Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:21])[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=3[O:19][CH3:20])=[C:6]2[N:5]=[C:4]([CH3:22])[CH:3]=1.[CH2:23]([NH2:26])[CH2:24][NH2:25].N.C(Cl)Cl>CC#N.CO>[NH2:25][CH2:24][CH2:23][NH:26][C:2]1[N:7]2[N:8]=[C:9]([CH3:21])[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=3[O:19][CH3:20])=[C:6]2[N:5]=[C:4]([CH3:22])[CH:3]=1
Reactant: COc1ccc(-c2c(C)nn3c(Cl)cc(C)nc23)c(OC)c1
Reactant: NCCN
Agent: N
Solvent: CO
Solvent: CC#N
Solvent: ClCCl
Product: COc1ccc(-c2c(C)nn3c(NCCN)cc(C)nc23)c(OC)c1
Temperature: 25 °C

Procedure:
Dissolve 7-chloro-2,5-dimethyl-3-(2,4-dimethoxyphenyl)-pyrazolo[1,5-a] pyrimidine in 25 mL CH3CN, then add excess ethylenediamine (5 mL) and heat to 80° C. for 3-6 h under N2 with attached reflux condenser. (TLC: [10% (2.0M NH3 in MeOH)/90% CH2Cl2] as eluent). Cool to ambient temperature and evaporate to yellow oil. Partition between CH2Cl2 (50 mL) and 1.0 N NaOH (50 mL), and extract aqueous layer 2×30 mL CH2Cl2. Pool organic layers, dry over Na2SO4, filter and evaporate to yellow-white foam. Use without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([I:27])=[CH:8][C:9]=1[N:10]([C:18]([CH:20]1[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][CH2:21]1)=[O:19])[CH:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1)=[O:4].C[Si](C)(C)OC1CCOC1.C([SiH](CC)CC)C.C([O-])(O)=O.[Na+]>[N+](C)([O-])=O.CO>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([I:27])=[CH:8][C:9]=1[N:10]([CH:11]1[CH2:12][CH2:13][CH:14]([OH:17])[CH2:15][CH2:16]1)[C:18]([CH:20]1[CH2:21][CH2:22][CH:23]([CH3:26])[CH2:24][CH2:25]1)=[O:19])=[O:4]
Reactant: COC(=O)c1sc(I)cc1N(C(=O)C1CCC(C)CC1)C1CCC(=O)CC1
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OC1CCOC1
Agent: O=C([O-])O
Solvent: CO
Solvent: C[N+](=O)[O-]
Product: COC(=O)c1sc(I)cc1N(C(=O)C1CCC(C)CC1)C1CCC(O)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 50.7 %

Procedure:
To a suspension of 5-iodo-3-[(4-methyl-cyclohexanecarbonyl)-(4-oxo-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester (2.5 g, 4.96 mmol) and FeCl3 (41 mg, 0.252 mmol) in nitromethane (15.0 mL) cooled to 0° C. was added neat trimethyl-(tetrahydro-furan-3-yloxy)-silane (955 mg, 5.95 mmol) followed by the dropwise addition of triethylsilane (0.947 mL, 5.92 mmol). The reaction was allowed to slowly warm to room temperature and stirred overnight. Sat. NaHCO3 was added and the reaction mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over Na2SO4 and concentrated to give a solid. The crude solid was heated in methanol, cooled and collected by filtration to provide 3-[(4-hydroxy-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-iodo-thiophene-2-carboxylic acid methyl ester (1.27 g, 44%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]([CH3:19])[C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([CH3:18])[CH:10]=2)=[CH:4][CH:3]=1.Cl.C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.[Fe]>[Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]([CH3:19])[C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([CH3:18])[CH:10]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(N(C)Cc2ccc(Cl)s2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Product: Cc1cc(N(C)Cc2ccc(Cl)s2)ccc1N
Reaction time: 0.83 h
Yield: 90.8 %

