Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([C:13]2[S:23][C:22]3[N:24]4[C:15](=[CH:16][N:17]=[C:18]4[CH:19]=[CH:20][CH:21]=3)[CH:14]=2)=[O:12])[CH2:5][CH2:4]1.C(N(CC)CC)C.[F:32][C:33]1[CH:43]=[CH:42][CH:41]=[CH:40][C:34]=1[O:35][CH2:36][CH2:37][CH2:38]Cl.[I-].[Na+]>C(O)C>[F:32][C:33]1[CH:43]=[CH:42][CH:41]=[CH:40][C:34]=1[O:35][CH2:36][CH2:37][CH2:38][N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([C:13]2[S:23][C:22]3[N:24]4[C:15](=[CH:16][N:17]=[C:18]4[CH:19]=[CH:20][CH:21]=3)[CH:14]=2)=[O:12])[CH2:5][CH2:4]1
Reactant: Fc1ccccc1OCCCCl
Reactant: O=C(NCC1CCNCC1)C1=Cc2cnc3cccc(n23)S1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(NCC1CCN(CCCOc2ccccc2F)CC1)C1=Cc2cnc3cccc(n23)S1

Procedure:
To a solution of 0.58 g (1.5 mM) of N-(piperidin-4-ylmethyl)-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride and 1.0 ml (7.5 mM) of triethylamine in ethanol were added 0.37 g (2.0 mM) of 3-(2-fluorophenoxy)-propyl chloride and 0.28 g (1.9 mM) of sodium iodide at room temperature and the mixture was refluxed under nitrogen for 20 hours. The solvent was then distilled off under reduced pressure and the residue was diluted with water and extracted with chloroform. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4. The resulting crude product was purified by column chromatography (methanol/ethyl acetate 30-50%) to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)([NH2:16])[CH:9]([NH2:15])[CH2:10][O:11][CH2:12][O:13][CH3:14])=[CH:4][CH:3]=1.CO[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#N)[CH:29]=1)=[NH:27].C(OCC)(=O)C>CO>[C:26]([C:28]1[CH:29]=[C:30]([C:34]2[NH:15][CH:9]([CH2:10][O:11][CH2:12][O:13][CH3:14])[C:8]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:16]=2)[CH:31]=[CH:32][CH:33]=1)#[N:27]
Reactant: COC(=N)c1cccc(C#N)c1
Reactant: COCOCC(N)C(N)(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: CO
Solvent: CCOC(C)=O
Product: COCOCC1NC(c2cccc(C#N)c2)=NC1(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 49.8 %

