Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][CH2:10][CH:11]([CH3:52])[CH:12]([C:32]1[CH:37]=[CH:36][C:35]([CH2:38][N:39]2[C:44](=[O:45])[CH2:43][O:42][C:41]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)=[N:40]2)=[CH:34][CH:33]=1)[C:13]([NH:15][C:16]1[C:17]([CH3:31])=[C:18]([CH2:22][CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])[CH:19]=[CH:20][CH:21]=1)=[O:14]>ClCCl>[CH3:8][O:9][CH2:10][CH:11]([CH3:52])[CH:12]([C:32]1[CH:37]=[CH:36][C:35]([CH2:38][N:39]2[C:44](=[O:45])[CH2:43][O:42][C:41]([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)=[N:40]2)=[CH:34][CH:33]=1)[C:13]([NH:15][C:16]1[C:17]([CH3:31])=[C:18]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH:19]=[CH:20][CH:21]=1)=[O:14]
Reactant: COCC(C)C(C(=O)Nc1cccc(CCC(=O)OC(C)(C)C)c1C)c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCC(C)C(C(=O)Nc1cccc(CCC(=O)O)c1C)c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.27 ml (3.45 mmol) of trifluoroacetic acid was added dropwise to a solution of 106 mg (0.17 mmol) of tert-butyl 3-{3-[(4-methoxy-3-methyl-2-{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}butanoyl)amino]-2-methylphenyl}propanoate (Example 170A) in 2 ml of dichloromethane, and the mixture was stirred at room temperature for 3 h. The reaction solution was then concentrated to dryness under reduced pressure. The residue obtained was purified by preparative HPLC. This gave 66 mg (0.12 mmol, 68% of theory) of the title compound as a mixture of diastereomers.
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:4][C:5]1([CH3:11])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH3:30][S:31]([O:1][CH2:2][CH:3]([NH:12][C:13]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:22])[CH2:4][C:5]1([CH3:11])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(CC(CO)NC(=O)OCc2ccccc2)CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(CC(COS(C)(=O)=O)NC(=O)OCc2ccccc2)CCCCC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A mixture of 0.3607 g (1.18 mmol) of benzyl 1-hydroxy-3-(1-methylcyclohexyl)propan-2-ylcarbamate, 0.4 mL (2.87 mmol, 2.43 equiv) of triethylamine, 0.1 mL (1.29 mmol, 1.09 equiv) of methanesulfonyl chloride in CH2Cl2 (10 mL) was stirred at 0° C. for 1.5 h. The reaction mixture was quenched with ice water, extracted with CH2Cl2, washed with aqueous NaHCO3, and dried over Na2SO4. After the solvent was removed in vacuo, the crude 2-(benzyloxycarbonylamino)-3-(1-methylcyclohexyl)propyl methanesulfonate was used directly in the next step without further purification. MS ESI +ve m/z 406 (M+Na).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:11]3[CH:12]=[CH:13][CH:14]=[C:10]3[O:9][C:8]=2[CH2:16][C:17]([OH:19])=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:23])(=O)=O>C1C=CC=CC=1>[Cl:23][C:8]1([CH2:16][C:17]([OH:19])=[O:18])[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:15]=[C:11]2[CH:12]=[CH:13][CH:14]=[C:10]2[O:9]1
Reactant: O=C(O)Cc1oc2cccc-2cc1-c1ccccc1
Reactant: O=S(=O)(Cl)Cl
Solvent: c1ccccc1
Product: O=C(O)CC1(Cl)OC2=CC=CC2=CC1c1ccccc1

