Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:32])([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[CH:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[CH:10]=2)[N:5]=[C:4]([C:33]([F:36])([F:35])[F:34])[C:3]=1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[OH:32])[CH:10]=2)[N:5]=[C:4]([C:33]([F:35])([F:34])[F:36])[C:3]=1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)(c2cccnc2)c2ccc3nc(C(F)(F)F)c(-c4ccccc4)c(Cl)c3c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC(c1cccnc1)(c1ccc2nc(C(F)(F)F)c(-c3ccccc3)c(Cl)c2c1)C1CCNCC1
Reaction time: 3 h

Procedure:
A solution of tert-butyl 4-((4-chloro-3-phenyl-2-(trifluoromethyl)quinolin-6-yl)(hydroxy)(pyridin-3-yl)methyl)piperidine-1-carboxylate (313 mg, 0.520 mmol, Example 69) in DCM (6 mL) was treated with 1.8 mL of TFA, stirred for 3 hours, and concentrated. The residue was partitioned between saturated NaHCO3 aqueous solution and DCM. The organic layer was dried (Na2SO4), filtered and concentrated to dryness to provide the title compound as a light brown solid. 1H NMR (400 MHz, CDCl3) δ 8.86 (s, 1H), 8.55 (s, 1H), 8.44 (d, J=4.55 Hz, 1H), 8.21 (d, J=9.09 Hz, 1H), 7.89-7.96 (m, 2H), 7.46-7.53 (m, 4H), 7.23-7.32 (m, 2H), 3.23-3.36 (m, 2H), 2.77-2.91 (m, 3H), 1.66-1.86 (m, 4H).
Reaction SMILES: O=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:5]=[CH:4][C:3]1=2.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27][CH2:28][NH2:29].[BH3-]C#N.[Na+]>Cl[Ti](Cl)(Cl)Cl>[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27][CH2:28][NH:29][CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCC3=O)nc1
Reactant: NCCc1cccs1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCCC3NCCc2cccs2)nc1

