Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([C:8]2[S:9][C:10]([CH2:22][CH3:23])=[CH:11][C:12]=2[C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[CH:5]=[CH:6][N:7]=1.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>C(O)C>[CH2:24]([N:26]([CH2:2][C:3]1[N:4]([C:8]2[S:9][C:10]([CH2:22][CH3:23])=[CH:11][C:12]=2[C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[CH:5]=[CH:6][N:7]=1)[CH2:27][CH3:28])[CH3:25]
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2ccnc2CCl)s1
Reactant: CCNCC
Solvent: CCO
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2ccnc2CN(CC)CC)s1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of 5.6 g of 2-chloromethyl-1-(3o-chlorobenzoyl-5-ethyl-2-thienyl)imidazole in 50 ml of ethanol is added 4 g of diethylamine, and the mixture is stirred at 50°C for 2 hours. After allowing the mixture to stand overnight, the solvent is distilled off under reduced pressure. The residue to which a water is added is extracted with ethyl acetate. The extract is washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The residual brown oil is chromatographed on 150 g of 70 - 325 mesh silica gel with chloroform as eluent. The eluates are combined and concentrated in vacuo to give 2-diethylaminomethyl-1-(3-o-chlorobenzoyl-5-ethyl-2-thienyl)imidazole as yellowish transparent oil (nD21 = 1.5813).
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8]([Cl:11])=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14]>C1COCC1.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.[Cu]I>[Cl:11][C:8]1[C:9]2[S:10][C:2]([C:17]#[C:16][Si:13]([CH3:15])([CH3:14])[CH3:12])=[CH:3][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C#C[Si](C)(C)C
Reactant: Clc1ncnc2cc(Br)sc12
Agent: Cl[Pd]Cl
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: N#Cc1ccccc1
Product: C[Si](C)(C)C#Cc1cc2ncnc(Cl)c2s1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of 6-bromo-4-chloro-thieno[3,2-d]pyrimidine (10.0 mmol), (trimethylsilyl)acetylene (12.0 mmol), Pd(PhCN)2Cl2, (1.0 mmol), CuI (1.0 mmol) and TEA (2.0 mmol) in dry THF (60.0 mL) was flushed with dry N2 for several minutes and stirred at 60° C. for 30 minutes under an atmosphere of N2. The solvent was removed and the residue purified by flash column chromatography on silica gel to provide 4-chloro-6-trimethylsilanylethynyl-thieno[3,2-d]pyrimidine (compound 48.1) in 65% yield. EIMS (m/z): calcd. for C11H11ClN2SSi (M+)+H 266.01. found 266.00.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][C@@H:7]([CH2:10][CH3:11])[CH:8]=[O:9])=[CH:4][CH:3]=1.C([Li])CCC.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[CH:26])[CH:20]=1>O1CCCC1.[Cl-].[Na+].O>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][C@@H:7]([CH2:10][CH3:11])[CH:8]([OH:9])[C:26]#[C:25][C:21]2[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=2)=[CH:4][CH:3]=1
Reactant: CC[C@@H](C=O)Oc1ccc(Br)cc1
Reactant: C#Cc1cccnc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC[C@H](Oc1ccc(Br)cc1)C(O)C#Cc1cccnc1
Temperature: -70 °C
Reaction time: 2 h

