Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([OH:16])=O)=[C:12]([CH3:17])[N:11]=[CH:10][CH:9]=2)=[C:4]([F:18])[CH:3]=1.S(Cl)(Cl)=O.[CH3:23][O:24][CH2:25][CH2:26][NH2:27].C(N(CC)CC)C>C(Cl)Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([NH:27][CH2:26][CH2:25][O:24][CH3:23])=[O:16])=[C:12]([CH3:17])[N:11]=[CH:10][CH:9]=2)=[C:4]([F:18])[CH:3]=1
Reactant: COCCN
Reactant: Cc1nccc(-c2ccc(Cl)cc2F)c1C(=O)O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: O
Product: COCCNC(=O)c1c(-c2ccc(Cl)cc2F)ccnc1C
Temperature: 70 °C
Reaction time: 4 h
Yield: 55.5 %

Procedure:
A solution of 4-(4-chloro-2-fluorophenyl)-2-methylnicotinic acid (2 g, 5.19 mmol), prepared as described in Example 16, Part E, in thionyl chloride (5 mL, 68.5 mmol) was heated at 70° C. for 2 h. After cooling, the volatiles were removed under reduced pressure. The residue was dissolved in 4 mL of anhydrous DCM and added to a pre-cooled solution of 2-methoxyethanamine (0.390 g, 5.19 mmol) and triethyl amine (3.62 mL, 26.0 mmol) in DCM (8 mL) at 0° C. The resulting reaction mixture was stirred at rt for 4 h. Water (30 mL) was then added and the solution was extracted with DCM (2×20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulphate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of EtOAc and hexane as eluant to yield 4-(4-chloro-2-fluorophenyl)-N-(2-methoxyethyl)-2-methylnicotinamide (1.3 g, 2.88 mmol, 56% yield) as a yellow oil. LC/MS (ESI) m/e 323.1 [(M+H)+, calcd for C16H17ClFN2O2 323.1]; LC/MS retention time (method D): tR=0.61 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[NH:7][C:6]=2[CH:15]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:26][C:25]=2[O:36][CH3:37])[C:20]([Cl:38])=[CH:19][N:18]=1>>[Cl:38][C:20]1[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)=[CH:26][C:25]=2[O:36][CH3:37])=[N:22][C:17]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[NH:7][C:6]=3[CH:15]=2)=[N:18][CH:19]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)CCC(=O)Nc2cc(N)ccc21
Product: COc1cc(N2CCOCC2)ccc1Nc1nc(Nc2ccc3c(c2)NC(=O)CCC3(C)C)ncc1Cl

Procedure:
Title compound was prepared from 8-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine in an analogous manner to Example 1221d. The product was isolated as a bright yellow solid (160 mg, 84%): MP 232-235, HPLC purity 95%, LCMS 524 (M+H), HMNR (CDCl3): 10.68 (s, 1H), 8.21 (s, 1H), 7.90 d, J=8.1 Hz, 1H), 7.82 (s, 1H), 7.49 (s, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.15 (d, J=8.4 Hz, 1H) 6.99 (s, 1H), 6.61 (s, 1H), 6.52 (d, J=9.0 Hz, 1H), 3.94 (m, 7H), 3.30 (m, 4H), 2.41 (t, J=7.0 Hz, 2H), 2.12 (t, J=7.2 Hz, 2H), 1.42 (s, 6H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[CH2:32][NH2:33]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:33][CH2:32][CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31][NH:26]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NCC1CCCCN1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3CCCCN3)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 1-(piperidin-2-yl)methanamine. MS obsd. (ESI+) [(M+H)+] 451, 1H NMR (400 MHz, CD3OD) δ ppm 8.07 (d, J=7.6 Hz, 1 H), 7.93 (s, 1 H), 7.85 (d, J=7.6 Hz, 1 H), 7.73-7.70 (m, 2 H), 7.62-7.58 (m, 2 H), 6.02 (s, 1 H), 5.35 (s, 2 H), 4.51 (s, 2 H), 3.75-3.71 (m, 4 H), 3.51-3.40 (m, 2 H), 2.98-2.92 (m, 1 H), 2.46 (s, 3 H), 2.11-2.05 (m, 1 H), 1.96-1.90 (m, 2 H), 1.78-1.56 (m, 3 H).
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][O:18][Si](C(C)(C)C)(C)C)=[CH:13][C:12]=1[CH2:26][O:27][C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>C(OCC)(=O)C>[C:1]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][C:12]=1[CH2:26][O:27][C:28](=[O:35])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(COC(=O)c2ccccc2)c(COC(=O)c2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CCOC(C)=O
Product: O=C(OCc1ccc(CO)cc1COC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
69 g (140 mmol) of 2-benzoyloxymethyl-4-(tert-butyldimethylsilanyloxymethyl)benzyl benzoate are placed in 450 ml of ethyl acetate in a round-bottomed flask and under a stream of nitrogen. 178 ml of tetrabutylammonium fluoride (1M/THF) are added. The medium is stirred for 30 minutes at room temperature. It is then poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and then evaporated. The residue is purified by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (40/60) to give 46.6 g (88%) of the expected product in the form of a white powder with a melting point of 92° C.
Reaction SMILES: [CH2:1]([S:3][CH:4](SCC)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:2].O.C(S)C>P(=O)(O)(O)O.CCOCC>[CH2:1]([S:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:2]
Reactant: CCCCCCC(SCC)SCC
Agent: O=P(O)(O)O
Solvent: CCOCC
Solvent: CCS
Solvent: O
Product: CCCCCC=CSCC
Yield: 1.8 %

