Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:53])[CH2:11][C:12]1[CH:13]=[C:14]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH:38]([O:43][Si](C(C)(C)C)(C)C)[C:39]([CH3:42])([CH3:41])[CH3:40])=[C:32]([CH3:51])[CH:31]=3)([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:21][C:20]=2[CH3:52])[CH:15]=[C:16]([OH:18])[CH:17]=1>ClCCl>[CH3:8][O:9][C:10](=[O:53])[CH2:11][C:12]1[CH:13]=[C:14]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([CH2:28][CH3:29])([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH:38]([OH:43])[C:39]([CH3:41])([CH3:42])[CH3:40])=[C:32]([CH3:51])[CH:31]=3)[CH2:26][CH3:27])=[CH:21][C:20]=2[CH3:52])[CH:15]=[C:16]([OH:18])[CH:17]=1
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(-c2cc(O)cc(CC(=O)OC)c2)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2cc(O)cc(CC(=O)OC)c2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
Trifluoroacetic acid (0.17 mL) was added to a solution of [4′-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-5-hydroxy-2′-methyl-biphenyl-3-yl]-acetic acid methyl ester (Example 164-(3); 23.1 mg, 0.0358 mmol) in dichloromethane (0.85 mL) at room temperature, and the mixture was stirred at room temperature for one hour. The solvent in the reaction solution was distilled off under reduced pressure, and the residue was diluted with diethyl ether. The mixture was adjusted to pH 7 with aqueous sodium bicarbonate solution, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=2/1) to give the title compound (17.5 mg, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:9])[C:7]=1F.[NH2:14][C:15]1[N:19]=[CH:18][NH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[NH2:14][C:15]1[N:16]([C:7]2[C:2]([Cl:1])=[CH:3][C:4]([C:10]([F:13])([F:12])[F:11])=[CH:5][C:6]=2[Cl:9])[N:17]=[CH:18][N:19]=1
Reactant: Fc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: Nc1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 100 °C

Procedure:
To a solution of 3,5-dichloro-4-fluorobenzotrifluoride (1.0 g) in dimethylformamide (5 ml) was added 3-amino-1,2,4-triazole (360 mg) and potassium carbonate (296 mg), the mixture was heated at 100° C. for 2 hrs. The reaction was cooled to room temperature, diluted with water (100 ml) and extracted with ether (100 ml). The organic extracts were evaporated to dryness to give the title compounds as pale yellow crystals.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:33]([CH3:34])=[CH:32][C:15]2[N:16]=[C:17]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([CH3:28])[C:23](=[O:29])[C:22]4([CH3:31])[CH3:30])[S:18][C:14]=2[C:13]=1[C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C1COCC1>CCO>[C:1]([O:5][C@@H:6]([C:12]1[C:33]([CH3:34])=[CH:32][C:15]2[N:16]=[C:17]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([CH3:28])[C:23](=[O:29])[C:22]4([CH3:30])[CH3:31])[S:18][C:14]=2[C:13]=1[C:35]1[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)C(C)(C)C(=O)N4C)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc2nc(-c3ccc4c(c3)C(C)(C)C(=O)N4C)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 50 °C

Procedure:
The crude (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1,3,3-trimethyl-2-oxoindolin-5-yl)benzo[d]thiazol-6-yl)acetate from the reaction above was treated with 1.0 M aq NaOH (2 mL), THF (4 mL), and absolute EtOH (2 mL). The reaction was heated to 50° C. for 19 h. The reaction was cooled to 23° C., and filtered (0.45 micron teflon syringe filter). The filtrate was purified by reverse phase HPLC, eluting by 5-100% acetonitrile in H2O with 0.1% TFA to give the desired product. LCMS-ESI+: calc'd for C31H31ClN2O4S: 563.2, 565.2 (M+H+); Found: 563.3, 565.3 (M+H+). +). 1H NMR (400 MHz, CD3OD): δ 8.05-7.94 (m, 2H), 7.81 (s, 1H), 7.73-7.64 (m, 1H), 7.64-7.54 (m, 3H), 7.14 (d, J=8.2 Hz, 1H), 5.26 (s, 1H), 3.27 (s, 3H), 2.61 (s, 3H), 1.41 (s, 6H), 0.98 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[C:12]([CH2:16][C:17](Cl)=[O:18])([CH3:15])([CH3:14])[CH3:13].N1C=CC=CC=1>ClCCl>[CH3:13][C:12]([CH3:15])([CH3:14])[CH2:16][C:17]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2)=[O:18]
Reactant: Nc1ccc2ncccc2c1
Reactant: CC(C)(C)CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)CC(=O)Nc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.5 %

