Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[CH:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[C:16]([F:25])[CH:15]=2)=[O:11])=[CH:6][CH:5]=[C:4]([C:26]([F:29])([F:28])[F:27])[N:3]=1.CN(C=O)C.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>CCOC(C)=O>[F:25][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:13][NH:12][C:10](=[O:11])[CH:9]=[CH:8][C:7]1[C:2]([N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[N:3][C:4]([C:26]([F:29])([F:28])[F:27])=[CH:5][CH:6]=1
Reactant: C1CCNC1
Reactant: CS(=O)(=O)Nc1ccc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2Cl)cc1F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2N2CCCC2)cc1F
Temperature: 110 °C
Reaction time: 12 h
Yield: 93 %

Procedure:
To a suspension of 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonylamino-benzyl)-acrylamide (40 mg, 0.088 mmol) in pyrrolidine (0.4 ml) was added DMF (0.5 ml). The mixture was stirred for 12 hours at 110° C. The reaction mixture was diluted with EtOAc and then washed two times with 1N-HCl and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was column-chromatographed to yield the title compound (40 mg, 93%).
Reaction SMILES: [Cl:1][C:2]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][NH:5][C:6](=O)[CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16])[CH3:8].ClC1C(C(F)(F)F)=CC=CC=1CNCC(C1C=CC=CC=1Cl)C>>[Cl:1][C:2]1[C:21]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][NH:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16])[CH3:8]
Reactant: COc1ccccc1C(C)C(=O)NCc1cccc(C(F)(F)F)c1Cl
Agent: CC(CNCc1cccc(C(F)(F)F)c1Cl)c1ccccc1Cl
Product: COc1ccccc1C(C)CNCc1cccc(C(F)(F)F)c1Cl
Yield: 28 %

Procedure:
The titled compound was prepared from N-(2-chloro-3-trifluoromethylbenzyl)-2-(2-methoxyphenyl)propionamide in 28% yield in the same manner as the preparation of N-(2-chloro-3-trifluoromethylbenzyl)-2-(2-chlorophenyl)propylamine in Example 184c. MS (ESI) 358 (MH+).
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].O.[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[C:22]3[N:23]([CH2:38][C@H:39]4[CH2:44][CH2:43][C@H:42]([CH3:45])[CH2:41][CH2:40]4)[C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][C@H:27]4[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[N:25][C:21]=3[CH:20]=[C:19]([C:46]#[N:47])[N:18]=2)[CH:14]=[N:15][CH:16]=1>C(O)C>[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[C:22]3[N:23]([CH2:38][C@H:39]4[CH2:44][CH2:43][C@H:42]([CH3:45])[CH2:41][CH2:40]4)[C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][C@H:27]4[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[N:25][C:21]=3[CH:20]=[C:19]([C:46](=[N:2][OH:3])[NH2:47])[N:18]=2)[CH:14]=[N:15][CH:16]=1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCOC[C@H]3c3ccccc3)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C[C@H]1CC[C@H](Cn2c(N3CCOC[C@H]3c3ccccc3)nc3cc(C(N)=NO)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
Hydroxylamine hydrochloride (5.4 mg, 0.08 mmol), sodium bicarbonate (9.9 mg, 0.12 mmol), and water (0.12 mL) were combined in a vial and stirred for 15 minutes. This solution was added to a vial containing 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (20.6 mg, 0.04 mmol) dissolved in ethanol (0.3 mL). The mixture was sealed and heated at 100° C. for 1 hour. The reaction was cooled to room temperature, quenched with water, and extracted with ethyl acetate (2×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to afford 4-(5-chloropyridin-3-yl)-N′-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide. MS ESI calc'd. for C30H34ClN7O2 [M+H]+ 560. found 560.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[N:5]=[C:4]([NH:11][CH:12](C)[CH3:13])[N:3]=1.CSC1N=C(NCC)N=C(NCC)N=1>>[Cl:1][C:2]1[N:3]=[C:4]([NH:11][CH2:12][CH3:13])[N:5]=[C:6]([NH:8][CH2:9][CH3:10])[N:7]=1
Reactant: CCNc1nc(Cl)nc(NC(C)C)n1
Agent: CCNc1nc(NCC)nc(SC)n1
Product: CCNc1nc(Cl)nc(NCC)n1

