Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[N:3]=1.[CH3:16][C@H:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1.C(N(CC)CC)C>CN1CCCC1=O>[C:26]([O:25][C:23]([N:19]1[CH2:20][CH2:21][N:22]([C:2]2[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][N:11]=3)[N:3]=2)[C@H:17]([CH3:16])[CH2:18]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1nc(-c2ccncn2)cc(=O)n1C
Yield: 74.4 %

Procedure:
A solution of 2-chloro-3-methyl-6-(pyrimidin-4-yl)-3H-pyrimidin-4-one (5.3 g, 24 mmol), tert-butyl (3R)-3-methylpiperazine-1-carboxylate (5.0 g, 25 mmol) and triethylamine (7.6 g, 75 mmol) in N-methyl-2-pyrrolidone (25 ml) was stirred for 6 hours at 90° C. The solution was partitioned between water and ethyl acetate, and the organic layer was washed with water, brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate) to afford (3R)-3-methyl-4-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (6.9 g, 71%).
Reaction SMILES: [NH2:1][C:2]1[C:31]([F:32])=[CH:30][C:5]([CH2:6][C@H:7]2[C@H:15]3[C@@H:11]([N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:19]=4)[C:13](=[O:16])[O:14]3)[CH2:10][S:9](=[O:29])(=[O:28])[CH2:8]2)=[CH:4][C:3]=1[CH2:33][CH3:34].CCN(C(C)C)C(C)C.[Cl:44][CH2:45][C:46](Cl)=[O:47].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:24]([C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][N:12]1[C@@H:11]2[C@H:15]([C@H:7]([CH2:6][C:5]3[CH:30]=[C:31]([F:32])[C:2]([NH:1][C:46](=[O:47])[CH2:45][Cl:44])=[C:3]([CH2:33][CH3:34])[CH:4]=3)[CH2:8][S:9](=[O:28])(=[O:29])[CH2:10]2)[O:14][C:13]1=[O:16])([CH3:26])([CH3:27])[CH3:25]
Reactant: O=C(Cl)CCl
Reactant: CCc1cc(C[C@@H]2CS(=O)(=O)C[C@H]3[C@H]2OC(=O)N3Cc2cccc(C(C)(C)C)c2)cc(F)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(C[C@@H]2CS(=O)(=O)C[C@H]3[C@H]2OC(=O)N3Cc2cccc(C(C)(C)C)c2)cc(F)c1NC(=O)CCl
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
To a solution of (3aR,7S,7aS)-7-(4-amino-3-ethyl-5-fluoro-benzyl)-3-(3-tert-butyl-benzyl)-5,5-dioxo-hexahydro-1-oxa-5lambda*6*-thia-3-aza-inden-2-one (0.245 g, 0.5 mmol) and DIPEA (0.52 mL, 3 mmol) in CH2Cl2 was slowly added a solution of 2-chloroacetylchloride (0.226 g, 2.0 mmol) dissolved in CH2Cl2 (2 mL) at 0-5° C. After stirring for 1 h at 0-5° C. the reaction mixture was poured onto cold saturated NaHCO3 solution and extracted with CH2Cl2. Combined organic extracts were washed with brine, dried over MgSO4, filtered and evaporated. The crude product was dissolved in MeOH, stirred for 0.5 h at 25° C., and evaporated again. The title compound was obtained after chromatographic purification (Combi Flash, 12 g silica gel, hexane-EtOAc) as a light yellow solid: TLC (toluene-EtOAc 1:1) Rf=0.44; UPLC RtD=1.799 min; ESIMS [M+NH4]+=582; 1H NMR (600 MHz, DMSO-d6): δ 9.70 (s, 1H), 7.39 (s, 1H), 7.32 (d, 1H), 7.27 (t, 1H), 7.13 (d, 1H), 6.98 (d, 1H), 6.95 (s, 1H), 4.42 (d, 1H), 4.28 (s, 2H), 4.21 (d, 1H), 4.19 (t, 1H), 3.72 (m, 2H), 3.48 (t, 1H), 3.14 (dd, 1H), 2.98 (m, 2H), 2.55 (m, 4H), 1.26 (s, 9H), 1.08 (t, 3H).
Reaction SMILES: [CH3:1][C@H:2]1[C@@:6]([C:8]([F:11])([F:10])[F:9])([OH:7])[CH2:5][CH2:4][NH:3]1.[Cl:12][C:13]1[CH:20]=[C:19](F)[CH:18]=[CH:17][C:14]=1[C:15]#[N:16].C(=O)([O-])[O-].[Li+].[Li+]>>[Cl:12][C:13]1[CH:20]=[C:19]([N:3]2[CH2:4][CH2:5][C@@:6]([OH:7])([C:8]([F:9])([F:11])[F:10])[C@@H:2]2[CH3:1])[CH:18]=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: C[C@@H]1NCC[C@@]1(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: C[C@@H]1N(c2ccc(C#N)c(Cl)c2)CC[C@@]1(O)C(F)(F)F

