Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=C(Cl)OC(Cl)(Cl)Cl.[Cl:9][CH2:10][C:11]([NH:13][C:14]1[S:15][CH:16]=[C:17]([C:19](=[N:23][O:24][CH3:25])[C:20]([OH:22])=O)[N:18]=1)=[O:12].[NH2:26][C@H:27]1[C@H:30]([N:31]=[N+:32]=[N-:33])[NH:29][C:28]1=[O:34].C1OC1C>C(Cl)Cl.C(N(CC)CC)C.CN(C=O)C>[N:31]([C@@H:30]1[NH:29][C:28](=[O:34])[C@H:27]1[NH:26][C:20](=[O:22])[C:19]([C:17]1[N:18]=[C:14]([NH:13][C:11](=[O:12])[CH2:10][Cl:9])[S:15][CH:16]=1)=[N:23][O:24][CH3:25])=[N+:32]=[N-:33]
Reactant: CON=C(C(=O)O)c1csc(NC(=O)CCl)n1
Reactant: [N-]=[N+]=N[C@@H]1NC(=O)[C@H]1N
Agent: CC1CO1
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON=C(C(=O)N[C@@H]1C(=O)N[C@H]1N=[N+]=[N-])c1csc(NC(=O)CCl)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.127 g of DMF in 5 ml of methylene chloride is added 0.104 ml of diphosgene at -10° C. The mixture is stirred for 30 minutes at room temperature, followed by addition of a solution of 15 ml of methylene chloride containing 0.483 g of 2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetic acid and 0.176 g of triethylamine at -70° C. The mixture is stirred for two hours at -25° C., then cooled to -70° C., followed by addition of 0.352 g of triethylamine, 0.40 g of tosyl salt of (3S,4S)-3-amino-4-azido-2-oxoazetidine and 2 ml of propylene oxide. The temperature of the mixture is raised up to room temperature in the course of one hour while stirring, followed by ice-cooling for one hour. The crystals separated out are collected by filtration to yield 0.383 g of (3S,4S)-4-azido-3-[2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetamido]-2-oxoazetidine.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6]C)[CH:4]=[CH2:5].[C:8](O)(C(F)(F)F)=O.[C:15](#N)[CH3:16]>>[CH3:8][CH2:1][O:2][CH:3]([O:6][CH2:15][CH3:16])[CH:4]=[CH2:5]
Reactant: C=CC(OC)OC
Reactant: CC#N
Reactant: O=C(O)C(F)(F)F
Product: C=CC(OCC)OCC
Reaction time: 0.5 h

Procedure:
0.16 gm of 13b.1 (0.192 mmol) and 42 mg of acrolein dimethyl acetal (0.41 mmol) were weighed into a 25 ml RB flask followed by addition of 40 mg of Montmorillonite clay, the flask was capped with a septum and 3 ml of ACN were added under nitrogen. The pH of the reaction was determined to be about 6. About 3 microliters of TFA were added. After additional stirring, the pH was found to be 3.5. After 30 minutes, 0.15 ml of acrolein dimethyl acetal was added and stirring continued at room temperature. The reaction was monitored by TLC and HPLC. The reaction was quenched after stirring for 5 hours with 2 ml of aqueous sodium bicarbonate and the solution was filtered over a bed of celite. The celite bed was washed with 20 ml of ACN, and the filtrates combined and concentrated on the rotavapor. The crude product was purified by reverse phase chromatography using methanol/water 4:1 to give 150 mg of acrolein acetal product, 14b.1.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][C@@H:7]([O:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH2:6][N:5]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:15])(=O)[NH2:2].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:36]2)=CC=1>O1CCCC1>[CH3:13][S:10]([O:9][C@H:7]1[CH2:6][N:5]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:4]([C:1](=[S:36])[NH2:2])[CH2:8]1)(=[O:12])=[O:11]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(N)=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CS(=O)(=O)O[C@@H]1C[C@@H](C(N)=S)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 2 h
Yield: 152.4 %

