Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=1[CH3:8].Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=1[O:26][CH3:27])=O>CC(C)=O>[CH3:27][O:26][C:19]1[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:18]=1[C:16]1[N:1]=[C:2]([C:3]2[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=2[CH3:8])[S:13][CH:15]=1
Reactant: COc1ccc(C(=O)CBr)c(OC)c1
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Solvent: CC(C)=O
Product: COC(=S)c1cc(-c2nc(-c3ccc(OC)cc3OC)cs2)c(C)s1
Yield: 54.8 %

Procedure:
Methyl 4-[4-(2,4dDimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate: 99 mg (0.424 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, U.K.) was dissolved in 5 mL of reagent grade acetone. 2-Bromo-2′,4′-dimethoxyacetophenone (0.440 mmol; 114 mg) was added and the solution was allowed to reflux for 2.5 h. The solution was allowed to cool and the crude product was collected as a solid and washed with methanol and dried yielding 91 mg (56% yield) of methyl 4-[4-(2,4-dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:26]([N+:27]([O-])=O)=[CH:25][C:12]2[N:13]=[C:14]([CH3:24])[N:15]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:11]=2[CH:10]=1.O.O.[Sn](Cl)(Cl)(Cl)Cl>C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[NH2:27][C:26]1[C:9]([O:8][C:7]2[CH:6]=[CH:5][C:4]([CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:3][C:2]=2[Cl:1])=[CH:10][C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:21])([CH3:23])[CH3:22])[C:14]([CH3:24])=[N:13][C:12]=2[CH:25]=1
Reactant: COC(=O)Cc1ccc(Oc2cc3c(cc2[N+](=O)[O-])nc(C)n3COCC[Si](C)(C)C)c(Cl)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(Oc2cc3c(cc2N)nc(C)n3COCC[Si](C)(C)C)c(Cl)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Under an N2 atmosphere, methyl 2-(3-chloro-4-(2-methyl-6-nitro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-benzo[d]imidazol-5-yloxy)phenyl)acetate (0.220 g, 0.435 mmol) was dissolved in ethyl acetate (10 mL) and tin chloride dihydrate (0.392 g, 0.174 mmol) was added. The reaction was allowed to stir at room temperature for 2.5 h. The reaction was diluted with 10% NaHCO3 (aq) and ethyl acetate. The layers were separated and the organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo, afforded the title compound. LC-MS ESI (pos.) m/z: 476.0 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](I)=[CH:9][N:10]=2)[CH:7]=1.C([Mg]Br)(C)C.[C:17](Cl)(=[O:21])[O:18][CH2:19][CH3:20].C(=O)(O)[O-].[Na+]>O1CCCC1.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:17]([O:18][CH2:19][CH3:20])=[O:21])=[CH:9][N:10]=2)[CH:7]=1
Reactant: CCOC(=O)Cl
Reactant: Brc1ccc2ncc(I)n2c1
Agent: CC(C)[Mg]Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cnc2ccc(Br)cn12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A mixture of 9.69 g 6-bromo-3-iodoimidazo[1,2-a]pyridine (compound in Production Example 49) and 450 mL anhydrous tetrahydrofuran was added little by little to 4.5 mL isopropyl magnesium bromide (0.75 M tetrahydrofuran solution) under ice-cooling in a stream of nitrogen. Then, this reaction solution was returned to room temperature and stirred for 1.5 hours. The reaction solution was cooled to −60° C. or less in a dry ice/acetone bath, 50 mL solution of 4.5 mL ethyl chlorocarbonate in anhydrous tetrahydrofuran was added dropwise thereto over 30 minutes, and the temperature of the reaction solution was increased to 0° C. After saturated sodium bicarbonate was added to the reaction solution, ethyl acetate and water were added thereto, and the organic layer was separated. The aqueous layer was saturated with common salt and then extracted with ethyl acetate. The combined organic layer was washed with brine and then dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was evaporated. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 5.09 g of the title compound as white crystals.
Reaction SMILES: [O:1]([C@@H:9]1[C@@H:16]2[N:12]([C:13](=[O:28])[N:14]([C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([Cl:26])[C:19]=3[CH3:27])[C@H:15]2[CH3:17])[CH2:11][CH2:10]1)[Si](C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:1][C@@H:9]1[C@@H:16]2[N:12]([C:13](=[O:28])[N:14]([C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([Cl:26])[C:19]=3[CH3:27])[C@H:15]2[CH3:17])[CH2:11][CH2:10]1
Reactant: Cc1c(N2C(=O)N3CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]3[C@@H]2C)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1c(N2C(=O)N3CC[C@H](O)[C@H]3[C@@H]2C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
To a solution of 61J (369 mg) in THF (4 mL) was added TBAF (1.0 M in THF, 1.3 mL). The reaction was stirred at rt for 1 h. The reaction was extracted with EtOAc which was washed three times with water, dried over MgSO4, filtered and concentrated. Purification by reverse phase HPLC (Phenomenex Luna 20×100 mm S5 C18, 10 min. grad, 20 mL/min, 20-100% B solvent, A=10% MeOH/water+0.1% TFA, B=90% MeOH/Water+0.1% TFA) provided the title compound (186 mg): MS (ES) m/z 306.42 [M+H]+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21]([C:26](O)=[O:27])=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:29]([O:31][C:32]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)=[O:33])[CH3:30]>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21]([C:26]([N:37]2[CH2:36][CH2:35][N:34]([C:32]([O:31][CH2:29][CH3:30])=[O:33])[CH2:39][CH2:38]2)=[O:27])=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Reactant: CCOC(=O)N1CCNCC1
Product: CCOC(=O)N1CCN(C(=O)c2cc3cc(C(=O)N4CCCN(C(=O)OC(C)(C)C)CC4)ccc3[nH]2)CC1

