Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[Cl:29][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][C:25]=1[Cl:28])[CH2:21][CH:18]1[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc(Cl)c(Cl)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc(CC2CCNCC2)cc1Cl
Reaction time: 1 h
Yield: 100.5 %

Procedure:
Trifluoroacetic acid (50 ml) was added to a solution of 1-(tert-butoxycarbonyl)-4-(3,4-dichlorobenzyl)piperidine (24 g, 69.7 mmol) in methylene chloride (150 ml) and the reaction mixture was stirred for 1 h. The solvent was removed under reduced pressure, followed by addition of ethyl acetate (200 ml), and the resulting mixture was made basic with 1N aqueous sodium hydroxide. The organic layer was separated, dried over magnesium sulfate and the solvent was removed under reduced pressure to give 4-(3,4-dichlorobenzyl)piperidine (17.1 g) as light brown solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[C:12]([O:14]C)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(#N)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[C:12]([OH:14])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(OC)c(OCc2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: COc1ccc(C(=O)O)cc1OCc1ccccc1
Temperature: 40 °C

Procedure:
A 25 g quantity of the methyl 3-benzyloxy-4-methoxybenzoate obtained in Reference Example 2 was dissolved in 100 ml of acetonitrile, and a solution of 11 g of sodium hydroxide in 100 ml of water was added. The mixture was stirred with heating at 40° C. for 5 hours. The reaction mixture was cooled with ice, and concentrated hydrochloric acid was added to give a pH of about 3. The precipitated crystals were collected by filtration and dried under reduced pressure to give 22.1 g of white crystalline 3-benzyloxy-4-methoxybenzoic acid.
Reaction SMILES: C[Si]([Br:5])(C)C.[CH2:6]([O:13][C:14]1[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:19]=[CH:18][C:15]=1[CH2:16]O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)(Cl)Cl>[CH2:6]([O:13][C:14]1[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:19]=[CH:18][C:15]=1[CH2:16][Br:5])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)c1ccc(CO)c(OCc2ccccc2)c1
Reactant: C[Si](C)(C)Br
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1ccc(CBr)c(OCc2ccccc2)c1
Reaction time: 1 h

Procedure:
2.9 ml of trimethylsilyl bromide are added to a solution, stirred at room temperature, of 4 g of 2-benzyloxy-4-tert-butyl-benzyl alcohol in 100 ml of chloroform. The reaction mixture is stirred for a further 1 hours and then partitioned between trichloromethane and water. The organic phases are dried with Na2SO4 and concentrated by evaporation, yielding the title compound: Rf (dichloromethane/hexane=8.2)=0.95.
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[C:10]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:28])[NH:20][N:19]=2)=[C:9]1[CH3:29])(C)(C)C.[F:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[CH:34][CH:33]=1>>[Cl:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:6]([OH:5])=[O:30])[C:9]([CH3:29])=[C:10]2[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](=[O:28])[N:20]([CH2:36][C:35]2[CH:38]=[CH:39][C:32]([F:31])=[CH:33][CH:34]=2)[N:19]=1
Reactant: Cc1c(-c2n[nH]c(=O)c3ccccc23)c2cc(Cl)ccc2n1CC(=O)OC(C)(C)C
Reactant: Fc1ccc(CBr)cc1
Product: Cc1c(-c2nn(Cc3ccc(F)cc3)c(=O)c3ccccc23)c2cc(Cl)ccc2n1CC(=O)O

