Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]Br.O>CN(C)C=O>[Br:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: BrCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2ccc(OCCCCCCBr)cc2)cc1
Yield: 54 %

Procedure:
40 g of 4-(4-hydroxyphenyl)benzonitrile, 42 g of potassium carbonate, and 250 g of 1,6-dibromohexane were mixed. The resultant mixture was then caused to react in dimethylformamide at 100° C. for 5 hours. After cooled, the resultant was poured into 1 L of water and extracted with chloroform. The resultant was purified by silica gel column chromatography, and then recrystallized from chloroform/hexane, to give the target compound (yielded amount 39 g, and yield 54%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:26])=[C:21]([CH:23]=[CH:24][CH:25]=2)[NH2:22])[CH:5]=[CH:4][N:3]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:28]=1>N1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[N:10][C:9]=2[C:19]2[C:20]([F:26])=[C:21]([NH:22][S:33]([C:29]3[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=3)(=[O:35])=[O:34])[CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Reactant: O=S(=O)(Cl)c1cccnc1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
To a solution of 3-(5-(2-chloropyrimidin-4-yl)-2-morpholinothiazol-4-yl)-2-fluoroaniline (3 g, 7.7 mmol) in pyridine (15 mL) was added pyridine-3-sulfonyl chloride (1.49 g, 8.4 mmol) dropwise to the mixture. The reaction was stirred at rt overnight. The reaction was washed with water (100 mL), and extracted with DCM (2×100 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (petroleum ether:EtOAc 5:1) to afford the title compound of Step A (2.9 g, 71.5% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.55-10.60 (br, 1H), 8.82-8.86 (m, 1H), 8.72-8.76 (m, 1H), 8.30 (d, J=5.3 Hz, 1H), 8.07-8.13 (m, 1H), 7.51-7.52 (m, 1H), 7.39-7.47 (m, 1H), 7.27-7.40 (m, 2H), 6.47 (d, J=5.3 Hz, 1H) 3.47-3.57 (m, 4H), 3.67-3.75 (m, 4H). MS (ES+): 533 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[I-].[CH3:16][S+](C)(C)=O.CC(C)([O-])C.[Na+]>C1COCC1.CN(C=O)C>[O:1]1[C:2]2([CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C[S+](C)(C)=O
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (0.50 g, 2.51 mmol) in THF/DMF (2:1, 6 mL) at 60° C. was added trimethylsulfoxonium iodide (0.58 g, 2.63 mmol) and sodium t-butoxide (0.25 g, 2.63 mmol). The reaction mixture was stirred at 60° C. for 30 min, cooled to RT and concentrated. Water was added and the mixture was extract with EtOAc twice. The combined organics were dried over Na2SO4, filtered and concentrated. Purification on silica gel (3:1, hexanes:EtOAc) gave tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate as a clear oil that solidified upon standing.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:18]#[CH:19])[CH:7]=[C:8]3[C:13]=2[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]3([CH3:17])[CH3:16])[CH2:3][CH2:2]1.[CH2:20]([O:22][C:23](=[O:33])[CH2:24][C:25]1[CH:30]=[CH:29][C:28](I)=[CH:27][C:26]=1[F:32])[CH3:21].C(N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH2:20]([O:22][C:23](=[O:33])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:19]#[C:18][C:6]2[CH:7]=[C:8]3[C:13](=[C:4]([CH:1]4[CH2:3][CH2:2]4)[CH:5]=2)[O:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]3([CH3:17])[CH3:16])=[CH:27][C:26]=1[F:32])[CH3:21]
Reactant: C#Cc1cc(C2CC2)c2c(c1)C(C)(C)CC(C)(C)O2
Reactant: CCOC(=O)Cc1ccc(I)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC(C)(C)O3)cc1F

Procedure:
Following general procedure F and using 8-cyclopropyl-6-ethynyl-2,2,4,4-tetramethylchroman (Intermediate 34, 0.096 g, 0.38 mmol), ethyl-2-fluoro-4-iodo phenyl acetate (Reagent C, 0.104 g, 0.34 mmol), triethyl amine (3 mL), tetrahydrofuran (3 mL), copper(I)iodide (0.020 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.060 g, 0.085 mmol) the title compound was obtained (0.14 g, 85%).
Reaction SMILES: [BrH:1].[CH2:2]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([CH2:10]O)[CH2:5]1)[CH3:3].O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Br:1][CH2:10][CH:6]1[CH2:7][CH2:8][CH2:9][N:4]([CH2:2][CH3:3])[CH2:5]1
Reactant: Br
Reactant: CCN1CCCC(CO)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCN1CCCC(CBr)C1

