Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].[SiH:23]([CH2:28][CH3:29])([CH2:26][CH3:27])[CH2:24][CH3:25]>O1CCCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[Si:23]([CH2:28][CH3:29])([CH2:26][CH3:27])[CH2:24][CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Cn2ccc3ccccc32)cc1
Reactant: CC[SiH](CC)CC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1cc2ccccc2n1Cc1ccccc1
Yield: 31.1 %

Procedure:
The reaction was conducted according to the General Procedure by heating 1-benzylindole (62 mg, 0.5 mmol, 1 equiv.), KOt-Bu (11 mg, 0.1 mmol, 0.2 equiv) and Et3SiH (239 microliters, 1.5 mmol, 3 equiv.) in 1 mL of tetrahydrofuran for 48 hours at 23° C. After aqueous work up, the crude reaction mixture was purified by chromatography on silica using hexanes (isochratic) to obtain 50 mg (31%) of the title compound as a colourless oily solid. 1H NMR (500 MHz, THF-d8) δ 7.56 (ddd, J=7.7, 1.3, 0.7 Hz, 1H), 7.25-7.07 (m, 4H), 7.02 (ddd, J=8.2, 6.9, 1.3 Hz, 1H), 6.98 (ddd, J=7.9, 6.9, 1.1 Hz, 1H), 6.92-6.86 (m, 2H), 6.80 (d, J=0.9 Hz, 1H), 5.52 (s, 2H), 1.06-0.88 (m, 9H), 0.85-0.69 (m, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].CN(C=O)C.[OH-].[Na+].Cl>O>[CH2:1]([O:3][C:4](=[CH:10][C:11]1[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=Cc1ccc([N+](=O)[O-])cc1)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyl 2-ethoxy-3-(4-nitrophenyl)acrylate containing 3.6 wt % DMF (26.07 g corrected, 98.3 mmol) was dissolved in IMS (500 ml) and a solution of NaOH (1.44 g, 36.1 mmol) in water (260 ml) was added. The resulting mixture was stirred at ambient temperature for 18 hr then acidified with 1M HCl (120 ml) and the resulting solid collected by filtration, washed with water (2×100 ml) and suction dried on the filter for 30 mins, followed by vacuum oven drying at 18° C. for 18 hr. 2-Ethoxy-3-(4-nitrophenyl)acrylic acid was thus obtained as an orange solid containing water of crystallisation (18.4 g, 79%).
Reaction SMILES: C[O:2][CH2:3][CH2:4][CH:5]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)[CH3:6].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:45][CH2:46][C:47]1[C:48]([OH:55])=[N:49][C:50]([CH3:54])=[CH:51][C:52]=1[CH3:53]>ClCCl>[OH:55][C:48]1[C:47]([CH2:46][NH:45][C:11](=[O:13])[C:10]2[CH:9]=[CH:8][C:7]([CH:5]([CH2:4][CH2:3][OH:2])[CH3:6])=[CH:15][CH:14]=2)=[C:52]([CH3:53])[CH:51]=[C:50]([CH3:54])[N:49]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: COCCC(C)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)CCO)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.8 %

Procedure:
A mixture of 4-(4-methoxybutan-2-yl)benzoic acid (177 mg, 0.85 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (245 mg, 1.3 mmol), N-hydroxybenzotriazole (176 mg, 1.3 mmol) and triethylamine (258 mg, 2.55 mmol) in dichloromethane (50 mL) was stirred for 30 minutes at room temperature. Then to the mixture, 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (130 mg, 0.85 mmol) was added. The resultant mixture was stirred at room temperature for 12 hours. Then the mixture was washed with water (30 mL×3). The organic layer was concentrated to give a residue and the residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(4-hydroxybutan-2-yl)benzamide (47 mg, 17%). LRMS (M+H+) m/z: calcd 324.19 found 324. 1H. NMR (300 MHz, CD3OD): δ 12.96 (s, 1H), 7.80 (s, 1H), 7.70 (d, J=7.8 Hz, 2H), 7.24 (d, J=7.8 Hz, 2H), 5.95 (s, 1H), 4.56 (d, J=5.7 Hz, 2H), 3.20-3.14 (m, 5H), 2.93 (q, J=7.2 Hz, 1H), 2.37 (s, 3H), 2.27 (s, 3H), 1.82 (q, J=6.9 Hz, 2H), 1.23 (d, J=6.9 Hz, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([CH3:16])[CH:5]=1)(=[O:3])[CH3:2].[CH3:17][Mg]I.[Mg].CI.Cl>CCOCC>[OH:3][C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([CH3:16])[CH:5]=1)([CH3:17])[CH3:2]
Reactant: C[Mg]I
Reactant: CC(=O)c1ccc(-c2ccccc2)c(C)c1
Agent: Cl
Agent: [Mg]
Solvent: CI
Solvent: CCOCC
Product: Cc1cc(C(C)(C)O)ccc1-c1ccccc1

