Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:13]=[N:12][C:11]2[NH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[CH:17]=[O:18].O>C1COCC1>[Cl:7][C:8]1[C:9]([CH:17]([CH:1]2[CH2:4][CH2:3][CH2:2]2)[OH:18])=[C:10]2[CH:16]=[CH:15][NH:14][C:11]2=[N:12][CH:13]=1
Reactant: O=Cc1c(Cl)cnc2[nH]ccc12
Reactant: Br[Mg]C1CCC1
Solvent: O
Solvent: C1CCOC1
Product: OC(c1c(Cl)cnc2[nH]ccc12)C1CCC1
Temperature: 25 °C

Procedure:
The solution of cyclobutylmagnesium bromide (0.28 M in THF, 56 mL, 63 mmol) was added to a solution of 5-chloro-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde (0.908 g, 5.03 mmol, Adesis) in THF (30 mL) at about 0° C. The reaction mixture was stirred and allowed to warm to ambient temperature and the reaction mixture was stirred for about 16 h. Water (10 mL) was added and the volatiles were removed under reduced pressure. The product was extracted into DCM (3×20 mL) and the combined organic phases were dried over anhydrous MgSO4, filtered, the solvent was removed under reduced pressure and the crude material was purified by column chromatography over silica gel using a 10 to 45% gradient of EtOAc in heptane as the eluent to provide (5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)(cyclobutyl)methanol as an off white solid (0.42 g, 32%); LC/MS (Table 2, Method a) Rt=2.02 min; m/z: 237 and 239 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([C:18]([F:21])([F:20])[F:19])[C:3]=1[NH:22][C:23](=[O:34])[C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26](F)[C:25]=1[F:33].C(=O)([O-])[O-].[NH4+:39].[NH4+].O.C(OCC)(=O)C>CS(C)=O>[NH2:39][C:26]1[C:25]([F:33])=[C:24]([CH:29]=[CH:28][C:27]=1[C:30]#[N:31])[C:23]([NH:22][C:3]1[C:4]([C:18]([F:20])([F:21])[F:19])=[CH:5][C:6]([C:8]([F:17])([C:13]([F:15])([F:14])[F:16])[C:9]([F:10])([F:12])[F:11])=[CH:7][C:2]=1[Br:1])=[O:34]
Reactant: [NH4+]
Reactant: N#Cc1ccc(C(=O)Nc2c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2C(F)(F)F)c(F)c1F
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(C(=O)Nc2c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2C(F)(F)F)c(F)c1N
Temperature: 100 °C
Reaction time: 5 h
Yield: 51 %

Procedure:
To a solution of N-(2-bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)-4-cyano-2,3-difluorobenzamide in 5 ml of DMSO was added 49.0 mg of ammonium carbonate, followed by stirring 100° C. for 5 hours. To the reaction liquid were added water and ethyl acetate, and the organic layer was washed with water, and then and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent solvent; hexane:ethyl acetate=8:1→4:1) to prepare 0.30 g (yield 51%) of a target compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([S:9]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C1CCNC1
Reactant: O=S(=O)(Cl)c1ccc(F)c(Br)c1
Solvent: ClCCl
Product: O=S(=O)(c1ccc(F)c(Br)c1)N1CCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
To a solution of 3-bromo-4-fluorobenzene-1-sulfonyl chloride (1.0 g, 3.66 mmol) in 20 mL dichloromethane at 0° C. was added pyrrolidine (0.635 mL, 7.68 mmol). The mixture was stirred at 0° C. for 30 minutes and then at room temperature overnight. The reaction mixture was diluted with dichloromethane, washed with 1% HCl solution and water, dried over anhydrous magnesium sulfate, filtered, and concentrated to give the title compound (0.86 g, 76% yield)
Reaction SMILES: C([O:3][C:4](=[O:23])[CH:5]([CH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1[Br:22])C(OCC)=O)C.[OH-].[Na+]>C(O)C.O>[Br:22][C:13]1[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:20])[F:19])=[CH:17][C:12]=1[CH2:11][CH2:5][C:4]([OH:23])=[O:3]
Reactant: CCOC(=O)C(Cc1cc(C(F)(F)F)ccc1Br)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCc1cc(C(F)(F)F)ccc1Br

