Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[C:19]([O:23][C:24]([NH:26][NH2:27])=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:27][NH:26][C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])=[O:14]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: CC(C)(C)OC(=O)NNC(=O)c1ccncc1Nc1ccc(I)cc1F

Procedure:
tert-butyl 2-{3-[(2-fluoro-4-iodophenyl)amino]isonicotinoyl}hydrazine-carboxylate was synthesized according to the procedure for General Method 1, outlined above, starting with 3 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 5 mmol of hydrazinecarboxylic acid tert-butylester. LC/MS [9.37 min; 473 (M+1)]
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([Cl:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].[C-:13]#[N:14].[K+]>CN(C=O)C.O>[Cl:12][C:4]1[C:3]([CH2:2][C:13]#[N:14])=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: [C-]#N
Reactant: O=C(O)c1cccc(CBr)c1Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1cccc(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(bromomethyl)-2-chlorobenzoic acid (6.39 g) in DMF (75 mL) was treated with a solution of potassium cyanide (3.34 g) in water (25 mL) and the resulting solution was stirred at room temperature overnight. The mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were discarded, whilst the aqueous phase was carefully acidified with concentrated hydrochloric acid (25 mL), venting any liberated HCN through a bleach solution via a stream of nitrogen. After being stirred for 2 hours, the aqueous phase was extracted twice more with ethyl acetate. The combined organic phases were washed three times with water, once with brine, then dried over anhydrous magnesium sulphate and concentrated in vacuo to afford the crude subtitled compound as a pale brown solid. Yield 4.12 g.
Reaction SMILES: [O:1]1[CH2:18][CH:2]1[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[C:11]([S:13](=[O:16])(=[O:15])[NH2:14])[O:10][C:9]=2[CH:17]=1.[CH3:19][OH:20]>S(=O)(=O)(O)O>[CH3:19][O:20][CH2:18][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[C:11]([S:13](=[O:15])(=[O:16])[NH2:14])[O:10][C:9]=2[CH:17]=1
Reactant: NS(=O)(=O)c1cc2ccc(OCC3CO3)cc2o1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COCC(O)COc1ccc2cc(S(N)(=O)=O)oc2c1
Reaction time: 18 h

Procedure:
One drop of concentrated sulfuric acid is added to a solution of 6-[2,3-epoxypropoxy]-2-sulfamoylbenzo[b]furan (7.0 mmol) in methanol (25 ml). After 18 hours, the methanol is removed under vacuum. The residue is dissolved in ethyl acetate (200 ml), washed with water (2×25 ml), brine (2×25 ml) and dried (Na2SO4). The ethyl acetate is removed under vacuum. The white solid remaining is recrystallized from boiling ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH:11]([C:14]1[N:15]=[C:16]([C:19](O)=[O:20])[S:17][CH:18]=1)([CH3:13])[CH3:12]>>[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[NH:1][C:19]([C:16]1[S:17][CH:18]=[C:14]([CH:11]([CH3:13])[CH3:12])[N:15]=1)=[O:20])(=[O:5])[NH2:6]
Reactant: CC(C)c1csc(C(=O)O)n1
Reactant: NC(=O)c1ccccc1N
Product: CC(C)c1csc(C(=O)Nc2ccccc2C(N)=O)n1
Yield: 56.8 %

