Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:28]=1[C:27]1[CH2:26][CH2:25][CH2:24][C:23]=1[S:22]2>CN(C)C=O>[C:28]12[C:21](=[CH:20][CH:19]=[CH:18][C:17]=1[O:13][CH:10]1[CH2:9][CH2:8][CH:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[CH2:12][CH2:11]1)[S:22][C:23]1[CH2:24][CH2:25][CH2:26][C:27]2=1
Reactant: O[C@H]1CC[C@H](N2CCOCC2)CC1
Reactant: Clc1cccc2sc3c(c12)CCC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cc(OC2CCC(N3CCOCC3)CC2)c2c3c(sc2c1)CCC3
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 30.8 %

Procedure:
To a solution of trans-4-(morpholin-4-yl)cyclohexan-1-ol (213 mg, 1.15 mmol, 2.00 equiv) in distilled N,N-dimethylformamide (10 mL) was added sodium hydride (69 mg, 2.88 mmol, 3.00 equiv, 60% dispersion in mineral oil) at room temperature and the resulting solution was stirred for 0.5 h at 80° C. in an oil bath under nitrogen. Then a solution of 12-chloro-7-thiatricyclo[6.4.0.0^[2,6]]dodeca-1(12),2(6),8,10-tetraene (120 mg, 0.57 mmol, 1.00 equiv) in 3 mL of DMF was added via syringe and the resulting mixture was stirred at 80° C. for 3 hours. After cooling, the reaction was quenched with water and extracted with 5×50 mL of dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated under vacuum. The crude product (100 mg) was purified by preparative HPLC under the following conditions (Waters): Column: Xbridge Prep C18, 5 μm, 19*50 m; water (with 0.05% NH4HCO3) and CH3CN (10% CH3CN up to 40% CH3CN in 10 min); flow rate: 20 mL/min; UV detection at 254 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the desired 4-(4-[7-thiatricyclo[6.4.0.0^[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yloxy]cyclohexyl)morpholine (62.7 mg) as a white solid. MS (ES): m/z 359 (M+H)+. 1H NMR (300 MHz, CDCl3): δ 1.51-1.72 (4H, m), 1.82-2.06 (2H, m), 2.22-2.30 (3H, m), 2.42-2.50 (2H, m), 2.68 (4H, m), 2.78-3.06 (4H, m), 3.51-3.96 (4H, m), 4.30-4.48 (1H, m), 6.63 (1H, d, J=5.4 Hz), 8.25 (1H, d, J=5.4 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C@@H:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:16][N:15]=2)[CH3:13])=[O:10])=[CH:4][CH:3]=1.Br[C:27]1[S:28][CH:29]=[CH:30][N:31]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(Cl)Cl.[Cu]>[S:28]1[CH:29]=[CH:30][N:31]=[C:27]1[O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:11][C@@H:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][CH2:21][C:22]([F:25])([F:23])[F:24])=[CH:16][N:15]=2)[CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: C[C@@H](NC(=O)Cc1ccc(O)cc1)c1ccc(NCC(F)(F)F)cn1
Reactant: Brc1nccs1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@@H](NC(=O)Cc1ccc(Oc2nccs2)cc1)c1ccc(NCC(F)(F)F)cn1
Yield: 24.3 %

