Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.[C:4]([C:6]1[CH:25]=[CH:24][C:9]([CH2:10][N:11]2[C:15]([CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[CH:14][N:13]=[CH:12]2)=[CH:8][C:7]=1[F:26])#[N:5].[CH:27]([Si:30]([CH:48]([CH3:50])[CH3:49])([CH:45]([CH3:47])[CH3:46])[O:31][C:32]1[CH:41]=[C:40]2[C:35]([CH:36]=[CH:37][CH:38]=[C:39]2[C:42](O)=[O:43])=[CH:34][CH:33]=1)([CH3:29])[CH3:28].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>>[C:4]([C:6]1[CH:25]=[CH:24][C:9]([CH2:10][N:11]2[C:15]([CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:42]([C:39]4[C:40]5[C:35](=[CH:34][CH:33]=[C:32]([O:31][Si:30]([CH:45]([CH3:47])[CH3:46])([CH:48]([CH3:50])[CH3:49])[CH:27]([CH3:28])[CH3:29])[CH:41]=5)[CH:36]=[CH:37][CH:38]=4)=[O:43])[CH2:20][CH2:19]3)=[CH:14][N:13]=[CH:12]2)=[CH:8][C:7]=1[F:26])#[N:5]
Reactant: CC(C)[Si](Oc1ccc2cccc(C(=O)O)c2c1)(C(C)C)C(C)C
Reactant: N#Cc1ccc(Cn2cncc2CCN2CCNCC2)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[Si](Oc1ccc2cccc(C(=O)N3CCN(CCc4cncn4Cc4ccc(C#N)c(F)c4)CC3)c2c1)(C(C)C)C(C)C
Reaction time: 8 h

Procedure:
The product from Step D (66.1 mg, 0.156 mmol), 7-triisopropylsilyloxy-1-naphthoic acid from Step F (53.8 mg, 0.156 mmol), EDC hydrochloride (33.0 mg, 0.172 mmol), HOBT (23.2 mg, 0.172 mmol), and N,N-diisopropylethylamine (0.136 mL, 0.781 mmol) were stirred in dry, degassed DMF (0.5 mL) at 20° C. overnight. The reaction was stirred overnight and then injected onto a C18 preparative HPLC column and purified with a mixed gradient of 5%-95% acetonitrile/0.1% TFA; 95%-5%/0.1% aqueous TFA over 15 min. The title compound was isolated after conversion to the free base.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=O.P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>>[NH2:1][C:2]1[N:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:3]=1[C:4]#[N:6]
Reactant: NC(=O)c1ccc(N)nc1N
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ccc(N)nc1N
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
2,6-Diamino-nicotinamide (520 mg) described in Manufacturing Example 7-1 and phosphorus oxychloride (5.0 g) were stirred for 0.5 hour at 100° C. The reaction solution was added to 0° C. dilute aqueous sodium hydroxide, which was then extracted with ethyl acetate. The organic layer was concentrated and the residue was purified with NH silica gel column chromatography (ethyl acetate) to obtain the titled compound (340 mg).
Reaction SMILES: [CH:1]([CH:21]1[CH2:26][C:25](=[O:27])O[C:22]1=[O:23])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[NH3:28]>>[CH:1]([CH:21]1[CH2:26][C:25](=[O:27])[NH:28][C:22]1=[O:23])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: N
Reactant: CCCCCCCCCCCCCCCCCCC=CC1CC(=O)OC1=O
Product: CCCCCCCCCCCCCCCCCCC=CC1CC(=O)NC1=O
Temperature: 160 °C

