Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=O)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)([Br:15])=O>>[Br:15][C:9]1[S:10][CH:11]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1
Reactant: O=P(Br)(Br)Br
Reactant: O=c1[nH]c(-c2ccccc2)cs1
Product: Brc1nc(-c2ccccc2)cs1
Temperature: 100 °C
Yield: 73.5 %

Procedure:
A mixture of 4-phenylthiazol-2(3H)-one (300 mg, 1.7 mmol) and POBr3 (4.85 g, 17.0 mmol) was heated to 100° C. in a sealed tube for 10 h. The reaction mixture was poured in ice water and the organic product was extracted with EtOAc. The combined extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluant 1% EtOAc in petroleum ether) to get 2-bromo-4-phenylthiazole (300 mg, yield 73%) as light brown colored liquid. 1H NMR (300 MHz, CDCl3) δ 7.88-7.85 (m, 2H), 7.46-7.35 (m, 4H). MS (ESI) m/z: Calculated for C9H6BrNS: 240.94. found: 242.0 (M+H)+
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21](=[O:42])[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]3[CH:41]=[CH:40][C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]=3)=[CH:26][CH:25]=2)=[CH:15][CH:14]=1.C(O)C.[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH:21]([OH:42])[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]3[CH:41]=[CH:40][C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]=3)=[CH:26][CH:25]=2)=[CH:15][CH:14]=1
Reactant: O=C(CCc1ccc(OCc2ccc3ccccc3n2)cc1)CCc1ccc(OCc2ccc3ccccc3n2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Product: OC(CCc1ccc(OCc2ccc3ccccc3n2)cc1)CCc1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Yield: 103.7 %

Procedure:
To a solution of 1,5-bis(4-(2-quinolylmethoxy)phenyl)-3-pentanone (2.21 g, 4 mmol), prepared as in step 3, in dioxane (15 mL) and ethanol (35 mL) was added NaBH4 (152 mg, 4 mmol) and the resulting mixture was refluxed for 30 minutes. The solution was then cooled to room temperature, acidified to pH 5 with 10% citric acid and concentrated in vacuo. To the residue was added water (50 mL) and the precipitated solid was filtered to afford 1,5-bis(4-(2-quinolylmethoxy)phenyl)-3-pentanol (2.3 g).
Reaction SMILES: O[N:2]1C(=O)C2=CC=CC=C2C1=O.[CH:13]1([CH2:18][CH2:19][CH2:20][OH:21])[CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([CH2:18][CH2:19][CH2:20][O:21][NH2:2])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: OCCCC1CCCC1
Product: NOCCCC1CCCC1

Procedure:
Prepared by a similar procedure as described for preparation 31. Starting materials: N-hydroxyphthalimide and 3-cyclopentyl-1-propanol (Aldrich). 13C-NMR (CDCl3) δ 76.5, 40.0, 32.7, 32.4, 27.7, 25.2.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4](O)[CH:3]=1.O=P(Cl)(Cl)[Cl:14]>C1(C)C=CC=CC=1>[Cl:14][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=1
Reactant: O=[N+]([O-])c1cnc(O)cc1Cl
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cnc(Cl)cc1Cl
Temperature: 60 °C
Reaction time: 6 h
Yield: 73.5 %

Procedure:
The product from Step 2 (40.0 g, 229 mmol) was suspended in toluene (300 mL) and POCl3 (65 mL, 697 mmol) was added over 10 min, then the mixture was heated to relux for 6 h then cooled to 60° C. and allowed to stir overnight at that temperature. The heterogeneous mixture was cooled and concentrated, the residue was carefully made basic with aq. K2CO3 solution and extracted with EtOAc. The organic layers were combined, washed with H2O and brine, dried (Na2SO4), filtered and the filtrate was concentrated to give an oil. The crude oil was passed through a plug of silica gel (50% EtOAc in hexanes) to give the title compound (32.5 g, 74%) as an orange oil which solidified on standing. MS (ES+) m/e 194 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6]3[S:13][CH:14]=[CH:15][C:5]=3[C:4]=2[C:3]=1[C:16]1[CH:21]=[CH:20][C:19]([CH:22]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH3:23])=[CH:18][CH:17]=1.[H-].[Na+].Cl[C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36].O>C1COCC1>[CH:38]([O:37][C:35]([O:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6]3[S:13][CH:14]=[CH:15][C:5]=3[C:4]=2[C:3]=1[C:16]1[CH:21]=[CH:20][C:19]([CH:22]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH3:23])=[CH:18][CH:17]=1)=[O:36])([CH3:40])[CH3:39]
Reactant: CC(C)OC(=O)Cl
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(-c2c(O)ccc3[nH]c(=O)c4sccc4c23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)OC(=O)Oc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)NC(=O)OC(C)(C)C)cc1
Reaction time: 1 h
Yield: 49.8 %