Procedure:
The title compound was prepared from the product of example 16, step c) and 4-fluorobenzyl bromide using the procedure described in example 14. 1H NMR (DMSO-d6) δ 13.25 (bs, 1H), 8.41 (d, J=6.6 Hz, 1H), 7.94-7.87 (m, 2H), 7.58 (d, J=8.7 Hz, 1H), 7.52 (d, J=9.0 Hz, 1H), 7.45 (dd, J=5.7, 8.4 Hz, 2H), 7.24-7.10 (m, 4H), 5.44 (d, J=14.4 Hz, 1H), 5.38 (d, J=14.4 Hz, 1H), 5.14 (s, 2H), 2.24 (s, 3H); MS: ESI (negative): 474, 476 (M−H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:24])[CH2:9][C:10]([N:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][O:14][C:13]2=[O:23])=[O:11])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[Br:34]N1C(=O)CCC1=O>ClCCl>[Br:34][C@H:9]([C@H:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[CH3:24])[C:10]([N:12]1[C@H:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:15][O:14][C:13]1=[O:23])=[O:11]
Reactant: C[C@H](CC(=O)N1C(=O)OC[C@H]1c1ccccc1)c1ccc(Br)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](c1ccc(Br)cc1)[C@@H](Br)C(=O)N1C(=O)OC[C@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of the product from Step B (2.87 g, 7.39 mmol) in dichloromethane (40 mL) was added N,N-diisopropylethylamine (1.93 mL, 11.1 mmol) and dibutylborontriflate (9.6 mL, 1M solution in dichloromethane, 9.60 mmol) at −78° C. The light yellow solution was stirred at −78° C. for 15 min, 0° C. for 1 h and recooled to −78° C. for 15 min. The above solution was transferred to a precooled suspension of N-bromosuccinimide (3.93 g, 22.2 mmol) in dichloromethane (40 mL) via cannula. The resultant mixture was stirred at −78° C. for 1 h and 0° C. for 3 h. The reaction was quenched by addition of 0.5N aqueous sodium bisulfite solution. The organic phase was separated and the aqueous phase was extracted with two portions of ethyl acetate. The combined organic layers were washed with brine and concentrated in vacuo. Purification by flash chromatography (silica gel, 83:17 hexanes/ethyl acetate) afforded the desired product.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]=[C:6]2[N:5]=[C:4]([CH3:15])[C:3]=1[CH3:16].[SH-:17].[Na+].Cl>O>[CH3:15][C:4]1[C:3]([CH3:16])=[C:2]([SH:17])[N:7]2[N:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]=[C:6]2[N:5]=1
Reactant: COC(=O)c1nc2nc(C)c(C)c(Cl)n2n1
Reactant: [SH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)c1nc2nc(C)c(C)c(S)n2n1
Reaction time: 1.5 h

Procedure:
The product obtained in Step 2 was added all at once at 0° C. to a solution of sodium hydrosulfide (40 g) in 800 ml of water with stirring under a nitrogen stream, the mixture was stirred at 0° C. for 30 minutes and then at room temperature for 1.5 hours, its pH was lowered to 2.0 with concentrated hydrochloric acid. The formed crystals were collected by filtration and washed with 300 ml of water and 200 ml of ethanol, affording 36 g of the objective compound as yellow crystals.
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[C:6]1([CH:13]=[CH:12][CH:11]=[C:9]([OH:10])[CH:8]=1)[OH:7].[Cl-].[Al+3].[Cl-].[Cl-].Cl>[N+](C1C=CC=CC=1)([O-])=O>[OH:7][C:6]1[CH:8]=[C:9]2[C:11]([C:3](=[O:4])[CH2:2][O:10]2)=[CH:12][CH:13]=1
Reactant: O=C(Cl)CCl
Reactant: Oc1cccc(O)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C1COc2cc(O)ccc21

Procedure:
Chloroacetyl chloride (28.25 g) was added dropwise over 1.5 hours to a stirred mixture of resorcinol (Aldrich Chemical Company) (22 g), aluminum chloride (33.3 g) and nitrobenzene (250 cc), the temperature being kept at 50°-55° C. during the chloroacetyl chloride addition and for an additional 15 minutes thereafter. The solution was then cooled and poured into an excess of ice and dilute hydrochloric acid. The organic layer was retained and extracted with aqueous sodium hydroxide (300 ml, 1M). The alkaline extract was acidified with concentrated hydrochloric acid and filtered to give 6-hydroxycoumaran-3-one, m.p. --238°-240° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[N:5]=[C:4]2[N:17]([CH2:20][C:21]([F:24])([F:23])[F:22])[N:18]=[CH:19][C:3]=12.Cl.[C@H:26]12[CH2:32][C@H:29]([NH:30][CH2:31]1)[CH2:28][O:27]2.C(N(CC)CC)C>C(O)C>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[C:4]3[N:17]([CH2:20][C:21]([F:24])([F:23])[F:22])[N:18]=[CH:19][C:3]3=[C:2]([N:30]3[CH2:31][C@@H:26]4[CH2:32][C@H:29]3[CH2:28][O:27]4)[N:7]=2)=[CH:9][CH:10]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(-c2nc(Cl)c3cnn(CC(F)(F)F)c3n2)cc1
Reactant: C1O[C@@H]2CN[C@H]1C2
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(-c2nc(N3C[C@@H]4C[C@H]3CO4)c3cnn(CC(F)(F)F)c3n2)cc1
Temperature: 120 °C
Yield: 118.9 %

