Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[O:7][CH:6]1[CH2:5][CH2:4][N:3]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:2]2.[FH:15].F.F.C(N(CC)CC)C.C(=O)(O)[O-].[Na+].C(Cl)Cl>ClCCCl>[F:15][C@@H:6]1[CH2:5][CH2:4][N:3]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:2][C@H:1]1[OH:7]
Reactant: F
Reactant: CC(C)(C)OC(=O)N1CCC2OC2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](F)[C@H](O)C1
Temperature: 80 °C
Reaction time: 18 h
Yield: 58.3 %

Procedure:
A mixture of tert-butyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (5.46 g, 27.4 mmol) and triethylamine trihydrofluoride (4.42 g, 27.4 mmol) in DCE (4 mL) was stirred at 80° C. (bath) for 18 hours. After cooling to room temperature, saturated sodium bicarbonate (20 mL) and DCM (30 mL) were added. The organic phase was separated, washed with brine, dried (sodium sulfate) and concentrated in vacuo. The residue obtained was purified by flash chromatography on silica gel (hexane:ethyl acetate 1:1) to give trans-tert-butyl 4-fluoro-3-hydroxypiperidine-1-carboxylate (3.5 g, 58%) as a solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[N:4][N:3]=1.[NH2:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)[CH2:25][CH2:24]1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6]([C:5]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)=[N:4][N:3]=[C:2]2[NH:22][CH:23]2[CH2:24][CH2:25][N:26]([CH2:29][C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=3)[CH2:27][CH2:28]2)=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2nnc(Cl)c3cc(OC)ccc23)c1
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Product: COc1cccc(-c2nnc(NC3CCN(Cc4ccc5ccccc5c4)CC3)c3cc(OC)ccc23)c1

Procedure:
This compound is obtained according to the procedure described in 1.4. by reacting 1-chloro-7-methoxy-4-(3-methoxyphenyl)phthalazine described in 7.3 with 4-amino-1-(naphthalen-2-ylmethyl)piperidine.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([O:12][CH3:13])=[O:11])[CH:3]=[CH:2]1.CC(C)([O-])C.[K+].Br[CH2:21][CH2:22][CH:23]([O:26][CH3:27])[O:24][CH3:25]>CS(C)=O.[I-].[K+]>[CH3:25][O:24][CH:23]([O:26][CH3:27])[CH2:22][CH2:21][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([O:12][CH3:13])=[O:11])[CH:3]=[CH:2]1
Reactant: COC(=O)c1cccc2cc[nH]c12
Reactant: COC(CCBr)OC
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1cccc2ccn(CCC(OC)OC)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
To a stirred solution of methyl 1H-indole-7-carboxylate (3.3 g, 18.8 mmol) in DMSO (18 mL) was added potassium tert-butoxide (2.1 g, 18.8 mmol) in portions. After stirring at room temperature for 1 h, a solution of 3-bromo-1,1-dimethoxypropane (10 g, 54.6 mmol) and potassium iodide (188 mg, 1.1 mmol) in DMSO (15 mL) was added and the mixture was stirred for 15 h. The reaction was quenched with saturated aqueous ammonium chloride and adjusted to pH 6. The aqueous phase was extracted with ethyl acetate (3×) and the combined extracts were washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 90:10 hexanes/ethyl acetate) to give methyl 1-(3,3-dimethoxypropyl)-1H-indole-7-carboxylate (4.8 g, 92%) as a light yellow oil: 1H NMR (500 MHz, CDCl3) δ 7.79 (d, J=7.5 Hz, 1H), 7.68 (d, J=7.5 Hz, 1H), 7.12 (d, J=3.0 Hz, 1H), 7.11 (t, J=7.5 Hz, 1H), 6.56 (d, J=3.5 Hz, 1H), 4.49 (t, J=7.0 Hz, 2H), 4.09 (t, J=6.0 Hz, 1H), 3.97 (s, 3H), 3.25 (s, 6H), 1.97 (q, J=6.0 Hz, 2H).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:9]=[CH:10][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[O:12]1[CH2:15][CH:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:23]=[CH:24][C:25]([NH2:28])=[N:26][CH:27]=3)[CH2:18][CH2:17]2)[CH2:13]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:8][C:6]1[CH:7]=[C:2]([NH:28][C:25]2[CH:24]=[CH:23][C:22]([N:19]3[CH2:20][CH2:21][N:16]([CH:14]4[CH2:13][O:12][CH2:15]4)[CH2:17][CH2:18]3)=[CH:27][N:26]=2)[C:3]2[N:4]([N:9]=[CH:10][N:11]=2)[CH:5]=1
Reactant: Nc1ccc(N2CCN(C3COC3)CC2)cn1
Reactant: Clc1cc(Br)c2ncnn2c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Clc1cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c2ncnn2c1
Temperature: 105 °C
Yield: 64.8 %

