Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-:1]#[N:2].[K+].O.[CH2:5]([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH:13]1[CH2:25]Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)C>[CH2:5]([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH:13]1[CH2:25][C:1]#[N:2])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [C-]#N
Reactant: ClCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Yield: 80 %

Procedure:
A mixture of 4.57 g (70.2 mmol) of potassium cyanide and 10 ml of water is heated to reflux. When the potassium cyanide has dissolved, 17 g (54 mmol) of the chloride obtained in Step b dissolved in 10 ml of ethanol are added slowly. When the addition is complete, the mixture is heated under reflux for 3 hours. After evaporation of the solvent, the mixture is taken up in chloroform and washed with water until the pH is neutral. The chloroform phase is dried over magnesium sulfate, filtered and evaporated off. The resulting residue is crystallised from hexane and yields 13.2 g of white crystals.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1)#[CH:12].N>>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:3]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=3)[O:1][N:2]=2)[CH:5]=1
Reactant: ON=C(Cl)c1cccnc1
Reactant: C#Cc1cccc(C)c1
Agent: N
Product: Cc1cccc(-c2cc(-c3cccnc3)no2)c1

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 1A (78 mg, 0.5 mmol) and 1-ethynyl-3-methylbenzene (Aldrich, 58 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 2.42 (s, 3H), 7.37 (d, J=7.7 Hz, 1H), 7.48 (t, J=7.6 Hz, 1H), 7.67 (ddd, J=8.0, 4.9, 0.7 Hz, 1 H), 7.74-7.84 (m, 3H), 8.38 (dt, J=7.9, 2.0 Hz, 1H), 8.76 (dd, J=4.7, 1.7 Hz, 1H), 9.15 (d, J=1.7 Hz, 1H) ppm; MS (DCI/NH3) m/z 237 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([N:7]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[CH:4]=[N:3][CH:2]=1.[F:20][C:21]([F:26])([F:25])[C:22]([O-:24])=[O:23]>>[OH:24][C:22]([C:21]([F:26])([F:25])[F:20])=[O:23].[N:7]1([C:5]2[CH:4]=[N:3][CH:2]=[N:1][CH:6]=2)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1
Reactant: O=C([O-])C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCN(c2cncnc2)CC1
Product: O=C(O)C(F)(F)F
Product: c1ncc(N2CCNCC2)cn1

Procedure:
This compound was synthesized from tert-butyl 4-(pyrimidin-5-yl)piperazine-1-carboxylate as described for example 46 step 4 (500 mg, crude) as a trifluoroacetate salt and it was carried through without further purification. MS (ESI) m/z: Calculated for C8H12N4: 164.11. found: 165.0 (M+H)+
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[C:4]([C:6]1[CH:19]=[CH:18][C:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[OH-].[Na+].[CH2:24]1[O:26][CH:25]1[CH2:27][OH:28]>O1CCOCC1.O>[CH2:20]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:19]=[CH:18][C:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:24][CH:25]([OH:26])[CH2:27][OH:28])=[CH:8][CH:7]=1)=[O:5])[CH3:21]
Reactant: CCN(CC)C(=O)c1ccc(Cc2ccccc2O)cc1
Reactant: OCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCN(CC)C(=O)c1ccc(Cc2ccccc2OCC(O)CO)cc1
Temperature: 90 °C
Reaction time: 18 h
Yield: 59 %

