Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]#[C:11][C:12]2[C:13]([CH3:24])=[N:14][CH:15]=[N:16][C:17]=2[N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:5][N:4]=1.[Cl:25][C:26]1[S:30][C:29]([S:31](Cl)(=[O:33])=[O:32])=[CH:28][CH:27]=1.N1C=CC=CC=1.O>C(Cl)Cl>[Cl:25][C:26]1[S:30][C:29]([S:31]([NH:9][C:8]2[C:3]([O:2][CH3:1])=[N:4][CH:5]=[C:6]([C:10]#[C:11][C:12]3[C:13]([CH3:24])=[N:14][CH:15]=[N:16][C:17]=3[N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[CH:7]=2)(=[O:33])=[O:32])=[CH:28][CH:27]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: COc1ncc(C#Cc2c(C)ncnc2N2CCOCC2)cc1N
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: COc1ncc(C#Cc2c(C)ncnc2N2CCOCC2)cc1NS(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C

Procedure:
To 100 mg (0.31 mmol) 2-Methoxy-5-(4-methyl-6-morpholin-4-yl-pyrimidin-5-ylethynyl)-pyridin-3-ylamine (E-9) in 5 mL DCM is added 112 mg (0.61 mmol) 5-chloro-thiophen-2-sulfonyl chloride and 72 μL (0.97 mmol) pyridine and the reaction mixture is stirred over night at RT. Water (2 mL) is added, the mixture is shaken for five minutes, the aqueous phase is separated and is extracted three times with 4 mL DCM. The combined organic phases are dried over MgSO4 and concentrated under reduced pressure. The crude product is purified by RP chromatography (C18, 20-80% ACN in water containing 1% formic acid). Yield: 101 mg (65%). HPLC-MS: M+H=506/508; tR=0.91 min.
Reaction SMILES: [C:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16](O)=[O:17])=[C:6]([CH2:24][CH2:25][CH3:26])[C:5]=1[OH:27])(=[O:3])[CH3:2].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][CH2:35][CH2:36][CH2:37][NH2:38])[CH:29]=1>>[C:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([NH:38][CH2:37][CH2:36][CH2:35][CH2:34][C:30]2[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=2)=[O:17])=[C:6]([CH2:24][CH2:25][CH3:26])[C:5]=1[OH:27])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCOc2cccc(C(=O)O)c2)ccc(C(C)=O)c1O
Reactant: NCCCCc1cccnc1
Product: CCCc1c(OCCCOc2cccc(C(=O)NCCCCc3cccnc3)c2)ccc(C(C)=O)c1O
Yield: 88 %

Procedure:
The reaction of 0.80 g of 3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]benzoic acid with 0.35 g of 3-pyridine butanamine according to Example 40 gave 0.95 g, mp 84°-86°, (88% yield) of 3-[3-(4-Acetyl-3-hydroxy-2-propylphenoxy)propoxy]-N-[4-(3-pyridinyl)butyl]benzamide, the title compound.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=1)[C:19]([O:21][CH3:22])=[O:20].[CH3:34][O:35][CH2:36][C@@H:37](O)[CH3:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:38][C@@H:37]([O:15][C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=1)[C:19]([O:21][CH3:22])=[O:20])[CH2:36][O:35][CH3:34]
Reactant: COC[C@H](C)O
Reactant: COC(=O)c1cc(O)cc(OCc2ccccc2)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC[C@@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 20 h
Yield: 67.2 %

Procedure:
DIAD (4.6 g, 0.029 mol) was added dropwise to a solution of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate (6 g, 0.023 mol), (S)-(+)-1-methoxy-2-propanol (2.59 g, 0.029 mol) and triphenylphosphine (7.53 g, 0.029 mol) in THF (100 mL), under argon, at 0° C. The reaction was stirred at 0° C. for 1 hour and at RT for 20 hours. The volatiles were removed in vacuo and isohexane/ethyl acetate 2:1 added followed by stirring for 1 hour. A white solid was removed by filtration and the filtrate was evaporated to a residue which was chromatographed on silica, eluting with a gradient of 0-20% ethyl acetate in isohexane, to give the desired compound (5.11 g).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[N:8]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:13][CH2:12][CH:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1>CCO>[CH2:6]([O:5][C:1]([CH2:2][CH2:3][N:17]1[CH2:16][CH2:15][CH:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:13][CH2:12]2)[CH2:19][CH2:18]1)=[O:4])[CH3:7]
Reactant: C=CC(=O)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCNCC2)CC1
Solvent: CCO
Product: CCOC(=O)CCN1CCC(C2CCN(C(=O)OC(C)(C)C)CC2)CC1
Reaction time: 8 h

