Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[NH:35][C:36]([C:38]1[C:39]([C:44]2[CH:49]=[CH:48][C:47]([N+:50]([O-])=O)=[CH:46][CH:45]=2)=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:37])[C:6]([N:8]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]1)=[O:24])[CH3:9])=[O:7].[H][H].[ClH:55]>CO.C(O)C.[OH-].[Pd+2].[OH-]>[ClH:55].[ClH:55].[NH2:50][C:47]1[CH:48]=[CH:49][C:44]([C:39]2[C:38]([C:36]([NH:35][C:34]3[CH:33]=[CH:32][C:5]([C:6]([N:8]([C:10]4[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=4[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([N:25]4[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]4)=[O:24])[CH3:9])=[O:7])=[CH:4][C:3]=3[O:2][CH3:1])=[O:37])=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:45][CH:46]=1
Reactant: [H][H]
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1ccccc1-c1ccc([N+](=O)[O-])cc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1ccccc1-c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 3-methoxy-4-(4′-nitrobiphenyl-2-carboxamido)-N-[4-methyl-2-[5-(4-methylpiperazin-1-ylcarbonyl)pent-1-yloxy]phenyl]-N-methylbenzamide (910 mg), 20% palladium hydroxide (200 mg) in methanol (30 ml) was stirred under atmospheric pressure of hydrogen at ambient temperature. After 5 hours, the reaction mixture was filtered through a bed of Celite, and the solvent was removed by evaporation and the crude product was purified by silica gel column chromatography (SiO2; 30 g, 5% methanol in chloroform) to give free product. To a solution of this product (810 mg) in ethanol (20 ml) was added 1N hydrochloric acid (2.39 ml) and stirred at ambient temperature for 10 minutes. The solvent was removed to give 4-(4′-aminobiphenyl-2-carboxamido)-3-methoxy-N-[4-methyl-2-[5-(4-methylpiperazin-1-ylcarbonyl)pent-1-yloxy]phenyl]-N-methylbenzamide dihydrochloride as amorphous.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=1)=[O:6].[CH2:18](Br)[CH:19]=[CH2:20]>>[CH3:17][N:2]([CH3:1])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([N:13]([CH2:20][CH:19]=[CH2:18])[C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=1)=[O:6]
Reactant: C=CCBr
Reactant: CC(=O)Nc1cccc(C(=O)C=CN(C)C)c1
Product: C=CCN(C(C)=O)c1cccc(C(=O)C=CN(C)C)c1

Procedure:
N-[3-[3-(Dimethylamino)-1-oxo-2-propenyl]phenyl]acetamide was alkylated by the procedure of Example 3, using 7.26 g of allyl bromide, giving 13.34 g of the desired compound, mp 91°-94° C.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]([CH:7]=[O:8])[CH2:3][CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:27][C:28]([Si](C)(C)C)([F:30])[F:29]>O1CCCC1>[F:27][C:28]([F:30])([F:29])[CH:7]([CH:4]1[CH2:5][CH2:6][S:1][CH2:2][CH2:3]1)[OH:8]
Reactant: O=CC1CCSCC1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(C1CCSCC1)C(F)(F)F
Yield: 89.7 %

Procedure:
According to Reference Example 8-12, by use of tetrahydro-2H-thiopyran-4-carbaldehyde (300 mg, 2.30 mmol) dissolved in tetrahydrofuran (6 mL), a 1 mol/L solution of tetrabutylammonium fluoride in tetrahydrofuran (0.460 mL, 0.460 mmol) and (trifluoromethyl)trimethylsilane (0.408 mL, 2.76 mmol), the mixture was stirred and reacted at room temperature for 2 hours. Then, purification by extraction gave 2,2,2-trifluoro-1-(tetrahydro-2H-thiopyran-4-yl)ethanol (Compound EH) (413 mg, yield: 90%).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12][CH2:11]1.O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:1]([N:9]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@H:10]1[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O[C@H]1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)CC1
Reaction time: 1 h

