Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:18]2[C:19]3[C:6]([CH2:7][C@@H:8]4[C@@H:13]([C:14]=3[CH:15]=[CH:16][CH:17]=2)[CH2:12][CH:11]([C:20]([OH:22])=O)[CH2:10][N:9]4[CH3:23])=[CH:5]1)([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:36][C@@H:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[OH:42].O>CN(C)C=O>[OH:42][CH:38]1[CH2:39][CH2:40][CH2:41][CH:37]1[NH:36][C:20]([C@H:11]1[CH2:12][C@H:13]2[C@H:8]([CH2:7][C:6]3[C:19]4[C:18](=[CH:17][CH:16]=[CH:15][C:14]2=4)[N:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=3)[N:9]([CH3:23])[CH2:10]1)=[O:22]
Reactant: N[C@@H]1CCC[C@H]1O
Reactant: CC(C)n1cc2c3c(cccc31)[C@H]1CC(C(=O)O)CN(C)[C@@H]1C2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1cc2c3c(cccc31)[C@H]1C[C@H](C(=O)NC3CCCC3O)CN(C)[C@H]1C2
Reaction time: 4 h

Procedure:
To a suspension of 6.24 g of 1-isopropyl-6-methylergoline-8-carboxylic acid in 120 ml of dimethylformamide under a nitrogen atmosphere were added 3.2 g of 1,1'-carbonyldiimidazole. After stirring for approximately four hours, a solution of 2.02 g of trans-2-aminocyclopentanol in 40 ml of dimethylformamide was added with stirring. After stirring at room temperature overnight, the mixture was added to water. The resulting precipitate was extracted three times into methylene chloride. The combined organic extracts were washed with a saturated sodium chloride solution, dried over sodium sulfate, and concentrated in vacuo. The resulting solid was purified by preparative high pressure liquid chromatography over silica gel eluting with methylene chloride/methanol/ammonium hydroxide (100:10:1). The appropriate fractions containing the more mobile diastereomer were combined, concentrated to dryness, and crystallized from methanol to provide 1.15 g of the desired title isomer, m.p. 260-263° C. NMR, MS.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:27][NH2:28]>>[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:27][NH:28][C:4]([C:6]1[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5]
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)c1nc(-c2ccccc2OC)n(C)c(=O)c1O
Product: COc1ccccc1-c1nc(C(=O)NCc2ccc(Cl)c(Cl)c2)c(O)c(=O)n1C

