Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13].[N:14]1[O:15][CH2:16][CH:17]2[CH2:21][O:20][CH2:19][C:18]=12.FC1C=CC=CC=1[Li].[Cl-].[NH4+]>CCCCCC.C1COCC1.C1(C)C=CC=CC=1.C1(C)C=CC=CC=1.CCOC(C)=O.O>[F:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C@:18]12[CH2:19][O:20][CH2:21][C@H:17]1[CH2:16][O:15][NH:14]2
Reactant: Fc1ccccc1Br
Reactant: C1OCC2CON=C12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Li]c1ccccc1F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Fc1ccccc1[C@]12COC[C@H]1CON2
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
A 2.77 M solution of n-butyllithium in hexane (30.7 mL) was added dropwise to a solution containing 2-bromofluorobenzene (15.6 g) in THF/toluene (50 mL/150 mL) under a nitrogen atmosphere at −78° C. The reaction solution was stirred at the same temperature for 1 h. A boron trifluoride-diethyl ether complex (10.7 mL) was added dropwise to a solution containing (±)-3a,4-dihydro-3H,6H-furo[3,4-c]isoxazole (4.8 g) in toluene (350 mL) under a nitrogen atmosphere at −78° C. Previously prepared 2-fluorophenyllithium was added dropwise to the reaction solution at the same temperature. After stirring at the same temperature for 1 h, aqueous ammonium chloride was added to the reaction solution, and the reaction solution was warmed to RT. Water and EtOAc were added to the reaction solution, and the organic layer was separated. The organic layer was washed with a saturated sodium chloride solution. The organic layer was dried over anhydrous MgSO4, and the insoluble matter was separated by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (5.6 g). 1H NMR (400 MHz, CDCl3) δ ppm 3.39-3.45 (m, 1H), 3.52-3.62 (brm, 1H), 3.84-3.92 (brm, 2H), 3.98 (brd, J=9.2 Hz, 1H), 4.16 (ddd, J=2.4, 6.4, 11.2 Hz, 1H), 4.50-4.58 (brm, 1H), 5.11 (brs, 1H), 7.06 (ddd, J=1.2, 8.4, 11.6 Hz, 1H), 7.16 (ddd, J=1.2, 7.6, 7.6 Hz, 1H), 7.25-7.31 (m, 1H), 7.84-7.95 (m, 1H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11](Cl)=[N:12][C:13]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[CH2:19][CH2:18]2)=[N:14][C:15]=1[OH:16].[NH2:34][C@@H:35]1[CH2:40][CH2:39][CH2:38][N:37]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:36]1.C(N(C(C)C)C(C)C)C>C(O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:15](=[O:16])[NH:14][C:13]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[CH2:19][CH2:18]2)=[N:12][C:11]=1[NH:34][C@@H:35]1[CH2:40][CH2:39][CH2:38][N:37]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:36]1
Reactant: O=C(OCc1ccccc1)N1CCC(c2nc(O)c(-c3nc4ccccc4s3)c(Cl)n2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2nc(C3CCN(C(=O)OCc4ccccc4)CC3)[nH]c(=O)c2-c2nc3ccccc3s2)C1
Temperature: 90 °C

Procedure:
A mixture of benzyl 4-[5-(1,3-benzothiazol-2-yl)-4-chloro-6-hydroxypyrimidin-2-yl]piperidine-1-carboxylate (48.1 mg, 0.10 mmol, 1.00 equiv), tert-butyl (3R)-3-aminopiperidine-1-carboxylate (20.1 mg, 0.10 mmol, 1.00 equiv), and N-ethyl-N-isopropylpropan-2-amine (25.4 mg, 0.20 mmol, 1.97 equiv) in ethanol (3 ml) was heated overnight at 90° C. in an oil bath. Upon concentrated under vacuum, the residue was purified by flash chromatography on a silica gel column eluting with petroleum ether/ethyl acetate (1:1) to afford the title compound. as a yellow solid. MS m/z [M+H]+ (ESI): 645.
