Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:10](=O)[C:9](=[CH:12]N3CCOCC3)[CH2:8][CH2:7][C:5]=2[N:6]=1.Cl.[NH2:20][C:21]([NH2:23])=[NH:22].[OH-].[Na+]>CCO>[CH3:1][C:2]1[S:3][C:4]2[C:10]3[N:20]=[C:21]([NH2:23])[N:22]=[CH:12][C:9]=3[CH2:8][CH2:7][C:5]=2[N:6]=1
Reactant: N=C(N)N
Reactant: Cc1nc2c(s1)C(=O)C(=CN1CCOCC1)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2c(s1)-c1nc(N)ncc1CC2
Yield: 0.1 %

Procedure:
A mixture of 2-methyl-6-morpholin-4-ylmethylene-5,6-dihydro-4H-benzothiazol-7-one (2.24 g, 8.47 mol), guanidine hydrochloride salt (0.89 g, 9.32 mol) and NaOH (0.37 g, 9.32 mol) in EtOH (150 mL) was heated under reflux for 4 h. The reaction mixture was concentrated under vacuum. Flash column chromatography (50% EtOAc:hexane) afforded the title product as a yellow solid (1.66 g, 90%): mp 241-243° C. Anal. RP-HPLC: tR 8.7 min (0-60% MeCN, purity 100%). 1H-NMR (CDCl3): δ 8.06 (s, 1H, Py-H), 5.01 (brs, 2H, NH2), 2.99 (m, 4H, CH2—CH2), 2.76 (s, 3H, CH3). MS (ESI+): m/z 219.02 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[S:11][C:12]([CH2:15][CH2:16][OH:17])=[N:13][N:14]=2)[CH:5]=1.[O:19]1[CH:24]=[CH:23][CH2:22][CH2:21][CH2:20]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[S:11][C:12]([CH2:15][CH2:16][O:17][CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24][O:19]3)=[N:13][N:14]=2)[CH:5]=1
Reactant: C1=COCCC1
Reactant: COC(=O)c1cccc(-c2nnc(CCO)s2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(-c2nnc(CCOC3CCCCO3)s2)c1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A mixture of 3-[5-(2-hydroxy-ethyl)-[1,3,4]thiadiazol-2-yl]-benzoic acid methyl ester (1.86 g), dihydropyrane (0.95 mL) and p-toluenesulfonic acid hydrate (0.13 g) in AcOEt (25 mL) was stirred at 20° C. for 1 h. The solution was diluted with AcOEt, washed with 5% NaHCO3 solution and with brine, dried and evaporated in vacuum. The residual oil was purified by chromatography on silica gel using AcOEt/hexane (1:2) as eluent to give 3-{5-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-[1,3,4]thiadiazol-2-yl]-benzoic acid methyl ester (1.60 g) as a pale-yellow oil.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[F:13][C:14]([F:28])([F:27])[C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][C:23]([NH:25][NH2:26])=[O:24])[CH:18]=[CH:19][CH:20]=1>O1CCCC1>[F:13][C:14]([F:27])([F:28])[C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][C:23]([NH:25][NH:26][C:10]([C:7]2[CH:8]=[CH:9][C:4]3[N:3]=[CH:2][S:1][C:5]=3[CH:6]=2)=[O:12])=[O:24])[CH:18]=[CH:19][CH:20]=1
Reactant: O=C(O)c1ccc2ncsc2c1
Reactant: NNC(=O)CCc1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: O=C(CCc1cccc(C(F)(F)F)c1)NNC(=O)c1ccc2ncsc2c1
Reaction time: 1 h
Yield: 66.6 %

