Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].I[C:14]1[C:22]2[C:17](=[N:18][CH:19]=[N:20][C:21]=2[NH2:23])[N:16]([CH:24]([CH3:26])[CH3:25])[N:15]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([CH:24]([CH3:26])[CH3:25])[N:15]=[C:14]([C:6]3[CH:5]=[C:4]([C:1](=[O:3])[CH3:2])[CH:9]=[CH:8][CH:7]=3)[C:22]=12
Reactant: CC(=O)c1cccc(B(O)O)c1
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
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: CCO
Solvent: COCCOC
Product: CC(=O)c1cccc(-c2nn(C(C)C)c3ncnc(N)c23)c1
Temperature: 80 °C
Yield: 18.2 %

Procedure:
A solution of 3-Acetylphenylboronic acid (23 mg, 0.14 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (40 mg, 0.13 mmol) in DME (12 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA55 (7 mg, 18% yield). ESI-MS (M+H)+ m/z calcd 296.1, found 296.1.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[CH2:10][CH2:9][NH:8][CH:7](C(OC(C)(C)C)=O)[CH2:6][C:5]=2[C:4]2[CH:19]=[CH:20][C:21]([N:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:30]=[N:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=4)=[CH:25][C:24]3=[O:39])=[N:22][C:3]1=2.C(Cl)[Cl:41]>Cl.CO.CCOCC>[ClH:41].[CH3:1][N:2]1[C:11]2[CH2:5][CH2:6][CH2:7][NH:8][CH2:9][C:10]=2[C:4]2[CH:19]=[CH:20][C:21]([N:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:30]=[N:31][C:32]([C:35]([F:36])([F:37])[F:38])=[CH:33][CH:34]=4)=[CH:25][C:24]3=[O:39])=[N:22][C:3]1=2
Reactant: ClCCl
Reactant: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nc5)cc4=O)nc31)CC(C(=O)OC(C)(C)C)NCC2
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nc5)cc4=O)nc31)CNCCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 79 %

Procedure:
A suspension of tert-butyl 10-methyl-2-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-1(2H)-yl)-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-d]azepine-6(5H)-carboxylate (149 mg, 0.276 mmol) in 1.25 M HCl in MeOH (3.0 mL) was stirred under N2 at ambient temperature for 18 h. CH2Cl2 (1.5 mL) was added to the suspension and the resulting solution was stirred at ambient temperature for 18 h. CH2Cl2 (1.0 mL) and 1.25 M HCl in MeOH (1.0 mL) were added to the solution, and the resulting solution was stirred at ambient temperature for 6 h. Additional 1.25 M HCl in MeOH (2.0 mL) was added to the solution, and the resulting solution was stirred for 18 h. The solution was diluted with Et2O, and the resulting solids were collected by filtration to afford the title compound (104 mg, 79%) as a light-yellow powder: mp 308-312° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.21 (d, J=2.0 Hz, 1H), 9.04 (s, 2H), 8.50 (dd, J=8.0, 2.0 Hz, 1H), 8.22 (d, J=8.0 Hz, 1H), 8.09-8.05 (m, 2H), 7.47 (d, J=8.0 Hz, 1H), 7.03 (d, J=2.0 Hz, 1H), 6.85 (dd, J=7.5, 2.0 Hz, 1H), 4.49 (s, 2H), 3.80 (s, 3H), 3.49-3.46 (m, 2H), 3.17-3.15 (m, 2H), 2.09-2.07 (m, 2H); ESI MS m/z 440 [M+H]+; HPLC (Method A) 98.1% (AUC), tR=13.4 min.
