Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([OH:3])=[O:2].[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22]>>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:8](=[O:10])[C:7]2=[CH:13][CH:14]=1)([OH:3])=[O:2]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: NCCCCCC(=O)O
Product: O=C(O)CCCCCN1C(=O)c2ccc(C(=O)O)cc2C1=O
Yield: 85 %

Procedure:
4-carboxyphthalic anhydride (1.0 g, 0.0052 mol) and 6-aminohexanoic acid (0.68 g, 0.0052 mol) were refluxed as above overnight. Crystallisation of the product from EtOH yielded 1.35 g (85%) of 104 as a white solid: mp=202–204° C.; Rf 0.80 (A): Rf 0.84 (B): Rf 0.47 (D): IR (cm−1): 2800–3250 (OH), 3103 (C═CH), 2675 (C—H), 1769 (C═O), 1709 (bs, C═O), 1625 (C═C), 1485 (C═C), 1403(C—O), 1303 (C—O), 730 (C═CH); MS m/z (rel intensity) 305 (16), 304 (100).
Reaction SMILES: [NH2-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[Cl:10].Cl[CH2:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19].O>CCOCC>[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]([CH2:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Reactant: CN(C)CCCCl
Agent: [NH2-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CN(C)CCCC(C#N)c1ccc(Cl)c(Cl)c1
Yield: 63 %

Procedure:
3.9 g of sodium amide are added in small portions to a solution of 18.6 g of 3,4-dichlorophenylacetonitrile in 200 ml of anhydrous ether. The mixture is refluxed for 2 hours, 12.1 g of 3-chlorodimethylaminopropane are added and refluxing is continued for 2 and a half hours. The mixture is cooled, water is added and the organic phase is decanted. It is washed with water and extracted with 10% hydrochloric acid. The aqueous phase is then neutralized with 30% sodium hydroxide and extracted with ether and the solvent is evaporated off to give 17 g of the expected product.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:4]1)=O.[OH:31][C:32]1([CH2:38][CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.Cl.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[OH:31][C:32]1([CH2:38][CH2:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:37][CH2:36][N:35]([CH2:1][C@@H:3]2[C@@H:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:6][N:5]([C@H:14]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:4]2)[CH2:34][CH2:33]1
Reactant: OC1(CCCc2ccccc2)CCNCC1
Reactant: O=C[C@H]1CN([C@@H](C(=O)OCc2ccccc2)C2CCCCC2)C[C@@H]1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)[C@@H](C1CCCCC1)N1C[C@H](CN2CCC(O)(CCCc3ccccc3)CC2)[C@@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A solution of 87 mg (0.21 mmol) of 2-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, benzyl ester (from EXAMPLE 1, Step I) and 69 mg (0.26 mmol) of 4hydroxy-4-(3-phenylpropyl)-piperidine.HCl in 5 mL of CH2Cl2 at rt was treated with 0.045 mL (0.25 mmol) of DIEA and 86 mg (0.40 mmol) of sodium triacetoxyborohydride and stirred at rt for 1 h. The reaction was diluted with 25 mL of CH2Cl2 and washed with 25 mL of 1.0 N NaHCO3. The layers were separated and the aqueous layer was extracted with 25 mL of CH2Cl2. The combined organic phases were washed with 50 mL of sat'd NaCl, dried over Na2SO4 and concentrated. Flash chromatography on silica gel using 50:1 v/v CH2Cl2/MeOH as the eluant afforded 110 mg (83%) of the title compound: RF: 0.46 (20:1 v/v CH2Cl2/MeOH); 1H NMR (300 MHz) δ 0.91-2.85 (m, 32H), 3.16-3.27 (m, 3H), 5.15 (ABq, J=12.2 Hz, 2H), 7.15-7.41 (m, 15H); NH3-CI-MS 609 (M+H).
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5].[NH2:8][C@@H:9]([CH2:13][S:14][C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]([OH:12])=[O:11].C(=O)([O-])[O-].[Na+].[Na+].Cl>O1CCCC1.O>[C:1]([NH:8][C@@H:9]([CH2:13][S:14][C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10]([OH:12])=[O:11])(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: C=CCCC(=O)Cl
Reactant: N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCCC(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
Pent-4-enoyl chloride (0.915 ml, 8.25 mmol) was added to a solution of (R)-2-amino-3-(tritylthio)propanoic acid (1.50 g, 4.13 mmol) and sodium carbonate (1.31 g, 12.4 mmol) in tetrahydrofuran (3.5 ml) and water (7 ml), and the mixture was stirred at room temperature for one hour. The reaction mixture was then adjusted to pH 2 by adding concentrated hydrochloric acid thereto at 0° C. After dilution with ethyl acetate, salting-out extraction was carried out by adding an appropriate amount of NaCl. The resulting organic extract was washed with brine, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by reverse-phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol=70/30→0/100) to afford (R)-2-(pent-4-enamido)-3-(tritylthio)propanoic acid (Compound 2h) (1.14 g, 62%).
Reaction SMILES: [OH:1][CH:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1/[CH:16]=[CH:17]/[CH:18]=[CH:19]/[CH:20]([O:29]C1CCCCO1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:1][CH:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1/[CH:16]=[CH:17]/[CH:18]=[CH:19]/[CH:20]([OH:29])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: CCCCCCCCC(/C=C/C=C/c1ccccc1C(O)CCCC(=O)OC)OC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CCCCCCCCC(O)/C=C/C=C/c1ccccc1C(O)CCCC(=O)OC
Temperature: 55 °C

