Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15]([OH:17])=[O:16])=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].[Br:20]Br>C(O)(=O)C>[Br:20][C:12]1[C:11](=[O:14])[C:10]([C:15]([OH:17])=[O:16])=[CH:9][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:19][CH:18]=2)[CH:13]=1
Reactant: BrBr
Reactant: N#Cc1ccc(Cn2ccc(=O)c(C(=O)O)c2)cc1
Solvent: CC(=O)O
Product: N#Cc1ccc(Cn2cc(Br)c(=O)c(C(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
To a solution of 1-(4-cyano-benzyl)-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid (preparation 12a, 2.57 g, 10.1 mmol) in glacial acetic acid (10 ml) is added bromine (2 mL). The reaction mixture is stirred for 6 days at room temperature and additional bromine (1 mL) is added on the first 2 days, respectively. The reaction mixture is evaporated under reduced pressure and co-evaporated with toluene twice. The remaining residue is purified by preparative reversed-phase HPLC (XBridge, gradient of methanol in water, 0.3% NH4OH, 60° C.). Yield: 566 mg (17% of theory); ESI mass spectrum: [M+H]+=333 (bromine isotope pattern); Retention time HPLC: 0.84 min (Z002—002).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([Cl:20])[CH:16]=3)[CH:11]=2)=[O:9])[CH2:4][CH2:3]1.[BH4-].[Na+]>C(O)C>[Cl:20][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([CH:8]([CH:5]1[CH2:6][CH2:7][NH:2][CH2:3][CH2:4]1)[OH:9])[CH:19]=[CH:18]2
Reactant: O=C(c1ccc2cc(Cl)ccc2c1)C1CCNCC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC(c1ccc2cc(Cl)ccc2c1)C1CCNCC1
Reaction time: 18 h

Procedure:
3.47 g (12.7 mmoles) of (6-chloro-2-naphthyl) 4-piperidyl ketone hydrochloride is suspended in 200 ml of absolute ethanol and 1.5 g (4 mmoles) of sodium borohydride added. The reaction mixture is stirred for 18 hours and concentrated in vacuo. The residue is triturated with water and aqueous sodium hydroxide added to produce a basic solution which is extracted with toluene/methylene chloride. The organic phase is washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to yield α-(6-chloro-2-naphthyl)-4-piperidinemethanol.
Reaction SMILES: C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2(O)[CH2:34][CH2:33][CH:32]([CH:35]3[CH2:39][CH2:38][CH:37]([CH2:40][CH2:41][CH3:42])[CH2:36]3)[CH2:31][CH2:30]2)=[C:25]([F:44])[C:24]=1[F:45])[CH3:21]>O>[CH2:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH2:34][CH2:33][CH:32]([CH:35]3[CH2:39][CH2:38][CH:37]([CH2:40][CH2:41][CH3:42])[CH2:36]3)[CH2:31][CH:30]=2)=[C:25]([F:44])[C:24]=1[F:45])[CH3:21]
Reactant: CCCC1CCC(C2CCC(O)(c3ccc(OCC)c(F)c3F)CC2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCC1CCC(C2CC=C(c3ccc(OCC)c(F)c3F)CC2)C1
Temperature: 25 °C
Yield: 82 %

