Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([C@H:6]([OH:10])[C:7]([OH:9])=[O:8])[C:3]([OH:5])=[O:4].[F:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH:19]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:20]([O:22][C@@H:23]2[CH:28]3[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]3)[CH2:24]2)=[O:21])=[CH:14][CH:13]=1>CC(C)=O>[C:3]([C@@H:2]([O-:1])[C@@H:6]([C:7]([OH:9])=[O:8])[O-:10])([OH:5])=[O:4].[F:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C@@H:19]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:20]([O:22][C@@H:23]2[CH:28]3[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]3)[CH2:24]2)=[O:21])=[CH:14][CH:13]=1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(Nc1ccc(F)cc1)c1ccccc1
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: CC(C)=O
Product: O=C(O)[C@@H]([O-])[C@H]([O-])C(=O)O
Product: O=C(O[C@H]1CN2CCC1CC2)[C@@H](Nc1ccc(F)cc1)c1ccccc1
Temperature: 25 °C
Yield: 90.2 %

Procedure:
(2S,3S)-2,3-Dihydroxysuccinic acid (0.23 g, 1.52 mmol) was added to a suspension of (R)-quinuclidin-3-yl 2-(4-fluorophenylamino)-2-phenylacetate (I8) (1.08 g, 3.05 mmol) in acetone (140 ml). The resulting mixture was heated at reflux and then allowed to cool at room temperature. The precipitate was collected by filtration to obtain (S)—((R)-quinuclidin-3-yl) 2-(4-fluorophenylamino)-2-phenylacetate (1S,2S)-1,2-dicarboxyethane-1,2-bis(olate) (689 mg, 45% yield, diastereomer 2 of 18). Evaporation of the mother solution gave (R)—((R)-quinuclidin-3-yl) 2-(4-fluorophenylamino)-2-phenylacetate (1S,2S)-1,2-dicarboxyethane-1,2-bis(olate) (535 mg, 41% yield, diastereomer 1 of I8).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([OH:17])=[C:5]([C:14]([OH:16])=O)[C:6](=[O:13])[N:7]2[CH3:12].C([N:20]([CH2:23][CH3:24])[CH2:21]C)C.S(Cl)(Cl)=O.[CH2:29]([Cl:31])Cl>>[C:2]1([C:11]2[CH:2]=[CH:3][C:8]([N:7]([CH3:12])[C:6]([C:5]3[C:14](=[O:16])[N:20]([CH3:21])[C:23]4[C:24]([C:4]=3[OH:17])=[C:29]([Cl:31])[CH:6]=[CH:5][CH:4]=4)=[O:13])=[CH:9][CH:10]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:3]=1
Reactant: CCN(CC)CC
Reactant: ClCCl
Reactant: Cn1c(=O)c(C(=O)O)c(O)c2c(Cl)cccc21
Solvent: O=S(Cl)Cl
Product: CN(C(=O)c1c(O)c2c(Cl)cccc2n(C)c1=O)c1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To an ice-cold solution of 5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxylic acid (1.6 g, 6.5 mmol), triethylamine (3 ml, 22.7 mmol), N-metyl-4-aminodiphenyl (1.3 g, 7 mmol) in methylene chloride (25 ml) was added dropwise during 10 minutes a solution of thionyl chloride (1.0 g, 8.4 mmol) in methylene chloride (10 ml). Stirring was continued at 4° C. for 4 hours. The solution was diluted with methylene chloride (10 ml), washed with cold 1 M sulphuric acid and then extracted with 1 M sodium hydroxide. The pH of the aqueous phase was adjusted to 8-8.5, clarified by filtration and then further acidified with hydrochloric acid solution to pH 4. After standing a crystalline precipitate was formed and was filtered off, washed with water and dried to give the title compound (1.9 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][C@H:12]1[C@@H:24]([N:26]=[N+]=[N-])[CH3:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>C1COCC1.O.C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13][C@H:12]1[C@@H:24]([NH2:26])[CH3:25])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](N=[N+]=[N-])[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: C[C@H](N)[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
(S,S)-1-Benzyloxycarbonyl-2-(1-azidoethyl)-4-tert-butyloxycarbonylpiperazine (8.1 g) was dissolved in 255 mL of 9:1 THF-water and triphenylphosphine (10.9 g) was added. The mixture was heated to 75° C. and stirred at this temperature overnight. The reaction mixture was cooled, diluted with 286 mL of CH2Cl2, poured into 250 mL of 1N HCl, and extracted with 750 mL of CH2Cl2. The aqueous phase was basified to pH>10 by addition of 5N NaOH, then extracted with 5×750 mL of EtOAc. The combined organic extracts were washed with 750 mL of brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography using 90:10 ethyl acetate-methanol to yield 3.07 g of the title compound. Mass spectrum (ESI) 308.3 (M−55).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:19][CH3:20])[C:5]([O:10][CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[C:6]([CH:9]=1)[CH:7]=[O:8].C1(C)C=CC(S([CH2:30][N+:31]#[C-:32])(=O)=O)=CC=1>CO>[Br:1][C:2]1[CH:3]=[C:4]([O:19][CH3:20])[C:5]([O:10][CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:16])([CH3:18])[CH3:17])=[C:6]([C:7]2[O:8][CH:32]=[N:31][CH:30]=2)[CH:9]=1
Reactant: COc1cc(Br)cc(C=O)c1OCOCC[Si](C)(C)C
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Solvent: CO
Product: COc1cc(Br)cc(-c2cnco2)c1OCOCC[Si](C)(C)C

