Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]([CH3:11])=[C:5]2[CH2:12][C:13]([OH:15])=[O:14].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH:21]=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:21]\[C:20]1[CH:23]=[C:24]([O:28][CH3:29])[C:25]([O:26][CH3:27])=[C:18]([O:17][CH3:16])[CH:19]=1)/[C:6]([CH3:11])=[C:5]2[CH2:12][C:13]([OH:15])=[O:14]
Reactant: CC1=C(CC(=O)O)c2cc(F)ccc2C1
Reactant: COc1cc(C=O)cc(OC)c1OC
Product: COc1cc(/C=C2/C(C)=C(CC(=O)O)c3cc(F)ccc32)cc(OC)c1OC

Procedure:
5-fluoro-2-methylindene-3-acetic acid (see Example 1, Part D) is allowed to react with 3,4,5-trimethoxybenzaldehyde according to the procedure of Example 1, part E to obtain (Z)-5-fluoro-2-methyl-1-(3,4,5-trimethoxybenzylidene)-3-indenylacetic acid. C22H21FO5 : 384.40; m.p. 168° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([C:14]([S:17]([C:20]2[S:21][CH:22]=[C:23]([CH3:25])[N:24]=2)(=[O:19])=[O:18])([CH3:16])[CH3:15])[N:11]=[C:10]([C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=2)[N:9]=1.C(=O)(O)[O-].[Na+].Cl[C:39]([O:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:40]>O1CCOCC1.C(OCC)C>[CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([C:14]([S:17]([C:20]2[S:21][CH:22]=[C:23]([CH3:25])[N:24]=2)(=[O:19])=[O:18])([CH3:16])[CH3:15])[N:11]=[C:10]([C:26]2[CH:27]=[CH:28][C:29]([NH:30][C:39](=[O:40])[O:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:31][CH:32]=2)[N:9]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1csc(S(=O)(=O)C(C)(C)c2cc(N3CCOC[C@@H]3C)nc(-c3ccc(N)cc3)n2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1csc(S(=O)(=O)C(C)(C)c2cc(N3CCOC[C@@H]3C)nc(-c3ccc(NC(=O)Oc4ccccc4)cc3)n2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 78.1 %

Procedure:
To a solution of 4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[2-[(4-methyl-1,3-thiazol-2-yl)sulfonyl]propan-2-yl]pyrimidin-2-yl]aniline (340 mg, 0.72 mmol) in 1,4-dioxane (4 mL) was added sodium bicarbonate (90 mg, 1.08 mmol). Phenyl chloroformate (0.104 mL, 0.83 mmol) was then added dropwise and the resulting mixture was stirred at RT for 6 hours. Reaction mixture was then evaporated and the residue was partitioned between DCM (5 mL) and water (5 mL). The organic layer was separated and aqueous re-extracted with more DCM (5 mL). The combined organic layers were combined and evaporated to dryness to afford an amber gum, which was taken up in diethyl ether (5 mL) and triturated with sonication. The resultant solid was collected by suction filtration and dried to afford the desired material (334 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:7]([CH2:21][CH2:22][N:23]=3)[C:8]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=3)=[N:9][C:10]=2[CH:11]=1.Cl[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[CH3:35][S:32]([C:29]1[CH:30]=[CH:31][C:26]([CH2:25][O:1][C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[N:7]([CH2:21][CH2:22][N:23]=4)[C:8]([NH:12][C:13](=[O:20])[C:14]4[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=4)=[N:9][C:10]=3[CH:11]=2)=[CH:27][CH:28]=1)(=[O:33])=[O:34]
Reactant: O=C(NC1=Nc2cc(O)ccc2C2=NCCN12)c1cccnc1
Reactant: CS(=O)(=O)c1ccc(CCl)cc1
Product: CS(=O)(=O)c1ccc(COc2ccc3c(c2)N=C(NC(=O)c2cccnc2)N2CCN=C32)cc1