Procedure:
To a Smith process vial containing a suspension of 4-chloro-6-(4-nitro-phenyl)-1-(2,2,2-trifluoro-ethyl)-1H-pyrazolo[3,4-d]pyrimidine (0.30 g, 0.84 mmol) and (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (0.12 g, 0.88 mmol) in ethanol (4 mL) was added triethylamine (0.33 mL, 2.5 mmol). The mixture was heated in the microwave reactor for 15 minutes at 120° C. The precipitate was collected by Buchner filtration, washed with methanol, and dried under house vacuum to provide (1S,4S)-5-(6-(4-nitrophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane as a bright yellow powder (0.42 g, >100%). MS (ES+): 421.1 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:18][CH2:17][CH2:16][C@:10]2([O:14][CH2:13][C:12](=C)[CH2:11]2)[C@@H:9]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[OH:26]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:18][CH2:17][CH2:16][C@:10]2([O:14][CH2:13][C:12](=[O:26])[CH2:11]2)[C@@H:9]1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C1CO[C@]2(CCCN(C(=O)OC(C)(C)C)[C@H]2c2ccccc2)C1
Reactant: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@]2(CC(=O)CO2)[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Through a cooled (-80° C.) solution of (6S,5R)-7-(tert-butoxycarbonyl)-3-methylene-6-phenyl-7-aza-1-oxa-spiro[4.5]decane (0.665 g; Desc.3) in dichloromethane (5 ml) and methanol (5 ml) was bubbled a mixture of ozone and oxygen for 0.75 hours. After the solution had been purged with nitrogen, dimethyl sulphide (0.5 ml) was added and then stirred under nitrogen at room temperature for 16 hours. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. The organic phase was dried (MgSO4), evaporated and the residue purified by chromatography on silica gel elutintg with hexane containing increasing proportions of ethyl acetate between 0% to 10%. Evaporation of the fractions gave the title compound. MS (ES+) m/z 332 (M+H), 232 (M+2H-tBuOCO--), 276 (M+2H-tBu). 1H NMR (250 MHz, CDCl3) δ 7.58 (2H, d, J 6.2 Hz), 7.37-7.26 (3H, m), 5.3 (1H, s), 4.15 and 4.09 (2H, AB d, J 17.4 Hz), 3.97 (1H, m), 2.80 (1H, td, J 12.9 Hz and 4.0 Hz), 2.74 and 2.48 (2H, ABd, J 18.1 Hz), 2.29 (2H, m), 1.88-1.63 (2H, m), 1.44 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=2)[CH:5]=[CH:4][N:3]=1>C(O)C.[Pt]>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([NH2:14])[CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cccc(-c2ccnc(Cl)n2)c1
Agent: [Pt]
Solvent: CCO
Product: Nc1cccc(-c2ccnc(Cl)n2)c1
Reaction time: 24 h
Yield: 90 %