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-2-methyl-3-(trifluoromethyl)pyrrolidin-3-ol 0.5 oxalate (200 mg), 2-chloro-4-fluorobenzonitrile (289 mg) and lithium carbonate (138 mg), the title compound was obtained as a colorless solid (yield: 100 mg, yield: 35%).
Reaction SMILES: [C:1](#[N:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:11][OH:12]>CCO>[OH:12][N:11]=[C:1]([NH2:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N#CC=Cc1ccccc1
Reactant: NO
Solvent: CCO
Product: NC(C=Cc1ccccc1)=NO
Yield: 70.1 %

Procedure:
Cinnamonitrile (1 g, 7.74 mmol) and hydroxylamine (0.71 cm3, 11.6 mmol, 1.5 eq) were reacted in EtOH (7 cm3) as described for AO6 (two chromatographic separations were needed in purification) to give N′-hydroxycinnamimidamide (0.88 g, 70%) as a light orange solid, mp 85-87° C. (lit 93° C.).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=C[C:3]=1[C:8]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16]([CH3:21])([CH3:20])[CH2:15][CH2:14][C:13]2([CH3:23])[CH3:22])=[CH2:9].C(N(CCCC)CCCC)CCC.[C]=O.[C:39]([O:42][CH2:43]C)(=[O:41])[CH3:40]>CO.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH3:20][C:16]1([CH3:21])[CH2:15][CH2:14][C:13]([CH3:22])([CH3:23])[C:12]2[CH:11]=[C:10]([C:8]([C:3]3[CH:2]=[CH:7][CH:6]=[CH:5][C:40]=3[C:39]([O:42][CH3:43])=[O:41])=[CH2:9])[CH:19]=[CH:18][C:17]1=2
Reactant: C=C(c1ccc2c(c1)C(C)(C)CCC2(C)C)c1ccccc1I
Reactant: CCOC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C]=O
Solvent: CO
Solvent: CCCCN(CCCC)CCCC
Product: C=C(c1ccc2c(c1)C(C)(C)CCC2(C)C)c1ccccc1C(=O)OC

Procedure:
A solution of 6-[1-(2-iodophenyl)vinyl]-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (9.5 g, 22 mmol), palladium diacetate (560 mg, 2.5 mmol)-and tributylamine (12 ml, 50 mmol) in methanol (500 ml) is heated for 3 h at 100° C. under a pressure of carbon monoxide (3 bar). After concentration on an evaporator under vacuum at 40° C., the oil obtained is diluted in ethyl acetate and washed three times with water. The product is purified by flash chromatography on a column of silica.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:20]CCCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(O)=O)[C:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)([CH3:12])[CH2:8][S:9]2)=[CH:4][CH:3]=1.[F:47][C:48]([F:75])([C:65]([F:74])([F:73])[C:66]([F:72])([F:71])[C:67]([F:70])([F:69])[F:68])[CH2:49][CH2:50][CH:51]([CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH:63]=[CH2:64])[C:52]([O:54]CC)=[O:53]>>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:20][CH2:64][CH2:63][CH2:62][CH2:61][CH2:60][CH2:59][CH2:58][CH2:57][CH:51]([CH2:50][CH2:49][C:48]([F:47])([F:75])[C:65]([F:73])([F:74])[C:66]([F:71])([F:72])[C:67]([F:68])([F:69])[F:70])[C:52]([OH:54])=[O:53])[C:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)([CH3:12])[CH2:8][S:9]2)=[CH:4][CH:3]=1
Reactant: C=CCCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCC
Reactant: CC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O
Product: CC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the allyl compound prepared in Example 8 and the ethyl 2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-9-decenoate prepared in Example 6, a procedure analogous to that as shown in Example 8 was repeated to give 11-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoic acid.
Reaction SMILES: [CH:1]1([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:10][CH2:9][NH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].C(N(CC)CC)C>C(Cl)Cl>[CH:1]1([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:10][CH2:9][N:8]2[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: c1ccc(C2CCNC(C3CCCCC3)C2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCC(c2ccccc2)CC1C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-cyclohexyl-4-phenylpiperidine (2.85 g, 11.71 mmol) in CH2Cl2 (58.5 ml) was added benzyl chloroformate (2.507 ml, 17.56 mmol) and triethylamine (2.45 ml, 17.56 mmol). The reaction was stirred at room temperature for 2 hours. Added water and extracted 3 times with CH2Cl2. The combined organics were dried, concentrated, and purified on silica gel 20% EtOAc/Hexanes. Separated cis and trans on the AD column, 20% IPA/Hexanes w/DEA. Peak 1 corresponds to the cis racemic mixture with one trans diastereomer and peak2 is a single trans diastereomer. Obtained 2.5 g racemic cis/trans peak1. Resolved on the OJ column 20% EtOH/Hexanes w/DEA: Peak 1: 0.68 g pure cis undesired, peak 2 1.75 g cis/trans mixture.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:25][CH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27]1>C(#N)C>[CH:26]1([NH:25][CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([C:11]3[C:15]4[S:16][CH:17]=[CH:18][C:14]=4[O:13][N:12]=3)[CH:6]=2)[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27]1
Reactant: BrCCOc1cccc(-c2noc3ccsc23)c1
Reactant: NC1CCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1cc(OCCNC2CCc3ccccc32)cc(-c2noc3ccsc23)c1