Procedure:
Toluene (50 ml) and p-toluenesulfonic acid monohydrate (0.15 g) were added to 1-(4-ethoxy-2,3-difluorophenyl)-4-(3-propylcyclopentyl)cyclohexanol (5.0 g) obtained in the first step, in a reaction vessel equipped with a Dean-Stark apparatus under an atmosphere of nitrogen. The mixture was refluxed for 1.5 hour, while forming water was removed with a Dean-Stark apparatus. After the mixture had been cooled to room temperature, the reaction solution was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate/n-heptane= 1/10 by volume) to give 1-ethoxy-2,3-difluoro-4-(4-(3-propylcyclopentyl)cyclohex-1-enyl)benzene (3.9 g).
Reaction SMILES: [CH2:1]([C@@H:8]1[C@@H:16]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C@H:15]([CH3:22])[O:14][C:13](=[O:23])[C@@H:12]([N:24](C(OC(C)(C)C)=O)C(=O)OC(C)(C)C)[CH2:11][O:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:39]>C(Cl)Cl>[Cl-:39].[CH2:1]([C@@H:8]1[C@@H:16]([O:17][CH2:18][CH:19]([CH3:20])[CH3:21])[C@H:15]([CH3:22])[O:14][C:13](=[O:23])[C@@H:12]([NH3+:24])[CH2:11][O:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CO[C@@H]1[C@@H](Cc2ccccc2)COC[C@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)O[C@H]1C
Reactant: Cl
Solvent: ClCCl
Product: CC(C)CO[C@@H]1[C@@H](Cc2ccccc2)COC[C@H]([NH3+])C(=O)O[C@H]1C
Product: [Cl-]
Reaction time: 1 h

Procedure:
To a solution of tert-butyl N-[(3S,7S,8R,9S)-7-benzyl-8-isobutoxy-9-methyl-2-oxo-1,5-dioxonan-3-yl]-N-tert-butoxycarbonylcarbamate (3.586 g, 6.69 mmol) in CH2Cl2 (33 mL) was added HCl (4M in dioxane; 33.5 ml, 134 mmol, 20 equiv). This solution was stirred for 1 h and concentrated to furnish (3S,7S,8R,9S)-7-benzyl-8-isobutoxy-9-methyl-2-oxo-1,5-dioxonan-3-aminium chloride as a white solid. The solid was suspended in CH2Cl2 (66 mL), and N-methylmorpholine (4.42 ml, 40.2 mmol, 6.00 equiv) was added, causing dissolution of the solid. To this solution were added 3-hydroxy-4-methoxypicolinic acid (1.70 g, 10.0 mmol, 1.50 equiv) and HATU (4.07 g, 10.71 mmol, 1.60 equiv). The resulting suspension was stirred at room temperature for 20 h, concentrated, and purified by automated silica gel column chromatography (2-12% acetone in CH2Cl2) to yield N-((3S,7S,8R,9S)-7-benzyl-8-isobutoxy-9-methyl-2-oxo-1,5-dioxonan-3-yl)-3-hydroxy-4-methoxypicolinamide (2.08 g, 63.9%) as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:12])([C:8]([F:11])([F:10])[F:9])/[CH:3]=[CH:4]/[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(NC(C)C)(C)C.[CH3:44][CH:45]([CH3:60])[CH:46]([NH:49][C:50]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[N:53]=[CH:52][CH:51]=1)[CH2:47][NH2:48].C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:12][C:2]([F:1])([C:8]([F:11])([F:10])[F:9])/[CH:3]=[CH:4]/[C:5]([NH:48][CH2:47][CH:46]([NH:49][C:50]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[N:53]=[CH:52][CH:51]=1)[CH:45]([CH3:60])[CH3:44])=[O:7]
Reactant: CC(C)C(CN)Nc1ccnc2ccccc12
Reactant: O=C(O)/C=C/C(F)(F)C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)NC(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C(CNC(=O)/C=C/C(F)(F)C(F)(F)F)Nc1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(E)-4,4,5,5,5-Pentafluoropent-2-enoic acid (29 mg, 0.15 mmol) was dissolved in anhydrous DMF (1 ml), HBTU (60 mg, 0.15 mmol) and diisopropylamine (26 μl, 0.15 mmol) were added and the mixture was stirred at room temperature for 15 minutes. 3-Methyl-N2-(4-quinolyl)butane-1,2-diamine (34.4 mg, 0.15 mmol) dissolved in 1 ml anhydrous DMF together with diisopropylethylamine (26 μl, 0.15 mmol) was added and the resulting mixture was stirred at room temperature for 3 hours. The mixture was evaporated to dryness under reduced pressure and the resulting residue was purified by preparative HPLC (gradient of water containing 0.1% NH3 and acetonitrile) to yield 7.3 mg (0.018 mmol, 12%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].Br[CH2:10][CH:11]([O:14][CH3:15])[O:12][CH3:13].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.C(Cl)Cl>[CH3:13][O:12][CH:11]([O:14][CH3:15])[CH2:10][N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1
Reactant: COC(CBr)OC
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC#N
Product: COC(Cn1cc([N+](=O)[O-])cn1)OC
Temperature: 85 °C

