Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=O)[CH:2]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[NH2:44][CH2:45][CH:46]([OH:58])[CH2:47][N:48]1[CH2:57][CH2:56][C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH2:49]1>C(Cl)Cl>[CH2:49]1[C:50]2[C:55](=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:56][CH2:57][N:48]1[CH2:47][CH:46]([OH:58])[CH2:45][NH:44][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][CH:15]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:8]=1
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: O=C(O)c1cccc(-c2cccnc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1cccc(-c2cccnc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.9 %

Procedure:
To a solution of 3-(pyridin-3-yl)benzoic acid (150 mg, 0.75 mmol) in DCM (6 mL) was added EDCI (215 mg, 1.10 mmol), HOBt (148 mg, 1.10 mmol), Et3N (228 mg, 2.25 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (185 mg, 0.90 mmol). The mixture was stirred at room temperature for 16 h. The reaction solution was then washed with water and extracted with DCM. The organic layer was concentrated, dried and the residue purified by prep-HPLC to give the desired title product (110 mg, Yield 34%). 1H NMR (400 MHz, MeOD) δ 8.80 (d, J=2.0 Hz, 1H), 8.52 (dd, J1=4.8 Hz, J2=3.6 Hz, 1H), 8.10 (s, 1H), 8.09 (dd, J1=8.8 Hz, J2=1.6 Hz, 1H), 7.83 (d, J=7.6 Hz, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.51-7.46 (m, 2H), 7.06-6.95 (m, 4H), 4.15-4.10 (m, 1H), 3.69 (s, 2H), 3.60-3.47 (m, 2H), 2.85-2.79 (m, 4H), 2.69-2.59 (m, 2H). LCMS (m/z): 388.2 (M+1).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C([O:16][C:17]1[CH:18]=[C:19](/[CH:25]=[CH:26]/[C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=2)=[O:28])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24])(=O)C.[CH3:37][C:38]1[O:42][C:41]([CH2:43]O)=[CH:40][CH:39]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(Cl)Cl>[OH:16][C:17]1[CH:18]=[C:19](/[CH:25]=[CH:26]/[C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH2:43][C:41]3[O:42][C:38]([CH3:37])=[CH:39][CH:40]=3)[CH:31]=2)=[O:28])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: Cc1ccc(CO)o1
Reactant: COc1ccc(/C=C/C(=O)Nc2cccc(O)c2)cc1OC(C)=O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(/C=C/C(=O)Nc2cccc(OCc3ccc(C)o3)c2)cc1O
Reaction time: 16 h
Yield: 1.7 %

Procedure:
Diethylazodicarboxylate (1.13 mL 5.83 mmol) was added dropwise to a solution of (E)-3-(3-acetoxy-4-methoxy-phenyl)-N-(3-hydroxy-phenyl)-acrylamide (0.763 g, 2.33 mmol), (5-methyl-furan-2-yl)-methanol (0.392 g, 3.5 mmol) and triphenylphosphine (1.53 g, 5.83 mmol) in dry THF (20 mL) at 0° C. The resulting solution was allowed to reach RT and stirred for 16 hrs. The reaction mixture was then diluted with DCM and washed with water, aqueous hydrochloric acid, and brine. The organic layer was then dried over sodium sulphate and evapored. The resulting raw material was taken up, without further purification, with a 3N methanolic solution of hydrochloric acid (5 mL-15 mmols) and stirred at RT for 16 hrs, concentrated under reduced pressure, taken up with solvent an re-evaporated (3 times with MeOH and once with acetone) to give a residue that was purified by silica gel column chromatography (eluant DCM/MeOH 98/2) to obtain 15 mg of the title (E)-3-(3-hydroxy-4-methoxy-phenyl)-N-[3-(5-methyl-furan-2-ylmethoxy)-phenyl]-acrylamide.
Reaction SMILES: [NH2:1][C@@H:2]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[C:15]([F:23])[CH:14]=1)[CH2:3][N:4]([CH3:12])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C(Cl)Cl.C1N=CN([C:32](N2C=NC=C2)=[O:33])C=1.[N:39]1[C:44]2[CH2:45][NH:46][CH2:47][CH2:48][C:43]=2[CH:42]=[N:41][C:40]=1[NH:49][C@@H:50]([CH3:53])[CH2:51][OH:52]>O>[F:23][C:15]1[CH:14]=[C:13]([C@H:2]([NH:1][C:32]([N:46]2[CH2:47][CH2:48][C:43]3[CH:42]=[N:41][C:40]([NH:49][C@@H:50]([CH3:53])[CH2:51][OH:52])=[N:39][C:44]=3[CH2:45]2)=[O:33])[CH2:3][N:4]([CH3:12])[C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:9])[CH3:10])[CH:18]=[CH:17][C:16]=1[C:19]([F:20])([F:21])[F:22]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C[C@@H](CO)Nc1ncc2c(n1)CNCC2
Reactant: CN(C[C@@H](N)c1ccc(C(F)(F)F)c(F)c1)C(=O)OC(C)(C)C
Solvent: O
Solvent: ClCCl
Product: C[C@@H](CO)Nc1ncc2c(n1)CN(C(=O)N[C@H](CN(C)C(=O)OC(C)(C)C)c1ccc(C(F)(F)F)c(F)c1)CC2
Reaction time: 0.5 h
Yield: 26.8 %