Procedure:
Prepared according to the procedure described for example 2 from 5-Hydroxy-2-(2-methoxy-phenyl)-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (45.6 mg, 0.15 mmol) and 3,4-dichlorobenzylamine (132 mg, 0.75 mmol). The title product was obtained as a pink solid (55.5 mg, 85% yield). 1HNMR (500 MHz, CDCl3) δ: 11.98 (1H, s), 7.95 (1H, t, J=5.19 Hz), 7.49 (1H, td, J=7.33, 1.83 Hz),7.40–7.38 (2H, m), 7.29 (1H, dd, J=7.63, 1.83 Hz), 7.15 (1H, dd, J=8.24, 1.83 Hz), 7.07 (1H, t, J=8.24 Hz), 4.51 (2H, d, J=6.41 Hz), 3.82 (3H, s), 3.35 (3H, s). HRMS (ESI) calcd for C20H18Cl2N3O4 (M+H): 434.0675; found: 434.0674.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:23][CH3:24])=[C:6]([CH:12]([OH:22])[CH2:13][NH:14][C:15](=O)[O:16]C(C)(C)C)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2].Cl.C(N(CC)CC)C.[Cl:33][CH2:34]C(Cl)=O>O1CCOCC1.C(Cl)Cl>[C:1]([C:4]1[C:5]([O:23][CH3:24])=[C:6]([CH:12]([OH:22])[CH2:13][NH:14][C:15](=[O:16])[CH2:34][Cl:33])[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1C(O)CNC(=O)OC(C)(C)C
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1c(C(C)=O)cc(Cl)c(C)c1C(O)CNC(=O)CCl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
tert-Butyl [2-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)-2-hydroxyethyl]carbamate (170 mg, 0.47 mmol) (Peak 1 from step 2) was treated with 4.0 M hydrogen chloride in 1,4-dioxane (12 mL) for 15 minutes. The solvents were evaporated, methylene chloride (6 mL) and triethylamine (200 μL, 1.4 mmol) were added and the mixture cooled to 0° C. Chloroacetyl chloride (45 μL, 0.56 mmol) was added slowly and was stirred for 10 minutes at 0° C. The solvents were evaporated to dryness. Water was added and the mixture was extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, and concentrated to give the crude residue as a single enantiomer. LCMS calculated for C14H17Cl2NO4Na (M+Na)+: m/z=356.1; found: 356.1.
Reaction SMILES: ClC1C=C(/C=C/C(N2CCC(=O)NCC2)=O)C=CC=1Cl.[F:21][C:22]1[CH:23]=[C:24]([CH:30]=[CH:31][C:32]=1[F:33])/[CH:25]=[CH:26]/[C:27]([OH:29])=O.Cl.Cl.[N:36]1([CH2:42][CH2:43][CH2:44][N:45]2[C:51](=[O:52])[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[F:21][C:22]1[CH:23]=[C:24](/[CH:25]=[CH:26]/[C:27]([N:48]2[CH2:49][CH2:50][C:51](=[O:52])[N:45]([CH2:44][CH2:43][CH2:42][N:36]3[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]3)[CH2:46][CH2:47]2)=[O:29])[CH:30]=[CH:31][C:32]=1[F:33]
Reactant: O=C(O)/C=C/c1ccc(F)c(F)c1
Reactant: O=C1CCNCCN1CCCN1CCCCC1
Agent: Cl
Agent: O=C1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCN1
Product: O=C(/C=C/c1ccc(F)c(F)c1)N1CCC(=O)N(CCCN2CCCCC2)CC1

Procedure:
In analogy to the procedure described in intermediate 1A, (E)-3,4-difluorocinnamic acid and 4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one-dihydrochloride (intermediate 4B, suspended in CH2Cl2 with 4 equivalent of Et3N) gave after purification on catridges, Si-Amine, 70 ml, 20 g (EtOAc) the title compound as a white powder. MS: 406.2 (MH+).
Reaction SMILES: CC1(C)[N:6](C(OC(C)(C)C)=O)[C@:5]([CH3:20])([C:14]2[O:15][C:16]([CH3:19])=[N:17][N:18]=2)[CH2:4][O:3]1.[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25]>ClCCl>[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25].[NH2:6][C@@:5]([C:14]1[O:15][C:16]([CH3:19])=[N:17][N:18]=1)([CH3:20])[CH2:4][OH:3]
Reactant: Cc1nnc([C@]2(C)COC(C)(C)N2C(=O)OC(C)(C)C)o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nnc([C@@](C)(N)CO)o1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 220 mg of tert-butyl (4S)-2,2,4-trimethyl-4-(5-methyl-1,3,4-oxadiazol-2-yl)-1,3-oxazolidine-3-carboxylate in 3.0 ml of dichloromethane was added 1.5 ml of trifluoroacetic acid, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was azeotropic distilled with methanol to obtain 266 mg of (2S)-2-amino-2-(5-methyl-1,3,4-oxadiazol-2-yl)propan-1-ol trifluoroacetate as a crude product, which was used for the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]3[CH2:18][O:17][CH2:16][C@H:15]([CH3:19])[N:14]3[C:10]=2[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:20])[CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.O>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)(Cl)Cl>[CH3:19][C@@H:15]1[N:14]2[C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[C:7]([O:20][CH2:29][CH2:30][N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)[CH:8]=4)[N:3]=[C:2]([NH2:1])[C:11]=3[N:12]=[C:13]2[CH2:18][O:17][CH2:16]1
Reactant: C[C@H]1COCc2nc3c(N)nc4ccc(O)cc4c3n21
Reactant: ClCCN1CCOCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: C[C@H]1COCc2nc3c(N)nc4ccc(OCCN5CCOCC5)cc4c3n21
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.9 %