Procedure:
A mixture of 1,1-di(ethylthio)-heptane (54.5 g., 10.25 mole) and 10 drops of 89% phosphoric acid is heated in a Claisen flask at a pressure of 200-250 mm. Care is taken that the vapor temperature does not exceed 165°. The receiver is cooled with water so that ethanethiol does not condense. The distillate is diluted with ether and washed with 2 N sodium hydroxide and water and dried. Distillation (87°-90°/12 mm.) afforded 1-ethylthio-1-heptene (30 g., 78%), nD20 1.4760.
Reaction SMILES: [N+](C(C1C=CC2C(=CC=C(O[C@H]3CC[C@H](C(F)(F)F)CC3)C=2)C=1)(C)CCC(O)=O)([O-])=O.C[O:33][C:34](=[O:67])[CH2:35][CH2:36][C:37]([N+:64]([O-:66])=[O:65])([C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[C:44]([O:53][C@H:54]3[CH2:59][CH2:58][C@H:57]([C:60]([F:63])([F:62])[F:61])[CH2:56][CH2:55]3)[C:45]=2[C:49]([F:52])([F:51])[F:50])[CH:40]=1)[CH3:38]>>[N+:64]([C:37]([C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[C:44]([O:53][C@H:54]3[CH2:55][CH2:56][C@H:57]([C:60]([F:61])([F:62])[F:63])[CH2:58][CH2:59]3)[C:45]=2[C:49]([F:50])([F:51])[F:52])[CH:40]=1)([CH3:38])[CH2:36][CH2:35][C:34]([OH:67])=[O:33])([O-:66])=[O:65]
Reactant: COC(=O)CCC(C)(c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(F)(F)F)CC3)ccc2c1)[N+](=O)[O-]
Agent: CC(CCC(=O)O)(c1ccc2cc(O[C@H]3CC[C@H](C(F)(F)F)CC3)ccc2c1)[N+](=O)[O-]
Product: CC(CCC(=O)O)(c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(F)(F)F)CC3)ccc2c1)[N+](=O)[O-]

Procedure:
4-Nitro-4-[5-trifluoromethyl-6-(trans-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-pentanoic acid was synthesized as per 4-nitro-4-[6-(trans-4-trifluoromethylcyclohexyloxy)-naphthalen-2-yl]-pentanoic acid (Example 280) in 93% yield, using 4-nitro-4-[5-trifluoromethyl-6-(trans-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-pentanoic acid methyl ester as starting material.
Reaction SMILES: COCN1C2C=C(C(=O)CC(=O)C)C=CC=2SC2N=CC=NC1=2.NO.COC[N:29]1[C:34]2[CH:35]=[C:36]([C:39]3[C:40]([CH3:44])=[N:41][O:42][CH:43]=3)[CH:37]=[CH:38][C:33]=2[S:32][C:31]2[N:45]=[CH:46][CH:47]=[N:48][C:30]1=2>>[N:48]1[C:30]2[NH:29][C:34]3[CH:35]=[C:36]([C:39]4[C:40]([CH3:44])=[N:41][O:42][CH:43]=4)[CH:37]=[CH:38][C:33]=3[S:32][C:31]=2[N:45]=[CH:46][CH:47]=1
Reactant: COCN1c2cc(-c3conc3C)ccc2Sc2nccnc21
Agent: COCN1c2cc(C(=O)CC(C)=O)ccc2Sc2nccnc21
Agent: NO
Product: Cc1nocc1-c1ccc2c(c1)Nc1nccnc1S2

