Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:21]=[O:22])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8](F)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23]1([CH2:29][O:30][C:31]([N:33]2[CH2:37][CH2:36][C@@H:35]([C:38]([OH:40])=[O:39])[NH:34]2)=[O:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C.C(O)(=O)C>ClCCl.CC#N>[CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:21]=[O:22])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]([N:34]2[C@H:35]([C:38]([OH:40])=[O:39])[CH2:36][CH2:37][N:33]2[C:31]([O:30][CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:32])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)F)OCc1ccccc1
Reactant: O=C(O)[C@@H]1CCN(C(=O)OCc2ccccc2)N1
Solvent: CC#N
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)O)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 62.3 %

Procedure:
(2R)-3-Cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl fluoride (4 g, 13.01 mmol) was added into the solution of (3S)-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidine carboxylic acid (3.58 g, 14.32 mmol) in dichloromethane (DCM) (52.9 ml), and followed by adding Hunig's base (6.80 ml, 39.0 mmol). The reaction mixture was stirred for 2.5 hrs at ambient temperature. The reaction was diluted with DCM (200 ml), and then acetic acid (9 ml) was added. The resulting solution was washed with aqueous NH4Cl (200 ml). The aqueous solution was extracted with DCM (2×50 ml). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give a residue. The desired product was precipitated while ethyl acetate (a few ml) was added. The desired product was filtered and washed with ethyl acetate. 3.49 g of desired product as a white solid was collected. The filtrate was purified by silica Gel chromatography (0-100% Ethyl acetate in Hexane). The solvent was removed under reduced pressure to give a solid. The solid was added about 10 ml of MeCN. The desired product (870 mg) as a white solid was collected via filtration. All desired products were combined to yield the final batch of (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid (4.36 g, 8.11 mmol, 62% yield). MS (ES+) m/z 538.1 (MH+).
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.Br[CH2:31][C:32]#[N:33]>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([CH2:31][C:32]#[N:33])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: N#CCBr
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3CC#N)CC1

Procedure:
In analogy to the procedure described for the synthesis of Example 1, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1) and bromoacetonitrile. The title compound was obtained in 38% yield as light green foam. MS (m/e): 445.2 (MH+, 100%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:3]=1.[CH3:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[CH3:28])[CH2:23][NH2:24]>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([NH:24][CH2:23][C:22]2[CH:25]=[CH:26][C:27]([CH3:28])=[C:20]([CH3:19])[CH:21]=2)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:3]=1
Reactant: Cc1ccc(CN)cc1C
Reactant: CS(=O)c1nc(N)nc(-c2cccnc2)c1C#N
Solvent: COCCOC
Product: Cc1ccc(CNc2nc(N)nc(-c3cccnc3)c2C#N)cc1C

Procedure:
From 2-amino-4-methanesulfinyl-6-pyridin-3-yl-pyrimidine-5-carbonitrile and 3,4-dimethylbenzylamine in DME. ES-MS m/e (%): 331 (M+H+, 100).
Reaction SMILES: C[O:2][C:3](=[O:39])[C@@H:4]([NH:23][C:24](=[O:38])[C:25]1[C:30]([Cl:31])=[CH:29][C:28]([O:32][CH2:33][CH2:34][CH2:35][NH2:36])=[CH:27][C:26]=1[Cl:37])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:22])[C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:21])=[CH:8][CH:7]=1.[OH-].[Li+]>C1COCC1.O>[NH2:36][CH2:35][CH2:34][CH2:33][O:32][C:28]1[CH:27]=[C:26]([Cl:37])[C:25]([C:24]([NH:23][C@@H:4]([CH2:5][C:6]2[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:22])[C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])=[CH:10][CH:11]=2)[C:3]([OH:39])=[O:2])=[O:38])=[C:30]([Cl:31])[CH:29]=1
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)c1c(Cl)cc(OCCCN)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NCCCOc1cc(Cl)c(C(=O)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 77.4 %

