Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.[CH3:4][N:5]1[C:9]([S:10][CH2:11][C:12]2[CH2:13][S:14][C@@H:15]3[CH:22]([NH:23][C:24](=[O:39])[C:25]([C:33]4[N:34]=[C:35]([NH2:38])[S:36][CH:37]=4)=[N:26][O:27][CH2:28][CH2:29][N:30]=[N+:31]=[N-:32])[C:21](=[O:40])[N:16]3[C:17]=2[C:18]([OH:20])=[O:19])=[N:8][N:7]=[N:6]1.C(=O)(O)[O-].[Na+:45]>O>[CH3:4][N:5]1[C:9]([S:10][CH2:11][C:12]2[CH2:13][S:14][C@@H:15]3[CH:22]([NH:23][C:24](=[O:39])[C:25]([C:33]4[N:34]=[C:35]([NH2:38])[S:36][CH:37]=4)=[N:26][O:27][CH2:28][CH2:29][N:30]=[N+:31]=[N-:32])[C:21](=[O:40])[N:16]3[C:17]=2[C:18]([O-:20])=[O:19])=[N:8][N:7]=[N:6]1.[Na+:45]
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCN=[N+]=[N-])c3csc(N)n3)[C@H]2SC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cn1nnnc1SCC1=C(C(=O)[O-])N2C(=O)C(NC(=O)C(=NOCCN=[N+]=[N-])c3csc(N)n3)[C@H]2SC1

Procedure:
1 ml of ethanol was added to a solution of 0.162 g of the product of Example 36 in 0.3 ml of a molar solution of sodium bicarbonate in water and the mixture was vacuum filtered. The filtrate was evaporated to dryness undere reduced pressure and the residue was taken up in ethanol. After efflorescence, the mixture was vaccum filtered to obtain 0.09 g of the syn isomer of sodium 3-[(1-methyl-1H-tetrazol-5-yl)-thiomethyl]-7-[2-(2-amino-4-thiazolyl)-2-(2-azidoethoxyimino)-acetamido]-ceph-3-eme-4-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4](Cl)[N:3]=1.[N:34]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[CH2:46][NH2:47])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.C(N(C(C)C)CC)(C)C>CC(O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([NH:47][CH2:46][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(Cl)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Reactant: NCc1ccccc1N1CCCCC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(NCc4ccccc4N4CCCCC4)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 120 °C

Procedure:
To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-chloropyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (200 mg, 0.6 mmol) and [2-(1-piperidinyl)phenyl]methanamine (CAS#: 72752-54-6) (105 mg, 0.8 mmol) in i-PrOH (2 mL) was added diisopropylethyl amine (0.5 mL). The reaction was heated to 120° C. for 2 h followed by heating to 140° C. for 1 h under microwave conditions, then cooled to RT and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((2-(piperidin-1-yl)benzyl)amino)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH2:34][NH2:35])=[CH:4][N:3]=1.O=[C:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:39][CH2:38]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C.ClCCl>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH2:34][NH:35][CH:37]2[CH2:42][CH2:41][N:40]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:39][CH2:38]2)=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(/C=C/CN)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)N1CCC(NC/C=C/c2cnc(N)c3c(-c4ccc(NC(=O)c5cc6ccccc6n5C)c(OC)c4)csc23)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a suspension of N-(4-{4-amino-7-[(1E)-3-aminoprop-1-enyl]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide (0.050 g, 0.104 mmol) and ethyl 4-oxo-1-piperidinecarboxylate (0.017 g, 0.087 mmol) in dichloroethane (1.5 mL) was added sodiumtriacetoxy borohydride (0.036 g, 0.173 mmol). The resulting solution was allowed to stir at room temperature for 12 hours. Upon completion, the reaction solution was treated with an aqueous solution of 10% sodium hydroxide (3 mL) and dichloromethane (3 mL). The two layers were stirred for 15 minutes, followed by filtration through an Empore™ cartridge, and removal of the solvent. The resulting crude product was purified by trituration of the residue in ethanol and collection of the title compound (0.030 g, 45%) as a white powder. LCMS (Conditions a) Rt 3.57 minutes, 639.4 (MH+); 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1 H), 8.01 (dd, J=8.2 Hz, J=7.8 Hz, 1 H), 7.95 (s, 1 H), 7.71 (d, J=8.2 Hz, 1 H), 7.62 (s, 1 H), 7.59 (d, J=8.2 Hz, 1 H), 7.35 (s, 1 H), 7.32 (d, J=8.5 Hz, 1 H), 7.21(d, J=1.9 Hz, 1 H), 7.15 (t, J=7.8 Hz, 1 H), 7.08 (dd, J=8.2 Hz, 1.9 Hz, 1 H), 6.67 (d, J=16.0 Hz, 1 H), 6.29 (td, J=16.4 Hz, J=5.9 Hz, 1 H), 5.61 (s (br), 1 H), 4.04 (s, 3 H), 4.02 (q, J=7.02 Hz, 2 H), 3.91 (s, 3 H), 3.88 (m, 2 H), 3.42 (d, J=5.5 Hz, 2 H), 2.87 (m, 2 H), 2.67 (m, 1 H), 1.83 (m, 2 H), 1.19 (m, 2 H), 1.18 (t, J=7.02 Hz, 3 H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:17](=[O:18])[O:16][C:14](=[O:15])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:20][O:21][C:22](=[O:32])[C@H:23]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH2:24].C(=O)([O-])[O-].[K+].[K+].O>C(O)(=O)C>[CH3:20][O:21][C:22](=[O:32])[C@H:23]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:24][C:17](=[O:18])[C@H:12]([CH2:13][C:14](=[O:15])[OH:16])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: O=C1C[C@H](NC(=O)OCc2ccccc2)C(=O)O1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)OCc1ccccc1
Reaction time: 3 h