Procedure:
To a solution of benzothiazole-6-carboxylic acid (358 mg, 2.00 mmol) in tetrahydrofuran (10 mL) was added N,N′-carbonyldiimidazole (341 mg, 2.10 mmol) at room temperature, and the resulting mixture was stirred for 1 hr. To this reaction mixture was added 3-[3-(trifluoromethyl)phenyl]propanohydrazide (557 mg, 2.40 mmol), and the mixture was further stirred at room temperature for 24 hr. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added to the residue. The precipitate was collected by filtration, purified by basic silica gel column chromatography (tetrahydrofuran) and recrystallized from hexane/tetrahydrofuran to give the title compound (524 mg, yield 67%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.[C:27]([O-])(=[O:29])[CH3:28].[Na+].O>C(OC(=O)C)(=O)C>[C:27]([N:12]1[C:6]2[CH:7]=[N:8][C:9]3[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][C:4]=3[C:5]=2[N:14]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:25])[C:22]#[N:23])=[CH:17][CH:16]=2)[C:13]1=[O:26])(=[O:29])[CH3:28]
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Cl)cc4c32)cc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)n1c(=O)n(-c2ccc(C(C)(C)C#N)cc2)c2c3cc(Cl)ccc3ncc21
Temperature: 25 °C

Procedure:
A mixture of 2-(4-(8-chloro-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 2, 80 mg, 0.22 mmol) and sodium acetate (27.06 mg, 0.33 mmol) was heated at 50° C. in acetic anhydride (2 ml) for 3 hours. Reaction mixture was cooled to RT. Water was added and extracted with chloroform. Chloroform layer was washed with brine, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 26 mg (29%); 1H NMR (CDCl3, 300 MHz): δ 9.796 (s, 1H), 8.039-8.070 (d, 1H, J=9.3 Hz), 7.764-7.792 (d, 2H, J=8.4 Hz), 7.499-7.537 (m, 3H), 6.861-6.868 (d, 1H, J=2.1 Hz), 2.822 (s, 3H), 1.83 (s, 6H); MS: m/z 405 (M+).
Reaction SMILES: [F:1][C:2]1[C:3]([C:32]([F:35])([F:34])[F:33])=[C:4]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[C:20]4[CH2:21][N:22](C(OC(C)(C)C)=O)[CH2:23][CH2:24][C:19]=4[NH:18][N:17]=3)=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[ClH:36]>C(Cl)Cl.CCOCC>[ClH:36].[F:1][C:2]1[C:3]([C:32]([F:35])([F:33])[F:34])=[C:4]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]([C:16]3[C:20]4[CH2:21][NH:22][CH2:23][CH2:24][C:19]=4[NH:18][N:17]=3)=[O:15])[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(C(=O)N3CCC(c4cccc(F)c4C(F)(F)F)CC3)c2C1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(c1n[nH]c2c1CNCC2)N1CCC(c2cccc(F)c2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
To a solution of tert-butyl 3-(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-6,7-dihydro-H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (31, 0.148 g, 0.30 mmol) in CH2Cl2 (2 mL) was added HCl (2 mL, 2.0 N solution in Et2O). The mixture stirred at ambient temperature for 18 h, was diluted with Et2O (30 mL), and the resulting solids were collected by filtration to give (4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone hydrochloride (32) as a white solid (0.097 g, 75%): 1H NMR (300 MHz, DMSO-d6) δ 9.46-9.20 (m, 2H), 7.74-7.61 (m, 1H), 7.46 (d, J=8.1 Hz, 1H), 7.37-7.25 (m, 1H), 4.70-4.44 (m, 2H), 4.34-4.22 (m, 2H), 3.50-3.10 (m, 4H), 2.93-2.76 (m, 3H), 1.86-1.60 (m, 4H); ESI MS m/z 468 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([CH2:20]OS(C)(=O)=O)[C:12](=[O:19])[N:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([CH2:20][N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)[C:12](=[O:19])[N:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CN1CCNCC1
Reactant: Cc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)cc1F
Product: Cc1ccc(-c2cc(CN3CCN(C)CC3)c(=O)n(CC(C)C)n2)cc1F
Yield: 93.4 %