Reaction SMILES: C1(=O)[N:5]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([C@@H:15]4[O:30][C@H:29]([CH2:31][O:32]C(C5C=CC(C)=CC=5)=O)[C@@H:18]([O:19]C(C5C=CC(C)=CC=5)=O)[C@@:16]4([CH3:42])[OH:17])[C:8]=3[N:9]=[CH:10][N:11]=2)C(=O)C2=CC=CC=C12.C(N)CCC>CO>[NH2:5][C:6]1[C:7]2[CH:14]=[CH:13][N:12]([C@@H:15]3[O:30][C@H:29]([CH2:31][OH:32])[C@@H:18]([OH:19])[C@@:16]3([CH3:42])[OH:17])[C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: Cc1ccc(C(=O)OC[C@H]2O[C@@H](n3ccc4c(N5C(=O)c6ccccc6C5=O)ncnc43)[C@](C)(O)[C@@H]2OC(=O)c2ccc(C)cc2)cc1
Solvent: CCCCN
Solvent: CO
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(N)ncnc21
Temperature: 25 °C
Reaction time: 27 h

Procedure:
To the toluene solution from Step B at ambient temperature were added methanol (25 L) and n-butylamine (3.13 kg, 42.9 mol). The reaction mixture was aged at 64° C. for 24 to 30 h. The mixture was concentrated to about 9 L, and 9 L of methanol was added. The solution was concentrated to 9 L, and the resulting slurry was aged at 60° C. for 60 min. Toluene (13 L) was added over 1.5 h. The slurry was aged at 60° C. for another 2 h and then allowed to cool to ambient temperature. The solid was filtered and the wet cake was washed with 9 L of 20% methanol in toluene then 9 L of 10% methanol in toluene. The solid was suction dried at ambient temperature under nitrogen to give 1.79 kg (94 wt % pure) of the title nucleoside 4-3 as the toluene solvate.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[C:4]2[CH2:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH2:13][C:3]=12.[CH2:16](OCC)C>C[Li]>[CH3:1][C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:16])=[C:4]2[CH2:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH2:13][C:3]=12
Reactant: Cc1sc(C(=O)O)c2c1CC(C)(C)CC2
Reactant: CCOCC
Agent: [Li]C
Product: CC(=O)c1sc(C)c2c1CCC(C)(C)C2
Temperature: 26 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (4.10 g, 18.28 mmol) in diethyl ether (300 mL), methyllithium (23 mL, 1.6 M solution in diethyl ether) is slowly added at rt. The reaction mixture becomes clear, yellow and slightly warm (26° C.), and is stirred for 15 min before it is quenched with water. The organic layer is separated, washed once more with water, dried over MgSO4 and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give 1-(3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-ethanone (2.80 g) as a pale yellow crystalline solid; LC-MS: tR=1.06 min, [M+1]=223.17; 1H NMR (CDCl3): δ 3.00 (t, J=7.0 Hz, 2H), 2.43 (s, 3H), 2.31 (s, 3H), 2.26 (s, 2H), 1.51 (t, J=7.0 Hz, 2H), 0.95 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:21]=[C:20]([I:22])[C:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH2:19][C:13]=3[CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:23](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O.O>ClCCl>[CH3:23][N:17]1[CH2:16][CH2:15][C:14]2[C:20]([I:22])=[CH:21][C:11]([S:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)(=[O:9])=[O:10])=[CH:12][C:13]=2[CH2:19][CH2:18]1
Reactant: O=S(=O)(c1ccc(F)cc1)c1cc(I)c2c(c1)CCNCC2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CN1CCc2cc(S(=O)(=O)c3ccc(F)cc3)cc(I)c2CC1
Reaction time: 2 h
Yield: 98 %

Procedure:
To a solution of 7-(4-fluorophenylsulfonyl)-9-iodo-1,2,4,5-tetrahydro-3-benzazepine (2.4 g, 5.5 mmol) in dichloromethane (20 ml) were added sodium triacetoxyborohydride (1.8 g, 8.5 mmol) and formalin (1 ml, 37%, 12 mmol). The mixture was stirred for 2 h without cooling then poured into water (100 ml) and extracted with more dichloromethane (100 ml). The resulting organic layer was washed with brine (100 ml), dried (MgSO4), and evaporated to give the subtitle compound as a white foam (2.4 g).