Procedure:
A solution of (11S)-6-amino-11-methyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-2-ol (500 mg, 1.85 mmol) dissolved in 15 mL of DMF was treated with cesium carbonate (1.80 g, 5.55 mmol), 4-(2-chloroethyl) morpholine hydrochloride (378 mg, 2.03 mmol), and tetrabutylammonium bromide (715 mg, 2.22 mmol). After stirring overnight at ambient temperature, the light brown mixture was poured into 150 mL of H2O and stirred for 30 minutes. The reaction mixture was extracted with CHCl3 (3×75 mL) and the combined extracts were dried over MgSO4, filtered and concentrated under reduced pressure to give an off-white solid. Chromatography (SiO2, 0-20% CMA/CHCl3) gave an off-white solid which was crystallized from acetonitrile to give 262 mg of the title compound as an off-white solid, mp 186-188° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].C(O[C:13]([S-])=[S:14])C.[K+]>CN(C=O)C>[S:14]=[C:13]1[NH:1][C:2]2[S:3][CH:4]=[CH:5][C:6]=2[C:7](=[O:8])[NH:9]1
Reactant: NC(=O)c1ccsc1N
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1[nH]c(=S)[nH]c2sccc12
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 69.5 %

Procedure:
2-Amino-thiophene-3-carboxlic acid amide (28.4 g, 0.2 mol) and potassium ethylxanthate (96 g, 3 eq) were mixed together and added to DMF (1000 mL). The resulting mixture was heated to 150° C. for about six hours. The solvent (DMF) was removed on the rotovap under high vacuum at 90° C. The residue was diluted with 600 mL of aqueous citric acid (5%) and cooled to 0° C. and stirred for about 30 minutes. The tan powder was filtered and dried overnight to give 25.6g of the title compound ((M+H)+=185, M.P. >300° C.).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:16])[CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[OH:8].Cl[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.O>CN(C)C=O>[CH3:16][N:4]([CH3:3])[CH2:5][CH2:6][CH:7]([O:8][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)[C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=1
Reactant: CN(C)CCC(O)c1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCC(Oc1ccc([N+](=O)[O-])cc1)c1ccc(Cl)cc1
Reaction time: 0.75 h
Yield: 116.1 %

Procedure:
2.85 g of sodium hydride in a 50% oil suspension were added at 20° C. to a solution of 6.32 g of α-[2-dimethylamino-ethyl]-4-chlorobenzene methanol in 60 ml of dimethylformamide and 5.1 g of p-chloronitrobenzene were added thereto under nitrogen. The mixture was stirred for 45 minutes and 100 ml of water were added thereto at 25° C. The mixture was extracted with methylene chloride and the organic phase was washed with water, dried and evaporated to dryness to obtain 11.5 g of N,N-dimethyl-γ-(4-nitrophenoxy)-4-chlorobenzene-propanamine in the form of an orange oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:21]=[C:22]4[C:28]([C:29]([C:31]5([CH3:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]5)=[O:30])=[CH:27][NH:26][C:23]4=[N:24][CH:25]=3)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:37][C:31]1([C:29]([C:28]2[C:22]3[C:23](=[N:24][CH:25]=[C:20]([C:16]4[CH:17]=[CH:18][CH:19]=[C:14]([N:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)[CH:15]=4)[N:21]=3)[NH:26][CH:27]=2)=[O:30])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3cnc4[nH]cc(C(=O)C5(C)CCCCC5)c4n3)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C(=O)c2c[nH]c3ncc(-c4cccc(N5CCNCC5)c4)nc23)CCCCC1
Reaction time: 16 h
Yield: 61.5 %