Procedure:
To 3ml of methanol is added 0.1g (0.21 mmol) of the titled product of Example 12 and 10mg of p-toluenesulfonic acid. The reaction mixture is heated to 55°C. for 3 hours. The solvent was removed under reduced pressure and the residue was flash chromatographed on silica gel column. Elution with 2:1 diethyl ether hexane produced 3 bands. The third band contained 0.30g of the titled products which was collected as fractions 8-18.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=O.[NH2:14][C:15]1[CH:16]=[C:17]2[C:21]3=[C:22]([CH2:24][S:25][CH2:26][CH2:27][N:20]3[C@H:19]3[CH2:28][CH2:29][N:30](C(OC(C)(C)C)=O)[CH2:31][C@@H:18]23)[CH:23]=1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH2:4][NH:14][C:15]1[CH:16]=[C:17]2[C:21]3=[C:22]([CH2:24][S:25][CH2:26][CH2:27][N:20]3[C@H:19]3[CH2:28][CH2:29][NH:30][CH2:31][C@@H:18]23)[CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCSC3
Reactant: O=Cc1cc(C(F)(F)F)ccc1Cl
Product: FC(F)(F)c1ccc(Cl)c(CNc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCSC3)c1

Procedure:
Using 2-chloro-5-(trifluoromethyl)benzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 33, Part B was converted into the title compound of EXAMPLE 153. 1H NMR(CDCl3) δ: 9.20-9.05 (broad m, 2H), 7.67 (s, 1H), 7.52-7.40 (m, 2H), 6.43 (broad s, 1H), 6.32 (broad s, 1H), 4.39 (broad s, 2H), 4.35-4.10 (m, 2H), 3.75-3.30 (overlapping m, 4H), 3.30-2.79 (overlapping m, 5H), 2.65-2.50 (m, 1H), 2.20-2.05 (m, 2H). LRMS (ES)+: 454.4 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[F:10][C:11]1[CH:27]=[CH:26][C:14]([CH2:15][C:16]2[O:20][C:19]([CH2:21][C:22](Cl)=[N:23][OH:24])=[CH:18][CH:17]=2)=[CH:13][CH:12]=1.C(N(CC)CC)C>O1CCCC1>[F:10][C:11]1[CH:27]=[CH:26][C:14]([CH2:15][C:16]2[O:20][C:19]([CH2:21][C:22]3[CH:2]=[C:1]([C:3]4[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=4)[O:24][N:23]=3)=[CH:18][CH:17]=2)=[CH:13][CH:12]=1
Reactant: C#Cc1cccnc1N
Reactant: ON=C(Cl)Cc1ccc(Cc2ccc(F)cc2)o1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ncccc1-c1cc(Cc2ccc(Cc3ccc(F)cc3)o2)no1
Temperature: 25 °C
Reaction time: 19 h
Yield: 6.1 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 3-ethynyl-pyridin-2-ylamine (50 mg, 0.423 mmol) described in Manufacturing Example 1-2-3 and (5-(4-fluorobenzyl)-furan-2-yl) acetohydroximoyl chloride (181 mg, 0.677 mmol) described in Manufacturing Example 208-1-5 was added triethylamine (147 μL, 1.06 mmol), which was stirred for 19 hours at room temperature. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:4 to 1:2) to obtain the title compound (9 mg, 6%).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]2[S:6][C:7]([C:9]3[C:18]([N:19]([CH:21]([CH3:23])[CH3:22])[CH3:20])=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:24]([O:26]C)=[O:25])[CH:15]=4)[N:10]=3)=[CH:8][C:4]=2[CH:3]=1.[OH-].[Na+].O>O1CCCC1>[F:1][C:2]1[CH:29]=[CH:28][C:5]2[S:6][C:7]([C:9]3[C:18]([N:19]([CH:21]([CH3:22])[CH3:23])[CH3:20])=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:24]([OH:26])=[O:25])[CH:15]=4)[N:10]=3)=[CH:8][C:4]=2[CH:3]=1
Reactant: COC(=O)c1ccc2nc(-c3cc4cc(F)ccc4s3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1cc2cc(F)ccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.5 %

