Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.[C:11](#[N:15])[CH2:12][C:13]#[N:14].C([O-])(=O)C.[NH4+].C(O)(=O)C>C(OCC)C.O.C1(C)C=CC=CC=1>[C:13]([C:12]([C:11]#[N:15])=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1)[CH3:9])#[N:14]
Reactant: N#CCC#N
Reactant: CC(=O)c1ccc(O)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(=C(C#N)C#N)c1ccc(O)cc1
Yield: 77 %

Procedure:
A mixture of 92.0 g of p-hydroxyacetophenone, 44.6 g of malononitrile, 5.2 g of ammonium acetate, 8.1 g of acetic acid and 500 ml of toluene was boiled on a water separator for 2 hours while stirring. After cooling, the two-phase mixture was diluted with 700 ml of diethyl ether. The dark red solution was washed four times with 50 ml of saturated sodium chloride solution, dried over sodium sulphate, filtered and evaporated. By fractional crystallization from diisopropyl ether there were obtained 95.7 g of p-(2,2-dicyano-1-methylvinyl)phenol, m.p. 120.5°-121.5° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[C@H:13](O)[CH2:12][N:11]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:27]([O:30][N:31]([C@H]1CN(C(OC(C)(C)C)=O)[C@H](CO[Si](C(C)(C)C)(C)C)C=C1C)[S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N+:41]([O-:43])=[O:42])(=[O:34])=[O:33])[CH:28]=[CH2:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[CH2:27]([O:30][N:31]([C@H:13]1[CH2:12][N:11]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3])[CH:15]=[C:14]1[CH:16]([CH3:17])[CH3:18])[S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N+:41]([O-:43])=[O:42])(=[O:34])=[O:33])[CH:28]=[CH2:29]
Reactant: CC(C)C1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C[C@H]1O
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1C(C)C)S(=O)(=O)c1ccccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (2S,5S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-5-hydroxy-4-isopropyl-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 36, 1.2 g, 3.11 mmol) following the procedure described for Intermediate 10, using 2.4 equivalents each of triphenylphosphine and diisopropylazodicarboxylate. The desired product was obtained as yellow foam (1.22 g, 62%).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([N:30]1[CH2:29][CH2:28][CH:27]([NH:26][C:24]([C:20]2[C:16]3=[N:17][CH:18]=[CH:19][C:14]([C:8]4[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)=[C:15]3[NH:22][C:21]=2[CH3:23])=[O:25])[CH2:32][CH2:31]1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ccnc2c1C(=O)NC1CCNCC1
Agent: Cl
Product: CC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-fluorophenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f7) and commercially acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([CH2:16][CH2:17][CH3:18])[C:13](O)=[S:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:22][CH:21]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([CH2:16][CH2:17][CH3:18])[C:13]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:24][CH:25]=2)=[S:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCC[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)C(O)=S
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCC[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)C(=S)Nc1ccc(CC(=O)OCC)cc1
Yield: 2.1 %

Procedure:
The procedure described in Example 180 was repeated, except that (R)-2-(4-chlorobenzenesulfonylamino)-4-methylthiobutanoic acid (715 mg) and ethyl 4-aminophenylacetate (430 mg) were condensed in dichloromethane (15 ml) in the presence of N,N'-dicyclohexylcarbodiimide (546 mg). The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was recrystallized from hexanechloroform to obtain (R)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-methylthiobutanamide (22.9 mg).
Reaction SMILES: C(C([N:7]1[CH2:12][CH2:11][N:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[NH:21][C:20]3=[O:28])[CH2:15][CH2:14]2)[CH2:9][CH2:8]1)=O)(C)(C)C.[OH-].[Na+]>Cl>[N:10]1([C@H:13]2[CH2:18][CH2:17][C@H:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[NH:21][C:20]3=[O:28])[CH2:15][CH2:14]2)[CH2:9][CH2:8][NH:7][CH2:12][CH2:11]1
Reactant: CC(C)(C)C(=O)N1CCN([C@H]2CC[C@H](n3c(=O)[nH]c4ccccc43)CC2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]c2ccccc2n1[C@H]1CC[C@H](N2CCNCC2)CC1