Procedure:
3-Phenyl-7-benzofuranacetic acid, 6.0 g., is heated for 15 minutes with 3.4 g. of sulfuryl chloride in 50 ml. of benzene then left at room temperature overnight to give 2-chloro-3-phenyl-7-benzofuranacetic acid which precipitates from the reaction mixture. Recrystallization from benzene-hexane gives material of m.p. 150.5°-152° C.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH2:18][CH2:19][NH:20][C:21](=[O:23])[CH3:22])=[CH:9][N:10]2C(OCC)=O)=[CH:6][C:5]=1[O:24][CH3:25])(=[O:3])[CH3:2]>[OH-].[K+]>[C:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH2:18][CH2:19][NH:20][C:21](=[O:23])[CH3:22])=[CH:9][NH:10]2)=[CH:6][C:5]=1[O:24][CH3:25])(=[O:3])[CH3:2]
Reactant: CCOC(=O)n1cc(CCNC(C)=O)c2cc(OC)c(C(C)=O)cc21
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(CCNC(C)=O)c[nH]c2cc1C(C)=O

Procedure:
N-[2-(6-Acetyl-5-methoxyindol-3-yl)ethyl]acetamide is prepared by alkaline hydrolysis of N-[2-(6-acetyl-1-carbethoxy-5-methoxyindol-3-yl) ethyl]acetamide in alcoholic potassium hydroxide.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[O:9]CCO1.[CH3:17][N:18]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:20]2([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:19]1=[O:32].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CN(C)C=O>[F:16][C:13]1[CH:12]=[CH:11][C:10]([C:5]([CH2:4][CH2:3][CH2:2][N:23]2[CH2:24][CH2:25][C:20]3([C:26]4[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:18]([CH3:17])[C:19]3=[O:32])[CH2:21][CH2:22]2)=[O:9])=[CH:15][CH:14]=1
Reactant: CN1C(=O)C2(CCNCC2)c2ccccc21
Reactant: Fc1ccc(C2(CCCCl)OCCO2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)C2(CCN(CCCC(=O)c3ccc(F)cc3)CC2)c2ccccc21

Procedure:
A mixture of 3.0 g of 4-chloro-1-(4-fluorophenyl)-1,1-ethylenedioxybutane, 2.0 g of 1-methyl-2-oxo-indoline-3-spiro-4'-piperidine, 2.8 g of anhydrous potassium carbonate, 0.1 g of potassium iodide and 30 ml of dimethylformamide was refluxed for 2 hours. The resulting mixture was poured into water and was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. To the residual oil were added 60 ml of methanol, 20 ml of water and 10 ml of concentrated hydrochloric acid. The mixture was refluxed for 25 minutes and concentrated in vacuo. The residual oil was made alkaline with 28% aqueous ammonia and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated. The residual oil was chromatographed over silica gel with ethyl acetate as an elueting agent to give 1'-[3-(4-fluorobenzoyl)propyl]-1-methyl-2-oxo-indoline-3-spiro-4'-piperidine, M.P. 95°-96.5° C.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([N:19]2[C:20]3[C:16](=[CH:15][C:14]([C:12]([N:9]4[CH2:8][CH2:7][N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[CH2:11][CH2:10]4)=[O:13])=[CH:22][CH:21]=3)[CH:17]=[C:18]2[C:23]([N:25]2[CH2:26][CH2:27][C:28]([F:31])([F:32])[CH2:29][CH2:30]2)=[O:24])=[CH:36][CH:35]=1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1ccc(Cl)cc1)N1CCN(C2CCCC2)CC1
Yield: 23 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 8), 4-chlorphenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a white solid (23%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[C:12]1([CH:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=2)[CH2:19][NH2:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:20][CH2:19][CH:18]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:21]1[CH:22]=[N:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=1)=[O:6]
Reactant: NCC(c1ccccc1)c1ccc(C(F)(F)F)nc1
Reactant: O=C(O)c1c(F)cccc1Cl
Product: O=C(NCC(c1ccccc1)c1ccc(C(F)(F)F)nc1)c1c(F)cccc1Cl

