Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]/[C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([F:27])[CH:25]=2)[N:20]([CH2:28][CH2:29][CH2:30][O:31][C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34][CH:33]=2)[C:19]=1[C:42]([O:44]CC)=[O:43].[OH-].[Na+]>O1CCCC1.CO>[NH2:3][CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]/[C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([F:27])[CH:25]=2)[N:20]([CH2:28][CH2:29][CH2:30][O:31][C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34][CH:33]=2)[C:19]=1[C:42]([OH:44])=[O:43]
Reactant: CCOC(=O)c1c(/C=C/CCCCN2C(=O)c3ccccc3C2=O)c2cc(F)ccc2n1CCCOc1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: NCCCC/C=C/c1c(C(=O)O)n(CCCOc2cccc3ccccc23)c2ccc(F)cc12
Temperature: 50 °C

Procedure:
(E)-ethyl 3-(6-(1,3-dioxoisoindolin-2-yl)hex-1-enyl)-5-fluoro-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate (The synthesis of this compound was described in EXAMPLE 160B as an intermediate.) was dissolved in a mixture of tetrahydrofuran and methanol and 5 equivalents of aqueous NaOH (10%) was added. The mixture was heated at 50° C. for 2 days. The reaction mixture was concentrated and the residue was purified by reverse phaseHPLC (mobile phase: 0-100% acetonitrile in 0.1% TFA aqueous solution during 60 min) on a C18 column to provide the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 8.18 (d, J=9.21 Hz, 1H), 7.82-7.89 (m, 1H), 7.57-7.70 (m, 4H), 7.42-7.55 (m, 4H), 7.37 (t, J=7.67 Hz, 1H), 7.01-7.14 (m, 2H), 6.84 (d, J=7.67 Hz, 1H), 6.14-6.29 (m, 1H), 4.80 (t, J=7.83 Hz, 2H), 4.13 (t, J=5.68 Hz, 2H), 2.70-2.97 (m, 2H), 2.11-2.37 (m, 4H), 1.41-1.76 (m, 4H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13]C)[C:9]([CH3:15])=[N:8][C:7]([C:16]1[CH:21]=[CH:20][C:19]([O:22]C)=[C:18]([O:24]C)[CH:17]=1)=[CH:6]2.C(=O)=O.CC(C)=O.B(Br)(Br)Br>C(Cl)(Cl)Cl.ClCCl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[C:9]([CH3:15])=[N:8][C:7]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([OH:24])[CH:17]=1)=[CH:6]2
Reactant: COc1ccc(-c2cc3cc(OC)c(OC)cc3c(C)n2)cc1OC
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Solvent: ClCCl
Product: Cc1nc(-c2ccc(O)c(O)c2)cc2cc(O)c(O)cc12
Temperature: -50 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
Compound 12a (250 mg, 0.74 mmol) was dissolved in 5 mL dry chloroform and chilled to -50° C. using a mixture of dry ice and acetone. To this mixture was added dropwise 7.4 mL of a 1.0 M solution of boron tribromide in dichloromethane. The reaction mixture was allowed to come to room temperature over a period of 4 h. The precipitate was filtered and washed twice with 2 mL portions of ether. This crude product was recrystallized from ethanol to give 13 in 98% yield as white needles; mp >280° C. dec; IR (Nujol) 3326, 1602, 1531; 1H NMR (CD3OD) δ 3.08 (s, 3H), 6.98 (d, 1H, J=8.1), 7.19 (dd, 1H, J=8.1, 1.9), 7.24 (s, 1H), 7.37 (s, 1H), 7.61 (s, 1H), 7.94 (s, 1H); 13C NMR (CD3OD) δ 17.8, 109.6, 110.6, 116.1, 117.3, 119.6, 121.2, 122.8, 125.6, 138.4, 142.5, 147.7, 149.5, 152.0, 154.3, 158.3; HRMS calcd for C16H13NO4 : 283.0844; found 283.0839.
Reaction SMILES: [CH2:1]([N:4]([C:19]([O:21]CC1C=CC=CC=1)=[O:20])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[C:7]([F:18])[CH:6]=1)[CH:2]=[CH2:3].[I-:29].O1CCNC1=O>>[I:29][CH2:3][CH:2]1[O:20][C:19](=[O:21])[N:4]([C:5]2[CH:6]=[C:7]([F:18])[C:8]([C:12]3[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=3)=[C:9]([F:11])[CH:10]=2)[CH2:1]1
Reactant: C=CCN(C(=O)OCc1ccccc1)c1cc(F)c(-c2ccncc2)c(F)c1
Reactant: [I-]
Agent: O=C1NCCO1
Product: O=C1OC(CI)CN1c1cc(F)c(-c2ccncc2)c(F)c1

