Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][C:2]1=[O:12].[H-].[Na+].[CH2:15](I)[CH3:16]>CC(N(C)C)=O>[CH2:15]([O:11][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:1][C:2](=[O:12])[CH:3]=1)[CH3:16]
Reactant: O=C1CC(=O)c2ccccc2N1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOc1cc(=O)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 6 g. of quinoline-2,4-dione in 50 ml. of dimethylacetamide is added 1.6 g. of sodium hydride (56% in mineral oil, pentane washed). The mixture is then stirred at room temperature for 90 minutes and 6 g. of ethyliodide is added and the resulting mixture is heated briefly at 35° C. followed by stirring at ambient temperature for 18 hours. The precipitate which forms is recovered by filtering and the filtrate is poured into 200 ml. of water and the resulting precipitate also recovered by filtering and dried. The two filter cakes above obtained are combined and crystallized from methanol to obtain 4-ethoxyquinolin-2(1H)-one, m.p. 223°-226° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[S:9])[NH2:8].Cl[CH:11]([C:16](=O)[CH3:17])[C:12]([O:14][CH3:15])=[O:13]>C(O)C>[CH3:17][C:16]1[N:8]=[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[S:9][C:11]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: NC(=S)c1ccccn1
Reactant: COC(=O)C(Cl)C(C)=O
Solvent: CCO
Product: COC(=O)c1sc(-c2ccccn2)nc1C
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of pyridine-2-carbothioamide (5.00 g) and ethanol (15 mL) was heated at 50° C. Methyl 2-chloro-3-oxobutanoate (4.41 mL) was slowly added to this solution over 10 minutes. The solution was heated at 70° C. for 18 hours. The solution was cooled to room temperature and 50% ethanol (20 mL) was added. The solution was cooled to 0° C. and stirred for 1 hour. The solution was filtered and dried over vacuum to obtain the title compound (4.90 g) with the following physical data.
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10]=2[CH:11]=1.C[O-:18].[Na+]>CO>[OH:18][C:2]1[C:3](=[O:16])[NH:4][C:5]2[CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10]=2[CH:11]=1
Reactant: C[O-]
Reactant: O=c1[nH]c2c(cc1Cl)-c1ccccc1CC2
Agent: [Na+]
Solvent: CO
Product: O=c1[nH]c2c(cc1O)-c1ccccc1CC2

Procedure:
Add 23.1 gm of 2-chloro-5,6-dihydro-benzo[f]quinolin-3(4H)-one to 300 ml of methanol containing 30 gm of sodium methoxide. Heat the system in a steel bomb at about 200° C. for 12 hours. Stop the reaction, remove solvent, treat with water, and isolate the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][N:15]([C:17]2[N:21]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:20]=[C:19]([CH3:30])[CH:18]=2)[C@H:14]([C:31]([NH:33][C:34]2([C:37]#[N:38])[CH2:36][CH2:35]2)=[O:32])[CH2:13]1)(=[O:11])=[O:10].Cl.[F:40][C:41]1([F:45])[CH2:44][NH:43][CH2:42]1>C(#N)C>[C:37]([C:34]1([NH:33][C:31]([C@@H:14]2[CH2:13][C@@H:12]([S:9]([C:3]3[CH:4]=[CH:5][C:6]([N:43]4[CH2:44][C:41]([F:45])([F:40])[CH2:42]4)=[CH:7][C:2]=3[Cl:1])(=[O:11])=[O:10])[CH2:16][N:15]2[C:17]2[N:21]([CH2:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:20]=[C:19]([CH3:30])[CH:18]=2)=[O:32])[CH2:36][CH2:35]1)#[N:38]
Reactant: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)n(CCc2ccccc2)n1
Reactant: FC1(F)CNC1
Agent: Cl
Solvent: CC#N
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(N4CC(F)(F)C4)cc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)n(CCc2ccccc2)n1