Procedure:
Using a method similar to Example 1, using 6-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-nicotinamide (Intermediate 2, 546 mg, 2.00 mmol), 2-thiopheneethylamine (305 mg, 2.40 mmol), Ti(iPrO)4 (1.14 g, 4.00 mmol), TiCl4 (1.0M/DCM, 4.00 ml, 4.00 mmol), and NaBH3CN (251 mg, 4.00 mmol) gives the title compound (491.mg) as a light yellow solid. Mass spectrum (ion spray): m/z=394 (M+1); 1HNMR (CDCl3): 8.58 (s, 1H), 8.15 (d, 1H), 7.36 (d, 1H), 7.15 (d, 1H), 6.95-6.89 (m, 3H), 6.85 (m, 2H), 5.87 (br. s, 2H), 3.81 (t, 1H), 3.12-3.02 (m, 3H), 2.98 (m, 1H), 2.83-2.68 (m, 2H), 1.98-1.82 (m, 3H), 1.73 (m, 1H).
Reaction SMILES: C(O[CH:4](OCC)[CH:5]([NH:7]/[C:8](/[C:12]1[CH:17]=[CH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:13]=1)=[CH:9]\[C:10]#[N:11])[CH3:6])C.FC(F)(F)C(O)=O>C(OCC)(=O)C>[CH3:21][O:20][C:18]([C:15]1[CH:14]=[CH:13][C:12]([C:8]2[NH:7][C:5]([CH3:4])=[CH:6][C:9]=2[C:10]#[N:11])=[CH:17][CH:16]=1)=[O:19]
Reactant: CCOC(OCC)C(C)N/C(=C\C#N)c1ccc(C(=O)OC)cc1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(-c2[nH]c(C)cc2C#N)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture (117.0 g) of (E)-3-(2,2-diethoxy-1-methylethylamino-3-(4-methoxycarbonylphenyl)acrylonitrile and (Z)-3-(2,2-diethoxy-1-methylethylamino)-3-(4-methoxycarbonylphenyl)acrylonitrile was treated with trifluoroacetic acid (200 ml) at 0° C. for 30 minutes and then at ambient temperature for 30 minutes. To the mixture ethyl acetate (300 ml) was added at 0° C. and this mixture was stirred at 0° C. for 15 minutes. The precipitates were collected by vacuum filtration to afford 2-(4-methoxycarbonylphenyl)-5-methylpyrrole-3-carbonitrile as an orange powder (54.8 g).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1)(=O)=O.[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[CH:34]1[CH2:35][CH2:36][N:37]([CH2:6][CH2:7][N:8]2[C:16]3[N:15]=[C:14]([NH2:17])[N:13]4[N:18]=[C:19]([C:21]5[O:22][CH:23]=[CH:24][CH:25]=5)[N:20]=[C:12]4[C:11]=3[CH:10]=[CH:9]2)[CH2:38][CH2:39]1
Reactant: Fc1ccc(C2CCNCC2)c(F)c1
Reactant: CS(=O)(=O)OCCn1ccc2c1nc(N)n1nc(-c3ccco3)nc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc2c(ccn2CCN2CCC(c3ccc(F)cc3F)CC2)c2nc(-c3ccco3)nn12
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of the title D compound of Example 1, 2-{5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl}ethyl methanesulfonate (0.06 g, 0.165 mmol) in dry DMF (5 mL), 4-(2,4-difluorophenyl)piperidine (0.33 mmol) and 0.06 mL of DIEA are added, and the solution is stirred at 100° C. for 5 h. The reaction mixture is cooled to RT, and the solvent is removed under reduced pressure. The crude product is purified by flash chromatography using a 95/5.0/0.5-mixture of DCM/MeOH/NH4OH as an eluent to give 7-(2-(4-(2,4-difluorophenyl)piperidin-1-yl)ethyl)-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine: LC/MS (M+1=463.98). 1H NMR (DMSO-d6, 400 MHz), δ 1.68 (m, 4H), 2.12 (m, 2H), 2.55 (m, 1H), 2.73 (t, 2H, J=6.0 Hz), 3.04 (m, 2H), 4.26 (t, 2H, J=6.4 Hz), 6.59 (d, 1H, J=3.6 Hz), 6.71 (m, 1H), 7.09 (m, 1H), 7.18 (m, 2H), 7.26 (m, 1H), 7.33 (m, 1H), 7 49 (br s, 2H, NH2), 7.91 (s, 1H).
Reaction SMILES: C([C@H:3]([S:7]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[N:9][C:10]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]3[N:33]([CH3:34])[N:32]=[C:31]([CH3:35])[CH:30]=3)=[O:28])[CH:21]=2)[CH:17]=1)=[O:11])=[O:8])[C:4]([O-])=[O:5])C.[CH3:42][NH2:43]>>[CH3:34][N:33]1[C:29]([C:27]([NH:26][C:22]2[CH:21]=[C:20]([C:19]#[C:18][C:16]3[CH:15]=[N:14][CH:13]=[C:12]([CH:17]=3)[C:10]([N:9]=[S@@:7]([CH2:3][C:4]([NH:43][CH3:42])=[O:5])(=[O:8])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:11])[CH:25]=[CH:24][CH:23]=2)=[O:28])=[CH:30][C:31]([CH3:35])=[N:32]1
Reactant: CN
Reactant: CC[C@@H](C(=O)[O-])S(=O)(=NC(=O)c1cncc(C#Cc2cccc(NC(=O)c3cc(C)nn3C)c2)c1)c1ccccc1
Product: CNC(=O)C[S@@](=O)(=NC(=O)c1cncc(C#Cc2cccc(NC(=O)c3cc(C)nn3C)c2)c1)c1ccccc1

Procedure:
In a manner similar to that described in Example 534, (S)-Ethyl[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]acetate and methylamine were reacted to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([N:8]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]3[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22](O)=[O:23])=[CH:16][CH:15]=3)[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[O:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[O:33][NH2:34].C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O.CCN=C=NCCCN(C)C.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]3[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([NH:34][O:33][CH:28]4[CH2:29][CH2:30][CH2:31][CH2:32][O:27]4)=[O:23])=[CH:16][CH:15]=3)[CH2:9]2)=[O:7])=[CH:25][CH:26]=1
Reactant: O=C(O)/C=C/c1ccc(N[C@@H]2CCN(C(=O)c3ccc(Cl)cc3)C2)nc1
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(/C=C/c1ccc(N[C@@H]2CCN(C(=O)c3ccc(Cl)cc3)C2)nc1)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.4 %