Procedure:
In another reaction vessel was placed 570 grams of the above isomerized eicosenyl succinic anhydride. This was heated to 160° C. and ammonia injection started. The temperature rose to 175° C. Ammonia injection was continued at 175° C. until the temperature dropped. Then 30" Hg vacuum was slowly applied to distill out water and ammonia. Additional ammonia was injected to be sure no anhydride remained. There was no further reaction so this ammonia was stripped out at 30" Hg vacuum at 170° C. yielding isomerized eicosenyl succinimide. This can then be reacted with formaldehyde as in Example 2 to form N-hydroxymethyl isomerized eicosenyl succinimide.
Reaction SMILES: [F:1][C:2]1[C:11]2[NH:10][CH2:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:15]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:16]=1[C:17]#[N:18]>C1COCC1>[F:1][C:2]1[C:11]2[N:10]([C:15]3[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:26])[F:25])=[CH:19][C:16]=3[C:17]#[N:18])[CH2:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cccc2c1NCCO2
Reactant: N#Cc1cc(C(F)(F)F)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2cccc(F)c21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
To a flask charged with 5-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (Combi-Blocks) (0.321 g, 2.096 mmol) was added THF (8.38 ml). The solution was cooled in an ice water bath prior to the addition of sodium hydride (60% in mineral oil) (0.092 g, 2.306 mmol). The resulting suspension was stirred for 30 mins at 0° C., the 30 mins at room temp. The resulting pale yellow suspension was cooled in an ice water bath prior to the addition of 2-fluoro-5-(trifluoromethyl)benzonitrile (Matrix Scientific) (0.436 g, 2.306 mmol). The mixture was stirred for 5 mins at 0° C., the 1 hr at room temperature when LC-MS indicated all starting material present. The tannish suspension was heated to reflux overnight providing a brown solution with about 80% conversion to product according to LC-MS. The mixture was cooled to room temperature and carefully added to ice water which was extracted with EtOAc (2×). The combined organics were dried with Na2SO4, filtered and dried under reduced pressure. The crude residue was purified with a 25 g column (25 m spherical silica gel, Interchim) ramping EtOAc in heptane (0-35%, with 10% DCM throughout) providing product which had partially coeluted with starting amine. The material obtained was filtered through a 5 g SCX-2 column washing with MeOH. The MeOH wash contained product, obtained as an off-white solid 2-(5-fluoro-2H-benzo[b][1,4]oxazin-4(3H)-yl)-5-(trifluoromethyl)benzonitrile (0.450 g, 1.396 mmol, 66.6% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.91-3.97 (m, 2 H) 4.22 (br. s., 2 H) 6.68 (ddd, J=10.86, 8.22, 1.37 Hz, 1 H) 6.82 (dt, J=8.41, 1.37 Hz, 1 H) 7.00 (td, J=8.31, 5.97 Hz, 1 H) 7.14 (dd, J=8.71, 2.25 Hz, 1 H) 7.67 (ddd, J=8.73, 2.23, 0.59 Hz, 1 H) 7.90 (dd, J=1.57, 0.59 Hz, 1 H). m/z (ESI) 323.3 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([S:13](Cl)(=[O:15])=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:19]([C:22]1[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[CH:26]=[C:25]([CH:32]([CH3:34])[CH3:33])[C:23]=1[NH2:24])([CH3:21])[CH3:20]>N1C=CC=CC=1>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([S:13]([NH:24][C:23]2[C:25]([CH:32]([CH3:33])[CH3:34])=[CH:26][C:27]([CH:29]([CH3:31])[CH3:30])=[CH:28][C:22]=2[CH:19]([CH3:21])[CH3:20])(=[O:15])=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)c1cc(C(C)C)c(N)c(C(C)C)c1
Solvent: c1ccncc1
Product: CC(C)c1cc(C(C)C)c(NS(=O)(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.4 %

