Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[O:21][C@H:20]([CH2:22][OH:23])[C@@H:7]([O:8][C@@H:9]2[O:17][C@H:16]([CH2:18][OH:19])[C@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[C@H:5]([OH:6])[C@H:3]1[OH:4].C1C(=O)NC(=O)N([C@@H]2O[C@H](COP(OP(O[C@H:47]3[O:52][C@H:51]([CH2:53][OH:54])[C@H:50]([OH:55])[C@H:49]([OH:56])[C@H:48]3[OH:57])(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=1.CCC(COC(C(N(CC[NH+](C)C)C)=O)(C1C=CC=CC=1)C1C=CC=CC=1)CC.[Cl-]>[As](C)(C)(=O)[O-].[Na+]>[O:13]([C@H:12]1[C@@H:14]([OH:15])[C@@H:16]([CH2:18][OH:19])[O:17][C@@H:9]([O:8][C@@H:7]2[C@@H:20]([CH2:22][OH:23])[O:21][CH:2]([OH:1])[C@H:3]([OH:4])[C@H:5]2[OH:6])[C@@H:10]1[OH:11])[C@H:47]1[O:52][C@H:51]([CH2:53][OH:54])[C@H:50]([OH:55])[C@H:49]([OH:56])[C@H:48]1[OH:57]
Reactant: O=c1ccn([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O[C@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O
Agent: CCC(CC)COC(C(=O)N(C)CC[NH+](C)C)(c1ccccc1)c1ccccc1
Agent: C[As](C)(=O)[O-]
Agent: [Cl-]
Product: OC[C@H]1O[C@H](O[C@H]2[C@@H](O)[C@@H](CO)O[C@@H](O[C@H]3[C@H](O)[C@@H](O)C(O)O[C@@H]3CO)[C@@H]2O)[C@H](O)[C@@H](O)[C@H]1O
Reaction time: 120 h
Yield: 58.9 %

Procedure:
A reaction mixture containing lactose (50 mg), UDP-Gal(20 mg), α(1-3)-galactosyltransferase (60 mU), alkaline phosphatase (20 U), 20 mM MnCl2 and 0.1% Triton X-100 in 50 mM sodium cacodylate buffer (3 mL) at pH 6.5, was incubated at 37° C. Additional UDP-Gal was added to the mixture after 24 hours (20 mg), and 48 hours (50 mg). After 120 hours, fresh α(1-3)-galactosyltransferase (20 mU) and UDP-Gal (10 mg) were added to the mixture, which was incubated for an additional 72 hours to give about 95% conversion to product. The reaction mixture was filtered through a 0.2 μm Nalgene nylon filter, the filtrate was applied to a Bio-Rad AG 1X8 column (C1-form 2.5×20 cm, 0.6 mL/min) and the column was eluted with water. Saccharide fractions were combined and lyophilized. The dry residue was dissolved in 50 mM potassium phosphate buffer, pH 7.5, β-galactosidase (150 mU) was added to the mixture to destroy unreacted lactose, and the sample left at ambient temperature (24° C.) for 18 hours. The mixture was then boiled for 2 minutes, filtered through a 0.2 μm filter and divided into three portions each of which was loaded onto a C-18 silica gel column (20 g). The columns were eluted with water (200 mL) and the aqueous eluents were concentrated to dryness under reduced pressure. The residue was dissolved in water (5 mL) and applied to a Bio-Gel P-2 column (2.5×100 cm, H2O, 0.2 mL/min). Fractions which contained the trisaccharide were combined and lyophilized to give 10.5 mg of αGal(1-3)βGal(1-4)Glc. 1H n.m.r. data (500 MHz, D2O): δ=5.22 (d, 0.36 H, J 3.6 Hz, H-1α), 5.14 (d, 1 H, J 3.0 Hz, H-1"), 4.66 (d, 0.64 H, J 8.0 Hz, H-1β), 4.51 (d, 1 H, J 8.0 Hz, H-1').
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.Cl[C:24](=[O:31])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(Cl)Cl>[CH2:8]([O:7][C:5](=[O:6])[CH:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][NH:2][C:24](=[O:31])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:9]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: CCOC(=O)C(CN)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)NCC(C(=O)OCC)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
Ethyl 3-amino-2-phenylpropanoate hydrochloride (4.38 g, 19.13 mmol) was suspended in methylene chloride (80 mL) and triethylamine (5.86 mL, 2.2 eq.). The mixture was cooled to 0° C. and treated dropwise with ethyl 3-chloro-3-oxopropanoate (2.69 mL, 1.1 eq.). The reaction was kept at room temperature for one hour, diluted with methylene chloride, washed with 1 N HCl and then with 5% NaHCO3, dried over Na2SO4 and evaporated to dryness. The crude material was chromatographed on silica gel, eluting with hexane/ethyl acetate 1/1, to give 3-(2-ethoxycarbonyl-acetylamino)-2-phenyl-propionic acid ethyl ester (4.24 g, Y=72%) as an oil.
Reaction SMILES: C(O)(=O)C(O)=O.C1(C(C2C=CC=CC=2)=C2CCN(CCCOC3C=CC=CC=3)CC2)C=CC=CC=1.[C:36]1([C:42]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)([CH:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[OH:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[CH3:56][O:57][C:58](=[O:70])[C:59]1[CH:64]=[CH:63][C:62]([O:65][CH2:66][CH2:67][CH2:68]Cl)=[CH:61][CH:60]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>CN(C)C=O>[CH3:56][O:57][C:58](=[O:70])[C:59]1[CH:64]=[CH:63][C:62]([O:65][CH2:66][CH2:67][CH2:68][N:47]2[CH2:48][CH2:49][CH:44]([C:42]([OH:43])([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:45][CH2:46]2)=[CH:61][CH:60]=1
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCNCC1
Reactant: COC(=O)c1ccc(OCCCCl)cc1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Yield: 74 %