Procedure:
48% Aqueous hydrogen bromide (16 ml) was added to N-ethyl-3-piperidinemethanol (1.53 g) and the stirring mixture refluxed for 6 hours. After cooling, the solvent was stripped, the residue treated with water and made basic by addition of 1M aq. potassium carbonate. The mixture was shaken with dichloromethane, filtered to remove unwanted solid, and the filtrate separated. The aqueous layer was further extracted with dichloromethane and the combined extracts washed with dilute brine, dried by passing through a phase separation cartridge and stripped to give the title compound as a pale oil (1.4 g).
Reaction SMILES: [I-].[CH:2]1([N+:12]2([CH3:17])[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[OH2:18]>>[OH-:18].[CH:2]1([N+:12]2([CH3:17])[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O
Agent: C[N+]1(C2CCCCCCCCC2)CCCC1
Agent: [I-]
Product: [OH-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-cyclodecyl-N-methyl-pyrrolidinium iodide (45 gm; 0.128 mol) was dissolved in 150 ml water in a 500 ml plastic bottle. To the solution, 160 gm of Ion-Exchange Resin-OH (BIO RAD® AH1-X8) was added and the mixture was stirred at room temperature overnight. The mixture Was filtered and the solids were rinsed with an additional 85 ml of water. The reaction afforded 0.12 mole of the SDA (N-cyclodecyl-N-methyl-pyrrolidinium hydroxide) as indicated by titration analysis with 0.1N HCl.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][CH:7]=1.[CH2:9]([N:11](CC)CC)C.C[Si](C#N)(C)C>C(#N)C>[C:9]([C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:11]
Reactant: CCN(CC)CC
Reactant: [O-][n+]1cccc(F)c1
Agent: C[Si](C)(C)C#N
Solvent: CC#N
Product: N#Cc1ncccc1F
Temperature: 25 °C
Yield: 70.3 %

Procedure:
Dissolve 3-fluoropyridine-N-oxide (1.0 g, 8.687 mmol) in anhydrous acetonitrile (100 mL). Add triethylamine (1.319 g, 1.82 mL, 13.031 mmol), trimethylsilylcyanide (3.447 g, 4.63 mL, 34.749 mmol) and heat the mixture to reflux overnight. Cool to ambient temperature and concentrate in vacuo. Dissolve the residue in EtOAc and wash with saturated aqueous NaHCO3. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 17:3) to give the desired intermediate as a solid (746 mg, 70%). GC-MS m/z: 122 (M+).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14].Br[CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C=O)C.C(OCC)C>[CH2:20]([O:19][C:17](=[O:18])[CH:16]([O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[F:7])[CH3:22])[CH3:21]
Reactant: Oc1ccccc1F
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccccc1F
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 94.1 %

Procedure:
Cesium carbonate (65.69 g, 201.61 mmol) is added to a solution of 2-fluorophenol (9 mL, 100.84 mmol, d=1.256) in anhydrous DMF (300 mL) at room temperature under an atmosphere of nitrogen. After five minutes, ethyl 2-bromopropionate (130.1 mL, 100.84 mmol, d=1.394) is added rapidly dropwise and the resultant mixture is allowed to stir at 90° C. for 18 h. The reaction mixture is diluted with diethyl ether, then extracted twice with 1N HCl and twice with water. The organic layer is dried, concentrated, and purified by flash chromatography (25% ether in hexanes) to provide the titled compound (20.14 g, 94%). 1H NMR (400 MHz, CDCl3): □. 7.07-6.96 (m 2H), 6.93-6.87 (m, 2H), 4.73, 4.71 (ABq, 1H, J=6.7 Hz). 4.21-4.15 (m, 2H), 1.61 (d, 3H, J=6.7 Hz), 1.21 (t, 3H, J=6.7 Hz). MS [EI+] 507 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3]Cl.[CH2:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>O>[CH2:6]([NH:13][CH2:3][CH:2]([F:5])[F:1])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCc1ccccc1
Reactant: FC(F)CCl
Solvent: O
Solvent: CCN(CC)CC
Product: FC(F)CNCc1ccccc1
Yield: 66 %