Procedure:
3,5-Bis(trifluoromethyl)benzenesulfonyl chloride (0.037 g, 0.12 mmol) was added to a solution of 2,4,6-triisopropylaniline (0.025 g, 0.11 mmol) in dry pyridine (1 mL). After stirring at room temperature for 1 day, the reaction was concentrated under vacuum. To this was added ethyl acetate (30 mL), and the mixture was washed with 0.1 N HCl (2×20 mL) followed by saturated NaHCO3 (2×20 mL) then saturated NaCl (2×20 mL). After drying the organic layer over MgSO4, the mixture was concentrated under vacuum. The crude compound was purified by silica gel chromatography using hexanes/ethyl acetate (4:1) to afford the title compound (0.040 g. 71% yield). ES-MS negative Q1 (m/z) 494.6. 1H NMR (CDCl3) 8.14 (s, 2H), 8.05 (s, 1H), 6.96 (s, 2H), 6.05 (s, 1H), 2.97 (m, 2H), 2.88 (m, 1H), 1.23 (d, 6H), 0.98 (d, 12H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:21](=[O:28])[CH2:22][CH2:23][C:24]([O:26]C)=[O:25])[CH:18]=3)[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:21](=[O:28])[CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH:18]=3)[CH2:13]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: COC(=O)CCC(=O)c1ccc2c(c1)CC(NS(=O)(=O)c1ccc(F)cc1)C2
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCC(=O)c1ccc2c(c1)CC(NS(=O)(=O)c1ccc(F)cc1)C2

Procedure:
Prepared analogously to Example 2 from methyl 4-(2-p-fluorobenzenesulphonamido-indan-5-yl)-4-oxobutyrate by hydrolysis with sodium hydroxide.
Reaction SMILES: [OH-].[Na+].Br(O)(=O)=O.Br[O-].[Na+].[CH2:10]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:28][C:29]3[CH:35]=[CH:34][C:33]([C:36](=[O:38])C)=[CH:32][C:30]=3[N:31]=2)=[CH:23][CH:22]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].Cl(O)(=O)=[O:40]>O.O1CCOCC1>[CH2:10]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:28][C:29]3[CH:35]=[CH:34][C:33]([C:36]([OH:40])=[O:38])=[CH:32][C:30]=3[N:31]=2)=[CH:23][CH:22]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCOc1ccc(-c2nc3cc(C(C)=O)ccc3o2)cc1
Reactant: [O-][Cl+2]([O-])O
Agent: [Na+]
Agent: [O-]Br
Agent: [O-][Br+2]([O-])O
Solvent: O
Solvent: C1COCCO1
Product: CCCCCCCCCCOc1ccc(-c2nc3cc(C(=O)O)ccc3o2)cc1
Temperature: -6.25 °C
Yield: 75 %

Procedure:
Example Compound I-51 was synthesized through the following steps: ##STR88## 1.61 g (40.3 m mole) of sodium hydroxide was dissolved in 10.7 ml of water, followed by cooling at -7.5--5° C. on ice-common salt bath. To the solution, 0.66 ml (25.6 m mole) of bromic acid was added dropwise under stirring, followed by cooling at ca. -5° C. To the mixture solution, 4.2 ml of dioxane was added dropwise under stirring to prepare sodium hypobromite solution. In a 200 ml three-neck flask, 1.50 g (3.81 m mole) of (4-decyloxyphenyl)-5-acetylbenzooxazole synthesized in Example 3, 30 ml of dioxane and 2.5 ml of water were placed, followed by keeping inner temperature below 5° C. under cooling with ice and stirring. To the mixture solution, the above-mentioned sodium hypobromite solution was added dropwise, and the reaction temperature was raised up to 45° C. and maintained for 90 minutes. After the reaction, the reaction mixture was poured into 150 ml of water. To the resultant reaction mixture, 3.2 ml of chloric acid was added to show pH=1 to precipitate a crystal. The crystal was filtered and washed with water, followed by recrystallizing from a mixture solvent of acetone-methanol to obtain 1.13 g of 2-(4-decyloxyphenyl)-5-carboxybenzooxazole (Yield: 75.0%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO>[C:1]([C:5]1[CH:10]=[C:9]([S:11][CH:17]([S:11][C:9]2[CH:8]=[C:7]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:6]([OH:16])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: O=Cc1ccccc1
Solvent: CO
Product: CC(C)(C)c1cc(SC(Sc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c2ccccc2)cc(C(C)(C)C)c1O
Yield: 66.3 %

