Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].F[C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1.O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Fc1ccc(C(F)(F)F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
A stirred solution of 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (134.8 g) in N,N-dimethylformamide (850 m) was cooled in an ice bath under a nitrogen atmosphere. Potassium tert butoxide (75.2 g) was added in portions such that the temperature did not exceed 22° C. and the resulting mixture was maintained at 0° C. for a further 1.5 hours when 4-fluorobenzotrifluoride (100 g) was added dropwise over 15 minutes. The reaction mixture was allowed to warm to room temperature and stirred overnight. Water (200 ml) was added and the mixture was extracted with tert butyl methyl ether (1×400 ml, 1×300 ml, 1×200 ml). The combined organic extracts were washed with water (2×400 ml), brine (200 ml) and then dried over magnesium sulphate and evaporated in vacuo to leave the title compound as an off-white/pale yellow solid (206.4 g)
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([NH:15][C:16]2[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=2)[CH:7]=[C:8]([C:10]2[CH:11]=[N:12][NH:13][CH:14]=2)[CH:9]=1.CN(C=O)C.[CH2:31]1[O:39][CH:32]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O>[CH3:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][N:13]([CH2:31][CH:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[OH:39])[CH:14]=2)[CH:7]=[C:6]([NH:15][C:16]2[N:21]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:19]=[CH:18][N:17]=2)[CH:5]=1
Reactant: c1ccc(C2CO2)cc1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cn[nH]c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn(CC(O)c3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
NaH (0.0075 g, 0.19 mmol, 60% dispersion) was added to N-(3-methyl-5-(1H-pyrazol-4-yl)phenyl)-4-(trifluoromethyl)pyrimidin-2-amine (0.02 g, 0.06 mmol) suspended in DMF (1 mL, 0.06 mmol). The reaction mixture was allowed to stir at ambient temperature for 15 minutes. Styrene oxide (0.01 g, 0.08 mmol) was then added. The vial was capped and allowed to stir at 45° C. for 12 hours. H2O (0.2 mL) was added and the reaction was concentrated under reduced pressure. The residue was taken up in DMSO (1.0 mL) and was passed through a syringe filter. The eluent was purified by reverse phase HPLC (0 to 95% ACN/water with 0.1% formic acid modifier) to afford racemic 2-(4-(3-methyl-5-((4-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-1H-pyrazol-1-yl)-1-phenylethanol. MS ESI calcd. for C23H21F3N5O [M+H]+ 440. found 440. 1H NMR (600 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.77 (d, J=4.8, 1H), 7.91 (s, 1H), 7.75 (s, 1H), 7.72 (s, 1H), 7.34-7.27 (m, 5H), 7.25-7.19 (m, 2H), 7.01 (s, 1H), 5.69 (d, J=4.6, 1H), 4.94 (d, J=5.2, 1H), 4.20 (d, J=6.4, 2H), 2.26 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=2)[CH:3]=1.[NH2:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]1[NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]>CN1C(=O)CCC1.C(OCC)(=O)C>[C:8]([C:5]1[N:6]=[N:7][C:2]([NH:20][C@@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]2[NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[CH:3][C:4]=1[NH:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=1)(=[O:9])[NH2:10]
Reactant: Cc1cc(C)cc(Nc2cc(Cl)nnc2C(N)=O)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)c1