Procedure:
To a solution of (2E)-3-(6-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylic acid (1.58 g) in DMF (16 mL) was added O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (546 mg), HOBt (744 mg), and EDCI HCl (1.06 mg) and the resulting mixture was stirred at ambient temperature for 4 hours. The reaction mixture was diluted with water and extracted with AcOEt. The organic phase was washed with sat NH4Cl aq solution and sat NaHCO3 aq solution, and brine, and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography eluted with chloroform:methanol=97.5:2.5 to give (2E)-3-(6-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (1.89 g) as colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[N:6][C:7]=1[Cl:8].[CH:23]#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(N(CC)CC)C>C(Cl)Cl.[Cu]I>[C:23]([C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[N:6][C:7]=1[Cl:8])#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc(Cl)c(Br)c1
Reactant: C#CCCCCCC
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCC#Cc1cc(OC[C@H]2CCCN2C(=O)OC(C)(C)C)cnc1Cl
Yield: 72.3 %

Procedure:
A mixture of 5-bromo-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine from Example 69a (425 mg, 1.1 mmol), 1-octyne (0.2 mL, 1.4 mmol), Pd(PPh)3Cl2 (20 mg), CuI (catalytic amount) and triethylamine (0.5 mL) in CH2Cl2 (8 mL) was heated at reflux for 16 hours. Heating was continued until no starting material remained. The solvent was removed, and the residue was washed with 10% NaOH then extracted with CH2Cl2. The organic extract was dried over MgSO4 and concentrated. The residue was chromatographed on a silica gel column, eluting with hexane:Et2O 100:6-100:15 to afford to give the title compound (335 mg, 72% yield). MS (CI/NH3) m/z 421 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ0.90 (m, 3H), 1.32 (m, 4H), 1.48 (s, 9H), 1.49 (m, 2H), 1.62 (m, 2H), 1.88 (m, 2H), 2.00 (m, 2H), 2.48 (m, 2H), 3.34 (m, 2H), 3.90 (m, 1H), 4.12 (m, 2H), 7.30 (br s, 1H), 7.98 (m, 1H).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]([N:13]1[CH2:17][CH2:16][CH2:15][NH:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:18]([O:20][C:21](=[O:26])[CH2:22][C:23](Cl)=[O:24])[CH3:19]>C(Cl)Cl>[CH2:3]([O:10][C:11]([N:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:23](=[O:24])[CH2:22][C:21]([O:20][CH2:18][CH3:19])=[O:26])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)CC(=O)Cl
Reactant: O=C(OCc1ccccc1)N1CCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOC(=O)CC(=O)N1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.3 %

Procedure:
To a solution of sodium hydroxide (93.0 mL of 1N solution, 93.0 mmol) is added CH2Cl2 (280 mL) followed by pyrazolidine-1-carboxylic acid benzyl ester (15.0 g, 61.8 mmol) and then ethyl-3-chloro-3-oxopropionate (11.1 mL, 86.5 mmol). After stirring the biphasic mixture vigorously for 3 hours at room temperature, the mixture is quenched by pouring into aqueous saturated NH4Cl. The organic phase is dried (MgSO4), filtered and concentrated in vacuo. The crude residue is purified over silica (10% EtOAc/hexanes) to afford 15.5 g (78% yield) of the desired product. 1H NMR (300 MHz, CDCl3) δ 7.38 (s, 5H), 5.23 (dd, J=11.8, 8.4 Hz, 2H), 4.19-4.07 (m, 4H), 3.65 (d, J=15.9 Hz, 1H), 3.31 (d, J=15.9 Hz, 1H), 3.20-3.15 (m, 2H), 2.20-2.04 (m, 2H), 1.26 (t, J=7.2 Hz, 3H); ESI+ MS: m/z (rel intensity) 321.0 (100, M++H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH:9]1([C:15]([O:17]C)=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.I[CH2:20][CH:21]([CH3:23])[CH3:22]>O1CCCC1>[CH2:20]([C:9]1([CH2:15][OH:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1)[CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)CI
Reactant: COC(=O)C1CCCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)CC1(CO)CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of lithium diisopropylamide (2.0 M, 7.74 mL) at −78° C. was added methyl cyclohexanecarboxylate (2.0 g) dropwise as a solution in tetrahydrofuran (20 mL). After stirring for 30 minutes, 1-iodo-2-methylpropane (1.956 mL) was added dropwise as a solution in tetrahydrofuran (1 mL). The reaction was allowed to warm to room temperature and stirred overnight. The reaction was quenched with 1N HCl (25 mL) and diluted with water (25 mL) and extracted into diethyl ether (50 mL). The ether layer was washed with brine (30 mL), dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in diethyl ether (25 mL) and lithium aluminum hydride (1.0M in tetrahydrofuran, 16.88 mL) was added dropwise. After stirring overnight, the reaction was quenched with water (0.65 mL), 15% aqueous NaOH (0.65 mL), more water (1.95 mL), then magnesium sulfate was added and the reaction filtered and concentrated. The residue was loaded onto silica gel and eluted using a gradient of 3% to 20% ethyl acetate/hexanes to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:14])[CH:11]=NO)[CH:5]=[CH:6][C:7]=1[CH3:8].S(=O)(=O)(O)[OH:16]>O>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]2[C:3]=1[C:11](=[O:16])[C:10](=[O:14])[NH:9]2
Reactant: O=S(=O)(O)O
Reactant: Cc1ccc(NC(=O)C=NO)cc1C
Solvent: O
Product: Cc1ccc2c(c1C)C(=O)C(=O)N2
Temperature: 85 °C
Reaction time: 2 h