Procedure:
To a solution of methyl 2-(5-fluorobenzo[b]thiophen-2-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (148 mg, 0.36 mmol) in tetrahydrofuran (25 mL) was added sodium hydroxide (43.4 mg, 1.08 mmol) and water (2 mL) with stirring overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (20 mL) and adjusted to pH 5 with hydrochloric acid (3N). The solids were collected by filtration to afford 2-(5-fluorobenzo[b]thiophen-2-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid (69 mg, 49%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[C:7](=[O:8])[O:6][CH:5]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([CH3:25])[CH2:14][C:15](C)=[CH:16]C(C)=CC(OC)=O.[O:26]=[O+][O-]>[Zn].C(O)(=O)C>[CH3:1][O:2][CH2:3][CH:4]1[C:7](=[O:8])[O:6][CH:5]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([CH3:25])[CH2:14][C:15](=[O:26])[CH3:16]
Reactant: O=[O+][O-]
Reactant: COCC1C(=O)OC1CCCCC(C)CC(C)=CC(C)=CC(=O)OC
Agent: [Zn]
Solvent: CC(=O)O
Product: COCC1C(=O)OC1CCCCC(C)CC(C)=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 400 mg (1.135 mmole) of methyl 11-(3-methoxymethyl-4-oxo-2-oxetanyl)-3,5,7-trimethyl-2,4-undecadienoate in 10 ml of CHCl2 at -78° C., was bubbled ozone for 8 minutes. The resulting mixture was stirred for 30 minutes at -78° C. then at room temperature for another 30 minutes. Acetic acid and zinc dust were added. After stirring for 1 hour at room temperature, the solution was filtered and the filtrate was concentrated to dryness. The product was purified by flash column chromatography to give 8-(3-methoxymethyl-4-oxo-2-oxetanyl)-4-methyl-2-octanone as a colorless oil. ##STR11##
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:15][CH2:14][CH2:13][C:7]=3[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1.[CH:16]([Sn](CCCC)(CCCC)CCCC)=[CH2:17]>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>[CH:16]([C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:15][CH2:14][CH2:13][C:7]=3[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1)=[CH2:17]
Reactant: O=c1[nH]c2cc(Br)ccc2c2c1CCC2
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C=Cc1ccc2c3c(c(=O)[nH]c2c1)CCC3
Temperature: 110 °C
Yield: 87.8 %

Procedure:
A solution of 2.0 g (7.6 mmol) of 7-bromo-1,2,3,5-tetrahydrocyclopenta[c]-quinolin-4-one, 2.6 ml (9.9 mmol) of vinyltributyltin and 0.44 g (0.38 mmol) of tetrakis(triphenylphosphine)palladium is degassed and aerated with nitrogen. After 6 hours of heating to 110° C., the batch is concentrated by evaporation and the residue is taken up on silica gel. Column chromatography on silica gel with hexane-ethyl acetate yields 1.41 g of product.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[C:16](=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)CCNc1ccc([N+](=O)[O-])cc1
Product: CC(=O)N(CCN(C)C)c1ccc([N+](=O)[O-])cc1