Procedure:
Following the procedure of Example 1(10), 6-(3-fluoro-4-methylphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 93.4%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]=[C:10]=[S:11])=[CH:4][C:3]=1[F:12].[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH2:17]>ClC(Cl)Cl>[NH2:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([NH:9][C:10]([NH:17][CH2:16][CH:15]([O:18][CH3:19])[O:14][CH3:13])=[S:11])=[CH:6][C:7]=1[F:8]
Reactant: Nc1c(F)cc(N=C=S)cc1F
Reactant: COC(CN)OC
Solvent: ClC(Cl)Cl
Product: COC(CNC(=S)Nc1cc(F)c(N)c(F)c1)OC

Procedure:
A solution of 4-amino-3,5-difluorophenyl isothiocyanate in trichloromethane is treated with an equimolar amount of aminoacetaldehyde dimethyl acetal. The solvent is evaporated, and the residue is recrystallized from ethanol to yield N-(4-amino-3,5-difluorophenyl)-N'-(β,β-dimethoxyethyl)thiourea. A suspension of this thiourea in concentrated sulfuric acid and water (1:4) was refluxed for three hours. The mixture then is cooled and the solid that forms is filtered, washed with water, and dried. Recrystallization from ethanol yields 1-(4'-amino-3',5'-difluorophenyl)imidazole-2-thiol.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=3)[CH:29]=[C:30](I)[CH:31]=2)=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2].[O:40]1[C:44]2[CH:45]=[CH:46][C:47](B(O)O)=[CH:48][C:43]=2[O:42][CH2:41]1>>[O:40]1[C:44]2[CH:45]=[CH:46][C:47]([C:30]3[CH:31]=[C:26]([O:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:18]4[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])=[C:7]([CH:15]=[CH:16][CH:17]=4)[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:27]=[C:28]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=4)[CH:29]=3)=[CH:48][C:43]=2[O:42][CH2:41]1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: O=C(O)CCCOc1cccc(CCCCCCOc2cc(I)cc(-c3cccc(F)c3)c2)c1CCC(=O)O
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(-c3cccc(F)c3)cc(-c3ccc4c(c3)OCO4)c2)c1CCC(=O)O
Yield: 62 %

Procedure:
A similar procedure as described in Example 5, step 2 was used, starting from 4-{2-(2-carboxy-ethyl)-3-[6-(3′-fluoro-5-iodo-biphenyl-3-yloxy)-hexyl]-phenoxy}-butyric acid (1.2 g, 1.85 mmol) and benzo[1,3]dioxol-5-yl-boronic acid (614 mg, 3.7 mmol) to obtain 4-{3-[6-(5-benzo[1,3]dioxol-5-yl-3′-fluoro-biphenyl-3-yloxy)-hexyl]-2-(2-carboxy-ethyl)-phenoxy}-butyric acid (737 mg, 62%) as an amorphous white solid: ES(+)-HRMS m/e calculated for C38H39FO8 (M+Na)+ 665.2521, found 665.2520.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:3]=1.CCN(C(C)C)C(C)C.[CH3:25][S:26]([N:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][CH2:37][NH2:38])[CH2:31][CH2:30]1)(=[O:28])=[O:27]>C1COCC1>[Cl:15][C:11]1[CH:10]=[C:9]([NH:8][C:4]2[N:3]=[C:2]([NH:38][CH2:37][CH2:36][CH2:35][N:32]3[CH2:33][CH2:34][N:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:30][CH2:31]3)[CH:7]=[CH:6][N:5]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cccc(Nc2nccc(Cl)n2)c1
Reactant: CS(=O)(=O)N1CCN(CCCN)CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CCN(CCCNc2ccnc(Nc3cccc(Cl)c3)n2)CC1
Temperature: 25 °C
Yield: 50 %