Procedure:
A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 1,4-dioxane (8 mL), 108c (250 mg, 1.07 mmol), 5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-amine (252 mg, 1 mmol), and cesium carbonate (700 mg, 2 mmol). Xantphos (30 mg, 0.08 mmol) and Pd2(dba)3 (55 mg, 0.08 mmol) were added, and the reaction mixture was heated at 105° C. for 3 h. After this time the reaction was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with CH2Cl2/MeOH (20:1) to afford 108d (250 mg, 60%). MS: [M+H]+ 386.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[C:10]([C:12]([OH:14])=O)[N:11]=2)=[CH:3][CH:2]=1.[NH2:15][C@@H:16]([CH3:32])[CH2:17][N:18]1[CH:22]=[CH:21][C:20]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([Cl:31])[CH:24]=2)=[N:19]1>>[Cl:31][C:25]1[CH:24]=[C:23]([C:20]2[CH:21]=[CH:22][N:18]([CH2:17][C@@H:16]([NH:15][C:12]([C:10]3[N:11]=[C:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)[S:8][CH:9]=3)=[O:14])[CH3:32])[N:19]=2)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1csc(-c2ccncc2)n1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(-c2ccncc2)n1
Yield: 47.5 %

Procedure:
(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(pyridin-4-yl)thiazole-4-carboxamide was prepared using the method of Example 34(d) starting from 2-(4-pyridyl)thiazole-4-carboxylic acid (0.190 g, 0.921 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.2 g, 0.767 mmol). The product triturated using diethyl ether. Yield 47.5%. 1H-NMR (400 MHz; MeOD): δ 1.33 (d, 3H), 4.40 (dd, 1H), 4.47 (dd, 1H), 4.60-4.65 (m, 1H), 6.77 (d, 1H), 7.63 (d, 1H), 7.74 (d, 1H), 7.82 (dd, 1H), 7.93 (d, 1H), 8.00 (dd, 1H), 8.01 (dd, 1H), 8.30 (s, 1H), 8.65 (dd, 1H), 8.66 (dd, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=1.[OH-].[Na+].O1CCCC1>C(O)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1
Reactant: COCCCCCCCOc1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COCCCCCCCOc1ccc(C(=O)O)cc1
Yield: 98.2 %

Procedure:
A mixture of methyl 4-(7-methoxy-n-heptyloxy)benzoate (1.5 g) and 1N-sodium hydroxide aqueous solution in ethanol (10 ml) and tetrahydrofuran (10 ml) was heated at 40-60° C. for 5 hours with stirring. The reaction mixture was concentrated under reduced pressure and water added to the residue and adjusted to pH 1 using hydrochloric acid. The precipitates were collected by filtration, washed with water and dried in vacuo to give 4-[7-methoxy-n-heptyloxy)benzoic acid (1.4 g) as a white solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C@@H:4](O)[C:5]([O:7][CH2:8][CH3:9])=[O:6].O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.N1C(C)=CC=CC=1C.[C:34]([O:38][C:39](=[O:42])[NH:40][NH2:41])([CH3:37])([CH3:36])[CH3:35]>C(Cl)Cl>[Br:1][CH2:2][CH2:3][C@H:4]([NH:41][NH:40][C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:42])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)[C@H](O)CCBr
Reactant: CC(C)(C)OC(=O)NN
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)[C@H](CCBr)NNC(=O)OC(C)(C)C
Reaction time: 0.08 h
Yield: 97 %