Procedure:
The title compound was synthesized in analogy to example 47a), from 5-(4-tert-butoxycarbonyl-[1,4]diazepane-1-carbonyl)-1H-indole-2-carboxylic acid and 4-ethoxycarbonylpiperazine. Off-white solid. MS (m/z): 505.2 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.O=C1CCC(=O)N1[O:17][C:18](=O)[C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26](=[O:35])[N:27]([CH3:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:21][CH:20]=1>>[CH3:1][N:2]([CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)[C:18]([C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26](=[O:35])[N:27]([CH3:34])[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:21][CH:20]=1)=[O:17]
Reactant: CNCc1cccnc1
Reactant: CN(C(=O)Oc1ccc(C(=O)ON2C(=O)CCC2=O)cc1)c1ccccc1
Product: CN(Cc1cccnc1)C(=O)c1ccc(OC(=O)N(C)c2ccccc2)cc1

Procedure:
The title product was prepared from methyl-pyridin-3-ylmethyl-amine and 4-(methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester. The crude product was subjected to preparative HPLC (method C) (48%, clear colourless oil). HPLC-MS m/z=376.2 (M+1), Rt: 2.37 min.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([CH:23]=[CH2:24])[CH:20]=[CH:19][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([CH3:16])([CH3:15])[O:13][B:12]([OH:17])[C:11]=2[CH:18]=1)=[O:5].[C:25]([Sn](CCCC)(CCCC)CCCC)(C)=C>>[Cl:1][C:2]1[CH:22]=[C:21]([C:23]([CH3:25])=[CH2:24])[CH:20]=[CH:19][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([CH3:16])([CH3:15])[O:13][B:12]([OH:17])[C:11]=2[CH:18]=1)=[O:5]
Reactant: C=C(C)[Sn](CCCC)(CCCC)CCCC
Reactant: C=Cc1ccc(C(=O)Nc2ccc3c(c2)B(O)OC3(C)C)c(Cl)c1
Product: C=C(C)c1ccc(C(=O)Nc2ccc3c(c2)B(O)OC3(C)C)c(Cl)c1

