Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C:15]1[N:19]=[C:18]([C:20]2[C:21]([CH3:40])=[C:22]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)[C:23]3[N:24]([N:26]=[C:27]([NH2:29])[N:28]=3)[CH:25]=2)[N:17]([C:41]2[CH:46]=[CH:45][C:44]([C:47]#[N:48])=[CH:43][CH:42]=2)[N:16]=1)(C)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:14][C:15]1[N:19]=[C:18]([C:20]2[C:21]([CH3:40])=[C:22]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)[C:23]3[N:24]([N:26]=[C:27]([NH2:29])[N:28]=3)[CH:25]=2)[N:17]([C:41]2[CH:42]=[CH:43][C:44]([C:47]#[N:48])=[CH:45][CH:46]=2)[N:16]=1
Reactant: Cc1c(-c2nc(NC(=O)OC(C)(C)C)nn2-c2ccc(C#N)cc2)cn2nc(N)nc2c1-c1cccc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(-c2nc(N)nn2-c2ccc(C#N)cc2)cn2nc(N)nc2c1-c1cccc(C(F)(F)F)c1
Reaction time: 2.5 h
Yield: 2.2 %

Procedure:
Trifluoroacetic acid (1 mL) was added to a solution of [5-[2-amino-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-1-(4-cyano-phenyl)-1H-[1,2,4]triazol-3-yl]-carbamic acid tert-butyl ester (Int. 38, 325 mg, 0.565 mmol) in DCM (5 mL) and the reaction mixture was stirred for 2.5 hrs. Saturated aqueous NaHCO3 solution (10 mL) was added and the phases were separated then the organics were concentrated in vacuo. The resulting residue was purified by HPLC, C 18 column, eluting with a gradient 40-80% MeCN in water (+0.1% formic acid) to give the title compound as a white solid (6 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[OH:22].Cl[C:24]1[N:29]=[C:28]([O:30][CH:31]([C:33]([O:35][CH3:36])=[O:34])[CH3:32])[CH:27]=[CH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[O:22][C:24]1[N:29]=[C:28]([O:30][CH:31]([CH3:32])[C:33]([O:35][CH3:36])=[O:34])[CH:27]=[CH:26][N:25]=1
Reactant: COC(=O)C(C)Oc1ccnc(Cl)n1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1ccnc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2Cl)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 49.3 %

Procedure:
339 mg of 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenol and 217 mg of 2-chloro-4-[1-(methoxycarbonyl)ethoxy]pyrimidine were dissolved in 2 ml of N,N-dimethylformamide, to this solution was added 150 mg of potassium carbonate, and the mixture was stirred for 2 hours at 80° C. The reaction solution was cooled to room temperature, then, this reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 256 mg of methyl 2-([2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}pyrimidin-4-yl]oxy)propionate [present compound 1-2].
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([OH:15])=[O:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5]1)([CH3:3])[CH3:2].[H-].[Na+].[CH3:18]I>CN(C)C=O>[CH:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15][CH3:18])=[O:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ccc2cc(C(=O)O)ccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(ccn2C(C)C)c1

Procedure:
A mixture of 2.20 g (8.97 mmol) of isopropyl 1-isopropyl-5-indolecarboxylate, 100 ml of 2N sodium hydroxide solution and 100 ml of ethanol was refluxed for an hour. The solvent was then distilled off under reduced pressure. Thereafter water was added to the residue and the resulting mixture was acidified with conc. hydrochloric acid. The precipitated solid was filtered and dried under reduced pressure to give 2.00 g of crude 1-isopropyl-5-indole-carboxylic acid. The reaction was carried out in a manner similar to Reference Example 4 using 2.00 g of the crude 1-isopropyl-5-indolecarboxylic acid, 0.44 g (11.1 mmol) of 60% sodium hydride, 2.87 g (20.2 mmol) of methyl iodide and 50 ml of dimethyl-formamide. Thus, 1.64 g (84.2%; yield based on isopropyl 1-isopropyl-5-indolecarboxylic acid) was obtained.
Reaction SMILES: [CH2:1]([CH:4]([CH2:7][OH:8])[CH2:5][OH:6])[CH2:2][CH3:3].[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([F:18])[CH:17]=1)[CH:13]=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([CH:4]1[CH2:7][O:8][CH:13]([C:12]2[CH:11]=[C:10]([F:9])[CH:17]=[C:16]([F:18])[CH:15]=2)[O:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCCC(CO)CO
Reactant: O=Cc1cc(F)cc(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCC1COC(c2cc(F)cc(F)c2)OC1
Yield: 48 %