Procedure:
Following the general procedure of PREPARATION 5 and making non-critical variations but starting with N-allyl-N-carbobenzyloxy-4-(4-pyridyl)-3,5-difluoraniline (PREPARATION 10, 241 mg, 0.634 mmol) is converted to the oxazolidinone iodide. The crude product is not purified further, NMR (CDCl3) δ 8.70, 7.44, 7.32, 4.85-4.73, 4.19, 3.80, 3.50, 3.40.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([CH2:14][CH2:15]O)[CH:3]=1.P(Br)(Br)[Br:18].O>C1(C)C=CC=CC=1>[Br:18][CH2:15][CH2:14][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrP(Br)Br
Reactant: OCCc1cc(Cl)ccc1-c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1ccc(-c2ccccc2)c(CCBr)c1
Reaction time: 20 h
Yield: 119.4 %

Procedure:
To a solution, maintained at 5° C., of 710 mg (3.05 mmol) of 2-(4-chlorobiphenyl-2-yl)ethanol, prepared in Example 51, in 10 ml of toluene are added 97 μl (1.02 mmol) of PBr3, and the reaction medium is allowed to return to room temperature. After stirring for 20 hours, the reaction medium is poured into 100 ml of water and extracted with ethyl acetate. The organic phase is washed with water, dried over Na2SO4 and then concentrated under vacuum to give a yellow liquid, which is purified by flash chromatography on a column of silica, in dichloromethane. 360 mg of a pale yellow oil are obtained.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][N:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[N:15][CH:16]=2)[C:11]1=[O:20]>C(#N)C>[Cl:1][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[N:15][CH:16]=2)[C:11](=[O:20])[N:10]([CH3:9])[CH:19]=1
Reactant: Cn1ccc2cnccc2c1=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: Cn1cc(Cl)c2cnccc2c1=O
Temperature: 65 °C
Yield: 49.7 %

Procedure:
N-chlorosuccinimide (0.8 g, 6.2 mmol) was added in portions to a solution of 2-methyl-2,6-naphthyridin-1-one (1.0 g, 6.2 mmol) in acetonitrile (25 mL) which was then heated at 65° C. for 18 h. Extractive work up with ethyl acetate and purification by silica gel chromatography (PE:EA=5:1-1:1) gave the title compound of step 1 (0.6 g, 56%) as a yellow solid. 1H NMR: (CDCl3, 400 MHz) δ 9.29 (s, 1H), 8.81 (d, J=3.6 Hz, 1H), 8.21 (d, J=5.2 Hz, 1H), 7.31 (s, 1H), 3.63 (s, 3H). LCMS: 195.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:13][CH:12]2[CH2:11][NH:10][CH2:9]3)=[CH:4][CH:3]=1.[F:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](Cl)=[O:19].Cl.FC1C=C(C=CC=1)CN1CC2C(C3C=CC(Cl)=CC=3)(C2)C1>>[F:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([N:10]1[CH2:11][CH:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)([CH2:13]2)[CH2:9]1)=[O:19]
Reactant: Clc1ccc(C23CNCC2C3)cc1
Reactant: O=C(Cl)c1cccc(F)c1
Agent: Cl
Agent: Fc1cccc(CN2CC3CC3(c3ccc(Cl)cc3)C2)c1
Product: O=C(c1cccc(F)c1)N1CC2CC2(c2ccc(Cl)cc2)C1

Procedure:
Likewise, 3-(m-fluorobenzoyl)-1-(p-chlorophenyl)-3-azabicyclo[3.1.0]hexane is prepared from 1-(p-chlorophenyl)-3-azabicyclo[3.1.0]hexane and m-fluorobenzoylchloride, then converted as above to 3-(m-fluorobenzyl)-1-(p-chlorophenyl)-3-azabicyclo[3.1.0]hexane hydrochloride, m.p. 241°-244° C.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:15][N:16](C)C=O>O.ClCCl>[CH3:1][N:2]([CH3:14])[C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[C:15]#[N:16]
Reactant: CN(C)c1cc(Br)cc(C(F)(F)F)c1
Reactant: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CN(C)c1cc(C#N)cc(C(F)(F)F)c1