Procedure:
The procedure used for the preparation of Example 24 was used to prepare the title compound from N-(8-hydroxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide (Example 2-5 in WO2004029055) and 1-(chloromethyl)-4-(methylsulfonyl)benzene (20 mg, 4%). TLC: Rf=0.91 in 10% MeOH/CH2Cl2, HPLC MS RT=1.91 min, MH+=476.2; 1H NMR (DMSO-d6) δ: 3.22 (3H, s), 4.00-4.15 (4H, m), 5.33 (2H, s), 6.93 (1H, d), 7.39 (1H, s), 7.51 (1H, dd), 7.71 (2H, d), 7.78 (1H, d), 7.95 (2H, d), 8.42 (1H, d), 8.70 (1H, m), 9.29 (1H, s), 12.31 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:10][O:11][CH:12]([O:16][CH3:17])[C:13](=O)[CH3:14].C(O)C.[OH-].[Na+]>O>[CH3:10][O:11][CH:12]([O:16][CH3:17])[C:13]1[CH:14]=[CH:8][C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[N:1]=1
Reactant: Nc1ncccc1C=O
Reactant: COC(OC)C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COC(OC)c1ccc2cccnc2n1
Temperature: 7.5 °C

Procedure:
The procedure described in J. Org. Chem., 2004, 69 (6), pp 1959-1966 was used. Into a 20 l 4-necked round-bottom flask was placed 2-aminopyridine-3-carbaldehyde (1000 g, 8.19 mol), 1,1-dimethoxypropan-2-one (1257 g, 10.64 mol), ethanol (10 l), and water (2 l). This was followed by the addition of a solution of sodium hydroxide (409.8 g, 10.24 mol) in water (1000 ml) drop wise with stirring at 0-15° C. The solution was stirred for 3 h at 0-20° C. and then concentrated under vacuum. The resulting solution was extracted with 3×1200 ml of ethyl acetate and the organic layers were combined. The mixture was dried over sodium sulfate and concentrated under vacuum. The residue was washed with 3×300 ml of hexane and the solid was collected by filtration. This resulted in the title compound as a yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ 9.11 (dd, 1H), 8.53 (d, 1H), 8.50 (dd, 1H), 7.73 (d, 1H), 7.67 (dd, 1H), 5.44 (s, 1H), 3.41 (s, 6H).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][S:6][CH:7]=1.[C:12](Cl)(Cl)=[S:13].C(=O)(O)[O-].[Na+]>O.ClCCl>[N:2]([C:3]1[C:4]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][S:6][CH:7]=1)=[C:12]=[S:13]
Reactant: S=C(Cl)Cl
Reactant: COC(=O)c1cscc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cscc1N=C=S
Reaction time: 1 h

Procedure:
19.4 g of methyl 4-aminothiophen-3-carboxylate hydrochloride were added to a suspension of 7.7 ml of thiophosgene and 18.5 g of sodium bicarbonate in 70 ml of water and 200 ml of dichloromethane at room temperature in the course of 30 minutes, and stirring was carried out for 1 hour at room temperature. After separation of the phases, the aqueous phase was extracted once with dichloromethane and the combined organic phases were washed once with water, dried over sodium sulfate and evaporated down.
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([CH2:12][CH3:13])[C:4]=1[CH:5]=[O:6])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([O:11][C:9]1[CH:8]=[C:7]([CH2:12][CH3:13])[C:4]([CH:5]=[O:6])=[C:3]([CH2:1][CH3:2])[CH:10]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: CCc1cc(O)cc(CC)c1C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCc1cc(OCc2ccccc2)cc(CC)c1C=O

Procedure:
4-Benzyloxy-2,6-diethyl-benzaldehyde was prepared from 2,6-diethyl-4-hydroxy-benzaldehyde, cesium carbonate and benzyl bromide in analogy to Example 213b): yellow oil; 1H-NMR (CDCl3): 1.25 (6H, t, 2×CH3), 2.98 (4H, q, 2×CH2), 5.12 (2H, s, OCH2), 6.72 (2H, s, 2×ArH), 7.33-7.45 (5H, m, Ph), 10.47 (1H, s, CH═O).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:12].C([O-])([O-])=O.[K+].[K+].[C:19](OC(=O)C)(=[O:21])[CH3:20].O>CN(C=O)C>[C:19]([O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:12])(=[O:21])[CH3:20]
Reactant: O=C1NCCc2c(O)cccc21
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Oc1cccc2c1CCNC2=O
Temperature: 25 °C
Reaction time: 60 h
Yield: 47.8 %