Procedure:
4.4 mL (40.6 mmol) ethyl acrylate were added to a solution of 10.0 g (37.3 mmol) tert.butyl [4,4′]bipiperidinyl-1-carboxylate in 100 mL EtOH and the reaction mixture was refluxed for 2 h. To complete the reaction a further 1 mL (9.2 mmol) ethyl acrylate were added, the mixture was refluxed for 1 h and left overnight at RT. The solvent was eliminated i.vac. and the crude product was further reacted without any purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]1[C:24]([OH:26])=[O:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][Si](C=[N+]=[N-])(C)C.C(O)(=O)C>CO.C1C=CC=CC=1.CCCCCC>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[CH2:13][CH:12]1[C:24]([O:26][CH3:27])=[O:25])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(C(=O)O)C1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCCCCC
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Reaction time: 0.17 h

Procedure:
1-Benzyloxycarbonyl-4-tert-butoxycarbonyl-piperazine-2-carboxylic acid (4.76 g, 13.0 mmol) (prepared as described by C. F. Bigge, S. J. Hays, P. M. Novak, J. T. Drummond, G. Johnson, T. P. Bobovski in Tetrahedron Letters, Vol. 30, 5193-5196, 1989) was dissolved in 10% methanol in benzene. A solution of trimethylsilyldiazomethane in hexane (8 mL, 2M) was added dropwise. After 10 min, glacial acetic acid (1 mL) was added. When gas evolution ceased, the solvents were removed in vacuo, and the residue partitioned between ethyl acetate and saturated sodium bicarbonate. The organic phase was washed with saturated brine and dried over magnesium sulfate. The crude product was chromatographed on silica gel with 15% ethyl acetate in hexane, then recrystallized from ethyl acetate/hexane to obtain the title compound as a white powder (1.8 g).
Reaction SMILES: [O:1]=[S:2]1(=[O:22])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:12]=[CH:11][C:10]([CH:13]([O:20][CH3:21])[C:14](N(OC)C)=[O:15])=[CH:9][CH:8]=1.[Br:23][C:24]1[C:29]([O:30][CH3:31])=[CH:28][C:27]([C:32]2[O:33][CH:34]=[CH:35][CH:36]=2)=[CH:26][C:25]=1[O:37][CH3:38]>>[Br:23][C:24]1[C:25]([O:37][CH3:38])=[CH:26][C:27]([C:32]2[O:33][C:34]([C:14](=[O:15])[CH:13]([C:10]3[CH:9]=[CH:8][C:7]([N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:22])=[CH:12][CH:11]=3)[O:20][CH3:21])=[CH:35][CH:36]=2)=[CH:28][C:29]=1[O:30][CH3:31]
Reactant: COc1cc(-c2ccco2)cc(OC)c1Br
Reactant: COC(C(=O)N(C)OC)c1ccc(N2CCCS2(=O)=O)cc1
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(N4CCCS4(=O)=O)cc3)o2)cc(OC)c1Br

Procedure:
1-(5-(4-Bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-(4-(1,1-dioxidoisothiazolidin-2-yl)phenyl)-2-methoxyethanone was synthesized from 2-(4-(1,1-dioxidoisothiazolidin-2-yl)phenyl)-N,2-dimethoxy-N-methylacetamide and 2-(4-bromo-3,5-dimethoxyphenyl)furan following the procedure used for the synthesis of Example 12. Purification by chromatography (EtOAc-hexanes) provided Example 19 as a yellow solid (0.111 g, 37% yield). MS: m/z 550.1 [M+H]+.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:31]=[C:20]3[N:21]=[CH:22][CH:23]=[C:24]([C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)[N:19]3[N:18]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.Br>CCOCC>[N:14]1([C:17]2[N:31]=[C:20]3[N:21]=[CH:22][CH:23]=[C:24]([C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)[N:19]3[N:18]=2)[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]1
Reactant: O=C(OCc1ccccc1)N1CCN(c2nc3nccc(-c4cccnc4)n3n2)CC1
Agent: Br
Solvent: CCOCC
Product: c1cncc(-c2ccnc3nc(N4CCNCC4)nn23)c1
Temperature: 25 °C