Procedure:
To a solution of tert-butyl 1-(4-(8-hydroxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)ethylcarbamate (44 mg, 0.10 mmol) in THF (2 mL) at 0° C. was added NaH (60%, 6 mg, 0.15 mmol) and the reaction was stirred at that temperature for 1 h. Isopropyl chloroformate (21 μL, 0.15 mmol) was added and the resulting mixture was stirred at rt for 3 h. Water was added and the mixture was extracted with dichloromethane (2×15 mL). The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (heptane/ethyl acetate) to afford the desired product (26 mg, 50%) as a solid: ESI MS m/z 523 [C28H30N2O6S+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22].[CH:35]1([S:38]([NH2:41])(=[O:40])=[O:39])[CH2:37][CH2:36]1>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:41][S:38]([CH:35]3[CH2:37][CH2:36]3)(=[O:40])=[O:39])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22]
Reactant: NS(=O)(=O)C1CC1
Reactant: Cc1ccccc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(C(=O)O)cnn12
Product: Cc1ccccc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(C(=O)NS(=O)(=O)C3CC3)cnn12
Yield: 62.4 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-methylphenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.30 g, 0.66 mmol) obtained in Example 39, step 2 and cyclopropanesulfonamide (0.40 g, 3.3 mmol), the title compound (0.23 g, 63%) was obtained.
Reaction SMILES: Cl[CH2:2][O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=2)[C@@:8]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=2[O:27][CH3:28])([F:19])[C:7]1=[O:29])=[O:5].[I-:30].[Na+]>CC(C)=O>[I:30][CH2:2][O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=2)[C:8]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=2[O:27][CH3:28])([F:19])[C:7]1=[O:29])=[O:5]
Reactant: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(C(=O)OCCl)c2cc(C(F)(F)F)ccc21
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(Cl)cc1C1(F)C(=O)N(C(=O)OCI)c2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.1 %

Procedure:
To a 25 mL flask containing (S)-3-(5-chloro-2-methoxy-phenyl)-3-fluoro-2-oxo-6-trifluoromethyl-2,3-dihydro-indole-1-carboxylic acid chloromethyl ester ((S)-XII) (0.633 g, 1.40 mmol) was added 6 mL anhydrous acetone, and sodium iodide (0.314 g, 2.10 mmol). The reaction was heated to reflux and stirred for 4 hours, then the reaction was cooled to room temperature, and the solvent was evaporated in vacuo. The crude oil was dissolved in dichloromethane and washed with a 1% aq. sodium thiosulfate solution. The organic layer was separated, dried (Na2SO4) and evaporated in vacuo producing the title compound (0.640 g, 84%) which was used in subsequent reactions without purification. 1H NMR (CDCl3 400 MHz): δ=8.38 (s, 1H), 7.78 (s, 1H), 7.48 (d, 1H, J=7 Hz), 7.36 (d, 1H, J=7 Hz), 7.31 (d, 1H, J=7 Hz), 6.77 (d, 1H, J=7 Hz), 6.28 (d, 1H, J=6.4 Hz), 6.18 (d, 1H, J=6.4 Hz), 3.56 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](=[O:12])[NH:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([NH2:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:19][CH:18]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:7][CH2:8][C:9](=[O:11])[NH:30][CH:23]([C:20]2[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:22][CH:21]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:12])=[CH:13][CH:14]=1
Reactant: COc1ccc(C(N)c2ccccc2)cc1
Reactant: O=C(O)CNC(=O)c1ccc(F)cc1
Product: COc1ccc(C(NC(=O)CNC(=O)c2ccc(F)cc2)c2ccccc2)cc1

