Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][S:4]([C:7]([F:31])([F:30])[C:8]([F:29])([F:28])[C:9]([F:27])([F:26])[C:10]([F:25])([F:24])[C:11]([F:23])([F:22])[C:12]([F:21])([F:20])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])(=[O:6])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:38]([O:42][C:43](=[O:46])[CH2:44]Br)([CH3:41])([CH3:40])[CH3:39]>CC(C)=O>[C:38]([O:42][C:43](=[O:46])[CH2:44][N:3]([CH2:1][CH3:2])[S:4]([C:7]([F:30])([F:31])[C:8]([F:28])([F:29])[C:9]([F:26])([F:27])[C:10]([F:24])([F:25])[C:11]([F:22])([F:23])[C:12]([F:20])([F:21])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])(=[O:6])=[O:5])([CH3:41])([CH3:40])[CH3:39]
Reactant: CCNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN(CC(=O)OC(C)(C)C)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 60 °C
Reaction time: 3 h

Procedure:
20 g (37.94 mmol) of N-ethylperfluorooctylsulfonamide and 15.73 g (113.8 mmol) of potassium carbonate are suspended in 200 ml of acetone, and 14.80 g (75.87 mmol) of bromoacetic acid-tert-butyl ester is added in drops at 60° C. It is stirred for 3 hours at 60° C. Salts are filtered out, and the filtrate is evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: hexane/dichloromethane/acetone=10:10:1). After the product-containing fractions are concentrated by evaporation, the residue is recrystallized from methanol/ether.
Reaction SMILES: [CH:1]([CH:3]([NH:8][C:9](=[O:26])[C@H:10]([CH2:22][CH:23]([CH3:25])[CH3:24])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:4][CH2:5][CH2:6][CH3:7])=O.Cl.[NH2:28][CH2:29][CH2:30][SH:31].C(N(CC)CC)C.S(=O)(=O)(O)O>CO>[S:31]1[CH2:30][CH2:29][NH:28][CH:1]1[CH:3]([NH:8][C:9](=[O:26])[C@H:10]([CH2:22][CH:23]([CH3:25])[CH3:24])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: NCCS
Reactant: CCCCC(C=O)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCCC(NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C1NCCS1
Yield: 103.2 %

Procedure:
In 20 ml of methanol was dissolved 1.0 g of N-benzyloxycarbonyl-L-leucine-(1-formyl)pentylamide obtained in the same manner as in Example 4-(b), and 400 mg of 2-aminoethanethiol hydrochloride, 0.4 ml of triethylamine, and a catalytic amount of concentrated sulfuric acid were added thereto. The mixture was allowed to react at room temperature for 12 hours. After completion of the reaction, the solvent was removed by distillation under redueed pressure. The residue was purified by medium-pressure column chromatography on silica gel to obtain 1.2 g of the titled compound as a colorless crystal.
Reaction SMILES: [C:1]([NH:6][NH:7][C:8]([NH2:10])=[O:9])([CH2:4][CH3:5])([CH3:3])[CH3:2].[N:11]([O-])=[O:12].[Na+].Cl>O.CO>[C:1]([N:6]([N:11]=[O:12])[NH:7][C:8]([NH2:10])=[O:9])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(C)(C)NNC(N)=O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCC(C)(C)N(N=O)NC(N)=O

Procedure:
1-tert-Pentyl semicarbazide (12 g) in a mixture of 50 ml of water and 25 ml of methanol is cooled in an ice bath and 5.6 g of sodium nitrite are added. Conc. hydrochloric acid is added dropwise to this solution until a pH of 4 to 5 is established.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]([C:6]1[C:7]([Cl:14])=[N:8][C:9](Cl)=[CH:10][C:11]=1[CH3:12])#[N:5]>O1CCOCC1.C(OCC)(=O)C>[Cl:14][C:7]1[C:6]([C:4]#[N:5])=[C:11]([CH3:12])[CH:10]=[C:9]([N:2]([CH3:3])[CH3:1])[N:8]=1
Reactant: Cc1cc(Cl)nc(Cl)c1C#N
Reactant: CNC
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(N(C)C)nc(Cl)c1C#N
Reaction time: 2 h