Procedure:
The 2-(4-diethylcarbamoylbenzyl)phenol (355 mg) obtained in Reference Example 1(d) was dissolved in a mixed solution of dioxane (3.6 ml) and water (3.6 ml), added with 1 N aqueous sodium hydroxide (63 μl) and glycidol (0.12 ml) and stirred at 90° C. for 18 hours. The reaction mixture was added with water (30 ml) and extracted twice with dichloromethane (30 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to obtain 263 mg of the title compound. Yield: 59%.
Reaction SMILES: [CH3:1]C1N(CCO)C([N+]([O-])=O)=CN=1.CCC(N1N=CN(C2C=CC(N3CCN(C4C=CC(OC[C@@H]5[O:47][C@:46]([C:54]6[CH:55]=[CH:56][C:57](Cl)=C[C:59]=6Cl)(CN6N=CN=C6)[O:45]C5)=CC=4)CC3)=CC=2)C1=O)C.CC[C@@H]1NC(=O)[C@H:104]([C@H:108]([OH:115])[C@@H:109]([CH2:111]/[CH:112]=[CH:113]/[CH3:114])[CH3:110])N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O.CCN1C(=O)C(=O)N(C(N[C@@H](C(N[C@@H]2C(=O)N3[C@@H](C(O)=O)C(C)(C)S[C@H]23)=O)C2C=CC=CC=2)=O)CC1.CO/N=C(\C(N[C@@H]1C(=O)N2C(C(O)=O)=C(COC(N)=O)CS[C@H]12)=O)/C1OC=CC=1>>[CH3:114][C:113]1[CH:112]=[CH:111][C:109]([CH3:110])=[C:108]([O:115][CH2:57][CH2:56][CH2:55][C:54]([C:46]([OH:45])=[O:47])([CH3:59])[CH3:1])[CH:104]=1
Reactant: Cc1ncc([N+](=O)[O-])n1CCO
Reactant: CCC(C)n1ncn(-c2ccc(N3CCN(c4ccc(OC[C@H]5CO[C@](Cn6cncn6)(c6ccc(Cl)cc6Cl)O5)cc4)CC3)cc2)c1=O
Reactant: C/C=C/C[C@@H](C)[C@@H](O)[C@H]1C(=O)N[C@@H](CC)C(=O)N(C)CC(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@H](C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N(C)[C@@H](C(C)C)C(=O)N1C
Agent: CCN1CCN(C(=O)N[C@@H](C(=O)N[C@@H]2C(=O)N3[C@@H]2SC(C)(C)[C@@H]3C(=O)O)c2ccccc2)C(=O)C1=O
Agent: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1ccco1
Product: Cc1ccc(C)c(OCCCC(C)(C)C(=O)O)c1

Procedure:
and finally mainly metronidazole, itraconazole, cyclosporine, piperacilline and cefuroxime.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:9])[CH:4]=[C:5]([CH3:8])[O:6][CH:7]=1.[OH-:10].[Na+].[CH2:12]=O.S(=O)(=O)(O)O>O>[OH:10][CH2:12][C:7]1[O:6][C:5]([CH3:8])=[CH:4][C:3](=[O:9])[C:2]=1[OH:1]
Reactant: [OH-]
Reactant: C=O
Reactant: Cc1cc(=O)c(O)co1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1cc(=O)c(O)c(CO)o1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-Hydroxy-2-methyl-4-pyrone, 6 g, was suspended in 25 ml of water and a pH of the suspension was adjusted to 10.5 with 50% sodium hydroxide. After 5 ml of 35% formalin was added to the suspension, the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was cooled to 5° C. and its pH was adjusted to 2.0 with 50% sulfuric acid. Then, the reaction solution was concentrated to about half and the resulting crystals were taken out by filtration and washed with a small quantity of chilled water to give 5.9 g of the title compound.
Reaction SMILES: C1(C2C(OCC3(C(F)(F)F)CCCCC3)=CC(F)=C(C=2)C(O)=O)CC1.[CH:26]1([C:29]2[C:30]([O:39][CH2:40][C:41]3([CH3:49])[CH2:46][CH2:45][C:44]([F:48])([F:47])[CH2:43][CH2:42]3)=[CH:31][C:32]([F:38])=[C:33]([CH:37]=2)[C:34](O)=[O:35])[CH2:28][CH2:27]1.CS(N)(=O)=O.[CH3:55][NH:56][S:57]([NH2:60])(=[O:59])=[O:58]>>[CH:26]1([C:29]2[C:30]([O:39][CH2:40][C:41]3([CH3:49])[CH2:46][CH2:45][C:44]([F:48])([F:47])[CH2:43][CH2:42]3)=[CH:31][C:32]([F:38])=[C:33]([CH:37]=2)[C:34]([NH:60][S:57](=[O:59])(=[O:58])[NH:56][CH3:55])=[O:35])[CH2:28][CH2:27]1
Reactant: CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)CCC(F)(F)CC1
Reactant: CNS(N)(=O)=O
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Product: CNS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC2(C)CCC(F)(F)CC2)cc1F

