Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[C:4]1[CH:23]=[CH:22][C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][CH:21]=2)[CH:12]=[C:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:6][CH:5]=1.[CH3:26][C:27]1[C:31]([CH3:32])=[C:30]([NH:33][C:34](=O)[O:35]C2C=CC=CC=2)[O:29][N:28]=1.NC1ON=C(C)C=1C.C(N(C(C)C)CC)(C)C>C(#N)C>[F:25][C:3]([F:2])([F:24])[C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][CH:21]=2)[CH:12]=[C:13]2[CH2:18][CH2:17][N:16]([C:34]([NH:33][C:30]3[O:29][N:28]=[C:27]([CH3:26])[C:31]=3[CH3:32])=[O:35])[CH2:15][CH2:14]2)=[CH:22][CH:23]=1
Reactant: Cc1noc(NC(=O)Oc2ccccc2)c1C
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)cc1
Agent: Cc1noc(N)c1C
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(NC(=O)N2CCC(=Cc3cccc(Oc4ccc(C(F)(F)F)cc4)c3)CC2)c1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-(3-(4-(Trifluoromethyl)phenoxy)benzylidene)piperidine hydrochloride (200 mg, 0.541 mmol, from Example 53, Step 5), phenyl 3,4-dimethylisoxazol-5-ylcarbamate (126 mg, 0.541 mmol, prepared according to the procedure described in Synthesis, 1997, 1189-1194 from 5-amino-3,4-dimethylisoxazole) and diisopropylethylamine (0.20 mL, 1.15 mmol) were combined in acetonitrile (5 mL) and stirred at room temperature. After 16 h, the reaction was concentrated and the residue was purified by silica gel chromatography (0-30% EtOAc:CH2Cl2) to afford the title compound (218 mg) as a white solid. MS APCI M+ 472.3, 431.2, 375.3, 334.2; 1H NMR (400 MHz, CD3OD) δ ppm 1.83 (s, 3H) 2.18 (s, 3H) 2.44 (td, J=5.77, 1.07 Hz, 2H) 2.54 (td, J=5.81, 1.16 Hz, 2H) 3.49-3.54 (m, 2H) 3.59-3.63 (m, 2H) 6.44 (s, 1H) 6.90-6.98 (m, 2H) 7.05-7.14 (m, 3H) 7.35-7.44 (m, 1H) 7.59-7.67 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]2[C:22]3[C:21](=[O:23])[CH2:20][CH2:19][CH2:18][C:17]=3[NH:16][C:15]3[CH2:14][CH2:13][CH2:12][C:11](=O)[C:10]2=3)[CH:6]=[CH:7][CH:8]=1)#[N:2].[BH4-].[Na+].C(O)C.O>C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]2[C:22]3[C:21](=[O:23])[CH2:20][CH2:19][CH2:18][C:17]=3[NH:16][C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=3)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(C2C3=C(CCCC3=O)NC3=C2C(=O)CCC3)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: N#Cc1cccc(C2C3=C(CCCC3)NC3=C2C(=O)CCC3)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of 9-(3-cyanophenyl)-3,4,6,7,9,10-hexahydro-1,8-(2H,5H)-acridinedione (3.18 g), sodium borohydride (2.50 g) and 50 mL of ethanol was stirred at 70° C. overnight. The mixture was treated with about 300 mL of water, stirred for several hours and the solid collected by suction filtration, slurried on the funnel with a little ethanol and sucked dry on the funnel. The solid (1.87 g) was combined with 0.49 g of material from a previous run and the combined material was chromatographed, with methanol:dichloromethane (2.5:97.5) as elutent. The solvent evaporated and the residue taken up in 50 mL of methanol and about 20 mL of methylene chloride. The solution was concentrated on a steam bath until crystals started to form, was treated with an equal volume of ethyl acetate and refrigerated overnight. The title compound was obtained as bright yellow crystals (1.16 g); mp 246°-249° C.; NMR: 1.47 (broad s,2, CH2), 1.65-1.87 (m,6, CH2), 2.11 (m,4, CH2), 2.39-2.51 (m,2, CH2), 4.25 (s,1, CH), 7.41-7.57 (m,4, Ar), 8.45 (s,1, NH); (CI, CH4) MS: m/z=305(M+1). Analysis for C20H20N2O: Calculated: C, 78.92; H, 6.62; N, 9.20; Found: C, 78.64; H, 6.65; N, 9.08.