Procedure:
Similar to Example 1223, 1-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-1,3-butanedione was treated with hydroxylamine to thereby give (10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-3-methylisoxazole. Further, this product was treated by the same method as the one of Example 9 to thereby give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.[H-].[Na+].[CH2:13](Br)[CH:14]=[CH2:15].C(OCC=C)C=C.C1(C)C=C(C)C=C(C)C=1>>[CH2:15]([C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]([O:9][CH3:10])[C:5]=1[OH:8])[CH:14]=[CH2:13]
Reactant: C=CCBr
Reactant: COc1cc(Cl)ccc1O
Agent: C=CCOCC=C
Agent: [H-]
Agent: [Na+]
Solvent: Cc1cc(C)cc(C)c1
Product: C=CCc1cc(Cl)cc(OC)c1O

Procedure:
Treatment of 4-chloro-2-methoxyphenol (30.0 g, 0.19 mol) with sodium hydride (9.1 g, 0.23 mol, 60 wt. %) and allyl bromide (27.46 g, 0.23 mol) followed by treatment of the resultant allyl ether in refluxing mesitylene generally according to the procedure described for Intermediate 8 gave 2-allyl-4-chloro-6-methoxyphenol as a yellow oil. Treatment of 2-allyl-4-chloro-6-methoxyphenol with sodium hydride (7.08 g, 0.177 mol, 60 wt. %) and benzyl bromide (30.27 g, 0.177 mol) generally according to the procedure described for Intermediate 13 provided 1-allyl-2-(benzyloxy)-5-chloro-3-methoxybenzene as a pale yellow oil. Treatment of the olefin (35.5 g, 0.123 mol) of with AD-mix-α (132.0 g) generally according to the procedure described for Intermediate 2 gave 35 g (54%) of (±)-3-[2-(benzyloxy)-5-chloro-3-methoxyphenyl]propane-1,2-diol as a white solid. mp. 65-68° C. Anal. calcd. for C17H19ClO4: C, 63.26; H, 5.93. Found: C, 65.29; H, 6.23.
Reaction SMILES: [F:1][CH:2]([F:44])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][N:17]([S:20]([CH3:23])(=[O:22])=[O:21])[CH2:16][CH2:15]3)[N:11]=[C:10]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:9]=2)[C:6]2[CH:30]=[C:31]([NH:36]C(=O)OC(C)(C)C)[CH:32]=[C:33]([O:34][CH3:35])[C:5]=2[N:4]=1.C(O)(C(F)(F)F)=O.N>C(Cl)Cl.O>[F:44][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][N:17]([S:20]([CH3:23])(=[O:21])=[O:22])[CH2:18][CH2:19]3)[N:11]=[C:10]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:9]=2)[C:6]2[CH:30]=[C:31]([NH2:36])[CH:32]=[C:33]([O:34][CH3:35])[C:5]=2[N:4]=1
Reactant: COc1cc(NC(=O)OC(C)(C)C)cc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(C)(=O)=O)CC2)n1
Agent: N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1cc(N)cc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(C)(=O)=O)CC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
A mixture of tert-butyl 2-(difluoromethyl)-4-methoxy-1-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazol-6-ylcarbamate (0.20 g, 0.31 mmol) and TFA (5 mL) in CH2Cl2 (20 mL) was stirred at room temperature for 2 hrs. The mixture was diluted with CH2Cl2 (100 mL) and water (100 mL), and the aqueous layer was made basic with aqueous NH3. The organic layer was dried and concentrated under vacuum. Recrystallization of the residue from CH2Cl2/MeOH gave 0.145 g (86% yield) of 2-(difluoromethyl)-4-methoxy-1-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazol-6-ylamine: mp 280-283° C.; 1H NMR (CDCl3) δ 7.59 (t, JHF=53.4 Hz, 1H), 7.05 (d, J=1.7 Hz, 1H), 6.26 (d, J=1.7 Hz, 1H), 5.45 (s, exchangeable with D2O, 2H), 3.93 (m, 4H), 3.87 (s, 3H), 3.80 (m, 4H), 3.69 (m, 4H), 3.24 (m, 4H), 2.91 (s, 3H); Anal. Calcd. for C21H27F2N9O4S: C, 46.75; H, 5.0; N, 23.4. Found: C, 47.0; H, 5.2; N, 23.4%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][S:5][C:6]=1[N:7]1[CH2:12][CH2:11][CH2:10][C@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:8]1.OS(O)(=O)=O.N([O-])=O.[Na+].[N-:30]=[N+:31]=[N-].[Na+].N#N.C([O-])([O-])=O.[Na+].[Na+]>O.CC(C)=O>[N:1]([C:2]1[CH:3]=[N:4][S:5][C:6]=1[N:7]1[CH2:12][CH2:11][CH2:10][C@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])[CH2:8]1)=[N+:30]=[N-:31]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2sncc2N)C1
Reactant: [N-]=[N+]=[N-]
Agent: N#N
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2sncc2N=[N+]=[N-])C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 36.7 %