Procedure:
1 g of 5-bromo-3-methoxy-2-(2-trimethylsilanylethoxymethoxy)benzaldehyde and 0.54 g of p-toluenesulfonylmethyl isocyanide are dissolved in 40 ml of methanol, 0.38 g of o-potassiumcarbonate is added in portions, and the reaction mixture is heated to reflux for 18 h. The solvent is then distilled off, and the crude product is purified by silica gel chromatography (ethyl acetate/heptane).
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:11]([OH:13])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O.ON1C2C=CC=CC=2N=N1.[OH:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][NH2:44])=[CH:38][CH:37]=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:11]([NH:44][CH2:43][CH2:42][C:39]1[CH:40]=[CH:41][C:36]([OH:35])=[CH:37][CH:38]=1)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1ccc(C(=O)O)cc1OCCCCCC
Reactant: NCCc1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCOc1ccc(C(=O)NCCc2ccc(O)cc2)cc1OCCCCCC
Temperature: 25 °C
Reaction time: 15 h
Yield: 104.2 %

Procedure:
3,4-Dihexyloxybenzoic acid (161 mg, 0.5 mmol) and 1-hydroxy-benzotriazole hydrate (45.9 mg, 0.3 mmol, 0.6 eq) were dissolved in DMF (5 ml), and to this solution were successively added 2-(4-hydroxyphenyl)ethylamine (82 mg, 0.6 mmol, 1.2 eq) and WSC hydrochloride (114 mg, 0.6 mmol, 1.2 eq) at room temperature. The mixture was stirred at room temperature for 15 hours. This reaction mixture was poured into ethyl acetate (75 ml), washed with water (5 ml×3) and saturated brine (15 ml). The organic layerwas dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (chloroform/methanol=50/1) to give 3,4-dihexyloxy-N-[2-(4-hydroxyphenyl)ethyl]benzamide (230 mg). The obtained solid was recrystallized from ethyl acetate-hexane to give 3,4-dihexyloxy-N-[2-(4-hydroxyphenyl)ethyl]benzamide (194 mg, 88%) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N:14]1[NH:15][C:16]([CH2:23][CH2:24][C:25](O)=O)=[C:17]2[C:22]=1[CH2:21][CH2:20][CH2:19][CH2:18]2.Cl[C:29]1[CH:34]=[CH:33][C:32](C2CCNCC2)=[CH:31][CH:30]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:25][CH2:24][CH2:23][C:16]3[N:15]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:14]=[C:22]4[C:17]=3[CH2:18][CH2:19][CH2:20][CH2:21]4)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(C2CCNCC2)cc1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: O=C(O)CCc1[nH]nc2c1CCCC2
Product: Fc1ccc(N2CCN(CCCc3c4c(nn3-c3ccccc3)CCCC4)CC2)cc1