Procedure:
To a 2.5 g amount of 4-[7-(3-pyridyl)[1,2,4]-triazolo[1,5-a]pyrimidin-2-yl]-1-piperazinecarboxylic acid benzyl ester was added 5.0 ml of hydrobromic acid (31% in glacial acetic acid). The mixture was allowed to react for 4 hours then was cooled to room temperature. Anhydrous ether was added, the mixture was swirled and the liquid decanted. This step was repeated several times. The residual precipitate was dissolved in water and the solution was filtered. The filtrate was made basic with 5N sodium hydroxide and extracted several times with dichloromethane. The extracts were combined and heated to boiling, then hexane was added to crystallize the product. Cooling and filtration gave 1.10 g of the deseired product as pale yellow crystals, mp 156°-158° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]([F:50])([CH2:46][CH2:47][CH2:48][CH3:49])[CH:13]([OH:45])[CH2:14][CH2:15][C@H:16]1[C@H:20]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH2:19][C@H:18]([OH:28])[C@@H:17]1[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36].C(N(CC)CC)C.O.[NH4+]>ClCCl>[F:50][C:12]([F:11])([CH2:46][CH2:47][CH2:48][CH3:49])[C:13](=[O:45])[CH2:14][CH2:15][C@H:16]1[C@H:20]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH2:19][C:18](=[O:28])[C@@H:17]1[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:36]
Reactant: CCCCC(F)(F)C(O)CC[C@@H]1[C@@H](CCCCCCC(=O)OCc2ccccc2)[C@@H](O)C[C@H]1OC1CCCCO1
Agent: O=C(Cl)C(=O)Cl
Agent: [NH4+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCCCC(F)(F)C(=O)CC[C@H]1[C@H](OC2CCCCO2)CC(=O)[C@@H]1CCCCCCC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
A solution of oxalyl chloride (57.0 ml, 653 mmol) in dichloromethane (635 ml) was cooled in a dry ice-methanol bath. Dimethylsulfoxide (92.7 ml, 1306 mmol) was added drop wise and the solution was stirred for 30 minutes. A solution of benzyl 7-[(1R,2R,3R,5S)-2-(4,4-difluoro-3-hydroxyoctyl)-5-hydroxy-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (18) (74.31 g, 130.7 mmol) in dichloromethane (191 ml) was added drop wise, and the mixture was stirred for approximately 1.5 hours. Triethylamine (273 ml, 1959 mmol) was added drop wise to the mixture and the reaction mixture was warmed to 0° C., saturated ammonium water (605 ml) was added to the solution and the mixture was stirred, let to stand and then separated into two layers. The aqueous layer was extracted twice with dichloromethane (302 ml). The organic layers were combined and sequentially washed with 0.35N-hydrochloric acid (302 ml), water (605 ml), saturated sodium bicarbonate water (605 ml) and saturated aqueous sodium chloride (605 ml). After drying with anhydrous magnesium sulfate (52 g), the solution was concentrated under reduced pressure. The residue was dissolved in a suitable amount of ethyl acetate/hexane solvent mix (1:10), and insoluble matter was filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (Fuji Silysia BW-300: 2260 g; ethyl acetate:hexane=1:4) to give benzyl 7-[(1R,2R,3R)-2-(4,4-difluoro-3-oxooctyl)-5-oxo-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (19) (71.44 g; 126.5 mmol; yield: 96.8%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([CH2:6][C:7]#[N:8])=O.O.[NH2:14][NH2:15]>C(O)C>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]1[CH:6]=[C:7]([NH2:8])[NH:14][N:15]=1
Reactant: NN
Reactant: N#CCC(=O)c1ccccc1Cl
Solvent: O
Solvent: CCO
Product: Nc1cc(-c2ccccc2Cl)n[nH]1
Temperature: 25 °C