Procedure:
A solution of 4-acetyl-2-methylbiphenyl (12.8g, 0.061 mole) in dry ether (340me) was added over 30 minutes to methyl magnesium iodide, (from magnesium, 1.8g, methyl iodide, 5.1ml, and ether 61 ml). The mixture was stirred under reflux for 5 hours, stirred overnight at room temperature and finally decomposed by the dropwise addition of hydrochloric acid (2N; 170ml). The product was isolated in ether washed with aqueous sodium thiosulphate and water, dried, evaporated, and distilled. The product solidified on standing and was recrystallized from light petroleum (b.p. 40°-60° C) to give 4-(1-hydroxy-1-methylethyl)-2-methylbiphenyl, m.p. 60°-64° C. A solution of this (5g) in ethyl acetate (50ml) containing concentrated sulphuric acid (3 drops) was hydrogenated over palladium-charcoal (10%, 0.5g) for 8 hours. The mixture was filtered and the filtrate was concentrated by evaporation. The residue was dissolved in ether (50ml), washed with aqueous sodium hydrogen carbonate, dried, evaporated and distilled to give 4-isopropyl-2-methylbiphenyl, b.p. 93°-94° C/0.3mm.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][C:12](Cl)=[O:13])=[CH:8][CH:7]=[CH:6][CH:5]=2.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:18][CH:17]=1.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][C:12]([N:26]1[CH2:25][CH2:24][N:23]([CH:22]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[C:19]3[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=3)[CH2:28][CH2:27]1)=[O:13])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1[nH]c2ccccc2c1CC(=O)Cl
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1[nH]c2ccccc2c1CC(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.6 %

Procedure:
Under a nitrogen atmosphere a 15 mL solution of 2-methylindol-3-ylacetyl chloride (0.013 mole) in tetrahydrofuran was added to a stirred solution of 3.9 grams (0.014 mole) of N-[bis(4-fluorophenyl)methyl]piperazine and 1.1 mL (0.013 mole) of pyridine in 50 mL of dried tetrahydrofuran. Upon completion of the addition the reaction mixture was stirred at ambient temperature for about 18 hours, after which the reaction mixture was poured into a mixture of 200 mL of ethyl acetate and 100 mL of aqueous saturated sodium bicarbonate solution. The organic layer was separated and washed with one portion of a saturated sodium chloride solution, dried with sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to a solid, which was taken up in hexane. This solution was concentrated under reduced pressure, yielding 3.2 grams of N-(2-methylindol-3-ylacetyl)-N′-[bis(4-fluorophenyl)methyl]piperazine, mp 93-103° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:20]([O:12][C:11](=[O:13])[CH:10]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(C(=O)O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NCC(C(=O)OCc1ccccc1)c1ccccc1

