Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:10]([C:24]([NH:26][CH3:27])=[O:25])=[N:11][C:12]([C:15]3[CH:16]=[N:17][N:18]([CH2:20][CH2:21][CH2:22][OH:23])[CH:19]=3)=[CH:13][CH:14]=2)[C:5]([C:28]([F:31])([F:30])[F:29])=[CH:4][N:3]=1.[NH2:32][C:33]1[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=1[O:48][CH3:49].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O>[OH:23][CH2:22][CH2:21][CH2:20][N:18]1[CH:19]=[C:15]([C:12]2[N:11]=[C:10]([C:24](=[O:25])[NH:26][CH3:27])[C:9]([NH:8][C:6]3[C:5]([C:28]([F:31])([F:30])[F:29])=[CH:4][N:3]=[C:2]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[CH:7]=3)=[CH:14][CH:13]=2)[CH:16]=[N:17]1
Reactant: CCOP(=O)(Cc1ccc(N)c(OC)c1)OCC
Reactant: CNC(=O)c1nc(-c2cnn(CCCO)c2)ccc1Nc1cc(Cl)ncc1C(F)(F)F
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCOP(=O)(Cc1ccc(Nc2cc(Nc3ccc(-c4cnn(CCCO)c4)nc3C(=O)NC)c(C(F)(F)F)cn2)c(OC)c1)OCC
Yield: 11.2 %

Procedure:
A solution of 3-{[2-chloro-5-(trifluoromethyl)pyridin-4-yl]amino}-6-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-N-methylpyridine-2-carboxamide (Compound 36C, 158 mg, 0.35 mmol) and diethyl (4-amino-3-methoxybenzyl)phosphonate (Compound 1F, 104 mg, 0.38 mmol) in 1,4-dioxane (4.0 mL) was treated with Pd(II)(OAc)2 (3.90 mg, 0.017 mmol), Xantphos (20.1 mg, 0.035 mmol) and Cs2CO3 (226 mg, 0.70 mmol). The mixture was purged with N2 for 2 minutes, sealed and irradiated in a microwave reactor for 40 minutes at 120° C. The cooled reaction mixture was poured into water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to a brown residue which was taken purified using a Teledyne ISCO Combiflash® system (0%-5%-10% MeOH/DCM) to afford 27 mg of a brown foam (11%). 1H NMR (400 MHz, CDCl3) δ 10.91 (s, 1H), 8.38 (s, 1H), 8.23 (q, J=5.6 Hz, 1H), 7.98 (s, 1H), 7.98 (s, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.76 (d, J=7.8 Hz, 1H), 7.51 (d, J=8.6 Hz, 1H), 6.86-6.94 (m, 3H), 6.70 (s, 1H), 4.38 (t, J=6.3 Hz, 2H), 3.93-4.05 (m, 4H), 3.88 (s, 3H), 3.66 (q, J=5.5 Hz, 2H), 3.12 (d, J=21.2 Hz, 2H), 3.06 (d, J=5.1 Hz, 3H), 2.79 (t, J=5.2 Hz, 1H), 2.13 (quin, J=6.1 Hz, 2H), 1.21 (t, J=7.0 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:3]=1.[N+:17]([O-])([OH:19])=[O:18].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[C:5]([OH:8])=[C:6]([N+:17]([O-:19])=[O:18])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1ccc(Cl)cc1CCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(Cl)cc(CCc2ccccn2)c1O
Reaction time: 2.5 h
Yield: 82.1 %

