Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][O:10][C:11]2[CH:16]=[C:15]([CH:17]([CH3:19])[CH3:18])[CH:14]=[CH:13][C:12]=2[CH3:20])=[C:4]([CH3:21])[N:3]=1.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:6]2[C:5]([CH2:9][O:10][C:11]3[CH:16]=[C:15]([CH:17]([CH3:19])[CH3:18])[CH:14]=[CH:13][C:12]=3[CH3:20])=[C:4]([CH3:21])[N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1ccc(C(C)C)cc1OCc1c(C)nc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1ccc(C(C)C)cc1OCc1c(C)nc(Cl)nc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2,4-dichloro-5-(5-isopropyl-2-methyl-phenoxymethyl)-6-methyl-pyrimidine (978 mg, 3.01 mmol) in DMA (4 mL) is added piperazine-1-carboxylic acid tert-butyl ester (560 mg, 3.01 mmol) and potassium carbonate (832 mg, 6.02 mmol). The resulting colorless suspension is stirred at room temperature under nitrogen for 16 h. The reaction mixture is partitioned between EtOAc (60 mL) and water (20 mL), the organic layer is separated, washed with water (20 mL×2), brine (20 mL), dried over sodium sulfate, filtered and evaporated at reduced pressure to obtain a colorless oil consisting of a ˜2:1 mixture of isomeric addition products. Purification on a 30 g cartridge of silica gel (10-30% EtOAc/Hexanes) affords the title compound (lower Rf material) as a colorless solid foam. 1H NMR (CDCl3) δ=7.11 (d, 1H), 6.83 (d, 1H), 6.75 (s, 1H), 4.84 (s, 211), 3.52 (m, 8H), 2.90 (m, 1H), 2.47, (s, 3H), 2.16, (s, 3H), 1.45, (s, 9H), 1.27 (d, 6H).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][NH:13][C:14]([C:16]2[CH:17]=[C:18]3[CH2:24][NH:23][C@@H:22]([CH:25]([CH3:27])[CH3:26])[C:19]3=[N:20][CH:21]=2)=[O:15])=[N:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].[F:28][C:29]([F:39])([F:38])[C@H:30]1[CH2:35][CH2:34][C@H:33]([CH:36]=O)[CH2:32][CH2:31]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][NH:13][C:14]([C:16]2[CH:17]=[C:18]3[CH2:24][N:23]([CH2:36][C@H:33]4[CH2:32][CH2:31][C@H:30]([C:29]([F:28])([F:38])[F:39])[CH2:35][CH2:34]4)[C@@H:22]([CH:25]([CH3:26])[CH3:27])[C:19]3=[N:20][CH:21]=2)=[O:15])=[N:10][CH:11]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)c1ccc(CNC(=O)c2cnc3c(c2)CN[C@H]3C(C)C)nc1
Reactant: O=C[C@H]1CC[C@H](C(F)(F)F)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCS(=O)(=O)c1ccc(CNC(=O)c2cnc3c(c2)CN(C[C@H]2CC[C@H](C(F)(F)F)CC2)[C@H]3C(C)C)nc1
Temperature: 70 °C