Procedure:
Freshly activated (dried in oven at 300° C.) powdered molecular sieves (20 g, 3 Å, <5 micron) were added to (2S)-2-(4-bromophenoxy)-1-butanol (5.24 g, Example 87b)) and pyridinium dichromate (12.07 g) in anhydrous dichloromethane (200 ml). This mixture was treated with anhydrous acetic acid (2 drops) and stirred under nitrogen for 2 hours. Celite® (10 g) was added to the reaction mixture which was stirred for 20 minutes. Isohexane (100 ml) was added to this and the mixture filtered. The filtrate was concentrated under reduced pressure and the residue obtained was triturated in diethyl ether. This was filtered through anhydrous magnesium sulfate and the filtrate concentrated under reduced pressure. The residue obtained was assumed to be (2S)-2-(4-bromophenoxy)-1-butanal and dissolved in anhydrous tetrahydrofuran (40 ml). n-Butyl-lithium (5.88 ml, 2.5M solution in hexanes) was added dropwise to a solution of pyridin-3-ylacetylene (1.6g, J. Amer. Chem. Soc. 1935, 57, 1284) in anhydrous tetrahydrofuran (80 ml) at −70° C., under nitrogen. After stirring for 20 minutes the solution of the (2S)-2-(4-bromophenoxy)-1-butanal in tetrahydrofuran was added dropwise, maintaining the reaction temperature at −70° C.. The reaction mixture was then allowed to warm slowly to 0° C. and poured into brine (200 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic fractions were combined and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give an oil which was purified by flash column chromatography over silica eluting with isohexane : ethyl acetate (2:1). This gave the sub-title compound as an oil (3.42 g).
Reaction SMILES: ClC(Cl)(Cl)COC(=O)C1C=CC=CC=1CSC1C=CC=C(CC(O[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=O)C=1.[Cl:38][C:39]([Cl:63])([Cl:62])[CH2:40][O:41][C:42](=[O:61])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[CH2:49][S:50][C:51]1[CH:56]=[CH:55][C:54]([CH2:57][C:58]([OH:60])=[O:59])=[CH:53][CH:52]=1.FC(F)(F)C1C=CC(CO)=CC=1.C(Cl)Cl>CN(C1C=CN=CC=1)C.CCCCCCC.CCOC(C)=O>[Cl:63][C:39]([Cl:38])([Cl:62])[CH2:40][O:41][C:42](=[O:61])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[CH2:49][S:50][C:51]1[CH:52]=[CH:53][C:54]([CH2:57][C:58]([O:60][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:29][CH:30]=2)=[O:59])=[CH:55][CH:56]=1
Reactant: O=C(O)Cc1ccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: O=C(Cc1cccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)c1)OCc1ccc(C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Agent: OCc1ccc(C(F)(F)F)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: ClCCl
Product: O=C(Cc1ccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)cc1)OCc1ccc(C(F)(F)F)cc1
Yield: 35 %

Procedure:
The titled compound was prepared according to the method described for 2-[3-(4-trifluoromethyl-benzyloxycarbonylmethyl)-phenylsulfanylmethyl]-benzoic acid 2,2,2-trichloro-ethyl ester above from 2-(4-carboxymethyl-phenylsulfanylmethyl)-benzoic acid 2,2,2-trichloro-ethyl ester (155 mg, 0.357 mmol), (4-trifluoromethyl-phenyl)-methanol (157 mg, 0.893 mmol), EDCxHCl (206 mg, 1.072 mmol), DMAP (4.4 mg, 0.036 mmol) and DCM (3 mL). The crude was submitted to flash chromatography using heptane and EtOAc (90/10) as eluent to yield the titled compound (74 mg, 35%) as an oil; 1H NMR (400 MHz, CDCl3): δ 3.64 (dd, 2H), 4.54 (s, 2H), 4.96 (s, 2H), 5.17 (s, 2H), 7.16 (d, 2H), 7.18-7.28 (m, 3H), 7.31-7.44 (m, 4H), 7.60 (d, 2H), 8.08 (d, 1H)); Mass spectrum: M−H− 590.
Reaction SMILES: OC(C(F)(F)F)=O.[C:8]([NH:12][C:13]([N:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=2)[C:17]([NH:28][CH2:29][C:30](=[O:36])[NH:31][CH:32]2[CH2:35][NH:34][CH2:33]2)=[N:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[CH2:37]([O:39][C:40]([CH:42]1[CH2:47][CH2:46][C:45](=O)[CH2:44][CH2:43]1)=[O:41])[CH3:38]>>[CH2:37]([O:39][C:40]([CH:42]1[CH2:47][CH2:46][CH:45]([N:34]2[CH2:33][CH:32]([NH:31][C:30](=[O:36])[CH2:29][NH:28][C:17]3[C:18]4[C:23](=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:25])[F:27])[CH:19]=4)[N:15]([C:13](=[O:14])[NH:12][C:8]([CH3:11])([CH3:9])[CH3:10])[N:16]=3)[CH2:35]2)[CH2:44][CH2:43]1)=[O:41])[CH3:38]
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: CC(C)(C)NC(=O)n1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1CCC(N2CC(NC(=O)CNc3nn(C(=O)NC(C)(C)C)c4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of 3-[(azetidin-3-ylcarbamoylmethyl)-amino]-5-trifluoromethyl-indazole-1-carboxylic acid tert-butyl amide TFA salt (as prepared in Example 81, Step D) and 4-oxo-cyclohexanecarboxylic acid ethyl ester using the procedure described in Step E of Example 1.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([CH2:11][CH2:12][OH:13])[N:6]2[N:5]=[CH:4][N:3]=1.CC(O)C.C(=O)=O.[Br:21]N1C(C)(C)C(=O)N(Br)C1=O>CN(C=O)C>[NH2:1][C:2]1[C:7]2=[C:8]([Br:21])[CH:9]=[C:10]([CH2:11][CH2:12][OH:13])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: Nc1ncnn2c(CCO)ccc12
Agent: O=C=O
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: Nc1ncnn2c(CCO)cc(Br)c12
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 184.1 %

