Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH2:14][CH:15]3[O:17][CH2:16]3)=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[NH2:2].[ClH:18]>C(Cl)(Cl)Cl>[C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][Cl:18])=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)c1cc2cccc(OCC3CO3)c2o1
Reactant: Cl
Solvent: ClC(Cl)Cl
Product: NC(=O)c1cc2cccc(OCC(O)CCl)c2o1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
There was suspended 2.3 g of 2-carbamoyl-7-(2,3-epoxypropoxy)benzofuran obtained in Reference Example 1 in 70 ml of chloroform, and thereto 15 ml of concentrated hydrochloric acid was added. Thereafter, the mixture was vigorously stirred at room temperature for 15 minutes. After the chloroform layer was washed with water and dried with magnesium sulfate, the solvent was distilled away from the reaction mixture under reduced pressure. The resultant residue was purified by silica-gel chromatography (eluent: 2 % ethanol-chloroform) to give the desired compound.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]([O:17]C)=O.[NH2:19][C:20]1[C:21](=[O:28])[C:22]([OH:27])=[CH:23][CH:24]=[CH:25][CH:26]=1>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:12])(=[O:13])[N:4]([CH3:14])[C:3]=1[C:15]([NH:19][C:20]1[C:21](=[O:28])[C:22]([OH:27])=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:17]
Reactant: Nc1ccccc(O)c1=O
Reactant: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2ccccc(O)c2=O)=C(O)c2ccccc2S1(=O)=O
Temperature: 25 °C
Yield: 90.4 %

Procedure:
A mixture of methyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (2.95 g) and 2-amino-7-hydroxy-2,4,6-cycloheptatrien-1-one (1.5 g) in xylene (103 ml) was refluxed for 52 hours. The reaction mixture was cooled to room temperature. The crystals were collected by filtration and washed successively with N,N-dimethylformamide and chloroform to give 4-hydroxy-N-(7-hydroxy-1-oxo-2,4,6-cycloheptatrien-2-yl)-2-methyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide (3.7 g).
Reaction SMILES: O[N:2]=[C:3]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[C:4]1[CH:18]=[CH:17][C:7]([CH2:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])=[CH:6][CH:5]=1>CCO.[Ni]>[NH2:2][CH:3]([C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1)[C:4]1[CH:5]=[CH:6][C:7]([CH2:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])=[CH:17][CH:18]=1
Reactant: CCOP(=O)(Cc1ccc(C(=NO)c2ccc(OC)cc2)cc1)OCC
Agent: [Ni]
Solvent: CCO
Product: CCOP(=O)(Cc1ccc(C(N)c2ccc(OC)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 12 h
Yield: 92 %

Procedure:
Diethyl 4-((hydroxyimino)(4-methoxyphenyl)methyl)benzylphosphonate, 32-e, (450 mg, 1.2 mmol) was dissolved in EtOH (10 ml), Raney Ni (50 mg) was added, and the resulting mixture was then stirred for 12 h at ambient temperature under hydrogen. The solution was filtered, filtrate was concentrated under reduce pressure, purified by column chromatography (DCM/MeOH=20:1). The product was obtained as a white solid, 32-f, (400 mg, 92%). 1H NMR (300 MHz, CDCl3) δ 1.18-1.23 (t, J=6.9 Hz 6H), 2.27 (s, 2H), 3.04-3.11 (d, J=21.6 Hz 2H) 3.74 (s, 3H), 3.93-3.99 (m, 4H), 5.12 (s, 1H), 6.78-6.81 (d, J=8.7 Hz, 2H), 7.18-7.28 (m, 6H). LC-MS 364 [MH]+.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH2:16][CH3:17])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[C:18]([OH:21])(=O)[CH3:19]>>[O:21]=[C:18]1[C:19]2[C:8](=[CH:7][CH:2]=[CH:3][CH:4]=2)[CH2:9][N:1]1[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH2:16][CH3:17])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CC(=O)O
Reactant: CCOc1cc(C(N)CC(=O)O)ccc1OC
Product: CCOc1cc(C(CC(=O)O)N2Cc3ccccc3C2=O)ccc1OC
Temperature: 25 °C
Yield: 62 %