Procedure:
To a solution of the starting 2-(4-hydroxyphenyl)-N-((1R)-1-{5-[(2,2,2-trifluoroethyl)amino]pyridin-2-yl}ethyl)acetamide (60.0 mg, 0.17 mmol) in 1.0 ml of dry DMF was added the 2-bromo-1,3-thiazole (30.6 mg, 0.186 mmol), Cs2CO3 (166 mg, 0.508 mmol), and copper powder (1.1 mg, 0.017 mmol). The mixture was irradiated with microwave at 100° C. for 1 h. The mixture was cooled, diluted with CH2Cl2, and washed with saturated sodium bicarbonate solution and brine. The combined aqueous washes were extracted with CH2Cl2. The combined organic phase was dried over Na2SO4, filtered and concentrated in vacuo. Purification by reverse phase chromatography gave 2-[4-(1,3-thiazol-2-yloxy)phenyl]-N-((1R)-1-{5-[(2,2,2-trifluoroethyl)amino]pyridin-2-yl}ethyl)acetamide as a white solid (18 mg, 24%). 1H NMR (CDCl3, 400 MHz) δ 8.227 (d, J=2.75 Hz, 1H); 7.329 (m, 2H); 7.242 (m, 5H); 6.825 (d, J=2.85 Hz, 1H); 6.765 (d, J=7.14 Hz, 1H); 5.106 (quintet, J=6.84 Hz, 1H); 4.381 (dd, J=7.87, 15.93 Hz, 2H); 3.592 (s, 2H); 1.411 (d, J=6.78 Hz, 3H); MS (ES): m/z 438.1 (M+H). FLIPR alpha1I IP=46 nM.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([C:17]#[N:18])[CH:16]=[C:11]2[C:10]([CH2:19]N(C)C)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:23]C(OCC)=O.O>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([C:17]#[N:18])[CH:16]=[C:11]2[C:10]([CH2:19][Cl:23])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)Cc1cn(C(=O)OC(C)(C)C)c2ncc(C#N)cc12
Reactant: CCOC(=O)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)n1cc(CCl)c2cc(C#N)cnc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 5-cyano-3-dimethylaminomethyl-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (634, 2.60 g, 8.66 mmol) in toluene (60.0 mL) under an atmosphere of nitrogen was added ethyl chloroformate (0.828 mL, 8.66 mmol). The reaction was stirred at room temperature for 3 hours, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate irn hexane to give a white solid (635, 400 mg, 16%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=2)=[CH:4][C:3]=1[N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24].[O:29]=[C:30]1[NH:34][C:33](=[O:35])[CH:32]([CH2:36][C:37]2[CH:47]=[CH:46][C:40]([O:41][CH2:42][C:43](O)=[O:44])=[CH:39][CH:38]=2)[S:31]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:29]=[C:30]1[NH:34][C:33](=[O:35])[CH:32]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:41][CH2:42][C:43]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([C:16]([CH3:19])([CH3:17])[CH3:18])[CH:10]=4)=[CH:4][C:3]=3[N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:44])=[CH:46][CH:47]=2)[S:31]1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(O)c(C(C)(C)C)c2)ccc1N
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(O)c(C(C)(C)C)c2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 93.8 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(3-t-butyl-4-hydroxyphenoxy)phenyl]-N-methylcarbamate (1.11 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (0.89 g), diethyl cyanophosphonate (0.52 g), triethylamine (0.32 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified to give the desired product (1.75 g).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([O:11][CH3:12])=[O:10].[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:21][C:22]([OH:36])=[C:23]([C:27]3[C:32]([CH3:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:28]=3[CH3:35])[C:24](=[O:26])[N:25]=2)=[CH:16][CH:15]=1>C(OCC)(=O)C>[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[S:21][C:22]([O:36][C:9]([O:11][CH3:12])=[O:10])=[C:23]([C:27]3[C:32]([CH3:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:28]=3[CH3:35])[C:24](=[O:26])[N:25]=2)=[CH:18][CH:19]=1
Reactant: COC(=O)Cl
Reactant: Cc1cc(C)c(-c2c(O)sc(-c3ccc(F)cc3)nc2=O)c(C)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)Oc1sc(-c2ccc(F)cc2)nc(=O)c1-c1c(C)cc(C)cc1C
Temperature: 20 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
1.0 g (10 mmol) of triethylamine and then 0.94 g (10 mmol) of methyl chloroformate in 10 ml of ethyl acetate are added dropwise at 0° C. to 3.4 g (10 mmol) of 2-(4-fluorophenyl)-6-hydroxy-5-(2,4,6-trimethyl-phenyl)-1,3-thiazin-4-one in 50 ml of ethyl acetate. The mixture is stirred for 8 hours at 20° C. and filtered, the organic phase is washed using half-concentrated sodium chloride elusion and dried over sodium sulphate, and the solvent is evaporated in vacuo. The residue is chromatographed on silica gel (35 to 70 μm) using toluene/acetone (20:1 parts by volume). 3.1 g of 2-(4-fluorophenyl)-6-methoxycarbonyloxy-5-(2,4,6-trimethylphenyl)-1,3-thiazin-4-one are obtained (yield: 78% of theory). M.p.=129° to 131° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:12]=[N:11][CH:10]=[C:9]([N:13]2[CH2:17][CH2:16][CH2:15][CH:14]2[CH2:18][O:19][CH3:20])[N:8]=1.O.CN([CH:25]=[O:26])C>>[Cl:6][C:7]1[C:12]([CH:25]=[O:26])=[N:11][CH:10]=[C:9]([N:13]2[CH2:17][CH2:16][CH2:15][CH:14]2[CH2:18][O:19][CH3:20])[N:8]=1
Reactant: COCC1CCCN1c1cncc(Cl)n1
Reactant: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COCC1CCCN1c1cnc(C=O)c(Cl)n1
Reaction time: 0.33 h
Yield: 64 %

