Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[CH3:4][S:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.[N:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[N+:15]=[N-:16]>CO.O>[CH3:21][O:20][C:18](=[O:19])[C:17]([N:14]=[N+:15]=[N-:16])=[CH:10][C:9]1[CH:12]=[CH:13][C:6]([S:5][CH3:4])=[CH:7][CH:8]=1
Reactant: COC(=O)CN=[N+]=[N-]
Reactant: CSc1ccc(C=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)C(=Cc1ccc(SC)cc1)N=[N+]=[N-]
Reaction time: 3 h
Yield: 82.2 %

Procedure:
To a solution of sodium methoxide prepared from Na metal (8.65 g, 0.38 m) in methanol(200 mL) at 0°-5° C., was added a solution of 4-(methylthio)benzaldehyde (12.6 ml, 94.7 mmol) and methyl azidoacetate (44 g, 0.382 mol) in methanol (30 mL). After stirring at the same temperature for 3 hours, the suspension was diluted with H2O (300 mL). The solids were filtered, washed with water and dried under vacuum to provide 19.4 g (82.0%) of methyl-2-azido-3-(4-methylthiophenyl)propenoate as a yellow 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.[OH-].[Na+].Cl[CH2:19][C:20]([OH:22])=[O:21]>O>[C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1)(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: O=C(O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)COc1ccc(C(=O)c2ccccc2)cc1
Temperature: 90 °C
Yield: 95 %

Procedure:
20.5 grams (103.4 mmol) of 4-hydroxybenzophenone were suspended in water and dissolved adding 3 equivalents of NaOH. The solution was heated up to 90° C. A solution of 15 grams of chloroacetic acid (1.6 eq.) in 40 mL of water was added dropwise to the reactor for 30 minutes. After that, the reactor was put on reflux at 100° C. for 14 hours or overnight. After that time the solution was cooled down to room temperature and acidified to pH 1-3. A white precipitate appeared. The solution was filtered and the solid dissolved in acetone. The acetone was filtered again and the acetone was evaporated to dryness. The product thus obtained was significantly contaminated with starting material. After crystallization in chloroform, 12 grams of a >95% (4-benzoylphenoxy)acetic acid was obtained (45% yield). FIG. 5 is the UPLC analysis of the compound after crystallization in CHCl3 at 264 nm, using the PCP_FAST method in a C18 column. This compound was used as an endcapping agent.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[CH3:14][O:15][C@@H:16]1[CH2:20][N:19]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[C@H:18]([C:31](OC)=[O:32])[CH2:17]1>C1COCC1>[F:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:31]([C@@H:18]2[CH2:17][C@H:16]([O:15][CH3:14])[CH2:20][N:19]2[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])=[O:32])=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)nc1
Reactant: COC(=O)[C@@H]1C[C@H](OC)CN1C(=O)OCc1ccccc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CO[C@H]1C[C@@H](C(=O)Nc2ccc(F)nc2)N(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
To a solution of 6-fluoropyridin-3-amine (500 mg, 4.46 mmol) in THF (15 mL) was added isopropylmagnesium chloride (2.0 M THF solution, 2.12 mL, 4.24 mmol) dropwise at 0° C. The resulting reaction mixture was stirred at room temperature for 30 min. A solution of (2S,4S)-1-benzyl 2-methyl 4-methoxypyrrolidine-1,2-dicarboxylate 18B (435 mg, 1.49 mmol) in THF (2 mL) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 4 h and quenched with methanol (3 mL). The crude product was purified by prep. HPLC to give (2S,4S)-benzyl 4-methoxy-2-(pyrazin-2-ylcarbamoyl)pyrrolidine-1-carboxylate 62A (424 mg, 80%) as an oil. LC/MS [M+H-Boc]+: 240; Ret time (Method F): 2.43 min.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[O:18][C@H:17]([CH2:19][O:20]C(=O)C)[C@@H:12]([O:13]C(=O)C)[C@H:7]([O:8]C(=O)C)[C@H:6]1[F:24])(=O)C>CO>[F:24][C@@H:6]1[C@@H:7]([OH:8])[C@H:12]([OH:13])[C@@H:17]([CH2:19][OH:20])[O:18][CH:5]1[O:4][CH3:1]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](F)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CO
Product: COC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1F
Temperature: 80 °C
Reaction time: 12 h
Yield: 44.9 %