Temperature: 140 °C
Reaction time: 7 h
Yield: 41.5 %

Procedure:
To a solution of 6-chloro-4-(3,5-dimethylphenylamino)pyridazine-3-carboxamide (44 mg, 159 μmol) in NMP (530 μL) was added tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (68.2 mg, 318 μmol) and the mixture heated to 140° C. for 20 h. Additional tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (68.2 mg, 318 μmol) was then added and heating continued for a further 7 h. Finally, another portion of tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (34.1 mg, 159 μmol) was added and the mixture heated for 16 h. The reaction mixture was cooled, and then diluted with ethyl acetate. The phases were separated and the organic phase then washed with water and brine. The organic phase was collected, concentrated in vacuo, and the residue obtained was purified by chromatography (silica, 30 to 70% ethyl acetate in hexanes) to give tert-butyl (1S,2R)-2-(6-carbamoyl-5-(3,5-dimethylphenylamino)pyridazin-3-ylamino)cyclohexylcarbamate (30 mg, 66.0 μmol, 42%) as a brown oil. MS (EI/CI) m/z: 455.2 [M+H].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:10][N:11]3[C:16]=2[CH2:15][CH2:14][CH2:13][N:12]3[CH3:17])[CH:5]=[CH:4][N:3]=1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>CN1CCCC1=O.O>[CH:25]1([NH:28][C:2]2[N:7]=[C:6]([C:8]3[C:9]([C:18]4[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=4)=[N:10][N:11]4[C:16]=3[CH2:15][CH2:14][CH2:13][N:12]4[CH3:17])[CH:5]=[CH:4][N:3]=2)[CH2:27][CH2:26]1
Reactant: NC1CC1
Reactant: CN1CCCc2c(-c3ccnc(Cl)n3)c(-c3ccc(F)cc3)nn21
Solvent: O
Solvent: CN1CCCC1=O
Product: CN1CCCc2c(-c3ccnc(NC4CC4)n3)c(-c3ccc(F)cc3)nn21

Procedure:
A solution of 3-(2-chloro-4-pyrimidinyl)-2-(4-fluorophenyl)-4,5,6,7-tetrahydro-7-methylpyrazolo[1,5-b]pyridazine (i.e. the product of Step B) (30.0 mg, 0.087 mmol) and cyclopropylamine (0.31 mL, 4.36 mmol) in 1-methyl-2-pyrrolidinone (2 mL) was heated under microwave irradiation at 150° C. for 30 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by medium pressure liquid chromatography using 20-80% ethyl acetate in hexanes as eluant to give 27 mg of the title product, a compound of the present invention, as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](Br)[N:8]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH:9]=1)=[O:4].C([Sn](CCCC)(CCCC)[C:24]([O:26][CH2:27][CH3:28])=[CH2:25])CCC>O1CCOCC1.O.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>[CH2:27]([O:26][C:24]([C:7]1[N:8]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH:9]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[N:6]=1)=[CH2:25])[CH3:28]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1cn(COCC[Si](C)(C)C)c(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: C=C(OCC)c1nc(C(=O)OC)cn1COCC[Si](C)(C)C
Temperature: 25 °C

Procedure:
Methyl-2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (10 g, 29.9 mmol) was dissolved in dioxane (200 ml). Tributyl(1-ethoxy-vinyl)stannane (16.2 g, 44.8 mmol) was added to the solution. The resulting mixture was degassed and purged with argon for 20 min. Then Pd(PPh3)4 (3.45 g, 2.99 mmol) was added and the mixture was refluxed overnight. The reaction mixture was cooled to RT and diluted with cold water. The mixture was extracted with EtOAc and washed with aqueous KF solution. The organic layer was concentrated to give the desired product. Yield 12.1 g. LC-MS: [M+1]=327.78.