Procedure:
Following the procedure of Example 1, Step 3, 6-nitroquinoline (2.5 g) and 5% palladium on carbon (0.10 g) in ethanol (40 mL) was hydrogenated to give 6-aminoquinoline (2.2 g). A mixture of 6-aminoquinoline (2.2 g, 15 mmol), t-butylacetyl chloride (2.2 mL, 16 mmol), and pyridine (2.5 mL, 31 mmol) in dichloromethane (40 mL) was then stirred at ambient temperature for 4 h and then extracted with 1 N HCl. The acidic layer was separated and treated with 50% NaOH until basic. The basic phase was extracted with dichloromethane. The combined extracts were dried (MgSO4) and concentrated. The crude material was triturated with hexane and the solid was collected by filtration to provide 3,3-dimethyl-N-quinolin-6-ylbutanamide (3.0 g). MS (ES) m/z 241.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9](O)[CH:10]([N+:12]([O-:14])=[O:13])[CH3:11].CCN(S(F)(F)[F:22])CC>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([F:22])[CH:10]([N+:12]([O-:14])=[O:13])[CH3:11]
Reactant: CC(C(O)c1ccc(Cl)cc1Cl)[N+](=O)[O-]
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C(F)c1ccc(Cl)cc1Cl)[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To a stirred mixture of erythro 1-(2,4-dichlorophenyl)-2-nitro-propan-1-ol (2.5 g, 10.0 mmol) in dry dichloromethane (20 ml) under nitrogen atmosphere DAST (1.3 ml, 10.0 mmol) in dichloromethane (5 ml) was added dropwise under cooling to 5° C. The solution was stirred at ambient temperature for 1 hour. Dichloromethane (80 ml) was added and the organic layer was washed sequentially with saturated NaHCO3 (50 ml), 1M HCl (30 ml) and sole (30 ml). The organic layer was dried over NaSO4, filtered, and concentrated. 2.5 g of 2,4-dichloro-1-(1-fluoro-2-nitro-propyl)-benzene was obtained in the form of a brown oil.
Reaction SMILES: [CH2:1]([C:4]1[CH:15]=[CH:14][C:7]2[O:8][CH:9]([C:11](=[O:13])[CH3:12])[O:10][C:6]=2[CH:5]=1)CC.[CH2:16]([Li])C>>[CH3:1][C:4]1[CH:15]=[CH:14][C:7]2[O:8][CH:9]([C:11](=[O:13])[CH2:12][CH3:16])[O:10][C:6]=2[CH:5]=1
Reactant: [Li]CC
Reactant: CCCc1ccc2c(c1)OC(C(C)=O)O2
Product: CCC(=O)C1Oc2ccc(C)cc2O1

Procedure:
Obtained in 30% (1st step) and 33% (2nd step) yields from 4-methylcatechol according to the typical procedure described for 1-(5-propyl-1,3-benzodioxol-2-yl)-1-ethanone, except the use of ethyl lithium instead of methyl lithium.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13])(=O)=O.O[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[C:27]([CH3:36])[C:26]=1[CH3:37]>>[CH3:23][O:22][C:19]1[N:18]=[CH:17][C:16]([C:8]2[C:7]([CH2:6][O:5][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[C:27]([CH3:36])[C:26]=3[CH3:37])=[C:11]([C:12]([F:15])([F:14])[F:13])[S:10][N:9]=2)=[CH:21][CH:20]=1
Reactant: Cc1c(O)ccc(CCC(=O)O)c1C
Reactant: COc1ccc(-c2nsc(C(F)(F)F)c2COS(C)(=O)=O)cn1
Product: COc1ccc(-c2nsc(C(F)(F)F)c2COc2ccc(CCC(=O)O)c(C)c2C)cn1

