Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH2:8][CH:7](C(OC)=O)[C:6](=[O:13])[CH2:5][CH2:4]1)#[N:2].CS(C)=O.CCOC(C)=O.CCCCCCC>[Cl-].[Na+].O.O>[CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[C:3]1([C:1]#[N:2])[CH2:4][CH2:5][C:6](=[O:13])[CH2:7][CH2:8]1
Reactant: COC(=O)C1CC(C#N)(c2ccc3ccccc3c2)CCC1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: N#CC1(c2ccc3ccccc3c2)CCC(=O)CC1
Temperature: 135 °C
Reaction time: 12 h
Yield: 63.5 %

Procedure:
A 12-L, four-neck flask equipped with a temperature probe, reflux condenser and overhead stirrer was charged with methyl 5-cyano-5-(naphthalen-2-yl)-2-oxocyclohexanecarboxylate (600 g, 1.9 mol), brine (1 L) and DMSO (6 L). The mixture was heated to 135° C. and stirred for 12 h. The progress of the reaction was monitored by TLC (2:3 EtOAc/Heptane). After 12 h, the reaction mixture was cooled to room temperature, diluted with water (6 L) and extracted twice with MTBE (5 L, 3 L). The combined organic phases were washed with brine (4×3 L), dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure at 40-45° C. to give a residue which was triturated with heptane/MTBE (1:1, 2 L). The resulting slurry was stirred for 2 h, filtered and dried under high vacuum for 12 h to yield the title compound (301 g, 62%) as an off-white solid. 1H NMR (DMSO-d6, 300 MHz): 6 8.1 (s, 1H), 8.0-7.9 (m, 4H), 7.8 (dd, 1H), 7.6 (m, 2H), 7.3 (dd, 1H), 7.2 (m, 1H), 3.1 (s, 1H), 2.8 (m, 2H), 2.2-2.6 (m, 8H), 1.2(s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:9]2[C:8]3[CH:19]=[CH:20][C:21]([O:23]C)=[CH:22][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1.Cl.[NH+]1C=CC=CC=1>O>[NH2:1][C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:9]2[C:8]3[CH:19]=[CH:20][C:21]([OH:23])=[CH:22][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: COc1ccc2c(ccc3nc(N)c(Cc4ccccc4)nc32)c1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: O
Product: Nc1nc2ccc3cc(O)ccc3c2nc1Cc1ccccc1
Temperature: 190 °C
Reaction time: 0.5 h
Yield: 46.5 %

Procedure:
A mixture of 3-amino-2-benzyl-8-methoxybenzo[f]quinoxaline (12) (125 mg, 396 μmol) and pyridinium hydrochloride (2.50 g, 21.6 mmol) was stirred at 190° C. (oil bath temperature) for 30 minutes and at 210° C. (oil bath temperature) for further 30 minutes. After cooling to room temperature, to the mixture was added water, the product was extracted with ethyl acetate (×3). The combined organic extract was washed successively with water (×1) and brine (×1), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate=1/1→1/10) to give 3-amino-2-benzylbenzo[f]quinoxalin-8-ol (14, v-coelenteramine) (55.5 mg, 184 μmol, 46.5%) as an ocherous solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1F.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(F)c(N2CCOCC2)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 117 %

