Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([F:33])[C:9]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:10]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:11]=2)[C:6](=[O:34])[C:5]([C:35]([O:37]CC2C=CC(OC)=CC=2)=[O:36])=[CH:4]1)[CH3:2].[OH-].[K+]>CO.O>[CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([F:33])[C:9]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)=[C:10]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[CH:11]=2)[C:6](=[O:34])[C:5]([C:35]([OH:37])=[O:36])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)OCc2ccc(OC)cc2)c(=O)c2c(F)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCn1cc(C(=O)O)c(=O)c2c(F)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Temperature: 90 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
To a suspension of 4-methoxybenzyl 1-ethyl-5-fluoro-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylate (68 g, 108 mmol) in a mixture of Methanol (250 mL) and Water (125 mL) was added KOH (12.16 g, 217 mmol) portionwise. The resulting mixture was stirred at 90° C. for 3 h. LCMS indicated completion of the reaction. The reaction mixture was cooled down to r.t. and concentrated, and was then diluted with water and adjusted pH to 1 using 6 N HCl (aq.). The precipitates were collected by filtration and dried to afford 1-ethyl-5-fluoro-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (50 g, 99 mmol, 91% yield) as a brown solid. LCMS: (M+H)+: 508.2.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19](O)=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].[CH:37]1([S:40]([NH2:43])(=[O:42])=[O:41])[CH2:39][CH2:38]1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:43][S:40]([CH:37]3[CH2:39][CH2:38]3)(=[O:42])=[O:41])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:25][CH2:26][CH:27]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH2:28][CH2:29]1)=[O:23]
Reactant: Cc1ccc(C)c(Nc2c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc3c(C(=O)O)cnn23)c1
Reactant: NS(=O)(=O)C1CC1
Product: Cc1ccc(C)c(Nc2c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc3c(C(=O)NS(=O)(=O)C4CC4)cnn23)c1
Yield: 31.3 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2,5-dimethylphenylamino)-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (97 mg, 0.20 mmol) obtained in Example 86, step 2 and cyclopropanesulfonamide (120 mg, 1.00 mmol), the title compound (37 mg, 32%) was obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[CH2:14](Br)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(Br)C1C=CC=CC=1>>[CH2:14]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: BrCCc1ccccc1
Agent: BrCc1ccccc1
Product: COC(=O)c1ccc2ccn(CCc3ccccc3)c2c1
Yield: 19.1 %

Procedure:
The same procedures used in Example 1 were repeated except for using 2.00 g of methyl indole-6-carboxylate and 2.54 g of phenethyl bromide instead of the indole-4-carbaldehyde and benzyl bromide used in Example 1 to give 0.61 g of methyl 1-phenethylindole-6-carboxylate as a yellow oily substance. The yield thereof was found to be 19%.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH:10]=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]>C(O)C.C1COCC1.[Pd]>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CC=C(c2c[nH]c3ncccc23)CC1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(c2c[nH]c3ncccc23)CC1
Yield: 47.3 %

Procedure:
3.3 g (12 mmol) of 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid ethyl ester were dissolved in 15 ml of ethanol and 5 ml of THF. Over this solution, 3.3 g of Pd over carbon at 10% were added. The crude mixture was hydrogenated at 30 psi for 48 hours. The catalyst was filtered off and the solvent removed under reduced pressure affording 1.55 g (54%) of 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylic acid ethyl ester.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH2:11][CH2:12][CH2:13][CH:14]([OH:15])[C:7]2=[N:6][C:5]=1[CH3:16].Cl.[F:18][C:19]1[CH:33]=[CH:32][C:22]2[C:23]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[N:24][O:25][C:21]=2[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>[I-].[K+].[BH4-].[Na+].C(#N)C>[CH3:16][C:5]1[N:6]=[C:7]2[N:8]([CH2:11][CH2:12][CH2:13][CH:14]2[OH:15])[C:9](=[O:10])[C:4]=1[CH2:3][CH2:2][N:29]1[CH2:28][CH2:27][CH:26]([C:23]2[C:22]3[CH:32]=[CH:33][C:19]([F:18])=[CH:20][C:21]=3[O:25][N:24]=2)[CH2:31][CH2:30]1
Reactant: Cc1nc2n(c(=O)c1CCCl)CCCC2O
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: CC#N
Product: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86 %