Procedure:
Intermediate 5 was dissolved in ethanol along with 5 mol % of 5% Pt/C. The mixture was stirred under an atmosphere of H2 for 24 hours and then filtered through a pad of Celite to remove catalyst. Removal of the solvent gave product in 90% yield. LC-MS showed purity >95% and the expected M+H+ of 206.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]([OH:14])=O)[CH2:7][CH2:6]2.[CH3:15][N:16]([CH3:34])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1>>[CH3:15][N:16]([CH3:34])[C:17]1[CH:18]=[CH:19][C:20]([CH2:23][N:24]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:32])[CH3:33])=[CH:27][CH:26]=2)[C:12]([CH:8]2[C:9]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[CH2:6][CH2:7]2)=[O:14])=[CH:21][CH:22]=1
Reactant: COc1ccc2c(c1)CCC2C(=O)O
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Product: COc1ccc2c(c1)CCC2C(=O)N(Cc1ccc(N(C)C)cc1)c1ccc(C(C)C)cc1
Yield: 86.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-methoxyindan-1-carboxylic acid (0.50 g) and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.80 g) as starting materials, N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-5-methoxyindan-1-carboxamide (1.00 g) was obtained.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:14][C:15]([OH:17])=O.[Cl:18][C:19]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[Cl:18][C:19]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:20]=1[CH2:21][N:22]1[CH2:23][CH2:24][N:25]([C:15](=[O:17])[CH2:14][N:3]2[CH2:4][CH2:5][CH2:6][CH:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:2]2=[O:1])[CH2:26][CH2:27]1
Reactant: Clc1ccc(CN2CCNCC2)c(Cl)c1
Reactant: O=C(O)CN1CCCC(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)C1=O)N1CCN(Cc2ccc(Cl)cc2Cl)CC1
Temperature: 25 °C

Procedure:
A solution of 2-(2-oxo-3-phenylpiperidin-1-yl)acetic acid (Example 91D, 0.050 g, 0.214 mmol), 1-(2,4-dichlorobenzyl)piperazine (0.058 g, 0.236 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.062 g, 0.322 mmol) in dichloromethane (0.5 mL) was allowed to stir at ambient temperature. After stirring overnight, the reaction was loaded directly onto a SF10-8 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 100% ethyl acetate/hexanes over 20 minutes, maintaining 100% ethyl acetate for an additional 5 minutes (flow=20 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.36-7.42 (m, 2H), 7.17-7.34 (m, 6H), 4.45 (d, J=15.5 Hz, 1H), 4.05 (d, J=15.5 Hz, 1H), 3.71 (dd, J=7.7, 6.0 Hz, 1H), 3.64 (t, J=4.9 Hz, 2H), 3.58 (s, 2H), 3.53-3.61 (m, 1H), 3.46-3.51 (m, 2H), 3.39-3.48 (m, 1H), 2.48-2.52 (m, 4H), 2.17-2.27 (m, 1H), 1.95-2.08 (m, 2H), 1.80-1.91 (m, 1H); MS (ESI+) m/z 460 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[S-:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Na+].Cl>C(O)C>[C:13]1([S:12][CH2:2][C:3]2[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: [S-]c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1ccc(CSc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88 %

Procedure:
A mixture of 4-(bromomethyl)benzoic acid (10 g, 46.5 mmol), sodium thiophenoxide (6.15 g, 46.5 mmol), and ethanol (100 mL) was stirred for 1.5 hours under reflux. This mixture was cooled to room temperature and acidified with 1 N hydrochloric acid. The precipitate thus produced was collected, dissolved in ethyl acetate, and washed with water. The organic layer was concentrated under a reduced pressure to obtain the title compound (10 g). The title compound was used in the following reaction without any further purification.
Reaction SMILES: ClC(Cl)(OC(=O)[O:6][C:7]([Cl:10])(Cl)Cl)Cl.[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]2[CH2:25][NH:24][CH2:23][CH:22]2[N:26]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[C:31]([F:39])[CH:30]=2)[CH3:27])[CH:17]=[CH:18][C:19]=1[Cl:20].N1C=CC=CC=1>C(Cl)Cl>[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]2[CH:22]([N:26]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:37])([F:38])[F:36])=[C:31]([F:39])[CH:30]=3)[CH3:27])[CH2:23][N:24]([C:7]([Cl:10])=[O:6])[CH2:25]2)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CN(Cc1ccc(C(F)(F)F)c(F)c1)C1CNCC1c1ccc(Cl)c(Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(Cc1ccc(C(F)(F)F)c(F)c1)C1CN(C(=O)Cl)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 137.3 %