Procedure:
To a solution of (S)-2-[4-(3-aminopropoxy)-2,6-dichlorobenzoylamino]-3-[4-(2,6-dichlorobenzoylamino)phenyl]propionic acid methyl ester (5.8 g, 7.98 mmol,) in THF (200 mL) was added a solution of lithium hydroxide (2.4 g, 100 mmol) in water (30 mL) at room temperature. The mixture was stirred for 15 h at room temperature at which time TLC analysis of the mixture indicated the absence of starting material. Then, the solvent was removed by rotary evaporation and the residue was purified by an HPLC method to obtain 3.7 g (65% yield) of (S)-2-[4-(3-aminopropoxy)-2,6-dichlorobenzoylamino]-3-[4-(2,6-dichlorobenzoylamino)phenyl]propionic acid as a white solid. ES(+)-HRMS m/e calcd. for C26H23Cl4N3O5 (M+H)+ 598.0465, obsd. 598.0465.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH3:12])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11].CO[C:15]1[C:24](=[O:25])[C:19]2[N:20]=[C:21]([CH3:23])[S:22][C:18]=2[C:17](=[O:26])[CH:16]=1>C(O)C>[CH3:12][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:15]1[C:24](=[O:25])[C:19]2[N:20]=[C:21]([CH3:23])[S:22][C:18]=2[C:17](=[O:26])[CH:16]=1)[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:15]1[C:24](=[O:25])[C:19]2[N:20]=[C:21]([CH3:23])[S:22][C:18]=2[C:17](=[O:26])[CH:16]=1
Reactant: CN(CCCCN)CCCCN
Reactant: COC1=CC(=O)c2sc(C)nc2C1=O
Solvent: CCO
Product: Cc1nc2c(s1)C(=O)C=C(NCCCCN(C)CCCCNC1=CC(=O)c3sc(C)nc3C1=O)C2=O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
6 mg (34 μmol) of N-(4-aminobutyl)-N-methylbutane-1,4-diamine is added to a solution of 15 mg (71 mmol; 2.1 equivalents) of 5-methoxy-2-methyl-1,3-benzothiazole-4,7-dione in 1.5 ml of ethanol, then the reaction mixture is stirred at 60° C. for 1 hour. The solvent is then evaporated off under reduced pressure and the expected product is obtained by purification by chromatography on a silica column (eluent: dichloromethane/methanol: 95/5) in the form of a red oil.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][C:6]1[N:7]([CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH:8]=[CH:9][N:10]=1.[F:21][C:22]([F:39])([F:38])[C:23]1[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[C:31]2[O:32][CH:33]=[C:34]([CH2:36]Cl)[N:35]=2)=[CH:25][CH:24]=1>>[F:39][C:22]([F:21])([F:38])[C:23]1[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[C:31]2[O:32][CH:33]=[C:34]([CH2:36][O:20][C:17]3[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][CH2:11][N:7]4[CH:8]=[CH:9][N:10]=[C:6]4[CH2:5][CH2:4][OH:3])=[CH:19][CH:18]=3)[N:35]=2)=[CH:25][CH:24]=1
Reactant: FC(F)(F)c1ccc(/C=C/c2nc(CCl)co2)cc1
Reactant: OCCc1nccn1CCCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Product: OCCc1nccn1CCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Yield: 66.4 %

Procedure:
Using 65% sodium hydride (40.6 mg), 4-[3-[2-(hydroxyethyl)-1H-imidazol-1-yl]propyl]phenol (246 mg) and [2-[(E)-2-(4-trifluoromethylphenyl)ethenyl]oxazol-4-yl]methyl chloride (316 mg), the same reaction as Example 17 was carried out to yield the titled compound (330 mg) as colorless needles.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:19]([C:28]([O:30][CH3:31])=[O:29])[CH2:18][CH2:17]2)=[CH:12][C:11]=1[O:32][CH3:33].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:44](OCC)=[O:45].[BH4-].[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@:19]([CH2:44][OH:45])([C:28]([O:30][CH3:31])=[O:29])[CH2:18][CH2:17]2)=[CH:12][C:11]=1[O:32][CH3:33]
Reactant: CCOC=O
Reactant: COC(=O)[C@@H]1CC[C@H](c2ccc(OCc3ccccc3F)c(OC)c2)N1C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)[C@]1(CO)CC[C@H](c2ccc(OCc3ccccc3F)c(OC)c2)N1C(=O)OC(C)(C)C
Temperature: -40 °C
Reaction time: 0.67 h
Yield: 45.7 %

