Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.C(ON=O)(C)(C)C.[C:19](#[N:21])C>>[Br:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([C:19]#[N:21])=[N:3][CH:4]=1
Reactant: Nc1ncc(Br)cc1[N+](=O)[O-]
Reactant: CC#N
Agent: CC(C)(C)ON=O
Product: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Yield: 41 %

Procedure:
Heat a solution of 2-amino-5-bromo-3-nitropyridine (2.18 g, 10 mmol), cuprous cyanide (1.33 g, 15 mmol) and tert-butylnitrite (2.0 mL, 15 mmol) in acetonitrile (50 mL) to 60° C. for 2 hours. Cool the solution and partition between ethyl acetate (100 mL) and saturated aqueous NaHCO3 (100 mL). Extract the aqueous solution with ethyl acetate (2×50 mL), wash with water (100 mL), brine (100 mL), dry (MgSO4) and evaporate. Purify the solid by flash chromatography on silica gel (25% ether/75% hexane) to obtain the title compound as a pale yellow solid (934 mg, 41%).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[C:19]2[C:14](=[C:15]([O:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[C:16]([O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:17][CH:18]=2)[CH2:13][CH:12]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:11]=1)=O)(C)(C)C.[ClH:40]>O1CCOCC1>[ClH:40].[NH2:8][CH2:9][C:10]1[C:19]2[C:14](=[C:15]([O:27][C:28](=[O:33])[C:29]([CH3:30])([CH3:31])[CH3:32])[C:16]([O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:17][CH:18]=2)[CH2:13][CH:12]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:11]=1
Reactant: CC(C)(C)OC(=O)NCC1=CC(c2ccccc2)Cc2c1ccc(OC(=O)C(C)(C)C)c2OC(=O)C(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)C(=O)Oc1ccc2c(c1OC(=O)C(C)(C)C)CC(c1ccccc1)C=C2CN
Reaction time: 2 h
Yield: 90 %

Procedure:
N-t-Butyloxycarbonyl-1-aminomethyl-5,6-bis(trimethylacetoxy)-3,4-dihydro-3-phenyl naphthalene (14 g, 26 mmol), from Step 2, was dissolved in 75 mL of dioxane and saturated with anhydrous hydrogen chloride. The reaction mixture was stirred for 2 h and concentrated in vacuo. The solid residue was dissolved in a minimum amount of methanol and the methanol solution was added dropwise to an excess amount (500 mL) of diethyl ether. The precipitate was filtered, washed with diethyl ether and dried to give 9.1 g 90% yield) of 1-aminomethyl-5,6-bis(trimethylacetoxy)-3,4-dihydro-3-phenyl-naphthalene hydrochloride as a white powder, m.p. 210°-212° C. 1H NMR (d6DMSO) delta 1.25 (s, 9H), 1.28 (s, 9H), 2.61 (dd, 1H), 2.89 (dd, 1H), 3.75-3.85 (m, 1H), 3.99 (s, 2H), 6.28 (d, 2H), 7.15 (d, 1H), 7.2-7.35 (m, 5H), 7.37 (d, 1H), 8.37 (br s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][O:4][N:3]=1.Cl[C:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:9]>C1COCC1>[O:4]1[CH:5]=[CH:6][C:2]([NH:1][C:8](=[O:9])[O:10][C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[N:3]1
Reactant: Nc1ccon1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: O=C(Nc1ccon1)Oc1ccc([N+](=O)[O-])cc1