Procedure:
A solution of 4-{3-[7-(1-methyl-cyclohexanecarbonyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (134 mg, 0.266 mmol) in DCM (10 ml) was treated with TFA (1.0 ml, 13.4 mmol) and allowed to stir for 16 hours. The reaction mixture was concentrated to dryness, and the resulting residue was partitioned between sat. NaHCO3 and EtOAc. The organic layers were collected, dried over MgSO4, filtered, and concentrated giving a yellow solid. The yellow solid was filtered through a Buchner funnel and washed with 1:2 Et2O/Hex to provide 66 mg (61%) of (1-methyl-cyclohexyl)-[2-(3-piperazin-1-yl-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone as a pale yellow solid. M+H=404.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=O)[CH2:20][CH2:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CN(C=O)C.C(Cl)(=O)C([Cl:35])=O>C(Cl)Cl>[Cl:35][C:24]([CH:21]1[CH2:22][CH2:23][N:18]([C:16]([O:15][CH2:14][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[O:17])[CH2:19][CH2:20]1)=[O:26]
Reactant: O=C(O)C1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 95.2 %

Procedure:
To a stirred solution of piperidine-1,4-dicarboxylic acid mono-(9H-fluoren-9-ylmethyl) ester (5 g, 14.2 mmol) in CH2Cl2 (50 mL) was added DMF (0.5 mL) and the resulting solution was cooled to 0° C. To this solution oxalyl chloride (3.6 g, 28.44 mmol) was added dropwise and the reaction mixture was stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure to afford (9H-fluoren-9-yl)methyl 4-(chlorocarbonyl)-piperidine-1-carboxylate (5 g, 95%) as brown liquid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:12])[CH:3]=1.[K+].[CH:14]([B-](F)(F)F)=[CH2:15]>>[Cl:12][C:4]1[CH:3]=[C:2]([CH:14]=[CH2:15])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(Br)cc1Cl
Reactant: C=C[B-](F)(F)F
Agent: [K+]
Product: C=Cc1ccc(C(=O)OC)c(Cl)c1

Procedure:
The title compound was prepared from methyl 4-bromo-2-chlorobenzoate and vinyltrifluoroborate potassium salt according to the procedure for the preparation of Example 135, part A. 1H NMR (400 MHz, CDCl3): δ 3.92 (3H, s), 5.41 (1H, d, J=11.2 Hz), 5.85 (1H, d, J=9.2 Hz), 6.66 (1H, dd, J=11.2 Hz, 17.6 Hz), 7.32 (1H, d, J=8.0 Hz), 7.47 (1H, s), 7.81 (1H, d, J=8.0 Hz).
Reaction SMILES: [CH2:1]([NH:4][C:5]([CH2:7][P:8](=[O:12])([O-:11])[O:9]C)=[O:6])[CH2:2][CH3:3].Br>C(O)(=O)C>[CH2:1]([NH:4][C:5]([CH2:7][P:8](=[O:9])([OH:12])[OH:11])=[O:6])[CH2:2][CH3:3]
Reactant: CCCNC(=O)CP(=O)([O-])OC
Agent: Br
Solvent: CC(=O)O
Product: CCCNC(=O)CP(=O)(O)O
Reaction time: 8 h

Procedure:
1 g. of Monomethyl propylcarbamoylmethylphosphonate was suspended in 10 ml. of hydrogen bromide in glacial acetic acid. The solution was allowed to stand overnight at room temperature. The solution was then concentrated to a viscous oil under reduced pressure. Upon the addition of methanol, the compound crystallized; m.p. 155°-160° C.; yield, 47%.
Reaction SMILES: [CH2:1]([N:5]([CH2:19][CH2:20][CH2:21][CH3:22])[C:6]([NH:8][C:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)=[S:7])[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl[CH2:26]C(O)=O>O>[CH2:1]([N:5]([CH2:19][CH2:20][CH2:21][CH3:22])[C:6]1[S:7][CH:26]=[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[N:8]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)CCl
Reactant: CCCCN(CCCC)C(=S)NC(=O)c1cccc(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCN(CCCC)c1nc(-c2cccc(OC)c2)cs1

