Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:29])[C:11]=1[C:12]([N:14]1[C:22]2[CH:21]=[CH:20][N:19]=[C:18](NC(C3CC3)=O)[C:17]=2[CH:16]=[CH:15]1)=[O:13])[C:5]([O:7]C)=[O:6].[OH-].[Na+].[O:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:29])[C:11]=1[C:12]([N:14]1[C:22]2[CH:21]=[CH:20][N:19]=[C:18]([C:36]([CH:35]3[CH2:33][CH2:34]3)=[O:32])[C:17]=2[CH:16]=[CH:15]1)=[O:13])[C:5]([OH:7])=[O:6]
Reactant: C1CCOC1
Reactant: COC(=O)c1cc(Cl)c(C(=O)n2ccc3c(NC(=O)C4CC4)nccc32)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(Cl)c(C(=O)n2ccc3c(C(=O)C4CC4)nccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To the stirred solution of methyl 3,5-dichloro-4-({4-[(cyclopropylcarbonyl)amino]-1H-pyrrolo[3,2-c]pyridin-1-yl}carbonyl)benzoate (500 mg, 1.1 mmol) in tetrahydrofuran and water (1:1, 5 mL) was added sodium hydroxide (46 mg, 1.1 mmol). The reaction mixture was stirred at room temperature for about 1 hour. The reaction mixture was then concentrated under vacuum and the aquoeus residue was neutralized using dilute hydrochloric acid. The precipitated solid was filtered, washed with water and dried to afford 3,5-dichloro-4-{[4-(cyclopropylcarbonyl)-1H-pyrrolo[3,2-c]pyridin-1-yl]carbonyl}benzoic acid (470 m g, 97%) as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.CO>CS(C)=O.C(Cl)Cl>[C:6]([NH:8][CH2:9][CH2:10][CH:11]=[O:12])([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: CC(C)(C)OC(=O)NCCCO
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 67 %

Procedure:
To a solution of 3-(t-butyloxycarbonylamino)propanol (1.419 g, 8.1 mmol) dissolved in DMSO (15 mL), IBX (2 eq, 4.5 g, 16.2 mmol) was added to form a slurry. The reaction was allowed to stir at rt for 5 hr. The solid IBX dissolved slowly, but a white precipitate formed after approximately 1 hr of reaction time. Distilled water (80 mL) was added to the reaction mixture, and the resultant aqueous solution filtered and then extracted with diethyl ether (3×175 mL). The organic layers were combined, dried over MgSO4, filtered, and evaporated. The crude oil was purified by silica gel chromatography using 10% CH3OH in CH2Cl2 as the eluent. The solvent was evaporated to leave a clear, colorless oil with a very pleasant flowery or candy-like scent: yield 67%; one spot on TLC, Rf=0.70 (10% CH3OH in CH2Cl2). 1H NMR (CDCl3) δ 9.80 (s, 1H), 4.94 (s, 1H), 3.47-3.38 (m, 2H), 2.27-2.65 (t, 2H), 1.47 (s, 9H). MS (ESI+) m/z 174 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH:24]([C:28]([O:30]CC)=[O:29])[CH2:23]4)=[O:21])=[C:14]([Cl:33])[C:13]=3[Cl:34])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[OH-].[K+].[OH-].[Na+]>C(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH:24]([C:28]([OH:30])=[O:29])[CH2:23]4)=[O:21])=[C:14]([Cl:33])[C:13]=3[Cl:34])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1
Reactant: CCOC(=O)C1CCCN(C(=O)/C=C/c2ccc(Sc3ccc4c(ccn4C)c3)c(Cl)c2Cl)C1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cn1ccc2cc(Sc3ccc(/C=C/C(=O)N4CCCC(C(=O)O)C4)c(Cl)c3Cl)ccc21