Procedure:
A stirred solution of 0.52 g of 1,3-dihydro-1-{trans-4-[4-(tert-butylcarbonyl)piperazin-1-yl]-1-cyclohexyl}-2H-benzimidazol-2-one in 15 mL of 1N HCl was heated to reflux for 1 h, cooled and basified with 6N NaOH. The basic mixture was extracted with 2×50 mL portions of chloroform. The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure. After drying overnight under vacuum, there was obtained 0.28 g of 1,3-dihydro-1-{trans-4-[1-piperazinyl]-1-cyclohexyl}-2H-benzimidazol-2-one as a white solid: 1H NMR (400 MHz, CDCl3) 7.16-7.03 (m, 4H), 4.27 (m, 1H), 2.94 (m, 4H), 2.61 (m, 4H), 2.25 (m, 2H), 2.1 (d, 2H), 1.97 (d, 2H), 1.54 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:22][CH2:23][OH:24]>C(O)C>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:22][CH2:23][OH:24])[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCN(CCO)CC1
Yield: 165.3 %

Procedure:
Piperidin-4-yl-carbamic acid tert-butyl ester (5 g, 25 mmol) is dissolved in 100 ml of ethanol. After addition of sodium carbonate (10.6 g, 100 mmol), 2-bromo-ethanol (3.55 ml, 50 mmol) is added dropwise. The reaction mixture is refluxed for 16 h and then evaporated. The residue is dissolved in 100 ml of dichloromethane and filtrated. The residue is washed with DCM. The combined filtrates are evaporated, which afforded 10.1 g of a yellow oil, which is further purified by flash chromatography (silicagel, DCM/methanol/conc. ammonia 90:9:1).
Reaction SMILES: [C:1]([NH:9][N:10]=[CH:11]/[CH:12]=[CH:13]/[CH3:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1>C1(C2C=CC=CC=2)C=CC=CC=1.CCOCC>[C:1]([N:9]1[CH:13]([CH3:14])[CH2:12][CH:11]=[N:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: C/C=C/C=NNC(=O)c1cccnc1
Solvent: CCOCC
Solvent: c1ccc(-c2ccccc2)cc1
Product: CC1CC=NN1C(=O)c1cccnc1
Reaction time: 3 h
Yield: 42.1 %

Procedure:
Nineteen grams of this hydrazone was suspended in 50 ml of biphenyl ether, followed by stirring at 200°-220° C. (bath temperature) for 3 hours. After cooling, the reaction liquid was purified by silica gel chromatography (CHCl3 :MeOH=100:1). Thus there was obtained 8.0 g of 1-nicotinoyl-5-methyl-2-pyrazoline in the form of an oil (bp. 143°-145° C./0.3 mmHg). The yield was 42.1%.
Reaction SMILES: [I:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9](O)[N:8]=2)=[CH:5][N:4]([CH:14]([CH3:16])[CH3:15])[N:3]=1.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:9]1[N:8]=[C:7]([C:6]2[C:2]([I:1])=[N:3][N:4]([CH:14]([CH3:16])[CH3:15])[CH:5]=2)[CH:12]=[CH:11][N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)n1cc(-c2ccnc(O)n2)c(I)n1
Product: CC(C)n1cc(-c2ccnc(Cl)n2)c(I)n1