Procedure:
To a solution of diethyl[2-bromo-5-(trifluoromethyl)benzyl]malonate (22.9 g, 57.6 mmol) in ethanol (100 mL) and water (50 mL) was added a 5 M solution of sodium hydroxide in water (30 mL). The mixture was heated to reflux for 2 h. Ethanol was removed by evaporation. The aqueous layer was extracted with ether and then acidified with concentrated HCl to pH 5 at which time a lot of white solid precipitated out. The solid was collected by filtration. The filtrate was extracted with ethyl acetate twice, and the extracts were washed with brine, dried (MgSO4) and concentrated to give a white solid.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([O:17][CH3:18])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][C:14]([OH:16])=O)[CH:7]=1.[CH2:20]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH2:30])=[CH:24][CH:23]=1)[CH3:21].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH2:20]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH:30][C:14]([CH2:13][O:12][C:8]2[CH:7]=[C:6]([CH2:5][CH:4]([O:17][CH3:18])[C:3]([OH:2])=[O:19])[CH:11]=[CH:10][CH:9]=2)=[O:16])=[CH:24][CH:23]=1)[CH3:21]
Reactant: CCc1ccc(CCN)cc1
Reactant: COC(=O)C(Cc1cccc(OCC(=O)O)c1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CCc1ccc(CCNC(=O)COc2cccc(CC(OC)C(=O)O)c2)cc1

Procedure:
The title compound was prepared from 3-(3-carboxymethoxy-phenyl)-2-methoxy-propionic acid methyl ester (PREPARATION 4, step 2) and 2-(4-ethyl-phenyl)-ethylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C22H27NO5 [M+H]+: 386.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[C:9]1([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[CH2:8][CH:7]2[CH2:16][C:17]([O:19]C)=[O:18].[Cl:21][C:22]1[C:32](Cl)=[CH:31][CH:30]=[CH:29][C:23]=1[CH:24]=[CH:25][C:26](O)=[O:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[C:9]1([CH2:10][CH2:11][N:12]([C:26](=[O:27])/[CH:25]=[CH:24]/[C:23]3[CH:29]=[CH:30][CH:31]=[CH:32][C:22]=3[Cl:21])[CH2:13][CH2:14]1)[CH2:8][CH:7]2[CH2:16][C:17]([OH:19])=[O:18]
Reactant: COC(=O)CC1CC2(CCNCC2)c2c(Cl)cccc21
Reactant: O=C(O)C=Cc1cccc(Cl)c1Cl
Product: O=C(O)CC1CC2(CCN(C(=O)/C=C/c3ccccc3Cl)CC2)c2c(Cl)cccc21

Procedure:
The title compound was prepared employing a procedure analogous to that described in Example 1 using methyl 2-(7-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate and 2,3-dichlorocinnamic acid followed by a procedure analogous to that described in Example 2. LC-MS Method 1 tR=1.88, min, m/z=444, 446, 448; 1H NMR (CDCl3) 1.40 (dd, 1H), 1.52 (d, 2H), 1.74 (m, 1H), 2.39 (m, 1H), 2.48 (m, 1H), 2.6-3.2 (4H), 3.30 (m, 1H), 3.62 (m, 1H), 4.11 (d, 1H), 4.80 (d, 1H), 6.92 (d, 1H), 7.05-7.30 (5H), 7.41 (m, 1H), 7.62 (m, 1H), 8.00 (d, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:71]=[CH:70][C:67]([C:68]#[N:69])=[CH:66][N:65]=1>>[C:68]([C:67]1[CH:70]=[CH:71][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[N:65][CH:66]=1)#[N:69]
Reactant: N#Cc1ccc(N)nc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)cn2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Yield: 4.1 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.3 g, 0.52 mmol), was reacted with diisopropylethylamine (0.34 g, 2.6 mmol), diphenylphosphinic chloride (0.24 g, 1 mmol), then reacted with 6-aminonicotinonitrile (Oakwood) (0.09 g, 0.8°mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (5-cyano-pyridin-2-yl)-amide as a yellow solid (Yield 12 mg, 4%).
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:36]=[CH:35][C:10]([O:11][C:12]3[CH:13]=[C:14]([C:24]4[NH:28][C:27]([C:29]5[O:30][C:31]([CH3:34])=[N:32][N:33]=5)=[CH:26][CH:25]=4)[CH:15]=[C:16]([O:18][C@@H:19]([CH3:23])[CH2:20][O:21]C)[CH:17]=3)=[C:9]([F:37])[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br.ClCCl.C(=O)([O-])O.[Na+]>ClCCl>[N:1]1([C:5]([C:7]2[CH:36]=[CH:35][C:10]([O:11][C:12]3[CH:17]=[C:16]([CH:15]=[C:14]([C:24]4[NH:28][C:27]([C:29]5[O:30][C:31]([CH3:34])=[N:32][N:33]=5)=[CH:26][CH:25]=4)[CH:13]=3)[O:18][C@@H:19]([CH3:23])[CH2:20][OH:21])=[C:9]([F:37])[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(-c2ccc(-c3nnc(C)o3)[nH]2)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nnc(-c2ccc(-c3cc(Oc4ccc(C(=O)N5CCC5)cc4F)cc(O[C@@H](C)CO)c3)[nH]2)o1
Temperature: 0 °C
Reaction time: 3 h
Yield: 20.9 %

