Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:12])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[OH-:13].[Na+].[CH2:15]=O>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:12])=[C:7]([CH2:15][OH:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Oc1ccnc2cc(F)ccc12
Reactant: [OH-]
Reactant: C=O
Agent: [Na+]
Product: OCc1cnc2cc(F)ccc2c1O
Reaction time: 5.5 h

Procedure:
A mixture of 7-fluoro-4-hydroxyquinoline (91.5 g., containing some 5-fluoro isomer), aqueous sodium hydroxide (1.0 N, 666 ml.) and aqueous formaldehyde (37%, 91.5 ml.) was stirred at 35°-37° for 5.5 hours. A further portion of aqueous formaldehyde (37%, 91.5 ml.) was added and stirring continued for 64 hours. The solid product was collected by filtration, added to water (600 ml.) and the mixture acidified to pH 4.0 with concentrated hydrochloric acid. The solid residue was collected, washed with water and dried to give the novel 7-fluoro-4-hydroxy-3-hydroxymethylquinoline, m.p. 295°-300° (containing some 5-fluoro isomer). Further product m.p. 295°-300°, was obtained from the alkaline filtrate of the reaction mixture by acidification to pH 4.0 with concentrated hydrochloric acid, and was combined with the first product.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])/[CH:3]=[N:4]/[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]>CO.[Pd]>[F:1][C:2]([F:13])([F:14])[CH2:3][NH:4][NH:5][C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7]
Reactant: CC(C)(C)OC(=O)N/N=C/C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NNCC(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.6 %

Procedure:
A mixture of (E)-tert-butyl 2-(2,2,2-trifluoroethylidene)hydrazinecarboxylate (4.00 g, 18.9 mmol) and 20% Pd/C (2.00 g) in MeOH (20.0 mL) was stirred under H2 atmosphere at 25° C. for 16 h. The solid was filtered off and the filtrate was evaporated to give the crude product, which was purified by silica gel chromatography eluting with EtOAc/petroleum ether (1:100) to afford tert-butyl 2-(2,2,2-trifluoroethyl)hydrazinecarboxylate (1.32 g, 33% yield) as pale yellow oil. LCMS (ESI) m/z: 159.3 [M-56+H+].
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][N:4]=1.[NH2:14][CH:15]1[C:20](=[O:21])[N:19]2[CH:22]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[C:23](=[O:29])[N:24]([CH:26]([CH3:28])[CH3:27])[CH2:25][CH:18]2[N:17]([S:38]([C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:42]=2[Cl:48])(=[O:40])=[O:39])[CH2:16]1>>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][CH:22]2[N:19]3[C:20](=[O:21])[CH:15]([NH:14][C:7](=[O:8])[C:6]4[CH:10]=[CH:11][C:3]([C:2]([F:13])([F:12])[F:1])=[N:4][CH:5]=4)[CH2:16][N:17]([S:38]([C:41]4[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:42]=4[Cl:48])(=[O:40])=[O:39])[CH:18]3[CH2:25][N:24]([CH:26]([CH3:28])[CH3:27])[C:23]2=[O:29])=[CH:32][CH:33]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)nc1
Reactant: CC(C)N1CC2N(C(=O)C(N)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Product: CC(C)N1CC2N(C(=O)C(NC(=O)c3ccc(C(F)(F)F)nc3)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O

Procedure:
Synthesis took place in analogy to Example 22 using 6-(trifluoromethyl)nicotinoyl chloride and 3-amino-6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropyl-hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW=731.08 (calculated, monoisotopic); measured value (M+H)+: 732.01
Reaction SMILES: [CH3:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.O[C:39]1[CH:44]=[CH:43][C:42]([C:45]2[S:46][C:47]([C:51]([O:53][CH2:54][CH3:55])=[O:52])=[C:48]([CH3:50])[N:49]=2)=[CH:41][C:40]=1[N:56]1[CH:60]=[N:59][N:58]=[N:57]1>O1CCCC1.O.C1(C)C=CC=CC=1>[OH:4][CH2:3][CH:2]([CH3:1])[CH2:5][O:6][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[S:46][C:47]([C:51]([O:53][CH2:54][CH3:55])=[O:52])=[C:48]([CH3:50])[N:49]=2)=[CH:41][C:40]=1[N:56]1[CH:60]=[N:59][N:58]=[N:57]1
Reactant: CC(CO)CO
Reactant: CCOC(=O)c1sc(-c2ccc(O)c(-n3cnnn3)c2)nc1C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1sc(-c2ccc(OCC(C)CO)c(-n3cnnn3)c2)nc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 168 %