Procedure:
The procedure of Example 1 is repeated using 23.84 grams of 2,6-di-tert-butyl-4-mercaptophenol, 5.31 grams of benzaldehyde, and 150 ml of methyl alcohol. The product is triturated with methyl alcohol to give 18.74 grams (66% yield) of white crystals, mp 122°-124° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH3:13])[CH:11]=1)[O:8][CH:7]([C:14]([F:17])([F:16])[F:15])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2.[C:23]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:23][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH3:13])[CH:11]=1)[O:8][CH:7]([C:14]([F:17])([F:15])[F:16])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C1=Cc2cc(O)cc(OC)c2OC1C(F)(F)F
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1=Cc2cc(OC)cc(OC)c2OC1C(F)(F)F
Temperature: 55 °C
Yield: 48.5 %

Procedure:
The ethyl 6-hydroxy-8-methoxy-2-(trifluoromethyl)-2H-chromene-3-carboxylate (0.1 g, 0.31 mmole) and K2CO3 (0.23 g, 1.64 mmole) was suspended in acetone (5.0 mL). lodomethane (0.44 g, 3.1 mmole) was added and heated to 55 ° C. for 3 hrs. The contents were filtered through a plug of celite and washed with acetone. The solution was concentrated in vacuo to give a yellow solid (0.05 g, 50%). GCMS m/z 332.0 (M+). LCMS m/z 333.0 (M+H). 1H NMR (CDCl3/400 MHz) 7.64 (s, 1H), 6.54 (s, 1H), 6.32 (s, 1H), 5.68 (q, 1H, J=7.0 Hz), 4.28 (m, 2H), 3.85 (s, 3H), 3.75 (s, 3H), 1.32 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=O.CO>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH2:8][N:10]1[CH2:11][CH2:12][O:13][CH2:14][CH2:15]1
Reactant: O=C(c1cnccc1Cl)N1CCOCC1
Solvent: CO
Solvent: C1CCOC1
Product: Clc1ccncc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
Dissolve (4-chloro-pyridin-3-yl)-morpholin-4-yl-methanone (1.17 g, 5.17 mmol) in dry THF (10 mL). Add a solution of 2 M BH3—Me2S/THF (15 mL, 31.0 mmol) dropwise at room temperature under nitrogen. Stir at room temperature for 15 hours under nitrogen. Add methanol (11.0 mL) very slowly dropwise. Heat at 60° C. for 3 hours, and cool to room temperature in vacuo to afford the title compound (1.1 g, 100%). MS (ES) m/z 213 [M+1]+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7](Cl)(=[O:17])[C:8]1[CH:16]=[CH:15][CH:14]=[C:10]([C:11](Cl)=[O:12])[CH:9]=1>O1CCCC1>[C:8]1([CH2:7][OH:17])[CH:16]=[CH:15][CH:14]=[C:10]([CH2:11][OH:12])[CH:9]=1
Reactant: O=C(Cl)c1cccc(C(=O)Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cccc(CO)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 94 %