Procedure:
A mixture of 1,2,4-trifluoro-5-nitrobenzene (4.0 mL, 35 mmol), morpholine (3.1 mL, 35 mmol), and K2CO3 (4.8 g, 35 mmol) in DMSO (35 mL) was stirred at room temperature overnight. The mixture was diluted with AcOEt and washed with water and brine. The organic layer was dried over MgSO4, and concentrated under reduced pressure. The residue was recrystallized from AcOEt to give the title compound (10 g, 63% yield) as a pale yellow solid: 1H NMR (300 MHz, DMSO-d6): δ ppm 3.15-3.49 (4H, m), 3.50-3.90 (4H, m), 7.13 (1H, dd, J=14.3, 7.5 Hz), 8.01 (1H, dd, J=13.6, 7.5 Hz). LC-MS (ESI) m/z 245 [M+H]+.
Reaction SMILES: F[C:2]1[C:11]2[O:10][CH:9]([CH2:12][NH2:13])[CH2:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.CN1C2C=CC=CC=2OC([C:25]([NH2:27])=[O:26])C1>>[C:25]([C:2]1[C:11]2[O:10][CH:9]([CH2:12][NH2:13])[CH2:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:26])[NH2:27]
Reactant: NCC1CNc2cccc(F)c2O1
Reactant: CN1CC(C(N)=O)Oc2ccccc21
Product: NCC1CNc2cccc(C(N)=O)c2O1

Procedure:
This compound is obtained following the same experimental conditions as those used for the synthesis of intermediate (2b) but replacing 3,4-dihydro-8-fluoro-2H-1,4-benzoxazine-2-carboxamide (4b) with 3,4-dihydro-4-methyl-2H-1,4-benzoxazine-2-carboxamide (4h). The title compound of formula (2h) is obtained.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH:14]=[C:15]([C:21](O)=[O:22])[NH:16]3)=[CH:2]1.[ClH:24].Cl.Cl.[C@H:27]1([CH2:37][N:38]2[CH2:43][CH2:42][CH:41]([NH2:44])[CH2:40][CH2:39]2)[C@@H:36]2[N:31]([CH2:32][CH2:33][CH2:34][CH2:35]2)[CH2:30][CH2:29][CH2:28]1>>[ClH:24].[ClH:24].[C@H:27]1([CH2:37][N:38]2[CH2:43][CH2:42][CH:41]([NH:44][C:21]([C:15]3[NH:16][C:17]4[C:13]([CH:14]=3)=[C:12]([O:11][CH2:10][C:3]3[C:4]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=5[O:1][CH:2]=3)[CH:20]=[CH:19][CH:18]=4)=[O:22])[CH2:40][CH2:39]2)[C@@H:36]2[N:31]([CH2:32][CH2:33][CH2:34][CH2:35]2)[CH2:30][CH2:29][CH2:28]1
Reactant: O=C(O)c1cc2c(OCc3coc4ccccc34)cccc2[nH]1
Reactant: NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1
Agent: Cl
Product: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4ccccc34)cccc2[nH]1

Procedure:
This compound is synthesized from 4-(benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (105) (preparation see below) and amine 61 analogously to the method described in example 1.
Reaction SMILES: FC1C=CC(CN2C3C(=CC(S(C)(=O)=O)=CC=3)C=C2C2SC=CN=2)=CC=1.FC1C=CC(CN2C3=NC=C(S(C)(=O)=O)C=C3C=[C:34]2[C:46]2[O:47]C=C[N:50]=2)=CC=1.[F:53][C:54]1[CH:78]=[CH:77][C:57]([CH2:58][N:59]2[C:67]3[C:62](=[CH:63][C:64]([S:68]([CH3:71])(=[O:70])=[O:69])=[CH:65][CH:66]=3)[CH:61]=[C:60]2[C:72]2OC=N[N:76]=2)=[CH:56][CH:55]=1>>[F:53][C:54]1[CH:78]=[CH:77][C:57]([CH2:58][N:59]2[C:67]3[C:62](=[CH:63][C:64]([S:68]([CH3:71])(=[O:70])=[O:69])=[CH:65][CH:66]=3)[CH:61]=[C:60]2[C:72]2[N:50]=[C:46]([CH3:34])[O:47][N:76]=2)=[CH:56][CH:55]=1
Reactant: CS(=O)(=O)c1ccc2c(c1)cc(-c1nnco1)n2Cc1ccc(F)cc1
Reactant: CS(=O)(=O)c1cnc2c(c1)cc(-c1ncco1)n2Cc1ccc(F)cc1
Agent: CS(=O)(=O)c1ccc2c(c1)cc(-c1nccs1)n2Cc1ccc(F)cc1
Product: Cc1nc(-c2cc3cc(S(C)(=O)=O)ccc3n2Cc2ccc(F)cc2)no1