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling (3-(6-methoxypyridin-3-yl)-5-(trifluoromethyl)isothiazol-4-yl)methyl methanesulfonate and 3-(4-hydroxy-2,3-dimethylphenyl)propanoic acid followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (300 MHz, CD3OD) δ 8.47 (s, 1H), 7.99-8.03 (m, 1H), 6.98 (d, J=8.4 Hz, 1H), 6.87 (d, J=8.7 Hz, 1H), 6.74 (d, J=8.1 Hz, 1H), 5.11 (s, 2H), 3.99 (s, 3H), 2.91 (t, J=7.2 Hz, 2H), 2.51 (t, J=7.5 Hz, 2H), 2.23 (s, 3H), 2.03 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C20H15F5N2O4S, 467.1 (M−H). found 467.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([CH3:11])=[O:10])=[CH:4][N:3]=1.[N-:12]=[N+]=[N-].[Na+].S(=O)(=O)(O)O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([CH3:11])(=[NH:12])=[O:10])=[CH:4][N:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)Cc1ccc(Cl)nc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CS(=N)(=O)Cc1ccc(Cl)nc1
Temperature: 0 °C
Yield: 34 %

Procedure:
To a stirred mixture of 2-chloro-5-[(methylsulfinyl)methyl]pyridine (B) (7.34 g, 39 mmol) and sodium azide (4.04 g, 62 mmol) in chloroform (80 mL) cooled to 0° C. was slowly added sulfuric acid at a rate such that the temperature did not rise above 8° C. After the addition was over, the ice-water bath was removed and the mixture was heated at 55° C. for 2.5 h. The solvent was decanted into a separation funnel and the residue was stirred and dissolved in water. After a few minutes, the aqueous mixture was made basic to pH 8 by slowly adding solid Na2CO3 and then saturated with solid NaCl. The extra salt was removed by filtration (a portion of the filtrate was sucked into trap and was not recovered) and the filtrate was extracted with CH2Cl2 three times. The combined organic layer was dried over Na2SO4, filtered, concentrated and the residue was triturated in CH2Cl2-ether (1:10, v/v) solvent. The white solid was filtered, washed with CH2Cl2-ether (1:10, v/v) and dried to give 2.70 g of -chloro-5-[(methylsulfon-imidoyl)methyl]pyridine (C) in 34% yield as a white solid (m.p. 134.5-136° C.). LC-MS (ELSD): mass calcd for C7H9ClN2OS [M+H]+ 203.67. Found: 203.22.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].N1C=CC=CC=1.ClCCl.[NH2:17][CH2:18][C@@H:19]1[O:23][C:22](=[O:24])[N:21]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]([O:34][CH3:35])[O:32][CH3:33])=[C:27]([F:36])[CH:26]=2)[CH2:20]1.C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O>>[C:1]([NH:17][CH2:18][C@@H:19]1[O:23][C:22](=[O:24])[N:21]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]([O:32][CH3:33])[O:34][CH3:35])=[C:27]([F:36])[CH:26]=2)[CH2:20]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COC(OC)c1ccc(N2C[C@H](CN)OC2=O)cc1F
Agent: O=C1c2ccccc2C(=O)C1(O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(OC)c1ccc(N2C[C@H](CNC(C)=O)OC2=O)cc1F

Procedure:
Acetic anhydride-pyridine-dichloromethane solution (1 to 1.5 to 3, 4 mL) was added to BAL resin immobilized 5-(S)-aminomethyl-3-[4′-dimethoxymethyl-3′-fluorophenyl]-oxazolidine-2-one, and the mixture was agitated for ca. 2 h (until negative ninhydrine test indicated completion of the acylation). The resin was filtered, washed liberally with methanol and dichloromethane and dried under vacuum.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:38]([NH2:40])=[O:39])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH2:26][N:27]5[CH2:31][CH2:30][CH2:29][CH:28]5[C:32]5C=CC=CC=5)[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[C:41]1([CH:47]2[CH2:51][CH2:50][CH2:49][NH:48]2)C=CC=CC=1>>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:38]([NH2:40])=[O:39])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH2:26][N:27]5[CH2:31][CH2:30][CH2:29][CH:28]5[CH2:32][N:48]5[CH2:41][CH2:47][CH2:51][CH2:50][CH2:49]5)[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CCCC5c5ccccc5)c4)cc23)CC1
Reactant: c1ccc(C2CCCN2)cc1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CCCC5CN5CCCCC5)c4)cc23)CC1
Yield: 32 %

