Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]([CH2:9][CH2:10][OH:11])C.[Cl:12][C:13]1C=NC=[CH:17][CH:18]=1.CN(C=O)C.[Cl-].[NH4+]>CCCCCC.C1COCC1>[Cl:12][C:13]1[C:9]([CH:10]=[O:11])=[N:7][CH:6]=[CH:17][CH:18]=1
Reactant: CN(C)CCO
Reactant: Clc1cccnc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1ncccc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 2.5 M solution of n-butyllithium (96 ml, 240 ml) in n-hexane was added to a solution of N,N dimethylaminoethanol (10.65 g, 120 mmol) in abs. THF (70 ml) at −5° C. under argon within 25 min. The reaction mixture was stirred for 30 min at 0° C. and cooled down to −70° C. At a temperature of −70 to −65° C., a solution of 3-chloropyridine (3.8 ml, 4.5 g, 40 mmol) in abs. THF (60 ml) was added within 10 min and stirred for a further hour at this temperature. Abs. DMF (12.3 ml, 11.7 g, 160 mmol) in THF (100 ml) was then added within 15 min at −65 to −60° C. The dark brown solution was heated within 1 h to 10° C. At a temperature of −20 to −10° C., the reaction mixture was hydrolysed with sat. ammonium chloride solution (120 ml). The mixture was then stirred for 30 min at 0° C. The phases were not separated. The organic solvents were removed under vacuum. The residue was extracted with DCM (120 ml). The phases were separated. The aqueous phase was extracted with DCM (3×120 ml). The organic phases were combined and concentrated without drying. The residue was a brown oil which was further purified by adding water (4×50 ml) and decanting. After the addition of DCM (250 ml) and sodium sulphate, the mixture was dried overnight and then concentrated. The crude product of the 3-chloropyridine-2-carbaldehyde (F) was obtained as a hydrate (brown oil 8.73 g, theoretical yield 6.3 g). Chromatographic purification of the crude product was not possible. The crude product was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9](OCC)=[O:10])[CH:5]=[CH:6][CH:7]=1.[H-].C([Al+]CC(C)C)C(C)C>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1cccc(Br)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: O=CCc1cccc(Br)c1

Procedure:
Important starting materials for the synthesis of the preferred compounds of the invention are 6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F), 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1-one (Compound G), and the isomeric bromo compound, 6-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound H). Compound G can be obtained as described in J. Med Chem. 1995, 38, 4764-4767, and as shown in Reaction Scheme 1. Thus, referring now specifically to Reaction Scheme 1, ethyl 3-bromophenylacetate (Compound B, made by esterification of 3-bromophenylacetic acid) is reduced with diisobutylaluminum hydride (DIBAL H) to yield (3-bromophenyl)acetaldehyde. (3-Bromophenyl)acetaldehyde is reacted in a Wittig reaction with (carbethoxymethylene)triphenylphosphorane to provide a mixture of E and Z ethyl 4-(3-bromophenyl)but-2-enoates. The latter compounds are hydrogenated to yield ethyl 4-(3-bromophenyl)butanoate (Compound D). Compound D is reacted with the Grignard reagent derived from methylbromide to give the tertiary alcohol 5-(3-bromophenyl)-2-methylpentan-2-ol (Compound E) (It should be apparent to those skilled in the art, that the choice of the Grignard reagent used in this reaction step determines the nature of the R1 substituent in the resulting compounds of the invention.) Compound E is then treated with acid to cyclize it and to form 6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F). Compound F is oxidized with chromium trioxide to yield 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G). The isomeric compound, 6-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound H) can be obtained, starting with ethyl (4-bromophenyl)acetate, in accordance with the sequence of reactions illustrated in Reaction Scheme 1 for Compound G. 6-Bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound H) can also be obtained in accordance with the published literature procedure: Mathur et al. Tetrahedron, 41, 1509-1516 (1985).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH2:15][C:16]1([CH3:21])[O:20][CH2:19][CH2:18][O:17]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].C(N(CC)CC)C.