Reaction SMILES: CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH2:43]([C:45]1[N:50]=[CH:49][NH:48][C:47](=O)[CH:46]=1)[CH3:44].[C:52]([O:56][C:57]([N:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1)=[O:58])([CH3:55])([CH3:54])[CH3:53]>CN(C=O)C>[C:52]([O:56][C:57]([N:59]1[CH2:64][CH2:63][N:62]([C:47]2[CH:46]=[C:45]([CH2:43][CH3:44])[N:50]=[CH:49][N:48]=2)[CH2:61][CH2:60]1)=[O:58])([CH3:55])([CH3:53])[CH3:54]
Reactant: CCc1cc(=O)[nH]cn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ncn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 57.9 %

Procedure:
4 mL DIPEA and 3 g PYBOP was added to 2.9 g 6-ethyl-3H-pyrimidin-4-one in 10 mL DMF. The reaction was stirred 5 min at ambient temperature and 1.1 g piperazine-1-carboxylic acid tert-butyl ester was added. The reaction was stirred overnight at RT. The solvent was removed and the residue was purified by HPLC to give 1 g of the desired compound.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH:19]([CH3:21])[CH3:20])[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5].CCN(C(C)C)C(C)C.[Cl:31][CH2:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36](Cl)=[O:37]>C(Cl)Cl>[Cl:31][CH2:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36]([NH:2][C@H:3]([CH:19]([CH3:21])[CH3:20])[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[CH2:8][CH2:7]1)=[O:5])=[O:37]
Reactant: O=C(Cl)c1cccc(CCl)c1
Reactant: CC(C)[C@@H](N)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[C@@H](NC(=O)c1cccc(CCl)c1)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
To a solution of (R)-2-Amino-1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methylbutan-1-one hydrochloride (30.5 mg, 0.092 mmol) in DCM (1 mL) cooled to 0° C. was added DIEA (17.4 μL, 0.1 mmol) followed by 3-chloromethyl benzoylchloride (14.2 μL, 0.1 mmol). Upon completion of addition, the reaction mixture was allowed to warm slowly to rt. where it stirred overnight. After this time, the solution was diluted with dichloromethane and quenched by the addition of aqueous NaHCO3. The layers were separated and the organic layer was dried over Na2SO4, filtered, and concentrated to yield a residue. The residue was purified via SiO2 chromatography to give the (R)-3-(chloromethyl)-N-(1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methyl-1-oxobutan-2-yl)benzamide as a clear glassy solid (23.7 mg, 58% yield). MS found: 447.3 (M+), 449.3 (M+2).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[C:24]1([C:30]2[CH:31]=[CH:32][C:33]3[NH:34][C:35]4[C:40]([C:41]=3[CH:42]=2)=[CH:39][C:38]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:37][CH:36]=4)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>O.C1(C)C(C)=CC=CC=1>[C:24]1([C:30]2[CH:31]=[CH:32][C:33]3[N:34]([C:2]4[CH:7]=[CH:6][C:5]([C:8]5[C:17]([C:18]6[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=6)=[N:16][C:15]6[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=6)[N:9]=5)=[CH:4][CH:3]=4)[C:35]4[C:40]([C:41]=3[CH:42]=2)=[CH:39][C:38]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[CH:37][CH:36]=4)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Brc1ccc(-c2nc3ccccc3nc2-c2ccccc2)cc1
Reactant: c1ccc(-c2ccc3[nH]c4ccc(-c5ccccc5)cc4c3c2)cc1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1C
Product: c1ccc(-c2ccc3c(c2)c2cc(-c4ccccc4)ccc2n3-c2ccc(-c3nc4ccccc4nc3-c3ccccc3)cc2)cc1
Yield: 81 %

Procedure:
First, into a 200-mL three-neck flask were placed 2.2 g (6.0 mmol) of 2-(4-bromophenyl)-3-phenylquinoxaline, 1.9 g (6.0 mmol) of 3,6-diphenyl-9H-carbazole, and 1.1 g (12.0 mmol) of sodium tert-butoxide. The air in the flask was replaced with nitrogen, and 60 mL of xylene was placed into this flask. The mixture was degassed by stirring under reduced pressure. To this mixture were added 0.2 mL of tri(tert-butyl)phosphine and 71 mg (0.12 mmol) of bis(benzylideneacetone)palladium(0). This mixture was stirred under a nitrogen stream at 140° C. for 6 hours. After the predetermined time had elapsed, water was added to the obtained mixture, and the mixture was separated into an organic layer and an aqueous layer. Organic substances were extracted with toluene from the aqueous layer. The solution of the obtained extract was combined with the organic layer, and the mixture was washed with saturated brine and dried with magnesium sulfate. The obtained mixture was gravity filtered, and the filtrate was concentrated to give an oily substance. This oily substance was purified by silica gel column chromatography (with a developing solvent of toluene), followed by recrystallization from toluene, whereby 3.0 g of a yellow powder of Cz1PQ-III, which is the substance to be produced, was obtained in 81% yield.