Procedure:
To a solution of 4-nitro-1H-pyrazole (1.50 g, 13.27 mmol) in MeCN (30 mL), 2-bromo-1,1-dimethoxyethane (2.34 mL, 19.90 mmol) and Cs2CO3 (6.48 g, 19.90 mmol) was added. The resulting mixture was refluxed (85° C.) for 20 h, then the reaction mixture was allowed to reach rt. The mixture was diluted with DCM, filtered, the filter cake was washed with DCM and the filtrate was concentrated in vacuo. The residue was partitioned between water and DCM, then the aq. layer was extracted with DCM (2×) and the comb. org. layers were dried (MgSO4), filtered and the solvent was removed under reduced pressure to yield 1-(2,2-dimethoxyethyl)-4-nitro-1H-pyrazole as a yellow oil which was used in the next step without further purification. LC-MS conditions B: tR=0.50 min, [M+H]+=no ionization.
Reaction SMILES: [SiH3:1][SiH2:2][SiH2:3][SiH2:4][SiH2:5][SiH2:6][SiH2:7][SiH2:8][SiH2:9][SiH2:10][SiH2:11][SiH2:12][SiH2:13][SiH2:14][SiH2:15][SiH3:16].[F:17][C:18]([F:24])([F:23])[S:19]([OH:22])(=[O:21])=[O:20]>ClCCl>[F:17][C:18]([F:24])([F:23])[S:19]([O:22][SiH2:16][SiH2:15][SiH2:14][SiH2:13][SiH2:12][SiH2:11][SiH2:10][SiH2:9][SiH2:8][SiH2:7][SiH2:6][SiH2:5][SiH2:4][SiH2:3][SiH2:2][SiH2:1][O:22][S:19]([C:18]([F:24])([F:23])[F:17])(=[O:21])=[O:20])(=[O:21])=[O:20]
Reactant: [SiH3][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH3]
Reactant: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(O[SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2]OS(=O)(=O)C(F)(F)F)C(F)(F)F

Procedure:
In an argon atmosphere, to a tetrahydrofuran solution (1 ml) of 68 mg (0.20 mmol) of octaethylcyclotetrasilane was added 0.72 ml (0.20 mmol) of a tetrahydrofuran solution (0.26M) of phenyldimethylsilyllithium, and stirred at 0° C. for 15 minutes. Then, tetrahydrofuran was distilled out under vacuum, and hexane (1 ml) was added to give a hexane solution (Solution 1). A dichloromethane solution (1 ml) of 71 mg (0.05 mmol) of hexadecasilane (6) obtained in Example 6 was treated with 15 mg (0.10 mmol) of trifluoromethanesulfonic acid at room temperature for 30 minutes to give 1,16-bis(trifluoromethanesulfonyloxy)hexadecasilane. Then, dichloromethane was distilled out under vacuum, and hexane (1 ml) was added to afford a hexane solution (Solution 2). The Solution 1 was added to the Solution 2 at -78° C., and stirred for 15 minutes. Methanol (0.1 ml) and triethylamine (0.1 ml) were added, then saturated aqueous sodium bicarbonate solution (2 ml) was added, stirred, the hexane layer was separated, and dried with magnesium sulfate. The resulting crude product was purified by a silica gel column (hexane) chromatography to give 46 mg (36% yield) of hexacosasilane (7) as a colorless crystal.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[S:14][C:13]3[CH:15]=[C:16]([O:19]C)[CH:17]=[CH:18][C:12]=3[C:11]=2[C:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:25][CH:24]=2)=[O:22])[CH:5]=[CH:6][C:7]=1[O:8]C.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[S:14][C:13]3[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:12]=3[C:11]=2[C:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:25][CH:24]=2)=[O:22])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(OC)c(F)c3)sc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCl
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(O)c(F)c2)sc2cc(O)ccc12
Yield: 39.1 %

