Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[C:10]([CH:11]([F:13])[F:12])=[CH:9][C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH3:22])[CH:15]=3)=[N:7][C:6]=12.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25]>>[F:12][CH:11]([F:13])[C:10]1[N:5]2[N:4]=[CH:3][C:2]([C:28]#[C:27][Si:24]([CH3:26])([CH3:25])[CH3:23])=[C:6]2[N:7]=[C:8]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH3:22])[CH:15]=2)[CH:9]=1
Reactant: C#C[Si](C)(C)C
Reactant: CCOc1cccc(-c2cc(C(F)F)n3ncc(Br)c3n2)c1
Product: CCOc1cccc(-c2cc(C(F)F)n3ncc(C#C[Si](C)(C)C)c3n2)c1
Yield: 96.1 %

Procedure:
Prepared from 3-bromo-7-difluoromethyl-5-(3-ethoxy-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.19 step 3a) (20.0 g, 54 mmol) and commercially available trimethylsilylacetylene (15 mL, 109 mmol) as described in example C. 1 step 3a to give the title compound (20 g, 95%) as alight brown solid. MS (ISP) 386 [(M+H)+].
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][O:10][C:6]=2[CH:5]=[C:4]2[NH:11][C:12](=[O:22])[N:13]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[F:21])[C:3]=12.C(N(CC)CC)C.[CH:30]1([S:33](Cl)(=[O:35])=[O:34])[CH2:32][CH2:31]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:30]1([S:33]([N:11]2[C:4]3=[CH:5][C:6]4[O:10][CH:9]=[N:8][C:7]=4[C:2]([F:1])=[C:3]3[N:13]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[F:21])[C:12]2=[O:22])(=[O:35])=[O:34])[CH2:32][CH2:31]1
Reactant: O=c1[nH]c2cc3ocnc3c(F)c2n1-c1ccc(I)cc1F
Reactant: O=S(=O)(Cl)C1CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1n(-c2ccc(I)cc2F)c2c(F)c3ncoc3cc2n1S(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 110.5 %

Procedure:
To a solution of 4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d]oxazol-6(7H)-one (30 mg, 0.07 mmol) in CH2Cl2 (3 mL) was added triethylamine (22 mg, 0.22 mmol) at 0° C. followed by cyclopropanesulfonyl chloride (16 mg, 0.11 mmol) and DMAP (5 mg). The mixture was stirred at room temperature for 1 h and washed with saturated NaHCO3 (aq.). The aqueous layer was extracted with CH2Cl2 (10 mL×2). The combined organic phase was washed with water (10 mL) and brine (10 mL) successively, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v) to give the corresponding product (40 mg, 100% yield). 1H NMR (400 MHz, CDCl3): δ 8.09 (s, 1H), 7.99 (s, 1H), 7.39-7.11 (d, 2H), 7.05, (m, 1H), 3.40 (m, 1H), 1.71 (m, 2H), 0.91-0.85 (m, 2H).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH:3]=[CH2:4].[S:6](Cl)([C:9]1[CH:15]=[CH:14][C:12]([CH3:13])=[CH:11][CH:10]=1)(=[O:8])=[O:7]>N1C=CC=CC=1>[CH2:1]([OH:5])[CH2:2][CH:3]=[CH2:4].[CH3:13][C:12]1[CH:14]=[CH:15][C:9]([S:6]([O-:5])(=[O:8])=[O:7])=[CH:10][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: C=CCCO
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 141.3 %

