Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)C.[H-].[Na+].[CH3:16][C:17]#[N:18]>C1(C)C=CC=CC=1>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:4](=[O:13])[CH2:16][C:17]#[N:18])[CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)c1cccc(OC)c1
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cccc(C(=O)CC#N)c1
Temperature: 90 °C
Yield: 50 %

Procedure:
To a solution of commercially available 3-methoxy-benzoic acid ethyl ester (3.2 g, 18 mmol) in dry toluene (25 mL), under N2, NaH (50-60% dispersion in mineral oil, 1.44 g, 36 mmol) was carefully added. The mixture was heated at 90° C. and anhydrous CH3CN was added dropwise (4.45 mL, 85.2 mmol). The reaction was heated for 18 hours and the product precipitated from the reaction mixture as Na salt. The reaction was allowed to cool down to room temperature and the solid formed was filtered and washed with ether, then it was redissolved in water and the solution acidified with 2N HCl solution to pH 3 when precipitation of title compound was observed. Filtration of the solid from the aqueous solution afforded 1.57 g of title product (50% yield).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:3]=1.[C:17]([O:20][CH2:21][CH2:22]Br)(=[O:19])[CH3:18]>>[C:17]([O:20][CH2:21][CH2:22][N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([Cl:1])=[N:3][C:4]=2[N:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1)(=[O:19])[CH3:18]
Reactant: CC(=O)OCCBr
Reactant: Clc1nc(N2CCOCC2)c2nc[nH]c2n1
Product: CC(=O)OCCn1cnc2c(N3CCOCC3)nc(Cl)nc21

Procedure:
4-(2-Chloro-9H-purin-6-yl)morpholine (75 mg) was reacted with 2-bromoethyl acetate via General Procedure C to give 2-(2-chloro-6-morpholino-9H-purin-9-yl)ethyl acetate which was reacted with 150 mg tert-butyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl carbonate via General Procedure A and purified via reverse phase HPLC to give 59.4 mg of 144 as a white solid. MS (Q1) 342.2 (M)+
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:10][C:11]([OH:13])=O)=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.C1N=CN(C(N2C=[N:30][CH:29]=[CH:28]2)=O)C=1.C(N(CC)CC)C.Cl.[CH3:40][O:41]NC>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:10][C:11]([N:30]([O:41][CH3:40])[CH2:29][CH3:28])=[O:13])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CNOC
Reactant: O=C(O)COc1c(Cl)nc(Cl)nc1N1CCOCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(OC)C(=O)COc1c(Cl)nc(Cl)nc1N1CCOCC1
Reaction time: 18 h

Procedure:
A mixture of (2,4-dichloro-6-morpholin-4-yl-pyrimidin-5-yloxy)-acetic acid (722 mg, 2.34 mmol) and CDI (493 mg, 3.04 mmol) in DCM (5 mL) was stirred at RT for 1.5 hours before the addition of triethylamine (457 μL, 3.28 mmol) and O,N-dimethyl-hydroxylamine hydrochloride (320 mg, 3.28 mmol). The resulting mixture was stirred for 18 hours then quenched with 1M HCl. The aqueous layer was extracted with DCM and the combined organic extracts were washed with brine, then dried (Na2SO4) and concentrated in vacuo to afford 2-(2,4-Dichloro-6-morpholin-4-yl-pyrimidin-5-yloxy)-N-methoxy-N-ethyl-acetamide as a yellow oil (830 mg, quantitative). LCMS: RT=2.83 min, [M+H]+=351/353/355.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH2:15][CH2:16][CH2:17][CH3:18])[CH:13]=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:21]=[C:22]([Mg]Br)[CH:23]=[CH:24][C:25]=1[Cl:26]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH2:15][CH2:16][CH2:17][CH3:18])[CH:13]([C:23]1[CH:22]=[CH:21][C:20]([Cl:19])=[C:25]([Cl:26])[CH:24]=1)[OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1ccc([Mg]Br)cc1Cl
Reactant: CCCCC1(C=O)CCCN1C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CCCCC1(C(O)c2ccc(Cl)c(Cl)c2)CCCN1C(=O)OC(C)(C)C
Reaction time: 0.33 h
Yield: 46 %