Procedure:
From 2-chloro-6-fluorobenzoic acid and 2-phenyl-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine. LCMS (MH+): m/z=423.1, tR (minutes, Method D)=0.80
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[CH3:7].[C:23]1([Mg]Br)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[NH4+].[Cl-]>O1CCCC1.CCOCC>[OH:2][C:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:4][CH2:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1)([C:15]1[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=1)[CH3:7]
Reactant: COC(=O)CCC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(CCC(O)(c1ccccc1)c1ccccc1)(c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
A solution of 4,4-bis(4-hydroxyphenyl)pentanoic acid methyl ester (4.58 g, 15.3 mmol) in 100 mL of anhydrous tetrahydrofuran was cooled to 0° C. and treated dropwise with phenylmagnesium bromide (10 mL of a 3M solution in ether). Additional tetrahydrofuran (50 mL) was added to the reaction mixture followed by phenylmagnesium bromide (10.4 mL of a 3M solution in ether). The reaction was warmed to room temperature and stirred for 3 hours. The reaction was cooled to 0° C. and treated with phenylmagnesium bromide (10.2 mL of a 3M solution in ether). The reaction mixture was warmed to room temperature and stirred for 18 hours. The reaction mixture was cooled to 0° C. and treated with saturated aqueous NH4Cl solution (100 mL). The organic phase was collected and the aqueous phase was extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated. The residue was purified by chromatography (silica gel, 40% ethyl acetate/hexanes) to give the title compound (6.22 g, 96%) as a white solid.
Reaction SMILES: C([O:4][C@@H:5]1[CH2:9][C:8](=O)[N:7]([C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[O:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:21]=2)[C:6]1=O)(=O)C.Cl>C1COCC1>[CH2:29]([O:28][C:22]1[CH:21]=[C:20]([CH2:19][CH2:18][O:17][C@@H:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]2[N:7]2[CH2:8][CH2:9][C@@H:5]([OH:4])[CH2:6]2)[CH:25]=[CH:24][C:23]=1[O:26][CH3:27])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COc1ccc(CCO[C@@H]2CCCC[C@H]2N2C(=O)C[C@@H](OC(C)=O)C2=O)cc1OCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(CCO[C@@H]2CCCC[C@H]2N2CC[C@@H](O)C2)cc1OCc1ccccc1
Temperature: 0 °C
Yield: 97 %

Procedure:
To a solution of (1R, 2R)-1-{2-[2-(3-Benzyloxy-4-methoxy-phenyl)ethoxy]cyclohexyl}-2,5-dioxopyrrolidin-3-(R)-yl acetate (42.0 g, 84.8 mmol) in anhydrous THF (300 mL) at 0° C. was added borane-THF complex solution (1.0 M, 297 mL, 3.5 mol equivalents) under N2 via an addition funnel over a period of 60 minutes. The reaction mixture was heated to reflux for 60 minutes. The reaction mixture was cooled to 0° C. and quenched slowly by addition of methanol (˜15 mL). The reaction mixture was concentrated under reduced pressure to remove the THF and to the residue was added methanolic-HCl solution (˜1.25 M in methanol, 297 mL, 3.5 equivalents). The solution was then heated at 70-80° C. for 2 hours. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure to give (3R)-1-[(1R,2R)-2-[2-(3-benzyloxy-4-methoxy-phenyl)ethoxy]cyclohexyl]-3-pyrrolidinol as a colorless syrup (35.0 g, 89% yield). The sample was used directly without further purification in the next step.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])=O)(C)(C)C.[ClH:22]>O1CCOCC1>[ClH:22].[NH2:8][C:9]1[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ccc(C(F)(F)F)cc1C(=O)O
Reaction time: 4 h