Procedure:
To 24.9 g (0.1 mole) of N-benzyloxycarbonyl-L-aspartic acid anhydride in 100.4 g of acetic acid were added 21.6 g (0.1 mole) of L-phenylalanine methyl ester hydrochloride and 7.6 g (0.055 mole) of potassium carbonate. The reaction was carried out for 3 hours with stirring at 15°-20.C. Thereafter 75.3 g of water was added and the mixture was stirred for one hour at 15°-20.C. The precipitated crystals were filtered, washed and dried to obtain crystals of N-benzyloxycarbonyl-α-L-aspartyl-phenylalanine methyl ester. Analysis of HPLC revealed that the crystals had an α-isomer:β-isomer ratio of 99.6:0.4. The yield of the α-isomer was 28.6 g. In the filtrate, 7.2 g of the α-isomer and 6.2 g of the β-isomer were present.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:16]=1[NH2:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23][CH2:24][C:25](Cl)=[O:26]>CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:16]=1[NH:17][C:25](=[O:26])[CH2:24][Cl:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1cc(Cl)ccc1-c1ccccc1OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(CCl)Nc1cc(Cl)ccc1-c1ccccc1OCc1ccccc1
Reaction time: 1 h

Procedure:
To a solution of the product from Step B (6.200 g, 19.07 mmol) in 100 mL of EtOAc and 100 mL of saturated NaHCO3 solution at 0° C. was added chloroacetyl chloride (2.28 mL, 28.6 mmol). After one hour, the solution was poured into EtOAc, washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The titled product was obtained as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N+:13]([O-])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.C(OC(=O)C)(=[O:19])C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][NH:13][C:12](=[O:19])[CH:11]=2)=[N:6][CH:7]=1
Reactant: [O-][n+]1ccc(OCc2ccc(F)cn2)cc1
Reactant: CC(=O)OC(C)=O
Product: O=c1cc(OCc2ccc(F)cn2)cc[nH]1
Temperature: 80 °C
Yield: 73 %

Procedure:
4-((5-Fluoropyridin-2-yl)methoxy)pyridine 1-oxide (1.76 g, 7.99 mmol) was heated to 140° C. in acetic anhydride (80 mL) for 5 h. The mixture was concentrated and then heated at 80° C. for 1 h in a mixture of MeOH (20 mL) and aqueous 1 N NaOH (15 mL). The resulting black solution was concentrated to a volume of 15 mL, and the solid was filtered off, rinsed with CH2Cl2 and dried under vacuum to provide the title compound (1.29 g, 73%) as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.59 (d, J=2.9 Hz, 1H), 7.79 (dt, J=8.7, 2.9 Hz, 1H), 7.60 (dd, J=8.7, 4.5 Hz, 1H), 7.26 (d, J=7.3 Hz, 1H), 5.95 (dd, J=7.4, 2.6 Hz, 1H), 5.78 (d, J=2.5 Hz, 1H), 5.12 (s, 2H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)=[O:13].[CH2:30]([NH2:36])[CH:31]1[O:35][CH2:34][CH2:33][CH2:32]1>>[CH3:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:36][CH2:30][CH:31]2[CH2:32][CH2:33][CH2:34][O:35]2)=[C:3]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH:4]=1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Reactant: NCC1CCCO1
Product: CS(=O)(=O)c1ccc(NCC2CCCO2)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Yield: 28 %