Procedure:
tert-butyl ((3S)-1-(4-azido-5-isothiazolyl)-3-piperidinyl) carbamate. A 25 mL, one neck round bottom flask was charged with tert-butyl ((3S)-1-(4-amino-5-isothiazolyl)-3-piperidinyl)carbamate (537 mg, 1.80 mmol), acetone (7 mL), water (7 mL) and a stirbar. The flask was immersed into a ice-water bath and stirred for 15 min. The solution was treated with 8 M H2SO4 (0.90 mL, 7.19 mmol), and stirred for 5 min. The homogenous solution was treated with NaNO2 (163 mg, 2.36 mmol) and stirred for 10 min. NaN3 (351 mg, 5.40 mmol) was added. The reaction was stirred cold for 30 min. The slurry was N2-pressure filtered cold through a 10 mL Bohdan glass frit fitted with a 0.22 μm PTFE, 25 mm syringe filter unit (Millipore, SLFG025NK). The filtrate was slowly added to a ice-cold solution of Na2CO3 (1.14 g, 10.79 mmol) in H2O (10 mL). The solids were washed with H2O (3×5 mL), and the washes were added to the Na2CO3 solution. The solids were dried in a vacuum oven (45° C., <1 mm Hg) for 20 min. The solids were dissolved in CHCl3, and treated with MgSO4. The resulting slurry was N2-pressure filtered through a 10 mL Bohdan glass frit fitted with a 0.22 μm PTFE, 25 mm syringe filter unit (Millipore, SLFG025NK). The solvent was removed in vacuo to afford tert-butyl ((3S)-1-(4-azido-5-isothiazolyl)-3-piperidinyl)carbamate (213 mg, 0.66 mmol, 37% yield). The material was used directly.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[NH2:30][C@H:31]([CH3:36])[CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+]>COCCO>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:29])[C:5]([C:3]([NH:30][C@H:31]([CH3:36])[CH2:32][C:33]([OH:35])=[O:34])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:10]1=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: C[C@@H](N)CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Product: C[C@H](CC(=O)O)NC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 68 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (35 mg, 0.090 mmol), (R)-3-amino-butyric acid (94 mg, 0.90 mmol) and NaOMe (39 mg, 0.73 mmol) in 2-methoxyethanol (10 mL) was refluxed for 3 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified to pH about 2 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 28 mg of the title compound as a yellow solid. MS: (+) m/z 458.30 (M+1).
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[C:21]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][C:36](=[O:43])[CH2:37][C:38]5[CH:42]=[CH:41][S:40][CH:39]=5)[CH:30]=4)=[N:22][N:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=34)[CH:17]=[CH:16][N:15]=2)[CH:8]=1)=O.O[Li].O>C1COCC1.O.C(Cl)Cl>[NH2:5][CH2:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[C:21]([C:29]4[CH:30]=[C:31]([NH:35][C:36](=[O:43])[CH2:37][C:38]5[CH:42]=[CH:41][S:40][CH:39]=5)[CH:32]=[CH:33][CH:34]=4)=[N:22][N:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=34)[CH:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: O=C(Cc1ccsc1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(CNC(=O)C(F)(F)F)c3)n2)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: NCc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)Cc5ccsc5)c4)nn4ccccc34)n2)c1
Temperature: 50 °C
Yield: 83 %