Procedure:
A solution of 3-amino isoxazole (220 uL, 2.973 mmol) and p-nitrophenyl chloroformate (659 mg, 3.271 mmol) in THF (8 mL) was stirred for 15 min at RT before the solution was concentrated in vacuo. The title compound was used immediately in the following reaction without further purification. MS (ESI, pos. ion) m/z: 250 (M+1). Mass calc'd for C10H7N3O5: 249.18.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][O:25][C:26]4[CH:39]=[CH:38][C:29]5[C@H:30]([CH2:33][C:34]([O:36]C)=[O:35])[CH2:31][O:32][C:28]=5[CH:27]=4)[CH:19]=3)=[C:13]([CH3:40])[CH:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[OH-].[Li+]>O1CCCC1.CO>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([O:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][O:25][C:26]4[CH:39]=[CH:38][C:29]5[C@H:30]([CH2:33][C:34]([OH:36])=[O:35])[CH2:31][O:32][C:28]=5[CH:27]=4)[CH:19]=3)=[C:13]([CH3:40])[CH:12]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OC5CCN(C(C)=O)CC5)cc4C)c3)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)N1CCC(Oc2cc(C)c(-c3cccc(COc4ccc5c(c4)OC[C@H]5CC(=O)O)c3)c(C)c2)CC1
Reaction time: 2 h
Yield: 75.5 %

Procedure:
(S)-Methyl 2-(6-((4′-((1-acetylpiperidin-4-yl)oxy)-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 6a (10 mg, 0.02 mmol) was dissolved in 2 mL of a mixture of the solvents tetrahydrofuran and methanol (V/V=1:1), followed by addition of 1M aqueous lithium hydroxide solution (0.2 mL, 0.20 mmol). The reaction solution was stirred for 2 hours. The resulting solution was concentrated under reduced pressure, 1M hydrochloric acid was added dropwise to adjust the pH to 5, and extracted with ethyl acetate (20 mL×2). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (S)-2-(6-((4′-((1-acetylpiperidin-4-yl)oxy)-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid 6 (8 mg, yield 84.2%) as a white solid.
Reaction SMILES: Br[C:2]1[C:3]2[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.C([Li])CCC.[Cl:17][CH2:18][C:19](N(OC)C)=[O:20]>O1CCCC1.CCOCC>[Cl:17][CH2:18][C:19]([C:6]1[S:5][C:4]2[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:3]=2[CH:2]=1)=[O:20]
Reactant: Fc1cccc2scc(Br)c12
Reactant: CON(C)C(=O)CCl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(CCl)c1cc2c(F)cccc2s1
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 15.4 %

Procedure:
A solution of 3-bromo-4-fluorobenzo[b]thiophene (0.76 g) in tetrahydrofuran (5 ml) was added dropwise under nitrogen at −60-−50° C. over 10 minutes to a stirred solution of n-butyllithium (2.5M solution in hexanes; 1.71 ml) in ether (40 ml), then the mixture was stirred at −50° C. for 30 minutes. A solution of 2-chloro-N-methoxy-N-methylacetamide (0.39 g) in tetrahydrofuran (10 ml) was added dropwise over 10 minutes, the mixture was stirred at −50° C. for 30 minutes and at 0° C. for 1 hour, then it was quenched by the addition of saturated aqueous ammonium chloride solution (30 ml). The organic layer was separated, washed with saturated aqueous sodium chloride solution (30 ml), dried (MgSO4) and the solvent was removed in vacuo. The residue was purified by flash chromatography over silica using a 10:1 mixture of petroleum ether (b.p. 60-80° C.) and ethyl acetate as eluant. Appropriate fractions were combined and the solvents removed in vacuo to give 2-chloro-1-(4-fluorobenzo[b]thiophen-2-yl]ethan-1-one (0.1 g) as a colourless solid which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:4]([N+:15]([O-])=O)[CH:3]=1.Cl[Sn]Cl>CCO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[C:4]([NH2:15])[CH:3]=1
Reactant: Cc1ccc(Sc2ccccc2)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Cc1ccc(Sc2ccccc2)c(N)c1
Yield: 55.4 %