Procedure:
A mixture of 2.0 g (12.3 mmol) of 3,4-dihydro-5-hydroxy-1(2H)-isoquinolinone, 2.0 g (52 mmol) of K2CO3 and 0.75 g of acetic anhydride in 20 ml of DMF was stirred at room temperature for 2.5 days. The mixture was then warmed to 70°-80° and an additional 1.5 g of acetic anhydride was added and stirring was continued for five hours. The reaction was poured into 250 ml of water and the resulting solid was collected, washed with water, and air dried. It was recrystallized from EtOH and then chromatographed (SiO2, 9:1 methylene chloride/MeOH) to give 0.72 g (29%) of product; mp 189°-193°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([CH3:40])[CH:34]=3)=[CH:29][C:28]=2[N:41]2[CH:45]=[CH:44][C:43]([CH3:46])=[N:42]2)[C:23]([F:26])([F:25])[F:24])[N:3]=1.[CH3:47][CH:48](O)[CH3:49]>S(Cl)(Cl)=O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([O:18][CH:48]([CH3:49])[CH3:47])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([CH3:40])[CH:34]=3)=[CH:29][C:28]=2[N:41]2[CH:45]=[CH:44][C:43]([CH3:46])=[N:42]2)[C:23]([F:26])([F:25])[F:24])[N:3]=1
Reactant: Cc1ccn(-c2cc(-c3ccc(C)c(C)c3)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1
Reactant: CC(C)O
Solvent: O=S(Cl)Cl
Product: Cc1ccn(-c2cc(-c3ccc(C)c(C)c3)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)OC(C)C)C4)nc(N)n2)C(F)(F)F)n1
Temperature: 25 °C

Procedure:
To a solution of the compound of Example 1m (400 mg, 0.53 mmol) in propan-2-ol (5 mL) was added thionyl chloride (2 drops) at 0° C. The mixture was warmed to RT and then heated to reflux for 2 h. Then the reaction mixture was cooled to RT, concentrated and neutralized with saturated aqueous NaHCO3 solution to pH 7-8. The aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated in vacuo and purified by flash column (0˜10% MeOH in DCM) on silica gel to afford the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:16])[CH:11]=[C:12]([CH3:15])[NH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:19][O-].[Na+].Cl>>[CH2:1]([O:8][C:9]1[C:10](=[O:16])[C:11]([Cl:19])=[C:12]([CH3:15])[NH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [O-]Cl
Reactant: Cc1cc(=O)c(OCc2ccccc2)c[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1[nH]cc(OCc2ccccc2)c(=O)c1Cl
Temperature: 25 °C
Yield: 86 %

Procedure:
To a solution of 5-(benzyloxy)-2-methylpyridin-4(1H)-one (9.00 g, 41.8 mmol) in 2M sodium hydroxide (62.5 mL, 125 mmol) under ice-water bath, a solution of 10-14% sodium hypochlorite (62.5 mL) was added slowly during 20 minutes. The reaction mixture was stirred at room temperature for another hour. The reaction mixture was carefully neutralized with 6N HCl to pH about 7 with external cooling to keep the internal temperature below 25° C. The solid was filtered and washed with water (3×), then dried in a vacuum oven for overnight. Thus, 5-(benzyloxy)-3-chloro-2-methylpyridin-4(1H)-one (9.03 g) was obtained as a white solid. Yield=86%; 1H NMR (DMSO-D6, 90 MHz) δ (ppm): 11.74 (br. s, 1H), 7.14-7.68 (m, 6H), 5.02 (s, 2H) and 2.33 (s, 3H).
Reaction SMILES: [CH2:1]=O.Cl.[CH2:4]([O:11][NH2:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Na+]>O>[CH2:4]([O:11][N:12]=[CH2:1])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C=O
Reactant: NOCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=NOCc1ccccc1
Reaction time: 2 h

