Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[NH:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[O:14].C([O-])([O-])=O.[K+].[K+].CNCCNC>O1CCOCC1.[Cu]I>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([N:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])=[CH:6][CH:7]=1
Reactant: Clc1ccc(I)cn1
Reactant: O=C1CCCN1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=C1CCCN1c1ccc(Cl)nc1
Yield: 103 %

Procedure:
To a solution of 2-chloro-5-iodopyridine (200 mg, 0.84 mmol) in 4 mL anhydrous dioxane was added 2-pyrrolidinone (60.8 μL, 0.79 mmol), K2CO3 (415.6 mg, 3 mmol), CuI (15.9 mg, 0.084 mmol), and N,N′-dimethyl-1,2-ethanediamine (11.8 μL, 0.083 mmol) in a 2 dram screw-top vial. The vial is evacuated and flushed with nitrogen. The reaction mixture was heated to reflux for 18 h. The reaction mixture was filtered through celite and filtrate was concentrated to afford the crude material. The mixture was purified by flash chromatography on silica gel, eluting with 50-100% EtOAc:heptane. Fractions containing the desired products were combined and concentrated to afford the desired product as a white solid (160 mg, yield: 97.4%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]1[N:12]([CH2:25][C:26]([F:29])([CH3:28])[CH3:27])[C:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:16]([O-])=[CH:15][C:14]=2[N:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+:30].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][C:11]1[N:12]([CH2:25][C:26]([F:29])([CH3:28])[CH3:27])[C:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[C:15]([NH2:30])[C:14]=2[N:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(F)Cn1c(CCOCc2ccccc2)nc2c[n+]([O-])c3cccnc3c21
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(F)Cn1c(CCOCc2ccccc2)nc2c(N)nc3cccnc3c21
Reaction time: 1 h

Procedure:
2-[2-(Benzyloxy)ethyl]-1-(2-fluoro-2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine 5-oxide (1.97 g, 5.00 mmol) was dissolved in 50 mL of CH2Cl2 and treated with 5 mL of concentrated aqueous NH4OH solution. The mixture was stirred rapidly and then p-toluenesulfonyl chloride (1.00 g, 5.33 mmol) was carefully added. Rapid stirring was continued for 1 hour. The reaction mixture was then treated with 20 mL of H2O. The layers were separated and the organic portion was washed successively with 5% Na2CO3 solution, H2O and brine. The organic portion was dried over Na2SO4, filtered, and concentrated under reduced pressure. Chromatography (SiO2, 10% CMA/CHCl3) gave 0.90 g of 2-[2-(benzyloxy)ethyl]-1-(2-fluoro-2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine as a yellow solid.
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH2:16][CH:9]1[CH2:10][NH:11][CH2:12]2)=O)(C)(C)C.Cl[C:18]1[N:19]=[N:20][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:22][CH:23]=1.C(O)(C(F)(F)F)=O>>[C:24]1([C:21]2[N:20]=[N:19][C:18]([N:11]3[CH2:12][CH:13]4[NH:8][CH:9]([CH2:16][CH2:15][CH2:14]4)[CH2:10]3)=[CH:23][CH:22]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1C2CCCC1CNC2
Reactant: Clc1ccc(-c2ccccc2)nn1
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(-c2ccc(N3CC4CCCC(C3)N4)nn2)cc1

Procedure:
Was prepared according to reaction-conditions of Method A from 9-tert-butoxycarbonyl-3,9-diazabicyclo[3.3.1]nonane and 3-chloro-6-phenylpyridazine at 130° C. for 3 days, followed by treatment with TFA. Workup procedure was done according to Method A. LC-ESI-HRMS of [M+H]+ shows 281.1761 Da. Calc. 281.176621 Da, dev. −1.9 ppm.
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Ni]>[C:1]([O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH2:23])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OC1CCN(Cc2ccccc2[N+](=O)[O-])CC1)c1ccccc1
Agent: [Ni]
Solvent: CCO
Product: Nc1ccccc1CN1CCC(OC(=O)c2ccccc2)CC1
Reaction time: 8 h
Yield: 62.8 %