Procedure:
To a solution of 12.5 g (54.56 mmol) 4-chloro-2-[2-(pyridin-2-yl)ethyl]phenol in 80 ml acetic acid is added portionwise to a nitrating mixture of 70% nitric acid (8.59 g, 136.39 mmol) in 20 ml acetic acid at 5-10° C. The reaction mixture is left to stir at this temperature for 2.5 hours. The pH of the reaction mixture is then adjusted to pH 5.5-6.0 (pH meter) by the addition of a saturated solution of sodium carbonate. The resulting reaction mixture is then extracted with EtOAc (3×300 ml). Concentration of the organic extracts in vacuo yielded a brown oil. This oil is purified by flash chromatography (SiO2, 30% EtOAc in hexane) to give the title compound as a yellow solid, (12.48 g, 82%), m.p. 97-100° C. δH (250 MHz, CDCl3), 11.1 (bs, 1H), 8.57-8.55 (m, 1H), 7.94 (d, J=2.6 Hz, 1H), 7.60 (dt, J=7.7,1.7 Hz, 1H), 7.35 (d, J=2.5 Hz, 1H), 7.17-7.11 (m, 2H), 3.21-3.08 (m, 4H).
Reaction SMILES: [CH3:1][C@@H:2]([OH:5])[CH2:3][CH3:4].[H-].[Na+].F[C:9]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][C:10]=1[C:11]#[N:12]>CN(C=O)C>[CH:17]([C:14]1[CH:15]=[CH:16][C:9]([O:5][C@H:2]([CH3:1])[CH2:3][CH3:4])=[C:10]([CH:13]=1)[C:11]#[N:12])=[O:18]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: CC[C@@H](C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@@H](C)Oc1ccc(C=O)cc1C#N
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 11.7 %

Procedure:
(2R)-2-Butanol (0.99 g, 0.013 mol) was dissolved in DMF (50 ml) and the solution cooled to 0° C. To this was added sodium hydride, 60% dispersion in mineral oil (1.54 g, 0.036 mol) in a portion-wise manner, the mixture was stirred at 0° C. for 10 minutes after complete addition. 2-Fluoro-5-formylbenzonitrile (2.0 g, 0.013 mol) was then added and the reaction mixture allowed to warm to room temperature (slowly within the ice bath) and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then cooled to 0° C., quenched with brine and diluted with EtOAc (˜25 ml). The mixture was partitioned and the organic fraction extracted with water (˜30 ml), the combined organics were dried by passing through a phase separating cartridge and evaporated to dryness under reduced pressure to give the crude product. The crude residue was purified on a 40+M Biotage cartridge, eluting with a 20 to 50% mixture of EtOAc in hexane. This gave the title compound (310 mg) as a yellow oil. δH (d6-DMSO, 400 MHz): 9.88 (1H, s), 8.30 (1H, s), 8.15 (1H, d), 7.49 (1H, d), 4.73-4.81 (1H, m), 1.63-1.79 (2H, m), 1.33 (3H, d), 0.95 (3H, t).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:10]([CH3:12])([CH3:11])[S:9][CH2:8][CH2:7][N:6]1[S:13]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[O:4].[CH2:23]([O:30][CH:31](O)[C:32]#[C:33][CH3:34])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([O:30][CH2:31][C:32]#[C:33][CH2:34][O:22][C:19]1[CH:18]=[CH:17][C:16]([S:13]([N:6]2[CH2:7][CH2:8][S:9][C:10]([CH3:12])([CH3:11])[CH:5]2[C:3]([O:2][CH3:1])=[O:4])(=[O:15])=[O:14])=[CH:21][CH:20]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC#CC(O)OCc1ccccc1
Reactant: COC(=O)C1N(S(=O)(=O)c2ccc(O)cc2)CCSC1(C)C
Product: COC(=O)C1N(S(=O)(=O)c2ccc(OCC#CCOCc3ccccc3)cc2)CCSC1(C)C
Yield: 42 %

