Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[C:6]([C:9]([O:11][CH3:12])=[O:10])=[N:7][S:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[CH:55]12[NH:62][CH:59]([CH2:60][CH2:61]1)[CH2:58][CH:57]([O:63][CH2:64][C:65]1[C:66]([C:73]3[CH:78]=[CH:77][CH:76]=[CH:75][C:74]=3[O:79][C:80]([F:83])([F:82])[F:81])=[N:67][O:68][C:69]=1[CH:70]1[CH2:72][CH2:71]1)[CH2:56]2>C1(C)C(C)=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:70]1([C:69]2[O:68][N:67]=[C:66]([C:73]3[CH:78]=[CH:77][CH:76]=[CH:75][C:74]=3[O:79][C:80]([F:81])([F:82])[F:83])[C:65]=2[CH2:64][O:63][CH:57]2[CH2:56][CH:55]3[N:62]([C:2]4[CH:14]=[CH:13][C:5]5[C:6]([C:9]([O:11][CH3:12])=[O:10])=[N:7][S:8][C:4]=5[CH:3]=4)[CH:59]([CH2:60][CH2:61]3)[CH2:58]2)[CH2:71][CH2:72]1
Reactant: FC(F)(F)Oc1ccccc1-c1noc(C2CC2)c1COC1CC2CCC(C1)N2
Reactant: COC(=O)c1nsc2cc(Br)ccc12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1C
Product: COC(=O)c1nsc2cc(N3C4CCC3CC(OCc3c(-c5ccccc5OC(F)(F)F)noc3C3CC3)C4)ccc12
Temperature: 120 °C

Procedure:
A microwave vial was charged with methyl 6-bromobenzo[d]isothiazole-3-carboxylate (WO07056582, 85 mg, 0.31 mmol), cesium carbonate (220 mg, 0.68 mmol), tris(dibenzylideneacetone)dipalladium(0) (13 mg, 0.014 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos) (14 mg, 0.028 mmol), and degassed xylene (1.5 mL). The mixture was degassed for 10 minutes and then 4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole (I-1H) (115 mg, 0.28 mmol) in xylene (1 mL) was added. The reaction flask was evacuated and backfilled with argon three times and then heated at 120° C. for 12 hours. The reaction mixture was cooled to rt, diluted with ethyl acetate and filtered through a CELITE® pad, the filtrate concentrated, and chromatographed on silica using linear gradient, 20-80%, EtOAc in Hexanes) to give the desired ester as a yellow solid. MS m/z 600.2 (M+1), 622.2. (M+23).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[CH3:21][O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[C:25]([CH3:32])[CH:24]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([O:22][CH3:21])=[CH:24][C:25]=2[CH3:32])=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: COc1ccc(C(=O)O)c(C)c1
Agent: Cl
Product: COc1ccc(C(=O)NCC(=O)NC(c2ccccc2)c2ccc(Cl)cc2)c(C)c1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 4-methoxy-2-methylbenzoic acid. MS (m/e): 421.0 (MH−, 100%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-])=O)=[CH:5][CH:4]=[C:3]1[C:10]([O:12][CH3:13])=[O:11]>[Pd].CO>[CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1ccc([N+](=O)[O-])n1C
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(N)n1C
Reaction time: 2 h