Procedure:
Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-(4-methoxy-phenyl)-C-phenyl-methylamine (CA [2538-34-3]).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]([C:15]2([C:18]3[CH:28]=[CH:27][C:21]4[O:22][C:23]([F:26])([F:25])[O:24][C:20]=4[CH:19]=3)[CH2:17][CH2:16]2)=[O:14])[N:3]=1.[OH:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[F:25][C:23]1([F:26])[O:22][C:21]2[CH:27]=[CH:28][C:18]([C:15]3([C:13]([NH:12][C:4]4[N:3]=[C:2]([C:34]5[CH:35]=[CH:36][C:31]([CH2:30][OH:29])=[CH:32][CH:33]=5)[C:11]5[C:6]([CH:5]=4)=[CH:7][CH:8]=[CH:9][CH:10]=5)=[O:14])[CH2:17][CH2:16]3)=[CH:19][C:20]=2[O:24]1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: O=C(Nc1cc2ccccc2c(Br)n1)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
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: COCCOC
Product: O=C(Nc1cc2ccccc2c(-c2ccc(CO)cc2)n1)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
N-(1-Bromoisoquinolin-3-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (45 mg, 0.10 mmol), 4-(hydroxymethyl)phenylboronic acid (23 mg, 0.15 mmol), and Pd(PPh3)4 (6 mg, 0.005 mmol) were combined in a reaction tube. DME (1 mL) and saturated Na2CO3 aqueous solution (100 μL) were added and the reaction vial was stirred under N2 atmosphere at 80° C. overnight. The mixture was filtered and concentrated. The residue was dissolved in DMSO and purified by reverse-phase HPLC to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(4-(hydroxymethyl)phenyl)isoquinolin-3-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 474.1. found 475.3 (M+1)+. Retention time 2.02 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.41 (s, 1H), 8.00-7.96 (m, 1H), 7.88-7.84 (m, 1H), 7.72 (t, J=7.1 Hz, 1H), 7.64-7.38 (m, 8H), 5.54 (s, 1H), 4.61 (s, 2H), 1.58-1.55 (m, 2H), 1.22-1.20 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=2[F:17])[N:5]=[C:4]([C:18]([OH:20])=[O:19])[C:3]=1[CH:21]=[CH2:22].I[CH2:24][CH2:25][CH2:26][CH3:27].C(=O)([O-])[O-].[Li+].[Li+]>CN(C=O)C>[CH2:24]([O:19][C:18]([C:4]1[C:3]([CH:21]=[CH2:22])=[C:2]([NH2:1])[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=2[F:17])[N:5]=1)=[O:20])[CH2:25][CH2:26][CH3:27]
Reactant: CCCCI
Reactant: C=Cc1c(N)nc(-c2ccc(Cl)c(OC)c2F)nc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=Cc1c(N)nc(-c2ccc(Cl)c(OC)c2F)nc1C(=O)OCCCC
Temperature: 60 °C
Yield: 52.7 %

