Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.S(Cl)([Cl:17])=O.CN(C=O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([Cl:17])=[O:14])[CH:6]=[CH:5]2
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc2cc(Br)ccc2c1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc2cc(Br)ccc2c1
Temperature: 60 °C

Procedure:
A suspension of 6-bromo-2-naphthoic acid (100 g), thionyl chloride (37.7 ml) and DMF (0.5 ml) in THF (1000 ml) was stirred at 60° C. with heating for 90 min. After cooling to room temperature, the solvent was evaporated under reduced pressure. The resulting solid was dissolved in toluene and the solvent was evaporated to give 6-bromo-2-naphthoyl chloride as a pale yellow powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([Mg]Br)=[CH:17][CH:16]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=2)([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a stirred solution of 1-t-butoxycarbonyl-3-pyrrolidinone (0.57 g, 3.23 mmol) in THF (10 mL) was added 4-chlorophenyl magnesium bromide (1.0 M, 5.2 mL) under the protection of argon at 0° C. The reaction was stirred at room temperature for 1 hour then quenched by the addition of saturated aqueous NH4OH (8 mL). The aqueous layer was extracted with EtOAc (50 mL×2), dried over MgSO4 and concentrated in vacuo. Chromatographic purification on silica gel (Hexane/EtOAc=3/1) provided 0.57 g 1-t-butoxycarbonyl-3-(4-chlorophenyl)-3-hydroxypyrrolidine (60%). m/z 298 (m+1)
Reaction SMILES: [S:1](Cl)([C:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:9]([N:10]([CH3:12])[CH3:11])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([C:30]2[C@@H:39]3[C@@H:34]([CH2:35][CH:36]=[CH:37][CH2:38]3)[C:33](=[O:40])[N:32]([CH:41]3[CH2:46][CH2:45][N:44](S(C4C=CC(C)=CC=4)(=O)=O)[CH2:43][CH2:42]3)[N:31]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH2:28]C)C>>[CH3:18][O:20][C:21]1[CH:22]=[C:23]([C:30]2[C@@H:39]3[C@@H:34]([CH2:35][CH:36]=[CH:37][CH2:38]3)[C:33](=[O:40])[N:32]([CH:41]3[CH2:46][CH2:45][N:44]([S:1]([C:4]4[C:16]5[C:8](=[C:9]([N:10]([CH3:12])[CH3:11])[CH:13]=[CH:14][CH:15]=5)[CH:7]=[CH:6][CH:5]=4)(=[O:3])=[O:2])[CH2:43][CH2:42]3)[N:31]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: CCOc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccc(C)cc4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCC
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4cccc5c(N(C)C)cccc45)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC

Procedure:
Prepared from dansylchloride and starting compound A1 as described for compound 1. Crystallisation from methanol. M. p. 198-200° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)([CH3:3])=[CH2:2].[S:10]1(=[O:16])(=[O:15])[CH2:14][CH2:13][CH2:12][NH:11]1.[OH-].C[N+](C)(C)CC1C=CC=CC=1>O.C(Cl)(Cl)Cl>[N:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH2:2][N:11]2[CH2:12][CH2:13][CH2:14][S:10]2(=[O:16])=[O:15])=[CH:5][CH:6]=1
Reactant: C=C(C)c1ccncc1
Reactant: O=S1(=O)CCCN1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(CN1CCCS1(=O)=O)c1ccncc1
Reaction time: 16 h