Procedure:
1,3,4,6-tetra-O-Acetyl-2-deoxy-2-fluoro-β-D-glucopyranose (Carbohydr. Res., 153, 1986, 168-170) (13.4 g, 38.3 mmol) was dissolved in methanol (150 mL) and Dowex 50w×8 (19 g) was added thereto, followed by stirring of the mixture at 80° C. for 12 hours. The reaction mixture was subjected to celite filtration and the filtered product was washed with methanol. The filtrate and the washing liquid were combined and distilled off under reduced pressure. The residue was purified using silica gel flash column chromatography (methylene chloride:methanol, 10:1-5:1, V/V) to obtain the desired title compound (3.37 g, yield 45%) as a colorless solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([O:13]CC)=[O:12])[C:2]=1[C:16]([O:18]CC)=[O:17].[OH-].[Na+]>C(O)C.O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=[O:12])[C:2]=1[C:16]([OH:18])=[O:17]
Reactant: CCOC(=O)c1cc2ccccc2nc1C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc2ccccc2nc1C(=O)O

Procedure:
To a solution of diethyl 2,3-quinolinedicarboxylate (0.162 mol) in ethanol (150 ml) is added a solution of sodium hydroxide (0.50 mol) in water (400 ml). The mixture is heated at reflux for 5 hours, and the ethanol then removed by distillation at atmospheric pressure. The solution is cooled in an ice bath, diluted with water (100 ml), and acidified with concentrated hydrochloric acid, added in small increments. The precipitate is filtered, washed with water, and air dried to afford the desired 2,3-quinolinedicarboxylic acid as the trihydrate; mp 271°-277° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([S:25][CH2:26][CH2:27][CH2:28]O)=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1.C1(C)C(S([Cl:39])(=O)=O)=CC=CC=1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[Cl:39][CH2:28][CH2:27][CH2:26][S:25][C:21]1[CH:20]=[C:19]2[C:24]([C:15]([C:8]3[C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[N:11][N:10]4[CH2:12][CH2:13][CH2:14][C:9]=34)=[CH:16][CH:17]=[N:18]2)=[CH:23][CH:22]=1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: OCCCSc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: ClCCCSc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of Preparation #21, 3-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-ylsulfanyl]-propan-1-ol (25.0 mg, 0.062 mmol) in dry pyridine (0.1 mL) is added toluene sulfonyl chloride (60.0 mg, 0.31 mmol) and the resulting mixture stirred at room temperature for 72 h. Saturated sodium bicarbonate solution is added and the resulting solution extracted with ethyl acetate. The organic layer is washed with brine, dried (sodium sulfate), filtered, and concentrated in vacuo. Purification of the residue on SiO2 (5% to 10% methanol in dichloromethane) gives the desired product, 11.2 mg (43%). MS ES+ m/e 421.1 (M+1).
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:18]=[CH:17][C:16]3[O:15][CH2:14][CH2:13][N:12]4[CH:19]=[C:20]([C:22]5[N:26]([CH:27]([CH3:29])[CH3:28])[N:25]=[CH:24][N:23]=5)[N:21]=[C:11]4[C:10]=3[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C[O:31]CCOC.Cl>>[CH:27]([N:26]1[C:22]([C:20]2[N:21]=[C:11]3[C:10]4[CH:9]=[C:8]([C:7]5[C:2](=[O:31])[NH:3][CH:4]=[CH:5][CH:6]=5)[N:18]=[CH:17][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:19]=2)=[N:23][CH:24]=[N:25]1)([CH3:29])[CH3:28]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(-c3cccnc3F)ncc1OCC2
Reactant: COCCOC
Agent: Cl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(-c3ccc[nH]c3=O)ncc1OCC2
Temperature: 80 °C

