: 35.9 %

Procedure:
A mixture of 4,5,8,9-tetrahydropyrrolo[3,2,1-jk]carbazol-10(7H)-one (364 mg) and hydroxylamine hydrochloride (479 mg) in pyridine (50 ml) was heated to 50° for 60 h, and was then poured into 2N hydrochloric acid (100 ml). The resultant precipitate was filtered off, washed with water (50 ml), and dried in vacuo at 50° for 6 h to give the title compound (140 mg). Filtration of the precipitate that formed subsequently in the filtrate gave a further crop of the title compound (104 mg), m.p. 271°-272°.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([S:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][C:24]=2[Cl:25])[C:21](=[O:26])[N:20](CC2C=CC(OC)=CC=2)[CH:19]=[CH:18]3)[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O>[Cl:25][C:24]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][NH:20][C:21]2=[O:26])=[CH:16][C:15]=1[S:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: COc1ccc(Cn2ccc3cc(SC4CCN(C(=O)OC(C)(C)C)CC4)c(Cl)cc3c2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]ccc2cc(SC3CCNCC3)c(Cl)cc12
Yield: 73.4 %

Procedure:
188 mg 4-[7-Chloro-2-(4-methoxy-benzyl)-1-oxo-1,2-dihydro-isoquinolin-6-ylsulfanyl]-piperidine-1-carboxylic acid tert-butyl ester (285) in 2 ml TFA were heated in the microwave at 150° C. for 1.5 h. After evaporation the residue is taken up in 1N HCl and extracted with dichloromethane and lyophilized. 79 mg of 7-Chloro-6-(piperidin-4-ylsulfanyl)-2H-isoquinolin-1-one could be obtained as the hydrochloride. Rt=0.93 min (Method B). Detected mass: 295.1/297.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[NH:13][C:12](=O)[CH:11]=[N:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:36]CCl>>[Cl:36][C:12]1[CH:11]=[N:10][N:9]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)[C:14](=[O:15])[N:13]=1
Reactant: ClCCl
Reactant: O=c1cnn(-c2cc(Cl)cc(Cl)c2)c(=O)[nH]1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=c1nc(Cl)cnn1-c1cc(Cl)cc(Cl)c1

Procedure:
In 30 ml of dichloromethane suspended with 1.00 g of 2-(3,5-dichlorophenyl)-2,3,4,5-tetrahydro-1,2,4-triazine-3,5-dione followed by addition of 2-fold morlar each of carbone tetrachloride and triphenylphosphine and refluxed for 12 hours. After the completion of the reaction, the resulted solution were purified by column chromatography (Merck Silica Gel 60 dichloromethane-carbontetrachloride=2:1). m.p. 148-149° C.
Reaction SMILES: [NH:1]1[BH:6][NH:5][BH:4][NH:3][BH:2]1.[CH3:7][C:8]#[C:9][CH3:10]>[C-]#[O+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Rh]>[CH:7]([B:2]1[NH:3][BH:4][NH:5][BH:6][NH:1]1)=[CH:8][CH2:9][CH3:10]
Reactant: B1NBNBN1
Reactant: CC#CC
Agent: [Rh]
Agent: [C-]#[O+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCC=CB1NBNBN1
Yield: 10.1 %

Procedure:
As in the previous examples, borazine (1.618 g, 20.1 mmol) and 2-butyne (20 mmol) were reacted in the presence of RhH(CO)(PPh3)3 (0.0165 g, 0.018 mmol) for four hours at room temperature. Fractionation of the resulting reaction mixture gave 0.2702 g (2.01 mmol) of B-butenyl-borazine stopping in a -55° C. trap. GLC analysis of the product indicates that it is composed of a 3:2 mixture of B-trans-(2-cis-butenyl)borazine and B-trans-(1-butenyl)borazine. Pure samples of each isomer were prepared by preparative G.L.C.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[F:28][C:29]1([F:35])[CH2:31][CH:30]1[C:32](O)=[O:33]>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:32]([CH:30]5[CH2:31][C:29]5([F:35])[F:28])=[O:33])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: O=C(O)C1CC1(F)F
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1)C1CC1(F)F