[F:37][C:38]([F:45])([F:44])[CH2:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl.O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([NH:29][S:40]([CH2:39][C:38]([F:45])([F:44])[F:37])(=[O:42])=[O:41])=[CH:27][CH:28]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH2:15][C:16]1([CH3:21])[O:20][CH2:19][CH2:18][O:17]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(CC3(C)OCCO3)ccc2n1Cc1ccc(N)cc1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(CC3(C)OCCO3)ccc2n1Cc1ccc(NS(=O)(=O)CC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 105.4 %

Procedure:
To a solution of crude 1-(4-amino-benzyl)-5-(2-methyl-[1,3]dioxolan-2-ylmethyl)-1H-indole-2-carboxylic acid ethyl ester (2 g, ≈5 mmol) in methylene chloride (25 ml) stirring at about -78° C. under nitrogen was added triethylamine (1.28 g, 1.76 ml, 12.7 mmol). The mixture was stirred for about two minutes, and 2,2,2-trifluoroethanesulfonyl chloride (2.03 g, 1.23 ml, 12.7 mmol) was added dropwise via syringe over about five minutes. The mixture was stirred at about -78° C. for about 45 minutes, then diluted with methylene chloride and water and warmed to room temperature. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo to an oil. The oil was taken up in methanol (30 ml) and triethylamine (1 ml) and stirred for about two hours at room temperature. The mixture was poured into half-saturated ammonium chloride and extracted into ethyl acetate. The ethyl acetate was washed with brine, dried over sodium sulfate, filtered, and evaporated to give the title compound (2.85 g) as a foam containing some impurities, which was reacted without further purification.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][C:9]1[CH:13]=[C:12]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([CH2:23][NH:24]C(=O)OC(C)(C)C)=[N:21][N:22]=3)[N:19]=2)[O:11][N:10]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:24][CH2:23][C:20]1[N:18]2[N:19]=[C:14]([C:12]3[O:11][N:10]=[C:9]([CH2:8][OH:7])[CH:13]=3)[CH:15]=[CH:16][C:17]2=[N:22][N:21]=1
Reactant: CC(C)(C)OC(=O)NCc1nnc2ccc(-c3cc(COC4CCCCO4)no3)nn12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1nnc2ccc(-c3cc(CO)no3)nn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (6-(3-((tetrahydro-2H-pyran-2-yloxy)methyl)isoxazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (4.73 g, 11.0 mmol) in dichloromethane (50 mL) was added trifluoroacetic acid (16.9 ml, 220 mmol). The mixture was stirred at room temperature for one hour, then was concentrated, taken up in 2.0 M ammonia in methanol and purified by MPLC chromatography (eluted with 0-10% (1:10:90 NH4OH:MeOH:DCM) in DCM) to yield the product as a tan solid. MS m/z=246.9 [M+1]+. Calc'd for C10H10N6O2: 246.1.
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([O:6][CH2:7][CH2:8][N:9]([C:23]1[CH:32]=[CH:31][C:30]2[C:29]([CH3:34])([CH3:33])[CH2:28][CH2:27][C:26]([CH3:36])([CH3:35])[C:25]=2[CH:24]=1)[C:10](=[O:22])[NH:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=1)[CH3:5].CO.Cl>C1COCC1.O>[CH2:4]([O:6][CH2:7][CH2:8][N:9]([C:23]1[CH:32]=[CH:31][C:30]2[C:29]([CH3:34])([CH3:33])[CH2:28][CH2:27][C:26]([CH3:35])([CH3:36])[C:25]=2[CH:24]=1)[C:10](=[O:22])[NH:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)[CH3:5]
Reactant: CCOCCN(C(=O)Nc1ccc(C(=O)OC)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCOCCN(C(=O)Nc1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 79.4 %

Procedure:
Lithium hydroxide hydrate (0.5 g) was added to a solution of methyl 4-[3-(2-ethoxy-ethyl)-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ureido]-benzoate (39) (520 mg) dissolved in 20 mL THF, 5 mL methanol and 5 mL and the reaction mixture was stirred at room temperature for two hours. The reaction mixture was diluted with 20 mL water, the pH was adjusted to 2 with concentrated HCl and extracted with three 25 mL portions of ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give 400 mg of 4-[3-(2-ethoxy-ethyl)-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ureido]-benzoic acid (33) as a colorless oil, which crystallized upon addition of hexanes. M.P.: 82-85° C.