Procedure:
In the same manner as in Example 102 except that 3-(4,5,6,7-tetrahydro-2-phenyl-2H-indazol-3-yl)propionic acid obtained in Starting Material Synthesis Example 11 and 1-(4-fluorophenyl)piperazine are used instead of 3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtained in Staring Material Synthesis Example 1 and 4-(4-chlorophenyl)piperidine, 3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2-phenyl-2H-indazole is obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:17]([CH3:29])[CH:16]=2)[NH:7][N:6]=1.[OH:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH3:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:34]4[CH2:35][CH2:36][CH:31]([OH:30])[CH2:32][CH2:33]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=1
Reactant: OC1CCNCC1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2C)cn1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCN5CCC(O)CC5)c34)cc2C)cn1
Yield: 25 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine and 4-hydroxypiperidine to give the title compound in 25% yield; NMR Spectrum: 1.35-1.39 (m, 2H), 1.67-1.69 (m, 2H), 2.15-2.19 (m, 2H), 2.19 (s, 3H), 2.43 (s, 3H), 2.77-2.82 (m, 4H), 3.39-3.42 (m, 1H), 4.42 (t, 2H), 4.53 (br s, 1H), 6.95 (d, 1H), 7.18-7.24 (m, 2H), 7.60-7.63 (m, 2H), 8.17 (s, 1H), 8.30 (s, 1H), 8.33 (s, 1H); Mass Spectrum: 476 (MH+).
Reaction SMILES: COC([NH:5][CH2:6][C@@:7]1([CH2:13][C:14]([OH:16])=[O:15])[CH2:11][CH2:10][C@@H:9]([CH3:12])[CH2:8]1)=O.[ClH:17]>O1CCOCC1.O>[ClH:17].[NH2:5][CH2:6][C@@:7]1([CH2:13][C:14]([OH:16])=[O:15])[CH2:11][CH2:10][C@@H:9]([CH3:12])[CH2:8]1
Reactant: COC(=O)NC[C@@]1(CC(=O)O)CC[C@@H](C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H]1CC[C@@](CN)(CC(=O)O)C1
Yield: 59 %

Procedure:
[(1S,3R)-1-(Methoxycarbonylamino-methyl)-3-methyl-cyclopentyl]-acetic acid (0.32 g, 1.4 mmol) was refluxed in a mixture of 1,4-dioxane (3 mL) and 6N Hydrochloric acid (8 mL) for 4 hours. The mixture was allowed to cool, diluted with water (200 mL), and washed with dichloromethane (2×200 mL). The aqueous layer was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate/methanol to give 0.17 g (59%) of ((1S,3R)-1-aminomethyl-3-methyl-cyclopentyl)-acetic acid hydrochloride;
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[C:5]([C:9]1[S:13][C:12]([NH2:14])=[N:11][N:10]=1)([CH3:8])([CH3:7])[CH3:6]>C(OCC)(=O)C>[C:5]([C:9]1[S:13][C:12]([N:14]=[C:1]=[O:2])=[N:11][N:10]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)c1nnc(N)s1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1nnc(N=C=O)s1
Reaction time: 16 h

Procedure:
A saturated solution of phosgene in ethyl acetate (100 ml) was charged into a glass reaction vessel equipped with a mechanical stirrer. A slurry of 5-t-butyl-2-amino-1,3,4-thiadiazole (10grams) in ethyl acetate (300 ml) was added to the reaction vessel and the resulting mixture was stirred for a period of about 16 hours resulting in the formation of a precipitate. The reaction mixture was then purged with nitrogen gas to remove unreacted phosgene. The purged mixture was then filtered to recover the desired product 5-t-butyl-1,3,4-thiadiazol-2-yl isocyanate dimer as a solid having a melting point of 261° to 263°C.
Reaction SMILES: Cl.[CH2:2]([N:4]([C:12]1[N:17]=[CH:16][N:15]=[C:14]2[N:18]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:22]=3[F:31])[N:19]=[CH:20][C:13]=12)[CH2:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[CH3:3].Br[C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][N:34]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:2]([N:4]([C:12]1[N:17]=[CH:16][N:15]=[C:14]2[N:18]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:22]=3[F:31])[N:19]=[CH:20][C:13]=12)[CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][N:34]=2)[CH2:10][CH2:11]1)[CH3:3]
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: CCN(CC1CCNCC1)c1ncnc2c1cnn2-c1ccc(S(C)(=O)=O)cc1F
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC1CCN(c2ccc(C(F)(F)F)cn2)CC1)c1ncnc2c1cnn2-c1ccc(S(C)(=O)=O)cc1F
Temperature: 165 °C
Yield: 51.4 %