Procedure:
To 4-chloro-N-(3-chlorophenyl)pyrimidin-2-amine (0.2 g, 0.837 mmol) in THF (10 mL) is added DIPEA (0.29 mL, 1.67 mmol) followed by 3-(4-(methylsulfonyl)piperazin-1-yl)propan-1-amine, 25, (0.0.369 g, 1.67 mmol). The resulting mixture is refluxed for 12 hours after which the reaction mixture is cooled to room temperature and the solvent removed in vacuo. To the resulting residue is added water (50 mL) and the solution is washed with EtOAc (3×100 mL). The combined organic layers are dried (MgSO4) and concentrated in vacuo. The residue which is obtained is purified over silica (10% MeOH in CH2Cl2) to afford 0.129 g (50% yield) of the desired compound. 1H NMR (DMSO-d6, 300 MHz) δ1.71 (m, 2H), 2.39-2.45 (m, 6H), 2.84 (s, 3H), 3.08 (m, 4H), 3.38 (m, 2H), 5.96 (d, J=5.7 Hz, 1H), 6.87 (d, J=7.8 Hz, 1H), 7.18-7.27 (m, 2H), 7.58 (d, J=7.5 Hz, 1H), 7.81 (bs, 1H), 8.12 (bs, 1H), 9.18 (s, 1H). MS (ESI, pos. ion) m/z: 425 (M+1). HRMS calcd for C18H25ClN6O2S, 425.1526 m/z (M+H)+; observed 425.1512 m/z.
Reaction SMILES: O=C1CCC(=O)N1O[C:9]([C:11]1[O:15][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[N:13][C:12]=1[CH2:23][CH2:24][CH3:25])=[O:10].[CH3:26][O:27][CH2:28][CH2:29][N:30]([CH3:38])[C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][N:32]=1>>[CH3:26][O:27][CH2:28][CH2:29][N:30]([CH3:38])[C:31]1[N:32]=[CH:33][C:34]([NH:37][C:9]([C:11]2[O:15][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])=[N:13][C:12]=2[CH2:23][CH2:24][CH3:25])=[O:10])=[CH:35][CH:36]=1
Reactant: CCCc1nc(-c2ccccc2Cl)oc1C(=O)ON1C(=O)CCC1=O
Reactant: COCCN(C)c1ccc(N)cn1
Product: CCCc1nc(-c2ccccc2Cl)oc1C(=O)Nc1ccc(N(C)CCOC)nc1

Procedure:
With a procedure similar to example 50 above, 2-(2-chloro-phenyl)-4-propyl-oxazole-5-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 2-(2-chloro-phenyl)-4-propyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester and N2-(2-methoxy-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C22H25ClN4O3 (m/e) 428, obsd 429 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].F[C:14]1[CH:21]=[CH:20][C:19]([CH:22]=[O:23])=[CH:18][C:15]=1[C:16]#[N:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CC(=O)OCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:14]2[CH:21]=[CH:20][C:19]([CH:22]=[O:23])=[CH:18][C:15]=2[C:16]#[N:17])=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Oc1ccc(F)c(C(F)(F)F)c1
Reactant: N#Cc1cc(C=O)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cc(C=O)ccc1Oc1ccc(F)c(C(F)(F)F)c1
Temperature: 130 °C
Yield: 101.4 %

Procedure:
A mixture of 4-fluoro-3-(trifluoromethyl)phenol (1 g, 5.55 mmol), 2-fluoro-5-formylbenzonitrile (0.828 g, 5.55 mmol) and K2CO3 (0.921 g, 6.66 mmol) in DMF (10 mL) was heated with a microwave condition at 130° C. for 2 h. The solution was diluted with EA and washed with water twice, dried over Na2SO4 and concentrated in vacuo to afford the title compound (1.74 g, 101% yield) as a brown oil. LCMS: rt=3.38 min, [M+H+]=310
Reaction SMILES: [CH:1]([NH:5][C:6](=[O:10])[CH2:7][CH2:8][CH3:9])([CH2:3][CH3:4])[CH3:2].C([Li])CCC.[CH3:16][C:17]1[N:18]=[C:19](S(C)=O)[O:20][CH:21]=1.O>O1CCOCC1>[CH:1]([N:5]([C:19]1[O:20][CH:21]=[C:17]([CH3:16])[N:18]=1)[C:6](=[O:10])[CH2:7][CH2:8][CH3:9])([CH2:3][CH3:4])[CH3:2]
Reactant: Cc1coc(S(C)=O)n1
Reactant: CCCC(=O)NC(C)CC
Agent: [Li]CCCC
Solvent: C1COCCO1
Solvent: O
Product: CCCC(=O)N(c1nc(C)co1)C(C)CC
Temperature: 10 °C
Reaction time: 0.25 h