Procedure:
140 ml of benzylbromide are added dropwise to a mixture of 61 g of trans-4-amino-cyclohexanol, 350 ml of water, 350 ml of ethanol and 110 g of potassium carbonate. The mixture is then heated to boiling for 1 hour, cooled and the crystalline residue is suction filtered. The residue is taken up in 1.51 of cyclohexane, the mixture is boiled, cooled and suction filtered. Washing with cyclohexane and drying in vacuo yields 108 g (92% of theory) of trans-4-dibenzylamino-cyclohexanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]2[S:14][C:13]([C:15]([O:17]C)=O)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[N:19]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[C@@H:21]([NH:27]C(C1SC(C3N=C(C)SC=3)=CC=1)=O)[CH2:20]2>>[N:19]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[C@@H:21]([NH:27][C:15]([C:13]1[S:14][C:10]([CH:9]=[CH:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)=[CH:11][CH:12]=1)=[O:17])[CH2:20]2
Reactant: Cc1nc(-c2ccc(C(=O)N[C@H]3CN4CCC3CC4)s2)cs1
Reactant: COC(=O)c1ccc(C=Cc2cccc(Cl)c2)s1
Product: O=C(N[C@H]1CN2CCC1CC2)c1ccc(C=Cc2cccc(Cl)c2)s1
Yield: 19 %

Procedure:
This compound is prepared from methyl 5-[2-(3-chlorophenyl)vinyl]-thiophene-2-carboxylate according to the procedure used to make the compound of Example 31, making non-critical variations. Yield 19%. MS for C20H21ClN2OS (ESI) (M+H)+ m/z 373.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[N:11][CH:10]=[CH:9][CH:8]=2)([O-])=O.[H][H]>[Pt].C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[N:11][CH:10]=[CH:9][CH:8]=2
Reactant: CC(C)(C)OC(=O)NCCCCNc1c([N+](=O)[O-])cnc2cccnc12
Reactant: [H][H]
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2cccnc12

Procedure:
1,1-Dimethylethyl N-{4-[(3-nitro[1,5]naphthyridin-4-yl)amino]butyl}carbamate (42.7 g, 0.12 mole), platinum on carbon (2 g) and ethyl acetate (500 mL) were combined and then hydrogenated on a Parr apparatus at 30 psi (2.1 Kg/cm2) hydrogen pressure for 1 hour. The catalyst was removed by filtration and rinsed with ethyl acetate. The filtrate was concentrated under vacuum to provide 1,1-dimethylethyl N-{4-[(3-amino[1,5]naphthyridin-4-yl)amino]butyl}carbamate as a bright yellow-orange solid.
Reaction SMILES: [O:1]=[C:2]1[N:8]2[C@H:4]([O:5][C:6]([CH:9]=[CH2:10])=[CH:7]2)[CH2:3]1.[CH2:11]([O:18][C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([O:18][C:19]([NH:21][C:22]1[CH:23]=[CH:24][C:25]([S:28][CH2:10]/[CH:9]=[C:6]2/[CH2:7][N:8]3[C@H:4]([O:5]/2)[CH2:3][C:2]3=[O:1])=[CH:26][CH:27]=1)=[O:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Nc1ccc(S)cc1)OCc1ccccc1
Reactant: C=CC1=CN2C(=O)C[C@H]2O1
Product: O=C(Nc1ccc(SC/C=C2/CN3C(=O)C[C@H]3O2)cc1)OCc1ccccc1

Procedure:
(5R)-7-Oxo-3-vinyl-4-oxa-1-azabicyclo[3.2.0]hept-2-ene (2.4 mmole) and p-benzyloxycarbonylaminophenyl mercaptan (0.775 g) were converted into the title compound using the process described in Example 1. The title compound was obtained as a colourless gum (63 mg), [α]D25 =34.6° (c 1.0, CHCl3), (Found: M+, 396.1136; C21H20N2O4S requires 396.1144). νmax (CHCl3): 3370, 3240, 1790, 1735, 1700, 1590, 1515 cm-1. δ(CDCl3): 2.71 (1H, d, J 16 Hz), 3.10-3.60 (4H, complex), 4.22 (1H, d, J 15 Hz), 4.38 (1H, t, J 7 Hz), 5.16 (2H, s), 5.32 (1H, d, J 2 Hz), 6.90 (1H, br.s), 7.10-7.45 (9 H, complex). m/e: 396 (M+, 6%), 138 (41), 108(20), 107(12), 96(46), 91(100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([NH:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:24][O:25][C:26](=[O:37])[C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]([N:34]=[C:35]=[O:36])[CH:28]=1.CCN(CC)CC>ClCCCl>[CH3:24][O:25][C:26](=[O:37])[C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]([NH:34][C:35]([N:17]([C:16]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[C:10]3[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]3)[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:36])[CH:28]=1
Reactant: COC(=O)c1ccc(C)c(N=C=O)c1
Reactant: Clc1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COC(=O)c1ccc(C)c(NC(=O)N(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c1