Procedure:
6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-vinyl-pyrimidine-4-carboxylic acid (0.150 g, 0.46 mmol), iodobutane (0.111 g, 0.60 mmol), and lithium carbonate (0.044 g, 0.6 mmol) were combined in DMF (1.5 mL) and heated at 60° C. overnight. The cooled reaction mixture was concentrated and partitioned between ethyl acetate and water. The organic phase was dried and concentrated. The product was purified by flash chromatography on silica gel (ethyl acetate/hexane gradient) to yield the title compound (0.092 g, 52.3% yield): 1H NMR (CDCl3) δ 7.65 (dd, 1H), 7.19 (dd, 1H), 7.75 (dd, 1H), 5.62-5.67 (m, 2H), 5.35 (br s, 2H), 4.34 (t, 3H), 3.99 (dd, 3H), 1.74 (m, 2H), 1.45 (m, 2H), 0.97 (t, 3H).
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[C:1]([N:8]1[CH2:12][C@H:11]([O:13][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
To a solution of methyl (2S,4R)-1-Bochydroxypyrrolidine-2-carboxylate (8 g, 32.65 mmol) prepared in Step B in DCM was added dropwise TEA (11.99 ml, 81.56 mmol) and methanesulfonyl chloride (3.77 ml, 48.9 mmol) at m° C. After the reaction mixture was stirred at rt for 3 h, the organic extracts were washed with a saturated NaHCO3 aqueous solution, 1N HCl and brine, dried over MgSO4, filtered, and concentrated in vacuo to give the title compound (9.4 g, 90%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].C(Cl)(Cl)Cl.[CH3:40][N:41]([CH3:47])[CH:42]1[CH2:46][CH2:45][NH:44][CH2:43]1.C(N(CC)C(C)C)(C)C>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:44]3[CH2:45][CH2:46][CH:42]([N:41]([CH3:47])[CH3:40])[CH2:43]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35]
Reactant: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Reactant: CN(C)C1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(N2CCC(N(C)C)C2)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 75.8 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)-benzamide (30 mg, 0.06 mmol) in THF (1 mL)/CHCl3 (1 mL) were added N,N-dimethyl-3-pyrrolidinamine (14 mg, 0.12 mmol) and N,N-diisopropylethylamine (0.6 mL, 3.0 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (25 mg, 76%). LC-MS m/z 550 (M+H)+; 1H-NMR (MeOD) δ 1.27 (d, 6H), 1.75 (m, 1H), 2.15 (m, 1H), 2.24 (s, 6H), 2.30 (s, 3H), 2.79 (m, 1H), 3.15 (m, 2H), 3.45 (m, 1H), 3.71 (m, 1H), 4.11 (s, 2H), 4.23 (m, 1H), 7.16 (t, 2H), 7.46 (d, 1H), 7.50 (m, 1H), 7.70 (s, 1H), 7.85 (d, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]1[NH:8][S:9](=[O:18])(=[O:17])[C:10]2[CH:16]=[CH:15][S:14][C:11]=2[C:12]=1[OH:13])=[O:5])[CH3:2].[H-].[Na+].[CH3:21]I>CN(C)C=O>[CH2:1]([O:3][C:4]([CH2:6][C:7]1[N:8]([CH3:21])[S:9](=[O:17])(=[O:18])[C:10]2[CH:16]=[CH:15][S:14][C:11]=2[C:12]=1[OH:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)CC1=C(O)c2sccc2S(=O)(=O)N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1=C(O)c2sccc2S(=O)(=O)N1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.93 G. (7 mmol) of 3-ethoxycarbonylmethyl-4-hydroxy-2H-thieno[2,3-e]-1,2-thiazine 1,1-dioxide are dissolved in 4 ml. of absolute dimethylformamide and added dropwise during 30 minutes at 0° C. to a stirred suspension of 0.185 g. (7.7 mmol) of sodium hydride in 2 ml. of absolute dimethylformamide. The mixture is stirred for a further 1 hour at room temperature. There are then added firstly 0.53 ml. (1.2 g.; 8.45 mmol) of methyl iodide and, after 30 minutes, a further 0.25 ml. (0.565 g; 4 mmol) of methyl iodide and the mixture is allowed to react for 1 hour. After distillation of the solvent, the residue is taken up in 30 ml. of 0.5-N hydrochloric acid and 30 ml. of methylene chloride, the organic phase is separated and the aqueous layer is back-extracted twice with a small amount of methylene chloride. The combined organic extracts are dried over sodium sulfate and evaporated. The crystalline residue is digested with a small amount of cold ethanol. There is obtained 3-ethoxycarbonylmethyl-4-hydroxy-2-methyl-2H-thieno[2,3-e]-1,2-thiazine 1,1-dioxide of melting point 161°-163° C. (crystal transformation at 151°-152° C).
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:11]=[N:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:18][N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:3]=1.[F:28][C:29]1[C:34](B(O)O)=[CH:33][CH:32]=[CH:31][N:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>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:28][C:29]1[C:34]([C:2]2[N:6]([S:7]([C:10]3[CH:11]=[N:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=3)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:18][N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:3]=2)=[CH:33][CH:32]=[CH:31][N:30]=1
Reactant: OB(O)c1cccnc1F
Reactant: COc1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2Br)cn1
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+]
Product: COc1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2cccnc2F)cn1

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl ({5-bromo-1-[(6-methoxypyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (463 mg), (2-fluoropyridin-3-yl)boronic acid (172 mg), sodium carbonate (260 mg) and tetrakis(triphenylphosphine)palladium (176 mg), the title compound was obtained as a pale-yellow oil (yield 293 mg, 45%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:62])[NH:4][CH:5]([C:9]([N:11]1[CH:17]([C:18]2[NH:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[C:34]([C:39]6[NH:40][C:41]([CH:44]7[CH:49]8[CH2:50][CH:46]([CH2:47][CH2:48]8)[N:45]7C(=O)C(C7CC7)NC(OC)=O)=[N:42][CH:43]=6)[CH:35]=5)[CH:30]=4)=[CH:25][CH:24]=3)=[CH:21][N:22]=2)[CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:63][O:64][C:65]([CH3:76])([CH3:75])[CH:66]([NH:70][C:71]([O:73][CH3:74])=[O:72])[C:67]([OH:69])=O>>[CH3:74][O:73][C:71](=[O:72])[NH:70][CH:66]([C:67]([N:45]1[CH:44]([C:41]2[NH:40][C:39]([C:34]3[CH:33]=[CH:32][C:31]4[C:36](=[CH:37][CH:38]=[C:29]([C:26]5[CH:27]=[CH:28][C:23]([C:20]6[NH:19][C:18]([CH:17]7[CH2:16][C:13]8([CH2:14][CH2:15]8)[CH2:12][N:11]7[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:62])[CH:6]([CH3:7])[CH3:8])=[N:22][CH:21]=6)=[CH:24][CH:25]=5)[CH:30]=4)[CH:35]=3)=[CH:43][N:42]=2)[CH:49]2[CH2:50][CH:46]1[CH2:47][CH2:48]2)=[O:69])[C:65]([O:64][CH3:63])([CH3:76])[CH3:75]
Reactant: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6C7CCC(C7)N6C(=O)C(NC(=O)OC)C6CC6)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)O)C(C)(C)OC
Product: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6C7CCC(C7)N6C(=O)C(NC(=O)OC)C(C)(C)OC)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Yield: 35 %