Procedure:
Dimethylamine (8 mL) was added to a solution of 3-cyano-2,6-dichloro-4-methylpyridine (11.6 g) in dioxan (100 mL). After stirring for 2 hours the reaction mixture was diluted with ethyl acetate (1 L), washed with water, dried, filtered, and evaporated to a volume of 20 mL. The crystalline material was filtered to give 5.4 g of the title compound, suitable for use in the next reaction.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]2[C:11]([CH3:12])=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:9][N:8]=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:25])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[O:6][C:5]([C:7]2[C:11]([CH2:12][Br:25])=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1onc(-c2ccc(Br)o2)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1onc(-c2ccc(Br)o2)c1CBr
Yield: 83.8 %

Procedure:
Ethyl 3-(5-bromofuran-2-yl)-4-methylisoxazole-5-carboxylate (1.7 g, 5.67 mmol), NBS (1.2 g, 6.8 mmol), and benzoyl peroxide (0.14 g, 0.567 mmol) were added to 50 mL of carbon tetrachloride and the mixture was refluxed for 16 h. Reaction mixture was concentrated and purified by chromatography (0-30% EtOAc/hexanes) to give 1.8 g of the title compound along with small amount of unreacted starting material. 1H NMR (CDCl3, 200 MHz): δ=7.09 (d, 1H, J=3.4 Hz), 6.54 (d, 1H, J=3.6 Hz), 4.84 (s, 2H), 4.51 (q, 2H, J=7.0 Hz), 1.49 (t, 3H, J=7.4 Hz).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH2:12]([C:14]1[CH:15]=[C:16]([CH3:26])[C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:18][CH:19]=1)[CH3:13]>>[CH2:12]([C:14]1[CH:15]=[C:16]([CH3:26])[C:17]([N:20]2[CH2:21][CH2:22][N:23]([C:6]([C:5]3[CH:4]=[N:3][C:2]([F:1])=[CH:10][C:9]=3[CH3:11])=[O:8])[CH2:24][CH2:25]2)=[N:18][CH:19]=1)[CH3:13]
Reactant: CCc1cnc(N2CCNCC2)c(C)c1
Reactant: Cc1cc(F)ncc1C(=O)O
Product: CCc1cnc(N2CCN(C(=O)c3cnc(F)cc3C)CC2)c(C)c1
Yield: 52.4 %

Procedure:
Using 6-fluoro-4-methylnicotinic acid (300 mg) and 1-(5-ethyl-3-methylpyridin-2-yl)piperazine (389 mg) described in Preparation Example 81 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (340 mg) was obtained.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[N:5]1([CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[N:19]([C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:11][CH2:10][N:5]2[CH2:9][CH2:8][CH2:7][CH2:6]2)=[CH:18][CH:17]=1)=[C:1]=[S:2]
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: S=C=Nc1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of thiophosgene (150 μL, 1.76 mmol, 1.2 equiv) in CHCl3 (2.7 mL) is added to a vigorously stirred mixture of 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (0.303 g, 1.47 mmol) in CHCl3 (7.5 mL) and a saturated aqueous solution of NaHCO3 (7.5 mL). The resulting dark mixture is stirred at RT for 1 h. The layers are separated and the aqueous phase is extracted with CHCl3. The organic phase is washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound as a dark oil: ES-MS: 249.0 [M+H]+; single peak at tR=6.90 min (System 1).
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]#[N:14])=[CH:8][C:7]=1[O:15]C.O>C(Cl)Cl>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]#[N:14])=[CH:8][C:7]=1[OH:15]
Reactant: COc1cc(CC#N)ccc1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: N#CCc1ccc(Cl)c(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
BBr3 (16.6 g, 66 mmol) was slowly added to a solution of 2-(4-chloro-3-methoxyphenyl)acetonitrile (12 g, 66 mmol) in DCM (120 mL) at −78° C. under N2. The reaction temperature was slowly increased to room temperature. The reaction mixture was stirred overnight and then poured into ice and water. The organic layer was separated, and the aqueous layer was extracted with DCM (40 mL×3). The combined organic layers were washed with water, brine, dried over Na2SO4, and concentrated under vacuum to give (4-chloro-3-hydroxy-phenyl)-acetonitrile (9.3 g, 85%). 1H NMR (300 MHz, CDCl3) δ 7.34 (d, J=8.4 Hz, 1H), 7.02 (d, J=2.1 Hz, 1H), 6.87 (dd, J=2.1, 8.4 Hz, 1H), 5.15 (brs, 1H), 3.72 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][N:8]1[C:14](=[O:15])[CH:13]([N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])[CH2:12][CH2:11][CH2:10][NH:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>ClCCl>[C:1]([O:5][C:6](=[O:27])[CH2:7][N:8]1[C:14](=[O:15])[CH:13]([N:16]2[C:17](=[O:26])[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24]2=[O:25])[CH2:12][CH2:11][CH2:10][N:9]1[S:36]([CH3:35])(=[O:38])=[O:37])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)CN1NCCCC(N2C(=O)c3ccccc3C2=O)C1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CN1C(=O)C(N2C(=O)c3ccccc3C2=O)CCCN1S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 81.2 %