Procedure:
Among the above compounds, 1-(4-fluorobenzyl)-5-methanesulfonyl-2-(thiazol-2-yl)indole; 1-(4-fluorobenzyl)-2-(oxazol-2-yl)-5-methanesulfonyl-1H-pyrrolo [2,3-b]pyridine; and 1-(4-fluorobenzyl)-5-methanesulfonyl-2-([1,3,4]oxadiazol-2-yl)indole and addition salts thereof with a pharmaceutically acceptable acid or base, and hydrates thereof are particularly preferred.
Reaction SMILES: CO[N:3]=[C:4]([C:8]1[N:9]=[N:10][S:11][CH:12]=1)[C:5]([OH:7])=[O:6].[ClH:13].[H][H]>CO.O>[ClH:13].[NH2:3][CH:4]([C:8]1[N:9]=[N:10][S:11][CH:12]=1)[C:5]([OH:7])=[O:6]
Reactant: CON=C(C(=O)O)c1csnn1
Reactant: [H][H]
Agent: Cl
Solvent: O
Solvent: CO
Product: NC(C(=O)O)c1csnn1
Reaction time: 1 h

Procedure:
A solution of 2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetic acid (mixture of syn- and anti-isomers) (500 mg) [prepared by the method described in Belgian Pat. No. 859384 (1978)] in a mixture of methanol (10 cm3) and water (2.3 cm3) was treated with 1N hydrochloric acid (2.7 cm3) and hydrogenated under 50 psi of hydrogen with 5% rhodium-on-charcoal (500 mg) for one hour. A further portion of catalyst (500 mg) was added and hydrogenation continued for one hour. After filtration the filtrate was evaporated to dryness in vacuo and the residue triturated with ether to give the title compound as an off-white solid, (490 mg).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([NH:14][C:15](=[NH:18])[NH:16][CH3:17])=[O:13])[CH3:2].[CH3:19]C(=O)CCC>CCCCCC>[CH2:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[N:11]1[CH:17]=[N:16][C:15]([NH:18][CH3:19])=[N:14][C:12]1=[O:13])[CH3:10]
Reactant: CCCC(C)=O
Reactant: CCc1cccc(CC)c1NC(=O)NC(=N)NC
Solvent: CCCCCC
Product: CCc1cccc(CC)c1-n1cnc(NC)nc1=O

Procedure:
The same procedure is followed as in Example 4 above using 1-(2',6'-diethylphenyl)-3-methylamidinourea as the starting material and using as the recrystallization medium a mixed solvent of pentanone and hexane (30:10).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH3:20])[S:17][C:16]=2[CH2:21][O:22][C:23]2[C:28]([F:29])=[CH:27][C:26]([CH2:30][CH2:31][C:32](OCC)=[O:33])=[CH:25][C:24]=2[F:37])=[CH:11][CH:10]=1)[CH3:8]>>[CH2:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH3:20])[S:17][C:16]=2[CH2:21][O:22][C:23]2[C:28]([F:29])=[CH:27][C:26]([CH2:30][CH2:31][CH2:32][OH:33])=[CH:25][C:24]=2[F:37])=[CH:11][CH:10]=1)[CH3:8]
Reactant: CCOC(=O)CCc1cc(F)c(OCc2sc(C)cc2-c2ccc(CC)cc2)c(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCc1ccc(-c2cc(C)sc2COc2c(F)cc(CCCO)cc2F)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 223 by LAH reduction of ethyl 3-(4-((3-(4-ethylphenyl)-5-methylthiophen-2-yl)methoxy)-3,5-difluoro phenyl)propanoate to give the desired product as off-white oil. 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J=7.0 Hz, 2H), 7.24 (d, J=7.1 Hz, 2H), 6.78 (s, 1H), 6.72 (d, J=7.8 Hz, 2H), 5.11 (s, 2H), 3.72 (t, J=8.1 Hz, 2H), 2.72 (m, J=5.2 Hz, 2H), 2.65 (m, J=7.5 Hz, 2H), 2.49 (s, 3H), 1.82 (m, J=5.8 Hz, 2H), 1.70 (br, s, 1H), 1.28 (t, J=7.2 Hz, 3H).
Reaction SMILES: O[C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.CCN(C1C=CC=CC=1)CC.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncc2c(n1)CCCC2
Solvent: CCN(CC)c1ccccc1
Product: Clc1ncc2c(n1)CCCC2