Procedure:
2-Aminobenzamide (2.04 g, 15 mmol) was reacted with 4-isopropylthiazole-2-carboxylic acid (2.5 g, 14.6 mmol) as described in example 47 which gave the title compound (2.4 g, 56%).
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.C(S)CC.[CH:10]1([O:15][C:16]2[CH:17]=[C:18]([C@@H:24]([C:48]3[CH:53]=[CH:52][C:51]([CH2:54][CH:55]4[O:59][CH2:58][CH2:57][O:56]4)=[CH:50][CH:49]=3)[CH:25]([C:42]3[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=3)C(N3[C@H]4CC5C(C)(C)[C@@]4(CC5)CS3(=O)=O)=O)[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[CH2:14][CH2:13][CH2:12][CH2:11]1.[OH-].[Na+].Cl>C1COCC1>[CH2:1]([O:59][CH:55]([O:56][CH2:57][CH3:58])[CH2:54][C:51]1[CH:52]=[CH:53][C:48]([C@H:24]([C:18]2[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:16]([O:15][CH:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH:17]=2)[CH2:25][C:42]2[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=2)=[CH:49][CH:50]=1)[CH3:2]
Reactant: [Li]CCCC
Reactant: COc1ccc([C@@H](c2ccc(CC3OCCO3)cc2)C(C(=O)N2[C@H]3CC4CC[C@@]3(CS2(=O)=O)C4(C)C)c2ccncc2)cc1OC1CCCC1
Agent: CCCS
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(Cc1ccc([C@@H](Cc2ccncc2)c2ccc(OC)c(OC3CCCC3)c2)cc1)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.7 %

Procedure:
n-Butyllithium (2.4M solution in hexane; 13.2 mL, 31.3 mmol) was added dropwise to a solution of 1-propanethiol (3.47 mL, 38.3 mmol) in THF (160 mL) at 0° C. After 30 min, (1R,5S)-N-{(3R)-3-(3-cyclopentyloxy-4-methoxyphenyl)-3-[4-(1,3-dioxolan-2-ylmethyl)phenyl]-2-(4-pyridyl)propanoyl}-10,10-dimethyl-3-thia-4-azatricyclo[5.2.1.01,5 ]decane-3,3-dioxide from Step 3 (12.2 g, 17.4 mmol) was added as a solid and the reaction mixture was stirred at room temperature for 2.5 h. The volatiles were then evaporated and the resulting residue was dissolved in EtOH (100 mL) and water (50 mL). Sodium hydroxide (5.57 g, 139 mmol) was added and the mixture heated to reflux for 2.5 h. The reaction mixture was cooled to room temperature and treated with 6N HCl to pH 4.5 then heated to reflux for 2 h. The reaction mixture was cooled to room temperature and treated with 1N NaOH to pH 14, then extracted with EtOAc (3×). The combined organics were washed successively with 25% aqueous NH4OAc buffer, water and brine, dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica (acetone/ether 1:9→1:4→1:3) to afford the title compound as an off-white gum (1.17 g, 14%).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C@H:7]([NH2:10])[CH2:8][OH:9])=[CH:3][CH:2]=1.C(=O)C1C=CC([O:18]C)=CC=1.O1CCCC1.ClC1C=C(C=CC=1)C(OO)=O>C(OC)(C)(C)C>[OH:18][NH:10][C@@H:7]([C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)[CH2:8][OH:9]
Reactant: N[C@H](CO)c1ccccc1
Reactant: COc1ccc(C=O)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: OC[C@@H](NO)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of (S)-phenylglycinol (15 g) and p-anisaldehyde (16.4 g) in methyl tert-butyl ether (150 mL) was heated to reflux, with a Dean-Stark trap attached, for about 3 hours. Tetrahydrofuran (60 mL) was added and the mixture cooled to 0° C. To this was added a solution of m-chloroperoxybenzoic acid (29.8 g) in methyl tert-butyl ether (80 mL), maintaining the temperature below 5° C. The mixture was stirred at 0° C. for about 3 hours. Then the reaction mixture was washed with 10% aqueous potassium carbonate (3×75 mL). The resulting organic layer was concentrated to a smaller volume. To this was added a solution of hydroxylamine hydrochloride (15.3 g) in methanol (19 mL) and water (27 mL), and the reaction was stirred at room temperature for about 3 hours. Heptane (30 mL) and water (30 mL) were added. The layers were separated, and the aqueous layer was washed with methyl tert-butyl ether (3×30 mL). The methanol was removed by vacuum distillation, and then methyl tert-butyl ether (75 ml) was added. After adjusting the pH to 7 with solid potassium carbonate, sodium chloride was added and the layers separated. The aqueous layer was further extracted with methyl tert-butyl ether (2×75 mL). The combined methyl tert-butyl ether extracts were filtered, concentrated to a small volume, and then heptane (70 mL) was added. The resulting slurry was stirred at room temperature for about 1 hour and then cooled to 0° C. After stirring for 1 hour, the mixture is filtered and the wetcake washed with heptane (20 mL). The wetcake was then dissolved in dichloromethane (100 mL) for use in the next step. 1H NMR (400 MHz, CDCl3) δ 3.83–3.91 (2H, m), 4.12 (1H, dd, J=6.9, 4.8 Hz), 4.84 (3H, br s), 7.27–7.36 (5H, m). 13C NMR (100 MHz, CDCl3) δ 63.8, 67.7, 127.5, 127.9, 128.4, 137.5.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:8][CH2:9][C:10]2[N:11]([CH3:27])[CH:12]=[C:13]([C:15](=[O:26])[CH2:16][CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:14]=2)[CH2:6][O:5]C(=O)[NH:3]1.O1CCCC1.CO.[OH-].[K+]>O>[NH2:3][C@:2]([CH3:1])([CH2:8][CH2:9][C:10]1[N:11]([CH3:27])[CH:12]=[C:13]([C:15](=[O:26])[CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:14]=1)[CH2:6][OH:5]
Reactant: Cn1cc(C(=O)CCCCc2ccccc2)cc1CC[C@]1(C)COC(=O)N1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(C(=O)CCCCc2ccccc2)cc1CC[C@@](C)(N)CO
Yield: 87.6 %