Procedure:
The title compound was prepared by the procedures described in Example 155, substituting the ethyl ester from Example 137 with ethyl ester from Example 337, and KOH with NaOH, to give a white solid. 1H NMR (d6-DMSO, 300 MHz) 3 1.29-1.45 (m, 1H), 1.45-1.78 (m, 2H), 1.78-2.02 (m, 1H), 2.20-2.40 (m, 1H), 2.82 (brt, J=10.5 Hz, 1H), 3.08 (brt, J=10.5 Hz, 1H), 3.80-4.07 (m, 2H), 3.86 (s, 3H), 4.384.50 (m, 1H), 6.42 (d, J=8.4 Hz, 1H), 6.54 (d, J=3.0 Hz, 1H), 7.19 (d, J=15.3 Hz, 1H), 7.32 (dd, J=1.8, 8.7 Hz, 1H), 7.48 (d, J=3.0 Hz, 1H), 7.64 (d, J=8.7 Hz, 1H), 7.67-7.77 (m, 2H), 7.87 (d, J=1.8 Hz, 1H). MS (ESI+) (M+H)+ at m/z 489,491,493. Anal. Calcd for C24H22Cl2N2O3S.0.56 CH2Cl2: C, 54.94; H, 4.34; N, 5.22. C, 54.89; H, 4.44; N, 5.32.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:18][CH2:19][CH2:20]Br.O>CS(C)=O>[CH2:18]([O:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)[CH2:19][CH3:20]
Reactant: CCCBr
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCOc1ccc(OCc2ccccc2)cc1
Yield: 97.1 %

Procedure:
In 75 ml of dimethylsulfoxide (DMSO) was dissolved 7.5 g (37.5 mmol) of 4-(benzyloxy)phenol, and an aqueous solution of sodium hydroxide (NaOH/H2O: 1.65 g/15 ml) was added thereto. The mixture was stirred until dissolving homogeneously. Next, 5.0 g (40.7 mmol) of n-propyl bromide was added to the mixture, and the resultant mixture was subjected to a reaction at a room temperature for 24 hours. The reaction mixture was poured into 1 L of an iced water, and a solid was formed by stirring. The resultant solid was collected by filtration, dried, and recrystallized from methanol to give 8.82 g (36.4 mmol) of 1-(n-propyloxy)-4-benzyloxybenzene.
Reaction SMILES: O1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]([NH:12][C:13]([C:15]2[CH:20]=[C:19]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:18]=[CH:17][N:16]=2)=[O:14])[CH:9]=[CH:10][CH:11]=1.[NH2:27][C@H:28]([CH3:31])[CH2:29][OH:30].FC(F)(F)C(O)=O>C(O)CCC>[OH:30][CH2:29][C@H:28]([N:27]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]([NH:12][C:13]([C:15]2[CH:20]=[C:19]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:18]=[CH:17][N:16]=2)=[O:14])[CH:9]=[CH:10][CH:11]=1)[CH3:31]
Reactant: C[C@@H](N)CO
Reactant: O=C(Nc1cccc(-c2nnco2)c1)c1cc(-c2cccnc2)ccn1
Solvent: CCCCO
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](CO)n1cnnc1-c1cccc(NC(=O)c2cc(-c3cccnc3)ccn2)c1
Temperature: 150 °C
Yield: 23 %

Procedure:
A suspension of N-(3-(1,3,4-oxadiazol-2-yl)phenyl)-3,4′-bipyridine-2′-carboxamide (210 mg, 0.61 mmol), (R)-2-amino-1-propanol (0.3 mL), and trifluoroacetic acid (0.05 mL) in n-butanol was heated in a microwave to 150° C. for 1 hour. The solvent was removed under reduced pressure and the residue was purified by reverse-phase HPLC to give (R)—N-(3-(4-(1-hydroxypropan-2-yl)-4H-1,2,4-triazol-3-yl)phenyl)-3,4′-bipyridine-2′-carboxamide as a white powder (55 mg, 0.138 mmol, 23% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][CH2:6][CH2:5]2.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[C:8](=[O:12])[O:7][CH2:6]1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1OCCc2cc(Br)ccc21
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1OCC(Br)c2cc(Br)ccc21