Procedure:
A solution of the product from Example 1e (1.17 g, 7.0 mmol) in 25 mL of absolute EtOH and SnCl2 (3.58 g, 29.8 mmol) was stirred at room temperature for 16 h. Adjusted to pH 12 with 1N NaOH and extracted with EtOAc. Dried over Na2SO4, filtered and concentrated under vacuum giving the title compound (835 mg, 82%) 1H NMR (300 MHz, CDCl3) δ ppm: 2.30 (2, 3H) 6.62 (d, J=8.83 Hz, 1H) 6.69 (s, 1H) 7.10 (m, 3H) 7.21 (m, 2H) 7.54 (d, J=7.72 Hz, 2H).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C([Sn]([C:48]#[N:49])(CCCC)CCCC)CCC.Cl[C:51]1[CH:52]=[CH:53][CH:54]=[C:55]2[C:60]=1[N:59]=[C:58]([C:61]1[CH:66]=[C:65]([CH3:67])[CH:64]=[CH:63][N:62]=1)[C:57]([CH3:68])=[C:56]2[NH:69][C:70]1[C:71]([C:82]2[CH:83]=[N:84][CH:85]=[C:86]([O:88][CH3:89])[CH:87]=2)=[N:72][CH:73]=[C:74]([N:76]2[CH2:81][CH2:80][O:79][CH2:78][CH2:77]2)[CH:75]=1>CN1CCCC1=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:89][O:88][C:86]1[CH:87]=[C:82]([C:71]2[C:70]([NH:69][C:56]3[C:55]4[C:60](=[C:51]([C:48]#[N:49])[CH:52]=[CH:53][CH:54]=4)[N:59]=[C:58]([C:61]4[CH:66]=[C:65]([CH3:67])[CH:64]=[CH:63][N:62]=4)[C:57]=3[CH3:68])=[CH:75][C:74]([N:76]3[CH2:77][CH2:78][O:79][CH2:80][CH2:81]3)=[CH:73][N:72]=2)[CH:83]=[N:84][CH:85]=1
Reactant: CCCC[Sn](C#N)(CCCC)CCCC
Reactant: COc1cncc(-c2ncc(N3CCOCC3)cc2Nc2c(C)c(-c3cc(C)ccn3)nc3c(Cl)cccc23)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN1CCCC1=O
Product: COc1cncc(-c2ncc(N3CCOCC3)cc2Nc2c(C)c(-c3cc(C)ccn3)nc3c(C#N)cccc23)c1
Temperature: 100 °C
Reaction time: 21.5 h

Procedure:
To a stirred solution of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (1.9 mg, 4.05 μmol), tri-n-butyltin cyanide (8.00 mg, 0.025 mmol), 8-chloro-N-(5′-methoxy-5-morpholino-2,3′-bipyridin-3-yl)-3-methyl-2-(4-methylpyridin-2-yl)quinolin-4-amine (0.014 g, 0.025 mmol) in 1-methylpyrrolidin-2-one (2.0 mL) was added Pd2dba3 (0.927 mg, 1.01 μmol). The reaction mixture was heated to 100° C. and stirred for 21.5 h. The crude product was filtered through a plug of alumina eluting with EtOAc. The filtrate was cond in vacuo. The crude product was purified by column chromatography on alumina (0 to 50% EtOAc in hexanes) to give the desired product. The desired product was further purified with HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution). The desired fractions were cond then diluted with EtOAc. After washing twice with satd aq. sodium bicarbonate solution, the solvent was removed under reduced pressure to yield pure product 4-(5′-methoxy-5-morpholino-2,3′-bipyridin-3-ylamino)-3-methyl-2-(4-methylpyridin-2-yl)quinoline-8-carbonitrile. 1H NMR (400 MHz, CD2Cl2) δ ppm 8.53 (1H, d, J=5.1 Hz), 8.42 (1H, d, J=1.8 Hz), 8.30 (1H, d, J=2.7 Hz), 8.06-8.15 (2H, m), 7.97 (1H, s), 7.84 (1H, m), 7.56 (1H, dd, J=8.4, 7.2 Hz), 7.39 (1H, dd, J=2.8, 1.9 Hz), 7.24 (1H, m), 6.30 (1H, br. s.), 5.47 (1H, s), 3.90 (3H, s), 3.64 (4H, t, J=4.9 Hz), 3.25 (4H, br. s.), 2.50 (3H, s), 2.43 (3H, s). Mass Spectrum (ESI) m/e=544.2 (M+1).
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[C:40]([CH2:43][C:44]1[CH:52]=[CH:51][C:47]([C:48](Cl)=[O:49])=[CH:46][CH:45]=1)([OH:42])=[O:41]>>[C:40]([CH2:43][C:44]1[CH:52]=[CH:51][C:47]([C:48]([O:1][CH:2]2[CH2:20][CH:19]3[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]4[C:16]([C:22]([NH:24][S:25]([CH:28]5[CH2:30][CH2:29]5)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]3=[O:21])[CH2:15]4)[CH2:3]2)=[O:49])=[CH:46][CH:45]=1)([OH:42])=[O:41]
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Reactant: O=C(O)Cc1ccc(C(=O)Cl)cc1
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(OC(=O)c3ccc(CC(=O)O)cc3)CN2C1=O
Yield: 7 %