Procedure:
An amount of 10 g (92 mmol) of 2,2-difluoro-1-chloroethane, 5 g (46 mmol) of benzylamine and 5.2 g (51 mmol) of triethylamine are heated in 20 g of water in an autoclave at an internal temperature of 120° C. for 6 hours. The two-phase solution is twice extracted with 50 ml of dichloromethane each time and the combined organic phases are washed with 50 ml of water and subsequently distilled. An amount of 5.2 g of N-benzyl-2,2-difluoroethanamine is obtained, which corresponds to a yield of 66%, based on benzylamine.
Reaction SMILES: [N+]1([O-])C=CC=CC=1.Br[C:9]1[C:10]([C:15]#[N:16])=[N:11][CH:12]=[CH:13][CH:14]=1.C[Si](C#N)(C)C.[CH3:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>C(#N)C>[C:15]([C:10]1[C:9]([C:27]2[CH:28]=[CH:29][C:24]([CH3:23])=[CH:25][CH:26]=2)=[CH:14][CH:13]=[CH:12][N:11]=1)#[N:16]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: N#Cc1ncccc1Br
Agent: C[Si](C)(C)C#N
Agent: [O-][n+]1ccccc1
Solvent: CC#N
Product: Cc1ccc(-c2cccnc2C#N)cc1

Procedure:
Synthetic Scheme XXVIII shows the 4-step preparation of the alkylating reagent 2-cyano-3-(4-bromomethylphenyl)pyridine (79) from 3-bromopyridine (80) (Aldrich). In step 1, the pyridine 80 was reacted with hydrogen peroxide in acetic acid at reflux to give the pyridine N-oxide 81. In step 2, the N-oxide 81 was converted to 3-bromo-2-cyanopyridine (82) by reaction with trimethysilylcyanide and triethyl anine in acetonitrile at reflux. In step 3, the nitrile 82 was coupled with 4-methylphenylboronic acid (56) (Scheme XXIV) using Snieckus conditions (Scheme XIII) to give 2-cyano-3-(4-methylphenyl) pyridine (83). In step 4, 83 was brominated with NBS/AIBN in carbon tetrachloride at reflux to give the desired alkylating reagent 79. ##STR91##
Reaction SMILES: O.[OH-].[Li+:3].[N:4]1([C:10]2[N:11]=[C:12]([CH2:17][C:18]([O:20]CC)=[O:19])[NH:13][C:14](=[O:16])[CH:15]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1>CO>[N:4]1([C:10]2[N:11]=[C:12]([CH2:17][C:18]([O-:20])=[O:19])[NH:13][C:14](=[O:16])[CH:15]=2)[CH2:5][CH2:6][O:7][CH2:8][CH2:9]1.[Li+:3]
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 94.3 %

Procedure:
7.5 ml of water and 197 mg of lithium hydroxide are added to a solution of 2 g of ethyl [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of Example 1 in 75 ml of methanol. After stirring for 48 hours at ambient temperature, the reaction mixture is concentrated under reduced pressure. 50 ml of water are added. The aqueous phase is then washed with ethyl acetate and then lyophilized. 1.73 g of lithium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate are obtained in the form of a white solid, the characteristics of which are similar to the product of stage 2.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=[O:5].[CH2:12]1[CH2:17][O:16][CH:15]=[CH:14][CH2:13]1>ClCCl.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>[Br:1][C:2]1[CH:9]=[C:8]([O:10][CH:15]2[CH2:14][CH2:13][CH2:12][CH2:17][O:16]2)[CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=[O:5]
Reactant: C1=COCCC1
Reactant: O=Cc1c(O)cc(O)cc1Br
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1c(O)cc(OC2CCCCO2)cc1Br
Yield: 91.2 %

