Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](O)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[F:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1>OS(O)(=O)=O>[F:11][C:12]1[C:17]2[C:1](=[O:9])[C:2]3[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=3)[S:4][C:16]=2[C:15]([OH:18])=[CH:14][CH:13]=1
Reactant: O=C(O)c1ccccc1S
Reactant: Oc1ccc(F)cc1
Agent: O=S(=O)(O)O
Product: O=c1c2ccccc2sc2c(O)ccc(F)c12
Reaction time: 24 h

Procedure:
Thiosalicylic acid (46.26 g, 0.3 mol) and 4-fluorophenol (56.05 g, 0.5 mol) were dissolved in conc. H2SO4 (750 ml) and the mixture was stirred under nitrogen for 24 hours. The reaction mixture was then poured onto ice (1.5 L) and the yellow precipitate was filtered and washed with water (300 ml). The precipitate was dried at 50° C. for 24 hours and was used without further purification (31.4 g, 42.5%). m/z (LC-MS, ESP): 247 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[CH:17]=[CH2:18]>CN(C=O)C>[CH2:18]([O:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Br:1])[CH:17]=[CH2:16]
Reactant: C=CCBr
Reactant: Oc1ccc(Cl)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(Cl)cc1Br
Temperature: 50 °C
Reaction time: 15 h
Yield: 101.1 %

Procedure:
To a solution of 2-Bromo-4-chlorophenol (7.7897 g, 37.549 mmol) in 20 mL DMF was added potassium carbonate (5.784 g, 41.85 mmol) and allyl bromide (3.30 mL, 38.1 mmol). The reaction mixture was stirred at 50° C. for 15 hours. The reaction mixture was partitioned between ethyl acetate and water, and the organic layer washed with brine, dried over magnesium sulfate, and evaporated in vacuo to yield 9.4 g (100%) of 1-(allyloxy)-2-bromo-4-chlorobenzene, which was carried forward without further purification. 1H NMR (400 MHz, CDCl3) δ: 7.54 (d, J=2.5, 1H), 7.21 (dd, J=8.8, 2.5, 1H), 6.81 (d, J=8.8, 1H), 6.10-5.98 (m, 1H), 5.46 (dd, J=17.3, 1.4, 1H), 5.31 (dd, J=10.6, 1.3, 1H), 4.59 (d, J=5.0, 2H).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:16][N:15]([CH2:17][C:18]([OH:20])=[O:19])[CH2:14][CH2:13][N:12]([CH2:21][C:22]([OH:24])=[O:23])[CH2:11][C:10]2[N:25]=[C:6]([CH:7]=[CH:8][CH:9]=2)[CH2:5][N:4]1[CH2:26][C:27]([OH:29])=[O:28].[I-].[K+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH2:32]([O:1][CH2:2][CH:3]1[CH2:16][N:15]([CH2:17][C:18]([OH:20])=[O:19])[CH2:14][CH2:13][N:12]([CH2:21][C:22]([OH:24])=[O:23])[CH2:11][C:10]2[N:25]=[C:6]([CH:7]=[CH:8][CH:9]=2)[CH2:5][N:4]1[CH2:26][C:27]([OH:29])=[O:28])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)CN1CCN(CC(=O)O)CC(CO)N(CC(=O)O)Cc2cccc(n2)C1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)CN1CCN(CC(=O)O)CC(COCc2ccccc2)N(CC(=O)O)Cc2cccc(n2)C1
Yield: 65.6 %