Procedure:
N-s-Butyl-butyramide (0.99 g, 0.0069 m) in dry dioxan (10 ml) was cooled to 10° C. under nitrogen during the dropwise addition of a 1.445 M solution of n-butyl lithium (4.8 ml, 0.0069 m). The mixture was stirred for 15 minutes at 10° C. and then 4-methyl-2-methylsulphinyloxazole (1.0 g, 0.0068 m) in dry dioxan (10 ml) was added and the mixture allowed to warm to room temperature. It was stirred for 3 hours and then hydrolysed with water. The solvent was removed in vacuo and the ether extract of the residue was chromatographed on silica using ether. The resulting compound (title product) was distilled in vacuo as a colourless oil 0.95 g, b.p. 75°-76° C./0.5 mm.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:23]=[C:22]2[C:14]([N:15]3[C:20](=[CH:21]2)[C:19](=[O:24])[NH:18][CH2:17][CH2:16]3)=[N:13][CH:12]=1.[CH3:25][C@H]1N[C@H](C)CC1>>[CH3:1][C@@H:2]1[CH2:6][CH2:5][C@@H:4]([CH3:25])[N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:23]=[C:22]2[C:14]([N:15]3[C:20](=[CH:21]2)[C:19](=[O:24])[NH:18][CH2:17][CH2:16]3)=[N:13][CH:12]=1
Reactant: C[C@H]1CCCN1CCCOc1cnc2c(c1)cc1n2CCNC1=O
Reactant: C[C@@H]1CC[C@@H](C)N1
Product: C[C@@H]1CC[C@@H](C)N1CCCOc1cnc2c(c1)cc1n2CCNC1=O
Yield: 19 %

Procedure:
The title compound was synthesized in analogy to example 2, from 7-(3-chloro-propoxy)-3,4-dihydro-2H-2,4a,5-triaza-fluoren-1-one (example 85, intermediate) and (2R,5R)-(−)-trans-2,5-dimethylpyrrolidine (commercially available), to give the desired product as a colorless solid (19%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](Br)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[Sn](C)(C)(C)[CH3:25]>CN1CCCC1=O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH3:25])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4]
Reactant: COC(=O)c1nc(Br)c2cc(Oc3ccccc3)ccc2c1O
Reactant: C[Sn](C)(C)C
Solvent: CN1CCCC1=O
Product: COC(=O)c1nc(C)c2cc(Oc3ccccc3)ccc2c1O
Temperature: 25 °C
Yield: 58.2 %