Procedure:
To a solution of (S)-N-((5-(ethylsulfonyl)pyridin-2-yl)methyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide (3.6 g, 9.25 mmol), trans-4-(trifluoromethyl)cyclohexane-1-carbaldehyde (3.3 g, 18.5 mmol) in anhydrous MeOH (100 mL) was added acetic acid dropwise until the pH was between 6 and 7. Sodium cyanoborohydride (1.7 g, 27.75 mmol) was added portionwise at rt. The mixture was heated to 70° C. for 1 h. Upon completion, the reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), then the organic phase was washed with water (3×100 mL) and brine (100 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 50% EtOAc in hexanes, gradient to 100%), then further purified by a chiral column using the following conditions: instrument: Berger MultiGram™ SFC, Mettler Toledo Co, Ltd; column: AD 300 mm×50 mm, 10 μm; mobile phase: A: supercritical CO2, B: iPrOH (0.05% diethylamine), A:B=60:40 at 200 mL/min; column temp: 38° C.; nozzle pressure: 100 bar; nozzle temp: 60° C.; evaporator temp: 20° C.; trimmer temp: 25° C.; wavelength: 220 nm. Isomer SFC tR=2.28 min in 12 min chromatography was isolated as the major isomer, which was then further purified by reverse-phase HPLC to give (S)-N-((5-(ethylsulfonyl)pyridin-2-yl)methyl)-7-isopropyl-6-((trans-4-(trifluoromethyl)cyclohexyl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide (2, HCl salt) as a light yellow solid. LC-MS tR=0.69 min in 1 min chromatography, MS (ESI) m/z 553.1 [M+H]+. 1H NMR (CD3OD, 400 MHz): δ 9.12 (s, 1H), 9.01 (d, J=2.0 Hz, 1H), 8.36-8.32 (m, 2H), 7.75 (d, J=8.0 Hz, 1H), 5.16 (d, J=15.6 Hz, 1H), 4.89-4.87 (m, 2H), 4.73 (d, J=15.2 Hz, 1H), 3.42-3.34 (m, 3H), 3.31-3.28 (m, 2H), 2.58-2.51 (m, 1H), 2.20-1.90 (m, 6H), 1.50-1.39 (m, 2H), 1.33 (d, J=7.2 Hz, 3H), 1.26 (t, J=7.2 Hz, 3H), 1.24-1.20 (m, 2H), 1.10 (d, J=6.8 Hz, 3H). HCl preparative HPLC method mobile phase A: water with 0.05% HCl; mobile phase B: CH3CN; flow rate: 80 mL/min; detection: UV 220 nm/254 nm; column: Phenomenex Gemini C18 (250 mm×50 mm×5 μm); column temperature: 30° C.
Reaction SMILES: [CH2:1]([C@@:4]12[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16](=[O:22])[CH2:15][CH2:14]4)[CH2:11][C:10](=[CH2:23])[C:9]1=[CH:8][C:7](=[O:24])[CH2:6][CH2:5]2)[C:2]#[CH:3].[Br:25]N1C(=O)CCC1=O>CC(C)=O.[N+]([O-])([O-])=O.[Ag+]>[Br:25][C:3]#[C:2][CH2:1][C@@:4]12[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16](=[O:22])[CH2:15][CH2:14]4)[CH2:11][C:10](=[CH2:23])[C:9]1=[CH:8][C:7](=[O:24])[CH2:6][CH2:5]2
Reactant: C#CC[C@]12CCC(=O)C=C1C(=C)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: O=C1CCC(=O)N1Br
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC(C)=O
Product: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(CC#CBr)CCC(=O)C=C12
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.3 %

Procedure:
A solution of 484 mg of 10β-(2-propynyl)-6-methylenestr-4-ene-3,17-dione in 20 ml of acetone is treated at room temperature with 312 mg of N-bromosuccinimide and 25 mg of silver nitrate, and stirred 4 hours at room temperature in the dark. The mixture is poured with stirring into ice-water and the formed precipitate is filtered off and dissolved in ethyl acetate. The resulting solution is washed with water, dried, evaporated to dryness in vacuo, and the crude is purified by flash chromatography on SiO2, eluting with n-hexane:diethylether 20:80 to give 363 mg of the title compound as a white crystalline product,
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[CH2:7][C@H:8]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:29])[CH3:28])=[CH:22][C:21]=1OCC1C=CC=CC=1)(=[O:19])=[O:18])[CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[CH3:39][O:40][C:41]([C:43]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:46]([CH2:53][CH2:54][OH:55])=[CH:45][CH:44]=1)=[O:42]>>[CH3:39][O:40][C:41]([C:43]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:46]([CH2:53][CH2:54][O:55][C:21]2[CH:22]=[C:23]([NH:26][C:27](=[O:29])[CH3:28])[CH:24]=[CH:25][C:20]=2[S:17](=[O:19])(=[O:18])[NH:16][CH:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:38])[CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])=[CH:45][CH:44]=1)=[O:42]
Reactant: COC(=O)c1ccc(CCO)c2ccccc12
Reactant: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(NC(C)=O)cc1OCc1ccccc1
Product: CCOC(OCC)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(NC(C)=O)cc1OCCc1ccc(C(=O)OC)c2ccccc12