Procedure:
To a solution of (2S,4R)-2-carbamoyl-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (7 g) in tetrahydrofuran (210 ml) was added 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (3.65 g) and the solution was stirred for 2 hours under refluxing. After the solvent was removed, the resulting oily residue was subjected to a column chromatography on silica gel (150 g) eluting with a mixture of n-hexane and ethyl acetate (2:3 V/V) to give (2S,4R)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)-2-thiocarbamoylpyrrolidine (5.55 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[Cl:9].[C:10]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]>>[C:13]([O:12][C:10]([N:17]1[CH2:22][CH2:21][N:20]([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=2[Cl:9])[CH2:19][CH2:18]1)=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: Fc1ccc(Br)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(F)cc2Cl)CC1

Procedure:
The title compound was prepared according to the procedure described for example AX from 1-bromo-2-chloro-4-fluorobenzene and N-Boc-piperazine (10%, off white solid, MS (m/e): 315.1(M+H, 100%)
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])=[CH:5][CH:4]=1.[NH:20]([C:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]([N+:34]([O-:36])=[O:35])[CH:25]=1)=[O:23])[NH2:21].O.S(C1C=CC(C)=CC=1)(O)(=O)=O>>[N+:34]([C:26]1[CH:25]=[C:24]([C:22]([NH:20][N:21]=[C:15]([C:12]2[C:13]([OH:14])=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:19])([F:18])[F:1])=[CH:4][CH:5]=3)[S:10][CH:11]=2)[CH3:17])=[O:23])[CH:33]=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29])([O-:36])=[O:35]
Reactant: COC(=O)c1ccc(C(=O)NN)cc1[N+](=O)[O-]
Reactant: CC(=O)c1csc(-c2ccc(C(F)(F)F)cc2)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COC(=O)c1ccc(C(=O)NN=C(C)c2csc(-c3ccc(C(F)(F)F)cc3)c2O)cc1[N+](=O)[O-]
Yield: 80.5 %

Procedure:
From 2-(4-trifluoromethylphenyl)-3-hydroxy-4-methylcarbonylthiophene (57.3 mg, 0.2 mmol), methyl 4-hydrazinocarbonyl-2-nitrobenzoate (47.8 mg, 0.2 mmol) and tosylic acid monohydrate (11.4 mg, 0.06 mmol), 81.7 mg of the desired product was obtained in the same manner as in Synthetic Example 65 as a pale yellow solid (yield 81%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1.O.CCOC(C)=O>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH:23]2[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]2)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(NC4CCN(C(=O)OC(C)(C)C)CC4)nc(Cl)nc32)cc1
Temperature: 70 °C
Reaction time: 20 h
Yield: 79.8 %

Procedure:
A mixture of 2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (171 mg, 0.500 mmol), 4-amino-1-N-Boc-piperidine (100 mg, 0.500 mmol) and TEA (0.150 mL, 1.08 mmol) in dioxane (4 mL) was stirred at 70° C. for 20 h. Water and EtOAc were added. The organic phase was separated, washed with 1N HCl, then with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give tert-butyl 4-(2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)piperidine-1-carboxylate (202 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:20])=[C:12]3[CH:18]=[C:17](I)[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:23][O:24][CH2:25][C:26]#[CH:27]>C(NCC)C.[Cu](I)I.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>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:20])=[C:12]3[CH:18]=[C:17]([C:27]#[C:26][CH2:25][O:24][CH3:23])[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(I)cc2c1O
Reactant: C#CCOC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: COCC#Cc1cc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc2s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 30 %