Procedure:
To a solution of 1-(1,1-dimethylethyl) 2-methyl (2S,5R)-5-[4-{[(2-fluorophenyl)methyl]oxy}-3-(methyloxy)phenyl]-1,2-pyrrolidinedicarboxylate (D58, 0.35 g, 0.76 mmol) in dry THF (6 ml) at −78° C. was added dropwise LiHMDS (0.80 ml, 0.80 mmol, 1M solution in THF). The mixture was allowed to warm to −40° C. and was stirred for 40 min at that temperature. Then the mixture was again cooled to −78° C. and ethyl formate (1.23 ml, 15.2 mmol) was added. The mixture was left stirring for another 8 h at the same temperature. The reaction was quenched with brine, diluted with water and extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered and evaporated. The crude material was dissolved in MeOH (5 ml) at 0° C. and NaBH4 (30 mg, 0.79 mmol) was added. The mixture was stirred for 1 h at the same temperature. The reaction was quenched with a 5% solution of aqueous NaHCO3, diluted with water and extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified by chromatography on silica gel using cyclohexane and ethyl acetate (9:1 to 75:25) to afford the title compound as a colourless oil (170 mg, 46%); Rt (HPLC): 5.78 min; MS: (ES/+) m/z: 512 [M+Na] C26H32FNO7 requires 489.
Reaction SMILES: [N:1]([C@@H:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:5][C:6]([NH2:8])=[O:7])=[N+]=[N-]>[Pd]>[NH2:1][C@@H:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:5][C:6]([NH2:8])=[O:7]
Reactant: CCCCCCCCCCCCC[C@@H](CC(N)=O)N=[N+]=[N-]
Agent: [Pd]
Product: CCCCCCCCCCCCC[C@H](N)CC(N)=O
Reaction time: 5 h
Yield: 68.3 %

Procedure:
A mixture of (S)-3-azidohexadecanamide (0.17 g) and 10% palladium on carbon (20 mg) was hydrogenated at atmospheric pressure for 5 hours. The catalyst was filtered off with celite, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate (3 ml) to give (S)-3-aminohexadecanamide (106 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:10][C@H:11]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]2)=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[Br:1][C:2]1[C:3]([NH:10][C@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([S:27]([CH3:26])(=[O:29])=[O:28])[CH2:12]2)=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CSc1ncc(Br)c(N[C@H]2CCCNC2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CSc1ncc(Br)c(N[C@H]2CCCN(S(C)(=O)=O)C2)n1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of (5-bromo-2-methylsulfanyl-pyrimidin-4-yl)-(S)-piperidin-3-yl-amine (2.9 g, 9.6 mmol) and diisopropylethylamine (3.7 g, 28 mmol) in dichloromethane (50 ml) was cooled to 5° C. and treated with a solution of methanesulfonyl chloride (1.21 g, 10.5 mmol) in dichloromethane (20 ml). This was stirred at room temperature for 14 hours, washed with water, dried (MgSO4) and evaporated to give (5-bromo-2-methylsulfanyl-pyrimidin-4-yl)-((S)-1-methanesulfonyl-piperidin-3-yl)-amine as a white solid. MS (ES+): 382 (2602-33).
Reaction SMILES: [CH2:1]([N:3]([C:6]1[CH:24]=[CH:23][C:9]([CH:10]([OH:22])[C:11]2[CH:16]=[CH:15][C:14]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:13][CH:12]=2)=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].[C:25]([NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:28])[CH2:26]O.C(C(C)=O)C>CS(O)(=O)=O.CN(C)C(=N)N(C)C.CCCCCC>[CH2:18]([N:17]([CH2:20][CH3:21])[C:14]1[CH:15]=[CH:16][C:11]([CH:10]([C:9]2[CH:23]=[CH:24][C:6]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:7][CH:8]=2)[O:22][CH2:26][C:25]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:28])=[CH:12][CH:13]=1)[CH3:19]
Reactant: CCN(CC)c1ccc(C(O)c2ccc(N(CC)CC)cc2)cc1
Reactant: O=C(CO)Nc1ccccc1
Agent: CN(C)C(=N)N(C)C
Agent: CS(=O)(=O)O
Solvent: CCC(C)=O
Solvent: CCCCCC
Product: CCN(CC)c1ccc(C(OCC(=O)Nc2ccccc2)c2ccc(N(CC)CC)cc2)cc1