Procedure:
0.345 g (0.00101 mol) of 1-(2-nitro-benzyl)-piperidin-4-yl benzoate was dissolved in 15 ml of ethanol and treated with 0.2 g of Raney-nickel. The mixture was hydrogenated at room temperature and under normal pressure for 8 hrs. The catalyst was filtered off and, after concentration, the residue was chromatographed on silica gel with ethyl acetate/ hexane (1:3) as the eluent. 0.197 g (61%) of 1-(2-amino-benzyl)-piperidin-4-yl benzoate was obtained as a colorless oil. MS: me/e=311 (C19H23N2 O2+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5]P(OCC)(OCC)=O)[CH3:2].C([Li])CCC.[C:20]([O:24][C:25](=[O:47])[NH:26][C@:27]([CH:45]=O)([CH3:44])[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:32][CH:31]=1)([CH3:23])([CH3:22])[CH3:21].C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:14])/[CH:5]=[CH:45]/[C@@:27]([NH:26][C:25]([O:24][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:47])([CH3:44])[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:32][CH:31]=1)[CH3:2]
Reactant: CCCCCCCOc1ccc(CC[C@](C)(C=O)NC(=O)OC(C)(C)C)cc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCOc1ccc(CC[C@](C)(/C=C/C(=O)OCC)NC(=O)OC(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (diethoxy-phosphoryl)-acetic acid ethyl ester (429 mg, 1.92 mMol) in dry THF (7 ml) is added n-butyllithium (0.66 ml, 2.5M in hexane, 1.66 mMol) at −78° C. The mixture was stirred at −78° C. for 1 hour. After that time, a solution of [(R)-1-formyl-3-(4-heptyloxy-phenyl)-1-methyl-propyl]-carbamic acid tert-butyl ester (500 mg, 1.28 mMol) in THF (4 ml) is added and stirring is continued at −78° C. for 1.5 hours. The mixture is allowed to warm to RT and then stirred at RT for 2 hours. The reaction mixture is then poured onto a biphasic mixture of AcOEt and NaHCO3 (saturated aqueous solution) and the aqueous phase is extracted twice with AcOEt. The combined organic layers are dried (Na2SO4) and concentrated under reduced pressure. Column chromatography eluting with 4% AcOEt in toluene gives the title compound as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[F:28])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:22][CH3:23])[C:10](=[O:21])[NH:11][C:12]=2[C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[C:7]1=[O:24].B(O)(O)[C:30]1[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=1.N1C=CC=CC=1.[NH4+].[OH-]>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[F:28])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:22][CH3:23])[C:10](=[O:21])[N:11]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)[C:12]=2[C:16]([N:18]([CH3:19])[CH3:20])=[O:17])[C:7]1=[O:24]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: COc1c2c(c(C(=O)N(C)C)[nH]c1=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1c2c(c(C(=O)N(C)C)n(-c3ccc(C)cc3)c1=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6-(3-chloro-4-fluorobenzyl)-4-methoxy-N,N-dimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide (0.10 g, 0.25 mmol), p-tolylboronic acid (0.13 g, 0.98 mmol), copper (II) acetate (67 mg, 0.37 mmol), activated molecular sieves type 4A (1 g), and pyridine (40 mg, 0.50 mmol) in dichloromethane (12 mL) was stirred at room temperature overnight. The reaction mixture was treated with a mixture of aqueous NH4OH (1 mL, 1M) and methanol (3 mL). After stirring at room temperature for 15 minutes, the slurry was filtered, and the filtrate concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a gradient of 0 to 15% of methanol in chloroform. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[Si]([O:27][CH2:28][CH:29]1[C:33]([CH2:34]Br)=[CH:32][CH2:31][CH2:30]1)(C(C)(C)C)(C)C>>[OH:27][CH2:28][CH:29]1[C:33]([CH2:34][N:7]2[C:8]([O:9][C:10]3[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]2=[O:18])=[CH:32][CH2:31][CH2:30]1
Reactant: CC(C)(C)[Si](C)(C)OCC1CCC=C1CBr
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(Oc2cc(C)cc(C)c2)n(CC2=CCCC2CO)c(=O)[nH]c1=O
Yield: 21.3 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and (5-t-butyldimethylsilyloxymethylcyclopent-1-en-1-yl)methyl bromide were reacted by the same method with example 6 to obtain the titled compound (52 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH2:13][CH2:14][C:15](OCC)=O)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[C:20]1([C:26]2[N:31]=[N:30][C:29]([NH:32][NH2:33])=[CH:28][CH:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CS(C)=O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH2:13][CH2:14][C:15]3[N:30]4[N:31]=[C:26]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH:27]=[CH:28][C:29]4=[N:32][N:33]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CCc1ccnc2cc(OC)ccc12
Reactant: NNc1ccc(-c2ccccc2)nn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc2c(CCc3nnc4ccc(-c5ccccc5)nn34)ccnc2c1