Procedure:
2-(5-{3-[4-(Azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrol-2-yl)-5-methyl-1,3,4-oxadiazole (379.2 mg, 0.748 mmol) synthesized in Example (66i) was dissolved in dichloromethane (15 mL), and a boron tribromide/dichloromethane solution (1M, 750 μL, 0.75 mmol) was added at −78° C. under nitrogen atmosphere, followed by stirring at 0° C. for 3 hours. To the reaction solution, a saturated aqueous sodium hydrogencarbonate solution was added, and extraction was carried out with ethyl acetate. The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/dichloromethane=2%-8%) to afford the desired compound (76.9 mg, yield 21%) as a pale yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:45])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[CH:35]=[C:34]([CH2:36][O:37]C3CCCCO3)[CH:33]=[N:32]2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:16][N:14]([CH3:15])[C:12]1[C:11]([C:17]([F:20])([F:18])[F:19])=[CH:10][C:9]2[NH:21][C:22](=[O:45])[CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N:31]4[CH:35]=[C:34]([CH2:36][OH:37])[CH:33]=[N:32]4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3cc(COC4CCCCO4)cn3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3cc(CO)cn3)c1)=N2

Procedure:
The title compound was prepared from (RS)-[5-dimethylamino-2-(3-oxo-3-{3-[4-(tetrahydro-pyran-2-yloxymethyl)-pyrazol-1-yl]-phenyl}-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M58) (590 mg, 0.91 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (299 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@H:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[CH:6]1[CH3:12].N1C=CN=C1.[C:18]([Si:22](Cl)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[CH3:21][C:18]([Si:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[O:1][CH2:2][CH2:3][CH2:4][C@H:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[CH:6]1[CH3:12])([CH3:19])[CH3:20]
Reactant: CC1C(=O)CCC[C@@H]1CCCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC1C(=O)CCC[C@@H]1CCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 111.9 %

Procedure:
To a solution of 13.5 g (79.6 mmole) of the (3R)-3-(3-hydroxypropyl)-2-methylcyclohexanone in 240 ml of DMF was added 10.82 g (159.2 mmole) of imidazole followed by a dropwise addition of a solution of 26.2 g (95.3 mmole) of t-butylchlorodiphenyl silane in 25 ml of DMF. After addition, the solution was stirred at room temperature for 3 hours, quenched with 260 ml of iced water and extracted with 2×750 ml of ether. The combined etheral extracts were washed with 3×200 ml of water which was back extracted with 2×200 ml of ether. The combined etheral extracts were washed with brine, dried over MgSO4, filtered and concentrated to give 36.4 g of the crude (3R)-3-[3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]propyl]-2-methylcyclohexanone which was used as such. An analytical sample was obtained by further purification of the above crude on a silica gel column (20:1, hexane/EtOAc). IR (CHCl3 ): 1130, 1700, 2850 cm-1. 1H NMR: δ0.98-1.05 (m, 12H), 1.15-1.70 (m, 7HO, 1.89 (m, 2H), 2.05 (m, 1H), 2.15 (m, 1H), 2.25 (m, 1H), 2.40 (m, 1H), 2.55 (m, 1H), 3.65 (m, 2H), 7.38 (m, 6H), 7.66 (m, 4H). Mass spectrum: M+ -CH3 (393). Anal. for C26H36O2Si: Calc. for C, 76.42; H, 8.88; Si, 6.87. Found: C, 76.16; H, 9.11; Si, 6.98.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:14][N:15]([CH3:20])[CH2:16][CH2:17][CH2:18]Cl.C1OCCOCCOCCOCCOCCOC1>C(#N)C>[CH3:14][N:15]([CH3:20])[CH2:16][CH2:17][CH2:18][N:3]1[CH2:4][CH2:5][S:1][C:2]1=[O:6]
Reactant: CN(C)CCCCl
Reactant: O=C1NCCS1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: CN(C)CCCN1CCSC1=O
Yield: 15.2 %