Procedure:
To a solution of 3-dimethylamino-5-trifluoromethylbromobenzene (7.3 g) in N,N-dimethylformamide (20 mL) is added cuprous cyanide (2.7 g) and the reaction heated at reflux for 12 hours. The reaction is diluted with water (40 mL) and dichloromethane is added. The dichloromethane fraction is washed with concentrated ammonium hydroxide, then water. The solution is dried over anhydrous magnesium sulfate, filtered and concentrated to give a yellow solid which is recrystallized from hexanes to give a yellow solid, (4.7 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][S:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)=[N:5][N:4]=[N:3]1.[CH3:18][N:19]1[N:23]=[N:22][C:21]([CH2:24][S:25][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-])=O)=[CH:28][CH:27]=2)=[N:20]1>C(O)(=O)C>[CH3:1][N:2]1[C:6]([CH2:7][S:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[N:5][N:4]=[N:3]1.[CH3:18][N:19]1[N:23]=[N:22][C:21]([CH2:24][S:25][C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)=[N:20]1
Reactant: Cn1nnc(CSc2ccc([N+](=O)[O-])cc2)n1
Reactant: Cn1nnnc1CSc1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)O
Product: Cn1nnc(CSc2ccc(N)cc2)n1
Product: Cn1nnnc1CSc1ccc(N)cc1

Procedure:
To 1-methyl-5-[[(4-nitrophenyl)sulfanyl]methyl]-1,2,3,4-tetrazole and 2-methyl-5-[[(4-nitrophenyl)sulfanyl]methyl]-1,2,3,4-tetrazole (6.3 g, 1:1) were added acetic acid (63 ml) and then, reduced iron (18.9 g), and the mixture was stirred for 18 hours at room temperature. The mixture was filtered with Celite, and washed with ethyl acetate. The solvent was removed under reduced pressure, and the obtained residue was dissolved in ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate and saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 4-[[(1-methyl-1,2,3,4-tetrazol-5-yl)methyl]sulfanyl]aniline (1.7 g) and 4-[[(2-methyl-1,2,3,4-tetrazol-5-yl)methyl]sulfanyl]aniline (1.6 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:6][CH:5]=1.[CH3:22][O-:23].[Na+]>COCCOCCO>[CH3:22][O:23][CH2:4][CH2:3][O:2][CH2:1][CH2:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:6][CH:5]=1
Reactant: C[O-]
Reactant: CCCCCCCCCCOc1ccc(C(=O)OC)cc1
Agent: [Na+]
Solvent: COCCOCCO
Product: CCCCCCCCCCOc1ccc(C(=O)OCCOCCOC)cc1

Procedure:
A mixture of 25 g (0.09 mol) of p-decyloxybenzoic acid methyl ester and 100 ml of diethylene glycol monomethyl ether was heated for 6 hours to 150° C. with a spatula tip of sodium methanolate. After the excess diethylene glycol monomethyl ether had been distilled off, the residue was taken up in methylene chloride, the solution was washed with water, treated with active carbon and concentrated by evaporation. 24.5 g (72%) of slightly contaminated p-decyloxybenzoic acid 2-(2-methoxyethoxy)-ethyl ester were obtained. Purification by column chromatography (SiO2, Merck/methylene chloride+5% of methanol) produced pure ester having a refractive index nD20 of 1.4945.
Reaction SMILES: C(O)CCO.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1.[Br:17][C:18]1[CH:19]=[CH:20][C:21]2[N:22]([C:24](I)=[CH:25][N:26]=2)[CH:23]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(OCC)C.CN(C)C=O>[Br:17][C:18]1[CH:19]=[CH:20][C:21]2[N:22]([C:24]([C:11]3[CH:12]=[CH:13][C:8]([O:7][CH3:6])=[CH:9][CH:10]=3)=[CH:25][N:26]=2)[CH:23]=1
Reactant: Brc1ccc2ncc(I)n2c1
Reactant: COc1ccc(B(O)O)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: OCCCO
Solvent: CN(C)C=O
Product: COc1ccc(-c2cnc3ccc(Br)cn23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
0.81 mL 1,3-propane diol was added to a suspension of 1.69 g 4-methoxyphenylboronic acid in 15 mL diethyl ether, and the mixture was stirred a room temperature for 1 hour. Formed water was removed, and the organic solvent was evaporated, whereby an oil was obtained. 2.7 g 6-bromo-3-iodoimidazo[1,2-a]pyridine (compound in Production Example 49), 3.5 g potassium phosphate, 483 mg tetrakistriphenyl phosphine palladium and 40 mL N,N-dimethylformamide were added thereto and heated at 90° C. for 3 hours under nitrogen atmosphere. Insolubles were filtered off, the solvent was removed, and the residue was purified by NH silica gel column chromatography (hexane/ethyl acetate) to give 2 g of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.[C:12]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)(=[O:14])[CH3:13]>CCOC(C)=O.O>[C:12]([N:15]1[CH2:20][CH2:19][N:18]([C:3]2[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[Cl:1])[CH2:17][CH2:16]1)(=[O:14])[CH3:13]
Reactant: CC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2Cl)CC1
Temperature: 25 °C