Procedure:
The title compound was prepared according to the general procedure for 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-phenyl-1-pyrrolidinyl)methyl]-3-thienyl}-1H-indole-7-carboxamide, substituting 1-(2-pyrrolidinylmethyl)piperidine (168.3 mg, 1.0 mmol) for 2-phenylpyrrolidine to afford 21 mg of the title compound (32%).
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[N:12][N:13]2C(OC(C)(C)C)=O)=[CH:9][CH:8]=1)=[O:5].[C:27]([C:31]1[CH:32]=[C:33]2[C:38](=O)[O:37][C:35](=[O:36])[C:34]2=[CH:40][CH:41]=1)([CH3:30])([CH3:29])[CH3:28]>C1COCC1.C(OCC)C>[NH:13]1[C:14]2[C:10](=[CH:9][CH:8]=[C:7]([NH:6][C:4](=[O:5])[C:3]3[CH:23]=[CH:24][CH:25]=[CH:26][C:2]=3[N:1]3[C:38](=[O:37])[C:33]4[C:34](=[CH:40][CH:41]=[C:31]([C:27]([CH3:29])([CH3:28])[CH3:30])[CH:32]=4)[C:35]3=[O:36])[CH:15]=2)[CH:11]=[N:12]1
Reactant: CC(C)(C)OC(=O)n1ncc2ccc(NC(=O)c3ccccc3N)cc21
Reactant: CC(C)(C)c1ccc2c(c1)C(=O)OC2=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)c1ccc2c(c1)C(=O)N(c1ccccc1C(=O)Nc1ccc3cn[nH]c3c1)C2=O
Reaction time: 72 h
Yield: 16.3 %

Procedure:
To a stirring solution of 2-amino-N-(1-Boc-6-indazolyl)benzamide (1 g, 2.8 mmol) in THF (30 mL) was added 4-t-butylphthalic anhydride (1.2 g, 5.9 mmol) and the solution was heated to reflux. After 72 h, the vessel was cooled and the volume was reduced to about 10 mL in vacuo. The mixture was diluted with diethyl ether (20 mL) and after sonication, a white solid was collected. This solid was processed by methods substatially equivalent to those described in Example 2-F to give 200 mg of N-(6-indazolyl)-2-(5-t-butyl-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)benzamide.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:25])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[NH:6][C:5]1=[O:24])[CH:2]=[CH2:3].Br[CH:27]([CH:33]1[CH2:35][CH2:34]1)[C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[CH2:1]([C@@:4]1([CH3:25])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([CH:27]([CH:33]2[CH2:35][CH2:34]2)[C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:5]1=[O:24])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)NC1=O
Reactant: CCOC(=O)C(Br)C1CC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C(C(=O)OCC)C2CC2)C1=O