Reaction SMILES: C([C:5]1([CH:13]=[CH:12][C:11](Br)=[CH:10][CH2:9]1)[C:6]([O-:8])=[O:7])(C)(C)C.[CH2:15]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[CH:26])=[CH:21][CH:20]=1)[CH2:16][CH3:17].[CH2:27]([C:30]1[CH:35]=CC(Br)=C[CH:31]=1)CC.C[Si](C#C)(C)C.Cl>O>[C:30]([O:8][C:6]([C:5]1[CH:9]=[CH:10][C:11]([C:26]#[C:25][C:22]2[CH:21]=[CH:20][C:19]([O:18][CH2:15][CH2:16][CH3:17])=[CH:24][CH:23]=2)=[CH:12][CH:13]=1)=[O:7])([CH3:35])([CH3:31])[CH3:27]
Reactant: CC(C)(C)C1(C(=O)[O-])C=CC(Br)=CC1
Reactant: CCCc1ccc(Br)cc1
Reactant: C#Cc1ccc(OCCC)cc1
Agent: C#C[Si](C)(C)C
Agent: Cl
Solvent: O
Product: CCCOc1ccc(C#Cc2ccc(C(=O)OC(C)(C)C)cc2)cc1

Procedure:
The reaction was conducted in the same manner as in the step (i) of the Example 31, except for using 1-tert-butyl-4-bromobenzoate synthesized in the step (i) and 4-n-propyloxyphenylacetylene synthesized in the step (iii) of the Example 32 instead of 1-n-propyl-4-bromobenzene and trimethylsilylacetylene, respectively. After completion of the reaction, the reaction mixture was poured into an iced water, and the resultant mixture was acidified by adding hydrochloric acid. The resultant solid was collected by filtration, washed with water, dried, and recrystallized from hexane to give 1-[4-(tert-butoxycarbonyl)phenyl]-2-(4-n-propyloxyphenyl)acetylene.
Reaction SMILES: [CH3:1][C:2]12[C:12](=[O:13])[CH2:11][CH2:10][CH2:9][C:8]1=[CH:7][C:5](=[O:6])[CH2:4][CH2:3]2.[CH3:14][C:15]1(CC)OCC[O:16]1.C(O)CO>O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:14]1[CH2:15][O:16][C:12]2([CH2:11][CH2:10][CH2:9][C:8]3[C:2]2([CH3:1])[CH2:3][CH2:4][C:5](=[O:6])[CH:7]=3)[O:13]1
Reactant: CCC1(C)OCCO1
Reactant: CC12CCC(=O)C=C1CCCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: OCCO
Product: CC12CCC(=O)C=C1CCCC21OCCO1
Temperature: 25 °C
Reaction time: 30 h
Yield: 93.6 %

Procedure:
A mixture of Wieland-Miescher ketone (5.086 g, 28.44 mmol), 2-methyl-2-ethyl-1,3-dioxolane (19.38 mL, 155.0 mmol), ethylene glycol (0.358 mL, 6.43 mmol) and p-toluenesulfonic acid monohydrate (0.4 g, 2.13 mmol) was stirred at room temperature for 30 hours. The reaction was quenched with dropwise addition of triethylamine, diluted with 20 mL of benzene, washed with water, dried over MgSO4, and concentrated under vacuum. The product was triturated from hexanes to yield monoacetal 201 (5.92 g, 94%). 1H NMR (CDCl3) δ 1.36 (s, 3H), 1.6-2.0 (m, 5H), 2.2-2.5 (m, 5H), 3.9-4.1 (m, 4H), 5.80 (d, J=Hz, 1H); 13C NMR (CDCl3) 198.91, 167.55, 125.38, 125.37, 112.12, 65.16, 64.84, 44.81, 33.70, 31.22, 29.81, 26.62, 21.51, 20.27.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[C:6]=2[N:7]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.O>CS(C)=O>[CH3:13][S:12][C:8]1[C:6]2[N:7]=[C:2]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:3]=[C:4]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:5]=2[N:11]=[CH:10][N:9]=1
Reactant: C1CNCCN1
Reactant: CSc1ncnc2c(N3CCCC3)nc(Cl)nc12
Solvent: CS(C)=O
Solvent: O
Product: CSc1ncnc2c(N3CCCC3)nc(N3CCNCC3)nc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.8 g (0.01 mol) of 2-chloro-8-methylthio-4-pyrrolidino-pyrimido[5,4-d]pyrimidine is dissolved warm in 300 ml of dimethylsulphoxide and then a solution of 4.3 g (0.05 mol) of piperazine is added. After being stirred for 1 hour at ambient temperature the solution is poured into 1.5 liters of water. The precipitate obtained is suction filtered, washed with water and dried.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[CH:14][N:13]=2)=[CH:7][N:6]=1)=[O:4].CO.O.[Li+].[OH-]>C1COCC1>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([C:15]2[CH:14]=[N:13][C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=3)=[N:17][CH:16]=2)=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccc(Nc2ncc(-c3ccc(OC)cc3)cn2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2cnc(Nc3ccc(C(=O)O)nc3)nc2)cc1