Procedure:
37% Formaldehyde (11.7 mL) was added to a slurry of benzyloxyamine hydrochloride (25.0 g, 0.156 mole) in 50 mL H2O. NaOH (6.3 g) in 25 mL H2O was then added over 20 minutes. The temperature rose to 40°. After stirring 2 hours, the reaction mixture was extracted 1×100 mL and 2×25 mL of ether. The ether extracts were combined, washed 2×50 mL saturated NaHCO3 and then 2×50 mL brine, dried and evaporated to yield title product as an oil, 20.0 g b.p. 195.5°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C@H:12]([O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[CH3:13])[CH2:11][O:10]1.[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1.[H-].[Na+].O>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([C@H:12]([O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)[CH3:13])[CH2:11][N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1
Reactant: C[C@@H](OC1CCCCO1)C1(c2ccc(F)cc2F)CO1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](OC1CCCCO1)C(O)(Cn1ccnc1)c1ccc(F)cc1F
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 85.4 %

Procedure:
To a solution of 2-(2,4-difluorophenyl)-2-[(1R)-1-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)ethyl]oxirane (1.7 g) and imidazole (0.49 g) in N,N-dimethylformamide (17 ml) was added 60% oily sodium hydride in mineral oil (0.29 g) by portions at 20° C. with constant stirring. After 5 minutes, the mixture was heated at 70° C. for 3 hours. The reaction mixture was cooled, then poured into water (50 ml) and extracted with ethyl acetate (20 ml×3). The ethyl acetate layers were combined, washed with saturated aqueous sodium chloride solution (20 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (3 cm×15 cm) using methanol-ethyl acetate (5:95) as the eluent. The desired fraction was concentrated under reduced pressure to give (3R)-2-(2,4-difluorophenyl)-1-(1-imidazolyl)-3-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-2-butanol (1.8 g) as a colorless syrup.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.C1(O)C=CC=CC=1.[Cl:23][C:24]1[CH:29]=[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:27]=[C:26]([Cl:38])[C:25]=1O>>[Cl:23][C:24]1[CH:29]=[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:27]=[C:26]([Cl:38])[C:25]=1[O:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: Oc1c(Cl)cc(OCc2ccccc2)cc1Cl
Solvent: Oc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(COc2c(Cl)cc(OCc3ccccc3)cc2Cl)CC1

Procedure:
As depicted in Scheme 1, an appropriately substituted hydroxy compound, for example, the commercially available tert-butyl 4-(hydroxymethyl)piperidinecarboxylate was coupled with a phenol (A), for example the known compound 2,6-dichloro-4-(phenylmethoxy)phenol, affording the corresponding tert-butyl 4-{[2,6-dichloro-4-(phenylmethoxy)phenoxy]methyl}piperidinecarboxylate (A1). The intermediate (A1) was in turn treated with hydrogen gas under catalytic conditions using, for example, a Parr hydrogenation apparatus, to convert the phenylmethoxy moiety of (A1) to a hydroxy moiety, thereby making the hydroxy moiety available for further reaction. The so-prepared hydroxy derivative (A2) was then reacted with an appropriate haloalkane, for example, 1,1,1,3-tetrachloropropane, under basic conditions, yielding the corresponding dihaloalkene derivative, a compound of formula I, for example, tert-butyl 4-{[4-(3,3-dichloroprop-2-enyloxy)-2,6-dichlorophenoxy]methyl}piperidinecarboxylate. Example 1, set forth below, provides detailed methods to how compounds of formula I shown in Scheme 1 were prepared.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[C:13]1([C:19]2[N:20]=[C:21]3[S:26][CH:25]=[C:24]([CH2:27][C:28]([NH:30][NH2:31])=[O:29])[N:22]3[N:23]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:31][NH:30][C:28](=[O:29])[CH2:27][C:24]1[N:22]2[N:23]=[C:19]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:20]=[C:21]2[S:26][CH:25]=1
Reactant: NNC(=O)Cc1csc2nc(-c3ccccc3)nn12
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: O=C(Cc1csc2nc(-c3ccccc3)nn12)NN=C1C(=O)Nc2ccc(I)cc21
Temperature: 100 °C
Yield: 48 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 2-(2-phenyl[1,3]thiazolo[3,2-b][1,2,4]triazol-6-yl)acetohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 28 mg of the title compound (48%) as a yellow powder in 94.7% purity by HPLC (Rt: 4.65, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH2:8][CH2:9][NH2:10])[CH2:5][CH2:6][NH2:7].C(=O)(O)[O-].[Na+].Cl[C:17]([CH3:23])([CH3:22])[CH:18]([N:20]=[O:21])[CH3:19]>C(#N)C>[CH3:22][C:17]([CH3:23])([NH:1][CH2:2][CH2:3][N:4]([CH2:8][CH2:9][NH2:10])[CH2:5][CH2:6][NH:7][C:17]([CH3:23])([CH3:22])[C:18](=[N:20][OH:21])[CH3:19])[C:18](=[N:20][OH:21])[CH3:19]
Reactant: NCCN(CCN)CCN
Reactant: CC(N=O)C(C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(=NO)C(C)(C)NCCN(CCN)CCNC(C)(C)C(C)=NO
Temperature: 25 °C
Reaction time: 72 h
Yield: 9.5 %