Procedure:
To a mixture of 1-bromo-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (500 mg, 1.34 mmol) in N-methylpyrrolidone (NMP) (7 mL) was added SnMe4 (358 mg, 2.0 mmol) and resin-bound-Pd(PPh3)2Cl2 (Sigma-Aldrich) (1-2 mmol/g) (40 mg, ca. 0.03 mmol). The resultant mixture was stirred in a 130° C. oil bath for 3 h. Reaction mixture was filtered and rinsed with NMP (1 mL). Filtrate was poured into water (120 mL) and stirred at room temperature until good precipitate formed. Solid was collected and rinsed with water (100 mL) and then hexanes (50 mL). Solid was dried and purified by silica gel chromatography, eluting with 2-50% EtOAc/hexanes, to provide the title compound 240 mg (0.78 mmol) in 58% yield. 1H NMR (200 MHz) CDCl3, δ in ppm: 11.68 (s, 1H), 8.37 (d, J=9.3 Hz, 1H), 7.48-7.08 (m, 7H), 4.07 (s, 3H), 2.75 (s, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([NH2:15])(=[NH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl:16][C:17]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:18]=1[CH:19]=[C:20]([C:23]#[N:24])[C:21]#[N:22]>CO>[NH2:24][C:23]1[C:20]([C:21]#[N:22])=[C:19]([C:18]2[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:17]=2[Cl:16])[N:15]=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:14]=1
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Reactant: N=C(N)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: N#Cc1c(N)nc(-c2ccccc2)nc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Potassium carbonate (4.34 g, 31.4 mmol) and benzamidine (2.59 g, 21.5 mmol) were added at to a suspension of 2-(2,4-dichloro-benzylidene)-malononitrile (4 g, 17.9 mmol) in methanol. The yellow mixture was stirred for 1 h at room temperature and then heated to reflux for an additional 2 h. After cooling, the solvent was removed at reduced pressure, the residue was taken up in ethyl acetate/ice. The organic phase was separated, washed with water, and dried over sodium sulfate. The solvent was evaporated, the orange residue was taken up in acetone, and 1.91 g potassium manganate was added. After stirring for 90 min, the reaction mixture was filtered through decalite and evaporated. Purification by flash chromatography (silica gel, EtOAc/hexanes) afforded the title compound, MS: m/e=340.8 (M+), as a solid (2.63 g, 43%).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[NH2:12])[CH2:3]1.CN1CCOCC1.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[S:35][C:34]([S:36](Cl)(=[O:38])=[O:37])=[CH:33][CH:32]=1>ClCCl>[CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[C:11]([NH:12][S:36]([C:34]3[S:35][C:31]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=4)=[CH:32][CH:33]=3)(=[O:37])=[O:38])[CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[CH2:3]1
Reactant: COc1ccc(N)cc1N1C[C@@H](C)N[C@@H](C)C1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(NS(=O)(=O)c2ccc(-c3ccccn3)s2)cc1N1C[C@@H](C)N[C@@H](C)C1
Reaction time: 18 h

Procedure:
3-(cis-3,5-Dimethyl-1-piperazinyl)-4-(methyloxy)aniline (D2) (100 mg, 0.42 mmol) in dichloromethane (10 ml) was stirred with morpholinomethyl-polystyrene HL resin (320 mg, 4 mmol/g loading, 1.28 mmol) at ambient temperature. 5-(2-Pyridinyl)-2-thiophenesulfonyl chloride (110 mg, 0.4 mmol) was added and the mixture stirred for 18 hours. Argopore-trisamine scavenger resin (100 mg, 4 mmol/g loading, 0.4 mmol) was then added and the mixture stirred for a further 30 minutes. The resin was removed by filtration, washed with dichloromethane and the filtrate concentrated in vacuo. The residue was purified by column chromatography (1:19 2M ammonia in methanol: dichloromethane) to afford the title product (El). MS (ES+) 459 [M+H]+.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:15]([NH2:17])[CH3:16])[CH:6]=[N:7][C:8]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].[C:18]([O:21][CH2:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([Cl:32])[N:31]=1)[C:26](O)=[O:27])(=[O:20])[CH3:19]>>[C:18]([O:21][CH2:22][C:23]1[CH:24]=[C:25]([C:26](=[O:27])[NH:17][CH:15]([C:5]2[CH:6]=[N:7][C:8]([O:9][CH2:10][C:11]([F:14])([F:12])[F:13])=[C:3]([CH3:2])[CH:4]=2)[CH3:16])[CH:29]=[C:30]([Cl:32])[N:31]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)OCc1cc(C(=O)O)cc(Cl)n1
Reactant: Cc1cc(C(C)N)cnc1OCC(F)(F)F
Agent: Cl
Product: CC(=O)OCc1cc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(C)c2)cc(Cl)n1
Yield: 21 %

Procedure:
The title compound is prepared in 21% yield (100 mg, a yellow solid) from 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (295 mg, 1.1 mmol, Amine-17, single enantiomer) and 2-(acetoxymethyl)-6-chloroisonicotinic acid (500 mg, 1.1 mmol, Step-1) by the similar manner in Step-1 of Example 8.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8](SC)=[CH:9][N+:10]([O-:12])=[O:11])[CH2:2]1.[CH3:15][NH:16][CH3:17]>C(#N)C>[O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8]([N:16]([CH3:17])[CH3:15])=[CH:9][N+:10]([O-:12])=[O:11])[CH2:2]1
Reactant: CSC(=C[N+](=O)[O-])NCC1CCOC1
Reactant: CNC
Solvent: CC#N
Product: CN(C)C(=C[N+](=O)[O-])NCC1CCOC1
Temperature: 25 °C