Procedure:
2-Propyl-1,3-propanediol (83.2 g; 704 mmol) and 3,5-difluorobenzaldehyde (100 g; 704 mmol) were dissolved in toluene (1 liter), and p-toluenesulfonic acid (hereinafter referred to as PTS; 5 g) was added. The mixture was refluxed for 3 hours while being dehydrated with a Dean-Stark's device. The resultant reaction mixture was washed sequentially with saturated sodium bicarbonate solution and saturated brine and dried over magnesium sulfate. Subsequently, the solvent was evaporated. The residue was recrystallized twice from heptane, to thereby obtain 82.0 g (338 mmol) of 5-propyl-2-(3,5-difluorophenyl)-1,3-dioxane. The yield of the compound from 3,5-difluorobenzaldehyde was 48.0%.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[CH:8]=[CH:9][C:10]([O:32][CH3:33])=[C:11]([C:13]2[N:17]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]4[CH3:31])=[C:22]([CH:24]=3)[NH2:23])[O:15][N:14]=2)[CH:12]=1>N1C=CC=CC=1>[F:6][C:7]1[CH:8]=[CH:9][C:10]([O:32][CH3:33])=[C:11]([C:13]2[N:17]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]4[CH3:31])=[C:22]([NH:23][S:2]([CH3:1])(=[O:4])=[O:3])[CH:24]=3)[O:15][N:14]=2)[CH:12]=1
Reactant: COc1ccc(F)cc1-c1noc(-c2ccc(N3CCCCC3C)c(N)c2)n1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COc1ccc(F)cc1-c1noc(-c2ccc(N3CCCCC3C)c(NS(C)(=O)=O)c2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methanesulfonyl chloride (20 μL; 0.26 mmol; 1.2 eq.) was added to a solution of Example 69 (83 mg; 0.22 mmol; 1 eq.) in pyridine (1 mL) and the resulting solution was stirred at room temperature for 16 hours. The solution was then partitioned between water and ethyl acetate. The two phases were separated and the aqueous layer was extracted with ethyl acetate. The combined organic phase was washed (3×) with 0.1M HCl, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography c-hexane/ethyl acetate, 60/40) afforded the title compound as a white solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1.C(N(CC)CC)C>CN(C)C=O>[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)=[CH:11][CH:10]=1
Reactant: OC1CCNCC1
Reactant: Fc1ccc(CBr)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: OC1CCN(Cc2ccc(F)cc2)CC1
Reaction time: 16 h

Procedure:
0.856 g (0.00846 mol) of 4-hydroxypiperidine was dissolved in 40 ml of dimethylformamide and cooled to 0°. 2.0 g (0.0106 mol) of 4-fluorobenzyl bromide and 3.3 ml (0.0233 mol) of triethylamine were added under argon and the mixture was left to come to room temperature. It was stirred for 16 hrs., the solvent was distilled off and the residue was chromatographed on silica gel with dichloromethane/methanol (17:3) as the eluent. An analytically pure sample was obtained after a second chromatography on silica gel with dichloromethane/methanol (17:3) as the eluent. The remainder was used directly in the next step. 0.176 g (8%) of 1-(4-fluoro-benzyl-piperidin-4-ol was obtained as a yellow oil. MS: me/e=210 (C12H17FNO+).
Reaction SMILES: [CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][CH:11]([OH:16])[CH2:10][C:9]2([CH3:18])[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19](Cl)(=[O:23])[C:20]([CH3:22])=[CH2:21].C(N(CC)CC)C>C(Cl)Cl>[CH:1]1([O:7][N:8]2[C:9]([CH3:18])([CH3:17])[CH2:10][CH:11]([O:16][C:19](=[O:23])[C:20]([CH3:22])=[CH2:21])[CH2:12][C:13]2([CH3:14])[CH3:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC1(C)CC(O)CC(C)(C)N1OC1CCCCC1
Reactant: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)OC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1

