Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[O:21][C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:26])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ncc(N)n3)s2)OCCO1
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2)o1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3nc(C)oc3-c3ccccc3)n2)s1

Procedure:
Following general procedure A followed by B, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-methyl-5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH2:11][O:12]C(=O)C)[N:10]=[C:6]2[N:5]=[C:4]([CH2:16][O:17]C(=O)C)[CH:3]=1.NC(N)=[S:23]>C(O)C>[OH:12][CH2:11][C:9]1[N:10]=[C:6]2[N:5]=[C:4]([CH2:16][OH:17])[CH:3]=[C:2]([SH:23])[N:7]2[N:8]=1
Reactant: CC(=O)OCc1cc(Cl)n2nc(COC(C)=O)nc2n1
Reactant: NC(N)=S
Solvent: CCO
Product: OCc1cc(S)n2nc(CO)nc2n1
Reaction time: 0.5 h
Yield: 72 %

Procedure:
In 300 ml of ethanol was dissolved 14 g of 7-chloro-2,5-bis(acetoxymethyl)-s-triazolo[1,5-a]pyrimidine, and 10.7 g of thiourea was added thereto and the mixture was refluxed for 10 minutes. After removing ethanol from the reaction mixture, the residue was dissolved in 230 ml of a 5 % potassium hydroxide. The mixture was stirred for 30 minutes, ice-cooled and adjusted to pH 2 with 2N hydrochloric acid. Precipitated crystal was collected by filtration, washed with water and dried to obtain 7.16 g of the title compound.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@H:5]([NH2:11])[CH2:4]2.[CH3:12]/[C:13](=[CH:17]\[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)/[C:14](O)=[O:15]>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@H:5]([NH:11][C:14](=[O:15])/[C:13](/[CH3:12])=[CH:17]/[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:4]2
Reactant: C/C(=C\c1ccccc1)C(=O)O
Reactant: N[C@@H]1CN2CCC1CC2
Agent: Cl
Product: C/C(=C\c1ccccc1)C(=O)N[C@@H]1CN2CCC1CC2

Procedure:
Prepared as free base by a method analogous to that described in Example 1 from (S)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-α-methyl-3-phenylpropenoic acid; MS (ES+) 271 (MH+).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([NH:1][N:2]2[N:11]=[C:10]([CH2:12][C:13]3[CH:14]=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:20])=[O:30])=[CH:24][CH:23]=1
Reactant: Nn1nc(Cc2ccc(Cl)nc2)c2ccccc2c1=O
Reactant: O=C(O)Cc1ccc(Cl)cc1
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(Cc2ccc(Cl)nc2)c2ccccc2c1=O

Procedure:
The product from Example 30A and 2-(4-chlorophenyl)acetic acid were processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.60 (s, 1H), 8.42 (d, J=2.5 Hz, 1H), 8.32 (dd, J=7.9, 1.3 Hz, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.97 (ddd, J=8.1, 7.2, 1.4 Hz, 1H), 7.90 (ddd, J=8.0, 7.2, 1.3 Hz, 1H), 7.73 (dd, J=8.2, 2.5 Hz, 1H), 7.46 (dd, J=8.2, 0.8 Hz, 1H), 7.39-7.43 (m, 2H), 7.35-7.38 (m, 2H), 4.39 (s, 2H), 3.68 (s, 2H); MS (APCI) M/Z 439 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1O[C:7](=[O:15])[C:8]2[CH:14]=[CH:13][N:12]=[CH:11][C:9]=2[N:10]=1)[CH:2]([CH3:4])[CH3:3].[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH2:16]([N:23]1[C:7](=[O:15])[C:8]2[CH:14]=[CH:13][N:12]=[CH:11][C:9]=2[N:10]=[C:5]1[CH2:1][CH:2]([CH3:3])[CH3:4])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccccc1
Reactant: CC(C)Cc1nc2cnccc2c(=O)o1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC(C)Cc1nc2cnccc2c(=O)n1Cc1ccccc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of 2-isobutyl-4H-pyrido[3,4-d][1,3]oxazin-4-one (3.0 g, 14.68 mmol) in CHCl3 was added benzylamine (1.73 g, 16.15 mmol) and the reaction was heated to 60° C. After 3 h, the reaction was cooled to room temperature and solvent removed in vacuo. The resulting residue was dissolved in ethylene glycol and sodium hydroxide (0.385 g, 9.62 mmol) was added. The reaction was stirred overnight at 140° C. After cooling to room temperature and extracting with DCM, the organic solution was washed with water. The solution was dried over sodium sulfate and filtered. Concentration of the organic solution provided the title compound as a brown oil. 1H NMR (500 MHz, CDCl3) δ 1.01 (d, J=7 Hz, 6H), 2.33-2.38 (m, 1H), 2.68 (d, J=7 Hz, 2H), 5.43 (s, 2H), 7.16 (d, J=7.5 Hz, 2H), 7.30-7.40 (m, 3H), 8.06 (d, J=5 Hz, 1H), 8.68 (d, J=5 Hz, 1H), 9.13 (s, 1H). MS [M+H] C18H19N3O=294.1.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[S:12][CH3:13].FC(F)(F)C(O)=O.C([SiH](CC)CC)C.[ClH:28].CCOCC>C(Cl)Cl.CCOCC>[ClH:28].[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][NH:3][O:2][CH3:1])=[C:6]([S:12][CH3:13])[CH:7]=1
Reactant: CON=Cc1ccc(F)cc1SC
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CONCc1ccc(F)cc1SC
Reaction time: 6 h
Yield: 93 %