Procedure:
A solution of 4,4'-bis(N,N-diethylamino)benzhydrol (11.0 g, 0.034 mole), glycolanilide (5.1 g, 0.034 mole), 37.5 ml of methyl ethyl ketone, 112.5 ml of n-hexane, and 7 drops of methanesulfonic acid was refluxed for about 2 hours, removing water as formed. The solution was then treated with 5 drops of tetramethyl-guanidine and filtered hot. On cooling, the filtrate yielded a tan precipitate. The precipitate was filtered, washed with n-hexane, and dried. The pale yellow solid was recrystallized from 80 ml of methylcyclohexane and 450 ml of acetone to give a solid product, mp 123°-125° C.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15](N)=[CH:14][N:13]=[C:12]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[ClH:23].N([O-])=O.[Na+].CC1C=CC(COC(NNC(C2C=NC=CN=2)=O)=O)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Cu]>[Cl:23][C:15]1[C:10]([NH:9][C:6]2[CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[NH:8][N:7]=2)=[N:11][C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:13][CH:14]=1
Reactant: Cl
Reactant: Nc1cnc(-c2ccccn2)nc1Nc1cc(C2CC2)[nH]n1
Agent: Cl[Cu]
Agent: Cc1ccc(COC(=O)NNC(=O)c2cnccn2)cc1
Agent: O=C([O-])[O-]
Product: Clc1cnc(-c2ccccn2)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To N4-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(pyridin-2-yl)pyrimidine-4,5-diamine (0.88 g, 0.003 mmol, 1 equiv.) in conc.HCl (3 mL) at ice-bath was added NaNO2 (0.23 g, 0.0033 mmol, 1.1 equiv.). After 1 h, CuCl (0.33 g, 0.0033 mmol, 1.1 equiv.) in conc.HCl (6 mL) was added at 0° C. After 30 min, the reaction mixture was allowed to stand at room temperature for further 3 h, poured into ice water and adjusted to pH10 with Na2CO3, extracted with EA (50 mL×3). The organic phase was combined, dried (Na2SO4), purified with silicon chromatography (EA: PE=2:1) to produce 5-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(pyridin-2-yl)pyrimidin-4-amine (Compound 182) (0.47 g, 50%). LC-MS (m/z)=313 [M+H]+; 1H NMR (400 MHz, DMSO-d6): δ 0.75-0.78 (m, 2H), 0.97-1.02 (m, 2H), 1.96-2.02 (m, 1H), 6.44-6.45 (m, 1H), 7.92-7.93 (m, 1H), 8.44 (s, 2H), 8.73 (d, J=2.8 Hz, 1H), 8.87 (d, J=3.6 Hz, 1H), 10.20 (bs, 1H)
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([N:10]([CH2:12][C:13]1[S:17][CH:16]=[C:15]([C:18]2[CH:19]=[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=2)[NH:23][CH:22]=[C:21]3[CH:30]2[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:38])=[O:37])[CH2:32][CH2:31]2)[CH:14]=1)[CH3:11])[CH3:9].CN[CH2:43][CH3:44]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:39]([S:36]([N:33]1[CH2:34][CH2:35][CH:30]([C:21]2[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=[C:18]([C:15]4[CH:14]=[C:13]([CH2:12][N:10]([CH2:8][C:9]5[O:4][CH:3]=[CH:43][CH:44]=5)[CH3:11])[S:17][CH:16]=4)[CH:19]=3)[NH:23][CH:22]=2)[CH2:31][CH2:32]1)(=[O:37])=[O:38])[CH3:40]
Reactant: CCNC
Reactant: CCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)Cc5ccco5)c4)cc23)CC1
Yield: 29 %