Procedure:
A solution of 10 g (=24.36 mmol) of 4-hydroxymethyl-3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9-triacetic acid (prepared according to Example 7(b) in 150 ml of dimethylformamide is combined with 0.5 g of potassium iodide, 4.17 g of benzyl bromide, and 5 g of sodium carbonate. The mixture is heated for 20 hours to 60° C., concentrated under vacuum, combined with 100 ml of water and 300 ml of ethanol, and the pH is set at 2 by addition of concentrated hydrochloric acid. The mixture is suctioned off from the precipitate, the precipitate is dissolved in 100 ml of water, and the solution is passed over a column with 50 g of "Reillex" (poly-4-vinylpyridine). The column is washed with 50 ml of water and the combined aqueous phases are subjected to freeze-drying, thus obtaining 8 g of the title compound as an amorphous powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=O)[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:21]([O:25][C:26](=[O:33])[C@H:27]([CH2:29][CH:30]([CH3:32])[CH3:31])[NH2:28])([CH3:24])([CH3:23])[CH3:22].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.CN1CCOCC1>C(Cl)Cl>[C:21]([O:25][C:26](=[O:33])[C@H:27]([CH2:29][CH:30]([CH3:31])[CH3:32])[NH:28][C:17](=[O:19])[C@H:12]([CH2:13][CH:14]([CH3:15])[CH3:16])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.5 %

Procedure:
Under atmosphere of argon, to a solution of N-benzyloxycarbonylleucine (26.5 g) and leucine t-butyl ester hydrochloride (22.4 g) in methylene chloride (20.0 ml) were added 1-hydroxybenzotriazole (HOBt) (14.2 g) and 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC) hydrochloride (20.1 g) at 0° C. Thereto was added N-methylmorpholine (11.5 ml) over a period of 5 minutes and the mixture was stirred for 20 hours at room temperature. The reaction solution was concentrated and to the residue were added ice-water and ethyl acetate. In order to dissolve HOBt that appeared, was added sodium bicarbonate. The aqueous layer was extracted with ethyl acetate and combined organic layer was washed with 10% aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate and saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and was concentrated to give the title compound (43.2 g) having the following physical data.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[C:40]1([CH3:64])[CH:45]=[CH:44][C:43]([S:46]([O:49][CH2:50][CH2:51][CH2:52]OS(C2C=CC(C)=CC=2)(=O)=O)(=[O:48])=[O:47])=[CH:42][CH:41]=1>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:52][CH2:51][CH2:50][O:49][S:46]([C:43]2[CH:42]=[CH:41][C:40]([CH3:64])=[CH:45][CH:44]=2)(=[O:47])=[O:48])=[CH:22][CH:21]=1)[C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(O)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)OCCCOS(=O)(=O)c2ccc(C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)OCCCOc2ccc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 100 mg (0.22 mmol) of di-tert-butyl (4S)—N-(tert-butoxycarbonyl)-4-(4-hydroxy-benzyl)-L-glutamate (Example 1b) in 10 mL N,N-dimethylformamide were added 210 mg (0.64 mmol) of cesium carbonate and 413 mg (1.07 mmol) of 1,3-propanediol di-p-toluenesulfonate (Aldrich) and the resulting suspension was stirred overnight at room temperature. The reaction mixture was then filtered, the solvent evaporated and the residue was taken up in dichloromethane and 1 M hydrochloric acid. The organic phase was separated off, washed with water until neutral, dried over sodium sulfate and filtered, and the filtrate was concentrated in vacuo. The crude product obtained in this manner was chromatographed on silica gel using a hexane/ethyl acetate gradient, and the appropriate fractions were combined and concentrated.
Reaction SMILES: [NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH2:2][C:3]([NH:5][C@H:6]([C:11]([OH:13])=O)[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:4].N(C(OCC1C=CC=CC=1)=O)CC(O)=O.[OH-].[Na+].CN1CCOCC1.[NH2:48][C@H:49]([C:57]([CH2:59][F:60])=[O:58])[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.Cl>C1COCC1.CN(C=O)C>[NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH2:2][C:3]([NH:5][C@H:6]([C:11]([NH:48][C@H:49]([C:57]([CH2:59][F:60])=[O:58])[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:13])[CH2:7][CH:8]([CH3:9])[CH3:10])=[O:4]
Reactant: N[C@@H](Cc1ccccc1)C(=O)CF
Reactant: CC(C)C[C@H](NC(=O)CNC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Agent: O=C(O)CNC(=O)OCc1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)CNC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)CF
Reaction time: 0.17 h
Yield: 54 %