Procedure:
Preparation D3, Step 1: A suspension of 2-(tert-butoxycarbonylamino)-5-(trifluoromethyl)benzoic acid (56.34 g, 185 mmol, see: S. Takagishi, et al., Synlett 1992) in dioxane (100 mL) was treated with the dropwise addition of 4 N hydrochloric acid solution in dioxane (250 mL, 1.0 mol), and the mixture was stirred for 4 h. Analysis by LC/MS indicated that the reaction was not complete, so additional 4 N hydrochloric acid solution in dioxane (250 mL, 1.0 mol) was added, and the mixture was stirred overnight. Analysis by LC/MS indicated that the reaction still contained c. 5% of the starting material, so additional 4 N hydrochloric acid solution in dioxane (100 mL, 0.4 mol) was added, and the mixture was stirred for 4 h. Analysis by LC/MS indicated that the reaction was now complete. The mixture was concentrated in-vacuo, and the residue was stripped 2× from methylene chloride to remove any remaining HCl. The 2-amino-5-(trifluoromethyl)benzoic acid, hydrochloride thus obtained was used immediately in the next step. MS (ES+)=206 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[CH3:23][C:24]1([CH2:28]O)[CH2:27][O:26][CH2:25]1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]3([CH3:28])[CH2:27][O:26][CH2:25]3)[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Reactant: CC1(CO)COC1
Product: CC1(Cn2nc(-c3ccccc3)c3c(Cl)c(-c4ccccc4)nnc32)COC1

Procedure:
Compound IIf was synthesized from 4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine and (3-methyloxetan-3-yl)methanol following the general procedure for the Mitsunobu reaction.
Reaction SMILES: [CH2:1]([N:7]=[C:8]=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[ClH:10].Cl.[CH2:12]([N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][SH:30])[CH2:23][CH2:22]1)[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C(Cl)Cl>[ClH:10].[ClH:10].[CH2:1]([NH:7][C:8](=[SH:30][CH2:29][CH2:28][CH2:27][N:24]1[CH2:23][CH2:22][N:21]([CH2:12][CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:26][CH2:25]1)[OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN=C=O
Reactant: SCCCN1CCN(CC=Cc2ccccc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCNC(O)=[SH]CCCN1CCN(CC=Cc2ccccc2)CC1
Yield: 64.2 %

Procedure:
The procedure described in Example 2 was followed, using 0.4 g of n-hexyl isocyanate, 1.0 g of 3-(4-cinnamylpiperazin-1-yl)propanethiol dihydrochloride, 0.6 g of triethylamine and 50 ml of methylene chloride, to give 0.44 g (31% of theory) of N-(n-hexyl)-S-[3-(4-cinnamylpiperazin-1-yl)propyl]thiocarbamate dihydrochloride as a white crystalline solid, M.p. 251°-253° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:29])=[C:4]([C:8]2[C:20]3[C:19]4[C:14](=[CH:15][C:16]([O:21][CH2:22][CH2:23][O:24][CH3:25])=[CH:17][CH:18]=4)[NH:13][C:12]=3[C:11]([C:26]([NH2:28])=[O:27])=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=[CH:33][N:32]=1>CC(O)C.C(OCC)(=O)C>[CH3:25][O:24][CH2:23][CH2:22][O:21][C:16]1[CH:15]=[C:14]2[C:19]([C:20]3[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:31]5[C:40]6[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=6)[N:34]=[CH:33][N:32]=5)[C:3]=4[CH3:29])=[CH:9][N:10]=[C:11]([C:26]([NH2:28])=[O:27])[C:12]=3[NH:13]2)=[CH:18][CH:17]=1
Reactant: Clc1ncnc2ccccc12
Reactant: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)ncc(-c3cccc(N)c3C)c12
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)ncc(-c3cccc(Nc4ncnc5ccccc45)c3C)c12
Temperature: 115 °C
Yield: 25.2 %