Reaction time: 12 h

Procedure:
To a suspension of 5-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]pyridine-2-carboxylic acid methyl ester 4 (0.3 mmol) in THF:MeOH:H2O=3:2:1 (5 mL), is added 6M LiOH (1.8 mmol). The reaction mixture is stirred at it for 12 h. After this time the solvent is removed under vacuum, the residue is diluted with H2O (6 mL) and the pH neutralized with 6M HCl. The solid that precipitates out is collected, washed with water and dried in a vacuum oven for 12 h to afford 5-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-pyridine-2-carboxylic acid 5 as a yellow solid, which is used in the next step without further purification. MS (m/z) (M+1)+: 323.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.[Cl:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O>>[Cl:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH3:13])([CH3:14])[C:6]=2[CH:15]=1
Reactant: CN1C(=O)OC(C)(C)c2cc(N)ccc21
Reactant: OB(O)c1cccc(Cl)c1Cl
Product: CN1C(=O)OC(C)(C)c2cc(Nc3cccc(Cl)c3Cl)ccc21

Procedure:
Prepared from 6-amino-1,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 2,3-dichlorophenyl boronic acid according to the coupling procedure described in example 1. MS (ESI) m/z 351/353/355 ([M+H]+); MS (ESI) m/z 349/351/353 ([M−H]−); Anal. calcd for C17H16Cl2N2O2: C, 58.13; H, 4.59; N, 7.98. Found: C, 58.59H, 4.61; N, 7.36.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](O)=[O:27])[N:9]=2)[CH:7]=1.Cl.[N:34]1([CH2:40][CH2:41][N:42]2[CH2:47][CH2:46][CH:45]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:44][CH2:43]2)[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:37]3[CH2:36][CH2:35][N:34]([CH2:40][CH2:41][N:42]4[CH2:43][CH2:44][CH:45]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:46][CH2:47]4)[CH2:39][CH2:38]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Reactant: CCOC(=O)C1CCN(CCN2CCNCC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCN(CCN2CCN(C(=O)Cn3cc(NC(=O)c4cnn5cccnc45)c(-c4cc(Cl)ccc4OC(F)F)n3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetic acid (150 mg, 0.32 mmol) in DMF (10 mL) was added ethyl 1-[2-(piperazin-1-yl)ethyl]piperidine-4-carboxylate hydrochloride (199 mg, 0.65 mmol), DIEA (126 mg, 0.97 mmol), HATU (148 mg, 0.39 mmol). The resulting solution was stirred at room temperature overnight and concentrated under vacuum. The residue was passed through a short pad of silica gel eluting with 3% MeOH in DCM. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (18.0% MeCN up to 27.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 18.0% in 2 min); Detector, UV 254/220 nm. This resulted in 66.1 mg (27%) of the formic acid salt of ethyl 1-[2-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]ethyl]piperidine-4-carboxylate. LCMS (Method 24) [M+H]+=714.2, RT=2.42 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.6, 6.8 Hz), 8.69-8.68 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.8, 8.8 Hz), 7.56 (d, 1H, J=2.4 Hz), 7.46 (d, 1H, J=8.8 Hz), 7.29 (dd, 1H, J=4.4, 6.8 Hz), 7.08 (t, 1H, J=73.2 Hz), 5.23 (m, 2H), 4.03 (q, 2H, J=6.8 Hz), 3.50-3.47 (m, 4H), 2.88-2.85 (m, 2H), 2.52-2.51 (m, 6H), 2.47-2.26 (m, 3H), 2.12-2.07 (m, 2H), 1.80-1.78 (m, 2H), 1.60-1.55 (m, 2H), 1.16 (t, 3H, J=7.2 Hz).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([C:28]3[S:29][C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[N:32]=3)[O:20][CH:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[CH:14]=2)[CH2:9]1)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[S:29]1[C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=[C:28]1[CH:19]([O:20][CH:21]1[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]1)[C:15]1[CH:14]=[C:13]([N:10]2[CH2:11][CH2:12][CH:8]([NH2:7])[CH2:9]2)[CH:18]=[CH:17][CH:16]=1