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].CC([O-])(C)C.[K+].Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=3)[CH:21]=2)[C:16]([Cl:31])=[CH:15][N:14]=1>COCCOC.CN1C(=O)CCC1>[Cl:31][C:16]1[C:17]2[C:22](=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=3)=[CH:19][CH:18]=2)[C:13]([NH:4][C:3]([NH2:5])=[NH:2])=[N:14][CH:15]=1
Reactant: N=C(N)N
Reactant: N#Cc1cccc(-c2ccc3c(Cl)cnc(Cl)c3c2)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: COCCOC
Product: N#Cc1cccc(-c2ccc3c(Cl)cnc(NC(=N)N)c3c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
A stirred suspension of guanidine hydrochloride (3.8 kg, 39.8 mol) and KOtBu (4.28 kg, 38.1 mol) in DME (17.6 L) was heated to reflux under N2 for 1 hour. The gum containing solution was cooled to room temperature, diluted with NMP (8.8 L) and 1,4-dichloro-7-(3-cyanophenyl)isoquinoline (4.4 kg, 14.7 mol) was added as a solid. The mixture was heated at reflux overnight, cooled to room temperature, filtered through a pad of celite and the pad washed with DME (4.4 L). Water (35.2 L) was added to the filtrate. The resultant slurry was stirred for 2 hour and the solid collected by filtration. The solid was washed with water (4.4 L) and dried in vacuo at 50° C. to give (4-chloro-7-(3-cyanophenyl)isoquinolin-1-yl)guanidine (4.55 kg, 14.1 mol, 96%) as a green solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11]([N:13]3[CH2:16][CH:15]([O:17][CH3:18])[CH2:14]3)=[O:12])[N:10]=2)[CH2:3]1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(N(CC)CC)C>C(Cl)Cl>[CH3:19][S:20]([O:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11]([N:13]3[CH2:16][CH:15]([O:17][CH3:18])[CH2:14]3)=[O:12])[N:10]=2)[CH2:3]1)(=[O:22])=[O:21]
Reactant: COC1CN(C(=O)c2csc(N3CC(O)C3)n2)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1CN(C(=O)c2csc(N3CC(OS(C)(=O)=O)C3)n2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
To a solution of 3-hydroxy-1-[4-(3-methoxyazetidine-1-carbonyl)-1,3-thiazol-2-yl]azetidine (480 mg, 1.71 mmol) (obtained as described in Reference Example 31(3)) in methylene chloride (25 ml) were added methanesulfonyl chloride (397 μl, 5.13 mmol) and triethylamine (719 μl, 5.13 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 1 hour. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:methanol (95:5) as the eluant to afford 3-methanesulfonyloxy-1-[4-(3-methoxyazetidine-1-carbonyl)-1,3-thiazol-2-yl]azetidine (568 mg, yield 96%) as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][C:9]#[C:10][C:11]([C:13]1[N:14]([CH2:24][CH3:25])[N:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:17]=1)=O)([CH3:4])([CH3:3])[CH3:2].O.[NH2:28][NH2:29]>CCO>[C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][C:9]1[NH:29][N:28]=[C:11]([C:13]2[N:14]([CH2:24][CH3:25])[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:17]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCn1nc(-c2ccccc2)cc1C(=O)C#CCNC(=O)OC(C)(C)C
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCn1nc(-c2ccccc2)cc1-c1cc(CNC(=O)OC(C)(C)C)[nH]n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To the above-prepared [4-(2-ethyl-5-phenyl-2H-pyrazol-3-yl)-4-oxo-but-2-ynyl]-carbamic acid tert-butyl ester in EtOH (5 mL), hydrazine monohydrate was added (excess, 5 drops), and the mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo to a thick oil, diluted with ethyl acetate, washed sequentially with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. Flash chromatography (silica gel, hexanes/ethyl acetate gradient) provided the title compound (175 mg, 98% yeild) as a white foam. 1H NMR (CDCl3, 400 MHz): 7.86 (d, 2H); 7.39 (dd, 2H); 7.28 (dd, 1H); 6.72 (s, 1H); 6.36 (s, 1H); 5.12 (broad dd, 1H); 4.58 (q, 2H); 4.31 (d, 2H); 1.49 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=[O:12])=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[CH:14]1C=CC=CC=1.C[Si](C=[N+]=[N-])(C)C>CO>[F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: O=C(O)c1ccc(F)c2cc[nH]c12