Procedure:
A solution of the product of Example 1 (0.65 g, 1.25 mmol), ethanethiol (0.46 mL, 6.32 mmol), and aluminum chloride (1.17 g, 8.78 mmol) in anhydrous CH2Cl2 (20 mL) was stirred for 3.5 h. The mixture was quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicaronate and brine, dried (sodium sulfate), and concentrated. The residue was purified by chromatography (silica gel, 5-10% MeOH in CH2Cl2) and crystallized from MeOH/CH2Cl2 to give 240 mg (39%) of the title product as a yellow solid: 1H NMR (MeOD-d4) d 1.62 (m, 2H), 1.80 (m, 4H), 3.11 (m, 4H), 3.34 (t, J=6.0 Hz, 2H), 4.32 (t, J=6.0 Hz, 2H), 4.86 (br s, 2H), 6.75 t, J=8.6 Hz, 1H), 6.88 (dd, J=2.2 Hz, 8.8 Hz, 1H), 6.92 (d, J=8.8 Hz, 2H), 6.97-7.06 (m, 3H), 7.27 (d, J=2.2 Hz, 1H), 7.43 (d, J=8.8 Hz, 1H), 7.73 (d, J=8.8 Hz, 2H); 13C NMR (DMSO-d6) d 21.8, 23.1, 53.0, 63.4, 107.1, 114.6, 115.4, 115.7, 116.0, 118.1, 123.4, 124.2, 125.0, 130.0, 130.4, 131.8, 131.9, 138.9, 139.3, 145.3, 145.5, 148.9, 152.1, 155.7, 162.0, 192.3; MS (FD) m/e 492 (MH+); Anal. calc'd. for C28H26FNO4S.0.75 H2O: C, 66.57; H, 5.65; N, 2.77. Found: C, 66.68; H, 5.78; N, 2.74.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:25])[C:7]([C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)=[C:8]([C:12]([F:15])([F:14])[F:13])[O:9]2)=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:38][S:39]([NH2:42])(=[O:41])=[O:40].C1CCN2C(=NCCC2)CC1>C1COCC1>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:25])[C:7]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([NH:42][S:39]([CH3:38])(=[O:41])=[O:40])=[O:21])=[CH:18][CH:17]=3)=[C:8]([C:12]([F:15])([F:14])[F:13])[O:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(-c2c(C(F)(F)F)oc3cc(O)ccc3c2=O)cc1
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CS(=O)(=O)NC(=O)c1ccc(-c2c(C(F)(F)F)oc3cc(O)ccc3c2=O)cc1
Reaction time: 2 h