Reaction SMILES: C(OC([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][N:11]2[CH:15]1[CH2:17][CH2:16]1)=O)(C)(C)C.[ClH:18].O1CCOCC1>>[ClH:18].[ClH:18].[CH:15]1([N:11]2[CH2:10][C@@H:9]3[CH2:14][C@H:12]2[CH2:13][NH:8]3)[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C1CC1
Agent: Cl
Solvent: C1COCCO1
Product: C1CC1N1C[C@@H]2C[C@H]1CN2
Temperature: 25 °C
Reaction time: 7 h
Yield: 85 %

Procedure:
4N—HCl/1,4-dioxane (10 mL) was added to (1S,4S)-(−)-2-cyclopropyl-2,5-diazabicyclo[2.2.1]heptan-5-ylcarboxylic acid tert-butyl ester (4.46 g, 18.71 mmol), and the mixture was stirred for 7 hours at room temperature. The reaction liquor was concentrated under reduced pressure, to obtain the title compound (3.34 g, 85%) as an oily matter.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.C(O[K])(C)(C)C.CC(O)(C)C.Br[CH2:24][CH2:25][O:26][CH2:27][CH2:28]Br>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([C:8]2=[O:11])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[CH:4][CH:3]=1
Reactant: BrCCOCCBr
Reactant: O=C1CCc2ccc(Br)cc21
Agent: CC(C)(C)O[K]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: O=C1c2cc(Br)ccc2CC12CCOCC2

Procedure:
To a solution of 6-bromo-1-indanone (1.033 g, 4.89 mmol) in anhydrous THF (100 mL) under N2 atmosphere at room temperature was added a solution of tBuOK in tBuOH (1 M, 10.3 mL, 10.3 mmol) within 30 min (the color turned to deep black upon a drop of tBuOK solution was added), followed by 1-bromo-2-(2-bromoethoxy)ethane (1.134 g, 0.62 mL, 4.89 mmol). The reaction was quenched with saturated aqueous NH4Cl, and extracted with ether two times. The combined organic phases were washed with H2O, brine, and dried over anhydrous Na2SO4, and filtered, and concentrated to give black tar. It was purified by flash chromatography on silica gel yield 300 mg of the desired product. MS ESI+ve m/z 281 (M+H)30.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][O:11][CH2:12]Cl.[C:14]([O:18][C:19]([N:21]1[CH2:26][C:25](=[O:27])[N:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[OH:34])[CH2:23][C:22]1([CH3:36])[CH3:35])=[O:20])([CH3:17])([CH3:16])[CH3:15].O>C(Cl)Cl>[C:14]([O:18][C:19]([N:21]1[CH2:26][C:25](=[O:27])[N:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH2:10][O:11][CH3:12])[CH2:23][C:22]1([CH3:36])[CH3:35])=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CC(=O)N(c2ccccc2O)CC1(C)C
Reactant: COCCl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1ccccc1N1CC(C)(C)N(C(=O)OC(C)(C)C)CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
0.72 ml of diisopropylethylamine (4.10 mmol) and 0.16 ml of methoxymethyl chloride (2.05 mmol) were added to a solution of 400 mg of 4-(2-hydroxyphenyl)-2,2-dimethyl-5-oxopiperazine-1-carboxylic acid t-butyl ester obtained in Example (10d) (1.36 mmol) in methylene chloride (14 ml), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:n-hexane/ethyl acetate=1/1) to obtain 497 mg of 2,2-dimethyl-4-(2-methoxymethoxyphenyl)-5-oxopiperazine-1-carboxylic acid t-butyl ester (yield: quant.).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][C:9]3[N:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:6]=2[N:7]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]2[S:10][C:9]3[N:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:6]=2[N:7]=1
Reactant: C1COCCN1
Reactant: Clc1nc(Cl)c2sc3ncccc3c2n1
Solvent: CO