Procedure:
N-(3,4-Dimethylphenyl)-2-hydroxyimino-acetamide (30 g, 0.156 mmol) was slowly added to an aqueous solution (17 ml) of concentrated sulfuric acid (85 ml), and the mixture was stirred at 85° C. for 2 hours. The obtained solution was poured into ice-cooled water, and the precipitated orange solid was filtered out. The obtained solid was dissolved in a 10% aqueous sodium hydroxide solution, activated carbon was added, and the mixture was stirred. The obtained solution was filtered, and acetic acid was used to adjust the pH to 3 to obtain 4,5-dimethyl-1H-indole-2,3-dione as crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)=[C:4]([O:20]C)[CH:3]=1.[NH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27](=[O:33])[NH:28]2.B(Br)(Br)Br>>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([C:8]([CH3:18])([CH3:19])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]2[NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][C:27](=[O:33])[NH:28]3)=[C:4]([OH:20])[CH:3]=1
Reactant: COc1cc(Br)ccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: Nc1cccc2[nH]c(=O)ccc12
Agent: BrB(Br)Br
Product: CC1(C)CC(O)(C(F)(F)F)C(Nc2cccc3[nH]c(=O)ccc23)c2cc(Br)cc(O)c21

Procedure:
Analogously to Example 10, the corresponding imine is produced starting from 800 mg of 4-(4-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 348 mg of 5-amino-quinolin-2(1H)-one. 16 mg of diastereomer A of 5-{[7-bromo-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one (fraction A) and 79 mg of diastereomer B of 5-{[7-bromo-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one are obtained by reaction of 800 mg of the imine with 7.9 ml of boron tribromide solution (1H in dichloromethane).
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:3]=1[C:4]([C:6]#[N:7])=O.C(=O)(O)O.[NH2:18][NH:19][C:20]([NH2:22])=[NH:21].[N+]([O-])(O)=O>CS(C)=O>[NH2:21][C:20]1[N:19]=[N:18][C:4]([C:3]2[CH:8]=[C:9]([Cl:13])[CH:10]=[C:11]([Cl:12])[C:2]=2[Cl:1])=[C:6]([NH2:7])[N:22]=1
Reactant: N#CC(=O)c1cc(Cl)cc(Cl)c1Cl
Reactant: N=C(N)NN
Agent: O=C(O)O
Solvent: O=[N+]([O-])O
Solvent: CS(C)=O
Product: Nc1nnc(-c2cc(Cl)cc(Cl)c2Cl)c(N)n1
Reaction time: 3 h