Procedure:
To a solution of ethyl (2R)-4-bromo-2-hydroxybutanoate (1.1 g, 5.2 mmol, prepared as described in J. Med. Chem. 2003, 46, 2057 or J. Am. Chem. Soc., 2004, 126, 12432 and Tetrahedron Letters 1997, 38, 4935-4938, in dry DCM (20 mL) at 0° C. was added Tf2O (1.62 g, 5.7 mmol) via syringe. After 5 min, 2,6-lutidine (0.67 g, 6.2 mmol) was added. After another 5 min, t-butylcarbazate (1.38 g, 10.4 mmol) in DCM (5 mL) was added. The solution was allowed to attain rt and stirred overnight. The solvent was evaporated and the residue was purified using flash chromatography (heptane/EtOAc 4:1, 3:1, 2:1) to give the slightly impure tert-butyl 2-[(1S)-3-bromo-1-(ethoxycarbonyl)propyl]hydrazinecarboxylate (1.65 g, 97%) as an oil.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH:33]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH3:34])=[CH:28][CH:27]=2)O1>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:26]1[CH:27]=[CH:28][C:29]([CH2:32][CH:33]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH3:34])=[CH:30][CH:31]=1
Reactant: CC(Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)NC(=O)OC(C)(C)C
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CC(C)NC(=O)OC(C)(C)C)cc1
Yield: 53.8 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (1.5 g, 4.4 mmol) was reacted with tert-butyl 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ylcarbamate (2.6 g, 7.3 mmol) to afford the desired product (1.1 g, 50%) as a brown solid: ESI MS m/z 465 [C26H28N2O4S+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:10])[CH2:7][CH2:8]O)([CH3:4])([CH3:3])[CH3:2].C(Br)(Br)(Br)[Br:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[C:1]([O:5][C:6](=[O:10])[CH2:7][CH2:8][Br:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)CCBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Hydroxy-propionic acid tert-butyl ester is dissolved in acetonitrile and carbon tetrabromide and triphenylphosphine is added. The mixture is stirred at room temperature overnight. After this time the mixture is concentrated in vacuo. The gummy solid is triturated with hexanes and the liquid decanted, passed through pad of silica to remove any triphenylphosphine oxide, and concentrated in vacuo. 1H NMR (400 MHz, CHLOROFORM-d) ppm 1.3 (9H, s), 2.06-2.27 (2H, m), 4.07-4.25 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10](OC)=[O:11])[CH:3]=1.S(=O)(=O)(O)O.[CH3:19][CH:20]([OH:22])[CH3:21]>>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:22][CH:20]([CH3:21])[CH3:19])=[O:11])[CH:3]=1
Reactant: COC(=O)c1cc(Cl)c(Cl)c(Cl)n1
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Product: CC(C)OC(=O)c1cc(Cl)c(Cl)c(Cl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 4,5,6-trichloropicolinate (14.19 grams (g), 59.0 millimoles (mmol)) was slurried in 2-propanol (150 milliliters (mL)) in a 250 mL round bottom flask equipped with a Dean-Stark trap and a reflux condenser. Sulfuric acid (98% H2SO4; 8.07 g, 82 mmol) was added, and the reaction mixture was heated to reflux. After 20 hours (h) at reflux, the majority of the 2-propanol (100 mL) was distilled overhead. The pot solidified upon cooling to room temperature. The resulting solid was stirred with ethyl acetate (EtOAc; 500 mL) and saturated (satd) aqueous (aq) sodium bicarbonate solution (NaHCO3; 500 mL). The organic layer was separated, washed with brine and then filtered through Celite. The organic extract was concentrated to 150 mL by rotary evaporation. Hexane (100 mL) was added, and the solution was stored at −20° C. overnight. Crystals were collected, washed with hexane and dried in air (7.58 g, mp 104.6-105.7° C.). A second crop was obtained by concentration of the filtrate to give a total of 10.36 g (65%) 1H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 1H, pyridine H), 5.16 (septet, J=6.3 Hz, 1H, CHMe2), 1.34 (d, J=6.3 Hz, 6H, CHMe2); 13C{1H} NMR (101 MHz, CDCl3) δ 161.9 (CO2R), 150.6, 145.9, 145.0, 133.1, 125.4 (C3), 70.7 (CHMe2), 21.7 (Me). Anal. Calcd for C9H8Cl3NO2: C, 40.26; H, 3.00; N, 5.22. Found: C, 40.25; H, 3.02; N, 5.22.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]([CH:17]3[CH2:21][CH2:20][NH:19][CH2:18]3)[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:6]=2[N:7]=1.[CH:28](O)=O.C=O>[OH-].[Na+]>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]([CH:17]3[CH2:21][CH2:20][N:19]([CH3:28])[CH2:18]3)[S:13]([CH3:16])(=[O:14])=[O:15])=[CH:8][C:6]=2[N:7]=1
Reactant: O=CO
Reactant: CS(=O)(=O)N(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)C1CCNC1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Product: CN1CCC(N(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)S(C)(=O)=O)C1
Temperature: 60 °C