Procedure:
1.31 g (7.4 mmol) of methyl N-methyl-5-nitro-2-pyrrolecarboxylate, 400 mg of palladium on carbon (10%) and 50 ml of methanol were introduced into a reactor. The mixture was hydrogenated at room temperature and at a pressure of 7 bar for 2 hours. The catalyst was filtered, washed twice with 25 ml of methanol and the filtrates evaporated. 1.1 g (100%) of the expected amine was recovered in the form of a dark red oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.N1C=CC=CC=1.[C:13]1([C:19](Cl)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C1C=CN=CC=1.O>[Br:1][C:2]1[CH:3]=[N:4][N:5]([C:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:6]=1
Reactant: Brc1cn[nH]c1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: Brc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
In a 75 mL sealed tube, 4-bromopyrazole (1.0 g, 6.8 mmol), pyridine (21.0 mL, 258 mmol), triphenylmethyl chloride (2.1 g, 7.5 mmol), and 4-dimethylaminopyridine (0.17 g, 1.4 mmol) were added. The mixture was stirred at 80° C. for 24 hours. The mixture was diluted with water, and the solids which crashed out were filtered, rinsed with water and air-dried to yield 4-bromo-1-trityl-1H-pyrazole as a white solid.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[C:16]([N:18]3[CH2:22][C@@H:21]([N:23]([CH2:35][C:36]4[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[C:38]([C:46]([F:49])([F:48])[F:47])[CH:37]=4)[C:24]4[N:29]=[CH:28][C:27]([C:30]5[CH:31]=[N:32][NH:33][CH:34]=5)=[CH:26][N:25]=4)[CH2:20][C@H:19]3[CH2:50][CH3:51])[C:15]([Cl:52])=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])C.[Li+].[OH-].Cl>CO>[F:49][C:46]([F:47])([F:48])[C:38]1[CH:37]=[C:36]([CH:41]=[C:40]([C:42]([F:43])([F:44])[F:45])[CH:39]=1)[CH2:35][N:23]([C:24]1[N:25]=[CH:26][C:27]([C:30]2[CH:34]=[N:33][NH:32][CH:31]=2)=[CH:28][N:29]=1)[C@@H:21]1[CH2:22][N:18]([C:16]2[C:15]([Cl:52])=[CH:14][N:13]=[C:12]([N:9]3[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]3)[N:17]=2)[C@H:19]([CH2:50][CH3:51])[CH2:20]1
Reactant: CCOC(=O)C1CCN(c2ncc(Cl)c(N3C[C@@H](N(Cc4cc(C(F)(F)F)cc(C(F)(F)F)c4)c4ncc(-c5cn[nH]c5)cn4)C[C@H]3CC)n2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cn[nH]c3)cn2)CN1c1nc(N2CCC(C(=O)O)CC2)ncc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
A 15 ml round-bottom flask is charged with 1-[4-((2R,4S)-4-{(3,5-bis-trifluoromethyl-benzyl)-[5-(1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidin-1-yl)-5-chloro-pyrimidin-2-yl]-piperidine-4-carboxylic acid ethyl ester, 2N LiOH (0.4 ml, 0.8 mmol) THF (0.5 ml) and MeOH (1 ml). The mixture is then stirred at rt for 1 hour. PH is adjusted to 6 using 1 N HCl and resulted solution is extracted with EtOAc. The organic layer is dried over Na2SO4 and removal of solvent, purification with reverse phase column give 1-[4-((2R,4S)-4-{(3,5-bis-trifluoromethyl-benzyl)-[5-(1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidin-1-yl)-5-chloro-pyrimidin-2-yl]-piperidine-4-carboxylic acid (13 mg, 0.017 mmol, 20% for 3 steps).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH3:7][C:8]1[N:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1.Cl[C:18]1[C:23]([Cl:24])=[CH:22][C:21]([CH:25]=[CH2:26])=[CH:20][N:19]=1>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>[Cl:24][C:23]1[C:18]([C:11]2[CH:12]=[N:13][C:8]([CH3:7])=[CH:9][CH:10]=2)=[N:19][CH:20]=[C:21]([CH:25]=[CH2:26])[CH:22]=1
Reactant: Cc1ccc(B(O)O)cn1
Reactant: C=Cc1cnc(Cl)c(Cl)c1
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: COCCOC
Solvent: O
Product: C=Cc1cnc(-c2ccc(C)nc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.2 %