Procedure:
To a stirred solution of 2-butyl-2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.753 g, 2.95 mmol) in THF (12 mL) at 0° C. and under nitrogen was added 3,4-dichlorophenylmagnesium bromide (11.8 mL of a 0.5 M solution in pentanes, 5.9 mmol) dropwise over 10 minutes. After 20 minutes, the reaction mixture was quenched by the addition of saturated aqueous NH4Cl (30 mL) then extracted with EtOAc. The combined extracts were washed with brine then dried (MgSO4), filtered and concentrated in vacuo to a yellow oil (1.9 g). Purification by chromatography (silica, 5-20% EtOAc in hexanes) gave 2-butyl-2-[(3,4-dichloro-phenyl)-hydroxy-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.548 g, 1.36 mmol, 46%) as a colourless gum and as an inseparable mixture of diastereomers
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([OH:6])=[O:5].[OH-].[K+].[F:9][C:10]([F:15])([F:14])[CH2:11][CH2:12][SH:13].Cl>CO>[F:9][C:10]([F:15])([F:14])[CH2:11][CH2:12][S:13][CH2:2][CH2:3][C:4]([OH:6])=[O:5]
Reactant: FC(F)(F)CCS
Reactant: O=C(O)CCBr
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCSCCC(F)(F)F
Temperature: 50 °C
Yield: 87.7 %

Procedure:
A 100-mL, 3-neck round bottom flask was charged with 3-bromopropanoic acid (500 mg, 3.27 mmol) and methanol (10 mL), potassium hydroxide (KOH, 403 mg, 7.19 mmol) was added, followed by 3,3,3-trifluoropropane-1-thiol (468 mg, 3.60 mmol). The mixture was heated at 50° C. for 4 hours, after which it was acidified with hydrochloric acid (2 N) and extracted with methyl tert-butylether (2×10 mL). The organic layer was concentrated to dryness to afford a light yellow oil (580 mg, 88%): 1H NMR (400 MHz, CDCl3) δ 2.83 (td, 0.1=7.1, 0.9 Hz, 2H), 2.78-2.64 (m, 4H), 2.48-2.32 (m, 2H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH3:10][C@@:11]12[C@@H:19]([OH:20])[CH2:18][CH2:17][C@H:16]1[C@@H:15]1[CH2:21][CH2:22][C:23]3[CH:28]=[C:27]([OH:29])[CH:26]=[CH:25][C:24]=3[C@H:14]1[CH2:13][CH2:12]2>N1C=CC=CC=1>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:1]([O:29][C:27]2[CH:26]=[CH:25][C:24]3[C@@H:14]4[C@H:15]([C@H:16]5[C@@:11]([CH2:12][CH2:13]4)([CH3:10])[C@@H:19]([O:20][C:1]([C:2]4[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=4)=[O:8])[CH2:18][CH2:17]5)[CH2:21][CH2:22][C:23]=3[CH:28]=2)=[O:8])[CH:3]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Solvent: c1ccncc1
Product: C[C@]12CC[C@@H]3c4ccc(OC(=O)c5cccnc5)cc4CC[C@H]3[C@@H]1CC[C@@H]2OC(=O)c1cccnc1
Temperature: 0 °C
Yield: 90.3 %