Procedure:
Coupling of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one (Example 71, Step D) and ethyl 2-bromo-2-cyclopropylacetate (Example 249, Step A) using the procedure as described in Example 9, step A afforded the title compound as a mixture of two diastereomers.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH2:17]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]2)=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH2:18][CH2:19][CH3:20]>>[CH2:17]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][CH:34]([NH:1][CH2:2][C@H:3]([OH:4])[C:5]3[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=3)[CH2:33][CH2:32]2)=[CH:27][CH:26]=1)(=[O:23])=[O:24])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCNS(=O)(=O)c1ccc(N2CCC(=O)CC2)cc1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: CCCCNS(=O)(=O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from N-[5-((1R)-2-Amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide and Reference Example 11, N-butyl-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide, according to the procedure of Example 1 as a white solid; mp 71-75° C.; 1H NMR (300 MHz, DMSO-d6) δ 0.80 (t, 3H), 1.10-1.40 (m, 6H), 1.80-1.95 (m, 2H), 2.50-2.90 (m, 5H), 2.92 (s, 3H), 3.70-3.90 (m, 2H), 4.45-4.55 (m, 1H), 6.82 (d, 1H), 7.02 (d, 3H), 7.02 (d, 3H), 7.19 (d, 1H), 7.54 (d, 2H); MS (ES) m/z: 541.0 (MH+); HRMS Calcd. for C24H37N4O6S2 (MH+): 541.2155. Found: 541.2136.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:13]2=[CH:14][N:15]([C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:24])[N:16]=[C:12]2[C:11]([Cl:25])=[CH:10][N:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:25][C:11]1[C:12]2[C:13](=[CH:14][N:15]([C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:24])[N:16]=2)[C:8]([NH2:7])=[N:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(Cl)c2nn(-c3c(Cl)cccc3Cl)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(Cl)c2nn(-c3c(Cl)cccc3Cl)cc12
Yield: 24845.2 %

Procedure:
A solution of [7-chloro-2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridin-4-yl]-carbamic acid tert-butyl ester (531 mg, contaminated with residual tert-butyl carbamate) and TFA (10 mL) in DCM (10 mL) was stirred at room temperature for 2 h and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and sodium bicarbonate (sat. aq.). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to afford the title compound as a beige solid (100 g, 30% yield over 2 steps). LCMS (Method D): RT=2.15 min, m/z: 313 [M+H+].
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:14][C@@H:15]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[NH:28][CH:29]=[C:30]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[CH:34][CH:33]=3)[N:31]=2)=[CH:23][CH:22]=1)[C:16]([O:18][CH3:19])=[O:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:14][C@@H:15]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[NH:28][CH:29]=[C:30]([C:32]4[CH:33]=[CH:34][C:35]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[CH:36][CH:37]=4)[N:31]=3)=[CH:25][CH:26]=2)[C:16]([O:18][CH3:19])=[O:17])=[O:11])=[CH:12][CH:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCCCOc1ccc(-c2c[nH]c(-c3ccc(C[C@H](N)C(=O)OC)cc3)n2)cc1
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(-c2c[nH]c(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)cc4)C(=O)OC)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.1 %

Procedure:
To a solution of 4-(tert-butyl)benzoic acid (25 mg, 0.14 mmol), (S)-methyl 2-amino-3-(4-(4-(4-(heptyloxy)phenyl)-1H-imidazol-2-yl)phenyl)propanoate (55 mg, 0.13 mmol), and TEA (53 μl, 0.38 mmol) in DMF (1 mL) was added HATU (53 mg, 0.14 mmol). The reaction mixture was stirred at RT for 2 h, diluted in DCM, and washed aq. NaHCO3. The organic layer was dried, concentrated and purified by chromatography (EA/hexane) to provide 14 mg (17%) of methyl (S)-2-(4-(tert-butyl)benzamido)-3-(4-(4-(4-(heptyloxy)phenyl)-1H-imidazol-2-yl)phenyl)propanoate. LCMS-ESI (m/z) calculated for C37H45N3O4: 595.8. found 596.4 [M+H]+, tR=2.33 min. (Method 8).
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C@@:13]1([C:21]2[S:22][CH:23]=[C:24]([Br:26])[CH:25]=2)[CH2:18][CH2:17][O:16][CH2:15][C@H:14]1[CH2:19][OH:20]>ClCCl>[C:1]([NH:9][C:10]([NH:12][C@@:13]1([C:21]2[S:22][CH:23]=[C:24]([Br:26])[CH:25]=2)[CH2:18][CH2:17][O:16][CH2:15][C@H:14]1[CH2:19][OH:20])=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: N[C@@]1(c2cc(Br)cs2)CCOC[C@H]1CO
Solvent: ClCCl
Product: O=C(NC(=S)N[C@@]1(c2cc(Br)cs2)CCOC[C@H]1CO)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzoyl isothiocyanate (66.5 μL) was added to a solution of (±)-[(3R*,4S*)-4-amino-4-(4-bromo-thiophen-2-yl)-tetrahydro-pyran-3-yl]methanol (144 mg) in dichloromethane (5 mL). The mixture was stirred at room temperature overnight, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (233 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([Cl:19])[CH:17]=3)[N:12]([S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH:11]=2)O)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[C:23]1([S:20]([N:12]2[C:13]3=[N:14][CH:15]=[C:16]([Cl:19])[CH:17]=[C:18]3[C:10]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([NH2:1])=[N:7][CH:6]=3)=[CH:11]2)(=[O:22])=[O:21])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1ccc(C(O)c2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)cn1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(Cc2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.8 %