Procedure:
To a solution of (S)-tert-butyl 2-amino-2-(3-fluoro-4-(trifluoromethyl)phenyl)ethyl(methyl)carbamate (0.220 g, 0.654 mmol) and DCM (5 mL) was cooled to 0° C. was added sequentially TEA (0.365 mL, 2.62 mmol) and CDI (0.106 g, 0.654 mmol). The reaction was stirred for 30 min then added to a solution of 138 (0.160 g, 0.654 mmol), TEA (0.365 mL, 2.62 mmol) and DCM (5 mL) at RT and the resulting solution was stirred at RT for 18 h. The solution was poured into water, and extracted with DCM. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with a DCM/MeOH gradient (500:10 to 500:20) to afford 0.100 g (26.8%) of tert-butyl (S)-2-(3-fluoro-4-(trifluoromethyl)phenyl)-2-(2-((S)-1-hydroxypropan-2-ylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carboxamido)ethyl(methyl)carbamate (318).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12](C(OCCCC)=O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.IC1C=C(C=CC=1)[C:28]([O:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:29]>>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([C:28]([O:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:29])[CH:14]=2)=[CH:7][CH:8]=1
Reactant: CCCCOC(=O)c1cccc(I)c1
Reactant: CCCCOC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Product: CCCCOC(=O)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Yield: 40 %

Procedure:
This compound was prepared by the procedure for butyl 4′-(trifluoromethyl)biphenyl-4-carboxylate (CS-16), except using butyl 3-iodobenzoate instead of butyl 4-iodobenzoate. The product was purified by column chromatography followed by vacuum distillation, collecting fraction bp 127-131° C./0.12 mm. The product was a colorless oil, and obtained in 40% yield. 1H NMR (CDCl3): δ 0.99 (t, 3H), 1.5 (m, 2H), 1.8 (m, 2H), 4.37 (t, 2H), 7.54 (d, 2H), 7.72 (s, 4H), 7.77 (d, 2H), 8.09 (d, 2H), 8.28 (s, 2H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][O:7][C@@H:6]1Br)(=[O:3])[CH3:2].[N-:20]=[N+:21]=[N-:22].[Na+].O>C(#N)C>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][O:7][C@H:6]1[N:20]=[N+:21]=[N-:22])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CO[C@@H]1Br
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CO[C@H]1N=[N+]=[N-]
Temperature: 60 °C
Reaction time: 4 h
Yield: 51 %