Procedure:
According to the procedure of Step 4 of Example 243, Mitsunobu coupling of 0.345 g (1.0 mmol) of 4-(4-hydroxy-benzenesulfonyl}2,2-dimethyl-thiomorpholine3-carboxylic acid methyl ester and 0.211 g (1.2 mmol) of -(benzyloxy)-2-butyn-1-ol provided 0.211 g (42%) of methyl 4-[(4-{[(benzyloxy)-2-butynyl]oxy)phenyl}-sulfonyl]-2,2-dimethyl-3- thiomorpholine carboxylate as a pale yellow oil. Electrospray Mass Spec: 504.2 (M+H)+
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[Br:5][C:6]1[N:7]=[C:8]([C:15]([C:17]2[CH:18]=[CH:19][C:20]3[N:25]=[C:24]([CH3:26])[O:23][C:22](=O)[C:21]=3[CH:28]=2)=[O:16])[N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=12.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[Br:5][C:6]1[N:7]=[C:8]([C:15]([C:17]2[CH:28]=[C:21]3[C:20](=[CH:19][CH:18]=2)[N:25]=[C:24]([CH3:26])[N:4]([CH2:1][CH2:2][CH3:3])[C:22]3=[O:23])=[O:16])[N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=12
Reactant: Cc1nc2ccc(C(=O)c3nc(Br)c4ccccn34)cc2c(=O)o1
Reactant: CCCN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCn1c(C)nc2ccc(C(=O)c3nc(Br)c4ccccn34)cc2c1=O
Temperature: 160 °C
Yield: 71.6 %

Procedure:
1.32 g (22.4 mmol) of n-propylamine are added, at 0° C. under an inert atmosphere, to 0.9 g (2.2 mmol) of 6-[(1-bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]-2-methyl-4H-3,1-benzoxazin-4-one in 15 ml of glacial acetic acid. The reaction medium is microwave-heated for 45 minutes at 160° C. The reaction medium is concentrated under reduced pressure. The residue obtained is taken up with a saturated aqueous solution of sodium carbonate. The precipitate obtained is filtered off and then dried under reduced pressure at 50° C. overnight. 0.67 g of a yellow solid is obtained.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:24][C:25]1[O:29][C:28]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[S:37][CH:38]=[CH:39][CH:40]=3)=[CH:32][CH:31]=2)=[N:27][C:26]=1[CH2:41][CH2:42]OS(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>C(O)C>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][C:5]([CH3:14])([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:42][CH2:41][C:26]2[N:27]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([C:36]4[S:37][CH:38]=[CH:39][CH:40]=4)=[CH:32][CH:31]=3)[O:29][C:25]=2[CH3:24])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:23]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4cccs4)cc3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: Cc1oc(-c2ccc(-c3cccs3)cc2)nc1CCOc1ccc(CC(C)(Oc2ccccc2F)C(=O)O)cc1

Procedure:
A mixture of 2-(2-fluoro-phenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethyl ester (0.030 mmol), toluene-4-sulfonic acid 2-(5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl)ethyl ester (0.030 mmol) (see Ex. 3, Part B) and 325 mesh K2CO3 (0.084 g, 0.60 mmol) in ethanol (2 mL) was heated to reflux for 24 h under N2. Aqueous 5N NaOH (0.5 mL) and additional ethanol (1 mL) was added to the reaction mixture and it was heated at reflux for an additional 2 h. The reaction was cooled and the solvent removed in vacuo. The residue was acidified with aqueous 1 N HCl (5 mL), extracted with water and CH2Cl2 and the organic layer dried by passing it through a Varian Chem Elut 1003 cartridge. The solvent was removed in vacuo to give 2-(2-fluoro-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionic acid. 1H NMR (400 MHz, CDCl3) δ 7.96 (d, 2H, J=8.60 Hz), 7.38 (d, 2H, J=3.52 Hz), 7.33 (d, 2H, J=3.52 Hz), 7.23 (d, 2H, J=8.60 Hz), 7.10 (dd, 2H, J=5.08 Hz, 3.52 Hz), 7.08–7.04 (m, 1H), 7.00–6.96 (m, 2H), 6.82 (d, 2H, J=8.60 Hz), 4.19 (t, 2H, J=6.65 Hz), 3.26 (d, 1H, J=14.08 Hz), 3.20 (d, 1H, J=14.08 Hz), 3.01 (t, 2H, J=6.65 Hz), 2.38 (s, 3H), 1.43 (s, 3H). MS (ES+) m/z mass calcd for C32H28FNO5S 558.17, number found 558.2.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Br:26])=[CH:4][N:3]=1.[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Br:26][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)=[C:7]2[N:8]=[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: Nc1ncc(Br)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Reactant: O=Cc1ccccc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(CN1CCN(c2c(Br)cnc3[nH]c(-c4ccccc4)nc23)CC1)Nc1nccs1
Temperature: 80 °C
Reaction time: 16 h
Yield: 60.2 %