Procedure:
In analogy to the procedure described in example 1.2, [2-(4-chloro-phenyl)-2H-indazol-3-yl]-cyclohexyl-amine (example 9.1) was reacted with 3-isocyanato-4-methyl-benzoic acid methyl ester in 1,2-dichloroethane in the presence of Et3N (2.2 eq.) for 3 days under reflux conditions to give the title compound as yellow oil. MS: m/e=517.2 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([CH2:13][CH2:14][CH3:15])[CH:10]=[C:9](/[CH:16]=[CH:17]/[C:18]([O:20][CH3:21])=[O:19])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].CO[CH2:24][N:25]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:26][Si](C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.FC(F)(F)C(O)=O>[CH2:31]([N:25]1[CH2:26][C@@H:16]([C:9]2[CH:10]=[C:11]([CH2:13][CH2:14][CH3:15])[CH:12]=[C:2]([Cl:1])[C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C@H:17]([C:18]([O:20][CH3:21])=[O:19])[CH2:24]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CCCc1cc(Cl)c(C(=O)OCC)c(/C=C/C(=O)OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1cc(Cl)c(C(=O)OCC)c([C@@H]2CN(Cc3ccccc3)C[C@H]2C(=O)OC)c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a solution of (E)-ethyl 2-chloro-6-(3-methoxy-3-oxoprop-1-enyl)-4-propylbenzoate (0.92 g, 2.96 mmol) in 20 mL of CH2Cl2 was added N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (0.77 g, 3.25 mmol) and trifluoroacetic acid (0.045 mL, 0.6 mmol). The solution was allowed to stir at 40° C. for 2 h. Starting material still remained by TLC analysis and so additional N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (0.1 g, 0.4 mmol) and trifluoroacetic acid (2 drops) were added and the reaction was stirred at 40° C. for an additional 30 min and then at ambient temperature for 18 h. The reaction was quenched with sat'd aq NaHCO3 and extracted with EtOAc. The organics were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (230-400 mesh silica gel, 6:1 hexane/EtOAc) to afford 1.17 g (90%) of the title compound as an oil. LRMS (ES)+: 444.25/446.24 (M+H)+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:23][O:24][C:25]1[CH:26]=[CH:27][C:28]2[NH:34][C:33](=[O:35])[N:32]([CH:36]3[CH2:41][CH2:40][N:39]([C:42]4[N:47]=[CH:46][N:45]=[C:44]([C:48]([OH:50])=O)[CH:43]=4)[CH2:38][CH2:37]3)[CH2:31][CH2:30][C:29]=2[CH:51]=1.Cl.Cl.[CH3:54][C:55]1([CH3:64])[CH2:60][NH:59][CH2:58][C:57]2[CH:61]=[N:62][NH:63][C:56]1=2.C(N(CC)CC)C>CN(C=O)C>[CH3:54][C:55]1([CH3:64])[CH2:60][N:59]([C:48]([C:44]2[N:45]=[CH:46][N:47]=[C:42]([N:39]3[CH2:40][CH2:41][CH:36]([N:32]4[CH2:31][CH2:30][C:29]5[CH:51]=[C:25]([O:24][CH3:23])[CH:26]=[CH:27][C:28]=5[NH:34][C:33]4=[O:35])[CH2:37][CH2:38]3)[CH:43]=2)=[O:50])[CH2:58][C:57]2[CH:61]=[N:62][NH:63][C:56]1=2
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)ncn3)CC1)C(=O)N2
Reactant: CC1(C)CNCc2cn[nH]c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4Cc5cn[nH]c5C(C)(C)C4)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
105 mg (0.28 mmol) TBTU were added to 100 mg (0.25 mmol) 6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 80.0 mg (0.36 mmol) 7,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine dihydrochloride, 120.0 μL (0.86 mmol) triethylamine in 1.0 mL DMF and stirred overnight at RT. The reaction mixture was purified by preparative HPLC, the product fractions were combined and then lyophilised.
Reaction SMILES: [CH2:1]([C@:3]1([OH:11])[CH2:7][CH2:6][NH:5][C@H:4]1[CH:8]([CH3:10])[CH3:9])[CH3:2].[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:5]2[CH2:6][CH2:7][C@:3]([CH2:1][CH3:2])([OH:11])[C@@H:4]2[CH:8]([CH3:10])[CH3:9])[CH:18]=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: CC[C@]1(O)CCN[C@H]1C(C)C
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC[C@]1(O)CCN(c2ccc(C#N)c(Cl)c2)[C@H]1C(C)C