Reactant: CN1CCC(OC(c2cccc(N3CCC(NC(=O)OC(C)(C)C)C3)c2)c2nc3ccccc3s2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCC(OC(c2cccc(N3CCC(N)C3)c2)c2nc3ccccc3s2)CC1

Procedure:
423AA solution of crude (1-{3-[benzothiazol-2-yl-(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-yl)carbamic acid tert-butyl ester (289 mg) in dichloromethane (3 mL) and trifluoroacetic acid (2.5 mL) is stirred at room temperature for one night. The mixture is concentrated under reduced pressure, diluted with ethyl acetate, washed with aqueous 1N sodium hydroxide, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane/methanol/ammonia from 95/5/0.5 to 80/20/0.5). The base is converted into its dioxalate salt in acetone to give 1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-ylamine, dioxalate melting at 145° C.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]3[S:21][N:20]=[CH:19][N:18]=3)(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[CH:26][N:27]2[C@H:32]([CH3:36])[C:33](O)=[O:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C=O)C>[F:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[CH:26][N:27]2[C@H:32]([CH3:36])[C:33]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]([S:13]([NH:16][C:17]3[S:21][N:20]=[CH:19][N:18]=3)(=[O:15])=[O:14])=[CH:11][CH:12]=2)[CH2:2][CH2:3]1)=[O:34]
Reactant: C[C@H](C(=O)O)n1ccc2c(F)cccc21
Reactant: O=S(=O)(Nc1ncns1)c1ccc(N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](C(=O)N1CCN(c2ccc(S(=O)(=O)Nc3ncns3)cc2)CC1)n1ccc2c(F)cccc21
Yield: 63.7 %

Procedure:
Synthesized according to general procedure 5, method B. The reaction was set up with 0.61 mmol 4-(piperazin-1-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide, 0.61 mmol (2R)-2-(4-fluoro-indol-1-yl)-propionic acid, 0.61 mmol HATU, 0.61 mmol N,N-diisopropyl ethyl amine and 2 mL (1:1) DMF:methylene dichloride to get (R)-4-{4-[2-(4-Fluoro-1H-indol-1-yl)propionyl]piperazin-1-yl}-N-[1,2,4]thiadiazol-5-yl benzenesulfonamide as a white solid (200 mg, 63% yield). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=515.3; tR=3.16 min. 1H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.56 (d, J=9.0 Hz, 2H), 7.47 (s, 1H), 7.37 (s, 1H), 7.15-7.09 (m, 1H), 6.94 (d, J=9.1 Hz, 2H), 6.84-6.79 (m, 1H), 6.54 (d, J=3.2 Hz, 1H), 5.87-5.82 (m, 1H), 3.66 (d, J=4.6 Hz, 2H), 3.58-3.53 (m, 2H), 3.17-3.09 (m, 4H), 1.59 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]#[C:15][C:16]2[CH:21]=[C:20]([C:22]#[C:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:19]=[C:18]([C:30]#[C:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:17]=2)=[CH:8][CH:7]=1.[Li+].[OH-].O.Cl>C1COCC1.CO>[C:24]1([C:23]#[C:22][C:20]2[CH:21]=[C:16]([C:15]#[C:14][CH2:13][O:12][C:9]3[CH:8]=[CH:7][C:6]([O:5][CH2:4][C:3]([OH:38])=[O:2])=[CH:11][CH:10]=3)[CH:17]=[C:18]([C:30]#[C:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:19]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)COc1ccc(OCC#Cc2cc(C#Cc3ccccc3)cc(C#Cc3ccccc3)c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COc1ccc(OCC#Cc2cc(C#Cc3ccccc3)cc(C#Cc3ccccc3)c2)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of {4-[3-(3,5-bis-phenylethynyl-phenyl)-prop-2-ynyloxy]-phenoxy}-acetic acid methyl ester (0.26 g, 0.51 mmol) in THF (5.6 ml) and methanol (1.1 ml) was added a ice-cold solution of LiOH (1 M, 5.6 ml). The reaction mixture was stirred at 0° C. for 45 min., after which water (37 ml) and aqueous HCl (1M, 7.5 ml) were added. The mixture was extracted with ethyl acetate (2×25 ml), and the combined organic phases were dried and evaporated to give the title compound in 240 mg (96%) yield.
