Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.C([Sn](CCCC)(CCCC)[C:14]1[S:18][C:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[N:16][CH:15]=1)CCC.C(Cl)Cl.C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:14]2[S:18][C:17]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[N:16][CH:15]=2)[N:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(-c2cccnc2)s1
Reactant: Brc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClCCl
Product: Brc1cccc(-c2cnc(-c3cccnc3)s2)n1
Temperature: 110 °C
Reaction time: 36 h
Yield: 34.8 %

Procedure:
A sealed tube was charged with 2,6-dibromopyridine (269 mg, 1.13 mmol), 3-(5-tributylstannanyl-thiazol-2-yl)-pyridine (511 mg, 1.13 mmol), Pd(PPh3)4 (131 mg, 0.11 mmol), [1,1-Bis(diphenylphosphino)ferrocene]palladium(II) chloride. CH2Cl2 (20 mg, 0.024 mmol) and anhydrous and degassed toluene (5 ml) and heated to 110° C. with stirring for 36 h. The cooled reaction mixture was treated with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure before purification by column chromatography on SiO2 using combiflash Companion®, eluting with cyclohexane/ethyl acetate to afford the title compound as a white solid (125 mg, 35%). 1H NMR (DMSO-d6, 300 MHz): δ=9.21 (d, J=1.7 Hz, 1H), 8.72 (s, 1H), 8.70 (m, 1H), 8.39 (m, 1H), 8.14 (d, J=7.8 Hz, 1H), 7.88 (dd, J=8.0; 7.8 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.57 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[CH:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)=[O:10]>>[CH3:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:14]1[CH:15]=[CH:16][C:11]([CH:9]=[O:10])=[CH:12][CH:13]=1
Reactant: Cc1ccccc1Br
Reactant: O=Cc1ccc(B(O)O)cc1
Product: Cc1ccccc1-c1ccc(C=O)cc1

Procedure:
The method described in Referential Example 237 was performed by use of 2-bromotoluene and 4-formylbenzene boronic acid, whereby the title compound was obtained.
Reaction SMILES: [CH3:1][Mg]Cl.[C:4]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:9][C:8]=1[O:17][CH3:18])(=[O:6])[CH3:5]>C1COCC1>[OH:6][C:4]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:9][C:8]=1[O:17][CH3:18])([CH3:1])[CH3:5]
Reactant: COc1cc(NC(C)=O)ccc1C(C)=O
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: COc1cc(NC(C)=O)ccc1C(C)(C)O
Temperature: 25 °C
Yield: 108 %