Procedure:
A solution of Intermediate 4-(3-iodo-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ol (438 mg, 1.33 mmol) in phosphorous oxychloride (10 ml) was heated at 110° C. for 16 h. The mixture was concentrated under vacuum, then aqueous sodium bicarbonate solution was carefully added and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to provide the title compound as a yellow solid. MS m/z 349.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=3[C:7]=2[C:6]([CH:19]=[O:20])=[CH:5][CH:4]=1.[Cl-].[Na+].S(=O)(=O)([OH:25])N>O1CCOCC1.O>[CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=3[C:7]=2[C:6]([C:19]([OH:25])=[O:20])=[CH:5][CH:4]=1
Reactant: NS(=O)(=O)O
Reactant: COc1ccc(C=O)c2c1oc1ccc([N+](=O)[O-])cc12
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(C(=O)O)c2c1oc1ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
4-Methoxy-8-nitro-dibenzofuran-1-carbaldehyde (1.03 g, 3.8 mmoles) is suspended in a mixture of dioxane (60 mL) and water (10 mL). Sodium chloride (0.445 g, 4.93 mmoles) and sulphamic acid (2.09 g, 21.6 mmoles) are added and the mixture is stirred at room temperature for 1 hour. The mixture is then diluted with water (100 mL) and extracted with AcOEt (200 mL). The organic layer is dried over Na2SO4 and the solvent is evaporated to yield 0.701 g of raw product which is employed in the next step without further purification.
Reaction SMILES: [O:1]=[C:2]1[C:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH2:4][CH2:3]1.[Cl-].[NH4+]>>[CH2:7]([CH:5]1[CH2:4][CH2:3][C:2](=[O:1])[CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:6][CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: COC(=O)CCCCCCC1=CCCC1=O
Agent: [Cl-]
Agent: [NH4+]
Product: CCCCCCC1CCC(=O)C1CCCCCCC(=O)OC
Temperature: -20 °C

Procedure:
The mixture is cooled to -20° C. and the methyl ester (VII) (30 g; 0.134 mole) is added dropwise, at the end of which a saturated ammonium chloride solution is added slowly. The phases are separated, the organic phase is washed to neutrality yielding a pale yellow oil (40.7 g; yield=98%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[C:3]1[CH3:13].[CH3:14][NH2:15].CO>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=[N:15][CH3:14])=[C:3]1[CH3:13]
Reactant: CN
Reactant: Cc1c(C=O)c2ccccc2n1C
Solvent: CO
Product: CN=Cc1c(C)n(C)c2ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 1,2-dimethylindole-3-carboxaldehyde (11.50 g, 66.4 mmole) was added a solution of 2 M methylamine in methanol (100 mL, 200 mmole). The reaction was stirred for 4 h at RT then was concentrated to dryness to afford the crude title compound: 1H NMR (400 MHz, CDCl3) δ 8.55 (d, J=1.4 Hz, 1H), 8.16 (d, J=7.5 Hz, 1H), 7.42 (d, J=7.8 Hz, 1H), 7.15 (t, 1H), 7.07 (t, 1H), 3.68 (s, 3H), 3.41 (s, 3H), 2.55 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH3:19])[CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH:15]=O)[CH:13]=2)[N:8]=[CH:7][C:6]=1[C:17]#[N:18].COC1C=CC(/C=[C:36]2/[C:37]([NH:39][C:40]([S:42]/2)=[NH:41])=[O:38])=CC=1OC1CCCC1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:41][C:40]1[S:42]/[C:36](=[CH:15]\[C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:17]#[N:18])=[C:5]3[O:4][CH2:3][C:2]([CH3:20])([CH3:19])[CH3:1])/[C:37](=[O:38])[N:39]=1
Reactant: CC(C)(C)COc1c(C#N)cnc2ccc(C=O)cc12
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)COc1c(C#N)cnc2ccc(/C=C3\SC(N)=NC3=O)cc12