Procedure:
To a solution of 2,2,2-trifluoro-N-[(3-{[4-(2-{3-[(3-thienylacetyl)amino]phenyl}-pyrazolo[1,5-a]pyridin-3-yl)-2-pyrimidinyl]amino}phenyl)methyl]acetamide (87 mg, 0.14 mmol) in THF (2 mL) was added LiOH hydrate (12 mg, 0.28 mmol) in water (0.5 mL). The solution was heated to 50° C. for 1.5 h, and then diluted with DCM, washed with 1N Na2CO3, dried over Na2SO4, and concentrated to generate the title compound in 83% yield. 1H NMR (400 MHz, d6-DMSO) 610.29 (s, 1H), 9.50 (s, 1H), 8.83 (d, J=6.8 Hz, 1H), 8.53 (d, J=8.8 Hz, 1H), 8.24 (d, J=5.2 Hz, 1H), 7.89 (s, 1H), 7.74-7.77 (m, 2H), 7.40-7.56 (m, 4H), 7.08-7.32 (m, 5H), 6.95 (d, J=7.5 Hz, 1H), 6.46 (d, J=5.1 Hz, 1H), 3.67 (s, 2H), 3.66 (s, 2H). ES-LC/MS m/z=532 [M+H]+.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH2:7][CH2:8][N:9]([C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:10][CH:11]=1)=[O:5].[CH2:19]1[CH2:23]O[CH2:21][CH2:20]1>>[C:19]1([C:23]2[CH:8]=[CH:7][CH:6]=[CH:11][CH:10]=2)[CH:16]=[CH:15][C:14]([C:4]([C:6]2[CH2:7][CH2:8][N:9]([C:12]3[N:13]=[CH:14][CH:15]=[CH:16][N:17]=3)[CH2:10][CH:11]=2)=[O:5])=[CH:21][CH:20]=1
Reactant: CON(C)C(=O)C1=CCN(c2ncccn2)CC1
Reactant: C1CCOC1
Product: O=C(C1=CCN(c2ncccn2)CC1)c1ccc(-c2ccccc2)cc1
Reaction time: 1 h
Yield: 30 %

Procedure:
To a solution of 1-pyrimidin-2-yl-1,2,3,6-tetrahydro-pyridin-4-carboxylic acid methoxy-methyl amide (48 mg, 0.196 mmol) in THF (1 ml), was added 1-biphenyl-4-yl magnesium bromide (0.5 M in THF) at 0° C. The mixture was stirred at this temperature for 1 hour and quenched with addition of water (5 ml) and EtOAc (20 ml). The aqueous phase was further extracted with EtOAc (2×8 ml). The combined organic layers were washed with brine (5 ml), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish the crude product. This material was purified by column chromatography (4% MeOH/CH2Cl2) to give the title compound (20 mg, 30%) as an off-white solid: 1H NMR (CDCl3, 400 MHz) δ 8.38 (d, J=6.4 Hz, 2H), 7.82-7.42 (m, 9H), 6.70 (m, 1H), 6.58 (t, J=6.4 Hz, 1H), 4.51 (m, 2H), 4.13 (t, J=5.6 Hz, 2H), 2.72 (m, 2H); MS calc'd for C22H20N3O [M+H]+: 342; Found: 342.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([Cl:13])[CH:6]=1)([CH3:3])[CH3:2].[CH:14]([C:16]1[N:17]=[CH:18][NH:19][CH:20]=1)=O.C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[Cl:13][C:7]1[CH:6]=[C:5]([N:4]([CH2:14][C:16]2[NH:17][CH:18]=[N:19][CH:20]=2)[CH:1]([CH3:3])[CH3:2])[CH:10]=[CH:9][C:8]=1[O:11][CH3:12]
Reactant: COc1ccc(NC(C)C)cc1Cl
Reactant: O=Cc1c[nH]cn1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(N(Cc2cnc[nH]2)C(C)C)cc1Cl
Temperature: 40 °C
Reaction time: 8 h
Yield: 48.6 %