Procedure:
To a stirred solution of 4-fluoro-2-methylsulfanyl-benzaldehyde-O-methyl-oxime (5.982 g, 29.58 mmol) in CH2Cl2 (30 mL) was added trifluoroacetic acid (30 mL) followed by triethylsilane (14 mL, 90 mmol). After stirring for 6 h, the reaction mixture was concentrated and the resulting residue was taken up in saturated aqueous NaHCO3 (100 mL) and extracted with ethyl acetate (3×75 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to give a viscous oil. The crude product was re-dissolved in anhydrous ether and 2M HCl/ether w (18 mL) was added. The resulting white solid was filtered and dried to yield the desired product as the HCl salt (6.666 g, 93% yield). 1HNMR (500 MHz, DMSO-d6) δ: 11.44 (1H, br s), 7.66–7.59 (1H, m), 7.24 (1H, dd, J=10.1, 2.1 Hz), 7.08 (1H, td, J=8.6, 2.4 Hz), 4.85 (2H, s), 3.82 (3H, s), 2.53 (3H, s). MS calcd for C9H13FNOS (M+H): 202.07. found: 202.07.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]([F:20])=[C:18]2[C:13]([C:14]([CH3:21])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[NH:22][S:23]([C:26]1([CH2:29][CH2:30][O:31][Si](C(C)(C)C)(C)C)[CH2:28][CH2:27]1)(=[O:25])=[O:24].Cl>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]([F:20])=[C:18]2[C:13]([C:14]([CH3:21])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[NH:22][S:23]([C:26]1([CH2:29][CH2:30][OH:31])[CH2:28][CH2:27]1)(=[O:24])=[O:25]
Reactant: Cc1ncnc2c(F)c(Nc3ccc(I)cc3F)c(NS(=O)(=O)C3(CCO[Si](C)(C)C(C)(C)C)CC3)cc12
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ncnc2c(F)c(Nc3ccc(I)cc3F)c(NS(=O)(=O)C3(CCO)CC3)cc12
Reaction time: 1 h

Procedure:
To a solution of N-(7-(2-fluoro-4-iodophenylamino)-8-fluoro-4-methylquinazolin-6-yl)-1-(2-(tert-butyldimethylsilyloxy)ethyl)cyclopropane-1-sulfonamide (36 mg, 0.056 mmol) in THF (2 ml) is added HCl (0.18 ml, 1.2 N in H2O, 0.22 mmol). After stirring for 1 h, the reaction is quenched with saturated aqueous NaHCO3 solution (3 ml) and extracted with EtOAc (2×10 ml). The combined organic solution is dried over Na2SO4 and concentrated. Silica gel chromatography yields the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.[Br:21]N1C(=O)CCC1=O>CN(C)C=O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[Br:21]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(N)n2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)c(N)n2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 7 %