Procedure:
1,1-bis(4-fluorophenyl)-3-methoxymethoxy-1,2-propanediamine (218 mg) was dissolved in methanol (3 mL), and to the solution was added 3-cyanobenzeneimidic acid methyl ester (266 mg), and the mixture was stirred at room temperature for 17 hrs. To the reaction mixture was added an additional amount of 3-cyanobenzeneimidic acid methyl ester (266 mg), and the reaction mixture was stirred at room temperature for 6 hrs. To the reaction mixture was added ethyl acetate (50 ml), and the organic layer was washed with saturated sodium hydrogen carbonate aqueous solution and saturated sodium chloride aqueous solution in this order, and dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and then the organic solvent was evaporated in vacuo. The obtained residue was purified by silica gel column chromatography (C-300; hexane: ethyl acetate=2:1) to give 2-(3-cyanophenyl)-4,4-bis(4-fluorophenyl)-5-[(methoxymethoxy)methyl]-2-imidazoline (146 mg) as colorless oil. The protected compound (115 mg) was dissolved in the mixture solution of 2N hydrochloric acid (1.5 mL) and tetrahydrofuran (1.5 ml), and the solution was stirred at 50° C. for 3 days. After cooling the mixture to the room temperature by standing it at room temperature and neutralizing with saturated sodium hydrogen carbonate aqueous solution, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and the organic solvent was evaporated in vacuo to give the title compound (105 mg).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]2[N:19]3[C:20]4[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=4[N:16]=[CH:17][C:18]3=[O:21])[CH2:10]2)[CH2:4][CH2:3]1.[S:23]1[C:32]2[CH:31]=[C:30]([CH:33]=O)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.CO>[S:23]1[C:32]2[CH:31]=[C:30]([CH2:33][NH:1][CH:2]3[CH2:7][CH2:6][N:5]([CH2:8][C@@H:9]4[N:19]5[C:20]6[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=6[N:16]=[CH:17][C:18]5=[O:21])[CH2:10]4)[CH2:4][CH2:3]3)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1
Reactant: O=Cc1cc2c(cn1)OCCS2
Reactant: NC1CCN(CC2Cn3c(=O)ccc4ncc(=O)n2c43)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=c1ccc2ncc(=O)n3c2n1C[C@@H]3CN1CCC(NCc2cc3c(cn2)OCCS3)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
Racemic 2-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione (for a preparation see Example 16A(j)) (360 mg, 1.195 mmol) was stirred with 2,3-dihydro[1,4]oxathiino[2,3-c]pyridine-7-carbaldehyde (for a synthesis see WO2004058144, Example 60) (195 mg, 0.9 eq.) in chloroform:methanol (9:1, v:v, 15 ml) at room temperature for 30 mins; the mixture was then treated with sodium triacetoxyborohydride (760 mg, 3.0 eq.) with vigorous stirring at room temperature for 30 mins. The reaction was quenched by addition of saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred at room temperature for 5 mins. The organic phase was separated, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica (eluting with 0-12% (2M ammonia in methanol) in DCM, appropriate fractions were combined and evaporated under reduced pressure to give the free base of the title compound as a pale yellow foam (235 mg, 42%).
Reaction SMILES: ClC1C=C(CCC[N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])NC2SC(SCC(O)=O)=CN=2)C=CC=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][C:41](O)=O)=[CH:35][CH:34]=1.C([O:46][C:47](=[O:58])[C:48]([S:51][C:52]1[S:56][C:55]([NH2:57])=[N:54][CH:53]=1)([CH3:50])[CH3:49])C>>[F:32][C:33]1[CH:34]=[CH:35][C:36]([CH2:39][CH2:40][CH2:41][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:57][C:55]2[S:56][C:52]([S:51][C:48]([CH3:49])([CH3:50])[C:47]([OH:46])=[O:58])=[CH:53][N:54]=2)=[CH:37][CH:38]=1
Reactant: O=C(O)CCc1ccc(F)cc1
Reactant: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Product: CC(C)(Sc1cnc(NC(=O)N(CCCc2ccc(F)cc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 3-(4-fluoro-phenyl)-propanoic-acid and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: O.[CH2:2]([O:9][C:10]([N:12]([CH2:19][CH:20](OCC)[O:21]CC)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(Cl)(Cl)Cl.FC(F)(F)C(O)=O>[CH2:2]([O:9][C:10]([N:12]([CH2:19][CH:20]=[O:21])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CN(CC(OCC)OCC)C(=O)OCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CN(CC=O)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 92.4 %

Procedure:
After adding water (60 ml) to a solution of the compound obtained in Step 1 (14.1 g) in chloroform (120 ml), trifluoroacetic acid (153 ml) was added dropwise over 2 hours under cooling with ice. The mixture was stirred under cooling with ice for 1 hour and at room temperature for 1.5 hours. After adding water to the reaction mixture and extracting with methylene chloride, the organic layer was washed with aqueous solution of 10% potassium carbonate, water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled off under reduced pressure to obtain the title compound (10.3 g).
Reaction SMILES: [CH3:1][N:2]([CH3:30])[CH2:3][CH2:4][N:5]([CH2:18][CH2:19][NH:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=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].O[CH2:32][CH2:33]N1CCCC1>>[N+:27]([C:24]1[CH:25]=[CH:26][C:21]([NH:20][CH2:19][CH2:18][N:5]([S:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])(=[O:7])=[O:8])[CH2:4][CH2:3][N:2]2[CH2:30][CH2:33][CH2:32][CH2:1]2)=[N:22][CH:23]=1)([O-:29])=[O:28]
Reactant: OCCN1CCCC1
Reactant: CN(C)CCN(CCNc1ccc([N+](=O)[O-])cn1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: O=[N+]([O-])c1ccc(NCCN(CCN2CCCC2)S(=O)(=O)c2ccccc2[N+](=O)[O-])nc1