Procedure:
In analogy to the procedure described in example 389, (2S,4R)-4-(2-chloro-4-fluorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(3-methyl-1-phenethyl-1H-pyrazol-5-yl)pyrrolidine-2-carboxamide was reacted with 3,3-difluoroazetidine hydrochloride (CAS Reg. No. 288315-03-7) in acetonitrile at 90° C. for 48 h to give the title compound as off-white foam. MS (ESI): m/z=629.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:20]3[C:21]4[C:16]([CH2:17][CH2:18][CH2:19]3)=[CH:15][CH:14]=[CH:13][C:12]=4[C:11]=2[CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][N:31]=3)[CH2:26][CH2:25]2)=[CH:6][CH:5]=1.Br[CH2:38][CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42].O>CN(C)C=O>[CH3:36][C:34]1[CH:33]=[CH:32][N:31]=[C:30]([N:27]2[CH2:26][CH2:25][N:24]([CH2:23][CH2:22][C:11]3[C:12]4=[C:21]5[C:16](=[CH:15][CH:14]=[CH:13]4)[CH2:17][CH2:18][CH2:19][N:20]5[C:10]=3[C:7]3[CH:8]=[CH:9][C:4]([O:3][CH2:38][CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])=[CH:5][CH:6]=3)[CH2:29][CH2:28]2)[CH:35]=1
Reactant: CCOC(=O)CCCBr
Reactant: Cc1ccnc(N2CCN(CCc3c(-c4ccc(O)cc4)n4c5c(cccc35)CCC4)CC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc(-c2c(CCN3CCN(c4cc(C)ccn4)CC3)c3cccc4c3n2CCC4)cc1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 21.5 %

Procedure:
Under a nitrogen atmosphere, 0.25 g of sodium hydride was added to 50 ml of dry dimethylformamide, and the solution was heated to a temperature of 80° C. A solution of 4 g of 2-(4-hydroxyphenyl)-1-{2-[4-(4-methylpyridin-2-yl)piperazin-1-yl]ethyl}-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (preparation see Example 8) in 75 ml of dimethylformamide was then added. The reaction mixture was stirred for 10 minutes, whereupon it assumed a greenish coloration. A solution of 1.6 g of ethyl 4-bromobutyrate in 40 ml of dimethylformamide was then added, and the reaction mixture was heated at 80° C. for 30 minutes. The reaction mixture was worked up by adding water and then extracting with dichloromethane. The organic phase was separated, washed, dried and concentrated. The residue which remained was purified by chromatography on a silica gel column, toluene to which amounts of ethanol increasing to 2% had been added being used as the eluent. 1 g of oily ethyl 4-[4-[1-{2-[4-(4-methylpyridin-2-yl)piperazin-1-yl]ethyl}-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-2-yl]-phenoxy]-butyrate was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1.Cl[CH2:18][C:19]1[N:20]=[C:21]([C:24]2[S:25][C:26]([CH3:29])=[CH:27][CH:28]=2)[O:22][CH:23]=1>>[N:12]1([CH2:11][CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:18][C:19]3[N:20]=[C:21]([C:24]4[S:25][C:26]([CH3:29])=[CH:27][CH:28]=4)[O:22][CH:23]=3)=[CH:3][CH:4]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: Oc1ccc(CCCCn2ccnc2)cc1
Reactant: Cc1ccc(-c2nc(CCl)co2)s1
Product: Cc1ccc(-c2nc(COc3ccc(CCCCn4ccnc4)cc3)co2)s1
Yield: 65 %

Procedure:
In substantially the same manner as in Working Example 109, 1-[4-(4-hydroxyphenyl)butyl]imidazole was allowed to react with 4-chloromethyl-2-(5-methyl-2-thienyl)oxazole to give 4-[4-[4-(1-imidazolyl)butyl]phenoxymethyl]-2-(5-methyl-2-thienyl)oxazole. The yield was 65%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 82-83° C.
Reaction SMILES: [CH2:1]([CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH2:1]([CH:9]1[CH2:10][O:11][CH:19]([C:18]2[CH:21]=[CH:22][C:15]([OH:14])=[CH:16][CH:17]=2)[O:13][CH2:12]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCCCCCC(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCCCC1COC(c2ccc(O)cc2)OC1
Yield: 45.7 %

Procedure:
A mixture of 2-n-octylpropane-1,3-diol (5.64 g, 0.03 m), 4-hydroxybenzaldehyde (3.66 g, 0.03 m), benzene (60 ml) and a catalytic amount of 4-toluenesulfonic acid was azeotropically refluxed until no more water was collected (about 16 hours). The solvent was evaporated and the residue was crystallized from 50% aqueous ethanol to yield p-(5-n-octyl-1,3-dioxan-2-yl)phenol (4 g, 48%) mp 96°-97° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]2[CH2:22][O:21]2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]2[C:26]=1[CH2:27][CH:28]([NH2:36])[CH2:29]2>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([OH:21])[CH2:22][NH:36][CH:28]2[CH2:29][C:30]3[C:26](=[C:25]([O:24][CH3:23])[CH:33]=[CH:32][C:31]=3[O:34][CH3:35])[CH2:27]2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(OC)c2c1CC(N)C2
Reactant: O=c1ccc2c([C@@H]3CO3)ccc(OCc3ccccc3)c2[nH]1
Solvent: Cc1ccccc1
Product: COc1ccc(OC)c2c1CC(NC[C@H](O)c1ccc(OCc3ccccc3)c3[nH]c(=O)ccc13)C2
Temperature: 110 °C
Reaction time: 4 h