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CN(C)C=O.C(N(C(C)C)C(C)C)C.[Cl:33][C:34]1[CH:48]=[CH:47][C:37]2[N:38]=[C:39]([N:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)[S:40][C:36]=2[CH:35]=1>>[Cl:33][C:34]1[CH:48]=[CH:47][C:37]2[N:38]=[C:39]([N:41]3[CH2:46][CH2:45][N:44]([C:9]([C:8]4[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:7]=4[N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[O:11])[CH2:43][CH2:42]3)[S:40][C:36]=2[CH:35]=1
Reactant: Clc1ccc2nc(N3CCNCC3)sc2c1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc([N+](=O)[O-])ccc1N1CCOCC1)N1CCN(c2nc3ccc(Cl)cc3s2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 0.25 mmol 2-morpholin-4-yl-5-nitro-benzoic acid (Example 2.1) in 0.7 ml dimethylformamide 0.26 mmol TBTU, 1.6 mmol N-ethyldiisopropylamine and 0.25 mmol 6-chloro-2-piperazin-1-yl-benzothiazole were successively added. The reaction was then stirred at RT for two hours, concentrated in vacuo and treated with 5 ml water. The solid is filtered off and recrystallized form methanol to yield the title compound as a yellow solid.
Reaction SMILES: C([N:4]1[C:9]2[CH:10]=[CH:11][C:12]([Br:14])=[CH:13][C:8]=2[O:7][CH2:6][CH2:5]1)(=O)C.[OH-].[Na+]>CO>[Br:14][C:12]1[CH:11]=[CH:10][C:9]2[NH:4][CH2:5][CH2:6][O:7][C:8]=2[CH:13]=1
Reactant: CC(=O)N1CCOc2cc(Br)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Brc1ccc2c(c1)OCCN2
Temperature: 50 °C
Reaction time: 2 h
Yield: 75.6 %

Procedure:
A solution of 4-acetyl-7-bromo-3,4-dihydro-2H-benzo[1,4]oxazine (9.5 g, Reference Example 13) in methanol (200 ml) was treated with aqueous sodium hydroxide (50 ml, 3M) was stirred at 50° C. for 2 hours. The mixture was evaporated to low bulk, then diluted with water (100 ml) and then extracted three times with dichloromethane (200 ml). The combined extracts were dried over magnesium sulphate then evaporated to give the title compound (6.0 g) as a brown oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH2:26][C@@H:27]([CH3:30])[CH2:28][OH:29]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:26][C@@H:27]([CH3:30])[CH2:28][OH:29])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: C[C@H](N)CO
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N[C@@H](C)CO)c2c1

Procedure:
The title compound was prepared in analogy to Example 8-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and (2S)-2-aminopropan-1-ol. MS obsd. (ESI+) [(M+H)+] 412, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.89 (t, J=6.32 Hz, 2 H), 7.75 (s, 1 H), 7.64 (t, J=7.20 Hz, 1 H), 7.55-7.43 (m, 1 H), 7.38-7.27 (m, 1 H), 7.27-7.14 (m, 1 H), 6.16 (d, J=8.08 Hz, 1 H), 6.07 (s, 1 H), 5.07 (brs, 2 H), 4.85 (brs, 1 H), 4.42 (brs, 1 H), 3.85 (dt, J=12.82, 6.35 Hz, 1 H), 3.70-3.47 (m, 3 H), 2.36 (s, 3 H), 1.23 (d, J=6.32 Hz, 3 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=O)[C:11]([C:15]#[N:16])=[CH:10][C:9]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:12]1[C:11]([C:15]#[N:16])=[CH:10][C:9]([C:17]2[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=2)=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1ccc(-c2cc(C#N)c(=O)[nH]c2-c2ccc(F)cc2)cc1
Product: CSc1ccc(-c2cc(C#N)c(Cl)nc2-c2ccc(F)cc2)cc1

Procedure:
A solution of 6-(4-fluorophenyl)-1,2-dihydro-5-[4-(methylthio)phenyl]-2-oxo-pyridine-3-carbonitrile (Example 1, Step 5) (3.7 g, 0.011 mole) in phosphorus oxychloride (45 ml) was stirred at 100° C. for 20 hours. After evaporation of the phosphorus oxychloride the residue was purified by silica gel chromatography and recrystallized from ethyl acetate-hexane.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[C:10]([OH:12])=[O:11]>C(O)(C(F)(F)F)=O>[CH3:5][O:6][C:7]1[C:15]([O:16][CH2:17][CH2:18][CH2:19][N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)=[CH:14][C:13]([N+:1]([O-:4])=[O:2])=[C:9]([CH:8]=1)[C:10]([OH:12])=[O:11]
Reactant: COc1cc(C(=O)O)ccc1OCCCN1CCOCC1
Reactant: O=[N+]([O-])O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)O)c([N+](=O)[O-])cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
Fuming nitric acid (1.5 ml, 36.2 mmol) was added slowly at 0° C. to a solution of 3-methoxy-4-(3-morpholinopropoxy)benzoic acid (7.78 g, 23.5 mmol) in TFA (25 ml). The cooling bath was removed and the reaction mixture stirred at ambient temperature for 1 hour. The TFA was removed by evaporation and ice was added to the residue. The precipitate was collected by filtration, washed with a minimum of water followed by toluene and ether. The solid was dried under vacuum over phosphorus pentoxide to give 5-methoxy-4-(3-morpholinopropoxy)-2-nitrobenzoic acid (7.54 g) which was used without flirther purification.