Procedure:
A solution of 2-chlorobenzoylacetonitrile (15.9 g, 89 mmol) and hydrazine hydrate (8.9 g, 0.18 mol) in ethanol (2 ml) was heated at reflux for 22 hr. After cooling to room temperature, the reaction was concentrated, in vacuo. The residue was dissolved in ethyl acetate, washed with water and brine, dried (MgSO4), and concentrated, in vacuo, to a brown oil. Flash chromatography using 10% ethyl acetate in methylene chloride, changing to 5% methanol in methylene chloride as eluant afforded title product I-1A-1a (17.3 g, quantitative): +ESI MS (M+1) 194.2; 1H NMR (400 MHz, CD3OD) δ 7.60–7.25 (m, 4H), 5.99 (br s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[O:10])[CH2:8][CH3:9])[CH:2]=1.[BH4-].[Na+].O>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([OH:10])[CH2:8][CH3:9])[CH:2]=1
Reactant: CCC(=O)c1cccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCC(O)c1cccnc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1-(pyridin-3-yl)propan-1-one (2.46 g, 18.20 mmol, purchased from Lancaster Synthesis Ltd.) in MeOH (15 mL) at rt under N2 atmosphere was added sodium borohydride powder (0.690 g, 18.20 mmol). After stirring at rt for 1.5 hr, to the reaction solution was added water (20 ml). The resulting mixture was stirred for 4 min, extracted with EtOAc (20 mL×3). The organic layers were combined, washed with water, sat. aq. NaCl solution and dried over MgSO4. Removal of the solvents provided the crude title compound as white solid. Mass Spectrum (ESI) m/z=138.0 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:21]=[CH:20][C:8]([O:9][Si:10]([CH:17]([CH3:19])[CH3:18])([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:13])[CH3:12])=[CH:7][CH:6]=1.[OH:22][C:23]1[CH:40]=[CH:39][C:38]([C:41]([O:43][CH3:44])=[O:42])=[CH:37][C:24]=1[C:25]([N:27]1[CH2:32][CH2:31][CH:30]([C:33]([O:35][CH3:36])=[O:34])[CH2:29][CH2:28]1)=[O:26]>>[CH3:44][O:43][C:41]([C:38]1[CH:39]=[CH:40][C:23]([O:22][CH2:2][CH2:3][CH2:4][C:5]2[CH:21]=[CH:20][C:8]([O:9][Si:10]([CH:17]([CH3:19])[CH3:18])([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:13])[CH3:12])=[CH:7][CH:6]=2)=[C:24]([CH:37]=1)[C:25]([N:27]1[CH2:28][CH2:29][CH:30]([C:33]([O:35][CH3:36])=[O:34])[CH2:31][CH2:32]1)=[O:26])=[O:42]
Reactant: CC(C)[Si](Oc1ccc(CCCBr)cc1)(C(C)C)C(C)C
Reactant: COC(=O)c1ccc(O)c(C(=O)N2CCC(C(=O)OC)CC2)c1
Product: COC(=O)c1ccc(OCCCc2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc2)c(C(=O)N2CCC(C(=O)OC)CC2)c1

Procedure:
Methyl 1-[5-(methoxycarbonyl)-2-(3-{4-[(triisopropylsilyl)oxy]phenyl}propoxy)-benzoyl]piperidine-4-carboxylate is prepared by the process described in Example XLI from [4-(3-bromopropyl)phenoxy](triisopropyl)silane and methyl 1-[2-hydroxy-5-(methoxycarbonyl)benzoyl]-4-piperidinecarboxylate.
Reaction SMILES: Cl.[OH:2][C@H:3]1[CH2:7][NH:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4]1.C(N(CC)CC)C.[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[CH2:19]([N:6]1[CH2:7][C@H:3]([OH:2])[CH2:4][C@H:5]1[C:8]([O:10][CH3:11])=[O:9])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: ClCc1ccccc1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@@H](O)CN1Cc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of methyl (2S,4R)-4-hydroxy-2-pyrrolidinecarboxylate hydrochloride (674 g) in dichloromethane (3.5 l) were added dropwise triethylamine (1.19 l) and benzyl chloride (552 ml) at 10°-20° C. under stirring and the mixture was refluxed for 6 hours. The mixture was cooled to ambient temperature, and the precipitates were removed by filtration. The filtrate was poured into 1N sodium hydroxide and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo to give methyl (2S,4R)-1-benzyl-4-hydroxy-2-pyrrolidinecarboxylate (663 g).
Reaction SMILES: [CH3:1][C:2]1([C:12]#[N:13])[CH2:11][CH2:10][C:5]2(OCC[O:6]2)[CH2:4][CH2:3]1.C(=O)(O)[O-].[Na+]>C(O)(=O)C.[Cl-].[Na+].O>[CH3:1][C:2]1([C:12]#[N:13])[CH2:11][CH2:10][C:5](=[O:6])[CH2:4][CH2:3]1
Reactant: CC1(C#N)CCC2(CC1)OCCO2
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC1(C#N)CCC(=O)CC1
Yield: 62.8 %