Procedure:
Ethyl 3-(7-methoxyquinolin-4-yl)propanoate (156 mg, 0.60 mmol) was combined with 1-(6-phenylpyridazin-3-yl)hydrazine (115 mg, 0.62 mmol) and pTsOH.H2O (140 mg, 0.72 mmol). The mixture was microwaved at 150° C. for 60 minutes. The residue was taken up in DMSO and purified by HPLC and neutralized to yield the desired product as an off-white solid. (ESI, pos. ion) m/z: 382.1 (M+H).
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([NH2:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CNC(=O)C1C=CC=CC=1SC1C=CC=CC=1>>[C:1]1([S:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[CH2:10][NH2:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)c1ccccc1Sc1ccccc1
Agent: CNC(=O)c1ccccc1Sc1ccccc1
Product: NCc1ccccc1Sc1ccccc1

Procedure:
By following essentially the same procedure described in Example 2 but substituting 2-(phenylthio)benzamide for the N-methyl-2-(phenylthio)benzamide, there is obtained 2-(phenylthio)benzylamine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[F:19][C:20]([F:30])([F:29])[CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH:28][CH:25]3[CH2:26][CH2:27][N:22]([CH2:21][C:20]([F:30])([F:19])[F:29])[CH2:23][CH2:24]3)=[O:15])=[CH:11][N:10]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C(O)c1ccc(-c2cc(F)cc(F)c2)nc1
Reactant: NC1CCN(CC(F)(F)F)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Product: O=C(NC1CCN(CC(F)(F)F)CC1)c1ccc(-c2cc(F)cc(F)c2)nc1
Yield: 7.2 %

Procedure:
6-(3,5-Difluoro-phenyl)-nicotinic acid (50 mg, 0.21 mmol), 1-(2,2,2-trifluoroethyl)piperidin-4-amine hydrochloride (48 mg, 0.22 mmol) N,N-diisopropylethylamine (0.296 mL, 1.69 mmol), HATU (101 mg, 0.26 mmol) in acetonitrile (5 mL) was shaken at room temperature for 12 h. The reaction mixture was concentrated and the crude reaction mixture purified by automated reversed phase chromatography to provide 6 mg (7%) of the title compound. 1H NMR (400 MHz, DMSO-d6) □ ppm 9.08 (1H, s), 8.47 (1H, d, J=7.0 Hz), 8.30 (1H, dd, J=8.4, 2.2 Hz), 8.19 (1H, d, J=8.1 Hz), 7.88 (2H, d, J=7.0 Hz), 7.36 (1H, t, J=10.1 Hz), 3.82 (1H, br. s.), 3.11-3.23 (2H, m), 2.95 (2H, d, J=11.0 Hz), 2.42-2.48 (2H, m), 1.76-1.87 (2H, m), 1.56-1.66 (2H, m).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][C:6]([CH3:9])([OH:8])[CH:5]([OH:10])[CH:4]2[C:11]([CH3:17])([CH3:16])[CH:12]3[CH2:15][C:3]12[CH2:14][CH2:13]3.[CH:19](=O)[CH2:20][CH3:21].[Br-].[Li+].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1COCC1>[CH2:20]([CH:21]1[O:10][CH:5]2[C:6]([CH3:9])([CH2:7][C:2]([CH3:18])([CH3:1])[C:3]34[CH2:15][CH:12]([CH2:13][CH2:14]3)[C:11]([CH3:17])([CH3:16])[CH:4]42)[O:8]1)[CH3:19]
Reactant: CC1(O)CC(C)(C)C23CCC(C2)C(C)(C)C3C1O
Reactant: CCC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Br-]
Solvent: C1CCOC1
Product: CCC1OC2C3C(C)(C)C4CCC3(C4)C(C)(C)CC2(C)O1
Reaction time: 1 h
Yield: 43 %