Procedure:
A solution of 1 g of 2-hydroxy-5,6,7,8-tetrahydroquinazoline and 0.1 g of diethylaniline in 10 mL of phosphorus oxychloride is refluxed for 2 h, and subsequently cooled and concentrated. The residue is taken up in chloroform and washed with excess 3 N NaOH solution. The organic layer is dried and concentrated to provide 2-chloro-5,6,7,8-tetrahydroquinazoline (1.1 g) as an orange solid.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([CH3:41])[C:17]2[C:18]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=3[CH3:40])=[CH:19][C:20]([C@H:23]3[NH:27][C@@:26]([CH3:32])([C:28](OC)=[O:29])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH3:46]>CO>[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([CH3:41])[C:17]2[C:18]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=3[CH3:40])=[CH:19][C:20]([C@H:23]3[NH:27][C@@:26]([CH3:32])([C:28]([NH2:46])=[O:29])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)=[O:15])[CH:4]=[C:3]([C:2]([F:44])([F:45])[F:1])[CH:8]=1
Reactant: N
Reactant: COC(=O)[C@@]1(C)CC[C@@H](c2cc(-c3ccc(F)cc3C)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)N1
Solvent: CO
Product: Cc1cc(F)ccc1-c1cc([C@@H]2CC[C@](C)(C(N)=O)N2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 48 h
Yield: 92 %

Procedure:
Methyl (5S)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-D-prolinate (Intermediate 20, 30 mg, 0.047 mmol) was dissolved in 7N ammonia solution in MeOH (3 ml) and the reaction mixture was stirred for 48 hours at 50° C. The solvent was evaporated affording the title compound (27 mg, 0.043 mmol, 92% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.31 (s, 1H) 8.04 (s, 1H) 7.89-7.99 (m, 1H) 7.60-7.87 (m, 2H) 7.44 (s, 1H) 6.90-7.24 (m, 4H) 4.39-4.60 (m, 1H) 3.21-3.32 (m, 1H) 2.53 (s, 3H) 2.21 (s, 3H) 1.45 (s, 6H) 1.38 (s, 3H) 1.16-2.37 (m, 4H) The spectrum of the sample consists of a mixture of conformers (broad lines in the spectrum at r.t). The relative stereochemistry syn was confirmed by dipolar correlation between: —CH3(8) at 1.31 ppm and CH(5) at 4.48 ppm. UPLC: Rt 0.75 min (broad peak), m/z 625 [M+H]+. HPLC: Rt 5.06 min.
Reaction SMILES: C(N)(C)(C)C.[Br:6]N1C(=O)CCC1=O.[CH3:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[C:18]([OH:25])[CH:19]=[CH:20][CH:21]=2)[N:16]=1>C1(C)C=CC=CC=1.CCCCCC>[Br:6][C:19]1[C:18]([OH:25])=[C:17]2[C:22]([CH:23]=[CH:24][C:15]([CH3:14])=[N:16]2)=[CH:21][CH:20]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2cccc(O)c2n1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CC(C)(C)N
Product: Cc1ccc2ccc(Br)c(O)c2n1
Temperature: -70 °C
Reaction time: 24 h
Yield: 67 %