Procedure:
A solution was prepared by dissolving 13.5 mg of 2-methypropan-1,3-diol in 1 mL of tetrahydrofuran and adding 39.3 mg of triphenylphosphine and 65 μL of a 40% toluene solution of diethyl azodicarboxylate to the mixture. After stirring the resultant solution at room temperature for 30 minutes, a reaction mixture solution prepared by adding 33.1 mg of ethyl 2-[4-hydroxy-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5-carboxylate to the solution was stirred at room temperature for 3 hours. After the addition of water to the reaction mixture solution, extraction was performed using ethyl acetate. The organic layer was washed with saline and then dried and concentrated under reduced pressure, followed by purifying by a conventional method to obtain 67.7 mg of ethyl 2-[4-(3-hydroxy-2-methylpropoxy)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:21]([O:23]CC2C=CC(OC)=CC=2)=[O:22])[CH:9]([C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[CH:6][CH:7]=1.COC1C=CC=CC=1.FC(F)(F)C(O)=O>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([CH:9]([C:11]2[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=2)[CH3:10])[C:21]([OH:23])=[O:22])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(C(C)C(C(=O)OCc2ccc(OC)cc2)c2cccc(Br)c2)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(C(C)C(C(=O)O)c2cccc(Br)c2)cc1
Reaction time: 1.5 h

Procedure:
The intermediate from Step B (0.8 g, 1.6 mmol) was treated with 4-methoxy benzene (2 mL) and trifluoroacetic acid (15 mL). After stirring for 1.5 hours the solution was concentrated and the residue purified by silica gel chromatography using a hexanes/ethyl acetate gradient (containing 0.05% acetic acid) to give the title compounds as mixture of diastereomers. 1H NMR (400 MHz, CDCl3): selected data δ 3.90 (s); 3.85 (s); 3.72-3.64 (m); 3.52-3.42 (m); 1.39 (d, J=6.8 Hz); 1.03 (d, J=7.0 Hz). LCMS1 3.34 min. (M+H)=377. LC1 3.57 min. (M+H)=377.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH:2](CC(O)=O)[OH:3].[C:10]([O-:13])(=[O:12])[CH3:11].[Na+:14]>C(O)(=O)C>[C:10]([OH:13])(=[O:12])[CH2:11][O:3][CH2:2][C:1]([O-:9])=[O:8].[Na+:14]
Reactant: CC(=O)[O-]
Reactant: O=C(O)CC(O)C(=O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C([O-])COCC(=O)O

Procedure:
In reaction ii, sodium bisulfate is reacted with sodium acetate to produce sodium sulfate and solid acetic acid. In reaction iii., malic acid is reacted with sodium acetate to produce sodium hydrogen diglycolate and solid acetic acid. In reaction iv., fumaric acid is reacted with sodium acetate to produce sodium hydrogen fumarate and solid acetic acid. In reaction v., tartaric acid is reacted with sodium acetate to produce sodium hydrogen tartrate and solid acetic acid. In reaction vi., adipic acid is reacted with sodium acetate to produce sodium hydrogen adipate and solid acetic acid. In reaction vii, sulfamic acid is reacted with sodium acetate to produce sodium sulfamate and solid acetic acid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.Br.[C:23]([NH:26][CH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[CH2:33][NH:32][CH2:31]2)(=[O:25])[CH3:24].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[C:23]([NH:26][CH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[CH2:33][N:32]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[C:9]([NH2:17])[C:10]=1[F:16])[CH2:31]2)(=[O:25])[CH3:24]
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: CC(=O)NCc1ccc2c(c1)CNC2
Agent: Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(=O)NCc1ccc2c(c1)CN(c1c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c1F)C2
Yield: 62.1 %