Procedure:
Synthesis: To a solution of 4-(7-hydroxy-4-oxo-2-(trifluoromethyl)-4H-chromen-3-yl)benzoic acid (synthesis is described in PCT/US2010/024035) (100 mg, 0.28 mmol) in THF (10 ml) was added CDI (139 mg, 0.86 mmol) at room temperature. The mixture was stirred for 2 hours. MeSO2NH2 (280 mg, 2.86 mmol) was added in one portion, followed by DBU (394 mg, 2.86 mmol). The mixture was stirred for 4 hours and partitioned between 1N HCl (30 ml) and ethyl acetate (100 ml). The organic phase was separated, washed with brine (50 ml), dried over Na2SO4 and concentrated to give the desired product contaminated with the acid starting material. The mixture was difficult to purify and the acid contaminant was converted into the methyl ester by treatment with SOCl2 (91 mg, 0.77 mmol) in MeOH (4 ml) at 0° C. When the addition was complete, the mixture was stirred for 3 days. The volatiles were removed under reduced pressure and the residue was purified by prep-HPLC to afford the desired product in Example 10 as a white powder (25 mg, 20.5%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([NH:12][NH:13][C:14](=S)[NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CCN=C=NCCCN(C)C.Cl>C1(C)C=CC=CC=1>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[O:11][C:14]([NH:15][CH2:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)=[N:13][N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: COc1ccc(CNC(=S)NNC(=O)c2ccc3[nH]ccc3c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: COc1ccc(CNc2nnc(-c3ccc4[nH]ccc4c3)o2)cc1
Temperature: 25 °C

Procedure:
A solution of 2-(1H-indole-5-carbonyl)-N-(4-methoxybenzyl)hydrazinecarbothioamide (0.1 g, 0.284 mmol) and EDC.HCl (0.109 g, 0.586 mmol) in toluene (10 mL) was heated to reflux for 12 h. The mixture was cooled to RT. The supernatant layer was decanted and the sticky material in the bottom was dissolved in EtOAc (20 mL). The organic layer was washed with water, brine, dried, filtered and concentrated to give the crude material. MS (ESI, pos. ion) m/z: 321 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:18]3[C:10](=[CH:11][C:12]4[CH2:13][CH2:14][NH:15][C:16]=4[CH:17]=3)[O:9][CH2:8]2)[CH2:4][CH2:3]1.[C:19]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34](O)=[O:35])=[CH:30][CH:29]=2)=[C:24]([CH3:37])[CH:23]=1)(=[O:21])[CH3:20]>>[C:19]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([N:15]3[C:16]4[CH:17]=[C:18]5[C:5]6([CH2:8][O:9][C:10]5=[CH:11][C:12]=4[CH2:13][CH2:14]3)[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]6)=[O:35])=[CH:30][CH:29]=2)=[C:24]([CH3:37])[CH:23]=1)(=[O:21])[CH3:20]
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCC3
Reactant: CC(=O)c1ccc(-c2ccc(C(=O)O)cc2)c(C)c1
Product: CC(=O)c1ccc(-c2ccc(C(=O)N3CCc4cc5c(cc43)C3(CCN(C)CC3)CO5)cc2)c(C)c1

Procedure:
The title compound was prepared from 1'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (D8) and 4'-acetyl-2'-methylbiphenyl-4-carboxylic acid (D19) using a procedure similar to that of Example 1 (35%).
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][CH:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C>C(O)(C(F)(F)F)=O>[C:21]([CH2:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[S:10][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:13][CH:12]=2)=[CH:19][CH:18]=1)#[N:22]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2ccc(CC#N)cc2)s1
Solvent: O=C(O)C(F)(F)F
Product: N#CCc1ccc(-c2ccc(S(N)(=O)=O)s2)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 72.6 %