Procedure:
The title compound was prepared according to the procedure described for example 301 from (2-Iodo-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (compound CK) and tetrahydrofurfurylamine (28% yield, MS (m/e): 512.4 (M+H, 100%)
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:35]1[CH:40]=C[C:38]([CH2:41][C:42]([NH:44][CH:45]2[CH2:47][CH2:46]2)=[O:43])=[CH:37][CH:36]=1.CN(C=O)C>CO.C([O-])(O)=O.[Na+]>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:19]=[C:20]([C:36]2[CH:35]=[CH:40][C:41]([C:42](=[O:43])[NH:44][CH:45]3[CH2:46][CH2:47]3)=[CH:38][CH:37]=2)[CH:21]=[CH:22][CH:23]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cc1ccc(Br)cc1)NC1CC1
Reactant: CC1(C)OB(c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccc(-c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)cc1
Temperature: 70 °C

Procedure:
A solution of (S)-2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (74 mg, 0.16 mmol), 2-(4-bromo-phenyl)-N-cyclopropyl-acetamide (41.6 mg, 0.16 mmol), and Pd[P(Ph)3]4 (12.7 mg, 6.7 mol %) in methanol (2 mL), NaHCO3 (sat. aq., 300 μL), and DMF (400 μL) was degassed and heated to 70° C. overnight in a sealed vial. The reaction was cooled, filtered, and purified by reverse phase HPLC to give the desired product. Yield 7.1 mg. MS: 498.2 (M+H+); H1-NMR (DMSO-d6): δ (ppm) 0.37-0.44 (m, 2H), 0.58-0.66 (m, 2H), 1.80-2.04 (m, 3H), 2.14-2.36 (m, 1H), 2.55-2.68 (m, 1H), 3.36-3.57 (m, 2H), 4.32-4.43 (m, 1H), 4.91-5.14 (m, 2H), 7.00-7.65 (m, 12H), 7.87-7.95 (m, 1H), 8.12-8.18 (m, 1H), 10.08-10.14 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.CC1C=CC(S(O)(=O)=O)=CC=1>CCO>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]2[C:4](=[O:5])[NH:6][CH:16]([C:15]3[CH:18]=[CH:19][CH:20]=[C:13]([F:12])[CH:14]=3)[NH:1][C:2]=2[N:10]=1
Reactant: O=Cc1cccc(F)c1
Reactant: NC(=O)c1ccc(Cl)nc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: O=C1NC(c2cccc(F)c2)Nc2nc(Cl)ccc21
Temperature: 25 °C
Yield: 52.3 %

Procedure:
To a solution of 2-amino-6-chloronicotinamide (200 mg, 1.17 mmol) and 3-fluorobenzaldehyde (160 mg, 1.29 mmol) in 20 mL of EtOH was added PTSA (20 mg, 0.12 mmol), and then the mixture was heated at reflux for 16 h. The solution was cooled to room temperature and filtered to give the product of 7-chloro-2-(3-fluorophenyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one (170 mg, yield: 52%) without further purification. 1H-NMR (CDCl3, 400 MHz) δ 8.09 (d, J=8.0 Hz, 1H), 7.41˜7.44 (m, 1H), 7.29˜7.36 (m, 2H), 7.15˜7.19 (m, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.03 (s, 1H), 5.75 (s, 1H), 5.35 (s, 1H). MS (M+H)+: 278/280.
Reaction SMILES: [OH-].[NH4+:2].[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10](=O)[CH2:11][C:12](=[O:22])[CH2:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=O)[CH:5]=1.Cl>C(O)(C)C>[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]2[NH:2][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:13][C:12](=[O:22])[CH:11]=2)[CH:5]=1
Reactant: O=C(CC(=O)c1ccccn1)CC(=O)c1cc(Cl)ccn1
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: CC(C)O
Product: O=c1cc(-c2ccccn2)[nH]c(-c2cc(Cl)ccn2)c1