Procedure:
To a solution of 10-(2-fluoropyridin-3-yl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine (0.087 g, 0.22 mmol) in 1,2-Dimethoxyethane (3.00 mL, 28.9 mmol) was added 10% aqueous HCl (3 mL). The reaction was allowed to stir and heat at 80° C. overnight. The reaction was allowed to cool to room temperature and concentrated under reduced pressure to give 269, analyzed by rHPLC. MS: (ESI+)=390.2. 1H NMR (500 MHz, DMSO) δ 9.76 (s, 1H), 8.45-8.39 (m, 2H), 8.04 (s, 1H), 7.93 (s, 1H), 7.47 (dd, J=6.1, 2.1 Hz, 1H), 6.37 (t, J=6.7 Hz, 1H), 5.91 (dt, J=13.3, 6.7 Hz, 2H), 5.91 (dt, J=13.3, 6.7 Hz, 1H), 4.61 (dd, J=13.1, 5.5 Hz, 4H), 1.52 (d, J=6.6 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9](/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:4]=1[C:5]([O:7][CH3:8])=[O:6].[Br:23]Br>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([Br:23])=[C:9](/[CH:15]=[CH:16]/[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(/C=C/c2ccccc2)cc(OC)cc1OC
Reactant: BrBr
Solvent: ClCCl
Product: COC(=O)c1c(OC)cc(OC)c(Br)c1/C=C/c1ccccc1
Yield: 87 %

Procedure:
Dissolve compound 6 (13.0 g, 0.046 mol) CH2Cl2 (150 ml), add bromine (8.1 g, 0.050 mol) dropwise at room temperature, react at room temperature for 1 h, after completion of the reaction, wash the organic layer successively with water, saturated NaHCO3 solution and brine, dry the organic solution over anhydrous MgSO4. Filter the solution and evaporate the solvent, redissolve the residue, feed the solution to a silica gel column, evaporate the solvent in the eluent to obtain a white solid (15.1 g, 87%). 1H NMR (400 MHz, CDCl3): 3.80 (s, 3H), 3.86 (s, 3H), 3.93 (s, 3H), 639 (d, J=15.6 Hz, 1H), 6.50 (s, 1H), 70 (d, J=15.6 Hz, 1H), 7.29 (t, J=7.6 Hz, 1H), 7.37 (t, J=7.6 Hz, 2H), 7.49 (d, J=7.6 Hz, 2H).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:30]=[CH:29][C:9]([O:10][C:11]2[C:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:13][N:14]([CH3:22])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:8][CH:7]=1.[ClH:31]>O>[Cl:31][C:6]1[CH:30]=[CH:29][C:9]([O:10][C:11]2[C:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:13][N:14]([CH3:22])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:8][CH:7]=1
Reactant: Cl
Reactant: Cn1nc(-c2ccccc2)c(Oc2ccc(N)cc2)c1-c1ccccc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cn1nc(-c2ccccc2)c(Oc2ccc(Cl)cc2)c1-c1ccccc1

Procedure:
A solution of sodium nitrite (3.1 g, 0.0442 mole) in water (10 ml) is added slowly at 0° C. to 5° C. to a well stirred, chilled solution of 4-(p-aminophenoxy)-1-methyl-3,5-diphenylpyrazole (15.1 g, 0.0442 mole) in concentrated hydrochloric acid (50 ml).
Reaction SMILES: [BH4-].[Na+].[CH:3]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[O:20][C@@H:21]3[CH2:26][C@H:25]([CH2:27][O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C@@H:24]([O:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C@H:23]([O:44][CH2:45][C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[C@H:22]3[O:52][CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[O:13])=[CH:8][CH:7]=2)[CH2:5][CH2:4]1.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>C1COCC1.O>[CH:3]1([C:6]2[CH:7]=[CH:8][C:9]([CH:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[O:20][C@@H:21]3[CH2:26][C@H:25]([CH2:27][O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C@@H:24]([O:36][CH2:37][C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[C@H:23]([O:44][CH2:45][C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[C@H:22]3[O:52][CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[OH:13])=[CH:10][CH:11]=2)[CH2:5][CH2:4]1
Reactant: O=C(c1ccc(C2CC2)cc1)c1ccncc1O[C@@H]1C[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [BH4-]
Solvent: O
Solvent: C1CCOC1
Product: OC(c1ccc(C2CC2)cc1)c1ccncc1O[C@@H]1C[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 14.5 h
Yield: 101 %