Procedure:
To a solution of 2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)ethanol (777 mg, 4.3 mmol) in DMF (22 mL) at −20° C. (IPA and dry ice) was added 1,3-dibromo-5,5-dimethyl-imidazolidine-2,4-dione (359 mg, 1.72 mmol) ) was added in 4 portions within 20 min. The reaction was stirred at −20° C. for 30 min. Analytical HPLC indicated 22% starting material remanded, additional B (90 mg, 0.30 mmol) was added and stirred for 20 min. The reaction was quenched with satd. Na2SO3 and warmed up to rt. The crude was extracted w/EtOAc 5×. The organic was washed with 5% aq K2CO3 and brine. Dried over Na2SO4 and concentrated. The crude was purified by MPLC with 0-7% MeOH/CH2Cl2 to give 814 mg of desired product (yield, 72.6%). MS [M+H]+=257.3; LCMS RT=1.14 min.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[S:10][C:9]2[S:11][C:12]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:13][C:8]=2[CH:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(=O)(O)[O-].[Na+]>CC(C)=O>[CH:2]([C:6]1[S:10][C:9]2[S:11][C:12]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:13][C:8]=2[CH:7]=1)=[O:1]
Reactant: NS(=O)(=O)c1cc2cc(C3OCCO3)sc2s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: NS(=O)(=O)c1cc2cc(C=O)sc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
5-(2-Dioxolanyl)thieno[2,3-b]thiophene-2-sulfonamide (2.59 g, 8.89 mmol) was suspended in acetone and p-toluenesulfonic acid (2.50 g, 13.1 mmol) was added. The mixture was stirred at room temperature for one hour at which time a solution was obtained. Water (2.0 mL) was added and stirring continued for 3 hours. A saturated solution of sodium bicarbonate (30 mL) was added dropwise, followed by the slow addition of water (40 mL). The resulting solution or mixture was seeded with a few crystals of product and the acetone was evaporated in vacuo. The crystals were collected, washed with water and dried in vacuo to give 2.10 g of 5-formylthieno[2,3-b]thiophene-2-sulfonamide, m.p. 188°-189° C. This product was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8][C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]([NH2:16])=[C:4]([N+:17]([O-])=O)[CH:3]=1.[Cl-].[NH4+].CC(C)=O>[Zn].O>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:17])[C:5]([NH2:16])=[CH:6][C:7]=1[S:8][C:9]1[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=1
Reactant: Cc1cccc(Sc2cc(N)c([N+](=O)[O-])cc2Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cccc(Sc2cc(N)c(N)cc2Cl)c1

Procedure:
To an ice bath cooled solution (0° C.) of 4-chloro-2-nitro-5-m-tolylsulfanyl-phenylamine (2.30 g, 7.80 mmol), ammonium chloride (6.26 g, 117 mmol), acetone (32.5 mL), and water (6.5 mL) was added portion-wise zinc powder (5.10 g, 78.0 mmol). The reaction mixture was removed from the ice bath and after 30 min, the reaction mixture was filtered through a pad of Celite® and washed with EtOAc. The filtrate was placed in a sep funnel and the organic layer was collected. The organic layers dried, filtered, and concentrated under reduced pressure. The crude material was used without further purification in the next reaction.
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:7]=[CH:8][C:9]=1[O:10]C(=O)C)=[O:3].Cl.[CH2:25]([O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C@@H:40]([NH2:47])[C:41]2[O:45][N:44]=[C:43]([CH3:46])[N:42]=2)=[CH:35][CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])(=O)C.C([O-])([O-])=O.[K+].[K+]>>[CH2:25]([O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C@@H:40]([NH:47][C:2]([C:4]2[CH:5]=[C:6]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][CH:15]=3)[CH:7]=[CH:8][C:9]=2[OH:10])=[O:3])[C:41]2[O:45][N:44]=[C:43]([CH3:46])[N:42]=2)=[CH:35][CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(=O)Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)Cl
Reactant: Cc1noc([C@H](N)Cc2ccc(OCc3ccccc3)cc2)n1
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Product: Cc1noc([C@@H](Cc2ccc(OCc3ccccc3)cc2)NC(=O)c2cc(-c3ccc(C(F)(F)F)cc3)ccc2O)n1