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 5.3 g (0.02 mole) of α,α-diphenyl-4-piperidinemethanol, 4.6 g (0.02 mole) of 4-(3-chloropropoxy)benzoic acid methyl ester, 7.4 g (0.07 mole) of anhydrous sodium carbonate and 0.5 g of potassium iodide in 100 ml of dimethylformamide give 6.8 g (74%) of title compound as a fluffy, white solid, mp 146°-147° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:22]([CH:24]1[C:28]2[CH:29]=[N:30][CH:31]=[CH:32][C:27]=2[C:26](=O)[O:25]1)[CH3:23].Cl>C1COCC1>[CH2:22]([CH:24]1[C:28]2[CH:29]=[N:30][CH:31]=[CH:32][C:27]=2[C:26](=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[O:25]1)[CH3:23]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: CCC1OC(=O)c2ccncc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC1OC(=C2C(=O)Nc3ccc(F)cc32)c2ccncc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.8 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (936 mg, 6.20 mmol.) in THF (6 mL) is cooled to 0° C. under an argon atmosphere and treated with a solution of lithium bis(trimethylsilyl)amide (12.4 mL of a 1 M solution in THF, 12.4 mmol) dropwise. The resulting solution is stirred at room temperature for 10 min. A solution of 3-ethyl-3H-furo[3,4-c]pyridin-1-one (674 mg, 4.13 mmol) in THF (7 mL) is added dropwise to the reaction mixture. The resulting solution is stirred for 4 h. The reaction mixture is poured into aqueous 10% HCl solution (160 mL). The resulting mixture is heated to 90° C. for 2 h and stirred at room temperature for 36 h. The precipitate which formed is collected by filtration, washed with small volumes of ethyl acetate (10×3 mL) and dried under vacuum to give the title compound as a yellow solid (720 mg, 59%).
Reaction SMILES: Cl.O[CH2:3][C:4]1[N:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.CCN(C(C)C)C(C)C.[O:20](C(OC(C)(C)C)=O)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=O>CN(C=O)C>[C:24]([O:23][C:21]([N:9]1[CH2:8][CH:7]([OH:10])[CH2:6][CH2:5][CH:4]1[CH3:3])=[O:20])([CH3:27])([CH3:26])[CH3:25]
Reactant: OCc1ccc(O)cn1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCC(O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.5 %