Procedure:
To a solution of tris-(2-aminoethyl)amine (1 ml, 6.68 mmol) in acetonitrile (10 ml) was added sodium bicarbonate (1.12 g, 13.36 mmol, 2 eq). A solution of 3-chloro-3-methyl-2-nitrosobutane (1.359 g, 10.02 mmol, 1.5 eq) in dry acetonitrile (5 ml) was added slowly. The reaction mixture was left to stir at room temperature for 3 days, and then filtered. The residue was washed well with acetonitrile, and the filtrate evaporated. The crude product was then purified by RP-HPLC (System L) to afford Compound 15 (164 mg, 7%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH2:17][C:18](=O)[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-].ClC1C=CC=C[N+]=1C.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]#[C:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)(=[O:15])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)CC(=O)c2ccc(Cl)cc2)CC1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)C#Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.2 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-(4-chlorobenzoylmethanesulfonyl)piperazine (640 mg) and 2-chloro-1-methylpyridinium iodide (650 mg) in dichloromethane (8 ml) was added dropwise triethylamine (4 ml) at 0° C., and the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated and purified with silica gel column chromatography (hexane/ethyl acetate=2/1) to give a colorless solid of 1-(tert-butoxycarbonyl)-4-[2-(4-chlorophenyl)ethynesulfonyl]piperazine (521 mg).
Reaction SMILES: P(Br)(Br)[Br:2].[Br:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10]O)=[C:8]([O:14][C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[CH:16]=2)[CH:7]=1>C(Cl)Cl>[Br:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][Br:2])=[C:8]([O:14][C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[CH:16]=2)[CH:7]=1
Reactant: COc1cc(OC)cc(Oc2cc(Br)ccc2CO)c1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: COc1cc(OC)cc(Oc2cc(Br)ccc2CBr)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 224.1 %

Procedure:
In an argon atmosphere, 4.7 mL (F.W. 270.70, d=2.850, 49.5 mmol) of phosphorus tribromide was added to a solution of 46 g (F.W. 339.19, 135 mmol) of alcohol (23) in 100 mL of methylene chloride at 0° C. and stirred at room temperature for 30 minutes. To the reaction mixture was added ice water and the resulting solution was further stirred at room temperature for 30 minutes. The obtained solution was extracted with ethyl acetate and the extract was washed with water and then with a saturated sodium chloride aqueous solution. The resulting extract was dried with anhydrous magnesium sulfate and then, concentrated. The residue was purified by silica gel column chromatography (developing solvent; ethyl acetate:hexane=1:5) to obtain 44.6 g (84%) of a bromide (24). (TLC; ethyl acetate:hexane=1:4)
Reaction SMILES: Br[C:2]1[C:3]([O:18][CH3:19])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1.C([Li])CCC.[C:25](=[O:27])=[O:26].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[F:17][C:13]1[CH:12]=[C:11]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([C:25]([OH:27])=[O:26])[C:3]=3[O:18][CH3:19])[NH:7][N:6]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: COc1c(Br)ccc2[nH]nc(-c3cccc(F)c3)c12
Reactant: O=C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1c(C(=O)O)ccc2[nH]nc(-c3cccc(F)c3)c12
Temperature: -78 °C