Procedure:
300 ml of acetonitrile was charged followed by 20.0 g of 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]-pyrimidin-4-one and 21.0 g of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride at room temperature. The reaction mass was stirred at room temperature for 5 minutes and 20.0 g of potassium carbonate and 0.7 g of potassium iodide were charged. Further, 0.2 g of sodium borohydride was charged and the temperature was raised to 65±2° C. The reaction mass was maintained at 65±2° C. for 25 hours. After reaction completion, the reaction mass was slowly cooled to room temperature. The solids were filtered, washed with 50 ml of acetonitrile and then dissolved in 800 ml of methylene chloride at room temperature. The contents were heated to 30-35° C., maintained for 10 minutes, filtered and washed with 20 ml of methylene chloride. The clear filtrate was distilled completely under vacuum below 35° C. and replaced with 50 ml of acetone. Further, 300 ml of acetone was charged, heated to 45° C. and stirred for 30 minutes. The reaction mass was cooled to room temperature and stirred for 1 hour. The product was filtered, washed with 20 ml of acetone and dried under vacuum at 50-55° C. to yield paliperidone (30 g, yield: 150% w/w, efficiency: 85.11%, keto impurity by HPLC: 0.01%, total impurity level by HPLC: 1.0%)
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:13]([C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)=[O:15])=[C:12](O)[C:11]2[C:6](=[CH:7][C:8]([C:26]([F:29])([F:28])[F:27])=[CH:9][CH:10]=2)[N:5]=1)[CH3:2].O=P(Cl)(Cl)[Cl:32].C([O-])(O)=O.[Na+]>CCCCCC>[Cl:32][C:12]1[C:11]2[C:6](=[CH:7][C:8]([C:26]([F:29])([F:28])[F:27])=[CH:9][CH:10]=2)[N:5]=[C:4]([S:3][CH2:1][CH3:2])[C:13]=1[C:14]([NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1)=[O:15]
Reactant: CCSc1nc2cc(C(F)(F)F)ccc2c(O)c1C(=O)NCc1cccc(F)c1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Product: CCSc1nc2cc(C(F)(F)F)ccc2c(Cl)c1C(=O)NCc1cccc(F)c1
Temperature: 130 °C
Yield: 48 %

Procedure:
A mixture of 1.0 g (2.36 mmol) 2-(ethylthio)-N-(3-fluorobenzyl)-4-hydroxy-7-(trifluoromethyl)quinoline-3-carboxamide and POCl3 (10 ml) was heated for 2 h at 130° C. After cooling to RT the mixture was adjusted to pH ˜8 with a saturated aqueous NaHCO3 solution and extracted with EE. The organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. Column chromatography (hexane/EE 22:3) of the residue yielded 0.5 g (1.1 mmol, 48%) 4-chloro-2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-7-(trifluoromethyl)-quinoline-3-carboxamide. MS: m/z 443.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH2:9][C:10]3[CH:21]=[CH:20][C:13]4[N:14]=[C:15](S(C)=O)[O:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[NH2:24][C@@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]1[OH:31].CCN(C(C)C)C(C)C.O>CC(N(C)C)=O>[Br:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH2:9][C:10]3[CH:21]=[CH:20][C:13]4[N:14]=[C:15]([NH:24][C@@H:25]5[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]5[OH:31])[O:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cc(Br)ccc43)cc2o1
Reactant: N[C@@H]1CCCC[C@H]1O
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(Br)ccc43)cc2o1
Temperature: 120 °C
Reaction time: 2 h
Yield: 74.8 %