Procedure:
N-(t-butoxycarbonyl)-2-phenyl-β-alanine was heated to reflux in acetone with benzyl bromide and potassium carbonate for 17 hours to yield DL-N-(t-butoxycarbonyl)-2-phenyl-β-alanine benzyl ester, m.p. 58°-59° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([Li])CCC.[CH3:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[CH:19]=1)=O.C1CCCCC1.CCOC(C)=O>O1CCCC1>[Br:24][C:20]1[CH:19]=[C:18]([C:16]([C:2]2[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=2)=[CH2:15])[CH:23]=[CH:22][CH:21]=1
Reactant: CC(=O)c1cccc(Br)c1
Reactant: COc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: C=C(c1ccc(OC)nc1)c1cccc(Br)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 5-bromo-2-methoxy-pyridine (10.0 g, 1 eq) in dry tetrahydrofuran (50 ml) was treated dropwise at −78° C. under a nitrogen atmosphere with n-butyllithium (1.6N in hexane, 30 ml, 0.9 eq). The mixture was stirred at −78° C. for 1 hour, then was added a solution of 3-bromo acetophenone (7.7 ml, 1.1 eq) in dry tetrahydrofuran (20 mL) at −78° C. The mixture was then allowed to warm to room temperature. The progress of the reaction was checked by TLC (cyclohexane/AcOEt 9:1). After 1 hour conversion to the desired product was complete. For the workup, saturated solution of ammonium chloride (30 ml) was added, the tetrahydrofuran layer was separated, and then the aqueous phase was extracted with dichloromethane (3×20 ml). The organic fractions were collected, dried over sodium sulphate and evaporated. The crude was dissolved in acetic acid (100 ml) and concentrated sulphuric acid (20 ml) was added, and mixture was stirred at room temperature for 2 hours. A solution of sodium hydroxide (15%) was added to the mixture until pH 6-5, then it was extracted with dichloromethane (3×25 ml). The organic phases were collected, dried and evaporated. The crude was purified by flash chromatography eluting with cyclohexane. 10.3 g of The 5-[1-(3-bromo-phenyl)-vinyl]-2-methoxy-pyridine was obtained as colorless oil (10.3 g, 71% of theory). MS (ISP): m/z=291.9 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N(CCCC)C2CCCCC2)CCCCC1.C(=O)CCCCCCC.C1(N([CH:55]([CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66]CCCC)[CH:56]([O:59][CH3:60])[O:57][CH3:58])C2CCCCC2)CCCCC1>>[CH2:9]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:55]([CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])[CH:56]([O:57][CH3:58])[O:59][CH3:60])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: CCCCCCCCCCC(C(OC)OC)N(C1CCCCC1)C1CCCCC1
Agent: CCCCCCCC=O
Agent: CCCCN(C1CCCCC1)C1CCCCC1
Product: CCCCCCC(C(OC)OC)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 24 h
Yield: 70 %

Procedure:
The product was prepared by above general procedure and the same chemicals except employing dibenzylamine (1a′) (98 mg, 0.5 mmol), and octanal (2c′) (96 mg, 0.75 mmol). After 24 h, the crude product was purified by flash column chromatography (silica gel; ethyl acetate or diethyl ether/hexane=1:100) to afford the desired product 3c as a light yellowish oil (0.129 g, 70% yield); Rf=0.77 (hexane:ethyl acetate=3:1); 1H NMR (CDCl3, 400 MHz) δ 7.37-7.35 (m, 4H), 7.30-7.26 (m, 4H), 7.23-7.18 (m, 2H), 4.37-4.36 (d, J=5.03 Hz, 1H), 3.81-3.65 (m, 4H), 3.35 (s, 3H), 3.32 (s, 3H), 2.73-2.68 (m, 1H), 1.59-1.36 (m, 3H), 1.25-1.17 (m, 5H), 1.15-1.08 (m, 2H), 0.88-0.85 (t, J=7.07 Hz, 3H) ppm; 13C NMR (CDCl3, 100 MHz) δ 140.8 (C×2), 129.0 (CH×4), 128.0 (CH×4), 126.6 (CH2×2), 107.5, 57.4, 54.8, 54.5 (CH2×2), 54.3, 31.9, 29.4, 26.9, 26.5, 22.7, 14.1 ppm; FTIR (neat): v=3015, 1215, 754, 700, 494 cm−1; HRMS (ESI, m/z): calcd for C24H36NO2+ [M+H]+ 370.2746, found: 370.2743.
Reaction SMILES: NN.[CH3:3][C:4]1([CH3:29])[C:12]2[C:7](=[CH:8][C:9]([N:17]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:10][C:11]=2[C:13]([F:16])([F:15])[F:14])[NH:6][C:5]1=[O:28]>CO.C(Cl)(Cl)Cl>[NH2:17][C:9]1[CH:8]=[C:7]2[C:12]([C:4]([CH3:29])([CH3:3])[C:5](=[O:28])[NH:6]2)=[C:11]([C:13]([F:16])([F:14])[F:15])[CH:10]=1
Reactant: CC1(C)C(=O)Nc2cc(N3C(=O)c4ccccc4C3=O)cc(C(F)(F)F)c21
Agent: NN
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC1(C)C(=O)Nc2cc(N)cc(C(F)(F)F)c21