Procedure:
The procedure of Example 3 is repeated using 5.11 grams of 1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-ol, 2.0 ml of methacryloyl chloride and 3.10 ml of triethylamine in methylene chloride. The above-named product is isolated as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:7]=2[O:6][CH:5]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].Cl>ClCCl>[CH3:26][S:27]([O:1][CH2:2][CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:7]=2[O:6][CH:5]=1)(=[O:29])=[O:28]
Reactant: COC(=O)COc1cccc2c(CCO)coc12
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)COc1cccc2c(CCOS(C)(=O)=O)coc12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 97 %

Procedure:
Methyl (3-(2-hydroxyethyl)benzofuran-7-yloxy)acetate (4.12 g) was dissolved in dichloromethane (120 ml) and triethylamine (3 ml) and methanesulfonyl chloride (1.35 ml) were added to the solution, followed by stirring the resulting solution at 0° C. for 1.5 hours. The reaction mixture was then poured into 1N hydrochloric acid and the resultant was extracted with dichloromethane. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution, water, and with saturated saline, and dried over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure. The residue was recrystallized from n-hexane/ethyl acetate to obtain the desired compound (5.25 g, yield: 97%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([S:12](Cl)(=[O:14])=[O:13])=[CH:9][CH:8]=1.[CH2:16]([C@H:23]([NH2:41])[C:24]([N:26]1[CH2:31][CH2:30][CH:29]([O:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[C:35]([F:40])[CH:34]=2)[CH2:28][CH2:27]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[CH2:16]([C@H:23]([NH:41][S:12]([C:10]1[S:11][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:8][CH:9]=1)(=[O:14])=[O:13])[C:24]([N:26]1[CH2:27][CH2:28][CH:29]([O:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[C:35]([F:40])[CH:34]=2)[CH2:30][CH2:31]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CCC(Oc2ccc(F)c(F)c2)CC1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Solvent: ClCCl
Product: O=C([C@H](Cc1ccccc1)NS(=O)(=O)c1ccc(-c2ccccn2)s1)N1CCC(Oc2ccc(F)c(F)c2)CC1
Reaction time: 12 h
Yield: 27.8 %

Procedure:
To a solution of 5-pyridin-2-yl-thiophene-2-sulfonyl chloride (0.072 g) [in CH2Cl2 (5 ml) and dimethyl amino pyridine (0.034 g)] was added a solution of the product of Example 5, Step (b) (0.100 g) in CH2Cl2 (1 ml). The reaction was left to stir for 12 hrs. The reaction mixture was then pre-absorbed onto flash silica and purified by flash silica column chromatography with 2% MeOH/97.5% CH2Cl2/0.5% aq NH3 as eluent. Further purification using flash silica chromatography with 10% MeCN/2% TEA/88% CH2Cl2 eluent gave the title compound as a solid (0.045 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.[Cl:8][C:9]1[C:10]([CH3:19])=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1>>[Cl:8][C:9]1[C:10]([CH3:19])=[C:11]([S:15]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH3:7])[N:6]=2)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1
Reactant: Cc1csc(N)n1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Product: Cc1csc(NS(=O)(=O)c2cccc(Cl)c2C)n1