Procedure:
Prepared by way of method I using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.175 mmol) and 4-caboxymethylbenzoyl chloride (70 mg, 0.35 mmol). The final trituration (diethyl ether/hexane) and filtration gave 9.0 mg (7.0%) of 18-(4-carboxymethylbenzoyloxy)-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 99.9% pure (HPLC), MS m/z 729 (M−H)−, HRMS: calcd. 731.2962 and found 731.2957 (M+H)+, mp 154-156° C.
Reaction SMILES: [CH2:1]([C:3]1[C:7](I)=[C:6]([CH3:9])[N:5]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][OH:18])=[CH:12][CH:11]=2)[N:4]=1)[CH3:2].[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:1]([C:3]1[C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:6]([CH3:9])[N:5]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][OH:18])=[CH:12][CH:11]=2)[N:4]=1)[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CCc1nn(-c2ccc(CCO)cc2)c(C)c1I
Product: CCc1nn(-c2ccc(CCO)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 12 from 2-[4-(3-ethyl-4-iodo-5-methyl-1H-pyrazol-1-yl)phenyl]ethanol (step 2) and benzeneboronic acid: MS (EI) m/z 306 [M]+.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:18][CH2:19][CH:20]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][C:23]1[CH:24]=[C:25]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:26]=[CH:27][C:28]=1[CH3:29].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:22][C:23]1[CH:24]=[C:25]([N:30]2[CH2:31][CH2:32][N:33]([CH2:20][CH2:19][CH2:18][C:9]3[CH:10]=[C:11]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH2:34][CH2:35]2)[CH:26]=[CH:27][C:28]=1[CH3:29]
Reactant: Cc1ccc(N2CCNCC2)cc1C
Reactant: O=CCCc1cc(-c2ccccc2)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCN(CCCc3cc(-c4ccccc4)n(-c4ccccc4)n3)CC2)cc1C

Procedure:
Example 1 by using 3-(1,5-diphenyl-1H-pyrazol-3-yl)propanal (55 mg, 0.199 mmol), 1-(3,4-dimethylphenyl)piperazine (32 mg, 0.166 mmol), DIPEA (0.035 mL, 0.199 mmol) and NaBH(OAc)3 (148 mg, 0.697 mmol).
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Br[C:18]1[CH:19]=[C:20]([CH:23]=[O:24])[S:21][CH:22]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:18]2[CH:19]=[C:20]([CH:23]=[O:24])[S:21][CH:22]=2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=Cc1cc(Br)cs1
Reactant: CCCCCCOc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCCCOc1ccc(-c2csc(C=O)c2)cc1
Temperature: 25 °C
Yield: 52.7 %