Procedure:
Phosphoryl chloride (1.2 mL) was added dropwise to DMF (10 mL) at 0° C., and the mixture was stirred for 20 min. To the reaction mixture was added a solution of 2-chloro-6-[2-(methoxymethyl)pyrrolidin-1-yl]pyrazine (1.45 g) in DMF (3 mL), and the mixture was stirred at 50° C. for 16 hr. Water was added to the reaction mixture, and the mixture was stirred for 2 hr, and extracted with ethyl acetate. The extract was washed with water and saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient: 5→50% ethyl acetate/hexane) to give the title compound (1.04 g, 64%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]2[O:11][CH:10]([CH3:13])[CH2:9][C:8]=2[C:7]([CH3:14])=[C:6]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:5]=1[CH3:21])[CH3:2].Br[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH3:31])=[CH:25][CH:24]=1>>[CH2:30]([O:29][C:26]1[CH:27]=[CH:28][C:23]([N:18]2[CH2:19][CH2:20][N:15]([C:6]3[C:5]([CH3:21])=[C:4]([O:3][CH2:1][CH3:2])[C:12]4[O:11][CH:10]([CH3:13])[CH2:9][C:8]=4[C:7]=3[CH3:14])[CH2:16][CH2:17]2)=[CH:24][CH:25]=1)[CH3:31]
Reactant: CCOc1ccc(Br)cc1
Reactant: CCOc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)C2
Product: CCOc1ccc(N2CCN(c3c(C)c4c(c(OCC)c3C)OC(C)C4)CC2)cc1
Yield: 64.8 %

Procedure:
By using 1-(7-ethoxy-2,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (580 mg, 2.0 mmol) synthesized in Reference example 89 and 1-bromo-4-ethoxybenzene (804 mg, 4.0 mmol), the reaction was carried out in the same manner as Example 23 to synthesize the title compound 532 mg (yield 65%). Melting point was 121 to 122° C. (ethanol-water).
Reaction SMILES: [CH3:1][C@@H:2]([OH:6])[C@H:3]([OH:5])[CH3:4].[Cl:7][C:8]1[CH:13]=[C:12](Cl)[N:11]=[C:10]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=2[F:24])[N:9]=1.[H-].[Na+]>O1CCCC1>[Cl:7][C:8]1[N:9]=[C:10]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=2[F:24])[N:11]=[C:12]([O:5][C@H:3]([CH3:4])[C@H:2]([OH:6])[CH3:1])[CH:13]=1
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Reactant: C[C@@H](O)[C@@H](C)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@@H](C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Reaction time: 0.25 h

Procedure:
To a solution of (2R,3R)-butane-2,3-diol (250 mg) and 4,6-Dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (the product of example 1 step (ii)) (427 mg) in anhydrous tetrahydrofuran (20 ml) at ambient temperature was added 60% sodium hydride (33.4 mg). After stirring for 15 minutes the reaction mixture was partitioned between aq. ammonium chloride solution and ethyl acetate. The organics collected, dried (MgSO4) and solvents removed under vacuo to give the subtitle compound as colourless gum. Yield: 525 mg.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].Cl.[NH2:14][CH2:15][CH2:16][SH:17].C1(C)C=CC=CC=1>O>[CH2:2]([CH:1]1[NH:14][CH2:15][CH2:16][S:17]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: NCCS
Reactant: CCCCCCCCCCC=O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCC1NCCS1

Procedure:
A mixture of 34 g. of undecylaldehyde and 22.8 g. of 2-aminoethanethiol hydrochloride in about 400 ml. of toluene was heated at reflux overnight. The water of condensation was collected in a Dean-Stark trap. The reaction mixture then was washed with aqueous sodium hydroxide and dried over anhydrous magnesium sulfate. After filtering the reaction mixture, the toluene was distilled under reduced pressure. The residue then was vacuum distilled, b.p. 130°-8°/0.1 mm, giving 2-decylthiazolidine. The following elemental microanalysis was obtained:
Reaction SMILES: [C:1]([O:12]C)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].[OH-].[K+].[OH-].Cl>O.C(O)(C)C>[C:1]([OH:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10]
Reactant: C=CCCCCCCCC(=O)OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: C=CCCCCCCCC(=O)O
Reaction time: 0.33 h
Yield: 97.2 %