Procedure:
To 5.3 g (0.03 mol) of nicotinoyl chloride in 30 mL of dry pyridine at 0° C. were added 2.0 g (0.0073 mol) of β-estradiol. The reaction mixture was refluxed for 1 hour, then was poured over 100 mL of ice water, and the resulting precipitate was collected by filtration. The precipitate was dried in vacuo over P2O5, affording 3.18 g (90%) of the title compound melting at 148°-150° C.
Reaction SMILES: [CH3:1][C@H:2]1[C@H:28](C)[C@@H:27]2[C@@:5]([C:31]([OH:33])=[O:32])([CH2:6][CH2:7][C@@:8]3([CH3:30])[C@:13]4([CH3:26])[CH2:14][CH2:15][C@H:16]5[C:21]([CH3:23])([CH3:22])[C@@H:20]([OH:24])[CH2:19][CH2:18][C@:17]5([CH3:25])[C@H:12]4[CH2:11][CH:10]=[C:9]32)[CH2:4][CH2:3]1.[CH3:34][O-].[Na+:36]>CO.C(Cl)(Cl)Cl>[CH3:25][C@@:17]12[C@H:12]3[CH2:11][CH:10]=[C:9]4[C@@H:27]5[CH2:28][C:2]([CH3:34])([CH3:1])[CH2:3][CH2:4][C@:5]5([C:31]([O-:33])=[O:32])[CH2:6][CH2:7][C@@:8]4([CH3:30])[C@:13]3([CH3:26])[CH2:14][CH2:15][C@H:16]1[C:21]([CH3:22])([CH3:23])[C@@H:20]([OH:24])[CH2:19][CH2:18]2.[Na+:36]
Reactant: C[C@H]1[C@H](C)CC[C@]2(C(=O)O)CC[C@]3(C)C(=CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@H]12
Reactant: C[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC1(C)CC[C@]2(C(=O)[O-])CC[C@]3(C)C(=CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]2C1
Reaction time: 0.5 h

Procedure:
30 mg of 3-O-(α-L-arabopyranosyl) ursolic acid was dissolved in methanol/chloroform (4 ml, 3/1), added with 5 mg of NaOMe, then stirred at room tempreature for 30 min and filtered to separate out a white solid. The solid was washed with methanol and dried to obtain 3-O-(α-L-arabopyranosyl) ursolic acid sodium salt.
Reaction SMILES: N[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1.Br[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]([Cl:22])=[CH:15][N:14]=1.I([O-])(=O)(=O)=O.[Na+].[OH2:29]>C1COCC1.[Os](=O)(=O)(=O)=O>[Cl:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([CH:13]=[O:29])=[N:3][CH:4]=1.[Cl:22][C:16]1[CH:17]=[C:18]([N+:19]([O-:21])=[O:20])[C:13]([CH:2]=[CH2:7])=[N:14][CH:15]=1
Reactant: Nc1ncc(Cl)cc1[N+](=O)[O-]
Reactant: O
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Br
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Product: C=Cc1ncc(Cl)cc1[N+](=O)[O-]
Product: O=Cc1ncc(Cl)cc1[N+](=O)[O-]
Yield: 72 %

Procedure:
2-Amino-3-(6-chloro-3-methoxy-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile (39 mg) was prepared quantitatively using a procedure similar to that described in Example 1, part b, except starting from 1-(6-chloro-3-methoxy-2H-pyrazolo[4,3-b]pyridin-2-yl)propan-2-one (32 mg). 1-(6-Chloro-3-methoxy-2H-pyrazolo[4,3-b]pyridin-2-yl)propan-2-one was prepared using a procedure similar to that described in Example 105 part a to d except using 5-chloro-3-nitropyridine-2-carboxaldehyde (1.2 g) and decaborane in part a to yield [2-(tert-butyldimethylsilanyloxy)propyl]-(5-chloro-3-nitropyridin-2-yl-methyl)amine (0.4 g, 17%). 5-Chloro-3-nitropyridine-2-carboxaldehyde was prepared using a procedure similar to that described in Example 136 part a to c except starting from 2-amino-5-chloro-3-nitropyridine in part a or using commercially available 2-bromo-5-chloro-3-nitropyridine in part b. Alternatively, oxidative cleavage using a 4% solution of osmium tetroxide in water (2 mL) and sodium periodate (1.2 g) was carried out in a mixture of THF and water (10:1, 20 mL) in part c instead of ozonolysis following a procedure similar to that described in Example 61 to afford 5-chloro-3-nitropyridine-2-carboxaldehyde (0.72 g, 72%) from 5-chloro-3-nitro-2-vinylpyridine (1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[NH:13][N:14]=[C:15]([NH2:21])[C:16]([O:18]CC)=O)=[O:5].[CH3:26][NH:27][CH3:28]>CO>[Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[NH:13][N:14]=[C:15]([NH2:21])[C:16](=[O:18])[N:27]([CH3:28])[CH3:26])=[O:5]
Reactant: CCOC(=O)C(N)=NNc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Reactant: CNC
Solvent: CO
Product: CN(C)C(=O)C(N)=NNc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Reaction time: 8 h
Yield: 85.5 %