Procedure:
The title compound was prepared from 2-amino-4-methylthiazole (285 mg) and 3-chloro-2-methylbenzenesulfonyl chloride (619 mg) according to METHOD A. This afforded 167 mg (22%) of a yellow solid after purification: 1H NMR (DMSO-4) δ 2.1 (s, 3H), 2.6 (s, 3H), 6.35 (s, 1H), 7.35 (t, 1H), 7.65 (d, 1H), 7.85 (d, 1H), 12.7 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH2:11][CH:10]([C:24]([O:26]C)=[O:25])[CH2:9]1)=[O:7].CC(C)([O-])C.[K+]>>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][CH:15]=2)[CH2:11][CH:10]([C:24]([OH:26])=[O:25])[CH2:9]1)=[O:7]
Reactant: COCCNC(=O)N1CC(C(=O)OC)CC(c2ccc(C(F)(F)F)cc2)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: COCCNC(=O)N1CC(C(=O)O)CC(c2ccc(C(F)(F)F)cc2)C1

Procedure:
2.94 g (7.57 mmol) of the compound from Example 104A and 8.49 g (75.70 mmol) of potassium tert-butoxide were reacted according to the General Method 9A. Yield: 2.46 g (80% of theory, 92% pure)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:26][N:27]2[CH:31]=[CH:30][N:29]=[CH:28]2)[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]C)=[O:23])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl>>[ClH:1].[C:22]([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][NH:15][C:13](=[O:14])[CH:12]([NH:11][S:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:10])=[O:9])[CH2:26][N:27]1[CH:31]=[CH:30][N:29]=[CH:28]1)([OH:24])=[O:23]
Reactant: COC(=O)CCCCCCNC(=O)C(Cn1ccnc1)NS(=O)(=O)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(O)CCCCCCNC(=O)C(Cn1ccnc1)NS(=O)(=O)c1ccc(Cl)cc1
Yield: 154.1 %

Procedure:
The procedure described in Example 92 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)-N-(6-methoxycarbonylhexyl)propanamide (36.3 mg) was hydrolyzed, and then reacted with HCl to obtain (RS)-N-(6-carboxyhexyl)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)propanamide hydrochloride (29.3 mg).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](S(C)=O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:27][C:28]1[CH:37]=[CH:36][C:31]2[NH:32][C:33](=[O:35])[NH:34][C:30]=2[CH:29]=1>>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21]([NH:27][C:28]4[CH:37]=[CH:36][C:31]5[NH:32][C:33](=[O:35])[NH:34][C:30]=5[CH:29]=4)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc2[nH]c(=O)[nH]c2c1
Reactant: CS(=O)c1ncc2ccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2n1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc5[nH]c(=O)[nH]c5c4)nn23)c1

Procedure:
Following the synthetic and purification procedures described in Example 1293d, a N-tert-butyl-3-(2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide (103 mg, 0.262 mmol) was coupled with 5-amino-1,3-dihydro-benzimidazol-2-one (67 mg, 0.45 mmol) at 105° C. for 72 h to afford the title compound. Yield of TFA salt: 82 mg (52%) of brown powder; LC/MS: 478 (M+H); HPLC: 97% pure, RT=2.83 min; 1H NMR: (DMSO, δ) 10.46 (s, 1H), 10.42 (s, 1H), 9.34 (s, 1H), 9.00 (s, 1H), 8.52 (s, 1H), 8.44 (d, J=8.0, 1H), 7.84 (d, J=8.3, 1H), 7.73 (appt, J=8.0, 1H), 7.63 (s, 1H), 7.47 (dd, J=8.1, 1.8, 1H), 7.23 (s, 1H), 7.19 (d, J=5.0, 1H), 6.98 (d, J=3.6, 1H), 6.93 (d, J=8.3, 1H), 1.11 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]([O:60]CC1C=CC=CC=1)[C:15](=[O:59])[CH2:16][CH2:17][C:18](=[O:58])[NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]([O:50]CC1C=CC=CC=1)[C:26](=[O:49])[CH2:27][CH2:28][C:29](=[O:48])[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N:36]([O:40]CC1C=CC=CC=1)[C:37](=[O:39])[CH3:38])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]([OH:60])[C:15](=[O:59])[CH2:16][CH2:17][C:18](=[O:58])[NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]([OH:50])[C:26](=[O:49])[CH2:27][CH2:28][C:29](=[O:48])[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N:36]([OH:40])[C:37](=[O:39])[CH3:38])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)N(CCCCCNC(=O)CCC(=O)N(CCCCCNC(=O)CCC(=O)N(CCCCCNC(=O)OC(C)(C)C)OCc1ccccc1)OCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 81 %