Procedure:
To a solution of (4R)-4-methyl-4-{2-[1-methyl-4-(5-phenylpentanoyl)pyrrol-2-yl]ethyl}-1,3-oxazolidin-2-one (11 mg, 0.03 mmol) obtained in Example (38a) in a mixed solvent of tetrahydrofuran (1 ml) and methanol (1 ml) was added a 5N aqueous potassium hydroxide solution (1 ml), and the resulting mixture was refluxed for 2 days. After cooling, water was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo to afford the crude product of (2R)-2-amino-2-methyl-4-[1-methyl-4-(5-phenylpentanoyl)pyrrol-2-yl]butan-1-ol (9 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:31])[CH2:25][C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[CH3:32][N:33]([CH3:46])[CH2:34][CH2:35][CH2:36][NH:37][C:38]1[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][C:39]=1[F:45]>CC(O)C.Cl>[CH3:46][N:33]([CH3:32])[CH2:34][CH2:35][CH2:36][NH:37][C:38]1[CH:43]=[CH:42][C:41]([NH:44][C:2]2[N:7]=[C:6]([C:8]3[C:9]([C:17]4[CH:18]=[C:19]([NH:23][C:24](=[O:31])[CH2:25][C:26]5[S:27][CH:28]=[CH:29][CH:30]=5)[CH:20]=[CH:21][CH:22]=4)=[N:10][N:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=34)[CH:5]=[CH:4][N:3]=2)=[CH:40][C:39]=1[F:45]
Reactant: CN(C)CCCNc1ccc(N)cc1F
Reactant: O=C(Cc1cccs1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1
Agent: Cl
Solvent: CC(C)O
Product: CN(C)CCCNc1ccc(Nc2nccc(-c3c(-c4cccc(NC(=O)Cc5cccs5)c4)nn4ccccc34)n2)cc1F
Temperature: 120 °C
Yield: 36.6 %