Procedure:
A solution of 2,3,5-trichlorobenzoyl cyanide (38.5 g, 0.16M) in dimethylsulphoxide (80 ml) was added dropwise to a stirred suspension of aminoguanidine bicarbonate (65.76 g, 0.32M) which had been treated with 8N aqueous nitric acid (560 ml). The mixture was stirred for 3 hours and then was left to stand at room temperature for 21 days. The solid was filtered off, washed with water (2×100 ml) and dried in vacuo. A suspension of the dried solid in a 10% solution of potassium hydroxide pellets in methanol (320 ml) was heated to reflux for 1 hour, the mixture was cooled and evaporated down in vacuo. The residue was treated with ice/water (200 ml), the resultant solid was filtered off and dried in vacuo. This dried solid was put on top of a dry column (25 mm diameter, 200 g of MFC silica gel) and eluted with a solution of ethyl acetate/methanol/acetic acid (90:2.5:2.5). Fractions 50 to 80 (900 drops per fraction) were collected, combined and evaporated down in vacuo. The resultant solid was recrystallised from ispropanol to give 3,5-diamino-6-(2,3,5-trichlorophenyl)-1,2,4 -triazine. Yield 0.77 g (1.6%), m.p. 232°-235° C. (uncorrected).
Reaction SMILES: [Si:1]([N:8]1[C@@H:11]([CH2:12]O)[CH2:10][C:9]1=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[SH:46][C:47]1[N:52]=[CH:51][CH:50]=[CH:49][N:48]=1>C1COCC1>[Si:1]([N:8]1[C@@H:11]([CH2:12][S:46][C:47]2[N:52]=[CH:51][CH:50]=[CH:49][N:48]=2)[CH2:10][C:9]1=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)C[C@@H]1CO
Reactant: Sc1ncccn1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)N1C(=O)C[C@@H]1CSc1ncccn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 94.9 %

Procedure:
To a solution of 1-(tert-butyldimethylsilyl)-4(R)-(hydroxymethyl)azetidin-2-one (2.75 g, 12.77 mmol) in THF (80 mL) was added PPh3 (6.70 g, 25.54 mmol). The reaction was cooled at 0° and DEAD (3.3 mL, 25.54 mmol) was added dropwise. After 5 min. 2-mercaptopyrimidine (3.60 g, 31.92 mmol) was added. After stirring for 15 min at 0° and 60 h at room temperature, the reaction mixture was concentrated. The residue was treated with EtOAc/hexane (1/1) and the resulting solid was filtered and rinsed with Et2O. The filtrate was concentrated and purified by flash chromatography (SiO2, 25% EtOAc/hexane) to provide 1-(tert-butyldimethylsilyl)-4(R)-(pyrimidin-2-ylsulfanylmethyl)azetidin-2-one (3.75 g, 95% yield) as clear oil. 1H NMR (400 MHz, CDCl3) δ 8.70 (d, J=4.8 Hz, 2H), 7.20 (t, J=4.9 Hz, 1H), 4.08-4.01 (m, 2H), 3.41-3.36 (m, 1H), 3.99 (dd, J=14.3, 10.8 Hz, 1H), 2.98 (dd, J=15.6, 2.5 Hz, 1H), 1.18 (s, 9H), 0.53 (s, 3H), 0.49 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH2:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][C@@H:28]1[CH3:33])[CH3:26]>>[CH2:25]([N:27]1[CH2:32][CH2:31][N:30]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:20])[CH2:29][C@@H:28]1[CH3:33])[CH3:26]
Reactant: CCN1CCNC[C@@H]1C
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: CCN1CCN(C(=O)c2ccc(-n3ncc(-c4ccc(C#N)cc4C)c3O)nc2)C[C@@H]1C