Procedure:
The title compound was prepared according to the general procedure of 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting 1-(2-furanyl)-N-methylmethanamine (111 mg, 1.0 mmol) for N-methylethanamine to afford 19.0 mg of the title compound (29.0%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.CS(O[CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[N:23]=[C:24](/[CH:27]=[CH:28]/[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:25][CH:26]=2)=[CH:16][CH:15]=1)(=O)=O>>[C:29]1(/[CH:28]=[CH:27]/[C:24]2[O:25][CH:26]=[C:22]([CH2:21][O:20][C:17]3[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][CH2:11][N:1]4[CH:5]=[CH:4][CH:3]=[CH:2]4)=[CH:19][CH:18]=3)[N:23]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CS(=O)(=O)OCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Reactant: c1cc[nH]c1
Product: C(=C/c1nc(COc2ccc(CCCn3cccc3)cc2)co1)\c1ccccc1
Yield: 57 %

Procedure:
In substantially the same manner as in Working Example 8, pyrrole was allowed to react with 3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl methansulfonate to give 2-[(E)-2-phenylethenyl]-4-[4-[3-(1-pyrrolyl)propyl]phenoxymethyl]oxazole. The yield was 57%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 108-109° C.
Reaction SMILES: [CH]Cl.C([N:10]([CH2:20][C:21]1[C:25]2[N:26]=[CH:27][NH:28][C:29](=[O:30])[C:24]=2[NH:23][CH:22]=1)[CH2:11][CH:12]1[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14][CH2:13]1)C1C=CC=CC=1>CO>[CH3:18][C:15]1([CH3:19])[O:16][CH2:17][CH:12]([CH2:11][NH:10][CH2:20][C:21]2[C:25]3[N:26]=[CH:27][NH:28][C:29](=[O:30])[C:24]=3[NH:23][CH:22]=2)[CH2:13][O:14]1
Reactant: CC1(C)OCC(CN(Cc2ccccc2)Cc2c[nH]c3c(=O)[nH]cnc23)CO1
Agent: [CH]Cl
Solvent: CO
Product: CC1(C)OCC(CNCc2c[nH]c3c(=O)[nH]cnc23)CO1
Yield: 49.6 %

Procedure:
cHCl was added to a stirred solution of 7-((benzyl((2,2-dimethyl-1,3-dioxan-5-yl)methyl)amino)methyl)-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one (50 mg, 131 μmol) in methanol (2 mL). After 0.5 h the reaction was concentrated in vacuo and co-distilled with methanol. The crude reaction was absorbed as a methanol solution onto silica gel and purified by chromatography on silica eluting with 20% 7N NH3/MeOH to afford, presumably, 7-(((2,2-dimethyl-1,3-dioxan-5-yl)methylamino)methyl)-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one (19 mg, 42.4% yield) as a white solid, which was committed to the next step without characterisation. A solution of 7-(((2,2-dimethyl-1,3-dioxan-5-yl)methylamino)methyl)-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one (19 mg, 55.5 μmol) and 10% palladium on carbon (56 mg, 526 μmol) in water (2 mL, 1.11E+05 μmol) was stirred under an atmosphere of hydrogen (0.101 mg, 50.2 μmol) for 72 h. The reaction was filtered through Celite® and the filtrate concentrated in vacuo to yield a crude residue which was purified by chromatography on silica gel, eluting with 5:4.5:0.5 DCM:MeOH:NH4OH to afford 7-((3-hydroxy-2-(hydroxymethyl)propylamino)methyl)-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one hydrochloride (4 mg, 27.6% yield) as a white solid. 13C NMR (D2O) δ 152.6, 145.0, 133.2, 131.7, 118.4, 102.8, 60.8 (2×CH2), 47.6, 41.1, 39.8.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:33]1([CH2:39][CH2:40][S:41][CH:42]([C:46](O)=[O:47])[C:43](O)=[O:44])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[OH:47][C:46]1[CH:16]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:10][CH:11]=2)[O:17][C:43](=[O:44])[C:42]=1[S:41][CH2:40][CH2:39][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Reactant: CC(=O)c1ccc(OCc2ccccn2)cc1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2ccc(OCc3ccccn3)cc2)cc(O)c1SCCc1ccccc1