Procedure:
The protocol was established from works by: D. E. Pearson et al. J. Org. Chem. 1967, 2358-2360. tert-butylamine (3.23 ml, 30.78 mmol) is stirred under argon in 100 ml of toluene for 2 hours at ambient temperature in the presence of an activated 4 Å molecular sieve (10 g). After cooling to −70° C., N-bromosuccinimide (5.48 g; 30.78 mmol) and 2-methyl-8-hydroxyquinoline (5.00 g; 30.78 mmol) are added in succession. The mixture is slowly brought to ambient temperature (approximately 4 hours). The reaction medium is filtered and the molecular sieve is washed with diethyl ether (20 ml). The filtrate is washed in water (3×50 ml), dried over anhydrous Na2SO4 and the organic phase is concentrated to yield a solid which is brought to reflux in 100 ml of hexane for 1 hour. After 24 hours at ambient temperature, the precipitate is filtered and dried under vacuum to yield 7-bromo-2-methyl-8-hydroxyquinoline in the form of a white powder (4.85 g; 20.47 mmol, yield=67%). NMR-1H (250 MHz, CDCl3) δ, ppm: 8.00 (d, 3J (H, H)=8.5 Hz, 1H); 7.52 (d, 3J (H, H)=9.0 Hz, 1H); 7.31 (d, 3J (H, H)=8.5 Hz, 1H); 7.16 (d, 3J (H, H)=9.0 Hz, 1H); 2.72 (s, 3H). NMR-13C (63 MHz, CDCl3) δ, ppm: 157.9; 149.2; 137.7; 136.2; 130.1; 125.4; 122.9; 118.2; 103.9; 24.8. MS (CID, NH3): m/z=238 (MH+). Analysis (%) for C10H8BrNO: calculated C, 50.45. H, 3.39. N, 5.88. found C, 50.02. H, 3.37. N, 6.12.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]([C:14]3[C:15]4[CH:22]=[N:21][N:20]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=5)[C:16]=4[CH:17]=[N:18][CH:19]=3)=[O:13])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:30][NH2:31].C(O)C>CNC=O.C(OCC)(=O)C.O>[CH3:30][NH:31][C:2]1[N:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]([C:14]3[C:15]4[CH:22]=[N:21][N:20]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=5)[C:16]=4[CH:17]=[N:18][CH:19]=3)=[O:13])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(NC1(c2ccc(Br)nc2)CC1)c1cncc2c1cnn2-c1ccc(F)cc1
Reactant: CN
Solvent: CNC=O
Solvent: O
Solvent: CCOC(C)=O
Product: CNc1ccc(C2(NC(=O)c3cncc4c3cnn4-c3ccc(F)cc3)CC2)cn1
Temperature: 160 °C
Reaction time: 36 h