Procedure:
Similar procedure as described in example 28c was used, starting from 4-(2,2-dimethyl-propoxy)-6-formyl-quinoline-3-carbonitrile (example 67b), pseudothiohydantoin, sodium acetate and acetic acid to give 6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-(2,2-dimethyl-propoxy)-quinoline-3-carbonitrile. LC-MS m/e 367 (MH+).
Reaction SMILES: N1C=CC=CC=1.[O:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)[CH2:9][CH2:8]1.[ClH:23].[C:24]([C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:33]([CH2:37][C:38](=[O:40])[NH2:39])=[C:32](O)[CH:31]=[CH:30]2)(=[NH:26])[NH2:25].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.O>[ClH:23].[ClH:23].[O:7]1[CH2:8][CH2:9][N:10]([CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([O:20][C:32]3[CH:31]=[CH:30][C:29]4[C:34](=[CH:35][CH:36]=[C:27]([C:24](=[NH:25])[NH2:26])[CH:28]=4)[C:33]=3[CH2:37][C:38](=[O:40])[NH2:39])=[O:19])=[CH:16][CH:15]=2)[CH2:11][CH2:12]1
Reactant: N=C(N)c1ccc2c(CC(N)=O)c(O)ccc2c1
Reactant: O=C(O)c1ccc(CN2CCOCC2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: N=C(N)c1ccc2c(CC(N)=O)c(OC(=O)c3ccc(CN4CCOCC4)cc3)ccc2c1
Reaction time: 2 h
Yield: 67.4 %

Procedure:
15 Milliliters of anhydrous pyridine was added to 612.2 mg of 4-morpholinomethylbenzoic acid, 703.9 mg of 6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 622.6 mg of DCC and 30.7 mg of DMAP, followed by stirring for 2 hours under cooling with ice and then 3 days under cooling with water. Thereafter, the same procedure as in Example 1 was carried out to obtain 440.7 mg of the desired product.
Reaction SMILES: [NH2:1][CH:2]([C:4]([OH:6])=[O:5])[CH3:3].C(N(CC)CC)C.[Cl-].[C:15](Cl)(=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[C:15]([NH:1][CH:2]([CH3:3])[C:4]([OH:6])=[O:5])(=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CC(N)C(=O)O
Reactant: CCCCCCCC(=O)Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: CCCCCCCC(=O)NC(C)C(=O)O