Procedure:
(R)-8-Benzyloxy-5-oxiranylcarbostyril (100 mg, 0.34 mmol), prepared from literature procedure (Beeley, Lee James; Dean, David Kenneth, PCT Int. Appl. WO 9525104) and 4,7-dimethoxy-indan-2-ylamine (66 mg, 0.34 mmol), prepared from literature procedure (Sindelar, R. D.; Mott, J.; Barfknecht, C. F.; Arneric, S. P.; Flynn, J. R.; Long, J. P.; Bhatnagar, R. K. J. Med. Chem. (1982), 25(7), 858-64), are dissolved in toluene (1 mL). The reaction mixture was heated to 110° C. and the solvent is allowed to evaporate. The residue is then stirred at 110° C. for 4 hours. The reaction is shown to be complete by TLC. The product is purified by flash column chromatography (silica, dichloromethane/methanol 20:1). TLC (silica, dichloromethane/methanol 25:1 Rf=0.10). ES+ MS m/e 487 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:6][N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=2)[N:9]([CH:19]2[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]2)[C:8]1=[O:27].Br[CH2:34][C:35]#[N:36].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:6][N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:34][C:35]#[N:36])[CH:14]=2)[N:9]([CH:19]2[CH2:20][CH2:21][S:22](=[O:26])(=[O:25])[CH2:23][CH2:24]2)[C:8]1=[O:27]
Reactant: N#CCBr
Reactant: COc1ccc(Cn2c(=O)c3cc(O)ccc3n(C3CCS(=O)(=O)CC3)c2=O)cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)c3cc(OCC#N)ccc3n(C3CCS(=O)(=O)CC3)c2=O)cc1OC
Yield: 72.1 %

Procedure:
A mixture of 0.055 g of the compound obtained in Step 18.2, 0.017 g of bromoacetonitrile and 0.078 g of Cs2CO3 in 2 ml of DMF is irradiated in a microwave field for 15 minutes at 100° C. The reaction mixture is evaporated under reduced pressure. The residue is taken up in DCM, washed with water, dried over Na2SO4 and filtered, and the filtrate is evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with an MeOH/DCM mixture from (0.5/99.5, v/v) to (5/95, v/v), to give 0.043 g of the expected product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([O-:3])=[O:2].CCN(C(C)C)C(C)C.[C:26](Cl)(=[O:28])[CH3:27]>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:26](=[O:28])[CH3:27])=[CH:6][C:5]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([O-:3])=[O:2]
Reactant: CC(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])c(N2CCCCC2)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc([N+](=O)[O-])c(N2CCCCC2)c1
Reaction time: 1 h
Yield: 78 %

Procedure:
4-Nitro-3-piperidin-1-yl-phenylamine (64 mg, 0.28 mmol, as prepared in the previous step) and DIEA (122 μL, 0.700 mmol) in 4 mL of CH2Cl2 was treated with acetyl chloride (28 μL, 0.40 mmol). The reaction was stirred for 1 h, diluted with CH2Cl2 (25 mL), washed with water (50 mL), and dried (Na2SO4). Concentration of the solvent in vacuo afforded 51 mg (78%) of N-(4-nitro-3-piperidin-1-yl-phenyl)-acetamide. Using a procedure similar to Example 3, step (c), 4-nitro-3-piperidin-1-yl-phenylamine (51 mg, 0.21 mmol) was stirred with 5% Pd—C (35 mg) under H2 to afford 40 mg (61%) of the title compound as a dark semi-solid. Mass spectrum (ESI, m/z): Calcd. for C13H19N3O, 234.1 (M+H), found 234.2.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].CC1(C)[O:24][C:23](=O)[CH2:22][C:21](=[O:26])[O:20]1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:8]=[C:7]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:23]([CH2:22][C:21]([OH:26])=[O:20])=[O:24]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: Nc1ccc(C(=O)c2ccc(Cl)cc2)cc1Br
Solvent: Cc1ccccc1
Product: O=C(O)CC(=O)Nc1ccc(C(=O)c2ccc(Cl)cc2)cc1Br
Temperature: 88 °C
Reaction time: 8 h