Procedure:
In a 5 L 5-neck round bottom flask, 1108.5 g of methyl 9-decenoate, 540 mL water, and 300 mL isopropanol were combined. The flask was connected to a mechanical stirrer, addition funnel, condenser, thermocouple, and stopper. Nitrogen was passed over the headspace for 20 minutes. An aqueous solution of potassium hydroxide (6.6 moles in 660 mL water) was added over 30 minutes, under an atmosphere of nitrogen, at ambient pressure. The reaction temperature peaked at 54° C. The mixture was stirred for a further 4 hours following the addition of aqueous hydroxide addition. After 4 hours, the temperature of the reaction was 28° C. The flask was placed in a water bath and aqueous hydrochloric acid (HCl, 37% (v/v)) was added in portions over 1 hr until the pH was 1-2. The temperature was kept below 40° C. by adding ice to the water bath during the addition of aqueous HCl. The solution was then transferred to a separatory funnel where the organic layer was washed three times with saturated sodium chloride and dried over magnesium sulfate. The magnesium sulfate was removed via vacuum filtration, and the solution was concentrated on the rotary evaporator. The crude product was distilled under reduced pressure (140° C., 2 torr) to provide 9-decenoic acid (995.2 g, 97% yield) as a colorless liquid.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH3:12][N:13]1[C:18]2=[CH:19][NH:20][C:21]([C:22]3[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=3)[C:25]#[N:26])=[C:17]2[C:16](=[O:30])[N:15]([CH3:31])[C:14]1=[O:32].[C:33]([O:37][CH3:38])(=[O:36])[CH:34]=[CH2:35]>C(#N)C>[C:25]([C:24]1[CH:23]=[C:22]([C:21]2[N:20]([CH2:35][CH2:34][C:33]([O:37][CH3:38])=[O:36])[CH:19]=[C:18]3[C:17]=2[C:16](=[O:30])[N:15]([CH3:31])[C:14](=[O:32])[N:13]3[CH3:12])[CH:29]=[CH:28][CH:27]=1)#[N:26]
Reactant: C=CC(=O)OC
Reactant: Cn1c(=O)c2c(-c3cccc(C#N)c3)[nH]cc2n(C)c1=O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)CCn1cc2c(c1-c1cccc(C#N)c1)c(=O)n(C)c(=O)n2C
Temperature: 25 °C
Reaction time: 96 h

Procedure:
DBU (0.656 mL, 4.35 mmol) was added to a solution of 3-(1,3-dimethyl-2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-yl)benzonitrile (Example 9 Step 4) (1.22 g, 4.35 mmol) and methyl acrylate (0.392 mL, 4.35 mmol) in acetonitrile (15 mL). The mixture was stirred at room temperature for 4 days. Further portions of methyl acrylate (0.392 mL, 4.35 mmol) and DBU (0.656 mL, 4.35 mmol) were added as required to allow the reaction to run to completion. The reaction was quenched with saturated NH4Cl(aq) and extracted with DCM (2×). The combined organic extracts were passed through a hydrophobic frit and evaporated under vacuum. Purification by chromatography on silica, eluting with 20-100% EtOAc/hexane afforded a crude material which was triturated with DCM/diethyl ether/hexane to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].F[P-](F)(F)(F)(F)F.[N:21]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH4+].[Cl-].CCN(C(C)C)C(C)C>CS(C)=O>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:21])=[O:5]
Reactant: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cccc([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 14 h
Yield: 98.5 %

Procedure:
To a solution of 2-amino-3-nitrobenzoic acid (5.00 g, 27.47 mmol) in DMSO (30 mL) were added BOP (18.21 g, 41.21 mmol), NH4Cl (4.41 g, 82.41 mmol) and DIPEA (10.63 g, 82.41 mmol) and the reaction mixture was stirred at rt for 14 h and it was quenched with ice-water and the precipitate obtained was filtered, washed with Et2O and dried to afford 4.90 g of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.48 (br s, 2H), 8.19-8.17 (m, 2H), 7.96-7.94 (d, J=7.2 Hz, 1H), 7.62 (br s, 1H), 6.71-6.65 (t, J=7.8 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[I:14](O)(=O)=O.II>C(O)(=O)C.S(=O)(=O)(O)O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([I:14])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: [O-][I+2]([O-])O
Agent: II
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: Brc1ccc(-c2ccc(I)cc2)cc1
Temperature: 65 °C
Reaction time: 4.5 h
Yield: 325.1 %