Procedure:
To a slurry of N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2-(2-thienyl)acetamide (100 mg, 0.22 mmol.) in i-PrOH (4 mL) was added N1-[3-(dimethylamino)propyl]-2-fluoro-1,4-benzenediamine (75 mg, 0.30 mmol) and 2 drops of conc. HCl. The reaction was heated in a microwave to 120° C. for 20 min. and allowed to cool to rt. A second batch of N1-[3-(dimethylamino)propyl]-2-fluoro-1,4-benzenediamine (75 mg, 0.30 mmol) was added and the reaction microwaved to 120° C. for 1 h further. The reaction was concentrated and the crude purified by HPLC (Agilent, 50-90% gradient over 15 min.) to give the title compound (50 mg, 36% yield) as an oil which solidified to a dark green solid. 1H NMR (400 MHz, d6-DMSO) δ 10.33 (s, 1H), 9.27 (s, 1H), 8.79 (d, J=7.0 Hz, 1H), 8.42 (bd, J=6.8 Hz, 1H), 8.15-8.17 (m, 2H), 7.85 (s, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.51 (d, J=14.3 Hz, 1H), 7.35-7.43 (m, 3H), 7.23 (d, J=7.5 Hz, 1H), 7.18 (d, J=8.6 Hz, 1H), 7.08 (t, J=7.8 Hz, 1H), 6.93-6.95 (m, 2H), 6.60 (t, J=9.4 Hz, 1H), 6.38 (d, J=5.3 Hz, 1H), 3.84 (s, 2H), 3.05 (t, J=7.0 Hz, 2H), 2.37 (t, J=7.0 Hz, 2H), 2.18 (s, 6H), 1.69 (quintet, J=7.0 Hz, 2H) ppm. ES-LC/MS m/z=621 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]([CH3:19])[CH:9]1[CH2:18][CH2:17][C:12]2(OCC[O:13]2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO>[CH2:1]([N:8]([CH3:19])[CH:9]1[CH2:18][CH2:17][C:12](=[O:13])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(Cc1ccccc1)C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CO
Product: CN(Cc1ccccc1)C1CCC(=O)CC1
Reaction time: 16 h
Yield: 74 %

Procedure:
N-Benzyl-N-methyl-1,4-dioxaspiro[4.5]decan-8-amine (1.0 g, 3.83 mmol, 1.0 eq.) was dissolved in MeOH (12 ml); 6 M HCl solution (12 ml) was added at 0° C., and stirring was carried out for 16 hours at RT. After monitoring by TLC, the solvent was removed under reduced pressure and the residue was taken up in water (50 ml), adjusted to pH 8-9 with NaCHO3 (solid) and extracted with DCM (2×50 ml). The combined org. phases were washed with water and sat. NaCl solution (in each case 50 ml), dried over sodium sulfate and concentrated under reduced pressure and dried. The crude product was used in the next stage without being purified further. Yield: 74% (620 mg, 2.857 mmol)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)/[CH:9]=[CH:10]/[C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=2)=[CH:4][C:3]=1[CH3:21].[NH2:22][C:23]([NH2:25])=[O:24]>Cl.O1CCOCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=3)[NH:22][C:23](=[O:24])[N:25]=2)=[CH:4][C:3]=1[CH3:21]
Reactant: Cc1cc(C(=O)/C=C/c2ccc(C(=O)O)cc2)ccc1O
Reactant: NC(N)=O
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(-c2cc(-c3ccc(C(=O)O)cc3)[nH]c(=O)n2)ccc1O
Temperature: 25 °C
Yield: 49.4 %