Procedure:
By adding a hydrazine aqueous solution to a methanol-chloroform solution of 2-[3,3-dimethyl-2-oxo-4-(trifluoromethyl)-2,3-dihydro-1H-indol-6-yl]-1H-isoindol-1,3-(2H)-dione and carrying out the reaction at room temperature for 10 hours, 6-amino-3,3-dimethyl-4-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@H:8]([NH:17][C:18](=[O:24])[O:19]C(C)(C)C)[C@H:9](O)[C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.C(N1C=CN=C1)(N1C=CN=C1)=O>Cl.O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([C@H:8]2[C@H:9]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)[O:24][C:18](=[O:19])[NH:17]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H](c1cccc(Br)c1)[C@H](O)c1cccnc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=C1N[C@@H](c2cccc(Br)c2)[C@H](c2cccnc2)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.8 %

Procedure:
To a mixture of (±)-tert-butyl (1R,2R)-1-(3-bromophenyl)-2-hydroxy-2-(pyridin-3-yl)ethylcarbamate (1.1 g, 2.80 mmol), was added 50 mL 4N HCl/Dioxane. The reaction mixture was allowed to stir at ambient temperature overnight and which time the white slurry was concentrated in vacuo and placed on high vac for 18 h. The resulting colorless solid was dissolved in tetrahydrofuran (25 mL) and Hunig's Base (0.586 mL, 3.36 mmol). To this solution was added carbonyldiimidazole (0.544 g, 3.36 mmol) and after 1 h, the reaction mixture was concentrated in vacuo and loaded with dichloromethane onto a 90 g silica gel cartridge prepacked with 25% ethyl acetate/hexanes. Elution was performed with 25 to 100% ethyl acetate/hexanes over 1200 mL then 100% ethyl acetate for 500 mL. Fractions containing the top spot (Rf=0.45 in 75% ethyl acetate/hexanes; UV) were pooled and concentrated to give 266 mg of trans-4-(3-bromophenyl)-5-(pyridin-3-yl)oxazolidin-2-one as a colorless solid. Anal. Calcd. for [M+H]+ C14H11BrN2O2: 319.00. found 318.85. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.66 (1H, dd, J=4.88, 1.53 Hz), 8.49 (1H, d, J=2.14 Hz), 7.72 (1H, dt, J=7.93, 1.98 Hz), 7.48-7.57 (2H, m), 7.40 (1H, dd, J=7.78, 4.73 Hz), 7.27-7.33 (1H, m), 7.22 (1H, d, J=7.63 Hz), 6.87 (1H, s), 5.30 (1H, d, J=7.63 Hz), 4.77 (1H, d, J=7.32 Hz). 13C NMR (126 MHz, CHLOROFORM-d) δ ppm 158.53, 150.80, 147.61, 140.18, 133.76, 132.84, 132.57, 131.09, 129.48, 125.23, 124.07, 123.64, 83.74, 64.20.
Reaction SMILES: [Na:1].[C:2]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:3].[F:10][C:11]([F:18])([F:17])[C:12](OCC)=[O:13]>C(O)C>[Na:1].[C:2]([C:4](=[C:12]([OH:13])[C:11]([F:18])([F:17])[F:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:3]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CCOC(=O)CC#N
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C#N)=C(O)C(F)(F)F
Temperature: 25 °C
Yield: 96 %