Reactant: c1ccccc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)c1ccc(F)c2cc[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 4-fluoro-7-carboxyindole in a mixture of MeOH (18 ml)/PhH (62 ml) was added (trimethylsilyl)diazomethane (8.8 ml, 17.6 mmol, 2 M in hexane). The resulting mixture was stirred at room temperature for 30 min., quenched with excess acetic acid and evaporated in vacuo. The crude oily material was purified by flash chromatography using a gradient elution (Hexane to 10% EtOAc/Hexane) to afford methyl (4-fluoro)indole-7-carboxylate as a white solid (1.04 g, 83% two steps)
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[CH2:3][C:4](=[O:8])[C:5]([OH:7])=[O:6].Cl[Si](C)(C)[CH3:12]>CO.COC(OC)(C)C>[CH3:12][O:6][C:5](=[O:7])[C:4](=[O:8])[CH2:3][CH:2]([CH3:9])[CH3:1]
Reactant: CC(C)CC(=O)C(=O)O
Reactant: C[Si](C)(C)Cl
Solvent: COC(C)(C)OC
Solvent: CO
Product: COC(=O)C(=O)CC(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-methyl-2-oxo-pentanoic acid (3.4 g, 26 mmol) in methanol (12 mL) and 2,2-dimethoxypropane (48 mL) is added chlorotrimethylsilane (0.38 mL). The reaction mixture is stirred at ambient temperature overnight. The reaction mixture is concentrated under reduced pressure to give the title compound as an oil, (3.8 g, quant.). 1H NMR (400 MHz, CDCl3): δ 3.86 (s, 3H), 2.72 (d, 2H), 2.16 (m, 1H), 0.96 (d, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:30](O)(=[O:36])[CH2:31][NH:32][C:33]([NH2:35])=[O:34]>>[C:33]([NH:32][CH2:31][C:30]([NH:21][C@@H:19]([CH3:20])[C@H:18]([O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[N:9]=[CH:10]2)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)=[O:36])(=[O:34])[NH2:35]
Reactant: NC(=O)NCC(=O)O
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)CNC(N)=O)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy) 1-(3-methoxyphenyl)propan-2-amine (6a, 200 mg, 0.51 mmol) and hydantoic acid (60 mg, 0.51 mmol).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.Cl.[NH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]3([C:33]4[C:24](=[CH:25][C:26]5[O:31][CH2:30][CH2:29][O:28][C:27]=5[CH:32]=4)[O:23][CH2:22]3)[C:14]2=[O:34])[CH2:8][CH2:7]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][CH:2]([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]3([C:33]4[C:24](=[CH:25][C:26]5[O:31][CH2:30][CH2:29][O:28][C:27]=5[CH:32]=4)[O:23][CH2:22]3)[C:14]2=[O:34])[CH2:8][CH2:7]1)[CH3:4]
Reactant: O=C1N(CC2CCNCC2)c2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)N1CCC(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of acetone (0.19 mL, 2.5 mmol) and 1,2-dichloroethane (5.0 mL), were added 1′-(piperidin-4-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one hydrochloride (0.36 g, 0.84 mmol), triethylamine (0.35 mL, 2.5 mmol) and sodium triacetoxyborohydride (0.534 g, 2.52 mmol). The mixture was stirred at ambient temperature for 16 h and concentrated in vacuo. The residue was purified by column chromatography and eluted with ethyl acetate/methanol/ammonium hydroxide (20/1/0.2) to afford 1′-{[1-(1-methylethyl)piperidin-4-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one. To a solution of this compound in methanol (5 mL) was added a 4 M solution of hydrogen chloride in 1,4-dioxane (1.0 mL, 4.0 mmol) and the mixture was stirred at ambient temperature for 