Procedure:
Methyl magnesium chloride (49.9 ml, 150 mmol, 3 M solution in THF) in 100 ml THF was cooled to zero degrees C., and N-(4-Acetyl-3-methoxy-phenyl)-acetamide (14.1 g, 68 mmol) in 200 ml THF was added via cannula to over 25 minutes. The reaction mixture was stirred and allowed to warm to room temperature over 2.5 hours. The reaction was quenched by addition of 1 N NH4Cl and extracted with EtOAc. The combined organic layers were washed with 1 N ammonium chloride, brine, dried over MgSO4, and concentrated under reduced pressure to afford N-[4-(1-Hydroxy-1-methyl-ethyl)-3-methoxy-phenyl]-acetamide (16.4 g, 100%).
Reaction SMILES: C(N1C2C(=CC=C(N[C:14](=[O:27])/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=3)C=2)C(C)(C)C1)(=O)C.C(N1C2C(=CC=C([N+]([O-])=O)C=2)C(C)(C)C1)(=[O:32])C.O.O.[Sn](Cl)Cl.Cl>C(OCC)C>[C:23]([C:20]1[CH:19]=[CH:18][C:17](/[CH:16]=[CH:15]/[C:14]([OH:27])=[O:32])=[CH:22][CH:21]=1)([CH3:24])([CH3:25])[CH3:26]
Reactant: CC(=O)N1CC(C)(C)c2ccc([N+](=O)[O-])cc21
Reactant: CC(=O)N1CC(C)(C)c2ccc(NC(=O)/C=C/c3ccc(C(C)(C)C)cc3)cc21
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)c1ccc(/C=C/C(=O)O)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(2E)-N-(1-Acetyl-3,3-dimethylindolin-6-yl)-3-[4-(tert-butyl)phenyl]prop-2-enamide. To a solution of 1-acetyl-3,3-dimethyl-6-nitroindoline, Example 31(c), (110 mg, 0.47 mmol) in ethyl ether (3 mL), magnetically stirred in a round-bottomed flask at 0° C., was added tin (II) chloride dihydrate (0.67 g, 2.96 mmol, Aldrich) and cond HCl (0.3 mL). The reaction mixture was stirred at 0° C. for 10 min, allowed to warm to 25° C. then stirred at that temperature overnight. The reaction mixture was washed with 10 N NaOH (10 mL), extracted with EtOAc and concentrated in vacuo. Analogous to the procedure used to prepare Example 1, the crude product and 4-tert-butyl-trans-cinnamic acid (92 mg, 0.45 mmol, EMKA-Chemie) provided, after purification by silica gel chromatography (2:3 hexane:EtOAc), the title product. MP 121° C. MS (ESI, pos. ion) m/z: 391 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:17])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][CH3:15])=[O:13])[C@@H:7]([CH3:16])[CH2:6][CH2:5]2.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(N(CC)CC)C.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[C:3]([O:17][C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][CH3:15])=[O:13])[C@@H:7]([CH3:16])[CH2:6][CH2:5]2
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC(=O)N1c2ccc(Br)c(O)c2CC[C@@H]1C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: COC(=O)N1c2ccc(Br)c(Oc3ccc(F)cc3)c2CC[C@@H]1C
Reaction time: 48 h
Yield: 68.9 %

Procedure:
A mixture of (S)-methyl 6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (2.00 g, 6.66 mmol), (4-fluorophenyl)boronic acid (1.865 g, 13.33 mmol), copper (II) acetate (1.33 g, 7.33 mmol), 4 Å molecular sieves (1 g), triethylamine (0.93 mL, 6.66 mmol), and pyridine (1.08 mL, 13.33 mmol) in dichloromethane (30 mL) was stirred opened to air at rt for two days. The reaction mixture was filtered through Celite and the filtrate was concentrated to afford a brown oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 0-10% ethyl acetate-hexane) to afford methyl (S)-6-bromo-5-(4-fluorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (1.81 g, 69%) as a colorless film. MS (ESI, pos. ion) m/z 394, 396 [M+H]+.