Procedure:
Sodium borohydride (40 mg, 1.06 mmol) was added to a solution of (4-cyclo-propylphenyl)-[3-((1R,2S,3S,4R,5R)-2,3,4-trisbenzyloxy-5-benzyloxymethylcyclohexyloxy)pyridin-4-yl]methanone (0.20 g, 0.26 mmol) in THF (1.37 mL) and water (0.67 mL) under cooling with ice and the reaction mixture was stirred at room temperature for 14.5 hours. To the reaction mixture, THF was added, and concentrated sulfuric acid (0.2 mL) was added thereto under cooling with ice and the reaction mixture was stirred for 10 minutes. To the obtained reaction mixture was added a saturated sodium hydrogencarbonate aqueous solution and the mixture was stirred at room temperature for 10 minutes. The resulting mixture was extracted with ethyl acetate and the organic layer was dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (3:2)] to obtain the title product (0.20 g, 100%) as a diastereomeric mixture.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C1COCC1.[Li]C(C)(C)C.Br[C:19]1[S:23][C:22]([C:24]2[N:28]3[N:29]=[C:30]([CH3:38])[CH:31]=[C:32]([CH:33]([CH2:36][CH3:37])[CH2:34][CH3:35])[C:27]3=[N:26][C:25]=2[CH3:39])=[C:21]([C:40]#[N:41])[CH:20]=1>CCOC(C)=O.[Cl-].[Cl-].[Zn+2].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>[CH2:34]([CH:33]([C:32]1[C:27]2[N:28]([C:24]([C:22]3[S:23][C:19]([C:2]4[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=4)=[CH:20][C:21]=3[C:40]#[N:41])=[C:25]([CH3:39])[N:26]=2)[N:29]=[C:30]([CH3:38])[CH:31]=1)[CH2:36][CH3:37])[CH3:35]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3C#N)c(C)nc12
Reactant: Ic1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4cccnc4)cc3C#N)c(C)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
To a −78° C. solution of 3-iodo-pyridine (0.32 g, 1.56 mmol), 0.5 M ZnCl2 in THF (3.20 mL, 1.59 mmol), and THF (2 mL) is added 1.7 M t-BuLi (1.85 mL, 3.15 mmol). The solution is warmed to ambient temperature and stirred for 30 minutes. 5-Bromo-2-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-thiophene-3-carbonitrile (0.21 g, 0.52 mmol) and Pd(PPh3)4 (0.03 g, 0.026 mmol) are added and the solution heated at 55° C. for 1 hour, cooled to ambient temperature and stirred overnight, diluted with EtOAc (50 mL), washed with sat. NH4Cl (2×40 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (15%-40% EtOAc/hexane gradient), furnish the title compound (0.15 g, 0.37 mmol, 71%). 1H NMR (CDCl3) δ 0.87 (t, J=7.5 Hz, 6H), 1.74-1.92 (m, 4H), 2.58 (s, 3H), 2.66 (s, 3H), 3.26-3.35 (m, 1H), 6.78 (s, 1H), 7.34-7.46 (m, 1H), 7.56 (s 1H), 7.91 (d, J=7.1 Hz, 1H), 8.62 (s, 1H), 8.91 (s, 1H). LC/MS (m/z): calcd. for C23H23N5S (M+H)+: 402.6; found: 402.4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].[CH:23](I)([CH3:25])[CH3:24]>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:23]([CH3:25])[CH3:24])[CH2:10][C@@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)I
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)N1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)O)C1
Reaction time: 1 h

Procedure:
To (2R)-1-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (4.5 g) and Na2CO3 (8.32 g) was added dry EtOH (135 ml) and isopropyl iodide (2.16 ml) and the mixture heated at reflux for 18 hours under argon. The solvent was then removed under reduced pressure, 5% MeOH/DCM (50 ml) added, the mixture stirred for 1 hour in a stoppered flask, filtered and washed through with DCM (2×10 ml). The filtrate was applied directly to a 120 g-silica Redisep® cartridge and purified using 10-70% MeOH/DCM. After evaporation, the product was isolated as a white foam (4.50 g), which was used without further purification.
Reaction SMILES: [BH4-].[Li+].[CH2:3]([C:5]([NH:27][C:28](OC)=[O:29])([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)[C:6]([O:8]CC)=O)[CH3:4].Cl.C(OCC)(=O)C>O1CCCC1>[CH2:3]([C:5]1([CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:18]=2)[CH2:6][O:8][C:28](=[O:29])[NH:27]1)[CH3:4]
Reactant: CCOC(=O)C(CC)(CCc1ccc(OCc2ccccc2)cc1)NC(=O)OC
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC1(CCc2ccc(OCc3ccccc3)cc2)COC(=O)N1
Reaction time: 2.5 h
Yield: 46.6 %