Procedure:
To a solution of [6-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-7-oxo-[1,2]diazepan-1-yl]-acetic acid tert-butyl ester (21) (155 mg, 0.42 mmol), triethylamine (0.5 mL) and 4-N,N-dimethylaminopyridine (DMAP) (101 mg, 0.50 mmol) in dichloromethane was added dropwise methanesulfonyl chloride (95 mg, 0.83 mmol). The mixture was stirred at 0° C. for 5 min then at room temperature for 16 hours. The mixture was quenched with water, extracted with dichloromethane. The organic solution was washed with water then brine, dried over anhydrous Na2SO4, filtered and purified by flash chromatography using dichloromethane/ethyl acetate (99/1 to 95/5) to afford 154 mg (82% yield) of the title compound. 1H-NMR (500 MHz, CDCl3) δ 1.47 (s, 9H), 2.05-2.21 (m, 2H), 2.83-2.87 (m, 1H), 3.27 (s, 3H), 3.53-3.58 (m, 1H), 4.07-4.11 (d, 1H), 4.29-4.33 (m, 1H), 4.50-4.53 (d, 1H), 5.42-5.44 (m, 1H), 7.70-7.85 (m, 4H). Analytical HPLC: 12.27 min. LC-MS (ES+): m/e=452 (M+H+).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH3:17])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([C:15]#[N:16])[CH:9]=2)=[O:5])C.Cl>O1CCOCC1.O>[C:15]([C:10]1[CH:9]=[C:8]2[C:13]([CH:14]=[C:6]([C:4]([OH:5])=[O:3])[N:7]2[CH3:17])=[CH:12][CH:11]=1)#[N:16]
Reactant: CCOC(=O)c1cc2ccc(C#N)cc2n1C
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Cn1c(C(=O)O)cc2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 6-Cyano-1-methyl-1H-indole-2-carboxylic acid ethyl ester (51 mg, 0.22 mmol) in 1,4-dioxane/water (5:1, 6 mL) add LiOH monohydrate (13 mg, 0.31 mmol). Stir the reaction mixture at rt overnight. Remove the solvent in vacuo and dissolve the residue in water (2 mL) to form a solution. Acidify with 1 M HCl solution to form a white suspension. Collect the solid by filtration and dry to give the desired product 6-cyano-1-methyl-1H-indole-2-carboxylic acid as a solid (44 mg, 0.22 mmol).
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][OH:7])(=[O:4])=[O:3].C(N(C(C)C)CC)(C)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH3:17][S:18]([O:7][CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])(=[O:20])=[O:19]
Reactant: CS(=O)(=O)CCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)CCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
In a 50 mL round-bottomed flask, 2-(methylsulfonyl)ethanol (1.24 g, 9.99 mmol, Eq: 1.00) was combined with DCM (5 mL). To the resulting solution was added diisopropylethylamine (2.1 mL, 12.0 mmol, Eq: 1.2) and methanesulfonyl chloride (1.37 g, 931 μL, 12.0 mmol, Eq: 1.2). The ice bath was removed and the reaction was stirred at rt overnight. The crude reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc and water. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 80 g, 10% to 80% EtOAc in hexanes) to give 2-(methylsulfonyl)ethyl methanesulfonate (1.01 g).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:17][C:18](=[O:35])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:23][CH:22]=1)[CH:12]=[CH:11]2)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:27]([C:24]1[CH:23]=[CH:22][C:21]([O:20][CH2:19][C:18](=[O:35])[CH2:17][N:13]2[C:14]3[C:10](=[CH:9][C:8]([C:6]([OH:7])=[O:5])=[CH:16][CH:15]=3)[CH:11]=[CH:12]2)=[CH:26][CH:25]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCc1ccc(OCC(=O)Cn2ccc3cc(C(=O)OC(C)(C)C)ccc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCc1ccc(OCC(=O)Cn2ccc3cc(C(=O)O)ccc32)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.222 g (0.465 mmol) tert-butyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylate is dissolved in 60 ml absolute dichloromethane and mixed with 3.98 g (34.9 mmol) trifluoroacetic acid. Having stirred at room temperature for 4 hours, concentration to dryness is carried out on the rotary evaporator. Two admixtures with hexane and respective concentration to dryness on the rotary evaporator leave as a crude product a brownish solid which is purified on an RP-HPLC column by means of chromatography (stationary phase: cromasil, mobile phase acetonitrile/water 80:20) and yields the product as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19].O>N1C=CC=CC=1>[C:18]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH:15]=1)(=[O:19])[C:17]([CH3:22])([CH3:21])[CH3:16]
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)C(=O)Oc1ccc(C(=O)c2ccccc2)cc1