Procedure:
A mixture of 4-(3-amino-2-methylphenyl)-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indole-1-carboxamide (51 mg, 0.131 mmol), and 4-chloroquinazoline (47.3 mg, 0.287 mmol) in 2-Propanol (5 mL) was heated at 115° C. under microwave for 30 min. The mixture was diluted with ethyl acetate (80 mL), washed with saturated NaHCO3 solution (20 mL) and brine (20 mL), and dried over anhydrous MgSO4. The solvent was removed under vacuum, and the residue was purified by reverse phase HPLC. The correct fractions were concentrated under vacuum, basified with saturated NaHCO3 solution, and extracted with ethyl acetate (3×30 mL). The combined extract was washed with brine (30 mL) and dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (18.0 mg, 0.033 mmol, 25.5% yield) as a yellow solid. LCMS (M+H)+=519.30. 1H NMR (500 MHz, DMSO-d6) δ: 11.65 (s, 1H), 10.17 (s, 1H), 8.61 (s, 1H), 8.55 (d, J=8.0 Hz, 1H), 8.29 (s, 1H), 8.19 (s, 1H), 7.89 (m, 1H), 7.80 (d, J=8.3 Hz, 1H), 7.75 (s, 1H), 7.66 (m, 1H), 7.55-7.49 (m, 2H), 7.38-7.36 (m, 2H), 7.33 (d, J=8.9 Hz, 1H), 6.80 (dd, J1=8.7 Hz, J2=2.4 Hz, 1H), 4.17 (m, 2H), 3.73 (m, 2H), 3.34 (s, 3H), 1.87 (s, 3H).
Reaction SMILES: [CH2:1]([C:8]1[S:9][C:10]([CH3:28])=[C:11]([CH3:27])[C:12]=1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:16]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:30]([C:33]1[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[C:35]([OH:42])[CH:34]=1)(=[O:32])=[O:31]>>[CH2:1]([C:8]1[S:9][C:10]([CH3:28])=[C:11]([CH3:27])[C:12]=1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][S:30]([C:33]2[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[C:35]([OH:42])[CH:34]=2)(=[O:32])=[O:31])=[C:17]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:16]=1)=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1sc(Cc2ccccc2)c(C(=O)c2ccc(O)c(C3CCCC3)c2)c1C
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Product: Cc1sc(Cc2ccccc2)c(C(=O)c2ccc(OS(=O)(=O)c3ccc(C(=O)O)c(O)c3)c(C3CCCC3)c2)c1C
Yield: 56.7 %

Procedure:
The title compound was prepared according to the procedure in Example 4 using (2-benzyl-4,5-dimethyl-thiophen-3-yl)-(3-cyclopentyl-4-hydroxy-phenyl)-methanone (0.505 g, 1.29 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.612 g, 2.58 mmol). Purification on 2% H3PO4/MeOH treated silica gel, eluting with 15% EtOAc/hexane gave 0.432 g (57%) of the title compound a pale yellow solid, mp 70-77° C. 1H NMR (DMSO-d6) δ 1.29-1.34 (m, 2H), 1.51-1.57 (m, 2H), 1.62-1.77 (m,4H), 1.79 (s, 3H), 2.25 (s, 3H), 2.99 (quintet, 1H), 3.84 (s, 2H), 6.98 (d, 2H), 7.12-7.25 (m, 4H), 7.39 (d, 2H), 7.52 (dd, 1H), 7.57 (d, 1H), 7.99 (d, 1H). IR (KBr) 3400, 2950, 1690, 1390 and 1190 cm−1. mass spectrum (+ESI) m/z 591 (M+H). Anal. Calcd. for C32H30O7S2.0.5H2O: C, 64.09; H, 5.21; N, 0.00. Found: C, 63.96; H, 5.30; N, 0.04.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH:25]([NH:28][C:29](=[O:32])[CH2:30]Cl)([CH3:27])[CH3:26].[H-].[Na+]>>[CH:25]([NH:28][C:29](=[O:32])[CH2:30][N:22]1[CH2:21][CH2:20][N:16]2[C:17]3[CH:18]=[CH:19][C:11]([O:10][CH:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[CH:12][C:13]=3[CH:14]=[C:15]2[C:23]1=[O:24])([CH3:27])[CH3:26]
Reactant: CC(C)NC(=O)CCl
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)NC(=O)CN1CCn2c(cc3cc(OC4CCN(C(C)C)CC4)ccc32)C1=O
Yield: 79 %

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), N-isopropyl chloroacetamide and sodium hydride, to give the desired product as a white solid (79%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[F:9][C:10]([F:17])([F:16])[C:11](OCC)=[O:12].C(N(CC)CC)C>ClCCl>[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][NH:1][C:11](=[O:12])[C:10]([F:17])([F:16])[F:9])[CH:4]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: NCc1cccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1cccnc1)C(F)(F)F
Yield: 93 %