Procedure:
To a solution of 2-thiazolidinone (4.15 g, 40.18 mmol) in acetonitrile (60 ml) were added potassium carbonate (13.3 g 96.2 mmol), N,N-dimethyl-3-aminopropyl chloride hydrochloride (7.63 g, 48.3 mmol), and 18-crown-6 (catalytic amount). The mixture was refluxed for 18 hours, solvent removed in vacuo, then redissolved in dichloromethane and 1 M potassium chloride (40 ml each). The aqueous phase was isolated and extracted twice with 30 ml portions of dichloromethane. The combined organic fraction was washed with saturated sodium chloride (˜50 ml), dried over sodium sulfate, filtered, and dried in vacuo. The crude product was purified via silica gel chromatography, using a 10:1 ratio of silica gel A, 200-425 mesh, and eluting with 5% methanol in chloroform, yielding 1.15 g (15%) pure product.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.C([Mg]Br)C.[Cl:30][C:31]1[CH:46]=[CH:45][C:34]([C:35]([C:37]2[N:41]([CH3:42])[CH:40]=[C:39]([CH:43]=[O:44])[CH:38]=2)=[O:36])=[CH:33][CH:32]=1.O>C(Cl)Cl.CCOCC>[Cl:30][C:31]1[CH:46]=[CH:45][C:34]([C:35]([C:37]2[N:41]([CH3:42])[CH:40]=[C:39]([CH:43]([OH:44])[C:2]3[N:3]=[CH:4][N:5]([C:7]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:6]=3)[CH:38]=2)=[O:36])=[CH:33][CH:32]=1
Reactant: Cn1cc(C=O)cc1C(=O)c1ccc(Cl)cc1
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC[Mg]Br
Solvent: CCOCC
Solvent: O
Solvent: ClCCl
Product: Cn1cc(C(O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1C(=O)c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 138.9 %

Procedure:
To 4.4 g (0.01 mole) 4-iodo-1-tritylimidazole in 80 mL of CH2Cl2 was added dropwise 3.3 mL of 3.0 M ethylmagnesium bromide in Et2O. After stirring for 1 h, a solution of 1.0 g (0.004 mole) of 5-(4-chlorobenzoyl)-1-methyl-1H-pyrrole-3-carboxaldehyde in 10 mL of CH2Cl2 was added dropwise. The resulting reaction mixture was stirred for 2.5 h after which it was poured into water. The solid was filtered off through celite. The organics from the filtrate were separated off, washed with water, brine and dried (Na2SO4). The solvent was evaporated in vacuo to give 3.1 g of (4-chlorophenyl)-{4-[hydroxy-(1-trityl-1H-imidazol-4-yl)-methyl]-1-methyl-1H-pyrrol-2yl}-methanone: CI-MS m/z=559 (M++H). 1HNMR (CDCl3) δ 7.7 (m, 5H) 7.4-7.0 (m, 16H); 6.5 (m, 1H); 3.75 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][N:6]=1)=[O:4].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1C=CC=CC=1>O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(N)cn1
Reactant: O=Cc1ccccc1
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)c1ccc(N=Cc2ccccc2)cn1

