Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([Cl:18])[CH:11]=2)[C:5]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][N:3]=1.[N:24]1[CH:25]=[CH:26][N:27]2[CH2:32][CH2:31][NH:30][CH2:29][C:28]=12.C(N(CC)CC)C.C(Cl)(Cl)Cl>C(OCC)(=O)C>[N:24]1[CH:25]=[CH:26][N:27]2[CH2:32][CH2:31][N:30]([C:2]3[N:7]=[C:6]([NH:8][CH2:9][C:10]4[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([Cl:18])[CH:11]=4)[C:5]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][N:3]=3)[CH2:29][C:28]=12
Reactant: CCOC(=O)c1cnc(Cl)nc1NCc1ccc(OC)c(Cl)c1
Reactant: c1cn2c(n1)CNCC2
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cnc(N2CCn3ccnc3C2)nc1NCc1ccc(OC)c(Cl)c1
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine (prepared in Example 95) 285 mg, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine 197 mg, triethylamine 0.22 ml and chloroform 3 ml is stirred at room temperature for 2,5 hours, followed by stirring at 60° C. for 2,5 hours. The mixture is diluted with ethyl acetate, and washed with water. The water layer is extracted with ethyl acetate, and the organic layer is washed with water and an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is purified with silica gel chromatography (silica gel 10 g, solvent; chloroform:methanol=50:1) and concentrated in vacuo and triturated with isopropyl ether to give 2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine as a colorless crystalline powder, 290 mg. mp 179–182° C.,
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.[CH2:16]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:39])[C@@H:28]([NH2:38])[CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:23][CH2:22]1)=[O:20])[CH3:17].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.O>[CH2:16]([O:18][C:19]([N:21]1[CH2:22][CH2:23][N:24]([C:27](=[O:39])[C@@H:28]([NH:38][C:13]([C:4]2[CH:3]=[C:2]([OH:1])[C:11]3[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=3)[N:5]=2)=[O:15])[CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:25][CH2:26]1)=[O:20])[CH3:17]
Reactant: CCOC(=O)N1CCN(C(=O)[C@@H](N)CCC(=O)OC(C)(C)C)CC1
Reactant: Cc1ccc2c(O)cc(C(=O)O)nc2c1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)c3ccc(C)cc3n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4 g of 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid and 6.7 g of 4-((S)-2-Amino-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid ethyl ester in 40 ml of DMF, 3 g of HOBT and 3.7 g of EDC was added and the reaction mixture was stirred for 2 h at RT. Then, the reaction mixture was diluted with water and extracted with DCM. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 9.4 g.
Reaction SMILES: [C:1]([CH2:3][C:4]([O-:6])=[O:5])#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.[C:20](OCC)(=O)[CH3:21]>CN(C=O)C>[CH2:20]([O:5][C:4]([C:3]1([C:1]#[N:2])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:6])[CH3:21]
Reactant: CCOC(C)=O
Reactant: BrCCCCCBr
Reactant: N#CCC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C#N)CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
To a solution of cyanoacetate (1 eq) in DMF at 0° C. was slowly added cesium carbonate (2.5 eq), followed by the slow addition of 1,5-dibromopentane. This mixture was allowed to stir for 30 minutes at 0° C. and at room temperature for two hours. The crude reaction mixture was diluted with ethyl acetate and washed three times with water, dried with anhydrous sodium sulfate, filtered, and concentrated. The compound was clean enough to continue without purification. 57% yield. 1H NMR (300 MHz, CDCl3) δ 4.25 (q, 2H), 2.12-1.68 (m, 10H), 1.31 (t, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:14])[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.O.[C:16](O[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])(OC(C)(C)C)=O.[Na+].[Cl-]>C1COCC1>[CH:6]([O:5][CH:4]([CH3:3])[CH3:16])([CH3:7])[CH3:13].[C:10]([C:9]1[CH:12]=[CH:13][C:6]([O:5][CH2:4][CH:3]([OH:14])[CH2:2][NH:1][C:24](=[O:25])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[CH:7][CH:8]=1)#[N:11]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(OCC(O)CN)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(O)COc1ccc(C#N)cc1
Product: CC(C)OC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 148.7 %