Procedure:
447 mg of 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 490 mg of 5-acetamidomethylisoindoline hydrobromide, 795 mg of DBU, and 3 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 436 mg of 7-(5-acetamidomethyl-2-isoindolinyl)-1-cyclopropyl-5-amino-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]([NH:26][C:27]([NH:29][CH2:30][C:31]([F:34])([F:33])[F:32])=[O:28])([C:12]2[CH:17]=[C:16]([O:18][C:19]([F:24])([F:23])[CH:20]([F:22])[F:21])[CH:15]=[C:14]([F:25])[CH:13]=2)[CH2:9][CH:10]=[CH2:11])=[CH:4][C:3]=1[C:35]([F:38])([F:37])[F:36].[CH2:39]([Zn]CC)C.ICI.Cl>C1(C)C=CC=CC=1>[CH:10]1([CH2:9][C@@:8]([NH:26][C:27]([NH:29][CH2:30][C:31]([F:32])([F:33])[F:34])=[O:28])([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:35]([F:38])([F:36])[F:37])[CH:4]=2)[C:12]2[CH:17]=[C:16]([O:18][C:19]([F:23])([F:24])[CH:20]([F:22])[F:21])[CH:15]=[C:14]([F:25])[CH:13]=2)[CH2:39][CH2:11]1
Reactant: CC[Zn]CC
Reactant: C=CC[C@](NC(=O)NCC(F)(F)F)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(C(F)(F)F)c1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ICI
Product: O=C(NCC(F)(F)F)N[C@@](CC1CC1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(C(F)(F)F)c1
Temperature: 110 °C
Reaction time: 0.08 h
Yield: 31.9 %

Procedure:
At 0° C. under argon, to a solution of (R)-1-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)but-3-enyl)-3-(2,2,2-trifluoroethyl)urea (40 mg, 0.070 mmol), prepared as described in Procedure 6 and 10, in dry toluene (1 mL) was added diethyl Zinc (1.0 M in hexane, 1.2 mL, 1.2 mmol), followed by dropwise addition of diiodomethane (0.2 mL). The reaction mixture was gradually warmed to 110° C., and heated at 110° C. for 1 h. After cooling, 1 N HCl was added and the reaction mixture was stirred at room temperature for 5 min. The reaction mixture was extracted with EtOAc and the organic layer was washed with H2O, sat. NaHCO3, sat. NaCl, dried over Na2SO4, filtered and concentrated. The residue was purified by Prep HPLC (phenomenex AXIA Luna 75×30 mm, 5 u column eluting with 50-100% MeOH in H2O with 0.1% TFA, 40 mL/min, monitoring at 220 nm) to give (R)-1-(2-cyclopropyl-1-(4-fluoro-3-(trifluoromethyl)-phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)ethyl)-3-(2,2,2-trifluoroethyl)urea (Example 317) as white solid (13 mg, yield 32%). LCMS: RT=3.26 min [M+H] 583.2 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 50-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm). 1H NMR (400 MHz, CDCl3) δ ppm 7.55 (d, J=6.6 Hz, 1H), 7.46 (m, 1H), 7.12 (t, J=9.3 Hz, 1H), 6.94-6.85 (m, 3H), 5.84 (tt, J=52.8, 2.8 Hz, 1H), 5.61 (br, s, 1H), 4.78 (br, t, J=6.1 Hz, 1H), 3.69 (m, 2H), 2.31 (m, 2H), 0.36 (m, 3H), 0.00 (m, 2H).
Reaction SMILES: CO[C:3](=[O:20])[C:4]([OH:19])=[CH:5][C:6](=[O:18])[N:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1)[CH3:8].C=O.NCC1C=CN=CC=1.ClC1C=[C:34](C=CC=1Cl)[CH2:35][N:36](C)[C:37]([C:39]1[CH2:40][N:41](C)[C:42](=O)[C:43]=1O)=O>>[Cl:17][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[Cl:16])[CH2:9][N:7]([CH3:8])[C:6]([C:5]1[CH:35]([CH3:34])[N:36]([C:37]2[CH:39]=[CH:40][N:41]=[CH:42][CH:43]=2)[C:3](=[O:20])[C:4]=1[OH:19])=[O:18]
Reactant: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(Cl)c(Cl)c1
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Agent: C=O
Agent: NCc1ccncc1
Product: CC1C(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C(=O)N1c1ccncc1
Yield: 5 %