Procedure:
In acetonitrile was dissolved 3 g of 2,3,4-tri-O-acetyl-α-D-xylopyranosyl bromide, and 2.88 g of dry sodium azide was added to the solution. The mixture was stirred at 60° C. for 4 hours. Water was added to the reaction and the mixture was extracted with chloroform. The chloroform layer was washed with water, dehydrated and subjected to silica gel column chromatography with a solvent system of chloroform-acetone (100:1) to obtain 1.36 g of 2,3,4-tri-O-acetyl-1-azido-1-deoxy-β-D-xylopyranose.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23](I)[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[Mg+].[Br-].[CH3:30][C:31]1[S:32][C:33]([CH3:38])=[CH:34][C:35]=1[CH:36]=[O:37]>C(Cl)Cl>[CH3:30][C:31]1[S:32][C:33]([CH3:38])=[CH:34][C:35]=1[CH:36]([C:23]1[N:22]=[CH:21][N:20]([C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:24]=1)[OH:37]
Reactant: Cc1cc(C=O)c(C)s1
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC[Mg+]
Agent: [Br-]
Solvent: ClCCl
Product: Cc1cc(C(O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c(C)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-trityl-4-iodo-imidazole (11.8 g, 27 mmol) in dry CH2Cl2 (200 mL) was added EtMgBr (11.0 mL, 3.0M in Et2O). After complete halogen-metal exchange this solution was cannulated into a solution of 2,5-dimethylthiophene-3-carboxaldehyde (3.5 g, 25 mmol) in 50 mL of CH2Cl2. The reaction mixture was stirred at room temperature for 1 hr and then quenched with aqueous NH4Cl. The mixture was transferred to a separatory funnel and the aqueous layer was extracted with a second portion of CH2Cl2. The combined extracts were dried (MgSO4) and filtered. The solvent was evaporated in vacuo to give a thick syrup which was triturated with Et2O to give a solid which was recrystallized from acetone to give (2,5-dimethylthien-3-yl)-1-trityl-imidazol-4-yl-methanol, A5. 1H NMR (CDCl3) supported the assigned structure. ##STR46##
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:31]=[CH:30][C:16]([CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26][CH3:27])=[O:25])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH:32]1([CH:35]=O)[CH2:34][CH2:33]1>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH2:35][CH:32]3[CH2:34][CH2:33]3)[C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26][CH3:27])=[O:25])=[CH:30][CH:31]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc(F)c(C(=O)OC)c3)cc2)cc1
Reactant: O=CC1CC1
Product: CCCCc1ccc(C#Cc2ccc(CN(CC3CC3)c3ccc(F)c(C(=O)OC)c3)cc2)cc1
Yield: 54.6 %

Procedure:
The title compound was prepared following procedure described in example 23, step b) from methyl 5-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2-fluorobenzoate (326 mg; 0.78 mmol) and cyclopropanecarboxaldehyde (Aldrich, 87.94 μl; 1.18 mmol). Purification of the crude by preparative HPLC using a X-Terra column gave 200 mg (54%) of the title compound as a beige oil. HPLC, Rt: 5.91 min (purity: 99.7%), LC/MS, M+(ESI): 470.4, 1H NMR (CDCl3) δ: 7.66 (m, 1H), 7.39 (d, J=7.9 Hz, 4H), 7.00-7.17 (m, 6H), 4.62 (s, 2H), 3.93 (s, 3H), 3.44 (m, 3H), 2.59 (t, J=7.7 Hz, 2H), 1.57 (m, 2H), 1.31 (m, 2H), 0.90 (t, J=7.2 Hz, 3H), 0.53 (d, J=7.2 Hz, 2H), 0.24 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][C:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:6]O.C(N(CC)CC)C.CS(Cl)(=O)=O.[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36]>C(Cl)Cl.CCOCC>[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36].[C:8]1([C:5]2([CH2:4][CH2:3][N:2]([CH3:21])[CH3:1])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:6]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CN(C)CCC(CO)(c1ccccc1)c1ccccc1O
Agent: CS(=O)(=O)Cl
Agent: O=C(O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CN(C)CCC1(c2ccccc2)COc2ccccc21
Reaction time: 3 h
Yield: 63 %