Procedure:
The title compound is prepared from 3-[3-(2-bromo-ethoxy]phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, 1-aminoindan and acetonitrile essentially as described above in example 35. Purity by LC/MS (APCI)=99%, [M+H]+=377.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.C([C@H]1CC[C@H](CC(Cl)=O)CC1)CCCC.CC1(C)CO[C:39]([CH:42]2[CH2:47][CH2:46][C:45](=O)[CH2:44][CH2:43]2)=[N:38]1>C1C=CC=CC=1>[C:39]([C@H:42]1[CH2:47][CH2:46][C@H:45]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C@H:10]3[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:12][CH2:11]3)=[CH:4][CH:3]=2)[CH2:44][CH2:43]1)#[N:38]
Reactant: CC1(C)COC(C2CCC(=O)CC2)=N1
Reactant: CCCCC[C@H]1CC[C@H](CCc2ccc(Br)cc2)CC1
Agent: CCCCC[C@H]1CC[C@H](CC(=O)Cl)CC1
Solvent: c1ccccc1
Product: CCCCC[C@H]1CC[C@H](CCc2ccc([C@H]3CC[C@H](C#N)CC3)cc2)CC1

Procedure:
1-(p-Bromophenyl)-2-(trans-4-n-pentylcyclohexyl)-ethane [obtainable by Friedel-Crafts acylation of benzene with trans-4-n-pentylcyclohexylacetyl chloride, Wolff-Kishner reduction of the carbonyl group and bromination of the aromatic in the p-position] is subjected to a Grignard reaction with 4-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-cyclohexanone. Detachment of water, with simultaneous removal of the oxazolyl protective group, by boiling with ethanolic H2SO4, hydrogenation of the double bond, conversion of the ethyl ester into the amide, dehydration analogously to Example 2 and customary working up gives 1-[p-(trans-4-cyanocyclohexyl)-phenyl]-2-(trans-4-n-pentylcyclohexyl)-ethane.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH3:11].O.[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.[Pd](Cl)Cl.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH3:11]
Reactant: OB(O)c1ccncc1Cl
Reactant: Cc1ccc([N+](=O)[O-])cc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc([N+](=O)[O-])cc1-c1ccncc1Cl
Temperature: 90 °C