Procedure:
The title compound was prepared using a procedure similar to that of 2-chloro-N-(1-hydroxy-3,3-dimethyl-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-vinyl-benzamide with isopropenyl tributylstannane replacing tributyl(vinyl)tin. Data: LCMS (M/Z): 356 (M+H); 1H NMR (DMSO-d6) δ: 1.44 (s, 6 H) 2.14 (s, 3 H) 5.24 (s, 1 H) 5.57 (s, 1 H) 7.38 (d, J=8.2 Hz, 1 H) 7.57 (ddd, J=1.5, 1.0, 0.8 Hz, 2 H) 7.62-7.66 (m, 1 H) 7.69 (dd, J=8.2, 2.0 Hz, 1 H) 8.05 (dd, J=1.6, 0.6 Hz, 1 H) 9.09 (br. s., 1 H) 10.49 (s, 1 H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6](O)=[O:7])#[N:2].C1(C)C=CC=CC=1.S(Cl)([Cl:23])=O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([Cl:23])=[O:7])#[N:2]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C(=O)O)cc1C#N
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Cl)cc1C#N
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To 3-cyano-4-methoxybenzoic acid (1.78 g), toluene (20 mL), N,N-dimethylformamide (3 droplets) and thionyl chloride (1.14 mL) were added, and then the mixture was stirred at 60° C. for 16 hours. The solvent was distilled off under reduced pressure and the obtained residue was azeotroped with toluene and used for the synthesis of (d).
Reaction SMILES: [C:1]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH:20]=O)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[C:22]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1C=CC=CC=1.CCOCC.O>[C:1]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH:20]=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:22]([O:30][CH2:31][CH3:32])=[O:29])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCCCCCCCCCCC#Cc1cnccc1C=O
Agent: O=C(O)c1ccccc1
Solvent: CCOCC
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCCCCCCC#Cc1cnccc1C=C(C(=O)OCC)C(=O)OCC
Yield: 45.8 %

Procedure:
A mixture of 3-(1-tridecynyl)pyridine-4-carboxaldehyde (7.13 g, 25 mmole, from Example 1), diethyl malonate (4.12 g), benzoic acid (0.145 g) and piperidine (0.18 ml) in benzene (45 ml) was refluxed under conditions of water removal for 24 hours. After cooling, ether was added and the solution was washed with dilute sodium bicarbonate solution and dried. Evaporation and distillation of excess diethyl malonate under reduced pressure afforded an oil which on silica gel chromatography gave 4.90 g (46%) of the title compound as a pale yellow oil, bp0.1 250° C. (Kugelrohr), νmax (film) 2930, 2850, 2220, 1730, 1640, 1250, 1215 cm-1 ; δ(CDCl3) 0.83 (3H, distorted t, terminal CH3), 1.12-1.65 (24H, m, ester CH3 +alkylene envelope), 2.43 (2H, t, J 6 Hz, CH2C≡C), 4.22 (2H, q, J 7 Hz, ester CH2), 4.30 (2H, q, J 7 Hz, ester CH2), 7.25 (1H, d, J 5 Hz, C-5H), 7.99 (1H, s, CH=C), 8.42 (1H, d, J 5 Hz, C-6H), 8.63 (1H, s, C-2H).
Reaction SMILES: [N:1]([C@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[N:10]1[CH2:14][CH2:13][C@@H:12]([NH:15]C(=O)OC(C)(C)C)[CH2:11]1)=[N+:2]=[N-:3]>Cl.O1CCOCC1>[N:1]([C@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[N:10]1[CH2:14][CH2:13][C@@H:12]([NH2:15])[CH2:11]1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN([C@@H]2CCCC[C@@H]2N=[N+]=[N-])C1
Agent: Cl
Solvent: C1COCCO1
Product: [N-]=[N+]=N[C@H]1CCCC[C@H]1N1CC[C@@H](N)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 124.5 %