Procedure:
A cooled (0° C.) solution of 4-[(3-amino-2-hydroxypropyl)oxy]benzonitrile (from step (b) above; 44.6 g, 0.23 mol) in THF:H2O (1.5 L of 1:1) was treated with di-tert-butyl dicarbonate (53 g, 0.24 mol). The mixture was stirred at rt overnight, after which NaCl was added and the resulting organic layer separated. The water layer was extracted with ether and the combined organics were dried and concentrated in vacuo. The resulting oil (70 g) was filtered through a plug of silica, and then crystallised from diethyl ether:di-iso-propyl ether to yield 50 g of the sub-title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.C(Cl)Cl.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>Cl.O>[CH3:21][S:22]([O:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=1)(=[O:24])=[O:23]
Reactant: OCCc1ccc(F)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OCCc1ccc(F)cc1
Temperature: 2.5 °C
Yield: 102.7 %

Procedure:
A suitable reactor maintained under nitrogen was charged with 4-fluorophenethyl alcohol (2.6 kg, 18.6 mol) and 18 L of methylene chloride. The stirred solution was cooled to and maintained at 0-5° C. while triethylamine 2.85 kg (28.2 mol) was added fairly rapidly. The reaction temperature was maintained at 0-5° C. while adding methanesulfonyl chloride (2.5 kg, 21.8 mol) over 1 hour. The stirred reaction mixture was maintained at 0-5° C. for 1 hour, then it was warmed to room temperature within approximately 2 hours. The reaction mixture was diluted with a solution of 0.5 kg of 33% hydrochloric acid in 10 L of water. The organic phase was separated and washed with a solution of 0.2 kg of 33% hydrochloric acid in 5 L of water. Both acidic extracts were combined and extracted with 5 L of methylene chloride. Both organic phases were combined, washed with 2×15 L of water, then dried with sodium sulfate (2 kg). Drying agent was filtered off and washed with 2×5 L of methylene chloride. The majority of the solvent was boiled off at atmospheric pressure, with the final amount distilled off at 35° C./500 torr to give 4-fluorophenethyl alcohol methanesulfonate (4.17 kg.)
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][C@H:3]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[C:29](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CO>[CH2:21]([N:1]([CH3:29])[C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][C@H:3]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1N
Reactant: O=Cc1ccccc1
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CN(Cc1ccccc1)[C@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
To a solution of (3R,4R)-di-tert-butyl 4-aminopyrrolidine-1,3-dicarboxylate (Org. Biomol. Chem. 2004, 2, 2763-2776) (430 mg, 1.5 mmol) in dichloromethane/methanol (18 mL/2 mL) was added benzaldehyde (153 uL, 1.5 mmol) and sodium triacetoxyborohydride (1.89 g, 9.0 mmol). The mixture was stirred overnight and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried with magnesium sulfate, filtered and evaporated. The residue was purified on silica gel eluting with ethyl acetate/hexane (1:3) to give the title compound (495 mg, 88%). MS (ESI+) m/z=377 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[OH:12].[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([NH2:9])[C:3]=1[OH:12]
Reactant: Cc1cc(F)c(O)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N)c(O)c(F)c1
Yield: 75.8 %