Procedure:
Z-Gly-LeuOH was made by mixed anhydride coupling of Z-GlyOH and LeuOBzl tosylate, followed by NaOH hydrolysis of the benzyl ester. To a solution of Z-Gly-LeuOH (0.223 g, 0.69 mmol) in THF (4 mL) at -20° C. was added NMM (76 uL, 0.69 mmol), followed by IBCF (90 uL, 0.69 mmol). After 10 minutes, a precooled solution of PheCH2F hydrochloride (0.15 g, 0.69 mmol) in DMF (1 mL) was added, followed by a second equivalent (76 uL, 0.69 mmol) of NMM. After 30 minutes of stirring, the mixture was quenched with 1M HCl (5 mL), extracted with ethyl acetate (20 mL), washed with saturated aqueous NaHCO3 (6 mL), brine (5 mL), dried over MgSO4, filtered, and evaporated to dryness. The residue was crystallized from ether/hexane to give 0.18 g (54%) of Z-Gly-Leu-PheCH2F.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].[C:11](=O)([O-])[O-].[K+].[K+].CI.C(OCC)(=O)C>CN(C=O)C.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([O:7][CH3:11])=[O:6]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccnc(Cl)c1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.6 %

Procedure:
2-Chloroisonicotinic acid (300 mg, 1.91 mmol), potassium carbonate (790 mg, 5.72 mmol) and methyl iodide (360 μL, 5.72 mmol) was dissolved in DMF (4.5 mL) and the solution was stirred at room temperature for 4 hours. The reaction mixture was added with saturated brine and ethyl acetate, and the organic layer was separated, followed by washing with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to obtain methyl 2-chloroisonicotinate (320 mg, 98%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([NH:14][NH2:15])=[O:13])(=[O:9])=[O:8])[CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([OH:30])=[C:25]([C:27](=O)[CH3:28])[CH:26]=1>CO.C(O)(=O)C>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([OH:30])=[C:25](/[C:27](=[N:15]/[NH:14][C:12](=[O:13])[C:11]2[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=2[S:7]([N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)(=[O:9])=[O:8])/[CH3:28])[CH:26]=1
Reactant: CC(=O)c1cc(Cl)ccc1O
Reactant: NNC(=O)c1ccccc1S(=O)(=O)N1CCOCC1
Solvent: CO
Solvent: CC(=O)O
Product: C/C(=N\NC(=O)c1ccccc1S(=O)(=O)N1CCOCC1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 21 %

Procedure:
2-(morpholinosulfonyl)benzohydrazide (30 mg, 0.105 mmol) and 1-(5-chloro-2-hydroxyphenyl)ethanone (17.94 mg, 0.105 mmol) was dissolved in Methanol (Volume: 4 ml) in the presence of acetic acid as a catalyst and then the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Reaction was monitored by TLC. After completion of the reaction, following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) afforded the title compound (E)-N′-(1-(5-chloro-2-hydroxyphenyl)ethylidene)-2-(morpholinosulfonyl)benzohydrazide (10 mg, 0.022 mmol, 21.28% yield) as a solid. 1H NMR (CD3OD, 400 MHz): δ 7.95 (d, 1H, J=8.0 Hz), 7.95-7.70 (m, 2H), 7.66 (d, 1H, J=7.6 Hz), 7.56 (d, 1H, J=2.8 Hz), 7.25 (dd, 1H, J=2.8 & 8.8 Hz), 6.91 (d, 1H, J=8.4 Hz), 3.66 (m, 4H), 3.2 (m, 4H), 2.36 (s, 3H). Mass [M+H]+: 438.1
Reaction SMILES: [F:1][CH:2]([F:15])[O:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:5]=1[C:6]([O:8]C)=[O:7].[OH-].[Li+]>O1CCOCC1.O>[F:15][CH:2]([F:1])[O:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1c(F)cccc1OC(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1c(F)cccc1OC(F)F
Reaction time: 15 h
Yield: 60.9 %