Procedure:
2-chloro-4-ethylamino-6-isopropylamino-1,3,5-triazine; 2-methylthio-4,6-bis-ethylamino-1,3,5,-triazine; etc.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:40])[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH:9]=[CH:8][C:7]=1[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[C:23]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:22]=[CH:21][C:20]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:10]2[CH:9]=[CH:8][C:7]([O:32][CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[C:6]([CH:11]=2)[C:5]([OH:40])=[O:4])=[CH:25][CH:24]=1
Reactant: COC(=O)c1cc(OCCCCCCOc2ccc(-c3ccccc3)cc2)ccc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(OCCCCCCOc2ccc(-c3ccccc3)cc2)ccc1OCc1ccccc1
Yield: 96 %

Procedure:
Sodium hydroxide hydrolysis of 5-[[6-([1,1'-biphenyl]-4-yloxy)hexyl]oxy]-2-(phenylmethoxy)benzoic acid methyl ester as described in Example 60 gave 5-[[6-([1,1'-biphenyl]-4-yloxy)hexyl]oxy]-2-(phenylmethoxy)benzoic acid (96% yield, mp 131°-133°).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:18](=[O:20])[CH3:19])[CH:8]=[C:9]([O:11][CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br-:21].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>C1COCC1.CO.C(OCC)(=O)C>[Br:21][CH2:19][C:18]([C:7]1[CH:8]=[C:9]([O:11][CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1)=[O:20]
Reactant: CC(=O)c1cc(OCCC(F)(F)F)cc(C(C)(C)C)c1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(OCCC(F)(F)F)cc(C(=O)CBr)c1

Procedure:
1-[3-tert-Butyl-5-(3,3,3-trifluoropropoxy)phenyl]ethanone (O2.107; 170 mg, 0.59 mmol) was dissolved in a mixture of THF (3 ml) and methanol (3 ml). While stirring, phenyltrimethylammonium tribromide (222 mg, 0.59 mmol) was introduced and the mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium hydrogencarbonate solution. After drying over sodium sulfate, the solvent was removed and the residue was purified by flash chromatography (n-heptane:ethyl acetate). Yield: 42 mg,
Reaction SMILES: C[O:2][C:3]([C:5]1[N:9]=[C:8]([C:10]([S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])([CH:12]2[CH2:24][C:15]3[NH:16][C:17]4[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][C:22]=4[C:14]=3[CH2:13]2)[F:11])[O:7][N:6]=1)=O.[OH-].[NH4+:35]>CCO>[C:28]1([S:25]([C:10]([CH:12]2[CH2:24][C:15]3[NH:16][C:17]4[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][C:22]=4[C:14]=3[CH2:13]2)([F:11])[C:8]2[O:7][N:6]=[C:5]([C:3]([NH2:35])=[O:2])[N:9]=2)(=[O:27])=[O:26])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: [NH4+]
Reactant: COC(=O)c1noc(C(F)(C2Cc3[nH]c4ccc(Cl)cc4c3C2)S(=O)(=O)c2ccccc2)n1
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1noc(C(F)(C2Cc3[nH]c4ccc(Cl)cc4c3C2)S(=O)(=O)c2ccccc2)n1
Yield: 86 %

Procedure:
To a stirred solution of 70 mg (0.14 mmol) of (RS,SR)-5-[benzenesulfonyl-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[1,2,4]oxadiazole-3-carboxylic acid methyl ester in 3 mL of EtOH, were added 0.5 mL of an ammonium hydroxide solution (25% in water) and stirred over night. The reaction mixture was partitioned between EtOAc and water. The organic phase was dried over Na2SO4, filtered and evaporated. Recrystallisation in Et2O afforded 60 mg (86%) of (RS,SR)-5-[benzenesulfonyl-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[1,2,4]oxadiazole-3-carboxylic acid amide as a light orange crystals, MS: 475 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].Cl.Cl.[N:26]12[CH2:33][CH2:32][CH:29]([CH2:30][CH2:31]1)[CH:28]([NH2:34])[CH2:27]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[N:26]12[CH2:33][CH2:32][CH:29]([CH2:30][CH2:31]1)[CH:28]([NH:34][CH2:22][C:19]1[CH:20]=[CH:21][C:2]([Cl:1])=[C:3]([CH:18]=1)[C:4]([NH:6][CH2:7][C:8]13[CH2:17][CH:12]4[CH2:11][CH:10]([CH2:16][CH:14]([CH2:13]4)[CH2:15]1)[CH2:9]3)=[O:5])[CH2:27]2
Reactant: O=Cc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Reactant: NC1CN2CCC1CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CNC2CN3CCC2CC3)ccc1Cl
Yield: 3.3 %