Procedure:
Synthesized by the Mitsunobu reaction between (S)-3-(4-Acetylamino-2-benzyloxy-benzenesulfonylamino)-4,4-diethoxy-butyric acid tert-butyl ester from step 8 of Route J and 4-(2-hydroxyethyl)-naphthlene-1-carboxylic acid methyl ester from above. 1H NMR (400 MHz, CD3OD) 8.96(d, 1H), 8.16(dd, 2H), 7.71(d, 2H), 7.61(m, 2H), 7.55(d, 1H), 6.69(d, 1H), 5.57(d, 1H), 4.42(t, 2H), 4.21(d, 1H), 3.98(s, 3H), 3.72(t, 2H) 3.62(m, 1H), 3.42(m, 2H), 3.40(m, 1H), 3.14(m, 1H), 2.37(d, 2H), 2.16(s, 3H), 1.37(s, 9H), 1.00(t, 3H), 0.90(t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[NH:7][C:6]=2[CH:15]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:25]=2[C:26]([NH:28][CH2:29][C:30]#[CH:31])=[O:27])[C:20]([Cl:37])=[CH:19][N:18]=1>>[Cl:37][C:20]1[C:21]([NH:23][C:24]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:25]=2[C:26]([NH:28][CH2:29][C:30]#[CH:31])=[O:27])=[N:22][C:17]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[NH:7][C:6]=3[CH:15]=2)=[N:18][CH:19]=1
Reactant: CC1(C)CCC(=O)Nc2cc(N)ccc21
Reactant: C#CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: C#CCNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)CCC3(C)C)ncc1Cl

Procedure:
2-[5-Chloro-2-(5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-prop-2-ynyl-benzamide was prepared from 8-amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-prop-2-ynyl-benzamide in an analogous manner to Example 308c. Product isolated as an orange foam (103 mg, 50%). LCMS (m/e) 507 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.40 (s, 1H), 8.10 (s, 1H), 7.55 (d, 1H, J=7.8 Hz), 7.47-7.33 (m, 3H), 7.26-7.17 (m, 2H), 7.07 (s, 1H), 6.79 (d, 1H, J=8.4 Hz), 6.59-6.50 (m, 1H), 4.19-4.15 (m, 2H), 2.38 (t, 2H, J=6.9 Hz), 2.25-2.20 (m, 1H), 2.08-2.04 (m, 2H), 1.37 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=[O:5].[C:11](OC(=O)C)(=[O:13])[CH3:12].C([O-])([O-])=O.[Na+].[Na+]>O>[F:10][C:6]1[C:3]([CH:4]=[O:5])=[C:2]([NH:1][C:11](=[O:13])[CH3:12])[CH:9]=[CH:8][CH:7]=1
Reactant: Nc1cccc(F)c1C=O
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1cccc(F)c1C=O
Temperature: 70 °C