Procedure:
Into a 1-mL round-bottom flask, was placed a solution of 2-bromo-4-[(4-chlorophenyl)carbonyl]aniline (28.62 g, 92.15 mmol, 1.00 equip) in toluene (400 mL), and 2,2-dimethyl-1,3-dioxane-4,6-dione (25.92 g, 179.84 mmol, 2.00 equip). The resulting solution was stirred overnight at 88° C. The solution was cooled to room temperature and the solids were collected by filtration to yield 2-([2-bromo-4-[(4-chlorophenyl)carbonyl]phenyl]carbamoyl)acetic acid as a yellow solid. LCMS (ES, m/z) 396 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH3:10].[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH2:10][Br:11]
Reactant: COc1cccc(Cl)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cccc(Cl)c1CBr
Yield: 72.7 %

Procedure:
442 g of 2-chloro-6-methoxytoluene are dissolved in 2420 ml of carbon tetrachloride and, together with 516 g of N-bromosuccinimide, heated at reflux for 2 h while 5.8 g of AIBN are added. The solid is filtered off and washed with a small amount of carbon tetrachloride, the filtrate is concentrated, and the residue which remains is fractionated. 483 g of colorless oil are obtained (b.p. 100° C./1.4 mbar, m.p. 44-47° C.).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]#[N:12])[C:5]=1[Cl:13])#[N:2].Cl.N[C:16]1[C:21]([F:22])=[C:20]([F:23])[CH:19]=[C:18]([F:24])[C:17]=1[SH:25]>>[F:22][C:21]1[C:16]2[N:2]=[C:1]([CH2:3][C:4]3[C:5]([Cl:13])=[C:6]([CH2:10][C:11]#[N:12])[CH:7]=[CH:8][CH:9]=3)[S:25][C:17]=2[C:18]([F:24])=[CH:19][C:20]=1[F:23]
Reactant: N#CCc1cccc(CC#N)c1Cl
Reactant: Nc1c(F)c(F)cc(F)c1S
Agent: Cl
Product: N#CCc1cccc(Cc2nc3c(F)c(F)cc(F)c3s2)c1Cl
Yield: 23.2 %

Procedure:
The procedure of Example 22-i) was repeated using 1,3-biscyanomethyl-2-chlorobenzene (953 mg, 5 mmol) and 2-amino-3,4,6-trifluorothiophenol hydrochloride (1,078 mg, 10 mmol) and the resultant product was crystallized from ethyl acetate-hexane to give 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]-2-chlorophenylacetonitrile (410 mg, 23%) as a colorless powder.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[CH2:16]([O:15][C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[C:4](=[CH:3][C:2]([C:26]#[C:25][Si:22]([CH3:24])([CH3:23])[CH3:21])=[CH:14][CH:13]=3)[CH2:5][C:6]=2[CH:7]=1)[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCOc1ccc2c(c1)Cc1cc(Br)ccc1-2
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCCCOc1ccc2c(c1)Cc1cc(C#C[Si](C)(C)C)ccc1-2
Yield: 51.5 %