Procedure:
A 4-neck one liter round bottom flask equipped with mechanical stirrer, thermometer and reflux condenser topped with nitrogen bubbler inlet was charged with 4-bromobiphenyl (23.31 g, 100 mmol) in acetic acid (400 mL), sulfuric acid (10 mL) and water (20 mL). To this stirring mixture was added iodic acid (4.84 g, 27.5 mmol) followed immediately by addition of iodine chips (11.17 g, 44.0 mmol). The reaction flask was immersed in a preheated tri(ethylene glycol) heating bath and heated at 65° C. internal temperature. After 30 min the bath temperature was increased such that the internal temperature raised to 85° C. after 20 min. Heating at this temperature was continued for 4.5 hours at which point HPLC analysis showed the reaction to be complete. After stirring overnight at room temperature the reaction mixture was vacuum filtered through a coarse fritted funnel and the solids were rinsed with water. The resulting white solid (32.1 g, 89% yield) had mp 177-179° C. and was used without further purification in the next step. NMR analysis confirmed the structure of Intermediate Compound 3,4-bromo-4′-iodobiphenyl. Purity (HPLC): >99%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:18])[C:5]([NH2:17])=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16].O.C(=O)(O)[O-].[Na+].[F:25][C:26]([F:37])([F:36])[C:27]([F:35])([F:34])[C:28]([F:33])([F:32])[C:29](O)=O>>[Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])=[CH:6][C:5]2[NH:17][C:29]([C:28]([F:32])([F:33])[C:27]([F:34])([F:35])[C:26]([F:37])([F:36])[F:25])=[N:18][C:4]=2[CH:3]=1
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)F
Reactant: Nc1cc(Cl)c(Oc2ccc(F)cc2F)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Fc1ccc(Oc2cc3[nH]c(C(F)(F)C(F)(F)C(F)(F)F)nc3cc2Cl)c(F)c1
Yield: 21 %

Procedure:
A solution of 4-chloro-5-(2,4-difluorophenoxy)benzene-1,2-diamine (100 mg, 0.37 mmol) in heptafluorobutanoic acid (2 ml) was stirred overnight at 90° C. The mixture was poured into water (100 ml), adjusted pH value of the solution to 8 with sodium bicarbonate (solution) and extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column with 10% ethyl acetate in petroleum ether to produce 5-chloro-6-(2,4-difluorophenoxy)-2-(heptafluoropropyl)-1H-1,3-benzodiazole as a pink solid (34.1 mg, 21%).
Reaction SMILES: ClCC1C=NC=CN=1.C(N)CN.[N:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[CH2:19][NH:20][CH2:21][CH2:22][NH2:23].[C:24]([NH:26][C:27](=[N:30][CH3:31])SC)#[N:25]>>[C:24]([NH:26][C:27]([NH:30][CH3:31])=[N:23][CH2:22][CH2:21][NH:20][CH2:19][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][N:13]=1)#[N:25]
Reactant: CN=C(NC#N)SC
Reactant: NCCNCc1cnccn1
Agent: ClCc1cnccn1
Solvent: NCCN
Product: CNC(=NCCNCc1cnccn1)NC#N

Procedure:
Reacting 2-chloromethylpyrazine with ethylenediamine by the procedure of Example 34 and reacting the resulting N-(2-pyrazinylmethyl)ethylenediamine with N-cyano-N', S-dimethylisothiourea by the procedure of Example 3 gives the title compound.
Reaction SMILES: [C:1]([C:5]1[C:6]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:11]([C:21]3[CH:26]=[CH:25][C:24]([C:27]#[CH:28])=[CH:23][CH:22]=3)[C:10](=[O:29])[C:7]=2[NH:8][N:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:31](=[N:37][OH:38])[C:32]([O:34][CH2:35][CH3:36])=[O:33].C(N(CC)CC)C>C1COCC1>[C:1]([C:5]1[C:6]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:11]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[O:38][N:37]=[C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:28]=4)=[CH:23][CH:22]=3)[C:10](=[O:29])[C:7]=2[NH:8][N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(Cl)=NO
Reactant: C#Cc1ccc(N2C(=O)c3[nH]nc(C(C)(C)C)c3C2c2ccccc2OC)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2ccc(N3C(=O)c4[nH]nc(C(C)(C)C)c4C3c3ccccc3OC)cc2)on1
Temperature: 0 °C
Reaction time: 4 h
Yield: 64.5 %