Procedure:
To a solution of methyl 2-[(difluoromethyl)oxy]-6-fluorobenzoate (800 mg) in anhydrous dioxane (20 ml) was added a solution of lithium hydroxide (260 mg) in water (10 ml). It was stirred for 15 hours, evaporated, dissolved in water (25 ml) and extracted with ethyl acetate (25 ml) and ether (25 ml). The aqueous phase was acidified with 5M hydrochloric acid and extracted with ethyl acetate (2×25 ml). The combined organic phases were washed with water (10 ml) and saturated brine (10 ml), dried over Na2SO4 and evaporated to give an oil which crystallised (616.3 mg). It was triturated with heptane (ca. 10 ml) and filtered off to give the title compound (456 mg).
Reaction SMILES: [CH3:1][NH:2][C:3](=[N:18][C:19]#[N:20])[NH:4][C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[CH2:13][C:14]([O:16]C)=[O:15])=[CH:7][CH:6]=1.[OH-].[Na+]>O1CCOCC1>[CH3:1][NH:2][C:3](=[N:18][C:19]#[N:20])[NH:4][C:5]1[CH:6]=[CH:7][C:8](/[CH:11]=[CH:12]/[CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:10]=1
Reactant: CNC(=NC#N)Nc1ccc(/C=C/CC(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CNC(=NC#N)Nc1ccc(/C=C/CC(=O)O)cc1
Yield: 56.8 %

Procedure:
1.56 g of methyl (E)-4-(4-(N3 -methyl-N2 -cyanoguanidino)phenyl)-3-butenoate was dissolved in 15 ml of dioxane, followed by the addition of 6.9 ml of a 1N aqueous solution of sodium hydroxide. The mixture was reacted at a room temperature for 8 hours. The reaction mixture was concentrated, followed by the addition of water. The obtained aqueous phase was washed with chloroform. The pH of the resulting aqueous phase was adjusted to about 3 by the addition of concentrated hydrochloric acid to precipitate a crystal. This crystal was recovered by filtration and washed with water to obtain 0.84 g of the title compound as a pale yellow powder (yield: 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.I[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:8]=[CH:7]2
Reactant: Ic1ccccc1
Reactant: Clc1cccc2cc[nH]c12
Product: Clc1cccc2ccn(-c3ccccc3)c12

Procedure:
Prepared by Procedure C and Scheme O using 7-chloro-1H-indole and iodobenzene: ESMS m/e: 228.0 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]#[N:12])[CH:5]=1.[H-].[Na+].CI.[CH3:18]COC(C)=O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:18])=[C:6]([C:11]#[N:12])[CH:5]=1
Reactant: CCOC(C)=O
Reactant: COC(=O)c1ccc(O)c(C#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)c(C#N)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-cyano-4-hydroxybenzoic acid methyl ester from step 1 (1 g, 3.6 mmol) was dissolved in DMF (18 ml) and treated with NaH (290 g, 7.2 mmol) and CH3I (450 μl, 7.2 mmol). The reaction mixture was stirred at room temperature for 24 hours. EtOAc was added to the mixture and extracted with 5% citric acid (2×10 mL), saturated NaHCO3 (2×10 mL) and brine (1×10 mL). The organic layer was dried (MgSO4), filtered, and concentrated to yield the desired product.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]([F:26])([F:25])[O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][CH2:17][C:16]3([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:15]2=[O:24])=[CH:10][CH:9]=1.[CH3:27][N:28]1[C:32]([S:33](Cl)(=[O:35])=[O:34])=[CH:31][CH:30]=[N:29]1>>[CH3:27][N:28]1[C:32]([S:33]([N:21]2[CH2:20][CH2:19][C:16]3([C:15](=[O:24])[N:14]([C:11]4[CH:12]=[CH:13][C:8]([O:7][C:6]([F:5])([F:25])[F:26])=[CH:9][CH:10]=4)[CH2:18][CH2:17]3)[CH2:23][CH2:22]2)(=[O:35])=[O:34])=[CH:31][CH:30]=[N:29]1
Reactant: Cn1nccc1S(=O)(=O)Cl
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Solvent: CC(=O)O
Product: Cn1nccc1S(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1