Procedure:
Made using the same procedure as for polymer-bound [2-(dimethylamino)ethyl]{2-[(5-nitro(2-pyridyl))amino]ethyl}[(2-nitrophenyl)sulfonyl]amine except that 1-(2-hydroxyethyl)pyrrolidine (4.9 mL, 42 mmol) was used.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]1([CH3:39])[CH:17]=[CH:16][C:15]([S:18]([N:21]2[CH2:25][CH:24]([O:26][S:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH2:23][CH:22]2[CH2:37][OH:38])(=[O:20])=[O:19])=[CH:14][CH:13]=1.Cl>N1C=CC=CC=1>[C:12]1([CH3:39])[CH:13]=[CH:14][C:15]([S:18]([N:21]2[CH2:25][CH:24]([O:26][S:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH2:23][CH:22]2[CH2:37][O:38][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])(=[O:19])=[O:20])=[CH:16][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)OC2CC(CO)N(S(=O)(=O)c3ccc(C)cc3)C2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CC(OS(=O)(=O)c3ccc(C)cc3)CN2S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
To a cooled solution of 1.83 g (9.6 mmoles) 4-toluenesulfonyl chloride in 10 mL pyridine at +10° C. was added 3.40 g (8 mmoles) of 1-(4-toluenesulfonyl)-2-hydroxymethyl-4-(4-toluenesulfonyloxy)-pyrrolidine and the mixture was stirred 18 hours. The solution obtained was then poured into 50 mL ice-cooled 2N hydrochloric acid. The precipitate was filtered, washed with water and ether. The crystalline product was purified in boiling water and ether. The crystalline product was purified in boiling ethanol to give 3.94 g of titled compound. MP 153° C. [α]D =+46.7° (c=1.9, acetone).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.CO.[CH3:12][NH2:13]>C(Cl)Cl.CO>[CH3:12][NH:13][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([OH:1])[CH:3]=1
Reactant: CN
Reactant: O=Cc1cccc(O)c1
Solvent: ClCCl
Solvent: CO
Product: CNCc1cccc(O)c1
Yield: 79 %

Procedure:
10.0 g of 3-hydroxybenzaldehyde and 9.55 g of a 40% methanol solution of methylamine were mixed, and then the solvent was evaporated. The resulting Schiff base was dissolved in 50 ml of ethanol, and with stirring under ice cooling, 10.0 g of sodium borohydride was added The mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate and a saturated aqueous sodium chloride solution. The organic layer was separated, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography [Wakogel C-100, 100 g; eluting solvent: methylene chloride/methanol=10/1→5/1to give 8.88 g (yield 79%) of N-methyl-3-hydroxybenzylamine as pale yellow crystals having a melting point of 138° to 140° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.ClC1C=C(C=CC=1)C(OO)=[O:26]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N+:8]([O-:26])=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: CN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CN1C(=O)C[N+]([O-])=C(c2ccccc2)c2cc(Cl)ccc21
Temperature: 20 °C
Reaction time: 1.5 h