Procedure:
Following the procedure as described in Example 158 step 5, and making variations as required to replace 5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)cyclohexyl)methoxy)-benzoic acid with 5-cyclopropyl-4-((4,4-difluoro-1-methylcyclohexyl)methoxy)-2-fluorobenzoic acid and to replace methanesulfonamide with (methylsulfamoyl)amine, the title compound was obtained (0.13 g, 47%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.77-8.62 (m, 1H), 7.66-7.56 (m, 1H), 6.65-6.51 (m, 1H), 5.30-5.18 (m, 1H), 3.76 (s, 2H), 2.82-2.71 (m, 3H), 2.09-1.73 (m, 7H), 1.69-1.59 (m, 2H), 1.17 (s, 3H), 1.01-0.90 (m, 2H), 0.70-0.61 (m, 2H); MS (ES+) m/z 435.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.O[CH2:14][CH:15]([CH2:17]O)O.[Na+].[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.OS(O)(=O)=O.O>>[CH3:9][C:8]1[C:2]([CH3:1])=[CH:3][C:4]([N+:10]([O-:12])=[O:11])=[C:5]2[C:7]=1[CH:14]=[CH:15][CH:17]=[N:6]2
Reactant: OCC(O)CO
Reactant: Cc1cc(N)c([N+](=O)[O-])cc1C
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Solvent: O
Product: Cc1cc([N+](=O)[O-])c2ncccc2c1C
Yield: 16.5 %

Procedure:
In a similar fashion using route 10 general procedure 20, 4,5-dimethyl-2-nitroaniline (1.0 g, 6.0 mmol), glycerol (1.0 g, 11.4 mmol), 3-nitrobenzenesulfonic acid sodium salt (2.2 g, 9.6 mmol) and H2SO4/H2O (3 ml, 7:1), further reagents added over 4 days, gave the title compound (200 mg, 16%) which was used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:16][CH2:17][N:18]([C:25](=[O:26])[C:24]3[CH:28]=[CH:29][CH:30]=[C:22]([F:21])[CH:23]=3)[CH2:19][CH2:20]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2cccc(F)c2)CC1
Reaction time: 2 h
Yield: 110 %

Procedure:
1-(5-Chloro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.030 g, 0.10 mmol, from Example 47, Step 1) was combined with 3-fluorobenzoyl chloride (0.019 mL, 0.16 mmol) and triethylamine (0.043 mL, 0.31 mmol) in methylene chloride (1.0 mL) at room temperature and stirred for 2 hours. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give the desired product (45.3 mg). LCMS calculated for C22H20ClFN3O2 (M+H)+: m/z=412.1; Found: 412.1.
Reaction SMILES: [Li+].[OH-].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13](/[CH:16]=[CH:17]/[C:18]([N:20]2[CH2:25][CH2:24][CH2:23][C@@H:22]([C:26]([O:28]CC)=[O:27])[CH2:21]2)=[O:19])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].CCO>O.O1CCCC1>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH2:12][CH:13](/[CH:16]=[CH:17]/[C:18]([N:20]2[CH2:25][CH2:24][CH2:23][C@@H:22]([C:26]([OH:28])=[O:27])[CH2:21]2)=[O:19])[CH2:14][CH2:15]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)[C@@H]1CCCN(C(=O)/C=C/C2CCN(C(=O)OC(C)(C)C)CC2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(/C=C/C(=O)N2CCC[C@@H](C(=O)O)C2)CC1
Reaction time: 3 h
Yield: 74.1 %

Procedure:
A solution of LiOH (0.32 g) in H2O (20 ml) was added to a solution of ethyl (R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)-(E)-acryloyl]-3-piperidinecarboxylate (4.46 g) in tetrahydrofuran (20 ml)-EtOH (20 ml) at 0° C. The reaction mixture was stirred for 3 hours at the same condition, and the solvent was evaporated in vacuo. The residue was resolved in ethyl acetate-water, and acidified with 10% aq. KHSO4. The whole was washed with water, brine, dried over MgSO4, and evaporated in vacuo, subsequently. The residue was recrystallized from diethyl ether to give (R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)-(E)-acryloyl]-3-piperidinecarboxylic acid as a white solid (3.07 g).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[OH:11][CH:12]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][N:19]=2)[C:14](=[O:21])[N:13]1[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=1.O>N1C=CC=CC=1>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]([N:13]2[CH:12]([O:11][C:2]([O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[O:3])[C:20]3[C:15](=[N:16][CH:17]=[CH:18][N:19]=3)[C:14]2=[O:21])=[N:23][CH:24]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1ccc(N2C(=O)c3nccnc3C2O)nc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(N2C(=O)c3nccnc3C2OC(=O)Oc2ccccc2)nc1
Temperature: 20 °C
Reaction time: 3 h
Yield: 93.1 %