Procedure:
A mixture of 4-isopropenyl pyridine (1.79 g) and isothiazolidine-1,1-dioxide (1.81 g) was heated at 130° C. during the addition of "Triton B" (Trade Mark, trimethylbenzylammonium hydroxide) (0.25 g added every hour for four hours; 40% solution in water). After stirring for 16 hours at 130° the mixture was cooled and taken in chloroform (50 cm3) and water (50 cm3). The aqueous phase was extracted with chloroform (3×20 cm3) and the dried (MgSO4) extracts were evaporated to given an oil. Chromatography on silica ("Merck 60. 9385") eluting with ethyl acetate gave 2-[2-(4-pyridyl)prop-1-yl]isothiazolidine-1,1-dioxide which crystallised from ethyl acetate-hexane as needles, m.p. 90°-92° (1.01 g).
Reaction SMILES: [CH2:1]([O:4][N:5]([CH:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH:20]=[C:19]1[CH2:40][O:41]CC1C=CC(OC)=CC=1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C(Cl)Cl.O>[CH2:1]([O:4][N:5]([CH:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[C@H:21]([CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH:20]=[C:19]1[CH2:40][OH:41])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCON(C1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1COCc1ccc(OC)cc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: ClCCl
Product: C=CCON(C1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1CO)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (2S)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(((4-methoxybenzyl)oxy)methyl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 170, 18.70 g, 25.48 mmol) in DCM/water (180 mL/20 mL), was added DDQ (6.94 g, 30.57 mmol) at 0° C. The mixture was stirred at room temperature for 1 hour before it was concentrated. The residue was purified on silica gel column eluting with 0-100% ethyl acetate/hexanes to give a pale yellow oil, 12.38 g, 79%.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:13])=O>C1COCC1.CN(C=O)C>[Br:1][C:2]1[O:6][C:5]([C:7]([Cl:13])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(Br)o1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Cl)c1ccc(Br)o1
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-bromo-2-furoic acid (2.1 g, 6.856 mmol) in THF (20 mL) was added oxalyl chloride (0.66 mL, 7.541 mmol). 2 drops of DMF were then added to the reaction mixture, with bubbles of CO observed to come out vigorously. Oxalyl chloride ((COCl)2) (0.1 mL) was then added. The reaction mixture was stirred at room temperature for 10 min and at 90° C. for 10 min. Solvent and excess (COCl)2 were taken off under vacuum to yield 5-bromo-furan-2-carbonyl chloride as a pale yellow crystalline solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([CH2:16][NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])(=[O:20])=[O:19])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[CH3:31][O:32][CH2:33][CH2:34]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([CH2:16][N:17]([CH2:34][CH2:33][O:32][CH3:31])[S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:28])[F:29])(=[O:20])=[O:19])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: COCCBr
Reactant: CS(=O)(=O)c1cccc(-c2ccc(CNS(=O)(=O)c3ccccc3C(F)(F)F)s2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COCCN(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)S(=O)(=O)c1ccccc1C(F)(F)F

Procedure:
In analogy to example 10, step 3, N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-trifluoromethyl-benzenesulfonamide (example 27, step 1) was reacted with 2-bromoethyl methyl ether and cesium carbonate in N,N-dimethylacetamide to give N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-N-(2-methoxy-ethyl)-2-trifluoromethyl-benzenesulfonamide as a light yellow oil. MS: 550.8 ([M+NH4]+)
Reaction SMILES: C(OC(=O)O[C@H:6]1[CH2:10][C@@H:9]([N:11]2[CH:19]=[N:18][C:17]3[C:12]2=[N:13][C:14]([Cl:21])=[N:15][C:16]=3[Cl:20])[CH:8]=[CH:7]1)C.[CH2:23]([C:25]1[N:26]=[N:27][NH:28][N:29]=1)[CH3:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:21][C:14]1[N:13]=[C:12]2[C:17]([N:18]=[CH:19][N:11]2[C@@H:9]2[CH2:10][C@H:6]([N:27]3[N:28]=[N:29][C:25]([CH2:23][CH3:24])=[N:26]3)[CH:7]=[CH:8]2)=[C:16]([Cl:20])[N:15]=1
Reactant: CCOC(=O)O[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Reactant: CCc1nn[nH]n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCc1nnn([C@@H]2C=C[C@H](n3cnc4c(Cl)nc(Cl)nc43)C2)n1
Reaction time: 0.08 h