Procedure:
5-(4-Cyanomethyl-phenyl)-thiophene-2-sulfonic acid tert-butylamide (260 mg) was suspended in TFA (10 mL) and stirred 2 h at 50° C. The mixture was evaporated to dryness and trituated with toluene (2 mL). The obtained precipitate was filtered off, washed with toluene and dried in vacuo to yield 5-(4-Cyanomethyl-phenyl)-thiophene-2-sulfonic acid amide (157 mg, 73%) as a white solid.
Reaction SMILES: C([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:37][C:38]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[C:42]([C:47]4[C:52]([F:53])=[CH:51][C:50]([CH2:54][O:55][CH3:56])=[CH:49][C:48]=4[F:57])[N:41]=3)=[O:39])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[C@@H:17]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C@H:16]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=O)C.C1COCC1.[OH-].[Na+]>CO>[Si:22]([O:21][C@@H:17]1[C@@H:18]([CH3:20])[CH2:19][N:14]([C:13]2[C:12]([NH:37][C:38]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[C:42]([C:47]4[C:52]([F:53])=[CH:51][C:50]([CH2:54][O:55][CH3:56])=[CH:49][C:48]=4[F:57])[N:41]=3)=[O:39])=[CH:11][N:10]=[C:9]3[CH:5]([OH:4])[CH2:6][CH2:7][C:8]=23)[CH2:15][C@H:16]1[NH:29][C:30](=[O:31])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])([C:25]([CH3:28])([CH3:26])[CH3:27])([CH3:24])[CH3:23]
Reactant: COCc1cc(F)c(-c2nc(C(=O)Nc3cnc4c(c3N3C[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](NC(=O)OC(C)(C)C)C3)CCC4OC(C)=O)ccc2F)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COCc1cc(F)c(-c2nc(C(=O)Nc3cnc4c(c3N3C[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](NC(=O)OC(C)(C)C)C3)CCC4O)ccc2F)c(F)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To the amide intermediate prepared as described above THF (5 mL), MeOH (5 mL) and 1.0 M aq. NaOH (5 mL, 5 mmol) were added. The mixture was stirred at room temperature for 20 min. The volatile organic solvents were removed under reduced pressure. The residue was extracted with EtOAc (2 times). The combined organic phases were then washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give an alcohol intermediate, tert-butyl ((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-{3-[({6-[2,6-difluoro-4-(methoxymethyl)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate.
Reaction SMILES: Cl.NO.C([N:6](C(C)C)C(C)C)C.C(O)C.[F:16][C:17]([F:50])([F:49])[C:18]1[CH:19]=[C:20]([CH:46]=[CH:47][CH:48]=1)[C:21]([NH:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][CH:45]=1)[O:27][C:28]1[CH:29]=[CH:30][C:31]([NH:34][C:35]([NH:37]C(=O)OCC)=S)=[N:32][CH:33]=1)=[O:22]>CO>[NH2:37][C:35]1[N:34]=[C:31]2[CH:30]=[CH:29][C:28]([O:27][C:26]3[CH:25]=[C:24]([NH:23][C:21](=[O:22])[C:20]4[CH:46]=[CH:47][CH:48]=[C:18]([C:17]([F:16])([F:49])[F:50])[CH:19]=4)[CH:45]=[CH:44][CH:43]=3)=[CH:33][N:32]2[N:6]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)NC(=S)Nc1ccc(Oc2cccc(NC(=O)c3cccc(C(F)(F)F)c3)c2)cn1
Agent: Cl
Agent: NO
Solvent: CO
Solvent: CCO
Product: Nc1nc2ccc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)cn2n1
Temperature: 60 °C
Yield: 122.2 %

Procedure:
To a solution of hydroxylamine hydrochloride (400 mg, 5.76 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.20 mL, 6.88 mmol) in methanol (8.0 mL)/ethanol (8.0 mL) was added ethyl ({[5-(3-{[3-(trifluoromethyl)benzoyl]amino}phenoxy)pyridin-2-yl]amino}carbonothioyl)carbamate (480 mg, 0.95 mmol) obtained above, and the mixture was stirred with heating at 60° C. for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (100 mL), washed with water (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50→0/100), and fractions containing the object product was concentrated under reduced pressure to give the title compound (0.48 g, quantitative) as a pale-yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]([OH:8])[CH:7]=1.Cl[C:19]1[N:20]=[N:21][C:22]([O:25][CH:26]2[CH2:31][C:30]([CH3:33])([CH3:32])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]2)=[CH:23][CH:24]=1.CC(OC)(C)C>O.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>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:19]2[N:20]=[N:21][C:22]([O:25][CH:26]3[CH2:31][C:30]([CH3:33])([CH3:32])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]3)=[CH:23][CH:24]=2)=[C:6]([OH:8])[CH:7]=1
Reactant: CC1(C)CC(Oc2ccc(Cl)nn2)CC(C)(C)N1
Reactant: CC1(C)OB(c2ccc(Cl)cc2O)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: COC(C)(C)C
Product: CC1(C)CC(Oc2ccc(-c3ccc(Cl)cc3O)nn2)CC(C)(C)N1
Product: Cl
Temperature: 89 °C
Reaction time: 16 h
Yield: 91.7 %