Procedure:
Alternatively the compound could be obtained by heating 14.2 g of 8-methyl-1,4-dioxa-spiro[4.5]decane-8-carbonitrile in 190 mL of 80% acetic acid under reflux until conversion was complete. The mixture was cooled and poured onto 1.2 L of cold, saturated sodium bicarbonate solution. 600 mL of brine were added and the mixture was extracted several times with ethyl acetate. The combined ethyl acetate layers were washed with brine, dried over magnesium sulphate and evaporated. The residue was taken up in water and acetonitrile and lyophilized to give 6.75 g of the desired product, that could be directly used in further conversions.
Reaction SMILES: 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.[N:47]12[CH2:55][CH2:54][CH:51]([CH2:52][CH2:53]1)[NH:50][CH2:49][CH2:48]2.Br[C:57]1[CH:69]=[CH:68][C:67]2[C:66]3[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=3)[C:60](=[O:70])[C:59]=2[CH:58]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:47]12[CH2:55][CH2:54][CH:51]([CH2:52][CH2:53]1)[N:50]([C:57]1[CH:69]=[CH:68][C:67]3[C:66]4[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=4)[C:60](=[O:70])[C:59]=3[CH:58]=1)[CH2:49][CH2:48]2
Reactant: O=C1c2ccccc2-c2ccc(Br)cc21
Reactant: C1CN2CCC(CC2)N1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2-c2ccc(N3CCN4CCC3CC4)cc21
Temperature: 90 °C
Yield: 43 %

Procedure:
A catalyst solution was prepared by mixing tris(dibenzylideneacetone)dipalladium (Pd2(dba)3; 20 mg, 0.022 mmol; Alfa) and racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP; 38 mg, 0.061 mmol; Strem) in toluene (1 mL) and heating the mixture to 90° C. for 15 min. The solution was cooled, and then added to a mixture of 1,4-diazabicyclo[3.2.2]nonane (112 mg, 0.889 mmol; see J. Med. Chem. 1993, 36, 2311) and 2-bromofluoren-9-one (320 mg, 1.24 mmol; Aldrich) in toluene (3 mL). Sodium tert-butoxide (120 mg, 1.25 mmol; Aldrich) was then added, and the reaction mixture was flushed with nitrogen and heated to 80-85° C. overnight. After cooling to room temperature, the mixture was filtered through diatomaceous earth and purified by chromatography (35 g silica gel, 1-16% gradient of NH4OH-MeOH (1:10) in CH2Cl2) to afford the title compound (116 mg, 0.382 mmol; 43% yield): 1H NMR (300 MHz, CD3OD) δ ppm 7.48 (d, J=7 Hz, 1H), 7.39-7.44 (m, 3H), 7.14 (ddd, J=7, 6, 3 Hz, 1H), 7.09 (d, J=3 Hz, 1H), 6.93 (dd, J=8, 3 Hz, 1H), 4.10-4.17 (m, 1H), 3.66 (dd, J=6, 5 Hz, 2H), 2.95-3.17 (m, 6H), 2.09-2.23 (m, 2H), 1.84 (ddd, J=19, 10, 5 Hz, 2H); MS (DCI/NH3): m/z 305 (M+1)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([CH2:12]O)[CH:9]=[CH:8][C:6]=2[N:7]=1.CCN(C(C)C)C(C)C.CS([Cl:27])(=O)=O>C(Cl)Cl.CN(C=O)C>[Cl:27][CH2:12][C:10]1[CH:9]=[CH:8][C:6]2[N:7]=[C:3]([S:2][CH3:1])[S:4][C:5]=2[CH:11]=1
Reactant: CSc1nc2ccc(CO)cc2s1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nc2ccc(CCl)cc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
To a solution of (2-(methylthio)benzo[d]thiazol-6-yl)methanol (4.1 g, 19.4 mmol) from Step 2 of this Example and DIEA (3.26 g, 25.3 mmol) in CH2Cl2 (200 mL) was added methanesulfonyl chloride (2.88 g, 25.3 mmol) slowly at 0° C. The mixture was then treated with 2 drops of DMF and stirred at rt overnight. The mixture was quenched with 300 mL of saturated aq NaHCO3. The separated aqueous layer was extracted with CH2Cl2 (2×250 mL). The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure to give 6-(chloromethyl)-2-(methylthio)benzo[d]thiazole as a light brown solid (4.4 g, 99%). 1H NMR (300 MHz, DMSO-d6) δ 8.10 (d, J=1.5 Hz, 1H), 7.84 (d, J=8.5 Hz, 1H), 7.53 (dd, J=1.6, 8.4 Hz, 1H), 4.89 (s, 2H), 2.80 (s, 3H). LCMS (ESI) m/z 231 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[S:19][C:20]([CH3:23])=[CH:21][N:22]=2)[C:3]1=[O:24].[C:25]([C:29]1[CH:30]=[C:31]2[C:36](=[C:37]([F:39])[CH:38]=1)[C:35](=[O:40])[N:34]([C:41]1[N:48]=[CH:47][CH:46]=[C:45](Cl)[C:42]=1[CH:43]=[O:44])[N:33]=[CH:32]2)([CH3:28])([CH3:27])[CH3:26].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>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].O.C(#N)C>[C:25]([C:29]1[CH:30]=[C:31]2[C:36](=[C:37]([F:39])[CH:38]=1)[C:35](=[O:40])[N:34]([C:41]1[N:48]=[CH:47][CH:46]=[C:45]([C:6]3[CH:5]=[C:4]([NH:17][C:18]4[S:19][C:20]([CH3:23])=[CH:21][N:22]=4)[C:3](=[O:24])[N:2]([CH3:1])[CH:7]=3)[C:42]=1[CH:43]=[O:44])[N:33]=[CH:32]2)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3nccc(Cl)c3C=O)ncc2c1
Reactant: Cc1cnc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: Cc1cnc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3C=O)cn(C)c2=O)s1
Temperature: 100 °C
Yield: 55.1 %