Procedure:
Carbonic acid (1S,4R)-4-(2,6-dichloro-purin-9-yl)-cyclopent-2-enyl ester ethyl ester (Intermediate AC) (3 g, 8.75 mmol), 5-Ethyl-2H-tetrazole (0.94 g. 9.62 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.40 g, 0.44 mmol) and triphenylphosphine (0.35 g, 1.32 mmol) are placed in an oven-dried flask under an atmosphere of argon. Dry deoxygenated THF (40 mL) is added and the reaction mixture is stirred gently for 5 minutes. Triethylamine (20 mL) is added and the reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is allowed to cool and the solvent is removed in vacuo. The residue was taken up in methanol (50 mL) and the solid was filtered off-product. 1H nmr (CDCl3, 400 MHz); 8.55 (s, 1H), 6.35 (m, 1H), 6.25 (m, 1H), 6.05 (m, 1H), 5.90 (m, 1H), 3.45 (m, 1H), 2.85 (q, 2H), 2.30 (m, 1H), 1.30 (t, 3H), MS (ES+) m/e 351 (MH+).
Reaction SMILES: C([SiH](CC)CC)C.[C:8]([C:12]1[C:17]2[CH:18]=[C:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[O:20][C:16]=2[CH:15]=[C:14]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:13]=1[OH:33])([CH3:11])([CH3:10])[CH3:9].FC(F)(F)C(O)=O>>[C:8]([C:12]1[C:17]2[CH2:18][CH:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[O:20][C:16]=2[CH:15]=[C:14]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:13]=1[OH:33])([CH3:10])([CH3:11])[CH3:9]
Reactant: CCCCCCCCc1cc2c(C(C)(C)C)c(O)c(C(C)(C)C)cc2o1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCC1Cc2c(cc(C(C)(C)C)c(O)c2C(C)(C)C)O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 27.1 %

Procedure:
Triethylsilane (17.4 ml) was added to 4,6-di-tert-butyl-5-hydroxy-2-octylbenzofuran (2.2 g) and trifluoroacetic acid (8.7 ml) was added dropwise to the mixture under cooling with ice. After stirring at 0° C. for 1 h, the mixture was poured into ice water and subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel chromatography (n-hexane) to afford 4,6-di-tert-butyl-5-hydroxy-2-octyl-2,3-dihydrobenzofuran [0.6 g (yield, 27%)].
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH2:4].C([Li])CCC.[Br:16][CH2:17][CH2:18][CH2:19]Br>O1CCOCC1>[Br:16][CH2:17][CH2:18][CH2:19][NH:4][C:3]1[C:5]([CH3:10])=[CH:6][C:7]([CH3:9])=[CH:8][C:2]=1[Cl:1]
Reactant: BrCCCBr
Reactant: Cc1cc(C)c(N)c(Cl)c1
Agent: [Li]CCCC
Solvent: C1COCCO1
Product: Cc1cc(C)c(NCCCBr)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 67.1 %

Procedure:
To a solution of the 2-chloro-4,6-dimethyl aniline (16.9 g g, 108 mmol) in 1,4-dioxane (80 mL) was added n-butyl lithium solution (2.5 M in hexanes, 48 mL), dropwise, at 0° C. under argon. The reaction mixture was warmed up to rt and stirred for 20 min. 1,3-Dibromopropane (109 g, 543 mmol) was added and the reaction mixture was stirred overnight. The mixture was filtered through celite and concentrated. Purification was carried out by reverse phase chromatography using water, methanol and trifluoroacetic acid to obtain product (20.01 g, 72.5 mmol, 67%) as brown oil. LC/MS: tR=1.5 min. [M+H] 277. 1H NMR (CD3OD) δ: 7.12 (s, 1H), 6.99 (s, 1H), 3.52 (t, J=6.65 Hz, 2H), 3.36 (t, J=6.75 Hz, 2H), 2.36 (s, 3H), 2.29 (s, 3H), 2.14 (m, 2H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([C:10]([C:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)=[O:11])[CH:7]=[CH:6][N:5]=1.Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=1>CN(C)C=O>[CH3:3][C:4]1[CH:9]=[C:8]([C:10]([C:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=3)[CH:13]=2)=[O:11])[CH:7]=[CH:6][N:5]=1
Reactant: Cc1cccc(CBr)n1
Reactant: Cc1cc(C(=O)c2c[nH]c3ccccc3c2=O)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cn(Cc3cccc(C)n3)c3ccccc3c2=O)ccn1