Procedure:
N-Isopropyl-3-chloro-4-methoxy-aniline (0.20 g, 1.0 mmol) was dissolved in methanol (10 ml). Then 4-formylimidazole (0.288 g, 3.0 mmol) and zinc chloride (0.545 g, 4.0 mmol) were added and the reaction mixture was cooled with an ice bath. After adding sodium cyanoborohydride (0.189 g, 3.0 mmol) the mixture was allowed to stir at 40° C. overnight. After cooling, the reaction mixture was poured onto ammoniumchloride/ice and extracted with ethyl acetate (3 times 20 ml). The organic layer was dried over magnesium sulfate and evaporated. The residue was purified using flash chromatography (column: Isolute® Flash-NH2 (Separtis); eluent: ethyl acetate/methanol=95:5) to yield a white solid (136 mg, 49%); MS (ISP): 280.0 ((M+H)+.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].Cl.Cl[CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[CH:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(ccn2CCN2CCCC2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A reaction mixture of 16.22 g (0.1 mol) of 5-nitroindole, 35 g (0.205 mol) of 1-(2-chloroethyl)pyrrolidine hydrochloride, and 51 g (0.369 mol) of potassium carbonate in 500 mL of DMF is stirred for 48 hours at ambient temperature and then filtered. The filtrate is evaporated down, the residue dissolved in dichloromethane, and dried over sodium sulfate. The desiccant is filtered off and the filtrate is evaporated down. Yield: 25 g (96.3% of theory); C14H17N3O2 (M=259.31); calc.: molecular ion peak (M+H)+: 260; found: molecular ion peak (M+H)+: 260; Rf value: 0.65 (silica gel, dichloromethane/methanol/ammonia (90:10:1)).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[CH3:23][CH:24]1[CH2:29][CH2:28][N:27]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][NH:2][CH:3]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:26][CH2:25]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: CC1CCNCC1
Product: CC1CCN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)CC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with 4-methylpiperidine (1.2 equiv) to give 167 (15.8 mg, M+1 395.1)
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[SH:12][CH:13]([CH:18]([CH3:20])[CH3:19])[C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[S:12][CH:13]([CH:18]([CH3:20])[CH3:19])[C:14]([O:16][CH3:17])=[O:15]
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Reactant: COC(=O)C(S)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(Sc1c(Cl)cccc1[N+](=O)[O-])C(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 2,3-dichloronitrobenzene (3.84 g), methyl 2-mercapto-3-methybutyrate (2.96 g), potassium carbonate (2.37 g), and N,N-dimethylformamide (40 ml) was stirred at room temperature for 5 hours, diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), from which the solvent was evaporated off, to give quantitatively methyl 2-(2-chloro-6-nitrophenylthio)-3-methylbutyrate as an oil.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]=[O:14])=[C:5]1[C:15]([F:18])([F:17])[F:16])[C:2]#[CH:3].O1CCCC1.[BH4-].[K+]>O>[CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][OH:14])=[C:5]1[C:15]([F:18])([F:16])[F:17])[C:2]#[CH:3]
Reactant: C#CCn1c(C(F)(F)F)c(C=O)c2ccccc21
Agent: [BH4-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C#CCn1c(C(F)(F)F)c(CO)c2ccccc21
Yield: 100.3 %

Procedure:
5.54 g of 1-(2-propynyl)-2-trifluoromethyl-3-formyl-(1H)-indol, 120 ml of tetrahydrofuran and 20 ml of water were mixed together at +5° and 2 g of potassium borohydride were added in small fractions. The mixture was concentrated to a small volume by distillation under reduced pressure and ethyl ether was added. The organic phase was washed with salted water and concentrated to dryness by distillation under reduced pressure to obtain 5.6 g of 1-(2-propynyl)-2-trifluoromethyl-(1H)-indol-3-yl methanol melting at 90° C.