Procedure:
1.37 g (9.85 mmol) 2-amino-6-fluoro-benzaldehyde are combined with 20 ml acetic anhydride and heated to 70° C. for 4 h. Then the reaction mixture is stirred into 200 ml dist. water, adjusted to pH 7 with Na2CO3 and extracted three times with 50 ml of ethyl acetate. Then the organic phase is dried with MgSO4, the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier material used is silica gel and the eluant used is a mixture of cyclohexane:ethyl acetate (80:20).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:12][C:13]3[C:18]([F:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[CH2:9][CH2:10][NH:11][C:5]2=[N:4][CH:3]=1.[N:22]1([CH:27]2[CH2:32][CH2:31][N:30]([C:33]([C:35]3[CH:40]=[CH:39][C:38](B4OC(C)(C)C(C)(C)O4)=[CH:37][CH:36]=3)=[O:34])[CH2:29][CH2:28]2)[CH2:26][CH2:25][CH2:24][CH2:23]1>>[Cl:21][C:14]1[C:15]([F:20])=[CH:16][CH:17]=[C:18]([F:19])[C:13]=1[CH2:12][N:8]1[CH2:9][CH2:10][NH:11][C:5]2[N:4]=[CH:3][C:2]([C:38]3[CH:39]=[CH:40][C:35]([C:33]([N:30]4[CH2:29][CH2:28][CH:27]([N:22]5[CH2:23][CH2:24][CH2:25][CH2:26]5)[CH2:32][CH2:31]4)=[O:34])=[CH:36][CH:37]=3)=[N:7][C:6]1=2
Reactant: CC1(C)OB(c2ccc(C(=O)N3CCC(N4CCCC4)CC3)cc2)OC1(C)C
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(Br)nc32)c1Cl
Product: O=C(c1ccc(-c2cnc3c(n2)N(Cc2c(F)ccc(F)c2Cl)CCN3)cc1)N1CCC(N2CCCC2)CC1

Procedure:
The entitled compound was prepared from 7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]pyrazine and [4-(pyrrolidin-1-yl)piperidin-1-yl][4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanone using Suzuki coupling conditions as described in Example 1.
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]1=[O:7].Br[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.C(=O)([O-])[O-].[K+].[K+].[I-]>O.CN(C)C=O>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]1=[O:7]
Reactant: Brc1ccccn1
Reactant: O=c1cccc[nH]1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1ccccn1-c1ccccn1
Temperature: 120 °C
Reaction time: 2 h
Yield: 21.8 %

Procedure:
25 ml of a dimethylformamide solution containing 4.00 g of 2(1H)-pyridone and 8.00 g of 2-bromopyridine was incorporated with 3.80 g of potassium carbonate and 0.51 g of cupurous iodide, followed by stirring at 120° C. for 2 hours. After the mixture was returned to room temperature, water was added thereto. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with water and brine, and then dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (ethyl acetate/hexane=1:1), to give 1.58 g of the title compound as a pale yellow wax.
Reaction SMILES: F[C:2]1[C:3]([O:20][C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[C:28]#[N:29])=[CH:4][C:5]([N+:17]([O-])=O)=[C:6]([NH:8][C:9]([C:11]2[CH:16]=[N:15][CH:14]=[CH:13][N:12]=2)=O)[CH:7]=1.[CH2:30]([S:32]([C:35]1[N:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1)(=[O:34])=[O:33])[CH3:31]>>[F:27][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]([C:28]#[N:29])[C:21]=1[O:20][C:3]1[C:2]([O:41][C:38]2[CH:39]=[N:40][C:35]([S:32]([CH2:30][CH3:31])(=[O:34])=[O:33])=[CH:36][CH:37]=2)=[CH:7][C:6]2[NH:8][C:9]([C:11]3[CH:16]=[N:15][CH:14]=[CH:13][N:12]=3)=[N:17][C:5]=2[CH:4]=1
Reactant: N#Cc1cccc(F)c1Oc1cc([N+](=O)[O-])c(NC(=O)c2cnccn2)cc1F
Reactant: CCS(=O)(=O)c1ccc(O)cn1
Product: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4cnccn4)nc3cc2Oc2c(F)cccc2C#N)cn1