Procedure:
The starting material is prepared as follows: The mixture of 17.4 g of 5-aminopyridine-2-carboxylic acid methyl ester, 14.0 g of benzaldehyde and 100 ml of benzene is stirred and refluxed on a water separator for 6.5 hours. The resulting clear solution is evaporated, and the residue recrystallized from benzene-hexane first, then from acetonitrile-diethyl ether, to yield the 5-benzylideneaminopyridine-2-carboxylic acid methyl ester, melting at 84°-89°.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:19])[C:7]([PH2]=O)=[C:8]([CH3:16])[CH:9](OCC)OCC)[CH3:4].[Br:20][C:21]1[CH2:25][CH2:24][CH2:23][C:22]=1[CH:26]=O>CN(C=O)C>[CH2:3]([O:5][C:6](=[O:19])/[CH:7]=[C:8](\[CH3:16])/[CH:9]=[CH:26]/[C:22]1[CH2:23][CH2:24][CH2:25][C:21]=1[Br:20])[CH3:4]
Reactant: O=CC1=C(Br)CCC1
Reactant: CCOC(=O)C([PH2]=O)=C(C)C(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C(C)/C=C/C1=C(Br)CCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
2.03 g of NaH (50% in mineral oil) was suspended in 120 ml of DMF. 4-(Diethoxy-phosphinyl-3-methyl-but-2-enoic acid ethyl ester (12.9 g) was added at 0° C. The mixture was stirred for 15 minutes at 0° C. and for 30 minutes at RT. After recooling to 0° C., 2-bromo-cyclopent-1-ene-carbaldehyde (5.72 g), dissolved in 11 ml of DMF, was added drop by drop and allowed to react for 10 minutes at 0° C. and for 2 hours at RT. The mixture was then poured into crashed ice. extracted with EtOEt, washed with sat. NaCl-solution, dried over Na2SO4, and evaporated to dryness. Purification of the residue by flash chromatography (silica gel, hexane/AcOEt=97/3) and crystallization from hexane/trace amounts of AcOEt yielded finally 3.408 g of pure (2E,4E)-5-(2-bromo-cyclopent-1-enyl)-3-methyl-penta-2,4-dienoic acid ethyl ester as yellowish crystals of mp. 85-86° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[C:22]([Cl:24])[C:21]([N+:25]([O-])=O)=[CH:20][C:19]=4[CH3:28])=[C:11]3[C:10]([I:29])=[N:9]2)=[CH:5][CH:4]=1.O.O.[Sn](Cl)Cl>C(O)C>[Cl:24][C:22]1[CH:23]=[C:18]([O:17][C:16]2[CH:15]=[CH:14][N:13]=[C:12]3[N:8]([CH2:7][C:6]4[CH:30]=[CH:31][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:9]=[C:10]([I:29])[C:11]=23)[C:19]([CH3:28])=[CH:20][C:21]=1[NH2:25]
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4cc(Cl)c([N+](=O)[O-])cc4C)ccnc32)cc1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: COc1ccc(Cn2nc(I)c3c(Oc4cc(Cl)c(N)cc4C)ccnc32)cc1
Temperature: 0 °C

Procedure:
To a 100 mL round bottom flask added 1-(4-methoxybenzyl)-4-(5-chloro-2-methyl-4-nitrophenoxy)-3-iodo-1H-pyrazolo[3,4-b]pyridine (544 mg, 0.99 mmol) and suspended in absolute ethanol (10 mL). Added tin(II)chloride dihydrate (1.1 g, 4.94 mmol) and stirred at 25° C. under N2(g) for 18 hours, during which a white precipitate formed. The reaction mixture was cooled to 0° C. and the solid was removed by filtration and washed with cold ethanol. The solid was air-dried to afford the desired product as white solid. Yield: 417 mg, 81%. LRMS (APCI pos) m/e 521.1 (M+H).
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[C:13]3[CH:23]=[C:22]([F:24])[C:21]([O:25][CH3:26])=[CH:20][C:14]=3[S:15][C:16]=2[N:17]([CH3:19])[CH3:18])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[H-].[Na+].[OH:29][CH2:30][CH2:31][N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>CN(C=O)C>[N:32]1([CH2:31][CH2:30][O:29][C:4]2[CH:5]=[CH:6][C:7]([C:10]([C:12]3[C:13]4[CH:23]=[C:22]([F:24])[C:21]([O:25][CH3:26])=[CH:20][C:14]=4[S:15][C:16]=3[N:17]([CH3:19])[CH3:18])=[O:11])=[CH:8][CH:9]=2)[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: OCCN1CCCC1
Reactant: COc1cc2sc(N(C)C)c(C(=O)c3ccc([N+](=O)[O-])cc3)c2cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2sc(N(C)C)c(C(=O)c3ccc(OCCN4CCCC4)cc3)c2cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 220.5 %