Procedure:
To a stirred solution of carbonic acid ditrichloromethyl ester (triphosgene) (37 mg, 0.125 mmol) in CH2Cl2 (10 ml) at −78° C., was added a solution of [(3RS,4SR)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-(3-fluoro-4-trifluoromethyl-benzyl)-methyl-amine (Intermediate VIII-1), (130 mg, 0.31 mmol) and pyridine (0.05 ml, 0.68 mmol) in CH2Cl2 (5 ml) over 30 minutes. The temperature was raised to RT, and stirring was continued for 2 hours. The organic phase was washed with H2O, dried over Na2SO4. Purification by flash chromatography (SiO2, EtOAc/Hx 1:2) yielded 83 mg (55%) of the title compound as a light yellow oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][PH:6]([C:8]([O:13][CH2:14][CH3:15])([O:10][CH2:11][CH3:12])[CH3:9])=[O:7])[CH3:4].Br[CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.O>O1CCCC1>[CH2:3]([O:5][P:6]([C:8]([O:13][CH2:14][CH3:15])([O:10][CH2:11][CH3:12])[CH3:9])([CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:7])[CH3:4]
Reactant: BrCC1CCCCC1
Reactant: CCO[PH](=O)C(C)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(C)(OCC)P(=O)(CC1CCCCC1)OCC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
21 g of 99% sodium hydride are suspended at room temperature under argon in 1000 ml of anhydrous tetrahydrofuran, and a solution of 172.2 g of 1,1-diethoxyethylphosphinic acid ethyl ester is added dropwise over a period of 2.5 hours, the temperature being maintained at from 20° to 25°. The reaction is exothermic and involves the evolution of gas. The batch is then stirred for 1.5 hours at room temperature, 142.2 g of bromomethylcyclohexane are added and heating under reflux is effected for 24 hours. The suspension is cooled to 4° and 250 rnl of water are carefully added. Two phases are formed. The tetrahydrofuran phase is separated off and the aqueous phase is extracted twice with 250 ml of dichloromethane each time. Concentration by evaporation yields a brown oil which, after distillation under reduced pressure, gives 1,1-diethoxyethyl(cyclohexylmethyl)phosphinic acid ethyl ester having a boiling point of 95° (1.8×10-4 mbar).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][C:11]([O:26][CH3:27])=[C:12]([NH:14][CH:15]3[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]3)[CH:13]=2)[CH:5]=[CH:4][N:3]=1.[CH3:28][NH2:29].CO>CN1C(=O)CCC1>[CH3:27][O:26][C:11]1[N:10]=[CH:9][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:29][CH3:28])[CH:7]=2)=[CH:13][C:12]=1[NH:14][CH:15]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]1
Reactant: COc1ncc(-c2ccnc(F)c2)cc1NC1CN(C(=O)OC(C)(C)C)C1
Reactant: CN
Solvent: CN1CCCC1=O
Solvent: CO
Product: CNc1cc(-c2cnc(OC)c(NC3CN(C(=O)OC(C)(C)C)C3)c2)ccn1
Temperature: 140 °C
Yield: 80 %