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:17])[C:7]=2[C:6]([NH:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])=[CH:5][CH:4]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].O.[OH-].[Na+]>N1C=CC=CC=1>[CH3:22][N:21]([CH3:23])[CH2:20][CH2:19][NH:18][C:6]1[C:7]2[C:8](=[O:17])[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[S:15][C:16]=2[C:3]([CH2:2][NH:1][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:4][CH:5]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN(C)CCNc1ccc(CN)c2sc3ccccc3c(=O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: CN(C)CCNc1ccc(CNS(C)(=O)=O)c2sc3ccccc3c(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
4-(Aminomethyl)-1-[[2-(dimethylamino)ethyl]amino]-thioxanthen-9-one (2 g, 6 mmol) in 30 mL of dry pyridine under nitrogen was stirred at room temperature until the solution was complete. The solution was chilled in an ice-bath and 0.52 mL(6.7 mmol) of methanesulfonyl chloride in chilled pyridine was added dropwise and the mixture was stirred for 1 h at room temperature. The reaction mixture was poured into 500 mL of water containing 0.51 g of sodium hydroxide, extracted into chloroform, the organic layer was washed with water (2x) and brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated in vacuo. The residue (2.5 g) was stirred in either, filtered, and dried to afford 2 g of N-[[1-[[2-(dimethylamino)ethyl]amino]-9-oxothioxanthen-4-yl]methyl]methane-sulfonamide, m.p. 126°-127° C. The free base was dissolved in MeOH and treated with methane sulfonic acid (0.48 g) to afford 2.0 g (67%) of the product as the methanesulfonate salt, m.p. 168° C. (dec.).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH:7]2[C:13]3=[CH:14][CH:15]=[CH:16][N:12]3[CH2:11][C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3[O:8]2)[CH2:3][CH2:2]1.[OH:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][CH2:27]Cl)=[CH:24][C:23]=1[O:31][CH3:32].C([O-])(O)=O.[Na+]>C(OCCCC)(=O)C>[OH:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][CH2:27][N:1]2[CH2:2][CH2:3][CH:4]([CH:7]3[C:13]4=[CH:14][CH:15]=[CH:16][N:12]4[CH2:11][C:10]4[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=4[O:8]3)[CH2:5][CH2:6]2)=[CH:24][C:23]=1[O:31][CH3:32]
Reactant: COc1cc(CCCl)ccc1O
Reactant: c1ccc2c(c1)Cn1cccc1C(C1CCNCC1)O2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCOC(C)=O
Product: COc1cc(CCN2CCC(C3Oc4ccccc4Cn4cccc43)CC2)ccc1O

Procedure:
A mixture of 11-(piperidin-4-yl)-5H,11H-pyrrolo[2,1-c][1,4]-benzoxazepine (5.1 g, 0.019 mole), 4-hydroxy-3-methoxyphenethyl chloride (4.25 g, 0.023 mole) and NaHCO3 (11 g) in 110 ml n-butyl acetate was heated at reflux for 18 hours. The reaction mixture was then cooled, filtered and concentrated to an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C:17]3[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=3[S:15][C:10]=2[NH:11][C:12](=[O:14])[N:13]=1.[H-].[Na+].[CH3:24]I.O>CN(C)C=O>[CH3:24][O:14][C:12]1[N:13]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[C:9]2[C:17]3[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=3[S:15][C:10]=2[N:11]=1
Reactant: CI
Reactant: O=c1nc(-c2ccccc2F)c2c3c(sc2[nH]1)CCCC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc(-c2ccccc2F)c2c3c(sc2n1)CCCC3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 16.1 g of 4-(o-fluorophenyl)-1,2,5,6,7,8-hexahydrobenzothieno[2,3-d]pyrimidin-2-one in 322 of dimethylformamide is added 2.88 g of 67% sodium hydride. The mixture is stirred for 1 hour at room temperature, and 22.83 g of methyl iodide in 68 ml of dimethylformamide is added thereto at 10°C. The resulting reaction mixture is stirred for 2 hours at room temperature, then poured into water and extracted with chloroform. The chloroform extracts are washed with water, dried over sodium sulfate, and the solvent is removed under reduced pressure. The residue is chromatographed on silica gel, using chloroform as an eluent. From the first fraction 2-methoxy-4-(o-fluorophenyl)-5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimidine is obtained as crystals having a melting point of 98° - 100°C. From the second fraction, 1-methyl-4-(o-fluorophenyl)-1,2,5,6,7,8-hexahydrobenzothieno[2,3-d]pyrimidin-2-one is obtained as crystals having a melting point of 221° - 222.5°C.