Procedure:
A solution of 3 g (42 mmol) 3-buten-1-ol in 10 mL dry pyridine was cooled in an ice bath. Tosyl chloride (7.9 g, 42 mmol), was added. After stirring for 3 h the mixture was poured into 30 mL of an ice/concentrated HCl 4/1 v/v solution, extracted with 60 mL diethyl ether and dried overnight in the freezer over MgSO4. The mixture was filtered and the ether evaporated to yield 7.22 g (76%) of 3-buten-1-ol 4-methylbenzene sulfonate as a yellow oil. 1H NMR (CDCl3): δ 2.39-2.53 (m, 2H, J=6.5 and 6.9 Hz, CH2—CH═CH2; and s, 3H, CH3—Ar), 4.08 (t, J=6.5 Hz, 2H, CH2OSO2), 5.09-5.15 (m, 2H, JZ=10.4, JE=16.6, Jgem=3.1 Hz, CH2—CH═CH2), 5.57-5.82 (m, 1H, JZ=10.4, JE=16.6, J=6.9 Hz, CH2—CH═CH2), 7.38 and 7.72 (d, 4H, J=8.6 Hz, Ar).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([NH:26][C:27]([C:29]2[N:33]3[C@@:34]([CH2:47][C:48]4[CH:53]=[CH:52][C:51]([C:54]#[N:55])=[CH:50][CH:49]=4)([CH3:46])[C:35](=[O:45])[N:36]([C:37]4[CH:42]=[C:41]([Cl:43])[CH:40]=[C:39]([Cl:44])[CH:38]=4)[C:32]3=[N:31][CH:30]=2)=[O:28])([C:14](=[O:25])[NH:15][C:16]2([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:16]1([NH:15][C:14]([C:11]2([NH:26][C:27]([C:29]3[N:33]4[C@@:34]([CH2:47][C:48]5[CH:53]=[CH:52][C:51]([C:54]#[N:55])=[CH:50][CH:49]=5)([CH3:46])[C:35](=[O:45])[N:36]([C:37]5[CH:42]=[C:41]([Cl:43])[CH:40]=[C:39]([Cl:44])[CH:38]=5)[C:32]4=[N:31][CH:30]=3)=[O:28])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:25])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cnc3n2[C@](C)(Cc2ccc(C#N)cc2)C(=O)N3c2cc(Cl)cc(Cl)c2)(C(=O)NC2(c3ccccn3)CC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)NC4(c5ccccn5)CC4)CCNCC3)n21
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
To a solution of 4-{[(R)-5-(4-cyanobenzyl)-7-(3,5-dichlorophenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-4-(1-pyridin-2-yl-cyclopropyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (140 mg, 0.18 mmol) in CH2Cl2 (0.5 mL) was added TFA (0.5 mL) and stirred at room temperature for 1 h. The solvent was removed in vacuo to afford (R)-5-(4-cyanobenzyl)-7-(3,5-dichlorophenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid [4-(1-pyridin-2-yl-cyclopropylcarbamoyl)-piperidin-4-yl]-amide as a white solid (120 mg), m/z 683.8 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:18](O)=[O:19])[C:15]([O:16][CH3:17])=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.Cl.[CH3:24][NH:25][OH:26]>>[F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:18]([N:25]([OH:26])[CH3:24])=[O:19])[C:15]([O:16][CH3:17])=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1
Reactant: CNO
Reactant: COc1c(C(=O)O)ncc2c1ccn2Cc1ccc(F)cc1
Agent: Cl
Product: COc1c(C(=O)N(C)O)ncc2c1ccn2Cc1ccc(F)cc1

Procedure:
The title compound was prepared by coupling of 1-(4-fluorobenzyl)-4-methoxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid with N-methyl hydroxylamine hydrochloride in a manner similar to step 8 of example 1. 1H NMR (DMSO-d6) 6; 9.70 (s, 1H), 8.50 (s, 1H), 7.76 (s, 1H), 7.33 (m, 2H), 7.16 (d, 2H, J=8.9 Hz), 6.76 (s, 1H), 5.51 (s, 2H), 4.00 (s, 3H), 2.96 (s, 3H). LCMS (APCI, M+H+): 330.1. HRMS calcd for C17H17FN3O3 (M+H) 330.1249, found 330.1250. HPLC: 98% purity.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:10]([O:18]C)=[N:11][C:12]([CH3:17])=[CH:13][C:14]=1[O:15][CH3:16])(C)(C)C>Cl.O.CCO>[NH2:7][CH2:8][C:9]1[C:10]([OH:18])=[N:11][C:12]([CH3:17])=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: COc1cc(C)nc(OC)c1CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cc(C)nc(O)c1CN
Yield: 63 %