Procedure:
A stirred mixture of phthalic dicarboxaldehyde (2.68 g, 20.0 mmol) and 3-amino-3-(3-ethoxy-4-methoxyphenyl)propionic acid (4.78 g, 20.0 mmol) in glacial acetic acid (50 mL) under nitrogen was heated to reflux for 5 minutes. The reaction mixture was then allowed to cool to room temperature and was concentrated in vacuo to afford a yellow solid. The crude product was recrystallized twice from refluxing ethanol (150 mL). The resulting solid was then dried in vacuo (60° C., <1 mm) to afford 4.4 g (62%) of 3-(1-oxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionic acid as a white solid: mp 193.5-194° C.; 1H NMR (DMSO-d6) δ12.40 (br s, 1H), 7.75-7.40 (m, 4H), 7.05-6.85 (m, 3H), 5.71 (m, 1H), 4.51 (d, J=17.7 Hz, 1H), 4.11 (d, J=17.7 Hz, 1H), 3.99 (m, 2H), 3.73 (s, 3H), 3.25-3.02 (m, 2H), 1.30 (t, J=6.9 Hz, 3H); 13C NMR (DMSO-d6) δ171.9, 166.9, 148.5, 147.9, 141.7, 132.2, 131.6, 131.4, 127.9, 123.5, 122.9, 119.3, 111.8, 63.7, 55.4, 51.2, 46.3, 36.8, 14.7; Anal. Calcd. for C20H21NO5. Theoretical: C, 67.59; H, 5.96; N, 3.94. Found: C, 67.64; H, 5.97; N, 3.92.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[C:17]3[O:16][CH:15]([CH2:18][N:19]=[N+]=[N-])[CH2:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd]>[C:1]1([CH2:7][CH2:8][C:9]2[C:17]3[O:16][CH:15]([CH2:18][NH2:19])[CH2:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=NCC1Cc2cccc(/C=C/c3ccccc3)c2O1
Agent: [Pd]
Product: NCC1Cc2cccc(CCc3ccccc3)c2O1
Yield: 55 %

Procedure:
Treatment of (±)-{7-[(E)-2-phenylvinyl]-2,3-dihydro-1-benzofuran-2-yl}methyl azide (2.2 g, 7.9 mmol) with palladium on carbon (0.22 g, 10 wt. %) generally according to the procedure described for Example 1 provided 1.1 g (48%) of (±)-1-[7-(2-phenylethyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 155-157° C.; Anal. calcd. for C17H19NOHCl: C, 70.46; H, 6.96; N, 4.83. Found: C, 70.11; H, 7.08; N, 4.62.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:12][C:13]1[N:14]([CH2:26][CH2:27][C:28]([NH2:30])=[O:29])[C:15]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[CH:17][C:16]=2[N:25]=1.[OH-].[NH4+:32].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:32][C:17]1[C:16]2[N:25]=[C:13]([CH3:12])[N:14]([CH2:26][CH2:27][C:28]([NH2:30])=[O:29])[C:15]=2[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:18]=1
Reactant: Cc1nc2cnc3ccccc3c2n1CCC(N)=O
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cc1nc2c(N)nc3ccccc3c2n1CCC(N)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
mCPBA (3.48 g, 15.1 mmol) was added to a solution of 3-(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propanamide (2.20 g, 8.65 mmol) in chloroform (100 mL). The reaction was stirred for two hours at ambient temperature and cooled to 0° C. Ammonium hydroxide (40 mL) was added followed by p-toluenesulfonyl chloride (3.21 g, 16.9 mmol), which was added over a period of five minutes. The reaction was stirred for two hours at ambient temperature and then concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with dichloromethane:methanol in a gradient from 90:10 to 80:20). The resulting solid was triturated with 10% aqueous sodium hydroxide, isolated by filtration, washed with water, and dried overnight in a vacuum oven at 60° C. to provide 0.145 g of 3-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propanamide as a off-white powder, mp 237-239° C.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[C:18]([O:19][C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)=[CH:17][C:16]([Br:28])=[CH:15][N:14]=1>>[C:1]([NH:9][C:10]([NH:12][C:13]1[C:18]([O:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]#[N:25])=[CH:26][CH:27]=2)=[CH:17][C:16]([Br:28])=[CH:15][N:14]=1)=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: N#Cc1ccc(Oc2cc(Br)cnc2N)cc1
Product: N#Cc1ccc(Oc2cc(Br)cnc2NC(=S)NC(=O)c2ccccc2)cc1