Reaction SMILES: [Mg].[CH2:2](Br)[C:3]#[CH:4].[Cl:6][CH2:7][C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12].[Cl-].[NH4+]>CCOCC>[Cl:6][CH2:7][C:8]([OH:13])([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:4][C:3]#[CH:2]
Reactant: CCCCC(=O)CCl
Reactant: C#CCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: C#CCC(O)(CCl)CCCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 2.1 g. of magnesium and 20 mg. of mercuric chloride in 25 ml. of ether is added 0.8 ml. of propargyl bromide. After a few minutes of vigorous stirring, to this is added a mixture of 10.75 g. of 1-chloro-2-hexanone and 7.2 ml. of propargyl bromide in 25 ml. of ether, at such a rate that the reaction mixture is maintained at 25°-28° C. After addition, the mixture is stirred at room temperature one hour, cooled in an ice-water bath and 30 ml. of saturated ammonium chloride is added dropwise. The mixture is filtered through celite and washed with ether. The ether solution is concentrated to give 11.0 g. of a yellow liquid which is vacuum distilled to give 6.9 g. of product as a colorless liquid at b.p. 60°-61° C./-4 mm.; PMRδ 3.62 (ABq, CH2Cl), 2.53 (d, J=3, C≡C--CH2), 2.06 (t, j=3, HC≡C).
Reaction SMILES: [Mg].[CH2:2]([CH:4]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1)[CH3:3].[N:18]1[C:25](Cl)=[N:24][C:22](Cl)=[N:21][C:19]=1[Cl:20]>O1CCCC1>[Cl:20][C:19]1[N:21]=[C:22]([C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH:4]([CH2:2][CH3:3])[CH2:14][CH2:15][CH2:16][CH3:17])=[CH:8][CH:9]=2)[N:24]=[C:25]([C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH:4]([CH2:2][CH3:3])[CH2:14][CH2:15][CH2:16][CH3:17])=[CH:8][CH:9]=2)[N:18]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCCCC(CC)COc1ccc(Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCC(CC)COc1ccc(-c2nc(Cl)nc(-c3ccc(OCC(CC)CCCC)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
3.65 g (0.15 mol) of magnesium turnings are placed in a 100 ml sulfonating flask fitted with stirrer, condenser, dry pipe, dropping funnel and internal thermometer under inert gas (dry nitrogen), and etching of the turnings is initiated with a few crystals of iodine. 150 ml of anhydrous tetrahydrofuran are added, and a solution of 42.8 g (0.15 mol) of 4-(2-ethylhexyloxy)bromobenzene in 30 ml of tetrahydrofuran is added dropwise over the course of 45 minutes (room temperature). After gentle heating on the waterbath (40 C.) the Grignard reaction starts up (clouding, exothermic). The mixture is stirred at 40 C. for one hour and then under reflux (66 C.) until virtually all of the magnesium has dissolved (about 30 minutes). After cooling to room temperature, the Grignard solution is added dropwise at 0-C. over the course of 60 minutes to a solution of 9.2 g (0.05 mol) of cyanuric chloride in 40 ml of tetrahydrofuran (350 ml sulfonating flask, stirrer, condenser, dry pipe, dropping funnel, internal thermometer, inert gas). The mixture is stirred under reflux (66 C.) overnight and then evaporated to dryness. The residue is stirred with 100 ml of ice-cold 2N hydrochloric acid and then subjected to extraction with 200 ml of toluene. The organic phase is shaken twice with 10% brine, dried over sodium sulfate and concentrated by evaporation. The crude product (40.3 g, red oil) is still heavily contaminated (thin-layer chromatogram). To purify it, it is dissolved in 80 ml of toluene/hexane (1/1) and the solution is chromatographed over silica gel (5 cm×45 cm). 