Procedure:
To a solution of tert-butyl 4-(6-aminopyridin-2-yl)piperazine-1-carboxylate (1.9 g, 8 mmol) in N,N-dimethylformamide (20 ml) was added dropwise 1-bromopyrrolidine-2,5-dione (1.4 g, 8 mmol) at 0° C. The reaction was allowed to stirred for 4 h at rt. The reaction mixture was quenched with water (30 mL), and extracted with acetic ester (30 mL×3). The combined organic phase was dried by anhydrous sodium sulphate, and then filtered. The filtrate was concentrated and purified by column chromatograph silica gel (elute: petroleum ether/ethyl acetate=1:1) to give tert-butyl 4-(6-amino-5-bromopyridin-2-yl)piperazine-1-carboxylate (0.2 g, 8.2%) as a yellow solid. LCMS (M+H) m/z: calcd. 356.08. found 357.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[H-].[Na+].[CH3:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16]Cl>C1(C)C=CC=CC=1>[CH3:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: CN(C)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN(C)CCCOc1cccc(C=O)c1
Yield: 66.6 %

Procedure:
The reaction between 61.0 g (0.50 mole) of 3-hydroxybenzaldehyde, 24.0 g of 50% NaH (0.50 mole), and 396 ml of 1.89N (0.75 mole) of 3-dimethylaminopropyl chloride in toluene in a procedure described for Example 2, part A, gives 69.0 g (66%) of colorless product, bp 155°-158°/3 mm.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]([OH:16])([C:10]#[C:11][Si](C)(C)C)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].O.C(=O)([O-])[OH:19].[Na+]>O1CCCC1.CN(C)C=O.S(=O)(=O)(O)O>[C:1]([N:4]1[CH2:9][CH2:8][C:7]([C:10](=[O:19])[CH3:11])([OH:16])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=C([O-])O
Reactant: CC(=O)N1CCC(O)(C#C[Si](C)(C)C)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N1CCC(O)(C(C)=O)CC1

Procedure:
To a solution of 1-acetyl-4-hydroxy-4-(2-trimethylsilylethynyl)piperidine (13 g) in a mixture of tetrahydrofuran (100 ml), water (25 ml) and N,N-dimethylformamide (10 drops) were added mercuric sulfate (1.6 g) and sulfuric acid (10 drops), and the resultant mixture was stirred at ambient temperature for 15 hours. After adjusting pH to around 8 with sodium hydrogen carbonate, the reaction mixture was filtered with "florisil" (trademark, made by Floridin Co.) and the residue was washed with ethyl acetate and tetrahydrofuran. Filtrate and washings were combined and evaporated in vacuo, and the residue was dissolved in ethyl acetate, dried over magnesium sulfate. Evaporation of the solvent gave 1,4-diacetyl-4-hydroxypiperidine (8.75 g).
Reaction SMILES: C(O[C:6](=[O:21])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)(C)(C)C.[CH2:22]([O:24][C:25](=[O:37])[CH:26](C(OCC)=O)[C:27](OCC)=[O:28])[CH3:23]>>[CH2:22]([O:24][C:25]([C:26]1[C:6](=[O:21])[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[N:8]2[CH:9]=[CH:10][CH:11]=[C:12]2[C:27]=1[OH:28])=[O:37])[CH3:23]
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1F)n1cccc1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1c(O)c2cccn2n(Cc2ccccc2F)c1=O

Procedure:
Prepared according to the thermal cyclization condition used in Example 1 step c) from (2-fluoro-benzyl)-pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.) and 2-ethoxycarbonyl-malonic acid diethyl ester (3.0 eq.). ESI (m/z): 331 (M+H)+.
Reaction SMILES: [C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:33]=2[N:34]=[CH:35][N:36]=1)[C@@H:15]1[O:32][C@H:22]([CH2:23][O:24][Si](C(C)(C)C)(C)C)[C@@H:17]([O:18][CH2:19]SC)[CH2:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCCCC=1.[N-:43]=[N+:44]=[N-:45].[Na+].[NH4+].[F-]>C(Cl)Cl>[C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:33]=2[N:34]=[CH:35][N:36]=1)[C@@H:15]1[O:32][C@H:22]([CH2:23][OH:24])[C@@H:17]([O:18][CH2:19][N:43]=[N+:44]=[N-:45])[CH2:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CSCO[C@H]1C[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Agent: [F-]
Agent: [NH4+]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1=CCCCC1
Product: [N-]=[N+]=NCO[C@H]1C[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1CO
Reaction time: 0.17 h
Yield: 48.1 %