Procedure:
The title compound, white solid (5 mg, 15%), MS (ISP) m/z=436.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25.8 mg, 0.070 mmol) and 2,2-difluorocyclopropanecarboxylic acid
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3](/[CH:6]=[CH:7]/[C:8]([OH:10])=[O:9])=[CH:2]1.[H][H]>[Pd]>[O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[CH2:2]1
Reactant: [H][H]
Reactant: O=C(O)/C=C/c1ccoc1
Agent: [Pd]
Product: O=C(O)CCC1CCOC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of trans-3-furanacrylic acid (10 g, 72.4 mmol) in industrial methylated spirits (50 mL) was added 10% palladium on carbon (1.0 g) at room temperature. The reaction vessel was charged with hydrogen gas to a pressure of 345 kPa and stirred at room temperature for 16 hours. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give the title compound as a colourless oil.
Reaction SMILES: C1(C[O:5][C:6](=[O:34])[CH:7]([C:12]2[CH:17]=[C:16]([O:18][CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:15]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[C:14]([Cl:33])[CH:13]=2)[CH2:8][CH:9]([CH3:11])[CH3:10])CC1.[OH-].[K+]>CCO.O>[Cl:33][C:14]1[CH:13]=[C:12]([CH:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6]([OH:34])=[O:5])[CH:17]=[C:16]([O:18][CH2:19][CH:20]2[CH2:22][CH2:21]2)[C:15]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:25][CH:24]=1
Reactant: CC(C)CC(C(=O)OCC1CC1)c1cc(Cl)c(-c2ccc(C(F)(F)F)cc2)c(OCC2CC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)CC(C(=O)O)c1cc(Cl)c(-c2ccc(C(F)(F)F)cc2)c(OCC2CC2)c1
Yield: 86.9 %

Procedure:
2-(2-Chloro-6-cyclopropylmethoxy-4′-trifluoromethyl-biphenyl-4-yl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.06 g, 0.12 mmol) was dissolved in a mixture of EtOH and H2O (9 mL/1 mL) and KOH (0.1 g, 1.76 mmol) was added. The reaction mixture was refluxed for 2 h and after cooling the solvent was evaporated. Then, 6 N HCl was added to adjust the pH to 5 and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over MgSO4 and evaporated under reduced pressure to give 2-(2-chloro-6-cyclopropylmethoxy-4′-trifluoromethyl-biphenyl-4-yl)-4-methyl-pentanoic acid as a yellowish solid (0.046 g, 85%). M.p.=115-116° C. 1H NMR (300 MHz, CDCl3/TMS): δ 7.67 (d, J=8.0 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H), 7.08 (s, 1H), 6.85 (s, 1H), 3.77 (d, J=6.4 Hz, 2H), 3.65 (t, J=7.7 Hz, 1H), 2.04-1.94 (m, 1H), 1.75-1.66 (m, 1H), 1.60-1.52 (m, 1H), 1.15-0.89 (m, 1H), 0.95 (d, J=6.4 Hz, 6H), 0.54-0.40 (m, 2H), 0.20-0.10 (m, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 179.0, 157.1, 140.3, 138.8, 133.8, 130.8, 129.3 (q), 128.2, 124.6, 124.3 (q, 1JCF=271.0 Hz), 121.6, 111.2, 73.4, 49.4, 42.0, 25.9, 22.6, 22.3, 10.0, 3.0.
Reaction SMILES: [C:1]([C:4]1[C:9]2[O:10][CH2:11][C:12]3[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=3[C:14](=[O:15])[C:8]=2[CH:7]=[CH:6][C:5]=1[OH:20])(=[O:3])[CH3:2].[Na].[C:22](OCC)(=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(O)C>[CH2:26]([O:25][C:23]([C:22]1[O:20][C:5]2[CH:6]=[CH:7][C:8]3[C:14](=[O:15])[C:13]4[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=4[CH2:11][O:10][C:9]=3[C:4]=2[C:1](=[O:3])[CH:2]=1)=[O:24])[CH3:27]
Reactant: CC(=O)c1c(O)ccc2c1OCc1ccccc1C2=O
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1cc(=O)c2c3c(ccc2o1)C(=O)c1ccccc1CO3
Temperature: 25 °C