18.2 g (69.5%) of 2-chloro-4,6-bis[4-(2-ethylhexyloxy)phenyl]-s-triazine are isolated as a yellow resin.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][Br:8].[S:9]1[CH2:13][C:12](=[O:14])[NH:11][C:10]1=[O:15].C(N(CC)CC)C>C(#N)C>[Br:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:11]1[C:12](=[O:14])[CH2:13][S:9][C:10]1=[O:15]
Reactant: O=C1CSC(=O)N1
Reactant: BrCCCCCCBr
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CSC(=O)N1CCCCCCBr
Temperature: 25 °C
Yield: 69.4 %

Procedure:
36.6 g of 1,6-dibromohexane, 5.9 g of 2,4-thiazolidinedione and 7.1 g of triethylamine were added to 125 ml of acetonitrile and the mixture was heated with stirring under reflux for 8 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure and the residue was poured into water. The mixture was extracted with methylene chloride and the methylene chloride layer was washed with saturated brine and dried over sodium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1→4:1) to obtain 9.8 g of the title compound as pale yellow oil (yield: 70%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:17])=[C:7]([S:13](Cl)(=[O:15])=[O:14])[CH:8]=2)[N:3]=1.[F-:18].[K+]>C(Cl)Cl.[Br-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[Cl:1][C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:17])=[C:7]([S:13]([F:18])(=[O:15])=[O:14])[CH:8]=2)[N:3]=1
Reactant: [F-]
Reactant: O=S(=O)(Cl)c1cc2nc(Cl)c(Cl)nc2cc1Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(F)c1cc2nc(Cl)c(Cl)nc2cc1Cl
Temperature: 25 °C
Reaction time: 17.5 h
Yield: 80.1 %

Procedure:
To a solution of 46 g of 2,3,7-trichloro-6-quinoxalinesulfonyl chloride in 200 ml of methylene chloride were added 0.42 g of benzyltriethylammonium bromide and a solution of 20.2 g of potassium fluoride in 20.9 ml of water. The resulting mixture was stirred for 17.5 hours at ambient temperature, filtered, dried over magnesium sulfate, treated with activated carbon and filtered again. Solvent was removed under vacuum, leaving a yellowish solid which was recrystallized from hexane to provide 35 g of 2,3,7-trichloro-6-quinoxalinesulfonyl fluoride as a light-yellow solid, having a melting point of 111°-113°.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[C:8](Cl)(=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].Cl>[OH-].[Na+].C(OCC)C>[C:8]([NH:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4])(=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)C(=O)Cl
Reactant: N[C@@H](CO)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(C)(C)C(=O)N[C@@H](CO)C(=O)O
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
5.25 g (50.0 mmol) of L-serine was dissolved in 1 N aqueous sodium hydroxide solution. 50 ml of 1 N aqueous sodium hydroxide solution and a solution of 5 ml (40.6 mmol) of pivaloyl chloride in 12 ml of diethyl ether were simultaneously added dropwise to the obtained solution in the ice bath for the duration of 25 minutes. After stirring for 2.5 hours, 70 ml of 1 N hydrochloric acid was added to the reaction mixture to make it acidic. After extracting with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound.