Product: Clc1nc(N2CCOCC2)c2sc3ncccc3c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To compound 4 (34.3 mg, 0.14 mmol) in dry methanol (1.5 mL) was added morpholine (25 μL, 0.29 mmol) in a dropwise fashion, and the resulting mixture was stirred for 1 h at rt. The mixture was then filtered, washed with water and then methanol, and the remaining solid was dissolved in CH2Cl2 and concentrated in vacuo to furnish 5 as a pale brown solid (30.1 mg, 0.098 mmol, 73%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[CH:19]=[CH:18][C:13]3[N:14]=[C:15]([NH2:17])[S:16][C:12]=3[CH:11]=2)=[N:6][CH:7]=1.[Br:20]Br.Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.C(OCC)(=O)C.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[CH:19]=[C:18]([Br:20])[C:13]3[N:14]=[C:15]([NH2:17])[S:16][C:12]=3[CH:11]=2)=[N:6][CH:7]=1
Reactant: BrBr
Reactant: Cc1ccc(CCc2ccc3nc(N)sc3c2)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(CCc2cc(Br)c3nc(N)sc3c2)nc1
Yield: 51.6 %

Procedure:
To a solution of 6-[2-(5-methyl-2-pyridyl)ethyl]-2-aminobenzothiazole (1.35 g) in acetic acid (15 ml) was dropwise added a solution of bromine (0.8 g) in acetic acid (2 ml) at 20° to 22° C. under stirring and the resultant mixture was stirred at ambient temperature for 5 hours. The reaction mixture was poured into a mixture of water and ethyl acetate and the mixture was acidified to pH 1.0 with 10% hydrochloric acid. The separated aqueous layer was adjusted to pH 8.0 with aqueous 20% potassium carbonate and extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and residue was recrystallized from a mixture of ethyl acetate and tetrahydrofuran to give 6-[2-(5-methyl-2-pyridyl)ethyl]-2-amino-4-bromobenzothiazole (0.9 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:31])[C:10]([NH:12][C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]#[CH:28])=[C:21]([O:29][CH3:30])[CH:20]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[Na+].S(C1C=CC(C)=CC=1)(O[C:38]#[C:39][CH3:40])(=O)=O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([O:31][CH2:40][C:39]#[CH:38])[C:10]([NH:12][C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]#[CH:28])=[C:21]([O:29][CH3:30])[CH:20]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC#COS(=O)(=O)c1ccc(C)cc1
Reactant: C#CCOc1ccc([C@@H]2CCCC[C@H]2NC(=O)C(O)c2ccc(Cl)c(Cl)c2)cc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: C#CCOc1ccc([C@@H]2CCCC[C@H]2NC(=O)C(OCC#C)c2ccc(Cl)c(Cl)c2)cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 0.4 g (0.85 mmol) of 2-(3,4-dichlorophenyl)-2-hydroxy-N-[trans-2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-cyclohexyl]-acetamide, 0.5 ml of 30% aqueous sodium hydroxide solution and 5 mg of tetrabutylammonium bromide in 3 ml dichloromethane is added 0.18 g (0.85 mmol) of propynyl tosylate during 1 hour. Upon completion of the addition the reaction mixture is stirred for additional 16 hours at room temperature. The mixture is then extracted with dichloromethane. The organic extract is concentrated under reduced pressure to a residue, which was subjected to column chromatography on silica gel, with 1 :2 ethyl acetate/isohexane as the eluant to obtain 2-(3,4-dichlorophenyl)-N-[trans-2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-cyclohexyl]-2-prop-2-ynyloxy-acetamide.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](F)=[CH:5][CH:4]=1)#[N:2].[C:14]1([NH:20][CH2:21][C@H:22]2[CH2:26][CH2:25][CH2:24][NH:23]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1([NH:20][CH2:21][C@H:22]2[CH2:26][CH2:25][CH2:24][N:23]2[C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: N#Cc1ccc(F)c2ccccc12
Reactant: c1ccc(NC[C@H]2CCCN2)cc1
Product: N#Cc1ccc(N2CCC[C@@H]2CNc2ccccc2)c2ccccc12
Yield: 18.3 %

Procedure:
The title compound (7 mg, 18% yield) was prepared as described for 196MBT2-4 from 1-cyano-4-fluoronaphthalene (20 mg, 0.117 mmol) and (R)-(−)-2-phenylaminomethylpyrrolidine (82 mg, 0.468 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@:10]([CH3:38])([NH:13][C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][CH:27]=2)[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:37])[C:19](=[O:36])[N:20](COCC[Si](C)(C)C)[N:21]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@:10]([CH3:38])([NH:13][C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][CH:27]=2)[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:37])[C:19](=[O:36])[NH:20][N:21]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3ccc(N[C@@]4(C)CCN(C(=O)OC(C)(C)C)C4)cc3N21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC1C(=O)NN=C2COc3ccc(N[C@@]4(C)CCN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 80 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
A mixture of (S)-3-methyl-3-[4-methyl-3-oxo-2-(2-trimethylsilanyl-ethoxymethyl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester (1.1 g, 2.016 mmol) in a solution of TBAF in THF (1 M, 20 mL, 20 mmoL) was stirred at 80° C. overnight. The reaction mixture was cooled to ambient temperature and diluted with water (25 mL). The aqueous solution was extracted with EtOAc (3×25 mL). The combined organic phase was washed with brine (10 mL), dried over sodium sulfate and filtered. The filtrate was concentrate in vacuo to give the residue, which was purified by column chromatography on silica gel (eluting with 10% EtOAc in petroleum) to give (S)-3-methyl-3-(4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.45 g, 54%). 1H NMR (400 MHz, CDCl3) δ 8.19-8.05 (m, 1H), 6.94-6.77 (m, 1H), 6.53-6.23 (m, 2H), 4.74-4.46 (m, 3H), 3.62-3.30 (m, 4H), 2.32-2.17 (m, 1H), 2.00-1.86 (m, 1H), 1.59-1.44 (m, 15H).
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:15]=[CH:14][C:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13][C:7]=2[CH:6]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[ClH:1].[CH2:9]1[C:8]2[CH:14]=[CH:15][C:5]([NH2:2])=[CH:6][C:7]=2[CH2:13][CH2:12][NH:11][CH2:10]1
Reactant: O=[N+]([O-])c1ccc2c(c1)CCNCC2
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1ccc2c(c1)CCNCC2
Yield: 166.4 %

Procedure:
To a solution of 2,3,4,5-tetrahydro-7-nitro-1H-3-benzazepine hydrochloride (1.68 g, 7.35 mmol) in ethanol (100 ml) was added 5% palladium on carbon (0.2 g) and the solution was placed on a Paar Hydrogenator Apparatus and pressurized with 45 psi of hydrogen. After the theoretical uptake of hydrogen had been achieved (2 h), the catalyst was filtered off and washed with water (25 ml). The filtrate was concentrated. Absolute ethanol was added and evaporated until all of the water had been evaporated and a solid formed. The solid was dissolved in hot ethanol (50 ml) and the product was precipitated by the addition of ether (75 ml). The solid was collected and air-dried to give the product as an off-white solid (2.43 g (94%)), m.p. 288°-91° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([O:8][CH2:9][CH2:10][OH:11])[C:3]=1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C(N(CC)CC)C.[C:26](OC(=O)C)(=[O:28])[CH3:27]>O1CCCC1.CN(C)C1C=CN=CC=1>[C:26]([O:11][CH2:10][CH2:9][O:8][C:4]1[C:3]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[C:2]([NH2:1])[N:6]([CH3:7])[N:5]=1)(=[O:28])[CH3:27]
Reactant: Cn1nc(OCCO)c(C(=O)OC(C)(C)C)c1N
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OCCOc1nn(C)c(N)c1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To tert-butyl 5-amino-3-(2-hydroxyethoxy)-1-methyl-1H-pyrazole-4-carboxylate (Preparation 11) (60 g) in tetrahydrofuran (500 ml), under nitrogen and at room temperature, was added triethylamine (41.7 ml), 4-dimethylaminopyridine (400 mg) followed by acetic anhydride (28.6 ml) dropwise. The reaction was stirred at room temperature overnight and was then concentrated under reduced pressure. The residue was diluted with ethyl acetate (300 ml) and washed with brine (2×100 ml). The organics were dried with magnesium sulfate, filtered and concentrated under reduced pressure to yield the desired product as white solid (71 g).