30 min and concentrated in vacuo. Sequential trituration of the residue in hexanes and diethyl ether afforded 1′-{[1-(1-methylethyl)piperidin-4-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one hydrochloride (0.21 g, 53%) as an off-white solid: mp 213-216° C.; 1H NMR (300 MHz, DMSO-d6) δ10.02-9.80 (br s, 1H), 7.40-7.02 (m, 4H), 6.51 (s, 1H), 6.18 (s, 1H), 4.74 (d, J=9.3 Hz, 1H), 4.62 (d, J=9.3 Hz, 1H), 4.23-4.06 (m, 4H), 3.73-3.21 (m, 4H), 3.00-2.78 (m, 2H), 2.20-1.52 (m, 5H), 1.32-1.12 (m, 7H); 13C NMR (75 MHz, DMSO-d6) δ176.8, 154.7, 144.0, 142.5, 137.7, 131.6, 128.7, 123.5, 122.8, 121.0, 111.1, 109.2, 98.6, 79.7, 64.1, 63.5, 57.1, 56.7, 47.1, 44.2, 32.1, 26.6, 26.4, 16.1; MS (ES+) m/z 435.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH3:40])=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([N:21](CC4C=CC(OC)=CC=4OC)[C:22]4[S:26][N:25]=[CH:24][N:23]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[C:11](=[O:38])[NH:10][N:9]=2)[CH:7]=1.C(Cl)Cl.C(O)(C(F)(F)F)=O.[NH4+].[OH-]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH3:40])=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:21][C:22]4[S:26][N:25]=[CH:24][N:23]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[C:11](=[O:38])[NH:10][N:9]=2)[CH:7]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4cc(Cl)ccc4OC)n[nH]c(=O)c3c2)c(OC)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Cl)cc1-c1n[nH]c(=O)c2cc(S(=O)(=O)Nc3ncns3)ccc12
Reaction time: 0.5 h
Yield: 60 %

Procedure:
A vial was charged with N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (70.7 mg, 0.282 mmol) and THF (938 μl). The resulting solution was cooled to −78° C. for 10 min. Then lithium bis(trimethylsilyl)amide (1M in THF) (413 μl, 0.413 mmol) was added drop wise. The vial was removed from the cold bath temporarily to ensure complete deprotonation of PMB-aminothiadiazole. When the suspension became homogenous, the reaction was cooled back down to −78° C. Then perfluorophenyl 1-(5-chloro-2-methoxyphenyl)-4-oxo-3,4-dihydrophthalazine-6-sulfonate (100 mg, 0.188 mmol) in 0.5 mL of THF was added drop wise. LCMS after 15 min showed complete conversion of SM to product. The reaction was warmed to rt, quenched with 1 mL of MeOH and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 70% EtOAc in heptane, to provide 1-(5-chloro-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-4-oxo-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydrophthalazine-6-sulfonamide (38 mg, 33.7% yield) as white solid. m/z (ESI) 600.0 (M+H)+, 622.0 (M+Na)+. 1-(5-Chloro-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-4-oxo-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydrophthalazine-6-sulfonamide (38 mg, 0.063 mmol) was dissolved in DCM (633 μl, 0.063 mmol) and then TFA (24.4 μl, 0.317 mmol) was added. After 30 min at rt, LCMS showed a complete conversion of SM to product. Purification was done with 0.1% NH4OH in ACN and water as mobile phase to afford 1-(5-chloro-2-methoxyphenyl)-4-oxo-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydrophthalazine-6-sulfonamide (17 mg, 59.7% yield) and NH4OH as a triplet at ˜7.07 ppm. To remove NH4OH, the product was dissolved in MeOH (1 mL) and loaded onto a 2 g SCX column. The product was flushed out with MeOH. Concentration afforded 1-(5-chloro-2-methoxyphenyl)-4-oxo-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydrophthalazine-6-sulfonamide as white solid. m/z (ESI) 450.0 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1([C:39]2[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=2)[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21](CCCCCCC(F)(F)C(F)(F)F)[C:22]([OH:24])=[O:23])[C:11]2[C:6](=[CH:7][C:8]([OH:38])=[CH:9][CH:10]=2)[S:5][CH2:4]1)[CH3:2].[F:46][C:47]([F:69])([C:65]([F:68])([F:67])[F:66])[CH2:48][CH2:49][CH2:50][CH2:51]C(CCCCCC=C)C(OCC)=O>>[CH2:1]([C:3]1([C:39]2[CH:40]=[CH:41][C:42]([OH:45])=[CH:43][CH:44]=2)[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([CH2:51][CH2:50][CH2:49][CH2:48][C:47]([F:46])([F:69])[C:65]([F:66])([F:67])[F:68])[C:22]([OH:24])=[O:23])[C:11]2[C:6](=[CH:7][C:8]([OH:38])=[CH:9][CH:10]=2)[S:5][CH2:4]1)[CH3:2]