Procedure:
To a suspension of 1-[2-(2-chlorobenzoyl)-4-chlorophenyl]-2-(1-amino-1-ethoxycarbonylmethylene)hydrazine (24.9 g) in methanol (300 ml), excess of gaseous dimethylamine is introduced at room temperature, and the reaction mixture is allowed to stand overnight. After evaporating the solvent under reduced pressure, the residue is recrystallized from ethanol to give 1-[2-(2-chlorobenzoyl)-4-chlorophenyl]-2-(1-amino-1-dimethylcarbamoylmethylene)hydrazine (21.3 g) as reddish orange crystals melting at 150 to 151° C. The yield is 85.5%.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH3:11])[CH:5]=[CH:6][CH:7]=1.C([O-])(=O)C.[NH4+:17].C([BH3-])#N.[Na+].[ClH:22]>CO>[Cl:22][C:2]1[CH:3]=[C:4]([CH:8]([NH2:17])[CH2:9][CH2:10][CH3:11])[CH:5]=[CH:6][CH:7]=1
Reactant: Cl
Reactant: CCCC(=O)c1cccc(F)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCC(N)c1cccc(Cl)c1
Yield: 28 %

Procedure:
To a solution of 1-(3-fluorophenyl)butan-1-one (430 mg, 2.4 mmol) and ammonium acetate (1.09 g, 14.1 mmol) in methanol (10 mL) under nitrogen was added sodium cyanoborohydride (2.35 ml, 1M solution in THF, 2.35 mmol). The solution was stirred at room temperature for 38 h. after which time conc. HCl was added to give a pH˜2. After bubbling had ceased the solvent was removed under reduced pressure and the residue dissolved in ethyl acetate and water. The organic phase was collected and the aqueous phase washed with ethyl acetate (20 mL). The aqueous phase was basified to pH˜10 with solid KOH and the product extracted into ethyl acetate (3×20 mL). The organic layers were combined, washed with brine, dried (Na2SO4) and concentrated to give a pure product (120 mg, 28%).
Reaction SMILES: C[O-].[Na+].CO.[CH3:6][O:7][CH:8]([C:13]([O:15]C)=O)[C:9](OC)=[O:10].C(O)(=O)C.[CH:21]([NH2:23])=[NH:22]>>[CH3:6][O:7][C:8]1[C:13]([OH:15])=[N:22][CH:21]=[N:23][C:9]=1[OH:10]
Reactant: COC(=O)C(OC)C(=O)OC
Reactant: N=CN
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1c(O)ncnc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.8 %

Procedure:
A 2-liter, three-necked, round-bottomed flask equipped with a mechanical stirrer and a reflux condenser was dried at 100° C. and cooled to 25° C. under N2. Methanol (260 mL) was added, followed by a solution of sodium methoxide in methanol (25% by weight, 670 mL, 3.10 mol). The resulting solution was cooled to 0° C. Dimethyl methoxymalonate (151 g, 0.930 mol) was added in one portion, followed by formamidine acetate (100 g, 0.96 mol). The temperature was kept below 10° C. The resulting suspension was then stirred at 0° C. for 30 min, and refluxed for 1 h. The resulting suspension was cooled to 0° C. and quenched with concentrated HCl (250 mL) over 30 min, during which time the temperature was kept below 10° C. Stirring was continued at 5° C. for 30 min. The suspension was then filtered. The filter cake was re-suspended in water (1000 mL) and refluxed until a nearly clear solution was obtained. The solution was filtered while hot. The filtrate was cooled to 0-5° C. and stirred for 1 h. The solid precipitate was collected by filtration, washed with cold methanol (500 mL), and dried in a vacuum oven at 50° C. for 1 h to give the title compound (96.2 g, 73% yield) as a white solid. Exact Mass calculated for C5H6N2O3: 142.0, LCMS m/z=143.2 (M+H+); 1H NMR (400 MHz, DMSO-d6) δ 3.63 (s, 3H), 7.81 (s, 1H), 11.75 (br s, 2H).
Reaction SMILES: [N:1]1([C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=[CH:2]1.P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.[NH2:32][C:33]1[CH:50]=[CH:49][C:36]([C:37]([N:39]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:42][CH2:41][CH2:40]2)=[O:38])=[CH:35][CH:34]=1.C(N(CC)CC)C>O1CCCC1>[N:1]1([C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([NH:32][C:33]2[CH:50]=[CH:49][C:36]([C:37]([N:39]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH2:42][CH2:41][CH2:40]3)=[O:38])=[CH:35][CH:34]=2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5]1
Reactant: Nc1ccc(C(=O)N2CCCc3ccccc32)cc1
Reactant: O=C(O)c1ccccc1-n1cccc1
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(=O)N2CCCc3ccccc32)cc1)c1ccccc1-n1cccc1
Temperature: 25 °C
Yield: 60.5 %