Procedure:
Prepared according to the method of Example 7, step C from benzoyl isothiocyanate and 4-(2-amino-5-bromopyridin-3-yloxy)benzonitrile.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:6][C@@H:5]([C@@H:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:8]([OH:10])=O)[C:4](=[O:15])[O:3]1.[F:17][C:18]1[CH:19]=[N:20][C:21]([N:24]2[CH2:29][CH2:28][NH:27][C@H:26]([CH3:30])[CH2:25]2)=[N:22][CH:23]=1>>[F:17][C:18]1[CH:19]=[N:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:8]([C@H:7]([C@@H:5]3[O:6][C:2]([CH3:1])([CH3:16])[O:3][C:4]3=[O:15])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:10])[C@H:26]([CH3:30])[CH2:25]2)=[N:22][CH:23]=1
Reactant: CC(C)C[C@@H](C(=O)O)[C@@H]1OC(C)(C)OC1=O
Reactant: C[C@@H]1CN(c2ncc(F)cn2)CCN1
Product: CC(C)C[C@H](C(=O)N1CCN(c2ncc(F)cn2)C[C@H]1C)[C@@H]1OC(C)(C)OC1=O

Procedure:
The title compound was prepared following the procedure of Example 4 (step a), but starting from (2R)-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-4-methylpentanoic acid and 5-fluoro-2-[(3R)-3-methylpiperazin-1-yl]pyrimidine. The crude was purified by chromatography on silica using a gradient of EtOAc: cHex (0/10 to 4/6). The title compound was isolated as a yellow oil (413 mg, 75%). TLC (EtOAc:cHex 3:7) Rf=0.25; 1H NMR (DMSO-d6) δ: 8.16 (s, 2H), 4.85-5.0 (m, 0.6H), 4.41-4.52 (m, 3.4H), 4.23 (m, 0.4H), 3.46-3.67 (m, 0.6H), 2.80-3.20 (m, 4H), 1.70-1.79 (m, 1H), 1.056 (m, 3H), 1.38 (s, 6H), 1.13-1.32 (m, 2H), 0.90 (m, 6H). HPLC (Condition A) Rt: 4.26 min (HPLC purity 96.1%). LC/MS: M+(ESI): 409.6.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH3:13])[CH:3]=1.[NH2:14][CH2:15][CH:16]1[CH2:20][CH2:19][CH:18]([CH3:21])[N:17]1[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([N:17]1[CH:18]([CH3:21])[CH2:19][CH2:20][CH:16]1[CH2:15][NH:14][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([Cl:11])[C:2]([NH2:1])=[CH:3][C:4]=1[O:12][CH3:13])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC1CCC(CN)N1Cc1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCC(C)N1Cc1ccccc1

Procedure:
By following general method B using 1.01 g. of 4-amino-5-chloro-2-methoxybenzoic acid and 1.0 g. of 2-aminomethyl-1-benzyl-5-methylpyrrolidine, 1.5 g. of N-(1-benzyl-5-methyl-2-pyrrolidinyl-methyl)-4-amino-5-chloro-2-methoxybenzamide was obtained.
Reaction SMILES: [N-]=[N+]=[N-].[Na+].[N:5]([CH2:8][CH:9]1[CH2:13][C:12]2[CH:14]=[CH:15][CH:16]=[C:17]([C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=3)[C:11]=2[O:10]1)=[N+]=[N-].[N-]=[N+]=[N-]>[Pd]>[F:26][C:24]([F:25])([F:27])[C:22]1[CH:23]=[C:18]([C:17]2[C:11]3[O:10][CH:9]([CH2:8][NH2:5])[CH2:13][C:12]=3[CH:14]=[CH:15][CH:16]=2)[CH:19]=[C:20]([C:28]([F:29])([F:30])[F:31])[CH:21]=1
Reactant: [N-]=[N+]=NCC1Cc2cccc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2O1
Agent: [Pd]
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Product: NCC1Cc2cccc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2O1
Yield: 47 %