Reaction SMILES: [C:1]([NH:5][C:6](=[O:8])[OH:7])([CH3:4])([CH3:3])[CH3:2].[CH:9]1([S:12]([NH2:15])(=[O:14])=[O:13])[CH2:11][CH2:10]1.[Li]CCCC.[CH3:21][O:22][CH2:23]Cl.Cl>C1COCC1>[C:1]([NH:5][C:6](=[O:7])[OH:8])([CH3:4])([CH3:3])[CH3:2].[CH3:21][O:22][CH2:23][NH:15][S:12]([CH:9]1[CH2:11][CH2:10]1)(=[O:14])=[O:13]
Reactant: COCCl
Reactant: NS(=O)(=O)C1CC1
Agent: CC(C)(C)NC(=O)O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCNS(=O)(=O)C1CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of cyclopropylsulfonylamine tert-butylcarbamate (1.0 g, 4.5 mmol) dissolved in THF (30 mL) cooled to −78° C., was added n-BuLi (6.4 mL, 10.2 mmol, 1.6 M in hexane) and the reaction mixture was stirred for 1 hour. To this solution was added a neat solution of chloromethyl methyl ether (0.40 mL, 5.24 mmol), and the mixture was slowly allowed to warm to room temperature overnight. The solution pH was adjusted to 3 using 1N aqueous HCl and was then extracted with ethyl acetate (4×50 mL portions). The combined extracts were dried (MgSO4), filtered, and concentrated to provide 1-methoxy-methylcyclopropylsulfonylamine tert-butylcarbamate, as a waxy solid (1.20 g, 100%) which was taken directly into the next reaction without further purification: 1H NMR (CDCl3) δ 1.03 (m, 2H), 1.52 (s, 9H), 1.66 (m, 2H), 3.38 (s, 3H), 3.68 (s, 2H), 7.54 (s, 1H); 13C NMR (CDCl3) δ 11.37, 28.29, 40.38, 58.94, 73.43, 83.61, 149.57.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([C:17]1[N:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]3=[N:19][N:18]=1)[CH:13]=[CH:12]2)(=O)=O.[NH:28]1[CH2:33][CH2:32][CH2:31][C@@H:30]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:29]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)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]>[N:19]1[N:18]=[C:17]([C:14]2[CH:13]=[CH:12][C:11]3[C:16](=[C:7]([N:28]4[CH2:33][CH2:32][CH2:31][C@@H:30]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:39])([CH3:38])[CH3:40])[CH2:29]4)[CH:8]=[CH:9][CH:10]=3)[N:15]=2)[N:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=12
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: O=S(=O)(Oc1cccc2ccc(-c3nnc4ccccn34)nc12)C(F)(F)F
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2cccc3ccc(-c4nnc5ccccn45)nc23)C1
Temperature: 92 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yl trifluoromethanesulfonate (0.040 g, 0.10 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (0.026 g, 0.13 mmol), cesium carbonate (0.050 g, 0.15 mmol), Pd2 dba3 (0.0046 g, 0.0051 mmol) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.0063 g, 0.010 mmol) were added to minimal degassed toluene and heated in a seal vial overnight at 92° C. After stirring overnight, DCM was added, solids removed through filtration (Waters filter), and the filtrate was concentrated. The crude material was purified by flash column chromatography (gradient elution of 6% NH4 in MeOH/DCM). The desired product (30 mg) was isolated, as a 1:1 mixture with the triflate starting material. The mixture was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15](=[O:24])[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=C(Cl)C=1.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]1[O:24][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)Nc1ccccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: Clc1cccc(Cl)c1