Procedure:
The mixture of tert-butyl [(3R)-1-(cis-2-azidocyclohexyl)pyrrolidin-3-yl]carbamate (0.57 g, 1.842 mmol) in 4 N HCl/dioxane (10 mL) was stirred at room temperature for 1 hour. The solution was concentrated to give 0.48 g of the title compound as HCl salt. MS (EI) calcd: (M+H)+=210.2. Found: 210.2.
Reaction SMILES: C[C:2]1(C)[C:14]2[CH:13]=[C:12](B(O)O)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][C:5](B(O)O)=[CH:6][CH:7]=2.IC1C=CC2C3C(=CC(I)=CC=3)C(C)(C)C=2C=1.C([O-])([O-])=O.[Na+].[Na+].Cl>C1COCC1.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.CCCCCC.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH:4]1[C:3]2[CH2:2][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: CC1(C)c2cc(B(O)O)ccc2-c2ccc(B(O)O)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)c2cc(I)ccc2-c2ccc(I)cc21
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: c1ccc2c(c1)Cc1ccccc1-2
Temperature: 25 °C

Procedure:
With 9,9-dimethylfluorene-2,7-diboronic acid and 2,7-diiodo-9,9-dimethyl fluorene, which are synthesized according to synthesis example 1, a Suzuki reaction is carried out. Under a nitrogen atmosphere, tetrakis(triphenylphosphine)palladium(0) (1.0 mmol) is dissolved in THF (50 ml), followed by adding thereto 2,7-diiodo-9,9-dimethyl fluorene (50 mmol), a solution of 2M Na2CO3 (50 ml) and 9,9-dimethylfluorene-2,7-diboronic acid (25 mmol)/THF (100 ml) in this order. Thereafter, after refluxing for 7 hr, a reaction is brought to an end. The solution is cooled to room temperature, followed by substituting with toluene and adding substantially 30 ml of 1N HCl, further followed by washing a toluene phase with water until neutrality is obtained. After drying with sodium sulfate, followed by filtering and distilling the solvent away, and thereby a crude product is obtained. After washing with substantially 100 ml of methanol, a colorless crystal is obtained. Furthermore, by passing through a short column from hexane/ethyl acetate to remove original components, finally followed by recrystallizing, and thereby fluorene trimer (20 mmol) is obtained.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:11]3[C:16]([F:17])=[C:15]([F:18])[CH:14]=[C:13]([F:19])[C:12]=3[F:20])[N:9]=[CH:10][C:3]=12.[O:21]1CC[O:23][BH:22]1.C([O-])(=O)C.[K+].C(Cl)Cl>CS(C)=O>[F:20][C:12]1[C:13]([F:19])=[CH:14][C:15]([F:18])=[C:16]([F:17])[C:11]=1[N:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([B:22]([OH:23])[OH:21])=[C:3]2[CH:10]=[N:9]1
Reactant: B1OCCO1
Reactant: Fc1cc(F)c(F)c(-n2ncc3c(I)ccnc32)c1F
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: OB(O)c1ccnc2c1cnn2-c1c(F)c(F)cc(F)c1F
Temperature: 105 °C

Procedure:
To a 48 mL pressure bottle under N2 was added the compound from Intermediate 69A (1.1 g, 2.8 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane (1.17 g, 4.61 mmol), potassium acetate (1.15 g, 11.72 mmol), and anhydrous DMSO (8 mL). Argon was bubbled into the reaction mixture for 5 min and then PdCl2(dppf).CH2Cl2 (71 mg, 0.097 mmol) was added. The reaction mixture was flushed with argon, securely capped, and heated at 105° C. for 75 min. After adding 30 mg more palladium catalyst and 60 mg more 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane, the reaction mixture was heated at 115° C. in an oil bath for an additional 75 min to give the desired intermediate. LC/MS (Condition B): ret. T=3.2 min, (M+H)+ 312.03.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)#[N:17].C([O-])([O-])=O.[Na+].[Na+]>CO.[Pd]>[C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=2)=[CH:20][CH:19]=1)#[N:17]
Reactant: COC(=O)c1cc(I)cc(C(=O)OC)c1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(C(=O)OC)cc(-c2ccc(C#N)cc2)c1
Reaction time: 1 h
Yield: 85 %