Procedure:
8.1 g of Na2CO3 (76 mmol), 3.5 g of 6-methylpyridin-3-ylboronic acid (11) (25 mmol), and 0.97 g of Pd(PPh3)4 were added to 4.9 g of compound (8) (28 mmol) prepared in Example 5 dissolved in 100 mL of 1,2-dimethoxyethane and 100 mL of distilled water, and refluxed under heating and stirring for 18 hours. The mixture was cooled to room temperature, and concentrated about 50% under reduced pressure. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried over magnesium sulfate, concentrated under reduced pressure. The residue was separated by column chromatography (eluting solvent: ethyl acetate/hexane=1/4) to obtain 5.2 g of 3-chloro-6′-methyl-5-vinyl-2,3′-bipyridine (yield 90%).
Reaction SMILES: Br[C:2]([CH3:24])([CH3:23])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[N:6]=1)=[O:4].[P:25]([O:30]C)([O:28][CH3:29])[O:26][CH3:27]>>[P:25]([O:28][CH3:29])([O:26][CH3:27])([O:4][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[N:6]=1)=[C:2]([CH3:24])[CH3:23])=[O:30]
Reactant: COc1ccc2c(C(=O)C(C)(C)Br)nn(CC(=O)C(C)(C)C)c2c1
Reactant: COP(OC)OC
Product: COc1ccc2c(C(OP(=O)(OC)OC)=C(C)C)nn(CC(=O)C(C)(C)C)c2c1

Procedure:
Reaction of 1-[3-(2-bromo-2-methylpropanoyl)-6-methoxy-1H-indazol-1-yl]-3,3-dimethylbutan-2-one from the above with trimethyl phosphite using the procedure as described in Method I Step B above provided the title compound identical to the one obtained with Method I.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:5]1=[O:19])([CH3:3])[CH3:2].[O:20]=[S:21]1(=[O:37])[C:25]2[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:24]=2[C:23](=[O:31])[N:22]1[CH2:32][CH2:33][CH2:34][CH2:35]Br>>[O:37]=[S:21]1(=[O:20])[C:25]2[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:24]=2[C:23](=[O:31])[N:22]1[CH2:32][CH2:33][CH2:34][CH2:35][N:16]1[CH2:17][CH2:18][CH:13]([N:6]2[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:4]([CH:1]([CH3:3])[CH3:2])[C:5]2=[O:19])[CH2:14][CH2:15]1
Reactant: O=C1c2cc(Cl)ccc2S(=O)(=O)N1CCCCBr
Reactant: CC(C)n1c(=O)n(C2CCNCC2)c2ccccc21
Product: CC(C)n1c(=O)n(C2CCN(CCCCN3C(=O)c4cc(Cl)ccc4S3(=O)=O)CC2)c2ccccc21

Procedure:
From 4-(3-isopropyl-2-oxo-1-benzimidazolinyl)piperidine and 1,1-dioxido-2-(4-bromobutyl)-5-chloro-1,2-benzisothiazol-3(2H)-one (prepared as shown in Example 22) using the procedures described in Example 1 there was obtained a white solid upon formation of the HCl salt (from methanol and diethyl ether), melting point 229-234° C. Analysis calculated for C26H31ClN4O4S.HCl.0.4 H2O: C, 54.33; H, 5.75; N; 9.75; found: C, 54.35; H, 5.60; N, 9.70. The NMR was consistent with the structure.
Reaction SMILES: [H][H].[CH:3]1([N:7]2[CH2:12][CH2:11][CH:10]([O:13][C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1>CO.[Pd]>[CH:3]1([N:7]2[CH2:12][CH2:11][CH:10]([O:13][C:14]3[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1
Reactant: O=[N+]([O-])c1ccc(OC2CCN(C3CCC3)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(OC2CCN(C3CCC3)CC2)cc1
Yield: 95.6 %

Procedure:
Hydrogen gas was bubbled through a solution of 1-Cyclobutyl-4-(4-nitrophenoxy)piperidine (94.9 g, 0.344 moles, obtained in above step) over 10% Pd/C (95 g) in methanol (2 L) at room temperature, for 5 hours. The mixture was filtered through a pad of celite, and the filtrate was concentrated under vacuum to obtain the title compound 81 g (Yield: 95.7%).
Reaction SMILES: [CH:1]([CH:19]1[CH2:24][C:23](=[O:25])[O:22][C:20]1=[O:21])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].O.C(O)(=O)CCC(O)=[O:31]>>[CH:1]([CH:19]([CH2:24][C:23]([OH:22])=[O:25])[C:20]([OH:31])=[O:21])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCC=CC1CC(=O)OC1=O
Reactant: O=C(O)CCC(=O)O
Solvent: O
Product: CCCCCCCCCCCCCCCCC=CC(CC(=O)O)C(=O)O
Temperature: 80 °C