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[C:10]1[C:11]([NH2:25])=[N:12][CH:13]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:15]=1.Br[C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)=[CH:29][C:28]=1[O:40][CH3:41].C(=O)([O-])[O-].[Na+].[Na+].COCCOC>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[CH3:41][O:40][C:28]1[CH:29]=[C:30]([N:33]2[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]2)[CH:31]=[CH:32][C:27]=1[C:14]1[CH:15]=[C:10]([C:2]2[O:1][C:9]3[C:4]([N:3]=2)=[N:5][CH:6]=[CH:7][CH:8]=3)[C:11]([NH2:25])=[N:12][CH:13]=1
Reactant: CC1(C)OB(c2cnc(N)c(-c3nc4ncccc4o3)c2)OC1(C)C
Reactant: COc1cc(N2CCN(C)CC2)ccc1Br
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(N2CCN(C)CC2)ccc1-c1cnc(N)c(-c2nc3ncccc3o2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
Compound [6] was prepared as follows. 3-oxazolo[4,5-b]pyridin-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (138 mg), 1-(4-bromo-3-methoxy-phenyl)-4-methyl-piperazine (97 mg), bis(triphenylphosphine) palladium (II) chloride (50.1 mg) and sodium carbonate (50.5 mg) were weighed out and sealed in a tube. DME (3 ml) and water (0.3 ml) were added. Argon was bubbled in the resulting mixture for 10 minutes then it was stirred at 100° C. for 1 hour. After cooling, the reaction mixture was diluted with ethyl acetate (5 ml), filtered, and purified by flash chromatography on silica gel eluting with 0 to 5% methanol in dichloromethane/ethyl acetate (1/1) then 5% methanolic ammonia 7N in dichloromethane/ethyl acetate (1/1). The solvent was evaporated to dryness and the product was triturated in acetonitrile (4 ml), collected by filtration, washed with Acetonitrile and dried under vacuum at 40° C., to give 5-[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]-3-oxazolo[4,5-b]pyridin-2-yl-pyridin-2-amine (78 mg). NMR Spectrum: (CDCl3) 2.40 (s, 3H), 2.61-2.69 (m, 4H), 3.27-3.36 (m, 4H), 3.85 (s, 3H), 6.58 (d, 1H), 6.62 (dd, 1H), 6.91 (bs, 2H), 7.25 (d, 1H), 7.30 (dd, 1H), 7.85 (dd, 1H), 8.46 (d, 1H), 8.47 (d, 1H), 8.56 (dd, 1H); Mass spectrum: M+H+ 417. There was no deprotection step.
Reaction SMILES: [CH2:1]1[CH:7](O)[NH:6][P:4]([N:9]([CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][Cl:12])(=[O:5])[O:3][CH2:2]1.[NH4+].[SH:17][CH2:18][CH2:19][S:20]([O-:23])(=[O:22])=[O:21].ClC(Cl)(Cl)C(O)=O.CCOCC>CN(C)C=O>[NH4+:6].[Cl:12][CH2:11][CH2:10][N:9]([CH2:13][CH2:14][Cl:15])[P:4]1(=[O:5])[NH:6][CH:7]([S:17][CH2:18][CH2:19][S:20]([O-:23])(=[O:22])=[O:21])[CH2:1][CH2:2][O:3]1
Reactant: O=P1(N(CCCl)CCCl)NC(O)CCO1
Reactant: O=S(=O)([O-])CCS
Agent: O=C(O)C(Cl)(Cl)Cl
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=P1(N(CCCl)CCCl)NC(SCCS(=O)(=O)[O-])CCO1
Reaction time: 20 h