Procedure:
A solution of 2-bromo-4,6-dihydroxy-benzaldehyde (4.69 g, 21.7 mmol) in dichloromethane (100 mL) was treated with DHP (3.94 mL, 43.4 mmol) and PPTS (200 mg) at room temperature for 1 h. The reaction mixture was concentrated to dryness. The residue purified by flash column chromatography (silica, hexanes/ethyl acetate=4:1) to give the title compound (5.96 g, 92%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 12.2 (s, 1H), 10.1 (s, 1H), 6.88 (d, J=2.1 Hz, 1H), 6.58 (d, J=2.1 Hz, 1H), 5.56 (s, 1H), 3.84-3.81 (m, 1H), 3.68-3.62 (m, 1H), 1.96-1.54 (m, 6H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C:11](=[O:13])[NH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N(CCCCCC)=C=[O:17].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:12][C:11](=[O:13])[NH:10][C:9]1=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:2]([C:1]([NH2:8])=[O:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCN=C=O
Agent: CN(C)c1ccncc1
Agent: O=C1CN(Cc2ccccc2)C(=O)N1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCC(N)=O
Temperature: 115 °C
Reaction time: 6 h

Procedure:
1-Benzylimidazolidine-2,4-dione (100 mg, 0.526 mmol) and 1-isocyanatohexane (80.3 mg, 0.63 mmol) and, if required, a catalytic amount of 4-dimethylaminopyridine were dissolved in 10 ml of toluene and 0.5 ml of pyridine and stirred at 115° C. for 6 h. Then a further 80 mg of 1-isocyanatohexane were added, and the mixture was stirred at 115° C. for a further 6 h. The reaction mixture was concentrated and the residue was taken up in ethyl acetate and H2O, and the org. phases were washed twice with water, concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 11.3 mg (7%), M+H+:318.14.
Reaction SMILES: [C:1]1([C:9]([C:11]([C:13]2[CH:20]=[CH:19][C:16]([O:17][CH3:18])=[CH:15][CH:14]=2)=O)=O)[CH:8]=[CH:7][C:4]([O:5][CH3:6])=[CH:3][CH:2]=1.Cl.[NH2:22][NH:23][C:24]([NH2:26])=[O:25].C([O-])(=O)C.[Na+].C(O)(=O)C>O>[OH:25][C:24]1[N:23]=[N:22][C:11]([C:13]2[CH:20]=[CH:19][C:16]([O:17][CH3:18])=[CH:15][CH:14]=2)=[C:9]([C:1]2[CH:8]=[CH:7][C:4]([O:5][CH3:6])=[CH:3][CH:2]=2)[N:26]=1
Reactant: COc1ccc(C(=O)C(=O)c2ccc(OC)cc2)cc1
Reactant: NNC(N)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(-c2nnc(O)nc2-c2ccc(OC)cc2)cc1

Procedure:
Two moles, 540 g., of anisil (4,4'-dimethoxybenzil), 222 g. (2 moles) of semicarbazide hydrochloride, 180 g. (2.2 moles) of sodium acetate and 2.5 liters of acetic acid were refluxed overnight. The cooled reaction mixture was poured into 5 liters of water. The crude solid product was collected by filtration, washed with water and recrystallized from acetic acid. The yield was 434 g. of 3-hydroxy-5,6-bis(4-methoxyphenyl)-1,2,4-triazine, mp about 272°-274°C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[CH3:17][C:18]1[C:22]([C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)=[O:24])=[C:21]([CH3:32])[NH:20][C:19]=1[CH:33]=O.N1CCCCC1>C(O)C>[CH3:17][C:18]1[C:22]([C:23]([N:25]2[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]2)=[O:24])=[C:21]([CH3:32])[NH:20][C:19]=1[CH:33]=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[NH:11][C:10]1=[O:16]
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccncc4)c32)c(C)c1C(=O)N1CCN(C)CC1
Temperature: 60 °C

Procedure:
A mixture of 4-pyridin-4-yl-1,3-dihydroindol-2-one (50 mg, 0.24 mmol), 3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (59 mg, 0.24 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 60° C. for 5 hours. The reaction was concentrated and the residue was column chromatographed to give the title compound.
Reaction SMILES: O.[Cl:2][C:3]1[CH:4]=[C:5]([CH:10]2[CH2:14][CH2:13][NH:12][CH2:11]2)[CH:6]=[C:7]([Cl:9])[CH:8]=1.[OH:15][C@H:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17]([OH:19])=[O:18]>CC(O)C>[OH:15][C@H:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17]([OH:19])=[O:18].[Cl:2][C:3]1[CH:4]=[C:5]([C@H:10]2[CH2:14][CH2:13][NH:12][CH2:11]2)[CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: Clc1cc(Cl)cc(C2CCNC2)c1
Agent: O=C(O)[C@H](O)c1ccccc1
Solvent: O
Solvent: CC(C)O
Product: Clc1cc(Cl)cc([C@H]2CCNC2)c1
Temperature: 85 °C
Reaction time: 0.08 h
Yield: 17.7 %