Procedure:
A solution of 2.0 g (1 mmol) of 4-hydroxybenzophenone and 1.25 g (1.5 mmol) of trimethylacetyl chloride in 30 ml of pyridine was heated to 50° C. for 2 h. The reaction mixture was stripped of most of the pyridine and then slurried into water. The crude product obtained by filtration was air-dried and recrystallized from ethanol. The first crop (2.35 g, 79.9%, M.P.≅100°-102° C.) was used for analysis and biological evaluation.
Reaction SMILES: C(OC([N:8]([CH:10]1[CH2:14][CH2:13][N:12]([S:15]([C:18]2[C:19]3[C:20]([Br:29])=[CH:21][N:22]=[C:23]([Cl:28])[C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:17])=[O:16])[CH2:11]1)[CH3:9])=O)(C)(C)C.Cl.C[OH:32]>>[OH:32][C:23]1[C:24]2[CH:25]=[CH:26][CH:27]=[C:18]([S:15]([N:12]3[CH2:13][CH2:14][CH:10]([NH:8][CH3:9])[CH2:11]3)(=[O:17])=[O:16])[C:19]=2[C:20]([Br:29])=[CH:21][N:22]=1.[ClH:28]
Reactant: CO
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(S(=O)(=O)c2cccc3c(Cl)ncc(Br)c23)C1
Agent: Cl
Product: CNC1CCN(S(=O)(=O)c2cccc3c(O)ncc(Br)c23)C1
Temperature: 60 °C
Reaction time: 30 h

Procedure:
Intermediate 24 (168 mg) obtained in Step A mentioned above is added with 10% hydrogen chloride/methanol (4 ml), and the mixture is stirred at 60° C. for 30 hours. The solvent is evaporated under reduced pressure to obtain the title compound as hydrochloride (123 mg (predictive yield)).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:12]=[C:11]([CH:26]=[CH2:27])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][O:29][CH2:30][CH2:31][NH2:32]>>[CH2:1]([NH:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:12]=[C:11]([CH2:26][CH2:27][NH:32][CH2:31][CH2:30][O:29][CH3:28])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCN
Reactant: C=Cc1cc(NCc2ccccc2)c([N+](=O)[O-])c(NCc2ccccc2)n1
Product: COCCNCCc1cc(NCc2ccccc2)c([N+](=O)[O-])c(NCc2ccccc2)n1
Yield: 96 %

Procedure:
N*2*,N*4*-Dibenzyl-3-nitro-6-vinyl-pyridine-2,4-diamine (50 mg, 0.14 mmol) was suspended in 2-methoxy-ethylamine (1 ml) and the mixture refluxed for 1 h. Excess reagents was removed in vacuo, the residue dissolved in DCM (10 ml), washed with 2×H2O, dried and concentrated. The crude material was purified by column chromatography on silica, eluting with DCM:MeOH, 92:8 to give the title compound as a yellow oil, (58 mg, 96%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=O.[NH2:17][CH2:18][C:19]1[C:20]([N:29]([CH2:32][CH:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[CH2:30][CH3:31])=[N:21][C:22]2[CH2:23][CH2:24][CH2:25][CH2:26][C:27]=2[CH:28]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH2:6][NH:17][CH2:18][C:19]1[C:20]([N:29]([CH2:32][CH:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[CH2:30][CH3:31])=[N:21][C:22]2[CH2:23][CH2:24][CH2:25][CH2:26][C:27]=2[CH:28]=1
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCN(CC1CCCC1)c1nc2c(cc1CN)CCCC2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCN(CC1CCCC1)c1nc2c(cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
To a solution of 3,5-bis-trifluoromethyl benzaldehyde (0.185 g, 0.76 mmol) in MeOH (3 mL) was added (3-aminomethyl-5,6,7,8-tetrahydro-quinoline-2-yl)-cyclopentylmethyl-ethylamine (0.2 g, 0.69 mmol), followed by the addition of acetic acid (0.08 mL, 1.39 mmol). This reaction mixture was stirred at RT for 1 h, after which time sodium cyanoborohydride (0.172 g, 2.78 mmol) was added, and stirring was continued for another 8 h. The solvent was then evaporated under vacuum and water was added, followed by extraction of the product with ethyl acetate. The organic layer was washed with saturated sodium bisulfite solution, the organic layer was separated and dried over sodium sulfate, and the solvent was evaporated to give the {3-[(3,5-bis-trifluoromethyl-benzylamino)-methyl]-5,6,7,8-tetrahydro-quinolin-2-yl}-cyclopentylmethyl-ethylamine (0.250 g, yield: 70%).
Reaction SMILES: [CH2:1]([N:3]([CH2:10][CH2:11][O:12][C:13](=[O:15])[CH3:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].O.CN([CH:20]=[O:21])C>>[CH2:1]([N:3]([CH2:10][CH2:11][O:12][C:13](=[O:15])[CH3:14])[C:4]1[CH:9]=[CH:8][C:7]([CH:20]=[O:21])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CN(C)C=O
Reactant: CCN(CCOC(C)=O)c1ccccc1
Solvent: O
Product: CCN(CCOC(C)=O)c1ccc(C=O)cc1
Temperature: 5 °C