Procedure:
A solution of dimethyl 5-iodoisophthalate (6 g, 18.75 mmol, 1 eq.), 4-cyanophenylboronic acid (2.95 g, 19.68 mmol, 1.05 eq.) and Na2CO3 (7.95 g, 74.98 mmol, 4 eq.) in 400 mL of MeOH was degassed by 4 thaw-freeze-pump cycles. Then 1.3 g of 5% Pd/C was added and nitrogen gas was bubbled through the solution for 10 min. The reaction under stirring was carried out at 80° C. for 1 h. Then, the mixture was filtered and washed with EtOH and CH2Cl2. All organic solvents were removed under vacuum and aqueous layer was extracted 4 times with CH2Cl2, the recombined organic layer were washed once with H2O, dried over MgSO4, filtered and evaporated under vacuum. An off-white solid was obtained with 85% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:16][CH2:17][CH2:18][CH2:19][Cl:20])=[CH:5][C:6]([N+:13]([O-])=O)=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9]>[Pd].C(O)=O>[CH3:1][O:2][C:3]1[CH:12]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:6]([NH2:13])=[CH:5][C:4]=1[O:16][CH2:17][CH2:18][CH2:19][Cl:20]
Reactant: COC(=O)c1cc(OC)c(OCCCCl)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: O=CO
Product: COC(=O)c1cc(OC)c(OCCCCl)cc1N
Reaction time: 8 h
Yield: 86.6 %

Procedure:
In a 50 mL volume glass flask equipped with a stirrer, a thermometer and a reflux condenser were placed 1.01 g (3.29 mmol) of methyl 5-methoxy-4-(3-chloropropoxy)-2-nitrobenzoate (purity: 99%) obtained in Reference Example III-4, 0.5 g of 10 wt. % palladium/carbon, and 10 mL of formic acid. The reaction was carried out at 60° C. for 8 hours. After the reaction was complete, the reaction mixture was filtered. The filtrate was analyzed by high performance liquid chromatography (absolute quantitative analysis). There was produced 0.78 g (reaction yield: 87.0%) of methyl 5-methoxy-4-(3-chloropropoxy)-anthranilate.
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.O[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26].C(N(CC)CC)C>C(#N)C>[CH2:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](=[O:26])[O:27][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: O=C(O)CCCCCCCCCCCCCCO
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CCCCCCCCCCCCCCO1
Yield: 84 %

Procedure:
To a refluxing solution of 510 mg (2.0 mmol) of 2-chloro-1-methylpyridinium iodide in 50 ml of acetonitrile, there was added a solution of 134 mg (0.5 mmol) of 15-hydroxypentadecanoic acid and 404 mg (4.0 mmol) of triethylamine in 40 ml of acetonitrile over a period of 8 hours at a continuous and uniform rate, and the reaction mixture was refluxed for an additional 30 minutes after the addition was completed. After evaporation of the solvent, the residue was separated chromatographically on a silica gel column. 1,15-pentadecanolide was obtained in 84% yield.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[F:30]>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[C:7]([CH3:17])[C:6]=3[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=2)=[CH:23][C:22]=1[F:30]
Reactant: OB(O)c1ccc(Cl)c(F)c1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCCNC2=O
Product: Cc1c2n(c3c(-c4ccc(Cl)c(F)c4)cc(C#N)cc13)CCCNC2=O