Procedure:
A mixture of 6-((5-bromo-1H-benzo[d]imidazol-1-yl)methyl)-2-(methyl sulfinyl)benzo[d]oxazole (206 mg, 0.53 mmol), (1R,2R)-2-aminocyclohexanol (91 mg, 0.79 mmol) and DIEA (136 mg, 1.06 mmol) in DMA (4 mL) was stirred at 120° C. for 2 h. The reaction mixture was cooled to rt, poured into water (30 mL) and extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give (1R,2R)-2-((6-((5-bromo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol as a light yellow solid (175 mg, 74.8%). 1H NMR (300 MHz, DMSO-d6) δ 8.46 (s, 1H), 7.81-7.84 (m, 2H), 7.56 (d, J=8.7 Hz, 1H), 7.33-7.36 (s, 1H), 7.12 (s, 2H), 5.48 (s, 1H), 4.68 (d, J=4.2 Hz, 1H), 3.35 (br s, 2H), 1.90 (br s, 2H), 1.62 (br s, 2H), 1.22 (br s, 4H). LCMS (ESI) m/z 442 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][S:11]([CH2:14][CH2:15][N:16]1[C:20](=[O:21])[C:19]([CH3:23])([CH3:22])[NH:18][C:17]1=[O:24])(=[O:13])=[O:12].C(O[Cl:30])(C)(C)C>CO>[Cl:30][N:18]1[C:19]([CH3:22])([CH3:23])[C:20](=[O:21])[N:16]([CH2:15][CH2:14][S:11]([CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])(=[O:13])=[O:12])[C:17]1=[O:24]
Reactant: CC(C)(C)OCl
Reactant: COCCOCCOCCS(=O)(=O)CCN1C(=O)NC(C)(C)C1=O
Solvent: CO
Product: COCCOCCOCCS(=O)(=O)CCN1C(=O)N(Cl)C(C)(C)C1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 52.8 %

Procedure:
A solution of 3-(2-((2-(2-(2-methoxyethoxy)ethoxy)ethyl)sulfonyl)ethyl)-5,5-dimethylimidazolidine-2,4-dione (1.9 g, 5.2 mmol) in methanol (10 ml) was cooled to 0° C. tert-Butylhypochlorite (613 ul, 5.45 mmol) was added. The resulting solution was stirred for 3 hours at 0° C., and then concentrated under reduced pressure. The crude material was purified by column chromatography, eluting from silica gel with a gradient of 5-12% methanol in dichloromethane to give 1.1 g of a clear oil. 1H NMR (D2O, 400 MHz) δ 1.39 (s, 6H), 3.28 (s, 3H), 3.43-3.47 (t, J=5.4 Hz, 2H), 3.51-3.61 (m, 10H) 3.85-3.88 (t, 5.2 Hz, 2H), 4.02-4.05 (m, 2H). LRMS (ESI/APCI) m/z 401 [M+H]+.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][OH:8].C[C:10](=[N:13]O)CC>>[CH3:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][OH:8].[N-:13]=[C:10]=[O:5]
Reactant: CCC(C)=NO
Solvent: CCCCOCCO
Product: [N-]=C=O

Procedure:
To the reactant, butyl cellosolve (72.7 parts by mass) was added. Subsequently, the temperature of the reactant was set to 50° C. To the reactant, 25.8 parts by mass of 2-butanone oxime (manufactured by Ardrich) was added dropwise to obtain a butyl cellosolve solution of isocyanate compound D having an average number of functional groups: 3.5.
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1.[C:14]([O:18][C:19](=[O:25])[NH:20][CH2:21][CH2:22][CH2:23]Br)([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:14]([O:18][C:19](=[O:25])[NH:20][CH2:21][CH2:22][CH2:23][O:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: O=Cc1ccc(O)c2c1CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCOc1ccc(C=O)c2c1CCCC2
Yield: 59.8 %