Procedure:
(E)-4-(3-(4-hydroxy-3-methylphenyl)-3-oxoprop-1-enyl)benzoic acid (14.7 g, 52.1 mmol) and urea (15.6 g, 0.26 mol) was suspended in 200 mL of 4N HCl solution in dioxane, and the reaction mixture was heated to reflux overnight, then cooled to room temperature. The resulted mixture was concentrated in vacuo to remove dioxane. The residues were suspended in 20 mL of methanol, filtered and washed with 50 mL of water, and dried in the air. 8.3 g (51%) of 4-(6-(4-hydroxy-3-methylphenyl)-2-oxo-2,3-dihydropyrimidin-4-yl)benzoic acid were obtained. 1H NMR (400 MHz, DMSO-d6): 10.25 (s, 1H), 8.28 (m, 2H), 7.92-8.05 (m, 4H), 7.58 (s, 1H), 6.95 (m, 1H), 2.18 (s, 3H). MS (EI) for C18H14N2O4: 323 (MH+).
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH3:29])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:21]#[C:22][C:23]2[CH:28]=[CH:27]C=CC=2)[N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][C:15]=12)=[O:10])[C:4]([NH:6][CH3:7])=[O:5].C1(B(O)O)CCCC=1.C(=O)([O-])[O-].[K+].[K+].O>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>[C:21]1([C:13]2[N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][C:15]3=[C:11]([C:9]([NH:8][C@@H:3]([C:2]([CH3:1])([CH3:29])[CH3:30])[C:4]([NH:6][CH3:7])=[O:5])=[O:10])[N:12]=2)[CH2:27][CH2:28][CH2:23][CH:22]=1
Reactant: CNC(=O)[C@@H](NC(=O)c1nc(C#Cc2ccccc2)n2c1CN(C)CC2)C(C)(C)C
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: OB(O)C1=CCCC1
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)[C@@H](NC(=O)c1nc(C2=CCCC2)n2c1CN(C)CC2)C(C)(C)C
Temperature: 100 °C

Procedure:
Compound 203 (100 mg, 0.26 mmol) was dissolved in dioxane (2 mL) and cyclopentenylboronic acid (58 mg, 0.52 mmol) was added, followed by potassium carbonate (72 mg, 0.52 mmol) and water (0.40 mL). The resulting solution was degassed with nitrogen gas and Pd(PPh3)4 (18 mg, 0.016 mmol) was added. The mixture was heated at 100° C. for 1 h under nitrogen. The organic layer was separated, solid NaCl was added and the mixture was extracted with ethyl acetate. The combined organic layers were filtered through PL-Thiol MP SPE tube to remove palladium catalyst. The filtrate was concentrated and then purified by prep LC/MS using 5-95% acetonitrile in water with 0.1% formic acid. The formic acid was removed using Strata SCX SPE tube to give a desired product (Compound 238) as a free base (81 mg, 82%). 1H-NMR (400 MHz, CDCl3) δ: 1.09 (s, 9H), 1.90-2.05 (m, 2H), 2.51 (s, 3H), 2.55-2.65 (m, 2H), 2.74-2.95 (m, 7H), 3.88-4.14 (m, 4H), 5.95 (s, 1H), 6.09 (m, 1H), 7.66 (d, 1H). LCMS (+ESI) m/z 374.2 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([Br:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[C:14](=[O:15])[N:13]([CH3:16])[N:12]=[N:11]1.C[O-].[Na+].[C:20](=O)(O)[O-:21].[Na+]>O1CCCC1>[CH3:20][O:21][CH2:2][C:3]1[C:8]([Br:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[C:14](=[O:15])[N:13]([CH3:16])[N:12]=[N:11]1
Reactant: O=C([O-])O
Reactant: Cn1nnn(-c2cccc(Br)c2CBr)c1=O
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1c(Br)cccc1-n1nnn(C)c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1-(2-bromomethyl-3-bromophenyl)-4-methyl-1,4-dihydrotetrazole-5-one 45.0 g, sodium methoxide 37.4 g and tetrahydrofuran 600 ml was stirred at room temperature for three hours. To the reaction mixture was added aqueous saturated sodium bicarbonate solution and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium bicarbonate solution and was dried over anhydrous magnesium sulfate. The resulting mixture was concentrated under reduced pressure to give 1-(2-methoxymethyl-3-bromophenyl)-4-methyl-1,4-dihydrotetrazole-5-one 36.2 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:24]=3)[CH2:19][C:18]2=O)[CH2:13][CH2:12]1.P(Cl)(Cl)([Cl:35])=O>>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:24]=3)[CH:19]=[C:18]2[Cl:35])[CH2:13][CH2:12]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)Cc1ccc2c(c1)N(C1CCN(c3ccc(OCC)cc3F)CC1)C(=O)C2
Product: CCOC(=O)Cc1ccc2cc(Cl)n(C3CCN(c4ccc(OCC)cc4F)CC3)c2c1
Yield: 97.9 %