Procedure:
Compound 4ff was prepared following the procedure outlined in Step 3 of Example 1 using 10.4 mg (0.26 mmol) of sodium hydride (60%), 53 mg (0.20 mmol) of 3-(2-methyl-pyridine-4-carbonyl)-1H-quinolin-4-one 3h, 3 mL of anhydrous dimethylformamide, and 48.7 mg (0.26 mmol) of 2-bromomethyl-6-methyl-pyridine. The crude product was purified by preparative HPLC to yield 15 mg of colorless solid 4ff: LC-MSD, m/z for C23H19N3O2, [M+H]+=370.5, [M+2H]+=371.5; Reverse phase HPLC (gradient acetonitrile 0.1% TFA 20-95% in 4 min) retention time=1.976 min; 1H NMR (400 MHz, CDCl3/HCl): δ 2.57 (s, 3H), 2.61 (s, 3H), 5.43 (s, 2H), 6.87 (d, 1H), 7.10 (d, 1H), 7.32-7.48 (m, 4H), 7.53 (t, 1H), 7.59 (t, 1H), 8.41 (d, 1H), 8.49 (d, 1H), 8.59 (d, 1H).
Reaction SMILES: [CH2:1]([PH2:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:8]([CH:10]=[O:11])=[O:9]>C(O)(C)C>[CH2:1]([P:7]1[CH:8]([OH:9])[CH:10]([OH:11])[P:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:8]([OH:9])[CH:10]1[OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=CC=O
Reactant: CCCCCCP
Solvent: CC(C)O
Product: CCCCCCP1C(O)C(O)P(CCCCCC)C(O)C1O
Temperature: 60 °C
Yield: 98 %

Procedure:
In a suitable autoclave equipped as in Example 1, are added 200 parts of mono-n-hexylphosphine (93% purity) and 500 parts of isopropanol, as solvent. The mixture is heated to 60° C. and 240 parts of a 40% aqueous glyoxal solution are added. The reaction is allowed to proceed for one-hour and the solid product formed is filtered and dried to give 272 parts (98% yield) of 1,4-di-n-hexyl-2,3,5,6-tetrahydroxy-1,4-diphosphorinane, m.p. 140-147° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=O)=[N:6][CH:7]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>ClCCCl.ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[N:6][CH:7]=1
Reactant: C1CCNC1
Reactant: O=Cc1ccc(Br)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: Brc1ccc(CN2CCCC2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2 g of 5-bromo-2-formylpyridine in 20 mL of 1,2-dichloroethane are successively added, under argon, 4.55 g of sodium triacetoxyborohydride and 0.94 mL of pyrrolidine. The reaction mixture is stirred at room temperature for 1 hour and then diluted with dichloromethane and the organic phase is washed with saturated sodium hydrogen carbonate solution, with water and with saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica, eluting with a mixture of dichloromethane and methanol (98/2 by volume) to give 0.93 g of 5-bromo-2-pyrrolidin-1-ylmethylpyridine, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:6][CH2:7][N:8]([C:17](=[O:27])[C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=3)[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]=2[N:12]=1.NN>C(O)C.[Pd]>[CH3:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:6][CH2:7][N:8]([C:17](=[O:27])[C:18]3[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=3)[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]=2[N:12]=1
Reactant: Cc1ncc2c(n1)-c1ccccc1N(C(=O)c1ccc([N+](=O)[O-])cc1)CC2
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: Cc1ncc2c(n1)-c1ccccc1N(C(=O)c1ccc(N)cc1)CC2
Yield: 90 %