Reactant: CCC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(=O)O
Reactant: C=CCCCCCC(CCCCC(F)(F)C(F)(F)F)C(=O)OCC
Product: CCC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCC(CCCCC(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the allyl compound prepared in Example 13 and the ethyl 2-(5,5,6,6,6-pentafluorohexyl)-8-nonenoate prepared in Example 9, the same procedure as shown in Example 13 was repeated to give 10-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]-2-(5,5,6,6,6-pentafluorohexyl)decanoic acid.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([NH:13][CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Cl)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(NC2CCNC2)cc1
Yield: 215.9 %

Procedure:
To a solution of tert.butyl-3-(4-chloroanilino)-1-pyrrolidinecarboxylate (130 mg, 0.438 mmol) in CH2Cl2 (5 mL) was added CF3COOH (1 mL). After 30 min the volatiles were removed in vacuo to give the subtitled product (186 mg) and was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH2:5][C@@:6]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:17][CH:16]=2)[CH3:14])[CH2:8][CH2:7]1)[C:3]#[N:4].Cl[C:38]1[N:39]=[N:40][C:41]([CH3:44])=[CH:42][CH:43]=1>>[CH3:36][C:2]([CH3:1])([CH2:5][C@@:6]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:20]=[CH:19][C:18]([C:38]3[N:39]=[N:40][C:41]([CH3:44])=[CH:42][CH:43]=3)=[CH:17][CH:16]=2)[CH3:14])[CH2:8][CH2:7]1)[C:3]#[N:4]
Reactant: Cc1ccc(Cl)nn1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O
Product: Cc1ccc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)C#N)(c4ccccc4)OC3=O)cc2)nn1

Procedure:
The title compound was prepared from 2,2-dimethyl-3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanenitrile and 3-chloro-6-methylpyridazine following a procedure analogous to that described in Example 459 Step 4. LC-MS Method 1 tR=1.41 min, m/z=455; 1H NMR (CDCl3) 8.20 (d, 1H), 7.92 (d, 1H), 7.74 (d, 2H), 7.37 (dt, 6H), 7.05 (d, 2H), 5.66 (q, 1H), 3.00 (dm, 1H), 2.93 (s, 3H), 2.49 (m, 2H), 2.34 (m, 1H), 2.17 (d, 2H), 1.58 (d, 3H), 1.39 (s, 3H), 1.33 (s, 3H).
Reaction SMILES: [NH2:1][OH:2].[C:3]1([C:9]2([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)[O:14][CH2:13]C=[CH:11][O:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C>C(O)C>[OH:2][N:1]=[C:19]([C:18]1[CH:17]=[CH:16][C:15]([C:9]2([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[O:14][CH2:13][CH2:11][O:10]2)=[CH:22][CH:21]=1)[NH2:20]
Reactant: N#Cc1ccc(C2(c3ccccc3)OC=CCO2)cc1
Reactant: NO
Solvent: CCN(CC)CC
Solvent: CCO
Product: NC(=NO)c1ccc(C2(c3ccccc3)OCCO2)cc1
Yield: 102 %

Procedure:
) Hydroxylamine (0.0449 mol) was added to a mixture of 4-(2-phenyl-1,3-dioxin-2-yl)benzonitrile (0.022 mol) in ethanol (88 ml). Then, N,N-diethylethanamine (0.0449 mol) was added dropwise and the resulting reaction mixture was stirred and refluxed for 3.5 hours. The solvent was evaporated. The residue was washed with water and this mixture was extracted with EtOAc. The separated organic layer was dried (Na2SO4), filtered and the solvent was evaporated, yielding 6.38 g of N′-hydroxy-4-(2-phenyl-1,3-dioxolan-2-yl)benzenecarboimidamide (interm. 10)