Procedure:
The title compound was prepared by Method A using 4'-(2-pyridinylmethoxy)acetophenone (1.14 g, 5.06 mmol), lithium bis(trimethylsilyl)amide (0.930 g, 5.56 mmol), chlorotrimethylsilane (0.705 mL, 5.56 mmol), THF (56 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. dec. 179° C.; 1H NMR (400 MHz, DMSO-d6) δ2.77 (t, 2 H), 2.98 (t, 2 H), 5.27 (s, 2 H), 6.68 (s, 1 H), 7.22 (m, 7 H), 7.36 (m, 1 H), 7.53 (d, 1 H), 7.77 (d, 2 H), 7.85 (t, 1 H), 8.60 (d, 2 H), 11.88 (bs, 1 H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[C:13]([F:16])([F:15])[F:14])[C:9](=[O:17])[CH:8]=[CH:7][C:6]2=[O:18].Br[CH:22]1[C:25]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:24]2[CH:23]1Br.BrC1C2=CC=CC=C2C1I.C1(C)C(C)=CC=CC=1>O>[F:1][C:2]([F:19])([F:20])[C:3]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]2[C:9](=[O:17])[C:8]3[C:7](=[CH:23][C:24]4[C:25]([CH:22]=3)=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:6](=[O:18])[C:5]=2[CH:4]=1
Reactant: O=C1C=CC(=O)c2cc(C(F)(F)F)c(C(F)(F)F)cc21
Reactant: BrC1c2ccccc2C1Br
Agent: BrC1c2ccccc2C1I
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C1c2cc(C(F)(F)F)c(C(F)(F)F)cc2C(=O)c2cc3ccccc3cc21

Procedure:
25 mmol of 6,7-bis-trifluoromethyl-1,4-naphthquinone, approx. 37 mmol of 1,2-dibromobenzocyclobutene [see J. Am. Chem. Soc. 79, pages 1701 et seq. (1957)] containing a little 1-bromo-2-iodobenzocyclobutene and 100 ml of xylene are kept under reflux for 16 hours in a water separator. The reaction mixture is cooled and the precipitate is filtered off and washed with xylene. The crystalline 2,3-di-(trifluoromethyl)-naphthacene-5,12-dione is obtained in a yield of 5.82 g (71%), melting point>280° C.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[C:14]1([O:20][C:21](Cl)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[O:20]([C:21]([O:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN(C)CCO
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN(C)CCOC(=O)Oc1ccccc1

Procedure:
To a 500 ml three-necked round-bottomed flask equipped with an internal thermometer, reflux condenser, mechanical stirrer, addition funnel, and argon inlet are added N,N-dimethylethanolamine (25.00 g, 0.281 mol), toluene (200 ml), and triethylamine (31.21 g, 0.309 mol). The mixture is treated with a solution of phenylchloroformate (43.91 g, 0.281 mol) dissolved in 50 ml of toluene over 15 min. After addition is complete, the mixture is heated to reflux for 3 h. The cooled mixture is washed with saturated sodium bicarbonate solution (2×100 ml) and water (100 ml). The organic phase is dried over MgSO4, filtered, and concentrated first by rotary evaporation at 50° C. (water aspirator vacuum) and then at 60° C. (0.05 mmHg) in a Kugelrohr oven to give 8 as a light yellow oil, 49.93 g (85%) that crystallizes on standing.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21]Cl)[CH:17]=3)[N:12]([CH3:23])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[N-:26]=[N+:27]=[N-:28].[Na+].O>CN(C=O)C>[N:26]([CH2:21][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:23])[CH:11]=[C:10]([C:8]([NH:7][CH2:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:25][CH:24]=1)=[O:9])[C:19]2=[O:20])=[N+:27]=[N-:28]
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)ccc21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN=[N+]=[N-])ccc21
Temperature: 25 °C
Yield: 90 %

Procedure:
A solution of N-(4-chlorobenzyl)-6-(chloromethyl)-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide from Preparation No. 35 (200 mg) and sodium azide (176.8 mg) in anhydrous DMF (7 mL) is heated at 60° C. overnight. The reaction is cooled to room temperature and poured into water to precipitate the product. The solid is adsorbed onto silica and purified by chromatography (eluent 100% CH2Cl2 (1 L), 0.5% MeOH in CH2Cl2 (1 L), and 1% MeOH in CH2Cl2 (1 L)). Fractions homogenous by TLC were combined and concentrated to afford 182.7 mg (90%) of the title compound as a white solid.