Procedure:
To a solution of 14.8 g (52 mmole) 4-dimethylamino-2-(2-hydroxyphenyl)-2-phenylbutanol in 300 ml CH2Cl2 and 21.5 ml (156 mmole) triethylamine which had been cooled in an ice bath for 20 minutes was added a solution of 6 ml (78 mmole) methanesulfonyl chloride in 50 ml CH2Cl2. After the mixture was stirred 3 hours at ice bath temperature, it was diluted with 800 ml CH2Cl2, washed with 10% NaOH solution (2×125 ml) and saturated NaCl solution (125 ml), and dried over MgSO4. Filtration and evaporation gave 14.0 g of a crude oil. A solution of 5 g of this material in 15 ml CH2Cl2 was added to excess oxalic acid in Et2O. The precipitated solid was recrystallized from ethanol to give 4.2 g (63%) of crystals, m.p. 158°-160°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH2:19][CH2:18][O:17][C:16]=3[CH:21]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.Cl[C:39]([O:41][C:42]1[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=1)=[O:40]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[N:20]([C:39]([O:41][C:42]4[CH:43]=[CH:44][C:45]([N+:48]([O-:50])=[O:49])=[CH:46][CH:47]=4)=[O:40])[CH2:19][CH2:18][O:17][C:16]=3[CH:21]=2)(=[O:11])=[O:10])=[CH:27][CH:28]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3)cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (INTERMEDIATE M, 0.200 g, 0.479 mmol) and Hunig's base (0.092 ml, 0.527 mmol) in DCM (2.395 ml) was added 4-nitrophenyl chloroformate (0.097 g, 0.479 mmol) (change from colorless to light yellow solution). The reaction was stirred at RT overnight, at which point starting material remained. Additional 4-nitrophenyl chloroformate (0.097 g, 0.479 mmol) was added and the reaction was stirred overnight once more until completion. After concentration in vacuo, the material was purified via MPLC (12-g Redi Sep Gold) eluting with 0-100% ethyl acetate in heptanes, to yield 4-nitrophenyl 7-(N-(4-methoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate as a white solid. m/z (ESI) 583.0 (M+H)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]#[C:34][C:35]([CH3:38])([OH:37])[CH3:36])=[N:31][CH:32]=2)=[CH:23][CH:22]=1.[N:39]1([CH2:44][C:45]2[CH:50]=[CH:49][C:48](O)=[CH:47][CH:46]=2)[CH2:43][CH2:42][CH2:41][CH2:40]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]#[C:34][C:35]([CH3:38])([O:37][C:48]3[CH:47]=[CH:46][C:45]([CH2:44][N:39]4[CH2:43][CH2:42][CH2:41][CH2:40]4)=[CH:50][CH:49]=3)[CH3:36])=[N:31][CH:32]=2)=[CH:23][CH:22]=1
Reactant: Oc1ccc(CN2CCCC2)cc1
Reactant: CC(C)(O)C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C#Cc1ccc(-c2ccc(Cl)cc2)cn1)Oc1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
131 mg (0.5 mmol) triphenylphosphane are added to a solution of 136 mg (0.5 mmol) 4-[5-(4-chloro-phenyl)-pyridin-2-yl]-2-methyl-but-3-yn-2-ol and 88 mg (0.5 mmol) 4-pyrrolidin-1-ylmethyl-phenol in 20 ml THF. Then 0.1 mL (0.5 mmol) diisopropyl azo-dicarboxylate is slowly added dropwise and the reaction mixture is stirred for 24 h at RT. The mixture is evaporated down i.vac., the residue is taken up in water, extracted exhaustively with EtOAc, the organic phase is washed with saturated NaCl solution and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by HPLC.
Reaction SMILES: [CH:1]1[N:2]=[CH:3][N:4]2[C:10]3[CH:11]=[CH:12][S:13][C:9]=3[C:8](=[O:14])[N:7]3[CH2:15][CH2:16][CH2:17][C@H:6]3[C:5]=12.[Cl:18]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:18][C:1]1[N:2]=[CH:3][N:4]2[C:10]3[CH:11]=[CH:12][S:13][C:9]=3[C:8](=[O:14])[N:7]3[CH2:15][CH2:16][CH2:17][C@H:6]3[C:5]=12
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C1c2sccc2-n2cncc2[C@@H]2CCCN12
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2sccc2-n2cnc(Cl)c2[C@@H]2CCCN12

Procedure:
3.0 (12.2 mmol) of (S)-10,11,12,12a-tetrahydro-8H-imidazo[5,1-c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepin-8-one in 20 ml of dimethylformamide are stirred at 65° for 40 minutes with 1.63 g (12.2 mmol) of N-chlorosuccinimide. The solution is poured into water and extracted with chloroform. The organic phase is washed several times with water, dried over magnesium sulphate and evaporated. By column chromatography on silica gel there is obtained (S)-1-chloro-10,11,12,12a-tetrahydro-8H-imidazo[5,1-c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepin-8 one of melting point 180°-183°.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([C@H:12]1[CH2:16][O:15][C:14]2([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[O:13]1)[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1([Mg]Cl)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+]>C(OCC)C.O1CCCC1>[CH2:1]([O:8][C@@H:9]([C@H:12]1[CH2:16][O:15][C:14]2([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[O:13]1)[CH:10]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[OH:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C[C@@H](OCc1ccccc1)[C@H]1COC2(CCCCC2)O1
Reactant: Cl[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC(c1ccccc1)[C@@H](OCc1ccccc1)[C@H]1COC2(CCCCC2)O1
Temperature: -5 °C
Reaction time: 2 h