Procedure:
A mixture of N-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-N-pyrrolidin-3-yl-methanesulfonamide (200 mg), formic acid (2.5 mL) and formaldehyde (37% solution, 0.37 mL) was heated at 60° C. overnight. The mixture was diluted with 2M NaOH then extracted with CH2Cl2. Combined extracts were dried (MgSO4), filtered and concentrated. Purification on silica yielded N-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-N-(1-methyl-pyrrolidin-3-yl)-methanesulfonamide (38 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)=[O:5].C([O:27][S:28](=O)(=[O:30])[OH:29])(=O)C.S(=O)(=O)(O)O.C(OC(=O)C)(=O)C.[OH-].[Na+:45]>ClCCCl.O.C(O)CC>[Na+:45].[Cl:1][C:2]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:28]([O-:30])(=[O:29])=[O:27])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)=[O:5]
Reactant: CC(=O)OS(=O)(=O)O
Reactant: O=C(c1ccc(Oc2ccccc2)cc1)c1cc(Cl)ccc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCO
Solvent: ClCCCl
Product: O=C(c1ccc(Oc2ccc(S(=O)(=O)[O-])cc2)cc1)c1cc(Cl)ccc1Cl

Procedure:
2,5-dichloro-4′-phenoxybenzophenone (A, 137.3 g, 400 mmol) was put in a 3 L three-necked flask equipped with a stirring device and cooling tube, and 500 mL of 1,2-dichloroethane (1,2-DCE) was added and dissolved. Furthermore, 2 M of acetyl sulfuric acid solution prepared by mixing 56 mL of concentrated sulfuric acid, 152 mL of acetic anhydride, and 400 mL of 1,2-DCE, was added to the flask while stirring, and the reaction was performed in an oil bath at 60° C. After the predetermined period, 300 mL of 1-propanol was added to stop the reaction. Next, the reaction liquid was concentrated to a volume of 400 mL, and NaOH aqueous solution (120 g (3 mol)/water 400 mL) was added. The remaining 1,2-DCE in the reaction liquid was removed by azeotropic distillation, and a transparent light yellow solution was obtained. The light yellow solution was cooled, and deposition was filtered. The deposition was dried in a vacuum at 70° C. to obtain a white fine powder of 4-[4-(2,5-dichlorobenzoyl)phenoxy]benzene sulfonic acid sodium salt (A—SO3Na) shown in Chemical Formula 3. The crude crystal was used in the next process without being purified.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].I[C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1.[CH:15]1[C:23]2[C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[O:20][C:19]=2[C:18](B(O)O)=[CH:17][CH:16]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([C:27]2[C:21]3[O:20][C:19]4[CH:18]=[CH:17][CH:16]=[CH:15][C:23]=4[C:22]=3[CH:24]=[CH:25][CH:26]=2)=[CH:9][CH:10]=1
Reactant: OB(O)c1cccc2c1oc1ccccc12
Reactant: Brc1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2cccc3c2oc2ccccc23)cc1