Procedure:
To a solution obtained by dissolving 24.0 g (1.04 mol) of sodium metal in 400 ml of ethanol, 113.1 g (1.00 mol) of ethyl cyanoacetate was dropwise added with stirring at the room temperature. After stirring for one hour, 150.0 g (1.05 mol) of ethyl trifluoroacetate was dropwise added to the reaction mixture and stirred for 3 hours at the same temperature. After finishing the reaction, the reaction mass was concentrated as intact under reduced pressure. Precipitated solid was the desired product. Ethyl 2-cyano-3-hydroxy-4,4,4-trifluoro-2-butenoate sodium salt thus obtained was 221.86 g. The yield was 96 %. Following results were obtained by NMR analysis. 1H-NMR (acetone-d6, bppm): 1.21(3H, t, J=6.9 Hz), 4.09(2H, q, J=6.9 Hz)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H:6]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[Cl:25])[N:7]=[C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[NH:9][C:10]=1[CH2:11]Br)=[O:4].[F:26][C:27]1([F:35])[CH2:33][CH:32]2[NH:34][CH:28]1[CH2:29][O:30][CH2:31]2>>[Cl:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[C@H:6]1[C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:10]([CH2:11][N:34]2[CH:28]3[C:27]([F:35])([F:26])[CH2:33][CH:32]2[CH2:31][O:30][CH2:29]3)[NH:9][C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[N:7]1
Reactant: FC1(F)CC2COCC1N2
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Product: COC(=O)C1=C(CN2C3COCC2C(F)(F)C3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Yield: 5.2 %

Procedure:
The title compound was prepared in analogy to Example 1a in Scheme 3 by using methyl (4R)-4-(2-chloro-4-fluoro-phenyl)-6-(bromomethyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate (compound C, 100 mg) and 6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octane 108a (200 mg). 6 mg of the title compound was isolated as yellow powder.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].C(O[CH:12](OCC)[CH2:13][Cl:14])C>>[Cl:14][CH2:13][CH:12]1[C:3]2[CH:4]=[CH:5][S:1][C:2]=2[CH2:6][CH2:7][O:8]1
Reactant: OCCc1cccs1
Reactant: CCOC(CCl)OCC
Product: ClCC1OCCc2sccc21

Procedure:
The title compound was synthesized from 2-(thiophen-2-yl)ethanol and chloroacetaldehyde diethyl acetal according to General Procedure A.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[CH2:21][NH:22][CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)C.[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1.C(OC(=O)CC1C=C(C2C=CC(F)=CC=2CN(C(OCC2C=CC=CC=2)=O)CC)C(OC)=CC=1)C.[Li+].[OH-]>C1COCC1>[CH:26]1([C:29]([N:22]([CH2:21][C:15]2[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=2[C:8]2[C:9]([O:12][CH3:13])=[CH:10][CH:11]=[C:6]([CH2:5][C:4]([OH:25])=[O:3])[CH:7]=2)[CH2:23][CH3:24])=[O:30])[CH2:28][CH2:27]1
Reactant: O=C(Cl)C1CC1
Reactant: CCNCc1cc(F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Agent: CCOC(=O)Cc1ccc(OC)c(-c2ccc(F)cc2CN(CC)C(=O)OCc2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCN(Cc1cc(F)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)C1CC1

Procedure:
{2′-[(Cyclopropanecarbonyl-ethyl-amino)-methyl]-4′-fluoro-6-methoxy-biphenyl-3-yl}-acetic acid (Compound 1-186) was prepared by reacting (2′-ethylaminomethyl-4′-fluoro-6-methoxy-biphenyl-3-yl)-acetic acid ethyl ester and cyclopropanecarbonyl chloride according to the procedure described in Example 1, Step 6 and then hydrolyzing the ester with aqueous LiOH in THF at room temperature
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1>CN(C=O)C.O>[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:8]2[C:9]3[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][CH:10]=3)[CH:6]=[N:7]2)=[CH:23][CH:22]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2ncc3c([N+](=O)[O-])cccc32)cc1
Temperature: 110 °C
Reaction time: 2 h
Yield: 51.8 %