Procedure:
1.50 g (9.28 mmol) of 6-Hydroxymethyl-pyridin-3-ol hydrochlorid was hydrogenated under the conditions described in intermediate 63B. The crude product was dissolved in 5 ml DMF, 5.60 ml (32.00 mmol) of Hunig's base and 3.56 g (16.00 mmol) of BOC2O were added and the yellow solution was stirred 18 h at RT. Evaporation, extraction (AcOEt/water/brine) and chromatography (silica gel, AcOEt/MeOH) gave 0.35 g (15%) (rac)-5-hydroxy-2-methyl-piperidine-1-carboxylic acid tert-butyl ester; MS: 216.4 (MH+)
Reaction SMILES: Br[C:2]1[S:10][C:9]2[N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:7](=[O:20])[N:6]3[N:21]=[CH:22][N:23]=[C:5]3[C:4]=2[CH:3]=1.[B-](F)(F)(F)[CH:25]=[CH2:26].[K+].ClCCl.C(N(CC)CC)C>C(O)CCC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:8]2[C:9]3[S:10][C:2]([CH:25]=[CH2:26])=[CH:3][C:4]=3[C:5]3=[N:23][CH:22]=[N:21][N:6]3[C:7]2=[O:20])=[CH:13][CH:14]=1
Reactant: COc1ccc(Cn2c(=O)n3ncnc3c3cc(Br)sc32)cc1
Reactant: C=C[B-](F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: CCCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=Cc1cc2c(s1)n(Cc1ccc(OC)cc1)c(=O)n1ncnc21
Temperature: 100 °C
Yield: 84 %

Procedure:
To mixture of 8-bromo-6-(4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (4.00 g, 10.2 mmol), potassium trifluoro(vinyl)borate (2.05 g, 15.3 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (417.5 mg, 0.51 mmol) in butan-1-ol (30 ml) was added triethylamine (1.43 ml, 0.01 mol). The resulting mixture was heated to 100° C. Next morning the crude mixture was cooled to room temperature at which time the solvent was removed under reduced pressure. The residue was purified over silica gel eluting with 0-20% IPA in ethyl acetate to yield 6-(4-methoxybenzyl)-8-vinylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one as a brown solid (2.90 g, 84%). 1H NMR (400 MHz, DMSO-d6) δ 3.74 (s, 3H), 5.24-5.30 (m, 1H), 5.34 (s, 2H), 5.52-5.63 (m, 1H), 6.94 (d, J=8.66 Hz, 2H), 7.41 (d, J=8.53 Hz, 2H), 7.60 (s, 1H), 8.51 (s, 1H). LCMS (MH+, 339.2).
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][O:12][C:13](/[CH:15]=[CH:16]/OC(=O)C1C=CC([N+]([O-])=O)=CC=1)=[O:14].C(N(CC)CC)C>ClCCl>[CH3:11][O:12][C:13]([C:15]1[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[N:2][O:1][CH:16]=1)=[O:14]
Reactant: COC(=O)/C=C/OC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O/N=C(\Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1conc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.1 %

Procedure:
To a mixture of (E)- and/or (Z)—N-hydroxy-benzenecarboximidoyl chloride (12.0 g, 77 mmol) and 4-nitro-benzoic-acid (E)-2-methoxycarbonyl-vinyl ester (9.7 g, 39 mmol) in dichloromethane (200 mL) was added triethylamine (20.9 mL, 150 mml) and the resulting solution stirred overnight at room temperature. The mixture was then diluted with dichloromethane (500 mL) and the organic extract removed and washed with water, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 4:1) afforded the title product (3.1 g, 40%) which was obtained as a light yellow oil. MS: m/e=204.2 [M+H]+.
Reaction SMILES: C([C@@H]([C@H](C(O)=O)O)O)(O)=O.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[C:17]([OH:19])=[O:18].C(N(CC)C(C)C)C.[F:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>[OH-].[Na+].CC(C)=O>[F:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[C:17]([OH:19])=[O:18])(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: O=C(O)[C@@H]1CCCCN1
Agent: CCN(CC)C(C)C
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(O)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.1 %