Procedure:
A total of 230 mg of 5-bromo-3-(3-fluoro-phenyl)-4-methoxy-1H-indazole obtained in Production Example II-2-c was dissolved in 4.78 ml of tetrahydrofuran, and 0.99 ml of a 1.59 M solution of n-butyllithium in hexane was added under stirring at −78° C. After stirring at −78° C. for 30 minutes, dry ice was added. After stirring at the same temperature for 10 minutes, saturated aqueous ammonium chloride solution was added. The mixture was extracted with ethyl acetate, and the resulting organic layer was washed with brine, dried over magnesium sulfate and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:1), to give 41.1 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[N:10][C:5]2=[N:4][C:3]=1[CH2:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][N:14]1C(OC(C)(C)C)=O>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[N:10][C:5]2=[N:4][C:3]=1[CH2:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][NH:14]1
Reactant: Cc1ccn2c(Cl)c(C[C@@H]3CCCCN3C(=O)OC(C)(C)C)nc2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2c(Cl)c(C[C@@H]3CCCCN3)nc2n1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 1,1-dimethylethyl (2S)-2-[(3-chloro-7-methylimidazo[1,2-a]pyrimidin-2-yl)methyl]-1-piperidinecarboxylate (D4) (0.085 g, 0.23 mmol) in DCM (2 ml), TFA (0.5 ml) was added dropwise at 0° C. and the solution was stirred for 1 h. The solvent was removed and the residue charged into a SCX column and eluted with methanol and ammonia 2 M in methanol. Collected fractions gave the title compound (0.060 g, 0.23 mmol, 97% yield) as a colorless oil. UPLC: rt=0.39, peak observed: 265 (M+1, 100%) and 267 (M+1, 33%). C13H17ClN4 requires 265. 1H NMR (400 MHz, CDCl3) δ(ppm): 8.12-8.21 (d, 1H), 6.80-6.88 (d, 1H), 3.02-3.14 (m, 2H), 2.78 2.91 (m, 2H), 2.60-2.72 (m, 4H), 1.28-1.84 (m, 6H).
Reaction SMILES: C(OC([N:8]([C:13]1[CH:14]=[C:15]([CH2:24][C:25]([O:27][CH2:28][C:29]([O:31][C@H:32]([C:43]2[CH:48]=[CH:47][C:46]([O:49][CH:50]([F:52])[F:51])=[C:45]([O:53][CH2:54][CH:55]3[CH2:57][CH2:56]3)[CH:44]=2)[CH2:33][C:34]2[C:39]([Cl:40])=[CH:38][N+:37]([O-:41])=[CH:36][C:35]=2[Cl:42])=[O:30])=[O:26])[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][CH:21]1[CH2:23][CH2:22]1)[S:9]([CH3:12])(=[O:11])=[O:10])=O)(C)(C)C.O1CCOCC1>C(Cl)Cl.Cl>[Cl:42][C:35]1[CH:36]=[N+:37]([O-:41])[CH:38]=[C:39]([Cl:40])[C:34]=1[CH2:33][C@H:32]([O:31][C:29](=[O:30])[CH2:28][O:27][C:25](=[O:26])[CH2:24][C:15]1[CH:16]=[CH:17][C:18]([O:19][CH2:20][CH:21]2[CH2:22][CH2:23]2)=[C:13]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])[CH:14]=1)[C:43]1[CH:48]=[CH:47][C:46]([O:49][CH:50]([F:52])[F:51])=[C:45]([O:53][CH2:54][CH:55]2[CH2:56][CH2:57]2)[CH:44]=1
Reactant: CC(C)(C)OC(=O)N(c1cc(CC(=O)OCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)ccc1OCC1CC1)S(C)(=O)=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1cc(CC(=O)OCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)ccc1OCC1CC1
Yield: 26.9 %

Procedure:
To a solution of crude (S)-4-(2-(2-(2-(3-(N-(tert-butoxycarbonyl)-methylsulfonamido)-4-(cyclopropylmethoxy)phenyl)acetoxy)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (theoric 0.501 mmol) in DCM (5 ml), HCl 4M in dioxane (1.309 ml, 5.23 mmol) was added and the mixture was reacted for 4 hours at RT. The solvents were evaporated to dryness, and the resulting crude was purified by preparative LC-MS recovering the desired product (102.5 mg, 0.135 mmol, 26.9% yield over two steps, MS/ESI+ 759.46 [MH]+, [αD]=+47.84, c=0.25, DCM).