Procedure:
To a mixture 2-[4-(2-amino-5-bromo-3-nitro-pyridin-4-yl)-piperazin-1-yl]-N-thiazol-2-yl-acetamide (0.05 g, 0.11 mmol) and ethanol (3 ml) was added benzaldehyde (15 μL, 0.29 mmol) and a freshly prepared aqueous solution of Na2S2O4 (1M; 450 μL, 0.45 mmol). The reaction mixture was stirred at 80° C. for 16 h then more benzaldehyde (15 μL, 0.29 mmol) and 1M aq. Na2S2O4 (450 μL, 0.45 mmol) were added. The reaction mixture was stirred at 80° C. for another 16 h then concentrated in vacuo. The crude product was purified by chromatography on silica gel (100% dichloromethane to dichloromethane/ethyl acetate 6:4 to dichloromethane/ethyl acetate 1:1+0.5% methanol) to give the title compound as a pale yellow solid (0.033 g, 58%); 1H-NMR (500 MHz, DMSO-d6) 2.80 (broad s, 4H, piperazine N(CH2)2), 3.42 (s, 2H, CH2), 3.72 (broad s, 4H, piperazine N(CH2)2), 7.24 (d, 1H, J=3.4 Hz, thiazole 4-H or 5-H), 7.49 (d, 1H, J=3.4 Hz, Thiazole 4-H or 5-H), 7.54 (m, 3H, Ar—H), 8.20 (dd, 2H, J=1.5, 8.0 Hz, 2,6-Ar—H), 8.25 (s, 1H, imidazo[4,5-b]pyrazine 5-H), 11.92 (broad s, 1H, NHCO), 13.54 (broad s, 1H, imidazo[4,5-b]pyrazine NH); LC-MS (ESI, m/z) Rt=5.89 min—498/500 [(M+H+), Br isotopic pattern, 100%]; ESI-HRMS: Found: 498.0716, calculated for C21H21BrN7OS (M+H+): 498.0712.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[CH:10][C:11](B4OC(C)(C)C(C)(C)O4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.Br[C:32]1[CH:36]=[N:35][N:34]([CH3:37])[N:33]=1.C([O-])([O-])=O.[Na+].[Na+].N#N>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.C(Cl)Cl.COCCOC>[CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[CH:10][C:11]([C:32]4[CH:36]=[N:35][N:34]([CH3:37])[N:33]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1
Reactant: Cn1ncc(Br)n1
Reactant: C[C@@H](Oc1cc(B2OC(C)(C)C(C)(C)O2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: C[C@@H](Oc1cc(-c2cnn(C)n2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Temperature: 140 °C
Yield: 76.4 %