Procedure:
(2S)-2-Piperidinecarboxylic acid L-tartrate (10 g) [see Preparation 1] was dissolved in 1N aqueous sodium hydroxide solution (107.4 ml) and diethylisopropylamine (9.35 ml) was added followed by a solution of 4-fluorobenzenesulphonyl chloride (10.45 g) in acetone (107 ml) at 0° C. The reaction mixture was warmed to room temperature and stirred for 18 hours after which time the solvent was removed under reduced pressure and the residue diluted with 1N aqueous sodium hydroxide solution. The aqueous solution was washed with diethyl ether and acidified with concentrated hydrochloric acid. The product was extracted with ethyl acetate, the organic layers dried over magnesium sulphate and the solvent was removed under reduced pressure to afford (2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidinecarboxylic acid (9.89 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][N:9]2[CH:13]=[CH:12][S:11][C:10]=12)=[O:5])C.[OH-].[Na+]>CO.O>[S:11]1[CH:12]=[CH:13][N:9]2[CH:8]=[CH:7][C:6]([C:4]([OH:5])=[O:3])=[C:10]12
Reactant: CCOC(=O)c1ccn2ccsc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccn2ccsc12
Temperature: 55 °C

Procedure:
A mixture of pyrrolo[2,1-b]thiazole-7-carboxylic acid ethyl ester (5.12 mmol) and sodium hydroxide (7.68 mmol) in MeOH (5.8 mL) and water (5.8 mL) is heated to 55° C. for 23 h. The mixture is concentrated in vacuo and made acidic by addition of hydrochloric acid (1.0 M). The obtained precipitate is filtered off and dried in vacuo to give the desired product. LC-MS: tR=0.87 min; [M+H]+=168.0.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1Cl.[Cr]([Cl:15])([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([Cl:15])[CH:3]=1
Reactant: OCc1ccc(Br)c(Cl)c1
Reactant: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: OCc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of (4-bromo-3-chlorophenyl)methanol (2.0 g, 9.0 mmol), pyridinium chlorochromate (2912 mg, 13.5 mmol) in dichloromethane (50 mL0 was stirred at 25° C. for 3 hours. The mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ethe/ethyl acetate=1:1) to give (4-bromo-2-chlorophenyl)methanol as a white solid (4.12 g g, 81%). 1H NMR (300 MHz, d6-DMSO): δ 9.96 (s, 1H), 7.69 (d, J=8.1, 1H), 7.53 (d, J=0.9, 1H), 7.19 (dd, J1=8.1, 1H J2=0.9, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Br:8])=[N:6][CH:7]=1.[CH3:9][C:10](=O)[CH2:11][CH2:12][C:13](=O)[CH3:14]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:4]=[CH:3][C:2]([N:1]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:9])=[CH:7][N:6]=1
Reactant: CC(=O)CCC(C)=O
Reactant: Nc1ccc(Br)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1ccc(Br)nc1
Yield: 75.1 %

Procedure:
To a 25 mL round bottom flask was added 5-amino-2-bromopyridine (600 mg, 3.5 mmol, 1.0 equiv), hexane-2,5-dione (420 mg, 4.2 mmol, 1.2 equiv), p-toluenesulfonic acid (5 mg), and toluene (3.5 mL). A Dean-Stark trap was fitted on top of the round bottom flask and the reaction mixture was heated to reflux for 2 h. The reaction was then concentrated and purified by silica gel column chromatography (5% ethyl acetate/hexanes) to give 660 mg (76%) of 2-bromo-5-(2,5-dimethyl-1H-pyrrol-1-yl)pyridine.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[F:26][C:27]1[CH:28]=[C:29]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:30]=[CH:31][CH:32]=1>C1(C)C=CC=CC=1>[F:26][C:27]1[CH:28]=[C:29]([N:33]2[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:35][CH2:34]2)[CH:30]=[CH:31][CH:32]=1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Reactant: Fc1cccc(N2CCNCC2)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CCN(c2cccc(F)c2)CC1
Temperature: 20 °C
Yield: 37.6 %