Procedure:
6-Bromo-3,4-dihydro-1H-isochromen-1-one (3.0 g, 13 mmol) was dissolved in CCl4 (150 ml) then added N-bromosuccinimide (2.4 g, 13 mmol) followed by benzoyl peroxide (0.096 g, 0.40 mmol) and refluxed for 3 hours. Filtered and concentrated then chromatographed through a 120 g ISCO Redi-sep. column and eluted with 0-25% EtOAc/Hexane to yield the title compound. LC-MS (IE, m/z): 306.9 [M+1]+.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[C@@H:12]([C:13]#[CH:14])[CH2:11][CH2:10][C@H:6]1[C:7](O)=[O:8])=[O:4].C[N:16]1CCOCC1.C(OC(Cl)=O)C(C)C.N.O1CCOCC1>C1COCC1.OS([O-])(=O)=O.[K+]>[Cl:1][CH2:2][C:3]([N:5]1[C@@H:12]([C:13]#[CH:14])[CH2:11][CH2:10][C@H:6]1[C:7]([NH2:16])=[O:8])=[O:4]
Reactant: C#C[C@H]1CC[C@@H](C(=O)O)N1C(=O)CCl
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: N
Agent: O=S(=O)([O-])O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: C#C[C@H]1CC[C@@H](C(N)=O)N1C(=O)CCl
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (5R)-1-(chloroacetyl)-5-ethynyl-L-proline (1.89 g, 8.76 mmol) in THF (50 mL) at −15° C. under nitrogen was added 4-methylmorpholine (1.16 mL, 10.52 mmol), and then isobutylchloroformate (1.25 mL, 9.64 mmol) over 3 minutes. A white precipitate formed. The reaction mixture was stirred at −15° C. under nitrogen for 30 minutes, and a solution of NH3 in dioxane (0.5 M, 88 mL, 43.8 mmol) was added. The reaction mixture was stirred at −15° C. for 30 minutes, warmed to room temperature, and stirred at that temperature for 16 hours. The reaction mixture was diluted with 4% KHSO4 to ˜pH 4 and extracted with ethyl acetate (3×). The extracts were combined, washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. Purification by flash column chromatography (60-75% ethyl acetate/hexane) provided the titled compound. MS (CI) m/z 215 (M+1)+.
Reaction SMILES: O=[C:2]1[CH2:8][C@H:7]2[N:4]([C:5](=[O:14])[C@@H:6]2[C:9]([O:12][CH3:13])([CH3:11])[CH3:10])[C@H:3]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[O:16].C(N(C(C)C)CC)(C)C.P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.[N:54]1[CH:59]=[CH:58][C:57]([SH:60])=[CH:56][CH:55]=1>CN(C1C=CN=CC=1)C.C(#N)C>[CH3:13][O:12][C:9]([C@H:6]1[C:5](=[O:14])[N:4]2[C@@H:7]1[CH2:8][C:2]([S:60][C:57]1[CH:58]=[CH:59][N:54]=[CH:55][CH:56]=1)=[C:3]2[C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=1)=[O:16])([CH3:11])[CH3:10]
Reactant: Sc1ccncc1
Reactant: COC(C)(C)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Agent: CN(C)c1ccncc1
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(C)(C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Sc3ccncc3)C[C@H]12
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
To a solution of 4-nitrobenzyl (2R, 5R, 6S)-3,7-dioxo-6-(1-methoxy-1-methylethyl)-1-azabicyclo[3.2.0]heptane-2-carboxylate (50.0 mg) and 4-(N,N-dimethylamino)pyridine (1.62 mg) in acetonitrile (2.5 ml) was added dropwise a solution of N,N-diisopropyl-N-ethylamine (27.8 μl) in acetonitrile (0.25 ml), followed by addition of a solution of diphenyl chlorophosphate (28.9 μl) in acetonitrile (0.26 ml) at 0° C. After stirring for one hour at 0° C., a solution of N,N-diisopropyl-N-ethylamine (92.7 μl) in acetonitrile (0.834 ml) and pyridine-4-thiol (15.6 mg) were successively added at -15° C., and the mixture was allowed to stand at -15° C. overnight. The resultant solution was concentrated in vacuo. The residue was diluted with ethyl acetate (10 ml) and washed twice with water and a saturated aqueous sodium chloride. After drying over magnesium sulfate, the ethyl acetate solution was filtered and evaporated. The residue (68.7 mg) was chromatographed on deactivated silica gel (1.5 g) with 10% water, eluting with a mixture of benzene and acetone (100:1 to 6:1) to give 4-nitrobenzyl (5R, 6S)-6-(1-methoxy-1-methylethyl)-7-oxo-3-(4-pyridylthio)-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (51.7 mg) as an amorphous solid.
Reaction SMILES: [Si]([O:8][C@H:9]([C:34]1[CH:45]=[CH:44][C:37]2[O:38][C:39]([CH3:43])([CH3:42])[O:40][CH2:41][C:36]=2[CH:35]=1)[CH2:10][NH:11][C@H:12]([CH3:33])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]23[CH2:29][CH:24]4[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]4)[CH2:21]2)[CH2:27]3)[C:15]=1[O:30][CH2:31][CH3:32])(C(C)(C)C)(C)C.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:8][CH:9]([C:34]1[CH:45]=[CH:44][C:37]2[O:38][C:39]([CH3:43])([CH3:42])[O:40][CH2:41][C:36]=2[CH:35]=1)[CH2:10][NH:11][CH:12]([CH3:33])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]23[CH2:27][CH:26]4[CH2:25][CH:24]([CH2:23][CH:22]([CH2:28]4)[CH2:21]2)[CH2:29]3)[C:15]=1[O:30][CH2:31][CH3:32]
Reactant: CCOc1c(C[C@@H](C)NC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc3c(c2)COC(C)(C)O3)cccc1C12CC3CC(CC(C3)C1)C2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1c(CC(C)NCC(O)c2ccc3c(c2)COC(C)(C)O3)cccc1C12CC3CC(CC(C3)C1)C2
Yield: 90.1 %