Procedure:
A mixture of 2-bromo-7-pentyloxyfluorene (12 g), trimethylsilylacetylene (7.1 g), dichlorobis(triphenylphosphine)palladium (0.3 g), copper iodide (0.08 g), triphenylphosphine (0.2 g) and triethylamine (200 mL) was heated for 3 hours while refluxing. Insoluble matters were removed from the reaction mixture by filtration, and triethylamine was distilled off under reduced pressure. The residue was purified by means of column chromatography (silica gel, eluting solvent: toluene) to obtain 6.5 g of 2-pentyloxy-7-trimethylsilylethynylfluorene. This was dissolved in tetrahydrofuran (100 mL) and cooled down to −60° C. on a dry ice-acetone bath. A 1M solution (46 mL) of tetraethylammonium fluoride was added thereto, and then the dry ice-acetone bath was removed, followed by stirring the solution until the temperature came up to −10° C. At a point of time when −10° C. was reached, water (30 mL) was added and stirred until the temperature came up to a room temperature, and then water was further added to terminate the reaction. The product was extracted with toluene, and the toluene layer was dried on anhydrous magnesium sulfate. A residue obtained by distilling the solvent off was purified by means of column chromatography (silica gel, eluting solvent: toluene). Then, it was recrystallized from ethanol to obtain 2-pentyloxy-7-ethynylfluorene (5 g) of colorless needle crystal. The melting point of this compound was 108° C.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:10])[CH:4]=[C:5]([CH3:9])[C:6](=[O:8])[CH:7]=1.[ClH:11].[CH3:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16][SH:17]>C(N(CC)CC)C.CC(C)=O>[ClH:11].[ClH:11].[CH3:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16][S:17][C:4]1[C:5]([CH3:9])=[C:6]([OH:8])[C:7]([S:17][CH2:16][CH2:15][CH2:14][N:13]([CH3:18])[CH3:12])=[C:2]([CH3:1])[C:3]=1[OH:10]
Reactant: CC1=CC(=O)C(C)=CC1=O
Reactant: CN(C)CCCS
Agent: Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(O)c(SCCCN(C)C)c(C)c(O)c1SCCCN(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 27.2 g (0.200 mole) of 2,5-dimethyl-1,4-benzoquinone, 31.1 g (0.200 mole) of 3-(dimethylamino)propanethiol hydrochloride and six drops of triethylamine in 300 ml of acetone was stirred at ambient temperature for 15 hours. The cream-colored, crude, solid product was collected on a filter and recrystallized from methanol to give the pure product, 2,5-bis((3-(dimethylamino)propyl)thio)-3,6-dimethyl-1,4-benzenediol dihydrochloride, as cream-colored platelets, mp 254.5° C.
Reaction SMILES: CC[O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)=[O:5].[OH-].[Na+]>O.CO>[NH:7]1[C:8]2[C:13](=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)[CH:14]=[C:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cc2cc(C(=O)O)ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2[nH]c(C(=O)O)cc2c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 59 %

Procedure:
A solution of 1H-indole-2,5-dicarboxylic acid 2-ethyl ester (20.0 g, 85.75 mmole) and NaOH (100 mmole) in a mixture of water/MeOH (1/1) (200 ml) was stirred at 50° C. for 4 h and then overnight at ambient temperature. The reaction mixture was evaporated in vacuo to dryness and the residue was dissolved in water (200 ml) and acidified with 1M HCl up to pH=3. The precipitates were collected on the filter and washed with water (3×50 ml) and dried over phosphorus pentoxide in dessicator to give indole-2,5-dicarboxylic acid 1 (10.38 g, 59%) of compound 1 as white crystals. MS: 203.7 (M−2H); 204.7 (M−H). 1H-NMR (DMSO-d6): δ 8.32 (m, 1H, H-4, indole); 7.80 (m, 1H, H-6, indole); 7.45 (d, 1H, H-7, indole); 7.22 (s, 1H, H-3, indole).
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[C:20]1[N:24]([CH3:25])[N:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1>CN(C=O)C>[Cl:8][C:21]1[C:22]([C:26]([F:29])([F:27])[F:28])=[N:23][N:24]([CH3:25])[C:20]=1[C:12]1[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:11]=1[O:10][CH3:9]
Reactant: COc1ccc([N+](=O)[O-])cc1-c1cc(C(F)(F)F)nn1C
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])cc1-c1c(Cl)c(C(F)(F)F)nn1C
Temperature: 0 °C

Procedure:
NCS (0.05 g, 0.37 mmol, 1.1 eq.) dissolved in DMF (⅔ mL) was added drop wise to a stirred solution of 5-(2-methoxy-5-nitro-phenyl)-1-methyl-3-trifluoromethyl-1H-pyrazole, see Example 1.99 (0.1 g, 0.33 mmol) in DMF (1⅓ mL) at 0° C. The reaction mixture was stirred 0° C. and TLC indicated no product. An additional equivalent of NCS was added and the reaction mixture was stirred at 80° C. overnight which resulted in completion of the reaction. The DMF was removed under vacuum and the crude mixture was diluted with EtOAc (50 mL) and washed with brine (3×10 mL). The EtOAc phase was dried over anhydrous MgSO4, filtered and evaporated to give the partially purified product 4-chloro-5-(2-methoxy-5-nitro-phenyl)-1-methyl-3-trifluoromethyl-1H-pyrazole (0.13 g) as a light yellow solid: LCMS m/z (%)=336 (M+H35Cl, 100), 382 (M+H37Cl, 33). 1H NMR (400 MHz, CDCl3) δ: 8.37 (dd, J=8.0, 4.0 Hz, 1H), 8.16 (d, J=4.0 Hz 1H), 7.09 (d, J=8.0 Hz, 1H), 3.92 (s, 3H), 3.69 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12])[CH:5]=[O:6].Br[CH2:15][CH2:16][OH:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH:17][CH2:16][CH2:15][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12])[CH:5]=[O:6]
Reactant: CC(C)Oc1ccc(C=O)cc1O
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(C=O)cc1OCCO