Procedure:
A mixture of 114.95 g (356.5 mmol) of N,N-di-n-butyl-N′-(3-methoxybenzoyl)thiourea (compound 1-24), 31.37 g (784.2 mmol) of sodium hydroxide, and 350 ml of water was prepared, to which was added 40.42 g (427.8 mmol) of chloroacetic acid. The mixture was stirred and heated on a steam bath for 23 hrs, then cooled. The mixture was extracted with methylene chloride, and the extracts were washed with water, dried over magnesium sulfate, and concentrated. The oily residue began to crystallize on standing. The yield of thiazole was 100.8 g and was used without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[O:9][CH2:8][N:7]([C:10]([CH3:19])([CH3:18])[C:11]([O:13]C(C)(C)C)=[O:12])[C:6](=[O:20])[C:5]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][CH2:3][C:4]1[O:9][CH2:8][N:7]([C:10]([CH3:19])([CH3:18])[C:11]([OH:13])=[O:12])[C:6](=[O:20])[C:5]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COCC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)OC(C)(C)C)CO1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)O)CO1
Yield: 79.2 %

Procedure:
A mixture of tert butyl 2-(2,3-dihydro-6-methoxymethyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanoate (2.6 g) and trifluoroacetic acid (2.05 g) was stirred in dichloromethane for 20 hours at 35° C. A further addition of trifluoroacetic acid (0.82 g) was made and the solution heated under reflux for 24 hours. The cooled mixture was diluted (dichloromethane) and extracted (sodium carbonate solution). The aqueous extract was acidified (2 M hydrochloric acid solution), extracted (ethyl acetate), dried (magnesium sulphate) and evaporated. The residue was dissolved in ethyl acetate and evaporated (three times) redissolved in hexane and evaporated to give 2-(2,3-dihydro-6-methoxymethyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanoic acid (1.74 g) as a white solid, m.p. 135-138° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](Cl)=[O:7])(=[O:3])[CH3:2].[C:9]1([N:15]2[C:19]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=3)=[CH:18][C:17]([CH2:30][CH2:31][NH2:32])=[C:16]2[CH3:33])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>C(Cl)Cl>[C:1]([O:4][CH2:5][C:6]([NH:32][CH2:31][CH2:30][C:17]1[CH:18]=[C:19]([C:20]2[CH:21]=[CH:22][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][CH:25]=2)[N:15]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:16]=1[CH3:33])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1c(CCN)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccccc1
Solvent: O
Solvent: ClCCl
Product: CC(=O)OCC(=O)NCCc1cc(-c2ccc(S(C)(=O)=O)cc2)n(-c2ccccc2)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
TEA (0.29 g, 0.296 mmol) and acetoxyacetyl chloride (0.323 g, 0.00237 mol) are added, at 0° C., to a solution of 2-[1-phenyl-2-methyl-5-(4-methylsulphonylphenyl)-1H-pyrrol-3-yl]-ethanamine (W2008014821), (0.7 g, 0.00197 mol), in CH2Cl2 (10 mL). It is stirred at RT for 2 h. Then it is poured into water and extracted with CH2Cl2, washed with NaHCO3 s.s., and then with H2O, dried and concentrated. The solid obtained (0.85 g, 95.5%) is used as it is for the next step.
Reaction SMILES: [Cl:1][C:2]1([Cl:22])[CH2:4][C:3]1([CH2:6][S:7][C:8]1[CH:21]=[CH:20][C:11]2[NH:12][C:13]([NH:15][C:16](=[O:19])[O:17][CH3:18])=[N:14][C:10]=2[CH:9]=1)[CH3:5].ClC1C=C(C=CC=1)C(OO)=[O:28]>C(Cl)(Cl)Cl.C(O)(=O)C>[Cl:22][C:2]1([Cl:1])[CH2:4][C:3]1([CH2:6][S:7]([C:8]1[CH:21]=[CH:20][C:11]2[NH:12][C:13]([NH:15][C:16](=[O:19])[O:17][CH3:18])=[N:14][C:10]=2[CH:9]=1)=[O:28])[CH3:5]
Reactant: COC(=O)Nc1nc2cc(SCC3(C)CC3(Cl)Cl)ccc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2cc(S(=O)CC3(C)CC3(Cl)Cl)ccc2[nH]1
Temperature: 25 °C
Yield: 45.2 %