Procedure:
3-(3,5-dichlorophenyl)pyrrolidine oxalate (471.6 g, 1.54 mol) was dissolved in 2 M aqueous NaOH solution (1000 mL) and extracted with ethyl acetate (3×350 mL). The combined organic extracts were dried over sodium sulfate and evaporated under reduced pressure to provide the free base of (R)-3-(3,5-dichlorophenyl)pyrrolidine (325.4 g, 98%) as a clear amber oil. A 5 L round bottom flask was fitted with a mechanical stirrer, a heating mantle, a J-Kem temperature probe/controller, a water cooled reflux condenser and a nitrogen inlet/outlet. The vessel was charged with 3-(3,5-dichlorophenyl)pyrrolidine (100 g, 0.46 mol) and 2-propanol (800 mL, 8 mL/g) under a nitrogen atmosphere at RT. (2R)-2-hydroxy-2-phenylacetic acid (70.4 g, 0.46 mol) was added as a solid in one portion, and the resulting solution was stirred for 5 min when a solid began to form. The suspension was heated at 85° C. for 5 min and then allowed to slowly cool to RT. The solid was filtered, washed with 2-propanol (2×250 mL) and dried under high vacuum. Repeated recrystallization of this salt (8×) in 2-propanol (1 mL/g) afforded (R)-3-(3,5-dichlorophenyl)pyrrolidine (R)-2-hydroxy-2-phenylacetate (30 g, 18%) in >96% ee. Absolute configuration was assigned based on X-ray analysis. 1H-NMR (400 MHz, DMSO-d6) δ 7.50 (t, J=1.8 Hz, 1H), 7.42-7.38 (m, 5H), 7.26-7.22 (m, 2H), 7.16 (dd, J=5.2, 9.3 Hz, 1H), 4.61 (s, 1H), 3.51 (dd, J=8.2, 10.9 Hz, 1H), 3.44-3.27 (m, 2H), 3.15-3.01 (m, 3H), 2.50 (t, J=1.8 Hz, 1H), 2.32-2.24 (m, 1H) and 1.91-1.81 (m, 1H) ppm. Chiral HPLC (Astec Chirobiotic, (25 cm×4.6 mm), 100% MeOH (0.1% TEA, 0.1% HOAc), 1.2 mL/min): tR=33.9 min (S), 34.9 min. (R).
Reaction SMILES: CO.[CH3:3][C:4]1[C:9]([CH:10]=O)=[CH:8][N:7]=[C:6]([NH:12][CH2:13][CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[N:5]=1.[F:23][C:24]1[C:25]([CH3:32])=[C:26]([NH2:31])[C:27]([NH2:30])=[CH:28][CH:29]=1>C1(C)C=CC=CC=1.O=[Mn]=O>[F:23][C:24]1[CH:29]=[CH:28][C:27]2[NH:30][C:10]([C:9]3[C:4]([CH3:3])=[N:5][C:6]([NH:12][CH2:13][CH2:14][CH2:15][CH:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[N:7][CH:8]=3)=[N:31][C:26]=2[C:25]=1[CH3:32]
Reactant: Cc1nc(NCCCC2CCN(C)CC2)ncc1C=O
Reactant: Cc1c(F)ccc(N)c1N
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1nc(NCCCC2CCN(C)CC2)ncc1-c1nc2c(C)c(F)ccc2[nH]1
Reaction time: 0.5 h