Procedure:
Prepared according to the method described in Example 31b from 2-chloro-5-formyl-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.30 g, Example 31a), 1-azabicyclo[2.2.2]octan-3-amine dihydrochloride salt (0.18 g), sodium triacetoxyborohydride (0.135 g) and 1,2-dichloroethane (10 ml). The residue was purified by chromatography over silica gel eluting with ethyl acetate: iso-hexane (1:1) followed by ethyl acetate: ethanol (95:5). Repurification by chromatography over silica gel eluting with dichloromethane: methanol (95:5) then (9:1) gave the title compound as a white gum (0.013 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[N:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[SH:16])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2OC2C=CC=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:57]([O:61][C:62]([N:64]1[C:72]2[C:67](=[CH:68][C:69](Br)=[CH:70][CH:71]=2)[CH:66]=[CH:65]1)=[O:63])([CH3:60])([CH3:59])[CH3:58].CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[C:57]([O:61][C:62]([N:64]1[C:72]2[C:67](=[CH:68][C:69]([S:16][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH2:9][N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:17])[CH3:8])=[CH:70][CH:71]=2)[CH:66]=[CH:65]1)=[O:63])([CH3:60])([CH3:58])[CH3:59]
Reactant: CC(C)(C)OC(=O)n1ccc2cc(Br)ccc21
Reactant: CN(Cc1ccccc1S)C(=O)OC(C)(C)C
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: Cc1ccccc1
Product: CN(Cc1ccccc1Sc1ccc2c(ccn2C(=O)OC(C)(C)C)c1)C(=O)OC(C)(C)C
Temperature: 160 °C
Yield: 19.6 %