Procedure:
A solution of 2,2,4,7,7-pentamethyltricyclo[6.2.1.01.6]undecane-4,5-diol (5b, 1.7 g, 6.6 mmol), propionaldehyde (2.0 g, 33 mmol), lithium bromide (75 mg) and p-toluenesulfonic acid (75 mg) in THF (30 ml) was stirred at r. t. for 1 h, then poured onto saturated aqueous sodium bicarbonate solution (50 ml) and extracted with MTBE (2×50 ml). The combined organic phases were washed with water (2×50 ml), dried (Na2SO4), concentrated in vacuo and the residue (1.9 g) purified by flash chromatography (MTBE/hexane 1:20) and bulb-to-bulb distillation to give 6-ethyl-2,2,4,10,10-pentamethyl-5,7-dioxatetracyclo[9.2.1.01.9,04.8]tetradecane (Ib, 2+98% mixture of isomeric pairs of enantiomers, 0.83 g, 42% yield, colourless oil).
Reaction SMILES: [CH2:1]([C@:3]1([CH3:28])[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([C:24]([CH3:26])=[CH2:25])[CH:17]=3)=[N:13][CH:14]=2)[C:5](=[O:27])[NH:4]1)[CH3:2]>CO>[CH2:1]([C@:3]1([CH3:28])[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([CH:24]([CH3:25])[CH3:26])[CH:17]=3)=[N:13][CH:14]=2)[C:5](=[O:27])[NH:4]1)[CH3:2]
Reactant: C=C(C)c1cc(Oc2ccc(N3C(=O)N[C@](C)(CC)C3=O)cn2)ccc1C#N
Solvent: CO
Product: CC[C@@]1(C)NC(=O)N(c2ccc(Oc3ccc(C#N)c(C(C)C)c3)nc2)C1=O
Reaction time: 1 h

Procedure:
To a solution of 4-({5-[(4R)-4-ethyl-4-methyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)-2-(1-methylethenyl)benzonitrile (Intermediate 207, 98 mg) in MeOH (10 mL) Pd 10% w/w on activate carbon (10 mg) was added and the reaction mixture was stirred for 1 hour under H2 atmosphere (P=1 atm). The catalyst was filtered off and the solvent removed under reduced pressure. The residue was purified by flash chromatography on silica gel (SNAP 10 g) eluting from 75:25 to 40:60 cyclohexane/ethyl acetate affording the title compound (80 mg) as white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][S:4][CH:3]=[C:2]1[C:7]([OH:9])=O.[NH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[N:14][C:15]([Cl:21])=[CH:16][CH:17]=2)[N:12]=1>O>[Cl:21][C:15]1[N:14]=[C:13]2[C:18]([CH:19]=[CH:20][C:11]([NH:10][C:7]([C:2]3[O:1][CH2:6][CH2:5][S:4][CH:3]=3)=[O:9])=[N:12]2)=[CH:17][CH:16]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: O=C(O)C1=CSCCO1
Solvent: O
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)C1=CSCCO1
Yield: 47.8 %

Procedure:
The procedure is similar to that described in Example 2, but starting with 5,6-dihydro-1,4-oxathiin-2-carboxylic acid (7.3 g), N,N'-carbonyldiimidazole (9.7 g) and 2-amino-7-chloro-1,8-naphthyridine (7.2 g). The product obtained by precipitation in water is purified by recrystallization in dimethylformamide (60 cc). N-(7-Chloro-1,8-naphthyridin-2-yl)-5,6-dihydro-1,4-oxathiin-2-carboxamide (5.9 g), m.p. 270° C., is thereby obtained.
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[Br:11][C:12]1[N:13]=[CH:14][N:15]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:16]=1Br>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Br:11][C:12]1[N:13]=[CH:14][N:15]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:16]=1[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: C[Sn](C)(C)c1cccnc1
Reactant: C[Si](C)(C)CCOCn1cnc(Br)c1Br
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOCn1cnc(Br)c1-c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.2 %