Procedure:
To a suspension of N-(4-chlorobenzyl)4-hydroxy-2-iodothieno[2,3-b]pyridine-5-carboxamide (Example No. 2) (1.00 g) in diethylamine (28 mL) is added copper iodide (0.128 g), and Pd(PPh3)2Cl2 (0.079 g) followed by addition of propargyl methyl ether (0.27 mL). The reaction is stirred at rt for 18 h. The reaction mixture is partitioned between H2O (100 mL) and CH2Cl2 (100 mL). The organic layer is removed, and the aqueous layer is extracted with CH2Cl2 (3×100 mL). Combined organic layers are washed with a saturated aqueous NH4Cl solution (200 mL), dried with MgSO4, filtered, and concentrated in vacuo. The resulting brown oil is purified via column chromatography (CH2Cl2:CH3OH; 98:2). The resulting impure material is re-purified via column chromatography (heptane:2-propanol, 10:1; CH2Cl2:CH3OH, 98:2). Fractions homogeneous by TLC are combined and concentrated in vacuo to yield to yield 0.260 g (30%) of the title compound as an off-white solid.
Reaction SMILES: OO.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.[OH:23][CH:24]1[CH2:29][C:28]([CH3:31])([CH3:30])[N:27]([OH:32])[C:26]([CH3:34])([CH3:33])[CH2:25]1.N=O.[C:37]([OH:41])([CH3:40])([CH3:39])[CH3:38]>O>[OH:23][CH:24]1[CH2:29][C:28]([CH3:30])([CH3:31])[N:27]([O:32][CH2:38][C:37]([OH:41])([CH3:40])[CH3:39])[C:26]([CH3:34])([CH3:33])[CH2:25]1
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: CC(C)(C)O
Agent: N=O
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: OO
Solvent: O
Product: CC(C)(O)CON1C(C)(C)CC(O)CC1(C)C
Temperature: 47.5 °C
Reaction time: 1 h

Procedure:
A solution of 32.3 g (475 mmol) of 50% aqueous hydrogen peroxide mixed with 35 mL of tert-butyl alcohol is added over six hours at 45-50° C. to a mixture prepared by adding sequentially 0.362 g (1.2 mmol) of ethylenediaminetetraacetic acid, 55 mL of tert-butyl alcohol and 17.2 g (100 mmol) of 4-hydroxy-1-oxyl-2,2,6,6-tetramethylpiperidine to a solution of 0.80 g (4 mmol) of ferrous chloride dissolved in 5 mL of water. Analysis by gas chromatography shows 15% starting nitroxyl compound remains at the end of the peroxide addition. The reaction mixture is stirred for one hour at 45-50° C. and then for 72 hours at 25° C. to complete the reaction. Analysis by gas chromatography shows the reaction mixture contains a ratio of 7 parts of the title compound to 1 part of 1-(2-hydroxy-2-methylpropoxy)-2,2,6,6-tetramethylpiperidin-4-one.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].[CH:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].O1CCCC1.C(N(CC)CC)C>C(OCC)(=O)C.[Cu]I>[C:9]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8])#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: Fc1ccccc1Br
Reactant: C#CCCCCCCCCC
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCCCCCCC#Cc1ccccc1F
Temperature: 55 °C
Reaction time: 3 h
Yield: 53.2 %

Procedure:
To a solution of 2-bromofluorobenzene (17.5 g), 1-undecyne (18.3 g), tetrahydrofuran (50 ml), and triethylamine (70 ml) was added bistriphenylphosphine palladium(II)chloride (1.2 g) and copper(I)iodide (162 mg). The reaction mixture was stirred at 55° C. for 3 hr, and an additional 2-bromofluorobenzene (2.0 g) and bistriphenylphosphine palladium(II)chloride (200 mg) were added. The mixture was stirred at 55° C. overnight, allowed to cool to room temperature, diluted with ethyl acetate and washed with water. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was chromatographed over silica gel (eluted with hexane). The appropriate fractions were collected and evaporated. The residue was distilled twice under vacuum to give 13.1 g (53%) of product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[NH:7][C:8](=[O:18])[N:9]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[CH:30]=[C:31]([CH3:43])[C:32]3[N:36]=[C:35]([CH:37]4[CH2:41][CH2:40][O:39][CH2:38]4)[NH:34][C:33]=3[CH:42]=2)[CH:23]=1.CCN(C(C)C)C(C)C.[OH-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[NH:7][C:8](=[O:18])[N:9]([CH:12]3[CH2:13][CH2:14][N:15]([C:22]4[CH:23]=[C:24]([O:28][C:29]5[CH:30]=[C:31]([CH3:43])[C:32]6[N:36]=[C:35]([CH:37]7[CH2:41][CH2:40][O:39][CH2:38]7)[NH:34][C:33]=6[CH:42]=5)[N:25]=[CH:26][N:27]=4)[CH2:16][CH2:17]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc2[nH]c(C3CCOC3)nc12
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)c5nc(C6CCOC6)[nH]c5c4)ncn3)CC1)C(=O)N2