Procedure:
To the solution containing 5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1.22 kg, 4.8 mol) from the previous step was added 3-chloro-6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazine (1.17 kg, 4.4 mol). K3PO4-3H2O (2.34 kg, 8.8 mol) was dissolved in water (5 L) then added to the above solution. The mixture was purged with nitrogen 3 times. Pd(PPh3)4 (500 g, 0.42 mol) was added under nitrogen, and the reaction mixture was heated to reflux at 89° C. for 16 hours. After 16 hours, HPLC showed that the reaction was complete. After cooling to room temperature, the mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. CH2Cl2 (10 L×3) and 10% K2CO3 solution (15 L) were added to the above residue. The organic layers were separated and combined, followed by washing with water twice (10 L×2) and concentration under reduced pressure to give yellow oil. MTBE (10 L) was used to dissolve the yellow oil. Petroleum ether (4 L) was added slowly with stirring. A few dark solids precipitated and were removed by filtration. The filtrate was concentrated under reduced pressure and dissolved in CH2Cl2 (20 L). 2N HCl (5 L) was added slowly and a large amount of precipitate formed. After stirring for another 1 hour, the solid was collected by filtration and washed with EtOAc (2 L). The solid was dried in vacuo at 50° C. to give 5-chloro-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenol hydrochloride (0.9 kg, 2.2 mol). MS m/z 362.0 [M+H]+; 1H-NMR: (DMSO-d6, 400 MHz) δ 9.26 (d, J=11.6 Hz, 1H), 8.49 (d, J=12 Hz, 1H), 8.38 (d, J=9.6 Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.44 (d, J=9.6 Hz, 1H), 7.07 (d, J=2 Hz, 1H), 7.02 (dd, Ja=2 Hz, Jb=8.4 Hz, 1H), 5.73 (m, 1H), 2.31 (dd, Ja=4 Hz, Jb=13.2 Hz, 2H), 1.84 (dd, Ja=11.6 Hz, Jb=2 Hz, 2H), 1.51 (s, 6H), 1.49 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH:8]2[CH2:10][O:9]2)=[CH:4][CH:3]=1.Cl.[NH:14]1[CH2:18][CH2:17][CH:16]([CH2:19][N:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[NH:22][C:21]2=[O:29])[CH2:15]1.C(=O)([O-])[O-].[Na+].[Na+]>CC(O)C>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH:8]([OH:9])[CH2:10][N:14]2[CH2:18][CH2:17][CH:16]([CH2:19][N:20]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[NH:22][C:21]3=[O:29])[CH2:15]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(OCC2CO2)cc1
Reactant: O=c1[nH]c2ccccc2n1CC1CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: O=c1[nH]c2ccccc2n1CC1CCN(CC(O)COc2ccc(Cl)cc2)C1
Yield: 35 %

Procedure:
A mixture of 4 parts of (4-chlorophenoxymethyl)oxirane, 5 parts of 1,3-dihydro-1-(3-pyrrolidinylmethyl)-2H-benzimidazol-2-one monohydrochloride, 6 parts of sodium carbonate and 80 parts of 2-propanol is stirred and refluxed for 5 hours. The reaction mixture is cooled, filtered and the filtrate is evaporated. The residue is crystallized from 4-methyl-2-pentanone, yielding 2.8 parts (35%) of 1-{1-[3-(4-chlorophenoxy)-2-hydroxypropyl]-3-pyrrolidinylmethyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 129° C.