Procedure:
To a suspension of (5-chloro-thiophen-2-ylmethyl)-(methyl)-(3-methyl-4-nitrophenyl)-amine (1.85 g, 6.23 mmol) and iron powder (2.09 g, 37.4 mmol) in ethanol (60 mL) was added 6 N HCl (12.5 mL, 75 mmol), and the mixture was stirred vigorously at +60° C. for 50 minutes. It was then poured into saturated aqueous sodium bicarbonate (200 mL) to which enough sodium carbonate was added to attain a pH>10. The resulting mixture was extracted with ethyl acetate (200 mL, then 2×100 mL), the extract was dried over sodium sulfate and volatiles were evaporated. The residue was purified on a FlashMaster system (silica, eluted with heptane/ethyl acetate mixtures) to yield the title compound as a brown oil (1.51 g, 91%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:14][CH2:13][C:12]([CH3:15])=[N:11][C:10]3[N:16]([CH3:25])[N:17]=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[C:9]2=3)=[C:4]([CH3:26])[CH:3]=1.C(O)(=O)C>ClCCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:14][CH2:13][CH:12]([CH3:15])[NH:11][C:10]3[N:16]([CH3:25])[N:17]=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[C:9]2=3)=[C:4]([CH3:26])[CH:3]=1
Reactant: CC1=Nc2c(c(-c3ccccn3)nn2C)C(c2ccc(Br)cc2C)SC1
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1cc(Br)ccc1C1SCC(C)Nc2c1c(-c1ccccn1)nn2C
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
A mixture of 4-(4-bromo-2-methyl-phenyl)-1,7-dimethyl-3-(2-pyridyl)-4,6-dihydropyrazolo[3,4-e][1,4]thiazepine (0.48 g, 1.13 mmol., Preparation J.1), acetic acid (0.194 mL, 3.40 mmol) and Na(AcO)3BH (0.29 g, 1.36 mmol) in DCE (30 mL) was stirred at rt for about 16 h. Additional acetic acid (0.194 mL, 3.4 mmol) and Na(AcO)3BH (0.29 g, 1.36 mmol) were added and stirring was continued for about another 24 h, at rt. The resulting mixture was concentrated in vacuo and partitioned between 5% aq sodium bicarbonate (60 mL) and ethyl acetate (35 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (35 mL). The combined organic layers were washed with water (20 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, ethyl acetate/hexanes 1:1) to give 4-(4-bromo-2-methyl-phenyl)-1,7-dimethyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine (0.413 g, 0.96 mmol, 85%) as a pale yellow oil as a racemic mixture of two diastereomers (ratio 63:37). LC-MS (Table 1, Method g) Rt=2.75 and 2.79 min; m/z 429, 431 (M+H)+
Reaction SMILES: [F:1][CH:2]1[CH:7](OCC(F)(F)F)[NH:6][C:5](=[O:14])[NH:4][C:3]1=[O:15].Cl>>[F:1][C:2]1[C:3](=[O:15])[NH:4][C:5](=[O:14])[NH:6][CH:7]=1
Reactant: O=C1NC(=O)C(F)C(OCC(F)(F)F)N1
Agent: Cl
Product: O=c1[nH]cc(F)c(=O)[nH]1
Temperature: 0 °C
Yield: 49.4 %

Procedure:
0.43 g of 5-fluoro-6-(2,2,2-trifluoroethoxy)-5,6-dihydrouracil obtained in Example 2B was placed in a reflux flask and then 1 ml of concentrated HCl was added to the flask. When the flask contents were brought to refluxing conditions, precipitation of a solid occurred. The flask was cooled to 0°C, and the contents were filtered and washed with acetone, producing 0.12 g of 5-fluorouracil.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:8]=[CH:9][C:10]=1[CH2:11][C:12]1[N:13]([CH3:27])[C:14]([C:18](=[O:26])[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[C:15]([CH3:17])[CH:16]=1)=[O:4].[OH-].[Na+].Cl>CO.C1COCC1.O>[C:3]([C:5]1[CH:6]=[C:7]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:8]=[CH:9][C:10]=1[CH2:11][C:12]1[N:13]([CH3:27])[C:14]([C:18](=[O:26])[C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[C:15]([CH3:17])[CH:16]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1cc(NS(C)(=O)=O)ccc1Cc1cc(C)c(C(=O)c2ccc(Cl)cc2)n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Cc2ccc(NS(C)(=O)=O)cc2C(=O)O)n(C)c1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 64 h
Yield: 70.4 %