Procedure:
2.8 g (10 mmol) of 4-hydroxycyclophosphamide and 1.6 g (10 mmol) of ammonium-2-mercaptoethanesulphonate were dissolved with a catalytic quantity of trichloroacetic acid in 10 ml of dimethylformamide and were stored in a refrigerator at -25° C. for 20 hours. After a further 5 hours at 0° C., the mixture was mixed with ether until clouding commenced and was triturated. The crystallised material was filtered with suction after 1 day at 0° C., washed dried and recrystallised from n-propanol.
Reaction SMILES: [C:1](O)(=[O:4])[CH2:2][CH3:3].CNC.C(=O)CC.[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH:16]=O>>[CH3:19][O:18][CH:15]([O:14][CH3:13])[CH:16]=[C:2]([CH3:3])[CH:1]=[O:4]
Reactant: COC(C=O)OC
Reactant: CCC(=O)O
Agent: CNC
Solvent: CCC=O
Product: COC(C=C(C)C=O)OC
Temperature: 40 °C

Procedure:
Propionic acid (24.7 mL) was added carefully to an aqueous solution of dimethylamine (40%, 41.6 mL), stirring and cooling (ice-water bath) to ensure the temperature of the mixture did not exceed 10° C. A pale yellow solution formed and the cooling bath was replaced with a heating mantle. From this point on, the temperature was controlled by a digital controller; a temperature probe was placed in the flask and the mantle was connected to the controller. The mixture was warmed to 40° C., the solution became colorless and dimethoxyacetaldehyde (aq. 60%, 100 mL) was added. The mixture was heated to 60° C. and propionaldehyde (42.26 g) was added dropwise at such a rate that the temperature did not exceed 68° C. (ca. 30 min). During the addition the color of the mixture changed, first from yellow to orange, and then to brown. The mixture was vigorously stirred and the temperature was maintained at 70° C. for 24 hours. The reaction mixture was allowed to cool down to a room temperature and then was extracted three times with dichloromethane (100 mL). The combined dichloromethane extracts were washed with water (150 mL). The organic layer was dried over anhydrous sodium sulfate (3 g) and the solvents were evaporated on a rotary evaporator at the room temperature. 117 g of a dark reddish-brown material was obtained. The crude product was distilled under reduced pressure (<0.5 mm Hg) using a modified version of a falling film apparatus at 78° C. (the b.p. of ethyl acetate, which was used as the heating medium). The clear distillate (of formula II, R1 and R2 are methyl; 101 g) was collected in a trap cooled in a dry ice bath.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][CH:21]=1)[CH2:11][CH:12]([CH3:18])[C:13](OCC)=[O:14].Cl>O1CCCC1>[CH3:18][CH:12]([CH2:11][C:10]1[CH:19]=[CH:20][CH:21]=[C:8]([CH3:7])[CH:9]=1)[CH2:13][OH:14]
Reactant: CCOC(=O)C(C)Cc1cccc(C)c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1cccc(CC(C)CO)c1
Yield: 85.6 %

Procedure:
500 ml of toluene, 207 g of ground potassium carbonate, 8 g of potassium iodide, 7 g of 18-crown-6 and 209 g of diethyl methylmalonate were initially introduced into a 2 l four-necked flask. The mixture was heated to 85° C. with stirring. 141 g of 3-methylbenzyl chloride were added dropwise in the course of half an hour and the mixture was then stirred at 90° C. for 8 hours. After cooling, the salts were removed by repeatedly shaking with water and the organic layer was distilled. 184 g of diethyl 2-methyl-2-(3-methylbenzyl)-malonate were obtained at a boiling point of 120° C. and a pressure of about 0.02 mbar. For hydrolysis, the ester was boiled under reflux with stirring for 16 hours with 60 g of NaOH, 170 ml of water and a spatula tip-full of tetradecyltrimethylammonium bromide, ethanol which formed in the meantime being distilled off. The dicarboxylic acid was liberated by acidifying with hydrochloric acid, separated off and heated in xylene for 4 hours under reflux for decarboxylation. The monocarboxylic acid was then esterified with ethanol (p-toluenesulfonic acid as catalyst, cyclohexane as entraining agent for water). 115 g of ethyl 2-(3-methylbenzyl)-propionate (boiling point 70°-73° C. at 0.03 mbar) were obtained. For hydrogenation, 21 g of LiAlH4 were dissolved or suspended in 800 ml of tetrahydrofuran in a 2 l four-necked flask under nitrogen. A mixture of 110 g of ethyl 2-(3-methylbenzyl)-propionate and 100 ml of tetrahydrofuran were then added dropwise with ice cooling. The mixture was then decomposed with ice and hydrochloric acid, extracted with ether and dried over K2CO3, and 75 g of 2-methyl-3-(3-methylphenyl)propan-1-ol (boiling point 68°-70° C. at 0.1 mbar) were obtained by distillation.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][O:5][C@@H:4]([CH2:8][OH:9])[CH2:3]1.[H-].[Na+].[C:12]1([N:18]2[CH2:23][CH2:22][N:21]([C:24](OC3C=CC([N+]([O-])=O)=CC=3)=[O:25])[CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[C:12]1([N:18]2[CH2:19][CH2:20][N:21]([C:24]([O:9][CH2:8][C@@H:4]3[O:5][CH2:6][CH2:7][N:2]([CH3:1])[CH2:3]3)=[O:25])[CH2:22][CH2:23]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccccc2)CC1
Reactant: CN1CCO[C@@H](CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCO[C@@H](COC(=O)N2CCN(c3ccccc3)CC2)C1
Reaction time: 0.5 h
Yield: 72.1 %