Procedure:
To a solution of 71 (0.82 g, 3.4 mmol) in anhydrous toluene (50 ml) were added 0.9 eq (1.10 g) of 4,5-dibromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (compound 72, LCMS (method A): Rt: 3.60 min, ([M+H]+=357)) and the resulting mixture was stirred for 2 hours under N2 (room temperature). To this reaction mixture were added 10 mol % of PdCl2(PPH3)2 (240 mg). After the addition, the temperature was raised to 100° C. and the resulting solution was stirred for 18 hours under N2. The reaction mixture was cooled, diluted with ethyl acetate, washed three times with a saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether followed by ethyl acetate) to afford 3-[5-bromo-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-yl]-pyridine (73) as an oil (385 mg, 36%). LCMS (method A): Rt: 3.40 min, ([M+H]+=355). 1H-NMR (400 MHz, CDCl3 and HMBC): δ 8.79 (d, J=2 Hz, 1H), 8.66 (dd, J=5 Hz, 2 Hz, 1H), 7.91 (dt, J=8 Hz, 2 Hz, 1H), 7.66 (s, 1H), 7.44-7.40 (m, 1H), 5.17 (s, 2H), 3.56-3.50 (m, 2H), 0.94-0.87 (m, 2H), 0.0 (s, 9H).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([CH:9]([C:14](=O)[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[CH2:10][C:11](O)=[O:12])[CH:6]=[CH:5][N:4]=1.C(O)C.[NH2:29][NH2:30].C(OCC)(=O)C>CCOCC>[CH3:1][S:2][C:3]1[N:8]=[C:7]([CH:9]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)=[N:30][NH:29][C:11](=[O:12])[CH2:10]2)[CH:6]=[CH:5][N:4]=1
Reactant: CSc1nccc(C(CC(=O)O)C(=O)c2cccc(C(F)(F)F)c2)n1
Reactant: NN
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CCO
Product: CSc1nccc(C2CC(=O)NN=C2c2cccc(C(F)(F)F)c2)n1

Procedure:
Compound 5 (6.58 g, 17.8 mmol), and ethanol (200 mL) were combined under argon. Hydrazine (835 μL, 26.6 mmol) was added and the resulting solution was heated at reflux for 4 h. The solution was cooled and rotary evaporated. Ethyl acetate was added followed by the addition of ether. The solution was again rotary evaporated to afford a foam (6) which was used as is for the synthesis of 7.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5](Cl)(=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[S:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.Cl>ClC1C=CC=CC=1>[CH2:5]([C:15]1[S:14][CH:18]=[CH:17][CH:16]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: c1ccsc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: c1ccc(Cc2cccs2)cc1
Temperature: 0 °C