Procedure:
28 mg (0.10 mmol) 7-methoxy-3-(piperidin-4-yl)-4,5-dihydro-1H-benzo[d][1,3]diazepin-2(3H)-one, 33 mg (0.10 mmol) 6-(6-chloropyrimidin-4-yloxy)-4-methyl-2-(tetrahydrofuran-3-yl)-1H-benzo[d]imidazole and 30 μL (0.20 mmol) DIPEA in 2.0 mL DMF were stirred at 50° C. over the weekend. The reaction mixture was purified by chromatography. The fractions containing product were combined and evaporated down i.vac. to leave the aqueous residue. This was neutralised with a 4 M aqueous NaOH solution. The precipitate formed was suction filtered, washed and dried.
Reaction SMILES: [C:1]1([C:13]2[C:14](=[O:29])[NH:15][C:16](=[O:28])[C:17]=2[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([Br:27])[CH:25]=3)[NH:20][CH:19]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1>CO>[C:1]1([C@H:13]2[C@H:17]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([Br:27])[CH:25]=4)[NH:20][CH:19]=3)[C:16](=[O:28])[NH:15][C:14]2=[O:29])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1c1c[nH]c2ccc(Br)cc12
Solvent: CO
Product: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@@H]1c1c[nH]c2ccc(Br)cc12

Procedure:
3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1yl)-4-(5-bromo-1H-indol-3-yl)pyrrole-2,5-dione, prepared as in Example 24, was reduced with Mg in methanol as described in Example 2, Procedure C, to yield (±)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1 yl)-4-(5-bromo-1H-indol-3-yl)pyrrolidine-2,5-dione. 1H NMR (CD3OD) δ: 2.18-2.26 (m, 2H), 2.96 (t, J=6.0 Hz, 2H), 4.12 (t, J=6.4 Hz, 2H), 4.40 (d, J=6.8 Hz, 1H), 4.52 (d, J=6.8 Hz, 1H), 6.86-6.96 (m, 2H), 7.08 (s, 1H), 7.13-7.30 (m, 5H)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])[C:5]([CH3:21])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1.CCN(CC)CC.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:21][C:5]1[CH:4]=[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[C:2]([N:1]([S:40]([CH3:39])(=[O:42])=[O:41])[S:40]([CH3:39])(=[O:42])=[O:41])=[N:7][C:6]=1[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:17][CH2:18][CH2:19][CH2:20]2)[CH2:12][CH2:11]1)=[O:9]
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(N)nc1C(=O)N1CCC(N2CCCC2)CC1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(N(S(C)(=O)=O)S(C)(=O)=O)nc1C(=O)N1CCC(N2CCCC2)CC1
Temperature: 50 °C
Reaction time: 5 h
Yield: 44.2 %

Procedure:
A solution of 0.22 g (0.5 mmol) of [6-amino-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 7) in 5.0 ml of DMF was treated with 0.43 ml=0.309 g (3.1 mmol) of Et3N and 0.006 g (0.05 mmol) of DMAP. To the stirred solution was added 0.08 ml=0.12 g (1.0 mmol) of methanesulfonyl chloride drop by drop and the reaction mixture was subsequently warmed up to 50° C. After 5 hours, it was poured into crashed ice and extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 4:1) to give 0.13 g (44%) of the title compound as yellow solid. MS: 589.1 (MH+).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][N:6]1[C@H:15]2[CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][C@@H:14]2[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([C:26]([F:29])([F:28])[F:27])[C:8]=2[C:7]1=[O:30].I[CH3:32]>C1COCC1.COC(C)(C)C>[CH3:32][O:3][CH2:4][CH2:5][N:6]1[C@H:15]2[CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][C@@H:14]2[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([C:26]([F:27])([F:29])[F:28])[C:8]=2[C:7]1=[O:30]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2c3cccc(C(F)(F)F)c3C(=O)N(CCO)[C@H]2C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: COCCN1C(=O)c2c(cccc2C(F)(F)F)[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H]21
Reaction time: 0.33 h
Yield: 37 %