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)-1-ethyl-2-methylpiperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.87-1.19 (m, 6H) 2.42 (s, 3H) 2.47 (br. s., 1H) 2.52-2.59 (m, 1H) 2.62-2.76 (m, 1H) 2.77-2.98 (m, 2H) 3.06 (d, J=10.61 Hz, 1H) 3.35 (br. s., 1H) 3.46-3.75 (m, 1H) 4.05 (br. s., 1H) 7.60 (dd, J=7.96, 1.64 Hz, 1H) 7.66 (d, J=1.26 Hz, 1H) 7.90 (d, J=8.34 Hz, 1H) 8.01 (dd, J=8.72, 2.15 Hz, 1H) 8.06 (s, 1H) 8.43 (d, J=8.59 Hz, 1H) 8.51 (d, J=1.77 Hz, 1H) 11.83-12.92 (m, 1H); ESI-MS m/z [M+H]+ 431.3.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH:7]=O)=[C:4]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)(=[O:11])=[O:10])[CH:3]=1.[CH3:18][O:19][C:20](=[O:33])[CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=2)[CH:24]=[C:23]1[CH3:32]>>[CH3:18][O:19][C:20](=[O:33])[CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=2)[C:24]([CH2:7][C:5]2[S:6][C:2]([Cl:1])=[CH:3][C:4]=2[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)(=[O:11])=[O:10])=[C:23]1[CH3:32]
Reactant: O=Cc1sc(Cl)cc1S(=O)(=O)c1ccccn1
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Product: COC(=O)Cn1c(C)c(Cc2sc(Cl)cc2S(=O)(=O)c2ccccn2)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 42b using 5-chloro-3-(pyridine-2-sulfonyl)thiophene-2-carbaldehyde and (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:21][O:22][C:23]([C:25]3[S:26][C:27]([CH3:30])=[CH:28][CH:29]=3)=[O:24])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]3[CH3:20])=[C:4]([O:31][CH3:32])[CH:3]=1.C(N(CC)CC)C.[N:40]1[CH:45]=[CH:44][CH:43]=[C:42]([N:46]=[C:47]=[O:48])[CH:41]=1>C(Cl)Cl>[CH3:32][O:31][C:4]1[CH:3]=[C:2]([O:1][C:47]([NH:46][C:42]2[CH:41]=[N:40][CH:45]=[CH:44][CH:43]=2)=[O:48])[CH:7]=[CH:6][C:5]=1[C:8]1[C:9]([CH2:21][O:22][C:23]([C:25]2[S:26][C:27]([CH3:30])=[CH:28][CH:29]=2)=[O:24])=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH3:18])([CH3:19])[CH:12]=[C:11]2[CH3:20]
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COC(=O)c1ccc(C)s1)C(C)=CC(C)(C)N2
Reactant: O=C=Nc1cccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(OC(=O)Nc2cccnc2)ccc1-c1ccc2c(c1COC(=O)c1ccc(C)s1)C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.5 %

Procedure:
6-(4-Hydroxy-2-methoxyphenyl)-5-(5-methylthiophen-2-ylcarbonyloxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 3-2, 31.0 mg, 0.0690 mmol) was dissolved in anhydrous methylene dichloride (1 mL), triethylamine (27 μL, 0.19 mmol) and 3-pyridyl isocyanate (17.0 mg, 0.142 mmol) were added thereto, and then the mixture was stirred at room temperature for 3 hours. The reaction mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (21.8 mg) as a pale yellow amorphous product. (Yield 57%)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:8][C:9]=1[NH2:10])([O-:3])=[O:2].[Br:17]N1C(=O)CCC1=O>CN(C=O)C>[Br:17][C:6]1[C:7]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:8][C:9]([NH2:10])=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: Nc1nc(-c2cccnc2)ccc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Nc1nc(-c2cccnc2)c(Br)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 16 h
Yield: 100.7 %

Procedure:
To a 0° C. cooled stirred solution of 5-nitro-2,3′-bipyridin-6-amine (4.8 g, 22.2 mmol) in DMF (50 mL), N-bromosuccinimide (4.75 g, 26.7 mmol) was added in portions. After stirring at room temperature for 16 h, the solvent was removed under reduced pressure. The crude residue was solved with ethyl acetate and washed with saturated potassium carbonate aqueous solution. The organic layer was washed with brine, dried (MgSO4) and evaporated. The residue was purified by silica gel flash chromatography (95:5 dichloromethane/methanol) to give the title compound (6.6 g, 100%) as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(C)=O.O>[CH2:20]([O:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH2:11][C:4]2[CH:5]=[CH:9][CH:10]=[CH:2][CH:3]=2)=[O:12])[C:5](=[CH:9][CH:10]=1)[C:6]([O:8][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:7])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1ccc(O)cc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(OCc1ccccc1)c1ccc(OCc2ccccc2)cc1C(=O)OCc1ccccc1
Yield: 165.7 %

Procedure:
4-Hydroxyphthalic acid (3.50 g, 19.2 mmol) and K2CO3 (23.9 g, 173 mmol) in acetone (100 mL) and water (50 mL) were stirred at rt for 15 min. Benzyl bromide (20.6 mL, 173 mmol) was added and the mixture was heated under reflux for 3 d. Vacuum distillation (45°-50° C./1.1 mm) removed residual benzyl alcohol and the distillation residue was purified by gradient flash chromatography (10-30% ethyl acetate:hexane) to give dibenzyl 4-benzyloxyphthalate (7.20 g, 83%) as a pale yellow oil. TLC Rf 0.65 (25% ethyl acetate:hexane). ##STR413## Step 2