Procedure:
27.2 g of 98.5% pure aluminium trichloride (sublimed) were suspended in 130 ml of chlorobenzene and cooled to 0° C. 28.7 g of benzoyl chloride were added dropwise while stirring and cooling over the course of 30 minutes, and the mixture was then stirred for 1 hour. Likewise at 0° C., a solution of 17.3 g of thiophene in 27 ml of chlorobenzene was added dropwise over the course of 30 minutes, and the mixture was stirred for 1 hour. Remaining hydrogen chloride was driven out by heating the mixture and stirring, finally under vacuum. The remaining solution was introduced over the course of 40 minutes into a solution of 12.7 g of dimethylamineborane in 70 ml of chlorobenzene while stirring at 70° C. The mixture was then stirred for 1 hour, cooled and discharged into a mixture of 200 g of ice and 50 g of concentrated aqueous hydrochloric acid while stirring. The aqueous phase was then separated off and extracted with chlorobenzene. The remaining organic phase was extracted by shaking with water. The organic phase and the extract from the aqueous phase were then combined, the solvent was removed therefrom by distillation, and 38.7 g of crude 2-benzylthiophene of 79.7% purity were obtained by distillation. This corresponds to 88.5% of theory. Redistillation resulted in 99.7% pure 2-benzylthiophene with a boiling point of 91° to 92° C./1.4 mbar.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:38][CH2:37][N:12]2[C:13]3[C:18]([C:19]([C:20]4[C:21](=[O:36])O[C:23](=[O:35])[C:24]=4[C:25]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]([CH3:34])[CH:26]=4)=[C:11]2[CH2:10]1)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:40](C)C=O>N>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:38][CH2:37][N:12]2[C:13]3[C:18]([C:19]([C:20]4[C:21](=[O:36])[NH:40][C:23](=[O:35])[C:24]=4[C:25]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]([CH3:34])[CH:26]=4)=[C:11]2[CH2:10]1)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C=O
Reactant: Cn1cc(C2=C(c3c4n(c5ccccc35)CCC(NC(=O)OC(C)(C)C)C4)C(=O)OC2=O)c2ccccc21
Agent: N
Product: Cn1cc(C2=C(c3c4n(c5ccccc35)CCC(NC(=O)OC(C)(C)C)C4)C(=O)NC2=O)c2ccccc21

Procedure:
A solution of 80 mg of 3-[8-t-butoxyformamido-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)furan-2,5-dione in 2 ml of dimethylformamide and 2 ml of 33% aqueous ammonia was heated to 100° C. for 1 hour. The solution was cooled and gave 60 mg of 3-[8-t-butoxyformamido-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione of melting point 153°-155° C.
Reaction SMILES: [CH:1]1([C:6]2[CH:34]=[CH:33][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[N:17]5[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:16]5=[C:15](I)[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:35]([F:38])([F:37])[F:36])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[CH3:40][Zn+]>C1COCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:1]1([C:6]2[CH:34]=[CH:33][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[N:17]5[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:16]5=[C:15]([CH3:40])[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:35]([F:38])([F:37])[F:36])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)CC1CCn2c1c(I)c1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Reactant: C[Zn+]
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1c2n(c3ccc(OCc4ccc(C5CCCC5)c(C(F)(F)F)c4)cc13)CCC2CC(=O)OC(C)(C)C
Temperature: 70 °C
Yield: 51.3 %

Procedure:
To a solution of tert-butyl 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-iodo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (50.0 mg, 0.078 mmol) in THF (1 mL) in a heavy-walled sealed microwave tube (0.5-2.0 mL) under N2 was added methylzinc(II) chloride (2.0 M in THF, 0.055 mL, 0.109 mmol) and bis(tri-t-butylphosphine)palladium(0) (3.60 mg, 7.04 μmol). The reaction mixture was then heated to 70° C. for 2 h, quenched with saturated NaHCO3 and filtered by vacuum filtration through a pad of Celite®. The pad of Celite® was washed with EtOAc (2×5 mL). The filtrate was extracted with EtOAc (3×5 mL). The organic layers were combined and washed with saturated NaCl (1×10 mL), dried over MgSO4 and filtered by vacuum filtration. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC to give the title compound as a colorless oil (21.1 mg). LCMS m/z=528.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.45 (s, 9H), 1.56-1.66 (m, 2H), 1.68-1.79 (m, 2H), 1.81-1.92 (m, 2H), 2.04-2.15 (m, 2H), 2.23 (s, 3H), 2.26-2.36 (m, 1H), 2.41 (dd, J=15.66, 10.11 Hz, 1H), 2.78-2.90 (m, 2H), 3.31-3.44 (m, 1H), 3.65-3.74 (m, 1H), 3.90-3.98 (m, 1H), 3.99-4.12 (m, 1H), 5.09 (s, 2H), 6.85 (dd, J=8.72, 2.40 Hz, 1H), 7.03 (d, J=2.15 Hz, 1H), 7.09 (d, J=8.72 Hz, 1H), 7.47 (d, J=8.08 Hz, 1H), 7.60 (d, J=8.21 Hz, 1H), 7.71 (d, J=1.39 Hz, 1H).