Procedure:
Phenyl chloroformate (16.4 g.) is run, over the course of 10 minutes, at a temperature of about 20° C., into a suspension of 5-hydroxy-6-(5-methylpyrid-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine (8.47 g.) in anhydrous pyridine (110 cc.). The reaction mixture is stirred for 3 hours at a temperature of about 20° C. and is then cooled to a temperature of about 5° C. Water (350 cc.) is then added over the course of 15 minutes. The insoluble product is filtered off, washed with water (4×50 cc.), acetonitrile (2×25 cc.) and diisopropyl ether (2×30 cc.). After drying, 6-(5-methylpyrid-2-yl)-7-oxo-5-phenoxycarbonyloxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine (11.8 g.), which melts at 176° C., is obtained.
Reaction SMILES: C1(SC([C@H:15]2[NH:18][C:17](=[O:19])[C@@H:16]2[C@H:20]([O:22][C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)=[O:24])[CH3:21])(C(OCC)=O)C)C=CC=CC=1.ClC1C=C[CH:40]=[C:39]([C:43]([O:45]O)=[O:44])C=1.[C:47]1(C)C=CC=C[CH:48]=1>ClCCl>[CH2:47]([O:45][C:43]([C:39]([N:18]1[CH2:15][CH:16]([C@H:20]([O:22][C:23]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=2)=[O:24])[CH3:21])[C:17]1=[O:19])=[CH2:40])=[O:44])[CH3:48]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccccc1
Reactant: CCOC(=O)C(C)(Sc1ccccc1)[C@H]1NC(=O)[C@@H]1[C@@H](C)OC(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: C=C(C(=O)OCC)N1CC([C@@H](C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)C1=O

Procedure:
A solution of (3S,4S)-4-(1-phenylthio-1-ethoxycarbonylethyl)- 3-(1-(R)-p-nitrobenzyloxycarbonyloxyethyl)-2-azetidinone (2.0 g) in dry dichloromethane (50 ml) was treated with m-chloroperbenzoic acid (0.69 g) for 3 hours while ice-cooling. The reaction mixture was washed successively with a saturated sodium bicarbonate solution and brine, and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo gave an oily residue which was dissolved in toluene (18 ml). The toluene solution was stirred under reflux for 1 hour and concentrated in vacuo. An oily residue was purified by silica gel chromatography to yield (3S,4S)-4-(1-ethoxycarbonylethenyl-3-(1-(R)-p-nitrobenzyloxycarbonyloxyethyl)-2-azetidinone.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)[CH3:2].OO.C(=O)([O-])[O-:12].[Na+].[Na+]>C(O)(=O)C>[CH2:1]([C:3]1[CH:4]=[N+:5]([O-:12])[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1cccnc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: CCc1ccc[n+]([O-])c1
Temperature: 80 °C

Procedure:
A mixture of 10.0 g of 3-ethylpyridine, 60 ml of acetic acid and 12 ml of 30% hydrogen peroxide solution was stirred while heating at 80° C. for 2.5 hours. To the reaction mixture, 7 ml of 30% hydrogen peroxide solution was added, and the reaction mixture was stirred while heating at 80° C. for further seven hours. The reaction mixture was cooled to room temperature, and sodium carbonate was added to the reaction mixture in small portions. The reaction mixture was filtered, and washed with ethyl acetate. The resultant filtrate was washed with a saturated aqueous solution of sodium hydrogensulfite and a saturated sodium chloride solution, dried over anhydrous water sodium carbonate. Activated carbon was added, followed by filtration through Celite™. The filtrate was concentrated under reduced pressure to give 6.0 g of 3-ethylpyridine N-oxide.
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:3]=1.[CH3:23][N:24]([CH3:44])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Sn](CCCC)(CCCC)CCCC)[N:26]=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:23][N:24]([CH3:44])[C:25]1[N:26]=[C:27]([C:2]2[C:10]3[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=3[CH:5]=[C:4]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:3]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(N(C)C)n1
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(Br)c2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(-c3cccc(N(C)C)n3)c2s1
Temperature: 100 °C
Yield: 4.3 %