Procedure:
A suspension of ethyl [1-[1-(2-fluorophenetyl)piperidin-4-yl]-2-oxoindolin-6-yl]acetate (32.5 g, 76.559 mmol) in phosphoryl chloride (75.0 ml) was refluxed under heating for 2.5 hours (after 30 min., the suspension was dissolved). After removing the solvent, ethyl acetate (100 ml) and a 2N aqueous sodium hydroxide solution were added thereto, to separate the organic layer. It was washed with a 2N aqueous sodium hydroxide solution, water and brine, and then added with anhydrous magnesium sulfate and activated clay. After filtering, the solvent was removed, to give the title compound (yield: 33.2 g, 74.952 mmol, 97.9%).
Reaction SMILES: Br[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:5]2=[C:4]([C:18]([OH:20])=[O:19])[N:3]=1.CON(C)[C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([Li])(C)(C)C>C1COCC1>[C:24]([C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:5]2=[C:4]([C:18]([OH:20])=[O:19])[N:3]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCn2c(Br)nc(C(=O)O)c2C1
Reactant: CON(C)C(=O)c1ccccc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCn2c(C(=O)c3ccccc3)nc(C(=O)O)c2C1
Temperature: -78 °C
Yield: 45.1 %

Procedure:
Under a nitrogen atmosphere Compound 11 (0.15 g, 0.43 mmol) was dissolved in THF (2 mL) and N-methoxy-N-methylbenzamide (0.14 g, 0.86 mmol) was added. The resulting solution was cooled to −78° C. and tert-Butyl lithium (1.7M in THF, 1.02 mL, 1.73 mmol) was added dropwise. The resulting mixture was stirred and cooled for 1 h and quenched with NH4Cl saturated solution. The solid was removed by filtration and the filtrate was concentrated, acidified to pH 6 with 5% TFA and extracted with 20% i-PrOH/DCM. The organic layer was concentrated, diluted with DCM, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give product 25A (0.072 g, 45%). LCMS (+ESI) m/z 372.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][CH2:24][CH2:25][C:26]([CH:28]2[C:33](=[O:34])[O:32][C:31]([CH3:36])([CH3:35])[O:30][C:29]2=[O:37])=O)=[O:22])=[CH:16][CH:15]=1.C(O)(=O)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH:28]2[C:29](=[O:37])[O:30][C:31]([CH3:35])([CH3:36])[O:32][C:33]2=[O:34])=[O:22])=[CH:16][CH:15]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(NC(=O)NCCC(=O)C3C(=O)OC(C)(C)OC3=O)cc2)C1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(NC(=O)NCCCC3C(=O)OC(C)(C)OC3=O)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 1-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)-3-(3-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-3-oxopropyl)urea (150 mg, 0.27 mmol, 1.00 equiv) in dichloromethane (10 mL) and acetic acid (1 mL) Sodium borohydride (42 mg, 1.11 mmol, 4.04 equiv) was added and the resulting solution was stirred overnight at room temperature. The resulting mixture was washed with saturated aqueous sodium chloride (3×10 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 30 mg (21%) of 1-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)-3-(3-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)propyl)urea as a yellow solid.
Reaction SMILES: C([O:8][C:9]1[C:14]([CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[C:19]([Cl:35])[C:20]([O:27][C@@H:28]4[CH2:32][C@H:31]([CH2:33][OH:34])[O:30][CH2:29]4)=[CH:21][C:22]=3[Cl:26])[C:17]2=[O:36])=[C:13]([CH3:37])[CH:12]=[C:11]([CH3:38])[N:10]=1)C1C=CC=CC=1>FC(F)(F)C(O)=O>[Cl:26][C:22]1[CH:21]=[C:20]([O:27][C@@H:28]2[CH2:32][C@H:31]([CH2:33][OH:34])[O:30][CH2:29]2)[C:19]([Cl:35])=[C:18]2[C:23]=1[CH2:24][CH2:25][N:16]([CH2:15][C:14]1[C:9](=[O:8])[NH:10][C:11]([CH3:38])=[CH:12][C:13]=1[CH3:37])[C:17]2=[O:36]
Reactant: Cc1cc(C)c(CN2CCc3c(Cl)cc(O[C@H]4CO[C@@H](CO)C4)c(Cl)c3C2=O)c(OCc2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(CN2CCc3c(Cl)cc(O[C@H]4CO[C@@H](CO)C4)c(Cl)c3C2=O)c(=O)[nH]1
Yield: 39.5 %