Procedure:
To 60 ml of dry DMF in a 250 ml-flask, equipped with a CaCl2-tube, cooled in an ice bath, 29.1 (310 mmol) of OPCl3 is dropwise added and the mixture is stirred for two h at 5° C. Then, 58.5 g (288 mmol) of 16, dissolved in 30 ml of dry DMF, is added and the reaction mixture is stirred for 3 h at 90° C. After cooling down, the mixture is poured into iced water, stirred for 30 min and extracted with dichloromethane. The organic layer is washed with a saturated NaHCO3-solution, with brine and dried over MgSO4. After evaporation of the solvent, the compound is purified with column chromatography (silicagel; eluent:dichloromethane/acetonitrile (90:10 v/v)) and collected as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:23])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=O)=[CH:13][C:12]=1[O:21][CH3:22].C([O:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([C:35]#[C:36][CH:37]2[CH2:41][CH2:40][CH2:39][NH:38]2)=[CH:31][CH:30]=1)=[O:28])C.C(Cl)CCl.Cl>CN(C1C=CN=CC=1)C.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:23])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([N:38]2[CH2:39][CH2:40][CH2:41][CH:37]2[C:36]#[C:35][C:32]2[CH:33]=[CH:34][C:29]([C:27]([OH:28])=[O:26])=[CH:30][CH:31]=2)=[O:20])=[CH:13][C:12]=1[O:21][CH3:22]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1F
Reactant: CCOC(=O)c1ccc(C#CC2CCCN2)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1cc(CC(=O)N2CCCC2C#Cc2ccc(C(=O)O)cc2)ccc1NC(=O)Nc1ccccc1F
Reaction time: 8 h