Procedure:
To a solution of 1-(7-bromo-5-pyridin-3-yl-benzothiazol-2-yl)-3-ethyl-urea (0.125 g, 0.33 mmol) in DMF (5 mL) was added dimethyl-(6-tributylstannanyl-pyridin-2-yl)-amine (0.14 g, 0.33 mmol) under nitrogen atmosphere at room temperature. The reaction mixture was then degassed for half an hour followed by the addition of bis(triphenylphosphine)palladium(II) dichloride (0.023 g, 0.033 mmol). The reaction mixture was then again degassed for half an hour and heated at 100° C. for 15 h under nitrogen atmosphere. After the completion of the reaction (TLC monitoring), DMF was distilled off; water was added to the reaction mixture and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The crude residue was purified by prep HPLC to get the title compound (0.006 g, 5.0%) as off-white solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1.Cl[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:32][CH:33]([CH3:35])[CH3:34])=[C:28]([CH:31]=1)[C:29]#[N:30].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:29]([C:28]1[CH:31]=[C:24]([CH:25]=[CH:26][C:27]=1[O:32][CH:33]([CH3:35])[CH3:34])[CH2:23][O:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1)#[N:30]
Reactant: CC(C)Oc1ccc(CCl)cc1C#N
Reactant: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(COc2ccc3c(c2)cc2n3CCC2CC(=O)OC(C)(C)C)cc1C#N
Temperature: 25 °C
Reaction time: 48 h
Yield: 62.7 %

Procedure:
tert-Butyl 2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (461 mg, 1.60 mmol) was dissolved in DMF (3.0 mL) and 5-(chloromethyl)-2-isopropoxybenzonitrile (337 mg, 1.60 mmol) and cesium carbonate (533 mg, 1.60 mmol) were added. The reaction mixture was stirred at room temperature for 2 days and partitioned between ethyl acetate and water. The organics were removed and the aqueous mixture was extracted two times with ethyl acetate. The combined extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The residual oil was dissolved in methanol (10 mL) and cooled to 0° C. The precipitate was collected by filtration and triturated with 10% ethyl acetate/hexanes to provide the title compound (462 mg). LCMS m/z=461.5 [M+H]+; NMR (400 MHz, DMSO-d6) δ ppm 1.31 (d, J=6.1 Hz, 6H), 1.44 (s, 9H), 2.15-2.25 (m, 1H), 2.51-2.68 (m, 2H), 2.71-2.81 (m, 1H), 3.53-3.61 (m, 1H), 3.91-3.99 (m, 1H), 4.04-4.13 (m, 1H), 4.78 (septet, J=6.1 Hz, 1H), 5.02 (s, 2H), 5.99 (s, 1H), 6.74 (dd, J=8.7, 2.4 Hz, 1H), 7.06 (d, J=2.4 Hz, 1H), 7.18 (d, J=8.7 Hz, 1H), 7.27 (d, J=9.0 Hz, 1H), 7.70 (dd, J=8.7, 2.3 Hz, 1H), 7.76 (d, J=2.1 Hz, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH2:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)([CH3:21])[CH3:20])C(=O)OC(C)(C)C)=[N:8][CH:9]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C1COCC1>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:19]([CH3:21])([CH3:20])[CH2:18][NH:10][C:7]2[N:8]=[CH:9][C:4]([CH2:3][CH2:2][NH:1][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:5][CH:6]=2)=[CH:23][CH:24]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N(CC(C)(C)c1ccc(F)cc1)c1ccc(CCN)cn1
Solvent: C1CCOC1
Product: CC(C)(CNc1ccc(CCNS(C)(=O)=O)cn1)c1ccc(F)cc1
Reaction time: 2 h
Yield: 4 %

Procedure:
To a 20 dram vial was added tert-butyl 5-(2-aminoethyl)pyridin-2-yl(2-(4-fluorophenyl)-2-methylpropyl)carbamate (140 mg, 0.34 mmol, 1.0 equiv), TEA (87 μL, 0.67 mmol, 2.0 equiv, THF (3 mL), and methanesulfonyl chloride (29 μL, 0.37 mmol, 1.1 equiv). The reaction was stirred for 2 h and then concentrated, followed by the addition of MeOH (1 mL) and 4N HCl/dioxane (3 mL). The reaction was stirred for 1 h, concentrated, and then purified by preparative TLC (5% MeOH/CH2Cl2) to give 5 mg of N-(2-(6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridin-3-yl)ethyl)-methanesulfonamide (m/z [M+H]=366).
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[C:9]([C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[Cl:51][C:52]1[CH:64]=[CH:63][C:62]([F:65])=[CH:61][C:53]=1[O:54][CH:55]1[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]1>CN(C=O)C.O>[Cl:51][C:52]1[CH:64]=[CH:63][C:62]([F:65])=[CH:61][C:53]=1[O:54][CH:55]1[CH2:56][CH2:57][N:58]([C:16](=[O:18])[CH2:15][NH:14][C:12]([C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:11][N:10]=2)=[O:13])[CH2:59][CH2:60]1
Reactant: Fc1ccc(Cl)c(OC2CCNCC2)c1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Oc2cc(F)ccc2Cl)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 8 h
Yield: 94.3 %