Procedure:
(2-Mercapto-benzyl)-methyl-carbamic acid tert-butyl ester (1.85 g, 7.30 mmol) in dry toluene (15 mL) is placed in an Emrys Optimizer EXP 20 mL tube. Tris(dibenzylideneacetone) dipalladium (334 mg, 0.37 mmol), bis(2-diphenylphosphinophenyl)ether (197 mg, 0.37 mmol), tert-butyl-5-bromoindole-1-carboxylate (2.38 g, 8.03 mmol) and potassium tert-butoxide (860 mg, 7.67 mmol) are added. The reaction vessel is sealed and subjected to microwave heating at 160° C. for 15 minutes. Upon cooling the mixture is poured onto a plug of silica and the product is eluted with ethyl acetate-heptane (1:4). 0.67 g (20%) of 5-{2-[(tert-butoxycarbonyl-methyl-amino)-methyl]-phenylsulfanyl}-indole-1-carboxylic acid tert-butyl ester is isolated and used in the next step without further purification. 5-{2-[(tert-butoxycarbonyl-methyl-amino)-methyl]-phenylsulfanyl}-indole-1-carboxylic acid tert-butyl ester (0.67 g, 1.43 mmol) in methanol (15 mL) and diethyl ether saturated with hydrochloric acid (15 mL) is stirred at room temperature for 1 hour and concentrated in vacuo. Ice/water is added to the remanence and 28% aqueous NaOH is added until pH 9. The aqueous fraction is extracted with ethyl acetate (3×15 mL). Combined organic fractions are dried with MgSO4 and concentrated in vacuo. The product is purified by silica gel chromatography eluting with ethyl acetate-triethyl amine (100:4) followed by ethyl acetate-ethanol-triethyl amine (100:5:5). Upon evaporation of the volatiles, 40 mg (10%) of [2-(1H-indol-5-ylsulfanyl)-benzyl]-methyl-amine is isolated.
Reaction SMILES: [H-].[Na+].C[O:4][C:5](=[O:8])[CH2:6][OH:7].[C:9]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:14]=[CH:13][C:12]([C:15]2[CH:35]=[CH:34][C:18]3[N:19]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:20](S(C)(=O)=O)=[N:21][C:17]=3[CH:16]=2)=[CH:11][CH:10]=1.Cl>C1COCC1.O.C(#N)C.O>[C:9]1([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:14]=[CH:13][C:12]([C:15]2[CH:35]=[CH:34][C:18]3[N:19]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:20]([O:7][CH2:6][C:5]([OH:4])=[O:8])=[N:21][C:17]=3[CH:16]=2)=[CH:11][CH:10]=1
Reactant: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2cc(-c3ccc(-c4ccccc4)cc3)ccc21
Reactant: COC(=O)CO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1c(OCC(=O)O)nc2cc(-c3ccc(-c4ccccc4)cc3)ccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A 20 mL scintillation vial equipped with a septum cap and a magnetic stirring bar was charged under N2 with NaH (6.0 mg, 60% suspension in mineral oil, 0.15 mmol). A solution of hydroxyacetic acid methyl ester (18.0 mg, 0.200 mmol) in THF (2.0 mL) was added dropwise to the vial and the resulting mixture was stirred at rt for 10 min. Then, a solution of 5-biphenyl-4-yl-2-methanesulfonyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole (compound 46-1, 51.3 mg, 0.100 mmol) in THF (1 mL) was added. The resulting mixture was stirred at rt for 10 mM, then diluted by dropwise addition of 1:1 ACN/water (2 mL) and left to stir at rt for 30 min. The reaction mixture was then diluted with water (5 mL), acidified with 5% aqueous HCl and extracted with EtOAc (three times, 3 mL). The organic layers were combined and washed with 5% aqueous HCl and water, and evaporated to dryness in vacuo to give the title compound as pale yellow solid. LR-MS (API-ES): mixture of two N-SEM isomers, calculated for C27H29ClN2O4Si 508.2, observed m/e 509.0 [(M+H)+, 100%], 465 (Rt 3.74 min). The compound was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:10])=[C:7]([CH:9]=1)N.OS(O)(=O)=O.N([O-])=O.[Na+].[BrH:20]>O>[Br:20][C:7]1[CH:9]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[CH3:10]
Reactant: Br
Reactant: COc1ccc(C)c(N)c1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COc1ccc(C)c(Br)c1
Temperature: 3 °C
Reaction time: 1 h

Procedure:
To a suspension of 5-methoxy-2-methylaniline (5.00 g, 36.4 mmol) in water (144 mL) at 10° C., was added conc. H2SO4 (56 mL), while maintaining internal temperature below 25° C. After 1 h at rt, the mixture was cooled to 3° C. and a solution of sodium nitrite (3.77 g, 54.7 mmol) in water (20 mL) was added dropwise over 30 min, keeping the internal temperature below 5° C. After 1 h at 3° C., the yellow heterogeneous mixture was poured into a 5° C. solution of CuBr (52.0 g, 364 mmol) in 48% aqueous HBr (260 mL). The dark mixture was heated at 60° C. for 2 h, allowed to cool to rt and extracted with Et2O (3×) (solid Na2S2O3 was added in the extraction process for partial decoloration). The combined organics were washed with 1 N NaOH (3×), 10% aq. Na2S2O3 and brine, dried (Na2SO4) and concentrated, affording the title compound as an orange liquid which was used without further purification in the next Step. 1H NMR (500 MHz, acetone-d6): δ 7.24 (d, 1H), 7.14 (d, 1H), 6.87 (dd, 1H), 3.80 (s, 3H), 2.31 (s, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:15][C:16]1[CH:34]=[CH:33][C:19]([CH2:20][NH:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH2:30][CH2:31][CH3:32])[CH2:27][CH2:28][CH3:29])=[CH:18][CH:17]=1)[CH2:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.[CH:35](O)=[O:36].C(N)=O>C(O)C>[CH2:30]([N:26]([CH2:27][CH2:28][CH3:29])[CH2:25][CH2:24][CH2:23][CH2:22][N:21]([CH2:20][C:19]1[CH:33]=[CH:34][C:16]([CH2:15][N:7]([CH2:6][C:2]2[NH:3][CH:4]=[CH:5][N:1]=2)[CH2:8][C:9]2[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=2)=[CH:17][CH:18]=1)[CH:35]=[O:36])[CH2:31][CH3:32]
Reactant: O=CO
Reactant: CCCN(CCC)CCCCNCc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Solvent: CCO
Solvent: NC=O
Product: CCCN(CCC)CCCCN(C=O)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Temperature: 10 °C
Reaction time: 3 h