Procedure:
The preparation is carried out analogously to the procedure of example 1A using 16.5 g (0.185 mol) of D,L-alanine, 41.23 g (0.407 mol) of triethylamine, 44.27 g (0.407 mol) of trimethylsilyl)l chloride and 30.12 g (0.185 mol) of octanoyl chloride. The product crystallizes from toluene/n-hexane.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH:24]=[N:23][N:22]([CH:25]([CH3:29])[C:26](=O)[CH3:27])[C:21]4=[O:30])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:31][C@@H:32]([C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1)[NH2:33].[Na].[NH4+].[OH-]>C(Cl)Cl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH:24]=[N:23][N:22]([CH:25]([CH3:29])[CH:26]([NH:33][CH:32]([C:34]5[C:43]6[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=6)[CH:37]=[CH:36][CH:35]=5)[CH3:31])[CH3:27])[C:21]4=[O:30])=[CH:18][CH:19]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: C[C@H](N)c1cccc2ccccc12
Reactant: CC(=O)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O
Agent: [NH4+]
Agent: [Na]
Agent: [OH-]
Solvent: ClCCl
Product: CC(NC(C)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (±)-2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2-(1-methyl-2-oxopropyl)-3H-1,2,4-triazol-3-one (0.018 mol), (S)-α-methyl-1-naphthalenemethanamine (0.0187 mol) and sodium tris(acetato-O)hydroborate (I-) (0.028 mol) in CH2Cl2 (150 ml) was stirred at room temperature overnight. A diluted NH4OH solution was added. The mixture was stirred for 1 hour. The precipitate was filtered off, washed with H2O and with CH2Cl2 (20 ml) and dried. The residue was crystallized from CH3CN. The precipitate was filtered off and dried, yielding 3.3 g (32%) of [R-(R*,S*)(S*)]-2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2-[1-metyl-2-[[1-(1-naphthalenyl)ethyl]amino]propyl]-3H-1,2,4-triazol-3-one (interm. 108).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:24]1[C:33]2[N:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH2:27][CH2:26][CH2:25]1)[CH2:12][CH2:13][CH2:14][NH:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20]N=1)=[O:17].[C:34](O)(=O)C>>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:24]1[C:33]2[N:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH2:27][CH2:26][CH2:25]1)[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:17])[C:18]1[CH:34]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(NCCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21)c1ccccn1
Reactant: CC(=O)O
Product: O=C(NCCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of the amine (80 mg, 0.18 mmol) in acetic acid (2 mL) was added hydrobromide saturated acetic acid (2 mL). The reaction mixture was stirred for 30 minutes. Then it was triturated with diethyl ether four times to afford the title compound as a yellow solid (99 mg), which was dried in vacuo. 1H NMR (D2O) δ 1.73-1.86 (m, 2H), 1.93-2.01 (m, 1H), 2.13-2.17 (m, 1H), 2.34-2.38 (m, 1H), 2.43-2.53 (m, 1H), 2.80-2.87 (m, 1H), 2.95-2.97 (br m, 2H), 3.17-3.23 (m, 1H), 3.28-3.35 (m, 1H), 3.53 (q, 1H, J=6.9 Hz), 4.28-4.54 (m, 3H), 7.31-7.38 (m, 4H), 7.49-7.51 (m, 3H), 7.63-7.72 (m, 3H), 8.24 (d, 1H, J=7.8 Hz), 8.55 (d, 1H, J=5.7 Hz). 13C NMR (D2O) δ 20.36, 20.49, 27.63, 28.08, 37.37, 48.27, 49.01, 60.18, 114.12, 125.86, 126.98, 129.20, 130.75, 132.67, 132.99, 139.30, 140.59, 147.99, 151.17, 172.84. ES-MS m/z 440 [M+H]+. Anal. Calcd. for C27H29N5O.2.1HBr.2.2H2O: C, 49.96; H, 5.51; N, 10.79; Br, 25.85. Found: C, 49.96; H, 5.45; N, 10.65; Br, 25.95.
Reaction SMILES: Br[CH2:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([O:11][CH3:12])=[O:10])=[CH:5][C:4]=1[Cl:21].[CH3:22][C:23]1[N:28]=[C:27]2[N:29]=[C:30]([CH2:32][CH3:33])[NH:31][C:26]2=[C:25]([CH3:34])[CH:24]=1>>[C:9]([CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[O:7][C:6]1[CH:19]=[CH:20][C:3]([CH2:2][N:29]2[C:27]3=[N:28][C:23]([CH3:22])=[CH:24][C:25]([CH3:34])=[C:26]3[N:31]=[C:30]2[CH2:32][CH3:33])=[C:4]([Cl:21])[CH:5]=1)([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C(Oc1ccc(CBr)c(Cl)c1)c1ccccc1
Reactant: CCc1nc2nc(C)cc(C)c2[nH]1
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(OC(C(=O)OC)c2ccccc2)cc1Cl
Yield: 69.9 %

Procedure:
The product of Step C (0.116 g, 0.31 mmol) was used to alkylate 0.050 g (0.29 mmol) of 5,7-dimethyl-2-ethylimidazo[4,5-b]pyridine according to the procedure described for Step B of Example 2, which after purification afforded 0.094 g (69%) of the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([OH:6])[CH3:5].[C:7](Cl)(=[O:11])[C:8]([CH3:10])=[CH2:9]>>[C:7]([O:6][CH:4]([CH3:5])[CH2:3][O:2][CH3:1])(=[O:11])[C:8]([CH3:10])=[CH2:9]
Reactant: C=C(C)C(=O)Cl
Reactant: COCC(C)O
Product: C=C(C)C(=O)OC(C)COC

Procedure:
In the forgoing reaction, 1-methoxy-2-propanol is reacted with methacryloyl chloride to yield 1-methyl-2-methoxyethyl methacrylate. 1-methoxy-2-propanol and methacryloyl chloride are commercially available compounds (e.g., 1-methoxy-2-propanol is available from the Dow Chemical Company under the product name of “Dowanol PM”).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:28](=[O:29])[N:27]([CH3:30])[C:11]3[N:12]([CH3:26])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[N:20]=[C:21]([CH2:24][OH:25])[S:22][CH:23]=2)=[CH:15][CH:14]=4)=[CH:4][CH:3]=1.I[CH2:32][CH3:33]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:28](=[O:29])[N:27]([CH3:30])[C:11]3[N:12]([CH3:26])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[N:20]=[C:21]([CH2:24][O:25][CH2:32][CH3:33])[S:22][CH:23]=2)=[CH:15][CH:14]=4)=[CH:4][CH:3]=1
Reactant: CCI
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2)cc2c3cc(-c4csc(CO)n4)ccc3n(C)c21
Product: CCOCc1nc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4)c(=O)n(C)c2n3C)cs1