Procedure:
A solution of 2-fluoro-4-methyl-6-nitrophenol (400 mg, 2.337 mmol) (D15) in ethanol (50 mL) was hydrogenated using a Pd/C cartridge in the H-cube™ hydrogenator at 1 mL/min and full hydrogen. Evaporation gave 2-fluoro-4-methyl-6-aminophenol (250 mg, 1.771 mmol, 76% yield) as a fawn solid.
Reaction SMILES: COC(=O)C1C(C)=CC(C2C=CC=C(C(F)(F)F)C=2)=NC=1OC.Cl[C:25]1[N:30]=[C:29]([C:31]([N:33]2[CH2:38][CH2:37][CH:36]([N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)[CH2:35][CH2:34]2)=[O:32])[C:28]([CH3:44])=[CH:27][C:26]=1[C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=1.[CH3:55][N:56]1[CH:60]=[C:59](B2OC(C)(C)C(C)(C)O2)[CH:58]=[N:57]1>>[CH3:44][C:28]1[C:29]([C:31]([N:33]2[CH2:38][CH2:37][CH:36]([N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)[CH2:35][CH2:34]2)=[O:32])=[N:30][C:25]([C:59]2[CH:58]=[N:57][N:56]([CH3:55])[CH:60]=2)=[C:26]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=2)[CH:27]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(Cl)nc1C(=O)N1CCC(N2CCCC2)CC1
Agent: COC(=O)c1c(C)cc(-c2cccc(C(F)(F)F)c2)nc1OC
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(-c2cnn(C)c2)nc1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for the preparation of intermediate 5C, [6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 3) was reacted with 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole to give the title compound as colorless solid. MS: 498.2 (MH+).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].C(C1C=CC(C)=C(O)C=1C(C)(C)C)(C)(C)C.[CH2:23]([OH:59])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][O:57][CH3:58].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:59][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][O:57][CH3:58])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)Cl
Reactant: COCCOCCOCCOCCOCCOCCOCCOCCOCCCCCCCCCCO
Agent: Cc1ccc(C(C)(C)C)c(C(C)(C)C)c1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1.87 g (0.018 mol) of methacrylyl chloride and a small amount of di-t-butylhydroxytoluene in methylene chloride are added to a solution of 8 g (0.0148 mol) of 11,14,17,20,23,26,29,32,35-Nonaoxahexatriacontan-1-ol and 1.82 g (0.018 mol) of triethylamine in 40 ml of methylene chloride at a temperature of -20° C. The mixture is stirred at room temperature for 12 hours, without cooling. The solvent is removed at room temperature and the crude product is worked up by flash chromatography over silica gel 60 (0.040-0.063 mm) using acetone/ether 50:50. The mobile phase is distilled off at room temperature and the product is obtained as a colorless liquid. 1HNMR: 1.2-1.8 ppm (m, 16H, (--CH2)8 --), 1.9 ppm (s, 1H, HO--), 3.4 ppm (s, 3H, --OCH3), 3.7 ppm (m, 34H, --(OCH2CH2)8 --O--),--(CH2)8 --CH2 --O--), 4.2 ppm (m, 2H, --COO--CH2 --CH 2 --), 5.5 ppm (s, 1H, H--CH=C(CH3)--COO--), 6.1 ppm (s, 1H, H--CH=C(CH3)--COO--). IR (film): 1700 cm-1 (C=O), 1620 cm-1 (C=C), 1110 cm-l (C--O).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[OH:9][C:10]1[CH:11]=[C:12]([C:16](=O)[CH3:17])[CH:13]=[CH:14][CH:15]=1>C(O)C.O.C(OCC)(=O)C>[OH:9][C:10]1[CH:11]=[C:12]([C:16](=[N:2][OH:3])[CH3:17])[CH:13]=[CH:14][CH:15]=1
Reactant: NO
Reactant: CC(=O)c1cccc(O)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=NO)c1cccc(O)c1
Temperature: 80 °C
Yield: 113.4 %

Procedure:
Hydroxylamine hydrochloride (1 g, 10 mmol) and sodium acetate (1 g, 10 mmol) were added to a solution of 1-(3-hydroxyphenyl)ethanone (Aldrich, Cat. #H18801) (1 g, 7 mmol) in ethanol (30 mL) and water (4 mL). The reaction was heated at 80° C. for 2 h. The reaction was allowed to cool to r.t. and taken up in ethyl acetate and washed with 1 N HCl. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give crude 1-(3-hydroxyphenyl)ethanone oxime (1.2 g, 100%) as yellow oil. Analytical LCMS (M+H)+: m/z=151.9.
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:30])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27](O)=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:50][C@H:51]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH3:52].Cl>CN(C=O)C.C(Cl)CCl>[C:56]([O:55][C:53](=[O:54])[C@@H:51]([NH:50][C:27]([C:18]1[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]2[CH2:10][CH2:11][CH2:12][C@H:8]2[C:6](=[O:7])[NH:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)=[O:30])[N:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:19]=1)=[O:28])[CH3:52])([CH3:59])([CH3:58])[CH3:57]
Reactant: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)OC(C)(C)C
Reaction time: 12 h