Procedure:
A pressure tube charged with 1-(4-fluoro-phenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid [1-(6-bromo-pyridin-3-yl)-cyclopropyl]-amide (0.200 g, 0.442 mmol), 33% methylamine in ethanol (0.250 mL, 1.99 mmol) in N-methylformamide (1 mL) is heated at 160° C. After 36 hours, the reaction is cooled to room temperature and diluted with ethyl acetate (20 mL) and water (20 mL). Phases are separated and the aqueous layer is extracted with ethyl acetate (3×20 mL). The combined organic layers are washed with saturated aqueous ammonium chloride (3×100 mL), saturated aqueous sodium bicarbonate (100 mL), brine (100 mL), dried over MgSO4, filtered and concentrated. The residue is purified by silica gel chromatography eluting with 0-15% methanol in dichloromethane to afford the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[CH3:13][C:14]1[CH:23]=[CH:22][C:17]([CH2:18][NH:19][O:20][CH3:21])=[CH:16][CH:15]=1>>[CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8]([N:19]([O:20][CH3:21])[CH2:18][C:17]2[CH:22]=[CH:23][C:14]([CH3:13])=[CH:15][CH:16]=2)=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CONCc1ccc(C)cc1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Product: CON(Cc1ccc(C)cc1)C(=O)C=C1OC(C)(C)OC1=O
Yield: 78 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(4-methylbenzyl)-O-methyl-hydroxylamine as described in the preparation of compound 1-A gave the title amide as white crystals (78% yield): mp 108-110° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.92 (6H, s, CH3), 2.5 (3H, s, CH3), 3.84 (3H, s, OCH3), 4.97 (2H, s, NCH2), 6.57 (1H, s, CH), 7.31 (2H, d, J=8.1 Hz, aromatics), 7.42 (2H, d, J=8.1 Hz, aromatics). Anal. calcd for C16H19NO5: C, 62.94; H, 6.27; N, 4.59. Found: C, 63.14; H, 5.93; N, 4.34.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>>[O:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: O=C(O)CCCCCCCCCCCO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Product: O=CCCCCCCCCCCC(=O)O

Procedure:
14 g 12-hydroxy dodecanoic acid (1 eq.) was oxidized with 27.9 g PCC (Pyridinium chlorochromate) (2 eq.) for about 25 min at 37° C. as described in example 1, step a.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10](/[CH:12]=[CH:13]/[C:14]([O:16]CC)=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].O>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10](/[CH:12]=[CH:13]/[C:14]([OH:16])=[O:15])[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)/C=C/C1CN(C(=O)OC(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC(/C=C/C(=O)O)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.9 %

Procedure:
3-((E)-2-Ethoxycarbonylvinyl)azetidine-1-carboxylic acid tert-butyl ester (0.95 g; 3.72 mmol) was dissolved in 1,4-dioxane (15 mL). Lithium hydroxide (0.098 g; 4.1 mmol) and water (10 mL) were added. The reaction mixture was stirred for 12 hours at room temperature. Water (70 mL) was added and the reaction mixture was washed with tert-butyl methyl ether (70 mL) and the phases were separated. The aqueous phase was adjusted to pH 2 with an aqueous solution of sodium hydrogensulfate (10%) and extracted with tert-butyl methylether (3×70 mL). The combined organic phases were dried (magnesium sulfate) and the solvent evaporated in vacuo to afford 0.76 g of 3-((E)-2-carboxyvinyl)azetidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[N:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:12][CH:13]=2)=[N:6][CH:7]=1.[F:23][C:24]1[C:29]([F:30])=[C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.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.O>[F:23][C:24]1[C:29]([F:30])=[C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:27]=[CH:26][C:25]=1[C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[N:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: CCCCCCCCc1ccc(B(O)O)c(F)c1F
Reactant: CCCCCCCCOc1ccc(-c2ncc(Br)cn2)cn1
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: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCCCCCCCOc1ccc(-c2ncc(-c3ccc(CCCCCCCC)c(F)c3F)cn2)cn1
Yield: 84.1 %

Procedure:
The reaction of 3.5 mmol of 5-bromo-2-(6-octyloxypyridin-3-yl)pyrimidine, 3.85 mmol of 2,3-difluoro-4-octylphenylboronic acid, 7 mmol of sodium carbonate and 0.04 mmol of tetrakis(triphenylphosphine)palladium(0) in 20 ml of toluene: 10 ml of ethanol and 10 ml of water it carried out analogously to the procedure indicated for Example 1a). The crude product is separated off by column chromatography on silica gel 60 using heptane/ethyl acetate 9:1 (v/v) as eluent and is recrystallized from acetonitrile, giving 1.5 g (83%) of colorless crystals, X 105 SC 104 SA 127 I.
Reaction SMILES: [Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([CH3:13])[CH2:8][CH2:7][C:6]=2[C:5]([N+:14]([O-])=O)=[CH:4][CH:3]=1.[H][H]>[Pt](=O)=O.C(O)C>[NH2:14][C:5]1[C:6]2[CH2:7][CH2:8][N:9]([CH3:13])[CH2:10][CH2:11][C:12]=2[C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: CN1CCc2c(Cl)ccc([N+](=O)[O-])c2CC1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Product: CN1CCc2c(N)ccc(Cl)c2CC1