Procedure:
928 mg (1.26 mmol) of the Intermediate 83 and 794 mg (2.52 mmol) of tetrabutylammonium fluoride trihydrate in 30 ml of anhydrous THF are stirred at room temperature overnight. The solution is concentrated and the residue is partitioned in ethyl acetate/water. The organic layer is washed with water, dried and concentrated. The residue is chromatographied on silicagel using dichloromethane/methanol 90:3 as eluent to give 590 mg (990% yield) of the desired compound as a yellowish oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([OH:20])=[O:19].[OH-].[Na+:22]>O>[OH2:16].[NH2:1][C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([O-:20])=[O:19].[Na+:22]
Reactant: Nc1c(CC(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1c(CC(=O)[O-])cccc1C(=O)c1ccc(Cl)cc1

Procedure:
A mixture of 3.5 g. (0.0125 mole) of 2-amino-3-(p-chlorobenzoyl)phenylacetic acid in a water solution containing 0.5 g. of sodium hydroxide (0.0125 mole) was refluxed 45 minutes, cooled and filtered. The filtrate was concentrated to an oily consistency and poured into a large volume of acetone. A yellow precipitate separated which was collected and identified by nuclear magnetic resonance spectrum as the desired product. The product (2.6 g.) 67%) melted at 265° C. (dec.) after crystallization from ethanol-ethyl ether.
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:93]=[CH:94][CH:95]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[CH:67][C:68]([N:73]5[CH2:78][CH2:77][N:76]([CH2:79][C@@H:80]([OH:82])[CH3:81])[CH2:75][CH2:74]5)=[N:69][C:70]=4[O:71][CH3:72])[CH:63]=3)[N:58](S(C3C=CC(C)=CC=3)(=O)=O)[CH:57]=2)[CH:53]=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([CH:93]=[CH:94][CH:95]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[CH:67][C:68]([N:73]5[CH2:74][CH2:75][N:76]([CH2:79][C@@H:80]([OH:82])[CH3:81])[CH2:77][CH2:78]5)=[N:69][C:70]=4[O:71][CH3:72])[CH:63]=3)[NH:58][CH:57]=2)[CH:53]=[N:52]1
Reactant: COc1nc(N2CCN(C[C@H](C)O)CC2)ccc1-c1cnc2c(c1)c(-c1cnn(Cc3cccc(F)c3)c1)cn2S(=O)(=O)c1ccc(C)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1nc(N2CCN(C[C@H](C)O)CC2)ccc1-c1cnc2[nH]cc(-c3cnn(Cc4cccc(F)c4)c3)c2c1
Yield: 30.1 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, (S)-1-(4-(5-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-6-methoxypyridin-2-yl) piperazin-1-yl)propan-2-ol (60 mg, 0.086 mmol) was hydrolyzed with lithium hydroxide (36 mg, 0.862 mmol) in THF/methanol/water (10/5/2 mL) to yield 14 mg (25% yield) of desired product. 1H NMR (CD3OD, 400 MHz): δ 8.615-8.612 (d, 1H), 8.51 (s, 1H), 8.20 (s, 1H), 7.95 (s, 1H), 7.82-7.80 (d, 1H), 7.76 (s, 1H), 7.41-7.36 (m, 1H), 7.14-7.12 (d, 1H), 7.08-7.01 (m, 2H), 6.61-6.59 (d, 1H), 5.44 (s, 2H), 4.52 (s, 2H), 4.29-4.24 (m, 1H), 3.96 (s, 3H), 3.74 (s, 2H), 3.36 (s, 2H), 3.26-3.11 (m, 4H), 1.28-1.27 (d, 2H). MS: m/z=542.2 (M+1), HPLC: 96.86% in method B.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[OH-].[K+].Br[CH2:18][CH2:19][O:20][CH3:21]>C(O)C>[CH3:21][O:20][CH2:19][CH2:18][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: COCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 50 °C
Reaction time: 16 h
Yield: 19.9 %