Procedure:
A mixture of 400 mg of 6,7-dihydro-2-methyl-7-(4-nitrobenzoyl)-5H-pyrimido[5,4-d] [1]benzazepine, 87 μl of anhydrous hydrazine and 40 mg of 10% Pd/C in 22 ml of ethyl alcohol is heated at reflux for 1.25 hours, filtered through diatomaceous earth and the pad washed well with methyl alcohol. The combined filtrates are evaporated in vacuo to a residue which is dissolved in ethyl acetate and filtered through a pad of hydrous magnesium silicate and the filtrate concentrated in vacuo to a residue which is dissolved in methyl alcohol and evaporated again to give 330 mg of the desired product as a yellow foam. HR FABMS: Exact mass (M+H): 331.1555.
Reaction SMILES: [OH:1][C:2]1([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[Cl:35][CH:36]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:37](Cl)=[O:38]>C(Cl)Cl>[Cl:35][CH:36]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:37]([N:16]([CH2:15][C:2]1([OH:1])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:4][CH2:3]1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=[O:38]
Reactant: O=C(Cl)C(Cl)c1ccccc1
Reactant: COc1ccc(CNCC2(O)CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN(CC2(O)CCN(C(=O)OC(C)(C)C)CC2)C(=O)C(Cl)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.3 %

Procedure:
To a mixture of tert-butyl 4-hydroxy-4-[[(4-methoxyphenyl)methylamino]methyl]piperidine-1-carboxylate (1.06 g, 3.01 mmol) and diisopropylethylamine (1 mL, 5.74 mmol) in DCM (15 mL) at 0° C. was added 2-chloro-2-phenyl-acetyl chloride (654 mg, 3.46 mmol) and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography using 0-100% EtOAc/DCM as eluent to give tert-butyl 4-[[(2-chloro-2-phenyl-acetyl)-[(4-methoxyphenyl)methyl]amino]methyl]-4-hydroxy-piperidine-1-carboxylate (1.11 g, 73%) as a pale yellow oil. ESI-MS m/z calc. 502.2. found 503.5 (M+1)+; Retention time: 1.90 minutes (3 min run).
Reaction SMILES: CN(C)C(=O)C.[NH2:7][C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][C:21]=1[NH2:22])[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].S([O-])(O)=O.[Na+].[CH:28]([C:30]1[O:34][C:33]([C:35]([OH:37])=[O:36])=[CH:32][CH:31]=1)=O>O>[C:11]([C:10]1[CH:19]=[CH:20][C:21]2[N:22]=[C:28]([C:30]3[O:34][C:33]([C:35]([OH:37])=[O:36])=[CH:32][CH:31]=3)[NH:7][C:8]=2[CH:9]=1)(=[O:12])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1N
Reactant: O=Cc1ccc(C(=O)O)o1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(c1ccccc1)c1ccc2nc(-c3ccc(C(=O)O)o3)[nH]c2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 63.2 %