Procedure:
110 ml of 25 per cent strength ammonium hydroxide solution are added to 1-(4-chloropyridin-2-yl)-5-pyridin-2-ylpentane-1,3,5-trione obtained as described above in 100 ml of isopropanol and the mixture is boiled under reflux for 4.5 hours. At room temperature, the pH is brought to 5 with 6N hydrochloric acid and the mixture is filtered. The residue is filtered through silica gel (eluent: chloroform/methanol/ammonium hydroxide solution 4:1:0.1) and evaporated. After recrystallization from acetone, 4-chloro-1′H-[2,2′;6′,2″]terpyridin-4′-one is obtained as a grey solid which is processed further without any particular purification steps. 1H-NMR (360 MHz, DMSO-de): 8.728.63 (m, 2H); 8.62-8.53 (m, 2H); 7.98 (ddd, 1H, J=7.7,7.7,1.8 Hz); 7.87 (d, 1H, J=2.2 Hz); 7.83 (d, 1H, J=2.2 Hz); 7.59 (dd, 1H, J=5.4,2.2 Hz); 7.43-7.51 (m, 1H); 2.07 (s, 1 H).
Reaction SMILES: [CH:1]([C:4]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:7](=[O:8])O[C:5]=1[C:15]([OH:17])=[O:16])([CH3:3])[CH3:2].[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>C(OCC)C>[F:18][C:19]1[CH:25]=[CH:24][C:22]([N:23]2[C:5]([C:15]([OH:17])=[O:16])=[C:4]([CH:1]([CH3:2])[CH3:3])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:7]2=[O:8])=[CH:21][CH:20]=1
Reactant: CC(C)c1c(C(=O)O)oc(=O)c2ccccc12
Reactant: Nc1ccc(F)cc1
Solvent: CCOCC
Product: CC(C)c1c(C(=O)O)n(-c2ccc(F)cc2)c(=O)c2ccccc12

Procedure:
A suspension of 4-isopropylisocoumarin-3-carboxylic acid (24.68 g) in 4-fluoroaniline (74 ml) was refluxed under argon for 15 minutes. After cooling, the reaction mixture was dissolved in diethyl ether and the resulting solution extracted with aqueous sodium hydroxide (3×300 ml; 1M). The combined aqueous phases were washed with diethyl ether and acidified to pH1 with aqueous hydrochloric acid (2M). The resultant precipitate was filtered, washed with water and dried at 100° C. to give 2-(4-fluorophenyl)-4-isopropyl-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid (25.2 g) in the form of a white solid, m.p. 276°-277° C. (with decomposition) [Elemental analysis: C, 69.9; H, 4.9; N, 4.3%; calculated: C, 70.15; H, 4.9; N, 4.3%].
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][C@H:8]([NH2:16])[CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[CH3:24][O:25][C:26](=[O:45])[C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[C:29]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:28]=1>C(Cl)Cl>[CH3:24][O:25][C:26](=[O:45])[C:27]1[CH:32]=[CH:31][C:30]([S:33](=[O:35])(=[O:34])[NH:16][CH:8]([CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:17])[CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])=[C:29]([O:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:28]=1
Reactant: CCOC(OCC)[C@@H](N)CC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)c(OCc2ccccc2)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(OCC)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(C(=O)OC)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To a solution of (S)-3-amino-4,4-diethoxy-butyric acid tert-butyl ester (3.38 g, 13.7 mmol) in anhydrous methylene chloride (130 mL) was added pyridine (3.3 mL, 41 mmol) followed by 3-benzyloxy-4-chlorosulfonyl-benzoic acid methyl ester (4.66 g, 13.7 mmol). The reaction was allowed to stir at room temperature overnight. Mass spectrometry and TLC analysis showed presence of starting material. An additional 2 equivalents of pyridine (2.2 mL, 27.3 mmol) was added and allowed to stir overnight. TLC analysis showed the reaction to be completed. The methylene chloride was evaporated and the reaction mixture was dissolved in ether and 5% aqueous citric acid. The organic layer was collected and washed with 5% citric acid and then brine, dried over magnesium sulfate, filtered, and concentrated to yield 3-benzyloxy-4-(1-tert-butoxycarbonylmethyl-2,2-diethoxy-ethylsulfamoyl)-benzoic acid methyl ester (6.82 g, 12.4 mmol, 90%) as an orange tar. MS (APCI) m/z 550.3 (M−1).
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=2[C:9](Cl)=[O:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH2:28][CH2:29][NH:30][CH2:31][CH:32]=2)=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH2:32][CH2:31][N:30]([C:9]([C:8]3[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:7]=3[N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:10])[CH2:29][CH:28]=2)=[CH:23][CH:22]=1
Reactant: Clc1ccc(C2=CCNCC2)cc1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Agent: Cl
Product: O=C(c1cc([N+](=O)[O-])ccc1N1CCOCC1)N1CC=C(c2ccc(Cl)cc2)CC1