Procedure:
Treatment of {7-[3,5-bis(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl methyl 4-methylbenzenesulfonate (0.75 g, 1.45 mmol) with sodium azide (0.24 g, 3.62 mmol) generally according to the procedure described for Intermediate 98 provided (±)-2-(azidomethyl)-7-[3,5-bis(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (10%, 0.075 g) generally according to the procedure described for Example 1 afforded 0.270 g (47%) of (±)-1-{7-[3,5-bis(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine as a white solid, hydrochloride salt. mp 174-175° C. (dec.); Anal. calcd. for C17H13F6NOHCl: C, 51.34; H, 3.55; N, 3.52. Found: C, 51.25; H, 3.57; N, 3.68.
Reaction SMILES: [ClH:1].C(OC([N:12]([CH2:20][CH:21]1[C:30]2[C:25](=[CH:26][C:27]([OH:32])=[C:28]([OH:31])[CH:29]=2)[CH2:24][CH2:23][NH:22]1)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)=O)C1C=CC=CC=1.Cl>C(O)(=O)C>[ClH:1].[F:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[NH:12][CH2:20][CH:21]1[C:30]2[C:25](=[CH:26][C:27]([OH:32])=[C:28]([OH:31])[CH:29]=2)[CH2:24][CH2:23][NH:22]1
Reactant: O=C(OCc1ccccc1)N(CC1NCCc2cc(O)c(O)cc21)c1cccc(F)c1
Agent: Cl
Solvent: CC(=O)O
Product: Oc1cc2c(cc1O)C(CNc1cccc(F)c1)NCC2
Yield: 94.2 %

Procedure:
A mixture of 1(N-benzyloxycarbonyl-m-fluoroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.3 g), conc. hydrochloric acid (3 ml) and acetic acid (3 ml) was refluxed for 1.5 hours in a stream of nitrogen. The reaction mixture was concentrated and the residue was pulverized with ether to give 1-(m-fluoroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.2 g), powder.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8](=[O:17])[CH:9]=[C:10]([C:12]([O:14]CC)=[O:13])[O:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.I[CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>C(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH3:22][CH:21]([CH3:23])[CH2:20][CH2:19][O:1][C:2]1[C:7]2[C:8](=[O:17])[CH:9]=[C:10]([C:12]([OH:14])=[O:13])[O:11][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(=O)c2c(O)cccc2o1
Reactant: CC(C)CCI
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(C)CCOc1cccc2oc(C(=O)O)cc(=O)c12

Procedure:
A mixture of 23.4parts of 5-hydroxy-4-oxo-4H-1-benzopyran-2-carboxylic acid, ethyl ester, 19.8 partsof 1-iodo-3-methylbutane, 11.65 parts of anhydrous potassium carbonate and 500 parts of acetone was refluxed for thirteen days. After cooling, the reaction mixture was filtered and the volatile components of the filtrate were removed by evaporation to give a residue which was dissolved in chloroform. The chloroform extract was washed with cold N sodium hydroxide solution, then with water and evaporated. The oily residue obtained was stirred in sodium bicarbonate solution at 100° C for 2 hour. After cooling, the solution was extracted with chloroform and the aqueous layer was separated. The aqueous extract was acidified with 2N hydrochloric acid and the mixture was extracted with chloroform. Evaporation of the chloroform gave 8.79 parts of 5-(3-methyl-n-butoxy)-4-oxo-4H-1-benzopyran-2-carboxylic acid m.p. 181°-183° C (after crystallisation from ethyl acetate/light petroleum.
Reaction SMILES: [OH:1][CH:2]([CH2:7][N:8]1[CH:12]=[C:11]([I:13])[CH:10]=[N:9]1)[C:3](OC)=[O:4].[NH3:14]>>[OH:1][CH:2]([CH2:7][N:8]1[CH:12]=[C:11]([I:13])[CH:10]=[N:9]1)[C:3]([NH2:14])=[O:4]
Reactant: N
Reactant: COC(=O)C(O)Cn1cc(I)cn1
Product: NC(=O)C(O)Cn1cc(I)cn1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
A mixture of methyl 2-hydroxy-3-(4-iodo-1H-pyrazol-1-yl)propanoate (4 g, 13 mmol) and ammonia (saturated in methanol, 100 mL) in a sealed tube was stirred at 60° C. for 12 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to afford 2-hydroxy-3-(4-iodo-1H-pyrazol-1-yl)propanamide. MS ESI calc'd. for C6H9IN3O2 [M+H]+ 282. found 282. 1H NMR (400 MHz, CDCl3) δ 7.72 (s, 1H), 7.50 (s, 1H), 4.53-4.49 (m, 1H), 4.36-4.29 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][O:44][CH2:45][CH3:46])=[C:37]([O:47][CH2:48][CH3:49])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH2:48]([O:47][C:37]1[CH:36]=[C:35]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)[CH:40]=[CH:39][C:38]=1[O:41][CH2:42][CH2:43][O:44][CH2:45][CH3:46])[CH3:49]
Reactant: CCOCCOc1ccc(OB([O-])[O-])cc1OCC
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.4 %