Procedure:
To (6-amino-pyridin-3-yl)-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol (598, 1.00 g, 0.00241 mol) in dichloromethane (25.0 mL) were added triethylsilane (3.00 mL, 0.0188 mol) and trifluoroacetic acid (1.50 mL, 0.0195 mol). The reaction was stirred at room temperature overnight, then concentrated, poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (599, 0.70 g, 73%).
Reaction SMILES: [F:1][C:2]1[C:11]([CH:12]([NH2:14])[CH3:13])=[C:10]([F:15])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Br[C:17]1[C:18]([NH2:24])=[N:19][CH:20]=[C:21]([Br:23])[N:22]=1.CCN(C(C)C)C(C)C>C(#N)C>[Br:23][C:21]1[N:22]=[C:17]([NH:14][CH:12]([C:11]2[C:2]([F:1])=[C:3]3[C:8](=[CH:9][C:10]=2[F:15])[N:7]=[CH:6][CH:5]=[CH:4]3)[CH3:13])[C:18]([NH2:24])=[N:19][CH:20]=1
Reactant: CC(N)c1c(F)cc2ncccc2c1F
Reactant: Nc1ncc(Br)nc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(Nc1nc(Br)cnc1N)c1c(F)cc2ncccc2c1F
Temperature: 180 °C
Yield: 35.2 %

Procedure:
A mixture of 1-(5,7-difluoroquinolin-6-yl)ethanamine (800 mg, 3.8 mmol), 3,5-dibromopyrazin-2-amine (972.0 mg, 3.8 mmol) and DIPEA (2.0 g, 15.4 mmol) in acetonitrile (50 mL) was heated with microwave irradiation at 180° C. for 45 min. The reaction mixture was concentrated under reduced pressure, diluted with water, extracted with DCM three times. The combined organic layers were separated and washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (DCM/MeOH) to give the title compound as a yellow solid (508 mg, 35%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.95 (d, 1H), 8.46 (dd, 1H), 7.63 (d, 1H), 7.60 (dd, 1H), 7.11 (s, 1H), 7.08 (dd, 1H), 6.36 (bs, 2H), 5.45 (m, 1H), 1.70 (d, 3H). LCMS (method A): [MH]+=380/382, tR=5.03 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2].C(=O)([O-])O.[Na+].[I-].[Na+].Cl[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30]>CN1CCCC1=O.O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:7]([O:9][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30])=[O:8])([O-:3])=[O:2]
Reactant: OCCCCCCCl
Reactant: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(OCCCCCCO)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 50 °C
Yield: 88.8 %

Procedure:
357.70 g (1.686 Mol) of 3,5-dinitrobenzoic acid are suspended in 750 ml of 1-methyl-2-pyrrolidone. The suspension is stirred up to 50° C. 386.36 g (4.599 Mol) of sodium hydrogen carbonate are added and the mixture was heated up to 90° C. 22.50 g (0.150 Mol) of sodium iodide and 204.0 ml (1.533 Mol) of 6-chlorohexanol are added to the reaction mixture which is heated to 100° C. for 1 h. After 1 h of reaction, the reaction is complete and the orange suspension is thrown on 2 l of ice and 1 l of water. The product is filtrated, washed water and dried at 50° C. under vacuum for 24 h to give 425.0 g (91%) of 6-hydroxyhexyl 3,5-dinitrobenzoate as a rose powder.