Procedure:
To a suspension of sodium hydride (8 mg of 60% dispersion in mineral oil, hexane-washed, 0.20 mmol) in 2 mL of THF was added (3aR,9bS)-tert-butyl 4-(2-hydroxyethyl)-5-oxo-6-(trifluoromethyl)-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate from Example 20, Part A (40 mg, 0.10 mmol) in 2 mL THF. The reaction was stirred for 20 min, at which time gas evolution had ceased. Then there was added iodomethane (0.125 mL of a 2M solution in tert-butyl methyl ether, 0.25 mmol) and the reaction was allowed to stir at ambient temperature for 18 h. TLC analysis showed that starting material remained. Additional sodium hydride (8 mg of 60% dispersion in mineral oil, 0.20 mmol) and iodomethane (0.125 mL of a 2M solution in tert-butyl methyl ether, 0.25 mmol) were added and the reaction was allowed to stir at 40° C. for 2 h. The reaction was quenched with 10 mL of 1N HCl and extracted with EtOAc. The organics were washed with sat'd aq NaHCO3 and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (230-400 mesh silica gel, elution with 4:1 hexane/EtOAc) to afford 15 mg (37%) of the title compound. 1H NMR (CDCl3): δ 7.79 (d, 1H, J=7.7 Hz), 7.57-7.52 (m, 2H), 7.25-7.22 (m, 1H), 4.15-4.10 (m, 1H), 4.08-3.98 (m, 2H), 3.82-3.77 (m, 1H), 3.61-3.54 (m, 2H), 3.50-3.27 (overlapping m, 4H), 3.31 and 3.28 (singlets, 3H), 1.50 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:11](=[CH:12][CH:13]=1)[CH:10]1[CH2:14][CH:6]2[CH2:7][C:8](=O)[NH:9]1.Cl>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:11](=[CH:12][CH:13]=1)[CH:10]1[CH2:14][CH:6]2[CH2:7][CH2:8][NH:9]1
Reactant: COc1ccc2c(c1)C1CC(=O)NC2C1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C1CCNC2C1
Temperature: -10 °C

Procedure:
1 M Borane tetrahydrofuran complex (70 mL) is added dropwise to a solution of 4-methoxy-9-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-10-one (3.0 g) in THF (20 mL) chilled in an ice bath. The resulting solution is stirred at reflux temperature for 5 h and then at room temperature overnight. The solution is cooled to ca. −10° C. and half-concentrated hydrochloric acid (50 mL) is added carefully. The mixture is stirred at room temperature for 1 h and an additional hour at reflux temperature. The solvent is removed and 2 M NaOH solution (50 mL) is added to the residue. The resulting mixture is extracted with dichloromethane and the combined organic extracts are dried (MgSO4). After removal of the solvent, the residue is taken up in ethanol (20 mL) and the resulting solution is treated with oxalic acid (3 mL) to obtain the oxalate salt of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][C:5]1[S:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([C:19]2[C:20]([C:25]3[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=3)=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:18])=[CH:8][CH:9]=1.[Li+].[OH-].Cl>CC#N>[CH3:32][O:31][C:29]1[CH:30]=[C:25]([C:20]2[C:19]([C:17]([NH:16][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:7]3[S:6][C:5]([CH2:4][C:3]([OH:37])=[O:2])=[CH:9][CH:8]=3)=[O:18])=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]=[C:27]([O:35][CH3:36])[C:28]=1[O:33][CH3:34]
Reactant: COC(=O)Cc1ccc(-c2ccccc2NC(=O)c2ccccc2-c2cc(OC)c(OC)c(OC)c2)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Product: COc1cc(-c2ccccc2C(=O)Nc2ccccc2-c2ccc(CC(=O)O)s2)cc(OC)c1OC
Yield: 99.3 %