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-3-ethyl-2-isopropylpyrrolidin-3-ol 0.5 oxalate (162 mg), 2-chloro-4-fluorobenzonitrile (125 mg) and lithium carbonate (126 mg), the title compound was obtained as pale-brown oil (yield: 151 mg, yield: 65%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]=[C:3](/[CH:7]=[CH:8]/[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2]1.[H][H]>[Pd].C(OCC)(=O)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2]1
Reactant: [H][H]
Reactant: CCOC(=O)/C=C/C1=CCCOC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCC1CCCOC1
Yield: 174.1 %

Procedure:
The above was repeated in the exact same fashion with a second batch. Hence a solution of ethyl (2E)-3-(5,6-dihydro-2H-pyran-3-yl)-2-propenoate (2.59 g) and palladium on carbon (147 mg, 10% wet) in ethyl acetate (65 ml) was hydrogenated at atmospheric pressure and room temperature. The hydrogen uptake (˜715 ml) was complete after 15 minutes. The catalyst was filtered through celite and the filtrate concentrated in vacuo. to afford a pale yellow oil which was combined with that of the first batch (5.34 g). This was purified by silica chromatography (120 g) (ISCO) using a gradient elution of 0-10% cyclohexane:ethyl acetate to afford the title compound as a clear oil (4.61 g).
Reaction SMILES: [C:1]1([S:7]([C:10]([CH:16]2[CH2:28][CH2:27][C:26]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([Cl:29])[CH:24]=4)[NH:19][C:18]=3[CH2:17]2)([F:15])[C:11]([NH:13][CH3:14])=[O:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[C:37]([O:41][C:42](=O)[O:43]C(C)(C)C)([CH3:40])([CH3:39])[CH3:38]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:37]([O:41][C:42]([N:19]1[C:18]2[CH2:17][CH:16]([C:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:8])=[O:9])([F:15])[C:11](=[O:12])[NH:13][CH3:14])[CH2:28][CH2:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[C:23]([Cl:29])[CH:24]=2)=[O:43])([CH3:40])([CH3:39])[CH3:38]
Reactant: CNC(=O)C(F)(C1CCc2c([nH]c3ccc(Cl)cc23)C1)S(=O)(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)C(F)(C1CCc2c(n(C(=O)OC(C)(C)C)c3ccc(Cl)cc23)C1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.5 %

Procedure:
To 950 mg (2.18 mmol) of (RS,SR)-2-benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-2-fluoro-N-methyl-acetamide (from example 56) in 10 mL of CH2Cl2 at RT were added 0.60 mL (4.36 mmol, 2 eq) of Et3N, 27 mg (0.22 mmol, 0.1 eq) of DMAP and 571 mg (2.62 mmol, 1.2 eq) of carbonic acid di-tert-butyl ester. The reaction mixture was stirred at RT for 2 hours and extracted with 1M HCl. The organic phases were dried over Na2SO4, filtered and evaporated. Column chromatography afforded 682 mg (59%) of (RS,SR)-2-(benzenesulfonyl-fluoro-methylcarbamoyl-methyl)-6-chloro-1,2,3,4-tetrahydro-carbazole-9-carboxylic acid tert-butyl ester as white solid, MS: 552 (MNH4+).
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH3:5].[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1>CCOCC>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]([OH:14])[CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:11][CH:10]=1
Reactant: CCCCC[Mg]Br
Reactant: O=Cc1ccc(Br)cc1
Solvent: CCOCC
Product: CCCCCC(O)c1ccc(Br)cc1
Temperature: 25 °C
Yield: 63 %