Procedure:
4-Hydroxy-5,6,7,8-tetrahydro-naphthalene-1-carbaldehyde (109, 4.6 g, 29.1 mmol) (3-Bromopropyl)-carbamic acid tert-butyl ester (110, 4.6 g, 32 mmol), and potassium carbonate (6.03 g, 43.7 mmol) were stirred in 140 mL of dry DMF over night. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with water and brine., dried with magnesium sulfate, filtered, concentrated and purified by flash chromatography (0-30% EtOAc/hexane) to give crude product, which was recrystallized from EtOAc/Hexane to give 5.8 g of 111, [3-(4-formyl-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-propyl]-carbamic acid tert-butyl ester.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[CH:4][C:3]=1[C:13]([O:15]CC)=O.[C:18]1([NH:24][NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[CH2:11]([O:10][C:8]([C:7]1[C:2]2[C:3]([C:13](=[O:15])[N:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:25]=2)=[CH:4][NH:5][CH:6]=1)=[O:9])[CH3:12]
Reactant: NNc1ccccc1
Reactant: CCOC(=O)c1cncc(C(=O)OCC)c1Cl
Solvent: CCO
Product: CCOC(=O)c1c[nH]cc2c(=O)n(-c3ccccc3)nc1-2

Procedure:
A mixture of diethyl 4-chloro-3,5-pyridinedicarboxylate (3.09 g, 12.0 mmol) and phenylhydrazine (1.42 ml, 14.4 mmol) in ethanol (100 ml) was degassed by evaporating under vacuum and refilling with nitrogen several times. The mixture was then stirred at reflux for 17 h under nitrogen. The mixture was left to cool in the fridge for a few hours, then filtered from a solid, which was washed with ethanol and ethyl acetate. The combined filtrates were evaporated in vacuo, and the residue was purified by flash chromatography (silica gel, 5% MeOH/CH2Cl2) to afford 1.559 g (46%) as an orange solid; 1H NMR (360 MHz, DMSO-d6) δ1.35 (3H t, J 7.1 Hz), 4.34 (2H, q, J 7.1 Hz), 7.18 (1H, t, J 7.3 Hz), 7.44 (2H, t, J 7.5 Hz), 8.14 (1H, s), 8.19 (2H, d, J 7.6 Hz), 8.57 (1H, s), 12.49 (1H, br s).
Reaction SMILES: Cl[C:2]1[C:14]2[N:13]=[C:12]3[N:7]([CH2:8][CH2:9][O:10][C:11]3([CH3:16])[CH3:15])[C:6]=2[N:5]=[C:4]([Cl:17])[N:3]=1.[C@H:18]12[CH2:24][C@H:21]([NH:22][CH2:23]1)[CH2:20][O:19]2.C(N(CC)CC)C>>[Cl:17][C:4]1[N:3]=[C:2]([N:22]2[CH2:23][C@@H:18]3[CH2:24][C@H:21]2[CH2:20][O:19]3)[C:14]2[N:13]=[C:12]3[N:7]([C:6]=2[N:5]=1)[CH2:8][CH2:9][O:10][C:11]3([CH3:16])[CH3:15]
Reactant: C1O[C@@H]2CN[C@H]1C2
Reactant: CC1(C)OCCn2c1nc1c(Cl)nc(Cl)nc12
Solvent: CCN(CC)CC
Product: CC1(C)OCCn2c1nc1c(N3C[C@@H]4C[C@H]3CO4)nc(Cl)nc12
Temperature: 140 °C
Yield: 97.6 %

Procedure:
A mixture of 1,3-dichloro-8,8-dimethyl-5,6-dihydro-8H-7-oxa-2,4,4b,9-tetraaza-fluorene (100 mg, 0.366 mmol), (1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]heptane (73 mg, 0.732 mmol) and triethylamine (77 μL, 0.55 mmol) in IMS (2 mL) was heated at 140° C. for 20 mins in a microwave reactor, then concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, 10% ethyl acetate in pentane) affording 3-chloro-8,8-dimethyl-1-(1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl-5,6-dihydro-8H-7-oxa-2,4,4b, 9-tetraaza-fluorene as a yellow solid (120 mg, 98%). LCMS (method A): RT=2.81 min, [M+H]+=336.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2].Br[C:20]1[S:21][C:22]([N+:25]([O-:27])=[O:26])=[N:23][N:24]=1.C([O-])([O-])=O.[K+].[K+].Cl>C(#N)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:20]3[S:21][C:22]([N+:25]([O-:27])=[O:26])=[N:23][N:24]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Reactant: O=[N+]([O-])c1nnc(Br)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CC1OB(O)c2cc(Oc3nnc([N+](=O)[O-])s3)cc(C)c21
Temperature: -20 °C
Reaction time: 84 h