Procedure:
4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid [2-(4-benzyloxy-phenyl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide was prepared from Acetic acid 3-chlorocarbonyl-4′-trifluoromethyl-biphenyl-4-yl ester (0.32 g, 0.93 mmol) and 2-(4-Benzyloxy-phenyl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylamine hydrochloride salt (0.32 g, 0.93 mmol) following the general procedure M. followed by the hydrolysis of the resulting acetate using K2CO3.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([CH3:20])[C:5]([S:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)=[C:6]([CH:8]([CH3:10])[CH3:9])[N:7]=1.[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C)C=O>[N:21]([CH2:2][C:3]1[N:4]([CH3:20])[C:5]([S:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)=[C:6]([CH:8]([CH3:10])[CH3:9])[N:7]=1)=[N+:22]=[N-:23]
Reactant: CC(C)c1nc(CCl)n(C)c1Sc1cc(Cl)cc(Cl)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1nc(CN=[N+]=[N-])n(C)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 80 °C
Yield: 100.2 %

Procedure:
To dry dimethylformamide solution (70 ml)of 23.7 g of 2-chloromethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-1H-imidazol (28a)was added 5.30 g of sodium azide, and the mixture was stirred with heating at 80° C. for 16 hours. The reaction mixture was added to ice-water, and extracted with diethyl ether. The organic layer was washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and 24.2 g of 2-azidomethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-1H-imidazole (29a) was obtained (yield about 100%). mp 84-85° C.
Reaction SMILES: [F:1][CH:2]([F:14])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11]C)=[CH:7][C:6]=1[F:13])=[O:4].B(Br)(Br)Br>C(Cl)Cl>[F:14][CH:2]([F:1])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[F:13])=[O:4]
Reactant: COc1ccc(C(=O)C(F)F)c(F)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(c1ccc(O)cc1F)C(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2,2-difluoro-1-(2-fluoro-4-methoxyphenyl)ethanone (45.0 g, 0.22 mol) in 400 mL of CH2Cl2 at −78° C. was added BBr3 (165.67 g, 0.66 mol) in 100 mL of CH2Cl2 dropwise. The resulting solution was stirred overnight at 25° C., and was quenched by dropwise addition of CH3OH (900 mL) at −30° C. and after stirring for 2 hours at −30° C. and for 1 hour at 25° C., the solvents were evaporated and the residue was purified by column chromatography (PE/EA 6:1) to afford 2,2-difluoro-1-(2-fluoro-4-hydroxyphenyl)ethanone as a solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[C:3]=1[C:4]#[N:5].O.C(Cl)Cl.CO>CCO>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[C:3]=1[CH2:4][NH2:5]
Reactant: N#Cc1c(F)cccc1-n1cncn1
Solvent: O
Solvent: CO
Solvent: CCO
Product: NCc1c(F)cccc1-n1cncn1
Temperature: 25 °C
Reaction time: 14 h
Yield: 89.5 %