Procedure:
A suspension of 12.0 g. (0.05 mole) of 6-chloro-3-methyl-9-nitro-2,3,4,5-tetrahydro-1H-3-benzazepine, 100 ml. of ethanol and 0.2 g. of platinum dioxide is hydrogenated on a Parr apparatus at 25° C. and an initial hydrogen pressure of 60 p.s.i. After the rapid hydrogen uptake is completed, the mixture is filtered and the filtrate is concentrated in vacuo to give 9-amino-6-chloro-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[N:10][N:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:19][C:20]1[C:21](=[O:27])[C:22](=[O:26])[C:23]=1OC>CO>[NH2:19][C:20]1[C:21](=[O:27])[C:22](=[O:26])[C:23]=1[NH:18][CH2:17][CH2:16][CH2:15][CH2:14][O:13][N:11]1[CH:12]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:9]=[N:10]1
Reactant: NCCCCOn1cc(CN2CCCCC2)cn1
Reactant: COc1c(N)c(=O)c1=O
Solvent: CO
Product: Nc1c(NCCCCOn2cc(CN3CCCCC3)cn2)c(=O)c1=O
Temperature: 20 °C
Reaction time: 12 h

Procedure:
2.5 g of 4-(4-piperidinomethylpyrazol-1-yloxy)butylamine and 1.2 g of 3-amino-4-methoxycyclobutene-1,2-dione are introduced into 80 ml of methanol, and the mixture is stirred for 12 hours at 20° C. The solid formed is then filtered off under suction.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[N:11]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[C:10]=1[CH:26]([CH3:28])[CH3:27])=[O:8].[OH-].[K+].Br[C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1>CN(C)C(=O)C.[Cu]>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)=[CH:15][CH:16]=2)[N:11]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[C:10]=1[CH:26]([CH3:28])[CH3:27])=[O:8]
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ccccn1
Reactant: Brc1cccnc1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(Oc3cccnc3)cc2n1Cc1ccccn1
Temperature: 130 °C
Reaction time: 0.08 h
Yield: 6.5 %

Procedure:
General Procedure G. To a solution of N-(3,4-difluorobenzyl)-2-isopropyl-6-hydroxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 220, 30 mg, 0.069 mmol) in N,N-dimethylacetamide (1.50 ml) stirring at room temperature, was added potassium hydroxide (80 mg, 1.43 mmol) and the reaction stirred for 5 minutes. 3-bromopyridine (0.05 mL, 0.08 g, 0.51 mmol) and then Copper powder (9.0 mg, 0.14 mmol) was then directly added and the resulting mixture heated at 120-140° C. for 18 h. The reaction was cooled to room temperature, quenched with water, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (50% EtOAc-hexanes, 100 % EtOAc) to yield N-(3,4-difluorobenzyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-6-(pyridin-3-yloxy)-1H-indole-3-carboxamide (Compound 222) as a yellow solid (2.3 mg). 1H NMR (300 MHz, METHANOL-d4) δ ppm 1.34 (d, J=7.0 Hz, 6 H), 4.59 (s, 2 H), 5.55 (s, 2 H), 6.72 (d, J=8.2 Hz, 1 H), 6.92 (dd, J=8.6, 2.2 Hz, 1 H), 7.02 (d, J=2.0 Hz, 1 H), 7.19-7.42 (m, 6 H), 7.62-7.74 (m, 2 H), 8.14-8.24 (m, 2 H), 8.49 (d, J=5.0 Hz, 1 H).