Procedure:
The title compound was prepared in analogy to example 180 step D from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one acetic acid salt (described in example 180 step C) and 2-methyl-2H-pyrazole-3-sulfonyl chloride. Off-white solid. MS (ESI): 459.3 (MH+)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1.[O:14]=[C:15]1[NH:23][CH:22]=[N:21][C:20]2[N:19]([CH2:24][CH2:25][C:26](OCC)=[O:27])[CH:18]=[N:17][C:16]1=2>C(#N)C>[O:14]=[C:15]1[NH:23][CH:22]=[N:21][C:20]2[N:19]([CH2:24][CH2:25][C:26]([NH:1][CH2:2][CH2:3][C:4]3[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:8][CH:9]=3)=[O:27])[CH:18]=[N:17][C:16]1=2
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Solvent: CC#N
Product: NS(=O)(=O)c1ccc(CCNC(=O)CCn2cnc3c(=O)[nH]cnc32)cc1
Yield: 68 %

Procedure:
0.500 g (2.50 mmol) of 4-(2-aminoethyl)benzenesulfonamide was placed into a 10 ml round bottom flask. The flask was heated until the solid had melted. The temperature was adjusted to 150° C. and 250 mg (1.06 mmol) of 3-(1.6-dihydro-6-oxo-9H-purin-9-yl)propionic acid, ethyl ester (AIT-0027) was added and the mixture was heated for one hour with stirring. At this time, 10 ml acetonitrile was added and the solid material was broken up with the aid of a spatula while being stirred. Stirring was continued until there were no more lumps (refluxing acetonitrile). The hot acetonitrile solution was quickly filtered by vacuum and the white solid was washed with acetonitrile and then with ether. This yielded 280 mg of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-N-[2-(4-aminosulfonylphenyl)ethyl]propanamide (AIT-0049) as a white solid. Yield: 68%. m.p. 212°-216° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][CH:7]=1.[CH3:9][N:10](C)C(Cl)=O.C[Si](C#N)(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(=O)Cl
Reactant: [O-][n+]1cccc(Cl)c1
Agent: C[Si](C)(C)C#N
Solvent: ClCCl
Product: N#Cc1ncccc1Cl
Temperature: 25 °C
Reaction time: 240 h
Yield: 59 %

Procedure:
A 2M solution of 3-chloropyridine 1-oxide (C125) (10 mL, 20 mmol) is combined with an additional 90 mL of CH2Cl2. Dimethylcarbamoyl chloride (2.03 mL, 22.0 mmol) is added drop-wise, followed by the addition of trimethyl silylcyanide (2.93 mL, 22.0 mmol) via syringe. The reaction stirred at rt for 10 days and is quenched with 10% K2CO3 (100 mL). The layers are allowed to separate, and the organic layer is dried over K2CO3, filtered, and concentrated to an orange solid. The crude material is chromatographed over 160 g slurry-packed silica eluting with 40% EtOAc/hexane. The fractions with the desired compound are collected and concentrated to yield 3-chloropyridine-2-carbonitrile (C126) as a white solid (59% yield). MS (EI) for C6H3ClN2, m/z: 138 (M)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[C:20]3[C:16]=2[CH:17]=[C:18]([C:35]([O:37]CC)=[O:36])[N:19]3[S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+:41].O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[C:20]3[C:16]=2[CH:17]=[C:18]([C:35]([O-:37])=[O:36])[N:19]3[S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:27])=[O:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3].[Li+:41]
Reactant: CCOC(=O)c1cc2c(CN3CCN(C(=O)OC(C)(C)C)CC3)c(OC)ccc2n1S(=O)(=O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(cc(C(=O)[O-])n2S(=O)(=O)c2ccccc2)c1CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 70 °C
Yield: 83 %

Procedure:
Ethyl 4-{[4-(tert-butoxycarbonyl)piperazin-1-yl]methyl}-5-methoxy-1-(phenylsulfonyl)-1H-indole-2-carboxylate (330 mg, 0.6 mmol, Intermediate 56) was dissolved in THF (10 mL) before lithium hydroxide (17 mg, 0.7 mmol) was added followed by 4 mL water. The reaction mixture was heated to 70° C. for 24 h before the reaction was completed. The reaction mixture was evaporated. This gave 3 g of a white solid which was washed with several portions of hot DCM and then hot THF. The combined wash phases were evaporated. This gave 270 mg of a slightly brown solid. Yield 83%. MS (ESI+) for C26H30N3O7SLi m/z 530 (M+H)+.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][CH2:8][CH2:9][C:5]=2[CH:4]=[C:3]([C:10](OCC)=[O:11])[N:2]=1.C1COCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>O>[CH:1]1[C:6]2[CH2:7][CH2:8][CH2:9][C:5]=2[CH:4]=[C:3]([CH2:10][OH:11])[N:2]=1
Reactant: CCOC(=O)c1cc2c(cn1)CCC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cc2c(cn1)CCC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.7 %