Procedure:
To a suspension of 4-nitro-1H-indazole (10 g, 61.30 mmol) and potassium carbonate (9.32 g, 67.43 mmol) in DMF (100 mL) at 25° C. was added 4-methoxybenzyl chloride (9.14 mL, 67.43 mmol). The resulting mixture was stirred at 110° C. for 2 hours. The reaction mixture was cooled and diluted with water. The aqueous layer was extracted with DCM (2×100 mL). The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel eluting with 0 to 2% ethyl acetate in dichloromethane. The solvent was evaporated to dryness to afford 1-(4-methoxybenzyl)-4-nitro-1H-indazole (9.00 g, 51.8%) as a orange solid. NMR Spectrum: (DMSOd6) 3.70 (s, 3H), 5.73 (s, 2H), 6.87 (d, 2H), 7.25 (d, 2H), 7.65 (dd, 1H), 8.17 (d, 1H), 8.34 (d, 1H), 8.54 (s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:28])[CH2:14][NH:15][C:16](=[O:27])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH2:9]1)=O)(C)(C)C.[OH:29][S:30]([OH:33])(=[O:32])=[O:31].C([O-])(O)=O.[Na+]>CO>[S:30]([OH:33])([OH:32])(=[O:31])=[O:29].[NH:8]1[CH2:11][CH:10]([NH:12][C:13]([CH2:14][NH:15][C:16](=[O:27])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[CH:18]=2)=[O:28])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)C1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Temperature: 20 °C

Procedure:
A 12-L 4-neck round bottom flask equipped with a thermocouple, a mechanical stirrer, a condenser, and a nitrogen inlet adapter was charged with Boc-protected intermediate 5 as prepared in the previous step (434 g; 1.08 mol) and methanol (3.5 L) and the solution was stirred at 20° C. under nitrogen. A solution of 9 M H2SO4 (140 mL; 1.26 mol) was added dropwise over 3 min, and then the mixture was warmed to 60° C. and stirred for 6 h. The reaction was cooled to 40° C. and NaHCO3 (420 g; 5.00 mol) was added as one portion and stirred at 12-16° C. for 1 h. The white solid was removed by filtration and washed with MeOH (200 mL×3) and then discarded after being checked by HPLC. The filtrate (total about 4.0 L) was concentrated at 50° C. under high vacuum (20 mmHg) and chased with MeOH (1 L) once to afford crude title compound, 6, as an off-white foamy solid, which was kept at 0° C. in the dark under N2 and used for futher reaction without additional purification. The structure of compound 6 was confirmed by 1H-NMR.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[N:7].[CH2:8]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)C(C)C)(C)C.[Cl-].[Na+]>CN(C)C=O.O>[CH2:16]([N:15]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[N:7])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N#CCCCCBr
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: N#CCCCCN(Cc1ccccc1)Cc1ccccc1
Temperature: 110 °C
Yield: 108.9 %

Procedure:
A solution of 5-bromopentanonitrile (16.20 g) in dry dimethylformamide (100 ml) was added dropwise over 15 minutes to a stirred solution of dibenzylamine (19.73 g) and N,N-diisopropylethylamine (35 ml, 26 g) in dry dimethylformamide (100 ml). The solution was heated (oil bath 110° C.) for 4 hours and was allowed to cool. The solution was poured onto a mixture of saturated aqueous sodium chloride (400 ml) and water (400 ml) and the mixture was extracted with ether (2×200 ml). The extracts were dried (Na2SO4) and concentrated in vacuo to give a mobile oil (30.32 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:11]1[S:12][C:13]([C:16]([OH:18])=[O:17])=[CH:14][N:15]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][Si](C=[N+]=[N-])(C)C.CCOCC>CO.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][CH:9]([C:11]1[S:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][N:15]=1)[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(NC(=O)OC(C)(C)C)c1ncc(C(=O)O)s1
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1cnc(C(C)NC(=O)OC(C)(C)C)s1
Temperature: 0 °C
Yield: 83 %

Procedure:
To a solution of 2-(1-(tert-butoxycarbonylamino)ethyl)thiazole-5-carboxylic acid (1.03 g, 3.8 mmol) in a mixture of MeOH (20 mL) and toluene (20 mL) cooled to 0° C. was added dropwise 2.0M trimethylsilyldiazomethane in ether (12 mL, 24 mmol). The resulting reaction mixture was warmed to room temperature overnight. Excess trimethylsilyldiazomethane was quenched with the addition of acetic acid and the solution concentrated to dryness. The residue was partitioned between EtOAc and saturated aqueous NaHCO3, the organic layer dried over anhydrous Mg2SO4 and concentrated to afford a yellow oil (0.90 g, 83%). LC-MS: (FA) ES+ 287.