Procedure:
N-{3-Methoxycarbonyl-4-[5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-ylmethyl]phenyl}methanesulfonamide (735 mg, 1.54 mmol) and 2.5 N sodium hydroxide (2.5 ml) were dissolved in a 1:1 mixture of methanol-THF (40 ml) and stirred at room temperature for 64 h. The mixture was diluted with water, acidified to pH 2 with 2.0 N HCl, and extracted with ethyl acetate. The organic extracts were washed with brine, dried over sodium sulfate and concentrated to dryness. Crystallization from methylene chloride-methanol gave N-{3-carboxy-4-[5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-ylmethyl]phenyl}-methanesulfonamide (500 mg, 70%) as a solid, mp 248-250° C. (dec.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH:15]([C:23]([OH:25])=[O:24])[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)(O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(=O)(=O)(O)O.[OH-].[Na+].C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C.S([O-])(O)(=O)=O.[K+]>C(Cl)(Cl)Cl.O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([CH:15]([C:23]([OH:25])=[O:24])[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(C(C(=O)O)c2ccc(F)cc2)CC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])O
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(C(C(=O)O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
20.0 g of 1-t-Butoxycarbonyl-4-[carboxy-(4-fluorophenyl)methyl]-4-hydroxypiperidine was suspended in 40 ml of chloroform, and 40 ml of conc. sulfuric acid was added dropwise with ice-cooling. The reaction solution was refluxed with heating for 3 hours and, after ice-cooling, 250 ml of 4M sodium hydroxide solution, 200 ml of 1,4-dioxane and 14.8 g of di-t-butyldicarbonate were added. After stirring at room temperature for 30 minutes, the reaction solution was made acidic with potassium hydrogensulfate, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (Wako-gel C-200, chloroform:methanol=10:1) to give 18.0 g of 1-t-butoxycarbonyl-4-[carboxy-(4-fluorophenyl)methyl]-3,6-dihydro-2H-pyridine as an oil.
Reaction SMILES: I[C:2]1[CH:33]=[CH:32][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[C:19]([C:22]([NH:24][CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:23])=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][C:3]=1[CH3:34].[S:35]1[CH:39]=[CH:38][CH:37]=[C:36]1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:34][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:2]=1[C:36]1[S:35][CH:39]=[CH:38][CH:37]=1)[C:6]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][N:11]2[C:19]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[O:23])=[CH:20][CH:21]=[C:10]2[CH2:9]1)=[O:7]
Reactant: OB(O)c1cccs1
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)ccc1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)ccc1-c1cccs1
Temperature: 90 °C
Yield: 123.7 %

Procedure:
A mixture of 10-(4-iodo-3-methylbenzoyl)-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 74 (0.300 g, 0.53 mmol), 2-thiopheneboronic acid (0.102 g, 0.80 mmol) and potassium carbonate (0.221 g, 1.60 mmol) in dimethoxyethane:water (8 mL:2 mL) was purged with nitrogen for 10 minutes. [1,1′-bis(Diphenylphosphino)ferrocene]dichloropalladium [II] (0.022 g, 0.0266 mmol) was then added and the reaction mixture heated to 90° C. for 4 hours. The cooled reaction mixture was partitioned between ethyl acetate (100 mL) and 1 M sodium hydroxide (100 mL). The organic phase was separated, washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to give a brown syrup (0.34 g). Purification by flash chromatography using 280:8:1 dichloromethane:ethanol:aqueous ammonia as solvent gave an orange foam that was crystallized from diethyl ether/hexane to afford the title compound (0.168 g, 61%) as a tan solid.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[F:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([N+:21]([O-:23])=[O:22])=[CH:16][C:15]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:44]([N:51]1[CH2:56][CH2:55][N:54]([CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[CH2:53][CH:52]1[CH2:64][OH:65])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C1COCC1>[CH2:44]([N:51]1[CH2:56][CH2:55][N:54]([CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[CH2:53][CH:52]1[CH2:64][O:65][C:18]1[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][CH:15]=[C:14]([F:13])[C:19]=1[F:20])[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: O=[N+]([O-])c1cc(O)c(F)c(F)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)c(F)c1OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 6043.8 %