Procedure:
n-Pentylmagnesium bromide (12.1 mL of a 2.0 M solution in Et2O, 24.0 mmol) was added to a solution of 4-bromobenzaldehyde 5 (4.0 g, 22.0 mmol) at −78° C. The reaction was then warmed to room temperature for 0.5 h and quenched with saturated aqueous NH4Cl. The mixture was extracted with EtOAc and the organic portion was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. FCC (silica gel, 9:1 hex/EtOAc) gave 3.6 g (63%) of the alcohol 6 as a clear, colorless oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]23[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]4)[CH2:10]2)[CH2:16]3)=[O:8])[CH2:2]1.Br[CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([CH2:23][CH2:22][CH2:21][CH2:20][N:1]2[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]34[CH2:18][CH:13]5[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]5)[CH2:10]3)[CH2:16]4)=[O:8])[CH2:2]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCCCCc1ccccc1
Reactant: O=C(N[C@H]1CCNC1)C12CC3CC(CC(C3)C1)C2
Product: O=C(N[C@H]1CCN(CCCCc2ccccc2)C1)C12CC3CC(CC(C3)C1)C2
Yield: 12.5 %

Procedure:
(S)-N-(Pyrrolidin-3-yl)-1-adamantanecarboxamide (0.38 g) and 4-bromobutylbenzene (0.39 g) were reacted under the same conditions as in Example 1 to give (S)-N-(1-(4-phenylbutyl)pyrrolidin-3-yl)-1-adamantanecarboxamide (0.073 g), melting point 82-84° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2.[CH2:15](Br)[CH:16]=[CH2:17].O>CN(C=O)C>[CH2:17]([C:12]1[C:11]([OH:14])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([F:3])[CH:13]=1)[CH:16]=[CH2:15]
Reactant: Oc1ccc(F)c2cccnc12
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCc1cc(F)c2cccnc2c1O
Temperature: 0 °C
Yield: 96.1 %

Procedure:
After a 100 mL three-neck flask equipped with a magnetic stirrer, a reflux condenser, a thermometer and a dropping funnel was replaced with Ar, 5 mL of DMF and NaH (0.88 g, 60 mass % article, 22.0 mmol) were placed therein and the temperature of the mixture was cooled to 0° C. or lower in an ice bath, followed by stirring of the mixture. 5-Fluoro-8-quinolinol (3.42 g, 21.0 mmol) dissolved in 30.0 mL of DMF was added dropwise to this over 1 hour. After the mixture was stirred at the same temperature for 30 minutes, allyl bromide (2.54 g, 21.0 mmol) was added dropwise thereto. Further, the mixture was stirred at the same temperature for 30 minutes, and then the internal temperature was slowly raised to 150° C. and the mixture was heated and stirred for 2 hours. This was cooled to room temperature, and then the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. Then, ethyl acetate was removed under reduced pressure and the resulting crude reaction product was purified by column chromatography (Hexane/AcOEt=100/0→1/1) using silica gel, followed by drying under reduced pressure to give 4.10 g of 7-allyl-5-fluoro-8-quinolinol as a white solid (yield: 96.0%).
Reaction SMILES: CI.[C:3](=O)(O)[O-].[Na+].[CH3:8][O:9][C:10]1[CH:26]=[CH:25][C:13]([CH2:14][S:15][C@@H:16]2[CH2:20][NH:19][C@H:18]([C:21](=[O:24])[NH:22][CH3:23])[CH2:17]2)=[CH:12][CH:11]=1.[Cl-].[Na+]>CN(C)C=O>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][S:15][C@@H:16]2[CH2:20][N:19]([CH3:3])[C@H:18]([C:21](=[O:24])[NH:22][CH3:23])[CH2:17]2)=[CH:25][CH:26]=1
Reactant: O=C([O-])O
Reactant: CNC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1
Agent: [Cl-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CNC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1C
Reaction time: 1 h
Yield: 21.1 %

Procedure:
244 μl of methyl iodide and 300 mg of sodium bicarbonate were added, whilst ice-cooling, to a solution of 1.00 g of (2S, 4S)-4-(4-methoxybenzylthio)-2-methylcarbamoylpyrrolidine [prepared as described in step (4) above] dissolved in 6 ml of dry dimethylformamide. The mixture was then stirred at 0° to 5° C. for 1 hour and allowed to stand overnight at room temperature. At the end of this time, the reaction mixture was poured into an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel (eluted with a 10:1 by volume mixture of ethyl acetate and methanol), to afford 222 mg of the title compound as colorless crystals, melting at 82°-84° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[N:3]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[Cl:8][C:6]1[CH:7]=[C:2]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=[C:4]([NH:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[N:5]=1
Reactant: C1CCNC1
Reactant: CC(C)(C)CNc1nc(Cl)cc(Cl)n1
Product: CC(C)(C)CNc1nc(Cl)cc(N2CCCC2)n1
Yield: 96.7 %