Procedure:
2-Chloro-1-fluoro-4-nitrobenzene (10 g, 57 mmol) and 1-acetylpiperazine (14.6 g, 114 mmol) were heated neat at 55° C. for 1 h. Then the reaction mixture was allowed to cool down to room temperature. The viscous orange solution was diluted with EtOAc and water. The organics were washed with water (3 times), brine, dried and evaporation of the solvent gave an orange oil which was triturated with isohexane. After evaporation of solvent the title compound was obtained as a yellow solid which was dried overnight in vac oven at 50° C. (15.68 g, 97%). It was used without further purification. NMR (400 MHz) 2.03 (d, 3H), 3.18 (dt, 4H), 3.62 (m, 4H), 7.30 (d, 1H), 8.17 (dd, 1H), 8.26 (d, 1H); m/z 284-286.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:10]([N:14]=[C:15]=[O:16])[CH2:11][CH2:12][CH3:13].[O-:17][S:18]([C:21]([F:24])([F:23])[F:22])(=[O:20])=[O:19].[Na+]>C(OCC)(=O)C.CO>[OH:20][S:18]([C:21]([F:24])([F:23])[F:22])(=[O:19])=[O:17].[CH2:10]([NH:14][C:15]([NH:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[O:16])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCN
Reactant: CCCCN=C=O
Reactant: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCCCCCNC(=O)NCCCC
Product: O=S(=O)(O)C(F)(F)F
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 117.8 %

Procedure:
A four necked flask equipped with a thermometer, stirrer and drip funnel was charged with 2.58 g of octylamine and 200 g of ethyl acetate. To this was added dropwise a solution of 1.98 g of n-butylisocyanate in 30 g of ethyl acetate with stirring over 30 minutes while maintaining the inner temperature at 10° C. and allowed to react until the absorption of isocyanato group (2240 cm-1) disappeared IR spectrometrically. After dissolving the solidified reaction product in 50 g of methanol, a mixture of 2.086 g of 35% hydrochlonic acid and 50 g of methanol was added dropwise to the solution over 30 minutes and allowed to react at room temperature for 20 hours. Then a solution of 3.44 g of sodium triflate in 50 g of methanol was added dropwise over 30 minutes and allowed to react at room temperature for 20 hours. The reaction mixture was then filtered to remove NaC1 by-product and evaporated to remove methano. 8.9 g of the title compound was obtained as a pale yellow liquid. This product is hereinafter referred to as "curing catalyst B". This product is soluble in aromatic hydrocarbon solvents such as toluene and xylene as well as esters such as butyl acetate and ethyl acetate.
Reaction SMILES: [N+:1]([C:4]1[C:5]([O:16][CH3:17])=[C:6]([Cl:15])[CH:7]=[C:8]([N+:12]([O-])=O)[C:9]=1[O:10][CH3:11])([O-:3])=[O:2].C1CCCCC=1>[Pd].C(O)C>[NH2:12][C:8]1[C:9]([O:10][CH3:11])=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([O:16][CH3:17])=[C:6]([Cl:15])[CH:7]=1
Reactant: COc1c(Cl)cc([N+](=O)[O-])c(OC)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: COc1c(N)cc(Cl)c(OC)c1[N+](=O)[O-]