Procedure:
tert-butyl((2,4-dimethoxy-6-methylpyridin-3-yl)methyl)carbamate (83 g, 294 mmol) was dissolved in 4 N HCl/H2O (830 ml). Then the mixture was refluxed for 4.5 h. (The reaction mixture was monitored by MS spectrum to make sure the methyl group at 2-position de-protect completely.) After the reaction completed, the mixture was concentrated under vacuum to give a brown oil. The oil was suspended in EtOH (300 ml) for 15 min to give a yellow precipitate. The precipitate was filtered, washed with ethanol (100 ml) and MTBE (100 ml) and dried under high vacuum to give 38 g of fraction 1 3-(aminomethyl)-4-methoxy-6-methylpyridin-2-ol (Purity 98% by LCMS, yield 63%) as a yellow powder. In the meantime, the filtration from fraction 1 was concentrated under vacuum and the residue was solidified by ethanol (100 ml). The precipitate was filtered, washed with ethanol (100 ml) and MTBE (100 ml) and dried under high vacuum to give 20 g of fraction 2 3-(aminomethyl)-4-methoxy-6-methylpyridin-2-ol (Purity 94% by LCMS, yield 33%) as a yellow powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:16][C:10]2[S:11][C:12](C=O)=[CH:13][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl.[NH2:18][OH:19].C(O)C.CCOC(C)=O>O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:16][C:10]2[S:11][C:12](=[N:18][OH:19])[CH2:13][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: NO
Reactant: CCOC(=O)C1CCc2cc(C=O)sc2C1
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCC2=C(C1)SC(=NO)C2
Yield: 56.7 %

Procedure:
A mixture of 6-ethoxycarbonyl-2-formyl-4,5,6,7-tetrahydrobenzo[b]thiophene (3.23 g), hydroxylamine hydrochloride (0.92 g), and ethanol (EtOH) (30 ml) was stirred at reflux for 30 minutes. The reaction mixture was added into a mixture of AcOEt and water. The separated organic layer was washed with water, and brine, and dried over MgSO4. After evaporation of the filtrate, the resulting precipitate was washed with a mixture of n-hexane and isopropyl ether to give 6-ethoxycarbonyl-2-hydroxyimino-4,5,6,7-tetrahydrobenzo[b]thiophene (1.81 g).
Reaction SMILES: C([O:4][CH2:5][C:6]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])([NH:12][C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17])[CH2:7][O:8]C(=O)C)(=O)C.C[O-].[Na+].CO.Cl.CO>CO>[CH2:19]([C:6]([NH:12][C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17])([CH2:7][OH:8])[CH2:5][OH:4])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCCCCCCCCCCC(COC(C)=O)(COC(C)=O)NC(=O)CCCC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCC(CO)(CO)NC(=O)CCCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1,3-Diacetoxy-2-octadecyl-2-(N-pentanoylamino)propane (400 mg) was dissolved in 8 ml of methanol and 17 mg of a 28% sodium methoxide-methanol solution was added thereto. The mixture was stirred at room temperature for 1 hour. Concentrated hydrochloric acid-methanol (1:11, 0.088 ml) was added thereto and the mixture was concentrated. The concentrate was subjected to silica gel column chromatography using chloroform-methanol (30:1) as an eluent. The resultant crystals were recrystallized from chloroform-hexane to give 312 mg of colorless, crystalline 2-octadecyl-2-(N-pentanoylamino)-1,3-propanediol.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[CH2:16](O)C.N1(CO)C2C=CC=CC=2N=N1.[BH4-].[Na+]>C(OCC)(=O)C>[CH3:16][NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13]
Reactant: CCO
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Agent: OCn1nnc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CN[C@@H]1CCCC[C@@H]1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a mixture of tert-butyl [(1S,2R)-2-aminocyclohexyl]carbamate (500 mg) and ethanol (10 mL) was added 1H-benzotriazol-1-yl methanol (350 mg), followed by stirring at room temperature for 7 hours. Sodium borohydride (180 mg) was added thereto under ice-cooling, followed by stirring at room temperature for 15 hours. To the reactant were added ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution, followed by liquid separation. The organic phase was dried over anhydrous magnesium sulfate and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=1:0:0-190:9:1) to obtain tert-butyl [(1S,2R)-2-(methylamino)cyclohexyl]carbamate (174 mg) as a pale yellow oily material.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH3:35][O:34][C:31]1[CH:30]=[CH:29][C:28]([S:25]([C:6]2([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:15][CH:14]=3)[CH2:8][CH2:7]2)(=[O:27])=[O:26])=[CH:33][CH:32]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2ccc(-c3ccccn3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(-c4ccccn4)cc3)CC2)cc1