Procedure:
Under an argon atmosphere, 300 mL of toluene and 150 mL of a 2-M aqueous solution of sodium carbonate were added to 28.3 g (100 mmol) of 4-iodobromobenzene, 22.3 g (105 mmol) of dibenzofuran-4-boronic acid, and 2.31 g (2.00 mmol) of tetrakis(triphenylphosphine)palladium(0), and the mixture was refluxed under heat for 10 hours.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5](N)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:21].[Na+]>O.C(OCC)C.C(O)(=O)C>[I:21][C:5]1[CH:7]=[CH:8][C:2]([I:1])=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc(I)cc1[N+](=O)[O-]
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=[N+]([O-])c1cc(I)ccc1I
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
4-Iodo-2-nitroaniline (6.60 g, 0.025 mol) was suspended in water (19 mL) and glacial acetic acid (17.5 mL) (Sapountzis et al., 2005, which is incorporated herein by reference). The mixture was cooled to 0° C. Sulfuric acid (17.5 mL, 0.328 mol) was added cautiously. The mixture was cooled to minus 5° C., and a solution of NaNO2 (1.90 g, 0.028 mol) in water (7.5 mL) was added dropwise at a rate that the temperature would not exceed 0° C. Upon completion of the addition the mixture was stirred for 30 minutes and was added in small portions to a boiling solution of sodium iodide (22.33 g, 0.149 mol) in water (7.5 mL) (CAUTION: vigorous nitrogen evolution!). The resulting mixture was kept at 60° C. for one hour, then cooled down to room temperature, followed by addition of diethyl ether (500 mL). The ether solution was separated, washed twice with water (150 mL) and once saturated NaHCO3 (150 mL). The solution was dried over Na2SO4 and concentrated in vacuo to a solid, which was recrystallized from ethanol to yield 1,4-diiodo-2-nitrobenzene (9.30 g, 99%). 1H NMR (400 MHz, CDCl3): δ 8.15 (d, 1H, J=2.0 Hz), 7.75 (d, 1 H, J=8.3 Hz), 7.56 (dd, 1 H, J=8.3 and 2.0 Hz).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][Si:7]([CH3:22])([CH3:21])[O:8][C@H:9]1[CH2:13][NH:12][C@H:11]([C:14]([O:16][Si:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:1][CH2:2][C:3]([N:12]1[CH2:13][C@H:9]([O:8][Si:7]([CH3:21])([CH3:22])[CH3:6])[CH2:10][C@H:11]1[C:14]([O:16][Si:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:4]
Reactant: C[Si](C)(C)OC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C)CN1
Reactant: O=C(Cl)CCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[Si](C)(C)OC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C)CN1C(=O)CCl
Temperature: 0 °C
Yield: 96.1 %

Procedure:
A solution of chloroacetyl chloride (1.0 mL, 12.6 mmol) in 1 mL of dichloromethane was added slowly into a stirred solution of trimethylsilyl (2S,4R)-4-(trimethylsilyoxy)pyrrolidine-2-carboxylate (3.62 g, 13.1 mmol) [which was contaminated with trimethylsilyl (2R,4R)-4-(trimethylsilyloxy)pyrrolidine-2-carboxylate in about 20% content] and di(isopropyl)ethylamine (3 ml, 17.2 mmol) in 100 mL of dry dichloromethane cooled on an ice bath. An additional 1.0 ml of di(isopropyl)ethylamine was added and the mixture was stirred an additional 30 minutes on the ice bath. The reaction solution was then evaporated to dryness by a vacuum pump. The residue was slurried in pentane and filtered. The filtrate was then evaporated by a vacuum pump to yield 4.26 g (96% crude yield) of crude trimethylsilyl (2S,4R)—N-chloroacetyl-4-(trimethylsilyloxy)pyrrolidine-2-carboxylate as an oil, which solidified upon cooling.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([S:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[N:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[CH:11]=[C:5]2[N:4]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:3]1=[O:34].S([O-])(O[O-])(=O)=[O:36].[K+].[K+].OOS([O-])=O.[K+]>>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([S:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[O:36])[N:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[CH:11]=[C:5]2[N:4]([CH2:30][CH:31]([CH3:32])[CH3:33])[C:3]1=[O:34]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Sc3ccccn3)n(Cc3cccc4ccccc34)cc21
Reactant: O=S(=O)([O-])O[O-]
Agent: O=S([O-])OO
Agent: [K+]
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(S(=O)c3ccccn3)n(Cc3cccc4ccccc34)cc21