Procedure:
To a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (0.038 g, 0.00013 mol) in DMF (2 mL) was added DIPEA (0.0872 g, 0.00067 mol), HOBt (0.023 g, 0.00017 mol) and EDCI.HCl (0.0325 g, 0.00017 mol) at ambient temperature. After 2 minutes 4-(2-chloro-5-fluoro-phenoxy)-piperidine hydrochloride (0.036 g, 0.0001349 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water. The resulting precipitate was isolated by filtration and dried to afford 0.056 g (91%) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-chloro-5-fluoro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 457.14 (M+1)+, 98.34%, 1H NMR (DMSO-d6): δ 13.7 (s, 1H), 8.0 (s, 1H), 7.8 (d, 2H), 7.44 (m, 2H), 7.38 (m, 1H), 7.24 (m, 1H), 7.1 (s, 1H), 6.8 (m, 1H), 4.8 (m, 1H), 4.2 (d, 2H), 3.6 (m, 2H), 3.4 (m, 2H), 1.9 (m, 2H), 1.7 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:14]1[N:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]2[C:22]([O:27][CH3:28])=[N:23][CH:24]=[CH:25][CH:26]=2)[N:15]=1>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[C:14]2[N:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]3[C:22]([O:27][CH3:28])=[N:23][CH:24]=[CH:25][CH:26]=3)[N:15]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc2cn[nH]c2c1
Reactant: COc1ncccc1Nc1ncnc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ncccc1Nc1ncnc(-n2ncc3ccc(Br)cc32)n1
Reaction time: 2 h

Procedure:
To a solution of 6-bromo-1H-indazole (172 mg, 0.87 mmol) in DMF (8 mL) was added NaH (60% in oil, 69.8 mg, 1.75 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 10 minutes before the addition of 4-chloro-N-(2-methoxypyridin-3-yl)-1,3,5-triazin-2-amine (311.18 mg, 1.31 mmol). Stirring was continued at RT for 2 hr. The reaction mixture was quenched with water and EtOAc added. The resultant precipitate was collected and further drying under vacuum gave the title compound as a beige solid; 1H NMR (250 MHz, CDCl3) δ 4.09 (3H, s), 7.05 (1H, d, J=2.28 Hz), 7.50 (1H, dd, J=8.53, 1.68 Hz), 7.62-7.70 (1H, m), 7.88-8.09 (2H, m), 8.30 (1H, d, J=0.76 Hz), 8.74 (1H, dd, J=7.77, 1.68 Hz), 8.83 (1H, s), 9.01 (1H, s); LC-MS: m/z=+397.9/399.8 (M+H)+.
Reaction SMILES: [C:1]1([CH2:10][C:11]#[N:12])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]#[N:9])[CH:2]=1>CO.[Ni]>[C:3]1([CH2:7][CH2:8][NH2:9])[CH:4]=[CH:5][CH:6]=[C:1]([CH2:10][CH2:11][NH2:12])[CH:2]=1
Reactant: N#CCc1cccc(CC#N)c1
Agent: [Ni]
Solvent: CO
Product: NCCc1cccc(CCN)c1
Reaction time: 48 h
Yield: 95.9 %

Procedure:
To a solution of 1,3-phenylenediacetonitrile (9.37 g, 60 mmol) in CH3OH (saturated with NH3,150 mL) was added Raney-Ni (ca. 20 g, previously washed with CH3OH several times) and the mixture was hydrogenated at 45 psi on a Parr apparatus for 48 h. The reaction mixture was filtered through celite and the filtrate evaporated to give the crude product (9.45 g, 96%) as a light green oil: 1H NMR (CDCl3) δ 0.80-1.50 (br s, 4H), 2.70-2.76 (m, 4H), 2.94-2.99 (m, 4H), 7.01-7.07 (m, 3H), 7.18-7.26 (m, 1H). This was used in the next step without further purification.