Procedure:
(1Ba) A solution of 4.7 g (27 mmol) of diethyl azodicarboxylate in 15 ml of THF was added dropwise at 15° C. while stirring to a solution of 3.9 g (22.5 mmol) of 2,3-difluoro-5-nitrophenol, 7.1 g (27 mmol) of triphenylphosphine and 8 g (0.27 mmol) of 1,4-dibenzyl-2-hydroxymethylpiperazine in 250 ml of THF. The yellow reaction solution was then stirred at room temperature for an additional 3 hours. After concentrating the reaction solution, the oily residue was stirred with a total of 2 l of hot n-hexane in several portions. The hexane solution was separated and cooled. The separated triphenylphosphine oxide was removed by filtration under suction, and the filtrate was concentrated. Chromatography on silica gel with ether/n-hexane (1:1) as the eluent gave 7.4 g of 1,4-dibenzyl-2-[(6-nitro-2,3-difluorophenoxy)methyl]-piperazine as a brown oil.
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.[CH3:21][C:22]([CH3:24])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:21][C:22]1([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
Reactant: CC(C)=O
Reactant: OCCc1c[nH]c2ccc(OCc3ccccc3)cc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC1(C)OCCc2c1[nH]c1ccc(OCc3ccccc3)cc21
Temperature: 25 °C

Procedure:
A mixture consisting of 5-benzyloxytryptophol (3.2 g, 0.012 mol), acetone (7 mL), benzene (300 mL) and p-toluene sulfonic acid (500 mg) is refluxed for 3.5 hours using a Dean-Stark trap to remove the water. The reaction mixture is cooled to room temperature and washed with 5% sodium bicarbonate (1×200 mL), water (200 mL) and brine (200 mL). It is dried (MgSO4), filtered and concentrated to give 5.0 g product as thick oil. The crude product is flash chromatographed with 15% ethyl acetate/hexane as an eluent to afford 2.5 g product, m.p. 128°-129° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([CH3:10])([OH:9])[C:5]([F:8])([F:7])[F:6].[C:11](=O)([O:20]N1C(=O)CCC1=O)[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl.O>[F:6][C:5]([F:8])([F:7])[C:4]([OH:9])([CH3:10])[CH2:3][NH:2][C:11](=[O:20])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(O)(CN)C(F)(F)F
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC(O)(CNC(=O)OCc1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirring suspension of amino-1,1,1-trifluoro-2-methylpropan-2-ol hydrochloride (Intermediate R) (1.5 g, 8.35 mmol) in DCM (50 ml) was added TEA 93.54 g, 35.0 mmol) followed by benzyl 2,5-dioxopyrrolidin-1-yl carbonate (1.983 g, 7.96 mmol). The mixture was stirred at RT for 6 hours and then diluted with water. The organic portion was separated using a phase separator and concentrated in vacuo. Purification by chromatography on silica eluting with 0-70% EtOAc in iso-hexane afforded the title product; 1H NMR (400 MHz, DMSO-d6) δ 7.34 (6H, m), 5.98 (1H, s), 5.05 (2H, s), 3.31 (1H, m), 3.18 (1H, m), 1.21 (3H, s)LC-MS: Rt 1.05 min; MS m/z 278.1 [M+H]+; Method 2 min LC_v003.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1.[Cl:18][C:19]1[C:28]2[C:23](=[CH:24][C:25]([S:29](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:31])=[O:30])=[CH:26][CH:27]=2)[N:22]=[CH:21][CH:20]=1>C1COCC1.[Cl-].[NH4+].O.CCOC(C)=O.CCCCCCC>[Cl:18][C:19]1[C:28]2[C:23](=[CH:24][C:25]([S:29]([N:6]([CH2:5][C:4]3[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=3[O:2][CH3:1])[C:7]3[S:11][N:10]=[CH:9][N:8]=3)(=[O:30])=[O:31])=[CH:26][CH:27]=2)[N:22]=[CH:21][CH:20]=1
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(Cl)ccnc2c1
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCCC
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Cl)ccnc3c2)c(OC)c1
Reaction time: 1 h
Yield: 81.6 %