Procedure:
Nitrogen was bubbled through a solution of 2-bromo-1-methyl-4-nitrobenzene (1 eq) in dimethoxyethane and water (3:1) for 0.5 h. Bis(diphenylphosphino)ferrocene Palladium(II)chloride (0.05 eq) followed by 3-chloro-4-pyridine boronic acid hydrate (1 eq) and sodium carbonate (3 eq) was added and the mixture was heated to 90° C. for 16 h under nitrogen. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was washed with brine and dried with sodium sulfate and concentrated. Purification on silica gel gave 3-chloro-4-(2-methyl-5-nitrophenyl)pyridine. MS: MH+=248.
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:20]([NH:22][NH:23][C:24]2[C:29]([F:30])=[C:28]([N:31]([CH3:40])[CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=3)[N:27]=[C:26]([CH3:41])[N:25]=2)=[O:21])[CH2:8][N:9]([O:12]CC2C=CC=CC=2)[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[Pd].[C]>[CH:1]1([CH2:6][C@@H:7]([C:20]([NH:22][NH:23][C:24]2[C:29]([F:30])=[C:28]([N:31]([CH3:40])[CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=3)[N:27]=[C:26]([CH3:41])[N:25]=2)=[O:21])[CH2:8][N:9]([OH:12])[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)c(F)c(N(C)CCc2ccncc2)n1
Agent: [Pd]
Solvent: CO
Product: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(O)C=O)c(F)c(N(C)CCc2ccncc2)n1
Reaction time: 5 h
Yield: 95.2 %

Procedure:
{(2R)-2-(Cyclopentylmethyl)-3-[2-(5-fluoro-2-methyl-6-{methyl[2-(4-pyridinyl)ethyl]amino}-4-pyrimidinyl)hydrazino]-3-oxopropyl}[(phenylmethyl)oxy]formamide (290 mg, 0.51 mmol) was dissolved in 10 mL of MeOH. 10% Pd/carbon (60 mg) was added, and the contents were stirred under a hydrogen balloon for approximately 5 h. The contents were then filtered to remove the catalyst, and the filtrate was concentrated in vacuo to provide {(2R)-2-(cyclopentylmethyl)-3-[2-(5-fluoro-2-methyl-6-{methyl[2-(4-pyridinyl)ethyl]amino}-4-pyrimidinyl)hydrazino]-3-oxopropyl}hydroxyformamide (230 mg, 96%). LCMS: (M+H)+: 474.3.
Reaction SMILES: [O:1]1[C:3]2([CH2:7][CH2:6][N:5]([C:8]3[N:13]=[C:12]4[N:14]([CH2:17][C:18]5[CH:19]=[C:20]6[C:25](=[CH:26][CH:27]=5)[N:24]=[CH:23][CH:22]=[CH:21]6)[N:15]=[N:16][C:11]4=[N:10][CH:9]=3)[CH2:4]2)[CH2:2]1.CO.[CH3:30][NH2:31].[I-].[K+]>CS(C)=O>[CH3:30][NH:31][CH2:2][C:3]1([OH:1])[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[C:12]3[N:14]([CH2:17][C:18]4[CH:19]=[C:20]5[C:25](=[CH:26][CH:27]=4)[N:24]=[CH:23][CH:22]=[CH:21]5)[N:15]=[N:16][C:11]3=[N:10][CH:9]=2)[CH2:4]1
Reactant: c1cnc2ccc(Cn3nnc4ncc(N5CCC6(CO6)C5)nc43)cc2c1
Reactant: CN
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: CS(C)=O
Product: CNCC1(O)CCN(c2cnc3nnn(Cc4ccc5ncccc5c4)c3n2)C1
Temperature: 80 °C
Yield: 24.9 %

Procedure:
To a solution of 6-{[6-(1-oxa-5-azaspiro[2.4]hept-5-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl]methyl}quinoline (130 mg, 0.36 mmol) in 2:1 MeOH:DMSO (3 ml) were added methylamine (24.7 mg, 0.80 mmol) and potassium iodide (300.4 mg, 1.81 mmol) at R.T. After heating at 80° C. for 3.5 h, the reaction mixture was cooled to R.T. and concentrated under reduced pressure. The resulting residue was purified via flash column chromatography eluted with 0-5% 7N N3 in MeOH: CH2Cl2 to give the desired product (35 mg, 25%).
Reaction SMILES: [CH:1]([CH:3]([CH2:9][N:10]1[CH2:14][CH:13]([CH2:15][CH2:16][CH3:17])[CH2:12][C:11]1=[O:18])[C:4]([O:6]CC)=O)=O.CCN(CC)CC.[C:26]1([CH2:32][NH:33][NH2:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl.Cl>C1(C)C=CC=CC=1>[CH2:32]([N:33]1[C:4](=[O:6])[CH:3]([CH2:9][N:10]2[CH2:14][CH:13]([CH2:15][CH2:16][CH3:17])[CH2:12][C:11]2=[O:18])[CH:1]=[N:34]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NNCc1ccccc1
Reactant: CCCC1CC(=O)N(CC(C=O)C(=O)OCC)C1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCC1CC(=O)N(CC2C=NN(Cc3ccccc3)C2=O)C1
Temperature: 40 °C
Yield: 14 %