Procedure:
To a solution of 500 mg 5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid in 5 ml DMF were added 186 mg HOBt, 232 mg EDC, 0.50 ml DIPEA and 220 mg L-Ala-OtBu×HCl. After stirring for 12 h it was concentrated and the residue dissolved in ethyl acetate. It was extracted with aqueous LiCl (4% w/w), aqueous NaHCO3 and 0.1 M HCl. The organic layer was dried over MgSO4 and concentrated to furnish the crude coupling product as colorless oil.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:19]1CCC(N=C=NC2CCCCC2)CC1>CO>[C:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)NCCCCCCCC(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CO
Product: COC(=O)CCCCCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
BocNH(CH2)7CO2H (prepared, Example 8, Step 1) (300 mg, 1.2 mmol) was dissolved in methanol (5 mL) and DCC (239 mg, 1.2 mmol) was then added. The solution was stirred at room temperature overnight. The DCU was removed by filtration and the solvent was removed in vacuo. The residue was then taken up in EtoAc and washed with dilute HCl (200 mL×3), water (200 mL×3), and then dried over MgSO4, filtered, and the solvent was removed in vacuo to yield an oil, 0.259 g (79% yield);
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2>C(O)(=O)C.O.[Zn]>[ClH:1].[ClH:1].[N:2]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[CH:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: O=C(NC1CN2CCC1CC2)c1cc2cc([N+](=O)[O-])ccc2s1
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc2sc(C(=O)NC3CN4CCC3CC4)cc2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
129 mg (0.35 mmol) of rac-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-nitro-1-benzothiophene-2-carboxamide hydrochloride are dissolved in a mixture of 5 ml of acetic acid and 3 ml of water. 114.7 mg (1.75 mmol) of zinc are added, and the mixture is stirred at RT for 5 h. The reaction mixture is filtered through kieselguhr, the solvent is removed and the residue is taken up in dichloromethane. The resulting solution is washed with 1N aqueous sodium hydroxide solution. The organic phase is dried over sodium sulfate and the solvent is then removed under reduced pressure. The resulting solid is dissolved in a little THF, and an excess of 1N HCl in diethyl ether is added. The THF is then distilled off. 103 mg (80% of theory) of the title compound are isolated.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[OH:7][C@H:8]([CH2:21][CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[C@H:9]([CH3:20])[O:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.Br[C:30]1[S:34][C:33]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:32][CH:31]=1>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:7][C@H:8]([CH2:21][CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[C@H:9]([CH3:20])[O:10][C:11]1[CH:16]=[CH:15][C:14]([C:30]2[S:34][C:33]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:32][CH:31]=2)=[CH:13][CH:12]=1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
Reactant: NS(=O)(=O)c1ccc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: C[C@H](Oc1ccc(-c2ccc(S(N)(=O)=O)s2)cc1)[C@H](O)CCc1cccnc1
Temperature: 90 °C

Procedure:
2M Aqueous sodium carbonate (0.75 ml), (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (Example 21a)), 0.19 g), and tetrakis(triphenylphosphine)palladium(0) (0.025 g) were added to a solution of 5-bromothiophene-2-sulfonic acid amide (0.242 g) in ethanol (2 ml). The mixture was heated at 90° C. for 2 hours. The mixture was cooled to room temperature and the solvents were evaporated under reduced pressure. The reaction mixture was triturated with acetone (10 ml) and filtered through a short silica gel column. The column was eluted with acetone and the resulting filtrate evaporated to give the title compound as a solid (0.064 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1[O:11][C:12]1[CH:17]=[CH:16][C:15](B2OC(C)(C)C(C)(C)O2)=[CH:14][CH:13]=1.Br[C:28]1[C:32]2=[N:33][CH:34]=[CH:35][CH:36]=[C:31]2[N:30]([CH:37]2[CH2:40][CH2:39][CH2:38]2)[N:29]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:37]1([N:30]2[C:31]3[C:32](=[N:33][CH:34]=[CH:35][CH:36]=3)[C:28]([C:15]3[CH:14]=[CH:13][C:12]([O:11][C:3]4[N:2]([CH3:1])[C:6]5=[N:7][CH:8]=[CH:9][CH:10]=[C:5]5[N:4]=4)=[CH:17][CH:16]=3)=[N:29]2)[CH2:40][CH2:39][CH2:38]1
Reactant: Brc1nn(C2CCC2)c2cccnc12
Reactant: Cn1c(Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)nc2cccnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cn1c(Oc2ccc(-c3nn(C4CCC4)c4cccnc34)cc2)nc2cccnc21
Yield: 99.1 %