Procedure:
A mixture of 2.0 g (5.34 mmol) of 2-dimethylamino-5-fluoro-6-methoxybenzo[b]thiophene-3-yl 4-nitrophenyl ketone (Part C) and 1.4 g (60% dispersion in mineral oil; 35.0 mmol; washed with hexanes) of NaH in 60 mL of DMF was treated with a solution of 3.75 mL (32.1 mmol) of 1-(2-hydroxyethyl)pyrrolidine in 10 mL of DMF in such rate to control the effervescence. After complete addition, the reaction was stirred at room temperature for 1 h and was quenched by the careful addition of 5 mL of MeOH. The mixture was diluted with 200 mL of EtOAc and was poured into 200 mL of H2O. The two layers were separated and the organic phase was washed with H2O (2×100 mL) and brine (100 mL). The organic phase was dried over K2CO3, filtered, and concentrated in vacuo to give 5.21 g of an amber oil. Purification by flash chromatography (SiO2; gradient of 2% then 5% MeOH in CH2Cl2) afforded 2.10 g (4.74 mmol; 89%) of the title compound as a bright yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH:4](Cl)[CH:5]=O.[NH2:9][C:10]([NH2:12])=[S:11].C>O>[CH3:1][O:2][C:3]([C:4]1[S:11][C:10]([NH2:12])=[N:9][CH:5]=1)=[O:8]
Reactant: NC(N)=S
Reactant: COC(=O)C(Cl)C=O
Agent: C
Solvent: O
Product: COC(=O)c1cnc(N)s1
Temperature: 25 °C
Yield: 44.2 %

Procedure:
A mixture of 2.4 g of 2-chloro-3-oxo-propionic acid methyl ester (7-2), water 20 ml and 1.75 g of thiourea was refluxed for 2 hours. The mixture was cooled to room temperature and 0.25 g of norit was added and filtered. A solution of 2.5N sodium hydroxide was added to the filtrate until neutral pH. The filtration yielded 1.23 g (44%) of 2-aminothiazole-5-carboxylic acid methyl ester (7-3).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:12])([CH3:11])[CH:3]1[CH2:13][C:14]#[N:15].CO/[CH:18]=[CH:19]/[CH:20]=[C:21]1\[S:22](=[O:32])(=[O:31])[C:23]2[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=2[C:25]\1=[O:26]>>[O:31]=[S:22]1(=[O:32])[C:23]2[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=2[C:25](=[O:26])/[C:21]/1=[CH:20]/[CH:19]=[CH:18]/[C:13](=[C:3]1/[N:2]([CH3:1])[C:10]2[C:5]([C:4]/1([CH3:12])[CH3:11])=[CH:6][CH:7]=[CH:8][CH:9]=2)/[C:14]#[N:15]
Reactant: CN1c2ccccc2C(C)(C)C1CC#N
Reactant: CO/C=C/C=C1/C(=O)c2ccccc2S1(=O)=O
Product: CN1/C(=C(C#N)/C=C/C=C2/C(=O)c3ccccc3S2(=O)=O)C(C)(C)c2ccccc21
Temperature: 210 °C

Procedure:
A mixture of (1,3,3-trimethyl-2,3-dihydro-1H-indol-2-yl)acetonitrile (397 mg, 2.00 mmol) and (2Z)-2-[(2E)-3-methoxyprop-2-en-1-ylidene]-1-benzothiophen-3(2H)-one 1,1-dioxide (501 mg, 2.00 mmol) were placed in a 10-mL one-necked round bottom flask. The flask was heated in an oil bath at 210° C. for 2 hours and then cooled to room temperature. The reaction mixture was extracted with dichloromethane (100 mL). The organic solution was passed through a short silica column, the dichloromethane was evaporated and the pure dye was obtained by recrystallization from methanol. The yield was 511 mg of green crystals (63% of theory).