Procedure:
A solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (10 g, 51.5 mmol) in ethanol (50 mL) was treated with KOH (3.47 g, 61.8 mmol) and 1-bromo-2-(methyloxy)ethane (5.81 mL, 61.8 mmol) at room temperature and the resulting mixture was stirred at 50° C. under nitrogen for 16 h then cooled to room temperature. 1-Bromo-2-(methyloxy)ethane (2 mL, 21.3 mmol) was added and the resulting mixture was stirred at 50° C. for 60 h then cooled to room temperature. The mixture was filtered through celite and the insoluble were washed with ethanol. The combined filtrate and washings were concentrated in vacuo. Purification of the residue on SP4 using a 100 G silica cartridge (gradient: 0 to 100% AcOEt in Hexanes) gave 1-[2-(methyloxy)ethyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.72 g, 10.25 mmol, 20%) as a yellow oil. LCMS (method G): Retention time 0.87 min, [M+H]+=252.9
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.Br[CH:44]1CC[S:46](=[O:50])(=[O:49])[CH2:45]1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH:14]3[CH2:44][CH2:45][S:46](=[O:50])(=[O:49])[CH2:15]3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: O=S1(=O)CCC(Br)C1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(C3CCS(=O)(=O)C3)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-bromo-tetrahydro-thiophene 1,1-dioxide and isolated as white solid. MS (m/e): 401.3 (MH+).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][N:5]([CH2:11][C:12]1[CH:13]=[C:14]([CH:48]=[CH:49][CH:50]=1)[C:15]([NH:17][C:18]1[S:19][C:20]2[CH2:47][CH2:46][CH2:45][CH2:44][C:21]=2[C:22]=1[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]2[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=2)=[CH:28][CH:27]=1)=[O:24])=[O:16])[CH:6]([CH2:9][CH3:10])[CH2:7][CH3:8].C(N(C(C)C)C(C)C)C.[N:60]([C@@H:63]([CH3:68])[C:64]([O:66][CH3:67])=[O:65])=[C:61]=[O:62].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.C1COCC1>[CH3:68][C@H:63]([NH:60][C:61](=[O:62])[N:2]([CH3:1])[CH2:3][CH2:4][N:5]([CH:6]([CH2:9][CH3:10])[CH2:7][CH3:8])[CH2:11][C:12]1[CH:13]=[C:14]([CH:48]=[CH:49][CH:50]=1)[C:15]([NH:17][C:18]1[S:19][C:20]2[CH2:47][CH2:46][CH2:45][CH2:44][C:21]=2[C:22]=1[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]2[CH:35]=[CH:36][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:42][CH:43]=2)=[CH:28][CH:27]=1)=[O:24])=[O:16])[C:64](=[O:65])[O:66][CH3:67]
Reactant: CCC(CC)N(CCNC)Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Reactant: COC(=O)[C@H](C)N=C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(CC)N(CCN(C)C(=O)N[C@@H](C)C(=O)OC)Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Reaction time: 1 h
Yield: 97.8 %

Procedure:
To a mixture of 250 mg of methyl 4-[2-(4-{[(2-{[3-({[2-(methylamino)ethyl](pentan-3-yl)amino}methyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, 0.20 mL of N-ethyl-N-isopropylpropan-2-amine and 10 mL of THF under ice cooling was added 70 mg of methyl(S)-(−)-2-isocyanatopropionate, followed by stirring for 1 hour at the same temperature and then for 2 hours at room temperature. Ethyl acetate and an aqueous sodium hydrogen carbonate solution were added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (10% methanol/chloroform), thereby obtaining 290 mg methyl 4-{2-[4-({[2-({3-[(4S)-4,7-dimethyl-3,6-dioxo-10-(pentan-3-yl)-2-oxa-5,7,10-triazaundecan-11-yl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:20]([OH:23])(=[O:22])=[O:21])[CH:5]=[C:6]2[C:11]=1[C:10]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:9][C:8]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:7]2.C1C(N=NC2C(=O)N(C3C=C[C:41]([S:44]([O-])(=O)=O)=CC=3)N=C2C([O-])=O)=CC=C(S([O-])(=O)=O)C=1.[Na+].[Na+].[Na+].C(Cl)(Cl)=S.C>O.Cl>[N:1]([C:2]1[CH:3]=[C:4]([S:20]([OH:23])(=[O:22])=[O:21])[CH:5]=[C:6]2[C:11]=1[C:10]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:9][C:8]([S:16]([OH:19])(=[O:17])=[O:18])=[CH:7]2)=[C:41]=[S:44]
Reactant: O=C([O-])C1=NN(c2ccc(S(=O)(=O)[O-])cc2)C(=O)C1N=Nc1ccc(S(=O)(=O)[O-])cc1
Reactant: Nc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)cc(S(=O)(=O)O)c12
Agent: Cl
Agent: S=C(Cl)Cl
Agent: [Na+]
Solvent: O
Product: O=S(=O)(O)c1cc(N=C=S)c2c(S(=O)(=O)O)cc(S(=O)(=O)O)cc2c1
Reaction time: 2 h