Procedure:
To a microwave tube equipped with a stifling bar, (R)-4-((R)-1-((1-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one: (120 mg, 0.292 mmol), 4-bromo-2-methyl-2H-1,2,3-triazole (94.5 mg, 0.584 mmol), 1,2-dimethoxyethane (3 mL), 1 N Na2CO3 aqueous solution (0.96 mL, 0.96 mmol) were added, the mixture was bubbled N2 for 5 minutes before Pd(PPh3)4 (33.7 mg, 0.029 mmol) was added. The tube was sealed and heated in microwave at 140° C. for 15 minutes. DCM (200 mL) was added and the resulting mixture was washed with saturated NaHCO3 aqueous solution (20 mL×4), brine (20 mL×1), dried over anhydrous Na2SO4, filtered, removed solvents in vacuo. The resulting residue was passed a ISCO silica gel column (MeOH:DCM=5:95) to give off-white solids, 81.7 mg (yield 76.4%). 1H NMR (300 MHz, DMSO-d6) δ 8.25 (s, 1H), 8.11 (broad s, 1H), 7.66 (s, 1H), 7.60 (broad s, 1H), 7.27 (s, 1H), 4.80 (p, J=6.0 Hz, 1H), 4.18 (s, 3H), 3.79-3.60 (m, 1H), 3.46-3.35 (m, 1H), 3.24-3.14 (m, 1H), 2.92-2.72 (m, 1H), 2.50-2.19 (m, 2H), 1.32 (d, J=6.0 Hz, 3H), 1.14-1.05 (m, 2H), 1.05-0.96 (m, 2H) ppm; MS (ESI+) m/z 367 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]([CH:12]=O)=[CH:5][CH:4]=1.[S:14]1[CH2:20][C:18](=[O:19])[NH:17][C:15]1=[S:16].C(O)(=O)C.C([O-])(=O)C.[Na+]>O>[C:8]([C:7]1[CH:11]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[CH:12]=[C:20]1[S:14][C:15](=[S:16])[NH:17][C:18]1=[O:19])([OH:10])=[O:9]
Reactant: O=C1CSC(=S)N1
Reactant: COc1ccc(C=O)c(C(=O)O)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(C=C2SC(=S)NC2=O)c(C(=O)O)c1

Procedure:
To a hot stirred solution of 0.90 g. (5.0 mM) of 5-methoxyphthalaldehydic acid and 0.67 g. (5.0 mM) of rhodanine in 4 ml. of acetic acid is added 1.35 g. (16.4 mM) of anhydrous sodium acetate. After refluxing 0.5 hour, the solid yellow mass is cooled, poured into water, and filtered to separate 5-(2-carboxy-4-methoxybenzylidene)rhodanine as a yellow solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[N:12][C:11]([N:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])C(OC(C)(C)C)=O)=[CH:10][N:9]=1)(=O)=O.[CH3:29][S-:30].[Na+].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH3:29][S:30][CH2:6][CH2:7][C:8]1[N:9]=[CH:10][C:11]([NH:14][C:22](=[O:23])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[N:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cnc(CCOS(C)(=O)=O)cn1
Reactant: C[S-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSCCc1cnc(NC(=O)OC(C)(C)C)cn1
Temperature: 85 °C
Reaction time: 3 h
Yield: 84.4 %

Procedure:
To 2-(5-(bis(tert-butoxycarbonyl)amino)pyrazin-2-yl)ethyl methanesulfonate (540 mg, 1.293 mmol) in DMF (7 mL) was added sodium thiomethoxide (408 mg, 5.82 mmol) and was stirred at 85° C. for 3 h, followed by LCMS. The reaction was let cool, 200 mL of ethyl acetate and saturated sodium bicarbonate was added. The organic layer was extracted and washed water (3×), saturated salt solution, dried sodium sulfate, filtered through 2 cm silica gel plug and flushed with ethyl acetate. The solvent was concentrated off to constant mass to give 294 mg of the desired product as free base used as is, (84% yield). LCMS (m/z): 270.4 (MH+), 0.84 min. 1H NMR (400 MHz, CDCl3) δ ppm 9.19 (s, 1H), 8.08 (d, J=1.2 Hz, 1H), 7.20 (br. s., 1H), 2.99-3.08 (m, 2H), 2.79-2.94 (m, 2H), 2.12 (s, 3H), 1.54 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5](Br)=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[CH2:7]2.[O:14]1[C:18]2([CH2:23][CH2:22][C:21](B3OC(C)(C)C(C)(C)O3)=[CH:20][CH2:19]2)[O:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].ClCCl>O1CCOCC1.O.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]2[CH2:22][CH2:23][C:18]3([O:17][CH2:16][CH2:15][O:14]3)[CH2:19][CH:20]=2)=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[CH2:7]2
Reactant: CN1Cc2c(Br)ccc(N)c2C1=O
Reactant: CC1(C)OB(C2=CCC3(CC2)OCCO3)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CN1Cc2c(C3=CCC4(CC3)OCCO4)ccc(N)c2C1=O