Procedure:
(R)-(4-Methyl-morpholin-2-yl)-methanol (Intermediate 11; 100 mg, 0.76 mmol) was added to a suspension of NaH (60% dispersion in oil; 90.0 mg, 2.28 mmol) in anhydrous THF (7 mL) and stirred under nitrogen for 30 min. 4-Nitrophenyl 4-phenylpiperazine-1-carboxylate (Intermediate 2; 300 mg, 0.92 mmol) was added and the reaction mixture was stirred at room temperature for 48 h. The reaction mixture was filtered through celite and the solid washed with THF (10 mL). The filtrates were combined and the solvent removed in vacuo. The residue was purified by column chromatography (normal phase silica, 5 g Isolute-Si column, gradient 1-5% MeOH in DCM). The solvents were removed in vacuo to give [(2R)-4-methylmorpholin-2-yl]methyl 4-phenylpiperazine-1-carboxylate (175 mg, 72%) as a light yellow gum
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[S:20])[CH2:10][N:9]=1.[OH-].[Na+].CO.Cl.[CH3:26][N:27]([CH2:29][CH2:30]Cl)[CH3:28]>O>[CH3:26][N:27]([CH3:28])[CH2:29][CH2:30][S:20][C:11]1[CH2:10][N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[N:12]=1
Reactant: CN(C)CCCl
Reactant: S=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(C)CCSC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 88.4 %

Procedure:
To a solution of 2.5 g of 1,3-dihydro-5-(2-chlorophenyl)-7-chloro-2H-1,4-benzodiazepine-2-thione in a solvent mixture comprising 10 ml of a 10% aqueous sodium hydroxide solution and 10 ml of methanol is added dropwise under ice cooling with stirring an aqueous solution of 1.7 g of N,N-dimethyl-2-chloroethylamine hydrochloride, and the resulting mixture is stirred at room temperature for 2.5 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is rinsed with a 5% aqueous sodium hydroxide solution, washed with water and then dried over magnesium sulfate. The solvent is distilled off from the solution to obtain as the residue 2.7 g of an oily 2-(2-dimethylaminoethylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine. The oily product thus obtained is treated, according to usual procedure, with maleic acid and recrystallized from an isopropyl alcohol-acetone mixture to obtain 2.6 g of 2-(2-dimethylaminoethylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine maleate, m.p. 140°-142° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]#[N:20])([CH2:14][CH2:15][C:16]([OH:18])=O)[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.O1CCC[CH2:22]1.CC(C)([O-])C.[K+]>C(O)(=O)C>[C:11]([CH:10]1[CH2:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)([C:19]#[N:20])[CH2:14][CH2:15][C:16]1=[O:18])([O:13][CH3:22])=[O:12]
Reactant: C1CCOC1
Reactant: N#CC(CCC(=O)O)(CCC(=O)O)c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: COC(=O)C1CC(C#N)(c2ccc(Cl)cc2)CCC1=O
Yield: 96 %

Procedure:
A reaction mixture consisting of 34.97 g. (0.108 mole) dimethyl ester of 4-(p-chlorophenyl)-4-cyanopimelic acid (prepared in Part a, above) dissolved in 700 ml. tetrahydrofuran with 24.4 gm. (0.218 mole) potassium tert-butoxide added is heated at the reflux temperature for 41/2 hours. After cooling, the reaction mixture is chilled in an ice-bath and 175 ml. 2.5 N acetic acid is added. The organic and aqueous phases separate and the organic phase is recovered. It is diluted with 600 ml. benzene before being washed successively with aqueous sodium bicarbonate, water, and brine. The organic solvents are then removed by distillation under reduced pressure. There is thus obtained 30.2 gm. (96% yield) of 2-carbomethoxy-4-(p-chlorophenyl)-4-cyanocyclohexanone having a melting point at 139° to 143° C.
Reaction SMILES: [CH3:1][C:2]([S@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[Cl:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([CH:15]=O)[C:10]=1[F:17].C([O-])([O-])=O.[Cs+].[Cs+]>C(Cl)Cl.CCOC(C)=O>[Cl:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11](/[CH:15]=[N:7]/[S@:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])[C:10]=1[F:17]
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=Cc1nccc(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)[S@](=O)/N=C/c1nccc(Cl)c1F
Yield: 106.5 %