Procedure:
To 0.4 g N6-benzoyl-3′-O-(methylthiomethyl)-5′-O-(tert-butyldimethylsilyl)-2′-deoxyadenosine (0.76 mmol) dissolved in 7 mL dry CH2Cl2 was treated with 0.4 mL cyclohexene and 155 μL SO2Cl2 (1.91 mmol) at 0° C. for 2 h. During this time the starting material completely converted to 7a which was shown by disappearance of the starting material and appearance of 3′-OH analog (5a) in TLC (EtOAC:Hex/7:3, Rf˜0.3; the 3-CH2Cl (7a) could not detected in TLC due to decomposition in TLC plate to 5a). Then solvent was removed by rotary evaporation and kept about 10 minutes in high vacuum pump. Then dissolved in 5 mL dry DMF and treated with 400 mg NaN3 (6.6 mmol) at room temperature for 3 h. Then the reaction mixture was partitioned in H2O/CH2Cl2, the combined organic part was dried over Na2SO4 and concentrated by rotary evaporation. The crude sample was then dissolved in 5 mL MeOH and treated with 300 mg NH4F (8.1 mmol) more than 38 h. Then MeOH was removed by rotary evaporation. After partioning in H2O/EtOAc, the combined organic part was dried over Na2SO4, concentrated, and purified by silica gel column chromatography (100% EtOAc to 98:2, EtOAc/MeOH) resulting 150 mg of 9a as white powder (48% yield in three steps). HR-MS: Obs. m/z 411.1530, calcd for C18H19O4N8 411.1529 [M+H]+. 1H-NMR (CDC3): δH 8.84 (brs, 1H), 8.70 (brs, 1H), 8.08 (m, 1H), 7.76-7.54 (m, 5H), 6.47 (t, J=5.6 Hz, 1H), 4.83 (m, 2H), 4.78 (m, 1H), 4.39 (m, 1H), 4.09 (d, J=12.78 Hz, H5′, 1H), 3.88 (d, J=12.78 Hz, H5″, 1H), 3.09 (m, H2′, 1H), and 2.65 (m, H2″, 1H) ppm.
Reaction SMILES: C([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[C:8]([CH3:16])=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)C.Cl[CH2:22][C:23]1[N:24]=[C:25]([C:29]2[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[C:31]([O:37][CH3:38])[CH:30]=2)[O:26][C:27]=1[CH3:28]>>[CH3:38][O:37][C:31]1[CH:30]=[C:29]([C:25]2[O:26][C:27]([CH3:28])=[C:23]([CH2:22][N:12]3[C:13]4[C:9](=[C:8]([CH3:16])[C:7]([CH2:6][CH:5]([O:17][CH2:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:15][CH:14]=4)[CH:10]=[CH:11]3)[N:24]=2)[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=1
Reactant: COc1cc(OC)cc(-c2nc(CCl)c(C)o2)c1
Reactant: CCOC(=O)C(Cc1ccc2[nH]ccc2c1C)OCC
Product: CCOC(Cc1ccc2c(ccn2Cc2nc(-c3cc(OC)cc(OC)c3)oc2C)c1C)C(=O)O

Procedure:
In analogy to the procedure described in example 44, rac-2-ethoxy-3-(4-methyl-1H-indol-5-yl)-propionic acid ethyl ester [preparation 10h)] was reacted with 4-chloromethyl-2-(3,5-dimethoxy-phenyl)-5-methyl-oxazole to give rac-3-{1-[2-(3,5-dimethoxy-phenyl)-5-methyl-oxazol-4-ylmethyl]-4-methyl-1H-indol-5-yl}-2-ethoxy-propionic acid as yellow solid.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.S(Cl)(Cl)=O.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[S:30][C:31]3[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:32]=3[N:33]=2)=[CH:25][CH:24]=1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[F:16][C:2]([F:1])([F:17])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[S:30][C:31]4[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:32]=4[N:33]=3)=[CH:27][CH:28]=2)=[O:13])=[CH:14][CH:15]=1
Reactant: COc1ccc2nc(-c3ccc(N)cc3)sc2c1
Reactant: O=C(O)c1ccc(OCCCC(F)(F)F)cc1
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc2nc(-c3ccc(NC(=O)c4ccc(OCCCC(F)(F)F)cc4)cc3)sc2c1
Temperature: 25 °C
Yield: 87.5 %