Procedure:
To a solution of (1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (2.55 g, 10.2 mmol) in anhydrous acetonitrile (150 mL) was added 2-bromo-5-nitro-[1,3,4]thiadiazole (3.0 g, 14.3 mmol) at 0° C. The reaction mixture was cooled to −20° C. and K2CO3 (9.87 g, 71.4 mmol) was added. After stirring at −20 to −25° C. for 3.5 days, the reaction mixture was acidified to pH 2 with dilute hydrochloric acid at 0° C. and extracted with EtOAc. The organic extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (EtOAc/hexanes/AcOH=2:1:trace) followed by recrystallization from methanol to give pure product as a white powder after lyophilization (1.35 g, 34.9%). 1HNMR (400 MHz, DMSO-d6) δ9.41 (s, 1H), 7.54 (d, J=2.34 Hz, 1H), 7.41 (d, J=1.76 Hz, 1H), 5.58 (dd, J=8.64, 2.78 Hz, 1H), 4.02 (q, J=7.22 Hz, 2H), 3.14 (dd, J=15.52, 2.63 Hz, 1H), 2.23-2.43 (m, 4H), 1.12 (t, 3H). MS (ESI) m/z=378 [M−H]−.
Reaction SMILES: C[C:2](C)([CH2:6][S:7][S:8][CH2:9][CH2:10][C:11]([NH2:13])=[O:12])[C:3]([NH2:5])=[O:4].[CH2:15](N)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>CO>[CH2:15]([NH:13][C:11](=[O:12])[CH2:10][CH2:9][S:8][S:7][CH2:6][CH2:2][C:3]([NH:5][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:4])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CC(C)(CSSCCC(N)=O)C(N)=O
Reactant: CCCCCCCCN
Solvent: CO
Product: CCCCCCCCNC(=O)CCSSCCC(=O)NCCCCCCCC
Temperature: 5 °C
Reaction time: 120 h
Yield: 76 %

Procedure:
238 g (1 mol) of dimethyl 3,3′-dithiodipropionamide and 280 g (2.17 mol) of n-octylamine were added into 300 ml of methanol in a 1,000 ml reaction flask, and the reactants stirred at 5° C. for 5 days (under nitrogen atmosphere, if desired). The reaction mixture was then cooled to −10° C., and separated by centrifuging to give 329 g of a solid of N,N′-di-n-octyl-3,3′-dithiodipropionamide (purity >95%, yield 76%). The mother liquor was recycled after methanol was recovered by evaporation.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[CH:14][C:13]=3[C:24]([F:27])([F:26])[F:25])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.OC1CCNC1.[C:34]([NH:37][CH:38]1[CH2:42][CH2:41][NH:40][CH2:39]1)(=[O:36])[CH3:35]>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:19]=[CH:20][N:21]=[C:22]([N:40]5[CH2:41][CH2:42][CH:38]([NH:37][C:34](=[O:36])[CH3:35])[CH2:39]5)[CH:23]=4)=[CH:14][C:13]=3[C:24]([F:25])([F:26])[F:27])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(=O)NC1CCNC1
Reactant: FC(F)(F)c1cc(-c2ccncc2)ccc1Sc1ccc2c(c1)OCCO2
Agent: OC1CCNC1
Product: CC(=O)NC1CCN(c2cc(-c3ccc(Sc4ccc5c(c4)OCCO5)c(C(F)(F)F)c3)ccn2)C1