Procedure:
The compound (82.9 mg) obtained in Example 52-3 was dissolved in ethanol (1.0 ml) and added with formic acid (50 μl) and formamide (50 μl). The whole was stirred at an outside temperature of 10° C. for 3 hours. The solution was added with additional formic acid (60 μl) and the whole was stirred for 15 hours. After completion of the reaction, the solvent was distilled off. The residue was dissolved in chloroform and added with a 1 mol/l sodium hydroxide aqueous solution to adjust the pH to 11. The aqueous layer was extracted with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate. The solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining a hydrochloride (27.0 mg) of the subject compound as a yellow solid.
Reaction SMILES: CC([O:4][C@@H:5]1[C@@:9]2([CH3:24])[CH2:10][CH2:11][C@@H:12]3[C:21]4[C:16](=[CH:17][C:18]([OH:23])=[C:19]([OH:22])[CH:20]=4)[CH2:15][CH2:14][C@H:13]3[C@@H:8]2[CH2:7][CH2:6]1)=O.CO.Cl.C([O-])(O)=O.[Na+]>CCOC(C)=O.O>[CH3:24][C@@:9]12[C@@H:5]([OH:4])[CH2:6][CH2:7][C@H:8]1[C@H:13]1[C@@H:12]([C:21]3[CH:20]=[C:19]([OH:22])[C:18]([OH:23])=[CH:17][C:16]=3[CH2:15][CH2:14]1)[CH2:11][CH2:10]2
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CCc4cc(O)c(O)cc4[C@H]3CC[C@]12C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@]12CC[C@@H]3c4cc(O)c(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O

Procedure:
To the crude product (100 g) of 2-hydroxyestradiol 17-acetate obtained by the process described in Example 3-a, MeOH (3600 ml) and concentrated HCl (400 ml) were added, and the solution was refluxed for 1 hour. After the reaction mixture was cooled, water and AcOEt were added to it and the solution was neutralized by addition of NaHCO3, and extracted with AcOEt. The organic layer was washed with brine, and dried over anhydrous Na2SO4, and then evaporated in vacuo to obtain a crude product (68.7 g), which was, in turn, subjected to silica gel chromatography (elution solvent, hexane:AcOEt=1:1) to afford 59 g (91% from 2-acetylestradiol 17-acetate) of the titled compound.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[O:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]1[O:19][C@H:20]1[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]1>>[NH:22]1[CH2:23][CH2:24][C@H:20]([O:19][N:10]2[C:11](=[O:18])[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]2=[O:8])[CH2:21]1.[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](ON2C(=O)c3ccccc3C2=O)C1
Solvent: O=C(O)C(F)(F)F
Product: O=C1c2ccccc2C(=O)N1O[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Trifluoroacetic acid (3.42 g, 30.0 mmol) was added to a solution of (S)-tert-butyl 3-(1,3-dioxoisoindolin-2-yloxy)pyrrolidin-1-carboxylate (3.32 g, 10.0 mmol) CH2Cl2 (25 ml) at 0° C. The reaction mixture was stirred at room temperature for 17 hours and concentrated in vacuo. The residue was triturated with diethyl ether (100 ml) to give (S)-2-(pyrrolidin-3-yloxy)isoindoline-1,3-dione)trifluoroacetic acid salt (2.77 g, 80%) as a white solid.
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:14]1[N:19]=[C:18]([C:20]2[CH:32]=[CH:31][C:23]3[N:24]=[C:25]([NH:27][C:28](=[O:30])[CH3:29])[S:26][C:22]=3[CH:21]=2)[CH:17]=[CH:16][N:15]=1>CS(C)=O>[C:1]1([S:7]([NH:10][C:14]2[N:19]=[C:18]([C:20]3[CH:32]=[CH:31][C:23]4[N:24]=[C:25]([NH:27][C:28](=[O:30])[CH3:29])[S:26][C:22]=4[CH:21]=3)[CH:17]=[CH:16][N:15]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: CC(=O)Nc1nc2ccc(-c3ccnc(Cl)n3)cc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)Nc1nc2ccc(-c3ccnc(NS(=O)(=O)c4ccccc4)n3)cc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.3 %