Procedure:
A solution of ethyl 6,7-dihydro-5H-cyclopenta[c]pyridine-3-carboxylate (427 mg, 2.233 mmol) in (THF) (20 ml) at −78° C. under argon was treated with LiAlH4 (1M in THF) (2.233 ml, 2.233 mmol) and allowed warm to rt. After 10 min at rt, water (1 ml), 2M aq NaOH (1 ml) and water (1 ml) were sequentially added and the mixture stirred at rt for 0.5 h. The mixture was then filtered through a short pad of Kieselguhr, eluting with THF (50 ml), organic extracts were then evaporated, chromatographed (0-20% methanol/DCM) to give product as an orange oil (189 mg, 57%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]([CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[C:12]([CH2:14][OH:15])[N:13]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:10][C:11]([CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[C:12]([CH2:14][O:15][S:32]([CH3:31])(=[O:34])=[O:33])[N:13]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nc(CO)c(COC3CCCCO3)o2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nc(COS(C)(=O)=O)c(COC3CCCCO3)o2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.44 g [2-(4-Methoxy-phenyl)-5-(tetrahydro-pyran-2-yloxymethyl)-oxazol-4-yl]-methanol were dissolved in 30 ml dichloromethane and cooled in an ice bath. 0.29 ml triethylamine were added, followed by the addition of 0.13 ml methanesulfonylchloride. The reaction mixture was stirred at 0° C. for one hour then the ice bath was removed and the resulting mixture stirred at room temperature for an additional hour. The reaction mixture was then washed with water and brine, dried over MgSO4 and the solvent removed in vacuo to obtain 0.55 mg of methanesulfonic acid 2-(4-methoxy-phenyl)-5-(tetrahydro-pyran-2-yloxymethyl)-oxazol-4-ylmethyl ester as an oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:5][NH:6][C:7]1[C:12]([C:13]([NH:15][CH2:16][C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:14])=[CH:11][N:10]=[C:9](S(C)=O)[N:8]=1.[CH3:31][N:32]1[CH2:35][C:34]2([CH2:38][NH:37][CH2:36]2)[CH2:33]1.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:5][NH:6][C:7]1[C:12]([C:13]([NH:15][CH2:16][C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:14])=[CH:11][N:10]=[C:9]([N:37]2[CH2:38][C:34]3([CH2:35][N:32]([CH3:31])[CH2:33]3)[CH2:36]2)[N:8]=1
Reactant: CN1CC2(CNC2)C1
Reactant: COc1ccc(CNc2nc(S(C)=O)ncc2C(=O)NCc2ncccn2)cc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2nc(N3CC4(CN(C)C4)C3)ncc2C(=O)NCc2ncccn2)cc1Cl
Reaction time: 8 h
Yield: 26.2 %

Procedure:
In THF (15 mL) were dissolved 4-((3-chloro-4-methoxybenzyl)amino)-2-(methyl sulfinyl)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-formamide (120 mg, 0.27 mmol) and 2-methyl-2,6-diazaspiro[3.3]heptane (45 mg, 0.40 mmol). The solution was cooled in an ice bath, and triethylamine (82 mg, 0.81 mmol) was added dropwisely. The reaction was conducted at ambient temperature for 8 h. The solvent was removed by rotary evaporation, followed by addition of water and extraction with DCM. The organic phase was dried over sodium sulfate and purified by silica gel column chromatography (DCM/methanol/triethylamine=10/1/0.008) to give 4-((3-chloro-4-methoxybenzyl)amino)-2-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-formamide as a white solid (35 mg, 26% yield).