Procedure:
A mixture of commercial available 4-(hexyloxy)phenylboronic acid (25, 5.55 g, 25.0 mmol), 4-bromothiophene-2-carbaldehyde (5.25 g, 27.5 mmol), tetrakis(triphenylphosphine)palladium(0) (0.6 g, 0.13 mmol), toluene (25 mL), ethanol (15 mL) and aqueous sodium carbonate (2 M, 25 mL) was stirred under reflux for 18 hours under a nitrogen atmosphere. The reaction mixture was cooled to ambient temperature and the aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic layers were washed with saturated sodium chloride (50 mL), and dried over magnesium sulfate. After filtration and concentration, the crude material was purified by recrystallization from ethyl acetate/petroleum ether (1/2, v/v) to afford the compound 1026 (3.8 g).
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[NH2:20])[CH2:8][CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2].N[C:22](N)=[O:23].C>C1(C)C=CC=CC=1>[C:1]([N:6]1[CH2:7][CH2:8][CH:9]([N:12]2[C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[NH:20][C:22]2=[O:23])[CH2:10][CH2:11]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)N1CCC(Nc2ccc(Cl)cc2N)CC1
Reactant: NC(N)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)CC1

Procedure:
A mixture of 24.7 g of 1-carbethoxy-4-(2-amino-4-chloroanilino)-piperidine and 7.2 g of urea was heated to 160°-180° C. for 3.5 hours. The melt was taken up in 250 ml of toluene and heated, while stirring, until everything had dissolved. The solution was clarified with active charcoal, filtered and concentrated to 50 ml. The product was precipitated with diisopropyl ether. Melting point: 160° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].C(=O)([O-])[O-].[K+].[K+].[CH3:22][CH2:23][CH2:24][CH2:25][CH2:26]Br>CN(C=O)C>[CH2:22]([O:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7])[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: COC(=O)c1ccc(O)cc1C(=O)OC
Reactant: CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCOc1ccc(C(=O)OC)c(C(=O)OC)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
Dimethyl 4-hydroxyphthalate (10.0 g, 47 mmol) was dissolved in DMF (100 ml), and potassium carbonate (30 g, 217 mmol) and n-amyl bromide (10 ml, 80 mmol) were added to this solution. The mixture was stirred at 90° C. for 2 hours, and the solid was removed by filtration through Celite. The filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (hexane/ethyl acetate=4/1) to give dimethyl 4-pentyloxyphthalate (12.7 g, 45.4 mmol, 97%) as a colorless oil.
Reaction SMILES: [NH:1]1[C@@H:9]2[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][C@H:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C(N(C(C)C)CC)(C)C.[Br:29][C@H:30]([CH3:34])[C:31](Cl)=[O:32]>ClCCl>[Br:29][C@H:30]([CH3:34])[C:31]([N:1]1[C@@H:9]2[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][C@H:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:32]
Reactant: C[C@@H](Br)C(=O)Cl
Reactant: O=C(OCc1ccccc1)[C@@H]1C[C@@H]2CCCC[C@@H]2N1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](Br)C(=O)N1[C@H](C(=O)OCc2ccccc2)C[C@@H]2CCCC[C@@H]21
Reaction time: 1 h

Procedure:
Introduce 200 g of benzyl (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylate and 1.5 liters of dichloromethane into a reactor, then bring the temperature of the reaction mixture to 0° C. and add 201 ml of diisopropylethylamine followed by 132 g of (2R)-2-bromo-propionyl chloride. Subsequently, bring the mixture to ambient temperature. After stirring for 1 hour at that temperature, wash the mixture with water and then with a dilute acetic acid solution. The benzyl (2S,3aS,7aS)-1-[(2R)-2-bromopropionyl]octahydro-1H-indole-2-carboxylate solution so obtained is used as it is in the following Step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:13]([CH2:18][C:19]2[N:20]=[N:21][N:22]([CH3:24])[N:23]=2)[C:14]([O:16]C)=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.O.[OH-].[Li+].Cl>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@H:13]([CH2:18][C:19]2[N:20]=[N:21][N:22]([CH3:24])[N:23]=2)[C:14]([OH:16])=[O:15])(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: COC(=O)[C@@H](Cc1nnn(C)n1)N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)[C@H](Cc2nnn(C)n2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
Methyl 2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-2-[(2-methyl-5-tetrazolyl)methyl]acetate (1.0 g, 2.27 mmol) is dissolved in tetrahydrofuran (11.3 mL) and water (11.3 mL). To this solution is added lithium hydroxide hydrate (0.095 g, 2.27 mmol), and the reaction is stirred at room temperature for 2 hours. The reaction is then acidified to pH=~3 using 1N hydrochloric acid, and extracted well with ethyl acetate. The combined organic extracts are washed with brine, dried (Na2SO4), and the solvent is evaporated to provide 2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-2-[(2-methyl-5-tetrazolyl)methyl]acetic acid (0.96 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].[C:23]([C:25]1[CH:29]=[CH:28][S:27][C:26]=1[C:30]1[O:35]C(C)(C)[O:33][C:32](=O)[CH:31]=1)#[N:24]>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:21][C:32](=[O:33])[CH2:31][C:30]([C:26]1[S:27][CH:28]=[CH:29][C:25]=1[C:23]#[N:24])=[O:35])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2sccc2C#N)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)CC(=O)c1sccc1C#N
Yield: 52.3 %