Procedure:
According to the procedure described for the synthesis of example 1, the title compound has been synthesized from 2-morpholin-4-yl-5-nitro-benzoyl chloride and 4-(4-Chloro-phenyl)-1,2,3,6-tetrahydro-pyridine hydrochloride (commercial). MS (m/e): 428.1 (MH+, 100%)
Reaction SMILES: Br[C:2]1[C:3]([Cl:9])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[F:15][C:16]1[C:23]([F:24])=[CH:22][CH:21]=[C:20]([O:25][CH3:26])[C:17]=1[CH:18]=[O:19]>O1CCCC1>[Cl:8][C:5]1[N:4]=[C:3]([Cl:9])[C:2]([CH:18]([C:17]2[C:20]([O:25][CH3:26])=[CH:21][CH:22]=[C:23]([F:24])[C:16]=2[F:15])[OH:19])=[CH:7][N:6]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: COc1ccc(F)c(F)c1C=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1ccc(F)c(F)c1C(O)c1cnc(Cl)nc1Cl
Temperature: -30 °C
Reaction time: 0.33 h
Yield: 85.1 %

Procedure:
A solution of 5-bromo-2,4-dichloropyrimidine (18.8 g, 82.5 mmol, Aldrich) in tetrahydrofuran (50 mL) was chilled to −30° C. and isopropylmagnesium chloride (41.25 mL, 82.5 mmol, 2M in tetrahydrofuran, Aldrich) was added. The mixture was stirred at −30° C. for 20 minutes and a solution of 2,3-difluoro-6-methoxybenzaldehyde (12.91 g, 75 mmol, Apollo) in tetrahydrofuran (40 mL) was added slowly at this temperature. The mixture was then stirred at 0° C. for one hour and quenched with aqueous ammonium chloride. Extraction with ethyl acetate and crystallization from ethyl ether/hexanes gave 20.5 g of rac-(2,4-dichloro-pyrimidin-5-yl)-(2,3-difluoro-6-methoxy-phenyl)-methanol as a light yellow solid, MP 99-101° C. MS(ES) MH+322
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11](Cl)=[C:12]([F:17])[CH:13]=2)[N:8]([CH:19]2[CH2:21][CH2:20]2)[CH:7]=1)=[O:5])C.[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][NH:26][CH2:27]2.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][N:26]([C:11]1[N:10]=[C:9]3[C:14]([C:15](=[O:16])[C:6]([C:4]([OH:3])=[O:5])=[CH:7][N:8]3[CH:19]3[CH2:20][CH2:21]3)=[CH:13][C:12]=1[F:17])[CH2:27]2
Reactant: Clc1cccc2c1CNC2
Reactant: CCOC(=O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(O)c1cn(C2CC2)c2nc(N3Cc4cccc(Cl)c4C3)c(F)cc2c1=O
Yield: 18.8 %

Procedure:
310 mg of 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4- oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester, 660 mg of 4-chloroisoindoline, 0.42 ml of triethylamine, and 5 ml of anhydrous chloroform were processed in the same manner as in Example 107 to produce 75 mg of 7-(4-chloro-2- isoindolinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8- naphthyridine-3-carboxylic acid.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[C:15]([B:17]2[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]2)[CH:14]=[N:13]1)C1C=CC=CC=1>CCO.[Pd]>[CH3:24][C:19]1([CH3:25])[C:20]([CH3:22])([CH3:23])[O:21][B:17]([C:15]2[CH:14]=[N:13][N:12]([CH2:11][CH2:10][CH2:9][OH:8])[CH:16]=2)[O:18]1
Reactant: CC1(C)OB(c2cnn(CCCOCc3ccccc3)c2)OC1(C)C
Agent: [Pd]
Solvent: CCO
Product: CC1(C)OB(c2cnn(CCCO)c2)OC1(C)C
Reaction time: 8 h