Procedure:
Prepared from the compound of Example 20, 3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-5-[(2-pyridinyl)thio]-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione and potassium peroxymonosulphate (commercially sold under the trade mark “OXONE”) following the method of Example 8 c).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([S:17]([C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22](Br)[CH:21]=3)(=[O:19])=[O:18])[CH3:16])[C:9]=2[CH:8]=[N:7]1)C.[F:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[F:32][C:33]1[CH:38]=[CH:37][C:36]([C:22]2[CH:23]=[C:24]([C:26]([F:28])([F:27])[F:29])[CH:25]=[C:20]([S:17]([N:15]([CH3:16])[C@@H:10]3[CH2:11][CH2:12][CH2:13][C:14]4[N:6]([CH2:5][C:4]([OH:3])=[O:31])[N:7]=[CH:8][C:9]3=4)(=[O:18])=[O:19])[CH:21]=2)=[CH:35][CH:34]=1
Reactant: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1cc(Br)cc(C(F)(F)F)c1
Reactant: OB(O)c1ccc(F)cc1
Product: CN([C@@H]1CCCc2c1cnn2CC(=O)O)S(=O)(=O)c1cc(-c2ccc(F)cc2)cc(C(F)(F)F)c1
Yield: 42 %

Procedure:
Starting with {(R)-4-[(3-bromo-5-trifluoromethyl-benzenesulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester (prepared by the method analogous to the one described for example 9-1, 1st step) and 4-fluoro-phenylboronic acid, using a method analogous to the one described for example 10-1, {(R)-4-[(4′-fluoro-5-trifluoromethyl-biphenyl-3-sulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid (5 mg, 42%) was obtained. MS cald. for C25H25F4N3O4S 539, obsd. (ESI+) [(M+H)+] 540.
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[CH2:9][C@H:8]1[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=O)=O.[N-:15]=[N+:16]=[N-:17].[Na+]>CS(C)=O>[N:15]([CH2:6][C@@H:7]1[CH2:9][C@H:8]1[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)[C@@H]1C[C@H]1COS(C)(=O)=O
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)[C@@H]1C[C@H]1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The trans-ethyl 2-methanesulfonyloxymethyl-1-cyclopropanecarboxylate from the previous step (1.655 g, 7.45 mmol) was dissolved in dry dimethyl sulfoxide (20 ml), treated with sodium azide (0.969 g, 14.89 mmol), and stirred at room temperature for 16 h. (tlc indicated no substrate left). After dilution with water, (50 ml), the reaction mixture was extracted with ether (3×50 ml) and the combined organic extracts washed several times (×6) with water and then brine (×3). After drying on anhydrous magnesium sulfate, evaporation of the solvent under reduced pressure gave an oil. Bulb to bulb distillation gave a clear liquid; 1.178 g (93%); bp 86°-90° C./4.0 mm Hg (air bath temperature); ir (film) νmax : 2090 (N3), 1725 cm-1 (C=O); 1Hmr (CDCl3) δ:4.13 (2H, q, J=7, CH2 --CH3), 3.21 (2H, d, J=6, CH2 --OMs), 2.0-0.6 (4H, m, cyclopropyl), 1.23 (3H, t, 5.7, CH2 --CH3). Anal. calcd for C7H11N3O2 : C 49.69, H 6.55, N 24.83; found: C 49.81, H 6.71, N 24.29.