Procedure:
This is lactonized-2-octadecenyl succinic acid which is prepared as follows: A half mole (175 g) of 2-octadecenyl succinic anhydride and 0.55 mole (10 g) of water were mixed and heated in a reaction flask for a half hour at 80° C. Infrared analysis showed that complete conversion of the anhydride to succinic acid had occurred. While stirring at 80° C., 0.5 g of concentration sulfuric acid was added, and the reaction temperature was increased to 130°-140° C. Heating at 140° C. for 1.5 hours completely converted the di-carboxylic acid to the desired lactone acid products. When the cooled mixture was diluted with ether, a white solid separated from solution. Infrared analysis of the isolated solids revealed the presence of a 5-ring lactone acid (strong bands at 5.67 and 5.82 microns). Cooling the supernatant gave more solids. Further fractional crystallization of later crops afforded 6-ring lactone acid products. The combined weight of all crops revealed that the yield of lactone acid product was quantitative. A recrystallized sample of 5-ring lactone product melted at 112° C. and analyzed for 71.50% carbon, 10.77% H and 16.67% oxygen. Theory requires 71.49% C, 11.18% H, and 17.32% O.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]([S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])([CH:6]1[CH2:11][CH2:10][CH2:9][C:8](=O)[CH2:7]1)[CH3:5].Cl.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31]N)=[CH:27][CH:26]=1.C([O-])(O)=O.[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:22])[C:4]([S:13]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)(=[O:15])=[O:14])([CH:6]1[CH2:11][CH2:10][C:9]2[C:29]3[C:28](=[CH:27][CH:26]=[C:25]([Cl:24])[CH:30]=3)[NH:31][C:8]=2[CH2:7]1)[CH3:5]
Reactant: NNc1ccc(Cl)cc1
Reactant: COC(=O)C(C)(C1CCCC(=O)C1)S(=O)(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)C(C)(C1CCc2c([nH]c3ccc(Cl)cc23)C1)S(=O)(=O)c1ccccc1
Temperature: 40 °C
Yield: 100.7 %

Procedure:
To 0.14 g (0.43 mmol) (RS,SR)-2-benzenesulfonyl-2-(3-oxo-cyclohexyl)-propionic acid methyl ester in glacial acetic acid (3 mL), 88 mg (0.47 mmol, 1.1 eq) of (4-chloro-phenyl)-hydrazine hydrochloride were added and the reaction mixture was stirred at 40° C. over night. An aqueous solution of NaHCO3 was added until pH=7 was reached, and the mixture was extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and evaporated. A column chromatography on silica gel with heptane/EtOAc 2:1 followed by a trituration with Et2O yielded 187 mg (65%) of (RS,SR)-2-benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-propionic acid methyl ester as a white solid, MS: 432 (MH+).
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C@@H:10]1[C@H:15]2[CH2:16][C@H:12]([C@H:13]([OH:17])[CH2:14]2)[N:11]1C(OC(C)(C)C)=O)=[O:9])#[N:2].[ClH:25]>O1CCOCC1.O>[ClH:25].[OH:17][C@H:13]1[C@H:12]2[CH2:16][C@H:15]([C@@H:10]([C:8]([N:4]3[CH2:5][CH2:6][CH2:7][C@H:3]3[C:1]#[N:2])=[O:9])[NH:11]2)[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@H]2O)[C@H]1C(=O)N1CCC[C@H]1C#N
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: N#C[C@@H]1CCCN1C(=O)[C@H]1N[C@@H]2C[C@H]1C[C@H]2O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solid of tert-butyl (1R,3S,4S,6R)-3-{[(2S)-2-cyano-1-pyrrolidinyl]carbonyl}-6-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate obtained in Example 42-8 (796 mg), was added a mixture of 4N hydrochloride in dioxane (1.87 mL) and water (0.13 mL). The mixture was stirred at room temperature for 5 minutes. The resulting mixture was evaporated in vacuo and the residual solid was washed with isopropyl alcohol. The solid was recrystalized from ethanol-water to give the target compound as a white crystal (367 mg)
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:20]([C:21]([O:23]C)=O)=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][N:17]=2)[N:12]=1)(=[O:4])=[O:3].[CH3:25]C(C[AlH]CC(C)C)C>C(Cl)Cl>[CH3:25][CH:21]([C:20]1[C:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:2]([CH3:1])(=[O:4])=[O:3])=[N:12][C:13]2[C:18]([CH:19]=1)=[N:17][CH:16]=[CH:15][CH:14]=2)[OH:23]
Reactant: COC(=O)c1cc2ncccc2nc1-c1ccccc1S(C)(=O)=O
Reactant: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CC(O)c1cc2ncccc2nc1-c1ccccc1S(C)(=O)=O
Reaction time: 4 h