Procedure:
A solution of 4.30 g (0.015 mmol) of α(S)-benzyloxy-1,4-dioxaspiro[4,5]decane-2(R)-acetaldehyde in 50 ml of anhydrous diethyl ether was cooled to -8° C. and 15 ml of a 2M solution of phenylmagnesium chloride in tetrahydrofuran were added dropwise over a period of 1 hour. The mixture was stirred at -5° C. for 2 hours, then allowed to warm to room temperature and poured into 50 ml of 10% ammonium chloride solution. The mixture was extracted twice with 100 ml of ethyl acetate each time. The ethyl acetate extracts were dried over anhydrous magnesium sulphate and evaporated. The residue was subjected to flash chromatography on silica gel using 5% methanol in dichloromethane for the elution. There were obtained 2.47 g of β(R)-benzyloxy-α(RS)-phenyl-1,4-dioxaspiro[4,5]decane-2(R)-ethanol in the form of a colourless gum; MS (C.I.): m/e 369 [M+H]+.
Reaction SMILES: Cl.[C:2]1([C:8]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@@H:16]3[C@@H:12]([CH2:13][NH:14][CH2:15]3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])([OH:17])[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH2:40][C:41](O)=[O:42])[CH:37]=[CH:38][CH:39]=1>>[C:26]1([C:8]2([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@@H:16]3[C@@H:12]([CH2:13][N:14]([C:41](=[O:42])[CH2:40][C:36]4[CH:37]=[CH:38][CH:39]=[C:34]([O:33][CH3:32])[CH:35]=4)[CH2:15]3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])([OH:17])[CH2:10][CH2:9]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CNC[C@H]21
Reactant: COc1cccc(CC(=O)O)c1
Agent: Cl
Product: COc1cccc(CC(=O)N2C[C@@H]3[C@H](C2)C(c2ccccc2)(c2ccccc2)CC[C@@]3(O)c2ccccc2OC)c1
Yield: 58.5 %

Procedure:
By working in accordance with Example 4, starting from 0.75 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)perhydroisoindol-4-ol hydrochloride and 0.28 g of (3-methoxyphenyl)acetic acid, 0.54 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(3-methoxyphenyl)acetyl]perhydroisoindol-4-ol is obtained in the form of white crystals which melt at 185° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:14][CH3:15].C([Li])CCC.C([O:23][CH2:24]C)C.[OH2:26]>O1CCCC1>[CH3:15][O:14][C:3]1[CH:4]=[C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:6]=[CH:7][C:2]=1[C:24]([OH:23])=[O:26]
Reactant: O
Reactant: COc1cc(N2CCOCC2)ccc1Br
Reactant: CCOCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(N2CCOCC2)ccc1C(=O)O
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 66 %

Procedure:
To a stirred solution of 4-bromo-3-methoxy-1-morpholinobenzene (104 mg, 0.382 mmol) in anhydrous tetrahydrofuran (3 mL) at −78° C. was slowly added n-butyl lithium (1.3 M solution in hexanes, 325 μL, 0.420 mmol) under nitrogen. The cooling medium was exchanged with an ice-bath, and the mixture was stirred for 5 min. After cooling again to −78° C., carbon dioxide from evaporation of dry ice was bubbled through the solution for 10 min. A precipitate was formed, and the reaction mixture was allowed to reach room temperature. Diethyl ether and water were added. The mixture was extracted, the layers were separated, and the aqueous layer was acidified to pH 4. The dark blue aqueous solution was extracted several times with diethyl ether and ethyl acetate at pH 4 to pH 6. The combined organic layers were dried (MgSO4), and the solvent was removed in vacuo affording 60 mg (66% yield) of the title compound as a white solid: mp 158-160° C.; EIMS m/z (relative intensity) 237 (100, M+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:10]2[CH:11]=[C:12](Br)[CH:13]=[CH:14][C:9]=2[O:8][C:7]=1[CH3:16])[CH3:2].[C:18]([Cu])#[N:19].[C-]#N.[Na+]>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:10]2[CH:11]=[C:12]([C:18]#[N:19])[CH:13]=[CH:14][C:9]=2[O:8][C:7]=1[CH3:16])[CH3:2]
Reactant: N#C[Cu]
Reactant: CCOC(=O)Cc1c(C)oc2ccc(Br)cc12
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1c(C)oc2ccc(C#N)cc12
Temperature: 165 °C
Yield: 77.3 %