Procedure:
Prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G39) (302 mg, 1.0 mmol) and 6-(3-cyano-thiophen-2-yl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J3) (250 mg, 1.06 mmol) according to the general procedure K. Obtained as alight yellow solid (251 mg).
Reaction SMILES: N1(C(N2C=CN=C2)=O)C=CN=C1.[C:13]([OH:17])(=O)[C:14]#[CH:15].[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C:26](=[O:39])[CH2:27][C:28]1[NH:32][C:31]2[CH2:33][CH:34]([CH3:38])[CH2:35][CH:36]([CH3:37])[C:30]=2[N:29]=1>C1COCC1>[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C:26]([C:27]1[CH:15]=[CH:14][C:13](=[O:17])[N:32]2[C:31]3[CH2:33][CH:34]([CH3:38])[CH2:35][CH:36]([CH3:37])[C:30]=3[NH:29][C:28]=12)=[O:39]
Reactant: CC1Cc2[nH]c(CC(=O)c3ccc(F)cc3F)nc2C(C)C1
Reactant: C#CC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC1Cc2c([nH]c3c(C(=O)c4ccc(F)cc4F)ccc(=O)n23)C(C)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
126.8 mg (0.78 mmol) of 1-(1H-imidazol-1-ylcarbonyl)-1H-imidazole and 45.5 mg (0.65 mmol) of propiolic acid are dissolved in 8 ml THF. The mixture is stirred for 3 h at rt. To this solution 131.7 mg (0.43 mmol) of 1-(2,4-Difluorophenyl)-2-(4,6-dimethyl-4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)ethanone (example X) are added and the mixture is stirred for 20 h at rt. The solvent is evaporated under vacuum and the crude is purified over preparative HPLC (RP18-column, eluent: acetonitrile-water-gradient. The isomers are isolated after purification over preparative HPLC (Daicel Chiralpak AD, eluent: iso-hexane-ethanol v/v 30:70):
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]1[CH:6]=[CH:7][C:8]2[O:14][C:12](=[O:13])[NH:11][C:9]=2[CH:10]=1.[Cl:15][CH2:16][CH2:17][C:18](Cl)=[O:19]>CN(C)C=O>[Cl:15][CH2:16][CH2:17][C:18]([C:6]1[CH:5]=[CH:10][C:9]2[NH:11][C:12](=[O:13])[O:14][C:8]=2[CH:7]=1)=[O:19]
Reactant: O=c1[nH]c2ccccc2o1
Reactant: O=C(Cl)CCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: O=C(CCCl)c1ccc2[nH]c(=O)oc2c1

Procedure:
56.1 g (0.42 mole) of aluminum chloride are weighed into a ground-necked flask, 10 cm3 of dimethylformamide are then added using a dropping funnel and the mixture is left stirring until it becomes homogeneous. 8.1 g (0.06 mole) of benzoxazolinone are then added and the mixture is left stirring for 10 minutes before adding (0.072 mole) of 3-chloropropionic acid chloride. This mixture is maintained in an oil bath at 80°-85° C. for approximately 2 hours 30 minutes. After cooling, the reaction mixture is poured into ice-cold water. The precipitate is drained and washed with water to neutrality. The product is recrystallized in ethanol.