Procedure:
4-(4-Methoxy-benzenesulfonyl)-1-(4-pyridin-2-yl-benzyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-methoxy-benzenesulfonyl)-1-(4-pyridin-2-yl-benzyl)-piperidine-4- carboxylic acid ethyl ester (1.83 g, 3.7 mmol) dissolved in THF:methanol (3:1 150 ml) and 10N NaOH (10 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.38 g (80%); off white solid; mp 217° C.; MS: 466.9 (M+H)+
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:13]=1[C:21]([F:24])([F:23])[F:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[Cl-]>CO.[Zn]>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=1[C:21]([F:22])([F:23])[F:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(OCCOCc2ccccc2)c(C(F)(F)F)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: Nc1ccc(OCCOCc2ccccc2)c(C(F)(F)F)c1
Temperature: 20 °C
Reaction time: 3 h
Yield: 60.7 %

Procedure:
To a mixture of 1-(2-(benzyloxy)ethoxy)-4-nitro-2-(trifluoromethyl)benzene (8.1 g, 23.73 mmol) in MeOH (100 mL) was added zinc (15.52 g, 237 mmol) and NH4Cl (12.70 g, 237 mmol). The mixture was stirred at 20° C. for 3 h. LCMS showed the reaction was finished. The mixture was filtered, and the filtrate was concentrated to give crude product, which was purified by silica gel column (PE/EA=5:1, Rf=0.4) to obtain 4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)aniline (5.1 g, 14.40 mmol, 60.7% yield). 1H NMR (400 MHz, CDCl3) 7.35-7.24 (m, 5H), 6.81 (t, J=8.4 Hz, 2H), 6.78 (d, J=2.8 Hz, 1H), 4.63 (s, 2H), 4.13 (t, J=4.8 Hz, 2H), 3.83 (t, J=3.6 Hz, 2H); ES-LCMS m/z 312 (M+H).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:29]=[C:30]([S:35]([NH2:38])(=[O:37])=[O:36])[CH:31]=[CH:32][C:33]=1[Cl:34]>>[Cl:34][C:33]1[CH:32]=[CH:31][C:30]([S:35](=[O:36])(=[O:37])[NH2:38])=[CH:29][C:28]=1[NH:27][C:12]([C:11]1[CH:10]=[N:9][N:8]2[C:3]([C:2]([F:26])([F:1])[F:25])=[CH:4][C:5]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:17][CH:16]=3)=[N:6][C:7]=12)=[O:13]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1cc(S(N)(=O)=O)ccc1Cl
Product: NS(=O)(=O)c1ccc(Cl)c(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-amino-4-chloro-benzenesulfonamide [CAS-No. 29092-34-0; commercially available] according to general procedure II. Light yellow solid. MS (ISP) 563.1 [(M−H−]; mp 300° C.
Reaction SMILES: C([C:4]1[N:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]=1C(O)=O)(O)=O>N1C2C(=CC=CC=2)C=CC=1>[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[N:5]1[CH:4]=[CH:8][C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6]1
Reactant: COc1ccccc1-n1cc(-c2ccccc2)c(C(=O)O)c1C(=O)O
Solvent: c1ccc2ncccc2c1
Product: COc1ccccc1-n1ccc(-c2ccccc2)c1
Yield: 45.1 %