Procedure:
The title compound, off-white solid (85 mg, 92%), MS (ISP) m/z=368.4 [(M+H)+], mp 247.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-11-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 17) (79.5 mg, 0.25 mmol) and commercially available 4-chloro-3-fluoro-phenylboronic acid (56.7 mg, 0.325 mmol).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[N:34][C:35]([S:38][CH2:39][C:40]5[N:44]([CH2:45][CH2:46][CH3:47])[CH:43]=[N:42][CH:41]=5)=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[N:34][C:35]([S:38]([CH2:39][C:40]5[N:44]([CH2:45][CH2:46][CH3:47])[CH:43]=[N:42][CH:41]=5)=[O:57])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cncn4CCC)nc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cncn4CCC)nc2)CCN3CC(C)C)cc1
Reaction time: 0.25 h
Yield: 28.6 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[6-[[(1-propylimidazol-5-yl)methyl]sulfanyl]-3-pyridinyl]-2,3-dihydro-1-benzazepine-4-carboxamide (1.4 g) was dissolved in methylene chloride (42 ml), and a solution of m-chloroperbenzoic acid (0.65 g) in methylene chloride (28 ml) was added dropwise to the solution at −78° C. The mixture was stirred for 15 minutes, and an aqueous solution of saturated sodium thiosulfate was added to the mixture. The mixture was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[6-[[(1-propylimidazol-5-yl)methyl]sulfinyl]-3-pyridinyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 297) (0.41 g).
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([OH:15])=[O:14])[CH2:5]1)#[N:2].[C:16](O)([CH3:19])([CH3:18])[CH3:17].C1(N=C=NC2CCCCC2)CCCCC1.C(OCC)C>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5]1)#[N:2]
Reactant: CC(C)(C)O
Reactant: CC1(C)O[C@H](CC#N)C[C@H](CC(=O)O)O1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CC#N)OC(C)(C)O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(±)-cis-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid (3.72 g, 17.44 mmol) is dissolved in 20 mL of dichloromethane, cooled to 0° C. and 0.2 g of 4-dimethylaminopyridine (DMAP) is added, followed by t-butyl alcohol and followed by 4.32 g of dicyclohexylcarbodiimide (DCC). This solution is allowed to slowly warm to room temperature over a 76.5-hour period. Thin layer chromatography (TLC) shows mainly product, and some slightly lower Rf by-products. The mixture is stirred one hour and 50 mL of dichloromethane is added and stirring continues five hours. An additional 100 mL of diethyl ether is added and the mixture filtered. The precipitate is washed with diethyl ether. The filtrate is concentrated to an oil. The crude product is chromatographed on silica gel eluting with 4:1 hexane:ethyl acetate. The eluate is concentrated to yield (±)-cis-1,1-dimethylethyl 6-(cyanomethyl)-2,2-dimethyl-1,3-dioxane-4-acetate.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[N:7][C:6]=2[CH:10]=1.[CH3:11][N:12](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[S:9]1[C:5]2[CH:4]=[CH:3][C:2]([C:11]#[N:12])=[CH:10][C:6]=2[N:7]=[CH:8]1
Reactant: CN(C)C=O
Reactant: Brc1ccc2scnc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc2scnc2c1
Temperature: 80 °C

Procedure:
Into a mixture of 5-bromo-1,3-benzothiazole (300 mg, 1.40 mmol, 1.00 equiv) and zinc cyanide (131.6 mg, 0.80 equiv) in N,N-dimethylformamide (6.0 mL) was added Pd(PPh3)4 (80.9 mg, 0.07 mmol, 0.05 equiv) and nitrogen was bubbled for 5 min. The resulting mixture was heated overnight at 80° C., quenched by water (15.0 mL), and extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with brine (2×15 mL) and dried over Na2SO4. After filtered and concentrated under reduced pressure, the residue was purified by flash chromatography on silica gel, eluting with a mixture of 5-10% ethyl acetate in petroleum ether to afford the title compound as a light yellow solid. MS m/z [M+H]+ (ESI): 161.