Procedure:
A mixture of 7-amino-4-bromo-2-methyl-2,3-dihydro-1H-isoindol-1-one (1.7 g, 7.0 mmol), 1,4-dioxa-spiro[4,5]dec-7-en-8-boronic acid pinacol ester (2.2 g, 8.5 mmol) (preparation: WO 2007/141517), potassium carbonate (2.9 g, 21 mmol) and [1,1-bis(diphenylphosphino)ferrocene] dichloropalladium(II), complex with dichloromethane (1:1) (0.57 g, 0.69 mmol) in 1,4-dioxane (40 mL) and H2O (10 mL) was evacuated and refilled with nitrogen (3×) and irradiated in the microwave at 100° C. for 30 min. The reaction mixture was partitioned between EtOAc and brine and separated. The aqueous layer was extracted with EtOAc (3×) and the combined organic fractions were dried over sodium sulfate, filtered, and concentrated. The compound was purified on an Isco Combiflash eluting with 30 to 100% EtOAc in heptane to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 7.14 (d, J=8.34 Hz, 1H), 6.55 (d, J=8.59 Hz, 1H), 6.08 (s, 2H), 5.60-5.66 (m, 1H), 4.39 (s, 2H), 3.91 (s, 4H), 2.98 (s, 3H), 2.50 (td, J=1.86, 3.60 Hz, 1H), 2.42-2.48 (m, 2H), 2.31-2.37 (m, 2H), 1.77 (t, J=6.44 Hz, 2H); MS (ES+): m/z: 302.1621 [MH+]. HPLC: tR=1.21 min (UPLC TOF MS: polar—3 min).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:31]([CH3:33])[CH3:32])[N:11](/[CH:20]=[CH:21]/[C@@H:22]([OH:30])[CH2:23][C@@H:24]([OH:29])[CH2:25][C:26]([OH:28])=[O:27])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(O)C.C(=O)([O-])O.[Na+:41]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:31]([CH3:33])[CH3:32])[N:11](/[CH:20]=[CH:21]/[C@@H:22]([OH:30])[CH2:23][C@@H:24]([OH:29])[CH2:25][C:26]([O-:28])=[O:27])[C:12]=2[C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)=[CH:4][CH:3]=1.[Na+:41]
Reactant: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1/C=C/[C@@H](O)C[C@@H](O)CC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1/C=C/[C@@H](O)C[C@@H](O)CC(=O)[O-]
Temperature: 25 °C
Yield: 104.5 %