Procedure:
A mixture consisting of 0.2 mole (52.5 g) of 3,5-dinitro-2,4-dimethoxychlorobenzene and 15.9 g of palladium on charcoal (10%) in 260 ml of absolute ethanol containing 110 ml of cyclohexene was heated to reflux for 1 hour.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH2:12][CH:13]3[CH2:15][C:14]3([F:17])[F:16])[S:7](=[O:11])(=[O:10])[N:8]([CH3:9])[C:4]=2[CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:23][C:22]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.CCOC(C)=O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:16][C:14]1([F:17])[CH2:15][CH:13]1[CH2:12][N:6]1[C:5]2[CH:18]=[CH:19][C:2]([C:22]3[CH:23]=[C:24]([CH:25]=[CH:26][C:21]=3[F:20])[C:27]([O:29][CH3:30])=[O:28])=[CH:3][C:4]=2[N:8]([CH3:9])[S:7]1(=[O:11])=[O:10]
Reactant: CN1c2cc(Br)ccc2N(CC2CC2(F)F)S1(=O)=O
Reactant: COC(=O)c1ccc(F)c(B(O)O)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(F)c(-c2ccc3c(c2)N(C)S(=O)(=O)N3CC2CC2(F)F)c1
Temperature: 100 °C

Procedure:
5-bromo-1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (4-1) (100 mg, 0.28 mmol, 1 eq), [2-fluoro-5-(methoxycarbonyl)phenyl]boronic acid (84 mg, 0.43 mmol, 1.5 eq), cesium carbonate (185 mg, 0.57 mmol, 2.0 eq) and bis(tri-t-butylphosphine)palladium(0) (29 mg, 0.06 mmol, 0.2 eq) were combined in dioxane (1.5 mL) and water (0.3 mL). The resulting mixture was heated in the microwave at 100° C. for 10 minutes. The reaction mixture was diluted with EtOAc (10 mL), washed with water (2 mL) and brine (2 mL), dried over MgSO4, filtered and concentrated. The crude residue was purified by flash chromatography (12 g SiO2, 0-70% EtOAc in hexanes) to afford methyl 3-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl}-4-fluorobenzoate (17-1) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.14 (dd, J=1.6, 6.0 Hz, 1 H); 8.01 (m, 1 H); 7.21 (m, 2 H); 6.95 (t, J=1.2 Hz, 1 H); 6.90 (d, J=6.4 Hz, 1 H); 3.94 (s, 3 H); 3.91 (d, J=5.6 Hz, 2 H); 3.33 (s, 3 H); 2.14 (m, 1 H); 1.64 (m, 1 H); 1.39 (m, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:21])=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:28](I)[CH3:29]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:21][CH2:28][CH3:29])=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(cnn2Cc2ccco2)c1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2c(cnn2Cc2ccco2)c1OCC
Reaction time: 10 h

Procedure:
300 g of 4-hydroxy-1-(2-furyl)methyl-1H-pyrazolo[3,4-b]-pyridine-5-carboxylic acid ethyl ester (1.05 mol) is dissolved in 1 liter of dimethylformamide. 210 g of potassium carbonate (1.5 mol) and 233 g of ethyl iodide are added. The mixture is heated at 60° with continuous stirring for 10 hours. The excess potassium carbonate is filtered off. On addition of 500 ml of water, 4-ethoxy-1-(2-furyl)methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester precipitates and is recrystallized from methanol, yield 280 g (85%), m.p. 93°-96°.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[NH:17][N:16]=[N:15][N:14]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>C(#N)C>[CH2:37]([N:15]1[N:16]=[N:17][C:13]([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:14]1)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH3:26]
Reactant: CCOC(=O)C(c1ccccc1)c1nnn[nH]1
Reactant: CCCCCCCCCCCCBr
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCCCCCCCCn1nnc(C(C(=O)OCC)c2ccccc2)n1
Temperature: 25 °C

Procedure:
The tetrazole ester (a) (47 g; 0.20 moles) was dissolved in acetonitrile (550 mL) containing one equivalent of triethylamine (20.2 g; 0.20 moles). The solution was heated to reflux and then 1-bromododecane (49.8 g; 0.20 moles) was added dropwise over 20 minutes. Upon completion, the solution was heated to reflux for 16 hours, cooled to room temperature, and concentrated in vacuo. The residue was triturated with ethyl acetate (1 L), filtered, and the filtrate was washed with aqueous HCl (1N), brine, and dried over magnesium sulfate. The drying agent was removed by filtration and the solvent concentrated in vacuo, leaving a viscous liquid containing both 1- and 2-isomers. The regioisomers were separated by silica gel chromatography using 75% hexane and 25% ethyl acetate as the eluent, obtaining the title compound as a colorless liquid. Yield: 33 g (41%).
Reaction SMILES: [ClH:1].[N+]([C:5]1[NH:6][CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[N:9]=1)([O-])=O>>[Cl:1][C:5]1[NH:6][CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[N:9]=1
Reactant: Cl
Reactant: O=[N+]([O-])c1c[nH]c([N+](=O)[O-])n1
Product: O=[N+]([O-])c1c[nH]c(Cl)n1
Yield: 67 %