Reaction SMILES: [C:1](=[O:47])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][C@H:3]([CH2:18][C:19]1[CH:27]=[C:26]([CH3:28])[C:25]2[C:21](=[CH:22][N:23]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[N:24]=2)[CH:20]=1)[C:4](=[O:17])[N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:7][CH2:6]1.[OH:48][C:49]1([C:55]2[C:56](=[O:65])[NH:57][C:58]3[C:63]([CH:64]=2)=[CH:62][CH:61]=[CH:60][CH:59]=3)[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[OH:48][C:49]1([C:55]2[C:56](=[O:65])[NH:57][C:58]3[C:63]([CH:64]=2)=[CH:62][CH:61]=[CH:60][CH:59]=3)[CH2:54][CH2:53][N:52]([C:1]([O:2][C@H:3]([CH2:18][C:19]2[CH:27]=[C:26]([CH3:28])[C:25]3[C:21](=[CH:22][N:23]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:34])[CH3:35])[N:24]=3)[CH:20]=2)[C:4](=[O:17])[N:5]2[CH2:6][CH2:7][CH:8]([N:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[CH2:9][CH2:10]2)=[O:47])[CH2:51][CH2:50]1
Reactant: Cc1cc(C[C@@H](OC(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N2CCC(N3CCCCC3)CC2)cc2cn(COCC[Si](C)(C)C)nc12
Reactant: O=c1[nH]c2ccccc2cc1C1(O)CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(O)(c3cc4ccccc4[nH]c3=O)CC2)C(=O)N2CCC(N3CCCCC3)CC2)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-3-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidin-1-yl)propan-2-yl 4-nitrophenyl carbonate (150 mg, 0.23 mmol) and 3-(4-hydroxypiperidin-4-yl)quinolin-2(1H)-one (55 mg, 1.0 equiv) in dimethylformamide (1 mL) was added diisopropylethylamine (79 μL, 0.45 mmol). The reaction was stirred at room temperature overnight. The reaction was concentrated and purified by column chromatography (3:97:1 methanol/dichloromethane/triethylamine) to give 90 mg (52%) as a foam solid. Mass spec.: 771.48 (MH)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.[CH2:9]([Br:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C>[Br-:16].[CH2:9]([N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH2:2]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCc1cccnc1
Reactant: BrCc1ccccc1
Solvent: CCO
Product: OCC1=CC=CN(Cc2ccccc2)C1
Product: [Br-]
Reaction time: 2 h

Procedure:
To a solution of 3-pyridyl carbinol (100 mmol) in 30 mL of ethanol is added benzyl bromide (110 mmol) dropwise via addition funnel at room temperature. Stirring is continued for 2 hours at room temperature and solvents are removed in vacuo. The residue is taken up into acetonitrile (100 mL) and washed with hexanes (3×100 mL). The acetonitrile layer is concentrated in vacuo and dried under vacuum to provide N-benzyl-3-pyridyl carbinol bromide.