Procedure:
This compound was prepared using the procedure used to prepare [1-(6-{5-[4-(6-{2-[2-(2-Cyclopropyl-2-methoxycarbonylamino-acetyl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (example from JJC) using 3-Methoxy-2-methoxycarbonylamino-3-methyl-butyric acid (0.020 g, 0.096 mmol) to provide [2-Methoxy-1-(3-{5-[6-(4-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.019 g, 35%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.37-7.88 (m, 4H), 7.84-7.35 (m, 8H), 5.81-5.33 (m, 2H), 4.88-4.57 (m, 2H), 4.34 (s, 1H), 3.91-3.54 (m, 9H), 3.46-3.16 (m, 4H), 3.09-2.82 (m, 1H), 2.24 (dd, 2H), 1.93 (m, 6H), 1.61 (s, 1H), 1.47-1.17 (m, 7H), 1.11 (d, 1H), 1.02-0.83 (m, 7H), 0.72 (s, 3H).
Reaction SMILES: C([O:3][C:4]([CH:6](C(OCC)=O)[C:7]([CH3:33])([CH3:32])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([CH3:31])([CH3:30])[CH:19](C(OCC)=O)[C:20]([O:22]CC)=[O:21])=[O:5])C.[OH-].[K+]>C(OCC)C>[CH3:30][C:18]([CH3:31])([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]([CH3:33])([CH3:32])[CH2:6][C:4]([OH:5])=[O:3])[CH2:19][C:20]([OH:22])=[O:21]
Reactant: CCOC(=O)C(C(=O)OCC)C(C)(C)CCCCCCCCCCC(C)(C)C(C(=O)OCC)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(C)(CCCCCCCCCCC(C)(C)CC(=O)O)CC(=O)O
Temperature: 25 °C

Procedure:
A mixture of 17.0 g of the tetra-ester of Example 1 and 300 ml of a 25% aqueous KOH solution was heated in an oil bath to reflux temperature and the mixture was refluxed until the organic phase has completely disappeared (about 48 hours). The aqueous solution was then cooled to room temperature, extracted with ether, further cooled by the addition of ice and acidified with concentrated aqueous hydrochloric acid, whereupon a solid precipitate was formed consisting of the corresponding tetracarboxylic acid. This solid precipitate was dissolved in diethyl ether and the solution dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The tetracarboxylic acid residue was decarboxylated by heating to 150°-160° C. on an oil bath until evolution of carbon dioxide was no longer observed. The crude product was cooled and recrystallized from a mixture of chloroform and petroleum ether (40°-60° C.). The pure product was obtained at a yield of 5.5 g.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]2[S:8][C:9]([CH3:11])=[CH:10][C:6]=2[CH:5]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.[C:19](=O)([O-])O.[Na+]>CO>[CH3:19][O:2][C:1]([C:4]1[CH:13]=[CH:12][C:7]2[S:8][C:9]([CH3:11])=[CH:10][C:6]=2[CH:5]=1)=[O:3]
Reactant: Cc1cc2cc(C(=O)O)ccc2s1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc2sc(C)cc2c1
Yield: 89 %

Procedure:
5-Carboxy-2-methylbenzo[b]thiophene (2.1 g, 10.9 mmol) was dispersed in methanol (50 ml), and concentrated sulfuric acid was added. The mixture was refluxed with heating for 6 hr. After cooling, a saturated aqueous solution of sodium hydrogencarbonate was added, and methanol was distilled away under reduced pressure. The residue was extracted with methyl t-butyl ether. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure to give the objective compound (2.0 g, 89%) as colorless crystals.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.CN(C)C=O.S(Cl)([Cl:20])=O>ClCCl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([Cl:20])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc2ccccc2[nH]1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc2ccccc2[nH]1

Procedure:
A mixture of indole-2-carboxylic acid (2.18 g), N,N-dimethylformamide (52 mg) and thionyl chloride (1.0 ml) in dry dichloromethane (22 ml) was refluxed for 1 hour to give a solution of 2-indolylcarbonyl chloride.