Procedure:
The reaction of 4,6-dichloro-2-(2,2-dimethylpropylamino)pyrimidine with pyrrolidine as described in Example 12 gives the title product in a yield of 96.7%, m.p.: 147°-150° C.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7]([CH2:11][CH2:12][CH3:13])=[N:8]2)=[C:4]([CH3:14])[N:3]=1.[CH3:15][NH:16][CH3:17]>C(O)C>[CH3:15][N:16]([CH3:17])[C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7]([CH2:11][CH2:12][CH3:13])=[N:8]2)=[C:4]([CH3:14])[N:3]=1
Reactant: CNC
Reactant: CCCc1nc2nc(Cl)nc(C)c2[nH]1
Solvent: CCO
Product: CCCc1nc2nc(N(C)C)nc(C)c2[nH]1
Temperature: 110 °C

Procedure:
To a solution of 2-Chloro-6-methyl-8-propylpurine (from Step 1 of Example 32) (0.1 g, 0.47 mmol) in ethanol (2 ml) was added condensed dimethylamine (1 ml) at 0° C. The mixture was then placed in a steel-bomb and heated at 110° C. for 7 hours. The reaction was cooled and the mixture was concentrated in vacuo. The residue was partitioned between CHCl3 and water, and the organic was separated and dried over MgSO4. The crude product obtained after removal of the solvent was purified by flash-chromatography on silica-gel using 5% MeOH in CHCl3 giving the titled compound as an amorphous solid (0.065 g, 64%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[N+]=[N-]>CCO.[Pd]>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][NH2:1])=[CH:13][CH:14]=1
Reactant: [N-]=[N+]=NCCCCCCCOc1ccc(Cl)cc1
Agent: [Pd]
Solvent: CCO
Product: NCCCCCCCOc1ccc(Cl)cc1
Reaction time: 1.25 h
Yield: 89.2 %

Procedure:
7-Azidoheptyltosylate (920 mg, 3.8 mmol) was dissolved in DMF (12 mL). 4-Chlorophenol (650 mg, 5.0 mmol) and K2CO3 (1.7 g, 12.3 mmol) were added and the mixture was heated to 90° C. for 4 h. The mixture was concentrated under reduced pressure, the residue was partitioned between EtOAc (100 mL) and water (25 mL). The organic layer was dried, filtered and concentrated under reduced pressure. Flash chromatography (silica gel, hexanes/EtOAc 95/5) yielded 1-azido-7-(4-chlorophenoxy)-heptane (579 mg, 49%). 1-Azido-7-(4-chlorophenoxy)-heptane (570 mg, 2.1 mmol) was dissolved in EtOH (3 mL). Pd/C (101 mg, 10%) was added and the mixture was stirred under an atmosphere of H2 for 75 min. The reaction mixture was filtered through celite and concentrated under reduced pressure to yield the title compound (453 mg, 89%). The product contained ˜25% of 7-(phenoxy)-heptylamine.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]=[C:14]=[O:15])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:16][C:17]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=O>>[Cl:26][C:24]1[CH:25]=[C:17]2[C:18]([C:19](=[O:21])[N:13]([S:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)(=[O:11])=[O:12])[C:14](=[O:15])[NH:16]2)=[CH:22][CH:23]=1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: O=C=NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)n1S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 32.3 %

Procedure:
1.13 g (4.95 mmol) of 4-nitrobenzenesulfonylisocyanate and 849 mg (4.95 mmol) of 2-amino-4-chlorobenzoic acid were treated in the same way as in Example 1 to obtain 610 mg of the above-identified compound (yield 32.3%). Properties: colorless crystal, Melting point: >250° C., PMR (δppm, DMSO-d6): 7.13 (1H,s), 7.24 (1H,d), 7.87 (1H,d), 8.42 (2H,d), 8.48 (2H,d), 11.93 (1H,br).