Procedure:
A mixture of 4-(4,4,4-trifluorobutoxy)benzoic acid (0.20 g, 0.806 mmol) and thionyl chloride (0.42 g, 3.54 mmol) in chloroform (5 ml) was heated under reflux for 8 h. The reaction mixture was cooled to room temperature and the excess reagent and solvent was removed under reduced pressure to give the crude acid chloride. The amide was prepared as described in the Amide Coupling section using the crude acid chloride and 2-(4-aminophenyl)-6-methoxybenzothiazole (0.206 g, 0.806 mmol) in dry pyridine (10 ml) to give the title compound (0.343 g, 87%) as a colourless solid after work-up.
Reaction SMILES: N1CCCCC1.[CH:7]1([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[CH:18][C:19]=3[N:20]3[CH2:26][C:25]([C:27](=[O:34])[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:24][C:23]4[CH:35]=[C:36]([O:39][CH3:40])[CH:37]=[CH:38][C:22]=4[C:21]=23)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH:48](=O)[CH:49]([CH3:51])[CH3:50]>CCO>[CH:7]1([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([C:41]([O:43][C:44]([CH3:46])([CH3:45])[CH3:47])=[O:42])=[CH:18][C:19]=3[N:20]3[CH2:26][C:25]([C:27](=[O:34])/[C:28](/[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:48]/[CH:49]([CH3:51])[CH3:50])=[CH:24][C:23]4[CH:35]=[C:36]([O:39][CH3:40])[CH:37]=[CH:38][C:22]=4[C:21]=23)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CC(C)C=O
Reactant: CCOC(=O)CC(=O)C1=Cc2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC(C)(C)C)cc3n2C1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)/C(=C\C(C)C)C(=O)C1=Cc2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC(C)(C)C)cc3n2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
Piperidine (17 μL, 0.18 mmol) was added to a stirring solution of tert-butyl 13-cyclohexyl-6-(3-ethoxy-3-oxopropanoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-10-carboxylate (1.0 g, 1.79 mmol) and isobutyraldehyde (16.4 mL, 179 mmol) in EtOH (9 mL) at room temperature. After 3 hrs of stirring an additional amount of piperidine (38 μL, 0.40 mmol) was added and the reaction was allowed to stir overnight at room temperature. The mixture was concentrated and was purified on silica gel (BIOTAGE®, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give the titled compound (950 mg, 1.55 mmol, 87% yield) consistent by LCMS and NMR as a yellow foamy sticky solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[C:12]=1[NH:13][CH3:14].[Cl:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([Cl:29])[C:25]=1[N:26]=[C:27]=S>C(#N)C>[Cl:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([Cl:29])[C:25]=1[NH:26][C:27]1[N:13]([CH3:14])[C:12]2[C:6]3[CH2:7][C:8]([CH3:11])([CH3:10])[O:9][C:5]=3[C:4]([C:15]([O:17][CH3:18])=[O:16])=[CH:3][C:2]=2[N:1]=1
Reactant: CNc1c(N)cc(C(=O)OC)c2c1CC(C)(C)O2
Reactant: S=C=Nc1c(Cl)cncc1Cl
Solvent: CC#N
Product: COC(=O)c1cc2nc(Nc3c(Cl)cncc3Cl)n(C)c2c2c1OC(C)(C)C2
Yield: 59.3 %

Procedure:
The title compound was prepared following the procedure described for step-1 of Intermediate-3 using methyl 5-amino-2,2-dimethyl-4-(methylamino)-2,3-dihydrobenzofuran-7-carboxylate (step-6 of Intermediate-49, 2.00 g, 8.0 mmol), 3,5-dichloro-4-isothiocyanatopyridine (Intermediate-2, 1.96 g, 9.6 mmol), N,N-di-isopropyl carbodimide (0.5 mL) and acetonitrile (10.0 mL) to afford 2.0 g of the desired product. 1HNMR (DMSO-d6): 1.47 (s, 6H), 3.49 (s, 2H), 3.56 (s, 3H), 3.73 (s, 3H), 7.10 (s, 1H), 8.46 (s, 2H), 10.79 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])#[N:2].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[N:2])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#Cc1ccccc1O
Reactant: BrCc1ccccc1
Product: N#Cc1ccccc1OCc1ccccc1

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 20 using 2-cyanophenol instead of tert-butyl N-(3′-hydroxybiphenyl-4-ylmethyl)-carbamate and benzyl bromide instead of 1-bromopropane.
Reaction SMILES: [Br:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].[Cl-].[NH4+].[CH2:16](O)C>O.[Fe]>[NH2:11][C:10]1[C:2]([Br:1])=[C:3]([CH:7]=[CH:8][CH:9]=1)[C:4]([O:6][CH3:16])=[O:5]
Reactant: CCO
Reactant: O=C([O-])c1cccc([N+](=O)[O-])c1Br
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: COC(=O)c1cccc(N)c1Br
Temperature: 80 °C