Procedure:
5.70 g (20 mmol) of 7-chloro-1-methyl-5-phenyl-1H-1,4-benzodiazepine-2(3H)on (manufactured by Sigma, No. T 8275) are dissolved in 150 ml of dichloromethane and 13.8 g (40 mmol) of 3-chloro-peroxybenzoic acid (manufactured by Aldrich, No. 27.303-1) are added under stirring at 20° C. Stirring of the solution is continued for 1.5 h at 20° C. Then the reaction mixture is washed first with 200 ml of 5% NH3 and subsequently with 200 μl of 0.1 n NaOH. The solvent is removed on an rotatione evaporator and the remaining oily residue is dissolved in 25 ml of isopropanol under heating to 40°-45° C. Subsequently, the product is allowed to crystallize under slow cooling down to room temperature. 2 hours after the onset of crystallization, the solid product 2 is drawn off and washed with 50 ml of isopropanol and 50 ml of diisopropylether. The mixture is then dried over night over paraffin in an exsiccator.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:14]=1.[H-].[Na+].Br[CH:21]([CH3:23])[CH3:22]>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH:21]([CH3:23])[CH3:22])[C:6]=2[N:14]=1
Reactant: CC(C)Br
Reactant: NC(=O)c1cc2c(nc1N)[nH]c1ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1c2ccccc2c2cc(C(N)=O)c(N)nc21
Reaction time: 0.17 h

Procedure:
To a solution of 2-amino-9H-pyrido[2,3-b]indole-3-carboxamide (5, 122 mg, 0.540 mmol) in DMF (5 mL) was added NaH (110 mg, 2.75 mmol) and the reaction was stirred for 10 min. 2-Bromopropane (111 μL, 0.688 mmol) was added and the mixture was stirred at RT for another 2.5 h. The reaction was quenched with water (50 mL), poured into a separatory funnel containing EtOAc (150 mL), the mixture was shaken and the layers were separated. The organic layer was washed with brine (100 mL), dried, filtered and concentrated. The crude product was purified by silica gel chromatography (MeOH/CH2Cl2 gradient) to yield 2-amino-9-isopropyl-9H-pyrido[2,3-b]indole-3-carboxamide as a white powder (13, 30 mg, 21%). NH4OAc standard conditions. DAD Retention time=6.95 min. M+H=269. 1H NMR (300 MHz, DMSO-d6): 8.72 (s, 1H), 7.82 (d, J=7.8 Hz, 1H), 7.61 (d, J=8.1 Hz, 1H), 7.54 (br s, 2H), 7.29 (ddd, J=8.4, 8.4, 1.2 Hz, 1H), 7.17 (ddd, J=7.5, 7.5, 0.9 Hz, 1H), 5.23 (septet, J=6.9 Hz, 1H), 1.60 (d, J=6.9 Hz, 6H).
Reaction SMILES: Br[C:2]1[C:3](=[O:31])[N:4]([CH2:22][C@H:23]([NH2:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:5](=[O:21])[N:6]([CH2:9][C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:13]=[CH:12][C:11]=2[F:20])[C:7]=1[CH3:8].[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.O1CCOCC1>[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:2]1[C:3](=[O:31])[N:4]([CH2:22][C@H:23]([NH2:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:5](=[O:21])[N:6]([CH2:9][C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:13]=[CH:12][C:11]=2[F:20])[C:7]=1[CH3:8]
Reactant: Cc1c(Br)c(=O)n(C[C@H](N)c2ccccc2)c(=O)n1Cc1c(F)cccc1C(F)(F)F
Reactant: OB(O)c1ccccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(-c2ccccc2Cl)c(=O)n(C[C@H](N)c2ccccc2)c(=O)n1Cc1c(F)cccc1C(F)(F)F
Temperature: 90 °C