Procedure:
A solution of 50 g (0.239 mol) N,N-dimethyl-N′-(4-nitro-phenyl)-ethane-1,2-diamine in 500 mL acetic anhydride was stirred for 3.5 h at 130° C., then evaporated down i. vac. and neutralised with saturated aqueous sodium bicarbonate. The residue was exhaustively extracted with EtOAc, the combined org. phases were dried over sodium sulphate and evaporated down i. vac.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1([O:24][CH3:25])[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][CH2:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:7][CH2:6]1.[NH2:26][C:27]1[C:35]([Cl:36])=[CH:34][C:30]([C:31](O)=[O:32])=[C:29]([O:37][CH3:38])[CH:28]=1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>C(N(CC)CC)C>[NH2:26][C:27]1[C:35]([Cl:36])=[CH:34][C:30]([C:31]([NH:3][CH2:4][C:5]2([O:24][CH3:25])[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][CH2:14][S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH2:7][CH2:6]2)=[O:32])=[C:29]([O:37][CH3:38])[CH:28]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: COC1(CN)CCN(CCCCS(=O)(=O)c2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1(OC)CCN(CCCCS(=O)(=O)c2ccccc2)CC1
Yield: 51.8 %

Procedure:
4-Aminomethyl-4-methoxy-1-(4-phenylsulfonylbutyl)piperidine dihydrochloride (2.2 g) as starting compound, triethylamine (2.2 ml), 4-amino-5-chloro-2-methoxybenzoic acid (1.07 g), 1-hydroxybenzotriazole (0.75 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.07 g) were reacted and treated in the same manner as in Example 270 to give 1.44 g of 4-amino-5-chloro-2-methoxy-N-((4-methoxy-1-(4-phenylsulfonylbutyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: C(N(CC)CC)C.C1C[O:11][CH2:10]C1.[C:13]([N:16]1[C:25]2[C:20](=[CH:21][C:22]([C:26]([NH:28][NH2:29])=[O:27])=[CH:23][CH:24]=2)[CH:19]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH2:18][CH:17]1[CH3:38])(=[O:15])[CH3:14]>O>[C:13]([N:16]1[C:25]2[C:20](=[CH:21][C:22]([C:26]3[O:27][C:10](=[O:11])[NH:29][N:28]=3)=[CH:23][CH:24]=2)[CH:19]([NH:30][C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)[CH2:18][CH:17]1[CH3:38])(=[O:15])[CH3:14]
Reactant: CC(=O)N1c2ccc(C(=O)NN)cc2C(Nc2ccc(Cl)cc2)CC1C
Reactant: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)N1c2ccc(-c3n[nH]c(=O)o3)cc2C(Nc2ccc(Cl)cc2)CC1C
Reaction time: 72 h
Yield: 89 %