Procedure:
Dissolve (5-{2-[(3′,4′,5′-Trimethoxy-biphenyl-2-carbonyl)-amino]-phenyl}-thiophen-2-yl)-acetic acid methyl ester (85) (56 mg, 0.11 mmol) in MeCN (3.8 mL) at rt and add 1M aqu LiOH (76 μL, 0.76 mmol). Stir reaction mixture 18 h at rt. Quench reaction mixture (cooling bath) with 2M aqu. HCl. Extract the mixture with EtOAc (3×), wash the combined organic layer with brine and dry with Na2SO4 to obtain (5-{2-[(3′,4′,5′-Trimethoxy-biphenyl-2-carbonyl)-amino]-phenyl}-thiophen-2-yl)-acetic acid (86) (55 mg, 99%) as a brown solid. 1H NMR (400 MHz, CDCl3): 3.76 (s, 6H), 3.80 (s, 3H); 3.83 (s, 2H); 6.32 (d, 1H, J=3.5 Hz); 6.60 (s, 2H); 6.78 (d, 1H, J=3.5 Hz); 7.07 (t, 1H, J=7.6 Hz); 7.23 (d, 1H, J=7.6 Hz); 7.32 (t, 1H, J=7.6 Hz); 7.36-7.54 (m, 3H); 7.69 (d, 1H, J=8.0 Hz); 8.43 (d, 1H, J=8.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1Cl.[NH:10]1[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1.C(N(CC)CC)C.C(OCC)(=O)C>C1(C)C(C)=CC=CC=1>[Cl:9][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[N:10]1[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1
Reactant: Clc1cncc(Cl)c1Cl
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: CCOC(=O)C1CCN(c2c(Cl)cncc2Cl)CC1

Procedure:
2.0 g (11 mmol) of 3,4,5-trichloropyridine, 1.7 g (11 mmol) of ethyl piperidine-4-carboxylate and 4.6 ml (33 mmol) of triethylamine were stirred in 20 ml of xylene under heating under reflux for 10 hours. After the treatment with ethyl acetate as the extraction solvent in an ordinary manner, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([N:15]1[CH2:20][CH2:19][O:18][C:17]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=2)([CH2:21][CH2:22][OH:23])[CH2:16]1)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>C(Cl)Cl.CS(C)=O>[C:7]([N:15]1[CH2:20][CH2:19][O:18][C:17]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=2)([CH2:21][CH:22]=[O:23])[CH2:16]1)(=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(c1ccccc1)N1CCOC(CCO)(c2ccc(F)c(F)c2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=CCC1(c2ccc(F)c(F)c2)CN(C(=O)c2ccccc2)CCO1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 103.6 %

Procedure:
A solution of 0.32 ml of oxalyl chloride in 7.3 ml of DCM is cooled to -78° C. under a nitrogen atmosphere and a solution of 0.51 ml of DMSO in 3.5 ml of DCM is added dropwise, followed by a solution of 1 g of the compound obtained in step A of EXAMPLE 27 in 7.5 ml of DCM and 0.7 ml of DMSO. The reaction mixture is stirred for 30 minutes at -60° C., 2 ml of triethylamine are then added and the reaction mixture is stirred while the temperature is allowed to rise to RT. It is washed with 1N HCl solution, with saturated Na2CO3 solution and with water, the organic phase is dried over MgSO4 and the solvent is evaporated off under vacuum to give 1.03 g of the expected product in the form of an oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:37]=[CH:36][C:9]2[N:10]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[C:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:17]=[C:16]4Cl)=[N:12][C:8]=2[CH:7]=1)=[O:5])C.[NH2:38][NH2:39].C1(N2C3C=CC(C(O)=O)=CC=3N=C2C2C=C3C(=CC=2)N=C(C2C=CC=CC=2)C=C3N(C)C)CCCCC1>>[CH:30]1([N:10]2[C:9]3[CH:36]=[CH:37][C:6]([C:4]([OH:3])=[O:5])=[CH:7][C:8]=3[N:12]=[C:11]2[C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=[C:16]3[NH:38][NH2:39])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: NN
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cc(Cl)c3c1)n2C1CCCCC1
Agent: CN(C)c1cc(-c2ccccc2)nc2ccc(-c3nc4cc(C(=O)O)ccc4n3C3CCCCC3)cc12
Product: NNc1cc(-c2ccccc2)nc2ccc(-c3nc4cc(C(=O)O)ccc4n3C3CCCCC3)cc12

Procedure:
In this reaction 102 mg (0.2 mmol) of crude 2-(4-chloro-2-phenyl-quinolin-6-yl)-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid ethyl ester was reacted with hydrazine as the nucleophile as described for the preparation of Compound 481. Yield: 3.7 mg.