Procedure:
To a solution of 7.2 g (0.2 mole) of [5-[[(2,2-dichloro-1-methylcyclopropyl)methyl]thio]-1H-benzimidazol-2-yl]carbamic acid, methyl ester in 120 ml of CHCl3 and 120 ml of acetic acid at -15° C there is added 4.2 g (0.02 mole) of 85% m-chloroperoxybenzoic acid and 40 ml of CHCl3 and with stirring is allowed to warm to room temperature. The mixture is stirred for an additional 2 hours. The CHCl3 is removed in vacuo and the remaining solution is neutralized with aqueous NaHCO3. The resulting solid is filtered off, dried, and crystallized from acetonitrile to yield 3.4 g of the title compound, m.p. 231-233° C.
Reaction SMILES: C1(C(C2C=CC=CC=2)=[N:8][C:9]2[CH:29]=[CH:28][C:12]3[C:13]4([CH2:26][CH3:27])[CH2:25][CH2:24][C:19]5([O:23][CH2:22][CH2:21][O:20]5)[CH2:18][CH:14]4[CH2:15][CH2:16][CH2:17][C:11]=3[CH:10]=2)C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO>[CH2:26]([C:13]12[CH2:25][CH2:24][C:19]3([O:20][CH2:21][CH2:22][O:23]3)[CH2:18][CH:14]1[CH2:15][CH2:16][CH2:17][C:11]1[CH:10]=[C:9]([NH2:8])[CH:29]=[CH:28][C:12]=12)[CH3:27]
Reactant: CCC12CCC3(CC1CCCc1cc(N=C(c4ccccc4)c4ccccc4)ccc12)OCCO3
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCC12CCC3(CC1CCCc1cc(N)ccc12)OCCO3
Temperature: 65 °C
Yield: 96.9 %

Procedure:
A flask with stir bar, condenser and nitrogen line was charged with rac-(4aR,11bS)—N-(diphenylmethylene)-11b-ethyl-1,2,4,4a,5,6,7,11b-octahydrospiro[dibenzo[a,c][7]annulene-3,2′-[1,3]dioxolan]-9-amine (21, R2=Ethyl) (0.550 g, 1.181 mmol), 10% Pd on carbon (0.094 g, 0.089 mmol) and MeOH (25 mL). Ammonium formate (1.12 g, 17.7 mmol) was added and the mixture was heated to about 65° C. After about 15 min the mixture was cooled to rt and filtered through a pad of Celite®. The pad was washed with MeOH (15 mL) then the filtrate was concentrated under reduced pressure. The residue was partitioned between EtOAc (20 mL), water (5 mL) and sat. aq. NaHCO3 (15 mL). The layers were separated and the aqueous layer was extracted with EtOAc (15 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to yield rac-(4aR,11bS)-11b-ethyl-1,2,4,4a,5,6,7,11b-octahydrospiro[dibenzo[a,c][7]annulene-3,2′-[1,3]dioxolan]-9-amine (22, R2=Ethyl) (0.345 g, 97%); LC/MS, method 3, Rt=2.50 min, MS m/z 302 (M+H)+. 1H NMR (400 MHz, DMSO) δ 6.83 (d, J=8.3 Hz, 1H), 6.36-6.28 (m, 2H), 4.75 (bs, 2H), 3.87-3.72 (m, 4H), 2.82-2.75 (m, 1H), 2.57-2.45 (m, 1H), 2.30-2.26 (m, 1H), 2.14-2.05 (m, 1H), 2.00-1.89 (m, 2H), 1.72-1.15 (m, 9H), 0.58 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[C:3](=[O:34])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[O:18][C:19]3[CH:25]=[CH:24][C:23]([C:26]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:27])=[CH:22][C:20]=3[CH:21]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:33].[BH4-].[Na+]>C1COCC1>[CH2:13]([C:12]([C:17]1[O:18][C:19]2[CH:25]=[CH:24][C:23]([C:26]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:27])=[CH:22][C:20]=2[CH:21]=1)([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]([OH:34])[C:2]([CH3:35])([CH3:36])[CH3:1])=[C:7]([CH3:33])[CH:8]=1)[CH2:15][CH3:16])[CH3:14]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2cc(C(=O)NCC(=O)O)ccc2o1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc2cc(C(=O)NCC(=O)O)ccc2o1
Reaction time: 4 h
Yield: 87.4 %