Procedure:
To stirred solution of above crude 2-bromo-3-nitrobenzoate (4 g, 15.38 mmol) in ethanol (20 mL), ammonium chloride (4 g, 74.0 mmol) dissolved in water (20 mL) and iron powder (6.87 g, 123 mmol) were added under stirring. The resulting reaction mixture was heated at 80° C. for 7 h. On completion, the reaction mixture was filtered through celite, washing with water and ethyl acetate and the filtrate extracted with ethyl acetate. The combined organic layers were dried and concentrated under reduced pressure giving the desired crude product (3 g).
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].CS(O[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=1)(=O)=O.CCOC(C)=O>CO.CN(C=O)C.[Cl-].[Na+].O>[CH3:28][S:25]([O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][CH2:16][S:3][C:1](=[O:4])[CH3:2])=[CH:19][CH:20]=1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)OCCc1ccc(OS(C)(=O)=O)cc1
Reactant: CC(O)=S
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)SCCc1ccc(OS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Thioacetic acid (0.28 g, 3.73 mmol) was dissolved in anhydrous MeOH (3 mL) and Cs2CO3 (1.10 g, 3.39 mmol) was added. After 15 min. stirring at room temperature the MeOH evaporated under reduced pressure and the remaining oil was redissolved in anhydrous DMF (3 ml). Methanesulfonic acid 4-(2-methanesulfonyloxy-ethyl)-phenyl ester (1.00 g, 3.39 mmol), dissolved in anhydrous DMF (2 mL) was added dropwise and the reaction was stirred at room temperature for 4 h. Additional thioacetic acid (0.14 g, 1.86 mmol) was added to the reaction mixture. After 30 min. stirring, the mixture was partioned between EtOAc and brine. The separated organic layer was dried (Na2SO4) and finally concentration under reduced pressure. The crude material was purified by flash chromatography on silica gel 60 using n-heptan/EtOAc 7:3 as the eluent to afford the title compound as an oil. 1H NMR (400 MHz, CDCl3): δ 7.17-7.25 (m, 4H), 3.10 (s, 3H), 3.05-3.08 (t, 2H), 2.83-2.86 (t, 2H), 2.30 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[C:12](=[O:13])[NH:11][N:10]=[C:9]1[CH2:14][C@@H:15]1[CH2:19][CH2:18][N:17]([C:20]([O:22]C(C)(C)C)=O)[CH2:16]1.Cl.C(N(CC)C(C)C)(C)C.[CH3:45][C:46](C)([CH3:50])[C:47](Cl)=O.[NH4+].[Cl-]>O1CCOCC1.ClCCl>[CH3:45][C:46]([CH3:50])([CH3:47])[C:20]([N:17]1[CH2:18][CH2:19][C@@H:15]([CH2:14][C:9]2[N:8]([C:7]3[CH:6]=[CH:5][C:4]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)=[CH:3][C:2]=3[F:1])[C:12](=[O:13])[NH:11][N:10]=2)[CH2:16]1)=[O:22]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1ccc(-c2ccc(-n3c(C[C@@H]4CCN(C(=O)OC(C)(C)C)C4)n[nH]c3=O)c(F)c2)cc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2ccc(-n3c(C[C@@H]4CCN(C(=O)C(C)(C)C)C4)n[nH]c3=O)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 8 mL screwcap vial was placed 1,1-dimethylethyl (3S)-3-({4-[3-fluoro-4′-(methyloxy)-4-biphenylyl]-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl}methyl)-1-pyrrolidinecarboxylate (0.162 mmol). Added to the vial was 4N HCl in dioxane (1 mL). The reaction was capped and stirred at room temperature for 2 h. The solution was concentrated in vacuo. Added to the vial were dichloromethane (1 mL) and N,N-diisopropylethylamine (0.573 mmol). In a separate vial, trimethylacetyl chloride (0.163 mmol) was taken up in 1 mL dichloromethane and was added to the starting material dropwise via pipette. The vial was capped and the reaction was stirred at room temperature for 2 h. Dichloromethane (2 mL) was added to the vial, followed by the addition of saturated aq NH4Cl. The vial was capped and lightly agitated for 1 min. The organic layer was separated, filtered through a plug of sodium sulfate, and concentrated in vacuo. Reverse phase HPLC (10-80% acetonitrile/water+0.1% NH4OH) was utilized in purifying the title compound (37 mg, 50%). MS(ES)+ m/e 453.1 [M+H]+.