Procedure:
A mixture of ethyl-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-piperidin-4-ylmethyl-amine hydrochloride salt (30 mg, 0.064 mmol), 2-bromo-5-trifluoromethylpyridine (188 mg, 0.83 mmol), and triethylamine (27 μL, 0.19 mmol) in DMF (1.0 mL) was heated under microwave irradiation for 20 minutes at 165° C. The crude mixture was purified by HPLC to provide compound A127 as a white solid (19 mg, 51%). Exact mass calculated for C26H27F4N7O2S 557.19, found 578.3 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])[CH2:23][C:24](N(OC)C)=[O:25])=[CH:18][CH:17]=1.[Cl-].[NH4+]>C1COCC1.O>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([CH:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])[CH2:23][C:24]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)=[O:25])=[CH:20][CH:21]=1
Reactant: COc1ccc(Br)cc1
Reactant: CON(C)C(=O)CC(c1ccc(Br)cc1)c1ccccc1C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C)cc1
Reaction time: 0.67 h
Yield: 86.3 %

Procedure:
A stirred solution of 4-bromoanisole (639 mg) in THF (15 ml) under argon was cooled to −78° C. A solution of n-butyllithium (2.07 ml, 1.6 M in hexane) was added slowly while keeping the temperature below −70° C. After stirring for 40 min, a solution of 3-(4-bromo-phenyl)-N-methoxy-N-methyl-3-o-tolyl-propionamide (400 mg, example 74, step 4) in THF (15 ml) was added while keeping the temperature below −70° C. The mixture was stirred at this temperature for 1 hour. The reaction was stopped by addition of saturated aqueous ammonium chloride solution (15 ml). Water was added and the mixture was extracted with ethyl acetate (3×). The combined organic phase was washed with water and brine, dried using MgSO4, filtered and concentrated to dryness. The product was purified by chromatography (SiO2, cyclohexane/ethyl acetate 1:0 to 3:2) to give the title compound (390 mg) as a light yellow oil, MS (ESI+): m/z=409.2 [M+H]+.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[N:10]([CH2:11][C:12]([OH:14])=[O:13])[N:9]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:7]=1[C:22]#[C:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[ClH:30]>>[Cl:30][C:22]1[C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:1][N:5]=[C:6]2[N:10]([CH2:11][C:12]([OH:14])=[O:13])[N:9]=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:7]=12
Reactant: O=N[O-]
Reactant: Nc1c(C#Cc2ccccc2)c(-c2ccc(F)cc2)nn1CC(=O)O
Reactant: Cl
Agent: [Na+]
Product: O=C(O)Cn1nc(-c2ccc(F)cc2)c2c(Cl)c(-c3ccccc3)nnc21
Temperature: -5 °C

Procedure:
To a cooled (cooling bath −5° C.) stirred suspension of sodium nitrite (320 mg, 4.65 mmol) in conc. HCl (5 mL) was added 2-(5-amino-3-(4-fluorophenyl)-4-(phenylethynyl)-1H-pyrazol-1-yl)acetic acid (521 mg, 1.55 mmol). A further 5 ml of conc. HCl was added and the cooling bath was removed and the reaction mixture was stirred at room temperature for 3.5 h. Water and CH2Cl2 were added to the reaction mixture. The aqueous phase was extracted with CH2Cl2 and the organic phases combined, dried over MgSO4, filtered and evaporated to give 2-(4-chloro-3-(4-fluorophenyl)-5-phenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid as a solid (419 mg), which was used as such in the subsequent step.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:11]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][N:28]([CH:31]4[CH2:34][O:33][CH2:32]4)[CH2:27][CH2:26]3)=[C:21]([O:35][CH2:36][CH2:37][O:38][CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][O:40]3)[CH:20]=2)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[C:45]([N:52]([C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])[C:53]1[CH:58]=[N:57][CH:56]=[C:55](B2OC(C)(C)C(C)(C)O2)[N:54]=1)([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46]>>[C:71]([O:70][C:68]([N:52]([C:45]([O:47][C:48]([CH3:50])([CH3:51])[CH3:49])=[O:46])[C:53]1[N:54]=[C:55]([C:2]2[N:3]=[C:4]([N:11]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][N:28]([CH:31]5[CH2:32][O:33][CH2:34]5)[CH2:27][CH2:26]4)=[C:21]([O:35][CH2:36][CH2:37][O:38][CH:39]4[CH2:44][CH2:43][CH2:42][CH2:41][O:40]4)[CH:20]=3)[C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[CH:7]=2)[CH:56]=[N:57][CH:58]=1)=[O:69])([CH3:72])([CH3:73])[CH3:74]
Reactant: CC(C)(C)OC(=O)N(c1ccc(N2CCN(C3COC3)CC2)c(OCCOC2CCCCO2)c1)c1nc(Br)cn2ccnc12
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cncc(B2OC(C)(C)C(C)(C)O2)n1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cncc(-c2cn3ccnc3c(N(C(=O)OC(C)(C)C)c3ccc(N4CCN(C5COC5)CC4)c(OCCOC4CCCCO4)c3)n2)n1