Procedure:
In a three neck flask, fitted with a magnetic stirrer, under inert atmosphere, ethyl 2-formyl-3-(2-oxo-4-propylpyrrolidin-1-yl)propanoate x280 (0.9 g) in PhMe (10 ml) is added onto a solution of Et3N (1.6 ml) and PhCH2NHNH2.2HCl (0.75 g, 0.0039 mol.) in PhMe (30 ml) at room temperature. The mixture is heated up to 40° C. for 12 h, cooled down to room temperature, washed with NH4Cl (saturated) and the aqueous layer is acidified to pH 3 by addition of HCl (5 N). After 3 extractions with EtOAc, the organic layers are dried over MgSO4, concentrated in vacuo to afford the crude reaction mixture which is purified by chromatography on silicagel (first purification with CH2Cl2/MeOH/NH4OH 98/018/0.02; second purification with EtOAC/iPrOH 95/5; third purification by preparative reverse phase LC/MS) to afford 2-benzyl-4-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-2,4-dihydro-3H-pyrazol-3-one x281 as a red oil (0.18 g).
Reaction SMILES: FC(F)(F)[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15](Cl)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23][CH2:22]1.C(N(CC)CC)C>ClCCl>[CH2:27]([N:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:15]([C:10]2[C:9]([C:6]3[CH:5]=[CH:4][CH:3]=[CH:8][CH:7]=3)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])[CH2:22][CH2:23]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CCN(Cc2ccccc2)CC1)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
3 g (0.014 mol) of 4′-trifluoromethyl-biphenyl-2-carboxylic acid chloride, dissolved in 30 ml of dichloromethane, are added dropwise at 15 to −20° C. to a solution of 2.65 ml (0.013 mol) of 4-amino-1-benzyl-piperidine and 6 ml (0.043 mol) of triethylamine in 100 ml of dichloromethane. The mixture is stirred for 14 hours at ambient temperature. The reaction solution is extracted with a mixture of I molar sodium hydrogen carbonate solution and 1N sodium hydroxide solution. The organic phase is dried over sodium sulphate and the solvent is eliminated. The residue is recrystallised from 650 ml of ethanol.
Reaction SMILES: ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.OC(C(F)(F)F)=O.[NH2:20][C@H:21]([CH2:41][C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=1)[C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH2:26][CH2:25]1)=[O:23].CCN(C(C)C)C(C)C.C([O:62][C:63](=O)[NH:64][CH2:65][CH2:66][CH2:67][NH2:68])(C)(C)C>>[Cl:48][C:45]1[CH:44]=[CH:43][C:42]([CH2:41][C@@H:21]([NH:20][C:63]([NH:64][CH2:65][CH2:66][CH2:67][NH2:68])=[O:62])[C:22]([N:24]2[CH2:25][CH2:26][N:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[NH:36][S:37]([CH3:40])(=[O:38])=[O:39])[CH2:28][CH2:29]2)=[O:23])=[CH:47][CH:46]=1
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: CS(=O)(=O)Nc1ccccc1N1CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Nc1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)NCCCN)CC1

Procedure:
Following the procedure of Example 51, N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}piperazinyl)-2-oxoethyl][(3-aminopropyl)amino]carboxamide, TFA salt was prepared from triphosgene (Avocado Chemical Company) (45 mg, 0.152 mmol), (2R)-2-amino-3-(4-chlorophenyl)-1-(4-{2-[(methylsulfonyl)amino]phenyl}piperazinyl)propan-1-one TFA salt (200 mg, 0.36 mmol), DIEA (0.32 mL, 0.916 mmol), and tert-butyl-N-(3-aminopropyl)carbamate (Aldrich Chemical Company) (96 mg, 0.55 mmol). The Boc protecting group was removed by treating the compound with a soln of 50% TFA and CH2Cl2 (2 mL) for 2 h. The organic solvent was removed in vacuo to give the desired product. Preparative TLC purification with 60% Hexane, 35% CH2Cl2 and 5% 2N NH3 in MeOH afforded 90% pure compound. This was further purified by preparative HPLC (TFA buffer) to afford the title compound (TFA salt) as a white solid (10 mg). MS (ESI, pos. ion) m/z: 537 (M+H); MS (ESI, neg. ion) m/z: 535 (M−H). Calc'd for C24H33ClN6O4S: 536.20.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[C:25]3[C:26]4=[C:27]5[C:22](=[CH:23][CH:24]=3)[CH:21]=[CH:20][C:19]([C:28]3[C:37]6[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=6)[C:31]([CH3:38])=[CH:30][CH:29]=3)=[C:18]5[CH:17]=[CH:16][C:15]4=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[Br:39]N1C(=O)CCC1=O.CN(C)C=O>O>[Br:39][C:21]1[C:22]2[C:27]3=[C:26]4[C:25](=[CH:24][CH:23]=2)[C:12]([C:5]2[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:13][CH:14]=[C:15]4[CH:16]=[CH:17][C:18]3=[C:19]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]([CH3:38])=[CH:30][CH:29]=2)[CH:20]=1
Reactant: Cc1ccc(-c2ccc3ccc4c(-c5ccc(C)c6ccccc56)ccc5ccc2c3c54)c2ccccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2ccc3ccc4c(-c5ccc(C)c6ccccc56)cc(Br)c5ccc2c3c54)c2ccccc12
Temperature: 25 °C
Yield: 88 %