Procedure:
To a mixture of 3-t-butyl-5-(4-ethynylphenyl)-4-(2-methoxyphenyl)-4,5-dihydro-1H-pyrrolo[3,4-c]pyrazol-6-one (1.51 g, 3.9 mmol), ethyl 2-chloro-2-hydroxyiminoacetate (1.19 g, 7.8 mmol) and THF (4 mL), triethylamine (1.09 mL, 7.8 mmol) in THF (3 mL) was added dropwise under ice-cooling conditions, and the mixture was stirred at 0° C. for 4 hr. Ethyl 2-chloro-2-hydroxyiminoacetate (1.19 g, 7.8 mmol) was added, and further triethylamine (0.81 mL, 5.9 mmol) in THF (3 mL) was added dropwise. The mixture was stirred at 0° C. for 2 hr and left stand overnight. The precipitate was removed by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) to give 3-t-butyl-5-[4-(3-ethoxycarbonyl-5-isoxazolyl)phenyl]-4-(2-methoxyphenyl)-4,5-dihydro-1H-pyrrolo[3,4-c]-pyrazol-6-one (1.26 g, 64%) as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][C:7]1([CH3:24])[CH2:12][CH2:11][C:10]2[CH:13]=[C:14]([C:21](=[O:23])[CH3:22])[C:15]([OH:20])=[C:16]([CH2:17][CH2:18][CH3:19])[C:9]=2[O:8]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Br:32][CH2:33][CH2:34][CH2:35]Br.CC(C)=O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][C:7]1([CH3:24])[CH2:12][CH2:11][C:10]2[CH:13]=[C:14]([C:21](=[O:23])[CH3:22])[C:15]([O:20][CH2:35][CH2:34][CH2:33][Br:32])=[C:16]([CH2:17][CH2:18][CH3:19])[C:9]=2[O:8]1)[CH3:2]
Reactant: BrCCCBr
Reactant: CCCc1c(O)c(C(C)=O)cc2c1OC(C)(CCC(=O)OCC)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c2c(cc(C(C)=O)c1OCCCBr)CCC(C)(CCC(=O)OCC)O2
Reaction time: 25 h

Procedure:
A mixture of 263 mg of racemic-6-acetyl-3,4-dihydro-7-hydroxy-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoic acid ethyl ester, 222 mg of anhydrous potassium carbonate, 0.39 ml of 1,3-dibromopropane, 6 ml of anhydrous acetone, and 3 ml of anhydrous N,N-dimethylformamide was stirred and refluxed for 16 hours. An additional 0.25 g of anhydrous potassium carbonate was added and stirring, and refluxing were continued for 25 hours. The mixture was cooled and volatile materials were removed first under water aspirator pressure and then high vacuum. The residue was treated with ether and acetone and the solids were removed by filtration. Concentration of the filtrate in vacuo afforded 359 mg of racemic-6-acetyl-7-(3-bromopropoxy)-3,4-dihydro-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoic acid ethyl ester as an orange oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[Cl:18][C:19]1[CH:20]=[C:21]([C:23]([CH3:26])=[CH:24][CH:25]=1)[NH2:22]>CN(C=O)C>[Cl:18][C:19]1[CH:25]=[CH:24][C:23]([CH3:26])=[C:21]([NH:22][C:2]2[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=2)[CH:20]=1
Reactant: Clc1ncnc(Cl)n1
Reactant: Cc1ccc(Cl)cc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(Cl)cc1Nc1ncnc(Cl)n1
Temperature: 0 °C

Procedure:
2,4-Dichloro-1,3,5-triazine (3 g, 20 mmol) was dissolved in DMF (20 mL) under N2 and cooled to 0° C. DIEA (2.58 g, 20 mmol) was added, followed by 3-chloro-6-methylaniline (2.83 g, 20 mmol). The reaction solution was stirred with gradual warming to RT. The reaction was quenched after 3 h with water, then extracted 3 times with EtOAc. The EtOAc extracts were washed with brine, combined, dried over Na2SO4, filtered, and concentrated. The crude was eluted through a 17×2.5 cm column of silica gel (25%, 40%, 60% EtOAc/Hexane step gradient) giving (5-chloro-2-methyl-phenyl)-(4-chloro-[1,3,5]triazin-2-yl)-amine as a white solid.