Procedure:
3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and 4-(amino-methyl)pyridine as described in the preparation of Compound 12. The resulting residue was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as a sticky orange solid (10.5 mg, 5% yield). 1H NMR (300 MHz, DMSO) δ: 8.75 (d, 2H, J=6.22), 7.63–7.52 (m, 4H), 7.25 (d, 2H, J=7.31), 4.80 (s, 2H), 4.59 (s, 2H), 4.1 (s, 2H), 2.99 (bs, 3H). HRMS (M−H) calcd for C19H16N3Cl2O3: 404.0568. found: 404.0554.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH:5]1[CH2:10][CH2:9][CH2:8][NH:7][CH2:6]1)[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[CH2:18]([Br:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[BrH:25].[CH2:1]([O:3][C:4]([CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:6]1)=[O:11])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C1CCCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Br
Product: CCOC(=O)C1CCCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 47.4 %

Procedure:
To a stirred mixture of 35.4 g (0.225 mole) of (±) ethylnipecotate and 31.8 g (0.3 mole) of anhydrous sodium carbonate in 300 ml of absolute ethanol was added dropwise 41 g (0.24 mole) of benzylbromide and the mixture was stirred at ambient temperature for 24 hr. The mixture was filtered and the filtrate was concentrated. The residue was partitioned between 250 ml of methylene chloride and 250 ml of a 5% sodium hydroxide solution. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to give a gummy residue. The residue was triturated with ethyl ether, filtered, and the filtrate treated with hydrogen bromide gas. The solid which precipitated was collected by filtration and recrystallized from 2-propanol to yield 35.0 g (47%) of the title compound as a white solid, mp 148°-152° C.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[CH2:3][CH2:4][C@@H:5]([C:16](=[O:38])[NH:17][CH:18]1[C:24](=[O:25])[NH:23][C:22]2[CH:26]=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:21]=2[C:20]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N:19]1)[C@H:6]([CH2:10][CH2:11][C:12]([F:15])([F:14])[F:13])[C:7]([OH:9])=O.[Cl-].[NH4+].CC[N:45](C(C)C)C(C)C>CS(C)=O>[CH3:31][O:30][C:28]1[CH:27]=[CH:26][C:22]2[NH:23][C:24](=[O:25])[C@@H:18]([NH:17][C:16](=[O:38])[C@H:5]([CH2:4][CH2:3][C:2]([F:39])([F:1])[F:40])[C@H:6]([CH2:10][CH2:11][C:12]([F:15])([F:14])[F:13])[C:7]([NH2:45])=[O:9])[N:19]=[C:20]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:21]=2[CH:29]=1
Reactant: COc1ccc2c(c1)C(c1ccccc1)=NC(NC(=O)[C@H](CCC(F)(F)F)[C@H](CCC(F)(F)F)C(=O)O)C(=O)N2
Reactant: CCN(C(C)C)C(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: COc1ccc2c(c1)C(c1ccccc1)=N[C@H](NC(=O)[C@H](CCC(F)(F)F)[C@H](CCC(F)(F)F)C(N)=O)C(=O)N2
Temperature: 25 °C