Procedure:
To a two-liter, 3-necked round-bottomed flask equipped with a 500-ml constant pressure addition funnel, an overhead stirrer, a thermocouple and a nitrogen inlet was added 27 g (0.74 mol) of lithium aluminum hydride (95%) and 1000 ml of anhydrous tetrahydrofuran (THF). The addition funnel was charged with a solution of 100 g (0.493 mol) of isophthaloyl dichloride in 400 ml of anhydrous THF. Diacylchloride was added slowly over a period of 2 hours with cooling in an ice bath. Once addition was complete the ice bath was removed and the suspension allowed to reach room temperature for four hours at which time it was re-cooled and 200 ml of ethyl acetate was slowly added to decompose the remaining hydride. The addition funnel was recharged with 200 ml of 2M NaOH, which was then added slowly with vigorous stirring until the ensuing suspension became granular in appearance. The suspension was filtered and well washed with ethyl acetate. The combined filtrate and washings were then washed with brine, dried over anhydrous magnesium sulfate and evaporated on a rotary evaporator to yield 64 g (94%) of the title compound as a clear, colorless oil which solidified upon standing.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:35][C:36]1[C:37]([CH3:42])=[CH:38][CH:39]=[CH:40][CH:41]=1>C1COCC1>[CH2:1]([O:8][C:9](=[O:23])[C:10]1([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[CH3:42])[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:14][CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1CBr
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)OCc2ccccc2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccccc1CC1(C(=O)OCc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cold (-78° C.) solution of N-t-butoxycarbonyl isonipecotic acid benzyl ester (13.34 g, 41.8 mmol) in 140 ml of dry THF was added a 1.0 M THF solution of sodium bis trimethysilylamide (59 ml, 59 mmol) over 15 min. The resulting orange solution was stirred at -78° C. for 1 h and then treated dropwise with α-bromo-o-xylene (6.8 ml, 50.7 mmol) and then allowed to warm slowly to room temp. overnight. The reaction was quenched with saturated aqueous NH4Cl, diluted with H2O, and extracted with EtOAc (2×). The combined organic extracts were washed with brine (2×), and concentrated in vacuo to an orange gum. Flash chromatography on silica with 20% to 30% EtOAc/hexane as eluent, combining appropriate fractions, and concentrating in vacuo, afforded the product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:17](=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:7]([C:12](OCC)=[O:13])[N:8]2[CH3:11])=[CH:4][CH:3]=1.O.[NH2:25][NH2:26]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:26][NH:25][C:12](=[O:13])[C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1
Reactant: CCOC(=O)C(=O)c1c(C(=O)OCC)n(C)c2cc(Cl)ccc12
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1n[nH]c(=O)c2c1c1ccc(Cl)cc1n2C

Procedure:
A solution of 4.38 g (13.5 mmol) of ethyl 6-chloro-2-(ethoxycarbonyl)-1-methyl-α-oxo-1H-indole-3-acetate (disclosed in WO-A-00/44751), of 65 ml of glacial acetic acid and of 2.7 ml (55.7 mmol) of hydrazine monohydrate is brought to reflux for 3 h.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][C@H:5]1[CH2:10][CH2:9][CH2:8][O:7][CH2:6]1.C(N(CC)CC)C.[S:26](Cl)([CH3:29])(=[O:28])=[O:27]>C(Cl)Cl>[CH3:29][S:26]([O:1][CH2:2][C@@H:3]([NH:11][C:12]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:18])[CH2:4][C@H:5]1[CH2:10][CH2:9][CH2:8][O:7][CH2:6]1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H](CO)C[C@H]1CCCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)C[C@H]1CCCOC1
Temperature: 25 °C
Yield: 111.6 %

Procedure:
To a solution of tert-butyl (S)-1-hydroxy-3-((R)-tetrahydro-2H-pyran-3-yl)propan-2-ylcarbamate (6.2 g, 23.9 mmol) and triethylamine (7.25 g, 71.8 mmol) in CH2Cl2 at 0° C. was added mesyl chloride (5.5 g, 47.8 mmol) dropwise. The reaction mixture was stirred at rt until the starting material disappeared. The reaction was quenched with ice-cold water and extracted with CH2Cl2 (3×100 ml). The combined organic layers were washed with water (3×50 ml), dried over Na2SO4, and concentrated under vacuo to give the (S)-2-(tert-butoxycarbonylamino)-3-((R)-tetrahydro-2H-pyran-3-yl)propyl methanesulfonate (9 g), which was used for the next step without purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10](OS(C)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:17][CH:18]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1>>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:20]2[CH2:21][CH2:22][CH2:23][CH:18]([OH:17])[CH2:19]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OC1CCCNC1
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Product: CC(C)(C)OC(=O)N1CC(N2CCCC(O)C2)C1
Temperature: 25 °C