Procedure:
In NON-PATENT DOCUMENT 3, after concentrated hydrochloric acid is added to 2,4-dinitroimidazole, the resultant solution is refluxed for 3 hours to perform chlorination reaction, and 2-chloro-4-nitroimidazole is produced at a yield of 67% by performing cooling, filtration and washing.
Reaction SMILES: Cl.[CH2:2]([N:4]1[N:8]=[N:7][C:6]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[O:26][CH3:27])[S:18][C:14]=3[C:13](=[O:28])[N:12]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[C:11]2=[O:35])=[N:5]1)[CH3:3].[CH2:36]([O:38][C:39]1[C:48]([O:49][CH3:50])=[CH:47][C:46]2[C:45]([C:51]3[CH:52]=[C:53]([CH:57]=[CH:58][CH:59]=3)[C:54](O)=[O:55])=[N:44][C@@H:43]3[CH2:60][CH2:61][S:62][CH2:63][C@@H:42]3[C:41]=2[CH:40]=1)[CH3:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH2:36]([O:38][C:39]1[C:48]([O:49][CH3:50])=[CH:47][C:46]2[C:45]([C:51]3[CH:52]=[C:53]([C:54]([N:32]4[CH2:33][CH2:34][CH:29]([N:12]5[C:13](=[O:28])[C:14]6[S:18][C:17]([C:19]7[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=7[O:26][CH3:27])=[CH:16][C:15]=6[N:10]([CH2:9][C:6]6[N:7]=[N:8][N:4]([CH2:2][CH3:3])[N:5]=6)[C:11]5=[O:35])[CH2:30][CH2:31]4)=[O:55])[CH:57]=[CH:58][CH:59]=3)=[N:44][C@@H:43]3[CH2:60][CH2:61][S:62][CH2:63][C@@H:42]3[C:41]=2[CH:40]=1)[CH3:37]
Reactant: CCOc1cc2c(cc1OC)C(c1cccc(C(=O)O)c1)=N[C@@H]1CCSC[C@H]21
Reactant: CCn1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccc(F)cc4OC)cc32)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc2c(cc1OC)C(c1cccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccc(F)cc6OC)cc5n(Cc5nnn(CC)n5)c4=O)CC3)c1)=N[C@@H]1CCSC[C@H]21

Procedure:
1-[(2-ethyl-2H-tetrazol-5-yl)methyl]-6-(4-fluoro-2-methoxyphenyl)-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (191 mg; compound B78) is reacted with 3-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (145 mg; compound C8) and HBTU (304 mg) in DCM/DMF (14 ml/1 ml) in the presence of DIPEA (377 mg) according to the procedure described in example 2 to afford the title compound after purification by flash column chromatography [amino phase silica gel, eluation gradient: Cyclohexane/EtOAc/DCM, 100/0/0 to 50/40/10 to 30/60/10 to 0/90/10 (v/v/v)] and preparative HPLC as a solid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Br:12][CH2:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([Cl:23])[CH:22]=1)[C:17]([NH2:19])=[O:18]>CN(C)C=O.C(OCC)(=O)C>[BrH:12].[NH2:19][C:17]([C:16]1[CH:15]=[C:14]([CH:22]=[C:21]([Cl:23])[CH:20]=1)[CH2:13][N:10]1[CH:9]=[C:8]([Cl:11])[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:2]1=[NH:1])=[O:18]
Reactant: NC(=O)c1cc(Cl)cnc1N
Reactant: NC(=O)c1cc(Cl)cc(CBr)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Br
Product: N=c1c(C(N)=O)cc(Cl)cn1Cc1cc(Cl)cc(C(N)=O)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
(Step 3) To a solution of 2-amino-5-chloronicotinamide (0.15 g) in N,N-dimethylformamide (3 ml) was added 3-(bromomethyl)-5-chlorobenzamide (0.26 g) obtained in Step 2, and the mixture was stirred at 100° C. for 3 hr. The reaction mixture was diluted with ethyl acetate. The precipitate was collected by filtration and washed with ethyl acetate. The obtained precipitate was recrystallized from methanol-ethyl acetate to give the title compound (110 mg).