Procedure:
A solution of (R)-2-methylpropane-2-sulfinamide (0.540 g, 4.32 mmol), 4-chloro-3-fluoropicolinaldehyde (0.627 g, 3.93 mmol) and Cs2CO3 (1.921 g, 5.89 mmol) in DCM (20 mL) was stirred for 1 h at rt. The reaction mixture was diluted with EtOAc and washed with brine (3×20 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo to provide the desired product (1.1 g, 100%). MS (ESI) m/z: 263.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[N:17]1([C:23]2[CH:31]=[CH:30][C:26]([C:27]([O-])=[O:28])=[CH:25][CH:24]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:24][CH:25]=2)=[CH:10][CH:9]=1)([C:5]1[CH:15]=[CH:16][C:2]([NH:1][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:24][CH:25]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: O=C([O-])c1ccc(N2CCCCC2)cc1
Reactant: Nc1ccc(C(=O)c2ccc(N)cc2)cc1
Product: O=C(Nc1ccc(C(=O)c2ccc(NC(=O)c3ccc(N4CCCCC4)cc3)cc2)cc1)c1ccc(N2CCCCC2)cc1

Procedure:
Compound 322 was prepared according to the procedure described in Scheme IV from 4,4′-diaminobenzophenone and 4-piperidinobenzoate. [M+H]+ calcd for C37H38N4O3: 587.30; found: 587.02.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:13][C:14](=O)[CH3:15])[CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:14]([CH3:15])[N:23]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([F:17])=[CH:19][CH:20]=2)[C:10](=[O:12])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCc1ccc(F)cc1
Reactant: CC(=O)CN(CC(=O)O)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC1CN(C(=O)OC(C)(C)C)CC(=O)N1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of N-[(tert-butoxy)carbonyl]-N-(2-oxopropyl)glycine (0.66 g, 2.87 mmol), 4-fluorobenzylamine (0.23 g, 1.87 mmol) in dichloroethane (14 mL) was stirred at room temperature for one hour. Sodium triacetoxyborohydride (0.79 g, 3.73 mmol) was added and the reaction mixture stirred at room temperature overnight. The resultant mixture was concentrated under vacuum. The residue was dissolved in DMF (12 mL), treated with EDC (0.55 g), and stirred at room temperature overnight. The resultant mixture was concentrated under vacuum. The residue was partitioned between ethyl acetate and dilute aqueous HCl. The organic extract was washed with brine (to pH 7), dried over anhydrous magnesium sulfate, filtered, and concentrated to provide the title compound.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:10]([CH2:11][CH3:12])=[N:9][C:8]2[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:7]=2[C:6]=1[NH:18][CH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[N+]=[N-]>[Pd].C(O)C>[NH2:1][CH2:4][C:5]1[C:10]([CH2:11][CH3:12])=[N:9][C:8]2[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:7]=2[C:6]=1[NH:18][CH:19]1[CH2:20][CH2:21][O:22][CH2:23][CH2:24]1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN=[N+]=[N-]
Agent: [Pd]
Solvent: CCO
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reaction time: 8 h

Procedure:
In a hydrogenation flask, ethanol (300 ml) was added to 10% palladium on carbon (9.9 g, 0.2 wt. equivalents, 50% wet), followed by 5-(azidomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (49.62 g, 151 mmol, 1 equivalent, e.g. which can be as prepared in Intermediate 6) in ethanol (900 ml). The mixture was hydrogenated overnight at room temperature and room pressure (using the Wright valve); during which the flask was vented and refilled once. The catalyst was removed by filtration and the filtrate was evaporated to give a grey solid. The residue was purified by column chromatography, using a relatively small amount of silica (1500 ml of 9385 silica), eluting initially with 5% methanol in dichloromethane (to elute some fast-moving impurities), followed by 10% and finally 15% methanol in dichloromethane to give the title compound as an almost white solid (41.25 g). LCMS m/z 304 [MH+]; TRET=1.65 and 1.69 min (split peak). NMR (d6-DMSO) showed a trace of methanol present in the product.