Procedure:
A mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (0.3 g), 3-ethoxy-4-(2-ethoxyethoxy)phenyl borate (0.18 g), 1M potassium carbonate solution (1.3 ml), ethanol (1.3 ml) and toluene (25 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (0.03 g), and the mixture was refluxed under argon atmosphere for 6 hours and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethanol to give 7-[3-ethoxy-4-(2-ethoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 126) (0.26 g) as colorless crystals.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:4]=[C:5]([C@@H:11]([NH3+:13])[CH3:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C([O:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:34]2[C:42]3[C:37](=[CH:38][C:39]([C:43](O)=[O:44])=[CH:40][CH:41]=3)[C:36]([CH3:46])=[C:35]2[CH3:47])=[CH:29][CH:28]=1)=[O:20])(C)(C)C>>[Cl:2][C:3]1[CH:4]=[C:5]([C@@H:11]([NH:13][C:43]([C:39]2[CH:38]=[C:37]3[C:42](=[CH:41][CH:40]=2)[N:34]([CH2:33][C:30]2[CH:29]=[CH:28][C:27]([C:22]4[C:21]([C:19]([OH:20])=[O:18])=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:32][CH:31]=2)[C:35]([CH3:47])=[C:36]3[CH3:46])=[O:44])[CH3:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: COc1ccc([C@H](C)[NH3+])cc1Cl
Agent: [Cl-]
Product: COc1ccc([C@H](C)NC(=O)c2ccc3c(c2)c(C)c(C)n3Cc2ccc(-c3ccccc3C(=O)O)cc2)cc1Cl

Procedure:
The title compound was prepared following the same general synthetic procedure as described in Steps 3-4, Example 2, starting with (S)-1-(3-chloro-4-methoxyphenyl)ethanaminium chloride and 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of (S)-1-(4-(tert-butyl)phenyl)ethanaminium chloride and 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 567 [M+1]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:11][C:10]2[C:9](=O)[NH:8][CH:7]=[N:6][C:5]=2[CH:4]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:9]1[C:10]2[S:11][C:3]([S:2][CH3:1])=[CH:4][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: CSc1cc2nc[nH]c(=O)c2s1
Reactant: O=P(Cl)(Cl)Cl
Product: CSc1cc2ncnc(Cl)c2s1
Reaction time: 0.17 h
Yield: 81 %

Procedure:
A mixture of 6-(methylthio)thieno[3,2-d]pyrimidin-4(3H)-one (900 mg) and phosphorous oxychloride (10 mL) was refluxed for 3 h. The reaction mixture was attained to rt and poured into ice cold water and stirred for 10 min. The precipitated solid was filtered, washed with water and dried to give the product as an off-white color solid (800 mg, 81%), mp 138-140° C. 1H NMR (400 MHz, CDCl3): δ 8.87 (1H, s), 7.25 (1H, s), 2.72 (3H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]=2[CH2:11]O)[CH:7]=1.S(Cl)([Cl:21])=O>C1(C)C=CC=CC=1>[Cl:21][CH2:11][C:10]1[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:8][N:6]2[CH:7]=[C:2]([CH3:1])[CH:3]=[N:4][C:5]=12
Reactant: Cc1cnc2c(CO)c(-c3ccccc3)nn2c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cnc2c(CCl)c(-c3ccccc3)nn2c1
Temperature: 80 °C