Procedure:
The entitled compound was obtained as a white solid in the same method as in Example 400 (step 3) or in accordance with the method or by combining it with an ordinary method but using pyrazine-2-carboxylic acid (5-fluoro-4-(2-cyano-6-fluoro-phenoxy)-2-nitro-phenyl)-amide obtained in Example 400 (step 2) and 6-ethanesulfonyl-pyridin-3-ol.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH2:11]([NH:18][C:8]([C:4]1[S:3][C:2]([Br:1])=[N:6][C:5]=1[CH3:7])=[O:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: Cc1nc(Br)sc1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.2 %

Procedure:
A solution of 2-bromo-4-methyl-thiazole-5-carboxylic acid (3.00 g, 13.51 mmol) in methylene chloride (20 mL) was added benzyl amine (1.60 mL, 14.86 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (6.57 g, 14.86 mmol) and N,N-diisopropylethylamine (4.71 mL, 27.02 mmol) and the mixture was stirred under nitrogen at room temperature for 16 hr. The reaction mixture was diluted with methylene chloride (100 mL), and washed with water (100 mL) and brine (2×100 mL). The organic phase was dried (Na2SO4) and evaporated. The residue was purified by flash-chromatography (eluent hexanes-ethyl acetate, 1:1) to provide 2-bromo-4-methyl-thiazole-5-carboxylic acid benzyl amide as a yellow solid (3.50 g, 83% yield). MS (M+H)+=312; Rt=1.31 min.
Reaction SMILES: Br[C:2]1[C:3]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[CH:4][C:5]([O:8][C:9]2[C:14]3[N:15]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[S:17][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[C:3]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[CH:4][C:5]([O:8][C:9]3[C:14]4[N:15]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[S:17][C:13]=4[CH:12]=[CH:11][CH:10]=3)=[N:6][CH:7]=2)=[CH:35][CH:34]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)c(Br)cn3)cccc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)c(-c4ccc(F)cc4)cn3)cccc2s1

Procedure:
To a mixture of N-{4-[5-bromo-4-(4-trifluoromethyl-phenyl)-pyridin-2-yloxy]-benzothiazol-2-yl}-acetamide, (Example 145(b)), (51 mg, 0.1 mmol) and 4-fluorophenylboronic acid (18 mg, 0.13 mmol, Aldrich) in dioxane (1 mL) was added Pd(PPh3)4 (6 mg, 0.005 mmol, Aldrich) and aqueous Na2CO3 (16 mg in 0.2 mL of water). The reaction mixture was heated in microwave synthesizer at 1600C for 30 min. Purification by silica gel chromatography (EtOAc/hexanes) gave the title compound as a white solid. MS (ESI, pos. ion) m/z: 524 (M+1). Mp: 112.3-130.1° C.
Reaction SMILES: [N:1]#[N:2].[C:3]1([S:13]([NH:16][C@H:17]([C:25](O)=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:24])[NH2:23])(=[O:15])=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.S(=Cl)=O.P(Cl)(Cl)(Cl)=O.P(Cl)(Cl)Cl.P(Cl)(Cl)(Cl)(Cl)Cl.P(Br)(Br)Br>>[N:1]#[N:2].[C:3]1([S:13]([NH:16][C@H:17]([C:25]([NH2:1])=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:24])[NH2:23])(=[O:15])=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: N=C(N)NCCC[C@H](NS(=O)(=O)c1cccc2ccccc12)C(=O)O
Agent: BrP(Br)Br
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: N#N
Solvent: ClP(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: N=C(N)NCCC[C@H](NS(=O)(=O)c1cccc2ccccc12)C(N)=O