Procedure:
10% Pd-C (227 mg) was added to a solution of (12) (0.346 g, 0.372 mmol) in MeOH (100 mL). The reaction flask was degassed three times with nitrogen and hydrogen gas was introduced at 1 atm. The mixture was rapidly stirred at room temperature for 20 minutes. After the reaction flask was evacuated and filled with nitrogen several times, the catalyst was filtered through a sintered glass filter (10-15μ) and solids were washed with MeOH. After solvent removal by rotary evaporation, the residue was passed through a short Sephadex LH-20 column, eluting with MeOH. The band was dried to provide 199 mg (81%) of (13) as an amorphous white solid: 300 MHz NMR (d6 -DMSO) δ 1.12-1.53 (m+s, 27 H), 1.95 (s, 3 H), 2.25 (t, 4 H, J=7), 2.52-2.60 (m, 4 H), 2.82-3.03 (m, 6 H), 3.43 (t, 6 H, J=6), 7.4 (m, 1 H), 7.8 (m, 2 H), 9.7 (br s, 3 H). The spectrum was identical to an authentic sample of (13).
Reaction SMILES: O.[NH3:2].[F:3][CH:4]([F:20])[O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:15])[F:14])=[CH:8][C:7]=1[S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl>[F:3][CH:4]([F:20])[O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:15])[F:14])=[CH:8][C:7]=1[S:16]([NH2:2])(=[O:18])=[O:17]
Reactant: N
Reactant: O=S(=O)(Cl)c1cc(OC(F)F)ccc1OC(F)F
Solvent: ClCCl
Solvent: O
Product: NS(=O)(=O)c1cc(OC(F)F)ccc1OC(F)F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 30 ml of methylene chloride, 30 ml of water and 50 ml of 30% ammonia solution is slowly added a solution of 12.7 g of crude 2.5-bis(difluoromethoxy)phenylsulfonyl chloride in 150 ml of methylene chloride. The reaction mixture is stirred for 5 hours at room temperature. The organic phase is washed with water, dried over sodium sulfate and evaporated to a volume of about 40 ml. From the residue crystallise 10.7 g of 2.5-bis(difluoromethoxy)phenyl-sulfonamide with a melting point of 73°-74° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][C@H:17]([CH2:21][NH2:22])[O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:23][N:24]=[C:25]=[O:26]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][C@H:17]([CH2:21][NH:22][C:25]([NH:24][CH3:23])=[O:26])[O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: NC[C@H]1CCc2ccc(S(=O)(=O)c3cccc(F)c3)cc2O1
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)NC[C@H]1CCc2ccc(S(=O)(=O)c3cccc(F)c3)cc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a solution of C—[(R)-7-(3-Fluoro-benzenesulfonyl)-chroman-2-yl]-methylamine (0.130 g, 0.405 mmol) in methylene chloride (10 mL) at 0° C. was added methyl isocyanate (0.115 g, 2.03 mmol). The mixture was stirred at room temperature for one hour, and was then quenched by addition of MeOH. The mixture was partitioned between water and methylene chloride, and the organic phase was washed with water and brine, dried (Na2SO4), filtered and contrated under reduced pressure. Purification of the residue by flash chromatography (hexanes:EtOAc 1:9) gave 0.153 g of 1-[(R)-7-(3-fluoro-benzenesulfonyl)-chroman-2-ylmethyl]-3-methyl-urea as a foam. MS (M+H)=379.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:23])[CH:10]([NH2:22])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[F:24][C:25]([F:40])([F:39])[C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[C:29](Cl)=[O:30].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([OH:23])[CH:10]([NH:22][C:29](=[O:30])[C:28]2[CH:32]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:34]=[C:26]([C:25]([F:24])([F:39])[F:40])[CH:27]=2)[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:7][CH:8]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.7 %