Procedure:
To a solution of tert-butyl 3-((2′-fluoro-6-methoxy-[3,4′-bipyridin]-5-yl)amino)azetidine-1-carboxylate (530 mg, 1.42 mmol) in NMP (3 mL) was added CH3NH2/MeOH (5 mL). The reaction mixture was stirred while being heated at 140° C. in a microwave for 1 h. The mixture was cooled to rt, the solvent was removed and diluted with ethyl acetate (100 mL). The organic layer was washed with water (60 mL), brine (60 mL), dried over Na2SO4, filtered, concentrated in vacuo, and the residue was purified by flash chromatography to obtain 436 mg of tert-butyl 3-((6-methoxy-2′-(methylamino)-[3,4′-bipyridin]-5-yl)amino)azetidine-1-carboxylate as a yellow solid (80%): 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J=5.3 Hz, 1H), 7.72 (d, J=2.1 Hz, 1H), 6.63 (dd, J=5.3, 1.5 Hz, 1H), 6.58 (s, 1H), 6.39 (d, J=1.7 Hz, 1H), 4.63 (d, J=6.7 Hz, 1H), 4.53 (d, J=6.5 Hz, 1H), 4.27 (dd, J=8.8, 7.1 Hz, 2H), 4.18 (ddt, J=9.4, 7.0, 3.4 Hz, 1H), 3.97 (s, 3H), 3.74 (dd, J=9.0, 4.6 Hz, 2H), 2.90 (d, J=4.2 Hz, 3H), 1.37 (s, 9H); MS (ES) m/z 386 (M+H).
Reaction SMILES: [Br:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:6](=[O:25])[NH:5][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:33][C:34]1[O:38][N:37]=[C:36]([CH2:39][CH3:40])[N:35]=1>CN(C=O)C>[Br:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:14][CH2:13]3)[C:6](=[O:25])[N:5]([CH2:33][C:34]3[O:38][N:37]=[C:36]([CH2:39][CH3:40])[N:35]=3)[C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(Br)sc3c2=O)CC1
Reactant: CCc1noc(CCl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1noc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(Br)cc32)n1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Tert-butyl 4-(6-bromo-2,4-dioxo-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (5.00 g, compound B53) and potassium carbonate (1.60 g) are suspended in dry DMF (50 ml) and 5-(chloromethyl)-3-ethyl-1,2,4-oxadiazole (1.70 g, compound D7) is added. The reaction mixture is stirred at 100° C. for 2 h and then poured into ice-cold water (250 ml). The resulting precipitate is filtered off and dried in vacuo to afford the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:31](=[O:33])[NH2:32])[CH:5]=[CH:6][CH:7]=1>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH2:23][C:24]([OH:26])=[O:25])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:31](=[O:33])[NH2:32])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cccc2c1c1c(OCC(=O)O)cccc1n2Cc1cccc(Cl)c1
Yield: 100.3 %

Procedure:
A solution of the {9-[(3-chlorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, tert-butyl ester (35.6 mg, 0.077 mM) in 2 mL of trifluoroacetic acid was stirred at room temperature for 6 hours. The solvent was removed in vacuo. The residue was triturated with ethyl acetate, then dried in vacuo to afford 31.4 mg (100%) of the {9-[(3-chlorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid as a white powder. 1H NMR (DMSO-d6) δ13.0 (br s, 1H), 7.75 (s, 1H), 7.6 (d, 1H, J=8 Hz), 7.4-7.25 (m, 7H), 7.2 (d, 1H, J=8 Hz), 7.0 (br t, 1H), 6.6 (d, 1H, J=8 Hz), 5.7 (s, 2H), and 4.8 (s, 2H). IR (KBr, cm−1) 3456, 3416, 3335, 1735, 1638, 1617, 1580, 1499, 1452, 1431, 1431, 1329, 1255, 1157, 772, 764, and 717. MS (ES) m/e 407, 409, 411.
Reaction SMILES: [C:1]([O:8]CC)(=O)/[CH:2]=[CH:3]\[C:4]([O-:6])=[O:5].[NH:11]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([O-:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1)[NH2:12].C(=O)([O-])[O-].[Na+].[Na+].Cl>O>[C:4]([CH:3]1[CH2:2][C:1](=[O:8])[N:11]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([OH:22])(=[O:20])=[O:21])=[CH:15][CH:14]=2)[NH:12]1)([OH:6])=[O:5]
Reactant: CCOC(=O)/C=C\C(=O)[O-]
Reactant: NNc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C1CC(=O)N(c2ccc(S(=O)(=O)O)cc2)N1
Temperature: 100 °C
Yield: 76 %

Procedure:
2 parts of monoethyl maleate are added with stirring to 25 parts of water containing 2 parts of p-hydrazinobenzene sulphonate and 1 part of sodium carbonate. The mixture is heated at 100° C for 5 hours. The resulting solution is warmed with sodium carbonate and the pH finally adjusted to 3-4 with hydrochloric acid. The 3carboxy-1-(4'-sulphophenyl)-5-pyrazolidone thus formed is filtered off and dried between 50°-100° C. The actual weight yield is 4 parts of strength 74% (determined by N.M.R.) which represents a yield of 76%.