Reaction SMILES: S(Cl)(C)(=O)=O.[Br:6][C:7]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([CH2:15][OH:16])=[CH:9][C:8]=1[O:17][CH3:18].[CH2:19](N(CC)CC)C.C[O-].[Na+].CO>COCCOC.O.C1(C)C=CC=CC=1>[Br:6][C:7]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([CH2:15][O:16][CH3:19])=[CH:9][C:8]=1[O:17][CH3:18]
Reactant: COc1cc(CO)cc(OC)c1Br
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: COCc1cc(OC)c(Br)c(OC)c1
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
Mesyl chloride (34.5 mL, 446 mmol) was added to a solution of (4-bromo-3,5-dimethoxyphenyl)methanol (100 g, 405 mmol) and triethylamine (67.5 mL, 484 mmol) in 1.2-dimethoxyethane (1000 mL) while cooling with ice, and the reaction mixture was stirred for 30 minutes. After adding a 28% sodium methoxide in methanol (350 mL, 1.72 mol) to the reaction mixture, it was further stirred for 3 hours at room temperature. Upon completion of the reaction, toluene (1000 mL) and water (1000 mL) were added to the reaction mixture, the aqueous layer was removed, and the organic extract was washed with water (1000 mL), 1N hydrochloric acid (500 mL) and water (500 mL) in that order and concentrated under reduced pressure to afford 105 g of the title compound as a colorless oil (99.5% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:13])[C:6]([N+:10]([O-:12])=[O:11])=[C:7]([OH:9])[CH:8]=1.Cl.[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18]Cl.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CC(=O)CC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:13])[C:6]([N+:10]([O-:12])=[O:11])=[C:7]([O:9][CH2:18][CH2:17][N:16]([CH3:20])[CH3:15])[CH:8]=1
Reactant: CN(C)CCCl
Reactant: COc1cc(C)c([N+](=O)[O-])c(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCC(C)=O
Product: COc1cc(C)c([N+](=O)[O-])c(OCCN(C)C)c1
Temperature: 25 °C
Yield: 63.1 %

Procedure:
A mixture of 5-methoxy-3-methyl-2-nitrophenol [J. Atkinson et al., J. Org. Chem. 56, 1991, 1788-1800](5.00 g, 27.3 mmol), 2-(dimethylamino)ethyl chloride hydrochloride (4.33 g, 30 mmol), K2CO3 (15.1 g, 109 mmol), NaI (0.41 g, 2.7 mmol), an butanone (50 mL) was heated at reflux for 1 h then cooled to room temperature. A mi8xture of 2-dimethylaminoethyl chloride hydrochloride (4.33 g, 30 mmol), K2CO3 (7.6 g, 54.6 mmol), and butanone (15 mL) that had been shaken for 5 min was added and the mixture was heated at reflux for 1.5 h. The mixture was concentrated and the remaining slurry was diluted with water and extracted with EtOAc (×4). The combined extracts were washed with 2 N aqueous Na2CO3 (×10) and extracted with 2 N aqueous HCl (×5). The combined extracts were washed with EtOAc, made basic with Na2CO3, and extracted with EtOAc (×4). These extracts were dried (MgSO4) and evaporated to give 2-(5-methoxy-3-methyl-2-nitrophenyloxy)-N,N-dimethylethanamine (4.38 g, 63%) as a yellow oil; 1H NMR (CDCl3) δ 6.38 (d, J=2.4 Hz, 1 H, H-6'), 6.32 (d, J=2.4 Hz, 1 H, H-4', 4.12 (t, J=5.8 Hz, 2 H, OCH2), 3.81 (s, 3 H, OCH3), 2.73 (t, J=5.8 Hz, 2 H, NCH2), 2.31 (s, 6 H, N(CH3)2), 2.28 (s, 3 H, 3(--CH3); 13C NMR δ 161.0 (C-5'), 151.8 (C-1'), 136.1 (C-2'), 132.7 (C-3'), 106.7 (C-4'), 97.9 (C-6'), 68.1 (OCH2), 57.4 (NCH2), 55.5 (OCH3), 45.8 (N(CH3)2), 17.7 (3'--CH3). Calc. for C12H18N2O4, M+254.1267. Found, 254.1276. Starting material (1.178 g, 24%) was recovered from the basic washes by acidification and extraction.
Reaction SMILES: [C:1]([C:9](=[C:12](SC)[S:13][CH3:14])[C:10]#[N:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([O-])(O)=O.[NH2:21][C:22]([NH2:24])=[NH:23].C(N(CC)CC)C.O>CN(C=O)C>[NH2:24][C:22]1[N:23]=[C:12]([S:13][CH3:14])[C:9]([C:10]#[N:11])=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:21]=1
Reactant: CSC(SC)=C(C#N)C(=O)c1ccccc1
Reactant: N=C(N)N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CSc1nc(N)nc(-c2ccccc2)c1C#N
Temperature: 25 °C
Yield: 82 %

Procedure:
Following the method of Rudorf and Augustin (J. Prakt. Chem. 1978, 320, 576), a solution of 15.9 g (63.9 mmol) 2-benzoyl-3,3-bis(methylthio)acrylonitrile, 9.36 g (76.7 mmol) guanidine nitrate and 22.3 ml (160 mmol) triethylamine in 200 ml DMF was heated at reflux for 6 h. The reaction mixture was then cooled to room temperature. On addition of 300 ml water, a precipitate appeared which was collected by filtration and washed with water to afford 12.7 g (86%) 2-amino-4-(methylthio)-6-phenyl-pyrimidine-5-carbonitrile as a sand-coloured solid. EI-MS m-e (%): 242 (M+, 32), 241 ([M—H]+, 100).