Procedure:
22.87 g of 3-(aminomethyl)pyridine was dissolved in 100 ml dichloromethane and stirred with 50.4 ml ethyl trifluoroacetate and 29.5 ml triethylamine at room temperature for 2 hours. The solvent was evaporated under reduced pressure to give a residue, which was then recrystallized from ethyl acetate to provide N-(3-pyridylmethyl)trifluoroacetic acid amide (40.15 g, 93%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][C:14]([NH2:16])=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4].[F:19][C:20]([F:32])([F:31])[C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.C(N(CC)CC)C.Cl>O1CCCC1>[F:18][C:2]([F:1])([F:17])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][C:14]([NH:16][S:27]([C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:31])[F:32])=[CH:26][CH:25]=3)(=[O:29])=[O:28])=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: Nc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(N1CCc2ccc(NS(=O)(=O)c3ccc(C(F)(F)F)cc3)cc2CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1 g (2.68 mmol) of 3-(trifluoroacetyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-7-amine and 947 mg (3.87 mmol) of 4-(trifluoromethyl)benzenesulfonyl chloride were dissolved in 20 ml of tetrahydrofuran at room temperature, and 1.62 ml (11.62 mmol) of triethylamine were added dropwise to the solution, which was stirred at room temperature overnight. After evaporation of the solvent, 20 ml of water were added and acidified with 1 mol of hydrochloric acid, and the aqueous phase was extracted with 50 ml of diethyl ether. The residue obtained after drying with sodium sulfate and after removal of the solvent was separated by column chromatography (cyclohexane/ethyl acetate 6:1).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([NH:11][C:12](=[O:48])[NH:13][C:14]1[N:19]=[CH:18][C:17]2[C:20]([C@@H:42]3[CH2:44][C@H:43]3[C:45](O)=[O:46])=[N:21][N:22](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:16]=2[CH:15]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.[CH3:67][CH2:68][N:69](C(C)C)C(C)C.C(N)C.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[CH2:68]([NH:69][C:45]([C@@H:43]1[CH2:44][C@H:42]1[C:20]1[C:17]2[CH:18]=[N:19][C:14]([NH:13][C:12]([NH:11][C@@H:4]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:3][O:2][CH3:1])=[O:48])=[CH:15][C:16]=2[NH:22][N:21]=1)=[O:46])[CH3:67]
Reactant: CCN(C(C)C)C(C)C
Reactant: COC[C@@H](NC(=O)Nc1cc2c(cn1)c([C@@H]1C[C@H]1C(=O)O)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CCN
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)[C@@H]1C[C@H]1c1n[nH]c2cc(NC(=O)N[C@H](COC)c3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
A mixture of trans-2-(6-(3-((S)-2-methoxy-1-phenylethyl)ureido)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)cyclopropanecarboxylic acid (13 mg, 0.020 mmol), 1-propanephosphonic acid cyclic anhydride (50% in EtOAc, 18.20 μl, 0.031 mmol), DIEA (10.68 μl, 0.061 mmol) and ethylamine (2M in THF) (102 μl, 0.204 mmol) in DCM (0.5 ml) was stirred at room temperature overnight and then concentrated. The residue was treated with TFA (500 μl, 6.49 mmol) and triethylsilane (7 μl, 0.044 mmol). The mixture was stirred at room temperature for 6 h and then concentrated. The residue was purified by preparative HPLC (Reverse phase C-18, Waters SunFire PrepODB, 150×19 mm, 5u), eluting with 10-90% Acetonitrile/Water+0.1% TFA (20 mL/min) over 15 min. to give trans-N-ethyl-2-(6-(3-((S)-2-methoxy-1-phenylethyl)ureido)-1H-pyrazolo[4,3-c]pyridin-3-yl)cyclopropanecarboxamide (4.5 mg, 52% yield). MS ESI calc'd. for C22H26N6O3[M+1]+ 423, found 423. MS ESI calc'd. for C22H26N6O3[M−1]− 421, found 421.