Procedure:
N,N-Dimethylacetamide (5 ml) was heated to 130° C., and 3,4-diaminobenzophenone (63 mg, 0.30 mmol) and sodium hydrogensulfite (37 mg, 0.36 mmol) were added and the mixture was stirred for 5 minutes. 5-Formyl-furan-2-carboxylic acid (50 mg, 0.36 mmol) was added and stirred at 130° C. for 1.5 hours. The reaction mixture was allowed to cool to room temperature with stirring, and after addition of water to reaction mixture, precipitate was collected by filtration to afford 5-(5-benzoylbenzimidazol-2-yl)-furan-2-carboxylic acid (63 mg, 64%) as a pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[C:9]([C:12](O)=[O:13])[C:8]=2[CH:15]=1)([O-:3])=[O:2].ClC1C=C2C(=CC=1)[NH:22]C=C2C1CCNCC1.C(N(CC)CC)C>C1COCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[C:9]([C:12]([NH2:22])=[O:13])[C:8]=2[CH:15]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1csc2ccc([N+](=O)[O-])cc12
Reactant: Clc1ccc2[nH]cc(C3CCNCC3)c2c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NC(=O)c1csc2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Nitro-3-benzothiophencarboxylic acid 1b (20 g) was converted into the corresponding carboxylic acid chloride as in Example 2. The acid chloride was dissolved in THF (200 ml) and added dropwise to a solution of 5-chloro-3-(4-piperidinyl)-1H-indole, 9a (19 g) and triethylamine (10 ml) in THF (200 ml) at 0-5° C. The mixture was stirred overnight at room temperature. THF was evaporated. Water was added to the remaining oil. Extraction with dichloromethane (2×100 ml) and work-up of the organic extracts afforded the crude 5-nitro-3-benzothiophencarboxylic acid amide, which was subsequently purified by column chromatography on silica gel (eluted with ethyl acetatelheptane 1:1). Yield 6.6 g, mp: 243-250° C. All of the amide was dissolved in 90% ethanol at reflux. Fe-powder (5 g) and concentrated aqueous HCl were added successively in small portions during 10 minutes. The mixture was refluxed for another 2.5 hours. Inorganic salts were filtered off and ethanol evaporated in vacuo. Water was added to the remaining oil and pH was adjusted to >9 by addition of diluted aqueous NH4OH. Extraction with dichloromethane (2×100 ml) and subsequent work-up of the organic phase yielded 4 g of the 5-amino-3-benzothiophencarboxylic acid amide as an oil. All of this oil was dissolved in methanol (100 ml). 0.5 g of Mg turnings were added. By heating to 35° C. an exothermic reaction started. Mg turnings were added in small portions (3×0.5 g) while keeping the temperature below 45° C. The mixture was finally poured into an aqueous NH4Cl solution and concentrated aqueous HCl (1 ml) was added. Extraction with dichloromethane (2×50 ml) and work-up of the organic extracts as above afforded 2 g of the 5-amino-2,3-dihydrobenzothiophen-3-carboxylic acid amide as an oil. To a suspension of LiAIH4 (0.6 g) in dry THF (50 ml) was added dropwise a solution of all of the carboxamide in THF (50 ml). The mixture was gently refluxed for 2 hours. After cooling to 10° C. water (2.4 ml ) and a 15% aqueous NaOH solution were cautiously added to destroy excess LiAIH4. Inorganic salts were filtered off and washed extensively with THF. The combined THF solutions were evaporated leaving 1.9 g of 3-[1-(5-amino-213-dihydrobenzothiophen-3-ylmethyl)piperidin-4-yl)-5-chloro-1H-indole as an oil.
Reaction SMILES: C(NC(C)C)(C)C.[Cl:8][C:9]1[C:14]([NH2:15])=[C:13]2[O:16][CH2:17][O:18][C:12]2=[C:11](I)[CH:10]=1.[CH2:20]([O:23][CH3:24])[C:21]#[CH:22]>C(OCC)(=O)C.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>[Cl:8][C:9]1[C:14]([NH2:15])=[C:13]2[O:16][CH2:17][O:18][C:12]2=[C:11]([C:22]#[C:21][CH2:20][O:23][CH3:24])[CH:10]=1
Reactant: Nc1c(Cl)cc(I)c2c1OCO2
Reactant: C#CCOC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: COCC#Cc1cc(Cl)c(N)c2c1OCO2
Temperature: 25 °C

Procedure:
Bis(Triphenyl-phosphine)palladium(II) chloride (472 mg), copper iodide (192 mg) and diisopropylamine (680 mg) were added to a stirred solution of 6-chloro-4-iodo-2,3-methylenedioxyaniline (1000 mg) and methyl propargyl ether (471 mg) in ethyl acetate (10 mls) at −20° C. The reaction was allowed to warm to ambient temperature over 16 hours. The reaction mixture was partitioned between ethyl acetate and saturated NaHCO3. The organics were washed with water and saturated brine and dried over magnesium sulfate. The product was purified by column chromatography on silica using a gradient of 80–100% Dichloromethane/isohexane as eluent. 6-chloro-4-(3-methoxyprop-1-ynyl)-2,3-methylendioxyaniline was thus obtained as a tan crystalline solid (200 mg); NMR Spectrum: (DMSOd6) 3.28 (s, 3H), 4.26 (s, 2H), 5.52 (s, 2H), 6.05 (s, 2H), 6.93 (s, 1H).