Procedure:
To a solution of 2-(1-pyrrolyl)benzoic acid (206 mg), diphenyl chlorophosphate (325 mg), 1-(4-aminobenzoyl}-1,2,3,4-tetrahydroquinoline (277 mg) in tetrahydrofuran (10 ml) was added triethylamine (333 mg) at 0° C. The resulting mixture was allowed to warm to ambient temperature where it was maintained for 5 hours. The solvent was evaporated and diluted with ethyl acetate and washed with water, saturated sodium bicarbonate aqueous solution and brine. The organic layer was dried over sodium sulfate and concentrated to give 1-{4-[2-(1-pyrrolyl)benzoylamino]benzoyl}-1,2,3,4tetrahydroquinoline (280 mg).
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])[C:9]2[C:8](=[O:20])[NH:7][C:6](=[O:21])[N:5]([CH3:22])[C:4]=2[N:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:30][CH3:31].[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>CN(C=O)C.O.CS(C)=O>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([F:18])[C:12]=1[CH2:11][N:10]1[C:9]2[C:8](=[O:20])[N:7]([CH2:30][CH3:31])[C:6](=[O:21])[N:5]([CH3:22])[C:4]=2[N:3]=[C:2]1[N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: C1CCNCC1
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Br)n2Cc1c(F)cccc1Cl
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)c2c(nc(N3CCCCC3)n2Cc2c(F)cccc2Cl)n(C)c1=O
Temperature: 50 °C
Yield: 19.4 %

Procedure:
A solution of 8-bromo-7-(2-chloro-6-fluorobenzyl)-3-methyl-3,7-dihydro-1H-purine-2,6-dione (200 mg, 0.52 mmol) and K2CO3 (357 mg, 2.6 mmol) in 4 mL DMF was treated with iodoethane (412 μL, 5.2 mmol). The reaction was heated to 50° C. for 48 hr. The reaction mixture was cooled, diluted with H2O, and extracted 3× with 50% EtOAc:hexanes. The organic layers were combined and the solvent removed under reduced pressure (116 mg, 54% yield). The crude product (52 mg, 0.13 mmol) was dissolved in 200 μL DMSO and treated with piperidine (37 μL, 0.38 mmol). The reaction mixture was heated to 100° C. for 15 hr. The reaction mixture was cooled, diluted with H2O, and extracted 3× with 50% EtOAc:hexanes. The organic layers were combined, dried with Mg2SO4, and evaporated under reduced pressure. The crude product was purified by preparative thin layer chromatography (silica gel, 1 mm plate, EM Science 20×20 cm silica gel 60 F264) eluting with EtOAc:hexane (1:1) to give 31 mg (56% yield) of the title compound as a white solid: 1H NMR (CDCl3, 400 MHz) 7.21-7.14 (m, 1H), 7.13-7.09 (m, 1H), 6.96-6.90 (m, 1H), 5.53 (s, 2H), 3.96 (q, 2H, J=7.0 Hz), 3.49 (s, 3H), 3.09-3.00 (m, 4H), 1.54-1.46 (m, 6H), 1.13 (t, 3H, J=7.0 Hz); MS (ESP+) m/e 420 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[Br:16])[C:12]([F:18])([F:17])[O:11][C:10]3([F:20])[F:19])[N:5]=[C:4]([C:21]#[N:22])[CH:3]=1.[F:23][C:24]([F:29])([F:28])[S:25]([O-])=[O:26].[Na+].S(C1C=CC(C)=CC=1)(O)(=O)=O.CNC.S(Cl)(Cl)=O>C1(C)C=CC=CC=1.O>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[Br:16])[C:12]([F:18])([F:17])[O:11][C:10]3([F:20])[F:19])[N:5]=[C:4]([C:21]#[N:22])[C:3]=1[S:25]([C:24]([F:29])([F:28])[F:23])=[O:26]
Reactant: N#Cc1cc(N)n(-c2cc3c(cc2Br)C(F)(F)OC3(F)F)n1
Reactant: O=S([O-])C(F)(F)F
Agent: CNC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: O
Product: N#Cc1nn(-c2cc3c(cc2Br)C(F)(F)OC3(F)F)c(N)c1S(=O)C(F)(F)F
Temperature: 55 °C
Yield: 20.3 %