Procedure:
To compound 2a (40 mg, 0.08 mmol) in 0.25 mL/0.75 mL of H2O/dioxane in a 4 mL vial was added 2-chlorophenyl boronic acid (0.12 mmol) and sodium carbonate (51 mg, 0.48 mmol, 6 eq). Nitrogen gas was bubbled through the solution for 1 minute and tetrakis(triphenylphosphine)palladium (9.24 mg, 0.008 mmol) was added. The resulting mixture was sealed and heated at 90° C. overnight. After cooling to ambient temperature, the precipitate was removed by filtration and was purified by prep. LC-MS to give 2b.
Reaction SMILES: [Na].[NH2:2][C:3]1[C:4]([SH:11])=[N:5][C:6]([SH:10])=[N:7][C:8]=1[NH2:9].[F:12][C:13]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Br.C([O:26][CH2:27][CH3:28])(=O)C=O>CO>[F:12][C:13]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][S:10][C:6]1[N:5]=[C:4]([S:11][CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[C:20]([F:21])[C:13]=2[F:12])[C:3]2[N:2]=[CH:28][C:27](=[O:26])[NH:9][C:8]=2[N:7]=1
Reactant: Fc1cccc(CBr)c1F
Reactant: CCOC(=O)C=O
Reactant: Nc1nc(S)nc(S)c1N
Agent: [Na]
Solvent: CO
Product: O=c1cnc2c(SCc3cccc(F)c3F)nc(SCc3cccc(F)c3F)nc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium (3.96 g) was dissolved in methanol (150 ml), 5,6-diamino-2,4-pyrimidinedithiol (15 g) was added, then 2,3-difluorobenzylbromide (30.9 g) slowly added and the reaction mixture was stirred at room temperature under nitrogen for 10 min. Ethyl glyoxalate (15 ml) was added followed by more sodium (2.5 g) and the reaction was left for a further 20 min. The reaction was then quenched with acetic acid (10 ml) and poured on to water (600 ml) with stirring. The resulting precipitate was filtered through celite and washed with water. The filtrate was discarded and the solid was washed through the celite using acetone. The solution was then evaporated to dryness and purified by silica gel column chromatography using 10% ethyl acetate in DCM to yield the sub-titled compound as a cream solid (8 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@:16]3([C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]([CH2:25][C:26]4[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=4)[C:29](O)=[O:30])[C:17]3=[O:35])[CH2:15]2)=[CH:10][CH:9]=1>>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[C@@:16]3([C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]([CH2:25][C:26]4[CH:34]=[CH:33][CH:32]=[C:28]([C:29]([N:1]5[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]5)=[O:30])[CH:27]=4)[C:17]3=[O:35])[CH2:15]2)=[CH:10][CH:9]=1
Reactant: C1CNCCN1
Reactant: O=C(O)c1cccc(CN2C(=O)[C@]3(C[C@@H]3c3ccc(Cl)cc3)c3ccccc32)c1
Product: O=C(c1cccc(CN2C(=O)[C@@]3(C[C@H]3c3ccc(Cl)cc3)c3ccccc32)c1)N1CCNCC1

Procedure:
The title compound was prepared in analogy to Example 60 starting from piperazine, (3-bromomethyl)-benzoate (commercially available), (1R,2S) and (1S,2R)-3-((2-(4-chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzoic acid prepared as in Scheme 1. LC/MS m/e calcd. for C28H26ClN3O2: 471, observed (M+H)+: 472.2 1H NMR (400 MHz, MeOD-d4) δppm 2.17-2.30 (m, 2 H) 3.51 (br. s., 8 H) 3.21-3.35 (m, 1 H) 5.04-5.23 (m, 2 H) 6.10 (d, J=7.58 Hz, 1 H) 6.74 (t, J=7.45 Hz, 1 H) 6.95 (d, J=7.83 Hz, 1 H) 7.05-7.16 (m, 1 H) 7.23 (d, J=8.34 Hz, 2 H) 7.29-7.38 (m, 2 H) 7.40-7.49 (m, 2 H) 7.49-7.58 (m, 2 H).
Reaction SMILES: O=[C:2]1[NH:7][N:6]=[CH:5][C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][CH:9]=2)=[CH:3]1.P(Cl)(Cl)([Cl:23])=O>CN(C=O)C>[Cl:23][C:2]1[N:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][CH:9]=2)[CH:3]=1
Reactant: CCOC(=O)C(C)c1ccc(-c2cn[nH]c(=O)c2)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)c1ccc(-c2cnnc(Cl)c2)cc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl 2-[4-(6-oxo-1,6-dihydropyridazin-4-yl)phenyl]propanoate (0.48 g, 1.7 mmol) in phosphoryl chloride (5.0 mL) and DMF (50 μL) was stirred at 100° C. for 3 h. The solvent was removed and the residue was diluted with methylene chloride, washed with saturated NaHCO3, water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in methylene chloride (0-20%) to afford the desired product. LCMS (M+H)+: m/z=299.1
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]2[CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClCCl.Cl.O1CCOCC1>CO>[O:16]1[CH2:15][CH2:14][CH:13]([C:11]2[N:10]=[C:9]([CH:19]3[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]3)[N:8]([CH2:7][CH2:6][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:12]=2)[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C3CCOCC3)cn2CCN2CCCC2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: c1c(C2CCOCC2)nc(C2CCNCC2)n1CCN1CCCC1
Reaction time: 1 h
Yield: 124.6 %