Procedure:
To a solution of (6-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methanol x143 (2.4 mmol, 1 eq, 0.58 g) in toluene (20 ml) is added thionyl chloride (4.8 mmol, 2 eq, 353 μ□l). The mixture is heated at 80° C. for 2 hours. The resulting mixture is cooled down to room temperature and the solvent removed under reduced pressure to afford 3-(chloromethyl)-6-methyl-2-phenylpyrazolo[1,5-a]pyrimidine x146, to which 5 ml of dry DMF are added.
Reaction SMILES: C([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH2:14][C@@H:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:11]1)(=O)C1C=CC=CC=1.[OH-].[Na+]>C1COCC1.CO>[CH3:26][CH:24]([CH2:23][CH2:22][CH2:21][C@H:20]([C@@H:19]1[C@:28]2([CH3:36])[C@H:16]([C@H:15]3[C@H:31]([CH2:30][CH2:29]2)[C@:32]2([CH3:35])[C@H:12]([CH2:11][C@@H:10]([OH:9])[CH2:34][CH2:33]2)[CH2:13][CH2:14]3)[CH2:17][CH2:18]1)[CH3:27])[CH3:25]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 16 h
Yield: 76 %

Procedure:
A solution of pyridazine 12 (113 mg, 0.22 mmol) in THF (1 mL) and MeOH (2 mL) was treated with 1M NaOH (0.29 mL, 0.29 mmol) and allowed to stand at ambient temperature for 16 h. The solvent was evaporated at reduced pressure and the residue was treated with CH2Cl2 (50 mL) and a 10% Na2CO3 solution (20 mL). The organic layer was separated, dried over MgSO4, filtered, and evaporated to dryness. The residue was purified by flash chromatography on 4 g of silica gel 60 using MeOH/CHCl3 (5:95) giving 65 mg (72%) of 13, which crystallized from CH2Cl2 /acetone, mp 203°-205° C. 1H NMR: δ3.71 (m, 1H), 3.13 (dd, 1H, J=5.6, 13.4 Hz), 3.10 (dd, 1H, J=6.8, 16.5 Hz), 2.95 (dd, 1H, J=10.6, 16.3 Hz), 2.61 (dd, 1H, J=12.8, 17.9 Hz), 2.27 (dd, 1H, J=6.1, 11.0 Hz), 2.23 (ddd, 1H, J=3.6, 3.6, 13.4 Hz), 1.06 (s, 3H), 0.99 (d, 3H, J=6.2 Hz), 0.89 (d, 6H, J=6.6 Hz), 0.80 (s, 3H). IR (Nujol): 3301, 1626, 1554, 1035 cm-1. EIMS (m/z): 410 (M+), 395 (M-Me). Anal. (C27H42N2O): C, H, N.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:11]2[C:15]3[CH:16]=[C:17]([CH2:20][CH2:21][CH2:22][CH2:23]OS(C)(=O)=O)[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)=[N:8][C:7]=1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[NH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:11]2[C:15]3[CH:16]=[C:17]([CH2:20][CH2:21][CH2:22][CH2:23][N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)=[N:8][C:7]=1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=1)=[O:5])[CH3:2]
Reactant: C1COCCN1
Reactant: CCOC(=O)c1sc(-n2cnc3ccc(CCCCOS(C)(=O)=O)cc32)nc1-c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1sc(-n2cnc3ccc(CCCCN4CCOCC4)cc32)nc1-c1cccc(Cl)c1
Yield: 74.3 %

Procedure:
A mixture of 0.107 g (0.2 mmole) of 4-(3-chloro-phenyl)-2-[6-(4-methanesulfonyloxy-butyl)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid ethyl ester (I.41e), 0.138 g (1 mmole) of potassium carbonate, 2 mL of acetonitrile and 0.035 mL (0.4 mmole) of morpholine was refluxed for 6 hours. The solid was removed by filtration and the filtrate concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with methanol-dichloromethane (gradient 0:100-5:95) to give 0.078 g of 4-(3-chloro-phenyl)-2-[6-(4-morpholin-4-yl-butyl)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid ethyl ester (I.41f) as a yellow solid.