Procedure:
A solution of 2-fluoro-6-[1,2,4]triazol-1-yl-benzonitrile (1.54 g, 8.20 mmol), as prepared in the previous step, in dry EtOH (70 mL) was bubbled with NH3 gas for 5 min. This solution was treated with a suspension of Raney Nickel 2800 in EtOH under air (15 mL) (prepared by diluting 2 mL of the Aldrich water slurry with 15 mL EtOH, centrifuging, decanting, diluting with 15 mL EtOH and transferring to the reaction). The flask was then sealed and evacuated until bubbles formed, and the evacuated flask was flushed with H2 gas via balloon pressure. After 14 h stirring at rt under balloon H2 pressure, TLC demonstrated very little starting material remaining. The bulk of the Raney nickel was removed with a magnet, the reaction mixture was filtered (0.22 μm), and the clear pale yellow filtrate was concentrated to give a green oil. Silica flash chromatography of the crude oil (40 mm×6″ column; 98:2 DCM/MeOH/saturated NH3 eluent; 30 mL fractions; fractions 12-19 combined) afforded the title compound as a yellow solid (1.41 g, 89%).
Reaction SMILES: O[CH2:2][C:3]1[S:17][C:6]2[O:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[NH:10][C:11](=[O:12])[C:5]=2[CH:4]=1.[CH2:18]([N:20](CC)[CH2:21]C)C.CS(Cl)(=O)=O>C(Cl)Cl>[CH3:18][N:20]([CH2:2][C:3]1[S:17][C:6]2[O:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[NH:10][C:11](=[O:12])[C:5]=2[CH:4]=1)[CH3:21]
Reactant: CCN(CC)CC
Reactant: O=C1Nc2ccccc2Oc2sc(CO)cc21
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CN(C)Cc1cc2c(s1)Oc1ccccc1NC2=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45.1 %

Procedure:
2-Hydroxymethylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one (1.0 g) was dissolved in methylene chloride (10 ml) and triethylamine (450 mg) and methanesulfonyl chloride (500 mg) were added. The mixture was stirred at room temperature for 15 minutes and the solvent was evaporated under reduced pressure. Thereto was added 2M dimethylamine/methanol and the mixture was stirred at room temperature for 14 hours. The solvent was evaporated under reduced pressure and chloroform was added to the residue. After washing with water, the aqueous layer was extracted twice with chloroform. The organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give 2-(N,N-dimethylaminomethyl)thieno[2,3-b][1,5]benzoxazepin-4(5H)-one (500 mg).
Reaction SMILES: C([C:4]1[N:9]=[N:8][C:7]2[C:10]3[CH:16]=[CH:15][C:14]([CH3:17])=[N:13][C:11]=3[S:12][C:6]=2[C:5]=1[OH:18])(O)=O>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.CCCCCC>[OH:18][C:5]1[C:6]2[S:12][C:11]3[N:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:10]=3[C:7]=2[N:8]=[N:9][CH:4]=1
Reactant: Cc1ccc2c(n1)sc1c(O)c(C(=O)O)nnc12
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: CCCCCC
Product: Cc1ccc2c(n1)sc1c(O)cnnc12
Temperature: 225 °C
Reaction time: 0.5 h
Yield: 66.5 %

Procedure:
A mixture of 2.4 g (0.009 mol) of 3-carboxy-4-hydroxy-7-methylpyrido[3',2':4,5]-thieno[3,2-C]pyridazine in 70 ml of Dowtherm-A was stirred at 225° C. for 30 minutes. It was cooled, diluted with hexane and filtered. The crude product was crystallized by 5% NaOH/HOAC giving 1.3 g (65%) of 4-hydroxy-7-methylpyrido[3',2':4,5]thieno[3,2-C]pyridazine, m.p.>300° C.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:5]([C:10]([O:12][CH3:13])=[O:11])=[N:6][CH:7]=[CH:8][N:9]=1.Cl[CH2:15][CH2:16][S:17](Cl)(=[O:19])=[O:18].C(=O)([O-])O.[Na+]>C1COCC1>[N:3]1[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][N:9]2[CH:8]=[CH:7][N:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=12
Reactant: COC(=O)c1nccnc1N
Reactant: O=S(=O)(Cl)CCCl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1=NC=CN2CCS(=O)(=O)N=C12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of sodium hydride (60%, 2.0 g) in dry THF (100 mL) were added under ice-cooling methyl 3-aminopyrazine-2-carboxylate (1.53 g) and 2-chloroethanesulfonyl chloride (2.1 mL), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 2-chloroethanesulfonyl chloride (2.1 mL), and the mixture was stirred at room temperature for 3 days. 2-Chloroethanesulfonyl chloride (2.1 mL) was added, and the mixture was stirred at room temperature for 3 days. The reaction mixture was added dropwise to aqueous sodium hydrogen carbonate (15.1 g) solution (400 mL) under ice-cooling, and the mixture was stirred at the same temperature for 1 hr. The precipitated was collected by filtration, washed successively with water and a small amount of methanol, and dried to give the title compound (1.62 g) as a pale-yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(O)C.[OH-].[Na+].[CH2:17](Br)[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19]>O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: O=C(CBr)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1ccc(OCC(=O)c2ccccc2)cc1[N+](=O)[O-]