Procedure:
8.04 g (30 mmol) 4-acetyl-6,11-dihydro-3-hydroxydibenz[b,e]oxepin-11-one is added to a solution of 4.14 g (180 mmol) sodium in 250 ml ethanol, it is heated for 10 minutes to reflux, cooled to room temperature, admixed with 14.6 g (100 mmol) diethyl oxalate, heated for 90 minutes to reflux, allowed to cool and filtered. The precipitate is taken up in 100 ml ethanol, the suspension is saturated with hydrogen chloride and subsequently heated for 1 hour to 50° C. After cooling it is poured onto ice and filtered. 7.8 g of the title compound (74% of theory) of melting point 178°-180° C. (from ethanol) remain.
Reaction SMILES: [C:1]([C:3]1[CH:7]=[CH:6][S:5][C:4]=1[N:8]=[C:9]([O:14][CH2:15][CH2:16][CH3:17])[O:10][CH2:11][CH2:12][CH3:13])#[N:2].[Cl:18]N1C(=O)CCC1=O>N1C=CC=CC=1>[Cl:18][C:6]1[S:5][C:4]([N:8]=[C:9]([O:14][CH2:15][CH2:16][CH3:17])[O:10][CH2:11][CH2:12][CH3:13])=[C:3]([C:1]#[N:2])[CH:7]=1
Reactant: CCCOC(=Nc1sccc1C#N)OCCC
Reactant: O=C1CCC(=O)N1Cl
Solvent: c1ccncc1
Product: CCCOC(=Nc1sc(Cl)cc1C#N)OCCC
Temperature: 60 °C
Reaction time: 3 h

Procedure:
In a sulfonation flask, 3.02 g (0.012 mol) 3-cyano-2-(1,1-dipropoxymethylenamino)thiophene, are added, with stirring to 15 ml of absolute pyridine. The internal temperature is then raised to 60° C. and 1.9 g (0.0144 mol) N-chlorosuccinimide are added in three portions. After stirring for 3 hours at 60° C., the pyridine is removed in a water jet vacuum and the residue taken up in ethylacetate. The organic phase is washed twice with water and after drying, the solvent is removed in a water jet vacuum. The crude product is purified by column chromatography over silica gel (eluant: tert.butylmethylether/hexane 1:6). Yield: 3.5 g of 5-chloro-3-cyano-2-(1,1-dipropoxymethyleneamino)thiophene in the form of brownish crystals, m.p. 55-57° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([CH2:13][C:14]1[C:15]([NH2:21])=[N:16][CH:17]=[C:18]([Br:20])[CH:19]=1)[CH2:7][C:8](OCC)=[O:9])[CH3:2].[H-].[Na+]>CS(C)=O.O>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]1[CH2:13][C:14]2[CH:19]=[C:18]([Br:20])[CH:17]=[N:16][C:15]=2[NH:21][C:8](=[O:9])[CH2:7]1)[CH3:2]
Reactant: CCOC(=O)CN(CC(=O)OCC)Cc1cc(Br)cnc1N
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)CN1CC(=O)Nc2ncc(Br)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.2 %

Procedure:
A solution of [(2-amino-5-bromo-pyridin-3-ylmethyl)ethoxycarbonylmethyl-amino]-acetic acid ethyl ester (6.52 g, 17.4 mmol) in DMSO (170 mL) was treated with NaH (0.70 g, 17.5 mmol). After stirring at room temperature overnight, the mixture was diluted with H2O (300 mL) and extracted with EtOAc (4×200 mL). The combined organic layers were washed with H2O (3×100 mL) and brine (100 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo to give the title compound (6.18 g, quantitative) as an off-white solid: MS (ESI) m/e 328 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:4](=[O:12])[NH:3]1.[CH3:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1.[O-]S([O-])(=O)=O.[Mg+2].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:11][O:10][C:8](=[O:9])[CH2:7][CH:5]1[C:4](=[O:12])[N:3]([CH2:13][C:14]2[CH:21]=[CH:20][C:17]([CH3:18])=[CH:16][CH:15]=2)[C:2](=[O:1])[NH:6]1
Reactant: COC(=O)CC1NC(=O)NC1=O
Reactant: Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CC1NC(=O)N(Cc2ccc(C)cc2)C1=O
Temperature: 25 °C
Yield: 97 %