Procedure:
A suspension of (3R,5S,E)-7-[4,5-bis-(4-fluorophenyl)-2-(1-methylethyl)-1H-imidazol-1-yl]-3,5-dihydroxy-6-heptenoic acid (200 mg) in sodium hydrogen carbonate (36.8 mg) and water (80 ml) was stirred at room temperature. After 19 h ethanol (20 ml) was added and the resulting clear solution stirred at room temperature. After 15 min the mixture was evaporated to dryness, the residue was dissolved in water (50 ml), filtered and then freeze dried to give the title compound (219 mg) as a white fluffy solid, [α]D +22.6° (C 0.53, H2O), δ(D2O) 1.20-1.55, 1.55-1.78 (m, 2H, CH(OH)CH2CH(OH)), 1.33 (d, J 7 Hz, 6H, CH(CH3)2), 2.26 (d, J 7 Hz, 2H, CH2CO2Na), 3.28 (septet, J 7 Hz, 1H, --CH(CH3)2, 3.67 (m, 1H, =CHCH(OH)CH2CH(OH)). 4.35 (m, 1H, CH=CHCH(OH)), 5.49 (dd, J 14 Hz and 7 Hz, 1H, NCH=CH), 6.72 (d, J 14 Hz, 1H, NCH=CH), 6.97 (t, 9 Hz, 2H, C-3 and C-5 protons of 4-fluorophenyl), 6.90-7.40 (m, 6H, aromatics).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@@H:13]([O:16][C@@H:17]([CH2:19][CH2:20][CH:21]=[CH2:22])[CH3:18])[CH2:14][CH3:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[OH:24][C@H:25]1[CH2:29][NH:28][C@H:27]([C:30]([O:32][CH3:33])=[O:31])[CH2:26]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@@H:13]([O:16][C@@H:17]([CH2:19][CH2:20][CH:21]=[CH2:22])[CH3:18])[CH2:14][CH3:15])[C:10]([N:28]1[CH2:29][C@H:25]([OH:24])[CH2:26][C@H:27]1[C:30]([O:32][CH3:33])=[O:31])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Reactant: C=CCC[C@@H](C)O[C@@H](CC)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCC[C@@H](C)O[C@@H](CC)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a round-bottom flask equipped with a stir bar was added (2S,3S)-2-((tert-butoxycarbonyl)amino)-3-(pent-4-en-1-yloxy)pentanoic acid (all material from step 1, 438 mg, 1.39 mmol), (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate-HCl salt (277 mg, 1.53 mmol), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (“HATU”, 528 mg, 1.39 mmol), and CH2Cl2 (10 mL). To the mixture was added N,N-diisopropylethylamine (0.728 mL, 4.17 mmol). The mixture was stirred at room temperature for 16 h. The reaction mixture was transferred to a separatory funnel and was thrice washed with aq. 1N HCl; then brine. The organic phase was dried over MgSO4; filtered; then concentrated in vacuo to afford (2S,4R)-methyl 1-((2S,3S)-2-((tert-butoxycarbonyl)amino)-3-((R)-hex-5-en-2-yloxy)pentanoyl)-4-hydroxypyrrolidine-2-carboxylate as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]2[CH3:21])[C:5]2[CH:10]([CH3:11])[S:9](=[O:13])(=[O:12])[CH:8]([CH3:14])[C:6]=2[N:7]=1.[CH:22]1([NH:25][C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=2)=[O:27])[CH2:24][CH2:23]1>>[CH:22]1([NH:25][C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([C:2]3[N:3]=[C:4]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]4[CH3:21])[C:5]4[CH:10]([CH3:11])[S:9](=[O:13])(=[O:12])[CH:8]([CH3:14])[C:6]=4[N:7]=3)=[CH:31][CH:30]=2)=[O:27])[CH2:24][CH2:23]1
Reactant: CC1c2nc(Cl)nc(N3CCOC[C@@H]3C)c2C(C)S1(=O)=O
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2)OC1(C)C
Product: CC1c2nc(-c3ccc(NC(=O)NC4CC4)cc3)nc(N3CCOC[C@@H]3C)c2C(C)S1(=O)=O

Procedure:
The title compound was synthesised following the procedure in Example 5 (step viii) using 2-chloro-5,7-dimethyl-4-((S)-3-methylmorpholino)-5,7-dihydrothieno[3,4-d]pyrimidine 6,6-dioxide and 1-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]=[C:16]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4C)[C:17]4[CH2:22][N:21]([CH3:23])[CH2:20][C:18]=4[N:19]=3)=[C:10]([F:31])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.ClC1N=C(N2CCOCC2)C2CN(C)CC=2N=1>>[CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]=[C:16]([N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)[C:17]4[CH2:22][N:21]([CH3:23])[CH2:20][C:18]=4[N:19]=3)=[C:10]([F:31])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CN(C)C2
Agent: CN1Cc2nc(Cl)nc(N3CCOCC3)c2C1
Product: CN1Cc2nc(-c3ccc(NC(=O)NC4CC4)cc3F)nc(N3CCOCC3)c2C1
Yield: 31 %

Procedure:
Method as described for (S)-1-cyclopropyl-3-(3-fluoro-4-(6-methyl-4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (example 147) using 4-(2-chloro-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)morpholine (intermediate 21). Residue was then purified by preparative HPLC at high pH to afford a yellow solid (31% yield).