Procedure:
To a stirred solution of Intermediate 7E (500 mg, 1.047 mmol), pyBOP (0.65 mg, 1.25 mmol), and ammonium chloride (0.28 mg, 5.23 mmol) in DMSO (6 mL), at 0° C. under a nitrogen atmosphere, was added dropwise a solution of N,N′-diisopropylethylamine (0.36 mL, 2.09 mmol) over two minutes. The ice bath was removed and the reaction mixture was stirred at room temperature for sixteen hours. The mixture was then poured into ice cooled water (20 grams) and stirred for one hour and then filtered. The crude residue was subjected to preparative HPLC purification/separation (Column-CHIRALCEL® ODH (250×4.6) mm 5 micron, Mobile Phase A: 0.2% diethylamine-hexane (80%), Mobile Phase B: ethanol (20%), @ 220 and 250 nm Flow-1 ml/Min, Run-20 min) to provide Intermediate 7F as a white solid: yield 180 mg (10%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.67 (s, 1H), 9.444-9.463 (d, J=7.6 Hz, 1H), 7.60-7.7 (brs, 1H), 7.51-7.54 (m, 3H), 7.44-7.47 (m, 2H), 7.24-7.28 (m, 2H), 7.14-7.19 (brs, 1H), 6.77-6.78 (d, J=4 Hz, 1H), 5.3-5.31 (d, J=4 Hz, 1H), 3.71 (s, 3H), 2.78-2.84 (m, 1H), 2.2.11-2.31 (m, 4H), 1.60-1.74 (m, 4H), MS (M−1)=571. HPLC RT=9.31 min (Xbridge Phenyl (4.6×150 mm), 3.5 micron; 1 mL/min flow rate; gradient 10% B-100% B over 12 min (A: 0.05% TFA in water/CH3CN (95:5), B: 0.05% TFA in water/CH3CN (5:95) @ 220 and 250 nm, 15 min run).
Reaction SMILES: [NH2:1][C:2](=[O:42])[CH:3]([C:5]1[CH:41]=[CH:40][CH:39]=[CH:38][C:6]=1[CH2:7][CH2:8][C:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]2[CH:21]=[N:22][N:23]([CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)[CH:24]=2)[N:10]=1)[CH3:4].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+].[OH-].[Na+]>C(Cl)Cl>[NH:28]1[CH2:27][CH2:26][CH:25]([N:23]2[CH:24]=[C:20]([NH:19][C:11]3[N:10]=[C:9]([CH2:8][CH2:7][C:6]4[CH:38]=[CH:39][CH:40]=[CH:41][C:5]=4[CH:3]([CH3:4])[C:2]([NH2:1])=[O:42])[C:14]([C:15]([F:16])([F:18])[F:17])=[CH:13][N:12]=3)[CH:21]=[N:22]2)[CH2:30][CH2:29]1
Reactant: CC(C(N)=O)c1ccccc1CCc1nc(Nc2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)ncc1C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C(N)=O)c1ccccc1CCc1nc(Nc2cnn(C3CCNCC3)c2)ncc1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
A solution of tert-butyl 4-(4-((4-(2-(1-amino-1-oxopropan-2-yl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate A66 (3.41 g, 5.80 mmol) in DCM (50 mL) was cooled to 0° C. and treated with TFA (4.44 mL, 0.058 mol). The mixture was stirred at 0° C. for 1 hour and then at room temperature for 3 hours. An extra aliquot of TFA (2.2 mL, 0.029 mol) was added to the mixture and stirring was continued for 2 hours at room temperature. Sat. aq. NaHCO3 (˜50 mL) was carefully added, followed by aq. NaOH (2 M, ˜50 mL). DCM was removed in vacuo and the resultant aqueous mixture was diluted with H2O (˜50 mL). The white suspension was sonicated for 10 minutes and vacuum filtered. The isolated solid was washed with water and air dried to give the title compound 56 as a white solid (2.8 g, 99%). 1H NMR (400 MHz, d6-DMSO) δ 10.20-10.08 (m, 1H), 8.69-8.56 (m, 1H), 8.02-7.93 (m, 1H), 7.58 (s, 1H), 7.44-7.35 (m, 1H), 7.27-7.14 (m, 4H), 6.92-6.80 (m, 1H), 4.21-4.08 (m, 1H), 3.91-3.79 (m, 1H), 3.18-2.91 (m, 6H), 2.61-2.50 (m, 2H), 1.92-1.86 (m, 2H), 1.81-1.68 (m, 2H), 1.33 (d, J=6.9 Hz, 3H). LCMS-A: rt 4.79 min; m/z 488 [M+H]+.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]([F:36])([F:35])[F:34])=[C:23]([CH3:37])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].Cl.C([O:45]CC)C.CCCCCC>CC(C)=O>[CH3:37][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([OH:45])=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([F:34])([F:36])[F:35]
Reactant: CCOCC
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CC(C)=O
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)O)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Reaction time: 8 h