Procedure:
The experiment is carried out as in Example 1, starting with 2(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide(8.4 g), triethylamine (4.2 cc) and 4-(3-fluorophenyl)piperazine (5.3 g) in toluene (100 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with dichloromethane and then a mixture of dichloromethane and ethyl acetate (5-50 vol) as eluant, and recrystallization from boiling acetonitrile (20 cc), 2-(3-[4-(3-fluorophenyl)-1-piperazinyl]propyl}naphtho[1,8cd]isothiazole 1,1-dioxide (4.7 g) is obtained, m.p. 103° C.
Reaction SMILES: [C:1]([C:3]1[S:11][C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]3[C:23](=[O:35])[N:24]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[N:25]=[CH:26][CH:27]=3)=[O:21])=[CH:15][C:14]=2[F:36])[CH:4]=1)#[N:2].[OH:37]S(O)(=O)=O>>[F:36][C:14]1[CH:15]=[C:16]([NH:19][C:20]([C:22]2[C:23](=[O:35])[N:24]([C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[N:25]=[CH:26][CH:27]=2)=[O:21])[CH:17]=[CH:18][C:13]=1[O:12][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[CH:4]=[C:3]([C:1]([NH2:2])=[O:37])[S:11][C:10]=12
Reactant: O=S(=O)(O)O
Reactant: N#Cc1cc2nccc(Oc3ccc(NC(=O)c4ccnn(-c5ccc(F)cc5)c4=O)cc3F)c2s1
Product: NC(=O)c1cc2nccc(Oc3ccc(NC(=O)c4ccnn(-c5ccc(F)cc5)c4=O)cc3F)c2s1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of N-(4-(2-cyanothieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (Example 173, Step B, 10 mg, 0.02 mmol) and H2SO4 (0.53 mL, 9.97 mmol) was stirred at room temperature for 17 hours. The reaction mixture was quenched with ice. The mixture was treated with 2N NaOH, extracted with CH2Cl2 (500 mL) and DMF (40 mL), dried over MgSO4, and concentrated to afford the desired product which was rinsed with Et2O. LRMS (APCI pos) m/e 520.3 (M+1). 1H-NMR (400 MHz, DMSO-d6) δ 11.72 (s, 1H), 8.59 (d, 1H), 8.38 (d, 1H), 8.27 (m, 2H), 8.06 (d, 1H), 7.69 (m, 2H), 7.57 (m, 2H), 7.42 (t, 2H), 6.79 (d, 1H); 19F NMR (376 MHz, CDCl3/CD3OD) δ −112.9, −128.3.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20](Cl)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:43]#[C:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:43]#[C:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(C#Cc2ccccc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(C#Cc2ccccc2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Temperature: 90 °C

Procedure:
In a 30 mL glass vial, tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (150 mg, 0.301 mmol), 4,4,5,5-tetramethyl-2-(phenylethynyl)-1,3,2-dioxaborolane (103 mg, 0.451 mmol) and PdCl2(PPh3)2 (105 mg, 0.150 mmol) were dissolved in dioxane (5 mL). To the reaction mixture was added 2N aqueous sodium carbonate solution (2 mL). The vessel was sealed with a cap and the reaction mixture was heated at 90° C. for 2 hours. The reaction mixture was subsequently diluted with water (10 mL) and was extracted with EtOAc (2×50 mL). The combined organic phase was dried over sodium sulfate and evaporated to give the intermediate, tert-butyl 6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-7-fluoro-3-oxo-4-(phenylethynyl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate. The intermediate was dissolved in dichloromethane (3 mL), TFA (3 mL) was added, and the mixture was stirred for 1 hour. The volatiles were subsequently evaporated and the residual material was dissolved in DMSO (5 mL) and purified by preparative HPLC, eluting with a gradient of 15-50% ACN (0.035% TFA) and water (0.05% TFA). The pure product fractions were combined, evaporated to a minimal volume, and lyophilized to give a TFA salt of the title compound as a pale yellow solid (32 mg, 29%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43 (br s, 3H), 1.66-1.91 (m, 5H), 3.63 (br s, 1H), 4.34-4.52 (m, 3H), 6.87 (d, J=7.07 Hz, 1H), 7.41-7.52 (m, 3H), 7.56-7.65 (m, 2H), 7.74 (br s, 3H), 8.48 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C21H21FN4O, 365. found, 365.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([N+:41]([O-:43])=[O:42])[CH:36]=1.CN(C=O)C>CO.C([O-])(O)=O.[Na+]>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:19]=[C:20]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([N+:41]([O-:43])=[O:42])[CH:36]=2)[CH:21]=[CH:22][CH:23]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OB(c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)OC1(C)C
Reactant: O=[N+]([O-])c1cccc(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(Nc1cccc(-c2cccc([N+](=O)[O-])c2)c1)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 70 °C