Procedure:
An N2 -naphthalenesulfonyl-L-argininamide is prepared by reaction of a corresponding N2 -naphthalenesulfonyl-L-arginyl halide and an amine. The N2 -naphthalenesulfonyl-L-arginyl halide is prepared by reacting a corresponding N2 -naphthalenesulfonyl-L-arginine with a halogenating agent such as thionyl chlorine, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, etc.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[C:11]3[C:12](=[O:28])[N:13]([CH3:27])[C:14]([C:23]([O:25]C)=[O:24])=[C:15]([C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=4)[C:10]=3[C:9]3[CH2:29][O:30][CH2:31][CH2:32][C:8]2=3)=[CH:4][CH:3]=1.CO.[Li+].[OH-].Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3[C:12](=[O:28])[N:13]([CH3:27])[C:14]([C:23]([OH:25])=[O:24])=[C:15]([C:16]4[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=4)[C:10]=3[C:9]3[CH2:29][O:30][CH2:31][CH2:32][C:8]2=3)=[CH:33][CH:34]=1
Reactant: COC(=O)c1c(-c2ccc(C)cc2)c2c3c(n(Cc4ccc(F)cc4)c2c(=O)n1C)CCOC3
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(C(=O)O)n(C)c(=O)c3c2c2c(n3Cc3ccc(F)cc3)CCOC2)cc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A solution of methyl 5-(4-fluorobenzyl)-7-methyl-6-oxo-9-(p-tolyl)-1,3,4,5,6,7-hexahydropyrano[3′,4′:4,5]pyrrolo[2,3-c]pyridine-8-carboxylate (0.4 g, 0.869 mmol) in Tetrahydrofuran (THF) (2.77 ml)/Methanol (2.77 ml) was treated with 2M LiOH (3.04 ml, 6.08 mmol) and heated to reflux (80° C. bath). After 18 h, the reaction mixture was cooled to ambient temperature and poured into 1M HCl. The layers were partitioned and the organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo to afford 5-(4-fluorobenzyl)-7-methyl-6-oxo-9-(p-tolyl)-1,3,4,5,6,7-hexahydropyrano[3′,4′:4,5]pyrrolo[2,3-c]pyridine-8-carboxylic acid as a beige solid. A solution of 5-(4-fluorobenzyl)-7-methyl-6-oxo-9-(p-tolyl)-1,3,4,5,6,7-hexahydropyrano[3′,4′:4,5]pyrrolo[2,3-c]pyridine-8-carboxylic acid in THF (10 mL) was treated with oxalyl chloride (0.110 ml, 1.303 mmol) and 1 drop of DMF. After 15 min, the reaction mixture was concentrated in vacuo to afford 5-(4-fluorobenzyl)-7-methyl-6-oxo-9-(p-tolyl)-1,3,4,5,6,7-hexahydropyrano[3′,4′:4,5]pyrrolo[2,3-c]pyridine-8-carbonyl chloride (375 mg, 0.807 mmol, 93% yield). An ice cold solution of 5-(4-fluorobenzyl)-7-methyl-6-oxo-9-(p-tolyl)-1,3,4,5,6,7-hexahydropyrano[3′,4′:4,5]pyrrolo[2,3-c]pyridine-8-carbonyl chloride (375 mg, 0.807 mmol, 93% yield) in 1,2-DME (10 mL) was treated with NaBH4 (0.161 g, 4.34 mmol) and then warmed to ambient temperature. After 1 h, the reaction mixture was cooled to 0° C. and quenched with MeOH (1 mL) and 1M HCl (˜20 mL). EtOAc was added and the layers were partitioned and the organic layer was washed with brine, dried (MgSO4), filtered and concentrated to afford 5-(4-fluorobenzyl)-8-(hydroxymethyl)-7-methyl-9-(p-tolyl)-3,4,5,7-tetrahydropyrano[3′,4′:4,5]pyrrolo[2,3-c]pyridin-6(1H)-one (333 mg, 0.770 mmol, 89% yield) as a white solid. The residue was used without further purification. LCMS (m/z) ES+=433 (M+1).
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]([NH:14][CH3:15])[S:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)=O.[NH2:16][OH:17]>CO>[OH:17][N:16]=[CH:1][C:3]1[N:4]=[C:5]([NH:14][CH3:15])[S:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1
Reactant: NO
Reactant: CNc1nc(C=O)c(-c2ccncc2)s1
Solvent: CO
Product: CNc1nc(C=NO)c(-c2ccncc2)s1
Reaction time: 2 h