Procedure:
A mixture of (5-bromo-2-methyl-benzofuran-3-yl)-acetic acid ethyl ester (6.8 g, 22.9 mmol) and CuCN (3.1 g, 34.3 mmol) in anhydrous DMF (20 mL) is heated for 16 h at reflux (165° C.) under an argon atmosphere. After cooling to room temperature a solution of NaCN (5.8 g, 114 mmol) in water (30 mL) is added. The reaction mixture is partitioned between water and toluene, the layers are separated and the aqueous phase is extracted with toluene. The combined organic layers are washed with a 10% aqueous NaCN solution and brine, dried over Na2SO4, filtered and concentrated at reduced pressure to afford the title compound as a brown solid (4.31 g, 17.7 mmol, 77%). 1H NMR (400 MHz, CDCl3, 298 K): δ=7.82 (d, J=1.7 Hz, 1H), 7.51-7.43 (m, 2H), 4.16 (q, J=7.1 Hz, 2H), 3.59 (s, 2H), 2.46 (s, 3H), 1.26 (t, J=7.1 Hz, 3H). MS (ES+): 244 (M(Cl4H13NO3)+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([N+:16]([O-])=O)[CH:9]=2)=[CH:6][C:5](=[N:19][C:20]2[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=2[CH3:28])[N:4]([CH3:29])[C:3]1=[O:30].Cl>CO.[Pd]>[NH2:16][C:10]1[CH:9]=[C:8]([C:7]2[N:2]([CH3:1])[C:3](=[O:30])[N:4]([CH3:29])[C:5](=[N:19][C:20]3[C:21]([CH3:28])=[CH:22][C:23]([CH3:27])=[CH:24][C:25]=3[CH3:26])[CH:6]=2)[CH:13]=[CH:12][C:11]=1[O:14][CH3:15]
Reactant: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(=O)n2C)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(=O)n2C)cc1N
Reaction time: 2 h
Yield: 72.3 %

Procedure:
To a solution of 3,4-dihydro-1,3-dimethyl-6-(4-methoxy-3-nitrophenyl)-4-(2,4,6-trimethylphenylimino)-2(1H)-pyrimidinone (0.94 g) in a mixture of methanol (20 ml) and conc. hydrochloric acid (0.4 ml) was added palladium on activated carbon (10%, 0.20 g). The mixture was stirred under hydrogen atmosphere (1 atm) for 2 hours, and filtered. The filtrate was poured into aqueous sodium bicarbonate, and extracted with chloroform. The organic layer was dried over sodium sulfate, and evaporated. The resulting mass was crystallized from ethanol, to give 3,4-dihydro-6-(3-amino-4-methoxyphenyl)-1,3-dimethyl-4-(2,4,6-trimethylphenylimino)-2(1H)-pyrimidinone (0.63 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[C:10]1[N:11]([CH2:29][C:30](OC)=[O:31])[C:12]2[C:17]([C:18]=1[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[CH:16][CH:15]=[C:14]([C:25]([O:27][CH3:28])=[O:26])[CH:13]=2.C[O-].[Na+]>CO.CCOC(C)=O>[CH:19]1([C:18]2[C:17]3[CH:16]=[CH:15][C:14]([C:25]([O:27][CH3:28])=[O:26])=[CH:13][C:12]=3[N:11]3[CH2:29][C:30](=[O:31])[NH:1][CH2:2][C:3]4[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=4[C:10]=23)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COC(=O)Cn1c(-c2ccc(F)cc2CN)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(=O)NCc1cc(F)ccc1-3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-[2-(aminomethyl)-4-fluorophenyl]-3-cyclohexyl-1-(2-methoxy-2-oxoethyl)-1H-indole-6-carboxylate (1 eq., from Step 3) in dry MeOH (0.05 M), 10% in weight of sodium methoxide was added and the mixture stirred at RT overnight. The volume of the solution was reduced in vacuo, before diluting with EtOAc. The organic phase was washed with HCl 1 N and brine, before being dried over Na2SO4, filtered and the solvent evaporated in vacuo to afford the title compound. The crude was used in the next step without further purification (83%); MS (ES+) m/z 421 (M+H)+.