Procedure:
A mixture of 1-(t-butoxycarbonyl)-3-methanesulphonyloxyazetidine (see International Patent Application Publication no. WO93/19059) (1.5 g, 4.78 mmol) and 3-hydroxypiperidine (1.9 g, 4 mol. equiv.) was heated at 110° C. for sixteen hours. The mixture was cooled to room temperature and partitioned between ethyl acetate (100 ml) and 5% aqueous sodium bicarbonate solution (100 ml). The layers were separated and the aqueous phase was extracted with a further portion of ethyl acetate (100 ml). The combined organic layers were dried over anhydrous magnesium sulphate. The solution was filtered, the solvent removed from the filtrate under reduced pressure and the crude product purified by column chromatography using silica gel eluting with methanol:dichloromethane (1:9, by volume) to give the title compound (1.4 g). TLC Rf=0.3 (silica, methanol:dichloromethane, 1:9, by volume).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[O:25][N:24]=3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:9]1)=O)(C)(C)C.O1CCOCC1>Cl>[NH:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[O:25][N:24]=3)=[CH:19][CH:18]=2)(=[O:15])=[O:16])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NS(=O)(=O)c2ccc(-c3noc(C(F)(F)F)n3)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=S(=O)(N[C@@H]1CCNC1)c1ccc(-c2noc(C(F)(F)F)n2)cc1
Reaction time: 12 h

Procedure:
(R)—N-(pyrrolidin-3-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzenesulfonamide was synthesized as (R)-3-[4-(5-trifluoromethyl-[1,2,4]oxadiazol-3-yl)-benzenesulfonylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester and the Boc protecting group removed as follows: (277 mg, 0.612 mmol) of the crude coupling product was dissolved in HCl in Dioxane (1531 μL, 6.12 mmol) and stirred for 12 hr. It was concentrated to dryness to receive a brown solid. The crude product was subjected to purification by reverse phase prep-HPLC (gradient elution, water/MeCN both containing 0.1% TFA). Fractions containing the desired compound were combined and freeze-dried. The resulting mixture was dissolved in a mix of AcCN/water. They were load in a PL-HCO3 MP cartridge (from StratoSpheres™ SPE) and eluted with ACN. The eluate was freeze-dried to yield the final compound.
Reaction SMILES: [CH:1]1([N:7]2[C:16](=[O:17])[C:15]3[NH:14][CH:13]=[N:12][C:11]=3[N:10]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:8]2=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:25][C:26](=[O:28])[CH3:27]>>[CH:1]1([N:7]2[C:16](=[O:17])[C:15]3[N:14]([CH2:25][C:26](=[O:28])[CH3:27])[CH:13]=[N:12][C:11]=3[N:10]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)[C:8]2=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)CCl
Reactant: O=c1c2[nH]cnc2n(C2CCCCC2)c(=O)n1C1CCCCC1
Product: CC(=O)Cn1cnc2c1c(=O)n(C1CCCCC1)c(=O)n2C1CCCCC1

Procedure:
1,3-Di-cyclohexyl-7-(2-oxopropyl)-xanthine was prepared from 1,3-di-cyclohexyl xanthine and chloroacetone using an analogous procedure to that described in Example 5. The title compound was isolated as a crystalline solid, m.p. 185° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.O1CCCC1.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(N(CC)CC)C>[NH:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][S:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:24])=[O:23])=[CH:10][CH:9]=2)[CH:5]=[N:6]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccc2[nH]ncc2c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(Nc1ccc2[nH]ncc2c1)c1ccccc1
Yield: 58.5 %

Procedure:
N-(1H-Indazol-5-yl)benzenesulfonamide can be obtained as described in Example 1 from 0.5 g of 5-amino-1H-indazole, 25 ml of tetrahydrofuran, 1.05 ml of triethylamine and 0.73 g of benzenesulfonyl chloride. 0.6 g of N-(1H-indazol-5-yl)benzenesulfonamide is thus obtained in the form of a cream solid melting at 179° C. (analysis C13H11N3O2S % calculated C, 57.13; H, 4.06; N, 15.37; O, 11.71; S, 11.73. % found C, 56.90; H, 4.24; N, 14.21; S, 10.67).