Procedure:
A solution of 1,4-anhydro-2-O-(2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-5,8-dichloro-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-deoxy-L-threo-pentitol (296o, 36 mg, 0.065 mmol) in trifluoroacetic acid (2 mL) was stirred at room temperature for three hours. The volatiles were removed under vacuum, and the residue partitioned between ethyl acetate (20 mL) and saturated aqueous sodium bicarbonate (20 mL). The aqueous layer was back-extracted with ethyl acetate (2×20 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (eluting with a gradient of 0-10% methanol in ethyl acetate) to yield 1,4-anhydro-3-deoxy-2-O-{5,8-dichloro-2-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl}-L-threo-pentitol (Example 296, 12 mg, 40% yield), as a solid, after lyophilization. 1H NMR (400 MHz, methanol-d4) δ 7.14 (s, 1H), 6.00 (s, 1H), 4.93-5.02 (m, 1H), 4.64 (s, 2H), 3.95-4.06 (m, 2H), 3.85 (dd, J=10.39, 4.28 Hz, 1H), 3.56-3.64 (m, 1H), 3.49-3.55 (m, 1H), 3.38 (t, J=6.17 Hz, 2H), 2.80 (t, J=6.24 Hz, 2H), 2.36 (ddd, J=14.09, 7.79, 6.60 Hz, 1H), 2.18 (s, 3H), 2.14 (s, 3H), 1.84 (dd, J=13.94, 5.50 Hz, 1H).
Reaction SMILES: [NH2:1]/[C:2](=[N:27]\[O:28][C:29](OCC)=[O:30])/[CH2:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]([NH:14][C:15]([C:17]2[NH:21][C:20]3[S:22][C:23]([Cl:25])=[CH:24][C:19]=3[CH:18]=2)=[O:16])[C:5]1=[O:26]>O1CCOCC1>[Cl:25][C:23]1[S:22][C:20]2[NH:21][C:17]([C:15]([NH:14][CH:6]3[CH2:7][C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[N:4]([CH2:3][C:2]4[NH:1][C:29](=[O:30])[O:28][N:27]=4)[C:5]3=[O:26])=[O:16])=[CH:18][C:19]=2[CH:24]=1
Reactant: CCOC(=O)O/N=C(\N)CN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Solvent: C1COCCO1
Product: O=C(NC1Cc2ccccc2N(Cc2noc(=O)[nH]2)C1=O)c1cc2cc(Cl)sc2[nH]1
Yield: 87 %

Procedure:
N-[1-((2Z)-2-Amino-2-{[(ethoxycarbonyl)oxy]imino}ethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide (Method 14) was dissolved in 1,4-Dioxane and the solvent distilled off with the oil bath temperature 140° C. This was repeated 4 times. The residual solid was triturated with refluxing Et2O (10 mL) and after cooling filtered, washed with Et2O (10 mL) and hexane (10 mL) to give the title product (184 mg, 87% (2 steps)) as a pale brown solid.