Procedure:
Triethylamine (744 μL, 534 μmol) was added to a THF (10 mL) solution of compound 115 (100 mg, 267 μmol) at room temperature, and 1,1′-carbodiimidazole (64.9 mg, 400 μmol) was further added thereto. The resulting mixture was stirred for 3 days at the same temperature. Water was added to the reaction liquid, and the mixture was extracted with chloroform. Subsequently, the organic layer was washed with saturated brine, dehydrated over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by using silica gel chromatography (hexane:ethyl acetate=1:1-÷ 1:2), and thus 94.8 mg (89%) of the title compound was obtained as a pale yellow amorphous substance (cis:trans=3:1).
Reaction SMILES: [CH:1]([C:3]1[C:4]([CH3:10])=[C:5]([C:8]#[N:9])[S:6][CH:7]=1)=[CH2:2].C1C(=O)N(Br)C(=[O:14])C1.[OH-].[Na+]>C(O)(C)(C)C.O>[CH3:10][C:4]1[C:3]([CH:1]2[CH2:2][O:14]2)=[CH:7][S:6][C:5]=1[C:8]#[N:9]
Reactant: C=Cc1csc(C#N)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1c(C2CO2)csc1C#N
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A suspension of 4-ethenyl-3-methylthiophene-2-carbonitrile (1.70 g, 11.4 mmol) in 30 mL of t-Bu-OH and 60 mL of water was added NBS (2.40 g, 13.7 mmol) portionwise. The mixture was stirred at 90° C. for 1 hour then cooled down to 10° C. Then a solution of NaOH (0.7 g in 10 mL of water, 17.5 mmol) was added dropwise and stirred for 15 minutes. The reaction mixture was extracted with EtOAc twice and concentrated. The residue was purified by silica column chromatography (petrol ether: EtOAc=20:1) to afford 3-methyl-4-(oxiran-2-yl)thiophene-2-carbonitrile.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=2)[N:4]([CH3:15])[N:3]=1.C([Mg]Cl)(C)C.[CH2:21]([Sn:25]([CH2:31][CH2:32][CH2:33][CH3:34])([CH2:27][CH2:28][CH2:29][CH3:30])Cl)[CH2:22][CH2:23][CH3:24]>C1COCC1>[CH3:15][N:4]1[C:5]2[C:10](=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=2)[C:2]([Sn:25]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:21][CH2:22][CH2:23][CH3:24])=[N:3]1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cn1nc(I)c2cc(C(F)(F)F)ccc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2ccc(C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.2 %

Procedure:
To a solution of 3-iodo-1-methyl-5-(trifluoromethyl)-1H-indazole (400 mg, 1.2 mmol) in dry THF (15 mL) was added isopropylmagnesium chloride (0.7 mL, 1.3 mmol, 2 M in THF) drop-wise at −16° C. under nitrogen atmosphere, stirred for 30 minutes, then tributylchlorostannane (0.4 mL, 1.3 mmol) was added drop-wise at −16° C. under nitrogen, the reaction mixture was warmed to room temperature slowly and stirred for 2 hours, then quenched with a solution of saturated NH4Cl (40 mL) and product extracted with EtOAc (3×30 mL) then dried over Na2SO4, filtered and concentrated, under reduced pressure to give 1-methyl-3-(tributylstannyl)-5-(trifluoromethyl)-1H-indazole (500 mg, crude) as an oil which was used directly to next step without any further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([F:15])[CH:14]=1)[NH:11][C:10]1[CH:9]([CH2:16][C:17]([OH:19])=[O:18])[CH2:8][CH2:7][CH2:6][C:5]2=1.[H-].[Na+].[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Br>CN(C=O)C.O>[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][N:11]1[C:10]2[CH:9]([CH2:16][C:17]([OH:19])=[O:18])[CH2:8][CH2:7][CH2:6][C:5]=2[C:4]2[C:12]1=[C:13]([F:15])[CH:14]=[C:2]([F:1])[CH:3]=2
Reactant: Clc1ccccc1CBr
Reactant: O=C(O)CC1CCCc2c1[nH]c1c(F)cc(F)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CC1CCCc2c1n(Cc1ccccc1Cl)c1c(F)cc(F)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.3 %