Product: CC(C)(C)OC(=O)N1CCCCC1Cc1nc2ccccc2o1
Reaction time: 48 h
Yield: 42.3 %

Procedure:
(RS)-2-[(2-Hydroxy-phenylcarbamoyl)-methyl]-piperidine-1-carboxylic acid tert butyl ester (1.25 g), 4-toluenesulphonic acid (0.07 g) and 4-N,N-dimethylaminopyridine (0.023 g) were combined in 1,3-dichlorobenzene (30 ml) and the mixture boiled for 48 h. The mixture was diluted with dichloromethane and washed with water. The organic phase was dried (MgSO4) and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, 0→1% methanol in dichloromethane) to give the title compound (0.50 g)
Reaction SMILES: [CH3:1][O:2][CH:3]([O:15][CH3:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10](I)=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[O:32][C:31]3[CH:30]=[CH:29][NH:28][C:27](=[O:33])[C:26]=3[CH:25]=2)=[CH:20][CH:19]=1.C([O-])([O-])=O.[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.[Cu]I>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[O:32][C:31]3[CH:30]=[CH:29][N:28]([C:10]4[CH:9]=[C:8]5[C:13](=[CH:12][CH:11]=4)[N:5]([CH2:4][CH:3]([O:15][CH3:16])[O:2][CH3:1])[N:6]=[CH:7]5)[C:27](=[O:33])[C:26]=3[CH:25]=2)=[CH:22][CH:23]=1
Reactant: O=c1[nH]ccc2oc(-c3ccc(Cl)cc3)cc12
Reactant: COC(Cn1ncc2cc(I)ccc21)OC
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: COC(Cn1ncc2cc(-n3ccc4oc(-c5ccc(Cl)cc5)cc4c3=O)ccc21)OC
Temperature: 128 °C
Reaction time: 5 h
Yield: 41.8 %

Procedure:
To a solution of 1-(2,2-dimethoxyethyl)-5-iodo-1H-indazole (3.14 g, 9.46 mmol) in DMSO (11.2 mL) was added 2-(4-chlorophenyl)-5H-furo[3,2-c]pyridine-4-one (2.32 g, 9.46 mmol), Cs2CO3 (3.39 g, 10.4 mmol), 8-hydroxyquinoline (0.274 g, 1.89 mmol) and CuI (2.16 g, 11.4 mmol). The solution was evacuated for 15 minutes under high vacuum then backfilled with argon. The process was repeated three times. The reaction mixture was stirred at 128° C. for 5 h; then the reaction mixture was cooled to 100° C. and maintained at this temperature for 18 h. The reaction mixture was diluted with 10% NH4OH in H2O (100 mL) and the resulting solids were washed with an additional 10% NH4OH in H2O solution (300 mL). The solids were dissolved in CH2Cl2 (100 mL) and washed with H2O (2×50 mL). The organics were filtered to remove any excess solids and then concentrated. Purification by flash chromatography (silica gel, hexanes with 0.1% Et3N to hexanes/MTBE/EtOAc 35:1.25:0.25 with 0.1% Et3N, to hexanes/MTBE/EtOH 35:1.25:0.25 with 0.1% Et3N, to CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 1:1) yielded the title compound (1.78 g, 41%) as a brown solid: 1H NMR (500 MHz, CDCl3) δ 8.06 (s, 1H), 7.73-7.71 (m, 3H), 7.60 (d, J=9.0 Hz, 1H), 7.43-7.41 (m, 3H), 7.35 (d, J=7.5 Hz, 1H), 7.25 (s, 1H), 6.67 (d, J=7.5 Hz, 1H), 4.78 (t, J=5.5 Hz, 1H), 4.51 (d, J=5.0 Hz, 2H), 3.38 (s, 6H); ESI MS m/z 450 [M+H]+.