Procedure:
To a solution of methyl 2-(2-(methylsulfonyl)phenyl)-1,5-naphthyridine-3-carboxylate (1.2 g, 3.5 mmol) in DCM (30 mL) was added DIBAL-H (35 mL, 35 mmol) at −78° C. The reaction mixture was stirred for 4 h at same temperature. The reaction mixture was quenched with satd solution of ammonium chloride and extracted with EtOAc. The organic layer was concentrated in vacuo to give methyl (2-(2-(methylsulfonyl)phenyl)-1,5-naphthyridin-3-yl)methanol: LC-MS (ESI) m/z 315.0 [M+H]+. It was carried on crude for next step.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.CC[O:13][C:14]([CH:16]1[CH2:22][CH2:21][C:19](=O)[CH2:18][CH2:17]1)=[O:15].[OH-].[Na+].[NH4+]>C(O)C>[F:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:19]1[CH2:21][CH2:22][CH:16]([C:14]([OH:15])=[O:13])[CH2:17][C:18]2=1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: NNc1ccc(F)cc1
Agent: Cl
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)C1CCc2[nH]c3ccc(F)cc3c2C1
Temperature: 62.5 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
In a 5-L cylindrical reactor, p-fluorophenylhydrazine HCl (400 g, 2.46 mol) was suspended in ethanol (2B) (1.2 kg; 1.5 L). The slurry was stirred and heated to 60-65° C. A solution of 4-cyclohexanone carboxylic acid ethyl ester (400 g, 2.35 mol) in ethanol (2B) (0.4 L) was added over 1 h. The reaction temperature may rise to reflux (78-82° C.). After addition, the suspension was stirred and heated at reflux for 1 h then cooled to 40-50° C. A 50% sodium hydroxide solution (470 g) was added over 30 min. The suspension was heated to reflux (80-82° C.). (This can cause evolution of ammonium gas during heating). After 1 h, the reaction mixture was distilled at atmospheric pressure to about 1.5 L, about half of its original volume, then cooled to 60-70° C. Water (2.5 L) was added. The mixtured was cooled to 30-40° C. before dilute HCl (0.333 L conc HCl+0.667 L water) was added over 20 min. The suspension was stirred at 20° C. for 1 h then filtered through a Buchner funnel. The solid product was washed with water (3×1 L) then dried under N2 overnight to give 534.5 g (97.5% yield) of off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][C@H:7]([C:15]([NH2:17])=O)[CH2:6][C:5]2=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][C@H:7]([CH2:15][NH2:17])[CH2:6][C:5]2=1
Reactant: NC(=O)[C@H]1CCc2[nH]c3ccc(F)cc3c2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NC[C@H]1CCc2[nH]c3ccc(F)cc3c2C1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
(3S)-6-Fluoro-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide (34.7 g, 150 mmol), was dissolved in 1 L of dry THF, and to the solution were added 300 ml of 1N lithium aluminum hydride in THF. The resulting solution, turning into suspension, was refluxed at vigorous stirring for 1 hr, completion checked by HPLC. The resulting suspension was cooled to 0-5° C., and quenched very slowly with the saturated solution of sodium potassium tartrate (Rochelle salt). The temperature was initially kept below 15° C., then let up to the ambient; 125 ml of the salt solution were added, while the solids in the suspension became crystalline and easily filterable. The reaction mixture was filtered through paper, the filtrate dried over sodium sulfate, evaporated, crystallized from MTBE, dried in the oven to give 26.9 g (82%) of the title compound as white crystals, mp: 121-123° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:29]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[CH:28][C:8]2[N:9]([CH3:27])[C:10]([NH:12][C:13]3[S:14][C:15]4[CH:21]=[C:20]([O:22][C:23]([F:26])([F:25])[F:24])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Li+]>>[CH2:33]([N:30]([CH2:31][CH3:32])[C:29]1[C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]2[N:11]=[C:10]([NH:12][C:13]3[S:14][C:15]4[CH:21]=[C:20]([O:22][C:23]([F:25])([F:26])[F:24])[CH:19]=[CH:18][C:16]=4[N:17]=3)[N:9]([CH3:27])[C:8]=2[CH:28]=1)[CH3:34]
Reactant: CCN(CC)c1cc2c(cc1C(=O)OC)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Agent: [Li+]
Agent: [OH-]
Product: CCN(CC)c1cc2c(cc1C(=O)O)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 60 %