Procedure:
To a suspension wherein 5-amino-1-(6-bromo-1,1,3,3-tetrafluoro-1,3-dihydroisobenzofuran-5-yl)-3-cyanopyrazole (754 mg, 2.00 ml), sodium trifluoromethane-sulfinate (406 mg, 2.60 mmol) and dimethylamine tosylate (652 mg, 3.00 mmol) are in toluene (5 ml), thionyl chloride (309, mg, 2.60 mmol) was added dropwise under ice cooling over a period of about 10 minutes and then stirred under heating at 50 to 60° C. for 10 hours. After allowing time to cool, the reaction solution was poured into water, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography to give 200 mg of 5-amino-1-(6-bromo-1,1,3,3-tetrafluoro-1,3-dihydroisobenzofuran-5-yl)-3-cyano-4-trifluoromethylsulfinylpyrazole.
Reaction SMILES: O.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:5][CH2:4]1.[C:20]1([CH3:29])[CH:25]=[CH:24][CH:23]=[C:22]([N:26]=[C:27]=[O:28])[CH:21]=1.Cl.CCOCC>>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([CH2:10][CH2:9][N:6]2[CH2:7][CH2:8][CH:3]([NH:2][C:27]([NH:26][C:22]3[CH:21]=[C:20]([CH3:29])[CH:25]=[CH:24][CH:23]=3)=[O:28])[CH2:4][CH2:5]2)=[CH:12]1
Reactant: Cc1cccc(N=C=O)c1
Reactant: NC1CCN(CCc2c[nH]c3ccccc23)CC1
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: Cc1cccc(NC(=O)NC2CCN(CCc3c[nH]c4ccccc34)CC2)c1
Yield: 83.2 %