Procedure:
To a solution of 2,2,2-trichloro-1-(10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)ethanone of Step E (2.3 g, 3.9 mmol) in acetone (20 mL) was added 2.5 N sodium hydroxide (3.1 mL, 7.8 mmol). After stirring overnight, the reaction mixture was acidified with 2 N hydrochloric acid (4.3 mL, 8.6 mmol) and then concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a brown solid. Trituration with diethyl ether/hexane provided the title compound (1.32 g) as a white solid, m.p. 233-235° C.
Reaction SMILES: [I:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][NH:4][N:3]=1.[H-].[Na+].Cl[CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17]>O1CCCC1>[I:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][N:4]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: N#Cc1c[nH]nc1I
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc(C#N)c(I)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 3-iodo-1H-pyrazole-4-carbonitrile (compound 256.1, 5.00 g, 22.8 mmol) in tetrahydrofuran (10 mL). The solution was cooled to 0° C. under nitrogen, then sodium hydride (1.1 g, 27.4 mmol, 60% dispersion in mineral oil) was added in portions. The resulting mixture was stirred at 0° C. for 30 min, then (2-(chloromethoxy)ethyl)trimethylsilane (6.05 mL, 34.2 mmol) was added to the reaction. The resulting mixture was stirred for overnight at room temperature, then carefully quenched with water/ice (30 mL). The aqueous phase was extracted with ethyl acetate (2×100 mL) and the combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by a silica gel chromatography with ethyl acetate/petroleum ether (20:1) as eluent to obtain the title compound as a colorless oil (7.2 g, 90%).
Reaction SMILES: COC1C=C(OC)C=CC=1C(Cl)=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][CH:20]=[C:19]2[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][C:30]=1[F:36].[CH3:37][O:38][C:39]1[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=[CH:41][C:40]=1[C:47]([N:49]=[C:50]=[S:51])=[O:48]>C1(C)C=CC=CC=1.C(O)C>[CH3:37][O:38][C:39]1[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=[CH:41][C:40]=1[C:47]([N:49]=[C:50]=[S:51])=[O:48].[CH3:37][O:38][C:39]1[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=[CH:41][C:40]=1[C:47]([NH:49][C:50]([NH:33][C:32]1[CH:34]=[CH:35][C:29]([O:28][C:19]2[C:18]3[C:23](=[CH:24][C:25]([O:26][CH3:27])=[C:16]([O:15][CH3:14])[CH:17]=3)[N:22]=[CH:21][CH:20]=2)=[C:30]([F:36])[CH:31]=1)=[S:51])=[O:48]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: COc1ccc(C(=O)Cl)c(OC)c1
Agent: COc1ccc(C(=O)N=C=S)c(OC)c1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(F)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
2,4-Dimethoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2,4-dimethoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2,4-dimethoxy-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (45 mg, yield 53%).
Reaction SMILES: [S:1]1([C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=O)[NH:4]1)(=[O:3])=[O:2].[C:13]1([Mg]Br)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1>[C:13]1([C:5]2([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[S:1](=[O:3])(=[O:2])[NH:4]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C1NS(=O)(=O)c2ccccc21
Solvent: C1CCOC1
Product: O=S1(=O)NC(c2ccccc2)(c2ccccc2)c2ccccc21

Procedure:
Various procedures have been reported for synthesizing 3-substituted-benz[d]isothiazole-1,1-dioxides and 3,3-disubstituted-2,3-dihydrobenz[d]isothiazole-1,1-dioxides from saccharin (3-oxo-2,3-dihydrobenz[d]isothiazole-1,1-dioxide) and from saccharin pseudo-chloride (3chlorobenz[d]isothiazole-1,1-dioxide). As reported by A. Mustafa et al, J. Chem Soc., 1952, p. 1339, the treatment of saccharin pseudo-chloride with excess phenylmagnesium bromide gave the corresponding 3,3-diphenyl-2,3-dihydrobenz[d]isothiazole-1,1-dioxide in almost quantitative yield. Methyl-, ethyl-, n-propyl- and n-butylmagnesium halides were reported by these authors to react analogously. R. A. Abramovitch et al, J. Chem. Soc., Perkin Trans I, 1974(22), p. 2589, reviewed and reinvestigated the reactions of saccharins with alkyl and aryl Grignard reagents and found that either the 3-alkyl (or 3-aryl)-benz[d]isothiazole-1,1-dioxide and/or the open-chain tertiary alcohol, o-CR2OH benzenesulfonamide wherein R is alkyl (or aryl) were obtained with one exception. When saccharin was treated with an excess of phenylmagnesium bromide in boiling tetrahydrofuran, 3,3-diphenyl-2,3-dihydrobenz[d]isothiazole-1,1-dioxide was obtained as the minor product together with the open-chain tertiary alcohol.