Procedure:
[5-(5-Fluoro-4-methyl-1 H-benzoimidazol-2-yl)-pyrimidin-2-yl]-3-(1-methyl-piperidin-4-yl)-propyl]-amine. A mixture of 4-methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidin-5-yl}-methanol (0.14 g, 0.49 mmol) in toluene (3 mL) was added MnO2 (0.22 g, 2.48 mmol). After 30 min at 70° C., the mixture was filtered through diatomaceous earth. The filtrate was concentrated and immediately dissolved in DMF. A portion of this solution (corresponding to 0.05 mg, 0.17 mmol of 4-methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidine-5-carbaldehyde) was then treated with 4-fluoro-3-methyl-benzene-1,2-diamine (1.1 equiv.) and Na2H2S2O5 (1.25 equiv.) at 90° C. for 12 h. The reaction mixture was purified by FCC to afford the title compound. MS: mass calcd. for C22H29FN6, 396.24; m/z found, 397.2 [M+H]+. 1H NMR (CD3OD): 8.62 (s, 1H), 7.55 (dd, J=8.0, 3.9 Hz, 1H), 7.17 (dd, J=10.3, 8.8 Hz, 1H), 3.60 (t, J=6.9 Hz, 2H), 3.10-2.99 (m, 2H), 2.71 (s, 3H), 2.66 (d, J=1.4 Hz, 3H), 2.44 (s, 3H), 2.26-2.17 (m, 2H), 1.98-1.88 (m, 2H), 1.87-1.77 (m, 2H), 1.55-1.36 (m, 5H).
Reaction SMILES: [Br:1][C@@H:2]1[C@H:8]2[CH2:9][C@H:5]([C:6](=[O:10])[O:7]2)[CH2:4][CH2:3]1.[NH3:11]>C1COCC1>[Br:1][C@H:2]1[CH2:3][CH2:4][C@@H:5]([C:6]([NH2:11])=[O:10])[CH2:9][C@H:8]1[OH:7]
Reactant: N
Reactant: O=C1O[C@@H]2C[C@H]1CC[C@@H]2Br
Solvent: C1CCOC1
Product: NC(=O)[C@@H]1CC[C@H](Br)[C@H](O)C1

Procedure:
(1R,4S,5R)-4-Bromo-6-oxabicyclo[3.2.1]octan-7-one (a) (2.13 g, 10.4 mmol) was taken up in THF (20 mL) and treated with 0.88 ammonia (5.3 mL) at 20° C. for 24 hours with stirring. The solvent was then removed in vacuo to give a white solid (2.31 g).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Br)#[N:2].[N-:11]=[N+:12]=[N-:13].[Na+]>C1COCC1.O>[N:11]([CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1[C:1]#[N:2])=[N+:12]=[N-:13]
Reactant: N#Cc1ccccc1CBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccccc1CN=[N+]=[N-]
Temperature: 23 °C
Reaction time: 18 h

Procedure:
To a solution of 90 g (459 mmol) 2-cyanobenzylbromide in 600 mL THF was added in one portion a solution of 36 g (553 mmol) sodium azide in 100 mL water. The two phase mixture was stirred at 23° C. for 18 hr. The THF layer was separated from the lower water layer and used in the next step without further purification.
Reaction SMILES: N([O-])=O.[Na+].[CH2:5]([C:7]1[CH:12]=[CH:11][C:10](N)=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15])[CH3:6].[ClH:17].NC(N)=O>O>[Cl:17][C:10]1[CH:11]=[CH:12][C:7]([CH2:5][CH3:6])=[C:8]([N+:14]([O-:16])=[O:15])[CH:9]=1
Reactant: Cl
Reactant: CCc1ccc(N)cc1[N+](=O)[O-]
Agent: NC(N)=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 90 %

Procedure:
A solution of sodium nitrite (0.11 g, 1.32 mmol) in water (1 mL) was added, dropwise, at 0° C., to a suspension of 4-ethyl-3-nitro-phenylamine (80%, 0.25 g, 1.20 mmol) in a mixture of concentrated hydrochloric acid (2 mL) and water (4 mL). The reaction mixture was stirred at 0° C. for 5 minutes and then urea (15 mg, 0.24 mmol) was added. The resulting mixture was stirred for 10 minutes and then was poured into a suspension of cuprous chloride (0.18 g, 1.8 mmol) in a mixture of concentrated hydrochloric acid (1.5 mL) and water (0.6 mL) at 80° C. The reaction mixture was stirred at 80° C. for 2 hours and then was extracted with ethyl acetate. The organic extracts were washed with an aqueous solution of sodium hydroxide (1 M) and water, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 200 mg (90% yield) of 4-chloro-1-ethyl-2-nitro-benzene as an oil.