Procedure:
tert-Butyl (6-bromoimidazo[1,2-a]pyrazin-8-yl)(4-(4-(oxetan-3-yl)piperazin-1-yl)-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)carbamate XXVI was reacted with XV according to the methods of CHEMISTRY B as described in Example 2 to provide the desired compound tert-butyl (6-(6-(bis(tert-butoxycarbonyl)amino)pyrazin-2-yl)imidazo[1,2-a]pyrazin-8-yl)(4-(4-(oxetan-3-yl)piperazin-1-yl)-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)carbamate XXVII.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].Cl.Cl[CH2:15][C:16]1[CH:20]=[CH:19][NH:18][N:17]=1.[Na]>C(O)C>[C:3]1(=[O:12])[N:2]([O:1][CH2:15][C:16]2[CH:20]=[CH:19][NH:18][N:17]=2)[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]12
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: ClCc1cc[nH]n1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1OCc1cc[nH]n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
1.96 g N-hydroxyphthalimide and 765 mg of 3-chloromethylpyrazole hydrochloride were added to a mixture of 0.28 g of sodium and 20 ml of ethanol under cooling in ice-bath and the resulting mixture was stirred for 2.5 hours at room temperature. The solvent was distilled off and water was added to the residue. The mixture was extracted with chloroform and the extract was washed with SSB and SSC and then dried with sodium sulfate. The solvent was distilled off and the residue was washed with ether to give 3-(phthalimidooxymethyl)pyrazole with mp 166°-168° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][CH2:13][OH:14])=[S:10])=[CH:4][CH:3]=1.[Br:15]Br>ClC(Cl)(Cl)Cl>[BrH:15].[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:8]=[C:9]([NH:11][CH2:12][CH2:13][OH:14])[S:10][C:6]=2[CH:7]=1
Reactant: BrBr
Reactant: OCCNC(=S)Nc1ccc(F)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: Br
Product: OCCNc1nc2ccc(F)cc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 6.4 parts of N-(4-fluorophenyl)-N'-(2-hydroxyethyl)thiourea and 80 parts of tetrachloromethane is added dropwise a solution of 4.8 parts of bromine in 40 parts of tetrachloromethane between 20° and 25° C. Upon completion, stirring is continued for 1 hour at reflux temperature. The reaction mixture is cooled to room temperature. The precipitated product is filtered off, washed with acetonitrile and dried, yielding 5.8 parts of 2-[(6-fluoro-2-benzothiazolyl)amino]ethanol monohydrobromide; mp. 163.6° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[S:10]([OH:12])=[O:11].C(N(CC)CC)C.I[CH:21]([CH3:23])[CH3:22]>CN(C=O)C>[F:9][C:6]1[CH:5]=[CH:4][C:3]([S:10]([CH:21]([CH3:23])[CH3:22])(=[O:12])=[O:11])=[C:2]([F:1])[C:7]=1[F:8]
Reactant: O=S(O)c1ccc(F)c(F)c1F
Reactant: CC(C)I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)c1ccc(F)c(F)c1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 20.4 mmol 2,3,4-trifluoro-benzenesulfinic acid (prepared in analogy to example 2.20(a) from 2,3,4-trifluoro-benzenesulfonyl chloride) and 61.2 mmol triethylamine in 20 ml DMF was added 40.8 mmol 2-iodopropane, and the mixture stirred at room temperature for 16 h. The reaction mixture was then poured onto water and extracted three times with ethyl acetate. The combined organic phases were then washed twice with saturated aq. NaCl solution, dried over Na2SO4, and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane 1:4) to afford the title compound.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][N:9]2[CH2:13][CH2:12][NH:11][C:10]2=[N:14][N+:15]([O-:17])=[O:16])=[CH:6][N:5]=1.I[CH2:21][CH2:22][CH2:23]I>CN(C=O)C>[Cl:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][N:9]2[CH2:13][CH2:12][N:11]([CH2:21][CH2:22][CH2:23][N:11]3[CH2:12][CH2:13][N:9]([CH2:8][C:7]4[CH:18]=[CH:19][C:4]([Cl:3])=[N:5][CH:6]=4)[C:10]3=[N:14][N+:15]([O-:17])=[O:16])[C:10]2=[N:14][N+:15]([O-:17])=[O:16])=[CH:6][N:5]=1