Procedure:
4.8 g of 2,3-dicarboxy-1-(2-methoxyphenyl)-4-phenyl-pyrrole and 2 g of Cu powder are heated for 2 hours to about 200° C. in 50 ml of quinoline. After cooling the Cu powder is filtered off. The filtrate is diluted with water, acidified with dilute aqueous HCl solution and extracted with ethyl acetate. The organic phase is washed successively with dilute, aqueous HCl solution, NaHCO3 solution and water and then dried. After the solvent has been distilled off in vacuo the remaining product is purified by chromatography on silica gel (cyclohexane:ethyl acetate 95:5). 1.6 g of 1-(2-methoxyphenyl)-3-phenyl-pyrrole are obtained in the form of a colourless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:23]3[O:22][C:21]([C:24]([O-])=[O:25])=[CH:20][C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.[Li+].[O:28]1[C:32]2[CH:33]=[CH:34][C:35]([CH2:37][NH2:38])=[CH:36][C:31]=2[O:30][CH2:29]1>>[O:28]1[C:32]2[CH:33]=[CH:34][C:35]([CH2:37][NH:38][C:24]([C:21]3[O:22][C:23]4[C:15]([N:12]5[CH2:13][CH2:14][N:9]([CH2:8][CH2:7][C:2]6[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=6)[CH2:10][CH2:11]5)=[CH:16][CH:17]=[CH:18][C:19]=4[CH:20]=3)=[O:25])=[CH:36][C:31]=2[O:30][CH2:29]1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: O=C([O-])c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1
Agent: [Li+]
Product: O=C(NCc1ccc2c(c1)OCO2)c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1

Procedure:
The compound was prepared according to the procedure disclosed in Example 1 starting from lithium 7-(4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxylate (80 mg, 0.21 mmol) and benzo[d][1,3]dioxol-5-ylmethaneamine (41 mg, 0.27 mmol). Yield: 78 mg (72%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:11]([CH2:32][CH:33]([CH3:35])[CH3:34])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)=[CH:17][C:16]([O:27][CH2:28][C:29](O)=[O:30])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N(OC(ON2C(=O)CCC2=O)=O)C(=O)C1.[CH3:54][S:55]([NH2:58])(=[O:57])=[O:56].C1CCN2C(=NCCC2)CC1>CN(C)C=O.O>[CH2:32]([C:11]1[C:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[C:19]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:27][CH2:28][C:29]([NH:58][S:55]([CH3:54])(=[O:57])=[O:56])=[O:30])[CH:17]=2)[N:12]=1)[CH:33]([CH3:35])[CH3:34]
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(OCC(=O)O)cc23)cc1
Reactant: CS(N)(=O)=O
Agent: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(OCC(=O)NS(C)(=O)=O)cc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
To a solution of {[3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]oxy}acetic acid (0.25 g, 0.52 mmol) in N,N-dimethylformamide (5 ml) was added di(N-succinimidyl) carbonate (0.42 g, 2.6 mmol), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture were added methanesulfonamide (0.25 g, 2.6 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene (0.40 ml, 2.6 mmol), and the mixture was stirred at 100° C. for 5 hrs. The reaction mixture was cooled to room temperature and water was poured thereinto. The mixture was extracted with ethyl acetate and the extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was crystallized from n-hexane-diisopropyl ether to give tert-butyl [(2-isobutyl-4-(4-methylphenyl)-6-{2-[(methylsulfonyl)amino]-2-oxoethoxy}quinolin-3-yl)methyl]carbamate (0.29 g, yield 98%) as pale-yellow crystals.
Reaction SMILES: [NH2:1][C@H:2]([CH2:24][CH3:25])[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[CH2:18][O:17][C:16]3([CH3:23])[CH3:22])=[CH:10][CH:11]=1)=[O:4].[C:26](=O)(OC(Cl)(Cl)Cl)[O:27]C(Cl)(Cl)Cl>C(Cl)Cl>[CH3:23][C:16]1([CH3:22])[C:15]2[C:19](=[CH:20][CH:21]=[C:13]([O:12][C:9]3[N:8]=[CH:7][C:6]([N:5]4[C:3](=[O:4])[C@@H:2]([CH2:24][CH3:25])[NH:1][C:26]4=[O:27])=[CH:11][CH:10]=3)[CH:14]=2)[CH2:18][O:17]1
Reactant: CC[C@@H](N)C(=O)Nc1ccc(Oc2ccc3c(c2)C(C)(C)OC3)nc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC[C@H]1NC(=O)N(c2ccc(Oc3ccc4c(c3)C(C)(C)OC4)nc2)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 167.5 %