Procedure:
Benzenesulfonamide (150 mg, 0.954 mmol) was dissolved in DMSO (1.5 mL) and NaH (56.1 mg, 1.40 mmol, 60% in mineral oil) was added, and the reaction mixture was stirred at RT for 1 hour. N-(6-(2-Chloropyrimidin-4-yl)benzo[d]thiazol-2-yl)acetamide (50.2 mg, 0.165 mmol) was added, and the reaction flask was placed in a preheated oil bath (125° C.) and stirred under nitrogen. The reaction was stirred for 21 hours, and then cooled to RT and quenched with MeOH. The suspension was filtered through a pad of Celite® (diatomaceous earth), which was washed with DCM and MeOH, and the filtrate was concentrated, and purified on an HPLC system (10-95% MeCN/water with 0.1% TFA over 30 minutes) to provide N-(6-(2-(phenylsulfonamido)pyrimidin-4-yl)benzo[d]thiazol-2-yl)acetamide (29 mg, 41%). MS (ESI pos. ion) m/z: 426 (MH+). Calculated exact mass for C19H5N5O3S2: 425. 1H NMR (400 MHz, DMSO-d6): 12.53 (s, 1H), 8.54-8.56 (m, 2H), 8.09 (d, J=9.0 Hz, 1H), 8.05 (d, J=7.5 Hz, 2H), 7.83 (d, J=8.5 Hz, 1H), 7.58-7.63 (m, 4H), 2.24 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][N:8]=1.[H][H]>C(O)C.[Pt](=O)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][NH:8]1
Reactant: c1ccc(C2=NCCc3ccccc32)nc1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Product: c1ccc(C2NCCc3ccccc32)nc1
Yield: 108.9 %

Procedure:
A solution of 6.1 g of 1-pyridin-2-yl-3,4-dihydro-isoquinoline in 220 ml of absolute ethanol was hydrogenated on 1.25 g of platinum dioxide at 20° C. and 1 bar hydrogen pressure for 90 min. After removal of the catalyst by filtration, [the filtrate] was concentrated under reduced pressure. There were obtained 6.71 g of (RS)-1-pyridin-2-yl-1,2,3,4-tetrahydro-isoquinoline as a colorless oil, b.p. 140° C./0.1 mbar (bulb-tube).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[NH2:24][C:25](=[O:30])[CH2:26][C:27](O)=[O:28]>>[NH2:24][C:25](=[O:30])[CH2:26][C:27]([O:23][C@@:9]1([C:14]#[C:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH2:12][C@@H:13]2[C@H:8]1[CH2:7][CH2:6][N:5]2[C:3]([O:2][CH3:1])=[O:4])=[O:28]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: NC(=O)CC(=O)O
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)CC(N)=O

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 3-amino-3-oxopropanoic acid to yield (3aR,4S,7aR)-methyl 4-(3-amino-3-oxopropanoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [M+H]=296 (ester elimination ion); RT=0.96 min; UPLC Method I
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([CH3:10])=[CH:8][C:7]([Cl:11])=[CH:6][C:5]=1[Cl:12].[Br:14]NC(=O)CCC(N)=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[C:5]([Cl:12])=[CH:6][C:7]([Cl:11])=[CH:8][C:9]=1[CH2:10][Br:14]
Reactant: NC(=O)CCC(=O)NBr
Reactant: COC(=O)c1c(C)cc(Cl)cc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(Cl)cc(Cl)cc1CBr

Procedure:
A mixture of 2,4-dichloro-6-methyl-benzoic acid methyl ester (0.71 g, 3.23 mmol), N-bromosuccinamide (0.693 g, 3.9 mmol), and benzoyl peroxide (0.012 g, 0.05 mmol) in carbon tetrachloride (20 mL) was heated at reflux until majority of ester was consumed (as analyzed by GC/MS). The resulting mixture was filtered, the filtrate was concentrated to afford 2-Bromomethyl-4,6-dichloro-benzoic acid methyl ester. The material was used without further purification.