Procedure:
Lithium borohydride (3.2 g) was added to a solution of ethyl 2-ethyl-2-methoxycarbonylamino-4-(4-benzyloxyphenyl)butanoate (29 g) in tetrahydrofuran (370 ml) and the mixture was refluxed under heating for 5 hours. 2 M Hydrochloric acid (40 ml) was added to the reaction mixture and the mixture was stirred for 2.5 hours. Ethyl acetate was added to the reaction mixture, the mixture was washed with water and a saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure. Treatment of the residue with hexane and ethyl acetate gave the subject compound (11 g). Then, the mother liquid was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane=1:2) to give the subject compound (11 g).
Reaction SMILES: [OH-:1].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[N:13]=[C:12]3[CH:24]=[O:25])[CH:4]=1>O.O1CCOCC1.[N+]([O-])([O-])=O.[Ag+]>[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[N:13]=[C:12]3[C:24]([OH:1])=[O:25])[CH:4]=1
Reactant: [OH-]
Reactant: O=Cc1nn(C2CCCCO2)c2ccc(-c3cccnc3)cc12
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1nn(C2CCCCO2)c2ccc(-c3cccnc3)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.5 %

Procedure:
To a solution of silver nitrate (0.55 g, 3.25 mmol) in water (10 mL) was added a solution of sodium hydroxide (0.26 g, 6.50 mmol) in water (5 mL) to give a brown precipitate. 5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (CXXXII) (0.40 g, 1.30 mmol) dissolved in 1,4-dioxane (3 mL) was added to the reaction which was stirred at room temperature for 2 h. The reaction was then extracted with diethyl ether. The aqueous layer was separated and carefully brought to pH=3 with 10% aqueous HCl. The aqueous layer was then extracted five times with iPrOH/chloroform (1/9). The combined organic layers were then dried (MgSO4) and concentrated to afford 5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylic acid (CXXXIII) (0.30 g, 0.93 mmol, 70% yield) as a white solid. 1H NMR (DMSO-d6) δ ppm 13.28 (br, 1H), 8.93 (s, 1H), 8.60 (d, J=4.1 Hz, 1H), 8.32 (d, J=0.83 Hz, 1H), 8.14-8.12 (m, 1H), 8.00 (d, J=8.8 Hz, 1H), 7.86 (dd, J=8.8, 1.7 Hz, 1H), 7.52 (dd, J=7.8, 4.7 Hz, 1H), 6.04 (dd, J=9.3, 2.3 Hz, 1H), 3.92-3.90 (m, 1H), 3.83-3.78 (m, 1H), 2.44-2.37 (m, 1H), 2.08-2.02 (m, 2H), 1.79-1.76 (m, 1H), 1.63-1.61 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][CH2:7][C:8]([C:10]1[CH:14]=[CH:13][S:12][CH:11]=1)=[O:9])=[O:5].[H-].[Na+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][CH:7]([C:8]([C:10]1[CH:14]=[CH:13][S:12][CH:11]=1)=[O:9])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:5]
Reactant: O=C(CNC(=O)c1ccccc1Cl)c1ccsc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(NC(=O)c1ccccc1Cl)C(=O)c1ccsc1
Yield: 97.3 %

Procedure:
11.0 g of N-(2-chlorobenzoyl)-N-[(3-thienylcarbonyl)methyl]amine, 2.17 g of 50% sodium hydride and 7.9 g of ethyl bromoacetate are treated in the same manner as described in Preparation 1-(4). 14 g of ethyl 3-(2-chlorobenzoylamino)-3-(3-thienylcarbonyl)propionate are thereby obtained as an oil. Yield: 97.2%
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([Cl:16])=[CH:14][N:13]=[C:12]([NH:17][CH:18]([CH2:21][OH:22])[CH2:19][CH3:20])[N:11]=2)=[CH:6][CH:5]=1.O.[OH-].[Li+]>C1COCC1.O.Cl>[Cl:16][C:15]1[C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:23])=[O:2])=[CH:5][CH:6]=2)=[N:11][C:12]([NH:17][CH:18]([CH2:21][OH:22])[CH2:19][CH3:20])=[N:13][CH:14]=1
Reactant: CCC(CO)Nc1ncc(Cl)c(-c2ccc(C(=O)OC)cc2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCC(CO)Nc1ncc(Cl)c(-c2ccc(C(=O)O)cc2)n1
Reaction time: 72 h