Procedure:
A mixture of 4-[N′-(2-fluorophenyl)ureido]-3-methoxyphenylacetic acid (255 mg, 0.8 mmol), 2-[2-(4-ethoxycarbonylphenyl)ethynyl]pyrrolidine (195 mg, 0.8 mmol), EDC (230 mg, 1.2 mmol), DMAP (98 mg, 0.8 mmol) in DMF (20 mL) was stirred overnight. The reaction mixture was poured into 1 N HCl and the resulting precipitate was collected with suction and dissolve in CHCl3. The solution was dried over MgSO4 and evaporated. The residue was chromatographed on silica gel with CHCl3-MeOH (100:1, v/v) as eluent to give the desired compound, which was dissolved in THF (8 mL). 0.25 N NaOH (8 mL) was added to this solution and the resulting mixture was stirred overnight. The mixture was poured into 1 N HCl and extracted with CHCl3. The extract was washed with brine, dried over MgSO4, and evaporated. The residue was recrystallized from CHCl3-n-hexane to give 144 mg (37%) 33 as a pale yellow crystalline powder. mp 152–155 (d); 1H-NMR (DMSO-d6) δ 1.92–2.27 (4 H, m), 2.50 (2 H, s), 3.33–3.78 (2 H, m), 3.80 and 3.82 (total 3 H, s, each), 4.88–5.12 (1 H, m), 6.77–7.24 and 7.99–8.20 (total 7 H, m), 7.48 and 7.52 (2 H, d, J=8.3 Hz, each), 7.91 (2H, d, J=8.3 Hz), 8.72 (1H, s), 9.18 (1H, s), 13.11 (1H, br-s); MS (FAB) m/z 516 (M++1); Anal. Calcd for C29H26N3O5F.2H2O: C, 63.15; H, 5.48; N, 7.62. Found: C, 63.58; H, 5.15; N, 7.22.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[C@:13]12[CH2:21][C@H:20]1[C:22]1[CH:30]=[C:29]2[C:25]([C:26]([C:31]3[CH:36]=[CH:35][C:34]([N:37]4[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]4)=[CH:33][CH:32]=3)=[N:27][NH:28]2)=[CH:24][CH:23]=1.[CH:43](=O)[CH3:44]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:43]([N:40]1[CH2:41][CH2:42][N:37]([C:34]2[CH:33]=[CH:32][C:31]([C:26]3[C:25]4[C:29](=[CH:30][C:22]([C@H:20]5[C@@:13]6([C:12]7[C:16](=[CH:17][CH:18]=[C:10]([O:9][CH3:8])[CH:11]=7)[NH:15][C:14]6=[O:19])[CH2:21]5)=[CH:23][CH:24]=4)[NH:28][N:27]=3)=[CH:36][CH:35]=2)[CH2:38][CH2:39]1)[CH3:44]
Reactant: CC=O
Reactant: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(-c4ccc(N5CCNCC5)cc4)n[nH]c3c1)C(=O)N2
Solvent: O=C(O)C(F)(F)F
Product: CCN1CCN(c2ccc(-c3n[nH]c4cc([C@@H]5C[C@@]56C(=O)Nc5ccc(OC)cc56)ccc34)cc2)CC1
Yield: 7.2 %

Procedure:
The title compound was synthesized according to the method of Example A96B, using (1R*,2S*)-5′-methoxy-2-(3-(4-(piperazin-1-yl)phenyl)-1H-indazol-6-yl)spiro [cyclopropane-1,3′-indolin]-2′-one 2,2,2-trifluoroacetate (40 mg, 0.069 mmol) and acetaldehyde (6.0 uL, 0.140 mmol). The crude reaction mixture was concentrated under reduced pressure to dryness, and purified by preparative HPLC to give the title compound as a white solid (3.0 mg, 7.0%); 1H NMR (400 MHz, CD3OD) δ 7.91 (d, J=8.6 Hz, 1H), 7.87 (d, J=8.5 Hz, 2H), 7.49 (s, 1H), 7.17 (d, J=8.6 Hz, 2H), 7.02 (d, J=8.8 Hz, 1H), 6.82 (d, J=8.5 Hz, 1H), 6.60 (d, J=8.9 Hz, 1H), 5.60 (s, 1H), 4.02-4.92 (m, 2H), 3.74-3.64 (m, 2H), 3.38-3.22 (m, 5H), 3.28 (s, 3H), 3.14-3.05 (m, 2H), 2.26-2.22 (m, 1H), 2.20-2.16 (m, 1H), 1.41 (t, J=7.2 Hz, 3H); MS ESI [M+H]+ 494.3, calcd for [C30H31N5O2+H]+ 494.26.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[C:15]([O:17]C(C)C)[C:14]([Cl:21])=[CH:13][C:12]=2[Cl:22])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.[Al+3].[Cl-].[Cl-].[Cl-].[Cl-].[Na+]>C(OCC)C>[C:1]([C:5]1[S:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[C:15]([OH:17])[C:14]([Cl:21])=[CH:13][C:12]=2[Cl:22])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)Oc1cc(-n2nc(C(C)(C)C)sc2=O)c(Cl)cc1Cl
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)c1nn(-c2cc(O)c(Cl)cc2Cl)c(=O)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
11.7 g of 5-t-butyl-3-(2,4-dichloro-5-isopropoxyphenyl)-1,3,4-thiadiazol-2(3H)-one (compound Nr. 48; 32.4 mmoles) and 250 ml of methylene chloride are charged into a 500 ml flask in a nitrogen atmosphere. AlCl3 (12.9 g; 96.7 mmoles) is added to this solution in portions and the mixture is maintained under stirring at room temperature for 2 hours. The mixture is then carefully poured into 100 g of ice to which 100 ml of a saturated solution of sodium chloride have been added. 200 ml of ethyl ether are added and, after separation of the phases, the organic phase is washed with a saturated solution of sodium chloride, anhydrified with sodium sulfate and concentrated with a rotavapor. 10 g of the desired product are obtained having m.p. 130°-132° C.