Reactant: ICCCI
Reactant: O=[N+]([O-])N=C1NCCN1Cc1ccc(Cl)nc1
Agent: O=[N+]([O-])/N=C1\NCCN1Cc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])N=C1N(CCCN2CCN(Cc3ccc(Cl)nc3)C2=N[N+](=O)[O-])CCN1Cc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (60% oil dispersion, 0.17 g, 4.25 mmol) was suspended in 10 ml of DMF. 1-(6-Chloronicotinyl)-2-nitroiminoimidazolidine (1.03 g, 4 mmol), which is commonly referred to as imidacloprid), was added to this suspension. This mixture was then stirred for 1 hour at room temperature. A solution of 1,3-diiodopropane (0.58 g, 2 mmol) in DMF (10 ml) was then added dropwise to this reaction mixture over the course of 30 minutes while cooling with ice. Following completion of dropping, the reaction mixture was stirred at room temperature for 4 hours.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[I-].C[S+](C)(C)=O.C[C:19](C)([O-:21])C.[K+]>CS(C)=O>[O:21]1[C:2]2([CH2:9][CH2:8][CH2:7][CH2:6][C:5]3([O:1][CH2:10]3)[O:4][CH2:3]2)[CH2:19]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CC(C)(C)[O-]
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: C1CCC2(CO2)OCC2(C1)CO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A dimethyl sulfoxide (40 mL) solution of 1,4-dioxaspiro[4.5]decan-8-one (6.25 g) was added dropwise to a solution of trimethylsulfoxonium iodide (8.8 g) and potassium t-butoxide (4.5 g) in dimethyl sulfoxide (50 mL). The mixture was stirred at room temperature overnight. The mixture was then poured over ice-water and extracted with diethyl ether (3×200 mL). The combined organic extracts were washed with water and brine, dried over Na2SO4, and filtered. Concentration of the filtrate gave the crude product.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:23])[CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[C:11]=1[C:12](OC)=[O:13])(=[O:9])=[O:8].[CH3:24][CH:25]([CH3:27])[O-:26].[Na+].C(O)(=O)C>C(O)(C)C>[ClH:1].[CH3:2][N:3]([CH3:23])[CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[C:11]=1[C:12]([O:26][CH:25]([CH3:27])[CH3:24])=[O:13])(=[O:9])=[O:8]
Reactant: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NCCN(C)C
Reactant: CC(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC(C)OC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NCCN(C)C
Yield: 31 %

Procedure:
A solution of methyl 2-[N-(2-dimethylaminoethyl)aminosulfonyl]-6-nitrobenzoate hydrochloride (12.0 g, 32.6 mmol) in dry isopropanol (500 mL) containing sodium isopropoxide (39 mmol) was stirred at reflux under N2 for 18 hours. After adding glacial acetic acid (1 mL) and concentrating under reduced pressure, the residue was partitioned between ethyl acetate and water. The ethyl acetate extract was washed with a saturated aqueous solution of sodium chloride, dried (Na2SO4), filtered and concentrated. The residue was converted to the hydrochloride salt with ethanolic anhydrous hydrogen chloride and recrystallized from methanol - ethyl acetate to give 4.0 g (31%) of product, m.p. 187.0-190.0° dec. Anal Calc'd for C14H21N3O6S.HCl: C, 42.47; H, 5.60; N, 10.61