Procedure:
A solution of (2,5-dioxo-imidazolidin-4-yl)-acetic acid, methyl ester (2.35 g, 13.7 mmol) in DMF (100 mL) is treated with p-methyl benzyl bromide (2.90 g, 15.7 mmol), MgSO4 (3.30 g, 27.4 mmol) and then K2CO3 (3.77 g, 27.3 mmol). The resultant mixture is stirred under N2 in an ice bath for 30 minutes and then warmed to room temperature for 16 h. The reaction mixture is then filtered, and then aqueous 1N HCl (150 mL) is added to the filtrate. The filtrate is extracted with EtOAc and the organic layer dried. The solvent is removed to give 4.11 g crude product which is purified by flash chromatography using 100% CH2Cl2 then 97.5:2.5 CH2Cl2:MeOH to give 3.67 g (97%) [1-(4-methyl-benzyl)-2,5-dioxo-imidazolidin-4-yl]-acetic acid methyl ester. 1H NMR. MS (ES+) Calc'd for C14H17N2O4 (M+1) 277. Found m/z 277 (100%).
Reaction SMILES: [Na].[C:2]([O:10]CC)(=O)[CH2:3][C:4]([O:6]CC)=O.[CH2:13]([NH:16][C:17]([NH2:19])=[O:18])[CH:14]=[CH2:15]>C(O)C>[CH2:13]([N:16]1[C:2](=[O:10])[CH2:3][C:4](=[O:6])[NH:19][C:17]1=[O:18])[CH:14]=[CH2:15]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: C=CCNC(N)=O
Agent: [Na]
Solvent: CCO
Product: C=CCN1C(=O)CC(=O)NC1=O
Temperature: 25 °C
Yield: 58 %

Procedure:
9.2 g sodium thread (0.4 mol) was added to 300 mL anhydrous ethyl alcohol with stirring at room temperature. After the Na was dissolved completely, 30 mL diethyl malonate (0.2 mol) and 20 g allyl urea (0.2 mol) were added and refluxed for 5 hours. After the completion of reaction, sucking filtration was performed when the reaction solution was still hot. The filter cake was dissolved in 150 mL anhydrous ethyl alcohol and HCl was used to adjust the pH to 2˜3. After sucking filtration, the filtrate was left to stand for crystallization. After sucking filtration again, washing with anhydrous ethyl alcohol and drying, a white solid (19.5 g) was obtained. Yield: 58%, MS: 169 (M+1).
Reaction SMILES: [C:1]12([C:9](Cl)=[O:10])[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[NH2:12][C@H:13]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:14]1>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][N:15]2[CH2:16][CH2:17][C@H:13]([NH:12][C:9]([C:1]34[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]3)[CH2:3][CH2:2]4)=[O:10])[CH2:14]2)=[CH:21][CH:22]=1
Reactant: O=C(Cl)C12CCC(CC1)CC2
Reactant: N[C@H]1CCN(CCc2ccc(F)cc2)C1
Product: O=C(N[C@H]1CCN(CCc2ccc(F)cc2)C1)C12CCC(CC1)CC2

Procedure:
Bicyclo[2.2.2]octane-1-carbonyl chloride and (S)-3-amino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine were reacted under the same conditions as in Example 53 to give (S)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)-bicyclo[2.2.2]octane-1-carboxamide.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH2:8][C@H:7]1[CH2:19][OH:20])=[O:5])[CH3:2].[F:21][C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1>>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9]([O:11][Si:12]([C:15]([CH3:16])([CH3:18])[CH3:17])([CH3:13])[CH3:14])[CH2:8][C@H:7]1[CH2:19][O:20][C:25]1[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=1)=[O:5])[CH3:2]
Reactant: Oc1ccc(F)cc1
Reactant: CCOC(=O)[C@@H]1CC(O[Si](C)(C)C(C)(C)C)C[C@H]1CO
Product: CCOC(=O)[C@@H]1CC(O[Si](C)(C)C(C)(C)C)C[C@H]1COc1ccc(F)cc1

Procedure:
The title compound was prepared in analogy to example 68 step 5 using (1R,2R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-hydroxymethyl-cyclopentanecarboxylic acid ethyl ester (example 68 step 4) and 4-fluorophenol. Colorless oil (74%). MS (EI): 397.2 (M+H)+.