Procedure:
3.0 G. 1-amino-4-hydroxy-2-nitrobenzene in 80 ml. aqueous ethanol, containing 0.80 g. sodium hydroxide, is reacted with 4.0 g. phenacyl bromide on a steam bath under nitrogen atmosphere for 2 hours, water is added and the product collected by filtration to afford 1-amino-2-nitro-4-phenacyloxybenzene. This latter compound is hydrogenated at one atmosphere pressure in 150 ml. methanol in the presence of hydrochloric acid and 2.0 g. palladized charcoal until the theoretical uptake of hydrogen has occurred. The catalyst is filtered off and the solution stripped uner vacuum to afford 1,2-diamino-4-[1-(2-hydroxy-2-phenyl)ethoxy]benzene. This latter compound is treated overnight at room temperature with 12 g. methoxy carbonyl isothiocyanate in 120 ml. acetone. The solution is evaporated and the residue triturated with water. Recrystallization from methanol yields 1,2-bis(3-methoxycarbonyl-2-thioureido)-4-[1-(2-hydroxy-2-phenyl)ethoxy]benzene.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[CH:8]=[N:9][C:10]([CH2:13][O:14]C(=O)C)=[CH:11][CH:12]=1)=[O:6].Cl>CO>[OH:14][CH2:13][C:10]1[N:9]=[CH:8][C:7]([C:5]([OH:6])=[O:4])=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc(COC(C)=O)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(CO)nc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Under ice cooling, 2 M aqueous sodium hydroxide solution (3.0 mL) was added to a solution of 6-acetoxymethylpyridine-3-carboxylic acid methyl ester (Reference Compound No. 9-1, 0.60 g, 2.9 mmol) in methanol (6.0 mL). The reaction mixture was stirred under ice cooling for 40 minutes and at room temperature for 4 hours. Under ice cooling, 2 M hydrochloric acid (3.1 mL) was added thereto, and then the solvent was evaporated under reduced pressure to give the title reference compound as an orange solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]2[N:10]=[C:9]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([CH3:24])([CH3:23])[CH2:21][OH:22])[CH2:16][CH2:15]3)=[O:13])[S:8][C:6]=2[N:7]=1.[CH2:31]([C:33]1[NH:34][C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1)[CH3:32].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:31]([C:33]1[N:34]([C:2]2[N:3]=[C:4]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:5]3[N:10]=[C:9]([CH2:11][C:12]([N:14]4[CH2:15][CH2:16][N:17]([C:20]([CH3:23])([CH3:24])[CH2:21][OH:22])[CH2:18][CH2:19]4)=[O:13])[S:8][C:6]=3[N:7]=2)[C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1)[CH3:32]
Reactant: CC(C)(CO)N1CCN(C(=O)Cc2nc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Reactant: CCc1nc2ccccc2[nH]1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC(=O)N3CCN(C(C)(C)CO)CC3)sc2n1
Temperature: 110 °C
Yield: 17.7 %

Procedure:
A mixture of 2-(5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-yl)-1-[4-(2-hydroxy-1,1-dimethylethyl)piperazin-1-yl]ethanone (65 mg, 0.14 mmol), 2-ethylbenzimidazole (23 mg, 0.16 mmol), tris(dibenzylideneacetone)dipalladium (4 mg, 2.5 mol %), XPhos (7 mg, 10 mol %) and Cs2CO3 (70 mg, 0.21 mmol) in dioxane (2 mL) was purged with argon then heated at 110° C. for 24 h in a sealed tube. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH/DCM. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-10%) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 20 nM NEt3 in water on a gradient acetonitrile 10-95%) affording 712 as a yellow solid (14 mg, 17%). LCMS (method I): RT 2.58 min, [M+H]+ 565.2. 1H NMR (CDCl3, 400 MHz): δ 8.01-7.98 (1 H, m), 7.76-7.75 (1 H, m), 7.29-7.29 (2 H, m), 4.41 (4 H, s), 4.18 (2 H, s), 3.93-3.75 (9 H, m), 3.56 (2 H, brd s), 3.34 (2 H, q, J=7.47 Hz), 2.90-2.70 (4 H, brd m), 1.43 (3 H, t, J=7.47 Hz), 1.23-1.21 (6 H, m)