Procedure:
The process is carried out as in Example 10 above, with the compound from Example 115, 3-(4-chlorophenyl)-6-(2-hydroxymethylthiazol-4-yl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and iodoethane.
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][C:46](C2C=CC=CC=2)(C2C=CC=CC=2)[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[CH:26][CH:25]=1)C1C=CC=CC=1.FC(F)(F)C(O)=O.O.C(OCC)(=O)C>C(Cl)Cl>[CH2:46]([O:45][CH2:44][CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:38][CH2:37][O:36][CH2:35][CH2:34][O:33][CH2:32][CH2:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][OH:8])=[CH:29][CH:28]=1)[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: c1ccc(COCCOCCOCCOCCOCCOc2ccc(OCCOCCOCCOCCOCCOC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: OCCOCCOCCOCCOCCOc1ccc(OCCOCCOCCOCCOCCOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
To an ice-cooled solution of Compound 23 (1.43 g, 1.62 mmol) in methylene chloride (20 ml), a methylene chloride solution containing 10% trifluoroacetic acid (10 ml) was added; water (1 ml) was added thereto, after which the ice bath was removed, and this was followed by stirring at room temperature for 2 hours and 30 minutes. The reaction solution was poured over a saturated aqueous solution of sodium hydrogen carbonate to stop the reaction, after which extraction from methylene chloride and chloroform was conducted. The combined organic phases were dried with sodium sulfate, filtered, and concentrated under reduced pressure, after which the residue obtained was subjected to silica gel column chromatography (Yamazen YFLC Gel, eluent (ethyl acetate containing 10% methanol)) to yield Compound 24 (light-yellow oil 875 mg, 85%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[CH:5]2.C(OC([N:20]1[CH2:25][CH2:24][C:23]2([CH2:30][CH2:29][CH:28](O)[CH2:27][CH2:26]2)[CH2:22][CH2:21]1)=O)(C)(C)C>>[CH2:22]1[C:23]2([CH2:30][CH2:29][CH:28]([O:1][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[O:8][C:7](=[O:12])[CH:6]=[CH:5]4)[CH2:27][CH2:26]2)[CH2:24][CH2:25][NH:20][CH2:21]1
Reactant: O=c1ccc2cc(O)ccc2o1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(O)CC2)CC1
Product: O=c1ccc2cc(OC3CCC4(CCNCC4)CC3)ccc2o1

Procedure:
Was prepared according to method A from 6-hydroxycoumarin and 9-hydroxy-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester. Mp. 192.9-193.6° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@H:8]([CH2:12][NH:13][C:14](=[O:25])OC2C=CC([N+]([O-])=O)=CC=2)[CH2:7]1.[NH2:30][CH2:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH2:38])=[O:37])=[CH:34][CH:33]=1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@H:8]([CH2:12][NH:13][C:14]([NH:30][CH2:31][C:32]2[CH:33]=[CH:34][C:35]([C:36]([NH2:38])=[O:37])=[CH:39][CH:40]=2)=[O:25])[CH2:7]1
Reactant: NCc1ccc(C(N)=O)cc1
Reactant: O=C(NC[C@@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(CNC(=O)NC[C@@H]2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)cc1
Yield: 74.1 %

Procedure:
Example 55 was prepared in an analogous manner to Example 43 from Intermediate 14 (0.109 g) and 4-aminomethylbenzamide (0.045 g) using N,N-dimethylformamide as solvent to yield the title compound (0.0828 g).