Reaction SMILES: [CH3:1][N:2]1[CH2:13][CH2:12][C:5]2([NH:9][C:8](=[O:10])[NH:7][C:6]2=[O:11])[CH2:4][CH2:3]1.CS(O[CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[C:32]3[N:34]([CH3:37])[CH2:35][N:36]=[C:31]3N(C#N)C=2)=[CH:24][C:23]=1[C:40]([F:43])([F:42])[F:41])(=O)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:37][N:34]1[C:32]2[CH:33]=[C:28]([C:25]3[CH:26]=[CH:27][C:22]([O:21][CH2:20][CH2:19][N:7]4[C:6](=[O:11])[C:5]5([CH2:12][CH2:13][N:2]([CH3:1])[CH2:3][CH2:4]5)[NH:9][C:8]4=[O:10])=[C:23]([C:40]([F:41])([F:42])[F:43])[CH:24]=3)[N:7]=[C:6]([C:5]#[N:9])[C:31]=2[N:36]=[CH:35]1
Reactant: CN1CCC2(CC1)NC(=O)NC2=O
Reactant: CN1CN=C2C1=CC(c1ccc(OCCOS(C)(=O)=O)c(C(F)(F)F)c1)=CN2C#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CN1CCC2(CC1)NC(=O)N(CCOc1ccc(-c3cc4c(ncn4C)c(C#N)n3)cc1C(F)(F)F)C2=O
Temperature: 90 °C
Reaction time: 14 h
Yield: 34.7 %

Procedure:
A solution of 8-methyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione (40 mg) in DMF (0.6 mL) was added to a solution of 2-(4-(4-cyano-1-methyl-1H-imidazo[4,5-e]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)ethyl methanesulfonate (50 mg) in DMF (0.4 mL), K2CO3 (41 mg) and tetrabutyl ammonium iodide (TBAI, 26 mg). The mixture was stirred at 90° C. for 14 hours. The crude mixture was directly purified by preparative HPLC (HPLC:column XBridge MS C18 30×100 mm, 5 μm, Eluent:A:NH4HCO3, 10 mmol, pH=9.5/B:Acetonitrile, Focused gradient/8 minutes/50 mL/min) to afford 1-methyl-6-{4-[2-(8-methyl-2,4-dioxo-1,3,8-triaza-spiro[4.5]dec-3-yl)-ethoxy]-3-(trifluoromethyl)-phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile (20 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:30][C:31]([O:33]C)=[O:32])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=4[Cl:28])(=[O:20])=[O:19])=[C:13]([F:29])[CH:12]=3)[C:3]=12>CO.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:30][C:31]([OH:33])=[O:32])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=4[Cl:28])(=[O:19])=[O:20])=[C:13]([F:29])[CH:12]=3)[C:3]=12
Reactant: COC(=O)Cn1nc(-c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)c(F)c2)c2c(N)ncnc21
Solvent: CO
Solvent: O
Product: Nc1ncnc2c1c(-c1ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)c(F)c1)nn2CC(=O)O
Temperature: 90 °C
Reaction time: 48 h
Yield: 52.6 %

Procedure:
In a resealable Schlenk flask, methyl 2-[4-amino-3-(4-{[(2,3-dichlorophenyl)sulfonyl]amino}-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]acetate (0.030 g, 0.057 mmol) was dissolved in methanol/water (1:1, 1 mL). The flask was sealed with a teflon screwcap and heated at 90° C. After 2 days, the reaction was cooled to ambient temperature. Purification by preparative HPLC (25 to 100% CH3CN in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersil HS C18, 250×21 mm column, Rt 6.3-6.7 min) afforded 2-[4-amino-3-(4-{[(2,3-dichlorophenyl)sulfonyl]amino}-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]acetic acid as a white solid (0.006 g, 0.030 mmol): RP-HP (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 250×4.6 mm column) Rt 6.42 min. 1H NMR (DMSO-d6, 400 MHz) δ 8.13 (s, 1H), 7.97 (d, 1H), 7.62 (d, 1H), 7.36 (t, 1H), 7.19 (m, 3H), 7.15 (d, 1H), 4.59 (s, 2H); MS: (M−H)− 509.