Procedure:
A deoxygenated mixture of 1-[3-(benzyloxy)propyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Compound 3F, 505 mg, 1.48 mmol) and 10% Pd—C (100 mg) in EtOH (15 mL) was stirred under an atmosphere of hydrogen overnight. The reaction mixture was filtered through a pad of celite and evaporated under reduced pressure to give the desired product as 370 mg of a light-yellow oil (99%). 1H NMR (CDCl3, 400 MHz): δ=7.80 (s, 1H), 7.71 (s, 1H), 4.32 (t, J=6.3 Hz, 2H), 3.63 (t, J=5.8 Hz, 2H), 2.06 (m, 3H), 1.33 (s, 12H).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]1[S:10][C:11]([CH2:16][CH2:17][OH:18])([CH3:15])[C:12](=[O:14])[N:13]=1.Cl.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:20]([O:18][CH2:17][CH2:16][C:11]1([CH3:15])[S:10][C:9]([NH:8][CH:2]2[CH2:3][CH:4]3[CH2:7][CH:1]2[CH2:6][CH2:5]3)=[N:13][C:12]1=[O:14])(=[O:27])[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: CC1(CCO)SC(NC2CC3CCC2C3)=NC1=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(CCOC(=O)c2ccncc2)SC(NC2CC3CCC2C3)=NC1=O
Temperature: 120 °C

Procedure:
A mixture of 2-(bicyclo[2.2.1]heptan-2-ylamino)-5-(2-hydroxyethyl)-5-methylthiazol-4(5H)-one (0.080 g, 0.30 mmol), isonicotinoyl chloride hydrochloride (0.056, 0.30 mmol), and N,N-diisopropylethylamine (0.13 mL, 0.75 mmol) in CH2Cl2 (1.0 mL) was heated in a sealed tube in a microwave oven (SmithSynthesizer from Personal Chemistry) at 120° C. for 10 min. The reaction mixture was conc. in vacuo, and the residue was partitioned between EtOAc and water. The organic portion was separated, washed with brine, conc. in vacuo, and purified by RP-HPLC to give the title compound as a white solid. MS m/z: 374.1 (M+H)+.
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].C1COCC1.[H-].[Na+].Cl[C:13]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[N:16]=[C:15]([NH:25][S:26](=[O:38])(=[O:37])[NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=2)[C:14]=1[O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[O:46][CH3:47]>CN(C=O)C>[CH2:1]([O:4][C:13]1[N:18]=[C:17]([C:19]2[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=2)[N:16]=[C:15]([NH:25][S:26](=[O:37])(=[O:38])[NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=2)[C:14]=1[O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[O:46][CH3:47])[CH:2]=[CH2:3]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1NS(=O)(=O)Nc1ccc(C(C)C)cc1
Reactant: C=CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C=CCOc1nc(-c2ccncc2)nc(NS(=O)(=O)Nc2ccc(C(C)C)cc2)c1Oc1ccccc1OC
Temperature: 80 °C

Procedure:
To a mixture of allyl alcohol (1 ml) and THF (2 ml) was added sodium hydride (100 mg, 60% dispersion in mineral oil) followed by the addition of 4-i-propyl-phenyl sulfamic acid-[6-chloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)pyrimidin-4-yl]-amide (100 mg, Referential Example 1e)). DMF (0.5 ml) was added and the reaction mixture was heated to 80° C. for 20 h. The solvents were evaporated, water (14 ml) and a 10% solution of citric acid was added until the pH was 3. The precipitate was filtered off and washed with water and purified by chromatography through silicagel with EtOAc/Hex=3:2 to give 4-i-propyl-phenyl sulfamic acid-[6-allyloxy-5-(o-methoxyphenoxy)-2-(4-pyridyl)pyrimidin-4-yl]-amide (10 mg). tR=5.36 min, (LC); [M+H]+=548.46 (ES+).