Procedure:
Condensation of 3-[2-(4-Aminopiperidyl)ethyl]indole, hydrate (1.31 g.) and 3-tolyl isocyanate (0.70 g., 5% excess) in the manner of Example 1 gave the crude title compound (1.70 g.) from which was obtained a pure hydrochloride (1.57 g., m.p. 228.9°, dec.) by treatment with ethanolic HCl/ether.
Reaction SMILES: Cl.[C@H:2]12[CH2:8][C@H:5]([NH:6][CH2:7]1)[CH2:4][N:3]2[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]#[N:20])=[CH:11][CH:10]=1.C(N(CC)C(C)C)(C)C.[CH3:30][O:31][CH2:32][C:33](Cl)=[O:34].O>ClCCl>[CH3:30][O:31][CH2:32][C:33]([N:6]1[CH2:7][C@@H:2]2[CH2:8][C@H:5]1[CH2:4][N:3]2[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]#[N:20])=[CH:11][CH:10]=1)=[O:34]
Reactant: COCC(=O)Cl
Reactant: N#Cc1ccc(N2C[C@@H]3C[C@H]2CN3)c2ccccc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COCC(=O)N1C[C@@H]2C[C@H]1CN2c1ccc(C#N)c2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
165RL09 (16.5 mg, 0.066 mmol) was dissolved in dichloromethane (1 mL). N,N-Diisopropylethylamine (DIPEA) (9.4 mg, 0.073 mmol) was added followed by methoxyacetyl chloride (7.9 mg, 0.073 mmol). The mixture was shaken in a vial at rt for 18 hours. Water (3 mL) was added and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×5 mL) and the combined organic layers were evaporated. The compound was further purified by column chromatography on silica gel using ethyl acetate/methanol (1:1) to give the title compound (21 mg, 97%).
Reaction SMILES: N=C=N.[OH:4][CH:5]1[C:14]2[C:9](=[N:10][C:11]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[N:13]=2)[N:8]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=O)[CH2:7][CH2:6]1.C1CCC(NCC(F)=C2CCCCC2)CC1.[CH3:54][S:55]([NH2:58])(=[O:57])=[O:56]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[OH:4][CH:5]1[C:14]2=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)[N:10]=[C:9]2[N:8]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([NH:58][S:55]([CH3:54])(=[O:57])=[O:56])=[O:37])[CH2:7][CH2:6]1
Reactant: CS(N)(=O)=O
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(CCCCCCC(=O)O)CCC3O)cc1
Agent: CN(C)c1ccncc1
Agent: FC(CNC1CCCCC1)=C1CCCCC1
Agent: N=C=N
Solvent: ClCCl
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(CCCCCCC(=O)NS(C)(=O)=O)CCC3O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of polymer supported carbodiimide (1.36 mmol/g, 60 mg, 0.082 mmol) in DCM (dry) at RT (2 ml) under nitrogen was treated with (R or S)-7-(8-Hydroxy-2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoic acid ([prepared according to the preparation procedures disclosed in PCT patent application PCT/EP2011/062028 Example 9.8a)(25 mg, 0.054 mmol), methanesulfonamide (5.17 mg, 0.054 mmol) followed by DMAP (6.65 mg, 0.054 mmol). The resulting orange suspension was stirred at RT overnight under an atmosphere of nitrogen. The reaction mixture was diluted with DCM (20 ml) and washed with 10% aqueous citric acid solution (20 ml×2), passing the organic portion through a phase separating column. The organic filtrate was concentrated under reduced pressure. Purification of the crude material by chromatography on silica eluting with EtOAc/iso-hexane followed by further purification by SFC (Chiralpak AD 250×10 mm; 30% IPA) afforded the titled compound;
Reaction SMILES: [Si:1]([N:8]1[C:11](=[O:12])[CH2:10][C@H:9]1[C:13]([OH:15])=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li+].[CH3:17]C([N-]C(C)C)C.CI>C1COCC1>[Si:1]([N:8]1[C:11](=[O:12])[C@H:10]([CH3:17])[C@H:9]1[C:13]([OH:15])=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)C[C@H]1C(=O)O
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: C[C@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1C(=O)O
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of (S)-1-(tert-butyldimethylsilyl)-4-oxoazetidine-2-carboxylic acid 4 (2.00 g, 8.73 mmol.) in THF (30 ml) at −78° C. was added LDA (19 ml, 2.0 eq.). After the solution was stirred for 20 min. at −78° C., it was warmed to 0° C. for 5 min. The solution was re-cooled to −78° C. and methyl iodide (3.10 g, 2.5 eq.) in THF (5 ml) was added. The reaction solution was warmed up to room temperature, quenched with aqueous KHSO4 solution (10%, 30 ml), extracted with ethyl acetate (3×). The combined organic layers were washed with brine twice and dried with MgSO4. After concentrating in vacuo, 47 was obtained. H1NMR (CDCl3): 0.15, 0.35 (s, 6H), 1.14 (s, 9H), 1.35 (d, 3H), 3.71 (d, 1H), 4.14 (m, 1H). C11H21NO3Si, Mol. Wt.: 243.37. Found: 244 (M+1).