Procedure:
The title compound was prepared analogously to intermediate 2 (4-methoxy-3-propoxy-benzaldehyde) by reaction of 3-hydroxy-4-isopropoxy-benzaldehyde ([CAS RN 94283-73-5], F. R. Hewgill, M. C. Pass Australian J. Chem. 1985, 38, 537-554) with 2-bromo-ethanol in DMF using K2CO3 as base. MS (ISP): 224.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:3]=1[C:4](/[N:6]=[C:7]1\[S:8][C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:10][N:11]\1[CH2:12][C@H:13]1[CH2:17][CH2:16][CH2:15][O:14]1)=[O:5].C(N(CC)CC)C.[CH3:37][S:38]([CH:41]=[CH2:42])(=[O:40])=[O:39].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:18]([C:9]1[S:8]/[C:7](=[N:6]\[C:4](=[O:5])[C:3]2[CH:22]=[C:23]([C:26]([F:29])([F:28])[F:27])[CH:24]=[CH:25][C:2]=2/[CH:42]=[CH:41]/[S:38]([CH3:37])(=[O:40])=[O:39])/[N:11]([CH2:12][C@H:13]2[CH2:17][CH2:16][CH2:15][O:14]2)[CH:10]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)c1cn(C[C@H]2CCCO2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2Br)s1
Reactant: C=CS(C)(=O)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)c1cn(C[C@H]2CCCO2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2/C=C/S(C)(=O)=O)s1
Temperature: 140 °C
Yield: 47 %

Procedure:
To a solution of Example 386B (172 mg, 0.350 mmol), triethylamine (53 mg, 0.525 mmol) and methylvinylsulfone (55.7 mg, 0.525 mmol) in acetonitrile (1 mL) was added palladium acetate (4.72 mg, 0.021 mmol) and tri(o-tolyl)phosphine (23.44 mg, 0.077 mmol). This mixture was heated in a microwave at 140° C. for 30 min. The reaction was heated another 30 min at 180° C. The reaction mixture was cooled to room temperature and filtered. The residue was purified by preparative HPLC on a Phenomenex Luna Combi-HTS C8(2) column (5 μm, 100 Å, 2.1 mm×30 mm), using a gradient of 10-100% acetonitrile (A) and 10 mM ammonium acetate in water (B), at a flow rate of 2.0 mL/min (0-0.1 min 10% A, 0.1-2.6 min 10-100% A, 2.6-2.9 min 100% A, 2.9-3.0 min 100-10% A. 0.5 min post-run delay) to provide the title compound (85 mg, 47%). 1H NMR (300 MHz, CDCl3) δ ppm 1.38 (s, 9H) 1.62-1.71 (m, 1H) 1.76-1.92 (m, 2H) 2.02-2.14 (m, 1H) 3.08 (s, 3H) 3.73-3.87 (m, 2H) 4.22-4.34 (m, 2H) 4.50 (d, J=11.10 Hz, 1H) 6.80 (d, J=15.47 Hz, 1H) 6.97 (s, 1H) 7.59-7.72 (m, 2H) 8.52 (s, 1H) 8.83 (d, J=15.47 Hz, 1H); MS (DCI/NH3) m/z 517 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:11][CH:10](O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-]#N.[Na+].[CH3:16][N:17](C)C=O>O>[CH2:1]([N:8]1[CH2:11][CH:10]([C:16]#[N:17])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: OC1CN(Cc2ccccc2)C1
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: N#CC1CN(Cc2ccccc2)C1

Procedure:
1.7 g of 13A and 1.2 g of sodium cyanide were stirred together in 1 ml of water and 20 ml of dimethylformamide at 60° C. for 16 hours. The solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel using isopropanol in dichloromethane as eluent to give 1-benzyl-3-cyanoazetidine (13B).