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 118 (0.033 g, 0.0779 mmol) and 3-hydroxypyrrolidine with 3-acetamidopyrrolidine. A yellow solid 124 was obtained (0.0369 g, 72%). 1H NMR (CDCl3, 400 MHz) δ 2.01 (s, 3H), 2.24–2.31 (m, 1H), 2.34–2.41 (m, 1H), 3.78–3.90 (m, 3H), 4.01–4.10 (m, 1H), 4.28–4.34 (m, 4H), 4.62–4.68 (m, 1H), 6.78 (s, 1H), 6.93–6.97 (m, 2H), 7.05 (dd, J=2.2 Hz, 8.4 Hz, 1H), 7.09–7.13 (m, 2H), 7.18 (br s, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.83 (s, 1H), 8.07 (d, J=6.6 Hz, 1H); MS (APCI) m/z 516 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:34])=[C:4]([S:9]([N:12]([CH2:21][C:22]2[CH:33]=[CH:32][C:25]([C:26](N(OC)C)=[O:27])=[CH:24][CH:23]=2)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:35]1([Mg]Br)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1COCC1>[C:26]([C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[S:9]([C:4]2[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=2[OH:34])(=[O:11])=[O:10])=[CH:33][CH:32]=1)(=[O:27])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CON(C)C(=O)c1ccc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1ccc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.2 %

Procedure:
To a solution of 4-((3,5-dichloro-N-(4-fluorobenzyl)-2-hydroxyphenylsulfonamido)methyl)-N-methoxy-N-methylbenzamide (0.105 g, 0.20 mmol) in THF (2 mL) was added phenylmagnesium bromide (3M in ether, 0.267 mL, 0.800 mmol). The resulting mixture was stirred at rt overnight. The mixture was quenched by adding cold saturated aq. NH4Ac solution and extracted with DCM. The combined organic extracts were dried and concentrated. The residue was purified by preparative HPLC. The desired fractions were combined, concentrated and lyophilized to dryness to give the title compound (46 mg, 42%) as a tan solid. MS (ESI): 544.1 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32]([OH:34])=O)[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[NH2:35][CH:36]1[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:28])[CH3:29])[C:21]([CH3:31])=[C:20]([C:32]([NH:35][CH:36]4[CH2:37][CH2:38][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:40][CH2:41]4)=[O:34])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1cc(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F
Product: Cc1cc(-c2ncnc3c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methylphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c11) and commercially available tert-butyl 4-amino-piperidine-1-carboxylate the title compound is obtained as pale yellow foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:23])([CH3:22])[CH2:12][C:13]([OH:21])([C:17]([F:20])([F:19])[F:18])[C:14](O)=[O:15])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[Li].C([O-])(O)=O.[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:23])([CH3:22])[CH2:12][C:13]([C:17]([F:20])([F:18])[F:19])([OH:21])[CH2:14][OH:15])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: CC(C)(CC(O)(C(=O)O)C(F)(F)F)c1cc(F)cc2c1OCC2
Agent: O=C([O-])O
Agent: [Li]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(CC(O)(CO)C(F)(F)F)c1cc(F)cc2c1OCC2
Temperature: 4 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
A solution of 6.6 mol 4-(5-fluoro-2,3-dihydro-benzofuran-7-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanoic acid in 77 ml of THF is cooled to 4° C. 12 mmol of lithium aluminumhydride is added portionwise to the solution. The mixture is stirred at 4° C. for 60 minutes, and stirred for 8-9 hours under reflux conditions. After complete reaction (TLC control) the mixture is cooled to 4° C. and treated with 1 ml of saturated NaHCO3 solution. The mixture is stirred for at least 2 hours whereupon the colour of the mixture turns from grey to white. The precipitated aluminium salts are filtered off and washed with 10 ml of hot THF. The solvent is evaporated under vacuum. The residue is purified by recrystallization from dichloromethane and n-heptane. (yield 73.7%).