Procedure:
A flask was charged with N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (302 mg, 1.204 mmol) and THF (5471 μl) to give a clear solution. The flask was cooled in a dry ice-acetone bath for 5 min, and then a solution of perfluorophenyl 4-chloroquinoline-7-sulfonate (448.3 mg, 1.094 mmol) in THF (1 mL with a 0.5 mL syringe wash) was added drop wise. After 1 h, the mixture was diluted with saturated aq. ammonium chloride, water, and EtOAc, and the layers were separated. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (40-g Redi-Sep Gold column, 20-70% EtOAc/Heptane) to give an off-white solid. The solid was taken up in heptane and filtered. The collected solid was washed with heptane (2×), then dried under a stream of N2 (g) for 2 h to give 4-chloro-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)quinoline-7-sulfonamide (426 mg, 0.893 mmol, 82% yield) as a white solid. m/z (ESI) 477.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[C:17]([O:24][CH3:25])[CH:16]=3)[CH:10]([O:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C@@H:12]([C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[C:17]([O:24][CH3:25])[CH:16]=2)[C@@H:10]([OH:11])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(C23CCN(C(=O)OC(C)(C)C)CC2O3)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1cc([C@@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2O)ccc1N
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of 6-(3-methoxy-4-nitro-phenyl)-7-oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylic acid tert-butyl ester (190 mg, 0.542 mmol) in methanol (10.00 mL) was added palladium on carbon 10% (40.00 mg), and the mixture was shaken in a Parr apparatus under an atmosphere of hydrogen (35 PSI) for 2 h. Filtration through Celite and evaporation of the solvent provided crude (±)-(3R,4S)-4-(4-amino-3-methoxy-phenyl)-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (173 mg, 99%), which was used without further purification.
Reaction SMILES: F[C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:11](=[O:12])[N:10]([C:13]3[S:17][C:16]([C:18]([OH:20])=O)=[C:15]([CH3:21])[CH:14]=3)[CH:9]=[N:8]2)=[CH:4][CH:3]=1.C(N1C(=O)N(C2SC(C(O)=O)=C(C)C=2)C=N1)C1C=CC=CC=1.[NH2:46][CH2:47][C:48]1[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=1>>[CH2:6]([N:7]1[C:11](=[O:12])[N:10]([C:13]2[S:17][C:16]([C:18]([NH:46][CH2:47][C:48]3[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=3)=[O:20])=[C:15]([CH3:21])[CH:14]=2)[CH:9]=[N:8]1)[C:5]1[CH:4]=[CH:3][CH:2]=[CH:23][CH:22]=1
Reactant: Cc1cc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: Cc1cc(-n2cnn(Cc3ccccc3)c2=O)sc1C(=O)O
Product: Cc1cc(-n2cnn(Cc3ccccc3)c2=O)sc1C(=O)NCc1cccnc1
Yield: 89 %