Reaction SMILES: [CH3:1][C:2]1([CH2:21][CH2:22][CH:23]=[C:24]2[S:28][C:27](=[O:29])[NH:26][C:25]2=[O:30])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH3:20])[C:6]([CH3:19])=[C:7]([O:12]C3CCCCO3)[CH:8]=2)[O:3]1.O>CO.Cl>[OH:12][C:7]1[CH:8]=[C:9]2[C:4](=[C:5]([CH3:20])[C:6]=1[CH3:19])[O:3][C:2]([CH2:21][CH2:22][CH:23]=[C:24]1[S:28][C:27](=[O:29])[NH:26][C:25]1=[O:30])([CH3:1])[CH2:11][CH2:10]2
Reactant: Cc1c(OC2CCCCO2)cc2c(c1C)OC(C)(CCC=C1SC(=O)NC1=O)CC2
Agent: Cl
Solvent: O
Solvent: CO
Product: Cc1c(O)cc2c(c1C)OC(C)(CCC=C1SC(=O)NC1=O)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-{3-[2,7,8-trimethyl-6-(tetrahydro-pyran-2-yloxy)-chroman-2-yl]-propylidene}-thiazolidine-2,4-dione from Step 3 (155 mg) in MeOH (10 mL) were added 10 drops of conc. HCl, and the mixture was stirred at RT for 3 h, then poured into water and extracted with EtOAc. The crude product was purified by silica gel column chromatography eluting with 30-40% EtOAc in hexane to give 5-[3-(6-hydroxy-2,7,8-trimethyl-chroman-2-yl)-propylidene]-thiazolidine-2,4-dione. 1H-NMR (300 MHz, CDCl3) δ (ppm): 7.08 (t, J=7.6 MHz, 1H), 6.38 (s, 1H), 2.70 (m, 2H), 2.37 (m, 2H), 2.14, 2.11 (2s, 6H), 2.00-0.180 (m, 4H), 1.25 (s, 3H) ppm. 13C-NMR (75 MHz, CDCl3) δ (ppm): 171.45, 167.17, 165.43, 146.63, 145.06, 139.75, 126.04, 125.86, 122.03, 117.81, 112.20, 74.41, 60.53, 37.52, 31.51, 26.30, 23.74, 22.06, 21.09, 14.18, 12.00, 11.90 ppm. MS (m/z): 348 (M+H+), 370 (M+Na+).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14].C(N(CC)CC)C.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>O1CCCC1>[O:14]=[C:4]1[CH:3]([CH2:2][O:1][C:30](=[O:31])[NH:29][C:26]2[CH:27]=[CH:28][C:23]([Br:22])=[CH:24][CH:25]=2)[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]1=2
Reactant: O=C=Nc1ccc(Br)cc1
Reactant: O=C1c2ccccc2SCCC1CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Br)cc1)OCC1CCSc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-hydroxymethyl-3,4-dihydro-2H-benzo[b]thiepin-5-one (224 mg, 1.08 mmol) in 14 ml of tetrahydrofuran were added, at room temperature, triethylamine (0.16 ml, 1.18 mmol) and 4-bromophenyl isocyanate (0.423 g, 2.15 mmol). The mixture was stirred at room temperature for 2 hours, concentrated and purified by column chromatography on silica gel (eluent: 1:2 tert-butyl methyl ether/cyclohexane). The product was obtained in a yield of 250 mg (57%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].CN([CH:13]=[O:14])C>O>[OH:14][C:13]1[NH:1][C:2]2[C:3]([CH3:9])=[CH:4][CH:5]=[CH:6][C:7]=2[N:8]=1
Reactant: Cc1cccc(N)c1N
Reactant: CN(C)C=O
Solvent: O
Product: Cc1cccc2nc(O)[nH]c12
Temperature: 92.5 °C

Procedure:
2,3-Diaminotoluene (5 g, 41 mmol), 1,1-carbonyldiimidazole (7.3 g, 45 mmol) and 50 ml of anhydrous DMF are successively introduced into a 250 ml two-necked flask under an argon atomosphere, equipped with a magnetic stirrer. After heating the mixture at 90-95° C. for 4 hours, the solvent is distilled off under vacuum and the residue obtained is taken up in water (250 ml) and extracted with ethyl acetate (3×250 ml). The insoluble product formed during the extraction is recovered (4.8 g) and the combined organic phases are washed again with saturated NaCl solution, dried over MgSO4, filtered and concentrated, allowing a further 1.2 g of desired product (6 g, quantitative) to be recovered. 1H NMR (300 MHz, δ ppm) DMSO-d6: 2.27 (s, 3H), 6.72 (m, 2H), 6.82 (m, 1H).
Reaction SMILES: CS(OS(C)(=O)=O)(=O)=O.[CH3:10][O:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]O.C(N(C(C)C)CC)(C)C.[CH3:29][O:30][C:31](=[O:54])[C@H:32]([CH2:41][C:42]1[N:46]=[CH:45][N:44](C(OC(C)(C)C)=O)[CH:43]=1)[NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>ClCCl>[CH3:29][O:30][C:31](=[O:54])[C@H:32]([CH2:41][C:42]1[N:46]([CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[O:11][CH3:10])[CH:45]=[N:44][CH:43]=1)[NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:38])[CH3:39])=[O:35]
Reactant: COC(=O)[C@H](Cc1cn(C(=O)OC(C)(C)C)cn1)NC(=O)OC(C)(C)C
Reactant: COc1ccccc1CO
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1cncn1Cc1ccccc1OC)NC(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
A solution of 8 g methanesulfonic anhydride in 45 mL dichloromethane is chilled to -50° C. and treated dropwise with a solution of 6.2 mL 2-methoxybenzyl alcohol, 8.0 mL diisopropylethylamine and 45 mL dichloromethane. The resulting solution is warmed to 0° C. over 30 min and treated dropwise with 15.0 g N,1-bis-BOC-histidine methyl ester dissolved in 45 mL dichloromethane. The mixture is then heated at reflux 24 hr, poured into 400 mL 0.25M, pH=7 potassium phosphate buffer and the organic layer is separated, dried and evaporated. Chromatography on silica gel, eluting with chloroform-methanol (99:1) gives 3-(2-methoxyphenyl)methyl-N-BOC-histidine methyl ester as a gum. NMR (CDCl3) 4.96 (s,2H,NCH2Ar).
Reaction SMILES: [CH3:1][O:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:9][O:10][CH2:11]CO.S([O-])(O)(=O)=O.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:9][O:10][CH2:11][CH2:1][O:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: COCCO
Reactant: COc1sccc1C
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COCCOc1sccc1C
Yield: 48.6 %

Procedure:
2-methoxy-3-methyl-thiophene, (1.5 g, 11.7 mmol) 2-methoxy-ethanol (3.8 g, 50.5 mmol, 4.3 equiv.) and sodium hydrogen sulfate anhydrous (100 mg, 0.833 mmol, 0.07 equiv.) were stirred in toluene at 120° C. for 3.5 hours. The mixture was diluted with ethyl acetate and extracted with sodium bicarbonate solution. The organic solvent washed with brine, dried over magnesium sulfate dihydrate, filtered and evaporated. After Kugelrohr distillation, 980 mg of the title compound were obtained as a light yellow oil GC-MS (EI) M=172.