Procedure:
A solution of (S)-2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (89.7 mg, 0.20 mmol), 1-bromo-3-nitro-benzene (41.3 mg, 0.20 mmol), and Pd[P(Ph)3]4 (15.5 mg, 6.7 mol %) in methanol (2 mL), NaHCO3 (sat. aq., 300 μL), and DMF (400 μL) was degassed and heated to 70° C. overnight in a sealed vial. The reaction was cooled, filtered, and purified by reverse phase HPLC to give the desired product. Yield 7.0 mg. MS: 446.1 (M+H+); H1 NMR (DMSO-d6): δ (ppm) 1.77-2.04 (m, 3H), 2.16-2.47 (m, 1H), 3.38-3.60 (m, 2H), 4.32-4.42 (m, 1H), 4.90-5.13 (m, 2H), 7.02-8.38 (m, 13H), 10.15-10.23 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[C:17]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:19][CH2:20][CH2:21][O:22][CH3:23])[N:10]=[CH:9][CH:8]=[C:7]2[O:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:33]([NH:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:34])=[CH:25][CH:24]=1)#[N:18]
Reactant: COCCOc1cc2nccc(Oc3ccc(N)cc3)c2cc1C#N
Reactant: O=C=Nc1ccccc1
Solvent: Cc1ccccc1
Product: COCCOc1cc2nccc(Oc3ccc(NC(=O)Nc4ccccc4)cc3)c2cc1C#N

Procedure:
4-(4-Aminophenoxy)-6-cyano-7-(2-methoxyethoxy)quinoline (600 mg) was suspended in toluene (15 ml), and the suspension was heated to reflux for dissolution, after which phenyl isocyanate (292 μl) was added dropwise and the mixture was heated to reflux for 30 minutes. After cooling, the precipitated solid was filtered out, washed with ether and ethyl acetate and dried to obtain 760 mg of the title compound.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2[F:11])[N:6]=1.C(N(C(C)C)CC)(C)C.[CH2:30]1[NH:33][CH2:32][CH:31]1[OH:34].Cl>C(Cl)Cl>[F:11][C:10]1[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:8]([CH3:18])[C:7]([C:19]#[N:20])=[C:5]2[C:4]=1[O:3][C:2]([N:33]1[CH2:30][CH:31]([OH:34])[CH2:32]1)=[N:6]2
Reactant: OC1CNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)c(F)c2oc(N3CC(O)C3)nc2c1C#N

Procedure:
2-Chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (100 mg, 0.35 mmol) was dissolved in methylene chloride (2 ml), then diisopropylethylamine (237 μl, 1.39 mmol) and 3-hydroxy-1-azetidine hydrochloride (76 mg, 0.70 mmol) were added, followed by heating under reflux in a sealed tube under nitrogen atmosphere for 6 hours. After cooling, dilution with methylene chloride and washing with water and saturated brine, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated away under reduced pressure. The resisting residue was recrystallized and purified with n-hexane/ethyl acetate to obtain the entitled compound (123 mg, quant) as a yellow white solid.