Procedure:
Following the procedure as described in Example 31, making variations as required to replace 5-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-3-methylthiophene-2-carboxylic acid with 5-(1-benzyl-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-3-methylthiophene-2-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a colorless solid in 89% yield: mp 180-181° C.; 1H NMR (300 MHz, CDCl3) δ 8.61 (s, 1H), 8.54 (s, 1H), 7.73 (s, 1H), 7.71 (d, J=8.1 Hz, 1H), 7.43-7.25 (m, 6H), 6.88 (s, 1H), 6.48 (t, J=5.6 Hz, 1H), 5.00 (s, 2H), 4.61 (d, J=5.6 Hz, 2H), 2.52 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.6, 150.4, 149.2, 149.0, 140.8, 135.6, 135.3, 134.5, 132.2, 128.8, 128.4, 128.2, 125.1, 120.0, 49.8, 41.4, 16.0: MS (ES+) m/z 406.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15]3([CH2:19][S:18][C:17]([N:20]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12](I)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[N:38]1[CH:43]=[CH:42][CH:41]=[C:40](B(O)O)[CH:39]=1.C(=O)([O-])[O-].[K+].[K+]>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>[Br:1][C:2]1[CH:3]=[C:4]2[C:15]3([CH2:19][S:18][C:17]([N:20]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:40]4[CH:39]=[N:38][CH:43]=[CH:42][CH:41]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)C1=NC2(CS1)c1cc(I)ccc1Oc1ncc(Br)cc12
Reactant: OB(O)c1cccnc1
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: [K+]
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)C1=NC2(CS1)c1cc(-c3cccnc3)ccc1Oc1ncc(Br)cc12
Temperature: 80 °C

Procedure:
A vial was charged with 3-bromo-7-iodo-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine (0.114 g, 0.155 mmol), pyridin-3-ylboronic acid (0.029 g, 0.233 mmol), potassium carbonate (0.107 g, 0.776 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.018 g, 0.016 mmol). The vial was flushed with Ar (g), then dioxane (1.035 mL) and water (0.517 mL) were added in sequence. The vial was sealed and heated at 80° C. for 2 hrs. After cooling to RT the reaction was diluted with EtOAc (25 mL) and washed with water (25 mL). The aqueous layer was extracted with EtOAc (3×15 mL), and the combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep 40 g, gradient elution 0-5% MeOH:DCM) to afford 3-bromo-7-(pyridin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine as a white solid.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[CH:10]([N:13]1[CH2:18][CH2:17][CH:16]([NH:19][S:20]([CH2:23][C:24]([NH2:27])([CH3:26])[CH3:25])(=[O:22])=[O:21])[CH2:15][CH2:14]1)([CH3:12])[CH3:11]>>[CH:10]([N:13]1[CH2:18][CH2:17][CH:16]([NH:19][S:20]([CH2:23][C:24]([NH:27][C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:9])([CH3:25])[CH3:26])(=[O:22])=[O:21])[CH2:15][CH2:14]1)([CH3:12])[CH3:11]
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: CC(C)N1CCC(NS(=O)(=O)CC(C)(C)N)CC1
Product: CC(C)N1CCC(NS(=O)(=O)CC(C)(C)NC(=O)c2ccc(Cl)s2)CC1

Procedure:
5-Chloro-thiophene-2-carboxylic acid [2-(1-isopropyl-piperidin-4-ylsulfamoyl)-1,1-dimethyl-ethyl]-amide was prepared by an analogous procedure as described in example 26 viii) starting from 195 mg (1 equiv.) 5-chloro-thiophene-2-carboxylic acid and 332 mg (1.2 mmol) 2-amino-2-methyl-propane-1-sulfonicacid (1-isopropyl-piperidin-4-yl)-amide. Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.1% TFA) gave pure 5-chloro-thiophene-2-carboxylic acid [2-(1-isopropyl-piperidin-4-ylsulfamoyl)-1,1-dimethyl-ethyl]-amide. The title compound was obtained as its trifluoroacetate in form of a colorless amorphous material.