Procedure:
6-Diethylamino-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (175 mg) was prepared by following General Procedure E starting from 6-diethylamino-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methyl ester (300 mg) and lithium hydroxide (102 mg). LC/MS: m/z 480.9. 1H NMR (DMSO-d6, 400 MHz): δ 12.45 (bs, 1H), 8.25 (bs, 1H), 7.96 (s, 1H), 7.85 (s, 1H), 7.80-7.62 (m, 1H), 7.38 (d, 1H), 3.68 (s, 3H), 3.41-3.25 (m, 4H), 0.94 (t, 6H), —COOH proton signal was not observed.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]3[NH:15][CH:16]=[C:17]([CH2:18][CH2:19][OH:20])[C:11]=3[CH:10]=2)=[CH:3][CH:2]=1.[C:21]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])(=O)[CH2:22][CH2:23][CH3:24].B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][C:21]1([CH2:22][CH2:23][CH3:24])[C:16]2[NH:15][C:12]3[C:11]([C:17]=2[CH2:18][CH2:19][O:20]1)=[CH:10][C:9]([O:8][CH2:7][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)=[CH:14][CH:13]=3)[CH3:31]
Reactant: OCCc1c[nH]c2ccc(OCc3ccccc3)cc12
Reactant: CCCC(=O)CC(=O)OCC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCCC1(CC(=O)OCC)OCCc2c1[nH]c1ccc(OCc3ccccc3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
A solution of 5-benzyloxytryptophol (4.72 g, 17 mmol) and ethyl butyrylacetate (3.16 g, 20 mmol) in methylene chloride (75 ml) is treated dropwise with boron trifluoride etherate (3 mL) and stirred under nitrogen at room temperature overnight. The reaction mixture is diluted with methylene chloride (250 mL) and sequentially washed with 5% aqueous sodium bicarbonate (2×100 mL) and water (2×50 mL). The organic phase is dried (MgSO4), filtered, and evaporated to afford 7.0 g of a crude dark oil. Purification by flash column chromatography (ethyl acetate:hexane, 1:9 eluent) on silica gel (50:1 ratio, 230-400 mesh) affords the title compound (5.5 g, 79%) as a slightly amber oil homogeneous by TLC.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH2:14])[C@@H:10]([OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:18]=[CH:19][C:20](F)=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=1.C(N(CC)CC)C>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:20]2[CH:19]=[CH:18][C:17]([Br:16])=[CH:22][C:21]=2[N+:23]([O-:25])=[O:24])[C@@H:10]([OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)[C@@H](O)C1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2ccc(Br)cc2[N+](=O)[O-])[C@@H](O)C1
Temperature: 25 °C
Yield: 110.9 %

Procedure:
Heat a mixture of (3S,4S)-4-amino-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.035 mol, 7.5 g), 5-bromo-2-fluoronitrobenzene (0.038 mol, 8.48 g) and triethyl amine (0.073 mol, 7.44 g) in ethyl acetate (250 mL) to reflux for 16 h. Cool the reaction mixture to room temperature, dilute with ethyl acetate and wash with water and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound (16.16 g, crude).