Procedure:
A solution of 200 mg of 6,8-difluoro-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid from Example 34 step II in 8 cc of DMF was added portionwise 40 mg of sodium hydride. The resulting mixture was stirred for 30 minutes at room temperature and 185 mg of o-chloro-benzyl bromide was then added. After stirring overnight at room temperature, the resulting mixture was diluted with water and washed with ether. The aqueous layer was acidified with (1N) HCl and extracted with ether. The ethereal layer was washed with brine, dried over Na2SO4 and evaporated to dryness. The crude product was purified on preparative plates (silica gel) eluting with CHCl3 :MeOH:NH4OH (8:4:1) to yield 98 mg of pure title product. m.p. 197°-198° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:24][CH2:23][C:5]2[N:6]([CH2:14][C:15]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[O:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[CH3:27]I>CN(C=O)C>[CH3:27][O:16]/[C:15](/[C:17]1[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=1)=[CH:14]\[N:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=2[C:4]2[CH2:3][N:2]([CH3:1])[CH2:24][CH2:23][C:5]1=2
Reactant: Cc1ccc2c(c1)c1c(n2CC(=O)c2ccncc2)CCN(C)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO/C(=C\n1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccncc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(2,8-Dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethanone (100 mg) was dissolved in DMF (5 mL). Sodium hydride was added at once under nitrogen atmosphere followed by addition of methyl iodide. The contents were stirred at RT overnight. The reaction was monitored by LCMS. The reaction mixture was poured into 25 mL ice cold water and extracted with EtOAc (20 mL×3). The combined organic layers were given water washing (30 mL×2), dried over sodium sulfate and concentrated under vacuum to obtain the crude product, which was purified by reverse phase column chromatography to get 2 mg product as the TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.78 (d, 2H), 8.22 (d, 2H), 7.70 (s, 1H), 7.34 (m, 2H), 7.18 (d, 1H), 4.80 (m, 1H), 4.40 (m, 2H), 3.80 (m, 1H), 3.60 (m, 1H), 3.40 (s, 3H), 3.26 (m, 2H), 3.16 (s, 3H), 2.44 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:27]4[CH2:26][CH2:25][N:24]([CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])[CH2:23][CH2:22][C:21]=4[CH:20]=[CH:19][CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]>Cl.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:27]4[CH2:26][CH2:25][N:24]([CH2:28][C:29]([OH:31])=[O:30])[CH2:23][CH2:22][C:21]=4[CH:20]=[CH:19][CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCN(CC(=O)OC(C)(C)C)CC4)no2)cc1Cl
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCN(CC(=O)O)CC4)no2)cc1Cl
Yield: 179.3 %

Procedure:
1,1-Dimethylethyl [6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl]acetate (Preparation 19) (120 mg, 0.241 mmol) was stirred at room temperature for 18 hours in 4M HCl in 1,4-dioxane (20 ml). Evaporation and trituration with diethylether yielded the HCl salt [6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl]acetic acid hydrochloride (110 mg, 0.216 mmol, 90% yield) as a cream powder. MS (ES) C23H2435ClN3O4 requires 441; found 442 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2=[N:12][N:13]=[C:14]([C:15]3[CH:19]=[CH:18][O:17][N:16]=3)[N:4]2[N:3]=1.[OH:20][CH2:21][C:22]1[N:26]([CH2:27][CH3:28])[N:25]=[N:24][CH:23]=1>>[CH2:27]([N:26]1[C:22]([CH2:21][O:20][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]3=[N:12][N:13]=[C:14]([C:15]4[CH:19]=[CH:18][O:17][N:16]=4)[N:4]3[N:3]=2)=[CH:23][N:24]=[N:25]1)[CH3:28]
Reactant: CCn1nncc1CO
Reactant: Clc1nn2c(-c3ccon3)nnc2c2ccccc12
Product: CCn1nncc1COc1nn2c(-c3ccon3)nnc2c2ccccc12

Procedure:
The title-compound was prepared from 6-chloro-3-(3-isoxazolyl) 1,2,4-triazolo[3,4-a]phthalazine (prepared as described in Example 34 step b) and 5-hydroxymethyl-1-ethyl-1,2,3-triazole (prepared as described in Example 97 part b), following the procedure given for Example 71 but performing the reaction at −456° C.; 1H NMR (360 MHz, CDCl3) δ 1.62 (3H, t, J=7.2 Hz, CH3), 4.58 (2H, q, J=7.3 Hz, CH2), 5.81 (2H, s, CH2), 7.25 (1H, d, J=1.8 Hz, Ar—H), 7.84 (1H, m, Ar—H), 7.99 (1H, m, Ar—H), 8.08 (1H, s, Ar—H), 8.14 (1H, d, J=7.8 Hz, Ar—H), 8.66 (1H, d, J=1.8 Hz, Ar—H), 8.72 (1H, d, J=7.8 Hz, Ar—H); MS (ES+) m/e 363 [MH]+; Anal. Found. d, 56.47; H 3.68; N, 30.82. C17H14N8O2 requires C, 56.35; H, 3.89; N, 30.92%.