Procedure:
4-[5-Chloro-2-(1-hydroxymethylpropylamino)-pyrimidin-4-yl]-benzoic acid methyl ester (68 mg, 0.20 mmol) was dissolved in 4 mL THF. To this solution 41 mg of lithium hydroxide monohydrate in 2 mL water was added and the reaction mixture stirred for 3 days. The reaction mixture was diluted with 1N HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to afford 4-[5chloro-2-(1-hydroxymethylpropylamino)-pyrimidin-4-yl]-benzoic acid as a yellow solid, 64 mg, 0.20 mmol. LCMS ES+=322.1.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([C:10]3[CH:11]=[C:12]([CH2:16][OH:17])[CH:13]=[CH:14][CH:15]=3)=[CH:6][N:5]2[CH:18]=1.[N:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21](B(O)O)[CH:20]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]([C:2]2[N:3]=[C:4]3[CH:9]=[CH:8][C:7]([C:10]4[CH:11]=[C:12]([CH2:16][OH:17])[CH:13]=[CH:14][CH:15]=4)=[CH:6][N:5]3[CH:18]=2)[CH:20]=1
Reactant: OB(O)c1cnc2ccccc2c1
Reactant: OCc1cccc(-c2ccc3nc(Cl)cn3c2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: OCc1cccc(-c2ccc3nc(-c4cnc5ccccc5c4)cn3c2)c1
Reaction time: 16 h
Yield: 12 %

Procedure:
In a screw reactor, 550 mg of [3-(2-chloroimidazo[1,2-a]pyridin-6-yl)phenyl]methanol, 550 mg of 3-quinolineboronic acid, 20 mg of palladium acetate, 70 mg of 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl and 900 mg of K3PO4 are placed in 8 ml of anhydrous toluene. The reactor is closed and heating is carried out at 115° C. for 16 h. After cooling, the reaction mixture is filtered through celite and rinsed with dichloromethane. The organic phase is washed with a saturated solution of NaCl, and then separated, dried and concentrated under reduced pressure. The residue is purified by silica gel chromatography, elution being carried out with a dichloromethane/methanol mixture. 90 mg of compound are obtained.
Reaction SMILES: [F:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:10][C:9]2[NH:8][CH:7]=[C:6]3[C:18](=[O:27])[N:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:20]=[C:5]3[C:4]=2[CH:3]=1.F[C:29]1C(F)=CC2C3C(C(=O)N(C4C=CC=CC=4)N=3)=CNC=2C=1.N1CCCNCC1>>[F:1][C:2]1[C:11]([N:12]2[CH2:13][CH2:14][CH2:29][NH:15][CH2:16][CH2:17]2)=[CH:10][C:9]2[NH:8][CH:7]=[C:6]3[C:18](=[O:27])[N:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:20]=[C:5]3[C:4]=2[CH:3]=1
Reactant: O=c1c2c[nH]c3cc(N4CCNCC4)c(F)cc3c-2nn1-c1ccccc1
Reactant: O=c1c2c[nH]c3cc(F)c(F)cc3c-2nn1-c1ccccc1
Agent: C1CNCCNC1
Product: O=c1c2c[nH]c3cc(N4CCCNCC4)c(F)cc3c-2nn1-c1ccccc1

Procedure:
The title compound was prepared following the procedure described in the synthesis of 28a using 27a and homopiperazine. 1H-NMR (DMSO-d6) δ (ppm): 1.98 (2H, brm), 2.48 (2H, brm), 2.67 (2H, brm), 3.45 (4H, brm), 7.15 (2H, m), 7.40 (2H, m), 7.76 (1H, d, J=2.91 Hz), 8.20 (2H, m), 8.64 (1H, s). m/z 378.2 (MH+).