Procedure:
To a solution of (1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (150 mg, 0.43 mmol) in ethyl acetate (5 ml) were-added 3,5-bis(trifluoromethyl)benzoyl chloride (117 ml, 0.64 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether-hexane to give the title compound (73 mg, 31%).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[CH:3]=1.[N:12]([O-])=[O:13].[Na+]>O>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[C:3]=1[N:12]=[O:13]
Reactant: O=N[O-]
Reactant: Cn1c(N)cc(=O)n(C)c1=O
Agent: [Na+]
Solvent: O
Product: Cn1c(N)c(N=O)c(=O)n(C)c1=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Commercially available 6-amino-1,3-dimethyl-1H-pyrimidine-2,4-dione (10 mmol) was dissolved in 1:1 water/glacial acetic acid (50 mL total volume) at 80° C. and sodium nitrite (20 mmol) added in portions. After the addition was complete the reaction mixture was stirred at 80° C. for 1 hr. Cooled in ice for 30 mins then filtered and washed with water. The precipitate was dried in vacuo to give crude 6-amino-1,3-dimethyl-5-nitroso-1H-pyrimidine-2,4-dione as a red-violet colored solid which was of sufficient purity for subsequent use without additional purification (89%).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13][N:12]=[C:11]([NH:26][C@@H:27]2[CH2:31][CH2:30][NH:29][CH2:28]2)[N:10]=1.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>>[CH2:36]([O:35][C:33]([N:29]1[CH2:30][CH2:31][C@@H:27]([NH:26][C:11]2[N:10]=[C:9]([NH2:8])[C:14]([C:15](=[O:16])[C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[O:24][CH3:25])=[CH:13][N:12]=2)[CH2:28]1)=[O:34])[CH3:37]
Reactant: COc1ccc(F)cc1C(=O)c1cnc(N[C@@H]2CCNC2)nc1N
Reactant: CCOC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CC[C@@H](Nc2ncc(C(=O)c3cc(F)ccc3OC)c(N)n2)C1

Procedure:
The same procedure as described in Example 60 was used, starting from (R)-[4-amino-2-(pyrrolidin-3-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 70, and ethyl chloroformate (Aldrich) to give (R)-3-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-pyrrolidine-1-carboxylic acid ethyl ester. MS (M+H)+, 404.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:15])[NH:4][C:5](=[O:14])[N:6]([CH2:9][CH:10]([CH3:13])[CH2:11][CH3:12])[C:7]=1[NH2:8].[CH:16](Cl)(Cl)Cl.CCOCC>C(O)=O>[CH3:13][CH:10]([CH2:11][CH3:12])[CH2:9][N:6]1[C:7]2[N:8]=[CH:16][NH:1][C:2]=2[C:3](=[O:15])[NH:4][C:5]1=[O:14]
Reactant: ClC(Cl)Cl
Reactant: CCC(C)Cn1c(N)c(N)c(=O)[nH]c1=O
Solvent: CCOCC
Solvent: O=CO
Product: CCC(C)Cn1c(=O)[nH]c(=O)c2[nH]cnc21

Procedure:
17.3 g of 5,6-diamino-1-(2-methyl-1-butyl)-2,4-(1H,3H)-pyrimidinedione (XXXXII) was refluxed in 30 ml of formic acid for 2 h. 20 ml of chloroform was added and ether was then added slowly. The received crystals were filtered off. Yield 17.0 g. The amide was refluxed in 50 ml of 2N NaOH for 2 hours and then neutralized with 5N HCl. The crystals were filtered off and recrystallized from 400 ml of ethanol. Yield 10 g (XXXXI) NMR (see Table I).