Procedure:
A mixture comprising 4.0 g of 1-[{(tetrahydro-3-furanyl)methyl}amino]-1-methylthio-2-nitroethylene, 10 ml of 50% aqueous dimethylamine solution and 50 ml of acetonitrile was stirred at room temperature for an hour. The reaction mixture was concentrated under a reduced pressure, and purified by silica gel column chromatography (eluent:ethyl acetate/acetone=1/1) to obtain 2.8 g of 1-[{(tetrahydro-3-furanyl)methyl}amino]-1-dimethylamino-2-nitroethylene.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[C:8]([O:12][CH3:13])(=[O:11])[CH:9]=[CH2:10]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C.CC#N>[N:5]1[CH:6]=[CH:7][C:2]([CH:10]=[CH:9][C:8]([O:12][CH3:13])=[O:11])=[CH:3][CH:4]=1
Reactant: Brc1ccncc1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C=Cc1ccncc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 93152.5 %

Procedure:
A mixture of 4-bromopyridine (40.6 g, 0.25 mmol), palladium acetate (1.16 g, 5.14 mmol), tri-(O-tolyl)phosphine (3.14 g, 10.3 mmol), CH3CN (129 mL), triethylamine (64.3 mL, 0.46 mmol) and methyl acrylate (46.8 mL, 0,514 mmol) was sealed in a bomb and placed in an oil bath at 120° C. for 4 hours. The mixture was cooled to 0° C., the bomb was vented, and the slurry thus obtained was partitioned between CH2Cl2 /water. The aqueous phase was separated, extracted with CH2Cl2 (2×200 mL) and the combined organic layers were dried over MgSO4. The solvent was removed in vacuo to afford 38 g of methyl 3-(4-pyridyl)propenoate.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[C:6]([CH3:12])=[N:7]2.[CH3:22][O:23][CH2:24][C:25](Cl)=[O:26]>O1CCCC1>[O:20]=[C:14]1[CH:13]([N:5]2[C:4](=[O:21])[C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3[NH:1][C:25](=[O:26])[CH2:24][O:23][CH3:22])[N:7]=[C:6]2[CH3:12])[CH2:18][CH2:17][C:16](=[O:19])[NH:15]1
Reactant: COCC(=O)Cl
Reactant: Cc1nc2cccc(N)c2c(=O)n1C1CCC(=O)NC1=O
Solvent: C1CCOC1
Product: COCC(=O)Nc1cccc2nc(C)n(C3CCC(=O)NC3=O)c(=O)c12
Temperature: 80 °C
Yield: 35.1 %

Procedure:
To a stirred mixture of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione (0.11 g, 0.35 mmol) in tetrahydrofuran (4 mL), was added methoxyacetyl chloride (0.06 mL, 0.70 mmol) and heated at 80° C. for one hour. The mixture was quenched with a few drops of methanol. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-yl]-2-methoxy-acetamide (44 mg, 35% yield) as a white solid; HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 6.77 min (96.3%); mp, 282-284° C.; 1HNMR (DMSO-d6) δ 2.20-2.22 (m, 1H, CHH), 2.60-2.85 (m, 6H, CHCH2, CH3), 3.40 (s, 3H, ° C. H3), 4.04 (s, 2H, ° C. H2), 5.30 (dd, J=6, 11 Hz, 1H, CH), 7.30-8.64 (m, 3H, Ar), 11.09 (s, 1H, NH), 12.31 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.77, 23.31, 30.62, 56.71, 59.04, 71.88, 107.95, 115.39, 120.94, 135.51, 138.89, 147.90, 154.84, 162.69, 169.12, 169.34, 172.64. LCMS MH=359; Anal Calcd For C7H18N4O5+0.7H2O: C, 55.04; H, 5.27; N, 15.10. Found: C, 54.75; H, 5.32; N, 14.91.