Procedure:
To a solution of (2R)-2-amino-N-[6-[(3,3-dimethyl-1H-isobenzofuran-5-yl)oxy]-3-pyridyl]butanamide (Intermediate 61, 18 mg, 0.0527 mmol) in DCM (4 mL) N,N-diethylethanamine (0.022 ml, 0.16 mmol) was added and the reaction mixture was cooled to 0° C. A solution of bis(trichloromethyl) carbonate (7.8 mg, 0.026 mmol) in DCM (1 mL) was slowly added and the reaction mixture was stirred for 30 minutes at the same temperature. The reaction was diluted with DCM (5 ml) and washed with an aqueous saturated solution of NH4Cl (10 ml). The organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a SNAP 10 g as column and cyclohexane/ethyl acetate from 80:20 to 10:90 as eluent affording the title compound (16 mg) as white solid.
Reaction SMILES: [CH:1]1[NH:2][CH:3]=[CH:4][C:5]2[C:9]=1[C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:6]=2.[H][H]>[Pd].CO>[CH2:1]1[C:9]2[C:5]([CH:6]=[CH:7][C:8]=2[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH2:3][NH:2]1
Reactant: [H][H]
Reactant: COC(=O)c1ccc2cc[nH]cc1-2
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1=C2CNCC=C2C=C1
Yield: 53.1 %

Procedure:
A hydrogenation bottle is charged with 2-pyrindine-7-carboxylic acid, methyl ester (0.8 g, 4.57 mmol), 5% Pd on carbon (2.0 g, wet) and methanol (125 ml). The slurry is hydrogenated (40 psi) until hydrogen uptake stops. The reaction mixture is filtered through celite and then evaporated to dryness to provide the product (430 mg) in 53% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@@H:10]([N:15]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([NH:29]CC4C=CC(OC)=CC=4)[N:24]=3)[C:16]2=[O:39])[CH2:11][C:12]([OH:14])=[O:13])[CH:7]=[N:8][CH:9]=1)[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[NH2:29][C:25]1[N:24]=[C:23]([CH2:22][CH2:21][CH2:20][N:17]2[CH2:18][CH2:19][N:15]([C@H:10]([C:6]3[CH:7]=[N:8][CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)[CH2:11][C:12]([OH:14])=[O:13])[C:16]2=[O:39])[CH:28]=[CH:27][CH:26]=1
Reactant: CCOc1cncc([C@H](CC(=O)O)N2CCN(CCCc3cccc(NCc4ccc(OC)cc4)n3)C2=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cncc([C@H](CC(=O)O)N2CCN(CCCc3cccc(N)n3)C2=O)c1
Temperature: 85 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 20-13 (0.031 g, 0.052 mmol) in dichloromethane (10 mL) was added TFA (1 mL). The solution was stirred for 16 hours at 85° C. after which the solvent was removed in vacuo and azeotroped twice with toluene (15 mL). The residue was chromatographed (silica gel, 15:10:1:1 followed by 10:10:1:1 ethyl acetate/EtOH/water/NH4OH) to give 20-14 as a white solid.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]3)[C:11]2=[O:21])=[CH:6][CH:5]=1.[CH3:24][C:25]([CH3:31])([CH3:30])[CH2:26][C:27](Cl)=[O:28]>>[CH3:24][C:25]([CH3:31])([CH3:30])[CH2:26][C:27]([N:17]1[CH2:18][CH2:19][C:12]2([C:11](=[O:21])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([CH2:3][C:2]([F:1])([F:22])[F:23])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:15][C:16]1=[O:20])=[O:28]
Reactant: O=C1CC2(CCN1)CCN(c1ccc(CC(F)(F)F)cc1)C2=O
Reactant: CC(C)(C)CC(=O)Cl
Product: CC(C)(C)CC(=O)N1CCC2(CCN(c3ccc(CC(F)(F)F)cc3)C2=O)CC1=O

Procedure:
This material was prepared as a white solid in analogy to example 3) from 2-(4-(2,2,2-trifluoroethyl)phenyl)-2,8-diazaspiro[4.5]decane-1,7-dione, product of example 10 step A), and 3,3-dimethyl-butyryl chloride. MS (ESI): 425.2 (MH+).