Procedure:
A mixture of 3-methyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-3H-imidazo[4,5-b]pyridine (252 mg), 3-bromo-1-cyclobutyl-1H-pyrazolo[4,3-b]pyridine (181 mg), Pd(PPh3)4 (25 mg) and Na2CO3 (266 mg) in DME (5 mL) and water (1 mL) was refluxed overnight under Ar atmosphere. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) and recrystallized from AcOEt/hexane to give the title compound (282 mg).
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]#N)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.O.[PH2]([O-])=[O:15].[Na+]>C(O)(=O)C.N1C=CC=CC=1.[Ni]>[CH3:1][C:2]1[C:10]([CH:11]=[O:15])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: O=[PH2][O-]
Reactant: Cc1c(C#N)ccc2[nH]ccc12
Agent: [Ni]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: Cc1c(C=O)ccc2[nH]ccc12

Procedure:
In analogy to the procedure described in preparation 5a), 4-methyl-1H-indole-5-carbonitrile was reacted with sodium hypophosphite monohydrate and Raney-Nickel in acetic acid/pyridine to give 4-methyl-1H-indole-5-carbaldehyde as light yellow solid.
Reaction SMILES: [CH:1](/[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[N:10]=1)=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:27]1[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[N:31][CH:32]=1.C[Sn](C)C.C[Sn](C)C>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:34][O:33][C:30]1[CH:29]=[CH:28][C:27]([C:14]2[CH:13]=[C:12]3[C:17]([C:9](/[CH:1]=[CH:2]/[C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=4)=[N:10][N:11]3[CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:23])([CH3:25])[CH3:24])=[CH:16][CH:15]=2)=[CH:32][N:31]=1
Reactant: C[Si](C)(C)CCOCn1nc(/C=C/c2ccccc2)c2ccccc21
Reactant: COc1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Sn](C)C
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc3c(/C=C/c4ccccc4)nn(COCC[Si](C)(C)C)c3c2)cn1
Yield: 40 %

Procedure:
6-(22-methoxypyridin-5-yl)-3-(((E)-styryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole was converted to 6-(2-methoxypyridin-5-yl)-3-E-styryl-1H-indazole in a similar manner to that described for Example 27(a). 1H NMR (300 MHz, CDCl3) □8.53 (d, 1H, J=2.1 Hz), 8.15 (d, 1H, J-9.2 Hz), 7.97 (dd, 1H, 1=2.6, 8.6 Hz), 7.79 (s, 1H), 7.74-7.34 (m, 8H), 6.94 (d, 1H, J=8.6 Hz). HRMS (FAB) [M+H]/z Calc'd 328.1450, found 328.1462. Anal. Calc'd, C (77.04), H (5.23), N (12.83). Found: C (77.00), H (5.28), N (12.65). The starting material was prepared as follows: A solution of 5-bromo-2-methoxypyridine (2.00 g, 6.10 mmol), hexamethylditin (1.15 g, 6.10 mmol), and Pd(PPh3)4 (0.28 g, 0.24 mmol) in degassed dioxane (10 ml) was refluxed under for 16 h. 6-Iodo-3-((E)-styryl)-1-(2-trimethylsilanylthoxymethyl)-1H-indazole (2.90 g, 6.10 mmol) was added to above mixture, followed by Pd(PPh3)4 (0.35 g 0.31 mmol). The reaction mixture was refluxed for 16 h. The mixture was then diluted with ethyl acetate (150 ml), and washed with brine (30 ml). The organics were dried over MgSO4, then concentrated under reduced pressure. Purification by silica gel chromatography gave 6-(2-methoxypyridin-5-yl)-3-((E)-styryl)-1-(2-trimethylsilanyl-ethoxymethyl)1H-indazole as a yellow solid (1.12 g, 40%). 1H NMR (300 MHz, CDCl3) δ 8.51 (d, 1H, J=2.5 Hz), 8.50 (d, 1H, J=9.1 Hz), 7.93 (dd, 1H, J=2.5, 8.6 Hz), 7.69 (s, 1H), 7.69-7.28 (m, 8H), 6.89 (d, 1H, J=8.6 Hz), 5.83 (s, 2H), 4.03 (s, 3H), 3.64 (t, 2H, J=8.3 Hz), 0.93 (t, 2H, 1=8.3 Hz), −0.03 (s, 9H).