Procedure:
To a solution of 32.0 g of 8-amino-1,3,6-naphthalenetrisulfonic acid, trisodium salt in 350 ml of water and 7.0 ml of concentrated hydrochloric acid was added 10.0 g of thiophosgene. The mixture was stirred 21/2 hours, treated with charcoal and filtered through diatomaceous earth. The filtrate was neutralized with 46 ml of 5N sodium hydroxide, chilled and the solid was collected and recrystallized from 40 ml of water by heating and then chilling in an ice bath. This solid was washed with ice water, acetone then ether and dried, giving 11.2 g of 8-isothiocyanato-1,3,6-naphthalenetrisulfonic acid, trisodium salt.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[C:12]=3[C:13]=2[CH3:14])=O)=[CH:5][CH:4]=1.NN.[OH-].[K+]>C(O)CO.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:9]2[O:10][C:11]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[C:12]=3[C:13]=2[CH3:14])=[CH:20][CH:21]=1
Reactant: COc1ccc(C(=O)c2oc3cccc(O)c3c2C)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: COc1ccc(Cc2oc3cccc(O)c3c2C)cc1
Temperature: 195 °C
Yield: 37270.7 %

Procedure:
A mixture of 2-(p-methoxybenzoyl)-3-methyl-4-hydroxybenzofuran (2.0 gm; 7.0 mmoles), 99% hydrazine (50 mL) and potassium hydroxide (2.7 gm; 49 mmoles) in ethylene glycol (50 mL) was heated at 140° C. for a period of 2.5 hours and at 195° C. for one hour. The reaction mixture was cooled, poured in water, and extracted with ethylacetate. The organic phase was washed with 20% citric acid, with brine, dried (Na2SO4), and concentrated in vacuo. The residue was chromatographed on silica gel using 20% ethylacetate in hexane as eluent to yield 700 gm (37%) of 2-(p-methoxybenzyl)-3-methyl-4-hydroxybenzofuran, mp.130°-133° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[C:3]=1[Br:9].[CH3:10][C:11]([CH3:17])=[C:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1.C([Li])CCC.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[Br:9][C:3]1[CH:2]=[CH:7][CH:6]=[C:5]2[C:4]=1[CH:13]1[C:12](=[C:11]([CH3:17])[CH3:10])[CH:16]2[CH:15]=[CH:14]1
Reactant: CC(C)=C1C=CC=C1
Reactant: Brc1cccc(Br)c1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: CC(C)=C1C2C=CC1c1c(Br)cccc12
Reaction time: 0.17 h
Yield: 66 %

Procedure:
To a stirred solution of 1,2,3-tribromo-benzene (4.34 g, 13.8 mmol) and 6,6-dimethylfulvene (2.38 g, assay 92.6%, 20.7 mmol) in dry toluene (60 ml) under a nitrogen atmosphere, 5.5 ml of a 2.5M toluene solution of n-butyllithium (14.5 mmol) were added dropwise at −5 to 0° C. within 10 minutes. After a further 10 minutes at 0° C. and 2 hours at ambient temperature, the reaction mixture was poured onto a saturated aqueous solution of ammonium chloride, extracted with ethyl acetate, washed with brine and water, dried over sodium sulphate and evaporated. Purification of the crude material on silca gel in hexane afforded 2.38 g of the desired product as a yellow oil (assay 84% by g.l.c., 55% yield). This reaction is also disclosed in WO 2007/068417.