Procedure:
A mixed solution of 1.7 g of 1,6-di(4-methylnaphthalen-1-yl)pyrene, 0.54 g of N-bromosuccinimide and 30 ml of dimethylformamide was stirred under a nitrogen gas stream at 60° C. for 6 hours. The solution was cooled to room temperature and 50 ml of water was poured into the solution, followed by extraction with 100 ml of dichloromethane. The organic layer was washed twice with 50 ml of water, dried over magnesium sulfate and then concentrated by evaporation. The resulting concentrate was recrystallized from toluene and then vacuum-dried at 70° C. to obtain 1.5 g of 1-bromo-3,8-di(4-methylnaphthalen-1-yl)pyrene as a pale yellow powder.
Reaction SMILES: Cl[CH:2]([C:4]1[C:5]([O:24][CH3:25])=[C:6]([CH:13]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]2)[C:7]([C:11]#[N:12])=[C:8]([CH3:10])[CH:9]=1)[CH3:3].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:32][C:33]1[C:41]2[C:36](=[N:37][CH:38]=[N:39][C:40]=2[NH2:42])[NH:35][N:34]=1>CN(C)C=O.C(OCC)(=O)C>[NH2:42][C:40]1[N:39]=[CH:38][N:37]=[C:36]2[N:35]([CH:2]([C:4]3[C:5]([O:24][CH3:25])=[C:6]([CH:13]4[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]4)[C:7]([C:11]#[N:12])=[C:8]([CH3:10])[CH:9]=3)[CH3:3])[N:34]=[C:33]([CH3:32])[C:41]=12
Reactant: COc1c(C(C)Cl)cc(C)c(C#N)c1C1CN(C(=O)OC(C)(C)C)C1
Reactant: Cc1n[nH]c2ncnc(N)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(C)c(C#N)c1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Reaction time: 18 h
Yield: 49.9 %

Procedure:
The tert-butyl 3-[3-(1-chloroethyl)-6-cyano-2-methoxy-5-methylphenyl]azetidine-1-carboxylate (2.3 g, 6.3 mmol) was dissolved in N,N-dimethylformamide (68 mL) with cesium carbonate (4.1 g, 13 mmol) and 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.4 g, 9.4 mmol) and was heated in an oil bath to 80° C. The reaction was stirred for 18 hrs and allowed to cool to room temperature. The reaction mixture was taken up in ethyl acetate, filtered, washed with water, brine, dried over magnesium sulfate and concentrated to give the crude product. The product was purified by FCC on silica gel eluting a (hexane: 10% ethanol ethyl acetate) gradient to give tert-butyl 3-{3-[-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-cyano-2-methoxy-5-methylphenyl}azetidine-1-carboxylate as a semisolid (1.5 g, 50%). LCMS calculated for C25H32N7O3(M+H)+: m/z=478.2; found: 478.2. The enantiomers were separated by Chiral column HPLC using: Phenomenex LUX Cellulose Column, 21.1×250 mm, 5 micron, 15% ethanol in hexane, 18 mL/min ˜5 mg/injection to give: First peak retention time: 2.1 minutes, tert-butyl 3-{3-[-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-cyano-2-methoxy-5-methylphenyl}azetidine-1-carboxylate; Second peak retention time: 3.9 minutes, tert-butyl 3-{3-[-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-cyano-2-methoxy-5-methylphenyl}azetidine-1-carboxylate.