Procedure:
A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 120b (174 mg, 0.50 mmol), 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-chloronicotinaldehyde 103b (180 mg, 0.50 mmol), K3PO4 (212 mg, 1.0 mmol), sodium acetate (82 mg, 1.0 mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (18 mg, 0.025 mmol), acetonitrile (8 mL), and water (0.5 mL). The reaction mixture was subjected to three cycles of vacuum/argon flush and heated at 100° C. for 1 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was diluted with dichloromethane (50 mL) and water (30 mL). The water layer was extracted with dichloromethane (2×30 mL). The combined organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure. The dark residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (80:1 to 30:1) to afford 120c (150 mg, 55%) as a yellow solid. MS-ESI: [M+H]+ 545.3
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][CH2:14][C:15]#[CH:16])(=[O:12])=[O:11])([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:24][CH2:25][Cl:26]>CC(C)=O>[Cl:26][CH2:25][CH2:24][N:13]([CH2:14][C:15]#[CH:16])[S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11]
Reactant: C#CCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: C#CCN(CCCl)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.9 %

Procedure:
To a mixture of 2-nitro-N-(prop-2-yn-1-yl)benzenesulfonamide (0.448 g, 1.86 mmol) and cesium carbonate (1.75 g, 5.37 mmol) in acetone (10 mL) was added neat 1-bromo-2-chloroethane (0.775 mL, 9.31 mmol) dropwise. The reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated and the residue partitioned between EtOAc (25 mL) and water (15 mL). The aqueous layer was extracted with additional EtOAc (20 mL), the combined organic layers dried over anhydrous MgSO4 and concentrated. Purification via silica chromatography (25-40% EtOAc/hexane) afforded an oil (0.540 g, 96%). LC-MS: (FA) ES+303. 1H NMR (400 MHz, CDCl3) δ 8.08 (dt, J=8.2, 3.7 Hz, 1H), 7.77-7.64 (m, 3H), 4.30 (d, J=2.5 Hz, 2H), 3.78-3.68 (m, 4H), 2.23 (t, J=2.5 Hz, 1H).