Procedure:
A solution of [(2-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethylpropyl}-benzofuran-5-carbonyl)-amino]-acetic acid (74 mg, 0.150 mmol) in THF (5.0 mL) at RT is treated with NaBH4 (11 mg, 0.300 mmol). The resulting mixture is stirred for 4 hour. The reaction is quenched with HCl (1.0 N, 1.0 mL) and extracted with EtOAc (2×20 mL). The organic layer is dried over Na2SO4, concentrated to afford the title compound (65 mg, 88%).
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[C:34]([C:37]1[C:38]2[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=2[S:40][CH:41]=1)(=[O:36])[CH3:35].O>O1CCCC1>[Br:1][CH2:35][C:34]([C:37]1[C:38]2[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=2[S:40][CH:41]=1)=[O:36]
Reactant: [Br-]
Reactant: CC(=O)c1csc2ccccc12
Agent: C[N+](C)(C)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(CBr)c1csc2ccccc12
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 63.5 %

Procedure:
A solution of phenyltrimethylammonium tribromide (9.6 g) in tetrahydrofuran (20 ml) was added dropwise over 15 minutes at ambient temperature to a stirred solution of 3-acetylbenzo[b]thiophen (5 g) in tetrahydrofuran (50 ml), then the mixture was stirred at ambient temperature for 35 minutes. Water (100 ml) was added, and the resulting solid was collected by filtration, washed with water (2×50 ml) and dried in vacuo at ambient temperature to give 3-(2-bromoacetyl)benzo[b]thiophen as a white solid (2.4 g).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:18][CH2:19][CH:20]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:22][C:23]1[CH:24]=[C:25]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:26]=[CH:27][C:28]=1[Cl:29].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[Cl:22][C:23]1[CH:24]=[C:25]([N:30]2[CH2:35][CH2:34][N:33]([CH2:20][CH2:19][CH2:18][C:9]3[CH:10]=[C:11]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH2:32][CH2:31]2)[CH:26]=[CH:27][C:28]=1[Cl:29]
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: O=CCCc1cc(-c2ccccc2)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccc(N2CCN(CCCc3cc(-c4ccccc4)n(-c4ccccc4)n3)CC2)cc1Cl

Procedure:
110 mg (72%) of target compound was obtained by using a method same as in Example 1 by using 3-(1,5-diphenyl-1H-pyrazol-3-yl)propanal (80 mg, 0.289 mmol), 1-(3,4-dichlorophenyl)piperazine (67 mg, 0.289 mmol), DIPEA (0.076 mL, 0.434 mmol) and NaBH(OAc)3 (184 mg, 0.868 mmol).