Procedure:
Combine tert-butyl 4-(1-(2-(pyrrolidin-1-yl)ethyl)-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl)piperidine-1-carboxylate (1.74 g, 4.03 mmol), dichloromethane (53 mL) and methanol (21 mL). Add 4 M hydrogen chloride in 1,4-dioxane (10.4 mL, 10.3 eq). After one hour, concentrate in vacuo. Dry the resulting residue under vacuum to give the title compound as a white solid (1.67 g, 94%). MS (ES) m/z=333 [M]+.
Reaction SMILES: C(OC([N:8]1[C:16]2[CH:15]=[CH:14][C:13]([Cl:17])=[CH:12][C:11]=2[C:10]2[CH2:18][CH:19]([C:21]([S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:28])=[O:27])([CH3:25])[CH2:22][O:23][CH3:24])[CH2:20][C:9]1=2)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:29]1([S:26]([C:21]([CH:19]2[CH2:20][C:9]3[NH:8][C:16]4[CH:15]=[CH:14][C:13]([Cl:17])=[CH:12][C:11]=4[C:10]=3[CH2:18]2)([CH3:25])[CH2:22][O:23][CH3:24])(=[O:27])=[O:28])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COCC(C)(C1Cc2c(n(C(=O)OC(C)(C)C)c3ccc(Cl)cc23)C1)S(=O)(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCC(C)(C1Cc2[nH]c3ccc(Cl)cc3c2C1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 27.2 %

Procedure:
52 mg (0.1 mmol) (RS,SR)-2-(1-benzenesulfonyl-2-methoxy-1-methyl-ethyl)-7-chloro-2,3-dihydro-1H-cyclopenta[b]indole-4-carboxylic acid tert-butyl ester were dissolved in 4 mL CH2Cl2 at 0° C. Then, 1 mL of TFA was added dropwise and the temperature was slowly raised to RT and the reaction was stirred for 20 minutes. The reaction was quenched with a saturated NaHCO3 solution. The organic phase was dried over Na2SO4, filtered and evaporated. Column chromatography on silica gel (EtOAc/heptane 1:2) yielded 11 mg (26%) (RS,SR)-2-(1-benzenesulfonyl-2-methoxy-1-methyl-ethyl)-7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indole as a white powder, MS: 404 (MH|).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][CH2:21][CH2:22][N:23]=2)=[CH:15][CH:14]=1)=O.C(=O)([O-])O.[Na+].ClCCl.CO>C(O)C>[I:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([C:19]4[O:20][CH2:21][CH2:22][N:23]=4)=[CH:17][CH:18]=3)[N:1]=2)[CH:4]=1
Reactant: O=C(CBr)c1ccc(C2=NCCO2)cc1
Reactant: Nc1ccc(I)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: Ic1ccc2nc(-c3ccc(C4=NCCO4)cc3)cn2c1

Procedure:
Subsequently, 2-amino-5-iodopyridine (88 mg) and 2-bromo-1-[4-(4,5-dihydro-1,3-oxazol-2-yl)phenyl]-1-ethanone mg) were dissolved in ethanol (7 mL), and sodium hydrogencarbonate (34 mg) was added to the solution, followed by refluxing for 13 hours. Dichloromethane-methanol solution was added to the reaction mixture, and the mixture was washed with water and saturated saline, followed by drying over sodium sulfate anhydrate. The solvent was evaporated, and the residue was subjected to silica gel chromatography. Fractions eluted by dichloromethane-methanol (100:5) were concentrated under reduced pressure, to thereby yield the title compound (89 mg).