Procedure:
A solution of 4-formyl-2-methylamino-5-(4-pyridyl)-thiazole (0.9 g) in methanol (15 ml) was added to a 1N-methanolic hydroxylamine solution (5.8 ml) at ambient temperature with stirring, which was continued under the same condition for 2 hours. The precipitate was collected by filtration and recrystallized from an aqueous tetrahydrofuran to afford 4-hydroxyiminomethyl-2-methylamino-5-(4-pyridyl)thiazole (1.02 g).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+].[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[CH:23]1[O:25][CH2:24]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>CO>[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[CH:23]([OH:25])[CH2:24][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C1CO1
Reactant: Oc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(O)COc1ccccc1
Reaction time: 16 h
Yield: 50.9 %

Procedure:
Phenol (1.50 g) and sodium methoxide (380 mg) were added to (2S)-1-(t-butoxycarbonyl)-2-(1,2-epoxyethyl)pyrrolidine (1.50 g) as obtained in Example 1-A) in methanol (30 ml ), followed by 16 hour' stirring under reflux. The reaction mixture was concentrated and the residue was dissolved in ether. The solution was washed with 1N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and saturated brine in order, and dried over magnesium sulfate, followed by concentration. The residue was purified by silica gel column chromatography (eluate: hexane-ethyl actate) to give 1.10 g of (2S)-1-(t-butoxycarbonyl)-2-(1-hydroxy-2-phenoxyethyl)-pyrrolidine.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[S:14]([CH3:17])(=[O:16])=[O:15].[OH:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[I:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([CH3:13])[C:3]([S:14]([CH3:17])(=[O:16])=[O:15])=[C:2]2[N:22]1[CH2:23][CH2:24][CH:19]([OH:18])[CH2:20][CH2:21]1
Reactant: Cc1nc2ccc(I)cc2c(Cl)c1S(C)(=O)=O
Reactant: OC1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccc(I)cc2c(N2CCC(O)CC2)c1S(C)(=O)=O
Yield: 62.1 %

Procedure:
4-Chloro-6-iodo-3-methanesulfonyl-2-methyl-quinoline (compound of example D.2) (300 mg, 0.786 mmol), 4-hydroxypiperidine (87 mg, 0.865 mmol) and N,N-diisopropyl ethyl amine (0.148 mL, 0.865 mmol) were heated in dry N,N-dimethylformamide (3 mL) for 0.5 h at 100° C. N,N-Dimethylformamide was evaporated at 40° C./0.1 mbar, and the residue directly purified by chromatography on silica gel in dichloromethane/methanol 20:1. One obtained a yellow oil which was triturated with ethyl acetate and the resulting white crystals were filtered off. One obtained 218 mg (62%) of white crystals. MS: m/z=447 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[BH4-].[Na+]>CO.CCOC(C)=O>[Cl:1][C:2]1[C:3]([CH2:4][OH:5])=[CH:6][CH:7]=[CH:8][C:9]=1[OH:10]
Reactant: O=Cc1cccc(O)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: OCc1cccc(O)c1Cl
Reaction time: 0.5 h

Procedure:
To a solution of 2-chloro-3-hydroxybenzaldehyde (8.10 g, 51.7 mmol) in MeOH was added NaBH4 (1.96 g, 51.7 mmol) at 0° C. The reaction was allowed to stir for 30 minutes. TLC showed clean conversion to a more polar spot. The reaction was diluted with EtOAc (400 mL), washed with water and brine, dried over sodium sulfate, and concentrated. The crude 2-chloro-3-(hydroxymethyl)phenol was used in Step B without further purification.